Institute of Medical Information, Chinese Academy of Medical Sciences/Peking Union Medical College
PMO is an open, extensible ontology aimed to integrate the terms in field of precision medicine.
The example of the relationship appearing in biomedical text.
The unique identifier of the relationship in PMO.
The unique identifier of the class in PMO.
The source of the example, usually PubMed.
The synonym of the resource in other databases.
The hierarchy of the resource in PMO tree.
The ID of the resource in other databases.
A disease that involving errors in metabolic processes of building or degradation of molecules.
Generalized metabolic disorder (disorder)
A bacterial infectious disease has_material_basis_in Bacteria.
Infectious systemic inflammatory response syndrome
Infectious systemic inflammatory response syndrome (disorder)
A viral infectious disease has_material_basis_in BK polyomavirus.
A viral infectious disease that results_in infection located_in joint, has_material_basis_in Chikungunya virus, which is transmitted_by Aedes mosquito bite. The infection has_symptom fever, has_symptom arthralgia, and has_symptom maculopapular rash.
An acquired metabolic disease that is characterized by abnormal carbohydrate metabolism.
An acquired metabolic disease that is characterized by abnormal mineral metabolism.
A primary bacterial infectious disease that results_in infection located_in skin, has_material_basis_in Erysipelothrix rhusiopathiae, which is transmitted_by contact with infected animals. The infection has_symptom redness of skin, has_symptom tenderness of skin and has_symptom warmth of skin.
Erysipelothrix Infections [Disease/Finding]
A disease that is the consequence of the presence of pathogenic microbial agents, including pathogenic viruses, pathogenic bacteria, fungi, protozoa, multicellular parasites, and aberrant proteins known as prions.
Adenovirus infection in conditions classified elsewhere and of unspecified site
A viral infectious disease that results_in inflammation located_in brain, has_material_basis_in La Crosse virus, which is transmitted_by treehole mosquito, Ochlerotatus triseriatus. The infection has_symptom seizures, has_symptom headache, has_symptom fever, has_symptom coma, and has_symptom paralysis.
California encephalitis virus disease (disorder)
A lymphatic system disease that is characterized by an expansion of the monocyte-macrophage population and intense hemophagocytosis. It can occur de novo, but more often occurs in the setting of another disorder, usually an infection or a malignancy. A clinical picture of fever, hepatosplenomegaly, lymphadenopathy and peripheral pancytopenia. The morphologic hallmark of this syndrome is the phagocytosis of hematopoietic elements by morphologically normal macrophages.
Haemophagocytic lymphohistiocytosis (disorder)
A dengue disease that involves the most severe form of dengue fever, has_material_basis_in Dengue virus [NCBITaxon:12637] with four serotypes (Dengue virus 1, 2, 3 and 4), which are transmitted_by Aedes mosquito bite. The infection has_symptom easy bruising, has_symptom blood spots, has_symptom bleeding gums, and has_symptom nosebleeds. It is accompanied by circulatory collapse, involves hypotension, narrow pulse pressure (less than or equal to 20mm Hg), or frank shock. The shock occurs after two to six days of symptoms, followed by collapse, weak pulse, and blueness around the mouth.
Secretory diarrhea is a diarrhea where there is an increase in the active secretion, or there is an inhibition of absorption causing little to no structural damage. The most common cause of this type of diarrhea is a cholera toxin that stimulates the secretion of anions, especially chloride ions.
Osmotic diarrhea is a dirrhea where diarrhea occurs when too much water is drawn into the bowels. This can be the result of maldigestion (e.g., pancreatic disease or Coeliac disease), in which the nutrients are left in the lumen to pull in water. Osmotic diarrhea can also be caused by osmotic laxatives (which work to alleviate constipation by drawing water into the bowels). In healthy individuals, too much magnesium or vitamin C or undigested lactose can produce osmotic diarrhea and distention of the bowel. A person who does not have lactose intolerance can have difficulty absorbing lactose after an extraordinarily high intake of dairy products.
Motility-related diarrhea is a diarrhea which is caused by the rapid movement of food through the intestines (hypermotility). If the food moves too quickly through the GI tract, there is not enough time for sufficient nutrients and water to be absorbed.
A gastrointestinal system infectious disease involving diarrhea that occurs when there is damage to the mucosal lining or brush border, which leads to a passive loss of protein-rich fluids, and a decreased ability to absorb these lost fluids. It can be caused by bacterial infections, viral infections, parasitic infections, or autoimmune problems such as inflammatory bowel diseases. It can also be caused by tuberculosis, colon cancer, and enteritis.
A superficial mycosis that is a superficial fungal infection of the hair shaft caused by Trichosporon beigelii. Infected hairs develop soft greyish-white nodules along the shaft.
A fungal infectious disease that results_in infection of the keratinized layers located_in skin, located_in hair or located_in nail, which extends deeper into the epidermis, has_material_basis_in Fungi and results_in_formation_of skin lesions.
A fungal infectious disease that results_in infection located_in skin or located_in subcutaneous tissue, has_material_basis_in Fungi, which penetrate the dermis or even deeper during or after a skin trauma.
A fungal infectious disease that results_in infection of internal organs and tissues located_in human body, has_material_basis_in Fungi, which enter the body via the respiratory tract, through the gut, paranasal sinuses or skin and spread through the bloodstream to multiple organs.
A diarrhea that is of rapid onset and course characterized by frequent loose or liquid bowel movements. Acute diarrhea is a common cause of death in developing countries and the second most common cause of infant deaths worldwide.
A dengue disease that results_in infection, has_material_basis_in Dengue virus [NCBITaxon:12637] with four serotypes (Dengue virus 1, 2, 3 and 4), which are transmitted_by Aedes mosquito bite. The infection has no manifestations of symptoms.
A primary ciliary dyskinesia that is characterized by sinusitis, bronchiectasis and situs inversus with dextrocardia resulting from dysfunction of the cilia during embryologic development.
Bronchiectasis, chronic sinusitis AND dextrocardia syndrome
Bronchiectasis-chronic sinusitis and dextrocardia syndrome
DEXTROCARDIA, BRONCHIECTASIS, AND SINUSITIS
DEXTROCARDIA-BRONCHIECTASIS-SINUSITIS SYNDROME
inflammation of adenoids (physical finding)
A respiratory system infectious disease that involves inflammation, edema, and subsequent obstruction of the larynx, trachea, and bronchi. The disease is caused by viruses, bacteria, allergies and inhaled irritants. It is marked by episodes of difficult breathing and hoarse metallic cough in infants and young children. Croup is caused by parainfluenza virus (types 1 and 2), Influenza A and B viruses, Measles virus, adenovirus, respiratory syncytial virus, Staphylococcus and Streptococcus.
Acute laryngotracheobronchitis (disorder)
A nervous system disease which is located in a part of the nervous system responsible for processing sensory information that consists of sensory receptors, neural pathways, and parts of the brain involved in sensory perception. Commonly recognized sensory systems are those for vision, hearing, somatic sensation (touch), taste and olfaction (smell).
A respiratory system disease which involves the lower respiratory tract.
Other disease of nasal cavity and sinuses
Other diseases of nasal cavity and sinuses
Other nasal cavity and sinus disease (disorder)
A West Nile encephalitis that results_in infection located_in brain, has_material_basis_in Kunjin virus, a subtype of West Nile Virus, which is transmitted_by Culex annulirostris mosquito bite. The infection has_symptom fever, has_symptom rigor, has_symptom headache, has_symptom confusion, and has_symptom lethargy.
A viral infectious disease that results_in inflammation located_in brain, has_material_basis_in Tick-borne encephalitis virus, which is transmitted_by Ixodes ticks. The infection has_symptom drowsiness, has_symptom confusion, has_symptom sensory disturbances, and has_symptom paralysis.
A genetic disease that is the result of one or more abnormal alleles and may be dominant (a single copy of the abnormal allele is sufficient to give rise to the disease), semi-dominant, or recessive (requiring both copies of the gene to have an abnormal allele).
A viral infectious disease that results_in inflammation located_in brain, has_material_basis_in Powassan virus, which is transmitted_by Ixodes and transmitted_by Dermacentor species of ticks. The infection has_symptom headache, has_symptom fever, has_symptom vomiting, has_symptom stiff neck, has_symptom sleepiness, has_symptom breathing distress, has_symptom tremors, has_symptom confusion, has_symptom seizures, has_symptom paralysis, and has_symptom coma.
A skin disease that is a type of allergic reaction located_in skin, which occurs in response to medications, infections, or illness.
A viral infectious disease that is a hemorrhagic fever, has_material_basis_in Junin virus, which is transmitted_by rodent, Calomys musculinus. The infection has_symptom fever, has_symptom fatigue, has_symptom malaise, has_symptom leukopenia, has_symptom thrombocytopenia, and has_symptom hemorrhagic manifestations.
Argentinian haemorrhagic fever (disorder)
A viral infectious disease that is a hemorrhagic fever, has_material_basis_in Machupo virus, which is transmitted_by vesper mouse, Calomys callosus. The infection has_symptom fever, has_symptom headache, has_symptom fatigue, has_symptom myalgia, has_symptom arthralgia, has_symptom bleeding from the oral and nasal mucosa, and has_symptom bleeding from the bronchopulmonary, gastrointestinal and genitourinary tracts.
A viral infectious disease that is a hemorrhagic fever, has_material_basis_in Guanarito virus, which is transmitted_by cotton rat, Sigmodon alstoni and transmitted_by cane mouse, Zygodontomys brevicauda. The infection has_symptom fever, has_symptom headache, has_symptom myalgia, has_symptom sore throat, has_symptom weakness, has_symptom anorexia, has_symptom nausea, has_symptom vomiting, has_symptom convulsions, has_symptom epistaxis, has_symptom bleeding gums, has_symptom hematemesis, has_symptom melena, and has_symptom menorrhagia.
Venezuelan haemorrhagic fever (disorder)
Venezuelan haemorrhagic fever [Ambiguous]
A viral infectious disease that is a hemorrhagic fever, has material basis in Sabia virus, which is transmitted by rodents. The infection has symptom fever, has symptom eye redness, has symptom fatigue, has symptom dizziness, has symptom muscle aches, has symptom loss of strength, and has symptom bleeding under the skin, internal organs, or from body orifices like the mouth, eyes or ears.
A viral infectious disease that is a hemorrhagic fever, has material basis in Chapare virus. The infection has symptom headache, has symptom joint pain, has symptom muscle pain, has symptom vomiting, has symptom shock, and has symptom bleeding.
Haemorrhagic fever caused by Chapare virus
Hemorrhagic fever caused by Chapare virus
Hemorrhagic fever caused by Chapare virus (disorder)
A viral infectious disease that is a hemorrhagic fever, has_material_basis_in Whitewater Arroyo virus, which is transmitted_by white-throated woodrats (Neotoma albigula). The infection has_symptom fever, has_symptom headache, has_symptom myalgia, and has_symptom hemorrhagic manifestations.
A viral infectious disease that is a hemorrhagic fever, located in kidney, has material basis in Hantaan virus, has material basis in Dobrava-Belgrade virus, has material basis in Seoul virus, or has material basis in Puumala virus, which are carried and transmitted by rodents. The infection has symptom headache, has symptom fever, has symptom muscle pains, has symptom facial flush, has symptom petechiae, has symptom hemorrhagic features, has symptom proteinuria, and has symptom renal failure.
HFRS (hemorrhagic fever with renal syndrome)
HFRS - Haemorrhagic fever with renal syndrome
An interstitial nephritis endemic to the regions along the Danube river, in the modern countries of Croatia, Bosnia and Herzegovina, Serbia, Romania and Bulgaria.
A viral infectious disease that results_in infection, has_material_basis_in Lujo virus, which has_symptom bleeding.
Hemorrhagic fever caused by Lujo virus (disorder)
A viral hepatitis that results_in inflammation, located_in liver, has_material_basis_in Human herpesvirus 4 and has_symptom headache, has_symptom fatigue, has_symptom fever, has_symptom abdominal pain, has_symptom nausea, and has_symptom jaundice.
hepatitis due to Epstein-Barr virus (diagnosis)
An influenza that results_in infection located_in respiratory tract of pigs and humans, has_material_basis_in Influenza C virus, or has_material_basis_in Influenza A virus subtypes (H1N1, H1N2, H3N1, H3N2, and H2N3), which are transmitted_by direct contact with infected pigs. The infection in humans has_symptom fever, has_symptom lethargy, has_symptom lack of appetite, has_symptom coughing, has_symptom runny nose, has_symptom sore throat, has_symptom nausea, has_symptom vomiting, and has_symptom diarrhea.
A parasitic protozoa infectious disease that involves infection of the central nervous system caused by Naegleria fowleri. The symptoms include headache, nausea, rigidity of the neck muscles, vomiting, delirium, seizures and coma.
A parasitic protozoa infectious disease that results in infection of the brain caused by Acanthamoeba or Balamuthia mandrillaris. The symptoms include headaches, altered mental status, and focal neurologic deficit, which progresses over several weeks to death.
GAE - Granulomatous amebic encephalomyelitis
GAE - Granulomatous amoebic encephalomyelitis
Granulomatous Amebic Encephalitis due to Acanthamoeba
A parasitic helminthiasis infectious disease that involves parasitic infection of the eyes by Philophthalmus species. External ocular philophthalmiasis manifests as follicular conjunctivitis and superficial keratitis. Sub-conjunctival ocular philophthalmiasis consists of a mild edema with minimal cellular reaction.
parasitic helminthiasis infectious disease
A parasitic helminthiasis infectious disease that involves infection by metacestode larval stage (coenurus) of Taenia multiceps or Taenia serialis. Coenuri in the skin or subcutaneous tissue present as painless nodules, which manifest on the trunk, sclera, subconjuctiva, neck, shoulders, head and limbs. Coenuri in the central nervous system may cause headache, fever, vomiting, nerve palsies, jacksonian epilepsy, pachymeningitis, obstructive or communicating hydrocephalus, and intracranial arteritis with transient hemiparesis. Coenuri in the eye cause both intraocular and orbital infections.
A parasitic helminthiasis infectious disease that involves parasitic cestode infection caused by Mesocestoides lineatus resulting in nausea, diarrhea, abdominal discomfort and vomiting.
A parasitic helminthiasis infectious disease that involves infection of the intestine caused by thorny-headed worms Macracanthorhynchus or Moniliformis moniliformis. The infection has_symptom abdominal pain, has_symptom distension, has_symptom fever, has_symptom decreased appetite, has_symptom nausea, has_symptom vomiting, has_symptom weight loss, has_symptom diarrhea, and has_symptom constipation or has_symptom bloody stools.
A parasitic helminthiasis infectious disease that involves parasitic infection of the intestine, central nervous system and eyes by Angiostrongylus cantonensis or Angiostrongylus costaricensis.
A parasitic helminthiasis infectious disease that involves parasitic infection of the intestine caused by the larvae of Baylisascaris procyonis, which can invade the spinal cord, brain, and eye of humans, resulting in permanent neurologic damage, blindness, or death.
A parasitic helminthiasis infectious disease that involves parasitic infection by the nematode Dioctophyme renale in humans after eating undercooked food. The larvae are found in the subcutaneous nodules and kidneys.
A parasitic helminthiasis infectious diseasea that involves infection of the eyes in humans by nematode Thelazia callipaeda causing varying degrees of inflammation and lacrimation. In heavier infections, photophobia, edema, conjunctivitis, and blindness occurs.
A parasitic ectoparasitic infectious disease that is an inflammatory skin disease caused by the parasitic infestation of the female chigoe flea, Tunga penetrans in animals and humans. The symptoms include skin inflammation, severe pain, itching, and a lesion at the site of infection that is characterized by a black dot at the center of a swollen red lesion, surrounded a white halo.
parasitic ectoparasitic infectious disease
A subcutaneous mycosis that involves a chronic inflammatory or granulomatous fungal infection of the subcutaneous tissue of the limbs, chest, back or buttocks caused by Basidiobolus ranarum. Lesions appear as subcutaneous nodules which develop into massive, firm, indurated, painless swellings which are freely movable over the underlying muscle, but are attached to the skin which may become hyperpigmented but not ulcerated.
Infection caused by Basidiobolus (disorder)
An subcutaneous mycosis that is a chronic inflammatory or granulomatous fungal infection caused by Conidiobolus species, which is restricted to the nasal submucosa and characterized by polyps or palpable restricted subcutaneous masses. Symptoms include nasal obstruction, drainage and sinus pain. Subcutaneous nodules develop in the nasal and perinasal regions.
Infection by Conidiobolus (disorder) [Ambiguous]
A parasitic infectious disease that involves parasitic infection by the members of the class Ichthyosporea, which are parasites of fish and other animals.
parasitic Ichthyosporea infectious disease
A systemic mycosis that results_in infection located_in human body, has_material_basis_in Fungi, which can overcome the physiological and cellular defences of the normal human host. The primary deep pathogens usually gain access to the host via the respiratory tract.
A viral infectious disease that is a hemorrhagic fever, has material basis in Alkhurma hemorrhagic fever virus, which is transmitted by Ornithodoros savignyi tick bite, transmitted by ingestion of unpasteurized camel milk, or transmitted by entry via skin wound. The infection has symptom headache, has symptom joint pain, has symptom muscle pain, has symptom vomiting, has symptom thrombocytopenia, and has symptom hemorrhagic fever.
A bacterial infectious disease that results_in infection by bacteria as a result of their presence or activity within the normal, healthy host, and their intrinsic virulence is, in part, a necessary consequence of their need to reproduce and spread.
A bacterial infectious disease that results_in infection by bacteria which are part of the normal human flora when one or more of the defense mechanisms designed to restrict them from the usually sterile internal tissues are breached by accident, by intent (surgery), or by an underlying metabolic or an infectious disorder.
A bacterial infectious disease that results_in infection by bacteria in individuals whose host defense mechanisms have been compromised.
opportunistic bacterial infectious disease
A central nervous system disease characterized by throbbing, pulling creeping or other unpleasant sensations in the legs and the irresistible urge to move them.
ADRENOLEUKODYSTROPHY, AUTOSOMAL NEONATAL
Infantile Form of Phytanic Acid Storage Disease
A skin disease characterized by a defect in the normal process of keratinization of the mucosa.
Deficiency of mevalonate kinase (disorder)
Hyperimmunoglobulin D with Periodic Fever Syndrome
Mevalonate Kinase Deficiency [Disease/Finding]
A congenital nervous system abnormality characterized by the absence of folds in the cerebral cortex and caused_by defective neuronal migration during the 12th to 24th weeks of gestation.
A congenital nervous system abnormality characterized by non proper migration of neurons during the early development of the fetal brain.
Bilateral Periventricular Nodular Heterotopia
HETEROTOPIA, PERIVENTRICULAR, X-LINKED DOMINANT
A primary bacterial infectious disease that results_in infection located_in skin or located_in subcutaneous tissue, has_material_basis_in Mycobacterium ulcerans, which could be transmitted_by insects. The bacterium produces a toxin, named mycolactone, which causes subcutaneous fat necrosis and inhibits an immune response. The infection has_symptom nodule, which is a painless, mobile swelling in the skin.
Cutaneous mycobacterium ulcerans infection
Mental Retardation, Unusual Facies, And Intrauterine Growth Retardation
ERYTHROKERATODERMIA FIGURATA, CONGENITAL FAMILIAL, IN PLAQUES
ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA
ERYTHROKERATODERMIA VARIABILIS WITH ERYTHEMA GYRATUM REPENS
ERYTHROKERATODERMIA, PROGRESSIVE SYMMETRIC
A syndrome that is characterized by an accumulation of protein-rich fluid (lymph) in the soft layers of tissue under the skin resulting in pleural effusions, lymphedema (due to lymphatic hypoplasia) and yellow dystrophic nails hat lack a cuticle, grow slowly, and are loose or detached.
Hereditary lymphedema and yellow nails (disorder)
An autosomal genetic disease characterized by short stature, bachycephaly and other facial abnormalities, brachydactyly, joint stiffness and distinctive ocular abnormalities.
Congenital Mesodermal Dysmorphodystrophies
Congenital Mesodermal Dysmorphodystrophy
Dysmorphodystrophies, Congenital Mesodermal
Dysmorphodystrophy, Congenital Mesodermal
A lipid metabolism disorder that has_material_basis_in X-linked inheritance of the tafazzin gene and is characterized by decreased production of an enzyme required to produce cardiolipin.
3-Methylglutaconic aciduria type 2 (disorder)
A primary bacterial infectious disease that results_in infection, has_material_basis_in Neorickettsia sennetsu, which is transmitted_by ingestion of raw or under-cooked gray mullet fish infected with the trematodes. The infection has_symptom fever, has_symptom malaise, has_symptom anorexia, has_symptom lymphadenopathy, has_symptom hepatosplenomegaly, has_symptom fatigue, has_symptom chills, has_symptom headache, has_symptom backache and has_symptom myalgia.
Human Ehrlichial infection, Sennetsu type
Cutaneous eruption (morphologic abnormality)
A viral infectious disease that results_in infection in infants and children, located_in skin, has_material_basis_in Human herpesvirus 6 or has_material_basis_in Human herpesvirus 7 and has_symptom sudden high fever, and has_symptom red rash that occurs first on the trunk then spreading to legs and neck.
A viral infectious disease that results in infection located in skin, has material basis in Variola virus, which is transmitted by droplets from oral, nasal or pharyngeal mucosa, transmitted by contact with the body fluids, or transmitted by fomites. The infection results in formation of lesions, first on the face, hands and forearms and later on the trunk.
A poliomyelitis that results in destruction located in motor neurons of central nervous system, has material basis in Human poliovirus 1, has material basis in Human poliovirus 2, or has material basis in Human poliovirus 3, which are transmitted by ingestion of food or water contaminated with feces, or transmitted by direct contact with the oral secretions. The infection has symptom loss of reflexes, has symptom muscle spasms, and has symptom acute flaccid paralysis.
A viral infectious disease that results_in infection located_in joint, has_material_basis_in O'nyong-nyong virus, which is transmitted_by Anopheles gambiae, and transmitted_by Anopheles funestus mosquitoes. The infection has_symptom fever, has_symptom arthralgia, has_symptom rash, and has_symptom lymphadenitis.
A viral infectious disease that results_in infection located_in joint, has_material_basis_in Barmah Forest virus, which is transmitted_by mosquito bite. The infection has_symptom fever, has_symptom arthralgia, and has_symptom rash.
A viral infectious disease that results_in infection located_in joint, has_material_basis_in Ross River virus, which is transmitted_by Culex, and transmitted_by Aedes mosquitoes. The infection has_symptom fever, has_symptom arthralgia, and has_symptom rash.
A viral infectious disease that results in infection, has material basis in Oropouche virus, which is transmitted by biting midge, Culicoides paraensis. The infection has symptom fever, has symptom chills, has symptom headache, has symptom anorexia, has symptom muscle pain, has symptom joint pain, and has symptom vomiting.
A hemorrhagic fever with renal syndrome that results in infection located in kidney, has material basis in Dobrava-Belgrade virus , which is transmitted by yellow-necked field mouse, Apodemus flavicollis. The infection has symptom headache, has symptom fever, has symptom muscle pains, has symptom facial flush, has symptom petechiae, has symptom hemorrhagic features, has symptom proteinuria, and has symptom renal failure.
A genetic disease that has_material_basis_in mutations in the MODY genes disrupting insulin production.
Diabetes mellitus autosomal dominant (disorder)
Diabetes, maturity-onset, of the young (MODY)
MODY - Maturity onset diabetes in youth type 1
MODY - Maturity onset diabetes in youth type I
A syndrome characterized by progressive weakness and atrophy of muscles in feet, legs and hands. In some patients the syndrome also causes decreased sensitivity to touch, heat or cold, particularly in the lower arms or legs.
Autosomal recessive axonal neuropathy with neuromyotonia
Autosomal recessive axonal neuropathy with neuromyotonia (disorder)
Autosomal recessive neuromyotonia with axonal neuropathy
Continuous muscle fiber activity syndrome
An amino acid metabolic disorder that involves an excess of the amino acid methionine, in the blood. This condition can occur when methionine is not broken down properly in the body.
Deficiency of Methionine Adenosyltransferase
Deficiency of methionine adenosyltransferase (disorder)
Hepatic Methionine Adenosyltransferase Deficiency
Hepatic methionine adenosyltransferase deficiency (disorder)
Hepatic methionine adenosyltransferase deficiency [Ambiguous]
ADRENAL INSUFFICIENCY, CONGENITAL, WITH 46,XY SEX REVERSAL, PARTIAL OR COMPLETE
An asphyxiating thoracic dystrophy that has_material_basis_in homozygous or compound heterozygous mutation in the DYNC2H1 gene on chromosome 11q22.
POLYDACTYLY WITH NEONATAL CHONDRODYSTROPHY, TYPE I
Polydactyly with Neonatal Chondrodystrophy, Type 1
SHORT RIB-POLYDACTYLY SYNDROME, TYPE IIB
SHORT-RIB THORACIC DYSPLASIA 3 WITH OR WITHOUT POLYDACTYLY
CLEFT LIP WITH OR WITHOUT CLEFT PALATE, NONSYNDROMIC, 1
An amino acid metabolic disorder that is an autosomal recessive neurometabolic disorder characterized by the significant elevation of urinary levels of hydroxyglutaric acid causing progressive brain damage.
COMBINED D-2- AND L-2 -HYDROXYGLUTARIC ACIDURIA
COMBINED D-2- AND L-2-HYDROXYGLUTARIC ACIDURIA
An impulse control disorder that involves the uncontrollable plucking of ones hair.
Hair pulling, chronic, compulsive, repetitive
An intestinal disease characterized by inflammation located_in all parts of digestive tract.
A parasitic helminthiasis infectious disease that has material basis in Taenia solium or has material basis in Taenia saginata, which are transmitted by ingestion of undercooked contaminated meat.
ACRODERMATITIS ENTEROPATHICA, ZINC-DEFICIENCY TYPE
Acrodermatitis enteropathica zinc deficiency type
An in situ carcinoma that is located_in the oral cavity.
An in situ carcinoma that is located_in the pharynx.
An in situ carcinoma that is located_in the gall bladder.
An in situ carcinoma that is located_in the bile duct.
Carcinoma in situ of Extrahepatic Bile Duct
Carcinoma in situ of Extrahepatic Bile Ducts
Carcinoma in situ of Extrahepatic Biliary Ducts
Carcinoma in situ of extrahepatic bile ducts (disorder)
Carcinoma in situ of extrahepatic bile ducts, NOS
Carcinoma in situ of the Extrahepatic Bile Duct
An in situ carcinoma that is located_in the bronchus.
An organ system cancer located_in the respiratory system that is characterized by uncontrolled cellular proliferation in the respiratory tract.
An organ system benign neoplasm that is located in the respiratory system which extends from the nasal sinuses to the diaphragm.
Benign neoplasm of respiratory system (disorder)
Benign neoplasm of respiratory system, unspecified
An organ system benign neoplasm that is located_in reproductive system organs.
An organ system benign neoplasm located_in gastrointestinal tract organs.
A sleep disorder that involves an altered circadian rhythm resulting in falling asleep in early evening and awaking very early in the morning.
Circadian rhythm sleep disorder, advanced sleep phase
Circadian rhythm sleep disorder, advanced sleep phase type
Circadian rhythm sleep disorder, advanced sleep phase type (diagnosis)
Sleep-wake schedule disorder, advanced phase type
Sleep-wake schedule disorder, advanced phase type (disorder)
sleep disorder circadian rhythm, advanced sleep phase type
An X-linked disease that has material basis in mutation at is in the gene encoding the monocarboxylate transporter-8 which alters the structure and function of the SLC16A2 protein which is then unable to transport the thyroid triiodothyronine (T3) hormone into nerve cells of the developing brain affecting normal brain development resulting in intellectual disability and problems with movement.
MENTAL RETARDATION, X-LINKED, WITH HYPOTONIA
MONOCARBOXYLATE TRANSPORTER 8 DEFICIENCY
Mct8 (Slc16a2)-Specific Thyroid Hormone Cell Transporter Deficiency
Amyloid cranial neuropathy with lattice corneal dystrophy
Familial Amyloid Neuropathy, Finnish Type
Familial amyloid neuropathy, Finnish type (disorder)
An amyloidosis that is characterized by a loss of sensation in the extremities, cardiomyopathy, nephropathy, vitreous opacities, and CNS amyloidosis resulting from abnormal deposits of amyloid protein in the body's organs and tissues and has_material_basis_in autosomal dominant inheritance of mutations in the TTR gene.
AMYLOIDOSIS, HEREDITARY, TRANSTHYRETIN-RELATED
Familial Transthyretin Cardiac Amyloidosis
HEREDITARY AMYLOIDOSIS, TRANSTHYRETIN-RELATED
Complete absence of all fingernails (anonychia), congenital
ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1
ARTERIAL CALCIFICATION, IDIOPATHIC INFANTILE
Arterial Calcification, Generalized, Of Infancy
Generalized Arterial Calcification of Infancy 1
A connective tissue disease that is characterized by elongation and generalized tortuosity of the major arteries including the aorta.
Arterial tortuosity syndrome (diagnosis)
A cancer that is classified based on the organ it starts in.
A cancer that is classified by the type of cell from which it is derived.
A specific developmental disorder and physical disorder that is characterized by physical, behavioral and learning birth defects resulting from maternal ingestion of alcohol during pregnancy.
Fetal Alcohol Spectrum Disorder (disorder)
A connective tissue disease that is an inflammation of the connective tissue of the umbilical cord.
inflammation of umbilical cord (physical finding)
A heart disease and a myopathy that is characterized by deterioration of the function of the heart muscle.
An amino acid metabolic disorder that has_material_basis_in mutations in the MCCC1 and MCCC2 genes causing inadequate levels of the enzyme 3-methylcrotonyl-CoA carboxylase that helps break down proteins containing the amino acid leucine. This disease has_symptom muscular hypotonia (weak muscle tone), has_symptom muscular atrophy, has_symptom feeding difficulties, has_symptom recurrent episodes of vomiting and diarrhea, and has_symptom lethargy.
3 Methylcrotonyl-CoA carboxylase deficiency
3-@METHYLCROTONYL-CoA CARBOXYLASE 1 DEFICIENCY
3-METHYLCROTONYL-CoA CARBOXYLASE 1 DEFICIENCY
3-Methylcrotonyl-CoA Carboxylase Deficiency
A mitochondrial metabolism disease that has_material_basis_in a mutation in the SCO2 gene which encodes a COX assembly factor and results in deficiency of cytochrome c oxidase.
CARDIOENCEPHALOMYOPATHY, FATAL INFANTILE, DUE TO CYTOCHROME c OXIDASE DEFICIENCY 1
CYTOCHROME c OXIDASE DEFICIENCY, FATAL INFANTILE, WITH CARDIOENCEPHALOMYOPATHY
Cardioencephalomyopathy, Fatal Infantile, due to Cytochrome C Oxidase Deficiency
fatal infantile cardioencephalomyopathy due to cytochrome c oxidase deficiency
An inherited metabolic disorder resulting from a deficiency in vitamin or vitamin cofactor transport or metabolism.
A vitamin metabolic disorder that has_material_basis_in mutations in the folate receptor 1 (FOLR1) gene coding for folate receptor alpha (FRalpha), is located_in the brain and is characterized by progressive movement disturbance, psychomotor decline, and epilepsy.
Cerebral folate transport deficiency (disorder)
NEURODEGENERATION DUE TO CEREBRAL FOLATE TRANSPORT DEFICIENCY
cerebral folate receptor alpha deficiency
An amino acid metabolic disorder that has_material_basis in deficiency of ornithine translocase resulting in the accumulation of ammonia in the blood.
HHH - Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome
HHH - Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
HHH-Hyperornithinaemia-hyperammonaemia-homocitrullinuria syn
HHH-Hyperornithinemia-hyperammonemia-homocitrullinuria syn
HYPERORNITHINEMIA-HYPERAMMONEMIA-HOMOCITRULLINURIA SYNDROME
An amino acid metabolic disorder that has_material_basis_in defects in the biosynthesis of the amino acid L-serine.
A carbohydrate metabolism disorder that is characterized by abnormal accumulation or depletion of liver glycogen.
A mitochondrial metabolism disease that is characterized by a deficiency of CoQ10 resulting from reduced biosynthesis.
A vitamin metabolic disorder that results from low blood levels of vitamin B12.
A monogenic disease that has_material_basis_in muations in genes on the X chromosome.
An autosomal genetic disease that is characterized by the presence of one disease-associated mutation of a gene which is sufficient to cause the disease.
An autosomal genetic disease that is characterized by the presence of two mutated copies of the gene, both of which must be present in order for the disease or trait to develop.
A monogenic disease that has_material_basis_in muations on the Y chromosome.
A monogenic disease that is has material basis in a mutation in a single gene on one of the non-sex chromosomes.
A syndrome that is characterized by hypotonia, congenital fiber type disproportion and dysharmonic skeletal maturation.
Dysharmonic skeletal maturation - muscular fibre disproportion
Dysharmonic skeletal maturation and muscular fiber disproportion syndrome
Dysharmonic skeletal maturation and muscular fibre disproportion syndrome
Dysharmonic skeletal maturation muscular fibre disproportion
Puerto Rican infant hypotonia syndrome (disorder)
(Alcohol dependence syndrome [including alcoholism]) or (alcohol problem drinking)
(Alcohol dependence syndrome [including alcoholism]) or (alcohol problem drinking) (disorder)
A mitochondrial metabolism disease that is characterized by hearing loss that begins early in life, problems with movement, impaired vision, and behavior problems, and has_material_basis_in mutations in the TIMM8A gene resulting in abnormal protein transport within the mitochondria.
DEAFNESS SYNDROME, PROGRESSIVE, WITH BLINDNESS, DYSTONIA, FRACTURES, AND MENTAL DEFICIENCY
DEAFNESS-DYSTONIA-OPTIC ATROPHY SYNDROME
Deafness (DFN-1) dystonia, mental deficiency and blindness
Deafness Dystonia Optic Atrophy Syndrome
Deafness Dystonia Optic Neuronopathy Syndrome
deafness-dystonia-optic neuronopathy syndrome
An acquired metabolic disease that characterized by excessive production of acid.
ASase - Adenylosuccinate lyase deficiency
A syndrome that is characterized by congenital joint contractures, renal tubular dysfunction, cholestasis, severe failure to thrive, ichthyosis, and a defect in platelet alpha-granule biogenesis. It has material basis in homozygous or compound heterozygous mutation in the VPS33B gene or has masterial basis in homozygous or compound heterozygous mutation in the VIPAR gene on chromosome 14q24.3.
ARC (arthrogryposis, renal dysfunction, cholestasis) syndrome
ARTHROGRYPOSIS, RENAL DYSFUNCTION, AND CHOLESTASIS
ARTHROGRYPOSIS, RENAL DYSFUNCTION, AND CHOLESTASIS 1
Arthrogryposis multiplex congenita, renal dysfunction, and cholestasis
Arthrogryposis renal dysfunction cholestasis syndrome
Arthrogryposis with renal dysfunction and cholestasis syndrome
Arthrogryposis with renal dysfunction and cholestasis syndrome (disorder)
An adrenal medulla cancer that is characterized by overproduction of adrenaline.
A Joubert syndrome that has_material_basis_in homozygous mutation in the INPP5E gene on chromosome 9q34.
A Meckel syndrome that has_material_basis_in an autosomal recessive mutation of MKS1 on chromosome 17q22.
A monogenic disease that is characterized by hypertelorism, hypospadias, and additional midline defects resulting from mutations to the MID1 gene in the X-linked form or from a deletion on chromosome 22q11.2 in the autosomal dominant form.
Autosomal Dominant Opitz Syndrome (ADOS)
CHROMOSOME 22q11.2 DELETION SYNDROME, OPITZ PHENOTYPE
HYPERTELORISM WITH ESOPHAGEAL ABNORMALITY AND HYPOSPADIAS
An X-linked disease resulting from a deficiency in N-terminal acetyltransferase, characterized by postnatal growth failure with severe delays and dysmorphic features in boys.
X-linked Malformation and Infantile Lethality Syndrome
A condition in which there is increased production of gastrin by a gastrin-secreting tumor (usually located in the pancreas, duodenum, or abdominal lymph nodes) that stimulates the gastric mucosa to maximal activity, with consequent gastrointestinal mucosal ulceration.
A syndrome that is haracterized by the development of a one or more tumors (gastrinoma) in the pancreas, duodenum, or both that secrete excessive levels of gastrin, a hormone that stimulates production of acid by the stomach.
A peroxisomal disease that is characterized by hypotonia and seizures in the neonatal period and neurological regression in early infancy.
STRAIGHT-CHAIN ACYL-CoA OXIDASE DEFICIENCY
An autosomal genetic disease that is characterized by microphthalmia or anophthalmia, pulmonary agenesis, and diaphragmatic defect.
ANOPHTHALMIA, CLINICAL, WITH MILD FACIAL DYSMORPHISM AND VARIABLE MALFORMATIONS OF THE LUNG, HEART, AND DIAPHRAGM
ANOPHTHALMIA/MICROPHTHALMIA AND PULMONARY HYPOPLASIA
Anophthalmia with pulmonary hypoplasia syndrome
Anophthalmia-Microphthalmia And Pulmonary Hypoplasia
A heart disease that is located_in the innermost layer of tissue that lines the chambers of the heart.
A vascular disease that is located_in an artery.
A cardiovascular system disease that is located_in the fibrous sac surrounding the heart.
An inherited metabolic disorder involving dysfunction of pyrimidine metabolism.
A pyrimidine metabolic disorder that is characterized by an excessive secretion of orotic acid in urine.
Comb orot ac phosphoribosyltr & orot-5-phos decarboxyl def
Combined orotic acid phosphoribosyltransferase and orotidine - 5 - phosphate decarboxylase deficiency
Hereditary orotic aciduria, type 1 (disorder)
A syndrome that is acterized by a pattern of congenital anomalies including choanal atresia and malformations of the heart, inner ear, and retina.
CHARGE ASSOCIATION--COLOBOMA, HEART ANOMALY, CHOANAL ATRESIA, RETARDATION, GENITAL AND EAR ANOMALIES
A sleep disorder characterized by repeated cessation and commencing of breathing that repeatedly disrupts sleep.
A sleep apnea that is characterized by repeated collapse and obstruction of the upper airway during sleep, which results in reduced airflow (hypopnea) or complete airflow cessation (apnea), oxygen desaturation, and arousals from sleep.
Oppositional defiant disorder (diagnosis)
Oppositional defiant disorder (disorder)
Oppositional defiant disorder of childhood or adolescence
A syndrome that is characterized by advanced bone age, failure to thrive, respiratory problems, dysmorphic facial features, and variable mental retardation.
accelerated skeletal maturation, Marshall-Smith type
Fibroma, no ICD-O subtype (morphologic abnormality)
A pancreas disease that is characterized by the failure of the pancreas to develop prior to birth.
A syndrome that is characterized by developmental delay, intellectual disability, muscle weakness (hypotonia), epilepsy, distinctive facial features and congenital malformations of the heart, urogenital tract and the central nervous system, and has_physical_basis_in either a chromosome 17 (17q21.31) microdeletion or a mutation in the KANSL1-gene.
Chromosome 17q21.31 Microdeletion Syndrome
KANSL1-related intellectual disability syndrome
A syndrome that is characterized by progressive proximal muscle weakness, steolytic bone lesions consistent with Paget disease, and frontotemporal dementia and has_physical_basis_in mutation in the valosin containing protein (VCP).
IBMPFD - Inclusion body myopathy with early onset Paget disease and frontotemporal dementia
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA 1
Inclusion Body Myopathy with Early-Onset Paget Disease of Bone and-or Frontotemporal Dementia
Inclusion Body Myopathy with Paget Disease of Bone and-or Frontotemporal Dementia
inclusion body myopathy with Paget disease of bone and frontotemporal dementia
A syndrome that is characterized by intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, genital abnormalities and has_physical_basis_in heterozygous mutation in the CDKN1C gene.
INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES
Intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomaly syndrome
Intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomaly syndrome (disorder)
intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, genital abnormalities
A cell type benign neoplasm that has_material_basis_in odontogenic epithelium.
A substance-related disorder that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol.
A disease of mental health that occur during a child's developmental period between birth and age 18 resulting in retarding of the child's psychological or physical development.
A developmental disorder of mental health that categorizes specific learning disabilities and developmental disorders affecting coordination.
Specific delays in development (disorder)
Specific developmental disorder (disorder)
specific developmental disorder (diagnosis)
A disease of mental health that involves the impairment in normal sexual functioning.
A factitious disorder that involves a care giver's deliberate exaggeration, fabrication, and/or induce physical, psychological, behavioral, and/or mental health problems in others.
Munchausen Syndrome by Proxy [Disease/Finding]
Münchausen syndrome by proxy (disorder)
An immune system disease that has material basis in abnormal immune responses.
A kidney disease that is characterized by hyperuricemia with renal uric acid under-excretion, gout and chronic kidney disease.
FAMILIAL JUVENILE HYPERURICEMIC NEPHROPATHY
A mitochondrial metabolism disease that is characterized by sideroblastic anemia and exocrine pancreas dysfunction.
A disease of cellular proliferation that results in abnormal growths in the body, which do not invade or destroy the surrounding tissue but, given enough time, will transform into a cancer.
A disease of cellular proliferation that results in abnormal growths in the body which lack the ability to metastasize.
An organ system cancer located_in the immune system that is characterized by uncontrolled cellular proliferation in organs of the immune system.
A benign neoplasm that is classified by the type of cell or tissue from which it is derived.
A benign neoplasm that is classified by the organ system from which it is arising from.
An organ system benign neoplasm that is located_in endocrine glands which secretes a type of hormone directly into the bloodstream to regulate the body.
An organ system benign neoplasm disease located_in the blood, heart, blood vessels or the lymphatic system.
An organ system benign neoplasm located_in the immune system organs.
An organ system benign neoplam that is located_in the thoracic cavity.
An organ system benign neoplasm that is located_in the muscular and skeletal organs.
An organ system cancer located_in the muscular and skeletal organs and characterized by uncontrolled cellular proliferation of the musculoskeletal organs.
A cell type benign neoplasm that has_material_basis_in glial cells.
An organ system benign neoplasm that is located_in the central nervous system or located_in the peripheral nervous system.
An organ system benign neoplasm that is located_in the serous membrane lining the abdominal cavity or coelom.
A disease of anatomical entity that is located_in the thoracic cavity.
An organ system benign neoplasm located_in the integumentary system organs.
An organ system cancer that is located_in the skin, hair and nails.
A disease of metabolism that has _material_basis_in enzyme deficiency or accumulation of enzymes or toxins which interfere with normal function due to an endocrine organ disease, organ malfunction, inadequate intake, dietary deficiency, or malabsorption.
An amino acid metabolic disorder that disrupts normal amino acid metabolism causing a building up of branched-chain amino acids.
A somatoform disorder that involves an excessive concern about and preoccupation with a perceived defect in his or her physical features (body image).
Body Dysmorphic Disorders [Disease/Finding]
A somatoform disorder that involves chronic pain in one or more areas, and is thought to be caused by psychological stress.
A recurrent hypersomnia that is characterized by recurring periods of excessive amounts of sleep and altered behavior.
An amino acid metabolic disorder characterized by impairment of the GABA catabolic pathway.
gamma-amino butyric acid metabolism disorder
A syndrome characterized by calcinosis, Raynaud's phenomeno, esophageal dysmotility, sclerodactyly and telangiectasia.
CREST - Calc, Raynaud, sclerodact, oesoph, telangiect
CREST - Calc,Rayn phen,oesoph dysf,sclerodact,telangiectasia
CREST - Calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia
CREST - Calcinosis, Raynaud's phenomenon, oesophageal dysfunction, sclerodactyly, telangiectasia
CREST - Calcinosis, Raynaud's phenomenon, sclerodactyly, esophageal involvement, telangiectasia syndrome
CREST - Calcinosis, Raynaud's phenomenon, sclerodactyly, oesophageal involvement, telangiectasia syndrome
A syndrome that is characterized by an asymmetric distribution of cartilagenous tumors, which may lead to skeletal deformities and limb-length discrepancy. This condition primarily affects the long bones and cartilage of the joints of the arms and legs, specifically the area where the shaft and head of a long bone meet.
Congenital multiple enchondromata with haemangioma (& [Kast's syndrome])
Congenital multiple enchondromata with haemangioma (& [Kast's syndrome]) (disorder)
Congenital multiple enchondromata with hemangioma (& [Kast's syndrome])
A 3MC syndrome that has_material_basis_in a compound heterozygous mutation in the COLEC10 gene on chromosome 8q24.
MALPUECH FACIAL CLEFTING SYNDROME, FORMERLY
A syndrome characterized by defects of the scalp (aplasia cutis congenita), abnormalities of the fingers, toes, arms and legs.
ABSENCE DEFECT OF LIMBS, SCALP, AND SKULL
APLASIA CUTIS CONGENITA WITH TERMINAL TRANSVERSE LIMB DEFECTS
A syndrome characterized by distinctive facial features including hypertelorism, large eyelid openings, ptosis, high-arched eyebrows, a broad nasal bridge and tip of the nose, a long space between the nose and the upper lip, full cheeks and a pointed chin; structural abnormalities of the brain might also be present.
IRIS COLOBOMA WITH PTOSIS, HYPERTELORISM, AND MENTAL RETARDATION
A syndrome characterized by a combination of multiple joint contractures and osteogenesis imperfecta.
Osteogenesis imperfecta with congenital joint contractures
A syndrome characterized by malformations of the outer, middle and inner ear and branchial and renal malformations. Mutations of the EYA1, SIX1 and SIX5 genes are associated with the syndrome.
A syndrome characterized by unusually sparse, brittle, curly hair, macrocephaly, a prominent forehead and bi-temporal narrowing, intellectual disability, failure to thrive, congenital heart defects, short stature and skin abnormalities; it is that has material basis in mutation in the BRAF, MAP2K1, MAP2kK2 and KRAS genes.
Cardio-facio-cutaneous syndrome (disorder)
A lipid metabolism disorder characterized by an enzymatic defect that prevents long-chain fatty acids from being transported into the mitochondria.
CPT2 - Carnitine palmitoyltransferase II deficiency
CPTII - Carnitine palmitoyltransferase deficiency type II
Carnitine Palmitoyltransferase 2 Deficiency
Carnitine Palmitoyltransferase II Deficiency
A purine-pyrimidine metabolic disorder characterized by deficiency of xanthine oxidase, resulting in excretion of large amounts of xanthine in the urine and the formation of xanthine stones.
Deficiency of xanthine oxidase (disorder)
Isolated xanthine oxidase deficiency (disorder)
A syndrome characterized by facial abnormalities such as telecanthus, epicanthus, broad flattened nose, large inverted W-shaped mouth and malformed ears, malformed extremities such as camptodactyly, clinodactyly, interdigital webbing and joint hyperlaxity and mental retardation.
Cerebro-facio-articular syndrome of Van Maldergem
Van Maldergem Wetzburger Verloes syndrome
A syndrome characterized by the combination of lower lip pits, cleft lip with or without cleft palate and cleft palate alone.
CLEFT LIP AND/OR PALATE WITH MUCOUS CYSTS OF LOWER LIP
Cleft lip and-or palate with mucous cysts of lower lip
An X-linked disease characterized by pre- and postnatal overgrowth and craniofacial, skeletal, cardiac and renal abnormalities.
A Robinow syndrome characterized by autosomal dominant inheritance of dysmorphic features resembling a fetal face, mesomelic limb shortening, hypoplastic external genitalia in males, and renal and vertebral anomalies that has_material_basis_in heterozygous mutation in the WNT5A gene on chromosome 3p.
ACRAL DYSOSTOSIS WITH FACIAL AND GENITAL ABNORMALITIES
Mesomelic Dwarfism-Small Genitalia Syndrome
A gastrointestinal system disease that is located_in the gallbladder.
SKIN PEELING, FAMILIAL CONTINUOUS GENERALIZED
COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6
ENCEPHALOMYOPATHY, MITOCHONDRIAL, X-LINKED
combined oxidative phosphorylation deficiency
A syndrome that is characterized by blepharophimosis, ptosis, dental hypoplasia, hearing impairment and intellectual disability.
MENTAL RETARDATION, CONGENITAL HEART DISEASE, BLEPHAROPHIMOSIS, BLEPHAROPTOSIS, AND HYPOPLASTIC TEETH
Mental retardation, congenital heart disease, blepharophimosis, blepharoptosis and hypoplastic teeth
Mental retardation, congenital heart disease, blepharophimosis, blepharoptosis and hypoplastic teeth (disorder)
Blepharophimosis and Mental Retardation Syndrome, Say-Barber-Biesecker-Young-Simpson Type
Blepharophimosis-Intellectual Deficit Syndrome, Say-Barber-Biesecker-Young-Simpson Type
Blepharophimosis-intellectual deficit syndrome, Say-Barber/Biesecker/Young-Simpson type
Blepharophimosis-mental retardation syndrome, Say-Barber-Biesecker-Young-Simpson type
Blepharophimosis-mental retardation syndrome, Say-Barber-Biesecker-Young-Simpson type (disorder)
Mental retardation unusual facies hypothyroidism
Ohdo Syndrome, Say-Barber-Biesecker Variant
Ohdo Syndrome, Say-Barber-Biesecker-Young-Simpson Variant
blepharophimosis-intellectual disability syndrome, SBBYS type
A syndrome characterized by craniofacial, neurologic, limb and ocular abnormalities.
Ectodermal dysplasia with ocular malformations syndrome
Ectodermal dysplasia-ocular malformation syndrome
Ectodermal dysplasia-ocular malformation syndrome (disorder)
BRACHYTELEPHALANGIC CHONDRODYSPLASIA PUNCTATA
CHONDRODYSPLASIA PUNCTATA 1, X-LINKED RECESSIVE
CHONDRODYSPLASIA PUNCTATA, BRACHYTELEPHALANGIC
CHONDRODYSPLASIA PUNCTATA, BRACHYTELEPHALANGIC, AUTOSOMAL
CHONDRODYSPLASIA PUNCTATA DUE TO VITAMIN K DEFICIENCY
autosomal dominant chondrodysplasia punctata
An upper respiratory tract disease characterized by the unusual growth of the adenoid tonsil; has symptom snoring, has symptom hyponasality, has symptom otitis media with effusion, has symptom mouth breathing.
A mouth disease characterized by a white patch on the side of the tongue with a corrugated or hairy appearance; caused by Epstein-Barr virus.
An orofaciodigital syndrome that is characterized by malformations of the face, oral cavity, and digits, has_material_basis_in X-linked dominant inheritance of the OFD1 gene with lethality in males and is associated with polycystic kidney disease.
An intestinal disease characterized by a protrusion of abdominal cavity contests through the inguinal canal.
A physical disorder characterized by a defect in the development of the abdominal wall muscles, resulting in the intestines, liver and other organs to remain outside of the abdomen in a sac.
A breast disease characterized by a collection of pus in the breast.
A spina bifida characterized by protrusion of the spinal cord through an opening, covered by meningeal membranes.
Meningomyelocele of unspecified site (disorder)
A female reproductive system disease characterized by the implantation of the embryo outside the uterine cavity.
A syndrome characterized by a unique combination of cardiac arrhythmias and intestinal pseudo-obstruction. It has material basis in the mutated SGOL1 protein. Distinctive clinical features include atrial dysrhythmias, sick sinus syndrome (SSS) and valve anomalies and chronic intestinal pseudo-obstruction (CIPO).
CAID (chronic atrial and intestinal dysrhythmia) syndrome
CHRONIC ATRIAL AND INTESTINAL DYSRHYTHMIA
Chronic atrial and intestinal dysrhythmia (disorder)
A genetic disease associated with mutations encoding defective proteins, which result in either abnormal function formation or function of cilia.
A physical disorder characterized by mandibular hypoplasia or agnathia, ventromedial auricular malposition (melotia) and/or auricular fusion (synotia), and microstomia with oroglossal hypoplasia or aglossia. Holoprosencephaly is the most commonly identified association, but skeletal, genitourinary and cardiovascular anomalies and situs inversus have been reported.
agnathia-holoprosencephaly-situs inversus syndrome
dysgnathia complex agnathia-holoprosencephaly
A syndrome characterized byvariable expression of microcephaly, ocular disorders including chorioretinopathy, congenital lymphedema of the lower limbs, and mild to moderate intellectual disability.
Chorioretinal dysplasia-microcephaly-mental retardation syndrome
LYMPHEDEMA AND RETINAL FOLDS WITH MICROCEPHALY AND MICROPHTHALMOS
LYMPHEDEMA, MICROCEPHALY, CHORIORETINOPATHY SYNDROME
Lymphedema, microcephaly and chorioretinopathy syndrome
MICROCEPHALY AND CHORIORETINOPATHY WITH OR WITHOUT MENTAL RETARDATION, AUTOSOMAL DOMINANT
MICROCEPHALY WITH OR WITHOUT CHORIORETINOPATHY, LYMPHEDEMA, OR MENTAL RETARDATION
An amino acid metabolic disorder characterized by the formation 2,8-dihydroxyadenine stones and renal failure secondary to intratubular crystalline precipitation. It has an autosomal recessive inheritance pattern.
ADENINE PHOSPHORIBOSYLTRANSFERASE DEFICIENCY
Adenine phosphoribosyl transferase deficiency
A syndrome characterized by childhood hypotonia, a distinctive facial appearance, speech impediments and developmental disability, as well as epilepsy, congenital and urogenetic defects, microcephaly, corpulence, and psychiatric disorders. It is caused either by a microdeletion in the chromosome region 9q34.3 or by a point mutation in the EHMT1 gene located in that region.
A lipid metabolism disorder characterized by malnutrition, failure to thrive, growth failure, vitamin E deficiency and the absence of chylomicrons and apolipoprotein B48 post-prandially. It has an autosomal recessive inheritance pattern and has material basis in mutations in the SAR1B gene on chromosome 5q31.1.
An inherited metabolic disorder characterized by the body's inability to break down proteins and fats to produce energy. It is a disorder of fatty acid, amino acid, and choline metabolism and has an autosomal recessive inheritance pattern. It has material basis in mutations in the ETFA, ETFB and ETFDH genes. It presents three clinical phenotypes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal.
Electron Transfer Flavoprotein Deficiency
multiple acyl-CoA dehydrogenase deficiency
Deficiency of glycerol kinase (disorder)
A syndrome characterized by malar and mandibular hypoplasia, typically associated with abnormalities of the ears and eyelids, and with alopecia.
MANDIBULOFACIAL DYSOSTOSIS WITH ALOPECIA
A lymphatic system disease characterized by he presence of intestinal lymphangiectasia, mental retardation, and characteristic facial anomalies. It is inherited in an autosomal recessive pattern. Most individuals with Hennekam syndrome have characteristic facial abnormalities, such as a flat face with accompanying puffy eyelids and hypertelorism; the nasal bridge is typically flat and the ears are typically small. Congenital extremity and genital lymphedema is present in most patients.
HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME
Hennekam lymphangiectasia lymphedema syndrome
Hennekam lymphangiectasia-lymphedema syndrome (disorder)
Hennekam lymphangiectasia-lymphoedema syndrome
Lymphangiectasies and lymphedema Hennekam type
A brachydactyly characterized by a nonarticulating great toe set dorsal and proximal to the typical position.
BRACHYDACTYLY WITH MAJOR PROXIMAL PHALANGEAL SHORTENING
Brachydactyly of the hands and feet with duplication of the first toes
OFD III - Orofacial-digital syndrome III
An orofaciodigital syndrome characterized by severe tibial dysplasia and has_material_basis_in homozygous or compound heterozygous mutation in the TCTN3 gene on chromosome 10q24.
An orofaciodigital syndrome that is characterized by postaxial polydactyly and median cleft of the upper lip and has_material_basis_in homozygous mutation in the DDX59 gene on chromosome 1q32.
Oro-facial digital syndrome type 5 (disorder)
A Joubert syndrome that is characterized by orofaciodigital defect.
Joubert syndrome with oro-facial-digital syndrome
Joubert syndrome with orofaciodigital defect (disorder)
Joubert syndrome with orofaciodigital defect
An orofaciodigital syndrome characterized by oral (tongue nodules, bifid tongue, midline cleft of the lip), facial (hypertelorism, alar hypoplasia), and digital abnormalities (clinodactyly).
An orofaciodigital syndrome characterized by hypertelorism or telecanthus, broad, bifid nasal tip, median cleft lip, tongue lobulation and/or hamartomas, oral frenula, high-arched or cleft palate, bilateral polydactyly, and duplicated halluces.
ORAL-FACIAL-DIGITAL SYNDROME WITH HYPOPLASTIC EPIGLOTTIS
An orofaciodigital syndrome characterized by mesomelic limb shortening.
ORAL-FACIAL-DIGITAL SYNDROME WITH FIBULAR APLASIA
OROFACIODIGITAL SYNDROME WITH FIBULAR APLASIA
An orofaciodigital syndrome characterized by skeletal anomalies and severe psychomotor delay.
ORAL-FACIAL-DIGITAL SYNDROME WITH SKELETAL ANOMALIES
An orofaciodigital syndrome characterized by retinal abnormalities, and a lobulated or hamartomatous tongue.
ORAL-FACIAL-DIGITAL SYNDROME WITH RETINAL ABNORMALITIES
OROFACIODIGITAL SYNDROME WITH RETINAL ABNORMALITIES
An autosomal dominant disease that is characterized by predisposition to hamartomatous benign polyps in the gastrointestinal tract, specifically in the stomach, small intestine, colon, and rectum.
TERMINAL CHROMOSOME 10q26 DELETION SYNDROME
CHROMOSOME 15q13.3 MICRODELETION SYNDROME
CHROMOSOME 16p11.2 DELETION SYNDROME, 220-KB
chromosome 16p11.2 deletion syndrome, 220kb
chromosome 16p12.1 deletion syndrome, 520kb
CHROMOSOME 16p12.2-p11.2 DELETION SYNDROME, 7.1- TO 8.7-MB
chromosome 16p12.2-p11.2 deletion syndrome
CHROMOSOME 17q11.2 DELETION SYNDROME, 1.4-MB
NEUROFIBROMATOSIS 1 MICRODELETION SYNDROME
neurofibromatosis type 1 microdeletion syndrome
chromosome 17q11.2 deletion syndrome, 1.4Mb
CHROMOSOME 17q23.1-q23.2 DELETION SYNDROME
Chromosome 1p36 deletion syndrome (disorder)
CHROMOSOME 1q21.1 DELETION SYNDROME, 200-KB
Radial Aplasia-Amegakaryocytic Thrombocytopenia
Radial Aplasia-Thrombocytopenia Syndrome
Radial aplasia-thrombocytopenia syndrome (disorder)
TAR - Thrombocytopenia with absent radius syndrome
Holoprosencephaly with Microphthalmia and First Branchial Arch Anomalies
CHROMOSOME 22q11.2 DELETION SYNDROME, DISTAL
DISTAL CHROMOSOME 22q11.2 DELETION SYNDROME
3p partial monosomy syndrome (diagnosis)
proximal 16p11.2 microduplication syndrome
CHROMOSOME 17q21.31 DUPLICATION SYNDROME
CHROMOSOME 22q11.2 MICRODUPLICATION SYNDROME
An amino acid metabolic disorder characterized by the body's inability to effectively break down lysine, arginine and ornithine and by renal hyperdiaminoaciduria, especially lysinuria, and by impaired formation of urea with hyperammonemia after protein ingestion. It has material basis in homozygous or compound heterozygous mutation in the amino acid transporter gene SLC7A7 on chromosome 14q11.
MESOMELIC DYSPLASIA, 2q31.1 DUPLICATION-RELATED
Chromosome 3q29 duplication syndrome (disorder)
chromosome 3q29 microduplication syndrome
CHROMOSOME Xp11.23-p11.22 DUPLICATION SYNDROME
microduplication Xp11.22-p11.23 syndrome
A syndrome characterized by classical lissencephaly and distinct facial features. Visible and submicroscopic deletions of 17p13.3, including the LIS1 gene, are found in almost 100% of patients.
A syndrome characterized by distinctive facial appearance, a cluster of minor and major anomalies and central nervous system dysfunction.
Congenital malformation due to valproate
A skin disease characterized by congenital blistering, skin atrophy, photosensitivity, skin fragility, and scaling.
BULLOUS ACROKERATOTIC POIKILODERMA OF KINDLER AND WEARY
POIKILODERMA, CONGENITAL, WITH BULLAE, WEARY TYPE
A syndrome characterized by multiple congenital anomalies and mental retardation. Other characteristics include a peculiar facial gestalt, short stature, skeletal and visceral abnormalities, cardiac anomalies, and immunological defects.
A kidney cancer that affects the kidneys and typically located_in children.
A viral infectious disease that has_material_basis in Zika virus, which is transmitted_by Aedes aegypti mosquitoes and targets neural progenitor cells and neuronal cells in all stages of maturity and has_symptom fever, has_symptom rash, has_symptom headaches and has_symptom joint pain.
A syndrome characterized by exocrine pancreatic insufficiency, bone marrow failure and skeletal abnormalities.
Metaphyseal Chondrodysplasia, Shwachman Type
Metaphyseal chondrodysplasia with pancreatic insufficiency AND neutropenia
A syndrome characterized by intellectual disability, specific facial gestalt and Hirschsprung's disease (HSCR). It has material basis in homozygous mutation in the KIAA1279 gene on chromosome 10q21.1.
Goldberg Shprintzen megacolon syndrome (disorder)
A syndrome characterized by microcornea, microphthalmia, anterior-segment dysgenesis, cataract, coloboma of various parts of the eye, abnormalities of the retinal pigment epithelium, and rod-cone dystrophy and a particular cleft ear lobule.
MICROPHTHALMIA, MICROCORNEA, ANTERIOR SEGMENT DYSGENESIS, CATARACT, OCULAR COLOBOMA, RETINAL PIGMENT EPITHELIUM ABNORMALITIES, ROD-CONE DYSTROPHY, AND ANOMALIES OF THE EXTERNAL EAR
SCHORDERET-MUNIER-FRANCESCHETTI SYNDROME
A syndrome characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma. It is cause by homozygous mutation in the AP1S1 gene on chromosome 7q22.
ERYTHROKERATODERMIA VARIABILIS 3 (disorder)
ERYTHROKERATODERMIA VARIABILIS, KAMOURASKA TYPE
Erythrokeratodermia variabilis Kamouraska type
Intellectual disability, enteropathy, deafness, peripheral neuropathy, ichthyosis, keratoderma syndrome
Intellectual disability, enteropathy, deafness, peripheral neuropathy, ichthyosis, keratoderma syndrome (disorder)
A syndrome characterize by seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance. It has material basis in homozygous or compound heterozygous mutation in the KCNJ10 gene on chromosome 1q23.
epilepsy, ataxia, sensorineural deafness and tubulopathy
seizures, sensorineural deafness, ataxia, mental retardation and electrolyte imbalance
A syndrome characterized by a distinct facial phenotype (high forehead, frontal bossing, large eyebrows, medially flaring and sparse in the middle part, hypertelorism, deep set but large eyes, large and uplifted ear lobes, with a central depression, saddle nose with prominent rounded nasal tip, prominent columella, open mouth, with M-shaped upper lip, frequent smiling, and a prominent but narrow and triangular pointed chin), moderate-to-severe intellectual deficiency, epilepsy and variable congenital malformations including Hirschsprung disease, genitourinary anomalies (in particular hypospadias in males), congenital heart defects, agenesis of the corpus callosum and eye anomalies. It has material basis in de novo heterozygous mutation in the ZEB2 gene on chromosome 2q22.
HIRSCHSPRUNG DISEASE-MENTAL RETARDATION SYNDROME
Hirschsprung disease mental retardation syndrome
MICROCEPHALY, MENTAL RETARDATION, AND DISTINCT FACIAL FEATURES, WITH OR WITHOUT HIRSCHSPRUNG DISEASE
Microcephaly, mental retardation and distinct features, with or without Hirschsprung disease
A syndrome characterized by parkinsonism, hypoventilation, depression, and weight loss; that has material basis in heterozygous mutation in the DCTN1 gene on chromosome 2p13.. The mean age at onset is 48 years; the mean disease duration is five years. Parkinsonism and psychiatric changes (depression, apathy, character changes, and withdrawal) tend to occur early; severe weight loss and hypoventilation manifest later.
PARKINSONISM WITH ALVEOLAR HYPOVENTILATION AND MENTAL DEPRESSION
A syndrome characterized by intellectual disability and developmental delay, breathing problems, recurrent seizures (epilepsy), and distinctive facial features. It has material basis in heterozygous de novo mutations in the TCF4 gene in chromosome 18q21.
ENCEPHALOPATHY, SEVERE EPILEPTIC, WITH AUTONOMIC DYSFUNCTION
MENTAL RETARDATION, SYNDROMAL, WITH INTERMITTENT HYPERVENTILATION
A syndrome mainly characterized by severe growth retardation and microcephaly. It is a new form of cohesinopathy showing defects in sister chromatid cohesion and hypersensitivity to chemicals that induce replication stress, thus combining distinct cytogenetic features seen in Roberts syndrome and Fanconi anemia, respectively. It has material basis in homozygous or compound heterozygous mutation in the DDX11 gene on chromosome 12p11.
A mitochondrial metabolism disease characerized by a highly variable phenotype. Some patients have multisystem involvement of the brain, heart, muscle, liver, and kidneys resulting in death in infancy, whereas others have only isolated cardiac or muscle involvement with onset in adulthood and normal cognition. It has material basis in homozygous or compound heterozygous mutation in the nuclear-encoded SDHA gene on chromosome 5p, the nuclear-encoded SDHAF1 gene on chromosome 19q, or the nuclear-encoded SDHD gene on chromosome 11q23.
isolated mitochondrial respiratory chain complex II deficiency
isolated succinate-CoQ reductase deficiency
isolated succinate-coenzyme Q reductase deficiency
isolated succinate-ubiquinone reductase deficiency
A syndrome characterized by d by the association of excessive hair growth (hypertrichosis), papery thin and fragile (atrophic) skin, outward turned eyelids (ectropion) and a large mouth (macrostomia). It is that has material basis in heterozygous mutation in the TWIST2 gene on chromosome 2q37.
HYPERTRICHOSIS, ATROPHIC SKIN, ECTROPION, AND MACROSTOMIA
A syndrome characterized by by the association of ablepharon, macrostomia, abnormal external ears, syndactyly of the hands and feet, skin findings (such as dry and coarse skin or redundant folds of skin), absent or sparse hair, genital malformations and developmental delay. Other reported manifestations include malar hypoplasia, absent or hypoplastic nipples, umbilical abnormalities and growth retardation. It is that has material basis in heterozygous mutation in the TWIST2 gene on chromosome 2q37.
Ablepharon macrostomia syndrome (disorder)
poikiloderma with neutropenia, Clericuzio type
A skin disease characterized by poikiloderma, hyperkeratotic nails, generalized hyperkeratosis on palms and soles, neutropenia, short stature, and recurrent pulmonary infections. It has material basis in mutation in the C16ORF57 gene on chromosome 16q13.
POIKILODERMA WITH NEUTROPENIA, CLERICUZIO-TYPE
A syndrome characterized by congenital nonprogressive joint contractures. The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth.
Congenital deformity of clavicle (disorder)
Israeli Bedouin type B multiple contracture syndrome
congenital deformity of clavicle (diagnosis)
lethal congenital contracture syndrome 3
A lethal congenital contracture syndrome that has material basis in homozygous or compound heterozygous mutation in the mRNA export mediator GLE1 on chromosome 9q34.
LETHAL CONGENITAL CONTRACTURE SYNDROME 1
Lethal autosomal recessive syndrome of multiple congenital contractures
Lethal congenital contracture syndrome type 1
Lethal congenital contracture syndrome type 1 (disorder)
MULTIPLE CONTRACTURE SYNDROME, FINNISH TYPE
Multiple contracture syndrome Finnish type
A lethal congenital contracture syndrome that can be that has material basis in homozygous mutation in the ERBB3 gene on chromosome 12q13.
LETHAL CONGENITAL CONTRACTURE SYNDROME 2
MULTIPLE CONTRACTURE SYNDROME, ISRAELI BEDOUIN TYPE A
multiple contracture syndrome, Israeli-Bedouin type
Disorder of the vertebral column (disorder)
A syndrome characterized by craniofacial (prominent occiputal and forehead, hypertelorism, ocular coloboma, cleft palate), cerebellar (Dandy-Walker malformation, cerebellar vermis hypoplasia) and cardiac (tetralogy of Fallot, atrial and ventricular septal defects) anomalies.
Cranio-cerebello-cardiac dysplasia syndrome
Cranio-cerebello-cardiac dysplasia syndrome (disorder)
DANDY-WALKER-LIKE MALFORMATION WITH ATRIOVENTRICULAR SEPTAL DEFECT
A syndrome characterized by Potter sequence, heart defect, cleft palate, polydactyly, and skeletal defects.
Complex congenital heart defect, renal agenesis, and cleft lip and palate
A Ritscher-Schinzel syndrome that has_material_basis_in mutation in the CCDC22 gene on chromosome Xp11.
A 3MC syndrome that has_material_basis_in homozygous mutation in the MASP1 gene on chromosome 3q27.
clefting-ocular anterior chamber defect-lid anomalies syndrome
A 3MC syndrome that has_material_basis_in homozygous mutation in the COLEC11 gene on chromosome 2p25.
PTOSIS OF EYELIDS WITH DIASTASIS RECTI AND HIP DYSPLASIA
A Noonan syndrome that has_material_basis_in the PTPN11 gene on chromosome 12q24.
A Noonan syndrome characterized by hypertrophic obstructive cardiomyopathy and that has_material_basis_in an autosomal recessive inheritance.
A Noonan syndrome that has_material_basis_in heterozygous mutation in the KRAS gene.
A Noonan syndrome that has_material_basis_in heterozygous mutation in the SOS1 gene on chromosome 2p22.
A Noonan syndrome that has_material_basis_in mutation in the RAF1 gene.
A Noonan syndrome that has_material_basis in heterozygous mutation in the NRAS gene on chromosome 1p13.
A Noonan syndrome that has_material_basis in heterozygous mutation in the BRAF gene.
A Noonan syndrome that has_material_basis_in aused by heterozygous mutation in the RIT1 gene on chromosome 1q22.
A Noonan syndrome that has_material_basis_in heterozygous mutation in the SOS2 gene on chromosome 14q21.
A Noonan syndrome that has_material_basis_in heterozygous mutation in the LZTR1 gene on chromosome 22q11.
A syndrome characterized by skeletal defects, including cleidocranial dysplasia and digital anomalies, and severe neurologic involvement with neuronal loss. Enlarged cytoplasmic vacuoles are found in neurons, muscle, and cartilage. It is usually lethal in infancy and has material basis in homozygous or compound heterozygous mutation in the FIG4 gene on chromosome 6q21.
CLEIDOCRANIAL DYSPLASIA WITH MICROGNATHIA, ABSENT THUMBS, AND DISTAL APHALANGIA
Cleidocranial dysplasia, micrognathia, absent thumbs, & distal aphalangia
cleidocranial dysplasia-micrognathia-absent thumbs syndrome
A syndrome characterized by aged bird-like facies, lack of subcutaneous fat, dwarfism, cachexia and microcephaly. Additional features include sun-sensitivity from birth, learning disabilities, hearing loss, and visual impairment. It has material basis in homozygous mutation in the ERCC4 gene on chromosome 16p13.
An immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia, and extensive human papillomavirus (HPV) infection. It has material basis in heterozygous mutation in the CXCR4 gene on chromosome 2q22.
WARTS, HYPOGAMMAGLOBULINEMIA, INFECTIONS, AND MYELOKATHEXIS SYNDROME
WHIM - Warts+hypogammaglobulinaemia+infections+myelokathexis
WHIM - Warts+hypogammaglobulinemia+infections+myelokathexis
WHIM - Warts, hypogammaglobulinaemia, infections and myelokathexis
WHIM - Warts, hypogammaglobulinemia, infections and myelokathexis
Warts, hypogammaglobulinaemia, infections, and myelokathexis
An X-linked disease that has_material_basis_in mutation in the NHS gene on chromosome Xp22. It is characterized by congenital cataract leading to profound vision loss, characteristic dysmorphic features and dental anomalies.
CATARACT, X-LINKED, WITH HUTCHINSONIAN TEETH
A peroxisomal disease that has_material_basis in homozygous mutation in the AMACR gene on chromosome 5p13.2-q11.1. It is characterized by retinitis pigmentosa resulting in progressive visual failure, learning difficulties, a peripheral neuropathy, and hypogonadism.
ALPHA-METHYLACYL-CoA RACEMASE DEFICIENCY
Alpha-methylacyl-CoA racemase deficiency disorder
Alpha-methylacyl-CoA racemase deficiency disorder (disorder)
A specific developmental disorder that is characterized by physical, behavioral and learning birth defects resulting from maternal ingestion of nicotine during pregnancy.
A syndrome that is characterized by marked dilatation of the bladder and microcolon and decreased intestinal peristalsis.
MEGACYSTIS-MICROCOLON-INTESTINAL HYPOPERISTALSIS SYNDROME
Megacystis microcolon intestinal hypoperistalsis syndrome
Megacystis, Microcolon, Hypoperistalsis Syndrome
Megacystis, Microcolon, Intestinal Hypoperistalsis Syndrome
A cleft palate that has_material_basis in mutation in the TBX22 gene on chromosome Xq21.
CLEFT PALATE WITH OR WITHOUT ANKYLOGLOSSIA, X-LINKED
X-linked cleft palate with or without ankyloglossia
A syndrome that has_material_basis_in heterozygous mutation in the TBX3 gene. It is characterized by posterior limb deficiencies or duplications, apocrine/mammary gland hypoplasia and, or dysfunction, abnormal dentition, delayed puberty in males, and genital anomalies.
A mitochondrial metabolism disease that is characterized by neurodevelopmental delay and regression, prominent pyramidal and extrapyramidal signs, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea; it has_material_basis_in homozygous or compound heterozygous mutation in the ETHE1 gene, which encodes a mitochondrial matrix protein, on chromosome 19q13.
Encephalopathy, Petechiae, and Ethylmalonic Aciduria
Syndrome of encephalopathy, petechiae, and ethylmalonic aciduria
A syndrome that is characterized by multiple congenital defects in endocrine, cerebral, and skeletal systems leading to neonatal mortality; it has_material_basis_in mutation in the gene encoding intestinal cell kinase (ICK).
endocrine-cerebro-osteodysplasia syndrome
A syndrome characterized by the clinical features of 46,XY complete gonadal dysgenesis in association with severe dwarfism with generalized chondrodysplasia.
CHONDRODYSPLASIA-PSEUDOHERMAPHRODITISM SYNDROME
Chondrodysplasia pseudohermaphrodism syndrome
Chondrodysplasia pseudohermaphroditism syndrome
Chondrodysplasia with disorder of sex development syndrome
Chondrodysplasia with disorder of sex development syndrome (disorder)
Pseudohermaphrodism and chondrodysplasia
chondrodysplasia-disorder of sex development syndrome
A syndrome that has_material_basis_in homozygous mutation in the CHUK gene on chromosome 10q24 and is characterized by multiple fetal malformations including defective face and seemingly absent limbs, which are bound to the trunk and encased under the skin.
Dicarboxylic aminoaciduria syndrome (disorder)
Glutamate and aspartate transport defect
LETHAL CONGENITAL CONTRACTURAL SYNDROME 3
MULTIPLE CONTRACTURE SYNDROME, ISRAELI BEDOUIN TYPE B
Multiple Contractural Syndrome, Israeli Bedouin Type B
A lethal congenital contracture syndrome that has_material_basis_in homozygous mutation in the MYBPC1 gene on chromosome 12q23.
LETHAL CONGENITAL CONTRACTURE SYNDROME 4
A skin disease that is characterized by autosomal recessive inheritance and abnormal skin scaling over the whole body due to a defect in keratinization.
autosomal recessive congenital ichthyosis
A congenital nervous system abnormality characterized by failure of the anterior neuropore to close resulting in partial or complete absence of the cranial vault accompanied by absence of overlying tissues, including the brain and cerebral hemispheres, skull and scalp.
An amino acid metabolic disorder characterized by recessive X-linked inhetiance, impaired monoamine metabolism, impulsive aggressiveness and mild mental retardation that has_material_basis_in mutation in the MAOA gene on chromosome Xp11.
Deficiency of monoamine oxidase A (disorder)
A hyperekplexia that has_material_basis_in heterozygous, homozygous, or compound heterozygous mutation in the GLRA1 gene on chromosome 5q32.
A hyperekplexia that has_material_basis_in compound heterozygous or homozygous mutation in the GLRB gene on chromosome 4q32.
A hyperekplexia that has_material_basis_in homozygous or compound heterozygous mutation in the SLC6A5 gene on chromosome 11p15.
A primary immunodeficiency disease characterized by immune dysregulation typically after viral infection, usually associated with Epstein-Barr viral infection.
A carbohydrate metabolic disorder that has_material_basis_in homozygous or compound heterozygous mutation in the NGLY1 gene on chromosome 1p24. It is characterized by global developmental delay, hypotonia, abnormal involuntary movements, and alacrima or poor tear production.
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iv, FORMERLY
congenital disorder of glycosylation type Iv
A chromosome deletion syndrome characterized by trigonocephaly, flattened occiput midface hypoplasia, long philtrum, prominent forehead, broad flat nasal bridge, anteverted nares, malformed external ears, hypertelorism, hypertonia, delayed psychomotor development and that has_material_basis_in a contiguous gene deletion on the short arm of chromosome 9.
A skin disease characterized by thin, tightly adherent translucent skin with erosions at flexure sites, superficial vessels, typical facial dysmorphism, and generalized joint ankylosis that has_material_basis_in heterozygous mutation in the LMNA gene on chromosome 1q22 or by homozygous or compound heterozygous mutation in the ZMPSTE24 gene on chromosome 1p34.
FETAL HYPOKINESIA SEQUENCE DUE TO RESTRICTIVE DERMOPATHY
Infantile restrictive dermopathy (disorder)
Lethal tight skin contracture syndrome (disorder)
A Robinow syndrome characterized by autosomal recessive inheritance of severe skeletal dysplasia characterized by dysmorphic facial features, including frontal bossing, hypertelorism, and broad nose, short-limbed dwarfism, vertebral segmentation, and genital hypoplasia that has_material_basis_in homozygous or compound heterozygous mutations in the ROR2 gene on chromosome 9q22.
COSTOVERTEBRAL SEGMENTATION DEFECT WITH MESOMELIA, FORMERLY
costovertebral segmentation defect-mesomelia syndrome
A Robinow syndrome characterized by autosomal dominant inheritance of mesomelic limb shortening, genital hypoplasia, and distinctive facial features that has_material_basis_in heterozygous mutation in the DVL1 gene on chromosome 1p36.
A Robinow syndrome characterized by autosomal dominant inheritance of mesomelia, genital hypoplasia, and distinctive facial features comprising frontal bossing, prominent eyes, and a depressed nasal bridge that has_material_basis_in heterozygous mutation in the DVL3 gene on chromosome 3q27.
A chromosome deletion syndrome characterized by mild-to-moderate infantile hypotonia, minor skeletal anomalies, prepubertal short stature, brachydactyly, ophthalmologic and otolaryngologic abnormalities, peripheral neuropathy, developmental delay, cognitive impairment, and behavioral abnormalities that has_material basis_in a 3.7-Mb interstitial deletion in chromosome 17p11.2 or sometimes by mutations in the RAI1 gene in the same region.
A diarrhea characterized by frequent loose or liquid bowel movements where the disease is present from birth.
A X-linked disease characterized by X-linked recessive inheritance of degenerative and proliferative changes of the neuroretina resulting in congenital blindness along with progressive mental disorders in about 50% of patients and sensorineural deafness in about 33% of patients that has_material_basis_in mutation in the NDP gene on chromosome Xp11.
Atrophia bulborum hereditaria (disorder)
Congenital Progressive Oculo-Acoustico-Cerebral Degeneration
A pancreas disease characterized by autosomal dominant inheritance of the annular pancreas (head of the pancreas forming a ring around the second portion of the duodenum) and duodenal stenosis.
Potocki-Lupski syndrome (dup(17)(p11.2p11.2))
A visceral heterotaxy characterized by complete atrioventricular septal defect with a common atrium and univentricular AV connection, total anomalous pulmonary drainage, and transposition or malposition of the great arteries and may be associated with bilateral trilobed lungs, midline liver, asplenia and situs inversus affecting other organs that has_material_basis_in homozygous mutation in the GDF1 gene on chromosome 19p12.
Asplenia with Cardiovascular Abnormalities
An autosomal genetic disease characterized by the classical triad of optic nerve hypoplasia, pituitary gland hypoplasia and midline brain defects that has_material_basis_in mutation in the HESX1 gene on chromosome 3p14.
Septo Optic Dysplasia with Growth Hormone Deficiency
A syndrome that has_material_basis_in homozygous deletion on chromosome 2p21 that disrupts the SLC3A1 and PREPL genes. The deletion ranges in size from 23.8 to 75.5 kb. Itis characterized_by neonatal and infantile hypotonia and failure to thrive, cystinuria type 1 and nephrolithiasis, growth retardation due to growth hormone deficiency, and minor facial dysmorphism.
HOMOZYGOUS 2p16 DELETION SYNDROME, FORMERLY
Hypotonia cystinuria syndrome (disorder)
A primary bacterial infectious disease caused by the bacteria of the genus Salmonella. It has sypmtoms diarrhea, fever, vomiting, and abdominal cramps 12 to 72 hours after infection. In most cases, the illness lasts four to seven days, and most people recover without treatment.
A characterized by autosomal dominant inheritance of hypoparathyroidism, sensorineural deafness and progressive renal failure that has material_basis_in chromosome deletion that results in haploinsufficiency of the GATA3 gene on chromosome 10p14.
HYPOPARATHYROIDISM, SENSORINEURAL DEAFNESS, AND RENAL DISEASE
HYPOPARATHYROIDISM, SENSORINEURAL DEAFNESS, AND RENAL DYSPLASIA SYNDROME
NEPHROSIS, NERVE DEAFNESS, AND HYPOPARATHYROIDISM
hypoparathyroidism-deafness-renal disease syndrome
A hypomagnesemia characterized by autosomal recessive inheritance of excessive urinary Ca(2+) and Mg(2+) excretion that has material_basis_in homozygous or compound heterozygous mutation in the CLDN16 gene on chromosome 3q28.
HYPOMAGNESEMIA, FAMILIAL, WITH HYPERCALCIURIA AND NEPHROCALCINOSIS
HYPOMAGNESEMIA, PRIMARY, DUE TO DEFECT IN RENAL TUBULAR TRANSPORT OF MAGNESIUM
A connective tissue disease characterized by ectopic ossification of the posterior longitudinal spinal ligament resulting in spinal cord compression, myelopathy and hyperreflexia.
OSSIFICATION OF THE POSTERIOR LONGITUDINAL LIGAMENT OF SPINE
Ossification of the posterior longitudinal ligament of the spine
A syndrome that has material basis in homozygous mutation in the CHRM3 gene on chromosome 1q43. It is characterized by megacystis (massively enlarged bladder) with disorganized detrusor muscle, cryptorchidism, and thin abdominal musculature with overlying lax skin.
Congenital prolapse of bladder mucosa (disorder)
A lissencephaly that has_material_basis_in homozygous mutation in the gene encoding reelin (RELN) on chromosome 7q22.
LISSENCEPHALY SYNDROME, NORMAN-ROBERTS TYPE
Lissencephaly syndrome Norman Roberts type
Lissencephaly syndrome Norman Roberts type (disorder)
A vascular disease caused by the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system.
A cell type cancer that has_material_basis_in abnormally proliferating cells derives_from precursor cells called blast cells.
A Meckel syndrome that has_material_basis_in an autosomal recessive mutation of TMEM216 on chromosome 11q12.2.
A Meckel syndrome that has_material_basis_in an autosomal recessive mutation of TMEM67 on chromosome 8q22.1.
A Meckel syndrome that has_material_basis_in an autosomal recessive mutation of CEP290 on chromosome 12q21.32.
A Meckel syndrome that has_material_basis_in an autosomal recessive mutation of RPGRIP1L on chromosome 16q12.2.
A Meckel syndrome that has_material_basis_in an autosomal recessive mutation of CC2D2A on chromosome 4p15.32.
A Meckel syndrome that has_material_basis_in an autosomal recessive mutation of NPHP3 on chromosome 3q22.1.
RENAL-HEPATIC-PANCREATIC DYSPLASIA WITH DANDY-WALKER CYST
A Meckel syndrome that has_material_basis_in an autosomal recessive mutation of TCTN2 on chromosome 12q24.31.
A muscular disease in which the muscle fibers do not function resulting in muscular weakness.
Disorder of skeletal AND/OR smooth muscle
A connective tissue disease that affects the structure or development of bone or causes an impairment of normal bone function.
A genetic disease that has_material_basis_in extra, missing, or re-arranged chromosomes.
A disease that has_material_basis_in a genetic abnormality, error with embryonic development, infection or compromised intrauterine environment.
A syndrome that involves abnormality of collagen synthesis in lamellar bones, with manifestations limited to the skeleton. The initial symptom is frequently spontaneous fractures.
Deficiency of N-acetylglucosamine-1-phosphotransferase
Incomplete closure of the vertebral arch
NAIL DISORDER, NONSYNDROMIC CONGENITAL, 1
NAIL DISORDER, NONSYNDROMIC CONGENITAL, 4
NAIL DISORDER, NONSYNDROMIC CONGENITAL, 5
ANONYCHIA/HYPONYCHIA AND ONYCHODYSTROPHY
NAIL DISORDER, NONSYNDROMIC CONGENITAL, 6
NAIL DISORDER, NONSYNDROMIC CONGENITAL, 7
NAIL DISORDER, NONSYNDROMIC CONGENITAL, 8
NAIL DISORDER, NONSYNDROMIC CONGENITAL, 9
NAIL DISORDER, NONSYNDROMIC CONGENITAL, 10
nonsyndromic congenital nail disorder 10
A syndrome that is characterized by delayed psychomotor development and visual impairment, often accompanied by short stature and has_material_basis_in homozygous or compound heterozygous mutation in the TUBGCP6 gene.
MICROCEPHALY AND CHORIORETINOPATHY, AUTOSOMAL RECESSIVE, 1
Microcephaly and Chorioretinopathy, Autosomal Recessive, Type 1
A syndrome that is characterized by delayed psychomotor development, visual impairment, and short stature and has_material_basis_in homozygous mutation in the PLK4 gene.
MICROCEPHALY AND CHORIORETINOPATHY, AUTOSOMAL RECESSIVE, 2
A syndrome that is characterized by congenital microcephaly and chorioretinal dysplasia associated with poor vision and nystagmus and has_material_basis_in compound heterozygous mutation in the TUBGCP4 gene.
MICROCEPHALY AND CHORIORETINOPATHY, AUTOSOMAL RECESSIVE, 3
MULTIPLE PTERYGIUM SYNDROME, ESCOBAR VARIANT
MULTIPLE PTERYGIUM SYNDROME, NONLETHAL TYPE
MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)
MITOCHONDRIAL NEUROGASTROINTESTINAL ENCEPHALOPATHY SYNDROME
MITOCHONDRIAL NEUROGASTROINTESTINAL ENCEPHALOPATHY SYNDROME, TYMP-RELATED
MYONEUROGASTROINTESTINAL ENCEPHALOPATHY SYNDROME
MITOCHONDRIAL DNA DEPLETION MYOPATHY, TK2-RELATED
MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC TYPE)
Mitochondrial DNA depletion syndrome 2 myopathic type
TK2-related mitochondrial DNA depletion myopathy
TK2-related mitochondrial DNA depletion syndrome myopathic form
TK2-related mitochondrial deoxyribonucleic acid depletion syndrome myopathic form
TK2-related mitochondrial deoxyribonucleic acid depletion syndrome myopathic form (disorder)
MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE)
A cerebral degeneration that results in progressive degeneration of grey matter in the cerebrum and has_symptom convulsions.
ALPERS DIFFUSE DEGENERATION OF CEREBRAL GRAY MATTER WITH HEPATIC CIRRHOSIS
ALPERS PROGRESSIVE INFANTILE POLIODYSTROPHY
MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE)
MITOCHONDRIAL NEUROGASTROINTESTINAL ENCEPHALOPATHY SYNDROME, POLG-RELATED
MITOCHONDRIAL DNA DEPLETION SYNDROME 5 (ENCEPHALOMYOPATHIC WITH OR WITHOUT METHYLMALONIC ACIDURIA)
MITOCHONDRIAL DNA DEPLETION SYNDROME, ENCEPHALOMYOPATHIC FORM, WITH OR WITHOUT METHYLMALONIC ACIDURIA, AUTOSOMAL RECESSIVE, SUCLA2-RELATED
MITOCHONDRIAL DNA DEPLETION SYNDROME 7 (HEPATOCEREBRAL TYPE)
OPHTHALMOPLEGIA, HYPOTONIA, ATAXIA, HYPOACUSIS, AND ATHETOSIS
Ophthalmoplegia, hypotonia, ataxia, hypacusis, and athetosis
MITOCHONDRIAL NEUROGASTROINTESTINAL ENCEPHALOPATHY SYNDROME, RRM2B-RELATED
LACTIC ACIDOSIS, FATAL INFANTILE, FORMERLY
MITOCHONDRIAL DNA DEPLETION SYNDROME 9 (ENCEPHALOMYOPATHIC TYPE WITH METHYLMALONIC ACIDURIA)
MITOCHONDRIAL DNA DEPLETION SYNDROME 12B (CARDIOMYOPATHIC TYPE), AUTOSOMAL RECESSIVE
MITOCHONDRIAL DNA DEPLETION SYNDROME 13 (ENCEPHALOMYOPATHIC TYPE)
Congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy syndrome
Congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy syndrome (disorder)
MITOCHONDRIAL DNA DEPLETION SYNDROME 10 (CARDIOMYOPATHIC TYPE)
MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 1
MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 2 WITH HYPERGLYCINEMIA
multiple mitochondrial dysfunctions syndrome 2
MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 3
MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 4
GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 3
MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 20
GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 4
MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 2
GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 7
MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 3
Instability mitotic non disjunction syndrome
Mosaic variegated aneuploidy syndrome (disorder)
A lipid metabolism disorder that is characterized by a deficiency of the enzyme medium chain acyl-CoA dehydrogenase that results in the inability to convert medium chain fatty acids to energy, particularly during fasting.
ACYL-CoA DEHYDROGENASE, MEDIUM-CHAIN, DEFICIENCY OF
Acyl-CoA Dehydrogenase, Medium-Chain Deficiency
Acyl-CoA dehydrogenase, medium chain, deficiency of
CARNITINE DEFICIENCY SECONDARY TO MEDIUM-CHAIN ACYL-CoA DEHYDROGENASE DEFICIENCY
Deficiency of medium-chain acyl-CoA dehydrogenase
medium chain acyl-CoA dehydrogenase deficiency
A lipid metabolism disorder that is characterized by deficiency of the enzyme short chain acyl-CoA dehydrogenase that results in the inability to convert short chain fatty acids.
ACYL-CoA DEHYDROGENASE, SHORT-CHAIN, DEFICIENCY OF
Acyl-CoA Dehydrogenase, Short-Chain Deficiency
short chain acyl-CoA dehydrogenase deficiency
A lipid metabolism disorder that is characterized by deficiency of the enzyme very long chain acyl-CoA dehydrogenase that results in the inability to convert very long chain fatty acids.
ACYL-CoA DEHYDROGENASE, VERY LONG-CHAIN, DEFICIENCY OF
Acyl-CoA Dehydrogenase, Very Long-Chain Deficiency
Acyl-Coa Dehydrogenase Very Long Chain Deficiency
SIDEROBLASTIC ANEMIA WITH MARROW CELL VACUOLIZATION AND EXOCRINE PANCREATIC DYSFUNCTION
very long chain acyl-CoA dehydrogenase deficiency
An immune system disease that is characterized by neonatal onset of recurrent fever, erythematous rash with painful nodules, painful joints, and lipodystrophy and has_material_basis_in autosomal recessive inheritance of homozygous loss-of-function mutations in the OTULIN gene encoding a deubiquitinase with linear linkage specificity on chromosome 5p15.
AUTOINFLAMMATION, PANNICULITIS, AND DERMATOSIS SYNDROME
OTULIN-RELATED AUTOINFLAMMATORY SYNDROME
autoinflammation, panniculitis and dermatosis syndrome
A gastrointestinal system disease that is characterized by abnormal development of the esophagus and trachea where the upper esophagus does not connect (atresia) to the lower esophagus and stomach and may also include tracheoesophageal fistula where the esophagus and the trachea are abnormally connected which allows fluids from the esophagus to get into the airways and interfere with breathing.
ESOPHAGEAL ATRESIA WITH OR WITHOUT TRACHEOESOPHAGEAL FISTULA
Esophageal Atresia Tracheoesophageal Fistula
Esophageal Atresia-Tracheoesophageal Fistula
TRACHEOESOPHAGEAL FISTULA WITH OR WITHOUT ESOPHAGEAL ATRESIA
esophageal atresia and/or tracheoesophageal fistula
tracheoesophageal fistula with or without esohageal atresia
esophageal atresia/tracheoesophageal fistula
An inherited metabolic disease that is characterized by significantly reduced activity of an enzyme that helps the body process drugs called thiopurines.
THIOPURINE S-METHYLTRANSFERASE DEFICIENCY
TPMT - Thiopurine methyltransferase deficiency
A physical disorder that is characterized as a spectrum of anomalies involving the urinary tract, genital tract, musculoskeletal system and sometimes the intestinal tract.
OMPHALOCELE-EXSTROPHY-IMPERFORATE ANUS-SPINAL DEFECTS
Omphalocele, exstrophy of the cloaca, imperforate anus, and spinal defects
bladder exstrophy-epispadias-cloacal exstrophy complex
Congenital extroversion of urinary bladder
A gastrointestinal system disease that is characterized by painful inflammation and ulceration of the mucous membranes lining the digestive tract.
Inflammatory disease of mucous membrane (disorder)
A syndrome that is characterized in neonates by microcephaly, craniofacial disproportion, spasticity, seizures, irritability and brainstem dysfunction including feeding difficulties, ocular abnormalities and findings on neuroimaging such as calcifications, cortical disorders and ventriculomegaly and has_material_basis_in the acquisition of Zika virus infection in utero.
A cell type cancer of vascular origin, characterized by proliferation of endothelial cells in and about the vascular lumen.
Malignant hemangioma (morphologic abnormality)
A syndrome characterized as a spectrum of disorders (Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and Proteus-like syndrome) caused by germline mutations of the PTEN gene.
PTEN hamartoma tumor syndrome (disorder)
A syndrome characterized by hypotonia, Moebius sequence (bilateral congenital facial palsy with impairment of ocular abduction), Pierre Robin complex (micrognathia, glossoptosis, and high-arched or cleft palate), delayed motor milestones, and failure to thrive.
A syndrome that is characterized by anterior chamber eye anomalies, short limbs with broad distal extremities, characteristic facial features, cleft lip/palate, and variable developmental delay/intellectual disability.
Peters Anomaly-Short Limb Dwarfism Syndrome
A kidney disease that is characterized by abnormally small kidneys with normal morphology and reduced number of nephrons.
Congenital hypoplasia of kidney (disorder)
A urinary system disease characterized by structural malformations in the kidney and/or urinary tract containing vesicoureteral reflux.
Congenital Anomalies Of Kidney And Urinary Tract
Congenital anomalies of the kidney and urinary tract
Congenital anomalies of the kidney and urinary tract (CAKUT)
A CAKUT that has_material_ basis_in heterozygous mutation in the DSTYK gene on chromosome 1q32.
A CAKUT that has_material_basis_in heterozygous mutation in the TBX18 gene on chromosome 6q14.
CONGENITAL ANOMALIES OF KIDNEY AND URINARY TRACT 2
Obstruction of pelviureteric junction (disorder)
multiple mitochondrial dysfunctions syndrome 5
A sleep apnea that is characterized by a combination of central and obstructive sleep apnea.
Mixed Central and Obstructive Sleep Apnea
Sleep Apnea, Mixed Central and Obstructive
A physical disorder that is characterized by fusion of maxilla and mandible with autosomal dominant inheritance.
CPLS - cleft palate-lateral synechia syndrome
Cleft palate lateral synechia syndrome (disorder)
Cleft palate-lateral synechia syndrome (disorder)
An monogenic disease that is characterized by congenital profound bilateral sensorineural hearing loss and generalized albino-like hypopigmentation of skin, eyes and hair that has_material_basis_in mutation in the MITF gene on chromosome 3p13.
Albinism-deafness syndrome of Tietz (disorder)
An intestinal disease that is characterized by autosomal recessive inheritance of unrestricted intestinal absorption of both cholesterol and plant-derived cholesterol-like molecules resulting in xanthomas, arthralgia, premature atherosclerosis, and hemolytic anemia with stomatocytosis and macrothrombocytopenia that has_material_basis_in homozygous or compound heterozygous mutation in the ABCG8 gene or in the ABCG5 gene, both of which are located on chromosome 2p21.
MACROTHROMBOCYTOPENIA/STOMATOCYTOSIS, MEDITERRANEAN
Macrothrombocytopenia-Stomatocytosis, Mediterranean
A vitamin metabolic disorder characterized by progressive spino-cerebellar ataxia, loss of proprioception, areflexia, and marked deficiency in vitamin E that has_material_basis_in homozygous or compound heterozygous mutation in the TTPA gene on chromosome 8q12.
ATAXIA, FRIEDREICH-LIKE, WITH SELECTIVE VITAMIN E DEFICIENCY
Ataxia with isolated vitamin E deficiency
Ataxia with vitamin E deficiency (disorder)
Familial isolated deficiency of vitamin E
CORTICOSTEROID-BINDING GLOBULIN DEFICIENCY
A peroxisomal disease characterized by, in severe cases, infantile-onset of hypotonia, seizures, and abnormal facial features with most dieing before age 2 years that has_material_basis_in homozygous or compound heterozygous mutation in the HSD17B4 gene on chromosome 5q2.
17-BETA-HYDROXYSTEROID DEHYDROGENASE IV DEFICIENCY
17-beta-hydroxysteroid dehydrogenase 4, deficiency of
Bifunctional peroxisomal enzyme deficiency
Bifunctional peroxisomal enzyme deficiency (disorder)
A primary immunodeficiency disease characterized by recurrent episodes of maculopapular skin rash triggered by exposure to cold associated with low-grade fever, general malaise, eye redness and arthralgia/myalgia.
COLD-INDUCED AUTOINFLAMMATORY SYNDROME, FAMILIAL
CRYOPYRIN-ASSOCIATED PERIODIC SYNDROME 1
Cold Induced Autoinflammatory Syndrome, Familial
FAMILIAL COLD AUTOINFLAMMATORY SYNDROME 1
A syndrome characterized by pancytopenia, immune deficiency and cutaneous malignancies.
ALBINISM, OCULAR, WITH LATE-ONSET SENSORINEURAL DEAFNESS
ALBINISM, OCULAR, WITH LATE-ONSET SENSORINEURAL DEAFNESS (disorder)
Albinism ocular late onset sensorineural deafness
Albinism, Ocular, With Sensorineural Deafness
OCULAR ALBINISM WITH SENSORINEURAL DEAFNESS
Ocular albinism with late-onset sensorineural deafness
An amino acid metabolic disorder characterized by autosomal recessive inheritance of hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits that has material_basis_in mutation in the PTS gene on chromosome 11q23.1.
6-PYRUVOYL-TETRAHYDROPTERIN SYNTHASE DEFICIENCY
HYPERPHENYLALANINEMIA, TETRAHYDROBIOPTERIN-DEFICIENT, DUE TO PTS DEFICIENCY
Hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency
Hyperphenylalaninemia, BH4-Deficient, Type A
A hypersensitivity reaction type II disease characterized by onset in infancy of refractory diarrhea, endocrinopathies, type 1 diabetes mellitus, and dermatitis that has material_basis_in mutation in the FOXP3 gene on chromosome Xp11.
X-linked autoimmunity-allergic dysregulation syndrome
autoimmunity-immunodeficiency syndrome, X-linked
Congen diab mell with fatal secretory diarrhea
Congen diab mell with fatal secretory diarrhoea
Congenital insulin-dependent diabetes mellitus with fatal secretory diarrhea
Congenital insulin-dependent diabetes mellitus with fatal secretory diarrhoea
immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome
A nervous system disease characterized by autosomal recessive inheritance of spinocerebellar ataxia and peripheral neuropathy that has_material_basis_in homozygosity for a mutation in the TDP1 gene on chromosome 14q32.11.
SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY
autosomal recessive spinocerebellar ataxia with axonal neuropathy
spinocerebellar ataxia type 1 with axonal neuropathy
A leukocyte disease characterized by autosomal dominant inheritance of lifelong, persistent elevated neutrophil counts primarily consisting of segmented neutrophils that has_material_basis_in heterozygous mutation in the CSF3R gene on chromosome 1p34.
A reproductive system disease characterized by autosomal dominant inheritance of increased extraglandular aromatization of steroids resulting in heterosexual precocity in males and isosexual precocity in females that has_material_basis_in fusion of the CYP19A1 gene with various partners, brought about by translocations and resulting in gain of function of the CYP19A1 gene.
Familial gynecomastia, due to increased aromatase activity
GYNECOMASTIA, FAMILIAL, DUE TO INCREASED AROMATASE ACTIVITY
Aromatic L-amino acid decarboxylase deficiency
Aromatic amino acid decarboxylase deficiency
Aromatic amino acid decarboxylase deficiency (disorder)
A nervous system disease characterized by congenital contractures at the elbows and knees, myopathy, absence of muscle spindles, congenital heart disease and spinal motor nueron depletion that has_material_basis_in variation in the chromosome region 5q35.
ARTHROGRYPOSIS MULTIPLEX CONGENITA, NEUROGENIC TYPE
ARTHROGRYPOSIS MULTIPLEX CONGENITA, NEUROGENIC TYPE (disorder)
Arthrogryposis multiplex congenita neurogenic type
Neurogenic arthrogryposis multiplex congenita
Neurogenic arthrogryposis multiplex congenita (disorder)
A lipid metabolism disorder characterized by autosomal recessive inheritance of impaired mitochondrial oxidation of long chain fatty acids in the liver and kidneys resulting in episodes of illness- or fasting-induced hypoketotic hypoglycemia that has_material_basis_in homozygous or compound heterozygous mutation in the CPT1A gene on chromosome 11q13.
CARNITINE PALMITOYLTRANSFERASE I DEFICIENCY
CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY
CPT1 - Carnitine palmitoyltransferase I deficiency
An endocrine system disease characterized by failure to regenerate the active glucocorticoid cortisol from cortisone resulting in adrenal hyperandrogenism.
11-beta-hydroxysteroid dehydrogenase, type i, deficiency of
Deficiency of (R)-20-hydroxysteroid dehydrogenase
Deficiency of (R)-20-hydroxysteroid dehydrogenase (disorder)
A cortisone reductase deficiency that has_material_basis_in heterozygous mutation in the HSD11B1 gene on chromosome 1q32.
A cortisone reductase deficiency that has_material_basis_in homozygous or compound heterozygous mutation in the H6PD gene on chromosome 1p36.
Cystathione gamma-lyase deficiency (disorder)
Cystathione gamma-lyase deficiency [Ambiguous]
Cystathionine gamma-lyase deficiency (disorder)
Deficiency of cystathionine gamma-lyase (disorder)
An inherited metabolic disorder characterized by decreased beta-hydroxylation of dopamine in nerves resulting in impaired autonomic noradrenergic neurotransmission and clinical features including severely decreased norepinephrine levels, orthostatic hypotension, ptosis, nasal stuffiness, and delayed eye opening that has_material_basis_in homozygous or compound heterozygous mutation in the DBH gene on chromosome 9q34.
Congenital dopamine beta hydroxylase deficiency
DOPAMINE BETA-HYDROXYLASE DEFICIENCY, CONGENITAL
Dopamine beta Hydroxylase Deficiency, Congenital
Dopamine beta-hydroxylase deficiency (disorder)
An advanced sleep phase syndrome that has material basis in heterozygous mutation in the PER2 gene on chromosome 2q37.
ADVANCED SLEEP PHASE SYNDROME, FAMILIAL, 1
familial advanced sleep phase syndrome 1
An advanced sleep phase syndrome that has material basis in heterozygous mutation in the CSNK1D gene on chromosome 17q25.
ADVANCED SLEEP PHASE SYNDROME, FAMILIAL, 2
familial advanced sleep phase syndrome 2
An advanced sleep phase syndrome that has material basis in heterozygous mutation in the PER3 gene on chromosome 1p36.23.
ADVANCED SLEEP PHASE SYNDROME, FAMILIAL, 3
familial advanced sleep phase syndrome 3
An Alport syndrome that has_material -basis_in heterozygous mutation in the COL4A3 gene.
Alport syndrome autosomal dominant (disorder)
alport's syndrome autosomal dominant (diagnosis)
An Alport syndrome that has_material -basis_in homozygous or compound heterozygous mutation in the COL4A3 or the COL4A4 gene, both of which map to chromosome 2q
Alport syndrome autosomal recessive (disorder)
alport's syndrome autosomal recessive (diagnosis)
An Alport syndrome that has material basis in mutation in the gene encoding the alpha-5 chain of basement membrane collagen type IV (COL4A5).
A cleft palate seen as an isolated malformation, distinct from cleft lip with or without cleft palate
Cleft velum is a fissure type embryopathy that affects in varying degrees the soft palate.
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance and ciliopathy with some type of intestinal atresia, variable ocular abnormalities, microcephaly, and has_material_basis_in compound heterozygous mutation in the CENPF gene on chromosome 1q41.
Oth congenital malformation syndromes, NEC
Other specified congenital malformation syndromes, not elsewhere classified
Other specified congenital malformation syndromes, not elsewhere classified in ICD10CM
apple peel syndrome with microcephaly and ocular anomalies
jejunal atresia with microcephaly and ocular anomalies
lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with a missing Nexin link, infantile onset of chronic sinopulmonary infections, and has_material_basis_in homozygous mutation in the DRC1 gene on chromosome 2p23.
CILIARY DYSKINESIA, PRIMARY, 21, WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 21 without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with outer and inner dynein arm defect, recurrent respiratory infections, persistent rhinosinusitis, otitis media, chronic cough, variable presence of situs abnormalities, and has_material_basis_in homozygous or compound heterozygous mutation in the ZMYND10 gene on chromosome 3p21.
CILIARY DYSKINESIA, PRIMARY, 22, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 22 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with inner dynein arm defect and axonemal disorganization, chronic upper and lower airway infections, and has_material_basis_in homozygous or compound heterozygous mutation in the CCDC39 gene on chromosome 3q26.
CILIARY DYSKINESIA, PRIMARY, 14, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 14 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with outer dynein arm defect, ciliary akinesia and variable occurence of situs inversus and has_material_basis_in homozygous or compound heterozygous mutation in the DNAH5 gene on chromosome 5p15.
CILIARY DYSKINESIA, PRIMARY, 3, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 3 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with oligocilia and early childhood onset of recurrent respiratory infections, and has_material_basis_in homozygous or compound heterozygous mutation in the CCNO gene on chromosome 5p15.
CILIARY DYSKINESIA, PRIMARY, 29, WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 29 without situs inversus
A primary ciliary dyskinesia that is characterized by reduced exercise tolerance, chronic wet cough, recurrent respiratory infections, bronchiectasis, and nasal symptoms, and has_material_basis_in homozygous mutation in the RSPH9 gene on chromosome 6p21.
CILIARY DYSKINESIA, PRIMARY, 12, WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 12 without situs inversus
A primary ciliary dyskinesia that is characterized by reduced exercise tolerance, chronic wet cough, recurrent respiratory infections, bronchiectasis, nasal symptoms, ear obstruction with consequent hearing problems, low weight, and short stature, and has_material_basis_in homozygous or compound heterozygous mutation in the RSPH4A gene on chromosome 6q22.
CILIARY DYSKINESIA, PRIMARY, 11, WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 11 without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with near absence of radial spokes, respiratory distress in term neonates, impaired mucociliary clearance, chronic respiratory infections, bronchiectasis, and infertility and has_material_basis_in homozygous or compound heterozygous mutation in the RSPH3 gene on chromosome 6q25.
CILIARY DYSKINESIA, PRIMARY, 32, WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 32 without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with outer and inner dynein arm defect, early infantile onset of recurrent sinopulmonary infections, male infertility, and variable occurence of situs inversus and has_material_basis_in homozygous mutation in the HEATR2 gene on chromosome 7p22.
CILIARY DYSKINESIA, PRIMARY, 18, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 18 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with chronic respiratory infections, chronic sinusitis, recurrent bronchitis, and pneumonia beginning in infancy or early childhood and has_material_basis_in mutation in the DNAH11 gene on chromosome 7p21.
CILIARY DYSKINESIA, PRIMARY, 7 (disorder)
CILIARY DYSKINESIA, PRIMARY, 7, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 7 with or without situs inversus
A primary ciliary dyskinesia that is characterized by partial outer dynein arm defect and has_material_basis_in mutation in the TXNDC3 gene on the chromosome 7p14.1.
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with outer and inner dynein arm defect, recurrent upper and lower airway disease, bronchiectasis, and decreased fertility and has_material_basis_in homozygous or compound heterozygous mutation in the SPAG1 gene on chromosome 8q22.
CILIARY DYSKINESIA, PRIMARY, 28, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 28 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with outer and inner dynein arm defect, chronic sinopulmonary infections, asthenospermia, and immotile cilia and has_material_basis_in homozygous mutation in the LRRC6 on chromosome 8q24.
CILIARY DYSKINESIA, PRIMARY, 19, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 19 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with outer dynein arm defect, respiratory distress and recurrent upper and lower airway infections, and variable occurence of situs inversus and has_material_basis_in homozygous or compound heterozygous mutation in the ARMC4 gene on chromosome 10p.
CILIARY DYSKINESIA, PRIMARY, 23, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 23 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with childhood onset of recurrent sinopulmonary infections and male infertility and has_material_basis_in homozygous mutation in the DNAJB13 gene on chromosome 11q13.
CILIARY DYSKINESIA, PRIMARY, 34, WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 34 without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with neonatal respiratory distress, recurrent upper and lower airway disease, and bronchiectasis and has_material_basis_in homozygous mutation in the CCDC65 gene on chromosome 12q13.
CILIARY DYSKINESIA, PRIMARY, 27, WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 27 without situs inversus
A primary ciliary dyskinesia that is characterized by outer and inner dynein arm absence, chronic otitis media, sinusitis, recurrent pneumonia and variable occurrence of situs inversus and has_material_basis_in homozygous mutation in the KTU gene on chromosome 14q21.
CILIARY DYSKINESIA, PRIMARY, 10, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 10 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with absence of ciliary outer dynein arms, early infantile onset of respiratory distress, and variable occurrence of situs inversus and has_material_basis_in homozygous mutation in the DNAL1 gene on chromosome 14q24.3.
CILIARY DYSKINESIA, PRIMARY, 16, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 16 with or without situs inversus
A primary ciliary dyskinesia that is characterized by partial absence of the inner dynein arms with variable occurrence of situs inversus and has_material_basis_in variation in the chromosome region 15q13.1-q15.1.
CILIARY DYSKINESIA, PRIMARY, 4, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 4 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with inner and outer dynein arm defect, recurrent upper and lower airway disease, bronchiectasis, decreased fertility and variable occurence of laterality defects and has_material_basis_in homozygous or compound heterozygous mutation in the DYX1C1 gene on chromosome 15q21.
CILIARY DYSKINESIA, PRIMARY, 25, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 25 with or without situs inversus
A primary ciliary dyskinesia that has_material_basis_in variation in the chromosome region 15q24-q25.
CILIARY DYSKINESIA, PRIMARY, 8, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 8 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with early onset of a progressive decline in lung function and has_material_basis_in homozygous mutation in the HYDIN gene on chromosome 16q22.
CILIARY DYSKINESIA, PRIMARY, 5, WITHOUT SITUS INVERSUS
Ciliary Dyskinesia, Primary, 5, with or without Situs Inversus
primary ciliary dyskinesia 5 without situs inversus
A primary ciliary dyskinesia that is characterized by inner and outer dynein arm defect, immotile cilia, and variable occurence of laterality defects and has_material_basis_in homozygous or compound heterozygous mutation in the LRRC50 gene on chromosome 16q23-q24.
CILIARY DYSKINESIA, PRIMARY, 13, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 13 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with recurrent upper and lower respiratory infections and has_material_basis_in homozygous mutation in the GAS8 gene on chromosome 16q24.
CILIARY DYSKINESIA, PRIMARY, 33, WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 33 without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with absent outer dynein arms, immotile cilia, variable occurence of laterality defects and recurrent upper and lower respiratory infections and has_material_basis_in homozygous mutation in the TTC25 gene on chromosome 17q21.
CILIARY DYSKINESIA, PRIMARY, 35, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 35 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with inner and outer dynein arm defect, early infantile onset of respiratory distress, and variable occurence of laterality defects and has_material_basis_in homozygous mutation in the CCDC103 gene on chromosome 17q21.
CILIARY DYSKINESIA, PRIMARY, 17, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 17 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with outer dynein arm defect, neonatal respiratory distress, sinusitis, otitis, bronchiectasis, and variable occurence of laterality defects and has_material_basis_in homozygous mutation in the DNAI2 gene on chromosome 17q25.
CILIARY DYSKINESIA, PRIMARY, 9, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 9 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with inner dynein arm defect, axonemal disorganization, recurrent respiratory infections and has_material_basis_in homozygous or compound heterozygous mutation in the CCDC40 gene on chromosome 17q25.
CILIARY DYSKINESIA, PRIMARY, 15, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 15 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with outer dynein arm defect, recurrent upper and lower airway disease, bronchiectasis, nasal blockages, polyps, otitis media, and variable occurence of laterality defects and has_material_basis_in homozygous mutation in the CCDC151 gene on chromosome 19p13.
CILIARY DYSKINESIA, PRIMARY, 30, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 30 without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with outer dynein arm defect, infantile onset of chronic sinopulmonary infections, and variable occurence of laterality defects and has_material_basis_in homozygous or compound heterozygous mutation in the CCDC114 gene on chromosome 19q13.
CILIARY DYSKINESIA, PRIMARY, 20, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 20 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with inner and outer dynein arm defect, otitis media, sinusitis, chronic cough, recurrent respiratory infections, and variable occurence of laterality defects and has_material_basis_in homozygous mutation in the DNAAF3 gene on chromosome 19q13.
CILIARY DYSKINESIA, PRIMARY, 2 (disorder)
CILIARY DYSKINESIA, PRIMARY, 2, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 2 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with inner and outer dynein arm defect, neonatal respiratory distress, recurrent upper and lower airway disease, bronchiectasis, and variable occurence of laterality defects and has_material_basis_in homozygous or compound heterozygous mutation in the C21ORF59 gene on chromosome 21q22.
CILIARY DYSKINESIA, PRIMARY, 26, WITH OR WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 26 with or without situs inversus
A primary ciliary dyskinesia that is characterized by autosomal recessive inheritance with sinopulmonary infection and subfertility and has_material_basis_in homozygous or compound heterozygous mutation in the RSPH1 gene on chromosome 21q22.
CILIARY DYSKINESIA, PRIMARY, 24, WITHOUT SITUS INVERSUS
primary ciliary dyskinesia 24 without situs inversus
An autosomal recessive disease that is characterized by diabetes mellitus, optic atrophy, and deafness as well as various other possible disorders and has_material_basis_in autosomal recessive inheritance of homozygous or compound heterozygous mutation in the WFS1 gene on chromosome 4p16.1.
DIABETES INSIPIDUS AND MELLITUS WITH OPTIC ATROPHY AND DEAFNESS
DIDMOAD - Diabetes insipidus, diabetes mellitus, optic atrophy and deafness
DIDMOAD - Diabetes insipidus,diabetes mellitus, optic atrophy and deafness
DIDMOAD-Diab insip,diab mel,optic atroph+deafness
Diab insipidus,diab mell,optic atrophy and deafness
An autosomal recessive neurodegenerative disorder characterized by diabetes mellitus, high frequency sensorineural hearing loss, optic atrophy or neuropathy, and defective platelet aggregation resulting in peptic ulcer bleeding. It has_material_basis_in autosomal recessive inheritance of homozygous or compound heterozygous mutation in the CISD2 gene on chromosome 4q24.
A rhizomelic chondrodysplasia punctata that has material basis in autosomal recessive inheritance of homozygous or compound heterozygous mutation in the PEX7 gene on chromosome 6q23.3.
RHIZOMELIC CHONDRODYSPLASIA PUNCTATA, TYPE 1
rhizomelic chondrodysplasia punctata type 1
A rhizomelic chondrodysplasia punctata that has material basis in autosomal recessive inheritance of homozygous or compound heterozygous mutation in the GNPAT gene on chromosome 1q42.2.
CHONDRODYSPLASIA PUNCTATA, RHIZOMELIC, DUE TO DIHYDROXYACETONEPHOSPHATE ACYLTRANSFERASE DEFICIENCY
Chondrodysplasia punctata, rhizomelic, due to DHAPAT deficiency
DIHYDROXYACETONEPHOSPHATE ACYLTRANSFERASE DEFICIENCY
GLYCERONEPHOSPHATE O-ACYLTRANSFERASE DEFICIENCY
rhizomelic chondrodysplasia punctata type 2
A rhizomelic chondrodysplasia punctata that has material basis in autosomal recessive inheritance of homozygous or compound heterozygous mutation in the AGPS gene on chromosome 2q31.2.
ALKYLDIHYDROXYACETONEPHOSPHATE SYNTHASE DEFICIENCY
ALKYLGLYCERONE-PHOSPHATE SYNTHASE DEFICIENCY
RHIZOMELIC CHONDRODYSPLASIA PUNCTATA, TYPE 3
rhizomelic chondrodysplasia punctata type 3
A rhizomelic chondrodysplasia punctata that has material basis in autosomal recessive inheritance of homozygous or compound heterozygous mutation in the PEX5 gene on chromosome 12p13.31.
RHIZOMELIC CHONDRODYSPLASIA PUNCTATA, TYPE 5
rhizomelic chondrodysplasia punctata type 5
A holoprosencephaly that has_material_basis_in mutation in the homeobox-containing SIX3 gene on chromosome 2p21.
A holoprosencephaly that has_material_basis_in heterozygous mutation in the GLI2 gene on chromosome 2q14.
PITUITARY ANOMALIES WITH HOLOPROSENCEPHALY-LIKE FEATURES
PITUITARY ANOMALIES WITH HOLOPROSENCEPHALY-LIKE FEATURES (disorder)
A holoprosencephaly that has_material_basis_in variation in the chromosome region 2q37.1-q37.3.
A holoprosencephaly that has_material_basis_in heterozygous mutation in the SHH gene on chromosome 7q36.
A holoprosencephaly that has_material_basis_in heterozygous mutation in the PTCH1 gene on chromosome 9q22.
A holoprosencephaly that has_material_basis_in heterozygous mutation in the CDON gene on chromosome 11q24.
A holoprosencephaly that has_material_basis_in heterozygous mutation in the ZIC2 gene on chromosome 13q32.
A holoprosencephaly that has_material_basis_in variation in the chromosome region 14q13.
A holoprosencephaly that has_material_basis_in heterozygous mutation in the TGIF gene on chromosome 18p11.
A congenital nervous system abnormality characterized by failed or incomplete separation of the forebrain early in gestation; it is accompanied by a spectrum of characteristic craniofacial anomalies.
Familial alobar holoprosencephaly (disorder)
Familial alobar holoprosencephaly -RETIRED-
A Joubert syndrome that has_material_basis_in X-linked recessive inheritance of mutation in the OFD1 gene on chromosome Xp22.2.
A Joubert syndrome that has_material_basis_in homozygous or compound heterozygous mutation in the TCTN1 gene on chromosome 12q24.
A Joubert syndrome characterized by severe mental retardation, hypoplasia of the cerebellar vermis and molar tooth sign on brain imaging, hypotonia, abnormal breathing pattern in infancy, and dysmorphic facial features that has_material_basis_in homozygous or compound heterozygous mutation in the TMEM237 gene on chromosome 2q33.
A Joubert syndrome characterized by ataxia, hypotonia, delayed psychomotor development, and variable mental retardation that has_material_basis_in homozygous mutation in the CEP41 gene on chromosome 7q32.
A Joubert syndrome characterized by molar tooth sign on brain imaging, oculomotor apraxia, variable coloboma, and rare kidney involvement that has_material_basis_in homozygous mutation in the TMEM138 gene on chromosome 11q.
A Joubert syndrome characterized by episodic hyperpnea, abnormal eye movements, ataxia, and global psychomotor retardation that has_material_basis_in compound heterozygous mutation in the C5ORF42 gene on chromosome 5p13.
A Joubert syndrome that has_material_basis_in homozygous mutation in the TCTN3 gene on chromosome 10q24.
A Joubert syndrome characterized by molar tooth sign on brain MRI, hypotonia, developmental delay, oculomotor apraxia, and breathing abnormalities that has_material_basis_in mutation in the TMEM216 gene on chromosome 11q12.2.
A Joubert syndrome that has_material_basis_in compound heterozygous mutation in the TMEM231 gene on chromosome 16q23.
A Joubert syndrome that has_material_basis_in homozygous or compound heterozygous mutation in the CSPP1 gene on chromosome 8q13.
A Joubert syndrome that has_material_basis_in homozygous mutation in the PDE6D gene on chromosome 2q37.
A Joubert syndrome characterized by delayed development, abnormal eye movements, and abnormal breathing pattern, and molar tooth sign on brain MRI that has_material_basis_in homozygous or compound heterozygous mutation in the KIAA0586 gene on chromosome 14q23.
A Joubert syndrome characterized by delayed psychomotor development and molar tooth sign on brain MRI that has_material_basis_in homozygous mutation in the TCTN2 gene on chromosome 12q24.
A Joubert syndrome characterized by delayed psychomotor development, oculomotor apraxia, and molar tooth sign on brain MRI that has_material_basis_in homozygous or compound heterozygous mutation in the CEP104 gene on chromosome 1p36.
A Joubert syndrome characterized by global developmental delay and cerebellar hypoplasia that has_material_basis_in homozygous mutation in the KIAA0556 gene on chromosome 16p12.
A Joubert syndrome that has_material_basis_in homozygous or compound heterozygous mutation in the B9D1 gene on chromosome 17p11.
A Joubert syndrome that has_material_basis_in homozygous or compound heterozygous mutation in the MKS1 gene on chromosome 17q23.
A Joubert syndrome that has_material_basis_in homozygous mutation in the AHI1 gene on chromosome 6q23.3.
A Joubert syndrome that has_material_basis_in deletions of the NPHP1 gene on chromosome 2q13.
A Joubert syndrome that has_material_basis_in mutation in the CEP290 gene on chromosome 12q21.
A Joubert syndrome that has_material_basis_in homozygous or compound heterozygous mutation in the TMEM67 on chromosome 8q22.
A Joubert syndrome that has_material_basis_in mutation in the RPGRIP1L gene on chromosome 16q12.2.
A Joubert syndrome that has_material_basis_in mutation in the ARL13B gene on chromosome 3q11.1-q11.2
A Joubert syndrome that has_material_basis_in homozygous or compound heterozygous mutation in the CC2D2A gene on chromosome 4p15.
A maturity-onset diabetes of the young that has_material_basis_in mutation in the HNF4A gene on chromosome 20.
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 1
Maturity onset diabetes of the young, type 1
Maturity onset diabetes of the young, type 1 (disorder)
maturity-onset diabetes of the young type 1
A maturity-onset diabetes of the young that has_material_basis_in heterozygous mutation in the GCK gene on chromosome 7p13.
DIABETES MELLITUS, TYPE II, AUTOSOMAL DOMINANT
Diabetes mellitus autosomal dominant type 2
Diabetes mellitus autosomal dominant type 2 (disorder)
Diabetes mellitus autosomal dominant type II
Diabetes mellitus autosomal dominant type II (disorder)
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 2
MODY - Maturity onset diabetes glucokinase-related
MODY - Maturity onset diabetes in youth type 2
maturity-onset diabetes of the young type 2
A maturity-onset diabetes of the young characterized by abnormal renal development resuting in non-diabetic kidney disease and diabetes that has_material_basis_in mutation in the HNF1B gene on chromosome 17q12.
CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT WITH DIABETES
Familial hypoplastic, glomerulocystic kidney
Familial hypoplastic, glomerulocystic kidney (disorder)
GLOMERULOCYSTIC KIDNEY DISEASE, HYPOPLASTIC TYPE
GLOMERULOCYSTIC KIDNEY, FAMILIAL HYPOPLASTIC
maturity-onset diabetes of the young type 5
A maturity-onset diabetes of the young that has_material_basis_in mutation in the HNF1A gene on chromosome 12q24.31.
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3 (disorder)
maturity-onset diabetes of the young - type 3
maturity-onset diabetes of the young type 3
A maturity-onset diabetes of the young that has_material_basis_in mutation in the PDX1 gene on chromosome 13q12.2.
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 4
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE IV (disorder)
Maturity-onset diabetes of the young, type 4 (disorder)
maturity-onset diabetes of the young - type 4
maturity-onset diabetes of the young type 4
A maturity-onset diabetes of the young that has_material_basis_in heterozygous mutation in the NEUROD1 gene on chromosome 2q31.
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 6
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 6 (disorder)
maturity-onset diabetes of the young - type 6
maturity-onset diabetes of the young type 6
A maturity-onset diabetes of the young that has_material_basis_in frameshift deletions in the variable number of tandem repeats of the CEL gene om chromosome 9q34.13.
DIABETES AND PANCREATIC EXOCRINE DYSFUNCTION
DIABETES-PANCREATIC EXOCRINE DYSFUNCTION SYNDROME
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 8, WITH EXOCRINE DYSFUNCTION
maturity-onset diabetes of the young type 8
A maturity-onset diabetes of the young that has_material_basis_in heterozygous mutation in the KLF11 gene on chromosome 2p25.
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 7
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 7 (disorder)
maturity-onset diabetes of the young - type 7
maturity-onset diabetes of the young - type 7 (diagnosis)
maturity-onset diabetes of the young type 7
A maturity-onset diabetes of the young that has_material_basis_in heterozygous mutation in the PAX4 gene on chromosome 7q32.1.
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 9
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 9 (disorder)
maturity-onset diabetes of the young - type 9
maturity-onset diabetes of the young - type 9 (diagnosis)
maturity-onset diabetes of the young type 9
A maturity-onset diabetes of the young that has_material_basis_in heterozygous mutation in the INS gene on chromosome 11p15.5.
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 10
Maturity-onset diabetes of the young, type 10 (disorder)
maturity-onset diabetes of the young - type 10
maturity-onset diabetes of the young - type 10 (diagnosis)
maturity-onset diabetes of the young type 10
A maturity-onset diabetes of the young that has_material_basis_in heterozygous mutation in the BLK gene on chromosome 8p23-p22.
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 11
Maturity-onset diabetes of the young, type 11 (disorder)
maturity-onset diabetes of the young - type 11
maturity-onset diabetes of the young - type 11 (diagnosis)
maturity-onset diabetes of the young type 11
A maturity-onset diabetes of the young that has_material_basis_in heterozygous mutation in the KCNJ11 gene on chromosome 11p15.
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 13
maturity-onset diabetes of the young type 13
A maturity-onset diabetes of the young that has_material_basis_in heterozygous mutation in the APPL1 gene on chromosome 3p14.
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 14
maturity-onset diabetes of the young type 14
A mitochondrial metabolism disease characterized by impaired function of one or more of the proteins making up the mitochondrial respiratory chain complex III.
Deficiency of isolated CoQ cytochrome c reductase
Deficiency of mitochondrial complex III (disorder)
Deficiency of ubiquinone cytochrome c oxidoreductase
MITOCHONDRIAL COMPLEX III DEFICIENCY (disorder)
An X-linked disease characterized by hypothyroidism that is present at birth, delayed testosterone increase in puberty, and testicular enlargement in adulthood that has_material_basis_in mutation of the IGSF1 gene on chromosome Xq26.
HYPOTHYROIDISM, CENTRAL, AND TESTICULAR ENLARGEMENT
X-linked central congenital hypothyroidism with late-onset macroorchidism
X-linked central congenital hypothyroidism with late-onset testicular enlargement
central hypothyroidism and testicular enlargement
A sleep disorder characterized by an extreme evening preference, sleep-onset insomnia, and difficulty in awakening at the desired time.
Circadian rhythm sleep disorder, delayed sleep phase
Circadian rhythm sleep disorder, delayed sleep phase type
Circadian rhythm sleep disorder, delayed sleep phase type (diagnosis)
Delayed Sleep Phase Type Circadian Rhythm Sleep Disorder
Sleep wake schedule disorder, delayed phase type
A mitochondrial metabolism disease characterized by impaired function of one or more of the proteins making up the mitochondrial proton-transporting ATP synthase complex.
mitochondrial complex V (ATP synthase) deficiency
A female reproductive system disease characterized by rupture of chorioamniotic membranes before 37 weeks of gestation.
PPROM - Preterm premature rupture of membranes
PRETERM PREMATURE RUPTURE OF THE MEMBRANES
Preterm premature rupture of membranes (disorder)
A blood coagulation disease characterized by development of a defect in clotting in the absence of previous bleeding symptoms, negative familial history, and occurrence in a relatively older age. Typically this develops secondarily to other disorders, such as lymphoproliferative, myeloproliferative, cardiovascular and autoimmune disorders.
Acquired von Willebrand syndrome (disorder)
Acquired von Willebrand's disease (disorder)
A chromosomal duplication syndrome characterized by growth deficiency, abnormal muscle tone, intellectual disability, and distinctive craniofacial malformations that has material basis in duplication of the distal portion of chromosome 4q.
An autosomal genetic disease characterized by camptodactyly, tall stature, scoliosis, and hearing loss that has_material_basis_in partial loss of function in the FGFR3 gene on chromosome 4p16.
CAMPTODACTYLY, TALL STATURE, AND HEARING LOSS SYNDROME
camptodactyly-tall stature-scoliosis-hearing loss syndrome
A skin disease characterized by localized epidermal thickening with hyperpigmentation that develops at or shortly after birth.
Epidermal nevus (morphologic abnormality)
Combined molybdoflavoprotein enzyme deficiency
Combined molybdoflavoprotein enzyme deficiency (disorder)
Combined xanthine oxid & sulph oxid & aldehyde oxidase def
Combined xanthine oxidase and aldehyde oxidase deficiency
Combined xanthine oxidase and aldehyde oxidase deficiency (disorder)
Combined xanthine oxidase and sulfite oxidase and aldehyde oxidase deficiency
Combined xanthine oxidase and sulphite oxidase and aldehyde oxidase deficiency
A congenital nervous system abnormality characterized by migration of neurons to ectopic locations in the brain where the neurons form areas that appear as band-like clusters of white tissue underneath the gray tissue of the cerebral cortex.
An intestinal disease that involves intestinal infection that has material basis in viruses, bacteria, fungi and parasites.
Intestinal infectious disease (diagnosis)
Intestinal infectious disease (disorder)
A female reproductive system disease that is characterized by an infection of the female reproductive organs.
7-71 INFLAMMATORY DISEASES OF THE FEMALE GENITAL ORGANS AND TISSUES
A parasitic helminthiasis infectious disease that involves infection of the bowel by Hymenolepis nana or Hymenolepis diminuta. The symptoms include diarrhea, gastrointestinal discomfort, itchy anus, poor appetite and weakness.
A parasitic helminthiasis infectious disease that involves parasitic infection caused by Diphyllobothrium latum through the consumption of raw or undercooked fish. The symptoms include abdominal discomfort, diarrhea, vomiting, weight loss and vitamin B12 deficiency with pernicious anemia.
A parasitic helminthiasis infectious disease that involves parasitic infection by the genus Spirometra. A painful nodule develops after the plerocercoid larvae migrate to the brain causing cerebral sparganosis. Subcutaneous tissue, breast, orbit, urinary tract, pleural cavity, lungs, abdominal viscera and inner ear can be infected.
A central nervous system disease that is located_in the skull and is characterized by a collection of pus (infected material) inside the skull.
A parasitic protozoa infectious disease that involves infection caused by parasitic protozoan of the genus Trypanosoma in animals and humans.
A primary bacterial infectious disease that results_in infection located_in skin, has_material_basis_in Treponema carateum, which is transmitted_by contact with skin and mucous membrane of an infected person. The infection has_symptom pruritic plaque, which slowly enlarges and becomes pigmented and hyperkeratotic.
A primary bacterial infectious disease that results_in infection located_in superficial peripheral nerves, located_in skin, located_in mucous membranes of the upper respiratory tract, located_in anterior chamber of the eyes, or located_in testes, has_material_basis_in Mycobacterium leprae, which is transmitted_by aerosol spread from infected nasal secretions to exposed nasal and oral mucosa. The infection has_symptom skin lesions, has_symptom sensory loss, has_symptom motor loss and has_symptom eye damage.
A primary bacterial infectious disease that results in infection located in leukocyte, has material basis in Ehrlichia chaffeensis or Anaplasma phagocytophilum, which are transmitted by lone start stick and transmitted by black-legged tick respectively. The infection has symptom headache, has symptom muscle aches, has symptom fatigue and has symptom rash.
A viral infectious disease that results in infection in sheep and rarely humans, has material basis in Louping ill virus, which is transmitted by sheep tick, Ixodes ricinus. The infection has symptom lethargy, has symptom muscle pains, has symptom fever, and has symptom focal neurological signs.
encephalitis due to louping ill virus (diagnosis)
A viral infectious disease that results in inflammation located in salivary gland, has material basis in Mumps virus, which is transmitted by droplet spread of saliva or mucus from the mouth, nose, or throat of an infected person, or transmitted by contaminated fomites. The infection has symptom fever, has symptom headache, has symptom muscle aches, has symptom tiredness, has symptom loss of appetite, has symptom swollen and tender salivary glands under the ears or jaw on one or both sides of the face.
A cardiovascular system disease that involves the heart's electrical conduction system.
Familial periodic paralysis (disorder) [Ambiguous]
A primary bacterial infectious disease that results in infection located in skin, located in joint or located in bone, has material basis in Treponema pallidum subsp pertenue, which is transmitted by direct skin contact with an infected person. The infection has symptom skin lesions.
A disease by infectious agent that results_in infection, has_material_basis_in Bacteria.
BACTERIAL INFECTIOUS DISEASES: GENERAL TERMS
A physical disorder that has material basis in abnormal segmentation of the vertebra during fetal development which results in fusion located in cervical vertebra.
Bonnevie-Ullrich and Klippel-Feil syndrome
An upper respiratory tract disease which involves inflammation of the tonsils resulting from bacterial (Group A streptococcus) and viral (Epstein-Barr virus, adenovirus) infections. Symptoms include a severe sore throat (which may be experienced as referred pain to the ears), painful/difficult swallowing, coughing, headache, myalgia (muscle aches), fever and chills. Tonsillitis is characterized by signs of red, swollen tonsils which may have a purulent exudative coating of white patches (i.e. pus). Swelling of the cheeks and neck may occur.
A primary bacterial infectious disease that results_in infection located_in respiratory tract, has_material_basis_in Legionella pneumophila, which is transmitted_by inhalation of droplets containing bacteria. The symptoms include dry cough, fever, headache and diarrhea.
An upper respiratory tract disease which involves inflammation of the mucous membranes of the nose, throat, eyes, and eustachian tubes with watery then purulent discharge. This is an acute contagious disease caused by rhinoviruses, human parainfluenza viruses, human respiratory syncytial virus, influenza viruses, adenoviruses, enteroviruses, or metapneumovirus.
(Acute nasopharyngitis or rhinitis) or (common cold)
(Acute nasopharyngitis or rhinitis) or (common cold) (disorder)
A muscular disease that is located_in the diaphragm.
Congenital absence, atresia and stenosis of jejunum
A pneumonia described as an inflammatory illness of the lung commonly caused by viruses such as influenza virus, parainfluenza, adenovirus, rhinovirus, herpes simplex virus, respiratory syncytial virus, hantavirus, and cytomegalovirus.
A central nervous system disease that involves encephalitis which occurs along with meningitis.
A vascular disease that is characterized by severe supine hypotension in late pregnancy, whose clinical presentation ranges from minimal cardiovascular alterations to severe shock, resulting from inferior vena cava compression by gravid uterus.
Maternal hypotension syndrome complicating labor and delivery, unspecified as to episode of care
Maternal hypotension syndrome, unspecified as to episode of care or not applicable
antepartum maternal hypotension syndrome
postpartum maternal hypotension syndrome
A hypercalcemia characterized byautosomal dominant inheritance with elevation of serum calcium levels and decreased urinary calcium excretion.
Calcium Metabolism Disorders [Disease/Finding]
An amino acid metabolic disorder that is caused by abnormalities of the renal tubules and is characterized especially by aminoaciduria involving only monocarboxylic monoamines, a dry red scaly rash, and episodic muscular incoordination due to the effects of the disease on the cerebellum.
Deficiency of tryptophan 2,3-dioxygenase
Deficiency of tryptophan 2,3-dioxygenase (disorder)
(Chronic steatorrhea) or (malabsorption due to intolerance to fat)
(Chronic steatorrhoea) or (malabsorption due to intolerance to fat)
(Chronic steatorrhoea) or (malabsorption due to intolerance to fat) (disorder)
Acquired short bowel syndrome (disorder)
An intestinal disease characterized by a dysbalance of the bacterial flora of the small intestine, causing derangement to the normal physiological processes of digestion and absorption.
Bacterial overgrowth syndrome (disorder)
Idiopathic Tropical Malabsorption Syndrome
A lysosomal storage disease characterized by the abnormal accumulation of cystine in the lysosomes. It follows an autosomal recessive inheritance pattern and has material basis in mutations in the CTNS gene, located on chromosome 17.
A personality disorder that involves a need for social isolation, anxiety in social situations, odd behavior and thinking, and often unconventional beliefs.
Schizotypal Personality Disorder [Disease/Finding]
A breast disease that is characterized by the progressive, excessive enlargement of breast connective tissue.
A breast disease characterized by painful infection of the breast tissue.
A breast disease that is characterized by the death of breast adipocytes, usually secondary to injury.
A parasitic helminthiasis infectious disease that involves parasitic infection by flukes of the genus Paragonimus. In the acute phase, the symptoms are diarrhea, abdominal pain, fever, cough, urticaria, hepatosplenomegaly, pulmonary abnormalities, and eosinophilia. Pulmonary manifestations include cough, expectoration of discolored sputum, hemoptysis, and chest radiographic abnormalities. Various organs like brain, spleen and liver can be infected.
A parasitic protozoa infectious disease that involves infection of the small intestine by a single-celled enteric protozoan parasite Giardia intestinalis. The symptoms include greasy and malodorous stools, diarrhea, abdominal pain, bloating, nausea, and vomiting.
A kidney disease characterized by the failure of the kidneys to adequately filter waste products from the blood.
A parasitic helminthiasis infectious disease that involves parasitic infection of the lymphatics and subcutaneous tissue by nematodes of the superfamily Filarioidea.
Chylocele of tunica vaginalis (disorder)
chylocele of tunica vaginalis (diagnosis)
A viral infectious disease that results in inflammation located in brain of horses and humans, has material basis in Eastern equine encephalitis virus, which is transmitted by Aedes, transmitted by Coquillettidia, and transmitted by Culex species of mosquitoes. The infection has symptom sudden onset of headache, has symptom high fever, has symptom chills, has symptom vomiting, has symptom disorientation, has symptom seizures, and has symptom coma.
A viral infectious disease that results_in inflammation located_in brain, has_material_basis_in Murray Valley encephalitis virus, which is transmitted_by Culex annulirostris mosquitoes. The infection has_symptom fever, has_symptom headache, has_symptom nausea, has_symptom vomiting, has_symptom drowsiness, has_symptom confusion, has_symptom fitting, and has_symptom weakness.
A viral infectious disease that results_in inflammation located_in brain of horses and humans, has_material_basis_in Western equine encephalomyelitis virus, which is transmitted_by Culex and transmitted_by Aedes species of mosquitoes. The infection has_symptom fever, has_symptom headache, has_symptom nausea, has_symptom vomiting, has_symptom anorexia, has_symptom malaise, has_symptom altered mental status, and has_symptom weakness.
Encephalomyelitis, Western Equine [Disease/Finding]
A viral infectious disease that results_in infection located_in brain, has_material_basis_in Japanese encephalitis virus, which is transmitted_by Culex tritaeniorhynchus mosquito bite. The infection has_symptom headache, has_symptom high fever, has_symptom neck stiffness, has_symptom stupor, has_symptom disorientation, has_symptom coma, has_symptom tremors, has_symptom convulsions, and has_symptom spastic paralysis.
Encephalitis, Japanese [Disease/Finding]
A viral infectious disease that results_in inflammation located_in brain, has_material_basis_in St. Louis encephalitis virus, which is transmitted_by Culex mosquitoes. The infection has_symptom headache, has_symptom high fever, has_symptom neck stiffness, has_symptom stupor, has_symptom disorientation, has_symptom coma, has_symptom tremors, has_symptom convulsions and has_symptom spastic paralysis.
Encephalitis, St. Louis [Disease/Finding]
Angiodysplasia of intestinal tract (disorder)
Angiodysplasia of intestine (without mention of haemorrhage)
Angiodysplasia of intestine (without mention of hemorrhage)
Angiodysplasia of intestine without mention of hemorrhage
Chromosomal imbalance syndrome, pair 18, trisomy
A viral infectious disease that results_in infection located_in skin, has_material_basis_in Human coxsackievirus A16 or has_material_basis_in Human enterovirus 71, which are transmitted_by contaminated fomites, and transmitted_by contact with nose and throat secretions, saliva, blister fluid and stool of infected persons. The infection has_symptom fever, has_symptom poor appetite, has_symptom malaise, has_symptom sore throat, has_symptom painful sores in the mouth, and has_symptom skin rash on the palms of the hands and soles of the feet.
(Hand, foot & mouth disease) or (vesicular stomatitis with xanthem)
(Hand, foot & mouth disease) or (vesicular stomatitis with xanthem) (disorder)
Enteroviral vesicular stomatitis with exanthem
Enteroviral vesicular stomatitis with exanthem (disorder)
Enteroviral vesicular stomatitis with exanthem (disorder) [Ambiguous]
A viral infectious disease that results in necrosis located in intercostal muscle, has material basis in Human enterovirus B. The infection has symptom severe chest pain, has symptom fever, has symptom malaise, has symptom pleuritis, and has symptom headache.
A viral infectious disease that results in infection located in mouth, has material basis in Human coxsackievirus A16, has material basis in Human enterovirus 71, has material basis in group B coxsackievirus, or has material basis in echoviruses, which are transmitted by ingestion of food contaminated with feces, transmitted by contact with pharyngeal secretions, or transmitted by droplet spread of oronasal secretions. The infection has symptom fever, has symptom sore throat, and has symptom lesions in the back area of the mouth, particularly the soft palate or tonsillar pillars.
Enteroviral vesicular pharyngitis (disorder)
Enteroviral vesicular pharyngitis (disorder) [Ambiguous]
A physical disorder characterized by an abnormally placed urethral opening on the underside of the penis or on the perineum.
A cognitive disorder where the memory is disturbed or lost and involves the loss of memories previously established, loss of the ability to create new memories, or loss of the ability to learn new information.
A gender identity disorder that is characterized by an individual's identification with a gender inconsistent or not culturally associated with their biological sex.
A personality disorder that involves a prolonged disturbance of personality function characterized by depth and variability of moods.
Borderline Personality Disorder [Disease/Finding]
Borderline personality disorder (disorder)
A personality disorder that is characterized by a pervasive psychological dependence on other people.
Dependent Personality Disorder [Disease/Finding]
Dependent personality disorder (disorder)
A personality disorder that is characterized by a pervasive pattern of preoccupation with orderliness, perfectionism, and mental and interpersonal control at the expense of flexibility, openness, and efficiency.
(Anankastic personality) or (anankastic personality disorder)
(Anankastic personality) or (anankastic personality disorder) (disorder)
obsessive-compulsive personality disorder
An anxiety disorder that involves unwanted and repeated thoughts, feelings, ideas, sensations (obsessions), or behaviors that make them feel driven to do something (compulsions).
A dissociative disorder that involves the simultaneous display of multiple distinct identities or personalities.
A disease of mental health in which the normally well-integrated functions of memory, identity, perception, or consciousness are separated (dissociated).
A personality disorder that is characterized by a lack of interest in social relationships, a tendency towards a solitary lifestyle, secretiveness, emotional coldness and sometimes sexual apathy, with a simultaneous rich, elaborate and exclusively internal fantasy world.
A disease of mental health that involves a failure to resist an impulsive act or behaviour that may be harmful to self or others.
Disruptive, Impulse Control, and Conduct Disorders
Disruptive, Impulse Control, and Conduct Disorders [Disease/Finding]
A personality disorder that is characterized by paranoia and a pervasive, long-standing suspiciousness and generalized mistrust of others.
Paranoid Personality Disorder [Disease/Finding]
A personality disorder that involves a pervasive pattern of disregard for, and violation of, the rights of others that begins in childhood or early adolescence and continues into adulthood.
(Amoral personality) or (antisocial or sociopathic personality disorder)
(Amoral personality) or (antisocial or sociopathic personality disorder) (disorder)
A specific developmental disorder that is characterized by co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.
attention deficit hyperactivity disorder
A kidney disease that is characterized by an inflammation of the kidneys.
A parasitic helminthiasis infectious disease that involves infection of the intestine, lungs, skin and central nervous system with nematode Strongyloides stercoralis.
A monogenic disease that is characterized by glomerulonephritis, endstage kidney disease, and hearing loss.
A female reproductive system disease that is located_in the ovary.
A dissociative disorder where he continuity of the patient's memory is disrupted. Patients with dissociative amnesia have recurrent episodes in which they forget important personal information or events, usually connected with trauma or severe stress.
A dissociative disorder in which the sufferer is affected by persistent or recurrent feelings of depersonalization and/or derealization.
A syndrome that results_in rheumatoid arthritis, splenomegaly and neutropenia.
Congenital Fissure of the Abdominal Cavity
A primary bacterial infectious disease that results_in systemic infection, has_material_basis_in Pasteurella multocida, which is transmitted_by animal bite, scratch, or lick. The infection has_symptom joint pain has_symptom fever, has_symptom rigors, has_symptom pneumonia, has_symptom meningeal irritation, and has_symptom tachycardia.
Pasteurella Infections [Disease/Finding]
A primary bacterial infectious disease that is caused by the bacteria of the genus Brucella, when humans come in contact with contaminated animals or animal products or ingestion of infected food products. The disease has_symptom fever, has_symptom sweat, has_symptom headache, has_symptom back pain, has_symptom physical weakness, has_symptom joint pain and has_symptom fatigue.
Brucellosis due to Brucella sp. (disorder)
A parasitic ectoparasitic infectious disease that involves parasitic infestation by members of the subclass Hirudinea. The leeches remain attached to their hosts and feed on blood until they become full, at which point they fall off to digest. While feeding, they release an anesthetic and use a combination of mucus and suction to stay attached and secrete an anti-clotting enzyme, hirudin, into the host's blood stream.
(Other infectious & parasitic disease) or (infestation: [leech] or [maggot]) or (myiasis) or (toxoplasmosis)
(Other infectious & parasitic disease) or (infestation: [leech] or [maggot]) or (myiasis) or (toxoplasmosis) (disorder)
A primary bacterial infectious disease that is a zoonotic infectious disease affecting multiple organs, has_material_basis_in Coxiella burnetii, which is transmitted_by inhalation of air contaminated by barnyard dust containing dried placental material, birth fluids, or excreta of infected herd animals, transmitted_by ingestion of contaminated milk, transmitted_by tick bites and transmitted_by contact with infected person. The infection has_symptom fever, has_symptom headache, has_symptom cough, has_symptom pleuritic chest pain, has_symptom myalgia and has_symptom arthralgia.
A primary bacterial infectious disease that is caused by the bacteria of the genus Bartonella.
A primary bacterial infectious disease that results in infection, located in endothelial cell of artery or located in endothelial cell of vein, has material basis in Rickettsia, which is transmitted by ticks and mites. The infection has symptom fever, has symptom headache, has symptom fatigue, has symptom muscle aches, and has symptom maculopapular or petechial rash. A distinctive eschar (blackened or crusted skin) may develop at the site of a tick bite.
A commensal bacterial infectious disease that results_in inflammation located_in respiratory tract, has_material_basis_in Bordetella pertussis, or has_material_basis_in Bordetella parapertussis, which produce toxins that paralyze the cilia of the respiratory epithelial cells. The infection is characterized by a prolonged, high-pitched, deeply indrawn breath (whoop).
A viral infectious disease that results_in infection located_in skin, has_material_basis_in human papillomavirus (types 2 and 4). This infection has_symptom raised wart with roughened surface, most common on hands, but can grow anywhere on the body.
A viral infectious disease that results_in infection located_in skin of vagina, cervix, uterus, anus, penis, scrotum, mouth, and throat, has_material_basis_in human papillomaviruses (types 6 and 11), which are transmitted_by direct contact with the skin during oral, genital, or anal sex with an infected partner. The infection has_symptom anogenital warts.
Anogenital Human papilloma Virus Infectious Disease
An upper respiratory tract disease which involves inflammation of both larynx and pharynx.
A T cell deficiency disease that is the result of a large deletion of chromosome 22 which includes the DGS gene needed for development of the thymus and related glands with subsequent lack of T-cell production.
Agenesis of the parathyroid AND thymus glands
A parathyroid gland disease characterized by decreased function of parathyroid glands with underproduction of parathyroid hormone (PTH), leading to abnormally low ionized calcium levels in the blood.
An endocrine system disease that is located_in the parathyroid gland.
Disease of parathyroid glands (disorder)
A substance abuse that involves the recurring use of opioid drugs despite negative consequences.
Diverticulosis of small intestine with haemorrhage
Diverticulosis of small intestine with hemorrhage
Diverticulosis of small intestine with hemorrhage (disorder)
diverticulosis of small intestine with hemorrhage (diagnosis)
A viral infectious disease that results in inflammation located in conjunctiva, has material basis in Human coxsackievirus A24 or has material basis in Human enterovirus 70, which are transmitted by contaminated fomites or transmitted by contact with contaminated hands. The infection has symptom vascular dilation, has symptom eyelid edema, has symptom photophobia, has symptom redness of the eyes, has symptom watering of the eye, has symptom conjunctival congestion, and has symptom superficial punctate epithelial keratitis.
Acute hemorrhagic conjunctivitis (disorder)
ANEMIA, HYPOCHROMIC MICROCYTIC, WITH DEFECT IN IRON METABOLISM
IRIDA (iron-refractory iron deficiency anaemia) syndrome
IRIDA (iron-refractory iron deficiency anemia) syndrome
A viral infectious disease that results in inflammation located in brain or located in spinal cord, has material basis in Rabies virus, which is transmitted by bite of an infected animal, or transmitted by contact of mucous membranes with saliva of an infected animal. The infection has symptom fever, has symptom headache, has symptom prickling or itching sensation at the site of bite, has symptom anxiety, has symptom confusion, has symptom agitation, has symptom delirium, has symptom difficulty swallowing, has symptom hydrophobia, and has symptom paralysis.
A primary bacterial infectious disease that results_in systemic infection, has_material_basis_in Chlamydia psittaci, which is transmitted_by inhaling aerosolized dried droppings or transmitted_by contact with infected birds. The infection has_symptom fever, has_symptom headache, has_symptom rash, has_symptom chills, and has_symptom pneumonia.
AIDS with viral/chlamydial disease NOS (disorder)
Acquired immunodeficiency syndrome (AIDS) with viral/chlamydial disease NOS
Acquired immunodeficiency syndrome (AIDS) with viral/chlamydial disease NOS (disorder)
A commensal bacterial infectious disease that is caused by Chlamydia trachomatis.
Chlamydia trachomatis infectious disease
A commensal bacterial infectious disease that results_in infection located_in eye, has_material_basis_in Chlamydia trachomatis (A, B, Ba and C serovars), which is transmitted_by contact with eye discharge from the infected person and transmitted_by congenital method. The infection causes eyelid to turn inward which makes eyelashes to scratch the cornea.
A viral infectious disease that is a hemorrhagic fever, has material basis in Kyasanur forest disease virus, which is transmitted by Haemaphysalis spinigera tick bite. The infection has symptom fever, has symptom headache, has symptom stiffness of the neck, has symptom severe muscle pain, has symptom cough, has symptom dehydration, and has symptom bleeding problems.
Kyasanur Forest Disease [Disease/Finding]
A psychotic disorder that involves schizophrenia symptoms over time period of one month.
A connective tissue disease that results in increasing fibrous constriction and ultimately in spontaneous amputation of the toes and especially the little toes. A painful constriction of the base of the fifth toe frequently followed by bilateral spontaneous amputation (autoamputation) a few years later.
A primary bacterial infectious disease that involves the inflammation of mucosa lining the nasal cavity, pharynx, larynx, trachea and bronchi that is characterized by the formation of granulomas, dense induration of the tissues and nodular deformity caused by Klebsiella rhinoscleromatis.
Infection by Klebsiella rhinoscleromatis
A commensal bacterial infectious disease that is characterized by systemic sepsis, ulcerative or necrotic lesions and multisystem abscesses caused by Fusobacterium necrophorum. The disease often first presents as a severe tonsillitis or pharyngitis with high-grade fever and chills together with leukocytosis, cervical pain and neck swelling.
A primary bacterial infectious disease that results in prolonged contraction of skeletal muscle fibers, has material basis in Clostridium tetani, which produces tetanospasmin, a neurotoxin, which is carried to the brain and spinal cord, where it binds irreversibly to receptors inhibiting neurotransmission. Damaged upper motor neurons cannot control reflex responses to afferent sensory stimuli.
Infection caused by Clostridium tetani (disorder)
Infection due to Clostridium tetani (disorder)
Diverticulum of bladder (disorder) [Ambiguous]
A viral infectious disease that results in infection, has material basis in Sandfly fever Naples virus, or has material basis in Sandfly fever sicilian virus, which are transmitted by Phlebotomus papatasi sandfly. The infection has symptom fever, has symptom severe frontal headaches, has symptom muscle ache, has symptom joint aches, has symptom flushing of the face, and has symptom tachycardia.
A parasitic helminthiasis infectious disease that involves parasitic infection due to migrating immature worms of Gnathostoma spinigerum or Gnathostoma hispidum, which occurs by eating undercooked fish or poultry containing third-stage larvae, or by drinking water containing infective second-stage larvae in Cyclops. Migration in the subcutaneous tissues causes intermittent, migratory, painful, pruritic swellings (cutaneous larva migrans). Migration to other tissues (visceral larva migrans), result in cough, hematuria, and ocular involvement, with the most serious manifestations eosinophilic meningitis with myeloencephalitis.
Cryptorchidism (unilateral or bilateral)
A central nervous system disease that is characterized by a collection of pus (infected material) between the outer covering of the brain and spinal cord and the bones of the skull or spine and is caused by infection in the area between the bones of the skull or spine, and the membranes covering the brain and spinal cord (meninges).
Empyema (collection of pus), subdural space
A cardiovascular system disease that involves the heart.
A primary bacterial infectious disease that is characterized by sore throat, low fever, and an adherent membrane (a pseudomembrane) on the tonsils, pharynx, and/or nasal cavity. A milder form of diphtheria can be restricted to the skin. It is caused by Corynebacterium diphtheriae, an aerobic Gram-positive bacterium. Diphtheria toxin spreads through the bloodstream and can lead to potentially life-threatening complications that affect other organs of the body, such as the heart and kidneys.
Corynebacterium Infections [Disease/Finding]
Peripheral autonomic neuropathy in disorders classified elsewhere
A heart disease that is caused by high blood pressure.
A syndrome that is a neurological disorder affecting the pupil of the eye and the autonomic nervous system. It is characterized by one eye with a pupil that is larger than normal and constricts slowly in bright light (tonic pupil), along with the absence of deep tendon reflexes, usually in the Achilles tendon.
A heart conduction disease characterized by orthostatic intolerance that has_material_basis_in heterozygous mutation in the SLC6A2 gene on chromosome 16q12.2.
Cardiovascular malfunction arising from mental factors
A primary bacterial infectious disease that results_in infection, has_material_basis_in Listeria monocytogenes, which is transmitted_by ingestion of contaminated food or raw milk or transmitted_by congenital method. Ingestion of Listeria by pregnant women has_symptom nausea, has_symptom vomiting, has_symptom diarrhea, has_symptom fever, has_symptom malaise, has_symptom back pain, and has_symptom headache. Maternal infection with Listeria can result in chorioamnionitis, premature labor, spontaneous abortion, or stillbirth.
Infection due to Listeria monocytogenes (disorder)
A peripheral nervous system disease that involves an acute loss of function of the lumbar plexus, neurologic elements (nerve roots) of the spinal canal below the termination (conus) of the spinal cord.
Cauda equina syndrome (disorder) [Ambiguous]
Dyspepsia and other specified disorders of function of stomach
A breast disease that is characterized by benign proliferation of glandular breast tissue and occurs in children less than one year of age.
Breast engorgement in newborn (disorder)
A syndrome characterized by hyperandrogenism, polycystic ovaries, hirsutism, oligomenorrhea or amenorrhea, anovulation and excessive body weight.
(Polycystic ovaries) or (Stein-Leventhal syndrome)
(Polycystic ovaries) or (Stein-Leventhal syndrome) (disorder)
Intermittent effusion of joint (disorder)
Chromosomal imbalance syndrome, pair 13, trisomy
Disorder characterized by hyperlipidemia
Other specified disorders resulting from impaired renal function
A substance abuse that involves the recurring use of antidepressant drugs despite negative consequences.
A genetic disease that is characterized by slow growth before and after birth, intellectual disability that is usually severe to profound, skeletal abnormalities involving the arms and hands, and distinctive facial features.
Brachmann-Cornelia de Lange (BCDL) syndrome (BDLS)
A primary bacterial infectious disease that results_in infection, has_material_basis_in Borrelia burgdorferi, which is transmitted_by blacklegged tick (Ixodes scapularis) or transmitted_by western blacklegged tick (Ixodes pacificus). The infection has_symptom fever, has_symptom headache, has_symptom fatigue, and has_symptom skin rash called erythema migrans. If left untreated, infection can spread to joints, the heart, and the nervous system.
Infection due to Borrelia burgdorferi sensu lato
A lower respiratory tract disease that affects the airways leading into the lungs, which is caused due to inflammation of the bronchi and bronchioles, infection, or blockage.
A pericardium disease that is characterized by an abnormal accumulation of fluid in the pericardial cavity.
A syndrome that is characterized by papulonodular skin lesions containing a proliferation of true macrophages associated with arthritis.
An organ system cancer that arises in the head or neck region. This region includes the nasal cavity, sinuses, lips, mouth, salivary glands, throat, or larynx.
Head and Neck Neoplasm (Excluding Central Nervous System)
Head and Neck Neoplasms [Disease/Finding]
A primary bacterial infectious disease that involves intoxication caused by botulinum neurotoxins (BoNTA, B, E and F) located in neuromuscular junction resulting in descending muscle paralysis, has material basis in Clostridium botulinum A, has material basis in Clostridium botulinum B, has material basis in Clostridium botulinum E and has material basis in Clostridium botulinum F.
(OS GIT infections) or (botulism) or (Campylobacter enteritis)
(OS GIT infections) or (botulism) or (Campylobacter enteritis) (disorder)
Food poisoning due to Clostridium botulinum
Intoxication with Clostridium botulinum toxin
A chromosomal disease that is characterized by weak muscle tone, feeding difficulties, poor growth, and delayed development. Beginning in childhood, affected individuals develop an insatiable appetite, which leads to chronic overeating and obesity.
OBESITY-CRYPTORCHIDISM-DWARFISM-SUBNORMAL MENTALITY SYNDROME
An immune system disease that is an exaggerated immune response to allergens, such as insect venom, dust mites, pollen, pet dander, drugs or some foods.
(Allergy, unspecified) or (hypersensitivity NOS)
(Allergy, unspecified) or (hypersensitivity NOS) (disorder)
A pervasive developmental disease that is characterized by normal early growth and development followed by a slowing of development, loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, problems with walking, seizures, and intellectual disability.
AUTISM, DEMENTIA, ATAXIA, AND LOSS OF PURPOSEFUL HAND USE
Autism Dementia Ataxia Loss of Purposeful Hand Use Syndrome
Autism-Dementia-Ataxia-Loss of Purposeful Hand Use Syndrome
Dieulafoy's vascular malformation (disorder)
A primary bacterial infectious disease that results_in infection, has_material_basis_in Spirillum minus, which is transmitted_by contact with urine or secretions from the mouth, eye, or nose of an infected animal or transmitted_by bite of an infected animal, especially rat. The infection has_symptom chills, has_symptom relapsing fever, has_symptom rash and has_symptom joint pain.
A female reproductive system disease that is located_in the vagina.
An X-linked disease that has_material_basis_in Factor VIII deficiency, which results in the formation of fibrin deficient clots which makes coagulation much more prolonged. The disease is inherited as an X-linked recessive trait.
A mood disorder that involves the presence of a low mood almost daily over a span of at least two years.
DSD - Detrusor and sphincter dyssynergia
Detrusor and sphincter dyssynergia (disorder)
detrusor sphincter dyssynergia (diagnosis)
A viral infectious disease that results in infection located in brain, or located in meninges, or located in brain and meninges, has material basis in Lymphocytic choriomeningitis virus, which is transmitted by common house mouse, Mus musculus. The infection has symptom fever, has symptom lack of appetite, has symptom headache, has symptom muscle aches, has symptom malaise, has symptom nausea, and has symptom vomiting.
ENCEPH LYMPHOCYTIC CHORIOMENINGITIS VIRUS
Encephalomyelitis caused by lymphocytic choriomeningitis virus
Encephalomyelitis caused by lymphocytic choriomeningitis virus (disorder)
Encephalomyelitis, Lymphocytic Choriomeningitis Virus
A parasitic helminthiasis infectious disease that involves parasitic infection of the liver of a variety of wild and domestic ruminants by Fascioloides magna.
An endocrine system disease that is located_in the thyroid.
B-80 HYPOTHYROIDISM, HYPERTHYROIDISM AND OTHER DISORDERS
A parasitic helminthiasis infectious disease that involves parasitic infection of the intestine by Metagonimus yokogawai. The symptoms are diarrhea and colicky abdominal pain. The heart and brain can also be infected.
A parasitic helminthiasis infectious disease that involves parasitic infection of the bile ducts of the liver by Dicrocoelium dendriticum. The symptoms include cholecystitis, liver abscesses and upper abdominal pain.
A viral infectious disease that results in infection, has material basis in Dengue virus [NCBITaxon:12637] with four serotypes (Dengue virus 1, 2, 3 and 4), which are transmitted by Aedes mosquito bite. The infection has symptom fever, has symptom severe headache, has symptom severe pain behind the eyes, has symptom joint pain, has symptom muscle and bone pain, has symptom rash, and has symptom mild bleeding.
A dengue disease that occurs when a person experiences a second infection with a heterologous Dengue virus serotype, which is transmitted_by Aedes mosquito bite. The infection has_symptom hemorrhagic lesions of the skin, has_symptom thrombocytopenia, has_symptom reduction in the fluid part of the blood, and has_symptom high fever.
A dementia and a synucleinopathy that is characterized by the development of abnormal proteinaceous (alpha-synuclein) cytoplasmic inclusions, called Lewy bodies, throughout the brain that results in progressive decline in mental abilities.
Hourglass stricture and stenosis of stomach
Hourglass stricture or stenosis of stomach
medulloadrenal hyperfunction (diagnosis)
A viral infectious disease that is a hemorrhagic fever, has_material_basis_in Crimean-Congo hemorrhagic fever virus, which is transmitted_by Hyalomma ticks. The infection has_symptom headache, has_symptom high fever, has_symptom back pain, has_symptom joint pain, has_symptom stomach pain, has_symptom vomiting, has_symptom red eyes, has_symptom flushed face, has_symptom red throat, has_symptom petechiae (red spots) on the palate, has_symptom jaundice, has_symptom nosebleeds, and has_symptom blood in the feces and urine.
A mood disorder that is characterized by mood reactivity (paradoxical anhedonia) and positivity, significant weight gain or increased appetite ("comfort eating"), excessive sleep or somnolence (hypersomnia), a sensation of heaviness in limbs known as leaden paralysis, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection.
atypical depressive disorder (diagnosis)
A bilirubin metabolic disorder that involves elevated levels of unconjugated bilirubin without elevation of liver alanine transaminase and aspartate transaminase enzymes as a result of the deficient ability of hepatocytes to secrete conjugated bilirubin into the bile.
Chronic idiopathic jaundice with pigmented liver
Male genital organ stricture NOS (disorder)
Male genital organ vascular diseases (disorder)
Vascular disorders of male genital organs
disorder of male genital organs vascular
vascular disorder of male genital organs
vascular disorder of male genital organs (diagnosis)
Fetishism (Psychiatric) [Disease/Finding]
A prolapse of female genital organ that is characterized by the descent of the urethra from the normal anatomic location toward or through the vaginal opening.
A primary bacterial infectious disease that results_in infection located_in epithelium of colon, has_material_basis_in Shigella boydii, has_material_basis_in Shigella dysenteriae, has_material_basis_in Shigella flexneri, or has_material_basis_in Shigella sonnei, which produce toxins that can attack the lining of the large intestine, causing swelling, ulcers on the intestinal wall, and bloody diarrhea. The bacteria are transmitted_by ingestion of food and water contaminated with feces.
A parasitic protozoa infectious disease involving infection caused by Balantidium coli. The trophozoites are capable of attacking the intestinal epithelium, creating ulcers and causing bloody diarrhea. The infectiou has_symptom cramping, has_symptom abdominal pain, has_symptom nausea and has_symptom foul breath.
DIABETES INSIPIDUS, NEUROHYPOPHYSEAL TYPE
An impulse control disorder that involves the uncontrollable impulse to gamble, irrespective of the interference the behaviour has on the individual's life.
An impulse control disorder that involves the repeated impulse to steal for no great gain, when he or she has sufficient money to pay for the item and no need for what is stolen.
An impulse control disorder that involves the episodic inability to control violent impulses with a disproportionate degree of aggressiveness.
Intermittent explosive disorder (disorder)
An impulse control disorder that involves the uncontrollable impulse to repeatedly set fires with no obvious motive.
Disorder of thyrocalcitonin secretion (disorder)
An anemia that is characterized by a deficiency of red blood cells, white blood cells and platelets produced by bone marrow.
An anemia that is characterized by a reduction in the number of red blood cells, white blood cells, and platelets.
(Coagulation defects) or (bleeding disorders)
(Coagulation defects) or (bleeding disorders) (disorder)
Blood Coagulation Disorders [Disease/Finding]
A parasitic helminthiasis infectious disease that involves infection of the intestine, liver and lungs caused by Capillaria species.
A parasitic helminthiasis infectious disease that involves parasitic infection located_in intestine in humans, has_material_basis_in Trichuris trichiura, which is transmitted_by ingestion of food contaminated with egg-carrying soil. The infection has_symptom abdominal pain, has_symptom diarrhea, has_symptom rectal prolapse and has_symptom growth retardation.
A viral infectious disease that results_in inflammation located_in liver, has_material_basis_in Hepatitis A virus, which is transmitted_by ingestion of contaminated food or water, or transmitted_by direct contact with an infected person. The infection has_symptom fever, has_symptom fatigue, has_symptom loss of appetite, has_symptom nausea, has_symptom vomiting, has_symptom abdominal pain, has_symptom clay-colored bowel movements, has_symptom joint pain, and has_symptom jaundice.
A parasitic helminthiasis infectious disease that involves parasitic infection of animals and humans by nematodes of the superfamily Trichostrongyloidea.
Trichostrongyloidiasis [Disease/Finding]
A kidney disease that is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs.
chromosome 5 short arm deletion syndrome
A nervous system disease that is characterized by complete paralysis of all voluntary muscles except for the ones that control the movements of the eyes.
A cell type benign neoplasm that is a benign tumor of smooth muscle cells.
An acquired metabolic disease that has_material_basis_in the presence of abnormally-high levels of prolactin in the blood.
Chiari-Frommel Syndrome [Disease/Finding]
A vascular disease that is located_in the capillaries.
A viral infectious disease that results_in infection located_in upper respiratory tract or located_in lower respiratory tract, has_material_basis_in Human respiratory syncytial virus, which is transmitted_by droplet spread of nasal secretions from an infected person while coughing or sneezing, or transmitted_by contaminated fomites. The infection has_symptom runny nose, has_symptom fever, has_symptom cough, has_symptom wheezing, and has_symptom respiratory distress.
RESPIRATORY TRACT, SYNCYTIAL VIRUS INFECTION
RSV - Respiratory syncytial virus infection
respiratory syncytial virus infectious disease
A female reproductive system disease that is characterized by the protrusion of the ovary and fallopian tube through a defect inthe abominal wall.
Prolapse and hernia of ovary and fallopian tube
Prolapse and hernia of ovary and fallopian tube, NOS
Prolapse or hernia of ovary and fallopian tube
prolapse and hernia of ovary and fallopian tube (diagnosis)
A substance abuse that involves the recurring use of hallucinogenic drugs despite negative consequences.
A lysosomal storage disease that involves the accumulation of glycosaminoglycans in the tissues and their excretion in the urine.
A female reproductive system disease that is characteried by the descent of one or more of the pelvic structures (bladder, uterus, vagina) from the normal anatomic location toward or through the vaginal opening.
A parasitic helminthiasis infectious disease that involves infection of skin, eyes, and viscera in humans by the parasitic nematodes Ancylostoma braziliense, Ancylostoma ceylanicum, Ancylostoma duodenale or Ancylostoma caninum. The larvae cause lesions on the skin at the site of penetration. The infection has_symptom intestinal bleeding, has_symptom abdominal pain, has_symptom anemia, has_symptom severe diarrhea and has_symptom malnutrition.
Infection caused by Uncinaria (disorder)
A disease of anatomical entity which occurs in the blood, heart, blood vessels or the lymphatic system that passes nutrients (such as amino acids and electrolytes), gases, hormones, blood cells or lymph to and from cells in the body to help fight diseases and help stabilize body temperature and pH to maintain homeostasis.
3-00 CARDIOVASCULAR DISORDERS: GENERAL TERMS
CHAPTER 3 DISEASES OF THE CARDIOVASCULAR SYSTEM
A somatoform disorder that involves an excessive preoccupation or worry about having a serious illness.
A central nervous system disease that results in the progressive deterioration of function or structure of neurons.
Degenerative Diseases and Syndromes of Nervous System
A specific developmental disorder marked by a pattern of repetitive behavior wherein the rights of others or social norms are violated.
Brachial-Basilar Insufficiency Syndromes
Insufficiency Syndrome, Brachial-Basilar
Insufficiency Syndromes, Brachial-Basilar
An amnestic disorder that is characterized by temporary but almost total disruption of short-term memory with a range of problems accessing older memories.
Amnesia, Transient Global [Disease/Finding]
A primary bacterial infectious disease that results_in infection, has_material_basis_in Borrelia, which is transmitted_by tick or transmitted_by body louse.
Hemangioma of subcutaneous tissue (disorder)
A syndrome that involves pre-excitation of the ventricles due to an accessory pathway providing an abnormal electrical communication from the atria to the ventricles.
Lown-Ganong-Levine Syndrome [Disease/Finding]
Syndrome of short P-R interval, normal QRS complexes AND supraventricular tachycardias
A nail disease characterized by often-tender bacterial or fungal hand infection or foot infection due to either bacteria or fungus (Candida albicans) where the nail and skin meet at the side or the base of a finger or toe nail. The infection can start suddenly (acute paronychia) or gradually (chronic paronychia). Puss is usually present, along with gradual thickening and browning discoloration of the nail plate.
Diverticulosis, Esophageal [Disease/Finding]
A primary bacterial infectious disease that results_in infection, has_material_basis_in Streptobacillus moniliformis, which is transmitted_by contact with urine or secretions from the mouth, eye, or nose of an infected animal or transmitted_by bite of an infected animal, especially rat. The infection has_symptom chills, has_symptom fever, has_symptom rash and has_symptom joint pain.
PCI - Pneumatosis cystoides intestinalis
Pneumatosis Cystoides Intestinalis [Disease/Finding]
A primary bacterial infectious disease that is a communicable systemic illness, has_material_basis_in Salmonella enterica subsp enterica serovar Typhi, which is transmitted_by ingestion of food or water contaminated with the feces of an infected person. The infection has_symptom fever, has_symptom diarrhea, has_symptom prostration, has_symptom headache, has_symptom splenomegaly, has_symptom liver enlargement, has_symptom eruption of rose-colored spots, and has_symptom leukopenia.
Fever: [typhoid] or [enteric] (disorder)
An inherited metabolic disorder that involves certain enzymes in the heme bio-synthetic pathway resulting in the overproduction and accumulation of the porphyrins.
Disorder of porphyrin and haem metabolism
Disorder of porphyrin and hem metabolism
Disorder of porphyrin and heme metabolism
Disorder of porphyrin and heme metabolism (disorder)
Disorder of porphyrin metabolism (disorder)
CEP - Congenital erythropoietic porphyria
Congenital erythropoietic porphyria (disorder)
A viral infectious disease that results_in infection, has_material_basis_in Rift Valley fever virus, which is transmitted_by Aedes mosquitoes. The virus affects domestic animals (cattle, buffalo, sheep, goats, and camels) and humans. The infection has_symptom jaundice, has_symptom vomiting blood, has_symptom passing blood in the feces, has_symptom ecchymoses (caused by bleeding in the skin), has_symptom bleeding from the nose or gums, has_symptom menorrhagia and has_symptom bleeding from venepuncture sites.
A peritonitis which involves inflammation of peritoneal cavity by Corynebacterium diphtheriae.
Exocrine Pancreatic Insufficiency [Disease/Finding]
Exocrine pancreatic insufficiency (diagnosis)
Exocrine pancreatic insufficiency (disorder)
A carbohydrate metabolic disorder that involves low blood glucose resulting from an excess of insulin.
Familial hyperinsulinaemia with pancreatic nesidioblastosis
Familial hyperinsulinemia with pancreatic nesidioblastosis
HYPERINSULINISM, FAMILIAL, WITH PANCREATIC NESIDIOBLASTOSIS
Hyperinsulinaemia due to nesidioblastosis
Hyperinsulinaemia due to nesidioblastosis [Ambiguous]
Hyperinsulinaemia due to pancreatic islet beta cell hyperplasia
Hyperinsulinaemia-pancreatic islet beta cell hyperplasia
A gender identity disorder that is characterized by having a sexual orientation or an attraction that is at odds with one's idealized self-image, causing anxiety and a desire to change one's orientation or become more comfortable with one's sexual orientation.
Ego-dystonic sexual orientation (finding)
Egodystonic sexual orientation disorder (diagnosis)
sexual disorder egodystonic sexual orientation
A plasma protein metabolism disease that has_material_basis_in defective production of the protease inhibitor alpha 1-antitrypsin (A1AT), leading to decreased A1AT activity in the blood and lungs, and deposition of excessive abnormal A1AT protein in liver cells.
.A connective tissue disease that is characterized by progressive ossification of skeletal muscle, fascia, tendons, and ligaments and has_material_basis_in heterozygous mutation in the ACVR1 gene.
Diffuse progressive ossifying polymyositis
FOP - Fibrodysplasia ossificans progressiva
A primary bacterial infectious disease that results in infection located in mucosa of mouth, located in skin or located in bone, has material basis in Treponema pallidum subsp endemicum, which is transmitted by contact or transmitted by sharing of domestic utensils. The infection has symptom moist patches in the mouth, has symptom lumps in long bones, tissues around the mouth, nose, and roof of the mouth. These lumps destroy tissue, causing bones to be deformed and disfiguring the face.
Nonvenereal endemic syphilis (& [Bejel] or [Njovera])
A primary bacterial infectious disease that results in septicemic infection, has material basis in Burkholderia mallei, which is transmitted by contact with tissues or body fluids of infected animals, or through mucosal surfaces such as the eyes and nose. The infection has symptom fever, has symptom chills, has symptom sweating, has symptom muscle aches, has symptom chest pain, has symptom muscle tightness, has symptom headache, has symptom mucopurulent nasal discharge, and has symptom nodular lesions in the lungs.
Intrinsic (urethral) sphincter deficiency (isd)
Intrinsic (urethral) sphincter deficiency [ISD]
Urethral intrinsic sphincter deficiency (finding)
GIGANTISM, PARTIAL, OF HANDS AND FEET, NEVI, HEMIHYPERTROPHY, AND MACROCEPHALY
Macrocephaly mesodermal hamartoma spectrum
Partial gigantism of hands and feet, nevi, hemihypertrophy, macrocephaly
A pervasive developmental disorder that is a rare condition characterized by late onset (>3 years of age) of developmental delays in language, social function, and motor skills where children who have had previously normal development who then appear to regress.
Childhood disintegrative disorder (disorder)
A filariasis that involves parasitic infection of the skin and eyes caused by the nematode Loa loa, which is transmitted through the bite of a deer fly or mango fly. The disease is characterized by episodic angioedema in the arms and legs, and cyst-like enlargements of the connective tissue around the sheaths of muscle tendons. Dead worms may cause chronic abscesses, which may lead to the formation of granulomatous reactions and fibrosis.
A parathyroid gland disease characterized by an overactivity of the parathyroid glands, leading to an excess of parathyroid hormone in the body.
Elevated blood parathyroid hormone level
A primary bacterial infectious disease that results_in infection located_in intestine, has_material_basis_in Campylobacter jejuni, which is transmitted_by ingestion of contaminated food or water or transmitted_by contact with infected people or animals. The infection has_symptom diarrhea or has_symptom dysentery, has_symptom abdominal cramps and pain, and has_symptom fever.
Campylobacter Infections [Disease/Finding]
Acquired Hyperostosis Syndrome [Disease/Finding]
Pustulo-Psoriatic Hyperostotic Spondyloarthritis
SAPHO - Synov,acne,pustul palm,hyperos,osteomyel syndrome
SAPHO - Synovitis, acne, pustulosis palmaris, hyperostosis, osteomyelitis syndrome
Neonatal urinary tract infection (disorder)
urinary tract infection of newborn (diagnosis)
neonatal urinary tract infectious disease
A parasitic helminthiasis infectious disease that involves parasitic infection of the bile ducts of the liver by Clonorchis sinensis. The symptoms include abdominal pain, nausea, diarrhea, and eosinophilia. In long-standing infections, cholangitis, cholelithiasis, pancreatitis, and cholangiocarcinoma can develop.
A parasitic helminthiasis infectious disease that involves parasitic infection of the liver, pancreas and gall bladder by Opisthorchis viverrini or Opisthorchis felineus. The symptoms include dyspepsia, abdominal pain, diarrhea, constipation, hepatomegaly, cholangitis, cholecystitis, and chlolangiocarcinoma.
A viral infectious disease that results_in benign epithelial tumors located_in skin of the sole or toes of the foot, has_material_basis_in human papillomavirus (types 1, 2, 4 or 63), has_symptom lesions that appear on the sole of the foot.
A primary bacterial infectious disease that is a sexually transmitted infection located in skin of the genitals, has material basis in Haemophilus ducreyi, which is transmitted by sexual contact. The infection has symptom painful and soft ulcers.
(Chancroid [& bubo]) or (Ducrey's chancre)
(Chancroid [& bubo]) or (Ducrey's chancre) (disorder)
A commensal bacterial infectious disease that results_in inflammation, located_in conjunctiva of the eye, has_material_basis_in Chlamydia trachomatis, which is transmitted_by sexual contact. The infection has_symptom swollen conjunctiva and eyelids and has_symptom discharge of pus and mucus.
Chronic conjunctivitis due to Chlamydia trachomatis
A viral infectious disease that results in infection located in pharynx or located in conjunctiva, has material basis in Human adenovirus 3 or has material basis in Human adenovirus 7, which are transmitted by droplet spread of respiratory secretions or transmitted by fomites. The infection has symptom fever, has symptom lymphadenopathy of the neck, and has symptom headache.
Adenoviral pharyngoconjunctivitis (disorder)
A commensal bacterial infectious disease that results_in infection located_in lymph nodes, has_material_basis_in Chlamydia trachomatis, which is transmitted_by sexual contact, and transmitted_by fomites. The infection has_symptom inguinal lymphadenitis, has_symptom abscesses in the groin area, and has_symptom lymphangitis.
Hypoactive sexual desire disorder (disorder)
Lack or loss of sexual desire (disorder)
Alpha High Density Lipoprotein Deficiency Disease
A peripheral system disease that is characterized by is damage affecting peripheral nerves (peripheral neuropathy) in roughly the same areas on both sides of the body, featuring weakness, numbness, pins-and-needles, and burning pain.
Polyneuropathy (multiple nerve disorder)
A somatoform disorder that involves persistently complaints of varied physical symptoms that have no identifiable physical origin.
A female reproductive system disease that is characterized by the absence of menstruation.
A schistosomiasis that involves parasitic infection of the urinary tract caused by a digenetic trematode Schistosoma haematobium causing cystitis, ureteritis, fibrosis of the bladder and haematuria, which can progress to bladder cancer.
Schistosoma hematobium infectious disease
Schistosomiasis due to schistosoma haematobium
A parasitic helminthiasis infectious disease that involves infection of the intestine, urinary tract, skin, liver and spleen caused by multiple species of the trematode fluke of the genus Schistosoma. The symptoms include fever, chills, nausea, abdominal pain, diarrhea, malaise, myalgia, liver and spleen enlargement, rash and hematuria.
A disease by infectious agent that is carried out by a parasite which by definition is a pathogen that simultaneously injures and derives sustenance from its host.
Parasitic endophthalmitis NOS (disorder)
A commensal bacterial infectious disease that results_in infection, has_material_basis_in Streptococcus pyogenes or has_material_basis_in Staphylococcus aureus , which produce toxins that are absorbed systemically and produce the systemic manifestations. The infection has_symptom fever, has_symptom rash, has_symptom hypotension, has_symptom multiorgan failure, has_symptom desquamation, has_symptom vomiting, has_symptom diarrhea, has_symptom headache, and has_symptom nonfocal neurologic abnormalities.
A urinary system disease which consists of the presence of bacteria in urine.
A female reproductive system disease that is characterized by an excessively mobile uterus secondary to lacerations of the broad and cardinal ligaments, specific tenderness with movement of the cervix and previous untoward obstetrics events, such as premature maternal voluntary efforts, precipate delivery, and forceps delivery.
Broad ligament laceration syndrome (disorder)
Adhesive capsulitis of shoulder (disorder)
A purine-pyrimidine metabolic disorder that is an autosomal recessive metabolic disorder in which there is absent or significantly decreased activity of dihydropyrimidine dehydrogenase, an enzyme involved in the metabolism of uracil and thymine.
DIHYDROPYRIMIDINE DEHYDROGENASE DEFICIENCY
Deficiencies, Dihydropyrimidine Dehydrogenase
Deficiency, Dihydropyrimidine Dehydrogenase
A chromosomal disease that is characterized by flat-looking facial features and weak muscle tone (hypotonia) in infancy and is caused by trisomy of all or a critical portion of chromosome 21 and is associated with intellectual disability.
Chromosomal imbalance syndrome, pair 21, trisomy
A urinary system disease that is located_in the ureter.
An X-linked disease that is characterized by moderate to severe mental retardation, macroorchidism, and distinct facial features, including long face, large ears, and prominent jaw, and has material basis in X-linked inheritance and a loss of FMR1 function.
Other disorder of pancreatic internal secretion NOS
Other disorder of pancreatic internal secretion NOS (disorder)
Other disorders of pancreatic endocrine secretion
Other disorders of pancreatic endocrine secretion (disorder)
Other disorders of pancreatic internal secretion
Other disorders of pancreatic internal secretion (disorder)
Autosomal Recessive Pachydermoperiostosis
HYPERTROPHIC OSTEOARTHROPATHY, PRIMARY, AUTOSOMAL RECESSIVE, 1
Hypertrophic Osteoarthropathy, Idiopathic
Hypertrophic Osteoarthropathy, Primary, Autosomal Recessive
Idiopathic Hypertrophic Osteoarthropathy
An anxiety disorder that is characterized by long-lasting anxiety that is not focused on any one object or situation.
Generalised anxiety disorder [Ambiguous]
A connective tissue disease that is characterized by tall stature, elongated extremities, mitral valve prolapse, aortic dilatation, aortic dissection, and subluxation of the lens.
An amino acid metabolic disorder that involves defective proteins called carnitine transporters, which bring carnitine into cells and prevent its escape from the body preventing the body cannot utilize fats for energy.
CARNITINE DEFICIENCY, SYSTEMIC, DUE TO DEFECT IN RENAL REABSORPTION OF CARNITINE
CARNITINE TRANSPORTER, PLASMA-MEMBRANE, DEFICIENCY OF
systemic primary carnitine deficiency disease
A parasitic helminthiasis infectious disease that involves parasitic infection by the larvae of the nematode Dracunculus medinensis, which are transmitted to humans by drinking water containing copepods infected with the larvae. The female, which contains larvae, burrows into the deeper connective tissues or adjacent to long bones or joints of the extremities. The worm emerges as a whitish filament in the center of a painful ulcer, accompanied by inflammation and frequently by secondary bacterial infection.
A nervous system disease that is characterized by hyperthermia, muscular rigidity, autonomic dysfunction and altered consciousness and is associated with administration of antipsychotic and other central dopaminergic blockers.
Neuroleptic Malignant Syndrome [Disease/Finding]
A viral infectious disease that results in infection located in lung, has material basis in Sin Nombre virus, transmitted by deer mouse (Myodes glareolus), has material basis in Black Creek Canal virus, transmitted by cotton rat (Sigmodon hispidus), has material basis in Bayou virus, transmitted by marsh rice rat (Oryzomys palustris), has material basis in Laguna Negra virus, transmitted by small vesper mouse (Calomys laucha), or has material basis in Andes virus, transmitted by rice rat (Oligoryzomys longicaudatus). The infection has symptom fever, has symptom muscle pain, has symptom headache, has symptom cough, has symptom vomiting, has symptom chills which rapidly progress to bilateral interstitial pulmonary infiltrates occurrence, pulmonary edema and hypoxia often resulting in death from shock or cardiac complications.
Hantavirus Associated Respiratory Distress Syndrome
Hantavirus Pulmonary Syndrome [Disease/Finding]
Hantavirus disease pulmonary syndrome (diagnosis)
A chromosomal deletion syndrome that is a nephroblastoma that results_in a rare genetic syndrome in which affected children are predisposed to develop Wilms tumor, Aniridia (absence of the colored part of the eye, the iris), genitourinary anomalies, and mental retardation. The condition results from a deletion on chromosome 11 resulting in the loss of several genes. As such, it is one of the best studied examples of a condition caused by loss of neighbouring (contiguous) genes.
11p partial monosomy syndrome (diagnosis)
11p partial monosomy syndrome (disorder)
Chromosome 11p13 deletion syndrome (disorder)
A syndrome characterized by acute brain damage and liver function problems. It has been associated with aspirin consumption by children with viral illness, although it also occurs in the absence of aspirin use.
A disease that is characterized by abnormally rapid cell division.
A thyroid gland disease which involves an underproduction of thyroid hormone.
A vascular disease that is characterized by blood vessel obstruction resulting from the release of cholesterol from the inside of blood vessels along the bloodstream.
Atheromatous embolus (morphologic abnormality)
A syndrome that is characterized by the presence of at least three of the following: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities.
Vertebral anomalies/dysgenesis, anal atresia, tracheo-esophageal fistula, esophageal atresia, renal anomalies, radial dysplasia (VATER) association
Vertebral anomalies/dysgenesis, anal atresia, tracheo-esophageal fistula, esophageal atresia, renal anomalies, radial dysplasia (VATER) association (disorder)
7-Dehydrocholesterol reductase deficiency
Hyperotosis Corticalis Generalisata Familiaris
POLYDACTYLY, SEX REVERSAL, RENAL HYPOPLASIA, AND UNILOBAR LUNG
An X-linked disease characterized by retardation, hyperactivity, hypotonia, broad thumbs, big first toes and a characteristic facial appearance including macrocephaly and has an X-linked recessive inheritance pattern.
MENTAL RETARDATION, LARGE HEAD, IMPERFORATE ANUS, CONGENITAL HYPOTONIA, AND PARTIAL AGENESIS OF CORPUS CALLOSUM
Mental Retardation, Large Head, Imperforate Anus, Congenital Hypotonia, and Partial Agenesis of the Corpus Callosum
Benign lymphangioma (morphologic abnormality)
An amino acid metabolic disorder that involves the accumulation of argininosuccinic acid (ASA) in the blood and urine.
A syndrome that is characterized by short stature, moderate to severe degrees of mental retardation, developmental abnormalities of the limbs, bones of the spine (vertebrae), extremities, and/or underdevelopment of the bones of the skeleton.
MACRODONTIA, MENTAL RETARDATION, CHARACTERISTIC FACIES, SHORT STATURE, AND SKELETAL ANOMALIES
Short stature, characteristic facies, macrodontia, mental retardation, and skeletal anomalies
Short stature-characteristic facies-mental retardation-macrodontia-skeletal anomalies syndrome
Short stature-characteristic facies-mental retardation-macrodontia-skeletal anomalies syndrome (disorder)
A monogenic disease that is characterized by malformation of ectodermal (skin, hair, teeth and sweat glands) structures including hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth).
Anhidrotic Ectodermal Dysplasia, X Linked
Anhidrotic Ectodermal Dysplasia, X-Linked
Anhidrotic ectodermal dysplasia syndrome, hereditary
Anhydrotic Ectodermal Dysplasia, X Linked
Anhydrotic Ectodermal Dysplasia, X-Linked
A syndrome that is a rare genetic disorder characterized by microcephaly, growth retardation and a characteristic facial appearance like small, round, triangular shaped with a pointed, receding chin, a broad, wide-tipped nose, and wide-set eyes with drooping eyelids.
Dwarfism-eczema-peculiar facies syndrome
A sensory system disease that is located_in the eye or the adnexa of the eye.
Unspecified background retinopathy (disorder)
A parasitic helminthiasis infectious disease that involves parasitic infection of humans and domestic animals caused by the larval stages of tapeworms of the genus Echinococcus in the liver, lungs, spleen, brain, heart and kidneys.
A primary bacterial infectious disease that is described as an acute, diarrheal illness caused by infection of the intestine with the bacterium Vibrio cholerae, which is characterized by profuse watery diarrhea, vomiting, leg cramps, circulatory collapse and shock.
(Cholera) or (Vibrio cholerae) (disorder)
Disorder of reproductive system (disorder)
A disorder that is a psychological or behavioral pattern associated with distress or disability that occurs in an individual and is not a part of normal development or culture.
A personality disorder that is characterized by a pervasive pattern of social inhibition, feelings of inadequacy, extreme sensitivity to negative evaluation, and avoidance of social interaction.
Avoidant personality disorder (disorder)
An intestinal disease located_in the cecum.
A thoracic disease which may involve inflammation of pleura, collection of air within the pleural cavity, abnormal collection of pleural fluid, abnormal growths on the pleura (pleural tumor) and pleural plaques. The main causes of pleural diseases including pleural effusions are congestive heart failure, malignancy, parapneumonic infections and pulmonary embolism.
A cell type cancer that has_material_basis_in abnormally proliferating cells derives_from two germinal layers of tissue.
Mixed Tumor, Malignant [Disease/Finding]
Mixed tumor, malignant (morphologic abnormality)
Immune Complex Diseases [Disease/Finding]
hypersensitivity reaction type III disease
A skin disease characterized by the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues.
A subcutaneous mycosis that is a chronic subcutaneous fungal infection, which presents as nodular or verrucoid, ulcerated, or crusted skin lesions on exposed areas of skin caused by Fonsecaea pedrosoi, Fonsecaea compacta, Cladophialophora carrionii or Phialophora verrucosa. Histological examination reveals muriform cells (with perpendicular septations) or thick walled, dark-colored, rounded forms (copper pennies) that are characteristic of this infection.
A disease by infectious agent that results_in infection, has_material_basis_in Fungi, which pass the resistance barriers of the human or animal body.
A substance abuse that involves the recurring use of alcoholic beverages despite negative consequences.
Alcohol abuse, unspecified drinking behavior
Alcohol abuse, unspecified drinking behaviour
2-00 RESPIRATORY DISEASES: GENERAL TERMS
CHAPTER 2 DISEASES OF THE RESPIRATORY SYSTEM
Disease of respiratory system (disorder)
Disease or syndrome of respiratory system
Diseases and Syndromes of Respiratory System
A disease of anatomical entity that is located_in the integumentary system comprising the skin and its appendages.
A skin disease characterized_by growth of keratin on the skin or mucous membranes.
A disease of cellular proliferation that is malignant and primary, characterized by uncontrolled cellular proliferation, local cell invasion and metastasis.
Chronic interstitial cystitis (disorder)
Chronic interstitial cystitis (disorder) [Ambiguous]
Chronic interstitial cystitis NOS (disorder)
A skin disease characterized by drying and scaling of skin with the accumulation of thick scales and cracks that may be painful or bleed.
A disease of anatomical entity that occurs in the muscular and/or skeletal system.
Disease of musculoskeletal system (disorder)
Disease of the musculoskeletal system, NOS
Disorder of musculoskeletal system (disorder)
Disorder of the musculoskeletal system, NOS
An organ system cancer located_in endocrine system that is characterized by uncontrolled cellular proliferation of the hormone producing glands of the endocrine system.
Endocrine Gland Neoplasms [Disease/Finding]
A lipid metabolism disorder that involves defects in steroid metabolism.
Steroid Metabolism, Inborn Errors [Disease/Finding]
An organ system cancer that is located in the peritoneum.
Malignant neoplasm of specified parts of peritoneum
Malignant neoplasm of specified parts of peritoneum (disorder)
Malignant neoplasm of specified parts of peritoneum NOS
Malignant neoplasm of specified parts of peritoneum NOS (disorder)
malignant neoplasm of specified parts of peritoneum (diagnosis)
An organ system cancer that located_in the heart and blood vessels.
Neoplasm of cardiovascular system (disorder)
A somatoform disorder that involves numbness, blindness, paralysis or fits without a neurological cause.
A cardiovascular system disease that primarily affects the blood vessels which includes the arteries, veins and capillaries that carry blood to and from the heart.
A pericardium disease that is characterized by an inflammation of the pericardium and has_symptom chest pain.
an inflammation of the membrane surrounding the heart
DISEASES AND SYNDROMES OF THE URINARY TRACT
A viral infectious disease that results_in inflammation located_in liver, has_material_basis_in Hepatitis C virus, which is transmitted_by blood from an infected person enters the body of an uninfected person. The infection has_symptom fever, has_symptom fatigue, has_symptom loss of appetite, has_symptom nausea, has_symptom vomiting, has_symptom abdominal pain, has_symptom clay-colored bowel movements, has_symptom joint pain, and has_symptom jaundice.
A hepatitis that involves viral infection causing inflammation of the liver.
A skin cancer that has_material_basis_in melanocytes.
Choreoathetosis Self Mutilation Hyperuricemia Syndrome
Choreoathetosis Self Mutilation Syndrome
Choreoathetosis Self-Mutilation Hyperuricemia Syndrome
Choreoathetosis Self-Mutilation Syndrome
Choreoathetosis Self-Mutilation Syndromes
An acquired metabolic disease that has_material_basis_in an abnormally high level of uric acid in the blood.
Disorders of Sex Development [Disease/Finding]
A gonadal disease that is characterized by diminished functional activity of the gonads.
A genetic disease that is characterized by underdevelopment of the tips of fingers or toes, underdevelopment or abscense of finger or toe nails and developmental disability.
Aortic Stenoses, Hypercalcemia-Supravalvar
Aortic Stenosis, Hypercalcemia-Supravalvar
CHROMOSOME 7q11.23 DELETION SYNDROME, 1.5- TO 1.8-MB
An organ system cancer that is manifested in the reproductive organs.
A parasitic protozoa infectious disease that is caused by singled-celled protozoan parasites Trichomonas vaginalis or Trichomonas tenax, which infect the urogenital tract and mouth respectively.
A female reproductive system disease that is located_in the fallopian tube.
Fallopian Tube Diseases [Disease/Finding]
A cognitive disorder that involves an excessive, irrational dread of everyday situations.
A specific developmental disorder that involves specific developmental disorders of speech and language.
Communication Disorders [Disease/Finding]
A viral infectious disease that results_in inflammation located_in liver, has_material_basis_in Hepatitis B virus, which is transmitted_by sexual contact, transmitted_by blood transfusions, and transmitted_by fomites like needles or syringes. The infection has_symptom fever, has_symptom fatigue, has_symptom loss of appetite, has_symptom nausea, has_symptom vomiting, has_symptom abdominal pain, has_symptom clay-colored bowel movements, has_symptom joint pain, and has_symptom jaundice.
A viral infectious disease that results_in inflammation located_in liver, has_material_basis_in Hepatitis delta virus, which is an incomplete virus that requires the helper function of Hepatitis B virus to replicate and only occurs among people who are infected with the Hepatitis B virus. The infection has_symptom fatigue, has_symptom lethargy, has_symptom anorexia, has_symptom nausea, has_symptom jaundice, has_symptom clay-colored stools, has_symptom dark urine, has_symptom changes in personality, has_symptom disturbances in sleep, has_symptom confusion, has_symptom abnormal behavior, has_symptom somnolence, and has_symptom coma.
An anxiety disorder which results from a traumatic experience that results in psychological trauma.
A female reproductive system diseaes that is located_in the vulva.
Intestinal Perforation [Disease/Finding]
A parasitic protozoa infectious disease that occurs in the intestinal tract of animals and humans caused by Coccidia protozoa. Immunocompromised persons are at greater risk of developing the infection.
A primary immunnodeficiency disease that is caused by a lack of infection-fighting antibody producing B cells (immunoglobulins) or B cells that are not functioning properly.
Other selective immunoglobulin deficiencies
Other selective immunoglobulin deficiency
Other selective immunoglobulin deficiency (finding)
A primary bacterial infectious disease that has material basis in Francisella tularensis, which is transmitted by dog tick bite (Dermacentor variabilis), transmitted by deer flies (Chrysops sp) or transmitted by contact with infected animal tissues.
Other specified tularemia NOS (disorder)
Coagulation Protein Disorders [Disease/Finding]
Blood Coagulation Disorders, Inherited [Disease/Finding]
A disease characterized by a group of signs and symptoms that occur together and characterize a particular abnormality.
A female reproductive system disease that is characterized by inflammation of the vagina and vulva.
An endocrine system disease that is located_in the gonads.
A reproductive system disease that impairs the ability to reproduce and is located in the uterus, vagina, cervix, ovaries or fallopian tubes.
7-70 DISEASES OF THE FEMALE GENITAL ORGANS: GENERAL TERMS
DISEASES OF THE FEMALE GENITAL ORGANS: GENERAL TERMS
Disease of female genital organ (disorder)
Disease of female genital organ [Ambiguous]
A primary bacterial infectious disease that involves systemic infection, has material basis in Leptospira, which is transmitted by contact with water, food, or soil containing urine from the infected animals. The infection has symptom jaundice, has symptom chills, has symptom fever, has symptom muscle pain, and has symptom hepatomegaly.
Haemorrhagic leptospirosis with jaundice
Hemorrhagic leptospiral or spirochetal jaundice
A specific developmental disorder that is characterized by repeated, rhythmic, purposeless movements or activities such as head banging, nail biting, or body rocking.
An opportunistic bacterial infectious disease that results_in disseminated infection in immunocompromised hosts, has_material_basis_in Nocardia asteroides. The infection has_symptom pneumonia, has_symptom cellulitis, has_symptom lesions in the brain or meninges, and has_symptom ascending regional lymphadenopathy.
A gastrointestinal system infectious disease that involves inflammation of the lining of the stomach and small and large intestines, which is caused by viruses, bacteria, or parasites. Chemicals and drugs also cause gastroenteritis. The symptoms include diarrhea, loss of appetite, nausea, vomiting, cramps, and discomfort in the abdomen.
Polyclonal hypergammaglobulinemia (disorder)
Polyclonal hypergammaglobulinemia NOS (disorder)
An inherited metabolic disorder that involves plasma protein metabolism malfunction.
Other disorder of plasma protein metabolism
Other disorder of plasma protein metabolism (disorder)
Other disorders of plasma protein metabolism
Other disorders of plasma protein metabolism NOS
Other disorders of plasma protein metabolism NOS (disorder)
A hemochromatosis characterized by autosomal recessive inheritance of early onset of severe iron loading with symptoms including; hypogonadotropic hypogonadism, cardiomyopathy, arthropathy, and liver fibrosis or cirrhosis.
Disorder of iron metabolism NOS (disorder)
Disorder of iron metabolism, unspecified
A metal metabolism disorder characterized by the accumulation of iron in various organs of the body.
A hematopoietic system disease that is characterized by a decrease in the normal number of red blood cells.
A viral infectious disease that results in inflammation located in brain, has material basis in West Nile virus, which is transmitted by Culex, transmitted by Aedes, and transmitted by Anopheles species of mosquitoes. The infection has symptom high fever, has symptom headache, has symptom neck stiffness, has symptom stupor, has symptom disorientation, has symptom coma, has symptom tremors, has symptom convulsions, has symptom muscle weakness, has symptom vision loss, has symptom numbness, and has symptom paralysis.
West Nile fever with encephalitis (diagnosis)
A viral infectious disease that results_in infection, has_material_basis_in West Nile virus, which is transmitted_by Culex and transmitted_by Aedes mosquitoes. The infection has_symptom fever, has_symptom sore throat, has_symptom headache, has_symptom body ache, has_symptom nausea, has_symptom maculopapular rash and has_symptom vomiting.
Disease caused by West Nile virus (disorder)
Disease due to West Nile virus (disorder)
A hematopoietic system disease characterized by oval or elliptical red blood cells, slight or absent hemolysis with little or no anemia; splenomegaly is often present.
A parasitic Ichthyosporea infectious disease that is a chronic granulomatous infection of the mucous membranes caused by the parasite Rhinosporidium seeberi, which manifests as vascular friable polyps that arise from the nasal mucosa or external structures of the eye. Disease of the skin, mouth, upper airways, ear, genitals, and rectum has also been observed.
Ganglioneuroma (Schwannian Stroma-Dominant)
Ganglioneuroma (morphologic abnormality)
A disease of metabolism that has_material_basis_in excessive growth hormone production which results_in enlargement located_in limb.
Hypersecretion Syndrome, Somatotropin (Acromegaly)
Hypersecretion Syndromes, Somatotropin (Acromegaly)
Hereditary Thrombophilia Due To Protein S Deficiency
A systemic mycosis that results_in fungal infection located_in human body of immunocompromised individuals, has_material_basis_in Fungi. The organisms invade via the respiratory tract, alimentary tract, or intravascular devices.
Disorder of phosphorus metabolism (disorder)
Disorder of phosphorus metabolism NOS (disorder)
Other congenital anomalies of nervous system
Other nervous system congenital anomalies
Other nervous system congenital anomalies (disorder)
A vascular disease that is characterized as a small vascular malformation of the gut.
Angiodysplasia (morphologic abnormality)
angiodysplasia of stomach and duodenum with hemorrhage
A syndrome that involves inflammation of the aorta that carries blood from the heart to the rest of the body.
An impulse control disorder that involves abnormalities in memory, social and sexual functioning and idiosyncratic behaviors resulting from damage from trauma or infection to both temporal lobes causing individuals to put objects in their mouths and engage in inappropriate sexual behavior.
A kidney disease that is characterized by the leaking of blood protein into the urine, swelling or edema, and degenerative lesions without inflammation.
Disease of spleen unspecified (disorder)
A genetic disease that is characterized by systemic shortening of the proximal bones (i.e. rhizomelia), seizures, recurrent respiratory tract infections, and congential cataracts and has material basis in mutations of the alkyldihydroxyacetonephosphate synthase (alkyl-DHAP synthase) gene.
CHONDRODYSPLASIA PUNCTATA, RHIZOMELIC FORM
Chondrodysplasia Punctata, Rhizomelic [Disease/Finding]
Chondrodysplasia punctata, autosomal recessive type
Chondrodysplasia punctata, rhizomelic type
Chondrodysplasia Punctata (Stippled Epiphyses) Group
Chondrodysplasia Punctata [Disease/Finding]
Chondrodysplasia punctata (disorder) [Ambiguous]
A cell type benign neoplasm that is a cartilaginous tumor encapsulated with a lobular growing pattern.
[M]Chondroma NOS (morphologic abnormality)
A cell type benign neoplam that is composed of epithelial tissue on papillae of vascularized connective tissue.
A cell type benign neoplasm that has_material_basis in mesothelium.
[M]Mesothelioma, unspecified (morphologic abnormality)
A cell type benign neoplasm that is composed_of glandular and fibrous tissues, with a relatively large proportion of glands.
Adenofibroma, no ICD-O subtype (morphologic abnormality)
Adenofibroma, no International Classification of Diseases for Oncology subtype
Adenofibroma, no International Classification of Diseases for Oncology subtype (morphologic abnormality)
A connective tissue disease that results_in inflammation located_in synovial membrane that lines a synovial joint which causes pain and swelling.
A vascular disease that is located_in the liver.
A skin disease characterized by itchy, erythematous, vesicular, weeping and crusting patches of skin.
A skin disease characterized by cutaneous pigmentation, premature graying, dystrophy of the nails, leukoplakia of the oral mucosa, continuous lacrimation due to atresia of the lacrimal ducts, often thrombocytopenia, anemia, testicular atrophy in the male carriers and predisposition to cancer.
Dyskeratosis Congenita [Disease/Finding]
Skin Diseases, Vesiculobullous [Disease/Finding]
Poikiloderma Congenitale of Rothmund-Thomson
A bilirubin metabolic disorder that involves elevated levels of unconjugated bilirubin as bilirubin is not being conjugated as a result of reduced glucuronyltransferase activity.
Benign unconjugated bilirubinaemia syndrome
Benign unconjugated bilirubinemia syndrome
An inherited metabolic disorder that involves elevated levels of bilirubin resulting from disruption of bilirubin metabolism.
Disorder characterized by elevated serum bilirubin
A personality disorder that involves an excessive preoccupation with issues of personal adequacy, power, prestige and vanity.
Narcissistic personality disorder (disorder)
A primary bacterial infectious disease that results_in infection, has_material_basis_in Mycobacterium avium complex (MAC), which is transmitted_by inhalation or transmitted_by ingestion of via the respiratory or gastrointestinal tract respectively. The bacteria cause disseminated infection in HIV infected people, while pulmonary disease in immunocompetent persons.
Infection caused by Mycobacterium intracellulare
Infection caused by Mycobacterium intracellulare (disorder)
Infection due to Mycobacterium intracellulare
Infection due to Mycobacterium intracellulare (disorder)
Infection, Mycobacterium avium intracellulare
Infection, Mycobacterium avium-intracellulare
A specific developmental disorder that is characterized by the persistent presence of involuntary brief movements or sounds occuring intermittently and unpredictably out of a background of normal motor activity.
A parasitic infectious disease that is caused by parasitic protozoa which are microorganisms classified as unicellular eukaryotes.
A parasitic helminthiasis infectious disease that involves infection of the small intestine of humans, dogs and cats by the nematode Necator americanus causing abdominal pain, diarrhea, cramps, weight loss and anemia. Cutaneous larvae migrans in humans is characterized by skin ruptures and severe itching.
A disease of anatomical entity that is located_in endocrine glands which secretes a type of hormone directly into the bloodstream to regulate the body.
CHAPTER B DISEASES OF THE ENDOCRINE SYSTEM
A sleep disorder that involves involuntarily grinding or clenching of the teeth while sleeping.
Euthyroid Sick Syndromes [Disease/Finding]
A carbohydrate metabolic disorder that is characterised by abnormally low levels of glucose-6-phosphate dehydrogenase (abbreviated G6PD or G6PDH).
Deficiencies, Glucose-6-Phosphate Dehydrogenase
Deficiencies, Glucosephosphate Dehydrogenase
Deficiency of Glucose 6 Phosphate Dehydrogenase
Deficiency of Glucose-6-Phosphate Dehydrogenase
glucosephosphate dehydrogenase deficiency
A female reproductive system disease characterized by the growth of endometrial tissue outside the uterine body.
A syndrome that is characterized by incomplete development of the ear, nose, soft palate, lip, and mandible. It is associated with anomalous development of the first branchial arch and second branchial arch.
C-50 DISEASES OF THE IMMUNE SYSTEM: GENERAL TERMS
DISEASES OF THE IMMUNE SYSTEM: GENERAL TERMS
Immunoproliferative Disorders [Disease/Finding]
hypersensitivity reaction type IV disease
A syndrome that is characterized by large cutaneous hemangiomata with hypertrophy of the related bones and soft tissues.
A viral infectious disease that results_in infection in birds and humans, has_material_basis_in Newcastle disease virus, which is transmitted_by contact with feces and urine of an infected bird, or transmitted_by fomites. The infection has_symptom conjunctivitis, has_symptom headache, and has_symptom lacrimation in humans, and has_symptom gasping, has_symptom coughing, has_symptom twisting of head and neck, has_symptom circling, has_symptom complete paralysis, has_symptom watery diarrhea, and has_symptom reduced egg production in birds.
A viral infectious disease that results_in inflammatory destruction located_in blood vessels of minks and rarely in humans, which has_material_basis_in Aleutian mink disease virus. The infection has_symptom weight loss, has_symptom hepatomegaly, has_symptom enlarged spleen, and has_symptom anemia.
A viral infectious disease that results_in infection located_in respiratory tract, has_material_basis_in SARS coronavirus (SARS-CoV), which is transmitted_by droplet spread of respiratory secretions, transmitted_by ingestion of contaminated food, or transmitted_by fomites. The infection has_symptom fever, has_symptom headache, has_symptom body aches, has_symptom dry cough, and has_symptom hypoxia.
SARS (Severe Acute Respiratory Syndrome)
Kidney Cortex Necrosis [Disease/Finding]
An inherited metabolic disorder that affect the catabolism and anabolism of carbohydrates.
Carbohydrate Metabolism, Inborn Errors [Disease/Finding]
disorder of carbohydrate transport and metabolism
inborn errors of carbohydrate metabolism
Kidney Papillary Necrosis [Disease/Finding]
A cell type cancer that has_material_basis_in abnormally proliferating cells derives_from germ cells.
Germ cell neoplasm (morphologic abnormality)
A substance-related disorder that involves a maladaptive pattern of substance use leading to significant impairment in functioning.
A disease of mental health involving the abuse or dependence on a substance that is ingested in order to produce a high, alter one's senses, or otherwise affect functioning.
Substance-Related Disorders [Disease/Finding]
A syndrome that is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia.
A carcinoma that derives_from the cells that line an organ.
Carcinoma, no subtype (morphologic abnormality)
A primary bacterial infectious disease that results_in infection located_in intestine, has_material_basis_in Salmonella enterica subsp enterica serovar Paratyphi A, B or C, which are transmitted_by ingestion of contaminated food. The infection has_symptom fever, has_symptom headache, has_symptom abdominal pain, has_symptom malaise, has_symptom anorexia, has_symptom constipation, has_symptom rosy spots on the central body, has_symptom non productive cough (in early stage of illness), has_symptom bradycardia, and has_symptom hepatosplenomegaly.
A cell type cancer that has material basis in glial cells and is located in brain or located in spine.
An organ system cancer located_in the nervous system that affects the central or peripheral nervous system.
Neoplasms, Nerve Tissue [Disease/Finding]
A vascular disease that is characterized by compression at the superior thoracic outlet[1] resulting from excess pressure placed on a neurovascular bundle passing between the anterior scalene and middle scalene muscles.
A parasitic helminthiasis infectious disease that involves parasitic infection of dogs, cats and foxes with Toxascaris leonina causing damage to the lining of the intestine. The symptoms include diarrhea, vomiting and loss of appetite.
A parasitic helminthiasis infectious disease that involves infection of the intestine of humans and birds with nematodes of the genus Ascaridia.
A gastrointestinal system disease that is located_in the liver and/or biliary tract.
DISEASES OF THE LIVER AND BILIARY SYSTEM
An organ system cancer located_in gastrointestinal tract that is manifested in organs of the gastrointestinal system.
Digestive System Neoplasms [Disease/Finding]
A porphyria that has_symptom abdominal pain, has_symptom neuropathy, has_symptom autonomic instability and has_symptom psychosis.
A skin disease characterized by loose, hanging, wrinkled skin lacking in elasticity.
An inherited metabolic disorder that involves the creation and degradation of lipids.
Lipid Metabolism, Inborn Errors [Disease/Finding]
INCONTINENTIA PIGMENTI, TYPE I, FORMERLY
A cell type benign neoplasm composed_of epithelial cells located_in the ectodermal or endodermal cells linking body cavities.
Neoplasms, Squamous Cell [Disease/Finding]
A viral infectious disease that results in inflammation located in spinal cord, has material basis in Human T-lymphotropic virus 1, which is transmitted by sexual contact, and transmitted by breast feeding. The infection has symptom spastic weakness of both legs, has symptom muscle stiffness, has symptom sensory disturbance, and has symptom spasms.
FAMILIAL SPASTIC PARAPARESIS, HTLV-1-ASSOCIATED
Familial Spastic Paraparesis, Htlv 1 Associated
HTLV I ASSOC MYELOPATHY TROPICAL SPASTIC PARAPARESIS
An inherited metabolic disorder that involve an abnormal accumulation of substances inside the lysosome resulting from defects in lysosomal function.
High Pressure Neurological Syndrome [Disease/Finding]
A vascular disease that is characterized by a restriction in blood supply to tissues.
A primary immunodeficiency disease where phagocytes have a diminished ability to fight bacterial infection.
Phagocyte Bactericidal Dysfunction [Disease/Finding]
A viral infectious disease that results in infection of primates, rodents and humans, located in skin, has material basis in Monkeypox virus, which is transmitted by contact with the animal's blood, body fluids, rash, or with the body fluids of a sick person, transmitted by fomites, and transmitted by respiratory droplets. The infection has symptom fever, has symptom muscle ache, has symptom headache, and has symptom lymphadenopathy.
A viral infectious disease that results_in infection, located_in skin, has_material_basis_in Vaccinia virus, which is used as a live vaccine against smallpox. The virus is transmitted_by contact with the vaccination site before it has healed, or transmitted_by fomites that have been contaminated with live virus from the vaccination site. The infection has_symptom rash, has_symptom fever, and has_symptom body aches.
A cell type benign neoplasm that is composed_of a mixture of gonadal elements.
Gonadoblastoma (morphologic abnormality)
A nervous system disease that affects either the spinal cord (myelopathy) or brain (encephalopathy) of the central nervous system.
A mood disorder that involves alternating periods of mania and depression.
A cell type benign neoplasm that from perivascular epithelioid cells.
Angiomyolipoma (morphologic abnormality)
A cell type benign neoplasm that is composed of lipocytes.
A personality disorder that is characterized by a pattern of excessive emotionality and attention-seeking, including an excessive need for approval and inappropriately seductive behavior, usually beginning in early adulthood.
Histrionic Personality Disorder [Disease/Finding]
A lysosomal storage disease that is characterized by a deficiency of the enzyme alpha-N -acetyl neuraminidase (sialidase).
A cell type cancer that has material basis in abnormally proliferating cells derives from embryonic connective tissue that is capable of developing into connective tissue, such as bone, and cartilage, the lymphatic system, and the circulatory system.
Benign Soft Tissue Neoplasm of Uncertain Differentiation
Benign Soft Tissue Tumor of Uncertain Differentiation
ANTIDIURETIC HORMONE INAPPROPRIATE SECRET
Antidiuretic Hormone, Inappropriate Secretion
INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE
INAPPROPRIATE VASOPRESSIN SECRET SYNDROME
A lymphatic system disease that is characterized by an excessive number of histiocytes.
Histiocytic infiltrate (morphologic abnormality)
A vascular disease that is characterized by obstruction of larger arteries not within the coronary, aortic arch vasculature, or brain.
Arterial Occlusive Diseases [Disease/Finding]
A lysosomal storage disease that has_material_basis_in deficiency of the alpha-D-manosidase enzyme resulting in the impairment of cell function from a build up of complex sugars derived from glycoproteins in the lysosome.
Deficiencies, Lysosomal alpha-D-Mannosidase
A female reproductive system disease that is located_in the uterus.
A thoracic disease that is located_in the breast.
A primary bacterial infectious disease that results_in infection, located_in lymph node, located_in vasculature or located_in lungs, has_material_basis_in Yersinia pestis, which is transmitted_by oriental rat flea (Xenopsylla cheopis) infected by feeding on rodents and other mammals, transmitted_by air, transmitted_by direct contact or transmitted_by ingestion of contaminated undercooked food.
A skin disease where there is a diffuse infection of connective tissue with severe inflammation of dermal and subcutaneous layers of the skin. Cellulitis can be caused by normal skin flora or by exogenous bacteria, and often occurs where the skin has previously been broken: cracks in the skin, cuts, blisters, burns, insect bites, surgical wounds, or sites of intravenous catheter insertion.
A nervous system disease that results from exposure to neurotoxicants and is characterized by an altered mental status, memory loss, and visual problems.
A lysosomal storage disease that has_material_basis_in deficiency of the beta-A-manosidase enzyme resulting in the disruption of N-linked glycoprotein oligosaccharide catabolism.
A carbohydrate metabolic disorder characterized by the buildup of lactic acid in the body and a variety of neurological problems and caused by a deficiency of one of the three enzymes in the pyruvate dehydrogenase complex.
ATAXIA, INTERMITTENT, WITH ABNORMAL PYRUVATE METABOLISM
ATAXIA, INTERMITTENT, WITH PYRUVATE DEHYDROGENASE DEFICIENCY
Ataxia, Intermittent, with Pyruvate Dehydrogenase, or Decarboxylase, Deficiency
Deficiency of alpha-ketoacid carboxylase
Deficiency of pyruvate decarboxylase (disorder)
A urinary system disease that is located_in the bladder.
A metabolic acidosis characterized by buildup of lactate.
Deficiency Disease, Pyruvate Carboxylase
Deficiency of pyruvate carboxylase (disorder)
A mitochondrial metabolism disease characterized by progressive loss of mental and movement abilities. Symptoms usually begin between ages of three months and two years and include loss of appetite, vomiting, irritability and seizure activity.
ENCEPHALOMYELOPATHY, NECROTIZING, SUBACUTE
Encephalomyelitides, Subacute Necrotizing
Encephalomyelopathies, Subacute Necrotizing
Encephalomyelopathy, Subacute Necrotizing
Infantile necrotizing encephalomyelopathy
A lysosomal storage disease characterized by increased sialic acid in the urine.
N-acetylneuraminic acid (NANA) storage disease (NSD)
Sialic Acid Storage Disease [Disease/Finding]
A parasitic protozoa infectious disease that involves infection of humans and cattle caused by a genus of parasitic protozoa Theileria, which is transmitted by ixodid ticks.
An acquired metabolic disease that is characterized by an insufficient intake of food or of certain nutrients, by an inability of the body to absorb and use nutrients, or by overconsumption of certain foods.
6-100 NUTRITIONAL DISORDERS: GENERAL TERMS
A bilirubin metabolic disorder that involves a build up of bilirubin as bilirubin is not being broken down as a result of a lack or deficiency of the enzyme uridine diphosphate glycosyltransferase (UGT).
Bilirubin UDP glucuronyl transferase deficiency
Bilirubin UDP glucuronyl transferase deficiency (disorder)
Bilirubin glucuronosyltransferase deficiency
INTESTINAL POLYPOSIS-CUTANEOUS PIGMENTATION SYNDROME
Adrenal Cortex Diseases [Disease/Finding]
A parasitic helminthiasis infectious disease that involves infection of the intestine in goats, pigs and humans by the nematode Oesophagostomum bifurcum. The symptoms are a low-grade fever, tenderness in the lower-right quadrant and painless cutaneous masses in the lower abdominal region. Rarely, Oesophagostomum spp will perforate the bowel wall, causing purulent peritonitis or migrate to the skin, producing cutaneous nodules.
A primary bacterial infectious disease that is located_in lungs, located_in lymph nodes, located_in pericardium, located_in brain, located_in pleura or located_in gastrointestinal tract, has_material_basis_in Mycobacterium tuberculosis, which is transmitted_by droplets released into the air when an infected person coughs or sneezes.
A disease is a disposition (i) to undergo pathological processes that (ii) exists in an organism because of one or more disorders in that organism.
Clinical disease AND/OR syndrome present
Clinical disease or syndrome present, NOS
A ureteral disease that is characterized_as a congenital anomaly in which the distal end of the ureter swells as it enters the bladder.
A stomach disease that is an inflammation of the lining of the stomach.
A gastrointestinal system disease that is located_in the mouth.
A parasitic helminthiasis infectious disease that results_in infection located_in intestinal mucosa with larvae of the nematodes transmitted_by ingestion of raw or poorly cooked saltwater fish, has_material_basis_in Anisakis simplex or has_material_basis_in Pseudoterranova decipiens and has_symptom abdominal pain, has_symptom nausea and vomiting. Invasive anisakiasis results in the infection of omentum, pancreas, liver, and lung.
Eosinophilic gastroenteropathy (disorder)
A heart disease involving one or more of the four valves of the heart (the aortic and mitral valves on the left and the pulmonary and tricuspid valves on the right).
A parasitic ectoparasitic infectious disease that involves parasitic infestation of blood feeding ticks of the families Ixodidae and Argasidae on animals and humans. Ticks are vectors of a number diseases, including Lyme disease, Q fever, Colorado tick fever, tularemia, tick-borne relapsing fever, babesiosis, ehrlichiosis and tick-borne meningoencephalitis, as well as anaplasmosis in cattle and canine jaundice.
A parasitic infectious disease that is caused by organisms that live primarily on the surface of the host.
Ectoparasitic Infestations [Disease/Finding]
An integumentary system disease that is located_in nail.
A gallbladder disease characterized by altered tonus of the sphincter of Oddi, disturbance in the coordination of contraction of the biliary ducts, and/or reduction in the speed of emptying of the biliary tree.
Biliary dyskinesia (disorder) [Ambiguous]
A primary bacterial infectious disease that is a sexually transmitted systemic disease, has_material_basis_in Treponema pallidum subsp pallidum, which is transmitted_by sexual contact, transmitted_by blood product transfusion, transmitted_by congenital method from mother to fetus or transmitted_by contact with infectious lesions. If left untreated, produces chancres, rashes, and systemic lesions in a clinical course with three stages continued over many years.
An immune system disease that is an overactive immune response of the body against substances and tissues normally present in the body resulting from an abnormal functioning of the immune system that results in the production of antibodies or T cell directed against the host tissues.
Ankylosing spondylitis and other inflammatory spondylopathies
hypersensitivity reaction type II disease
AHO - Albright hereditary osteodystrophy
Albright hereditary osteodystrophy (AHO)
Disorder of glucose metabolism (disorder)
A hair disease characterized by hair growth that is abnormal in quantity or location.
An integumentary system disease that is located_in hair.
A female reproductive system disease that is characterized by the occlusion of some part of the female genital tract, especially occlusion of the vagina.
A viral infectious disease that is a hemorrhagic fever, has material basis in Zaire ebolavirus, has material basis in Sudan ebolavirus, has material basis in Cote d'Ivoire ebolavirus, or has material basis in Bundibugyo ebolavirus, which are transmitted by contact with the body fluids of an infected animal or person, transmitted by contaminated fomites, or transmitted by infected medical equipment. The infection has symptom fever, has symptom headache, has symptom joint pain, has symptom muscle aches, has symptom sore throat, has symptom weakness, has symptom diarrhea, has symptom vomiting, has symptom stomach pain, has symptom rash, has symptom red eyes, has symptom hiccups, and has symptom internal and external bleeding.
A viral infectious disease that is a hemorrhagic fever, has_material_basis_in Marburgvirus, which is transmitted_by contact with the body fluids of an infected person. The infection has_symptom fever, has_symptom chills, has_symptom headache, has_symptom myalgia, has_symptom maculopapular rash on the trunk, has_symptom nausea, has_symptom vomiting, has_symptom chest pain, has_symptom sore throat, has_symptom abdominal pain, has_symptom diarrhea, and has_symptom bleeding.
Burning Mouth Syndrome [Disease/Finding]
A female reproductive system disease that is characterized by epithelium-lined fluid-filled cysts in the adnexa adjacent to the fallopian tube and ovary.
Diverticulosis, Stomach [Disease/Finding]
A viral infectious disease that results_in inflammation located_in liver, has_material_basis_in Hepatitis E virus, which is transmitted_by ingestion of contaminated food. The infection has_symptom fever, has_symptom fatigue, has_symptom loss of appetite, has_symptom nausea, has_symptom vomiting, has_symptom abdominal pain, has_symptom clay-colored bowel movements, has_symptom dark urine, has_symptom joint pain, and has_symptom jaundice.
Enterically Transmitted Non A, Non B Hepatitis
Enterically transmitted non-A non-B hepatitis
Enterically-Transmitted Non-A, Non-B Hepatitis
A syndrome affecting returning military veterans and civilian workers of the Gulf War.
An influenza that results in infection located in respiratory tract of humans, domestic and wild birds, has material basis in Influenza A virus, which is transmitted by contact with infected poultry. Five strains of avian influenza A viruses (H5N1, H7N3, H7N2, H7N7 and H9N2) are known to cause human infections. The infection has symptom fever, has symptom cough, has symptom sore throat, has symptom muscle aches, has symptom nausea, has symptom diarrhea, has symptom vomiting, has symptom neurologic changes, has symptom pneumonia, and has symptom acute respiratory distress.
influenza A subtype H5N1 infection (diagnosis)
A genetic disease that is characterized by malformations of the face, oral cavity, and digits.
Orofaciodigital Syndromes [Disease/Finding]
A syndrome that affects growth, cranial development, hair growth and dental development.
A hair disease that is characterized by sparse hair on the scalp resulting from abnormal hair follicle development and has_material_basis in mutations in proteins involved in hair growth, division or proliferation of cells within hair follicles.
An amnestic disorder that involves a loss of one's pre-existing memories to conscious recollection.
A parasitic helminthiasis infectious disease that involves infection of the intestine with the nematode Ascaris lumbricoides. Larvae migrating through the lungs cause cough, wheezing and hemoptysis. Bowel or biliary obstruction causes cramping abdominal pain, nausea, and vomiting. Peritonitis, enlargement of the liver or spleen, toxicity and pneumonia are observed when larvae get into the portal circulation.
BIE - Bullous ichthyosiform erythroderma
BULLOUS CONGEN ICHTHYOSIFORM ERYTHRODERMA
BULLOUS CONGENITAL ICHTHYOSIFORM ERYTHRODERMA
BULLOUS ERYTHRODERMA ICHTHYOSIFORMIS CONGENITA OF BROCQ
Absence of Cerebral Hemispheres, Congenital
Cerebral Hemispheres, Absence, Congenital
Congenital Absence of Cerebral Hemispheres
A syndrome that is an adverse physical reaction to low levels of many common chemicals.
A disease of mental health that involves physical symptoms suggesting a physical illness where the biological or medical cause of the symptoms is indeterminate.
A reproductive system disease that affects male reproductive organs.
7-50 DISEASES OF THE MALE GENITAL ORGANS: GENERAL TERMS
DISEASES OF THE MALE GENITAL ORGANS: GENERAL TERMS
Disease of male genital organ (disorder)
A syndrome that is characterized by bone loss (osteolysis) which is often associated with swelling or abnormal blood vessel growth (angiomatous proliferation). Bone loss can occur in just one bone or spread to soft tissue and adjacent bones.
A viral infectious disease that results_in infection, has_material_basis_in Colorado tick fever virus, which is transmitted_by rocky mountain wood tick, Dermacentor andersoni. The infection has_symptom fever for 2-3 days, followed by an afebrile period of similar duration and then another 2-3 days of fever, has_symptom headache, has_symptom myalgia, and has_symptom fatigue.
An in situ carcinoma that derives_from epithelial cells of glandular origin.
Adenocarcinoma in Situ [Disease/Finding]
Adenocarcinoma in situ (morphologic abnormality)
A poliomyelitis that results in atrophy located in muscle, many years after the initial infection, has material basis in Human poliovirus 1, has material basis in Human poliovirus 2, or has material basis in Human poliovirus 3. It is characterized by new weakening in muscles that were previously affected by the polio infection and in muscles that were unaffected. The infection has symptom muscle weakness, has symptom muscle pain, has symptom sleep apnea, and has symptom breathing problems.
A viral infectious disease that results in destruction located in motor neurons, has material basis in Human poliovirus 1, has material basis in Human poliovirus 2, or has material basis in Human poliovirus 3, which are transmitted by ingestion of food or water contaminated with feces, or transmitted by direct contact with the oral secretions. The infection has symptom fever, has symptom sore throat, has symptom headache, has symptom vomiting, has symptom fatigue, has symptom neck stiffness, has symptom muscle spasms, and has symptom acute flaccid paralysis.
An anxiety disorder that involves discress but neither delusions nor hallucinations.
A nervous system disease that results_from damage located_in left parietal lobe, has_symptom agraphia, has_symptom acalculia, has_symptom finger agnosia.
Aphasia-angular gyrus syndrome (disorder)
A commensal bacterial infectious disease that results_in infection, has_material_basis_in Actinobacillus ureae, which is a commensal of the human respiratory tract. The pathogen causes meningitis, endocarditis, bacteremia, atrophic rhinitis, bronchitis, pneumonia, conjunctivitis, peritonitis, and otitis media.
Lymphatic edema (morphologic abnormality)
A poliomyelitis that results in destruction located in motor neurons, has material basis in Human poliovirus 1, has material basis in Human poliovirus 2, or has material basis in Human poliovirus 3, which are transmitted by ingestion of food or water contaminated with feces, or transmitted by direct contact with the oral secretions. The infection has symptom fever, has symptom sore throat, has symptom headache, has symptom vomiting, has symptom fatigue, has symptom neck stiffness, and has symptom muscle spasms.
Acute non-paralytic poliomyelitis, unspecified type poliovirus
Acute nonparalytic poliomyelitis (disorder)
Acute nonparalytic poliomyelitis, poliovirus, unspecified type
Acute nonparalytic poliomyelitis, unspecified type poliovirus
Anterior acute poliomyelitis specified as nonparalytic
Anterior acute poliomyelitis, nonparalytic
Epidemic acute poliomyelitis specified as non paralytic
A primary bacterial infectious disease that results_in infection, has_material_basis_in Burkholderia pseudomallei, which is transmitted_by contact with the contaminated water or soil. The infection has_symptom fever, has_symptom respiratory distress, has_symptom chest pain, and has_symptom stomach pain.
Infection due to Burkholderia pseudomallei
Infection due to Malleomyces pseudomallei
Infection due to Pseudomonas pseudomallei
Infection due to Pseudomonas pseudomallei NOS
A substance abuse that involves the recurring use of phencyclidine (PCP) drugs despite negative consequences.
A cell type benign neoplasm that has_material_basis_in glial-type cells.
Ganglioglioma, no ICD-O subtype (morphologic abnormality)
Ganglioglioma, no International Classification of Diseases for Oncology subtype
Ganglioglioma, no International Classification of Diseases for Oncology subtype (morphologic abnormality)
An organ system cancer located_in the thoracic cavity that develops in the different types of cells within the lungs, as well as less common cancers of the esophagus, the trachea, or the chest wall.
A viral infectious disease that results_in infection, which affects dopaminergic neurotransmission located_in central nervous system, has_material_basis_in Borna disease virus, which is transmitted_by contact with infected oronasal secretions. The infection has_symptom mood disturbances, has_symptom behaviour disturbances, has_symptom cognitive disturbances, has_symptom neurologic disturbances, and has_symptom movement impairment.
An in situ carcinoma that is located_in the endometrium.
Carcinoma in situ of endometrium (disorder)
A carbohydrate metabolic disorder that has_material_basis_in a deficiency of fructose-1,6-bisphosphatase resulting in hypoglycemia and metabolic acidosis on fasting due to insufficient fructose bisphosphatase for gluconeogenesis.
Deficiencies, Fructose-1,6-Bisphosphatase
Deficiencies, Fructose-1,6-Diphosphatase
A carbohydrate metabolic disorder that involves deficient or defective glycosylation of a variety of tissue proteins and/or lipids.
CDG - Carbohydrate-deficient glycoprotein syndrome
Carbohydrate Deficient Glycoprotein Syndrome
Carbohydrate deficiency glycoprotein syndrome
Carbohydrate-Deficient Glycoprotein Syndrome
Carbohydrate-Deficient Glycoprotein Syndromes
A viral infectious disease that results in destruction of immune system, leading to life-threatening opportunistic infections and cancers, has material basis in Human immunodeficiency virus 1 or has material basis in Human immunodeficiency virus 2, which are transmitted by sexual contact, transmitted by transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk, transmitted by congenital method, and transmitted by contaminated needles. The virus infects helper T cells (CD4+ T cells) which are directly or indirectly destroyed, macrophages, and dendritic cells. The infection has symptom diarrhea, has symptom fatigue, has symptom fever, has symptom vaginal yeast infection, has symptom headache, has symptom mouth sores, has symptom muscle aches, has symptom sore throat, and has symptom swollen lymph glands.
E-363-365 DISEASES DUE TO IMMUNODEFICIENCY VIRUS
HIV - Human immunodeficiency virus infection
human immunodeficiency virus infectious disease
A gastrointestinal system disease that is located_in the intestine.
5-40-45 DISEASES OF THE INTESTINAL TRACT
DISEASES OF THE SMALL AND LARGE INTESTINES
An endocrine system disease that is located_in the pituitary gland.
An amnestic disorder that involves the impaired or lost ability to memorize new things.
A viral infectious disease that results_in infection located_in mouth, has_material_basis_in human papillomavirus (types 13 or 32), has_symptom papules or nodules in the oral cavity.
Focal Epithelial Hyperplasia [Disease/Finding]
A psychotic disorder that is characterized by recurring episodes of mood fluctuations and a loss of contact with reality.
A psychotic disorder that is characterized by a disintegration of thought processes and of emotional responsiveness.
A pre-malignant neoplasm that is characterized by abnormal growth of dysplastic squamous epithelial cells on the surface of the eye that arises from the conjunctiva that is restricted within the epithelium.
CIN - conjunctival intraepithelial neoplasia
Conjunctival intraepithelial neoplasia (disorder)
Intraepithelial Neoplasia of Conjunctiva
Intraepithelial Neoplasia of the Conjunctiva
conjunctival intraepithelial neoplasia (diagnosis)
A parasitic ectoparasitic infectious disease that involves infestation of lice, which are blood-feeding ectoparasitic insects of the order Phthiraptera.
A urinary system disease that is located_in the kidney.
A syndrome characterized by overgrowth (macrosomia), an increased risk of childhood cancer and congenital malformations.
Beckwith-Wiedemann Syndrome [Disease/Finding]
Psychogenic inhibited male orgasm (finding)
Psychosexual dysfunction with inhibited male orgasm
inhibited male orgasmic disorder (diagnosis)
Nerve Compression Syndromes [Disease/Finding]
A nervous system disease that affects the peripheral nervous system.
DISORDERS OF THE PERIPHERAL NERVOUS SYSTEM
Disorder of peripheral nervous system NOS
Disorder of the peripheral nervous system
Disorder of the peripheral nervous system (disorder)
Disorder of the peripheral nervous system, NOS
Proteinuria syndrome (disorder) [Ambiguous]
Oral Submucous Fibrosis [Disease/Finding]
An organ system cancer located_in the retroperitoneal space that is manifested in retroperitoneal space in the abdominal cavity behind the peritoneum.
Neoplasm of the retroperitoneum (disorder)
Neoplasm of the retroperitoneum [dup] (disorder)
An anxiety disorder where fear and anxiety are triggered by a specific stimulus or situation.
An anxiety disorder that is characterized by unexpected and repeated episodes of intense fear accompanied by physical symptoms that may include chest pain, heart palpitations, shortness of breath, dizziness, or abdominal distress.
A breast disease that is characterized by a haphazard infiltration of small, uniformly open, and round glands which are lined by a monolayer of flat to cuboidal epithelial cells that lack a myoepithelial layer, the absence of stromal desmoplasia and the presence of a thickened basement membrane.
A heart disease that is characterized by any structural or functional cardiac disorder that impairs the ability of the heart to fill with or pump a sufficient amount of blood throughout the body.
3-16 HEART FAILURE AND OTHER FUNCTIONAL DISORDERS
A gastrointestinal system disease that is located_in the esophagus.
(Examination fear) or (flying phobia) or (stage fright) or (acute stress reaction NOS)
(Examination fear) or (flying phobia) or (stage fright) or (acute stress reaction NOS) (disorder)
An immune system disease that results when one or more essential parts of the immune system is missing or not working properly at birth due to a genetic mutation.
An in situ carcinoma that is located_in the nasal cavity.
Carcinoma in situ of nasal cavity (disorder)
A leukocyte disorder that is a decrease in the number of white blood cells (leukocytes) found in the blood, which places individuals at increased risk of infection.
Corneal intraepithelial neoplasia (disorder)
corneal intraepithelial neoplasia (diagnosis)
Blood Protein Disorders [Disease/Finding]
Gastrointestinal multiple polyposis syndrome
POLYPOSIS, SKIN PIGMENTATION, ALOPECIA, AND FINGERNAIL CHANGES
A primary immunodeficiency disease that is the result in a mutation of a gene encoding one of the thirty complement system proteins, produced predominantly in liver, which function to defend against infection and produce inflammation.
Complement deficiency disease (disorder)
A primary immunodeficiency disease that involves multiple components of the immune system, including both humoral immunity and cell-mediated immunity.
Combined immunity deficiency NOS (disorder)
combined T cell and B cell immunodeficiency
A disease that has_material_basis_in genetic variations in the human genome.
A Human immunodeficiency virus infectious disease that results_in reduction in the numbers of CD4-bearing helper T cells below 200 per ��L of blood or 14% of all lymphocytes thereby rendering the subject highly vulnerable to life-threatening infections and cancers, has_material_basis_in Human immunodeficiency virus 1 or has_material_basis_in Human immunodeficiency virus 2, which are transmitted_by sexual contact, transmitted_by transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk, transmitted_by congenital method, and transmitted_by contaminated needles. Opportunistic infections are common in people with AIDS.
AIDS - Acquired immunodeficiency syndrome
AIDS, Acquired Immunodeficiency Syndrome
A viral infectious disease that involves reactivation of JC polyomavirus in immune-compromised individuals which causes the loss of white matter (which is made up of myelin, a substance the surrounds and protects nerve fibers) in multiple areas of the brain. The symptoms include hemiparesis, aphasia, dysarthria, hemianopia, cognitive impairment and coma.
LEUKOENCEPHALOPATHY, PROGRESSIVE MULTIFOCAL
Leukoencephalopathies, Progressive Multifocal
progressive multifocal leukoencephalopathy
Encephalitis in viral disease NOS (disorder)
An inherited metabolic disorder involving dysfunction of purine and pyrimidine metabolism.
Other disorder of purine or pyrimidine metabolism NOS
Other disorder of purine or pyrimidine metabolism NOS (disorder)
Other disorders of purine and pyrimidine metabolism
Other disorders of purine and pyrimidine metabolism (disorder)
[X]Other disorders of purine and pyrimidine metabolism
Disorder of hyperalimentation (disorder)
A disease of metabolism that is characterized by enzyme deficiency or accumulation of enzymes or toxins which interfere with normal function due to inherited enzyme abnormality.
A cell type benign neoplasm that is composed_of epithelial tissue in which tumor cells form glands or glandlike structures.
A syndrome that occurs in human immunodeficiency virus (HIV) positive patients, which is accompanied by decreased kidney function. The spectrum of kidney involvement includes acute or chronic kidney disease, primarily tubular proteinuria and dense lymphocytic tubulointerstitial infiltrates predominantly composed of CD8 T cells.
DILS - diffuse infiltrative lymphocytosis syndrome
Diffuse Infiltrative Lymphocytosis Syndrome
Diffuse infiltrative lymphocytosis syndrome (disorder)
A syndrome that affects the teeth, nails, hair, and/or skin. It is characterized by absence (hypodontia) and/or malformation of certain primary (deciduous) and secondary (permanent) teeth occurring in association with improper development of the nails, particularly the toenails.
Hypoplastic enamel-onycholysis-hypohidrosis syndrome
Hypoplastic enamel-onycholysis-hypohidrosis syndrome (disorder)
A syndrome that involves arachnodactyly, receding lower jaw, and joint laxity limited to the hands and feet.
Arachnodactyly, receding lower jaw, and joint laxity limited to the hands and feet
Dysostoses and increased ligament laxity
Paroxysmal hematoma of the finger (disorder)
A syndrome that is characterized by congenital hypoplasia of lymph vessels, which causes lymphedema of the legs and recurrent cholestasis in infancy, and slow progress to hepatic cirrhosis and giant cell hepatitis with fibrosis of the portal tracts.
Cholestasis-edema syndrome, Norwegian type
Cholestasis-edema syndrome, Norwegian type (disorder)
A syndrome that involves occipital head aches, nystagmus on head movement, tinnitus, spasms, blurred vision, corneal hyperaesthesia, and corneal ulcers.
Posterior Cervical Sympathetic Syndrome [Disease/Finding]
An orofacial cleft characterized by a fissure of the soft and/or hard palate, due to faulty fusion of the two plates of the skull that form the hard palate.
(Palatoschisis) or (unspecified cleft palate)
(Palatoschisis) or (unspecified cleft palate) (disorder)
A disease that manifests in a defined anatomical structure.
An inherited metabolic disorder that involves mitochondrial metabolism dysfunction.
Mitochondrial Diseases [Disease/Finding]
Female urinary stress incontinence (finding)
An organ system benign neoplasm that is located_in the kidneys, ureteres, bladder or urethra.
A urinary system disease that is located_in the urethra.
Eosinophilic Hyperplastic Lymphogranuloma
Eosinophilic Hyperplastic Lymphogranulomas
Eosinophilic Lymphofollicular Granulomas
Granuloma, Eosinophilic Lymphofollicular
Granulomas, Eosinophilic Lymphofollicular
An immune system disease that has_material_basis_in hematopoietic cells.
A primary bacterial infectious disease that results_in infection located_in skin, located_in lung lymph nodes or located_in gastrointestinal tract, has_material_basis_in Bacillus anthracis, transmitted_by contact with infected animals or animal products, transmitted_by airborne spores or transmitted_by ingestion of undercooked meat from infected animals and has_symptom skin ulcer, has_symptom nausea, has_symptom poor appetite, has_symptom bloody diarrhea, has_symptom fever or has_symptom shortness of breath.
A parasitic helminthiasis infectious disease that involves infection of the anus by the pinworm Enterobius vermicularis. The major symptom is perianal itching. Infected people experience perianal pruritus and excoriations from scratching.
An intestinal disease characterized by the formation and inflammation of diverticula within the bowel wall.
Diverticulitis (morphologic abnormality)
An immune system disease that is located_in the lymphatic system.
Peptic Ulcer Perforation [Disease/Finding]
Peptic ulcer with perforation (disorder)
A primary bacterial infectious disease that is a sexually transmitted infection, located_in uterus, located_in fallopian tube, located_in urethra, located_in mouth, located_in throat, located_in eye or located_in anus, has_material_basis_in Neisseria gonorrhoeae, which is transmitted_by contact with the penis, vagina, mouth, or anus or transmitted_by congenitally from mother to baby during delivery. The infection has_symptom burning sensation during urination, has_symptom discharge from the penis, has_symptom increased vaginal discharge, or has_symptom vaginal bleeding between periods.
Complete transposition (morphologic abnormality)
A gastrointestinal system disease that is located_in the stomach.
A disease of anatomical entity that is located_in the gastrointestinal tract.
CHAPTER 5 DISEASES OF THE DIGESTIVE SYSTEM
DISEASES OF THE DIGESTIVE SYSTEM: GENERAL CONDITIONS
Digestive System Diseases [Disease/Finding]
A psychotic disorder that involves an uncommon psychiatric condition in which patients present with circumscribed symptoms of non-bizarre delusions, but with the absence of prominent hallucinations and no thought disorder, mood disorder, or significant flattening effect.
Infectious disorder of kidney (disorder)
Disease of larynx unspecified (disorder)
A parasitic ectoparasitic infectious disease that involves infestation of mites belonging to the family Sarcoptidae, Trombiculidae and Demodicidae.
Infestation by Sarcoptes scabiei var hominis
A thyroid gland disease that is characterized by excess thyroid hormone.
A thyroid gland disease that involves an over production of thyroid hormone.
A substance abuse that involves the recurring use of cocaine despite negative consequences.
A connective tissue disease that is characterized by marked reduction, absence, and/or the redistribution of adipose tissue.
A central nervous system disease that is characterized by neuron inflammation.
Intestinal Obstruction [Disease/Finding]
Postgastrectomy Syndromes [Disease/Finding]
A syndrome that is characterized by absence or underdeveloped tissue connecting the left and right halves of the brain, infantile spasms and chorioretinal lacunae, which are defects in the light-sensitive tissue at the back of the eye.
Agenesis of Corpus Callosum with Chorioretinal Abnormality
Agenesis of Corpus Callosum with Infantile Spasms and Ocular Abnormalities
A viral infectious disease that results in infection, located in respiratory tract, has material basis in Influenzavirus A, has material basis in Influenzavirus B, or has material basis in Influenzavirus C, which are transmitted by droplet spread of oronasal secretions during coughing, sneezing, or talking from an infected person. It is a highly contagious disease that affects birds and mammals and has symptom chills, has symptom fever, has symptom sore throat, has symptom runny nose, has symptom muscle pains, has symptom severe headache, has symptom cough, and has symptom weakness.
A commensal bacterial infectious disease that results in infection, which is characterized by contiguous spread, suppurative and granulomatous inflammation, and formation of multiple abscesses and sinus tracts that may discharge sulfur granules, has material basis in Actinomyces israelii, has material basis in Actinomyces gerencseriae, has material basis in Actinomyces naeslundii, has material basis in Actinomyces odontolyticus, has material basis in Actinomyces viscosus, has material basis in Actinomyces meyeri, has material basis in Propionibacterium propionicum, which require a break in the integrity of the mucous membranes and the presence of devitalized tissue to invade deeper body structures.
Active Rheumatic fever with unspecified type of heart involvement
Active rheumatic fever with heart involvement
Acute Rheumatic fever with unspecified type of heart involvement
Acute rheumatic fever with heart involvement
A lower respiratory tract disease in which the function of the lungs is adversely affected by narrowing or blockage of the airways resulting in poor air flow, a loss of elasticity in the lungs that produces a decrease in the total volume of air that the lungs are able to hold, and clotting, scarring, or inflammation of the blood vessels that affect the ability of the lungs to take up oxygen and to release carbon dioxide.
A female reproductive system disease that is characterized by a fluid-filled swelling in the Bartholin's glands.
A substance abuse that involves the recurring use of barbiturate drugs despite negative consequences.
Barbiturate and similarly acting sedative or hypnotic abuse, in remission
Sedative, hypnotic or anxiolytic abuse, in remission
CARDIOESOPHAGEAL RELAXATION, GASTROESOPHAGEAL REFLUX
A viral infectious disease that results_in infection located_in nerve fiber, has_material_basis_in Human herpesvirus 3, which reactivates after appearing as chickenpox in childhood. The virus is transmitted_by direct contact with the rash, which can develop into chickenpox in newly-infected individuals. The infection has_symptom rash which is followed by blisters, has_symptom headache, has_symptom fever, has_symptom malaise, has_symptom itching, has_symptom burning pain, and has_symptom paresthesia.
A syndrome that involves prolonged and severe tiredness or weariness that is unrelated to exertion, is not relieved by rest and for a minimum of six months and is not directly caused by other conditions.
A genetic disease that is characterized by a drastic and uncontrolled increase in skeletal muscle oxidative metabolism, which overwhelms the body's capacity to supply oxygen, remove carbon dioxide, and regulate body temperature.
A viral infectious disease that results_in_formation_of lesions, located_in mouth, located_in face, located_in genitalia, or located_in hands, has_material_basis_in Human herpesvirus 1 or has_material_basis_in Human herpesvirus 2, which are transmitted_by direct contact with an active lesion or body fluid of an infected person.
A viral infectious disease that results in inflammation, located in pharynx, has material basis in Human herpesvirus 4 and has symptom fever, has symptom fatigue, has symptom lymphadenopathy, and has symptom splenomegaly.
Gammaherpesviral mononucleosis (disorder)
An amino acid metabolic disorder that involves failures of carboxylation enzymes.
acute vascular insufficiency of intestine
An upper respiratory tract disease described as an acute contagious disease caused by Group A bacteria of the genus Streptococcus (especially various strains of S. pyogenes) and characterized by inflammation of the nose, throat, and mouth, generalized toxemia, and a red rash.
A herpes simplex that results_in infection located_in skin of the finger, toe, or thumb, has_material_basis_in Human herpesvirus 1 and has_material_basis_in Human herpesvirus 2 and has_symptom lesions, has_symptom fever, and has_symptom swollen lymph nodes.
A sleep disorder that involves recurring bouts of excessive amounts of sleepiness.
diplegia upper extremities (physical finding)
A viral infectious disease that results_in infection located_in skin, has_material_basis_in Measles virus, which is transmitted_by contact with oronasal secretions, or semen of an infected person. The infection has_symptom fever, has_symptom cough, has_symptom coryza, has_symptom conjunctivitis, and has_symptom maculopapular, erythematous rash.
A physical disorder that is the result of structural, biochemical or electrical abnormalities in the brain or spinal cord, or in the nerves leading to or from them, can result in symptoms such as paralysis, muscle weakness, poor coordination, loss of sensation, seizures, confusion, pain and altered levels of consciousness.
Diseases of the nervous system (G00-G99)
Chronic intestinal ischaemic syndrome, NOS
chronic intestinal vascular insufficiency
An in situ carcinoma that is located_in the prostate.
Carcinoma in situ of prostate (disorder)
Other specified gastritis NOS (disorder)
Other specified transient mental disorders due to conditions classified elsewhere, other
Other specified transient organic mental disorder
Other specified transient organic mental disorders
A vascular disease that is characterized by inflammation of the blood vessels.
A viral infectious disease that results_in infection located_in skin, has_material_basis_in Human herpesvirus 3, which is transmitted_by direct contact with secretions from the rash, or transmitted_by droplet spread of respiratory secretions. The infection has_symptom anorexia, has_symptom myalgia, has_symptom nausea, has_symptom fever, has_symptom headache, has_symptom sore throat, and has_symptom blisters.
Varicella with no complication NOS (disorder)
Varicella without mention of complication
A vascular disease that is located_in a vein.
Other venous embolism and thrombosis (disorder)
An in situ carcinoma that is located_in the lip.
Carcinoma in situ of lip, oral cavity and pharynx
Carcinoma in situ of lip, oral cavity and pharynx (disorder)
Carcinoma in situ of lip, oral cavity and pharynx NOS
Carcinoma in situ of lip, oral cavity and pharynx NOS (disorder)
Carcinoma in situ of lip, oral cavity and/or pharynx
Carcinoma in situ of lip, oral cavity and/or pharynx (disorder)
Carcinoma in situ of lip, oral cavity, and pharynx
A specific developmental disorder that is characterized by abnormal eating habits that may involve either insufficient or excessive food intake to the detriment of an individual's physical and emotional health.
Enterocolitis, Necrotizing [Disease/Finding]
Necrotizing enterocolitis in fetus OR newborn
A carcinoma in situ that is characterized by the spread of cancer in skin and the lack of invasion of surrounding tissues.
Carcinoma in situ of skin NOS (disorder)
Carcinoma in situ of skin, site unspecified
A nervous system disease that is located_in nerves or nerve cells.
A herpes simplex that results_in infection located_in genital system, or located_in rectum, has_material_basis_in Human herpesvirus 1 or has_material_basis_in Human herpesvirus 2, which is transmitted_by sexual contact. The infection has_symptom sores, has_symptom fever, and has_symptom swollen glands.
A carcinoma that is an early development defined by the absence of invasion of surrounding tissues.
A dementia that involves impairments in cognitive function caused by problems in blood vessels that feed the brain.
A viral infectious disease that results_in infection of cattle and humans, located_in skin, has_material_basis_in Pseudocowpox virus, which is transmitted_by contact with the infected cow teats, or transmitted_by fomites. The infection results_in_formation_of lesions on the fingers, hands, and forearms and has_symptom fever, has_symptom lymphangitis, and has_symptom lymphadenopathy.
A viral infectious disease that results_in infection located_in skin, has_material_basis_in Rubella virus, which is transmitted_by droplet spread of oronasal secretions from the infected person through coughing and sneezing, and transmitted_by congenital method. The infection has_symptom rash on the face which spreads to the trunk and limbs, has_symptom fever, has_symptom lymphadenopathy, has_symptom joint pains, has_symptom headache, and has_symptom conjunctivitis.
An in situ carcinoma that is located_in the breast.
Breast Carcinoma In Situ [Disease/Finding]
A carcinoma in situ that is characterized by the spread of cancer in the eye and the lack of invasion of surrounding tissues.
carcinoma in situ of eyeball (diagnosis)
An in situ carcinoma that is located_in the lung.
Carcinoma in situ of bronchus and lung (disorder)
Carcinoma in situ of bronchus or lung NOS
Carcinoma in situ of bronchus or lung NOS (disorder)
An in situ carcinoma that is located_in the trachea.
An in situ carcinoma that is located_in the colon.
Carcinoma in situ of colon NOS (disorder)
A parasitic infectious disease that occurs when part of the body is infested with parasitic worms such as cestodes, nematodes and trematodes.
A parasitic helminthiasis infectious disease that involves parasitic infection of the bile ducts of the liver by Fasciola hepatica or Fasciola gigantica. During the acute phase, manifestations include abdominal pain, hepatomegaly, fever, vomiting, diarrhea, urticaria and eosinophilia. Occasionally, infection occurs in intestinal wall, lungs, subcutaneous tissue, and pharyngeal mucosa.
Actinic keratosis (morphologic abnormality)
A viral infectious disease that results_in infection located_in skin, has_material_basis_in Molluscum contagiosum virus, which is transmitted_by contact with the skin, and transmitted_by fomites. The infection has_symptom lesions which are flesh-colored with a pit in the center.
An in situ carcinoma that is located_in the penis.
A parasitic helminthiasis infectious disease that involves parasitic infection of the intestine by Fasciolopsis buski. The symptoms include diarrhea, abdominal pain, fever, ascites, anasarca and intestinal obstruction.
A superficial mycosis that is a superficial fungal infection of the skin characterized by brown to black macules which usually occur on the palmar aspects of hands and occasionally the plantar and other surfaces of the skin, caused by Hortaea werneckii, which is a common saprophytic fungus believed to occur in soil, compost, humus and on wood in humid tropical and sub-tropical regions.
Infection by Cladosporium werneckii (disorder)
Infection caused by Cladosporium werneckii
Infection caused by Cladosporium werneckii (disorder)
Nigra: [tinea] or [keratomycosis] (disorder)
A cutaneous mycosis that results_in fungal infection located_in skin, located_in hair, and located_in nail, has_material_basis_in Epidermophyton, has_material_basis_in Microsporum, or has_material_basis_in Trichophyton, which invade the dead keratin and has_symptom itchy patches, and has_symptom red rash on the skin.
A specific developmental disorder that involves difficulty in scholastic skills such as reading, writing, spelling, reasoning, recalling and/or organizing information resulting from the brain's inability to receive and process information.
Dupuytren's contracture of foot (disorder)
A viral infectious disease that results_in infection in rodents, cows, and humans, located_in skin, has_material_basis_in Cowpox virus, which is transmitted_by contact with an infected animal. The infection results_in_formation_of vesicopustular lesions on the hands or face.
An inherited metabolic disorder that involves metabolic disturbances in the processing or distribution of dietary minerals.
Metal Metabolism, Inborn Errors [Disease/Finding]
A viral infectious disease that results_in infection located_in brain, has_material_basis_in Measles virus which is immune resistant (which can be a result of a mutation of the virus itself).
A sleep disorder that involves an excessive urge to sleep at inappropriate times, such as while at work.
An in situ carcinoma that is located_in the uterine cervix.
CERVICAL INTRAEPITHELIAL NEOPL GRADE III
CIN 3 - Cervical intraepithelial neoplasia grade 3
A syndrome that is characterized by the sudden death of an infant that is not predicted by medical history and remains unexplained after a thorough forensic autopsy and detailed death scene investigation.
A syndrome that occurs in humans with psoriasis who also experience symptoms similar to arthritis.
An in situ carcinoma that is located_in the larynx.
Carcinoma in situ of larynx NOS (disorder)
An in situ carcinoma that is located_in the intestine.
Carcinoma in situ of other and unspecified parts of intestine
Carcinoma in situ/other+unspecified parts of intestine
Other and unspecified parts of intestine
[X]Carcinoma in situ of other and unspecified parts of intestine
[X]Carcinoma in situ of other and unspecified parts of intestine (disorder)
[X]Carcinoma in situ/other+unspecified parts of intestine
A peroxisomal disease that is characterized by the reduction or absence of functional peroxisomes in the cells of an individual that has_material_basis_in autosomal recessive inheritance of a mutation in the peroxisome biogenesis factor (PEX) genes.
PEROXISOME BIOGENESIS DISORDER 1A (ZELLWEGER)
An in situ carcinoma that is located_in the bladder.
An inherited metabolic disorder that involves peroxisome malfunction.
Disorder of peroxisomal function (disorder)
A superficial mycosis that is a chronic, superficial fungal infection of the skin caused by Malassezia furfur, which is characterized by well-demarcated white, pink, fawn, or brownish lesions, often coalescing, and covered with thin furfuraceous scales.
A commensal bacterial infectious disease that is characterized by widespread erythema, peeling, and necrosis of the skin, that is caused by a toxin produced by a bacterium of the genus Staphylococcus (S. aureus). The infection has_symptoms redness of skin, has_symptom fluid-filled blister formation, has_symptom fever and has_symptom irritability.
A lupus erythematosus that is an inflammation of connective tissue marked by skin rashes, joint pain and swelling, inflammation of the kidneys and inflammation of the tissue surrounding the heart.
A B-cell lymphocytic neoplasm characterized by an uncontrolled increase of B-cells.
An in situ carcinoma that is located_in the anus.
Anal intraepithelial neoplasia grade III
Anal intraepithelial neoplasia grade III (disorder)
Anal intraepithelial neoplasia, grade III
A sleep disorder that involves abnormal behavior including the acting out of violent or dramatic dreams during the sleep phase with rapid eye movement.
Behavior Disorder, Rapid Eye Movement Sleep
An in situ carcinoma that is located_in the esophagus.
Carcinoma in situ of esophagus (disorder)
Erythematosquamous dermatosis (disorder)
Erythematosquamous dermatosis NOS (disorder)
erythematosquamous dermatosis (diagnosis)
An in situ carcinoma that is located_in the uterus.
Carcinoma in situ of other and unspecified parts of uterus
Carcinoma in situ of other and unspecified parts of uterus (disorder)
A primary bacterial infectious disease that results_in infection located_in skin or located_in mucosa of genital tract, has_material_basis_in Klebsiella granulomatis, transmitted by sexual contact or transmitted_by contact with the open sores. The infection has_symptom painless genital ulcers.
(Granuloma inguinale) or (donovanosis) or (pudendal ulcer)
(Granuloma inguinale) or (donovanosis) or (pudendal ulcer) (disorder)
Calymmatobacterium granulomatis infection
An acquired metabolic disease that involves abnormal deposited of amyloid proteins in organs and/or tissues.
Eczema herpeticum (disorder) [Ambiguous]
An in situ carcinoma that is located_in the liver.
Carcinoma in situ of liver and biliary system
Carcinoma in situ of liver and biliary system (disorder)
Carcinoma in situ of liver and/or biliary system
Carcinoma in situ of liver and/or biliary system (disorder)
Carcinoma in situ of liver or biliary system NOS
Carcinoma in situ of liver or biliary system NOS (disorder)
Carcinoma in situ of liver, gallbladder and bile ducts
An in situ carcinoma that is located_in the stomach.
Carcinoma in situ of stomach NOS (disorder)
A smallpox that results_in milder infection, located_in skin, has_material_basis_in Variola virus. The infection results_in_formation_of lesions.
A commensal bacterial infectious disease that results in infection, located in muscle tissue, has material basis in Clostridium perfringens, which produce gas that becomes trapped in the infected tissue. Gas gangrene usually develops after injuries or surgery. The infection has symptom large blisters, has symptom pain in the infected area, has symptom myonecrosis, has symptom gas production, and has symptom sepsis.
Clostridial myositis as a result of gas gangrene
An esophageal disease that is characterized by an inability of the esophagus to move food toward the stomach resulting from the lower esophogeal sphincter not fully relaxing during swallowing.
ECZEMA-THROMBOCYTOPENIA-IMMUNODEFICIENCY SYNDROME
Eczema Thrombocytopenia Immunodeficiency Syndrome
Eczema, thrombocytopenia, immunodeficiency syndrome
Eczema-Thrombocytopenia-Immunodeficiency Syndromes
An in situ carcinoma that is located_in the rectum.
A parasitic protozoa infectious disease that involves infection caused by the amoeba Entamoeba histolytica. Amebic invasion of the intestinal lining causes dysentery, colitis or diarrhea. The infection can also spread through the blood to the liver and, rarely, to the lungs, brain or other organs.
A sleep disorder that involves involuntary limb movement during sleep.
EXCESSIVE PERIODIC SLEEP RELAT LEG MOVEMENTS
Excessive Periodic Sleep Related Leg Movements
Excessive Periodic Sleep-Related Leg Movements
Nocturnal Myoclonus Syndrome [Disease/Finding]
PERIODIC LEG MOVEMENTS EXCESSIVE SLEEP RELAT
A viral infectious disease that results_in inflammation located_in facial nerve, which leads to paralysis of one side of the face, has_material_basis_in Human herpesvirus 3, which reactivates after appearing as chickenpox in childhood. The infection has_symptom vesicular rash of the ear or mouth, has_symptom tinnitus, has_symptom vertigo, has_symptom otalgia, and has_symptom headache.
(Geniculate herpes zoster) or (Ramsey Hunt syndrome)
(Geniculate herpes zoster) or (Ramsey Hunt syndrome) (disorder)
A sleep apnea that is characterized by a malfunction of the basic neurological controls for breathing rate and the failure to give the signal to inhale, causing the individual to miss one or more cycles of breathing.
An in situ carcinoma that is located_in the kidney.
Carcinoma in situ of other and unspecified urinary organs
[X]Carcinoma in situ of other and unspecified urinary organs
[X]Carcinoma in situ of other and unspecified urinary organs (disorder)
Cerebral Amyloid Angiopathy [Disease/Finding]
Cerebroacrovisceral Early Lethality Complex
HYPOTHALAMIC HAMARTOBLASTOMA, HYPOPITUITARISM, IMPERFORATE ANUS, AND POSTAXIAL POLYDACTYLY
A syndrome that results_in multiple congenital anomalies, including hydrops fetalis, facial and visceral abnormalities, short ribs, and short limbs without polydactyly.
Beemer-Langer type short rib polydactyly syndrome
A syndrome that is an autosomal recessive disorder, which is characterized by corpus callosum agenesis, polydactyly, multiple dysmorphic features, motor and mental retardation.
HALLUX DUPLICATION, POSTAXIAL POLYDACTYLY, AND ABSENCE OF CORPUS CALLOSUM
An inherited metabolic disorder that is characterized by impaired synthesis and degradation of amino acids.
Amino Acid Metabolism, Inborn Errors [Disease/Finding]
An amino acid metabolic disorder that involves an accumulation of homocysteine in the serum and an increased excretion of homocysteine in the urine.
An amino acid metabolic disorder that involves deficiency in histidine.
Disorder of histidine metabolism (disorder)
Disorders of histidine metabolism, unspecified
Disturbance of histidine metabolism NOS (disorder)
An amino acid metabolic disorder that involves the formation of cystine stones in the kidneys, ureter, and bladder.
An amino acid metabolic disorder that involves a deficiency of one of the enzymes in the urea cycle which is responsible for removing ammonia from the blood stream.
6-A5 DISORDERS OF THE UREA CYCLE METABOLISM
Disorder of the urea cycle metabolism (disorder)
Disorder of the urea cycle metabolism, NOS
Disorder of urea cycle metabolism, unspecified
An amino acid metabolic disorder that involves abnormally high levels of the amino acid glycine in bodily fluids and tissues.
Disorder of glycine cleavage enzyme complex
An amino acid metabolic disorder that involves phenylalanine and tyrosine metabolism with the accumulation of homogentisic acid, a toxic tyrosine byproduct.
An amino acid metabolic disorder that involves an abnormal increase of lysine in the blood.
Deficiencies, L-Lysine:NAD-Oxido-Reductase
Deficiencies, Lysine:Alpha-Ketoglutarate Reductase
Deficiency, L-Lysine:NAD-Oxido-Reductase
Deficiency, Lysine:Alpha-Ketoglutarate Reductase
An amino acid metabolic disorder that involves impaired break down of the amino acid tyrosine.
An amino acid metabolic disorder that involves an abnormally large level of homocysteine in the blood.
An amino acid metabolic disorder that involves accumulation of ammonia in the blood.
CARBAMOLY PHOSPHATE SYNTHETASE I DEFIC DIS
CARBAMOYL PHOSPHATE SYNTHASE AMMONIA DEFIC DIS
CARBAMOYL PHOSPHATE SYNTHASE I DEFIC DIS
CARBAMOYL PHOSPHATE SYNTHETASE I DEFICIENCY
CARBAMOYLPHOSPHATE SYNTHETASE I DEFIC DIS
CARBAMYL PHOSPHATE SYNTHETASE I DEFIC DIS
carbamoyl phosphate synthetase I deficiency disease
An amino acid metabolic disorder that is characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional.
Complete unilateral cleft lip (disorder)
Unilateral complete cleft lip (situation)
A parasitic helminthiasis infectious disease that involves zoonotic infection caused by Moniezia expansa, the common tapeworm of sheep.
A lymphatic system disease that is characterized by inflammation of the lymphatic channels which occurs as a result of infection at a site distal to the channel. It is caused by Streptococcus pyogenes (Group A strep) or Staphylococcus aureus. Lymphangitis is also sometimes called blood poisoning.
A disease by infectious agent that results in infection, has material basis in Viruses.
A central nervous system disease that is located_in the brain.
Seminal vesiculitis unspecified (disorder)
A syndrome that is a chronic unilateral (or rarely bilateral) iridocyclitis appearing with the triad of heterochromia, predisposition to cataracts and glaucoma, and keratitic percipitates on the posterior corneal surface.
Fuchs' heterochromic cyclitis (diagnosis)
Fuchs' heterochromic cyclitis (disorder)
An upper respiratory tract disease which involves inflammation of the epiglottis due to infection. Haemophilus influenzae type B is the most common bacterial causative agent, although some cases are attributable to Streptococcus pneumoniae or Streptococcus pyogenes. The infection can cause the epiglottis to either obstruct or completely close off the windpipe. Epiglottitis typically affects children, and is associated with fever, difficulty in swallowing, drooling, hoarseness of voice, and stridor.
A pituitary gland disease characterized by the decreased secretion of one or more of the eight hormones normally produced by the pituitary gland.
Anterior Pituitary Hyposecretion Syndrome
Deficient secretion of one OR more pituitary hormones
A lysosomal storage disease that involves the accumulation of harmful amounts of lipids (fats) in some of the body's cells and tissues.
A parasitic protozoa infectious disease that involves infection of the large intestine by a protozoan parasite Dientamoeba fragilis. The symptoms include diarrhea, stomach pain and cramping, loss of appetite and weight, nausea, and fatigue.
A central nervous system disease that is characterized by an inflammation of the pia-arachnoid meninges. It can be caused by growth of bacteria, fungi, or parasites within the subarachnoid space or by the growth of bacteria or viruses within the meningeal or ependymal cells.
Meningitis of unspecified cause (disorder)
(Meckel's diverticulum) or (persistent omphalomesenteric duct) or (persistent vitelline duct)
(Meckel's diverticulum) or (persistent omphalomesenteric duct) or (persistent vitelline duct) (disorder)
(Persistent omphalomesenteric duct) or (persistent vitelline duct)
(Persistent omphalomesenteric duct) or (persistent vitelline duct) (disorder)
C-40 WHITE BLOOD CELL DISORDERS: GENERAL TERMS
Disease of white blood cells, unspecified
Disorder of white blood cells, unspecified
A substance abuse that involves the recurring use of cannabis despite negative consequences.
A viral infectious disease that results_in infection, has_material_basis_in Lassa virus, which is transmitted_by multimammate rat of the genus Mastomys. The infection has_symptom fever, has_symptom retrosternal pain, has_symptom sore throat, has_symptom back pain, has_symptom cough, has_symptom abdominal pain, has_symptom vomiting, has_symptom diarrhea, has_symptom conjunctivitis, has_symptom facial swelling, has_symptom proteinuria (protein in the urine), and has_symptom mucosal bleeding.
Disorder of blood vessels affecting skin
SECTION 0-3 VASCULAR DISEASES OF THE SKIN
Skin Diseases, Vascular [Disease/Finding]
An endocrine system disease that is located_in the adrenal gland.
Adrenal Gland Diseases [Disease/Finding]
A ciliopathy that is characterized by impaired function of the cilia lining the respiratory tract (lower and upper, sinuses, Eustachian tube, middle ear) and fallopian tube.
Ciliary Motility Disorders [Disease/Finding]
A viral infectious disease that results_in inflammation located_in brain of horses and humans, has_material_basis_in Venezuelan equine encephalitis virus, which is transmitted_by Culex mosquitoes. The infection has_symptom fever, has_symptom chills, has_symptom malaise, has_symptom severe headache, has_symptom photophobia, and has_symptom myalgia in the legs and lumbosacral region.
Disorder caused by Venezuelan equine encephalitis virus
Disorder caused by Venezuelan equine encephalitis virus (disorder)
Disorder due to Venezuelan equine encephalitis virus
Disorder due to Venezuelan equine encephalitis virus (disorder)
A urinary system disease that is located_in the lower urinary tract and is characterized by the formation of a stone.
Calculus of lower urinary tract (disorder)
Calculus of lower urinary tract, unspecified
Lower urinary tract calculus NOS (disorder)
A primary bacterial infectious disease that results_in infection located_in intestine caused by eating food contaminated with enterotoxins produced by bacteria, has_material_basis_in Staphylococcus aureus. The infection has_symptom diarrhea, has_symptom vomiting, has_symptom nausea, has_symptom cramps, and has_symptom weakness.
Food poisoning caused by staphylococcus (disorder)
Food poisoning due to staphylococcus (disorder)
A ureteral disease characterized by backward flow of urine from the urinary bladder into the ureter.
Inflammatory condition of oral mucous membrane
A parasitic protozoa infectious disease that has_symptom mild fevers and has_symptom anemia described as malaria-like symptoms caused by a protozoan of genus Babesia, which reproduce in red blood cells and cause hemolytic anemia. They are transmitted by Ixodid ticks or by blood transfusion. Babesiosis is a zoonotic disease.
Leukoplakia and other disturbances of oral epithelium, including tongue
Leukoplakia of oral mucosa, including tongue
A viral infectious disease that results in infection, has material basis in Yellow fever virus, which is transmitted by Aedes, transmitted by Haemagogus, or transmitted by Sabethes species of mosquitoes. The infection has symptom fever, has symptom muscle pain, has symptom backache, has symptom headache, has symptom shivers, has symptom loss of appetite, has symptom jaundice, and has symptom bleeding from the mouth, nose, eyes or stomach leading to vomitus containing blood.
Obstruction of gallbladder NOS (disorder)
Biliary Tract Diseases [Disease/Finding]
A syndrome that is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause.
A parasitic helminthiasis infectious disease that involves parasitic infection of animals and humans by Trichinella spiralis, Trichinella nativa or Trichinella britovi. Intestinal invasion causes diarrhea, abdominal pain and vomiting. Larval migration into muscle tissues can cause periorbital and facial edema, conjunctivitis, fever, myalgias, splinter hemorrhages, rashes, and blood eosinophilia. Myocarditis, central nervous system involvement, and pneumonitis can also occur.
Other and unspecified helminthiases (disorder)
A parasitic helminthiasis infectious disease that involves zoonotic infection of humans by the larvae of Toxocara canis or Toxocara cati. The larvae invade multiple tissues like liver, heart, lungs, brain, muscle and eyes causing various symptoms including fever, anorexia, weight loss, cough, wheezing, rashes, hepatosplenomegaly, hypereosinophilia and ophthalmologic lesions.
A withdrawal disorder that is characterized by a group of problems that occur in a newborn who was exposed to addictive illegal or prescription drugs while in the mother's womb or postnatally following the discontinuance of drug treatment.
Drug withdrawal syndrome in newborn (disorder)
Neonatal Abstinence Syndrome [Disease/Finding]
Intestinal Disaccharidase Deficiency and Disaccharide Malabsorption
Intestinal disaccharidase deficiencies and disaccharide malabsorption
hereditary fructose intolerance syndrome
A carbohydrate metabolic disorder that involves a defect in galactose metabolism resulting in toxic levels of galactose 1-phosphate in various tissues.
A viral infectious disease that is a hemorrhagic fever, has_material_basis_in Omsk hemorrhagic fever virus, which is transmitted_by Dermacentor and transmitted_by Ixodes species of ticks. The infection has_symptom fever, has_symptom chills, has_symptom headache, has_symptom pain in lower and upper extremities, has_symptom stiff neck, has_symptom papulovesicular rash on the soft palate, has_symptom cervical lymphadenopathy, has_symptom conjunctival suffusion, has_symptom blood in the urine, and has_symptom blood in the sputum.
Hemorrhagic Fever, Omsk [Disease/Finding]
A specific developmental disorder that involves disordered motor skills where coordinated muscle movement is impaired.
Developmental coordination disorder (disorder)
An adrenal gland disease that is characterized by failure of the adrenal gland due to bleeding into the gland.
Purpura Fulminans (Waterhouse-Friderichsen Syndrome)
Waterhouse-Friderichsen Syndrome [Disease/Finding]
Deviation from the norm of height with respect to that which is expected according to age and gender norms.
An abnormal functionality of the genital system.
Abnormality of reproductive system physiology
A height above that which is expected according to age and gender norms.
The presence of any abnormality of the genitourinary system.
Congenital Abnormality of the Genitourinary System
Prolonged and excessive menses at regular intervals in excess of 80 mL or lasting longer than 7 days.
Abnormally heaving bleeding during menstruation
Bleeding of subgingival space (disorder)
An abnormality of the sensory perception of sound.
Congenital anomaly of neck NOS (disorder)
Pterygium colli is a congenital skin fold that runs along the sides of the neck down to the shoulders. It involves an ectopic fibrotic facial band superficial to the trapezius muscle. Excess hair-bearing skin is also present and extends down the cervical region well beyond the normal hairline.
Congenital neck webbing, unspecified (disorder)
Congenital webbing of neck NOS (disorder)
An increased amount of subcutaneous fat tissue around the neck.
Increased adipose tissue around the neck
Increased inferior-superior length of the neck.
A thickening of the skin thickness in the posterior aspect of the fetal neck. A nuchal fold measurement is obtained in a transverse section of the fetal head at the level of the cavum septum pellucidum and thalami, angled posteriorly to include the cerebellum. The measurement is taken from the outer edge of the occiput bone to the outer skin limit directly in the midline. A measurement 6 mm or more is considered significant between 18 and 24 weeks and a measurement of 5 mm or more is considered significant at 16 to 18 weeks (pmid:16100637).
Increased side-to-side width of the neck.
Any abnormality of the eye, including location, spacing, and intraocular abnormalities.
CONGENITAL ANOMALIES OF THE EYE AND ORBIT
Congenital Diseases and Syndromes of Eye
Congenital abnormality of eye (disorder)
An abnormality in voluntary or involuntary eye movements or their control.
Abnormal motility of the globe of the eye
Abnormal movement of the globe of the eye
Glaucoma refers loss of retinal ganglion cells in a characteristic pattern of optic neuropathy usually associated with increased intraocular pressure.
Abnormality of eyesight (visual perception).
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
An abnormality in the process of focusing of light by the eye in order to produce a sharp image on the retina.
An abnormality of the uvea, the vascular layer of the eyeball.
A developmental defect characterized by a cleft of some portion of the eye or ocular adnexa.
COI - Coloboma of iris, choroid and retina
An anomaly of the pharynx, i.e., of the tubular structure extending from the base of the skull superiorly to the esophageal inlet inferiorly.
Atrophy of the eyeball with blindness and decreased intraocular pressure due to end-stage intraocular disease.
4-90 CONGENITAL ANOMALIES OF THE NERVOUS SYSTEM: GENERAL TERMS
Abnormalities, Congenital, Nervous System
An abnormality of mental functioning including various affective, behavioural, cognitive and perceptual abnormalities.
Abnormality of nervous system physiology
An abnormality of the peripheral nervous system, which is composed of the nerves that lead to or branch off from the central nervous system. This includes the cranial nerves (olfactory and optic nerves are technically part of the central nervous system).
Abnormality of nervous system morphology
Abnormal peripheral nervous system morphology
Abnormal development of large mammary glands in males resulting in breast enlargement.
Any abnormality of the diaphragm, the sheet of skeletal muscle that separates the thoracic cavity from the abdominal cavity.
The presence of a hernia of the diaphragm present at birth.
Abnormality of the thymus, an organ located in the upper anterior portion of the chest cavity just behind the sternum and whose main function is to provide an environment for T lymphocyte maturation.
Congenital absence of the normal opening of a structure of the urinary tract.
An abnormality of the tricarboxylic acid cycle.
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Passing the age when puberty normally occurs with no physical or hormonal signs of the onset of puberty.
Delay in sexual development AND/OR puberty
Delay in sexual development AND/OR puberty (disorder)
Delay in sexual development AND/OR puberty (finding)
Insufficient production of growth hormone, which is produced by the anterior pituitary gland. Growth hormone is a major participant in control of growth and metabolism.
Abnormality of circulating hormone level
An abnormality of the parathyroid gland.
A type of diabetes mellitus related not to lack of insulin but rather to lack of response to insulin on the part of the target tissues of insulin such as muscle, fat, and liver cells. This type of diabetes is typically associated with increases both in blood glucose concentrations as will as in fasting and postprandial serum insulin levels.
Abnormality of the adrenal glands, i.e., of the endocrine glands located at the top of the kindneys.
Adrenogenital syndrome is also known as congenital adrenal hyperplasia, which results from disorders of steroid hormone production in the adrenal glands leading to a deficiency of cortisol. The pituitary gland reacts by increased secretion of corticotropin, which in turn causes the adrenal glands to overproduce certain intermediary hormones which have testosterone-like effects.
Adrenal Hyperplasia, Congenital [Disease/Finding]
Adrenal hyperplasia syndrome, congenital
An abnormally increased activity of the renin-angiotensin system, causing hypertension by a combination of volume excess and vasoconstrictor mechanisms.
An abnormality of the renin-angiotensin system.
Abnormality of the renin-aldosterone axis
A form of diabetes insipidus related to a failure of vasopressin (AVP) release from the hypothalamus.
Abnormality of the pituitary gland (also known as hypophysis), which is an endocrine gland that protrudes from the bottom of the hypothalamus at the base of the brain. The pituitary gland secretes the hormones ACTH, TSH, PRL, GH, endorphins, FSH, LH, oxytocin, and antidiuretic hormone. The secretion of hormones from the anterior pituitary is under the strict control of hypothalamic hormones, and the posterior pituitary is essentially an extension of the hypothalamus, so that hypothalamus and pituitary gland may be regarded as a functional unit.
Abnormality of the hypothalamus-pituitary axis
A state of excessive water intake and hypotonic (dilute) polyuria. Diabetes insipidus may be due to failure of vasopressin (AVP) release (central or neurogenic diabetes insipidus) or to a failure of the kidney to respond to AVP (nephrogenic diabetes insipidus).
The bones of the skeleton undergo a series of characteristic changes in size, shape, and calcification from fetal life until puberty. An abnormality of this process can include delayed or accelerated skeletal maturation, or deviation of some, but not all bones from the expected patterns of maturation.
An abnormality of the skull, the bony framework of the head which is comprised of eight cranial and fourteen facial bones.
Radiographic evidence of articular calcification that represent calcium pyrophosphate depositions in soft tissue surrounding joints and at the insertions of tendons near joints (Entheses/Sharpey fibers) .
CPDD - Calcium pyrophosphate deposition disease
CPPD - Calcium pyrophosphate deposition disease
An abnormal accumulation of fluid beneath the skin, or in one or more cavities of the body.
Abnormality of fatty tissue below the skin
An abnormality affecting one or both hands.
An abnormality of the placenta (the organ that connects the developing fetus to the uterine wall) or of the umbilical cord (the cord that connects the fetus to the placenta).
Abnormality of prenatal development or birth
Abnormalities of placenta or umbilical cord
Single umbilical artery (SUA) is the absence of one of the two umbilical arteries surrounding the fetal bladder and in the fetal umbilical cord.
Abnormality of the fetal cardiovascular system
Single Umbilical Artery [Disease/Finding]
Single artery AND vein of umbilical cord
An abnormality of the fetus or the birth of the fetus, excluding structural abnormalities.
Spontaneous detachment (amputation) of an appendage from the body.
Seizures are an intermittent abnormality of the central nervous system due to a sudden, excessive, disorderly discharge of cerebral neurons and characterized clinically by some combination of disturbance of sensation, loss of consciousness, impairment of psychic function, or convulsive movements. The term epilepsy is used to describe chronic, recurrent seizures.
Syncope refers to a generalized weakness of muscles with loss of postural tone, inability to stand upright, and loss of consciousness. Once the patient is in a horizontal position, blood flow to the brain is no longer hindered by gravitation and consciousness is regained. Unconsciousness usually lasts for seconds to minutes. Headache and drowsiness (which usually follow seizures) do not follow a syncopal attack. Syncope results from a sudden impairment of brain metabolism usually due to a reduction in cerebral blood flow.
Abnormality of cardiovascular system physiology
A condition characterized by intermittent involuntary contraction of muscles (spasms) related to hypocalcemia or occasionally magneisum deficiency.
Bulbar weakness (or bulbar palsy) refers to bilateral impairment of function of the lower cranial nerves IX, X, XI and XII, which occurs due to lower motor neuron lesion either at nuclear or fascicular level in the medulla or from bilateral lesions of the lower cranial nerves outside the brain-stem. Bulbar weakness is often associated with difficulty in chewing, weakness of the facial muscles, dysarthria, palatal weakness and regurgitation of fluids, dysphagia, and dysphonia.
Bulbar Palsy, Progressive [Disease/Finding]
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
An abnormality of the function of the electrical signals with which nerve cells communicate with each other or with muscles as measured by electrophysiological investigations.
Abnormal nervous system electrophysiology
An abnormal structure or form of the joints, i.e., one or more of the articulations where two bones join.
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Flexion deformity (morphologic abnormality)
Abnormality of the musculature of the lower limbs
A structural abnormality of the abdomen ('belly'), that is, the part of the body between the pelvis and the thorax.
Abnormality of the musculature of the pelvis
Abnormality of the hip-girdle musculature
Abnormality of the musculature of the limbs
Abnormality of the musculature of the upper limbs
Aplasia/Hypoplasia of the musculature of the pelvis
A deficiency or slowing down of growth pre- and postnatally.
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
(Fetal growth retardation NOS) or (intrauterine growth retardation)
(Fetal growth retardation NOS) or (intrauterine growth retardation) (disorder)
Fetal Growth Retardation [Disease/Finding]
Overgrowth of only one side of the body.
Congenital hemihypertrophy (morphologic abnormality)
Accumulation of fluid in the peritoneal cavity.
An abnormal reduction in quantity or strength of fetal movements.
Decreased fetal movements, unsp trimester, unsp
Decreased fetal movements, unspecified trimester, not applicable or unspecified
Abnormality of the amniotic fluid, which is the fluid contained in the amniotic sac surrounding the developing fetus.
The presence of excess amniotic fluid in the uterus during pregnancy.
Diminished amniotic fluid volume in pregnancy.
Abnormally increased production of urine by the fetus resulting in polyhydramnios.
An abnormality of the integument, which consists of the skin and the superficial fascia.
A loss of the ability to move the vocal folds.
Paralysis of vocal cords or larynx, unspecified
Hoarseness refers to a change in the pitch or quality of the voice, with the voice sounding weak, very breathy, scratchy, or husky.
A type of speech characterized by the presence of an abnormally increased nasal airflow during speech.
An impairment in the ability to produce voice sounds.
An abnormal increase in the pitch (frequency) of the voice.
The birth of a baby of less than 37 weeks of gestational age.
A position of the fetus at delivery in which the fetus enters the birth canal with the buttocks or feet first.
Any abnormality of the cardiovascular system.
Cardiovascular Abnormalities [Disease/Finding]
Abnormality of the cardiovascular system
Abnormality of cardiovascular system morphology
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Necrosis of the myocardium caused by an obstruction of the blood supply to the heart and often associated with chest pain, shortness of breath, palpitations, and anxiety as well as characteristic EKG findings and elevation of serum markers including creatine kinase-MB fraction and troponin.
Paroxysmal chest pain that occurs with exertion or stress and is related to myocardial ischemia.
Premature rupture of membranes (PROM) is a condition which occurs in pregnancy when the amniotic sac ruptures more than an hour before the onset of labor.
Fetal Membranes, Premature Rupture [Disease/Finding]
Spontaneous detachment of a foot from the body.
An abnormality of the hematopoietic system.
Abnormality of blood and blood-forming tissues
Any structural abnormality of erythrocytes (red-blood cells).
An abnormal susceptibility to bleeding, often referred to as a bleeding diathesis. A bleeding diathesis may be related to vascular, platelet and coagulation defects.
Polycythemia is diagnosed if the red blood cell count, the hemoglobin level, and the red blood cell volume all exceed the upper limits of normal.
A reduction in erythrocytes volume or hemoglobin concentration.
The formation of a blood clot inside a blood vessel that subsequently travels through the blood stream from the site where it formed to another location in the body, generally leading to vascular occlusion at the distant site.
Embolism and thrombosis of unspecified site
Other venous embolism and thrombosis of unspecified site
A cancer of the blood and bone marrow characterized by an abnormal proliferation of leukocytes.
A form of amyloidosis that affects the kidney.
An abnormality of the process of blood coagulation. That is, altered ability or inability of the blood to clot.
Abnormal acid accumulation or depletion of base.
Elevated body temperature due to failed thermoregulation.
Body temperature above reference range (finding)
Presence of elevated levels of ketone bodies in the body.
Depletion of acid or accumulation base in the body fluids.
Abnormality of nitrogen compound homeostasis
A type of diabetic metabolic abnormality with an accumulation of ketone bodies.
Any anomaly of the scalp, the skin an subcutaneous tissue of the head on which head hair grows.
Venous or arterial thrombosis (formation of blood clots) of spontaneous nature and which cannot be fully explained by acquired risk (e.g. atherosclerosis).
The process of hematopoiesis occurring outside of the bone marrow (in the liver, thymus, and spleen) in the postnatal organisms.
Malabsorption caused by intolerance to protein
Malabsorption caused by intolerance to protein (disorder)
Malabsorption due to intolerance to protein
Malabsorption due to intolerance to protein (disorder)
Acidosis resulting from accumulation of ketone bodies.
A structural abnormality of the central nervous system.
Abnormality of the central nervous system
Morphological abnormality of the central nervous system
An abnormality of the viscera of the abdomen.
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) and perceived to originate in the abdomen.
Reduced body temperature due to failed thermoregulation.
The inability to maintain a comfortably body temperature in warm or hot weather.
Malignant hyperthermia is characterized by a rapid increase in temperature to 39-42 degrees C in response to inhalational anesthetics such as halothane or to muscle relaxants such as succinylcholine.
An abnormality of the respiratory system, which include the airways, lungs, and the respiratory muscles.
An abnormality of the upper respiratory tract.
Abnormality of the upper respiratory tract
A functional defect characterized by reduced total lung capacity (TLC) not associated with abnormalities of expiratory airflow or airway resistance. Restrictive lung disease may be caused by alterations in lung parenchyma or because of a disease of the pleura, chest wall, or neuromuscular apparatus.
(Symptom: [SOB] or [breathlessness] or [dyspnea]) or (breathlessness)
(Symptom: [SOB] or [breathlessness] or [dyspnoea]) or (breathlessness)
(Symptom: [SOB] or [breathlessness] or [dyspnoea]) or (breathlessness) (finding)
Asthma is characterized by increased responsiveness of the tracheobronchial tree to multiple stimuli, leading to narrowing of the air passages with resultant dyspnea, cough, and wheezing.
An increased concentration of proteins in the blood.
Abnormality of circulating protein level
An increased concentration of nitrogen compounds in the blood.
Pseudobulbar signs result from injury to an upper motor neuron lesion to the corticobulbar pathways in the pyramidal tract. Patients have difficulty chewing, swallowing and demonstrate slurred speech (often initial presentation) as well as abnormal behavioral symptoms such as inappropriate emotional outbursts of uncontrolled laughter or weeping etc.
An abnormality of the autonomic nervous system.
Abnormality of the peripheral nervous system
Abnormality of the autonomic nervous system
Cephalgia, or pain sensed in various parts of the head, not confined to the area of distribution of any nerve.
An involuntary and painless delay in the relaxation of skeletal muscle following contraction or electrical stimulation.
Delayed relaxation of muscle fibers after contraction
Inability to elicit tendon reflexes in the lower limbs.
A sudden and transient episode of bilateral loss of muscle tone, often triggered by emotions.
A general term describing features characterized by abnormal development of bones and connective tissues.
Osteochondrodysplasia syndrome (disorder)
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to bone.
Bone pain (diffuse not joint pain or arthritis)
An abnormally increased tendency to fractures of bones caused by an abnormal reduction in bone strength that is generally associated with an increased risk of fracture.
An organ or organ-system abnormality that consists of uncontrolled autonomous cell-proliferation which can occur in any part of the body as a benign or malignant neoplasm (tumour).
A cancer originating in lymphocytes and presenting as a solid tumor of lymhpoid cells.
Failure of the immune system to protect the body adequately from infection, due to the absence or insufficiency of some component process or substance.
Osteomyelitis is an inflammatory process accompanied by bone destruction and caused by an infecting microorganism.
Any morphological abnormality of cartilage.
Increased resistance to the passage of air in the upper airway.
Calcification (abnormal deposits of calcium) in the tracheal tissues.
An abnormal reduction on the vital capacity, which is defined as the total lung capacity (volume of air in the lungs at maximal inflation) less the residual volume (i.e., volume of air in the lungs following maximal exhalation) of the lung.
An anomaly of the rhythm or depth of breathing.
One or more flexion contractures (a bent joint that cannot be straightened actively or passively) that are present at birth.
Congenital contracture (morphologic abnormality)
Contracture of joint of multiple sites (disorder)
Contracture of multiple joints (disorder)
contracture of multiple sites (diagnosis)
An abnormal punctate (speckled, dot-like) pattern of calcifications in soft tissues within or surrounding bones (as observed on radiographs).
Inspiration of a foreign object into the airway.
The presence of a melanoma, a malignant cancer originating from pigment producing melanocytes. Melanoma can originate from the skin or the pigmented layers of the eye (the uvea).
Clonal hematopoietic stem cell disorders characterized by dysplasia (ineffective production) in one or more hematopoietic cell lineages, leading to anemia and cytopenia.
Hematopoeitic - Myelodysplastic Syndrome (MDS)
MYELODYSPLASTIC SYNDROME, SUSCEPTIBILITY TO
A tumor (abnormal growth of tissue) of the pancreas.
An increased amount of bilirubin in the blood.
Conjugated hyperbilirubinemia (disorder)
An abnormality of chromosome segregation.
An abnormal functionality of the thyroid gland.
Leydig cell insensitivity to gonadotropin
A reduction in aldehyde oxidase activity.
Abnormality of carboxylic acid metabolism
Deficiency of aldehyde oxidase (disorder)
Altered immune function characterized by lymphoid proliferation, immune activation, and excessive autoreactivity often leading to autoimmune/inflammatory complications.
The occurrence of an immune reaction against the organism's own cells or tissues.
An abnormality of the calf, i.e. of the posterior part of the lower leg.
Prolongation of the time taken for a standardized skin cut of fixed depth and length to stop bleeding.
Abnormality originating in one or more muscles, i.e., of the set of muscles of body.
A decreased concentration of protein in the blood.
An elevated lipid concentration in the blood.
Abnormality of the homeostasis (concentration) of a monoatomic ion.
An abnormality detectable by sonography of the heart (echocardiography).
An abnormal concentration of a hormone in the blood.
An abnormality in the of lipid metabolism.
A contrqacture (chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin) that prevent normal movement of one or more joints of the limbs.
A increased concentration of serotonin in the blood.
An abnormally high level of uric acid in the urine.
Increased serum 1,25-dihydroxyvitamin D3
An increased concentration of 5-aminolevulinic acid (CHEBI:17549) in the urine.
Abnormality of the heme biosynthetic pathway
Elevated urinary delta-aminolevulinic acid
An abnormal increased concentration of parathyroid hormone.
Abnormality of calcium-phosphate metabolism
Elevated serum parathyroid hormone level
Elevated circulating parathyroid hormone level
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Breakdown of muscle fibers that leads to the release of muscle fiber contents (myoglobin) into the bloodstream.
Rhabdomyolysis (morphologic abnormality)
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
The intracellular accumulation of autofluorescent storage material.
Intracellular accumulation of autofluorescent lipopigment storage material
A decreased rate of pyruvate carboxylase activity.
An abnormality of Krebs cycle metabolism that is characterized by a decreased rate of methylmalonyl-CoA mutase activity.
Decreased methylmalonyl CoA mutase activity
Decreased methylmalonyl-CoA mutase activity
A type of chromosomal aberration reduced resistance of chromosomes to change or deterioration.
Increased cellular sensitivity to UV light
Increased phosphoribosylpyrophosphate synthetase
An abnormality of the process of DNA repair, that is, of the process of restoring DNA after damage.
An abnormality of the coagulation cascade, which is comprised of the contact activation pathway (also known as the intrinsic pathway) and the tissue factor pathway (also known as the extrinsic pathway) as well as cofactors and regulators.
Blood Coagulation Disorders, Diseases and Syndromes
Abnormality of carbohydrate metabolism/homeostasis
A type of hyperbilirubinemia with neonatal onset.
Icterus neonatorum, unspecified (disorder)
Abnormal increased size of the viscera of the abdomen.
Any anomaly in the composite material or the layered arrangement of the bony skeleton.
Deficiency of glutathione synthase (disorder)
A reduction in the level of thymic horomone.
Sudden and involuntary contractions of one or more muscles.
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the back.
Abnormal results of investigations using electromyography (EMG).
Hyperexcitability of the neuromuscular system related to abnormally low level of calcium in the blood, resulting in carpopedal or generalized spasms.
An elevated concentration of a gonadotropin hormone (stimulating hormone or luteinizing hormone) in the urine, consistent with the diagnosis of primary hypogonadism.
An abnormality of Krebs cycle metabolism that is characterized by a decreased rate of fumarate hydratase activity.
An abnormally increased number of mitochondria in the cytoplasma adjacent to the sarcolemma (muscle cell membrane), whereby the mitochondria also possess an abnormal morphology.
Muscle abnormality related to mitochondrial dysfunction
Subsarcolemmal accumulations of abnormally shaped mitochondria
Any abnormality of the soft tissues, including both connective tissue (tendons, ligaments, fascia, fibrous tissues, and fat).
A condition in which muscles cannot be moved quickly without accompanying pain or spasm.
The term dystrophy means abnormal growth. However, muscular dystrophy is used to describe primary myopathies with a genetic basis and a progressive course characterized by progressive skeletal muscle weakness and wasting, defects in muscle proteins, and histological features of muscle fiber degeneration (necrosis) and regeneration. If possible, it is preferred to use other HPO terms to describe the precise phenotypic abnormalities.
Congenital progressive muscular dystrophy
Dystrophic Muscle Diseases and Syndromes
An increased erythrocyte sedimentation rate (ESR). The ESR a test that measures the distance that erythrocytes have fallen after one hour in a vertical column of anticoagulated blood under the influence of gravity. The ESR is a nonspecific finding. An elevation may indicate inflammation or may be caused by any condition that elevates fibrinogen.
Increased erythrocyte sedimentation rate
Absence of molybdenum cofactor(2-), a cofactor for enzymes including sulfite oxidase, xanthine oxidoreductase, and aldehyde oxidase.
Increased concentration of total (conjugated and unconjugated) bilirubin in the blood.
Increased time to coagulation in the partial thromboplastin time (PTT) test, a measure of the intrinsic and common coagulation pathways. Phospholipid, and activator, and calcium are mixed into an anticoagulated plasma sample, and the time is measured until a thrombus forms.
Prolonged activated partial thromboplastin time
An abnormality of glycoprotein metabolism related to a decreased rate of alpha-1,6-mannosylglycoprotein 2-beta-N-acetylglucosaminyltransferase activity.
Deficient N-acetylglucosaminyltransferase II
Reduced activity of N-acetylglucosaminyltransferase II
An abnormally reduced activity of the enzyme cytochrome C oxidase in muscle tissue.
Cytochrome c oxidase deficiency in skeletal muscle
Decreased activity of cytochrome C oxidase in muscle tissue
Decreased skeletal muscle cytochrome c oxidase activity
Cytochrome C oxidase-negative muscle fibers
Reduced strength and weakness of the muscles of the arms and legs.
Hypertrophy (increase in size) of muscle cells (as opposed to hyperplasia, which refers to an increase in the number of muscle cells).
Generalized muscular appearance from birth
A type of myopathy associated with mitochondrial disease and characterized by findings on biopsy such as ragged red muscle fibers.
Mitochondrial Myopathies [Disease/Finding]
An abnormal, increased fatiguability of the musculature.
Formation of calcium deposits in any soft tissue.
The presence of any abnormality affecting the abdominal wall.
Abnormality of external features of the abdomen
The presence of a hernia in the abdominal wall.
Any abnormality of the skeletal muscle cell. Muscle fibers are subdivided into two types. Type I fibers are fatigue-resistant and rich in oxidative enzymes (they stain light with the myosin ATPase reaction), and type II fibers are fast-contracting, fatigue-prone, and rich in glycolytic enzymes (these fibers stain darkly). Normal muscle tissue has a random distribution of type I and type II fibers.
Abnormal skeletal muscle fiber morphology
The presence of a fistula connecting the urinary bladder to another organ or the skin. The fistula can involve the bowel, the vagina, or rarely, the skin.
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
An abnormal increase or decrease of weight or an abnormal distribution of mass in the body.
An abnormality of the anterior segment of the eyeball (which comprises the structures in front of the vitreous humour: the cornea, iris, ciliary body, and lens).
Abnormal morphology of the posterior segment of the globe
Abnormality of an amino acid metabolic process.
An abnormality of a pyrimidine base metabolic process.
An abnormality of the metabolism of a carboxylic acid.
An abnormality of proteoglycan metabolism.
An abnormality of fatty acid metabolism.
An abnormality of the balance or maintenance of the balance of acids and bases in bodily fluids, resulting in an abnormal pH.
An abnormal concentration of leptin in the blood.
The presence of an abnormal concentration of nitrogen compounds.
An abnormality of a glycoprotein metabolic process.
An abnormality of temperature homeostasis.
A tumor (abnormal growth of tissue) of the nervous system.
Neoplasms located in the blood and blood-forming tissue (the bone marrow and lymphatic tissue).
An abnormality of alkaline phosphatase activity.
Abnormality of alkaline phosphatase activity
A kind of congenital defect of the anterior abdominal wall in which the intestines are evident through the thin, lax, and protruding abdominal wall in affected infants.
The formation of a blood clot inside an artery.
Arterial thrombosis, NOS, of unspecified artery
The presence of abnormally shaped erythrocytes.
Decreased cervical spine flexion due to contractures of posterior cervical muscles
An abnormal increase in the binding affinity of hemoglobin for oxygen.
The presence of a fistula between the bowel and the perineum.
The term Maturity-onset diabetes of the young (MODY) was initially used for patients diagnosed with fasting hyperglycemia that could be treated without insulin for more than two years, where the initial diagnosis was made at a young age (under 25 years). Thus, MODY combines characteristics of type 1 diabetes (young age at diagnosis) and type 2 diabetes (less insulin dependence than type 1 diabetes). The term MODY is now most often used to refer to a group of monogenic diseases with these characteristics. Here, the term is used to describe hyperglycemia diagnosed at a young age with no or minor insulin dependency, no evidence of insulin resistence, and lack of evidence of autoimmune destruction of the beta cells.
Abnormality of the pulmonary vasculature
Formation of a blood clot (thrombus) inside a vein, causing the obstruction of blood flow.
Premature delivery because of cervical insufficiency or membrane fragility
A pregnancy that ends at a stage in which the fetus is incapable of surviving on its own, defined as the spontaneous loss of a fetus before the 20th week of pregnancy.
An abnormality of the humoral immune system, which comprises antibodies produced by B cells as well as the complement system.
Disseminated intravascular coagulation is characterized by the widespread activation of coagulation, which results in the intravascular formation of fibrin and ultimately thrombotic occlusion of small and midsize vessels.
Coagulation (DIC), Disseminated Intravascular
Coagulations, Disseminated Intravascular
Coagulations, Intravascular Disseminated
Lymphoproliferative Disorders [Disease/Finding]
Lymphoproliferative disease (morphologic abnormality)
An abnormal prolongation (delay) in the time required by whole blood to produce a visible clot.
Abnormality of the kinin-kallikrein system
An anomaly of the form or number of cells in the bone marrow.
Abnormality of bone marrow cell morphology
The presence of abnormal calcium deposition of the intervertebral disk.
Intervertebral disk calcification (disorder)
Multiple intervertebral disk calcifications
Progressively worsening joint contractures.
Decreased respiratory function (finding)
Disordered thermoregulation characterized by an impaired ability to maintain a balance between heat production and heat loss, with resulting instability of body temperature.
A type of diabetes mellitus initially characterized by insulin resistance and hyperinsulinemia and subsequently by glucose interolerance and hyperglycemia.
A congenital form of torticollis resulting from shortening of the sternocleidomastoid muscle and leading to a limited range of motion in both rotation and lateral bending.
Abnormality of the musculature of the neck
Congenital contracture of sternocleidomastoid
Congenital contracture of sternocleidomastoid (muscle)
Congenital contracture of sternocleidomastoid muscle
Congenital sternomastoid torticollis (disorder)
Congenital sternomastoid torticollis (disorder) [Ambiguous]
Congenital sternomastoid torticollis -RETIRED-
Excess skin around the neck, often lying in horizontal folds.
Absence (due to failure to form) or underdevelopment of the bones of the upper limbs.
Absent/underdeveloped bones of the upper limbs
Aplasia/hypoplasia involving bones of the upper limbs
An anomaly of one or more epiphyses of one or both legs.
Abnormal shape of end part of lower limb end bone
Abnormality involving the epiphyses of the lower limbs
Abnormality of lower limb epiphysis morphology
An abnormality of the pulmonary lymphatic chain.
Obstruction of conducting airways of the lung.
Lung Diseases, Obstructive [Disease/Finding]
Chest wall pain in the area of the costochondral junctions.
The presence of a malignant neoplasm of the genital system.
A malignant plasma cell tumor growing within soft tissue or within the skeleton.
A non-malignant neoplasm of the genitourinary system.
MYELOPROLIFERATIVE DISORDER, CHRONIC, WITH EOSINOPHILIA
Stiffness of the limbs (acondition in which muscles cannot be moved quickly without accompanying pain or spasm) occurring in an asymmetric pattern.
A tumor (abnormal growth of tissue) of the gastrointestinal tract.
Abnormality of the gastrointestinal tract
A tumor (abnormal growth of tissue) of the genitourinary system.
Fibrous connective tissue resulting from incomplete healing of a wound (i.e., a scar) located in the choroid and retina or the eye.
Unspecified chorioretinal scar (disorder)
Abnormality of the vasculature of the eye
A tumor (abnormal growth of tissue) of the skin.
Virilization (deepening of voice, facial hirsutism and scalp hair loss) with onset during pregnancy (usually towards the end of the first trimester) and regression several months post-partum.
The presence of abnormal punctate (speckled, dot-like) calcifications in one or more tarsal bones.
Hyperapobetalipoproteinemia is defined as the combination of a normal low density lipoprotein (LDL) cholesterol in the face of an increased LDL apolipoprotein B (apoB) protein.
FCHL - Familial combined hyperlipidaemia
Neonatal unconjugated hyperbilirubinaemia
Neonatal unconjugated hyperbilirubinemia (disorder)
Neonatal unconjugated hyperbilirubinemia
No secondary sexual characteristics are present at puberty.
No secondary sexual characteristics at puberty
Absence of secondary sex characteristics
Insufficient amount of androgenic activity.
Defective biosynthesis of testicular androgen
Defective biosynthesis of testicular androgen NOS
Defective biosynthesis of testicular androgen, NOS
Deficiency of testosterone biosynthesis (disorder)
An increased amount of unconjugated (indirect) bilurubin in the blood.
Unconjugated hyperbilirubinemia (disorder)
The presence of aplasia or developmental hypoplasia of the ear.
An abnormal increase in the amount of intramuscular fat tissue.
Underdevelopment of the serratus anterior muscle, which is involved in abduction, upward Rotation, and elevation of the scapula.
Abnormality of the musculature of the thorax
The presence of an abnormally increased amount of connective tissue.
Underdevelopment of the latissimus dorsi muscle, which is involved in adduction, extension, internal rotation, and transverse extension of the shoulder and assists in movement of the scapula.
Generalized weakness of the muscles of the arms and legs.
Impairment in the physical production of speech sounds.
Interruption of the innervation of the diaphragm.
A congenital failure of muscular development of part or all of one or both hemidiaphragms, resulting in superior displacement of abdominal viscera and altered lung development.
Diaphragmatic Eventration [Disease/Finding]
A decrease in the strength of the diaphragm.
Absence (due to failure to form) or underdevelopment of one or more components of the skeleton.
Aplasia/hypoplasia involving the skeleton
An abnormality of the axial skeleton, which comprises the skull, the vertebral column, the ribs and the sternum.
An abnormality of adipose tissue, which is loose connective tissue composed of adipocytes.
An increase in adipose tissue mass by hyperplastic growth (increase in the number of adipocytes) or by hypertrophic growth (increase in the size of adipocytes occurring primarily by lipid accumulation within the cell).
A disease or lesion affecting the muscles of the thorax.
Depletion of mitochondrial dna in skeletal muscle tissue
Depletion of mitochondrial DNA in muscle tissue
Duplication of bones involving the upper extremities
A benign or malignant neoplasm (tumour) originating in striated muscle, either skeletal muscle or cardiac muscle.
Chronic pain in the limbs with no clear focal etiology.
Congenital developmental defect arising from the primitive branchial apparatus.
Maternal diabetes can either be a gestational, mostly type 2 diabetes, or a type 1 diabetes. Essential is the resulting maternal hyperglycemia as a non-specific teratogen, imposing the same risk of congenital malformations to pregnant women with both type 1 and type2 diabetes.
A form of diabetes insipidus caused by failure of the kidneys to respond to vasopressin (AVP).
Diabetes Insipidus, Nephrogenic [Disease/Finding]
Nephrogenic diabetes insipidus (disorder)
A structural abnormality of a diaphysis of the arm.
Abnormality involving the diaphyses of the upper limbs
Abnormality of shaft of long bone of the upper limbs
Diaphyseal abnormality of the upper limbs
Abnormality of the joints of the upper limbs
Absence (due to failure to form) or underdevelopment of the extremities.
Limb shortening because of underdevelopment of one or more bones of the extremities.
Hypoplasia involving bones of the extremities
Congenital absence (aplasia) of one or more limbs.
Congenital absence of limb NOS (disorder)
The distal parts of the limbs are missing leading to a stump formation.
Absence or underdevelopment of the breasts.
The presence of hypertrophy of the breast.
Absence or underdevelopment of the diaphragm.
Increased urinary excretion of oligosaccharides (low molecular weight carbohydrate chains composed of at least three monosaccharide subunits), derived from a partial degradation of glycoproteins.
An abnormality in the synthesis or catabolism of heme. Heme is composed of ferrous iron and protoporphyrin IX and is an essential molecule as the prosthetic group of hemeproteins such as hemoglobin, myoglobin, mitochondrial and microsomal cytochromes.
Abnormally increased excretion of porphyrins in the urine.
The presence of an abnormal connection between the urethra and another organ or the skin.
Amniotic constriction rings affecting the arms.
Abnormal increase in size of the upper limbs (due to an increase of the size of cells).
Amniotic constriction rings affecting the legs.
Abnormal increase in size of the lower limbs (due to an increase of the size of cells).
A developmental defect in which the legs are fused together.
(Sirenomelia (& [mermaid] or [sympus]) (disorder)
Absence or underdevelopment of the thymus.
The presence of ectopic thymus tissue. Normally, cells of the ventral bud of the third pharyngeal pouch detach and migrate in the eighth gestational week caudally and medially towards the location of the mature thyroid. They migrate further retrosternally into the superior mediastinum. There are two main ways ectopic thymus tissue can develop. Either cells detach along the descensus path and proliferate, thereby forming accessory thymus tissue, or the entire gland fails to descend.
An abnormal increase in quantity or strength of fetal movements.
A disordered proliferation of mature tissues that is native to the site of origin, e.g., exostoses, nevi and soft tissue hamartomas. Although most hamartomas are benign, some histologic subtypes, e.g., neuromuscular hamartoma, may proliferate aggressively such as mesenchymal cystic hamartoma, Sclerosing epithelial hamartoma, Sclerosing metanephric hamartoma.
A tumor (abnormal growth of tissue) of the skeleton.
A form of amyloidosis that affects the conjunctiva.
The presence of abnormal punctate (speckled, dot-like) calcifications in one or more epiphyses.
Rupture of the eyeball not due to trauma.
Deposition of calcium salts in a tissue or location in which calcification does not normally occur.
The presence of a neoplasm of the urinary system.
A tumor (abnormal growth of tissue) of the genital system.
An incomplete closure of the abdominal wall.
Congenital anterior abdominal wall defect
An abnormal level of a circulating protein in the blood.
An abnormality of the umbilical cord, which is the cord connecting the developing embryo or fetus to the placenta.
Shortening of the extremities affecting primarily the distal parts of the limbs (hands and feet) in relation to the other segments of the limbs.
A disease where there is cellular death (necrosis) of bone components due to interruption of the blood supply.
Aseptic Necrosis of Head and Neck of Femur
Aseptic necrosis of head AND/OR neck of femur
Aseptic necrosis of head AND/OR neck of femur (disorder)
An abnormality of a nucleobase metabolic process.
An abnormality of the upper urinary tract.
An abnormality of the lower urinary tract.
A finding of a focus of increased echogenicity upon prenatal ultrasound examination of the fetus. The foci may be present in one or both ventricles. Echogenic intracardiac focus (EICF) is defined as a focus of echogenicity comparable to bone, in the region of the papillary muscle in either or both ventricles of the fetal heart.
Echogenic bowel is defined as fetal bowel with homogenous areas of echogenicity that are equal to or greater than that of surrounding bone.
An first-trimester prenatal ultrasound finding of abnormal blood flow in the ductus venosus.
Abnormality of ductus venosus blood flow
An abnormality of the fetal circulation system or fetal echocardiogram.
Abnormality of the fetal circulation system
An first-trimester prenatal ultrasound finding of abnormal blood flow in the umbilical vein.
Abnormality of umbilical vein blood flow
By the 14th week of gestation it is nearly always possible to visualized the fluid-filled fetal stomach bubble on prenatal sonography. This term refers to the absence of a normal fetal stomach bubble on fetal ultrasonography performed at around 16 to 20 weeks' gestation.
Absence of stomach bubble on fetal sonography
An abnormality of liposaccharide metabolism.
Abnormality of liposaccharide metabolism
An abnormality of an erythrocyte cell surface molecule.
A functional abnormality of the immune system.
An abnormality of the morphology or counts of the cells that make up the immune system.
An abnormality of the abdominal musculature.
Abnormality of the abdominal musculature
An abnormality of dicarboxylic acid metabolism.
Abnormality of dicarboxylic acid metabolism
An abnormality of monocarboxylic acid metabolism.
Abnormality of monocarboxylic acid metabolism
An abnormality of the metabolism of polysaccharide.
Abnormality of polysaccharide metabolism
An abnormality of the metabolism/homeostasis of a carbohydrate.
An abnormality of chromosome condensation.
An abnormality of the gastrointestinal tract.
Abnormal functionality of the cardiovascular system.
An abnormality of the regulation of body fluids.
An impairment of a fructose metabolic process.
The presence of amyloid deposition in one or more tissues. Amyloidosis may be defined as the extracellular deposition of amyloid in one or more sites of the body.
An abnormal concentration of corticotropin in the blood.
Abnormality of circulating adrenocorticotropin level
An abnormality of the concentration or function of circulating immune proteins.
Abnormality of immune serum protein physiology
Any morphological abnormality of the skin.
Any abnormality of the physiological function of the skin.
An abnormally increased sensitivity to the effects of ionizing radiation.
Increased sensitivity to ionising radiation
Increased sensitivity to ionizing radiation
An abnormality of the skin adnexa (skin appendages), which are specialized skin structures located within the dermis and focally within the subcutaneous fatty tissue, comprising three histologically distinct structures: (1) the pilosebaceous unit (hair follicle and sebaceous glands); (2) the eccrine sweat glands; and (3) the apocrine glands.
An abnormal elevation of the C-reactive protein level in serum.
Abnormally increased variability in the size of erythrocytes.
Abnormality of the urinary system physiology
Delivery of a fetus through surgical incisions made through the abdominal wall (laparotomy) and the uterine wall (hysterotomy).
Delivery of newborn by means of a ventouse, a vacuum device used to assist the delivery of a baby when the second stage of labour has not progressed adequately.
Shoulder dystocia occurs when the fetal anterior shoulder impacts against the maternal symphysis following delivery of the vertex.
Shoulder (girdle) dystocia during labor and delivery
Shoulder (girdle) dystocia during labour and delivery
An abnormality of chloride homeostasis or concentration in the body.
An finding upon obstetric ultrasound examination performed at around 16 to 20 weeks of gestation that is abnormal but not clearly identifiable as a fetal anatomic malformation or growth restriction. Such findings are known as soft markers since they are associated with increased risk for fetal aneuploidy or other disorders.
Fetal choroid plexus cysts (CPCs) are sonographically discrete, small cysts (3 mm or more) found in the choroid plexus within the lateral cerebral ventricles of the developing fetus at 14 to 24 weeks gestation. Imaging of the choroid plexus is performed in the transverse plane of the fetal head at the same level that the lateral cerebral ventricle is evaluated. The choroid plexus should be inspected bilaterally for the presence of cysts. The size of CPCs is not of clinical relevance (pmid:16100637).
The cisterna magna is measured on a transaxial view of the fetal head angled 15 degrees caudal to the canthomeatal line. The anterior/posterior diameter is taken between the inferior/posterior surface of the vemis of the cerebellum to the inner surface of the cranium. An enlarged cisternal magna is defined by an anterior/posterior diameter of 10 mm or more (pmid:16100637).
A short femur length is defined as either a measurement below the 2.5th percentile for gestational age or a measurement that is less than 0.9 of that predicted by the measured biparietal diameter. The femur should be measured with the bone perpendicular to the ultrasound beam and with epiphyseal cartilages visible but not included in the measurement (pmid:16100637).
A short humerus length is defined as a length below the 2.5th percentile for gestational age or as a measurement less than 0.9 of that predicted by the measured biparietal diameter. The humerus should be measured with the bone perpendicular to the ultrasound beam and with epiphyseal cartilages visible but not included in the measurement (pmid:16100637).
Short fetal long bone in upper arm length
On prenatal ultrasound, the nasal bone is a thin echogenic line within the bridge of the fetal nose. The fetus is imaged facing the transducer with the fetal face strictly in the midline. The angle of insonation is 90 degrees, with the longitudinal axis of the nasal bone as the reference line. Calibres are placed at each end of the nasal bone. Absence of the nasal bone or measurements below 2.5th percentile are considered significant (pmid:16100637).
Fifth finger clinodactyly is defined by a hypoplastic or absent mid-phalanx of the fifth digit. Ultrasound identification of the fetal hand must first be undertaken and then appropriate magnification accomplished. The evaluation requires stretching of the 5 fingers. The diagnosis is established when the middle phalanx of the fifth finger is markedly smaller than normal or absent, which often causes the finger to be curved inward (pmid:16100637).
An abnormally elevated or decreased level of a maternal serum marker analytes used in screening for aneuploidy.
A medical history of a fetus or child born to a mother with an autoimmune disease.
An anomaly of the control or production of movement in the central nervous system.
Cognitive, psychiatric or memory anomaly.
Abnormality of digestive system physiology
An abnormality of the pulmonary situs, i.e., of the sidedness of the morphological right and left lungs, which is defined by characteristics such as the number of lobes per lung and the relationship of the pulmonary arteries to their bronchi.
An abnormality of the abdominal situs, i.e., of the sidedness of the abdomen and its organs.
Systemic desaturation of a liveborn baby resulting from persistent pulmonary hypertension with a patent ductus arteriosus and patent foramen ovale, such that the circulation in postnatal life follows the fetal course.
(Persistent) pulmonary hypertension of newborn
ALVEOLAR CAPILLARY DYSPLASIA WITH MISALIGNMENT OF PULMONARY VEINS
ALVEOLAR CAPILLARY DYSPLASIA WITH MISALIGNMENT OF PULMONARY VEINS AND OTHER CONGENITAL ANOMALIES
An abnormality of cortical sensation. Assuming the primary sensory modalities are intact and the patient is alert and cooperative, the presence of an abnormality of sensory function usually indicates a lesion of a parietal cortex or of the thalamocortical projections to the parietal cortex.
Any structural anomaly of the adrenal glands.
A functional abnormality of the adrenal glands.
A structural abnormality of the parathyroid gland.
Abnormality of the parathyroid morphology
A functional abnormality of the parathyroid gland.
Abnormality of the parathyroid physiology
A structural abnormality of the thyroid gland.
Neoplasm categorized according to type of histological abnormality.
Neoplasm categorized according to the anatomical site of origin of the neoplasm.
A functional abnormality of a skeletal muscle.
A structural abnormality of a skeletal muscle.
An abnormality of the form, structure, or size of the skeletal system.
An abnormality of the function of the skeletal system.
An abnormality of the appendicular skeletal system, consisting of the of the limbs, shoulder and pelvic girdles.
Abnormal appendicular skeleton morphology
A discrete mass of neoplastic monoclonal plasma cells either in the bone marrow or in an extramedullary location.
Extramedullary plasmacytoma (clinical disorder) (disorder)
Extramedullary plasmacytoma (clinical disorder) [Ambiguous]
Malignant plasma cell neoplasm, extramedullary plasmacytoma
Malignant plasma cell neoplasm, extramedullary plasmacytoma (disorder)
Any anomaly in the function of thrombocytes.
Abnormal number of platelets per volume of blood. In a healthy adult, a normal platelet count is between 150,000 and 450,000 per microliter of blood.
An anomaly in platelet form, ultrastructure, or intracellular organelles.
Anomalous size of platelets. Most normal sized platelets are 1.5 to 3 micrometers in diameter. Large platelets are 4 to 7 micrometers. Giant platelets are larger than 7 micrometers and usually 10 to 20 micrometers.
Abnormal bleeding of the umbilical stump following separation of the cord at approximately 7-10 days after birth.
Bleeding sufficiently severe as to require red cell transfusion (WHO Grade 3 or 4).
Significant bleeding or hemorrhage without significant precipitating factor.
Prolonged or protracted bleeding following an invasive procedure or intervention.
Anomaly in the level or the function of hemoglobin, the oxygen-carrying protein of erythrocytes.
Abnormal calcification in the cardiovascular system.
An abnormality of the pectoral muscle, comprising the pectoralis major, a thick, fan-shaped muscle of the anterior chest and the pectoralis minor, a thin, triangular muscle situated underneath the pectoralis major.
Amyloid deposition in the walls of leptomeningeal and cortical arteries, arterioles, and less often capillaries and veins of the central nervous system.
Persistence of blood flow through the ductus venosus for longer than the normal time after birth.
A congenital defect of the vasculature such that there is a shunt (by-pass) of blood directly from the portal vein to the vena cava (i.e., the blood from the portal vein is not filtered through the liver).
An abnormal concentration of a hormone in the urine.
A form of focal dystonia that affects the vocal cords, associated with involuntary contractions of the vocal cords causing interruptions of speech and affecting the voice quality and often leading to patterned, repeated breaks in speech.
Increased excretion of glycopeptides in the urine. Glycopeptides are peptides with carbohydrate moieties covalently attached to the side chains of the amino acid residues.
An abnormal catecholamine concentration in the blood.
Abnormality of circulating catecholamine level
An abnormal concentration of creatinine in the blood.
An anomaly of the mitochondrion, the membranous cytoplasmic organelle the interior of which is subdivided by cristae. The mitochondrion is a self replicating organelle that is the site of tissue respiration.
An abnormality of the concentration of a glucocorticoid in the blood.
Abnormality of circulating glucocorticoid level
Deviation from normal concentration of albumin in the blood.
Abnormality of bone marrow stromal cells
An anomaly of erythroid lineage cells, that is, of the erythropoietic cells in the lineage leading to and including erythrocytes.
Abnormality of cells of the erythroid lineage
Abnormal erythroid lineage cell morphology
A deviation from the normal count of erythroid precursor cells, that is, erythroid lineage cells in the bone marrow.
An anomaly of cells involved in the formation of a granulocytes, that is, of the granulocytopoietic cell.
Abnormal granulocytopoietic cell morphology
Any structural anomaly of megakaryocytes. Mature blood platelets are released from the cytoplasm of megakaryocytes, which are bone-marrow resident cells.
Abnormality of multiple cell lineages in the bone marrow
An increased concentration of protoporphyrins in erythrocytes.
Increased erythrocyte protoporphyrin concentration
Excessive vomiting in early pregnancy, leading to the loss of 5% or more of body weight.
Excessive vomiting in pregnancy (disorder)
Hyperemesis Gravidarum [Disease/Finding]
Increased concentration of porphobilinogen in the urine.
Blood clot formed within muscle tissue following leakage of blood into the tissue.
An increased concentration of urocanic acid in the urine.
Urocanate hydratase deficiency (disorder)
A structural or developmental anomaly of any of the tissues involved in the genital system.
A structural anomaly of the respiratory system.
Any structural anomaly of the pseudostratified ciliated epithelium that lines much of the conducting portion of the airway, including part of the nasal cavity and larynx, the trachea, and bronchi.
Abnormal respiratory epithelium morphology
Any functional anomaly of the respiratory motile cilia.
Abnormal respiratory motile cilium physiology
A form of amyloidosis that affects the liver.
amyloid infiltration of liver (diagnosis)
An abnormal functionality of the hypothalamus.
A tumor (abnormal growth of tissue) of the head and neck region with origin in the lip, oral cavity, nasal cavity, paranasal sinuses, pharynx, or larynx.
The presence of amyloid deposition in the superficial dermis.
Any neoplasm composed of fibrous tissue.
Fibrosarcoma (excluding infantile fibrosarcoma)
An anomaly in the processes involved in the maintenance of an internal equilibrium.
Any anomaly in the utilization of energy (calories).
An anomaly of a glycosylation process, i.e., a process involved in the covalent attachment of a glycosyl residue to a substrate molecule.
A structural anomaly of the globe of the eye, or bulbus oculi.
A subjective feeling of tiredness characterized by a lack of energy and motivation.
An altered ability of any enzyme or their cofactors to act as catalysts. This term includes changes due to altered levels of an enzyme.
Reduced carnitine O-palmitoyltransferase activity, i.e., reduced activity of the reaction: palmitoyl-CoA + L-carnitine = CoA + L-palmitoylcarnitine.
Reduced carnitine O-palmitoyltransferase activity
An abnormal concentration of aldolase in the serum. Aldolase is an enzyme responsible for converting fructose 1,6-bisphosphate into the triose phosphates dihydroxyacetone phosphate and glyceraldehyde 3-phosphate.
An abnormality of the partial pressure of oxygen or carbon dioxide in the arterial blood.
Amniotic fluid containing the earliest stools of a mammalian infant.
Intermittent and recurrent bouts of a subjective feeling of tiredness characterized by a lack of energy and motivation.
Subjective feeling of tiredness characterized by a lack of energy and motivation that persists for six months or longer.
Any anomaly in the process by which myelin sheaths are formed and maintained around neurons.
A complication of pregnancy and delivery in which the umbilical cord wraps around the fetal neck once or multiple times.
An abnormally decreased amount of thyroxin-binding globulin (TBG) in blood. TBG is responsible for carrying the thyroid hormones thyroxine (T4) and 3,5,3'-triiodothyronine (T3) in the bloodstream.
An abnormally decreased amount of catalase activity.
An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.
Persistent pain, usually defined as pain that has laster longer than 3 to 6 months.
Pain due to a stimulus that does not normally provoke pain.
An anomaly in the communication from a neuron to a target across a synapse. This is a four step process, comprising (i) synthesis and storage of neurotransmitters; (ii) neurotransmitter release; (iii) activation of postsynaptic receptors by the neurotransmitter; and (iv) inactivation of the neurotransmitter. Thus, this term is defined as an anomaly of neurotransmitter metabolic process.
Abnormality of neurotransmitter metabolism
A detrimental reaction to a food, beverage, food additive, or compound found in foods that produces symptoms in one or more body organs and systems that is not mediated by an immune reaction.
malabsorption syndrome due to intolerance
malabsorption syndrome due to intolerance (diagnosis)
Hemorrhage between the skull and periosteum of a newborn resulting from rupture of blood vessels that cross the periosteum.
A deviation from equal (50%) inactivation of each parental X chromosome in maternal cells.
Muscle fibers degeneration resulting in fatty replacement of skeletal muscle fibers
An anomaly in the amount of force per unit area exerted by the intraocular fluid within the eye.
A functional anomaly of the nervous system.
A structural anomaly of the nervous system.
A deviation from the norm of the intracranial pressure.
Any anomaly of the inflammatory response, a response to injury or infection characterized by local vasodilation, extravasation of plasma into intercellular spaces and accumulation of white blood cells and macrophages.
A functional brain anomaly detectable by positron emission tomography (PET). PET scanning is a method for functional brain imaging, and its measurements reflect the amount of brain activity in the various regions of the brain.
Abnormal brain positron emission tomography
An anomaly of the pineal gland,a small endocrine gland in the brain that produces melatonin.
A structural abnormality of the pineal gland.
A functional abnormality of the pineal gland.
A functional anomaly of the large intestine.
An anomaly of metabolism in the brain identified by magnetic resonance spectroscopy (MRS).
Abnormal structure of the gastrointestinal tract.
Morphological anomaly of the digestive system
Morphological abnormality of the gastrointestinal tract
Abnormal functionality of the gastrointestinal tract.
Functional abnormality of the gastrointestinal tract
A sudden, audible expulsion of air from the lungs through a partially closed glottis, preceded by inhalation.
C/O - cough (context-dependent category)
A deviation from normal of the neurological development of a child, which may include any or all of the aspects of the development of personal, social, gross or fine motor, and cognitive abilities.
A deviation from normal of the length of the arm span (length from one end of an individual's arms (measured at the fingertips) to the other when raised parallel to the ground at shoulder height at a one-hundred eighty degree angle.
A deviation from normal of the relation between the upper and the lower segment of the body, where the lower segment is defined as the length between the top of pubic symphysis to floor, and the upper segment is defined as the top of head to top of pubic symphysis.
A tumor (abnormal growth of tissue) of the ear.
A benign or malignant neoplasm that arises from the hair follicles, sebaceous glands, or sweat glands.
Adnexal and skin appendage neoplasm (morphologic abnormality)
Adnexal and skin appendage neoplasm NOS (morphologic abnormality)
Adnexal and skin appendage tumor (qualifier value)
Muscle hypertrophy affecting the muscles of the neck.
Any structural anomaly of a cell of the monocyte, granulocyte, mast cell, megakaryocyte, or erythroid lineage.
A reduction in the numbers of pro-B cells (defined by coexpression of CD34 and CD19). Earlier B-cell precursors are defined by expressing surface CD34 and cytoplasmic TdT in the absence of CD19.
Any functional abnormality of erythrocytes (red-blood cells).
Any deviation from the normal number of red blood cells per volume in the circulation.
Any deviation from the normal concentration of hemoglobin in the blood.
Downward movement of the trachea during inspiration due to downward traction on the tracheobronchial tree.
An increased concentration of prostate specific antigen (PSA) in the circulation.
Elevated prostate-specific antigen level
A deviation from normal range of the erythrocyte sedimentation rate (ESR), a test that measures the distance that erythrocytes have fallen after one hour in a vertical column of anticoagulated blood under the influence of gravity. The ESR is a nonspecific finding. An elevation may indicate inflammation or may be caused by any condition that elevates fibrinogen. A decreased ESR may be seen in polycythemia or in certain blood diseases in which red blood cells have an irregular or smaller shape that causes slower settling.
A reduced erythrocyte sedimentation rate (ESR). The ESR is a test that measures the distance that erythrocytes have fallen after one hour in a vertical column of anticoagulated blood under the influence of gravity. The ESR is a nonspecific finding. A decreased ESR may be seen in polycythemia or in certain blood diseases in which red blood cells have an irregular or smaller shape that causes slower settling.
Decreased erythrocyte sedimentation rate
4-50 CONGENITAL ANOMALIES OF THE DIGESTIVE SYSTEM: GENERAL TERMS
CONGENITAL ANOMALIES OF THE DIGESTIVE SYSTEM
CONGENITAL ANOMALIES OF THE DIGESTIVE SYSTEM: GENERAL TERMS
Congenital anomaly NOS of digestive system NOS
A functional anomaly of the digestive system.
A structural anomaly of the digestive system.
Abnormality of digestive system morphology
A deviation from normal of the mean corpuscular volume, or mean cell volume (MCV) of red blood cells, usually taken to be 80 to 100 femtoliters.
A sudden violent, spasmodic, audible expiration of breath through the nose and mouth.
An intrauterine state characterized by suboptimal values in the fetal heart rate, oxygenation of fetal blood, or other parameters indicative of compromise of the fetus. Signs of fetal distress include repetitive variable decelerations, fetal tachycardia or bradycardia, late decelerations, or low biophysical profile.
Lactase is produced in the small intestine in humans, Lactase is a member of the beta-galactosidase family of enzymes, and hydrolyzes D-lactose to form D-galactose and D-glucose, which can be absorbed by the small intestine. There are many ways of assessing lactase activity. In one test, an endoscopic biopsy from the postbulbar duodenum is incubated with lactose on a test plate, and a color reaction develops within 20 min as a result of hydrolyzed lactose (a positive result) in patients with normolactasia, whereas no reaction (a negative result) develops in patients with severe hypolactasia. Other, less direct, tests include the hydrogen breath test, and blood tests following lactose challenges.
Decreased small intestinal mucosa lactase activity
A deviation from normal concentration of the hormone estrogen in the blood circulation.
Ectopic deposition of calcium salts found in the gingiva.
A symptom or manifestation indicating a systemic or general effect of a disease and that may affect the general well-being or status of an individual.
[D]Chill(s) NOS (context-dependent category)
Involuntary contraction or twitching of the muscles.
Severe chills with violent shivering. A rigor is an episode of shaking or exaggerated shivering which can occur with a high fever.
Rigor - Temperature-associated observation
A fiunctional anomaly of the hepatobiliary system
Abnormality of hepatobiliary system physiology
Inability to be weaned from intravenous (parenteral) nutrition, as judged by the hydration status (urine output, blood urea nitrogen, creatinine, urine sodium concentration), ability to maintain weight, stool output, and serum electrolyte status.
An increased concentration of sedoheptulose in the urine. Sedoheptulose is a monosaccharide with seven carbon atoms and a ketone functional group.
An abscess-like lesion located within the abdomen. The lesions are localized in the spleen, liver, abdominal lymph nodes. The lesions represent visceral sterile collections of mature neutrophils that do not respond to antibiotics but regress quickly when treated with corticosteroids, but relapses occur frequently.
A deviation from the normal concentration in blood of an apolipoprotein, i.e., of a protein that binds lipids to form lipoprotein and is thereby responsible for the transport of lipids in the blood and lymph circulation.
A structural anomaly of a synovial bursa.
Abnormality of synovial bursa morphology
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the foot.
Any functional anomaly of the skin adnexa (skin appendages), which are specialized skin structures located within the dermis and focally within the subcutaneous fatty tissue, comprising three histologically distinct structures: (1) the pilosebaceous unit (hair follicle and sebaceous glands); (2) the eccrine sweat glands; and (3) the apocrine glands.
Hyperhidrosis that occurs with gustatory stimulation (e.g., moisture on face from sweating that occurs after eating).
Sweating provoked by cold temperature rather than by heat.
An anomaly of cellular morphology or physiology.
A structural anomaly of the growth plates (epiphyseal plates), areas of cartilage located near the ends of long bones that are located between the metaphysis (widened part of the shaft of the bone) and the epiphysis (end of the bone) and in which growth occurs in the developing bone. After conclusion of bone growth, the growth plates ossify (harden into solid bone).
Areas of subcutanous fat tissue that are resistant to (do not respond as expected to) diet, life-style alteration, or bariatric surgery.
Diet-resistant subcutaneous adipose tissue
An abnormality in which the eyes are held permanently wide open.
A state characterized by a feeling of weakness and loss of strength leading to a generalized weakness of the body.
The presence of free air in the mediastinum.
Any anomaly of the function of the bronchi.
Any anomaly of the vocalizing of an infant's crying, i.e.,the typically loud voice production that is accompanied by tears and agitation.
A type of crying in an abnormally high-pitched voice.
A type of cry that is abnormal because it is consists of unusually shortened and detached vocalizations.
Reduced activity of the enzyme lecithin cholesterol acyl transferase.
Decreased lecithin cholesterol acyl transferase activity
An abnormality of the function of the cardiac atria.
An abnormality of the processes that maintain the redox environment of a cell or compartment within a cell, that is, the balance between reduction and oxidation chemical reactions.
A deviation from the normal concentration of beta globulin. The beta globulins are a group of globular (globe-shaped) proteins in blood.
Abnormal circulating beta globulin level
Calcified deposits in soft tissue structures outside a joint.
A deviation from the normal concentration of thyroglobulin, a protein produced in the thyroid gland that acts as a precursor to thyrroid hormones.
Abnormal circulating thyroglobulin level
The percentage of fat as a part of total body weight above the norm, usually defined as 32% for females and 25% for males.
A deviation from the normal range of the average amount of hemoglobin per red blood cell (27 to 31 picograms/cell). A reduced mean corpuscular hemoglobin (MCH) may indicate a hypochromic anemia, but the MCH may be normal if both the total hemoglobin and the red blood cell count are reduced.
Abnormal mean corpuscular hemoglobin concentration
An increase above the normal concentration of ribitol in the blood.
Elevated circulating ribitol concentration
A functional anomaly of the muscles of the eye.
A bent (flexed) finger or toe joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
A neoplasm derived from nervous tissue (not necessarity a neoplasm located in the nervous system).
An anomalous concentration of testosterone in the blood.
An abnormally increased degree of bleeding following a superfical injury to the surface of the skin.
Excessive bleeding from superficial cuts
An abnormal high amount of bleeding following the procedure of taking a blood sample.
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) and perceived to originate in the flank.
Occurence of excessive sweating during sleep.
Abnormalities of the overall muscle bulk based on clinical observation.
The occurence of an elevated body temperature of the mother during pregnancy.
Increased growth of callus, the bony and cartilaginous material that forms a connecting bridge across a bone fracture during fracture healing.
2,3-diphosphoglycerate (2,3-DPG) controls the movement of oxygen from red blood cells to tissues. Anemia is usually accompanied by an increased level of 2,3-DPG in order to promote tissue oxygenation. This term refers to an inappropriate low 2,3-DPG concentration in erythrocytes.
Reduced erythrocyte 2,3-diphosphoglycerate concentration
An altered ability of any enzyme to act as catalysts within erythrocytes. This term includes changes due to altered levels of an enzyme.
An anomalous structure of the periosteum, i.e., of the membrane that covers the outer surface of bones.
An anomaly of the circulating level of a gonadotropin, that is, of a protein hormone secreted by gonadotrope cells of the anterior pituitary of vertebrates. The primary gonadotropins are luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
An anomaly in the blood concentration of an androgen, that is, of a steroid hormone that controls development and maintenance of masculine characteristics. The androgens include testosterone and Dehydroepiandrosterone.
An anomalous level of insulin-like growth factor 1 (IGF1) in the blood circulation.
Abnormal serum insulin-like growth factor 1 level
Vaginal birth after Caesarian (VBAC) refers to the situation where the mother has had a previous Cesarean delivery but has now delivered vaginally.
The Odon device is an instrument for assisted vaginal deliveries that is applied on the head of the baby and used to apply traction to assist the birth process.
Vaginal delivery following induction of labor, a procedure used to stimulate uterine contractions during pregnancy before labor begins on its own.
Delivery by means of therapeutic termination of pregnancy. Therapeutic abortion may be done to end a pregnancy if the mother's life is in danger or if the baby has abnormalities involving the major organ systems and is not expected to survive after birth or by choice.
Retinal phenotype characterised by cone photoreceptor dysfunction and preserved rod system. The abnormality is typically stationary or very slowly progressive and findings may include reduced central vision, colour vision abnormalities, nystagmus and photophobia.
Any structural anomaly of the heart and great vessels.
A deviation from the normal circulating concentration of adiponectin, a 30-kDa complement C1-related protein that is the most abundant secreted protein expressed in adipose tissue, and that plays a crucial role in the regulation of insulin sensitivity and glucose metabolism.
A deviation from the normal concentration of glucagon in the blood circulation.
Loss of one twin occurring after midgestation (17 weeks gestation).
Intrauterine fetal demise of one twin after midgestation
An increase in mean adipocyte cell size. This feature can be measured by determining the average cell diameter of adipocytes microscopically using abdominal subcutaneous adipose tissue obtained by biopsy.
Pain in the ear can be a consequence of otologic disease (primary or otogenic otalgia), or can arise from pathologic processes and structures other than the ear (secondary or referred otalgia).
An anomaly in the process of visual accommodation, which is the process of adjustment of the eye to enable sharp vision of objects at different distances. Accommodation is mediated by contraction of the ciliary muscles, which alter the convexity of the lens and, consequently, its refractive power.
An anomalous (adventitious) sound produced by the breathing process.
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the neck.
(Cervicalgia) or (neck pain NOS) (disorder)
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the shoulder.
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the elbow.
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the wrist.
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the finger.
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the hip.
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the knee.
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the ankle.
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the toe.
Extracellular deposition in cardiac tissue of a proteinaceous material that, when stained with Congo red, demonstrates apple-green birefringence under polarized light and that has a distinct color when stained with sulfated Alcian blue. Viewed with electron microscopy, the amyloid deposits are seen to be composed of a beta-sheet fibrillar material. These nonbranching fibrils have a diameter of 7.5 to 10 nm and are the result of protein misfolding.
An abnormality in which the internal thoraco-abdominal organs demonstrate abnormal arrangement across the left-right axis of the body.
An abnormality of the cardiac ventricular function.
A functional anomaly of that portion of the cardiosvascular system that carries deoxygenated blood from the heart to the lungs and returns oxygenated blood back to the heart.
Any anomaly measure by pulmonary function testing, which includes spirometry, measures of diffusing capacity, and plethysmography.
Abnormality on pulmonary function testing
Pulmonary vasodilator testing is performed during right-heart catheterization and involves a short-acting vasoactive agent such as adenosine, epoprostenol, or inhaled nitric oxide. The current definition of a normal (positive) response is a drop in mean pulmonary artery pressure of at least 10 mm Hg (or 20 percent) to below 40 mm Hg.
Abnormal response to short acting pulmonary vasodilator
Increased activity of the enzyme gamma-glutamyltransferase (GGT). GGT is mainly present in kidney, liver, and pancreatic cells, but small amounts are present in other tissues.
Elevated gamma-glutamyltransferase activity
Excessive formation of fibrous bands of scar tissue in between muscle fibers.
An anomaly of the electrical conduction physiology of the heart.
Abnormality of cardiovascular system electrophysiology
A chronic deviation from normal pressure in the systemic arterial system.
A subjective feeling of tiredness characterized by a lack of energy and motivation and that is induced by exertion or exercise.
An increased blood concentration of the carcinoembryonic antigen (CEA). CEA is a member of the immunoglobulin supergene family. The human CEA gene family is clustered on chromosome 19q and comprises 29 genes. CEA is highly expressed in embryonic tissue and in some cancers, and is a widely used tumor marker.
An increased blood concentration of carcinoma antigen 125 (CA-125). CA-125, also known as mucin 16, can exhibit increased blood levels in certain types of cancer.
A deviation from normal blood concentration of retinol-binding protein (RBP). The most commonly used indicator of vitamin A status is the serum retinol concentration (retinol is one of the several compounds known as vitamin A). The serum RBP concentration is used as a surrogate measure for serum retinol.
A deviation from the normal blood concentration of the insulin like growth factor binding protein acid labile subunit (IGFALS; Entrez Gene ID 3483). The acid-labile subunit (IGFALS) acts in the insulin-like growth (IGF) system by binding circulating IGF1 in a ternary complex with binding protein (IGFBP)-3 to prevent IGF1 from crossing the endothelial barrier.
Abnormal insulin like growth factor binding protein acid labile subunit level
Presence of a protracted or persistent infection by a pathogen potentially related to an underlying abnormality of the immune system that is not able to clear the infection.
A decreased blood concentration of growth hormone binding protein.
Reduced growth-hormone binding protein level
Blood concentration of insulin-like factor 3 (ILF3) is below normal limits.
Increased blood concentration of vascular endothelial growth factor (VEGF).
Elevated vascular endothelial growth factor level
Difficulty in performing one or more activities normally performed every day, such as eating, bathing, dressing, grooming, work, homemaking, and leisure.
Impairment of activities of daily living
This term applies to an individual who requires help to bathe more than one part of the body, get in or out of the tub or shower, or who requires total bathing.
This applies to an individual who needs help with dressing or needs to be completely dressed.
This term applies to an individual who requires help transferring to the toilet, cleaning self or who uses bedpan or commode.
Applies to an individual who needs help in moving from bed to chair or requires a complete transfer.
Applies to an individual who needs partial or total help with feeding or requires parenteral feeding.
Partial or total incontinence of bowel or bladder.
Any anomaly of the structure of an organ ofthe endocrine system.
Any anomaly of the function of the endocrine system.
An anomalous response to a test that is designed to probe the function of the endocrine system.
Abnormal response to endocrine stimulation test
An anomalous response to the glucagon stimulation test, which like the insulin tolerance test (ITT) stimulates the release of both adrenocorticotropic hormone (ACTH) and growth hormone (GH).
Abnormal response to glucagon stimulation test
An anomalous response to intravenous stimulation by human chorionic gonadotrophin. Stimulation with hCG stimulates testicular Leydig cells to secrete androgens via the Leydig hormone receptors.
Abnormal response to hCG stimulation test
Abnormal response to human chorionic gonadotrophin stimulation test
A reduced concentration of prealbumin in the blood. Prealbumin, also known as transthyretin, has a half-life in plasma of about 2 days, much shorter than that of albumin. Prealbumin is therefore more sensitive to changes in protein-energy status than albumin, and its concentration closely reflects recent dietary intake rather than overall nutritional status.
The abrupt and transient increase in the annual growth rate normally observed in adolescent individuals does not occur.
Any anomaly of the structure of the breast.
Any anomaly of the function of the breast.
Any deviation from the normal concentration of iInhibins, which are heterodimeric protein hormones secreted by granulosa cells of the ovary in females and Sertoli cells of the testis in males. Inhibins suppress the secretion of pituitary follicle-stimulating hormone.
Any deviation from the normal range of the antimullerian hormone, a peptide produced by the granulosa cells of follicles. Anti-Mullerian hormone (AMH), also known as Mullerian inhibiting substance, is produced by the granulosa cells of small antral follicles of the ovary. AMH has an inhibiting role in the ovary, contributing to follicular arrest. AMH levels in women are low until the age of 8, rise rapidly until puberty and decline steadily from the age of 25 until menopause, when AMH production ceases.
Failure of secretion of milk following childbirth associated with an inability to breastfeed an infant.
Failure of lactation - delivered (disorder)
As a result of sharing a single placenta, the blood supplies of monochorionic twin fetuses can become connected, so that they share blood circulation: although each fetus uses its own portion of the placenta, the connecting blood vessels within the placenta allow blood to pass from one twin to the other.Depending on the number, type and direction of the interconnecting blood vessels (anastomoses), blood can be transferred disproportionately from one twin (the donor) to the other (the recipient). This state of transfusion causes the donor twin to have decreased blood volume, retarding the donor's development and growth. The blood volume of the recipient twin is increased, which can strain the fetus's heart and eventually lead to heart failure.
A deviation from the normal circulating concentration of B-type natriuretic peptide (BNP).
Abnormal B-type natriuretic peptide level
A pregnancy that extends to 42 weeks of gestation or beyond.
Fetal masculinization of female external genitalia.
Head is bent in the posterior direction in a permanent fashion.
An abnormality of the concentration of pregnenolone in the blood.
Abnormality of circulating pregnenolone level
Reduction in the activity of lysosomal acid lipase (LAL) in the blood. Lysosomal lipase activity is measured. LAL hydrolyzes cholesteryl esters derived from cell internalization of plasma lipoproteins.
An increased concentration of circulating alpha polypeptide of glycoprotein hormones (Entrez Gene 1081). This alpha subunit is common to luteinizing hormone (LH) , follicle stimulating hormone (FSH) , thyroid stimulating hormone (TSH) and human chorionic gonadotropin (hCG), which are glycoprotein hormones composed of an identical alpha subunit together with a beta subunit that confers biological specificity. The alpha subunit is used as a marker for tumors that produce these hormones.
Increased pituitary glycoprotein alpha subunit level
Reduction in the activity of lipoprotein lipase in the blood.
Decreased circulating dehydroepiandrosterone level
A reduced concentration of dehydroepiandrosterone-sulfate in the blood.
Decreased circulating dehydroepiandrosterone-sulfate level
Sudden feelings of warmth that are generally most pronounced over the face, neck and chest.
A state of increased circulating antidiuretic hormone despite hyponatremia and hypo-osmolality with normal or increased plasma volume.
Inappropriate antidiuretic hormone secretion
An elevated concentration of thyroxine-binding globulin (TBG) in the blood.
Increased circulating thyroxine-binding globulin level
The state in which profound and widespread reduction of effective tissue perfusion leads first to reversible, and then if prolonged, to irreversible cellular injury.
Any structural anomaly of cardiomyocytes, which are terminally differentiated muscle cells in the heart that are interconnected end to end by gap junctions, which allows coordinated contraction of heart tissue.
A structural anomaly of lysosomes, membrane-enclosed organelles that contain an array of enzymes capable of catabolizing proteins, nucleic acids, carbohydrates, and lipids.
An unpleasant sensation of tightness or pressure in the chest.
Any abnormality in the multiplication or reproduction of cells, which may result in the expansion of a cell population.
Abnormal amount of a protein that is normally present on the cell surface of lymphocytes.
Abnormal lymphocyte surface marker expression
A deviation from the normal level of major histocompatibility complex class II molecules expressed at the cell surface.
An impaired immune response mediated by cells expressing specific receptors for antigen produced through a somatic diversification process, and allowing for an enhanced secondary response to subsequent exposures to the same antigen (immunological memory).
Any structural anomaly of a chromosome, which is a thread like molecule consisting of DNA and proteins (chromatin) that contains DNA sequences for genes and other genetic elements in linear order.
Any deviation from the normal quantity of secretion of nasal mucus, a thick viscous liquid produced by the mucous membranes of the nose.
A decreased concentration of sex-hormone binding protein in the circulation.
Reduced sex -hormone binding protein level
A deviation from the normal concentration of beta-C-terminal telopeptide of type I collagen in the blood circulation, a marker of the rate of bone turnover.
Abnormal circulating beta-CrossLaps level
Abnormal circulating beta-C-terminal telopeptide level
A deviation from the normal concentration of osteocalcin in the blood circulation.
An anomaly of the expressive patterns of speech that involve intonation, stress pattern, loudness variations, pausing, articulatory force, and rhythm.
A speech pattern characterized by abnormally reduced or lacking variability of the pitch of the voice.
A speech pattern characterized by abnormally elevated variability of the pitch of the voice.
Exposure of pregnant women to toxins from any source, such as environmental toxins or chemicals, that may potentially cause problems such as miscarriage, preterm delivery, low birth weight, and, in some cases, developmental delays in infants.
An abnormal increase in the amount of subcutaneous fat in the legs.
Lower extremity subcutanous fat hypertrophy
A pregnancy in which the fertilized egg inserts in a location outside of the main cavity of the uterus (usually in the Fallopian tube).
A tumor (abnormal growth of tissue) that arises from the soft tissue. The most common types are lipomatous (fatty), vascular, smooth muscle, fibrous, and fibrohistiocytic neoplasms.
Abnormal reduction in length of a tendon which tends to pull (retract) the attached muscle tissue with shortening of the muscle fibers often accompanied by atrophy and fatty degeneration of the affected muscle tissue.
Any structural anomaly of the cells of the mucosa of the oral cavity in the region of the cheek (buccal mucosa cells).
A benign or malignant neoplasm that arises from and is composed of epithelial cells. This category include adenomas, papillomas, and carcinomas [NCIT:C3709].
Epithelial neoplasm (morphologic abnormality)
An abnormal enlargement or swelling in the abdomen.
An abnormal enlargement or swelling in the pelvic region.
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the groin region.
Any abnormal result of flow cytometry, a method that suspends cells in a stream of fluid and passes them through an electronic detection apparatus in order to assess cell count or measure biomarkers or surface molecules.
Reduced level of a protein that is normally present on the cell surface as assessed by flow cytometry.
Eye strain, i.e., a feeling of fatigue or discomfort of the eyes related to 'overuse' of the eyes in activities such as reading or working at the computer and often accompanied by lacrimation or headache.
An anomaly in the system of mucociliary transport, which functions to transport the mucous layer lining the respiratory epithelium by ciliary beating.
Weakness in the supporting structures of the pelvic floor allowing the pelvic viscera to descend or one or more of the pelvic organs drop from their normal position.
Any functional abnormality of a cardiac valve.
Any abnormal noise generated by the beating heart.
An infection that is caused by a pathogen that would generally not be able to cause an infection in a host with a normal immune system. Such pathogens take advantage of the opportunity, so to speak, that is provided by a weakened immune system.
Opportunistic Infections [Disease/Finding]
Any deviation from the normal concentration of glycerol in the blood.
Any functional anomaly of the vocal cord.
An abnormally decreased concentration of parathyroid hormone.
Decreased serum parathyroid hormone level
Decreased circulating parathyroid hormone level
A deviation from normal of the waist to hip ratio, defined as the waist measurement divided by hip measurement.
Altered level of the enzyme that catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate via transfer of the 5-phosphoribosyl group from 5-phosphoribosyl 1-pyrophosphate.
Abnormal 6-hydroxypurine phosphoribosyltransferase level
Abnormal hypoxanthine-guanine phosphoribosyltransferase level
An abnormal level of catalysis of the reaction: 2 superoxide + 2 H+ = O2 + hydrogen peroxide.
Abnormal superoxide:superoxide oxidoreductase activity
Presence of a chemical substance found within an individual that is not naturally produced or expected to be present in human tissues or bodily fluids.
The presence of a xenobiotic in body tissues or fluids can be the result of ingestion of or exposure to substances such as drugs, environmental pollutants, food additives, hydrocarbons, and pesticides.
Any deviation from the normal ratio of the volume of red blood cells to the total volume of blood.
Isomerism in the context of the congenitally malformed heart is defined as a situation where some paired structures on opposite sides of the left-right axis of the body are, in morphologic terms, symmetrical mirror images of each other.
The presence of an infectious agent in the blood circulation.
Presence of viable bacteria in the blood.
Any functional anomaly of Langerhans cells, which are dendritic cells in the epidermis and some other locations. Langerhans cells play roles iin immune surveillance and homeostasis.
Any deviation from the normal concentration of hepcidin in the blood circulation.
Increased amount of stacking of erythrocytes into long chains. Rouleaux (singular: rouleau) is derived from a French word that can refer to a stack of coins put into a cylindircal paper roll. Rouleaux formation is observed with increased serum proteins, particularly fibrinogen and globulins, and represents the cause of increased erythrocte sedimentation rate because rouleaux sediment more readily than isolated red blood cells.
Any deviation from the normal circulating concentration of mast cell beta-tryptase concentration.
Abnormal serum mast cell beta-tryptase concentration
Any deviation from the normal circulating concentration of selenium.
A functional abnormality affecting one or more of the cranial nerves, which emerge directly from the brain stem.
A halo or spoke-wheel arrangement of cells surrounding a central core or hub. The central hub may consist of an empty-appearing lumen or a space filled with cytoplasmic processes. The cytoplasm of each of the cells in the rosette is often wedge-shaped with the apex directed toward the central core; the nuclei of the cells participating in the rosette are peripherally positioned and form a ring or halo around the hub.
Any deviation from the normal value of the serum anion gap, which is calculated from the electrolytes measured in the chemical laboratory, is defined as the sum of serum chloride and bicarbonate concentrations subtracted from the serum sodium concentration.
Red blood cell distribution width (RDW) is a simple parameter of the standard full blood count and a measure of heterogeneity in the size of circulating erythrocytes. It is provided by automated hematology analyzers and it reflects the range of the red cell size. It is calculated by dividing the standard deviation of erythrocyte volume by the mean corpuscular volume (MCV) and multiplied by 100 to convert to a percentage.
Increased red blood cell distribution width
Any deviation from the normal concentration of urea nitrogen in the blood.
Presyncope is a state of lightheadedness, muscular weakness, blurred vision, and feeling faint. Presyncope is most often cardiovascular in cause.
Abnormal appearance of material expectorated (coughed up) from the respiratory system and that is composed of mucus but may contain other substances such as pus, blood, microorganisms, and fibrin.
Eosinophil infiltration of skeletal muscle.
Eosinophilic infiltration of skeletal muscle
A reduced concentration of circulating alpha-1 antitrypsin, which is a 52-kDa glycoprotein mainly synthesised and secreted by hepatocytes into the bloodstream. Alpha-1 antitrypsin is a serine-proteinase inhibitor that it is crucial in maintaining protease-antiprotease homeostasis in the lungs.
Any deviation from the normal concentration of bicarbonate, HCO3[-], in the circulation.
Abnormal serum bicarbonate concentration
An abnormality of the composition of sweat or the levels of its components.
OXOPROLINURIA DUE TO 5-OXOPROLINASE DEFICIENCY
Oxoprolinuria Due To Oxoprolinase Deficiency
PLATELET-ACTIVATING FACTOR ACETYLHYDROLASE DEFICIENCY
An endocrine tumor arising from an APUD cell.
Neoplasm of Diffuse Neuroendocrine System
Neoplasm of the Diffuse Neuroendocrine System
The presence of an abnormal concentration of neopterin.
The presence of an abnormal concentration of biopterin.
An abnormal concentration of insulin in the body.
An increased tendency towards thrombosis in the mother during a pregnancy.
Clincial phenotype characterized by delayed bleeding accelerated break down of blood clot (fibrinolysis)
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the jaw.
A deviation from the normal serum concentration/activity of lactate dehydrogenase (LDH), which catalyzes the reduction of pyruvate to form lactate.
Anomaly in the weight-to-height squared ratio, calculated by dividing the individual's weight in kilograms by the square of the individual's height in meters and used as an indicator of obesity and underweight compared to averages.
An early onset of puberty, in this case early does not refer to precocious.
Malignant mesothelioma is a form of cancer that originates from the cells of the mesothelium, a thin tissue layer surrounding the body's internal organs. Malignant mesothelioma is almost exclusively caused by asbestos exposure, pleural mesothelioma beeing the most common form, affecting the lining of the lungs called the pleura. Other forms such as perioneal-, percardial- or testicular- mesothelioma are much rarer.
A tumor (abnormal growth of tissue) of the eye.
A tumor (abnormal growth of tissue) of the breast.
Folds of membranous tissue (peritoneum, mesothelium) attached to the wall of the abdomen and enclosing viscera. Examples include the mesentery for the small intestine; the transverse mesocolon, which attaches the transverse portion of the colon to the back wall of the abdomen; and the mesosigmoid, which enfolds the sigmoid portion of the colon. Cells of the same embryologic origin also surround the other organs of the body such as the lungs (pleura) or the heart (pericardium).
An abnormality of movement with a neurological basis characterized by changes in coordination and speed of voluntary movements.
A connective tissue neoplasm formed by proliferation of mesodermal cells. Bone and soft tissue sarcomas are the main types of sarcoma. Sarcoma is usually highly malignant.
A contraction of the diaphragm that repeats several times per minute. In humans, the abrupt rush of air into the lungs causes the epiglottis to close, creating a hic sound. Also known as synchronous diaphragmatic flutter (SDF), or singultus, from the Latin singult, the act of catching one's breath while sobbing. The hiccup is an involuntary action involving a reflex arc.
Recurrent synchronous diaphragmatic flutter
Deposition of calcium salts in muscle tissue.
An abnormality of the structure or form of the tendons, also often called sinews.
Hyponasal speech is when there is an abnormally reduced nasal airflow during speech often in a setting of nasal obstruction or congestion.
The presence of amyloid deposition in the nerves of the peripheral nervous system.
Immunological states where the immune system produces harmful responses upon reexposure to sensitising antigens.
Abnormality of the joints of the lower limbs
Contractures of one ore more joints of the feet meaning chronic loss of joint motion due to structural changes in non-bony tissue.
Joint contractures involving the joints of the feet
A decreased concentration of ammonia in the blood.
An anomaly in the metabolism of a vitamin.
A tumor (abnormal growth of tissue) of the thymus.
An abnormality of phosphate homeostasis or concentration in the body.
Inflammation of the eye, parts of the eye or the periorbital region.
Eversion of a hollow organ and exposure, inside out, and protruded through the abdominal wall.
Congenital overgrowth of lower limb (disorder)
A growth pattern that displays an abnormal difference between the left and the right side.
Uneven or disproportionate growth of one body part compared to another
A difference in length or diameter between the left and right leg.
Difference in length or size between the right and left arm.
A tumor (abnormal growth of tissue) of the endocrine system.
The presence of a fistula affecting the genitourinary system.
Pregnancy-induced toxic reactions of the mother that can be as harmless as slight Maternal hypertension or as life threatening as Eclampsia.
A tumor (abnormal growth of tissue) of the lip.
A tumor (abnormal growth of tissue) of the respiratory system.
Neoplasm of respiratory system (disorder)
Neoplasm of respiratory tract (disorder)
A medical history of exposure during the fetal period to hyperphenylalaninemia because the mother had phenylketonuria with inadequate control during pregnancy.
High blood phenylalanine level in mother
Neuroendocrine neoplasm (morphologic abnormality)
A tumor (abnormal growth of tissue) of the oral cavity.
A chronic condition in which the pancreas produces little or no insulin. Type I diabetes mellitus is manifested by the sudden onset of severe hyperglycemia with rapid progression to diabetic ketoacidosis unless treated with insulin.
A bacterial infection and inflammation of the skin und subcutaneous tissues.
An abnormality of Sharpey's fibers (bone fibers, or perforating fibers), which are a matrix of connective tissue consisting of bundles of strong collagenous fibres connecting periosteum to bone.
Swelling of lymph nodes within the mediastinum, the central compartment of the thoracic cavities that contains the heart and the great vessels, the esophagus, and trachea and other structures including lymph nodes.
An abnormality of coagulation associated with an increased risk of thrombosis.
A tumor (abnormal growth of tissue) of the parathyroid gland.
Neoplasm of parathyroid gland (disorder)
A benign or malignant neoplasm (tumour) originating in the vascular system.
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the chest.
A serious and potentially life-threatening condition that arises when a considerable mass of body tissue dies (necrosis).
An anomaly of the lymphatic system, a network of lymphatic vessels that carry a clear fluid called lymph unidirectionally towards either the right lymphatic duct or the thoracic duct, which in turn drain into the right and left subclavian veins respectively.
Lymphangiomas are rare congenital malformations consisting of focal proliferations of well-differentiated lymphatic tissue in multi cystic or sponge like structures. Lymphangioma is usually asymptomatic due to its soft consistency but compression of adjacent structures can be seen due to the mass effect of a large tumor.
An abnormality of the placenta, the organ that connects the developing fetus to the uterine wall to enable nutrient uptake, waste elimination, and gas exchange.
Excessive growth or abnormal thickening of bone tissue.
Systemic inflammatory response to infection.
(Septicaemia NOS) or (sepsis) (disorder)
Spontaneous flow of milk from the breast, unassociated with childbirth or nursing.
Galactorrhea due to non-obstetric cause (disorder)
Galactorrhea not associated with childbirth
Galactorrhea not associated with childbirth (disorder)
Vitamin K is a fat-soluble vitamin with a role in promoting the coagulation cascade.
Underdevelopment of the areola, the circular area of pigmented skin surrounding the nipple.
Congenital mesoblastic nephroma is a type of kidney tumor that is usually found before birth by ultrasound or within the first 3 months of life. It contains fibroblastic cells (connective tissue cells), and may spread to the other kidney or to nearby tissue.
An abnormality in the placement of the ocular globe (eyeball).
An abnormality in the size of the ocular globe (eyeball).
A tumor (abnormal growth of tissue) of adipose tissue.
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the mandible.
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the eye.
The presence of a characteristic high-pitched cry that sounds similar to the meowing of a kitten.
Any abnormality of the part of the nervous system that consists of the nerves and ganglia outside of the brain and spinal cord.
Any abnormality of the part of the peripheral nervous system associated with sensation and skeletal muscle voluntary control of body movements.
Abnormality of the somatic nervous system
An abnormality of nerve cell cluster or a group of nerve cell bodies located in the autonomic nervous system.
An abnormality of nerve cell cluster or a group of nerve cell bodies located in the peripheral autonomic nervous system.
Abnormality of ganglion of peripheral nervous system
An abnormality of nerve cell cluster or a group of nerve cell bodies located in the autonomic nervous system of the cranium.
Pain that is localized to the region of the upper abdomen immediately below the ribs.
Body odor characterized by an offensive body odor and the smell of rotting fish due to the excessive excretion of trimethylaminuria (TMA) in the urine, sweat, and breath of affected individuals.
A decrease in the level of 1,5 anhydroglucitol in the serum. 1,5-Anhydrosorbitol is a validated marker of short-term glycemic control. This substance is derived mainly from food, is well absorbed in the intestine, and is distributed to all organs and tissues.
Decreased level of 1,5-anhydro-D-glucitol in serum
Decreased level of 1,5-anhydroglucitol in serum
Decreased level of 1,5 anhydroglucitol in serum
An increase in the level of allantoin in the serum.
A decrease in the level of erythritol in the urine.
An increase in the level of D-threitol in the plasma.
An increase in the level of D-threitol in the cerebrospinal fluid.
Increased level of D-threitol in cerebrospinal fluid
An increase in the level of D-threitol in the urine.
A decrease in the level of D-mannose in the urine.
An increase in the level of galactitol in the plasma.
An increase in the level of galactitol in the urine.
An increase in the level of galactonate in the red blood cells.
Increased level of galactonate in erythrocytes
Increased level of galactonate in red blood cells
An increase in the level of galactitol in the red blood cells.
Increased level of galactitol in erythrocytes
Increased level of galactitol in red blood cells
An increase in the level of hippuric acid in the blood.
Increased level of N-benzoylglycine in blood
Increased level of hippuric acid in blood
An increase in the level of hippuric acid in the urine.
Increased level of N-benzoylglycine in urine
Increased level of hippuric acid in urine
An increase in the level of L-fucose in the urine.
An increase in the level of propylene glycol in the blood.
Increased level of propane-1,2-diol in blood
Increased level of propylene glycol in blood
An increase in the level of ribitol in the urine.
An increase in the level of ribitol in the cerebral spinal fluid.
Increased level of ribitol in cerebrospinal fluid
An increase in the level of ribose in the urine.
An increase in the level of ribose in the cerebrospinal fluid.
Increased level of ribose in cerebrospinal fluid
An increase in the level of xylitol in the urine.
An increase in the level of xylitol in the cerebrospinal fluid.
Increased level of xylitol in cerebrospinal fluid
An abnormality in biotinidase activity, an enzyme that releases biotin from biocytin, the product of biotin-dependent carboxylases degradation.
An increase in the level of N-acetylneuraminic acid in the urine.
Increased level of N-acetylneuraminic acid in urine
An increase in the level of N-acetylneuraminic acid in cultured fibroblasts.
Increased level of Neu5Ac in fibroblasts
Increased level of sialic acid in fibroblasts
Increased level of N-acetylneuraminic acid in fibroblasts
Any abnormality of the shoulder muscles.
An increase in the level of ketone bodies in the blood.
Increased level of ketone bodies in blood
An anomaly in the level of glucose-6-phosphate dehydrogenase.
Abnormal glucose-6-phosphate dehydrogenase level
An abnormality in uridine diphosphate glucose-4-epimerase activity, an enzyme that catalyzes the reaction: UDP-glucose = UDP-galactose.
Abnormal UDP-glucose 4-epimerase activity activity
Abnormal uridine diphosphate glucose-4-epimerase activity
Any deviation from the normal concentration of nicotinurate in the blood.
Abnormal circulating N-nicotinoylglycine level
A perceived unpleasant smell given off by the body.
Pain in and around the anus or rectum (perianal region).
A deviation from the normal circulating concentration of the normal gonadotropin-releasing hormone level secreted from the pituitary gland.
Abnormality of gonadotropin-releasing hormone level
Abnormal test result of cardiovascular physiology.
Abnormal results of a MRI for the heart.
Abnormal cardiac magnetic resonance imaging
Abnormal results from the diagnostic tests resulting from cardiac catheterization.
Abnormal results of exercise on heart function.
Resting energy expenditure (REE) can be measured with indirect calorimetry using a metabolic cart, which is used to measure the oxygen consumption (VO2) and carbon dioxide production (VCO2).
Abnormal resting energy expenditure from metabolic cart test
Abnormal blood test results measuring creatine kinase (CK), CK-MB, troponin (TROPI), myoglobin, and/or cardiac enzymes.
Presence of a xenobiotic in gastric fluid.
Structure of blastomere (body structure)
Structure of embryo stage 2 (body structure)
Embryo stage 1 structure (body structure)
Extraembryonic membranes (body structure)
Extraembryonic membranes structure (body structure)
Chorionic villi structure (body structure)
Structure of ductus arteriosus (body structure)
Structure of truncus arteriosus of fetus
Structure of truncus arteriosus of fetus (body structure)
Structure of truncus arteriosus of foetus
Structure of atrioventricular canal cushion
Structure of atrioventricular canal cushion (body structure)
Umbilical cord structure (body structure)
Structure of umbilical artery (body structure)
Structure of umbilical vein (body structure)
Structure of paramesonephric duct (body structure)
Food - Animal Products and Poultry Products, Egg, Yolk Gallus sp.
Structure of yolk stalk (body structure)
Structure of mesonephric duct (body structure)
Amputation stump (morphologic abnormality)
Structure of head of caudate nucleus (body structure)
Malignant neoplasm of abdomen (disorder)
Peritoneum (serous membrane) structure (body structure)
Abdominal wall structure (body structure)
Connective tissue structure (body structure)
Structure of fascial sheath of eyeball (body structure)
Granulation tissue (morphologic abnormality)
Structure of round ligament of uterus (body structure)
Broad ligament structure (body structure)
Ligament of joint, unspecified (body structure)
Structure of Wharton's jelly (body structure)
Structure of corneal endothelium (body structure)
Hair follicle structure (body structure)
Structure of spermatogenic epithelium (body structure)
Transitional Epithelium of the Urinary Tract
Exocrine gland structure (body structure)
Bartholin's gland structure (body structure)
Bulbourethral gland structure (body structure)
Lacrimal apparatus structure (body structure)
Minor salivary gland structure (body structure)
Salivary duct structure (body structure)
Apocrine gland structure (body structure)
Eccrine gland structure (body structure)
Structure of exocrine pancreas (body structure)
Lymphocytic tissue structure (body structure)
Bursa of Fabricius structure (body structure)
Follicular dendritic cell (body structure)
Aggregated lymphoid follicle of small intestine
Aggregated lymphoid nodules of small intestine
Lymphoid aggregate [dup] (body structure)
Noduli lymphoidei aggregati intestini tenuis
Structure of basilar membrane of cochlea
Structure of basilar membrane of cochlea (body structure)
Esophageal mucous membrane structure (body structure)
Gastric mucous membrane structure (body structure)
Intestinal mucous membrane structure (body structure)
Serous membrane structure (body structure)
Pericardial sac structure (body structure)
Pleural membrane structure (body structure)
Striated muscle (tissue) (body structure)
Cardiac muscle (tissue) (body structure)
Skeletal muscle fiber, type II (cell structure)
Skeletal muscle fiber, type I (cell structure)
Myelin sheath structure (body structure)
Myelin sheath structure (cell structure)
Cellular AND/OR subcellular structure (body structure)
Cell membrane structure (body structure)
Cell membrane structure (cell structure)
Cell Wall Skeleton [Chemical/Ingredient]
Erythrocyte inclusion (morphologic abnormality)
Viral inclusion body (morphologic abnormality)
Ring chromosome (morphologic abnormality)
Sex chromosome structure (body structure)
Chromosomes, Artificial, P1 Bacteriophage
Subcellular structure, isolated by fractionation technique
Subcellular structure, isolated by fractionation technique (body structure)
Subcellular structure, isolated by fractionation technique (cell structure)
Mitochondrial structure (body structure)
Mitochondrial structure (cell structure)
Dendritic spine apparatus (body structure)
Dendritic spine apparatus (cell structure)
Micronuclei, Chromosome-Defective [Disease/Finding]
GER aggregate (body structure) [Ambiguous]
Neuropil thread (morphologic abnormality)
Alzheimer's neurofibrillary degeneration
Neurofibrillary degeneration (morphologic abnormality)
Neurofibrillary tangles composed of disordered microtubules in neurons
Lysosome of male germ cell (body structure)
Acanthocyte [dup] (morphologic abnormality)
Cells, Granulocyte-Macrophage Progenitor
Progenitor Cells, Granulocyte Macrophage
Cell, Megakaryocyte-Erythroid Progenitor
Cells, Megakaryocyte-Erythroid Progenitor
Megakaryocyte Erythroid Progenitor Cells
Megakaryocyte-Erythroid Progenitor Cells
Erythroid precursor cell (body structure)
Red blood cell precursor (body structure)
Circulating Endothelial Progenitor Cells
Foreign body giant cell (body structure)
Amine Precursor Uptake and Decarboxylation Cells
Amine precursor uptake and decarboxylation cell
Amine precursor uptake and decarboxylation cell group
Structure of sertoli cell (body structure)
Structure of sertoli cell (cell structure)
Enterochromaffin-like cell (body structure)
Adrenocorticotropin-Secreting Cell, Pituitary
Adrenocorticotropin-Secreting Cells, Pituitary
Cells, Pituitary Adrenocorticotropin-Secreting
Pituitary Growth Hormone Secreting Cells
Pituitary Growth Hormone-Secreting Cells
External supporting cell of organ of Corti
Structure of supporting cell of organ of Corti
Structure of supporting cell of organ of Corti (body structure)
Hepatic parenchymal cell (body structure)
Perineuronal satellite cell (body structure)
Amacrine cells of retina (body structure)
Bipolar cells of retina (body structure)
Spinal Cord Ventral Horn Interneuron Renshaw
Structure of postganglionic sympathetic fiber
Structure of postganglionic sympathetic fiber (body structure)
Structure of postganglionic sympathetic fibre
Myelinated nerve fiber structure (body structure)
Non myelinated nerve fiber (body structure)
Gelatinous substance of posterior horn of spinal cord
A series of biochemical reactions which occurs in a known sequence and can result in all or part of the initiation, progression or completion of a biological process or function.
A sequence of biological or biochemical events that are involved in embryological or cellular development.
Cell Differentiation or Development Pathway
The heparan sulfate proteoglycan agrin is well known as the key assembly factor of postsynaptic differentiation at the neuromuscular junction (NMJ), but recent data suggest it also plays a direct role in the organization of the cytoskeleton in the skeletal muscle. Signaling through muscle-specific proteins such as muscle specific kinase (MuSK) and or acetylcholine receptor (AchRs)/rapsyn, agrin can activate ubiquitously expressed Rac, Cdc42, and p21-activated kinase (PAK) that are involved in actin polymerization. Agrin also engages signaling pathways of several potent oncogenes (i.e., SFK, ErbB receptors, and cortactin). (This definition may be outdated - see the DesignNote.)
Heart formation is cued by a combination of positive and negative signals from surrounding tissues. Inhibitory signals that block heart formation in anterior paraxial mesoderm include Wnt family members expressed in dorsal neural tube and anti-BMPs expressed in the axial tissues (i.e., noggin in the notochord). Wnt signaling pathway, which is essential for setting up the entire body pattern during embryonic development, involves glycogen synthase kinase-3 (GSK3). In the absence of Wnt signaling, GSK3 is active and phosphorylates b-catenin resulting in its degradation by ubiquitin-mediated proteolysis. Activation of Wnt signaling inhibits GSK3, thereby preventing phosphorylation of b-catenin, which is then able to move to the nucleus. There it associates with members of the LEF-1/TCF family of transcription factors, which activate the transcription of genes like cyclin-D1, myc, and MMPs. The Wnt signaling pathway is blocked by a family of secreted proteins such as crescent and Dkk-1 sufficient for induction of heart formation in posterior mesoderm. BMP signaling can also be blocked by the BMP antagonists noggin and chordin, which are secreted from the notochord and cooperate with Wnts to prevent cardiogenesis. Receptors for BMPs, members of the transforming growth factor-beta (TGFb) superfamily, are persistently expressed during cardiac development, yet mice lacking type II or type IA BMP receptors die at gastrulation and cannot be used to assess potential later roles in creation of the heart. Activin receptor-like kinase 3 (ALK3) is specifically required at mid-gestation for normal development of the trabeculae, compact myocardium, interventricular septum, and endocardial cushion. Cardiac muscle lacking ALK3 is specifically deficient in expressing TGFb2, an established paracrine mediator of cushion morphogenesis. In humans, congenital heart defects occur with a prevalence of at least 1% in newborns, and are even more common in death before term. Most frequent are defects in septation and the cardiac valves, and few single gene etiologies are known. The invariable defects in myocardium and AV cushion resulting from congenital deletion of ALK3 provide strong support for its assessment as a candidate gene in human congenital heart disease. (This definition may be outdated - see the DesignNote.)
Axon guidance represents a key stage in the formation of neuronal network. Axons are guided by a variety of guidance factors, such as netrins, ephrins, Slits, and semaphorins. These guidance cues are read by growth cone receptors, and signal transduction pathways downstream of these receptors converge onto the Rho GTPases to elicit changes in cytoskeletal organization that determine which way the growth cone will turn.
Bone density and structure is maintained through a balance of bone resorption by osteoclasts and bone deposition by osteoblasts. The combination of simultaneous resorption and deposition creates continual remodeling of bone while excess osteoclast activity leads to an imbalance and a loss of bone density, causing osteoporosis. RANK (receptor activator of NF-kB ligand) is a receptor in the TNF receptor gene family that is involved in osteoclast differentiation. RANK-ligand, also called osteoprotegerin-ligand, binds to RANK, induces receptor dimerization, and activates downstream signaling. Osteoprotegerin is a decoy receptor for RANK-ligand that suppresses osteoclast activity and bone remodeling, helping to maintain balanced bone remodeling. RANK-ligand and osteoprotegerin are produced by osteoblasts and some factors regulate osteoclast activity indirectly through their action on the expression of these factors by osteoblasts. Binding of RANK-ligand to RANK activates signaling through TRAF-6. TRAF-6 induces several downstream signaling events, including activation of NF-kB, c-Fos and the kinase JNK1. Jnk-1 activation contributes to fos activation by RANK-ligand and may be involved in the modulation of RANK-ligand by other factors such as estrogen. Mice lacking the c-Fos gene have overly dense bone and decreased bone resorption due to reduced osteoclast differentiation, indicating that c-Fos is an important mediator of osteoclast differentiation. One of the results of c-Fos induction is transcriptional activation of interferon-beta. Interferon-beta binds to its receptor on neighboring osteoclast precursor cells to block RANK-ligand signaling and down-regulate c-Fos expression, inhibiting further osteoclast differentiation. Mice lacking interferon-beta or the interferon-beta receptor lose bone due to uncontrolled osteoclast activity, demonstrating the importance of this mechanism in vivo. Interferon-beta signaling could be used as a mechanism to prevent osteoporosis and other conditions involving excessive osteoclast resorption of bone. (This definition may be outdated - see the DesignNote.)
The differentiation of keratinocytes constantly replenishes the upper layers of human skin we lose each day. One factor that contributes to terminal keratinocyte differentiation is increased levels of intracellular calcium. Adding calcium to the medium of cultured keratinocytes elevates intracellular calcium and triggers differentiation. Intracellular calcium levels are also increased in response to phospholipase C activation, producing IP3 and releasing calcium from stores in the ER. Intracellular calcium alters multiple signaling pathways, one of which is binding to calmodulin to activate the serine-threonine protein phosphatase calcineurin. Calcineurin dephosphorylates and activates the transcription factor NFAT and both calcineurin and NFAT are expressed in differentiating keratinocytes. Activated NFAT can regulate transcription through binding its own cognate DNA binding site. One marker of keratinocyte differentiation, the p21 gene, is activated by NFAT by a different mechanism, with NFAT activating the p21 promoter by acting as a coactivator for the transcription factors Sp1 and Sp3.Another protein activated by calcium that may be involved in keratinocyte differentiation is protein kinase C (PKC). One substrate of activated PKC is MARCKS (myristoylated alanine-rich kinase C substrate). Phosphorylation of MARCKS by PKC in intact keratinocytes is not induced during calcium-induced differentiation, but does increase when tested in vitro. PKC activity is increased by calcium during keratinocyte differentiation but PKC MARCKS phosphorylation is blocked by the formation of a complex between calmodulin and MARCKS. The immunosuppressants cyclosporin-A (CsA) and FK506 inhibit T cell activation through indirect inhibition of NFAT activation and have several side effects including changes in the skin, suggesting that calcineurin activity may play a role in normal skin physiology. CsA is used to treat psoriasis, a disease involving abnormal proliferation of skin cells. The activity of CsA in treating psoriasis may involve inhibition of immune cells, but may also directly involve inhibition of calcineurin activity in keratinocytes. (This definition may be outdated - see the DesignNote.)
Effects of calcineurin in Keratinocyte Differentiation
Stem cells in the bone marrow produce a variety of hematopoietic cell types from common progenitor cells under the influence of cytokines and growth factors. CFU-GEMM cells are a key intermediate in the differentiation of granulocytes, erythrocytes, monocytes and megakaryocytes. Erythropoietin (EPO) is a cytokine produced in the kidneys that, along with other cytokines, induces red blood cell (erythrocyte) differentiation in the bone marrow from CFU-GEMM cells. As the erythrocyte lineage progresses, cells lose their nuclei, and move out of the bone marrow into circulation. The ability of EPO to selectively induce red blood cell differentiation has allowed extensive therapeutic use of the recombinant form of this cytokine to treat anemias. (This definition may be outdated - see the DesignNote.)
SLRPs (Small leucine-rich proteoglycans) are extracellular molecules that bind to TGF-betas, collagens and other matrix molecules. In vitro, SLRPs were shown to regulate collagen fibrillogenesis, a process essential in development, tissue repair, and metastasis. The resilience and strength of bone is due to the orderly mineralization of a specialized extracellular matrix (ECM) composed of type I collagen (90%) and a host of non-collagenous proteins that are, in general, also found in other tissues. Biglycan (an SLRP encoded by the gene Bgn) is an ECM proteoglycan that is enriched in bone and other non-skeletal connective tissues. In vitro studies indicate that Bgn may function in connective tissue metabolism by binding to collagen fibrils and TGF-beta, and may promote neuronal survival. The effects of an individual SLRP deficiency are tissue specific and a variety of morphological phenotypes are the result of variations in level of expression of individual SLRPs in different tissues and synergisms between different SLRPs (and likely other macromolecules) in determining matrix structures. For example collagen structural phenotypes demonstrate a cooperative, sequential, timely orchestrated action of the SLRPs that altogether shape the architecture and mechanical properties of the collagen matrix. Disruption of the bgn gene results in reduced skeletal growth and bone mass leading to generalized osteopenia, particularly in older animals. In addition, other SLRP-deficient mice develop a wide array of diseases (osteoporosis, osteoarthritis, muscular dystrophy, Ehlers-Danlos syndrome, and corneal diseases), most of them resulting primarily from an abnormal collagen fibrillogenesis. (This definition may be outdated - see the DesignNote.)
Function of SLRP in Bone: An Integrated View
Small Leucine-Rich Proteoglycans in Bone Pathway
The process of hematopoiesis is regulated by various cytokines. The combination of cytokines stimulates the proliferation and/or differentiation of the various hematopoietic cell types. Bone marrow stromal cells are the major source of hematopoietic cytokines in the non-infectious state. In the presence of infection, cytokines produced by activated macrophages and TH cells induce hematopoietic activity. The induction by cytokines results in rapid expansion of the population of white blood cells to fight infection. (This definition may be outdated - see the DesignNote.)
Regulation of hematopoiesis by cytokines
Homeodomain transcription factors comprise a large family of DNA binding factors that regulate transcription and development. Many homeodomain genes arranged in genomic clusters determine anterior-posterior patterning, while others determine the fate of cells in specific tissues. The proliferation of cardiac myocytes and their differentiation early in development are dependent on the coordinate expression and action of serum response factor (SRF), GATA4 and the homeodomain factor Nkx2-5. All three of these factors are expressed in developing cardiomyocytes and induce expression of cardiac genes. Disruption of the Nkx2-5 gene in mice leads to embryonic lethality and defective cardiac development. SRF also plays a dual role in cardiac development, influencing both cardiomyocyte proliferation and differentiation depending on the stage and other signals that are present. In addition, the Hop (Homeodomain Only Protein) gene encodes a factor expressed early in cardiac development that is involved in cardiac differentiation. Hop inactivation in vertebrates leads to severe defects in cardiac development, acting downstream of Nkx2-5. Cardiac cells from mice lacking the Hop gene fail to exit the cell cycle in the normal manner, continuing to proliferate past the normal developmental stage. Many of the genes disregulated in the absence of Hop are involved in the cell cycle and are also targets of SRF. Although Hop is a homeodomain protein, it lacks a DNA-binding domain indicating that it must not regulate gene expression directly. Hop appears to regulate the expression of cardiac genes by binding to SRF and blocking DNA binding of SRF. The sequestration of SRF by Hop blocks the activation of cardiac genes, preventing normal cardiac development. The influence of Hop on the opposing processes of cardiomyocyte differentiation and proliferation reflect the interaction of Hop with SRF and the duel role SRF plays. In early cardiac development, Hop opposes differentiation induction by SRF, while at later stages Hop opposes the proliferation induced by SRF. (This definition may be outdated - see the DesignNote.)
The epidermis, which provides a protective barrier that undergoes a constant renewal, is a multi-layered tissue with the proliferating cells located in the basal layer. As cells leave the basal layer they undergo significant differentiation and biochemical and morphological remodeling. The final differentiation results in the formation of corneocytes. In vitro keratinocytes mimic this process. Several genes mark keratinocyte specific differentiation. Among the most frequently tracked markers are transglutaminase, cystatin and involucrin. Keratinocyte differentiation studies have identified and provided significant detail regarding the involvement of three of the 4 major MAP kinase pathways from several diverse stimuli such as EGF, FAS, TNF and calcium influx. The keratinocyte differentiation cascades also provide for detailed study of the functions of individual PKC isoforms and it is interesting to note the contrasting functions of the PKC isoforms in this process. In recent studies it has been determined that the cPKC (conventional/classical Protein Kinase C) isoforms, which are calcium-, phospholipid-, and diacylglycerol-dependent are inhibitory where as the nPKC (novel Protein Kinase C) isoforms which are calcium independent are stimulatory for keratinocyte differentiation markers. (This definition may be outdated - see the DesignNote.)
Lissencephaly-1 Gene in Neuronal Migration and Development
Terminal differentiation of cells is often accompanied by repression of cellular proliferation, suggesting that there is a mechanism by which these cellular functions are coordinated. Macrophage differentiation is one model system in which this occurs; as macrophages differentiate, they also stop proliferating. Transcriptional regulation plays a key role in cell cycle progression as well as many differentiation processes. Ras stimulates cell cycle progression in part through Ets transcription factors that bind to cell cycle regulatory genes to activate their expression. Ets transcription factors also help to induce early macrophage differentiation. The activation of Ras signaling by M-CSF activates transcription of genes involved in differentiation through the coordinate expression of both Ets factors and AP-1. Other genes involved in cell cycle regulation coordinate action of E2F-1 and Ets transcription factors. Mets is a factor related in sequence to Ets2 that is upregulated during macrophage differentiation. Increased expression of the Mets protein during macrophage differentiation allows the creation of heterodimers with DP103 to act as transcriptional repressors of cell cycle progression genes, recruiting corepressor to promoters they interact with. DP103 is a gene previously identified as an RNA helicase involved in RNA processing that interacts with EBNA factors from Epstein Barr Virus. The transcriptional repression involving Mets with DP103 is selective, and does not involve all Ets regulated genes. While cell cycle genes are repressed by Mets, other genes activated by Ets factors such as those involved in differentiation are not repressed by Mets. The transcriptional repression by Mets also involved members of the Rb family of tumor suppressors, such as p107 and p130. This requirement for additional factors involved in regulating proliferation may allow for another level of control on cell proliferation and coordination with differentiation. (This definition may be outdated - see the DesignNote.)
METS affect on Macrophage Differentiation
Studies with homozygous knockout mice have suggested that stem cell factor (SCF or KITLG), c-Kit, microphthalmia (Mitf), and B-cell CLL/lymphoma 2 (Bcl2) genes regulate melanocytic development. The SCF activation of Kit receptor leads to Mitf phosphorylation through the MAP kinase pathway. The activated Mitf recruits p300 and up-regulates Bcl2 transcription, which plays an important role in modulating the development and survival of the melanocyte lineage. (This definition may be outdated - see the DesignNote.)
Melanocyte Development and Pigmentation Pathway
Nephrin/Neph1 signaling in the kidney podocyte
Nephrin Signaling Pathway in the Kidney Podocyte
Axons extend significant distances to innervate target tissues. At the site of innervation, target tissues release neurotrophins including NGF, BDNF and neurotrophin-3 that stimulate the survival of the associated neuron. Local signaling by activated Trk receptors at the synaptic terminus mediates some presynaptic neuronal responses to neurotrophins. Map kinase pathways activated by Trk receptor activate Erk1 and Erk2 at the terminus stimulating axonal growth, and PI3K activates AKT in the terminus as well. Activation of these kinases does not propagate a signal to the cell body though and does not induce a transcriptional response. This local signaling at the terminus or local signaling at the cell body appears distinct from the signaling pathway that transduces the survival signal from the target tissue. Retrograde axonal transport plays an essential role in neuronal survival induced by neurotrophins released at the target tissue. Failure of retrograde neurotrophin signaling may play a role in neurodegenerative conditions. The neuronal survival signal is initiated by binding of neurotrophins to Trk receptors in the presynaptic membrane, and then travels back along the axon to the neuronal cell body. To transmit the signal back along the axon, activated Trk receptors are internalized through receptor-mediated endocytosis and receptor containing vesicles then rapidly travel back to the cell body along axonal microtubules. Several reports indicate that neurotrophins remain receptor-bound during the retrograde axonal transport to the cell body, but recently it was reported that retrograde transport of NGF was not required to induce neuronal survival. Once in the cell body, Trk receptors activate multiple pathways. A key pathway activated by Trk after retrograde transport involves Erk5, also called BMK1. Trk activates Mek5, which activates Erk5, inducing phosphorylation of the CREB and Mef2 transcription factors. Erk5 does not directly phosphorylate CREB, but translocates into the nucleus and phosphorylates the kinase Rsk, which phosphorylates CREB in turn. Both CREB and Mef2 induce a transcriptional program that contributes to neuronal survival. Local activation of Erk5 on the cell body does not appear to induce the same signaling system or neuronal survival, indicating that the retrograde transport is an essential part of the survival signaling system. Also, activation of Erk1 and Erk2 in the cell body can induce CREB activation and neuronal survival, but these kinases are not activated by neurotrophins applied to the axonal terminus. Another pathway activated by retrograde neurotrophin signaling though Erk5 is PI3 Kinase. (This definition may be outdated - see the DesignNote.)
Neurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Neurotrophins exert their functions through engagement of Trk tyrosine kinase receptors or p75 neurotrophin receptor (p75NTR). Neurotrophin/Trk signaling is regulated by connecting a variety of intracellular signaling cascades, which include MAPK pathway, PI-3 kinase pathway, and PLC pathway, transmitting positive signals like enhanced survival and growth. On the other hand, p75NTR transmits both positive and negative signals. These signals play an important role for neural development and additional higher-order activities such as learning and memory.
Progesterone (Pg) binds to both intracellular iPR and plasma membrane-bound mPR. After binding to Pg, iPR is recruited to the membrane associated protein tyrosine kinase p60c-src, which induces activation of the MAPK signaling pathway. This results in activation of p90Rsk and the subsequent phosphorylation and inactivation of Myt1, which favors formation of the activated cell cycle complex cyclin B-Cdc2. Activation of cyclin B-Cdc2 causes breakdown of the germinal vesicle and the initiation of oocyte maturation. In contrast, binding of Pg to mPR leads to inhibition of adenylyl cyclase (AC) through activation of Gai or inhibition of Gas. This leads to a decrease in the cAMP-dependent kinase PKA, which relieves inhibition of Cdc25C and also indirectly promotes the activation of MAPK signaling. PKA also regulates the initiation of oocyte maturation through other effects that are independent of PKA activity. (This definition may be outdated - see the DesignNote.)
How Progesterone Initiates the Oocyte Maturation
Xenopus oocytes are naturally arrested at G2 of meiosis I. Exposure to either insulin/IGF-1 or the steroid hormone progesterone breaks this arrest and induces resumption of the two meiotic division cycles and maturation of the oocyte into a mature, fertilizable egg. This process is termed oocyte maturation. The transition is accompanied by an increase in maturation promoting factor (MPF or Cdc2/cyclin B) which precedes germinal vesicle breakdown (GVBD). Most reports point towards the Mos-MEK1-ERK2 pathway [where ERK is an extracellular signal-related protein kinase, MEK is a MAPK/ERK kinase and Mos is a p42(MAPK) activator] and the polo-like kinase/CDC25 pathway as responsible for the activation of MPF in meiosis, most likely triggered by a decrease in cAMP.
Progesterone-Mediated Oocyte Maturation Pathway
In most animal species, the anteroposterior body axis is generated by the formation of repeated structures called segments. In vertebrate segmentation, a specialized mesodermal structure called the somite gives rise to skeletal muscles, vertebrae, and some dermis. Formation of the somites is a rhythmic process that involves an oscillator, the segmentation clock, driven by Wnt and Notch signaling. The clock ticks in somite precursors and halts when they reach a specific maturation stage defined as the wavefront, established by FGF and Wnt signaling. Lunatic fringe was shown to act downstream of Notch and to bind and negatively regulate its own promoter. Another cyclic gene is hes1. It acts also downstream of Notch and codes for an unstable protein able to negatively regulate its own promoter too. (This definition may be outdated - see the DesignNote.)
The differentiation of muscle cells is regulated by many factors, including the MyoD/MEF2 family of transcription factors. The MyoD/MEF2 dimer binds to promoters to activate genes involved in muscle cell differentiation. One of the factors that regulates the role of MyoD/MEF2 in myogenesis is the protein MEF2-interacting transcription repressor (MITR), a transcriptional repressor. When MITR is bound to MEF2, myogenesis genes are repressed rather than being activated. The transcriptional repression by MITR occurs in part at least through interaction with the CtBP (carboxy-terminal binding protein) corepressor. The inhibitory activity of MITR is itself regulated by the calmodulin dependent protein kinase CAMK. When CAMK is activated by factors such as IGF-1, it phosphorylates two specific residues in MITR, ser218 and ser448. Phosphorylated MITR does not bind to MEF2, but does bind to the protein 14-3-3, helping to block the repression of myogenesis. CAMK also plays a role in myogenesis through phosphorylation of histone deacetylase (HDAC), in which HDAC alters chromatin to repress myogenesis. Like MITR, phosphorylation of HDAC removes the repression, allowing myogenesis to continue. MITR shares sequence homology with HDAC, but itself lacks the enzyme motif. (This definition may be outdated - see the DesignNote.)
Signal Dependent Regulation of Myogenesis by Corepressor MITR
Signal Dependent Regulation of Myogenesis Pathway
The differentiation of muscle cells is transcriptionally regulated, in part by the myocyte enhancer factor-2, MEF2. During myogenesis MEF2 binds to MyoD and other basic helix-loop-helix factors to activate transcription of genes involved in muscle cell differentiation. Transcriptional activation by MEF2 is blocked by interaction with HDAC5 and other histone deacetylases. In undifferentiated myoblasts, HDAC5 is present in the nucleus where it binds to MEF2 to block activation of muscle genes. When activated by IGF-1 signaling, CaM kinase phosphorylates HDAC proteins, causing them to be exported from the nucleus, releasing the block on MEF2 transcriptional activation and allowing differentiation to proceed. Transcription cofactors also interact with MEF2 to contribute to gene regulation and myogenesis. The transcriptional regulator NFAT, for example, acts as a cofactor for MEF2 when calcium and calcineurin signaling activate it. There are four members of the Mef2 gene family, Mef2a-2d. Mef2a is expressed in brain, heart and skeletal muscle. Mef2c is involved in myogenesis in cardiac and skeletal muscle. Mef2d is widely expressed, and may be involved in the regulation of T cell function as well as muscle. Several factors regulate Mef2 transcription factors, including Map kinases and histone deacetylase (HDAC) enzymes. Mef2 is phosphorylated by p38 map kinase, and phosphorylation of Mef2c by p38 contributes to skeletal muscle differentiation. BMK-1 (also called Erk5) is another member of the Map kinase family that regulates the activity of Mef2 family members and is unique in that it appears itself to possess a transcriptional activation domain and act as a transcriptional coactivator. Mekk3 disruption prevented normal cardiovascular development in mice and appears to signal through p38 and Mef2c in normal cardiovascular development. (This definition may be outdated - see the DesignNote.)
Control of skeletal myogenesis by HDAC & calcium/calmodulin-dependent kinase (CaMK)
The small leucine-rich proteoglycans (SLRPs) are a family of proteins that are present in extracellular matrix and that share in common multiple repeats of a leucine-rich structural motif, flanked by cysteine residues. These proteins appear to interact in many cases with collagen, modifying the deposition and arrangement of collagen fibers in the extracellular matrix, and also with cells and with soluble growth factors. The interaction of SLRPs with cells and with growth factors like TGF-beta may affect the proliferation of cells in addition to modifying the extracellular environment. Post-translational modification of SLRPs with carbohydrates and sulfate-containing groups appears to modify the function of SLRPs. Changes in SLRP expression and modification in cornea, atherosclerotic plaque, joints, bone, tendons, and kidney may be associated with disease progression in those tissues. Decorin is one SLRP expressed throughout the body that stabilizes collagen fibrils and that also antagonizes the action of the cytokine TGF-beta, blocking cell cycle progression, and potentially playing a role in cancer and wound healing. The SLRP biglycan is expressed in bone and other connective tissues and genetic disruption of biglycan in mice causes low bone mass similar to osteoporosis. (This definition may be outdated - see the DesignNote.)
Small Leucine-Rich Proteoglycan (SLRP) Molecules
Small Leucine-Rich Proteoglycan (SLRP) Pathway
The postsynaptic density (PSD) is a submembranous structure at the postsynaptic membrane mainly at the excitatory synapses. The neurotransmitter receptors are assembled and fixed at the PSD, and several molecules implicated in the synaptic plasticity are also enriched. PSD-95/synapse-associated protein (SAP) 90 is involved in the molecular organization of these components of the PSD and essential for learning and memory. The common feature of these postsynaptic proteins is that they have PSD-95/Dlg/ZO-1 (PDZ) modular domains for protein-protein interaction. PDZ domains of these proteins directly recognize the C termini of their target proteins and are believed to play a central role in targeting and clustering of receptors to proper synaptic membranes. (This definition may be outdated - see the DesignNote.)
Synaptic Proteins at the Synaptic Junction
Helper T cells are found in two distinct cell types, Th1 and Th2, distinguished by the cytokines they produce and respond to and the immune responses they are involved in. Th1 cells produce pro-inflammatory cytokines like IFN-g, TNF-b and IL-2, while Th2 cells produce the cytokines IL-4, IL-5, IL-6 and IL-13. The cytokines produced by Th1 cells stimulate the phagocytosis and destruction of microbial pathogens while Th2 cytokines like IL-4 generally stimulate the production of antibodies directed toward large extracellular parasites. IL-5 stimulates eosinophil responses, also part of the immune response toward large extracellular parasites. Th1 and Th2 are produced by differentiation from a non-antigen exposed precursor cell type, Thp. Exposure of Thp cells to antigen by antigen-presenting cells may result in their differentiation to Th0 cells, not yet committed to become either Th1 or Th2 cells, although the existence of Th0 cells is controversial. Cells committed as either Th1 or Th2 cells are called polarized, whether they are effector cells actively secreting cytokines or are memory cells. The stimulation of Thp cells by exposure to antigen-presenting cells induces the proliferation of undifferentiated cells, and their expression of IL-2 and IL-2 receptor. The differentiation of Th1 cells and Th2 cells depends on the cytokines they are exposed to. IL-12 causes Th1 differentiation and blocks Th2 cell production, while IL-4 causes Th2 differentiation and antagonizes Th1 development. IL-18 also induces Th1 differentiation. Polarized Th1 and Th2 cells also express distinct sets of chemokine receptors that further modify their homing and other cellular responses. Improved understanding of Th1 and Th2 differentiation will improve our overall understanding of the immune system, its response to infection, and aberrant responses that lead to disease. (This definition may be outdated - see the DesignNote.)
An elaboration of the known steps and interactions required to allow cell movement.
Mammalian cell motility requires actin polymerization in the direction of movement to change membrane shape and extend cytoplasm into lamellipodia. The polymerization of actin to drive cell movement also involves branching of actin filaments into a network oriented with the growing ends of the fibers near the cell membrane. Manipulation of this process helps bacteria like Salmonella gain entry into cells they infect. Two of the proteins involved in the formation of Y branches and in cell motility are Arp2 and Arp3, both members of a large multiprotein complex containing several other polypeptides as well. The Arp2/3 complex is localized at the Y branch junction and induces actin polymerization. Activity of this complex is regulated by multiple different cell surface receptor signaling systems, activating WASP, and Arp2/3 in turn to cause changes in cell shape and cell motility. Wasp and its cousin Wave-1 interact with the Arp2/3 complex through the p21 component of the complex. The crystal structure of the Arp2/3 complex has revealed further insights into the nature of how the complex works. Activation by Wave-1, another member of the WASP family, also induces actin alterations in response to Rac1 signals upstream. Wave-1 is held in an inactive complex in the cytosol that is activated to allow Wave-1 to associate with Arp2/3. While WASP is activated by interaction with Cdc42, Wave-1, is activated by interaction with Rac1 and Nck. Wave-1 activation by Rac1 and Nck releases Wave-1 with Hspc300 to activate actin Y branching and polymerization by Arp2/3. Different members of this gene family may produce different actin cytoskeletal architectures. The immunological defects associated with mutation of the WASP gene, the Wiskott-Aldrich syndrome for which WASP was named, indicates the importance of this system for normal cellular function. (This definition may be outdated - see the DesignNote.)
Alpha4/Beta1 and Alpha4/Beta7 Integrin Signaling Pathway
Paxillin-dependent events mediated by a4b1
Paxillin-Dependent Alpha4/Beta1 Integrin Signaling Pathway
Paxillin-independent events mediated by a4b1 and a4b7
Paxillin-Independent Alpha4/Beta1 and Alpha4/Beta7 Integrin Signaling Pathway
Alpha6/Beta1 and Alpha6/Beta4 Integrin Signaling Pathway
The mammalian calpain gene family currently contains 13 distinct large subunit products most of which complex with one of two smaller 30kDa subunits. Spreading cells display newly transiently formed integrin adhesion clusters containing Calpain1 (mu-Calpain), cleaved Talin, B3-Integrin, and SPTAN1 (Spectrin). Recruitment of Rac to these clusters leads to the activation of Rac and the formation of Rac-induced focal clusters. The Calpain1 in the integrin clusters initially inactivates RhoA allowing for the formation of lamellipodia. The subsequent activation of newly synthesized RhoA transforms these clusters into Focal Adhesion Complexes and the formation of contractile actin-myosin stress fibers. These mature adhesions do not contain calpain. (This definition may be outdated - see the DesignNote.)
The mammalian calpain gene family currently contains 13 distinct large subunit products most of which complex with one of two smaller 30kDa subunits. One of the most carefully studied functions of the calpains is the regulation of integrin-mediated cell migration. Calpains digest the links between the actin cytoskeleton and several focal adhesion complex proteins; talin, paxillin and focal adhesion kinase. The release from the focal adhesion complex facilitates migration. Calpastatin is an inhibitor expressed in most cells. Calpastatin binds the four inhibitory domains of calpain. Release from calpastatin does not activate calpain. Activation requires additional signaling, coactivators, and an appropriate calcium concentration. During cell migration calpain1 (mu-calpain) acts at the leading edge as a response to integrin signals or calcium fluctuations due to the stretch activated calcium channels. Calpain1 cleaves the target proteins, talin, ezrin, paxillin, and the cytoplasmic tail of the integrins B1(a) and B3(b) to release the adhesion and form new adhesions. Calpain2 (M-calpain) is believed to be membrane bound and functions at the trailing edge of the migrating cell to cleave the integrins in response to growth factor receptor signals. PKA functions to down regulate or inhibit calpain2. In Alzheimer's disease, amyloid peptides interfere with calpain activity causing a mislocalization of cdk5. Deregulated cdk5 hyperphosphorylates tau promoting cell death in neurons. Mutations in the muscle specific calpain p94 lead to Limb Girdle muscular dystrophy 2A (LGMD2A). Over activity of calpains due to elevated calcium leads to tissue damage in the heart and brain. (This definition may be outdated - see the DesignNote.)
Migration of cells is involved in essential functions such as development, invasiveness of cancer cells, leukocyte movement toward chemotactic signals, and fibroblast response to injury. Cells can migrate in a specific direction in response to extracellular signals through pathways that trigger changes in the cytoskeleton, particularly actin filaments, increasing lamellipodia and filopodia formation and decreasing focal adhesions. Factors like PDGF activate PI3 kinase and multiple pathways downstream to stimulate cell migration. One pathway regulating migration through the p85 regulatory subunit of PI3 kinase does not require PI3-kinase activity. In this pathway, p85 of PI3-kinase activates cdc42, which activates N-Wasp (Wiskott-Aldrich Syndrome Protein) to regulate ARP-2/3. ARP-2/3 is a complex of proteins localized at the leading edge of moving cells that nucleates the formation of new actin fibers and interacts with Wasp to stimulate migration. The cdc42 pathway also regulates p21-activate kinase 1 (PAK1). Another pathway by which PI3 kinase regulates migration is through the small GTPase Rac. PAK1 is a downstream target of Rac as well as cdc42. Downstream of Rac and PAK1, Myosin light chain kinase (MLCK) phosphorylates myosin light chain to increase cell migration. The regulation of the localization and activity of signaling factors creates coordinated pathways linking extracellular signals and cellular migration. (This definition may be outdated - see the DesignNote.)
Role of PI3K subunit p85 in regulation of Actin Organization and Cell Migration
Activation of the MAPK kinase pathway has been identified as a mechanism that integrins use to regulate gene expression, leading to cell shape changes during cell spreading or migration. Epithelial cells respond to extracellular matrix (ECM) causing integrin-mediated FAK phosphorylation; this, in turn, phosphorylates the surrounding proteins (paxillin, Fyn/shc, and src) and leads to signal amplification. FAK also binds PI-3 kinase and acts upstream in the MAP kinase pathway. When MAP kinase or PI-3 kinase is inhibited, actin reorganization is blocked. Src phosphorylates p190RhoGAP, inactivating its GAP function and allowing RhoGTP to stay active longer, promoting further signal amplification. Activated RhoGTP binds to downstream kinases such as Rho-associated coiled coil-containing protein kinase (p160ROCK) and p140 diaphanous (p140Dia) to increase actin polymerization and contraction. Actin reorganization assists integrin clustering, allowing more ECM binding that increase FAK phosphorylation and other signal transduction events. (This definition may be outdated - see the DesignNote.)
Erk and PI-3 Kinase Are Necessary for Collagen Binding in Corneal Epithelia
Cell-matrix adhesions play essential roles in important biological processes including cell motility, cell proliferation, cell differentiation, regulation of gene expression and cell survival. At the cell-extracellular matrix contact points, specialized structures are formed and termed focal adhesions, where bundles of actin filaments are anchored to transmembrane receptors of the integrin family through a multi-molecular complex of junctional plaque proteins. Some of the constituents of focal adhesions participate in the structural link between membrane receptors and the actin cytoskeleton, while others are signaling molecules, including different protein kinases and phosphatases, their substrates, and various adapter proteins. Integrin signaling is dependent upon the non-receptor tyrosine kinase activities of the FAK and src proteins as well as the adaptor protein functions of FAK, src and Shc to initiate downstream signaling events. These signaling events culminate in reorganization of the actin cytoskeleton; a prerequisite for changes in cell shape and motility, and gene expression. Similar morphological alterations and modulation of gene expression are initiated by the binding of growth factors to their respective receptors, emphasizing the considerable crosstalk between adhesion- and growth factor-mediated signaling.
cell adhesion mediated by integrin complex
Cell adhesion is a fundamental feature of multicellular organisms including their defense mechanisms. In the later case in mammals, leukocytes play central role. They bind bacteria, parasites, viruses, tumor cells etc. Furthermore, their interactions with the endothelium are of special importance. During an inflammation or immune reaction, specialized leukocytes (eosinophilic granulocytes) adhere to and pass through the endothelium of the blood vessels and the underlying matrix. The reaction passes through the following steps: 1. Rolling (the flow of cells is slowed down by first making contacts to the endothelium via P-, E-, and L-selectins and their receptors); 2. Adhesion (After activation of leukocyte integrins, firm contacts are established between them and endothelium molecules of the Ig superfamily - LFA-1, Mac-1, VLA-4 etc.); 3. Flattening of the cells and diapedesis (Adhering leukocytes crawl to an intercellular junction of the endothelium and then transmigrate to or even through the intercellular matrix. This is mediated by homophilic interactions of PECAM and CD31. (This definition may be outdated - see the DesignNote.)
LIS1 can bind to MT bundles; however, phospho-LIS1 binding to MT bundles is mediated through the distal zinc finger motif of CLIP-170. When the distal zinc finger motif of CLIP-170 is mutated, the phospho-LIS1 isoform can no longer bind to MT bundles. This can also explain why p150/dynactin is not recruited to the MT bundles. CLIP-170 targets the dynein/dynactin complex to the MT, using phopho-LIS1 as an adapter; the motor complex, being in the proximity of the MT, associates with it. The initial static link to the MT provided by CLIP-170 is released by its hyperphosphorylation and the retrograde dynein/dynactin-dependent movement of the cargo (endocytic vesicle, kinetochore, etc.) takes place. Doublecortin (DCX) is placed close to the LIS1 pathway based on its interaction with LIS1 and its role in microtubule dynamics. (This definition may be outdated - see the DesignNote.)
Lissencephaly gene (LIS1) in neuronal migration and development
PAFAH1B1 Gene in Neuronal Migration and Development
Cell adhesion is a fundamental feature of multicellular organisms including their defense mechanisms. In the later case in mammals, leukocytes play a central role. They bind bacteria, parasites, viruses, tumor cells, etc. Furthermore, their interactions with the endothelium are of special importance. Generally, lymphocyte adhesion and passage from the bloodstream to the lymphatic system occurs in the high endothelial venules of the lymph nodes. This way the lymphocytes can communicate with each other in the lymphatic system and search for foreign compounds after their recirculation to the bloodstream, thus fulfilling their role in the immune system. The reaction passes through the following steps: 1. Rolling, the flow of cells is slowed down by first making contacts to the endothelium via P-, E-, and L-selectins and their receptors; 2. Adhesion, after activation of leukocyte integrins, firm contacts are established between them and endothelium molecules of the Ig superfamily (e.g., LFA-1, Mac-1, VLA-4); 3. Flattening of the cells and diapedesis, adhering leukocytes crawl to an intercellular junction of the endothelium and then transmigrate to or even through the intercellular matrix. This is mediated by homophilic interactions of PECAM and CD31. (This definition may be outdated - see the DesignNote.)
A sequence of biological or biochemical events that are manifest during the course of a disease.
Myocardial infraction (MI) is the condition of irreversible necrosis of the heart muscle that results from prolonged ischemia. Nearly 1.5 million people in US sustain an MI each year, and this event proves fatal in approximately one third of patients. Approximately 90% of MI results from formation of an acute thrombus that obstructs an atherosclerotic coronary artery. The thrombus transforms a region of plaque narrowing to one of complete vessel occlusion. The responsible thrombus appears to be generated by interactions between the atherosclerotic plaque, the coronary endothelium, circulating platelets, and dynamic vasomotor tone of the vessel wall, all of which overwhelm natural protective mechanisms. The endogenous protective mechanisms against thrombosis include: 1) Inactivation of thrombin by antithrombin III (ATIII), the effectiveness of which is enhanced by binding of ATIII to heparin sulfate. The antithrombin binding region of commercial heparin consists of sulfated disaccharide units; 2) Inactivation of clotting factors Va and VIIIa by activated protein C (protein C*), an action that is enhanced by protein S. Protein C is activated by the thrombomodulin (TM)-thrombin complex; 3) Inactivation of factor VII/tissue factor complex by tissue factor pathway inhibitor (TFPI). Coumarin drugs (Warfarin) blocks the g-carboxylation of Glu residues in prothrombin and factors VII, IX and X which results in incomplete molecules that are biologically inactive in coagulation (left panel); 4) Lysis of fibrin clots by tissue plasminogen activator (tPA); 5) Inhibition of platelet activation by prostacyclin and EDRF-NO. Platelets adhere to exposed collagen and are activated at the site of endothelial damage in the blood vessel. Activated platelets release adenosine diphosphate (ADP), serotonin (5-HT), and thromboxane A2 (TXA2), which activate additional platelets. Binding of thrombin further activates the platelets. Three adjoining platelets are shown in the process of viscous metamorphosis (top right). Increased cellular Ca2+ facilitates binding of fibrinogen. If the intraluminal thrombus at the site of plaque disruption totally occludes the vessel, blood flow beyond the obstruction will cease, prolonged ischemia will occur and MI (usually Q-wave MI) will likely result. (This definition may be outdated - see the DesignNote.)
After transplantation of organ allografts, there are two pathways of antigen presentation. In the direct pathway, recipient T cells react to intact allogeneic MHC molecules expressed on the surface of donor cells. This pathway would activate host CD4 or CD8 T cells. In contrast, donor MHC molecules (and all other proteins) shed from the graft can be taken up by host APCs and presented to recipient T cells in the context of self-MHC molecules - the indirect pathway. Such presentation activates predominantly CD4 T cells. A direct cytotoxic T-cell attack on graft cells can be made only by T cells that recognize the graft MHC molecules directly. Nontheless, T cells with indirect allospecificity can contribute to graft rejection by activating macrophages, which cause tissue injury and fibrosis, and are also likely to be important in the development of an alloantibody response to graft.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease that may result in arrhythmia, heart failure, and sudden death. The hallmark pathological findings are progressive myocyte loss and fibrofatty replacement, with a predilection for the right ventricle. A number of genetic studies have identified mutations in various components of the cardiac desmosome that have important roles in the pathogenesis of ARVD/C. Disruption of desmosomal function by defective proteins might lead to death of myocytes under mechanical stress. The myocardial injury may be accompanied by inflammation. Since regeneration of cardiac myocytes is limited, repair by fibrofatty replacement occurs. Several studies have implicated that desmosome dysfunction results in the delocalization and nuclear translocation of plakoglobin. As a result, competition between plakoglobin and beta-catenin will lead to the inhibition of Wnt/beta-catenin signaling, resulting in a shift from a myocyte fate towards an adipocyte fate of cells. The ryanodine receptor plays a crucial part in electromechanical coupling by control of release of calcium from the sarcoplasmic reticulum into the cytosol. Therefore, defects in this receptor could result in an imbalance of calcium homeostasis that might trigger cell death.
Arrhythmogenic right ventricular cardiomyopathy (ARVC)
Arrhythmogenic Right Ventricular Cardiomyopathy Pathway
Inhaled allergens encounter antigen presenting cells (APC) that line the airway. Upon recognition of the antigen and activation by APC, naive T cells differentiate into Th2 cells, a process that is promoted by interleukin 4 (IL-4). Activated Th2 cells stimulate B cells to produce IgE antibodies in response to IL-4 and IL-13. IgE binds the high affinity IgE receptor at the surface of mast cells, the proliferation and differentiation of which is promoted by IL-9.The crosslinking of mast-cell-bound IgE by allergens leads to the release of biologically active mediators (histamine, leukotrienes) by means of degranulation and, so, to the immediate symptoms of allergy. Activated mast cells and Th2 cells also induce the production of IL-5. IL-5 travels to the bone marrow and regulates the differentiation and egress of eosinophils from the bone marrow into the blood. Moreover activated mast cells and Th2 cells in the lung generate the cytokines interleukin IL-4, IL-13 and tumour necrosis factor (TNF)-alpha. These cytokines stimulate the generation of eotaxin by lung epithelial cells, fibroblasts and smooth muscle cells. Eotaxin then stimulates the selective recruitment of eosinophils from the airway microvessels into the lung tissue. The activation of eosinophils leads to release of toxic granules and oxygen free radicals that lead to tissue damage and promote the development of chronic inflammation.
The classification of autoimmune thyroid disease (AITD) includes Hashimoto's thyroiditis (HT) or chronic autoimmune thyroiditis and its variants, Graves' disease (GD) and autoimmune atrophic thyroiditis or primary myxedema.
Two major types of genetic events are crucial for the molecular pathogenesis of acute myeloid leukemias (AML): activating mutations of signal transduction intermediates and alterations in myeloid transcription factors governing hematopoietic differentiation. Both aberrant and constitutive activation of signal transduction molecules are found in about 50% of primary AML bone marrow samples, and seem to contribute to the increased proliferation and apoptosis resistance. The most common of these activating events were observed in the RTK Flt3, in N-Ras and K-Ras, in Kit, and sporadically in other RTKs. Specific haematopoietic transcription factors are crucial for differentiation to particular lineages during normal differentiation, but are frequently disrupted in AML. Some mechanisms of disruption involve the effect of fusion proteins that are generated by chromosomal translocations on haematopoietic transcription factors. In other cases, the transcription factors themselves are mutated.
The development of basal cell carcinoma is associated with constitutive activation of sonic hedgehog signaling. Normally, ligand-dependent signaling by Hedgehog (Hh) homologs proceeds through binding to the Patched receptor. This binding relieves the Patched-mediated inhibition of signaling through the Smoothened (SMOH) gene product. This signaling ultimately results in the dissociation of the Gli1 transcription factor from an inhibitory complex in the cytoplasm, its subsequent translocation to the nucleus, and activation of target gene expression. The mutations in SMOH, PTCH1, and SHH in BCCs result in continuous activation of target genes. At a cellular level, sonic hedgehog signaling promotes cell proliferation. Mutations in TP53 are also found with high frequency (>50%) in sporadic BCC.
Bladder cancers arise and progress along two distinctive pathways. The first of these is often preceded by simple and papillary hyperplasia and exhibits a tumour morphology that is low-grade, superficial and papillary. Papillary carcinoma has a tendency to recur locally, but rarely invades and metastasizes. These tumors frequently show a constitutive activation of the receptor tyrosine kinase-Ras pathway, exhibiting activating mutations in the HRAS and fibroblast growth factor receptor 3 (FGFR3) genes. The second tumour pathway is characterized by high-grade muscle-invasive tumours, which either originate from flat carcinoma in situ (CIS)/severe dysplasia or arise de novo. Over half of these tumours show defects in the tumour suppressors p53 and/or the retinoblastoma protein (RB) genes and pathways, and over 50% of these tumours progress to local and distant metastases. Some of the cell cycle-related molecules show evidence of epigenetic modulation through aberrant promoter hypermethylation in invasive bladder cancer. Invasion and metastases are promoted by several factors that alter the tumour microenvironment, including the aberrant expression of E-cadherins (E-cad), matrix metalloproteinases (MMPs), angiogenic factors such as vascular endothelial growth factor (VEGF).
Chronic myelogenous leukaemia (CML) is a biphasic disease, initiated by expression of the BCR/ABL fusion gene product in self-renewing, haematopoietic stem cells (HSCs). HSCs can differentiate into common myeloid progenitors (CMPs), which then differentiate into granulocyte/macrophage progenitors (GMPs). HSCs can also differentiate into common lymphoid progenitors (CLPs), which are the progenitors of lymphocytes such as T cells and B cells. The initial chronic phase of CML (CML-CP) is characterized by a massive expansion of the granulocytic-cell series. Acquisition of additional genetic mutations beyond expression of BCR/ABL causes the progression of CML from chronic phase to blast phase (CML-BP), characterized by an accumulation of myeloid or lymphoid blast cells.
Classically, colorectal cancer (CRC) has been believed to develop from normal mucosa through the premalignant adenoma by the step-wise accumulation of mutations. All CRC display either microsatellite instability (MSI) or chromosome instability (CIN). MSI occurs in 15% of colon cancers and results from inactivation of the DNA mismatch repair (MMR) system by either MMR gene mutations or hypermethylation of the MLH1 promoter. MSI promotes tumorigenesis through generating mutations in target genes that possess coding microsatellite repeats, such as beta-catenin, TGFBR2 and BAX. CIN is found in the majority of colon cancers and leads to a different pattern of gene alterations that contribute to tumor formation. Genes involved in CIN are those coding for APC, K-ras, SMAD4 and p53.
Two types of endometrial carcinoma are distinguished with respect to biology and clinical course.
Glioblastoma multiforme (GBM) formation is either de novo (primary GBMs) or due to the progression of a lower grade glioma to a higher grade one through the acquisition of additional mutations (secondary GBMs). In primary GBM, disruption of the p53 pathway often occurs through loss of ARF, or less frequently through amplification of MDM2. Disruption of the RB pathway occurs through loss of INK4A. Amplification and/or mutation of the epidermal growth factor receptor (EGFR) is the most frequently detected genetic defect that is associated with primary GBM. In secondary GBM, loss of p53 and activation of the growth-factor-receptor-tyrosine-kinase signaling pathway (such as through overexpression of PDGF/PDGFR) initiates tumour formation, whereas disruption of the retinoblastoma (RB) pathway contributes to the progression of tumour development. Loss of PTEN has been implicated in both pathways, although it is much more common in the pathogenesis of primary GBM.
Five distinct stages have been proposed in the evolution of melanoma on the basis of histological criteria: common acquired and congenital nevi without dysplastic changes; dysplastic nevi with structural and architectural atypia; radial-growth phase (RGP) melanoma; vertical-growth phase (VGP) melanoma; and metastatic melanoma. Oncogenic NRAS mutations activate both effector pathways Raf-MEK-ERK and PI3K-Akt. The Raf-MEK-ERK pathway may also be activated via mutations in the BRAF gene. The PI3K-Akt pathway may be activated through loss or mutation of the inhibitory tumor suppressor gene PTEN. These mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Moreover, melanoma development is strongly associated with inactivation of the p16INK4a/CDK4,6/pRb and p14ARF/HMD2/p53 tumor suppressor pathways. The vertical-growth phase and metastatic melanoma are notable for striking changes in the control of cell adhesion. Recently, amplification of the MITF gene was demonstrated in 10% of primary melanomas and 20% of metastatic melanomas, suggesting that MITF is a melanoma oncogene.
Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of lung cancer and represents a heterogeneous group of cancers, consisting mainly of squamous cell (SCC), adeno (AC) and large-cell carcinoma. Molecular mechanisms altered in NSCLC include activation of oncogenes, such as K-RAS and c-erbB-2, and inactivation of tumor suppressor genes, such as p53, p16INK4a, RAR-beta, and RASSF1. Point mutations within the K-RAS gene inactivate GTPase activity and the p21-RAS protein continuously transmits growth signals to the nucleus. Overexpression of c-erbB-2 or EGFR leads to a proliferative advantage. Inactivating mutation of p53 can lead to more rapid proliferation and reduced apoptosis. The protein encoded by the p16INK4a gene inhibits formation of CDK-cyclin-D complexes by competitive binding of CDK4 and CDK6. Loss of p16INK4a expression is a common feature of NSCLC RAR-beta is a nuclear receptor that bears vitamin-A-dependent transcriptional activity. RASSF1A is able to form heterodimers with Nore-1, an RAS effector. Therefore, loss of RASSF1A might shift the balance of RAS activity towards a growth-promoting effect.
Normal duct epithelium progresses to infiltrating cancer through a series of histologically defined precursors (PanINs). The overexpression of HER-2/neu and activating point mutations in the K-ras gene occur early, inactivation of the p16 gene at an intermediate stage, and the inactivation of p53, SMAD4, and BRCA2 occur relatively late. Activated K-ras engages multiple effector pathways. Although EGF receptors are conventionally regarded as upstream activators of RAS proteins, they can also act as RAS signal transducers via RAS-induced autocrine activation of the EGFR family ligands. Pancreatic ductal adenocarcinoma (PDA) show elevated expression of EGF receptors (e.g. HER2/neu) and their ligands (e.g. TGF-alpha) consistent with the presence of this autocrine loop. Moreover, PDA shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in p53 and BRCA2 are likely to contribute to these phenotypes. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor-beta signaling pathway.
Papillary thyroid carcinoma (PTC), the most frequent neoplasia originating from the thyroid epithelium, accounts for about 80% of all thyroid cancers. Chimeric oncogenes, created by chromosomal rearrangements involving prevalently RET and, to a less extent, NTRK1 loci, are implicated in the development of papillary carcinoma. These are inappropriately expressed and stimulate constitutive signaling, bypassing the need for receptor activation by growth factors. Alternatively, mutant RAS directly stimulates BRAF, whereas mutant BRAF directly stimulates MEK.
The identification of key molecular alterations in prostate-cancer cells implicates carcinogen defenses (GSTP1), growth-factor-signaling pathways (NKX3.1, PTEN, and p27), and androgens (AR) as critical determinants of the phenotype of prostate-cancer cells. Glutathione S-transferases (GSTP1) are detoxifying enzymes that catalyze conjunction of glutathione with harmful, electrophilic molecules, thereby protecting cells from carcinogenic factors. Cells of prostatic intraepithelial neoplasia, devoid of GSTP1, undergo genomic damage mediated by such carcinogens. NKX3.1, PTEN, and p27 regulate the growth and survival of prostate cells in the normal prostate. Inadequate levels of PTEN and NKX3.1 lead to a reduction in p27 levels and to increased proliferation and decreased apoptosis. After therapeutic reduction in the levels of testosterone and dihydrotestosterone, the emergence of androgen-independent prostate cancer has been associated with mutations in the androgen receptor (AR) that permit receptor activation by other ligands, increased expression of androgen receptors accompanying AR amplification, and ligand-independent androgen-receptor activation.
Renal cell carcinoma (RCC) is a heterogeneous term comprising a group of neoplasms of renal origin. There are 4 major histologic subtypes of RCC: conventional (clear cell RCC, 75%), papillary (15%), chromophobic (5%), and collecting duct (2%). Multiple genes are involved in the molecular pathogenesis of RCC. VHL is a tumor suppressor gene responsible for hereditary (von Hippel-Lindau) and sporadic variants of conventional (clear cell) RCC. In the absence of VHL, hypoxia-inducible factor alpha (HIF-alpha) accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. An oncogene, MET has been found to be mutant in cases of hereditary papillary renal cancer (HPRC), although the incidence of c-MET mutations is low in sporadic papillary RCC. Once activated, MET mediates a number of biological effects including motility, invasion of extracellular matrix, cellular transformation, prevention of apoptosis and metastasis formation. Mutations in the fumarate hydratase (FH) gene cause hereditary leiomyomatosis and renal cancer syndrome (HLRCC) papillary renal tumors, although the incidence of FH mutations in sporadic tumors is unknown. Loss of functional FH leads to accumulation of fumarate in the cell, triggering inhibition of HPH and preventing targeted pVHL-mediated degradation of HIF-alpha. BHD mutations cause the Birt-Hogg-Dube syndrome and its associated chromophobe, hybrid oncocytic, and conventional (clear cell) RCC. The incidence of BHD mutations in sporadic renal tumors is not known.
Small cell lung carcinoma (SCLC) is a highly aggressive neoplasm, which accounts for approximately 20% of all lung cancer cases. Molecular mechanisms altered in SCLC include induced expression of oncogene, MYC, and loss of tumor suppressor genes, such as p53, PTEN, RB, and FHIT. The overexpression of MYC proteins in SCLC is largely a result of gene amplification. Such overexpression leads to more rapid proliferation and loss of terminal differentiation. Mutation or deletion of p53 or PTEN can lead to more rapid proliferation and reduced apoptosis. The retinoblastoma gene RB1 encodes a nuclear phosphoprotein that helps to regulate cell-cycle progression. The fragile histidine triad gene FHIT encodes the enzyme diadenosine triphosphate hydrolase, which is thought to have an indirect role in proapoptosis and cell-cycle control.
BRCA1 and BRCA2 were identified genetically as breast cancer susceptibility genes when a single copy of the gene is mutated and are involved in the cellular response to DNA damage, including blocking cell cycle progression and inducing DNA repair to preserve the integrity of the genome during cell division. BRCA1 and BRCA2 induce double-stranded repair of breaks using homologous recombination, in part through activation of RAD51. BRCA1 acts as a ubiquitin ligase targeting the protein FancD2 that activates checkpoint control, integrating the ATM response to ionizing radiation and the FA response to cross-linking agents like mitomycin C. Mutation of one of the several components of the FA complex involved in maintaining integrity of the genome leads to the condition Fanconi anemia. One member of the FA complex was recently identified as BRCA2, which leads to Fanconi anemia when both copies of the gene are mutated. Another related factor involved in the response of cells to DNA damage is the kinase ATM. ATM is mutated in patients with AT, a condition with many similar traits to Fanconi anemia. Like ATM, ATR serves as a checkpoint kinase that halts cell cycle progression and induces DNA repair when DNA is damaged. Loss of ATR results in a loss of checkpoint control in response to DNA damage, leading to cell death. Deletion of the ATR gene in mice is embryonic lethal. ATRIP is a protein that interacts with ATR and is a substrate for its kinase activity. ATRIP is required for ATR function, and removal of ATRIP also leads to a loss of checkpoint control of the cell cycle. ATR and ATM kinase targets include repair enzymes like Rad51, and the checkpoint kinases Chk1 and Chk2, as well as BRCA1 and BRCA2. The close relationship of the genes involved in breast cancer and Fanconi anemia has helped illuminate this signaling system, and may help lead to improved understanding and treatment of these conditions. (This definition may be outdated - see the DesignNote.)
Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility
One of responses to increased blood pressure is cardiac hypertrophy through increased size of ventricular myocardial cells leading to increased thickness of the ventricular walls. Cardiac hypertrophy allows the heart to handle the increased stress caused by elevated blood pressure but is also a risk factor associated with heart disease. Cardiac hypertrophy results from cross-talk between G-protein coupled receptor signaling and the EGF receptor pathway. Several GPCR ligands are known to stimulate cardiac hypertrophy, including factors that regulate blood pressure such as angiotensin II and endothelin-1. These factors stimulate phospholipase C through Gq activation, and the production of 1P3 and diacylglycerol second messengers. PKC-delta is activated by DAG and interacts with the metalloproteinase ADAM12. ADAM12 cleaves the membrane-bound HB-EGF to release soluble EGF ligand that activates EGF receptor in myocardial cells. EGF receptor activation downstream through small G proteins and the MAP kinase pathway ultimately leads to cardiac hypertrophy. Signals by GPCR ligands such as angiotensin II result in transcriptional translation of immediate early genes like fos and other genes involved in long-term remodeling of heart tissue and the physiological response to stress in the heart such as the atrial natriuretic factor. Factors such as the AKT kinase, reactive oxygen species (ROS) and NE-kB also are involved in signaling that leads to hypertrophy, although their role is not yet clear. Blocking this pathway at various steps may prevent heart disease through the prevention of cardiac hypertrophy, but may also have other consequences. (This definition may be outdated - see the DesignNote.)
Role of EGF Receptor Transactivation by GPCRs in Cardiac Hypertrophy
Dilated cardiomyopathy (DCM) is a heart muscle disease characterised by dilation and impaired contraction of the left or both ventricles that results in progressive heart failure and sudden cardiac death from ventricular arrhythmia. Genetically inherited forms of DCM ("familial" DCM) have been identified in 25-35% of patients presenting with this disease, and the inherited gene defects are an important cause of "familial" DCM. The pathophysiology may be separated into two categories: defects in force generation and defects in force transmission. In cases where an underlying pathology cannot be identified, the patient is diagnosed with an "idiopathic" DCM. Current hypotheses regarding causes of "idiopathic" DCM focus on chronic viral myocarditis and/or on autoimmune abnormalities. Viral myocarditis may progress to an autoimmune phase and then to progressive cardiac dilatation. Antibodies to the beta1-adrenergic receptor (beta1AR), which are detected in a substantial number of patients with "idiopathic" DCM, may increase the concentration of intracellular cAMP and intracellular Ca2+, a condition often leading to a transient hyper-performance of the heart followed by depressed heart function and heart failure.
Graft-versus-host disease (GVHD) pathophysiology can be summerized in a three-step process. During step 1, the conditioning regimen (irradiation and/or chemotherapy) leads to damage, activation of host tissues and induction of inflammatory cytokines [tumour necrosis factor (TNF-alpha) and interleukin (IL-1)] secretion. Increased expression of major histocompatibility complex (MHC) antigens and adhesion molecules leads to enhancement of the recognition of host MHC and/or minor histocompatibility antigens by mature donor T cells.
Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with an autosomal dominant pattern of inheritance that is characterized by hypertrophy of the left ventricles with histological features of myocyte hypertrophy, myofibrillar disarray, and interstitial fibrosis. HCM is one of the most common inherited cardiac disorders, with a prevalence in young adults of 1 in 500. Hundreds of mutations in 11 genes that encode protein constituents of the sarcomere have been identified in HCM. These mutations increase the Ca2+ sensitivity of cardiac myofilaments. Increased myofilament Ca2+ sensitivity is expected to increase the ATP utilization by actomyosin at submaximal Ca2+ concentrations, which might cause an imbalance in energy supply and demand in the heart under severe stress. The inefficient use of ATP suggests that an inability to maintain normal ATP levels could be the central abnormality. This theory might be supported by the discovery of the role of a mutant PRKAG2 gene in HCM, which in active form acts as a central sensing mechanism protecting cells from depletion of ATP supplies. The increase in the myofilament Ca2+ sensitivity well account for the diastolic dysfunction of model animals as well as human patients of HCM. It has been widely proposed that left ventricular hypertrophy is not a primary manifestation but develops as compensatory response to sarcomere dysfunction.
Hypoxic stress, like DNA damage, induces p53 protein accumulation and p53-dependent apoptosis in oncogenically transformed cells. Unlike DNA damage, hypoxia does not induce p53-dependent cell cycle arrest, suggesting that p53 activity is differentially regulated by these two stresses. Hypoxia induces p53 protein accumulation, but in contrast to DNA damage, hypoxia fails to induce endogenous downstream p53 effector mRNAs and proteins, such as p21, Bax, CIP1, WAF1, etc. Hypoxia does not inhibit the induction of p53 target genes by ionizing radiation, indicating that p53-dependent transactivation requires a DNA damage-inducible signal that is lacking under hypoxic treatment alone. The phosphatidylinositol 3-OH-kinase-Akt pathway inhibits p53-mediated transcription and apoptosis. Mdm2, a ubiquitin ligase for p53, plays a central role in regulation of the stability of p53 and serves as a good substrate for Akt. Mdm-2 targets the p53 tumor suppressor for ubiquitin-dependent degradation by the proteasome, but, in addition, the p53 transcription factor induces Mdm-2, thus, establishing a feedback loop. Hypoxia or DNA damage by abrogating binding of HIF-1 with VHL and p53 with Mdm-2, respectively, leads to stabilization and accumulation of transcriptionally active HIF-1 and p53. At the molecular level, DNA damage induces the interaction of p53 with the transcriptional activator p300 as well as with the transcriptional corepressor mSin3A. In contrast, hypoxia primarily induces an interaction of p53 with mSin3A, but not with p300. (This definition may be outdated - see the DesignNote.)
Hypoxia and p53 in the Cardiovascular system
A sequence of biological or biochemical events that are the result of contracting an infection.
Entamoeba histolytica, an extracellular protozoan parasite, is a human pathogen that invades the intestinal epithelium. Infection occurs upon ingestion of contaminated water and food. The pathogenesis of amoebiasis begins with parasite attachment and disruption of the intestinal mucus layer, followed by apoptosis of host epithelial cells. Intestinal tissue destruction causes severe dysentery and ulcerations in amoebic colitis. Several amoebic proteins such as lectins, cysteine proteinases, and amoebapores are associated with the invasion process. The parasite can cause extraintestinal infection, like amoebic liver abscess, by evading the immune response.
One of the key causes of anthrax virulence is the action of three specific factors produced by the bacterium Bacillus anthracis. Even with successful antibiotic treatment, anthrax toxins can remain in the circulation and cause lethality. The toxins produced by anthrax bacteria are lethal factor (LF), protective antigen (PA) and edema factor (EF). The entry of toxin into cells begins with the recognition of a cellular receptor in the plasma membrane by PA. Proteolytic cleavage of cell-bound PA creates a smaller fragment that then multimerizes into a pore-like structure in the plasma membrane. The LF and EF proteins bind to the PA pre-pore, followed by internalization of the entire structure through receptor-mediated endocytosis. In the endosomal compartment, the acidic pH causes a conformational change that inserts PA fragments and releases LF and EF into the cytoplasm. In the cytoplasm, LF acts as a protease that cleaves MAP kinase kinase (MAPKK 1 and MAPKK 2), inhibiting pathways that rely on this kinase family and causing cell death. Edema factor is an adenylate cyclase that inhibits the immune response, including phagocytosis by macrophages. (This definition may be outdated - see the DesignNote.)
Many pathogenic bacteria can invade phagocytic and non-phagocytic cells, colonize them intracellularly, and then become disseminated to other cells. Invasive bacteria induce their own uptake by non-phagocytic host cells (e.g. epithelial cells) using two mechanisms referred to as zipper model and trigger model. Listeria, Staphylococcus, Streptococcus, and Yersinia are examples of bacteria that enter using the zipper model. These bacteria express proteins on their surfaces that interact with cellular receptors, initiating signaling cascades that result in close apposition of the cellular membrane around the entering bacteria. Shigella and Salmonella are the examples of bacteria entering cells using the trigger model. These bacteria use type III secretion systems to inject protein effectors that interact with the actin cytoskeleton.
Bacterial Invasion of Epithelial Cell Pathway
The neuromuscular junction communicates action potentials from motor neurons across a synapse to skeletal muscle. When an action impulse arrives at the neuromuscular junction, the entry of calcium through voltage-gated calcium channels causes synaptic vesicles to fuse with the presynaptic plasma membrane and release the neurotransmitter acetylcholine into the synaptic cleft. Acetylcholine diffuses across the cleft and binds to muscle acetylcholine receptors, causing depolarization and an action potential that travels throughout the length of the muscle cell triggering muscle contraction. The release of neurotransmitter at the synapse involves the fusion of synaptic vesicles with the neuronal plasma membrane and requires several proteins that act together to form a synaptic fusion complex. These proteins, collectively called SNARE proteins, include SNAP-25, syntaxin, and synaptobrevin. Homologs of these proteins are also involved in membrane fusion in other aspects of vesicle trafficking. Synaptobrevin (also called VAMP2) is localized at the synaptic vesicle membrane, while SNAP-25 and syntaxin are associated with the plasma membrane. Calcium release causes the formation of a complex, bringing the synaptic vesicle in close proximity with the plasma membrane and allowing fusion of the membranes. Biological toxins often disrupt nervous function, particularly the action of motor neurons. Botulinum toxin, synthesized by the bacteria Clostridium botulinum, is one of the most potent toxins known and acts by blocking neurotransmitter release at the neuromuscular junction. Botulinum toxin is a protein composed of two subunits joined by a disulfide bond, a 100 kD heavy subunit and a 50 kD light subunit that is a protease. There are seven serotypes of botulinum with distinct toxins. Tetanus toxin is similar in structure and in mechanism of action to botulinum toxin. The toxins can be absorbed in the intestine to travel in the blood to its site of action, at the neuromuscular junction. At the synapse botulinum toxin binds to the presynaptic membrane, and large subunit mediates internalization into the neuron through endocytosis. Once inside the neuron, the light chain is translocated across the vesicular membrane to act as a protease on cytoplasmic substrates. The targets of the toxin protease include the components of the synaptic fusion complex. Tetanus toxin and botulinum B, D, F and G toxins degrade synaptobrevin, while botulinum A, C and E toxins cleave SNAP-25. Syntaxin is also targeted by serotype C toxin. Destruction of these proteins by botulinum toxin prevents vesicular fusion in response to action potentials, blocking the release of acetylcholine. This blockade of communication between the nervous system and skeletal muscle can cause paralysis and can lead to death if the paralysis is severe enough to prevent breathing. In addition to acting as a toxin during botulism infection, botulinum toxin is also now being used as a pharmaceutical. Careful administration of very small doses of toxin can restrict its action locally to reduce overactive muscles, such as those involved in twitching of the eyes. Relaxing the muscles around the eyes can also reduce wrinkles in the eye region, leading to cosmetic use of this potent bacterial toxin. The potency of botulinum toxin has also caused concern that it could be used as a biological weapon, creating interest in the identification of inhibitors of this toxin. (This definition may be outdated - see the DesignNote.)
Blockade of Neurotransmitter Relase by Botulinum Toxin
Trypanosoma cruzi is an intracellular protozoan parasite that causes Chagas disease. The parasite life cycle involves hematophagous reduviid bugs as vectors. Once parasites enter the host body, they invade diverse host cells including cardiomyocytes. Establishment of infection depends on various parasite molecules such as cruzipain, oligopeptidase B, and trans-sialidase that activate Ca2+ signaling. Internalized parasites escape from the parasitophorous vacuole using secreted pore-forming TcTOX molecule and replicate in the cytosol. Multiplied parasites eventually lyse infected host cells and are released in the circulation. During these events, the parasites manipulate host innate immunity and elicit cardiomyocyte hypertrophy. T lymphocyte responses are also disturbed.
Chagas disease (American trypanosomiasis)
Two major virulence factors of H. pylori are the vacuolating cytotoxin (VacA) and the cag type-IV secretion system (T4SS) and its translocated effector protein, cytotoxin-associated antigen A (CagA).
Epithelial cell signaling in Helicobacter pylori infection
Epithelial Cell Signaling Pathway in Helicobacter pylori Infection
Hepatitis B is a small DNA virus that contains only 4 open reading frames in its genome. Three of these ORFs have been identified as the envelope, capsid and polymerase genes, while the function of the fourth has remained unknown until recently. The fourth reading frame has been called the X gene and produces HBx protein that is essential for viral replication in liver cells and acts broadly to activate a variety of transcription factors. One hypothesis of HBx activity has been that it enters the nucleus to act as a transcriptional regulator. One piece of evidence supporting this mechanism of HBx action is that HBx interacts with the transcription factor CREB and increases its DNA-binding activity. This mechanism does not explain all of the effects of HBx however. Another hypothesis for the HBx mechanism of action is that HBx increases calcium release into the cytoplasm. This mechanism of action is consistent with the variety of transcription factors and kinases affected by HBx since calcium signaling affects many different signaling pathways. HBx does not appear to interact directly with Ras or protein kinases but does appear to activate the calcium activate protein kinase Pyk2. A dominant negative form of Pyk2 blocks HBx activity and the involvement of calcium in HBx activation of Pyk2 is indicated by the action of several molecular probes that alter cytosolic calcium signaling. BAPTA-AM chelates cytosolic and blocks HBx action. Cyclosporin A blocks mitochondrial calcium signaling and also blocked HBx signaling. CGP37157 is a compound that blocks the mitochondrial sodium calcium pump and also blocks hepatitis B viral replication, indicating that mitochondrial calcium signaling is the target of HBx function. Compounds that elevate cytoplasmic calcium levels (valinomycin and thapsigargin) increase the rate of replication of viruses that lack HBx, further supporting the role of HBx as an inducer of intracellular calcium signaling. The mechanism by which HBx causes calcium release is not yet known. Src activation appears to induce viral replication while Ras signaling does not, suggesting that the activation of Ras signaling by HBx may play a distinct function, perhaps the induction of cancer. (This definition may be outdated - see the DesignNote.)
Calcium Signaling by HBx of Hepatitis B virus
Cells have many defenses against viral infection, including intracellular proteins that interfere with viral replication. Just as mammals have evolved defenses against viruses, viruses have evolved countermeasures to defeat cellular defenses. Vif is a viral gene produced by the HIV virus whose molecular function has remained unclear, but many aspects of its behavior have been revealed. Vif proteins are required for the production of infectious viral particles in many cells, acting to repress an intracellular T cell antiviral defense. Vif interacts with viral RNA and may help package viral genomic RNA to form mature virus. Some Vif is also found packaged in virion particles and multimerization of Vif appears to play a role in its activity. CEM15 is a cellular protein that provides an intracellular defense against HIV replication in T cells by acting against Vif. Viruses lacking the Vif gene are only able to replicate in cells lacking CEM15 and expressing CEM15 in cells is sufficient to prevent HIV infection. Although this research partially clarifies the function of Vif in HIV replication, many questions remain to be answered. CEM15 may or may not interact directly with Vif to block its function. Vif has been shown to bind to HIV genomic RNA and CEM15 has homology to cytidine deaminases, enzymes that edit RNA. This homology suggests that CEM15 may itself have an enzyme activity that modifies HIV RNA to render virus non-infectious. (This definition may be outdated - see the DesignNote.)
HIV-1 defeats host-mediated resistance by CEM15
HIV-1 Nef: Negative Effector Pathway for Fas and TNF-Alpha
HIV-1 Nef: Negative effector of Fas and TNF-alpha
To replicate in host cell, viruses commandeer cellular signaling pathways. Cytomegalovirus (CMV) is a DNA virus that is widespread in the population but usually causes disease only in immunocompromised individuals and is also a viral cause of birth defects. One of the actions of CMV in the host cell is to stimulate MAP kinase pathways. Both p38 and ERK kinases are activated by CMV infection through activation of map kinase kinases and inhibition of phosphatases. One result of Map kinase activation by CMV is activation of transcription of viral genes, increasing the production of viral gene products. Both p38 and ERK kinases contribute to the activation of viral genes by cellular transcription factors acting through the viral UL4 promoter at upstream and basal transcription elements. Another target of prolonged p38 activation during infection is Rb, contributing to viral replication. Activation of MKK1 and MKK2 leads to Erk1 and Erk2 activation, and phosphorylation of downstream targets. The MEKK1 kinase regulates the immediate early promoter indirectly through downstream kinase signaling and perhaps more directly through activation of NF-kB. Map kinase pathways activated by CMV converge on increased transcription of viral genes and increased replication of the viral genome. Better understanding of the mechanisms involved in the interaction of CMV with cellular signaling machinery will provide improved ways to treat CMV-mediated disease. (This definition may be outdated - see the DesignNote.)
Human Cytomegalovirus and Map Kinase Pathways
Leishmania is an intracellular protozoan parasite of macrophages that causes visceral, mucosal, and cutaneous diseases. The parasite is transmitted to humans by sandflies, where they survive and proliferate intracellularly by deactivating the macrophage. Successful infection of Leishmania is achieved by alteration of signaling events in the host cell, leading to enhanced production of the autoinhibitory molecules like TGF-beta and decreased induction of cytokines such as IL12 for protective immunity. Nitric oxide production is also inhibited. In addition, defective expression of major histocompatibility complex (MHC) genes silences subsequent T cell activation mediated by macrophages, resulting in abnormal immune responses.
Plasmodium protozoa are parasites that account for malaria infection. Sporozoite forms of the parasite are injected by mosquito bites under the skin and are carried to the liver where they develop into the merozoite form. Sporozoite invasion of hepatocytes is mediated by parasite surface protein like CSP. Subsequent infection into red blood cells (RBCs) by merozoites causes malaria disease via aberrant cytokine production and sequestration of parasite-infected red blood cells (pRBCs) to host endothelium. Microvasculature sequestration in the brain brings about cerebral malaria that can result in death or persisting neurological impairment. PfEMP1 has been suggested as the key adhesive molecule of pRBCs.
The role of Hemophilus influenzae in ear infections and chronic obstructive pulmonary disease includes the induction of an inflammatory response through activation of the transcription factor NF-kB. In addition to activation of inflammatory cytokine genes like IL-1 and TNF, H. influenzae activates TLR2 expression and genes involved in mucus production. Hemophilus influenzae activates NF-kB by multiple mechanisms, starting with activation of the Toll-like receptor 2 (TLR2) by the p16 protein in the H. influenzae outer membrane. TLR2 plays a key role in innate immune responses and is expressed in high levels in lymphoid cells as well as low levels in epithelial cells. The role of TLR2 was supported by blocking NF-kB activation with a dominant negative TLR2 and increasing it with transfection of a normal TLR2 gene. TLR2 in turn activates TAK1, which activates two divergent signaling pathways. One of these pathways leads to IkB kinase activation, IkB phosphorylation, and degradation, releasing the NF-kB heterodimer to translocate into the nucleus and activate transcription of target genes. In the alternate pathway, TAK1 also activates NF-kB through a Map kinase pathway, activating p38 and NF-kB in a nuclear translocation independent manner. Investigation of the mechanisms of H. influenzae signaling involved in NF-kB activation may provide the information needed to develop better treatments for inflammatory conditions caused by this pathogen. Other pathways modulate the role of NF-kB in H. influenzae pathogenesis. Glucocorticoids, widely used as anti-inflammatory drugs, increase TLR2 activation by H. influenzae through the NIK/I-kB kinase pathway, while they repress the p38 dependent activation of NF-kB. The repression of the p38 pathway by glucocorticoids occurs through activation of the MAP kinase phosphatase-1 (MKP-1) which dephosphorylates and deactivates p38. Another aspect of the inflammatory response to H. influenzae infection is the production of excessive mucus, contributing to the overall symptoms of infection. NF-kB activation of the Muc2 gene contributes to mucus overproduction, in addition to H. influenzae activation of the TGF-beta receptor, activating SMAD transcription factors SMAD3 and SMAD4. Understanding mechanisms that modify H. influenzae signaling will contribute to further understanding the pathogenesis and treatment of ear infections and chronic obstructive pulmonary disease. (This definition may be outdated - see the DesignNote.)
NFkB activation by Nontypeable Hemophilus influenzae
Enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) are closely related pathogenic strains of Escherichia coli. The hallmark of EPEC/EHEC infections is induction of attaching and effacing (A/E) lesions that damage intestinal epithelial cells. The capacity to form A/E lesions is encoded mainly by the locus of enterocyte effacement (LEE) pathogenicity island. Tir, Map, EspF, EspG are known LEE-encoded effector proteins secreted via the type III secretion system, which is also LEE-encoded, into the host cell. EPEC and EHEC Tir's link the extracellular bacterium to the cell cytoskeleton. Map and EspF are involved in mitochondrion membrane permeabilization. EspG interacts with tubulins and stimulates microtubule destabilization. LEE-encoded adhesin or intimin (Eae) is exported via the general secretory pathway to the periplasm, where it is inserted into the outer membrane. In addition to Tir, two potential host cell-carried intimin receptors, beta1 integrin (ITGB1) and nucleolin (NCL), have so far been identified. The distinguishing feature of EHEC is the elaboration of Shiga-like toxin (Stx). Stx cleaves ribosomal RNA, thereby disrupting protein synthesis and killing the intoxicated epithelial or endothelial cells.
Pathogenic Escherichia coli Infection Pathway
Pathogenic Salmonella enter cells such as those of the intestinal epithelium by altering cellular cytoskeletal structure and inducing membrane ruffling of the infected cell. Salmonella is able to alter the cytoskeleton and membrane through the action of secreted bacterial Sip proteins, SopE, SopB, and SptP that are inserted into the cytosol of the infected cell. Sip proteins encoded by Salmonella are required for the action of SopE and for the invasion of epithelial cells. SipA stabilizes actin filaments, inducing membrane ruffling and perhaps focusing membrane changes where bacteria are localized to allow their entry. SipC produces a similar effect on actin filaments and cytoskeletal structure. SopE acts as an exchange factor on Rac1 and Cdc42, two GTPases in the Rho family that regulate actin cytoskeleton. The activation of Rac2 and Cdc42 by Salmonella SopE induces changes in cytoskeleton structure that allow bacterial entry into the cell. SopB is another salmonella protein that acts as an inositol polyphosphate phosphatase and also stimulates Cdc42 and Rac1. One of the cellular targets of both Cdc42 and Rac1 that affects actin structure is the Arp2/3 complex. Cdc42 and Rac1 activate Wasp, which activates Arp2/3. Activated Arp2/3 induces the formation of actin Y branches, which in combination with changes in actin caused by SipA and SipC help to form lamellipodia, and causes membrane ruffling, leading to entry of Salmonella into the affected cell. After the initial infection, cells quickly return to their normal morphology, a process that depends on the action of the bacterial protein SptP. While SopE acts as an exchange factor, SptP acts as a GTPase activating protein to inactivate Rac1 and Cdc42 once again. This inactivation of the original entry mechanism provides an example of the delicate balance between infectious organisms and their host. (This definition may be outdated - see the DesignNote.)
Severe Acute Respiratory Syndrome (SARS) has affected thousands of individuals, causing fever, and pneumonia with a mortality rate estimated at 10-18%. Human coronaviruses cause mild respiratory illness and account for about a third of all cases of the common cold. A novel coronavirus has been identified as the causative agent of SARS and its genome has been sequenced. The enveloped SARS virus contains a large plus strand RNA genome, approximately 30,000 nucleotides. Examination of the SARS coronavirus sequences reveals that the rep gene covers over 20,000 nucleotides and encodes two overlapping polyproteins cleaved by viral proteases into smaller protein products. Translation of the longer polyprotein encoded by the rep gene requires a ribosomal frameshift. Other viral genes are predicted to encode the transmembrane spike protein S involved in viral fusion with host cells, the envelope protein E, the membrane protein M and the nucleocapsid protein N that binds to the RNA genome as well as several additional open reading frames with unknown functions. Viral entry into the cell is followed by translation of the viral rep gene, which codes for a viral protease within the polyprotein, Mpro or 3CLpro. The SARS 3CLpro has also been verified in vitro to cleave after the Gln residue at Leu-Gln-(Ser, Ala, Gly). Polypeptides released from the polyproteins by the main viral protease Mpro or 3CLpro include the viral polymerase and a protease. Both products are essential for viral replication and transcription. Structural crystals of a porcine coronavirus protease with a transition state inhibitor suggest that inhibitors of the distantly related rhinovirus protease like the drug AG7088 may be modified to produce drugs that block the SARS protease and viral replication. Blocking entry of the SARS virus into cells, involving recognition of cellular receptors by the S spike protein, may provide another strategy for the development of drugs to treat SARS. (This definition may be outdated - see the DesignNote.)
Shigellosis, or bacillary dysentery, is an intestinal infection caused by Shigella, a genus of enterobacteria. Shigella are potential food-borne pathogens that are capable of colonizing the intestinal epithelium by exploiting epithelial-cell functions and circumventing the host innate immune response. During basolateral entry into the host-cell cytoplasm, Shigella deliver a subset of effectors into the host cells through the type III secretion system. The effectors induce membrane ruffling through the stimulation of the Rac1-WAVE-Arp2/3 pathway, enabling bacterial entry into the epithelial cells. During multiplication within the cells, Shigella secrete another subset of effectors. VirG induces actin polymerization at one pole of the bacteria, allowing the bacteria to spread intracellularly and to infect adjacent cells. OspF, OspG and IpaH(9.8) downregulate the production of proinflammatory cytokines such as IL-8, helping bacteria circumvent the innate immune response.
Cholera toxin (CTX) is one of the main virulence factors of Vibrio cholerae. Once secreted, CTX B-chain (CTXB) binds to ganglioside GM1 on the surface of the host's cells. After binding takes place, the entire CTX complex is carried from plasma membrane (PM) to endoplasmic reticulum (ER). In the ER, the A-chain (CTXA) is recognized by protein disulfide isomerase (PDI), unfolded, and delivered to the membrane where the membrane-associated ER-oxidase, Ero1, oxidizes PDI to release the CTXA into the protein-conducting channel, Sec61. CTXA is then retro-translocated to the cytosol and induces water and electrolyte secretion by increasing cAMP levels via adenylate cyclase (AC) to exert toxicity.
Myocarditis is a cardiac disease associated with inflammation and injury of the myocardium. It results from various etiologies, both noninfectious and infectious, but coxsackievirus B3 (CVB3) is still considered the dominant etiological agent. Myocarditis may be caused by direct cytopathic effects of virus, a pathologic immune response to persistent virus, or autoimmunity triggered by the viral infection. The virus enters the myocyte through internalization of the coxsackie-adenoviral receptor (CAR) and its coreceptor, decay-accelerating factor (DAF). Viral proteases cleave various proteins in the host cell. One example is viral protease 2A, which cleaves eukaryote initiation factor 4G (eIF4G) and the dystrophin protein, resulting in a complete shutdown of cap-dependent RNA translation and cytoskeletal destruction in infected cardiomyocytes, respectively. CVB3 also cleaves the member of the Bcl-2 family Bid, leading to apoptosis. CVB3 infection also induces the cleavage of cyclin D protein through a proteasome-dependent pathway, leading to the host cell-growth arrest. Viral infection and necrosis of myocytes may lead to the release of intracellular antigens, resulting in activation of self-reactive T cells. CVB infection is a significant cause of dilated cardiomyopathy (DCM) as well as myocarditis. Epidemiologically, myocarditis underlies a significant portion of patients with DCM.
A description of the life cycle of the West Nile virus.
The insulin resistance of type II diabetes appears to be caused in part by the presence of high levels of lipids in cells such as skeletal muscle where this would not normally be found. The presence of excess lipid stores in skeletal muscle cells interferes with energy metabolism, impairing glucose oxidation and insulin response. Skeletal muscle is one of the primary glucose-consuming tissues, giving it a central role in insulin resistance. The increased risk of diabetes associated with obesity may be caused by increased lipid deposits in skeletal muscle and liver, creating insulin resistance. Leptin is a peptide hormone secreted by adipose tissue that has been associated with many processes. One of the target tissues of leptin is the hypothalamus where it can act to regulate feeding behavior and metabolism. Another leptin target is skeletal muscle. Activation of leptin signaling in skeletal muscle activates the AMP-activated protein kinase (AMP-kinase), known to play a key role in signaling in response to nutrients throughout evolution. AMPK phosphorylates and inactivates the enzyme ACC, acetyl-CoA carboxylase. ACC catalyzes the production of malonyl-CoA from acetyl-CoA. Malonyl-CoA in turn is an inhibitor of the import of fatty acids into mitochondria by carnitine palmitoyltransferase I for oxidation and energy production. In the presence of leptin, AMPK is activated, ACC is inhibited, and malonyl-CoA levels fall, increasing the oxidation of fatty acids and reducing the lipid content of cells. The reduced lipid content in skeletal muscle allows insulin signaling and glucose consumption to return to their normal levels, reducing insulin resistance. (This definition may be outdated - see the DesignNote.)
Reversal of Insulin Resistance by Leptin
Low-density lipoprotein (LDL) is a plasma lipoprotein particle whose lipid component includes cholesterol and triglycerides and is commonly referred to as bad cholesterol due to its role promoting atherogenic heart disease. LDL in the plasma originates from very-low density lipoprotein (vLDL) produced by the liver with the apoprotein B-100. vLDL is converted to LDL by the action of lipoprotein lipase, an enzyme that hydrolyzes triglycerides in vLDL, removing them from the vLDL particle and releasing free fatty acids. The removal of triglycerides from vLDL by lipoprotein lipase leaves a greater proportion of cholesterol, increasing the density of the particle and changing it to LDL. Atherogenic heart disease involves the formation of plaques in arterial walls that narrow the arterial passage, restricting blood flow and increasing the risk of occlusion of blood flow by a myocardial infarction. One of the first steps in the development of atherogenic heart disease is the passage of LDL out of the arterial lumen and into the arterial wall. Once there, the lipids in LDL are chemically modified and oxidized. Oxidized LDL stimulates inflammatory signaling by neighboring endothelial cells, releasing chemokines and cytokines such as M-CSF and MCP-1 and recruiting monocytes into the arterial wall. Once there, monocytes differentiate into macrophages and internalize modified LDL. These macrophages continue to internalize LDL, becoming enlarged and full of lipid. These cells accumulate in tissue and are transformed into foam cells, dying and forming part of the atherogenic plaque. Therapeutic intervention in atherogenic heart disease focuses first on lowering plasma LDL levels through diet and medication. The statins are drugs commonly used to block cholesterol production and increase the expression of the LDL receptor by the liver, removing LDL from circulation. Blocking LDL oxidation may also protect against atherogenesis, and may be the mechanism by which antioxidants such as vitamin E are proposed to reduce heart disease. Blocking the uptake of LDL by macrophages or inhibiting the inflammatory reaction against modified LDL may also offer routes to reduce the formation of atherogenic plaques. (This definition may be outdated - see the DesignNote.)
Low-density lipoprotein (LDL) pathway during atherogenesis
About 2-5% of type II diabetic patients suffer from a monogenic disease with autosomal dominant inheritance. This monogenic form of type II diabetes is called maturity onset diabetes of the young (MODY).
Type II Diabetes Mellitus in Young Patients Pathway
Maturity Onset Diabetes of the Young Pathway
Obesity is associated with many adverse health effects, including an increased risk of diabetes and heart disease. The combined condition of obesity, diabetes, and heart disease is sometimes referred to as the metabolic syndrome. One of the factors that best correlates obesity with the rest of the metabolic syndrome is not overall body mass, but the distribution of adipose tissue in the abdominal region, visceral obesity. Glucocorticoids have been associated as a risk factor for the metabolic syndrome, but most obese individuals have normal levels of circulating corticosteroids. Active corticosteroids such as cortisol and corticosterone activate the glucocorticoid receptor, a nuclear hormone receptor and transcription factor. Obese individuals have elevated levels in adipose tissue of a key enzyme in glucocorticoid metabolism, 11beta hydroxysteroid dehydrogenase type 1 (11betaHSD-1). 11betaHSD-1 interconverts inactive corticosteroids and the active form. When present in cells, 11betaHSD-1 can convert inactive corticosteroids from the blood to create locally high concentrations in a tissue such as adipose tissue. When activated in adipose tissue, GR increases the level of visceral fat, induces insulin resistance and dyslipidemias that increase the risk of heart disease. The mechanisms by which GR might induce the various aspects of the metabolic syndrome are a key area of research. One of the genes activated by GR is lipoprotein lipase. When GR is activated in visceral adipose tissue, it will increase the expression of lipoprotein lipase (LPL). This enzyme hydrolyzes triglycerides in plasma, releasing free fatty acids into tissues, where they can be reassembled into triglycerides. In visceral adipose, this GR-driven overexpression of lipoprotein lipase will result in the increased deposits of visceral fat that are observed. Genes thought to be involved in insulin resistance also appear to be affected by altered 11betaHSD-1 corticosteroid metabolism in visceral fat. This includes downregulation of resistin and adipoQ, and induction of TNF-alpha. The elevated free fatty acids and active corticosteroids released from visceral fat may account for the metabolic changes in liver associated with the metabolic syndrome. Antidiabetic thiazoidinedione drugs such as troglitazone and Avandia act as agonists of another nuclear receptor, PPAR-gamma. These drugs activate PPAR-gamma and repress expression of 11betaHSD-1 in visceral tissue, perhaps accounting in part for the antidiabetic insulin sensitizing properties of these drugs. (This definition may be outdated - see the DesignNote.)
Visceral Fat Deposits and the Metabolic Syndrome
Approximately 30% of breast carcinomas lack ER expression. Presumably, these breast cancers become estrogen independent through genetic alterations that bypass the requirement for ER-dependent stimulation of cell proliferation. As such, estrogen receptor is a key regulator of proliferation and differentiation in mammary epithelia and represents a crucial prognostic indicator and therapeutic target in breast cancer. Mechanistically, estrogen receptor induces changes in gene expression through direct gene activation of a number of genes (e.g., cathepsin D, HSP27, alpha-tubulin, glyceraldehyde-3-phosphatase, Pdzk1, Greb) and also through the biological functions of target loci. The product of human MTA3 has been identified as an estrogen-dependent component of the Mi-2/NuRD transcriptional corepressor in breast epithelial cells and demonstrates that MTA3 constitutes a key component of an estrogen-dependent pathway regulating growth and differentiation. The absence of estrogen receptor or of MTA3 leads to aberrant expression of the transcriptional repressor Snail, a master regulator of epithelial to mesenchymal transitions. Aberrant Snail expression results in loss of expression of the cell adhesion molecule E-cadherin, an event associated with changes in epithelial architecture and invasive growth. MTA3 is the mechanistic link between estrogen receptor status and invasive growth of breast cancers. (This definition may be outdated - see the DesignNote.)
Downregulated of MTA-3 in ER-negative Breast Tumors
Cyclin-dependent kinase 5 (cdk5), a multi-functional kinase, and its neuron-specific activator p35 are required for neurite outgrowth and cortical lamination. Proteolytic cleavage of p35 produces p25, which accumulates in the brains of patients with Alzheimer's disease. Conversion of p35 to p25 causes prolonged activation and mislocalization of cdk5 and the hyperphosphorylates tau, leading to the formation of paired helical filaments and promotion of apoptosis. In cultured primary cortical neurons, excitotoxins, hypoxic stress and calcium influx induce the production of p25. In fresh brain lysates, addition of calcium can stimulate cleavage of p35 to p25. Specific inhibitors of calpain1 effectively inhibit the calcium-induced cleavage of p35. In vitro, calpain1 directly cleaves p35 to release a fragment with relative molecular mass 25,000. Application of the amyloid beta-peptide A beta induces the conversion of p35 to p25 in primary cortical neurons. Inhibition of cdk5 or calpain activity reduces cell death in A beta-treated cortical neurons. These observations indicate that cleavage of p35 to p25 by calpain may be involved in the pathogenesis of Alzheimer's disease. GSK3B also phosphorylates tau but does not induce hyperphosphorylation in response to calpain activating stimuli. Additionally, down-regulation or inhibition of PP2A increases the hyper-phosphorylation of tau. (This definition may be outdated - see the DesignNote.)
Deregulation of CDK5 in Alzheimers Disease
Alzheimer's disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-beta (Abeta), a major component of senile plaques, has various pathological effects on cell and organelle function. The extracellular Abeta oligomers may activate caspases through activation of cell surface death receptors. Alternatively, intracellular Abeta may contribute to pathology by facilitating tau hyper-phosphorylation, disrupting mitochondria function, and triggering calcium dysfunction. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specifically the more amyloidogenic form, Abeta42. FAD-linked PS1 mutation downregulates the unfolded protein response and leads to vulnerability to ER stress.
Alzheimer's disease is associated with dense aggregations of proteins in the brain called amyloid plaques that contain beta-amyloid fragments as a primary component. If the development of amyloid plaques is responsible for neurodegeneration in Alzheimer's disease, reduction of beta-amyloid formation may prevent the development and progression of disease symptoms. Beta-amyloid fragments are derived from proteolytic processing of amyloid precursor protein (APP) in neurons, and the subsequent release of fragments into the extracellular space. APP in the ER is cleaved at residue 17 by alpha-secretase protease activity encoded by ADAM-10 and TACE. Beta-secretase activity, recently identified as BACE, cleaves in the N-terminus of the beta-amyloid fragment. Gamma-secretase cuts APP within the transmembrane domain at amino acids 40 and 42, releasing the beta-amyloid fragment containing residues 1-40/42 as well as shorter products such as p3 (residues 17-40/42) that requires alpha-secretase cleavage. The gamma-secretase activity requires the transmembrane protein Presenilin-1 that is itself cleaved into an N-terminal and C-terminal fragment that both are required for gamma-secretase activity. Mutations in presenilin-1 have been genetically associated with familial forms of Alzheimer's disease, further supporting the role of APP processing the development of the disease. Inhibition of the beta- or gamma-secretases may provide a mechanism to treat this disease. Other mechanisms may include altering degradation of beta-amyloid, and the use of vaccines against beta-amyloid to remove aggregates. (This definition may be outdated - see the DesignNote.)
Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of motor neurons. The hallmark of this disease is the selective death of motor neurons in the brain and spinal cord, leading to paralysis of voluntary muscles. Mutant superoxide dismutase 1 (SOD1), as seen in some familial amyotrophic lateral sclerosis (FALS) cases, may be toxic because it is unstable, forming aggregates in the motor neuron cytoplasm, axoplasm and mitochondria. Within mitochondria, mutant SOD1 may interfere with the anti-apoptotic function of Bcl-2, affect mitochondrial import by interfering with the translocation machinery (TOM/TIM), and generate toxic free radicals (ROS) via aberrant superoxide chemistry. These changes may then result in abnormal mitochondrial energy metabolism, Ca2+ handling, and release of pro-apoptotic factors. Reactive oxygen species (ROS), produced within mitochondria, inhibit the function of EAAT2, the main glial glutamate transporter protein, responsible for most of the reuptake of synaptically released glutamate. Glutamate excess causes neurotoxicity by increasing intracellular calcium, which enhances oxidative stress and mitochondrial damage. Mutant SOD1 can also trigger oxidative reactions by various means including by increasing levels of peroxynitrite, which can then cause damage through the formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. Nitration may target neurofilament proteins, disrupting their phosphorylation and affecting axonal transport. Collectively, these mechanisms (or a combination thereof) are predicted to disturb cellular homeostasis (within glial and/or motor neurons), ultimately triggering motor neuron death.
Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). HD is caused by a CAG repeat expansion in the IT15 gene, which results in a long stretch of polyglutamine close to the amino-terminus of the HD protein huntingtin (Htt). Mutant Htt (mHtt) has effects both in the cytoplasm and in the nucleus. In the cytoplasm, full-length mHtt can interfere with BDNF vesicular transport on microtubules. This mutant protein also may lead to abnormal endocytosis and secretion in neurons, because normal Htt form a complex with the proteins Hip1, clathrin and AP2 that are involved in endocytosis. In addition, mHtt affects Ca2+ signaling by sensitizing InsP3R1 to activation by InsP3, stimulating NR2B/NR1 NMDAR activity, and destabilizing mitochondrial Ca2+ handling. As a result, stimulation of glutamate receptors leads to supranormal Ca2+ responses in HD MSN and mitochondrial Ca2+ overload. The mHtt translocates to the nucleus, where it forms intranuclear inclusions, though they are not primarily responsible for toxicity. Nuclear toxicity is believed to be caused by interference with gene transcription, leading to loss of transcription of neuroprotective molecules such as BDNF. While mHtt binds to p53 and upregulates levels of nuclear p53 as well as p53 transcriptional activity. Augmented p53 mediates mitochondrial dysfunction.
Huntington's disease is a neurodegenerative condition caused by a dominant mutation in a gene encoding a protein now called huntingtin. Large polyglutamine repeats in the huntingtin protein are the genetic defect responsible for this condition, caused by expansion of a three-base pair repeat in the gene. Similar expansions of polyglutamine repeats are also found in other genes involved in neurodegenerative conditions. The polyglutamine repeat makes huntingtin protein insoluble and triggers the formation of protein aggregates. There are a few hypotheses for the connection between these aggregates and the neurodegeneration observed in Huntington's disease. One hypothesis is that mutant huntingtin moves into the nucleus and interferes with transcriptional activation involving the transcriptional coactivator CBP (CREB binding protein) and other coactivators. CBP interacts with transcriptional regulatory factors and with the basal transcriptional machinery to help regulate transcription. CBP is a large protein with multiple domains and in addition to interacting with several different transcription factors also has a histone acetylase enzyme activity. Mutant huntingtin binds to CBP, drawing it into insoluble protein aggregates. Mutant huntingtin also interacts directly with the acetyltransferase domain of CBP, blocking this activity. Activation of CBP acetyltransferase activity by transcriptional regulators results in the acetylation of histones in the promoter and enhancer regions of active genes, contributing to transcriptional activation by making these genes more accessible in chromatin. The lack of CBP in Huntington's affected neurons may lead to transcriptional repression of key genes that in turn leads to neurodegeneration. One potential treatment being tested is the treatment of Huntington's affected individuals with histone deacetylase inhibitors to restore normal acetylation levels and transcription. The repression of transcription may also be involved in other neurodegenerative conditions caused by proteins with expansions of polyglutamine repeats. (This definition may be outdated - see the DesignNote.)
Inhibition of Huntington's disease neurodegeneration by histone deacetylase inhibitors
Inhibition of Huntington's Disease Pathway
The motor defects of Parkinson's disease are related to the loss of dopaminergic neurons in specific brain regions. Examination of these neurons in diseased tissue has revealed the presence of Lewy bodies, dense aggregates that include the protein alpha-synuclein. A genetic basis for most cases of Parkinson's disease has not yet been identified, but mutations in alpha-synuclein have been associated with at least one rare form of the disease, and mutations in another protein, the parkin gene, are associated with another inherited form of Parkinson's disease. Parkin is found in Lewy bodies along with alpha-synuclein and the parkin protein is an enzyme, an E3 ubiquitin ligase. This ligase tags specific proteins in normal cells with ubiquitin, targeting them for destruction in the proteasome. One of the proteins that parkin normally targets for destruction is a specific O-glycosylated form of alpha-synuclein. Failure of parkin-mediated degradation of alpha-synuclein may be a key factor leading to the death of dopaminergic neurons. Another substrate of parkin is a GPCR-like protein called Pael-R that accumulates in the ER of affected cells and may cause neuronal cell death. The involvement of Parkin and alpha-synuclein mutations in genetic forms of Parkinson's suggests that failure of ubiquitination and protein degradation may be causative in other forms of Parkinson's. Questions remaining include the cause of the lack of effective ubiquitination in individuals lacking obvious genetic defects in this pathway and how to use this knowledge of ubiquitination and protein degradation in Parkinson's disease to identify therapeutic strategies. (This definition may be outdated - see the DesignNote.)
Alpha-synuclein and Parkin-mediated proteolysis in Parkinson's disease
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that results primarily from the death of dopaminergic neurons in the substantia nigra. Mutations in alpha-synuclein, UCHL1 (ubiquitin carboxy-terminal hydrolase L1), parkin, DJ1 (a parkin-associated protein involved with oxidative stress), and PINK1 (a putative serine threonine kinase) are known to cause early-onset PD. Mutations or altered expression of these proteins contributes to PD pathogenesis through common mechanisms that result in proteasome dysfunction, mitochondrial impairment, and oxidative stress. Point mutations in alpha-synuclein and the recently described functional duplication of alpha-synuclein lead to excessive intracellular accumulation and protofibril formation. Decrease in the amount of soluble alpha-synuclein tends to increase free cytoplasmic dopamine and the formation of reactive oxygen species (ROS). Indeed, formation of protofibrils or aggregates and Lewy bodies (LBs) diminishes the availability of the physiological forms of alpha-synuclein, favoring an increase in TH (tyrosine hydroxylase) and DAT (dopamine transporter), but diminishes formation of vesicles and neuronal plasticity. Modification of parkin and UCHL1 are associated with the ubiquitin-proteasome system pathway and may increase proteotoxic stress. Mutations in parkin, DJ1, and PINK1 may alter mitochondrial activity, potentially impairing proteasomal function. Environmental toxins such as N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone can cause mitochondrial dysfunction and oxidative stress.
Prion diseases, also termed transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative diseases that affect humans and a number of other animal species. The etiology of these diseases is thought to be associated with the conversion of a normal protein, PrPC, into an infectious, pathogenic form, PrPSc. The conversion is induced by prion infections (for example, variant Creutzfeldt-Jakob disease (vCJD), iatrogenic CJD, Kuru), mutations (familial CJD, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia (FFI)) or unknown factors (sporadic CJD (sCJD)), and is thought to occur after PrPC has reached the plasma membrane or is re-internalized for degradation. The PrPSc form shows greater protease resistance than PrPC and accumulates in affected individuals, often in the form of extracellular plaques. Pathways that may lead to neuronal death comprise oxidative stress, regulated activation of complement, ubiquitin-proteasome and endosomal-lysosomal systems, synaptic alterations and dendritic atrophy, corticosteroid response, and endoplasmic reticulum stress. In addition, the conformational transition could lead to the lost of a beneficial activity of the natively folded protein, PrPC.
Transmissible spongiform encephalopathy (TSE) is thought to result from the structural conversion of cellular prion protein, PrP(C), into a misfolded oligomeric form, PrP(Sc). PrP is a cell membrane GPI anchored glycoprotein that is expressed in most tissues and in high levels in the nervous system. Some likely cellular functions of PrP are (1) cell protection against oxidative stress, (2) induction of neuronal cell adhesion, neurite extension and maintenance, and (3) neuroprotective signaling through a cAMP/PKA-dependent pathway. (This definition may be outdated - see the DesignNote.)
Hypertrophy associated with both hypertension and obstruction to ventricular outflow leads to pathologic cardiac growth and it is associated with increase morbidity and mortality. Symptomatic ventricular disease takes a growing toll on the health of nations. As other cardiovascular diseases such as stroke and myocardial infarction are in decline as causes of mortality, the heart failure problem becomes increasingly urgent. Congenital heart defects occur in 1% of live births and fetal heart malformations are implicated in many pregnancies that end in still-birth or spontaneous abortion. The current paradigm suggests that the heart adapts to excess of hemodynamic loading by compensatory hypertrophy, which under condition of persistent stress, over time evolves into dysfunction and myocardial failure. There is considerable evidence that direct effects of increased mechanical stress are sensed within the ventricular wall and that signal is critical for the generation of growth responses. Despite compelling statistics we still do not understand biochemically why heart defects are so prevalent. A single transcriptional regulator initially associated with the activation of the T-cells (NFATc4) has been shown to link genetic and environmental causes of one class of congenital heart disorders, birth defects involving valve and septum formation. Within the endocardium, specific inductive events appear to activate NF-ATc: it is localized to the nucleus only in endocardial cells that are adjacent to the interface with the cardiac jelly and myocardium, which are thought to give the inductive stimulus to the valve primordia. Treatment with FK506, a specific calcineurin inhibitor, prevents nuclear localization of NF-ATc4. Activated CaMK stimulates calcineurin, which than acts through NF-ATc4 in association with GATA4, to induce hypertrophy. A model for the proposed role of calreticulin in the regulation of cardiac development requires a myogenic signal from extracellular space to activate the production of IP3 that results in the release of Ca2+ from ER under the regulation of calreticulin (CRT). Increased intracellular Ca2+ binds to calmodulin (CaM) and activates calcineurin (CaN). CaN dephosphorylates NF-ATc4 that translocates to the nucleus. In the nucleus NF-AT forms complexes with the GATA-4 and other transcription factors leading to activation of transcription of genes (e.g., ANF, a-actin, b-myosin, TNFa, ET-1, Adss1) essential for cardiac development. (This definition may be outdated - see the DesignNote.)
NFAT and Hypertrophy of the heart (Transcription in the broken heart)
Primary immunodeficiencies (PIs) are a heterogeneous group of disorders, which affect cellular and humoral immunity or non-specific host defense mechanisms mediated by complement proteins, and cells such as phagocytes and natural killer (NK) cells. These disorders of the immune system cause increased susceptibility to infection, autoimmune disease, and malignancy. Most of PIs are due to genetic defects that affect cell maturation or function at different levels during hematopoiesis. Disruption of the cellular immunity is observed in patients with defects in T cells or both T and B cells. These cellular immunodeficiencies comprise 20% of all PIs. Disorders of humoral immunity affect B-cell differentiation and antibody production. They account for 70% of all PIs.
Skeletal muscle atrophies with disuse while with increased use and increased load skeletal muscle exhibits hypertrophy, with an increase in the size of existing muscle fibers. One signaling pathway involved in regulating skeletal muscle atrophy and hypertrophy is the AKT/mTOR pathway. The mTOR pathway activity increases in response to muscle activity during hypertrophy and decreases in activity during atrophy. Blocking this pathway genetically or with the mTOR inhibitor rapamycin blocks hypertrophy and genetic activation of the pathway induces hypertrophy. One agent that promotes muscle hypertrophy is the growth factor IGF-1. IGF-1 activates AKT, GSK-3 beta, and mTOR to promote hypertrophy. In contrast, the calcineurin pathway is not involved in hypertrophy and is down-regulated by agents such as IGF-1 that promote hypertrophy. Calcineurin may modulate other aspects of muscle function such as the development of slow muscle fibers through transcriptional regulation. These pathways lead to regulation of protein translation, with increased translation apparently acting as a key regulatory point in skeletal muscle hypertrophy. Agents such as IGF-1 that stimulate skeletal muscle hypertrophy may provide treatments for muscle atrophy and wasting. (This definition may be outdated - see the DesignNote.)
Skeletal muscle hypertrophy is regulated via AKT/mTOR pathway
Systemic lupus erythematosus (SLE) is characterized by circulating IgG autoantibodies that are specific for self-antigens, such as DNA, nuclear proteins and certain cytoplasmic components. Immune complexes comprising autoantibody and self-antigen is deposited particularly in the renal glomeruli and mediate a systemic inflammatory response by activating complement or via Fc-gamma-R-mediated neutrophil and macrophage activation. Activation of complement leads to injury both through formation of the membrane attack complex (C5b-9) or by generation of the anaphylatoxin and cell activator C5a. Neutrophils and macrophages cause tissue injury by the release of oxidants and proteases.
Type I diabetes mellitus is a disease that results from autoimmune destruction of the insulin-producing beta-cells. Certain beta-cell proteins act as autoantigens after being processed by antigen-presenting cell (APC), such as macrophages and dendritic cells, and presented in a complex with MHC-II molecules on the surface of the APC. Then immunogenic signals from APC activate CD4+ T cells, predominantly of the Th1 subset. Antigen-activated Th1 cells produce IL-2 and IFNgamma. They activate macrophages and cytotoxic CD8+ T cells, and these effector cells may kill islet beta-cells by one or both of two types of mechanisms: (1) direct interactions of antigen-specific cytotoxic T cells with a beta-cell autoantigen-MHC-I complex on the beta-cell, and (2) non-specific inflammatory mediators, such as free radicals/oxidants and cytokines (IL-1, TNFalpha, TNFbeta, IFNgamma).
Insulin resistance is strongly associated with type II diabetes. "Diabetogenic" factors including FFA, TNFalpha and cellular stress induce insulin resistance through inhibition of IRS1 functions. Serine/threonine phosphorylation, interaction with SOCS, regulation of the expression, modification of the cellular localization, and degradation represent the molecular mechanisms stimulated by them. Various kinases (ERK, JNK, IKKbeta, PKCzeta, PKCtheta and mTOR) are involved in this process.
A sequence of biological or biochemical events that play a role in DNA repair.
BRCA1 is a breast and ovarian cancer tumor suppressor protein that associates with BARD1 to form a RING/RING heterodimer. The BRCA1/BARD1 RING complex functions as an ubiquitin (Ub) ligase with activity substantially greater than individual BRCA1 or BARD1 subunits. The BRCA1 tumor suppressor forms a heterodimer with the BARD1 protein, and the resulting complex functions as an E3 ubiquitin ligase that catalyzes the synthesis of polyubiquitin chains. UbcH5c and UbcH7 also interact with the BRCA1/BARD1 complex with similar affinity (not shown on this figure). Although the in vivo substrate(s) is not yet known, BRCA1 has been observed to undergo autoubiquitination and is capable of monoubiquitinating histones 2A and 2AX in vitro. (This definition may be outdated - see the DesignNote.)
Base excision repair (BER) is the predominant DNA damage repair pathway for the processing of small base lesions, derived from oxidation and alkylation damages. BER is normally defined as DNA repair initiated by lesion-specific DNA glycosylases and completed by either of the two sub-pathways: short-patch BER where only one nucleotide is replaced and long-patch BER where 2-13 nucleotides are replaced. Each sub-pathway of BER relies on the formation of protein complexes that assemble at the site of the DNA lesion and facilitate repair in a coordinated fashion. This process of complex formation appears to provide an increase in specificity and efficiency to the BER pathway, thereby facilitating the maintenance of genome integrity by preventing the accumulation of highly toxic repair intermediates.
Homologous recombination (HR) is essential for the accurate repair of DNA double-strand breaks (DSBs), potentially lethal lesions. HR takes place in the late S-G2 phase of the cell cycle and involves the generation of a single-stranded region of DNA, followed by strand invasion, formation of a Holliday junction, DNA synthesis using the intact strand as a template, branch migration and resolution. It is investigated that RecA/Rad51 family proteins play a central role. The breast cancer susceptibility protein Brca2 and the RecQ helicase BLM (Bloom syndrome mutated) are tumor suppressors that maintain genome integrity, at least in part, through HR.
DNA mismatch repair (MMR) is a highly conserved biological pathway that plays a key role in maintaining genomic stability. MMR corrects DNA mismatches generated during DNA replication, thereby preventing mutations from becoming permanent in dividing cells. MMR also suppresses homologous recombination and was recently shown to play a role in DNA damage signaling. Defects in MMR are associated with genome-wide instability, predisposition to certain types of cancer including HNPCC, resistance to certain chemotherapeutic agents, and abnormalities in meiosis and sterility in mammalian systems.
Nonhomologous end joining (NHEJ) eliminates DNA double-strand breaks (DSBs) by direct ligation. NHEJ involves binding of the KU heterodimer to double-stranded DNA ends, recruitment of DNA-PKcs (MRX complex in yeast), processing of ends, and recruitment of the DNA ligase IV (LIG4)-XRCC4 complex, which brings about ligation. A recent study shows that bacteria accomplish NHEJ using just two proteins (Ku and DNA ligase), whereas eukaryotes require many factors. NHEJ repairs DSBs at all stages of the cell cycle, bringing about the ligation of two DNA DSBs without the need for sequence homology, and so is error-prone.
Nucleotide excision repair (NER) is a mechanism to recognize and repair bulky DNA damage caused by compounds, environmental carcinogens, and exposure to UV-light. In humans hereditary defects in the NER pathway are linked to at least three diseases: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). The repair of damaged DNA involves at least 30 polypeptides within two different sub-pathways of NER known as transcription-coupled repair (TCR-NER) and global genome repair (GGR-NER). TCR refers to the expedited repair of lesions located in the actively transcribed strand of genes by RNA polymerase II (RNAP II). In GGR-NER the first step of damage recognition involves XPC-hHR23B complex together with XPE complex (in prokaryotes, uvrAB complex). The following steps of GGR-NER and TCR-NER are similar.
An elaboration of a sequence of physiological events that are elicited by the administration of a drug.
Acetaminophen is one of the world's most commonly used drugs, used for the treatment of pain and fever. Like other NSAIDs (non-steroidal anti-inflammatory drugs), acetaminophen has a unique activity profile based in part on its action at its molecular targets, the cyclooxygenase enzymes that produce prostaglandins responsible for pain, fever and inflammation. Until very recently, only two Cox enzymes, Cox-1 and Cox-2, were known to be targets of NSAIDS. Cox-1 is expressed in a constitutive manner throughout most tissues, and plays an essential role in maintaining the integrity of the stomach mucosal lining. Cox-2 is an inducible enzyme whose expression is induced by inflammation. NSAIDS selective for Cox-2 have been developed to avoid the development of ulcers by some non-selective NSAIDs, including aspirin. While these two isoforms were sufficient to account for most NSAIDs pharmacology, the actions of acetaminophen remained hard to explain on the basis of inhibiting Cox-1 and Cox-2 alone, such as its efficacy at reducing pain and fever but lack of anti-inflammatory effects. A novel Cox enzyme isoform encoded by the Cox-1 gene, Cox-3, contains an additional 30-34 amino acids and is expressed selectively in the brain. This insertion alters the pharmacology of the Cox enzyme, making Cox-3 sensitive to selective inhibition by acetaminophen and other drugs that reduce pain and fever but have weak anti-inflammatory activity, explaining the pharmacology of these drugs. Another characteristic of acetaminophen is its liver toxicity when taken at high doses. The target of this toxicity has also been recently been revealed. The nuclear receptor CAR is activated by many different exogenous compounds, including acetaminophen, inducing expression of three cytochrome P450 enzymes that transform acetaminophen into NAPQI, a reactive and toxic metabolite. Blocking CAR activation with an antagonist protects against acetaminophen liver toxicity, suggesting a strategy to treat acetaminophen toxicity. (This definition may be outdated - see the DesignNote.)
Mechanism of Acetaminophen Activity and Toxicity
Activation of the protease-activated GPCRs in platelets contributes to platelet activation in clotting. The protease-activated receptors PAR1 and PAR4 are cleaved by the protease thrombin, releasing a tethered peptide ligand that activates the receptor and triggers intracellular calcium release. Platelets from mice lacking the PAR4 gene are not activated by thrombin and are impaired in clotting, supporting the importance of thrombin signaling through PAR4 in clotting. Human platelets express both PAR1 and PAR4, with PAR1 playing a more dominant role in clotting in humans. Calcium release induced by PARs activates PKC, modulating integrin alpha IIB beta 3 (glycoprotein IIb/IIIa) and opening integrin ligand binding sites to contribute to platelet aggregation. Intracellular calcium increases induced by thrombin activate phospholipase A2, liberating arachidonic acid, the first step in prostaglandin and thromboxane biosynthesis. Ras/Map kinase activation by the PAR receptors also activates phospholipase A2. The activation of PAR-induced platelet aggregation is inhibited by aspirin, indicating that thromboxane production induced by PAR signaling contributes to platelet activation. Arachidonic acid is converted to the prostaglandin PGG2 by the enzyme Cox-1 in platelets, and Cox-1 is inhibited by aspirin, reducing thromboxane A2 production by platelets. Thromboxane is a potent vasoconstrictor and platelet activator, so inhibition of Cox-1 in platelets by aspirin may explain some of the cardioprotective actions of aspirin. (This definition may be outdated - see the DesignNote.)
Aspirin Blocks Signaling Pathway Involved in Platelet Activation
Aspirin Inhibition of Platelet Activation Pathway
Myocardial infarction damages heart tissue both during the initial ischemia and the subsequent reperfusion of tissues with oxygen. Corticosteroids can protect cardiac tissue from damage following a heart attack, but the mechanisms by which corticosteroids are cardioprotective have not been clear and negative side effects such as reduced wound healing may result from their use. Corticosteroids exert a variety of actions through binding to the glucocorticoid receptor (GR), a member of the steroid hormone receptor gene family. GR acts as a ligand-dependent transcription factor, but some of the cardioprotective effects mediated by GR-bound corticosteroids are non-transcriptional in nature. Glucocorticoids are commonly used as anti-inflammatory drugs in a variety of conditions, and some of their effects in the heart result from inhibition of the inflammatory response of heart tissue to ischemia and reperfusion. NF-kB is a transcription factor involved in signaling by inflammatory factors such as TNF, and is repressed by glucocorticoids. Annexin-1 is a calcium-dependent phospholipid binding protein whose expression is induced by corticosteroids and inhibits the infiltration of neutrophils into tissue, blocking reperfusion-induced inflammatory heart damage. A non-transcriptional cardioprotective effect of glucocorticoids is activation of NO production by endothelial nitric oxide synthase (eNOS). Glucocorticoids activate eNOS through activation of PI3 kinase and AKT and increased NO produced by eNOS can diffuse into surrounding tissues to prevent clotting and cause vasodilation. The beta-2 adrenergic receptor can also activate PI3 kinase and may synergize with glucocorticoids in this pathway. The atrial natriuretic factor (ANF) is a peptide secreted by the atrial wall in response to increased atrial pressure such as occurs during cardiac failure and to be decreased by myocardial infarction. Glucocorticoids increase the secretion of ANF by acting at the transcriptional level to increase expression of the pro-ANF peptide, perhaps inducing increased water excretion in the kidneys to reduce blood volume and reduce atrial pressure. The exploration of glucocorticoid responses may allow the identification of compounds that retain the cardioprotective activities but do not inhibit wound healing. Alternative mechanisms of eNOS activation may also provide a route to identify cardioprotective drugs. (This definition may be outdated - see the DesignNote.)
Flumazenil is a benzodiazepine receptor antagonist. It is used clinically to reverse the effects of benzodiazepines in conscious sedation, general anesthesia, and management of suspected benzodiazepine overdose. Kochs and colleagues reported that flumazenil might be beneficial in protecting against cerebral ischemia. Rapid administration of flumazenil produced minimal coronary and left ventricular hemodynamic responses. Thus this agent may be a potential candidate for clinical application in patients with ischemic heart diseases if it can mimic preconditioning to protect the heart. The study by Zhang and Yao indicates that flumazenil mimics preconditioning in cardiomyocytes via the generation of H2O2 as the reactive oxygen species (ROS). H2O2 opens mitochondrial KATP channels and inhibits GABA receptors via protein kinase C-epsilon in cardiomyocytes inducing ischemic preconditioning. This signal transduction and preconditioning protects ischemic cardiomyocytes. Zhang et al. indicate that the potential beneficial effects of Allitridum appear to mimic the same effects as flumazenil, to precondition cardiomyocytes, via the stimulation of PKC. Allitridum is an extract of garlic taken as a medicine in China for over 3000 years. (This definition may be outdated - see the DesignNote.)
Drug addiction is associated with long-term behavioral changes, suggesting a long-lived transcriptional regulator that responds to chronic drug exposure might cause long-term changes in neuronal function. Neurons in the nucleus accumbens and striatum are involved in addiction and have altered synaptic properties in response to chronic drug exposure. Along with JunD, delta-FosB is a component of an AP-1 transcription factor that accumulates in these key brain regions after chronic exposure to drugs of abuse, including morphine, amphetamine, alcohol, and cocaine. Delta-FosB is an unusually stable splice variant of the immediate early FosB gene, accumulating and persisting in the brain long after drug is removed. One component of FosB stability is post-translational modification through phosphorylation. Genetically modified mice that selectively overexpress this protein in neurons have increased sensitivity to cocaine and increased apparent reward response to drug administration, as expected in addiction, supporting the role of delta-FosB in addiction. The target genes regulated by delta-FosB include the GluR2 subunit of the AMPA glutamate receptor. Increased expression of GluR2 modifies the conductance and calcium flux of neurons, and may be responsible for increased reward responses to drug. Another target of delta-FosB is the dynorphin gene, the ligand for the kappa opioid receptor, further altering reward responses to drugs. The cell cycle checkpoint kinase cdk2 is activated by delta-FosB and acts on Darpp-32 to alter dopaminergic signaling. Although delta-FosB is very stable, it does degrade after several weeks, while the behavioral changes of drug addiction persist much longer after drug exposure ends. Changes in chromatin structure or changes in synaptic structure induced initially by delta-FosB may persist long after delta-FosB is no longer present, allowing behavioral changes to persist. (This definition may be outdated - see the DesignNote.)
The drug Gleevec (also known as imatinib mesylate or STI-571) was approved by the FDA in 2001 for the treatment of CML, chronic myeloid leukemia. While traditional cytotoxic cancer treatments such as chemotherapy or radiation therapy kill all dividing cells, Gleevec acts on a molecular target by a mechanism that is more specific to cancer cells. Traditional cytotoxic cancer agents have serious side effects such as nausea, weight loss, hair loss and severe fatigue that result from their lack of specificity in killing cells. Gleevec was designed as an inhibitor of a specific receptor associated with CML, and so produces less severe side effects than other cancer agents. CML is associated in most cases with a specific chromosomal defect, a translocation between chromosomes 9 and 22 that creates the Philadelphia chromosome. This translocation creates the abnormal bcr-abl protein, a fusion of the Abl gene with another gene called Bcr. The kinase activity of Abl in the bcr-abl fusion is activated and unregulated, driving the uncontrolled cell growth observed in CML. White blood cells containing the bcr-abl mutation become able to proliferate in the absence of growth factors they normally require. Gleevec inhibits Abl kinase activity, helping to reverse uncontrolled cell growth. Gleevec also inhibits the PDGF tyrosine kinase and the c-kit tyrosine kinase. There are a variety of cellular substrates of the bcr-abl kinase that may be involved in cellular transformation. Some of the downstream factors in bcr-abl signaling include PI3 kinase/AKT and STAT transcription factors. The activation of bcr-abl also represses apoptosis through induction of anti-apoptosis factors such as Bad, allowing transformed cells to divide. JAK2 kinase activity appears to be one target of bcr-abl. Grb-2 phosphorylation by bcr-abl may play a role in down-regulation of tyrosine kinase signaling. STAT5 may be involved in the failure of apoptosis in bcr-abl cells. In addition to supporting the idea that cancer therapies targeting specific molecular targets should be efficacious with fewer side effects, Gleevec has also demonstrated that drugs inhibiting protein kinases can be developed successfully. Tyrosine kinases are important in a range of cellular processes, including other cancers, and will provide additional drug targets. Gleevec itself has already demonstrated potential in other cancers such as gastrointestinal stromal tumor that do not respond to existing treatments. Although Gleevec has produced very strong clinical responses in patients with early stage CML, patients with late stage disease have had an initial response followed by a relapse of drug resistant CML cells. Cancer cells in patients with Gleevec resistant cancer either had amplification of the bcr-abl gene, or mutation of a key amino acid involved in binding drug from threonine to isoleucine. (This definition may be outdated - see the DesignNote.)
Inhibition of Cellular Proliferation by Gleevec
Inhibition of Cellular Proliferation by Gleevec Pathway
A sequence of biological or biochemical events that are involved in the conversion of genetic information into physiologically active molecules, such as functional RNA and proteins.
A complex network of interacting proteins and enzymes is required for DNA replication. Generally, DNA replication follows a multistep enzymatic pathway. At the DNA replication fork, a DNA helicase (DnaB or MCM complex) precedes the DNA synthetic machinery and unwinds the duplex parental DNA in cooperation with the SSB or RPA. On the leading strand, replication occurs continuously in a 5 to 3 direction, whereas on the lagging strand, DNA replication occurs discontinuously by synthesis and joining of short Okazaki fragments. In prokaryotes, the leading strand replication apparatus consists of a DNA polymerase (pol III core), a sliding clamp (beta), and a clamp loader (gamma delta complex). The DNA primase (DnaG) is needed to form RNA primers. Normally, during replication of the lagging-strand DNA template, an RNA primer is removed either by an RNase H or by the 5 to 3 exonuclease activity of DNA pol I, and the DNA ligase joins the Okazaki fragments. In eukaryotes, three DNA polymerases (alpha, delta, and epsilon) have been identified. DNA primase forms a permanent complex with DNA polymerase alpha. PCNA and RFC function as a clamp and a clamp loader. FEN 1 and RNase H1 remove the RNA from the Okazaki fragments and DNA ligase I joins the DNA.
About 8% of human genes have been estimated to carry out transcription from both DNA strands, resulting in significant level of endogenous antisense RNA. In the cytoplasm the antisense RNA leads to formation of long dsRNA, which activates the interferon and RNA-dependent protein kinase antiviral pathway. Most endogenous antisense RNA is made in the nucleus and two responses have been suggested for the nuclear dsRNA. First, the dsRNA may be processed by enzymes of the family of adenosine deaminases that act on RNA (ADAR). The deaminated dsRNAs contain various levels of inosines. dsRNA containing high level of inosines are tightly bound by a protein complex that results in their nuclear retention. dsRNA containing low level of inosines may be able to exit the nucleus. Second, the nuclear dsRNA can lead to gene silencing and heterochromatin formation. (This definition may be outdated - see the DesignNote.)
Double Stranded RNA Biosynthesis Pathway
Packaging of DNA into chromatin allows the cell to store its genetic information efficiently and has an important role in regulating gene expression. Recent studies have revealed that chromatin structure can be altered by covalent modification of nucleosomes, in particular acetylation and methylation of the core histone tails. Histone hyperacetylation usually characterizes active chromatin, while histone deacetylation correlates with repressed transcription. The Polycomb group (PcG) proteins are constituents of evolutionary highly conserved molecular pathways regulating cell fate in several tissues through diverse mechanisms, including 1) regulation of self-renewal/proliferation, 2) regulation of senescence/immortalization, 3) interaction with the initiation transcription machinery, 4) interaction with chromatin-condensation proteins, 5) modification of histones, 6) inactivation of paternal X chromosome, and 7) regulation of cell death. The PcG proteins form multimeric protein complexes, PRC1 and PRC2 which are involved in the heritable, stable repression of genes through modification of chromatin structure. The EED-EZH2 complex (PRC 2 complex) acts early in development to set the stage for the long term repressive PRC1 complex. The PRC2 complex is probably tethered to promoters of affected genes through the interaction with specific DNA binding factors, such as YY1, a zinc finger transcription factor that acts as both a positive and negative regulator of transcription of cellular and viral genes. The EED-EZH2 proteins interact with histone deacetylase core complex consisting of the histone deacetylases HDAC1 and HDAC2 and the histone binding proteins RbAp48 and RbAp46. Histone deacetylation is probably a prerequisite for subsequent methylation, as histone tails cannot be acetylated and methylated in the same time. The PRC complex specifically methylates nucleosomal histone H3 at lysine 27, providing an epigenetic mark for binding of PRC1 complex. The histone methyltransferase activity of PRC2 is dependent on an intact SET domain in the EZH2 protein. PRC1 complex blocks chromatin remodeling by SWI/SNF factors, thus preventing transcription of repressed chromosome regions. (This definition may be outdated - see the DesignNote.)
The PRC2 Complex Sets Long-term Gene Silencing Through Modification of Histone Tails
Control of translation is one of the major regulatory events in eukaryotic gene expression. Internal ribosome entry sites (IRES) were first discovered in picornavirus RNAs but it is now clear that IRESs are also present in the 5' untranslated region of many eukaryotic genes including those encoding growth factors (e.g., VEGF, FGF2 and PDGF), genes whose protein products are associated with apoptosis (e.g., Apaf-1, IXAP), transcription factors (e.g., c- myc), and the potassium channel Kv1.4. IRES allows the ribosomes to be recruited to an initiator AUG, which is some distance from the 5' end of the message RNA to bypass the Kozak scanning mechanism. In the Kozak scanning model, the 40S ribosomal subunit bearing Met-tRNAmet and initiation factors, binds near the capped 5' end of the mRNA and travels along the mRNA until it comes to the first AUG. IRES-dependent initiation of protein synthesis occurs during apoptosis or some viral infection (e.g., picornavirus). A component of the cap-binding complex eIF-4F, translation initiation factor eIF-4G, is cleaved (by caspases or viral protein 2A) to give a modified form of cap-binding complex that is cap-independent. (This definition may be outdated - see the DesignNote.)
Basal Transcription Factor Assembly Pathway
After transcription, eukaryotic mRNA precursors contain protein-coding exons and noncoding introns. In the following splicing, introns are excised and exons are joined by a macromolecular complex, the spliceosome. The standard spliceosome is made up of five small nuclear ribonucleoproteins (snRNPs), U1, U2, U4, U5, and U6 snRNPs, and several spliceosome-associated proteins (SAPs). Spliceosomes are not a simple stable complex, but a dynamic family of particles that assemble on the mRNA precursor and help fold it into a conformation that allows transesterification to proceed. Various spliceosome forms (e.g. A-, B- and C-complexes) have been identified.
Gene expression requires the coordination and integration of multiple processes, including transcription, splicing, polyadenylation, nucleocytoplasmic export, and translation of mRNAs. Posttranscriptional addition of poly (A) to the 3' end of mRNA is an important process conserved from bacteria to humans. In eukaryotes, polyadenylation is essential for the stability of many mRNAs and also influences the efficiency of translation. Most histone-mRNAs and all snRNAs (except U6), however are not polyadenylated. The mature mRNA moves to the nuclear surface and is exported through nuclear pores. (This definition may be outdated - see the DesignNote.)
The scanning translation initiation model suggests that 40S ribosomal subunit preloaded with factors bind to the 5' end of the mRNA near the cap. The 48S subunit moves along the mRNA until it finds the initiation triplet and in complex with tRNA and 60S subunit forms the first peptide bond. Translation control is mostly regulated at the protein initiation step through translation initiation factors such as eIF2 or eIF4. (This definition may be outdated - see the DesignNote.)
The correct processing, quality control and turnover of cellular RNA molecules are critical to many aspects in the expression of genetic information. In eukaryotes, two major pathways of mRNA decay exist and both pathways are initiated by poly(A) shortening of the mRNA. In the 5' to 3' pathway, this is followed by decapping which then permits the 5' to 3' exonucleolytic degradation of transcripts. In the 3' to 5' pathway, the exosome, a large multisubunit complex, plays a key role. The exosome exists in archaeal cells, too. In bacteria, endoribonuclease E, a key enzyme involved in RNA decay and processing, organizes a protein complex called degradosome. RNase E or R interacts with the phosphate-dependent exoribonuclease polynucleotide phosphorylase, DEAD-box helicases, and additional factors in the RNA-degrading complex.
Unlike the RNA polymerase II that transcribes a large variety of genes that encode proteins, RNA polymerase III transcribes only a limited number of genes (i.e., 5S rRNA, tRNA, 7SL RNA, U6 snRNA, and a few other small stable RNAs); however, the transcriptional activities of RNA pol III along with pol I account for 80% of total RNA synthesis. The A and B block sequences found in most pol III promoters are recognized by a multisubunit complex, TFIIIC. The binding of TFIIIC recruits TFIIIB, a complex of polypeptides (in human, TATA-binding protein (TBP), TFIIB-related factor (BRF), and one or more unidentified protein). Once TFIIIB is brought to the general location by TFIIIC and optimally positioned by TBP, the transcription initiates about 30bp downstream. The transcription process requires the melting of dsDNA and participation of TFIIIB. Unlike pol I and II, pol III termination occurs efficiently at four or more T residues without other protein factors. La protein can stimulate the release of RNA and pol III transcription; however, deletion of La has no apparent effect on pol III activity. (This definition may be outdated - see the DesignNote.)
RNA Polymerase III Transcription Pathway
The assembly of the spliceosome is a dynamic process that involves both small ribonucleoprotein particles (snRNPs), and non-snRNP proteins. The complete spliceosome consists of 5 snRNPs (U1, U2, U4, U5, and U6) and 50-100 non-snRNP factors. The snRNPs themselves contain a snRNA and a number of different proteins. These proteins can be subdivided into two classes, those specific to the individual snRNP, and those common to all snRNPs. The later group consists of eight polypeptides; B, B', D1, D2, D3, E, F, and G, which bind together in a tight association, and are referred to as the sm proteins. While some of the particle-specific proteins have been well studied, i.e.U1-70K or U1-A, many have only been identified by their molecular weight and have yet to be cloned. These snRNP components are recruited to the pre-mRNA in an ordered manner, and begin with the recognition of exon-intron boundaries. The 5' end of the U1 snRNP recognizes the 5' splice site of the pre-mRNA. This interaction is mediated through conventional base pairing. Subsequently snRNP U1 recognizes and binds to the conserved branch point adenosine site. This step in the splicing cycle is called the commitment complex (CC) and is defined as a point where the formation of a stable splicing complex commits the spliceosome to assemble. Binding of the U1 snRNP encourages binding of U2 snRNP, and is helped by U2AF protein. SR proteins such as ASF/SF2 and SC35, or other intron bridging proteins, mediate the interaction between U1, U2 and U2AF. Binding of these factors facilitate recognition of the 3' splice site, and this whole complex is called the E (Early) complex. Spliceosomal A Complex is formed following recruitment of U2 snRNP to the branch point sequence. Meanwhile, snRNPs U4/U6 and U5 have formed a functional tri-snRNP complex. The association of the tri-snRNP U4/U6-U5 with the pre-spliceosome creates the B complex. Several RNA:RNA interactions occur following this point, including the disassociation of the U4/U6 snRNP and the pairing of the 3' end of U6 with the 5' end of U2. These, and other, complex RNA rearrangements are required for mature spliceosomal formation, which is a pre requisite for the transesterification reactions that create the spliced mRNA. (This definition may be outdated - see the DesignNote.)
While transcriptional regulation is often viewed as the most prevalent way extracellular signals act to regulate gene expression, post-transcriptional regulation of splicing, RNA stability, and translation are also regulated by extracellular signals. Sam68, a member of a family of RNA-binding proteins called STAR proteins, mediates alternative splicing in response to extracellular signals, such as altered splicing of CD44 in response to phorbol ester treatment of T cells. RNA binding and activity of SAM68 is regulated by upstream signals through phosphorylation and modulating of its interaction with other proteins, itself, and with RNA. Phorbol ester treatment of T cells stimulates the ras/ Map kinase pathway, activating Erk and phosphorylation of Sam68, inducing alternative splicing of CD44 and perhaps other cellular RNA targets. Sam68 is localized in the nucleus to a specific substructure called the Sam68/SLM Nuclear Bodies, colocalizing with splicing factors and helping to link signal transduction with RNA processing. Sam68 has been suggested to play a role in a variety of pathways, including insulin signaling and HIV gene expression, substituting for the activity of viral Rev protein, and being regulated by arginine methylation as well as phosphorylation. In addition to the role of Sam68 regulating posttranscriptional gene expression, Sam68 also interacts with transcription factors such as CBP and appears to regulate gene expression. Sam68 also appears to play a role in cell cycle progression through influencing RNA processing. During mitosis SAM68 is tyrosine phosphorylated and associated with Src. The interaction of Sam68 with RNA is repressed by this phosphorylation, whereas interaction of Sam68 with Ras-GAP is stimulated by phosphorylation. Sam68 appears to be downregulated in tumors and transformed cells and its expression is reduced during mitosis, suggesting it inhibits proliferation. The RNA binding domain in Sam68, called a KH domain, is absent in a splice isoform that is expressed in cells that display contact inhibition of cellular growth. Sam68 with the KH domain appears in some settings to stimulate the G1/S transition, while blocking mitosis in some reports. (This definition may be outdated - see the DesignNote.)
Telomeres, which define the ends of chromosomes, consist of short, tandemly repeated DNA sequences loosely conserved in eukaryotes. Telomerase is a ribonucleoprotein complex which in vitro recognizes a single-stranded G-rich telomere primer and adds multiple telomeric repeats to its 3-prime end by using an RNA template. Telomerase may also have a role in de novo formation of telomeres. Telomerase has been identified in many cultured cell lines and actively dividing cell types. The active reverse transcriptase component has been identified as the TERT protein. The presence of this factor determines the availability of the telomerase function. The TERT protein has a high turnover rate and its expression is regulated by factors that promote growth (c-MYC, v-k-ras, Bcl-2, and E6) and inhibiting factors (RB and p53) that promote cell death or that block cell division. It appears that the regulation of active telomerase has many levels and can be inhibited by TEP1 not releasing TERT or by TRF1 which binds the end repeats and prevents access to the chromosome ends. Additional modulation is due to phosphorylation by PKC and AKT or dephosphorylation by PP2A. Human telomeres consist of many kilobases of (TTAGGG)n together with various associated proteins. Small amounts of these terminal sequences are lost from the tips of the chromosomes during each S phase because of incomplete DNA replication, but de novo addition of TTAGGG repeats by the enzyme telomerase compensates for this loss. Many human cells progressively lose terminal bases with each cell division, a loss that correlates with the apparent absence of telomerase in these cells. There has been considerable interest in the possible relationship between human telomeres and cellular senescence and immortalization. This interest includes the question of a role in the malignant process and the question of the use of telomerase inhibitors as anti-tumor drugs. (This definition may be outdated - see the DesignNote.)
Telomeres, Telomerase, Cellular Aging, and Immortality
Tumorigenesis is known to be a multistep process in which defects in various cancer genes accumulate. Epigenetic modifications, most importantly DNA methylation events, are frequently involved in transcriptional changes in both tumor suppressor genes and oncogenes. Methylation of cytosine at CpG dinucleotides is a common feature of higher eukaryotic genomes. DNA methylation in the promoter regions of genes is generally correlated with gene silencing. Two underlying mechanisms have been identified. First, binding of transcription factors or enhancer blocking elements, such as CTCF, may be inhibited by DNA methylation. The second and more general mechanism involves proteins that detect methylated DNA through methyl CpG-binding domains (MBDs). Four of these proteins-MBD1, MBD2, MBD3, and MeCP2-have been implicated in methylation-dependent repression of transcription. These proteins mediate recruitment of repressor complexes that include histone deacetylases (HDACs). HDACs remove acetyl groups from lysine residues of histones H3 and H4 that results in condensation of chromatin and thus limit access of transcription factors to promoter regions of genes localized nearby. Well-studied co-repressor complexes include Sin3A and Mi-2/NuRD. MeCP2, a polypeptide characterized by an MBD and a transcriptional repression domain that specifically binds methylated DNA, copurifies with the Sin3A/HDAC corepressor complex. MeCP1 complex is composed of 10 major polypeptides including MBD2 and all of the known NuRD complex components. The two protein complexes share four polypeptides: HDAC1, HDAC2, RbAp46, and RbAp48. In addition, each complex contains unique polypeptides (Sin3A, SAP30, and SAP18 in the Sin3 complex, and Mi2, MTA1, MTA2 and MBD3 in the NuRD complex). The NuRD complex possesses nucleosome remodeling activity because of the presence of Mi2, a member of the SWI2/SNF2 helicase/ATPase family. This complex preferentially binds, remodels, and deacetylates methylated nucleosomes. MTA1 or MTA2 (metastasis-associated protein 1 or 2) expression levels are elevated in metastatic cancer cells, MTA2 modulates the enzymatic activity of the histone deacetylase core complex. (This definition may be outdated - see the DesignNote.)
Mechanisms of Transcriptional Repression by DNA Methylation
Transcriptional Repression by DNA Methylation Pathway
Protein ubiquitination plays an important role in eukaryotic cellular processes. It mainly functions as a signal for 26S proteasome dependent protein degradation. The addition of ubiquitin to proteins being degraded is performed by a reaction cascade consisting of three enzymes, named E1 (ubiquitin activating enzyme), E2 (ubiquitin conjugating enzyme), and E3 (ubiquitin ligase). Each E3 has specificity to its substrate, or proteins to be targeted by ubiquitination. Many E3s are discovered in eukaryotes and they are classified into four types: HECT type, U-box type, single RING-finger type, and multi-subunit RING-finger type. Multi-subunit RING-finger E3s are exemplified by cullin-Rbx E3s and APC/C. They consist of a RING-finger-containing subunit (RBX1 or RBX2) that functions to bind E2s, a scaffold-like cullin molecule, adaptor proteins, and a target recognizing subunit that binds substrates.
An elaboration of the known steps and interactions for the metabolism of a compound.
Metabolic pathway, function (observable entity)
Amino Acid Metabolism - Reference Pathway
Alanine, aspartate and glutamate metabolism
Alanine, Aspartate and Glutamate Metabolism Pathway
Urea Cycle and Metabolism of Amino Groups
Glutamine is converted to glutamate by glutaminase, or several other enzymes, by the removal of the amide nitrogen. Proline is first converted to a Schiff base and then converted by hydrolysis to glutamate-5-semialdehyde. All of these changes occur on the same carbon. Arginine and histidine contain 5 adjacent carbons and a sixth carbon attached through a nitrogen atom. The catabolism of these amino acids is thus slightly more complicated than glutamine or proline. Arginine is converted to ornithine and urea. Ornithine is further transaminated to produce glutamate-5-semialdehyde. Glutamate-5-semialdehyde is converted to glutamate. Tetrahydrofolate is the cofactor in the final step converting histidine to glutamate. Transamination or deamination of glutamate produces a-ketoglutarate which feeds into the citric acid cycle. (This definition may be outdated - see the DesignNote.)
Catabolic Pathways for Arginine, Histidine, Glutamate, Glutamine, and Proline
Arginine, Histidine, Glutamate, Glutamine, and Proline Degradation Pathway
In animals, the sulfur-containing amino acid cysteine is synthesized from homocysteine, which is itself derived from metabolism of the amino acid methionine. Methionine is an essential amino acid for animals, making cysteine indirectly an essential amino acid as well. Homocysteine condenses with serine to form cystathionine, which is deaminated and hydrolyzed to form cysteine and alpha-ketobutyrate. While the sulfur in cysteine comes from homocysteine, the rest of the molecule comes from the initial serine residue. Cysteine biosynthesis occurs by a distinct mechanism in plants and prokaryotes. Cysteine is an important amino acid for all organisms due to the role it plays in protein folding. The formation of disulfide linkages between cysteine residues helps to stabilize the tertiary and quaternary structure of proteins. Disulfide linkages are most common in secreted proteins, where proteins are exposed to more oxidizing conditions that are found in the cellular interior. Elevated blood levels of homocysteine are a risk factor for the development of cardiovascular disease. One of the causes of elevated homocysteine is a genetic lack of cystathionine beta-synthase and excess methionine intake may be another explanation. Control of methionine intake and supplementing folic acid and vitamin B12 in the diet are used to lower homocysteine levels. (This definition may be outdated - see the DesignNote.)
Mammalian Pathway for Cysteine Biosynthesis
Intermediates in energy production pathways such as glycolysis and the Kreb's cycle are commonly the starting point for the biosynthesis of amino acids. The glycolytic intermediate 3-phosphoglycerate is the starting point for the biosynthesis of serine and glycine. First, 3-phosphoglycerate is oxidized and then transaminated to produce 3-phosphoserine. Phosphoserine hydrolase hydrolyzes the phosphate in 3-phosphoserine to produce serine. The side chain carbon of serine is removed to create glycine, which has only hydrogen as its side chain. The removal of the serine side chain is accomplished by transferring the carbon to tetrahydrofolate, a carrier of one-carbon groups. Genetic deficiency of the first enzyme in the pathway, 3-phosphoglycerate dehydrogenase, leads to impaired myelination of neurons and impaired development of the central nervous system. (This definition may be outdated - see the DesignNote.)
Biosynthesis of Glycine and Serine Pathway
The polyamines spermidine and spermine are expressed in a variety of tissues and are involved in the regulation of apoptosis, cellular proliferation, and progression through the cell cycle. Depletion of polyamines appears to reduce cell growth, and increased polyamine expression is associated with the cancer development and progression, making polyamine biosynthesis a target for the control of cancer. As positively charged amines, spermine and spermidine interact with DNA and may exert some of their effects through this interaction. Ornithine, one of the starting materials for polyamine biosynthesis, is derived from the amino acid arginine as part of the urea cycle. The enzyme ornithine decarboxylase produces putrescine from ornithine. Amino-propyl groups from decarboxylated adoMet are progressively added to putrescine to produce first spermidine and then spermine. Ornithine decarboxylase expression appears to be induced in some types of cancer, particularly skin cancer, and ODC inhibition to cause tumor regression. (This definition may be outdated - see the DesignNote.)
Biosynthesis of Spermidine and Spermine Pathway
Aspartate and asparagine are catabolized into oxaloacetate and the Kreb's cycle in a fairly direct pathway for amino acids with four carbons. The first step for asparagine catabolism is hydrolysis by the enzyme asparaginase, releasing aspartate and ammonia. Aspartate is then transaminated by aspartate transaminase to exchange its amino group onto alpha-ketoglutarate and be converted into oxaloacetate. As part of the Kreb's cycle, the carbon skeleton of oxaloacetate can generate energy and provide material for biosynthesis. The enzyme asparaginase is used as a cancer treatment through injection. Some cancers such as leukemias are highly dependent on asparagine circulating in the blood that comes from the diet. The required asparagine helps to support the rapid growth of malignant cells. Injection of asparaginase metabolizes the asparagine in the blood, withdrawing the supply of this essential nutrient from tumor cells, and causing asparagine-dependent tumor cells to die. Normal cells provide enough asparagine for their own needs through biosynthesis and are affected to a lesser extent by this treatment. (This definition may be outdated - see the DesignNote.)
Catabolic Pathway for Asparagine and Aspartate
Amino acids in the diet have one of two fates - either they are incorporated into proteins or they are broken down for energy and metabolic intermediates. They are not stored and the body also does not excrete them intact. The metabolic pathways that lead to degradation of amino acids funnel their carbon chains into metabolic intermediates that generate energy, and their amino groups into the urea cycle to be excreted. The amino acids alanine, glycine, serine, cysteine, tryptophan and threonine all have a common endpoint, the metabolic intermediate pyruvate. Threonine is converted to glycine through the removal of an acetaldehyde group, and glycine is then converted to serine, then pyruvate. More than one path can remove the sulfur and nitrogen groups of serine to create pyruvate. Part of tryptophan is found in alanine, which is converted directly to pyruvate through transamination. The removal of amino nitrogens commonly occurs through transamination, transferring the nitrogen to alpha-ketobutyrate to create glutamate. All of these amino acids are termed glucogenic since the pyruvate resulting from their metabolism can enter gluconeogenesis to create glucose. Pyruvate can also be converted by pyruvate dehydrogenase into acetyl-CoA, which can enter into the Kreb's cycle to generate ATP, be converted to ketone bodies, or be directed into fatty acid biosynthesis. The importance of amino acid degradation is demonstrated by a genetic defect in serine hydroxymethyl transferase. In individuals with this condition, glycine accumulates to toxic levels in the body due to a lack of other mechanisms of metabolism. (This definition may be outdated - see the DesignNote.)
Conversion of Alanine, Glycine, Serine, Cysteine, Tryptophan, and Threonine into Pyruvate
Catabolic Pathways for Alanine, Glycine, Serine, Cysteine, Tryptophan, and Threonine
Cysteine and Methionine Metabolism Pathway
Serine is derived from 3-phospho-D-glycerate, an intermediate of glycolysis, and glycine is derived from serine. Threonine is an essential amino acid, which animals cannot synthesize. In bacteria and plants, threonine is derived from aspartate.
Glycine, Serine and Threonine Metabolism
Glycine, Serine and Threonine Metabolism Pathway
The carbon chains of methionine, isoleucine, threonine, and valine are broken down to produce succinyl-CoA, which feeds into the Citric Acid Cycle. Methionine donates its methyl group via S-adenosylmethionine to one of several acceptors and the four remaining carbons are the backbone of propionyl-CoA that is subsequently converted to succinyl-CoA. The transdeamination and decarboxylation of valine are followed by a series of steps resulting in the formation of propionyl-CoA. Isoleucine also undergoes transdeamination, followed by oxidative decarboxylation. These steps yield propionyl-CoA as well as acetyl-CoA. Deficiency in the steps that convert isoleucine to propionyl-CoA causes sudden unexplained infant death, Reye-like syndrome, cardiomyopathy, and skeletal myopathy. (This definition may be outdated - see the DesignNote.)
Catabolic Pathways for Methionine, Isoleucine, Threonine and Valine
Methionine, Isoleucine, Threonine and Valine Degradation Pathway
Phenylalanine, Tyrosine and Tryptophan Biosynthesis
Phenylalanine, Tyrosine and Tryptophan Biosynthesis Pathway
Valine, Leucine and Isoleucine Biosynthesis
Valine, Leucine and Isoleucine Biosynthesis Pathway
Valine, Leucine and Isoleucine Degradation
Valine, Leucine and Isoleucine Degradation Pathway
Biosynthesis of Secondary Metabolites - Reference Pathway
Biosynthesis of Secondary Metabolites Pathway
Butirosin and Neomycin Biosynthesis Pathway
Flavonoids, Stilbene and Lignin Biosynthesis
Flavonoids, Stilbene and Lignin Biosynthesis Pathway
The acetyl-CoA produced by mitochondrial beta-oxidation of fatty acids enters the Kreb's cycle to produce energy, but that is not the only fate of acetyl-CoA. In liver mitochondria, some acetyl-CoA is converted to acetoacetate, beta-hydroxybutyrate, and acetone, collectively called ketone bodies. Ketone bodies are transported to other tissues such as brain, muscle or heart where they are converted back to acetyl-CoA to serve as an energy source. The brain normally uses only glucose for energy, but during starvation ketone bodies can become the main energy source for the brain. In the metabolic condition called ketosis, ketone bodies are produced faster than they are consumed by tissues and the smell of acetone can be detected on a person's breath. The smell of acetone is one indication that a person may have diabetes. The consumption of high-fat/low carbohydrate diets has been used as a weight loss program by many, intentionally inducing ketosis to consume fat stores, but these ketogenic diets can cause unwanted side effects related to increased urea production resulting from protein intake and risk of heart disease from increased cholesterol and fat intake. (This definition may be outdated - see the DesignNote.)
Formation of Ketone Bodies from Acetyl-CoA
Formation of Ketone Bodies from Acetyl-CoA Pathway
Indole and Ipecac Alkaloid Biosynthesis Pathway
Isoquinoline Alkaloid Biosynthesis Pathway
Tropane, piperidine and pyridine alkaloid biosynthesis
Tropane, Piperidine and Pyridine Alkaloid Biosynthesis Pathway
An elaboration of a sequence of biological or biochemical events that play a role in the metabolism of carbohydrates.
Carbohydrate Metabolism - Reference Pathway
Amino sugar and nucleotide sugar metabolism
Amino and Nucleotide Sugars Metabolism Pathway
Ascorbate and Aldarate Metabolism Pathway
The citrate cycle (TCA cycle, Krebs cycle) is an important aerobic pathway for the final steps of the oxidation of carbohydrates and fatty acids. The cycle starts with acetyl-CoA, the activated form of acetate, derived from glycolysis and pyruvate oxidation of carbohydrates and from beta oxidation of fatty acids. The two-carbon acetyl group in acetyl-CoA is transferred to the four-carbon compound of oxaloacetate to form the six-carbon compound of citrate. In a series of reactions two carbons in citrate are oxidized to CO2 and the reaction pathway supplies NADH for use in the oxidative phosphorylation and other metabolic processes. The pathway also supplies important precursor metabolites including 2-oxoglutarate. At the end of the cycle the remaining four-carbon part is transformed back to oxaloacetate. According to the genome sequence data, many organisms seem to lack genes for the full cycle, but contain genes for specific segments.
The glycolytic pathway begins with the simple sugar glucose and leads to pyruvate and eventually the Kreb's cycle. Dietary carbohydrates include a variety of sugars that are funneled into glycolysis to supply energy, including other monosaccharides, disaccharides, and polysaccharides like starch. Fructose is an abundant monosaccharide in fruit, and is also found along with glucose in the common disaccharide sucrose. Fructose enters glycolysis by different pathways in the liver and muscle. In muscle, fructose is a substrate of hexokinase, like glucose, and enters the pathway directly as fructose 6-phosphate. In liver, hexokinase is present in very low levels and fructose passes through a more complex pathway. Fructose is first phosphorylated to form fructose 1-phosphate, which is then split into glyceraldehyde and dihydroxyacetone phosphate to enter glycolysis as glyceraldehyde 3-phosphate. The sugar mannose also enters glycolysis at this point, first being converted to mannose 6-phosphate that is then isomerized to produce fructose 6-phosphate. Lactose is a disaccharide found in milk, and is composed of glucose and galactose. Galactose only differs from glucose in its stereochemistry at one position, but must be converted to glucose to enter glycolysis. The first step is phosphorylation to produce galactose 1-phosphate. Then, a UDP nucleotide group is exchanged between galactose 1-phosphate and UDP-glucose. The result of this reaction is the production of glucose 1-phosphate and UDP-galactose. UDP-galactose is enzymatically converted to UDP-glucose, which is then converted to glucose 1-phosphate in the next round of this loop. Glucose 1-phosphate is isomerized to produce glucose 6-phosphate, part of the glycolytic pathway. The complex polysaccharides starch and glycogen differ in their source and in their structure (they have different bonds between each individual sugar unit) but they are both composed entirely of glucose subunits polymerized together. Starch is found in plants and is digested to release individual glucose molecules in the digestive tract that are absorbed and transported to the tissues. Glycogen is the main storage carbohydrate in animals, and is mobilized by liver and muscle to release glucose when hormones like adrenalin indicate that a burst of energy is required. When glucose is mobilized from glycogen, it is released as glucose 1-phosphate. In muscle, there is no enzyme present that converts glucose 1-phosphate to glucose, so the only fate of this glucose 1-phosphate is to enter glycolysis after being converted glucose 6-phosphate. Deficiencies in the enzymes that direct sugars into glycolysis have distinct clinical effects in some cases. Lactose intolerance is very common in many parts of the world, and is caused in adults by a reduction in the enzyme that breaks lactose down into galactose and glucose in the intestine. Some individuals suffer from the genetic condition galactosemia, in which they lack the enzymes to convert galactose to glucose. The accumulation of galactose leads to mental retardation, liver damage and cataracts unless dietary intake of galactose is controlled. (This definition may be outdated - see the DesignNote.)
In glycolysis, the six-carbon sugar glucose is oxidized and split in two halves, to create two molecules of pyruvate (3 carbons each) from each molecule of glucose. Along the way, the cell extracts a relatively small amount of energy from glucose in the form of ATP, 2 ATP molecules collected for each glucose molecule that starts down the glycolytic path. The pyruvate produced has one of three metabolic fates, to either become acetyl-CoA, ethanol, or lactate. When oxygen is available, the pyruvate can be converted to acetyl-CoA and enter the Krebs Cycle, where the acetyl-CoA will be completely oxidized and generate ATP through oxidative phosphorylation. Fermentation is much less efficient than oxidative phosphorylation in making ATP, creating only 2 ATP per glucose while oxidative phosphorylation creates 36 ATP per glucose in mammalian cells. Oxidative phosphorylation does not work in the absence of oxygen, however, and in the absence of oxygen glycolysis is forced to a halt due to a lack of NAD+, unless NAD+ is regenerated through fermentation. In mammalian muscle, strenuous exertion can create conditions in which oxygen is consumed faster than blood can provide it, forcing the muscle to use fermentation and create lactic acid; it is the lactic acid that makes your muscles sore after a workout. There are ten enzymes that catalyze the steps in glycolysis that convert glucose into pyruvate, and the entire pathway is located in the cytoplasm of eukaryotic cells. The activity of the pathway is regulated at key steps to ensure that glucose consumption and energy production match the needs of the cell. The steps along the pathway each involve a change in the free energy of the products and reactants, and as long as the overall change in free energy is negative, the reaction continues forward, like water flowing down hill to its lowest energy point. The key steps in the regulation of glycolysis, or any pathway, are those that catalyze the rate-limiting, irreversible steps along the pathway. In glycolysis in mammals, the key regulatory enzyme is phosphofructokinase, which catalyzes the rate-limiting committed step. Phosphofructokinase is activated by AMP and inhibited by ATP, among other regulatory mechanisms. Thus, when ATP is low (and AMP is high), phosphofructokinase will be activated and generate more ATP. Similarly, when ATP is abundant, phosphofructokinase will be inhibited to prevent wasting glucose on making energy when it is not needed. Failure to provide energy can have lethal consequences for cells - the absence of oxygen caused by a stroke or a heart attack that prevents ATP generation can have lethal consequences for the cells involved. Cancer cells often generate energy through glycolytic fermentation more than oxidative phosphorylation, suggesting that manipulation of metabolism may provide a therapeutic strategy. Well known glycolytic enzymes such as glyceraldehyde-3-phosphate dehydrogenase may play roles in other cellular processes such as apoptosis. (This definition may be outdated - see the DesignNote.)
Glycolysis is the process of converting glucose into pyruvate and generating small amounts of ATP (energy) and NADH (reducing power). It is a central pathway that produces important precursor metabolites: six-carbon compounds of glucose-6P and fructose-6P and three-carbon compounds of glycerone-P, glyceraldehyde-3P, glycerate-3P, phosphoenolpyruvate, and pyruvate. Acetyl-CoA, another important precursor metabolite, is produced by oxidative decarboxylation of pyruvate. When the enzyme genes of this pathway are examined in completely sequenced genomes, the reaction steps of three-carbon compounds from glycerone-P to pyruvate form a conserved core module, which is found in almost all organisms and which often corresponds to operon structures in bacterial genomes. Gluconeogenesis is a synthesis pathway of glucose from non-carbohydrate precursors. It is essentially a reversal of glycolysis with minor variations of alternative paths.
Glyoxylate and Dicarboxylate Metabolism Pathway
The synthesis of glycosidic bonds between monosaccharides requires energy input, energy that is provided by joining sugar monomers to a nucleotide such as UDP. Glycosyltransferases join two sugar monomers together, with UDP as the leaving group that drives the reaction forward. One glycosyltransferases is galactosyltransferase. Galactosyltransferase catalyzes the formation of a glycosidic bond between galactose and N-acetyl-D-glucosamine to create N-acetyllactosamine (D-galactosyl-N-acetyl-D-glucosamine), found in the oligosaccharides of glycoproteins. Galactosyltransferase is broadly expressed. This enzyme also catalyzes the synthesis of the disaccharide lactose, the sugar found in milk. Although this enzyme is broadly expressed, lactose production only occurs in mammary glands. Lactose production is restricted to the mammary glands because galactosyltransferase alone does not have the substrate specificity required to produce lactose. The complete lactose synthase complex includes galactosyltransferase and another non-catalytic subunit, alpha-lactalbumin. In the presence of alpha-lactalbumin, galactosyltransferase substrate specificity is switched to use glucose, resulting in lactose production rather than N-acetyllactosamine. The folding of alpha-lactalbumin, which is related to lysozyme, has been studied extensively as a model of the mechanisms involved in protein folding. (This definition may be outdated - see the DesignNote.)
Galactose is a hexose sugar found in the disaccharide lactose. Galactose has six carbons like glucose and differs from glucose only in the stereochemistry of one carbon, C4. The enzymes of carbohydrate metabolism are specific enough that galactose must be changed to glucose before it can enter glycolysis. To convert galactose to glucose, it is first phosphorylated by galactokinase to produce galactose-1-phosphate. Galactose is then exchanged with the glucose group in UDP-glucose to create UDP-galactose and release glucose-1-phosphate. An epimerase enzyme changes the stereochemistry of C4 in UDP-galactose, creating UDP-glucose. In the next round of the transfer reaction, this glucose is released as glucose-1-phosphate. Once released, glucose-1-phosphate is converted to glucose-6-phosphate and can enter glycolysis to generate energy. Mutation of the kinase, the transferase or the epimerase can result in clinical deficiencies in galactose metabolism known as galactosemias. Galactosemias range in severity depending on the nature of the genetic change, and are usually treated through avoidance of galactose in the diet, primarily from lactose in dairy products. (This definition may be outdated - see the DesignNote.)
One form of chemical energy used to drive biosynthetic reactions forward is the reducing power of the energy carrier NADPH. NADPH is essential to drive the biosynthesis of fatty acids and cholesterol for example. While NADPH is an important energy carrier and is closely related to the high-energy electron carrier NADH, NADPH is distinct from NADH in several ways. NADH in oxidative phosphorylation in mitochondria transports chemical energy from the Kreb's cycle to the electron transport chain, but NADPH does not play this role. The cell keeps its pools of NADH and NADPH isolated biochemically, through the specificity of the enzymes that use and generate these cofactors. Enzymes that metabolize NADH and NADPH are highly specific for one cofactor or the other and are in different pathways. While NADH is produced in mitochondria by the Kreb's cycle, NADPH is produced through a pathway called the pentose phosphate pathway. Since one of the main purposes of this pathway is to produce NADPH for biosynthesis, this pathway occurs most predominantly in tissues like liver, fat cells, or adrenal glands that are involved in fatty acid and cholesterol biosynthesis. This pathway starts with glucose-6-phosphate, the first committed step in glycolysis, and can provide an alternative route to glycolysis for energy production. The first portion of the pentose phosphate pathway involves the oxidation of glucose in three steps, with the concomitant production of NADPH. The first step in the pentose phosphate pathway is catalyzed by glucose-6-phosphate dehydrogenase. In normal red blood cells, the NADPH produced by glucose-6-phosphate dehydrogenase is used to regenerate glutathione and protect cell membranes. Genetic deficiency in the activity of this enzyme is very common in some populations, and can result in anemias caused by fragile red blood cells. In the second and third steps, further oxidation makes more NADPH and releases carbon dioxide, shortening the sugar from six carbons to five (D-ribulose 5-phosphate). After isomerization, D-ribose 5-phosphate is produced and provides the starting point for a series of reactions that converts the 5-carbon ribose into 6-carbon fructose-6-phosphate and 3-carbon glyceraldehyde-3-phosphate. Ribose is also used to make nucleotides for RNA and DNA. (This definition may be outdated - see the DesignNote.)
Oxidative Phase of the Pentose Phosphate Pathway
Oxidative Reactions of the Pentose Phosphate Pathway
Pentose and Glucuronate Interconversions
Pentose and Glucuronate Interconversions Pathway
The pentose phosphate pathway is a process of glucose turnover that produces NADPH as reducing equivalents and pentoses as essential parts of nucleotides. There are two different phases in the pathway. One is irreversible oxidative phase in which glucose-6P is converted to ribulose-5P by oxidative decarboxylation, and NADPH is generated. The other is reversible non-oxidative phase in which phosphorylated sugars are interconverted to generate xylulose-5P, ribulose-5P, and ribose-5P. Phosphoribosyl pyrophosphate (PRPP) formed from ribose-5P is an activated compound used in the biosynthesis of histidine and purine/pyrimidine nucleotides. This pathway map also shows the Entner-Doudoroff pathway where 6-P-gluconate is dehydrated and then cleaved into pyruvate and glyceraldehyde-3P.
The Krebs cycle, also called the citric acid cycle, is a fundamental metabolic pathway involving eight enzymes essential for energy production through aerobic respiration, and, like glycolysis, arose early in evolution. This pathway is also an important source of biosynthetic building blocks used in gluconeogenesis, amino acid biosynthesis, and fatty acid biosynthesis. The Krebs cycle takes place in mitochondria where it oxidizes acetyl-CoA, releasing carbon dioxide and extracting energy primarily as the reduced high-energy electron carriers NADH and FADH2. NADH and FADH2 transfer chemical energy from metabolic intermediates to the electron transport chain to create a different form of energy, a gradient of protons across the inner mitochondrial membrane. The energy of the proton gradient in turn drives synthesis of the high-energy phosphate bonds in ATP, the common energy currency of the cell used to drive a huge variety of reactions and processes. An acetyl-CoA molecule (2 carbons) enters the cycle when citrate synthase condenses it with oxaloacetate (4 carbons) to create citrate (6 carbons). One source of the acetyl-CoA that enters the Krebs cycle is the conversion of pyruvate from glycolysis to acetyl-CoA by pyruvate dehydrogenase. Acetyl-CoA is a key metabolic junction, derived not only from glycolysis but also from the oxidation of fatty acids. As the cycle proceeds, the Krebs cycle intermediates are oxidized, transferring their energy to create reduced NADH and FADH2. The oxidation of the metabolic intermediates of the pathway also releases two carbon dioxide molecules for each acetyl-CoA that enters the cycle, leaving the net carbons the same with each turn of the cycle. This carbon dioxide, along with more released by pyruvate dehydrogenase, is the source of CO2 released into the atmosphere when you breathe. The Krebs cycle, like other metabolic pathways, is tightly regulated to efficiently meet the needs of the cell and the organism. The irreversible synthesis of acetyl-CoA from pyruvate by pyruvate dehydrogenase is one important regulatory step, and is inhibited by high concentrations of ATP that indicate abundant energy. Citrate synthase, alpha-ketoglutarate dehydrogenase and isocitrate dehydrogenase are all key regulatory steps in the cycle and are each inhibited by abundant energy in the cell, indicated through high concentrations of ATP or NADH. The activity of the Krebs cycle is closely linked to the availability of oxygen, although none of the steps in the pathway directly use oxygen. Oxygen is required for the electron transport chain to function, which recycles NADH back to NAD+ and FADH2 back to FADH, providing NAD+ and ADH required by enzymes in the Krebs cycle. If the oxygen supply to a muscle cell or a yeast cell is low, NAD+ and FADH levels fall, the Krebs cycle cannot proceed forward, and the cell must resort to fermentation to continue making ATP. Some Krebs cycle enzymes require non-protein cofactors for activity, such as thiamine, vitamin B1. Insufficient quantities of this vitamin in the diet leads to decreased activity of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, and a decrease in the ability of the Krebs cycle to meet metabolic demands, causing the disease beriberi. Although the elucidation of the Krebs cycle remains one of the landmarks of biochemistry, aspects of the Krebs cycle and its enzymes are still actively researched in the modern proteomic era. (This definition may be outdated - see the DesignNote.)
Metabolism of Cofactors and Vitamins - Reference Pathway
Cofactors and Vitamins Metabolism Pathway
Nicotinate and Nicotinamide Metabolism Pathway
Pantothenate and CoA Biosynthesis Pathway
Porphyrin and Chlorophyll Metabolism Pathway
Ubiquinone (UQ), also called coenzyme Q, and plastoquinone (PQ) are electron carriers in oxidative phosphorylation and photosynthesis, respectively. The quinoid nucleus of ubiquinone is derived from the shikimate pathway; 4-hydroxybenzoate is directly formed from chorismate in bacteria, while it can be formed from either chorismate or tyrosine in yeast. The following biosynthesis of terpenoid moiety involves reactions of prenylation, decarboxylation, and three hydroxylations alternating with three methylations. The order of these reactions are somewhat different between bacteria and yeast. Phylloquinone (vitamin K1), menaquinone (vitamin K2), and tocopherol (vitamin E) are fat-soluble vitamins. Phylloquinone is a compound present in all photosynthetic plants serving as a cofactor for photosystem I-mediated electron transport. Menaquinone is an obligatory component of the electron-transfer pathway in bacteria.
Ubiquinone and other terpenoid-quinone biosynthesis
A sequence of biological or biochemical events that result in the catabolism of large molecules or polymers.
Drug Metabolism by Cytochrome P450 Pathway
Drug Metabolism by Non-CYP450 Enzymes Pathway
An inactivating and detoxification pathway for a variety of exogenous and endogenous molecules, including drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids and bile acids. Glucuronic acid is highly soluble in water and is often linked to poisonous substances to allow for subsequent elimination and to hormones to allow for easier transport. Also, drugs are commonly conjugated to glucuronic acid to allow for easier delivery. Excretion occurs via urine or bile.
Metabolism of xenobiotics by cytochrome P450
Metabolism of Xenobiotics by Cytochrome P450 Pathway
Cyclins are proteins that associate with cyclin-dependent protein kinases to regulate their activity and the progression of the cell cycle through specific checkpoints. The cyclical increase and decrease in cyclin levels is a key to cell cycle regulation. Disruption of cyclin action can lead to either cell cycle arrest, or to uncontrolled cell proliferation. When cyclin E is abundant it interacts with the cell cycle checkpoint kinase cdk2 to activate cdk2 and allow progression of the cell cycle from G1 to S phase. One of the key targets of activated cdk2 complexed with cyclin E is the tumor suppressor Rb. When dephosphorylated in G1, Rb complexes with and blocks transcriptional activation by E2F transcription factors. When Rb is phosphorylated by cdk2/Cyclin E, it dissociates from E2f, allowing E2F to activate the transcription of genes required for S phase. One of the genes activated by E2F is cyclin E itself, leading to a positive feedback cycle as cyclin E accumulates. The decision by the cell to either remain in G1 or progress into S phase is the result in part of the balance between cyclin E production and proteolytic degradation in the proteasome. Cyclin E is targeted for destruction by the proteasome through ubiquitination when associated with a complex of proteins called the SCF or F box complex. Proteins included this complex include an F box protein that targets specific substrates such as Cyclin E for degradation. In the case of cyclin E the F box protein Fbw7, also called hCdc4, associates with phosphorylated free cyclin E to recruit it into the SCF complex for degradation. SCFFbw7 is a ubiquitin ligase recruited into the complex that specifically targets cyclin E. Cul3, skp1, and Rbx1 also are part of the complex that degrades cyclin E. There may be redundancy for some components of the complex since cul1 deletion also disrupts cyclin E degradation, and multiple F box proteins may contribute to cyclin E degradation. The interaction of multiple different factors in cyclin E accumulation integrates different signaling pathways with cell cycle regulation and may play a role in the unregulated cell cycle progression of cancer. (This definition may be outdated - see the DesignNote.)
The degradation of endogenous mRNA in a sequence-specific manner can be induced by dsRNA [RNA interference (RNAi)], antisense transcription, or viral infection. In the current model for posttranscriptional gene silencing by RNAi, the ribonuclease III like enzyme Dicer processes dsRNA into small fragments (siRNA) of 21-25 nts. The siRNA is incorporated into the RNA-induced silencing complex (RISC), which targets and degrades the homologous mRNA. Most of the proteins in the RISC (with the exception of Ago2 and Dicer have not been identified) but likely contain endonuclease, helicase, exonuclease and homology scanning activity. (This definition may be outdated - see the DesignNote.)
E2F-1 is a transcription factor that regulates the expression of genes involved in the cell cycle and that is involved in progression of the cell cycle from G1 into S phase. Over-expression of E2F-1 can induce cellular transformation and under-expression can repress apoptosis. Association with the tumor suppressor Rb represses E2F-1 activity, and this repression is relieved when the cdk2/cyclin E complex at the G1 to S phase transition phosphorylates Rb. Like many cell cycle regulators, E2F-1 is regulated through phosphorylation by a cyclin-dependent protein kinase, cdk2/cyclin A, and by proteolytic degradation. Phosphorylation of E2F-1 by cdk2/cyclin A leads to E2F-1 inactivation, blocking DNA binding. E2F-1 is also regulated through degradation in the proteasome at the S/G2 transition. The F box complex that degrades E2F-1 contains components shared with the complexes that target other cell cycle factors for degradation. The F box protein that specifically recruits E2F for ubiquitination and degradation is Skp2. Other components of the SCF complex include Skp1, Cul1, and cdc34. Skp2 expression is cyclical, increasing in the S/G2 transition as E2F-1 is degraded. Knowledge of E2F-1 activity and its regulation form part of the complex set of interactions regulating the cell cycle and potential targets for the treatment of cancer. (This definition may be outdated - see the DesignNote.)
The endoplasmic reticulum (ER) of the cell operates a quality control system that identifies misfolded proteins, transports them into the cytoplasm and then targets them for degradation by the proteasome. Aberrant protein degradation is the mechanism underlying many diseases, including cystic fibrosis and heritable forms of lung and liver disease. The pathways that orchestrate the destruction of aberrant proteins are collectively termed ER-associated degradation (ERAD). Most of the proteins synthesized in the ER are cotranslationally modified with N (asparagine)-linked glycans by addition of triglycosylated, branched oligosaccharides at asparagines residues. Rapid glucose trimming by ER glucosidases generates monoglucosylated N-glycans (Glc0-3Man9GlcNAc2). Productive folding of the polypeptides to which the glycans are attached requires the services of an ER lectin chaperone called calnexin (CNX) that recognize the Glc1Man9GlcNAc2 oligosaccharide and assists the folding of newly synthesized glycoproteins. Because the half-time of monoglucose in the nascent glycoproteins is about 2 min, the protein should be repeatedly reglycosylated by UDP-glucose: glycoprotein glucosyltransferase (UGGT) resulting in association with CNX. Next, the mannose residue from the middle branch of the Man9GlcNAc2 oligosaccharide is removed by ER -mannosidase I, then correctly folded glycoproteins bearing Man8GlcNAc2 isomer B (Man8B form) are transported out of the ER to the Golgi apparatus. If the native structure of the glycoprotein cannot be achieved it is retained in the ER. When substrates are released from CNX by glucosidase II, they may be transferred to one of 2 pathways: EDEM for degradation or UUGT for reentry into CNX cycle. A glycoprotein with permanent structural defects is modified by the slow-acting enzyme ER mannosidase I. This enzyme attaches Man8 glycans to misfolded glycoproteins and in so doing generates a signal that results in ER-associated glycoprotein degradation (GERAD). A glycoprotein with a glycan in the form Glc0-3Man8GlcNAc2 is released from the calnexin cycle, recognised by a mannosidase- like protein EDEM and dislocated from the ER to the cytosol. Here the protein binds to the glycan-specific F box protein Fbx2 and is targeted to the SCF-Fbx2-type E3 ubiquitin ligase complex. This results in the protein being polyubiquitinated. The protein is subsequently deglycosylated by a cytosolic peptide N-glycanase (PNGase) that is closely associated with the ubiquitin ligase complex and/or the 19S lid of the proteasome. Finally, the ubiquitinated, deglycosylated protein is degraded by the proteasome. (This definition may be outdated - see the DesignNote.)
ER-associated degradation (ERAD) Pathway
Endoplasmic Reticulum Degradation Pathway
Lysosomes are membrane-delimited organelles in animal cells serving as the cell's main digestive compartment to which all sorts of macromolecules are delivered for degradation. They contain more than 40 hydrolases in an acidic environment (pH of about 5). After synthesis in the ER, lysosomal enzymes are decorated with mannose-6-phosphate residues, which are recognized by mannose-6-phosphate receptors in the trans-Golgi network. They are packaged into clathrin-coated vesicles and are transported to late endosomes. Substances for digestion are acquired by the lysosomes via a series of processes including endocytosis, phagocytosis, and autophagy.
The proteasome is a protein-destroying apparatus involved in many essential cellular functions, such as regulation of cell cycle, cell differentiation, signal transduction pathways, antigen processing for appropriate immune responses, stress signaling, inflammatory responses, and apoptosis. It is capable of degrading a variety of cellular proteins in a rapid and timely fashion and most substrate proteins are modified by ubiquitin before their degradation by the proteasome. The proteasome is a large protein complex consisting of a proteolytic core called the 20S particle and ancillary factors that regulate its activity in various ways. The most common form is the 26S proteasome containing one 20S core particle and two 19S regulatory particles that enable the proteasome to degrade ubiquitinated proteins by an ATP-dependent mechanism. Another form is the immunoproteasome containing two 11S regulatory particles, PA28 alpha and PA28 beta, which are induced by interferon gamma under the conditions of intensified immune response. Other regulatory particles include PA28 gamma and PA200. Although PA28 gamma also belongs to a family of activators of the 20S proteasome, it is localized within the nucleus and forms a homoheptamer. PA28 gamma has been implicated in the regulation of cell cycle progression and apoptosis. PA200 has been identified as a large nuclear protein that stimulates proteasomal hydrolysis of peptides.
Once retinoids are bound by the RAR/RXR heterodimer they became transcriptional activated. As a consequence they are degraded by the proteasome. Phosphorylation in the activation domain one (AF1) and presence of the activation domain 2 (AF2) trigger the ubiquitination of the receptors. Moreover, heterodimerization of RAR and RXR accelerate degradation of the receptors. (This definition may be outdated - see the DesignNote.)
Degradation of the RAR and RXR by the proteasome
The motor defects of Parkinson's disease are related to the loss of dopaminergic neurons in specific brain regions. Examination of these neurons in diseased tissue has revealed the presence of Lewy bodies, dense aggregates that include the protein alpha-synuclein. A genetic basis for most cases of Parkinson's disease has not yet been identified, but mutations in alpha-synuclein have been associated with at least one rare form of the disease, and mutations in another protein, the parkin gene, are associated with another inherited form of Parkinson's disease. Parkin is found in Lewy bodies along with alpha-synuclein and the parkin protein is an E3 ubiquitin ligase. Parkin appears to work in conjunction with ubiquitin activating (Uba)1, an E1 protein and the ubiquitin-conjugating (Ubc) enzymes UbcH7 and 8. The E1 delivers ubiquitin to the E2 in a cycle that creates an increasing chain of ubiquitin. The Parkin E3 ligates this onto substrates and so tags these proteins in normal cells, targeting them for destruction in the proteasome. One of the proteins that parkin normally targets for destruction is a specific O-glycosylated form of alpha-synuclein. Failure of parkin-mediated degradation of alpha-synuclein may be a key factor leading to the death of dopaminergic neurons. Another substrate of parkin is a GPCR-like protein called Pael-R that accumulates in the ER of affected cells and may cause neuronal cell death. The involvement of Parkin and alpha-synuclein mutations in genetic forms of Parkinson's suggests that failure of ubiquitination and protein degradation may be causative in other forms of Parkinson's. Questions remaining include the cause of the lack of effective ubiquitination in individuals lacking obvious genetic defects in this pathway and how to use this knowledge of ubiquitination and protein degradation in Parkinson's disease to identify therapeutic strategies. (This definition may be outdated - see the DesignNote.)
Role of Parkin in the Ubiquitin-Proteasomal Pathway
Endocytosis is a mechanism for cells to remove ligands, nutrients, plasma membrane (PM) proteins, and lipids from the cell surface, bringing them into the cell interior. Transmembrane proteins entering through clathrin-dependent endocytosis (CDE) have sequences in their cytoplasmic domains that bind to the APs (adaptor-related protein complexes) and enable their rapid removal from the PM. In addition to APs and clathrin, there are numerous accessory proteins including dynamin. Depending on the various proteins that enter the endosome membrane, these cargoes are sorted to distinct destinations. Some cargoes, such as nutrient receptors, are recycled back to the PM. Ubiquitylated membrane proteins, such as activated growth-factor receptors, are sorted into intraluminal vesicles and eventually end up in the lysosome lumen via multivesicular endosomes (MVEs). There are distinct mechanisms of clathrin-independent endocytosis (CIE) depending upon the cargo and the cell type.
Acetyl-CoA is produced in mitochondria through the metabolism of fatty acids and the oxidation of pyruvate to acetyl-CoA. When ATP is needed, this acetyl-CoA can enter the Krebs cycle to drive oxidative phosphorylation. When ATP supplies are abundant, the acetyl-CoA can be diverted to other purposes like energy storage in the form of fatty acids. The biosynthesis of fatty acids from this acetyl-CoA cannot take place directly however, since it is produced inside mitochondria while fatty acid biosynthesis occurs in the cytosol. Also, there is not a mechanism that directly transports acetyl-CoA out of mitochondria. To be transported, the acetyl-CoA must be chemically converted to citric acid using a pathway called the tricarboxylate transport system. Inside mitochondria, the enzyme citrate synthase joins acetyl-CoA with oxaloacetate to make citrate. This citrate is transported from the mitochondria to the cytosol, thus transporting the acetyl-CoA in the form of citrate. Once in the cytosol, the citrate is converted back to oxaloacetate, which is then reduced to malate. Malate can be oxidized to pyruvate by the malic enzyme, with production of NADPH as well, that can contribute to fatty acid biosynthesis. Pyruvate can be reimported back into the mitochondria. Alternatively, malate can be transported itself back into the mitochondria and used to produce NADH once inside mitochondria. (This definition may be outdated - see the DesignNote.)
Shuttle for transfer of acetyl groups from mitochondria to the cytosol
The body gets energy through the oxidation of food such as glucose and fatty acids. The chemical energy contained in these foods is extracted and converted until it reaches a common form, the high-energy phosphate bonds of ATP. The hydrolysis of ATP is highly favorable and is coupled to a variety of energetically unfavorable processes to drive them forward. Most of the energy of glucose or fatty acids is extracted through oxidation to produce the reduced high-energy electron carriers NADH and FADH2. From there, the energy is transferred next to the electron transport system associated with the mitochondrial inner membrane. This chain includes a series of protein complexes and non-membrane cofactors that transfer the electrons from NADH and FADH2 in a series of redox reactions from carrier to carrier. Oxygen is the final electron acceptor at the end of the chain, resulting in the production of water. The oxygen we breathe, and which is transported by hemoglobin in the blood to all of the tissues, serves this purpose and allows electron transport to occur. As the electrons pass through the chain, they transfer their energy to the complexes, which use the energy to pump protons out of the mitochondrial matrix, creating a proton gradient across the inner mitochondrial membrane. The chemical energy that started with glucose, and was transferred to NADH and FADH2, is then converted to the energy of a concentration gradient. The inner mitochondrial membrane is impermeable to protons on its own, so the energy of the proton gradient is stable, waiting to be recaptured. The energy is recaptured by ATP synthase in the inner mitochondrial membrane. This enzyme allows protons to flow back down their concentration gradient across the membrane, and in the process uses the energy of the gradient to drive ATP synthesis. The movement of the electrons through electron transport, the proton gradient and ATP synthesis are all coupled processes that require each other to occur. The cell does not store energy as ATP, but only has enough ATP on hand for its immediate energy needs. If electron transport ceases or is inhibited, then ATP synthesis also rapidly halts. This regulation ensures that ATP production closely matches the needs of the cell. Glycolysis and the Krebs cycle are also closely linked to the energy needs of the cell. The abundance of ATP, NADH and pathway intermediates regulates key steps in these pathways so that they are activated when energy is required to feed the electron transport system and they are inhibited when not needed to save metabolic energy. If oxygen is absent, electron transport and the Krebs cycle rapidly halt, leaving glycolysis and fermentation as the main means of energy production. During aerobic exercise, the rapid consumption of ATP leads to use of the proton gradient to make more ATP, increased electron transport to regenerate the proton gradient, increased oxygen consumption, and increased activity of the Krebs cycle and glycolysis to supply high energy electrons to drive electron transport. Uncoupling agents allow protons to flow across the mitochondrial membrane without producing ATP. The chemical compound dinitrophenol (DNP), for example, can transport protons across the inner mitochondrial membrane without ATP synthase. In the presence of dinitrophenol, energy is consumed to pump protons out of mitochondria, but this energy is not recaptured in chemical form in ATP. Instead, this energy is released as heat. Dinitrophenol was once used as diet remedy to lose weight without exercise or diet, but this compound is a metabolic poison and resulted in deaths in when purposefully given to humans. Proteins also can act as uncoupling agents in the mitochondria. A mitochondrial uncoupling protein is found in brown adipose tissue. An increase in the activity of uncoupling proteins increases heat production by allowing protons to flow down their gradient without making ATP and may serve as protection against cold, as well as a potential means of obesity control. (This definition may be outdated - see the DesignNote.)
Electron Transport Reaction in Mitochondria
Excess amino acids in the body can be used as a source of energy, with their carbon skeleton converted to metabolic intermediates such as acetyl-CoA or intermediates in the Krebs cycle. The metabolic breakdown of amino acids releases nitrogen that must be converted to a relatively non-toxic form and then excreted. In mammals, the nitrogen is converted to urea in the liver through a series of reactions called the urea cycle. The ammonia released through the deamination of amino acids is reacted to produce carbamoyl phosphate, a reaction catalyzed by carbamoyl phosphate synthase. The enzyme ornithine transcarbamoylase is found in mitochondria and converts ornithine into citrulline. Citrulline is exported into the cytoplasm where another nitrogen for urea is acquired from aspartate, followed by the release of fumarate to form the amino acid arginine. Urea is released from arginine by the enzyme arginase, bringing the cycle back around to ornithine. The general route of entry for amino acids into the urea cycle is through transamination, the transfer of their amino group to alpha-ketoglutarate to form glutamate. The amino group from glutamate is released by glutamate dehydrogenase to create an ammonium ion. The ammonium ion is used to make carbamoyl phosphate, and ultimately urea through the urea cycle. Different amino acids can enter this pathway by different routes. The transfer of the amino group from aspartate to alpha-ketobutyrate creates oxaloacetate, a Krebs cycle intermediate. Alanine goes through transamination to release pyruvate, which can be used as fuel. Genetic defects that completely block the urea cycle are not observed in people, perhaps since such a defect would be fatal. Mutations that reduce the activity of the urea cycle have been observed, with serious affects on mental functioning and other toxicities caused by elevated levels of ammonia. (This definition may be outdated - see the DesignNote.)
The reactions that feed amino groups into the urea cycle
Feeding Amino Groups into the Urea Cycle
Most of the energy derived from the oxidation of glucose is not extracted directly as ATP, but as reduced NADH that transfers high-energy electrons to the electron transport chain in the inner mitochondrial membrane. This NADH comes primarily from the Krebs cycle in the mitochondrial matrix and is therefore directly accessible to electron transport. NADH generated during glycolysis cannot reach the electron transport chain directly however and there is no direct mechanism for the transfer of NADH across the mitochondrial membrane. Instead shuttle mechanisms have evolved to move the energy of reduced NADH across the membrane in the form of other reduced molecules. One shuttle is the glycerophosphate shuttle and another is the malate-aspartate shuttle. The malate-aspartate shuttle occurs in mammalian tissues. First, oxaloacetate on the cytoplasmic side is reduced by NADH, creating malate and NAD+. Malate and the electrons it carries are transported into the mitochondria across the inner mitochondrial membrane, in exchange for alpha-ketoglutarate, which is transported out of the mitochondria. Once inside, the energy in malate is extracted again by reducing NAD+ to make NADH, regenerating oxaloacetate. This NADH is then free to transfer its high energy electrons to the electron transport chain. The oxaloacetate is transaminated with glutamate to make aspartate and alpha-ketoglutarate. Aspartate is returned to the cytosol by the aspartate-glutamate transporter, which moves glutamate into the mitochondria as it transports aspartate out. The overall result is that NADH is transported into the mitochondria, and can be used to generate 3 ATP per every NADH transported in from the cytosol, a very efficient process. (This definition may be outdated - see the DesignNote.)
Oxidative phosphorylation, function (observable entity)
Glycan Biosynthesis and Metabolism - Reference Pathway
Glycan Biosynthesis and Metabolism Pathway
Blood Group Glycolipid Biosynthesis - Lact Series
Blood Group Glycolipid Biosynthesis - Neolact Series
Glycosphingolipid biosynthesis - lacto and neolacto series
Blood Group Glycolipid Biosynthesis - Lacto and Neolacto Series Pathway
Glycosaminoglycans (GAGs) are linear polysaccharide chains consisting of repeating disaccharide units and form proteoglycans by covalently attaching to their core proteins. Chondroitin sulfate (CS) is a glycosaminoglycan with the disaccharide unit GalNAc(b1-4)GlcA(b1-3), modified with ester-linked sulfate at certain positions. Dermatan sulfate (DS) is a modified form of CS, in which a portion of D-glucuronate residues is epimerized to L-iduronates. CS and DS are linked to serine residues in core proteins via a linkage tetrasaccharide formed by the transfer of xylose and three more residues. The assembly process of CS is initiated by the transfer of N-acetylgalactosamine to the linkage tetrasaccharide. The polymerization step is catalyzed by bifunctional enzymes (chondroitin synthases) that have both b-3 glucuronosyltransferase and b1-4 N-acetylgalactosaminyltransferase activities. Chondroitin polymerization also requires the action of the chondroitin polymerizing factor. Sulfation of chondroitin in vertebrates is a complex process, with multiple sulfotransferases involved in 4-O sulfation and 6-O sulfation of N-acetylgalactosamine residues. Additional enzymes exist for epimerization of glucuronic acid to iduronic acid in DS, sulfation at the C-2 position of the uronic acids, and other patterns of sulfation found in unusual species of chondroitin.
Chondroitin / Heparan Sulfate Biosynthesis
Chondroitin/Heparan Sulfate Biosynthesis Pathway
Glycosaminoglycan Biosynthesis - Chondroitin Sulfate
Glycosaminoglycan Biosynthesis Pathway - Chondroitin Sulfate
Glycosaminoglycan biosynthesis - heparan sulfate
Glycosaminoglycan Biosynthesis Pathway - Heparan Sulfate
Keratan sulfate (KS) is a glycosaminoglycan with the basic disaccharide unit of N-acetyllactosamine, Gal(b1-4)GlcNAc(b1-3), with sulfate esters at C-6 of GlcNAc and Gal residues. There are two types of KS distinguished by the protein linkage: type I for N-linked via the N-glycan core structure and type II for O-linked via the O-glycan core 2 structure.
Glycosaminoglycan Biosynthesis - Keratan Sulfate
Glycosaminoglycan Biosynthesis Pathway - Keratan Sulfate
The biosynthesis pathway of N-glycans is a costly system with respect to the number of enzymes that are involved in the synthesis and trimming of N-glycans. While the structural diversity of N-glycans in mature proteins in the cell surface is introduced by glycosyltransferases in the Golgi complex, the core glycans in the ER are universal from yeast to mammal and have been considered as intermediates. (This definition may be outdated - see the DesignNote.)
Steps in the Glycosylation of Mammalian N-linked Oligosaccarides
Glycosylation of N-linked Oligosaccarides Pathway
Cell surface proteins can be attached to the cell membrane via the glycolipid structure called glycosylphosphatidylinositol (GPI) anchor. Hundreds of GPI-anchored proteins have been identified in many eukaryotes ranging from protozoa and fungi to mammals. All protein-linked GPI anchors share a common core structure, characterized by the substructure Man (a1-4) GlcN (a1-6) myo-inositol-1P-lipid. Biosynthesis of GPI anchors proceeds in three stages: (i) preassembly of a GPI precursor in the ER membrane, (ii) attachment of the GPI to the C-terminus of a newly synthesized protein in the lumen of the ER, and (iii) lipid remodeling and/or carbohydrate side-chain modifications in the ER and the Golgi. Defects of GPI anchor biosynthesis genes result in a genetic disorder, paroxysmal nocturnal hemoglobinuria.
Glycosylphosphatidylinositol(GPI)-anchor Biosynthesis
Glycosylphosphatidylinositol-Anchor Biosynthesis Pathway
N-glycans or asparagine-linked glycans are major constituents of glycoproteins in eukaryotes. N-glycans are covalently attached to asparagine with the consensus sequence of Asn-X-Ser/Thr by an N-glycosidic bond, GlcNAc b1-Asn. Biosynthesis of N-glycans begins on the cytoplasmic face of the ER membrane with the transferase reaction of UDP-GlcNAc and the lipid-like precursor P-Dol (dolichol phosphate) to generate GlcNAc a1-PP-Dol. After sequential addition of monosaccharides by ALG glycosyltransferases, the N-glycan precursor is attached by the OST (oligosaccharyltransferase) complex to the polypeptide chain that is being synthesized and translocated through the ER membrane. The protein-bound N-glycan precursor is subsequently trimmed, extended, and modified in the ER and Golgi by a complex series of reactions catalyzed by membrane-bound glycosidases and glycosyltransferases. N-glycans thus synthesized are classified into three types: high-mannose type, complex type, and hybrid type. Defects in N-glycan biosynthesis lead to a variety of human diseases known as congenital disorders of glycosylation.
O-glycans are a class of glycans that modify serine or threonine residues of proteins. Biosynthesis of O-glycans starts from the transfer of N-acetylgalactosamine (GalNAc) to serine or threonine. The first GalNAc may be extended with sugars including galactose, N-acetylglucosamine, fucose, or sialic acid, but not mannose, glucose, or xylose. Depending on the sugars added, there are four common O-glycan core structures, cores 1 through 4, and an additional four, cores 5 though 8. Mucins are highly O-glycosylated glycoproteins ubiquitous in mucous secretions on cell surfaces and in body fluids. Mucin O-glycans can be branched, and many sugars or groups of sugars are antigenic. Important modifications of mucin O-glycans include O-acetylation of sialic acid and O-sulfation of galactose and N-acetylglucosamine.
The lipid anandamide derived from arachidonic acid binds to the cannabinoid G-protein coupled receptors CB-1 and CB-2 to exert its biological effects. The CB-1 receptor is also the site of action of the psychoactive components of marijuana, including tetrahydrocannabinol (THC), and responsible for the effects of cannabinoids to repress learning, memory, and anxiety, relieve pain and nausea, and to stimulate appetite. The CB-2 receptor is expressed mainly in cells of the immune system and appears to modulate immune functions, but not to be involved in the effects of cannabinoids in the central nervous system. In addition to the illicit use of cannabinoids as drugs of abuse, the pharmaceutical use of natural and synthetic cannabinoids is being intensely studied, including a possible role in neurodegenerative diseases. Another therapeutic approach is the pharmacological modulation of levels of the endogenous cannabinoid anandamide. Although the subject of some controversy, the most likely route for the biosynthesis of anandamide starts with the formation of phosphatidylethanolamine from arachidonic acid and ethanolamine. Phosphatidylethanolamine is converted by N-acyltransferase to the phospholipid N-arachidonoyl-phosphatidylethanolamine (NAPE) and hydrolysis by phospholipase D releases phosphatidic acid and anandamide, which binds to the cannabinoid receptors. The signal it induces is terminated in part by degradation of anandamide by anandamide hydrolase (FAAH). 2-arachidonoyl-glycerol (2-AG) and 2-arachidonoyl glyceryl ether have also been shown to bind the cannabinoid receptors, and has been suggested to be important endocannabinoids. Also complicating cannabinoid pharmacology is the suggestion that some effects of cannabinoids might be moderated by additional receptor subtypes that have not yet been identified or by the vanilloid receptors. (This definition may be outdated - see the DesignNote.)
Metabolism of Anandamide, an Endogenous Cannabinoid
Fatty acids provide highly efficient energy storage, storing much more energy for their weight than carbohydrates like glucose. Fatty acids are stored as triglycerides in adipose tissue, in which each triglyceride molecule contains three fatty acids and one glycerol. Triglycerides form fatty droplets that exclude water and take up minimal space. Fatty acids are also more highly reduced than carbohydrates, so they provide more energy during oxidation. The efficiency of energy storage in fats is probably an important reason why animals store most of their energy as fats and only a small amount of energy as carbohydrates. When glucose levels are low during long periods between meals the enzyme glucagon secreted by the pancreas stimulates adipose lipase activity to release fatty acids from triglycerides. Epinephrine can stimulate the same activity to release energy during the fight or flight response. Once released, these fatty acids travel through the blood to other tissues such as muscle where they are oxidized to provide energy through the mitochondrial beta-oxidation pathway. Since fatty acid beta-oxidation occurs in the mitochondrial matrix, long-chain fatty acids must be actively transported from the cytoplasm into mitochondria by carnitine palmitoyltransferase. The chemical energy contained in fatty acids is released through the beta-oxidation of fatty acids in mitochondria. The beta-oxidation pathway includes four reactions that occur in repeating cycles with each fatty acid molecule. In each cycle, a fatty acid is progressively shortened by two carbons as it is oxidized and its energy captured by the reduced energy carriers NADH and FADH2. At the end of each cycle of four reactions, one acetyl-CoA two-carbon unit is released from the end of the fatty acid, which then goes through another round of beta-oxidation, continuing to oxidize and shorten even-chain fatty acids until they are entirely converted to acetyl-CoA. Fatty acids with an odd number of carbons in the acyl chain are left at the end with propionyl-CoA, with 3 carbons, which cannot enter another round of beta-oxidation. The propionyl-CoA produced in this manner is converted to succinyl-CoA that then enters the Krebs cycle. The acetyl-CoA generated in beta-oxidation enters the Krebs cycle, where it is further oxidized to CO2, producing more reduced energy carriers, NADH and FADH2 (See Krebs cycle pathway). These carriers produced in the Krebs cycle, along with those produced directly in beta-oxidation, transfer their energy to the electron transport chain where they drive the creation of the proton gradient that supports mitochondrial ATP production. Another destination of acetyl-CoA is the production of ketone bodies by the liver that are transported to tissues like the heart and brain for energy. Defects in fat metabolism associated with clinical disorders include lack of carnitine or carnitine transferase, which can lead to weakness and muscle pain during exercise. Defects in acyl-CoA dehydrogenase, which catalyzes the first step in beta-oxidation, appear to be involved in some cases of sudden infant death syndrome. (This definition may be outdated - see the DesignNote.)
Bile acids are steroid carboxylic acids derived from cholesterol in vertebrates. The primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized in the liver and conjugated with taurine or glycine before secretion via bile into the intestine. The conversion from cholesterol to cholic and chenodeoxycholic acids involves four steps: 1) the initiation of synthesis by 7alpha-hydroxylation of sterol precursors, 2) further modifications to the ring structures, 3) side-chain oxidation and shortening (cleavage) by three carbons, and 4) conjugation of the bile acid with taurine or glycine.
Biosynthesis of Unsaturated Fatty Acids Pathway
The eicosanoids are a family of lipophilic hormones derived from the twenty carbon fatty acid arachidonic acid. Although they are diverse in structure, many eicosanoids have roles in inflammation, including regulation of vasodilation, vascular permeability, pain, and recruitment of leukocytes. Most members of this family are rapidly metabolized near their site of synthesis, so they act locally on neighboring cells, not distant parts of the body. They are also not stored in cells, but synthesized rapidly in response to stimuli, making regulation of their synthesis a key to their activity. Many drugs act through modulating the production of eicosanoids or modulating their signaling pathways. Hormones in the eicosanoid family include the prostaglandins, thromboxanes, leukotrienes, and prostacyclins. The first step in the production of eicosanoids is the release of arachidonic acid from either diacylglycerol or phospholipids by membrane bound phospholipases in response to extracellular stimulus. Arachidonic acid has several possible fates, including oxygenation by lipoxygenases to make HPETEs (hydroperoxyeicosatetraenoic acids), or production of prostaglandin H2 by PGH2 synthase. 5-lipoxygenase acts with the membrane bound protein FLAP (five lipoxygenase activating protein) to produce the epoxide leukotriene LTA4 which is hydrolyzed to produce LTB4 or has glutathione added by a glutathione S-transferase to produce LTC4 and LTD4. A G-protein coupled receptor for LTD4, CysLT1, mediates an important component of the inflammatory response of leukotrienes on airway constriction and recruitment of leukocytes, and several marketed asthma drugs act as antagonists of the CysLT1 receptor. PGH2 synthase actually consists of two enzyme components, a cyclooxygenase and a peroxidase, and there are more than one type of cyclooxygenase, including Cox-1 and Cox-2. Recent NSAIDS acting selectively as Cox-2 inhibitors like Vioxx are widely used for the treatment of arthritis and other inflammatory conditions, inhibiting the production of downstream thromboxanes and prostaglandins. PGH2 also has several possible fates, including conversion by thromboxane synthase to Tpx2, an eicosanoid with potent coagulation and vasoconstriction activity. PGI2, or prostacyclin, synthesized by prostacyclin synthase, has properties opposite those of thromboxane, causing vasodilation and a reduction in clotting through the IP receptor, causing thromboxanes and PGI2 to act in opposition to each other. Thromboxane antagonists and prostacyclin agonists both provide tools and drugs to reduce vasoconstriction. The prostaglandins include PGD2, PGE2 and PGF2, with varying degrees of selectivity among their receptors, DP, EP and FP, respectively. PGE2 exerts biological effects including induction of pain, fever and vasodilation through at least four receptors, EP1, EP2, EP3 and EP4, and EP3 is found in multiple splice variants. The diversity of the eicosanoids and their receptors and their involvement in many disease states makes it likely that this pathway will continue as a major research focus. (This definition may be outdated - see the DesignNote.)
Fatty Acid Elongation Pathway in Mitochondria
Nuclear receptors are transcription factors that are activated upon binding to its ligands. Initially, they had been classified as classic endocrine nuclear hormone receptors and orphan receptors. However, further studies have led to the identification of lipid ligands for some of these receptors, which are responsible for lipid metabolism, storage, and elimination. One of the characteristics of these receptors is that they act by forming heterodimers with retinoid X receptor (RXR). The receptors include peroxisome proliferators-Activated receptors (PPARs) for fatty acids, liver X receptor (LCR) for oxysterols, Farnesoid X receptors (FXR) for bile acids, and steroid xenobiotic receptor/X receptor (SXR/PXR or Nsil2) for xenobiotics. Other orphan receptors also requiring RXR for its functions are vitamin D receptor (VDR) for vitamin D and retinoic acid receptor (RAR) for retinoid acids, although these receptors are not involved in lipid metabolism. Upon binding to various ligands, three classes of proteins are synthesized including lipid binding proteins, the ATP-binding cassette (ABC) transporters and cytochrome P450 member proteins which catalyze lipid anabolism, metabolism, and elimination. In addition to lipid metabolism, some members of the cytochrome P450 family genes are responsible for activation of procarcinogens, detoxification of environmental toxins, and metabolism of drugs and xenobiotics. In particular, CAR, Nsil2, and recently identified VDR are important in up-regulation of these cytochromes. Of all the human cytochrome P450 genes, only a few CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 account for most toxicity effects, specifically CYP3A is responsible for clearing approximately half of the clinically prescribed drugs. For instance, acetaminophen, one of the most commonly used drug, is toxic in high doses due to the activation of CAR and the drug's subsequent conversion to acetyl-p-benzoquinone imine (NAPQI) by CYP1A2, CYP2E1 and CYP3A. (This definition may be outdated - see the DesignNote.)
Nuclear Receptors in Lipid Metabolism and Toxicity
Sterol-regulatory element binding proteins (SREBPs) play a key role in transcriptional regulation of cholesterol metabolism in response to cholesterol levels in the cell. When cholesterol is abundant in the cell, the SREBPs are retained in the ER. When cholesterol levels decrease, SREBPs are cleaved and released to act as transcription factors, binding to the promoters of genes such as the LDL receptor and HMG CoA Synthase. Binding of SREBPs to the LDL receptor promoter increases the expression of LDL receptor on the cell surface and increases the internalization of LDL from plasma, increasing cellular cholesterol levels and lowering LDL cholesterol in the plasma. Upregulation of genes such as HMG CoA synthase increases the biosynthesis of cholesterol. The SREBP proteins are cleaved and activated by two proteases, S1P (Site 1 protease) and S2P (Site 2 protease). S1P cleaves SREBP region in the ER lumen and S2P cleaves in the transmembrane region of SREBPs. Regulation by sterols is provided by SCAP. SCAP activates S1P when sterols are low, inducing SREBP activation, and does not activate S1P when sterol levels increase. Drugs acting at various steps in this process can alter cholesterol metabolism and plasma cholesterol levels that contribute to coronary heart disease. The statins such as lovastatin are drugs that inhibit cholesterol biosynthesis, lowering intracellular cholesterol levels and activating SREBP cleavage to increase LDLR expression on the cell surface. Inhibition of S1P may provide another mechanism to alter plasma cholesterol levels, as suggested by the low cholesterol levels in mice lacking the S1P gene. Ligands that bind to SCAP also lower cholesterol levels through induction of LDLR expression. (This definition may be outdated - see the DesignNote.)
While the main route of fatty acid metabolism is through beta-oxidation, some minor metabolic pathways such as omega oxidation also contribute to the metabolism of fatty acids and other molecules. Omega oxidation occurs in the endoplasmic reticulum rather than the mitochondria, the site of beta-oxidation. The omega carbon in a fatty acid is the carbon furthest in the alkyl chain from the carboxylic acid. In the omega oxidation pathway, this carbon is progressively oxidized first to an alcohol and then to a carboxylic acid, creating a molecule with a carboxylic acid on both ends. The first step in the pathway is catalyzed by a cytochrome P450 mixed function oxidase and requires both oxygen and NADPH. Oxidation of the alcohol is catalyzed by an alcohol dehydrogenase and aldehyde dehydrogenase catalyzes the formation of the dicarboxylic acid. If the initial substrate was a long chain fatty acid, then the resulting dicarboxylic acid can enter the beta-oxidation pathway to be shortened at both ends of the molecule at the same time. When beta-oxidation is complete, the product is short chain dicarboxylic acids like succinate or adipate. Succinate enters the Kreb's cycle, and adipate's presence in blood or urine can be monitored to determine the degree of omega oxidation in an individual. Other molecules in addition to fatty acids can also enter the omega oxidation pathway. Other molecules with long alkyl chains also enter omega oxidation, becoming more water-soluble as a result and more easily excreted from the body. Although omega oxidation is normally a minor pathway of fatty acid metabolism, failure of beta-oxidation to proceed normally can result in increased omega oxidation activity. A lack of carnitine or carnitine palmitoyltransferase activity (see Mitochondrial Carnitine Palmitoyltransferase pathway) prevents fatty acids from entering mitochondria can lead to an accumulation of fatty acids in the cell and increased omega oxidation activity. (This definition may be outdated - see the DesignNote.)
The beta-oxidation of fatty acids in mitochondria progressively shortens fatty acids two-carbons at a time as acetyl-CoA units are removed with each round of the cycle. Fatty acids that enter beta-oxidation with an even number of carbons are converted entirely to acetyl-CoA, with the last round producing two acetyl-CoA molecules from one four carbon fatty acid. A fatty acid that enters beta-oxidation with 18 carbons, for example, will produce 9 acetyl-CoA units. Fatty acids that have an odd number of carbons present a special challenge. The last round of beta-oxidation with a five-carbon chain releases acetyl-CoA and the 3-carbon chain propionyl-CoA. Propionyl-CoA is not a common metabolic intermediate in other pathways, so it must be converted into something else to be effectively metabolized. In addition to production from fatty acids, propionyl-CoA is derived from the metabolism of several fatty acids, including isoleucine, valine and methionine. Propionyl-CoA is converted to succinyl-CoA, an intermediate in the Kreb's cycle. Propionyl-CoA has three carbons and succinyl-CoA has four carbons, so one of the first steps in this pathway is the carboxylation of propionyl-CoA with an input of energy from ATP. Mutation of propionyl-CoA carboxylase has been observed to cause a genetic condition called propionic acidemia. The rearrangement of this molecule, first between two stereoisomers, and then two structural isomers, results in succinyl-CoA. (This definition may be outdated - see the DesignNote.)
Conversion of Propionyl-CoA to Succinyl-CoA
Oxidation of Odd-Numbered Chain Fatty Acid, from Propionyl-CoA to Succinyl-CoA
Oxidation of Odd-Numbered Chain Fatty Acid Pathway
Unsaturated fatty acids are those that contain one or more double bonds in their alkyl-chain. Polyunsaturated fats with two double bonds usually have one between carbons 9 and 10 in the alkyl chain and another three carbons away (carbons 12-13). The presence of a double bond in the fatty acid chain changes the shape of the side group, and alters membrane fluidity when present in phospholipids. Polyunsaturated fatty acids in the diet such as omega-3 fatty acids from fish oil may have a positive influence on health, reducing cardiovascular disease and cancer. The double bonds in polyunsaturated fats cannot proceed directly through beta-oxidation to generate energy. Beta-oxidation will proceed normally through the first few rounds with a polyunsaturated fat, up until the point where the beta-oxidation enzymes encounter the first double bond. The enzymes of beta-oxidation are unable to act on substrates containing a double bond between the beta and gamma carbons. To solve this problem, the enzyme enoyl-CoA isomerase moves the first double bond to a position that the beta oxidation enzymes can act on, one carbon closer to the end of the alkyl chain. Beta-oxidation can then proceed for one cycle and part of the next, until it encounters the next double bond, which usually starts at an even-numbered carbon. A reductase then reduces the fatty acid, leaving a trans-3 double bond in mammals. The enzyme 3,2 enoyl-CoA isomerase moves this double bond closer to the end of the fatty acid chain, where the fatty acid can serve as a substrate for the normal beta-oxidation enzymes to continue beta-oxidation to completion. (This definition may be outdated - see the DesignNote.)
Oxidation of Polyunsaturated Fatty Acid Pathway
The main components of biological membranes are phosphoglyceride lipids composed of a glycerol unit esterified to two fatty acids and a polar alcohol group. The properties of phospholipids give lipid bilayer membranes their self-organizing structure. The polar alcohol group is hydrophilic and organizes itself in the membrane facing outward toward water, while the hydrophobic fatty acid alkyl chains face inward toward other fatty acid chains. One of the primary membrane phospholipids is phosphatidylcholine, in which the polar head group is composed of phosphocholine. The biosynthesis of phosphatidylcholine and phosphatidylethanolamine follow similar routes. The first step in phosphatidylcholine is the phosphorylation of choline to make phosphocholine, which is then activated by CTP. CDP-choline reacts with diacylglycerol to produce phosphatidylcholine (This definition may be outdated - see the DesignNote.)
Phosphatidylcholine Biosynthesis Pathway
Plasmalogens are a class of glycerophospholipids that contain one vinyl-ester linked long chain alcohol group in place of one ester-linked fatty acid chain found in other glycerophospholipids. As with the common glycerophospholipids, the polar head group of the plasmalogens is composed of ethanolamine, serine, or choline. Plasmalogens are relatively rare in some tissues but form a significant fraction of the membranes in nervous tissue. Some of the steps in plasmalogen biosynthesis are localized in peroxisomes, and some peroxisomal disorders impair plasmalogen biosynthesis. One of the starting materials for plasmalogen biosynthesis is dihydroxyacetone phosphate from glycolysis, which is used to form the glycerol backbone of the plasmalogen. In the first step, the three-carbon backbone is esterified with a fatty acid. This fatty acid ester is then exchanged leaving an ether-linked long-chain alcohol bound. Reduction of the carbonyl on the dihydroxyacetone backbone leaves a hydroxy group to be esterified with another fatty acid side chain. The polar head group such as ethanolamine is then added, and the alcohol chain modified in the last step to form the vinyl-alcohol side chain that characterizes plasmalogens. Plasmalogens serve as a starting point for the release of arachidonic acid by phospholipase A2 and the synthesis of signaling molecules derived from arachidonic acid such as prostaglandins. One plasmalogen called PAF acts through a G-protein coupled receptor as a potent platelet activator and clotting agent. The double bond of plasmalogens makes them more sensitive to oxidation than other membrane lipids, and may help to protect cells from oxidative damage. A decrease in the abundance of plasmalogens has been observed in some neurological disorders such as Alzheimer's disease. (This definition may be outdated - see the DesignNote.)
Prostaglandin and Leukotriene Metabolism
Prostaglandin and Leukotriene Metabolism Pathway
Sphingophospholipid Biosynthesis Pathway
Steroid hormones derived from cholesterol are a class of biologically active compounds in vertebrates. The cholesterol side-chain cleavage enzyme CYP11A1 catalyzes conversion of cholesterol, a C27 compound, to the first C21 steroid, pregnenolone, which is converted by a bifunctional enzyme complex to the gestagen hormone, progesterone. Pregnenolone and progesterone are the starting materials for the three groups of steroids: C21 steroids of glucocorticoids and mineralocorticoids, C19 steroids of androgens, and C18 steroids of estrogens. (i) Progesterone is converted by hydroxylations at carbons 21 and 11 to corticosterone, which is further modified by hydroxylation and oxydoreduction at carbon 18 to yield aldosterone, a mineralcorticoid. Cortisol, the main glucocorticoid, is formed from 17alpha-hydroxyprogesterone with 11-deoxycortisol as an intermediate. (ii) Male hormone testosterone is formed from pregnenolone by two pathways, delta5 pathway via dehydroepiandrosterone and delta4 pathway via androstenedione. The enzyme CYP17A1 is responsible for the 17,20 lyase and 17alpha-hydroxylase activities in respective pathways. (iii) Female hormones estrone and estradiol are formed from testosterone and 4-androstene-3,17-dione by oxidative removal of the C19 methyl group and subsequent aromatization of ring A. In addition to these three groups, recent studies show that there is another group, termed neurosteroids, synthesized in the brain rather than the peripheral endocrine gland.
Synthesis and Degradation of Ketone Bodies
Synthesis and Degradation of Ketone Bodies Pathway
Phosphoglycerides are lipids that contain glycerol with a phosphate ester on one end and two fatty acid ester side chains. Phosphoglycerides such as phosphatidylethanolamine and phosphatidylserine are the major component of lipid bilayer membranes in which their detergent-like properties help to provide membranes the quality of self-assembly. Phosphatidylglycerol is a phospholipid in which the phosphate ester on glycerol is joined to another glycerol. Phosphatidylglycerol is a precursor in the synthesis of both cardiolipin and phosphatidylinositol. In cardiolipin, two phosphatidylglycerol units are joined together. Cardiolipin was first identified in the heart, thus its name, and is abundant in the heart. Antibodies against cardiolipin have been observed in the blood of individuals with autoimmune disorders such as lupus. In mammals, cardiolipin is localized in mitochondria and may play a role in oxidative phosphorylation. Changes in cardiolipin levels with age might alter mitochondrial function and contribute to the aging process. Another derivative of phosphatidylglycerol is phosphatidylinositol in which the sugar inositol forms the phosphate ester. Inositol is an important intermediary in intracellular signaling pathways. Esterification of inositol with phosphates at various positions alters its interaction with different signaling proteins. Phosphatidylinositol can be phosphorylated at two positions to create PIP2. Hydrolysis of PIP2 by phospholipase C in response to GPCR activation releases IP3, which acts as a cytoplasmic second messenger to stimulate calcium release. (This definition may be outdated - see the DesignNote.)
Synthesis of Cardiolipin & Phosphatidylinositol
Synthesis of Cardiolipin and Phosphatidylinositol Pathway
Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. Melanogenesis is under complex regulatory control by multiple agents. The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melanocortic peptides. MC1R activates the cyclic AMP (cAMP) response-element binding protein (CREB). Increased expression of MITF and its activation by phosphorylation (P) stimulate the transcription of tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and dopachrome tautomerase (DCT), which produce melanin. Melanin synthesis takes place within specialized intracellular organelles named melanosomes. Melanin-containing melanosomes then move from the perinuclear region to the dendrite tips and are transferred to keratinocytes by a still not well-characterized mechanism.
Metabolism of Other Amino Acids - Reference Pathway
Natural products containing carbon-phosphorous bonds, so-called C-P compounds, are derivatives of phosphonate and phosphinate with substitution of alkyl group for hydrogen of phosphorus-hydrogen bonds. C-P compounds have been found in many organisms, but only protists and bacteria, mostly Actinobacteria, have biosynthetic capacity. A common reaction in the biosynthetic pathway is C-P bond forming reaction from phosphoenolpyruvate (PEP) to phosphonopyruvate (PnPy) catalyzed by PEP phosphomutase. 2-Aminoethylphosphonate (AEP) is the most abundant C-P compound in the natural world. AEP derivatives include phosphonoprotein, phosphonoglycan, and phosphonolipid. Other known C-P compounds are bioactive substances used in medicine (antibiotics) and agriculture (herbicide) such as fosfomycin, FR-33289, rhizocticin, and bialaphos.
D-Arginine and D-Ornithine Metabolism Pathway
D-Glutamine and D-Glutamate Metabolism Pathway
Taurine and Hypotaurine Metabolism Pathway
The oxidation of fatty acids is an important source of energy for ATP production in mitochondria through the entry of acetyl-CoA into the Krebs cycle. Fatty acids are oxidized inside the mitochondrial matrix but the fatty acids to be oxidized come from the cytosol. Fatty acids are activated in the cytosol by esterification with Coenzyme A (CoA) to form acyl-CoA (RCO-CoA, where R is the fatty acid acyl group). Activated medium-chain fatty acids (C8 and C10) freely diffuse into mitochondria to be oxidized but long chain fatty acids must be transported in. The transport of long chain fatty acids into mitochondria for oxidation is accomplished by the carnitine palmitoyltransferase system (CPTI and CPTII). CPTI exchanges carnitine for the CoA attached to long chain fatty acids to form a fatty acid-carnitine conjugate (RCO-carnitine). The fatty acid-carnitine is transported into the matrix by a transporter protein in the inner mitochondrial membrane. Once the fatty acid-carnitine is inside the matrix, CPTII exchanges CoA for carnitine to produce fatty acid-CoA once again, ready to enter fatty acid oxidation in the matrix to produce energy. The free carnitine is transported back out to renew the cytoplasmic pool of carnitine and allow the transfer process to continue. (This definition may be outdated - see the DesignNote.)
Mitochondrial Carnitine Palmitoyltransferase (CPT) System
Mitochondrial Carnitine Palmitoyltransferase Pathway
Neurotransmitters are signaling molecules used by neurons to communicate across chemical synapses. The receptors for neurotransmitters include G-protein coupled receptors (GPCRs) and ligand-gated ion channels. The biogenic amines are neurotransmitters derived from amino acids, and include dopamine, epinephrine, GABA, histamine and serotonin. For each of these, decarboxylation of an amino acid is a key step. GABA, gamma-aminobutyric acid, is a key inhibitory neurotransmitter and is synthesized through the decarboxylation of glutamate in a single step. Glutamate is itself an abundant excitatory neurotransmitter. Histamine signals are involved in inflammation and acid secretion in the stomach, acting through GPCRs. Histamine is synthesized in a single step from the amino acid histidine through decarboxylation. Serotonin is a neurotransmitter with a large range of effects, including roles in mood and depression, and is synthesized by first adding a hydroxyl group to tryptophan, followed by decarboxylation. A common mechanism of antidepressant action is to block the reuptake of serotonin at synapses. Dopamine is involved in movement and mood and is derived from tyrosine through addition of a hydroxyl group and decarboxylation. Additional reactions create norepinephrine and epinephrine from dopamine. These molecules, also called adrenalin and noradrenalin, act on the adrenergic receptors to exert responses including alteration of blood pressure, heart rate, metabolic activity, and bronchodilation. Many common drugs such as asthma and heart pressure medications act on adrenergic receptors. Alterations in these biosynthetic pathways can lead to significant clinical consequences. For example, deficiency in tyrosine hydroxylase activity leads to a movement disorder similar to Parkinson's disease and may play a role in Parkinson's disease and the development of an autoimmune response against glutamate decarboxylase (GAD) may trigger the destruction of insulin-secreting cells and type I diabetes. Numerous studies have searched for a potential genetic role of tryptophan hydroxylase mutations in neuropsychiatric indications, with conflicting results. (This definition may be outdated - see the DesignNote.)
Nucleotide Metabolism - Reference Pathway
Peroxisomes are essential organelles that play a key role in redox signaling and lipid homeostasis. They contribute to many crucial metabolic processes such as fatty acid oxidation, biosynthesis of ether lipids and free radical detoxification. The biogenesis of peroxisomes starts with the early peroxins PEX3, PEX16 and PEX19 and proceeds via several steps. The import of membrane proteins into peroxisomes needs PEX19 for recognition, targeting and insertion via docking at PEX3. Matrix proteins in the cytosol are recognized by peroxisomal targeting signals (PTS) and transported to the docking complex at the peroxisomal membrane. Peroxisomes' deficiencies lead to severe and often fatal inherited peroxisomal disorders (PD). PDs are usually classified in two groups. The first group is disorders of peroxisome biogenesis which include Zellweger syndrome, and the second group is single peroxisomal enzyme deficiencies.
Cholesterol is essential for life but a key in the development of heart disease. Cholesterol homeostasis is achieved through regulation of cholesterol uptake, cholesterol biosynthesis, cholesterol conversion to bile acids and excretion of bile acids. Inhibition of cholesterol biosynthesis up regulates LDLR expression and is the mechanism of action of many drugs used to lower plasma LDL to reduce coronary heart disease. Many aspects of cholesterol homeostasis are regulated by the nuclear receptors FXR and LXR, both nuclear receptor transcription factors that form heterodimers with the retinoic acid RXR receptors and that are activated by cholesterol metabolites. One of the primary tissues in cholesterol metabolism is the liver, a key site of cholesterol biosynthesis and where cholesterol low-density lipoprotein (LDL) is taken up from the plasma by the LDL-receptor. When cholesterol accumulates in liver cells, some of the cholesterol is oxidized to create oxysterols. Oxysterols activate LXR through LXR/RXR heterodimers to activate genes such as the CYP7A1 enzyme that catalyzes the rate-limiting step in bile acid biosynthesis and a major route for the elimination of cholesterol. Animals lacking the CYP7A1 enzyme accumulate cholesterol in the liver. In the intestine LXR activates the ABC-1 gene, a transporter that actively transports cholesterol out of cells to clear it from the body. Activation of ABC-1 expression by LXR in macrophages in atherosclerotic plaques appears to be another mechanism by which LXR plays a role in heart disease. The FXR receptor is activated by bile acids. In the liver, activation of FXR-RXR heterodimers by bile acids results in the feedback inhibition of CYP7A expression and reduced biosynthesis of bile acids. In the intestine, FXR activates expression of I-BABP, a protein that increases the transport of bile acids back to the liver from the intestine, reducing their excretion. Drugs targeting the FXR and LXR receptors could play an important role in modulating cholesterol homeostasis and heart disease in the future. (This definition may be outdated - see the DesignNote.)
FXR and LXR Regulation of Cholesterol Metabolism
Regulation of Cholesterol Metabolism Pathway
Cyclin-dependent kinase inhibitor-2A (CDKN2A) goes by the colloquial designation p16, which is sometimes referred to as p16(INK4). The alpha transcript of CDKN2A has been shown to encode p16(INK4a), a recognized tumor suppressor that induces a G1 cell cycle arrest by inhibiting the phosphorylation of the RB protein by the cyclin-dependent kinases CDK4 and CDK6. The beta transcript of CDKN2A encodes p14(ARF). The predicted 132-amino acid p14(ARF) is shorter than the corresponding mouse protein, p19(ARF), and the 2 proteins share only 50% identity. However, both proteins have the ability to elicit a p53 response, manifest in the increased expression of both CDKN1A and MDM2, and resulting in a distinctive cell cycle arrest in both the G1 and G2/M phases. Two unrelated proteins encoded by the INK4A-ARF locus function in tumor suppression. ARF binds to MDM2 and promotes the rapid degradation of MDM2. This interaction is mediated by the E1-beta-encoded N-terminal domain of ARF and a C-terminal region of MDM2. ARF-promoted MDM2 degradation is associated with MDM2 modification and concurrent p53 stabilization and accumulation. The p19(Arf) tumor suppressor inhibits production of ribosomal RNA, retarding processing of 47/45S and 32S precursors. These effects correlate with but do not strictly depend upon inhibition of rRNA biosynthesis or cell cycle arrest, are not mimicked by p53, and require neither p53 nor Mdm2. Arf mutants lacking conserved amino acid residues 2-14 do not block rRNA synthesis and processing or inhibit cell proliferation. Evolution may have linked a primordial nucleolar Arf function to Mdm2 and p53, creating a more efficient checkpoint-signaling pathway for coordinating ribosomal biogenesis and cell cycle progression. (This definition may be outdated - see the DesignNote.)
Tumor Suppressor Arf Inhibits Ribosomal Biogenesis
An elaboration of the known or inferred interactions controlling the expression of a product.
Vascular endothelial growth factor (VEGF) plays a key role in physiological blood vessel formation and pathological angiogenesis such as tumor growth and ischemic diseases. Hypoxia is a potent inducer of VEGF in vitro. The increase in secreted biologically active VEGF protein from cells exposed to hypoxia is partly because of an increased transcription rate, mediated by binding of hypoxia-inducible factor-1 (HIF1) to a hypoxia responsive element in the 5'-flanking region of the VEGF gene. bHLH-PAS transcription factor that interacts with the Ah receptor nuclear translocator (Arnt), and its predicted amino acid sequence, exhibits significant similarity to the hypoxia-inducible factor 1alpha (HIF1a) product. HLF mRNA expression is closely correlated with that of VEGF mRNA. The high expression level of HLF mRNA in the O2 delivery system of developing embryos and adult organs suggests that in a normoxic state, HLF regulates gene expression of VEGF, various glycolytic enzymes, and others driven by the HRE sequence, and may be involved in development of blood vessels and the tubular system of lung. VEGF expression is dramatically induced by hypoxia due in large part to an increase in the stability of its mRNA. HuR binds with high affinity and specificity to the VRS element that regulates VEGF mRNA stability by hypoxia. In addition, an internal ribosome entry site (IRES) ensures efficient translation of VEGF mRNA even under hypoxia. The VHL tumor suppressor (von Hippel-Lindau) regulates also VEGF expression at a post-transcriptional level. The secreted VEGF is a major angiogenic factor that regulates multiple endothelial cell functions, including mitogenesis. Cellular and circulating levels of VEGF are elevated in hematologic malignancies and are adversely associated with prognosis. Angiogenesis is a very complex, tightly regulated, multistep process, the targeting of which may well prove useful in the creation of novel therapeutic agents. Current approaches being investigated include the inhibition of angiogenesis stimulants (e.g., VEGF), or their receptors, blockade of endothelial cell activation, inhibition of matrix metalloproteinases, and inhibition of tumor vasculature. Preclinical, phase I, and phase II studies of both monoclonal antibodies to VEGF and blockers of the VEGF receptor tyrosine kinase pathway indicate that these agents are safe and offer potential clinical utility in patients with hematologic malignancies. (This definition may be outdated - see the DesignNote.)
A representation of the sequence of biological or biochemical events that are involved in the regulation of or result in apoptosis.
Programmed cell death is induced by many different factors and involves numerous signaling pathways, some dependent on caspase proteases and others that are caspase independent. Like cytochrome C, AIF (apoptosis-inducing factor) is a protein found in mitochondria that is released from mitochondria by apoptotic stimuli. While cytochrome C is linked to caspase-dependent apoptotic signaling, AIF release stimulates caspase-independent apoptosis, moving into the nucleus where it binds DNA. DNA binding by AIF stimulates chromatin condensation, and DNA fragmentation, perhaps through recruitment of nucleases. DNA-binding by AIF occurs through a distinct domain of the protein in a manner that does not rely on specific DNA sequences. AIF also has another domain that acts as an NADH oxidase, a redox enzyme. The NADH oxidase activity of AIF is separable from its DNA-binding activity and is not required for AIF to induce apoptosis. In this role, AIF protects against apoptosis rather than inducing apoptosis. In mice down regulation of the AIF gene created harlequin mice with oxidative damage to neurons and increased neuronal cell death. Loss of AIF also increased sensitivity to peroxides, suggesting that AIF may act as a peroxide scavenger. The mechanism by which AIF protects against peroxide damage is not clear, but may involve a more indirect mechanism than direct peroxide scavenging since the enzyme does not appear to have this activity in vitro. Elucidating further the role of AIF as a redox enzyme will shed further light on its normal function in mitochondria as well as its role in apoptosis and disease. (This definition may be outdated - see the DesignNote.)
Opposing roles of AIF in Apoptosis and Cell Survival
The cellular activation of the caspase cascade resulting in cell death is triggered by chemical damage to DNA which stimulates a sequence resulting in the cleavage of BID or directly initiates the permeability transition of the mitochondrial membrane. The permeability transition releases several factors including cytochrome c, AIF and other factors in to the cytoplasm. Cytochrome c, a key protein in electron transport, is released from mitochondria in response to apoptotic signals, and activates Apaf-1, a protease released from mitochondria. Activated Apaf-1 activates caspase-9 and the rest of the caspase cascade. The caspases are a class of cysteine proteases that includes several representatives involved in apoptosis. The caspases convey the apoptotic signal in a proteolytic cascade, with caspases cleaving and activating other caspases that then degrade other cellular targets that lead to cell death. (This definition may be outdated - see the DesignNote.)
Apoptotic Signaling in Response to DNA Damage
Apoptosis is a genetically controlled mechanism of cell death involved in the regulation of tissue homeostasis. The 2 major pathways of apoptosis are the extrinsic (Fas and other TNFR superfamily members and ligands) and the intrinsic (mitochondria-associated) pathways, both of which are found in the cytoplasm. The extrinsic pathway is triggered by death receptor engagement, which initiates a signaling cascade mediated by caspase-8 activation. Caspase-8 both feeds directly into caspase-3 activation and stimulates the release of cytochrome c by the mitochondria. Caspase-3 activation leads to the degradation of cellular proteins necessary to maintain cell survival and integrity. The intrinsic pathway occurs when various apoptotic stimuli trigger the release of cytochrome c from the mitochondria (independently of caspase-8 activation). Cytochrome c interacts with Apaf-1 and caspase-9 to promote the activation of caspase-3. Recent studies point to the ER as a third subcellular compartment implicated in apoptotic execution. Alterations in Ca2+ homeostasis and accumulation of misfolded proteins in the ER cause ER stress. Prolonged ER stress can result in the activation of BAD and/or caspase-12, and execute apoptosis.
Mechanism that allows cells to self-destruct when it is necessary
Apoptotic cell death can be triggered by many different cellular stimuli, resulting in activation of apoptotic signaling pathways including caspases and mitochondria. A cellular response that is characteristic of apoptosis is fragmentation of the nuclear genome to create a nucleosomal ladder. This activity is conducted by multiple nucleases activated by apoptotic signaling pathways. One nuclease involved in apoptosis is DNA fragmentation factor (DFF), a caspase-activated DNAse (CAD). DFF/CAD is activated through cleavage of its associated inhibitor ICAD by caspases proteases during apoptosis. DFF/CAD interacts with chromatin components such as topo II and histone H1 to condense chromatin structure and perhaps recruit CAD to chromatin. Another apoptosis activated protease is endonuclease G, EndoG. EndoG is encoded in the nuclear genome but is localized to mitochondria in normal cells. EndoG may play a role in the replication of the mitochondrial genome, as well as in apoptosis. Apoptotic signaling causes the release of EndoG from mitochondria. Mitochondria are involved in apoptotic signaling in other ways as well, through the release of cytochrome c induced by Bid to activate the caspase protease cascade. These pathways are independent since the EndoG pathway still occurs in cells lacking DFF. (This definition may be outdated - see the DesignNote.)
Apoptotic DNA fragmentation and tissue homeostasis
Apoptosis, programmed cell death, is triggered by a variety of stimuli, including cell surface receptors like FAS, mitochondrial response to stress, and cytotoxic T cells. Caspases are a class of cysteine proteases that includes several representatives involved in apoptosis. The caspases convey the apoptotic signal in a proteolytic cascade, with caspases cleaving and activating other caspases that then degrade other cellular targets that lead to cell death. The caspases at the upper end of the cascade include caspase-8 and caspase-9. Caspase-8 is the initial caspase involved in response to receptors with a death domain like FAS. The mitochondrial stress pathway begins with the release of cytochrome c from mitochondria, which then interacts with Apaf-1, causing self-cleavage and activation of caspase-9. Caspase-3, -6, and -7 are downstream caspases that are activated by the upstream proteases and act themselves to cleave cellular targets. Granzyme B and perforin proteins released by cytotoxic T cells induce apoptosis in target cells, forming transmembrane pores, and triggering apoptosis, perhaps through cleavage of caspases, although caspase-independent mechanisms of Granzyme B mediated apoptosis have been suggested. (This definition may be outdated - see the DesignNote.)
Dentatorubropallidoluysian Atrophy (DRPLA)
Dentatorubropallidoluysian Atrophy (DRPLA) Pathway
Apoptosis is specifically induced via signaling through a family of receptors known collectively as 'death receptors' including Fas, TNFR, DR3, -4 and -5. Death receptor ligands characteristically initiate signaling via receptor oligomerization, recruitment of specialized adaptor proteins and activation of caspase cascades. Apo3L recruits initiator caspase 8 via the adapter protein FADD. Caspase 8 then oligomerizes and is activated via autocatalysis. Activated caspase 8 stimulates apoptosis via two parallel cascades: it directly cleaves and activates caspase-3, and it cleaves Bid (a Bcl-2 family protein). Truncated Bid (tBid) translocates to mitochondria, inducing cytochrome C release, which sequentially activates caspases 9 and 3. DR-3L can deliver pro- or anti-apoptotic signals. DR-3 promotes apoptosis via the adaptor proteins TRADD/FADD and the activation of caspase 8. Alternatively, apoptosis is inhibited via an adaptor protein complex including RIP which activates NF-kB and induces survival genes including IAP. Induction of apoptosis via Apo2L requires caspase activity, but the adaptor requirement is unclear. (This definition may be outdated - see the DesignNote.)
Induction of apoptosis through DR3 and DR4/5 Death Receptors
DR3 and DR4/5 Mediated Apoptosis Pathway
Erythropoietin (Epo) is most commonly known as the cytokine secreted by the kidneys that stimulates red blood cell production and is used as a drug for the treatment of anemias. Epo is also secreted in the brain in response to hypoxia, such as ischemic stroke. Epo production in the brain is stimulated by the hypoxia-inducible transcription factor HIF-1 (see HIF pathway). Administration of Epo to the brain in rodents before hypoxic stress or other neuronal stresses is neuroprotective, preventing neuronal apoptosis. The erythropoietin receptor (EpoR) is known to associate with JAK kinases that phosphorylate and activate the STAT family of transcription factors. The neuroprotection by Epo involves cross-talk between Epo receptor and anti-apoptotic pathways through activation of NF-kB by the JAK2 kinase. Epo stimulates JAK2 phosphorylation of I-kB, releasing NF-kB to translocate into the nucleus and activate transcription of neuroprotective genes. Neuroprotective genes activated by NF-kB include the anti-oxidant enzyme manganese superoxide dismutase and calbindin-D28k. The erythropoietin receptor is also essential for proper brain development in mice. The absence of EpoR causes high levels of neuronal apoptosis in the developing mouse brain, further confirming the important role of Epo as a neuroprotective agent. (This definition may be outdated - see the DesignNote.)
Erythropoietin mediated neuroprotection through NF-kB
Oxidative stress is one factor that can trigger programmed cell death. Activated neutrophils responding to inflammatory stimulation produce reactive oxygen species like superoxide free radicals to kill invading bacteria, but these reactive oxygen species can also attack endothelial cells lining the vascular wall and trigger apoptosis. Endothelial cells also produce reactive oxygen species inside the cell that can contribute to oxidative stress and apoptosis, such as during reperfusion injury following ischemia. Superoxide dismutase (SOD) converts highly reactive and damaging superoxide free radicals to peroxides that are less reactive than superoxide but stimulate apoptosis. The glutathione (GSH) peptide reducing agent removes toxic metabolites and repairs damage created by reactive oxygen species. Glutathione peroxidase (GPx), for example, removes peroxides using glutathione as a reducing agent, and glutathione reductase (GSR) regenerates reduced glutathione. Inside the endothelial cell peroxide can be converted to hydroxyl ions in the presence of iron. Peroxides and hydroxyl radicals activate NF-kB and activate expression of inflammatory genes including adhesion molecules, TNF and IL-8. The apoptotic response of endothelial cells to oxidative stress may be involved in the development and progression of atherosclerosis. (This definition may be outdated - see the DesignNote.)
One mechanism used by cytotoxic T cells to kill tumor cells and virus-infected cells is the release of perforin and granzyme proteins. Perforin proteins form pores in the membranes of the attacked cell, allowing the entry of Granzyme A and Granzyme B. Granzyme B induces caspase activation and cleavage of factors like ICAD, releasing DFF40 to fragment DNA, one of the hallmarks of apoptotic cell death. Granzyme A is also an abundant granzyme released by cytotoxic T cells and is important in cytotoxic T cell induced apoptosis, activating caspase independent pathways. Once in a cell, Granzyme A activates DNA nicking by the recently identified DNAse NM23-H1, a tumor suppressor gene product whose expression is reduced in transformed, metastatic cells. The previous identification of NM23-H1 as a tumor suppressor indicates that its DNAse activity plays an important role in immune surveillance to prevent cancer through the induction of tumor cell apoptosis. The activation of NM23-H1 occurs indirectly, through the cleavage of proteins that inhibit NM23-H1 in the SET complex, which includes SET, Ape1, pp32 and HMG2. SET is a substrate for the Granzyme A protease, and SET cleavage relieves NM23-H1 inhibition to cause apoptotic DNA degradation. In addition to inhibiting NM23-H1, SET has nucleosome assembly activity and also may help the interaction of transcriptional regulation with chromatin structure by interacting with the transcriptional coactivator CBP. The targets of Granzyme A found in the SET complex also have other important functions. Ape1 repairs oxidative DNA damage, reduces transcription factors involved in immediate early responses, and its cleavage by Granzyme A may contribute to DNA degradation and apoptosis. HMG2 is an acidic chromatin-associated protein that bends DNA, alters chromatin structure and alters the accessibility of genes for transcription. In addition to acting as a nucleosome assembly factor and an inhibitor of NM23-H1, SET inhibits DNA and histone methylation by the CBP transcriptional coactivator. The tumor suppressor pp32 is not cleaved by Granzyme A but is part of the SET complex. Other targets of Granzyme A include nuclear lamins responsible for maintaining nuclear structure and histones, the basic building blocks of chromatin structure. The common involvement of the proteins of the SET complex in chromatin structure and DNA repair suggest that they work together to protect chromatin and DNA structure and that inactivation of the complex contributes to apoptosis by blocking the maintenance of DNA and chromatin structural integrity. (This definition may be outdated - see the DesignNote.)
HIV infection is associated with immunosuppression caused by a dramatic reduction in the helper T cell population. The loss of helper T cells may be caused by HIV-induced apoptosis of both infected and uninfected helper T cells. HIV uses the CCR5 chemokine receptor as a coreceptor for macrophage cell entry and upregulates fas-ligand on these cells. CD4 on helper T cells is essential for viral cell entry and infection. Cross-linking of CD4 on the T cell surface may be involved in upregulation of Fas and sensitization of T cells to apoptosis induced by the Fas/Fas-ligand interaction. (This definition may be outdated - see the DesignNote.)
HIV infection leads to drastic declines in CD4 T helper cells, in part through apoptosis of uninfected cells. Apoptosis of uninfected cells may be induced through the expression of Fas ligand on the surface of HIV-infected cells, stimulating the Fas-dependent apoptotic pathway in cells that come in contact with infected cells. The NEF protein expressed by HIV may play a role in the inducing the expression of Fas-ligand by infected cells. If this is the case, then a question that arises is how infected cells themselves escape Fas-mediated apoptosis. The NEF protein appears to play a role in this process as well. NEF interacts with the ASK1 kinase (apoptosis signal-regulating kinase) involved in apoptotic signaling by TNF and Fas-ligand. Interaction of NEF with ASK1 prevents phosphorylation of downstream MAP kinases and JNK kinases involved in apoptotic signaling. (This definition may be outdated - see the DesignNote.)
HIV-I Nef: negative effector of Fas and TNF
IGF-1R, the type 1 receptor for insulin-like growth factor, mediates cell survival and growth in response to its ligands IGF-1 and IGF-2. This tyrosine kinase receptor is widely expressed in many cell types and is a key mediator of growth. Overexpression or activation of IGF-1R may be involved in the proliferation of transformed cells, making inhibition of IGF-1R signaling a strategy for the development of cancer drugs. IGF-1R activates three signaling pathways that converge to phosphorylate BAD protein and block apoptosis. The first pathway activated by IGF-1R stimulates PI3-kinase and the AKT pathway to phosphorylate BAD and block apoptosis. A second pathway activated by IGF-1R involves ras mediated activation of the map kinase pathway to block apoptosis. A third pathway involves interaction of raf with mitochondria in response to IGF-1R activation. The convergence of these pathways to block apoptosis may enhance the IGF-1R response. (This definition may be outdated - see the DesignNote.)
Multiple antiapoptotic pathways from IGF-1R signaling lead to BAD phosphorylation
Nerve Growth Factor Receptor Signaling Pathway
Nicotinic acetylcholine receptors are essential for neuromuscular signaling and are also expressed in non-neuronal tissues, where their function is less clear. Although nicotinic acetylcholine receptors are primarily known for their action as ligand-gated ion channels transducing action potentials across synapses, they may have other actions. Nicotinic acetylcholine receptors in neurons alter apoptotic signaling, protecting against cell death in some settings, and this action may in some cases be directed through alternative signaling pathways. In neurons the alpha-7 nicotinic receptor activates PI3 kinase through a src-family kinase, activating the anti-apoptotic kinase AKT (See AKT signaling pathway). One pathway involved in AKT signaling involves phosphorylation of the forkhead transcription factor FKHRL1, causing its retention in the cytoplasm associated with 14-3-3, and blocking expression of the apoptotic fas protein. The PI3 kinase/AKT pathway protects a broad range of neurons against apoptotic cell death and may block apoptosis triggered by beta-amyloid fragments that contributes to the progression of Alzheimer's disease. If so, nicotinic agents may prove useful in the treatment of this and other neurodegenerative conditions. There are several proteins that modulate the response of nicotinic acetylcholine receptors, include synapse formation. Prior to synapse formation, nicotinic receptors are randomly dispersed in the post-synaptic membrane. A neuronal protein, agrin, binds to the Musk receptor in the muscle membrane, stimulating clustering of nicotinic receptors and synapse formation. Rapsyn is present at high levels at synapses with nicotinic receptors, bringing them together at high densities and anchoring clustered receptors to the cytoskeleton. Members of the Src family of tyrosine kinases also play a role in clustering caused by Rapsyn, phosphorylating the nicotinic receptors, rapsyn, and other targets. Nicotinic receptors expressed in non-neuronal tissues may also be involved in the response to smoking. In lung epithelial cells, nicotine from cigarette smoke blocks apoptosis by activating the anti-apoptotic kinase AKT, contributing perhaps to carcinogenesis and resistance to chemotherapy. Activation of nicotinic acetylcholine receptors in dermal fibroblasts may contribute to the altered wound healing and skin elasticity related to smoking. Activation of keratinocyte nicotinic receptors may also alter the properties of skin. (This definition may be outdated - see the DesignNote.)
Role of nicotinic acetylcholine receptors in the regulation of apoptosis
Mef2 (Myocyte enhancer factor 2) transcription factors play a role in T-Cell calcium induced apoptosis. Several factors regulate Mef2 transcription factors, including Map kinases and histone deacetylase (HDAC) enzymes. (This definition may be outdated - see the DesignNote.)
As tissues grow they require angiogenesis to occur if they are to be supplied with blood vessels and survive. Factors that inhibit angiogenesis might act as cancer therapeutics by blocking vessel formation in tumors and starving cancer cells. Thrombospondin-1 (TSP-1) is a protein that inhibits angiogenesis and slows tumor growth, apparently by inducing apoptosis of microvascular endothelial cells that line blood vessels. TSP-1 appears to produce this response by activating a signaling pathway that begins with its receptor, CD36, at the cell surface of the microvascular endothelial cell. The non-receptor tyrosine kinase fyn is activated by TSP-1 through CD36, activating the apoptosis inducing proteases such as caspase-3 and p38 protein kinases. p38 is a mitogen-activated kinase that also induces apoptosis in some conditions, perhaps through AP-1 activation and the activation of genes that lead to apoptosis. (This definition may be outdated - see the DesignNote.)
TSP-1 Induced Apoptosis in Microvascular Endothelial Cell
ATF-2 Transcription Factor Signaling Pathway
The function of the pro-apoptotic molecule BAD is regulated by phosphorylation of three sites (ser 112, 136, and 155). Phosphorylation at these sites results in loss of the ability of BAD to heterodimerize with the survival proteins BCL-XL or BCL-2. Phosphorylated BAD binds to 14-3-3 and is sequestered in the cytoplasm. While ser-136 phosphorylation is concordant with the activation of Akt, Ser-112 phosphorylation requires activation of the Ras-MAPK pathway. BAD Ser 155 was found to be a major site of phosphorylation induced following stimulation by growth factors and prevented by protein kinase A inhibitors. (This definition may be outdated - see the DesignNote.)
Exposure to divalent cadmium ions (Cd2+) is a known cancer risk factor, but the molecular mechanisms responsible for the inappropriate induction of cellular proliferation by cadmium are still being figured out. One cellular model used to study this process is macrophages grown in culture. In cultured macrophages, cadmium acts both at the cell surface and in the cytoplasm to induce proliferation. At the cell surface, cadmium interacts with a pertussis-sensitive cell surface receptor, probably a Gi-coupled GPCR, to stimulate proliferation. Cadmium can enter cells through calcium ion channels and once in cells affects calcium release by the ER. In addition to changes in intracellular calcium, the proliferative effects of cadmium are mediated by the Ras/Map kinase pathway, and also NF-kB. Inhibition of phospholipase C, map kinases, or NF-kB with a variety of pharmacological inhibitors all blocked the activation of cellular proliferation by cadmium. Protein kinase C is also activated by cadmium, upstream of the Map kinase pathway. Changes in transcription induced by cadmium include induction of immediate early genes like fos, jun, and myc. In addition to inducing cellular proliferation, cadmium also is slightly genotoxic due to inhibition of DNA repair, activates stress genes, and inhibits the immune system. The immunomodulatory effects observed with cadmium treatment may also involvement transcriptional disregulation, including the expression of cytokines such as IL-4, IL-10, and TNF-alpha. Although macrophages have been used for many studies, other cell types are also the target of cadmium's toxicity. (This definition may be outdated - see the DesignNote.)
Cadmium induces DNA synthesis and proliferation in macrophages
The calcium/calmodulin-dependent kinases (CaMKs) are involved in a large number of cellular responses induced by hormones, neurotransmitters and other signaling. Elevation of calcium functions as a major second messenger, where the intracellular concentration of calcium can be maintained at extremely low levels and subsequently increased following specific calcium-mobilizing stimuli. There are many buffers to the calcium fluctuations including membrane pumps and calcium-binding proteins that create discrete spatial control of its effectors and their targets. The current family of multifunctional calcium/calmodulin (CaM)-dependent protein kinases (CaMKs) consists of CaMKI, CaMKII and CaMKIV. These kinases translate and co-ordinate the calcium fluctuations into the appropriate cellular responses via phosphorylation. These kinases are partially regulated by the intracellular calcium receptor calmodulin (CaM), and have common as well as unique features in their structure, regulation and activation. CaMKII, CaMKI and CaMKIV, have an autoregulatory domain that restricts or inhibits enzymatic activity in the absence of calcium/CaM. Calcium/CaM binding alone produces maximal activity of CaMKII, whereas CaMKI and CaMKIV have an activation loop that requires phosphorylation of a threonine residue by CaMK kinase (CaMKK) for maximal activity. Two genes (alpha and beta) for CaMKK, which is also regulated by CaM, have been identified. The highest expression of these isoforms occurs in the brain but the activity of the CaMKs has been identified in most cell types. CaMKIV has a post-calmodulin autophosphorylation step that is not observed in CaMKI. The CaMKII multimer can autophosphorylate either the autoregulatory domain or the CaM-binding domain, producing diverse effects in its regulation and sensitivity to Calcium/CaM. Autophosphorylation of CaMKII can produce Calcium/CaM- independent activity (autonomous activity), without affecting its maximal Calcium/CaM-stimulated activity. The CaMKII autophosphorylation involves a kinase cascade of sorts, with each subunit of the multimeric enzyme acting as both kinase and kinase kinase. Autophosphorylation establishes a 1000-fold increase in the affinity for its activator Calcium/CaM (also known as CaM trapping); however, autophosphorylation within the CaM-binding domain following CaM dissociation of activated/autophosphorylated enzyme restricts or prevents CaM from rebinding (CaM capping). The mechanisms and consequences of autophosphorylation are central to the CaMKII enzyme's complex regulatory behavior enabling it to become differentially activated at different frequencies and levels of calcium spikes. The target proteins for the CaMKs are very similar. An example target of the CaMKs is the transcriptional activating protein CREB. The phosphorylation states of CREB after CaMK phosphorylation differ by the additional phosphorylation of CREB at serine 142 that functions as an additional inhibitory site. This difference appears to be the result of adjacent amino acids. (This definition may be outdated - see the DesignNote.)
Ca++/ Calmodulin-dependent Protein Kinase Activation
Several forms of post-translational modification regulate protein activities. Recently, protein methylation by CARM1 (coactivator-associated arginine methyltransferase 1) has been observed to play a key role in transcriptional regulation. CARM1 associates with the p160 class of transcriptional coactivators involved in gene activation by steroid hormone family receptors. CARM1 also interacts with CBP/p300 transcriptional coactivators involved in gene activation by a large variety of transcription factors, including steroid hormone receptors and CEBP. One target of CARM1 is the core histones H3 and H4, which are also targets of the histone acetylase activity of CBP/p300 coactivators. Recruitment of CARM1 to the promoter region by binding to coactivators increases histone methylation and makes promoter regions more accessible for transcription. Another target of CARM1 methylation is a coactivator it interacts with, CBP. Methylation of CBP by CARM1 blocks CBP from acting as a coactivator for CREB and redirects the limited CBP pool in the cell to be available for steroid hormone receptors. Other forms of post-translational protein modification such as phosphorylation are reversible in nature, but as of yet a protein demethylase is not known. (This definition may be outdated - see the DesignNote.)
Transcription Regulation by Methyltransferase of CARM1
Initiation of DNA replication in eukaryotes is a highly conserved, multi-step process (replication licensing) designed to restrict initiation events to once per replication origin per S phase. Its control has been uncovered by the discovery of the cyclin dependent kinases (CDKs) as master regulators of the cell cycle and the initiator proteins of DNA replication, such as the Origin Recognition Complex (ORC), Cdc6/18, Cdt1 and the mini-chromosome maintenance complex (Mcm). The proteins and the sequence of events involved in this process are conserved throughout the eukaryotic kingdom. First, the ORC comprised of six proteins binds to replication origins in the chromosomal DNA. At the end of mitosis, ORC, Cdc6/18 and Cdt1 assist the binding of Mcm proteins 2-7 to chromatin, and chromatin becomes licensed for replication. The activated Mcm complex functions as a replicating helicase and moves along with the replication fork to bring the origins to the unlicensed state. The cycling of CDK activity in the cell cycle regulates the two states of replication origins, the licensed state in G1-phase and the unlicensed state for the rest of the cell cycle. The restriction on licensing is relieved when CDK falls off at the completion of mitosis to allow a new round of replication. (This definition may be outdated - see the DesignNote.)
A representation of the sequence of biological or biochemical events that are involved in the regulation of the cell cycle.
Chromatin packaging of the genome is dynamic, changing with the cell cycle and with transcriptional regulation. During mitosis, chromatin is condensed for segregation of chromosomes, while for transcription chromatin is more open. The nuclear matrix, or scaffold, is a protein network in the nucleus providing structure and regulating chromatin condensation. Regulated interactions of matrix proteins with each other, DNA and other factors in different phases of the cell cycle alter the structure and function of chromatin. AKAP95 (A-kinase anchoring protein) is a nuclear matrix associated protein that also binds DNA and different proteins during different phases of the cell cycle. The interaction of AKAP95 with DNA and proteins alters the condensation and transcription of chromatin. A specific domain of AKAP95 regulates its interaction with the nuclear matrix and another regulates its association with DNA. One key protein that AKAP95 interacts with is the cAMP-dependent protein kinase, PKA. AKAP95 binds to PKA through a PKA RII regulatory subunit, an interaction that requires PKA phosphorylation by Cdk1. PKA activity and cAMP are reduced during entry into mitosis, but PKA recruited by AKAP95 to condensed chromosomes is essential to maintain the condensed state. Another protein recruited by AKAP95 is Eg7, a 150 kD protein recruited during mitotic chromatin condensation. Eg7 is a part of a multiprotein condensin complex, recruiting another key component of mitotic chromatin condensation. Modification of the core histones through phosphorylation regulates chromatin condensation. Histone H3 interacts with the condensin complex, and is phosphorylated during mitosis. Histone H3 phosphorylation by Aurora-2 induces chromatin condensation, and dephosphorylation by PP1 promotes chromatin decondensation for reentry into interphase. AKAP95 may play a role during the regulation of chromatin structure for transcription during interphase as well. The interaction of AKAP95 with the p68 RNA helicase recruits this enzyme to the nuclear matrix during interphase. Other nuclear RNA helicases interact with transcription factors and cofactors, suggesting that the p68 RNA helicase also may regulate interactions of transcription complexes. (This definition may be outdated - see the DesignNote.)
AKAP95 role in mitosis and chromosome dynamics
BTG2 is found to be one of the immediate early genes up-regulated by neural growth factor (NGF) and epidermal growth factor (EGF). Its transcriptional level is also up-regulated by p53, gamma radiation, adriamycin, and UV treatment of cells. BTG seems to be important for the cell cycle progression as BTG2 is preferentially expressed in quiescent cells. Over-expression of BTG2 decreases the growth of NIH3T3 cells and induces neuronal differentiation and prevention apoptosis of PC12 cells. Molecularly, BTG2 expression induces hypophosphorylation of RB and G1 arrest which could be rescued by overexpression of cyclin D1. BTG1 and BTG2 interact with PRMT1 (predominant cellular arginine N-methyltransferase) and increase PRMT1 methyltransferase activity. Box C domain in BTG1 and 2 are responsible for the interaction. Box C domain alone acts as a dominant negative which blocks PRMT1 activity. PRMT1 activity is essential for NGF induced PC12 differentiation, and blocking PRMT1 by Box C domain of BTG1 or 2 induces apoptosis. In addition, BTG2 and HoxB9 interaction enhances the transcription of Hoxb9. Lastly, association of BTG2 and BTG1 with Caf1 is also reported to modulate transcriptional activity of CAF1. (This definition may be outdated - see the DesignNote.)
BTG family proteins and cell cycle regulation
Cdc25 is a protein phosphatase responsible for dephosphorylating and activating cdc2, a crucial step in regulating the entry of all eukaryotic cells into the M-phase of the cell cycle. Cdc25 is phosphorylated throughout interphase but not in mitosis. The primary site for phosphorylation of cdc25 is Ser216. Phosphorylated cdc25 binds to members of the 14-3-3 family of proteins which prevents its activation of cdc2. Chk1, a protein kinase involved in the DNA damage checkpoint response in fission yeast, has been shown to phosphorylate cdc25 at Ser216 in vitro. (This definition may be outdated - see the DesignNote.)
cdc25 and chk1 Regulatory Pathway in response to DNA damage
Mitotic cell cycle progression is accomplished through a reproducible sequence of events, DNA replication (S phase) and mitosis (M phase) separated temporally by gaps known as G1 and G2 phases. Cyclin-dependent kinases (CDKs) are key regulatory enzymes, each consisting of a catalytic CDK subunit and an activating cyclin subunit. CDKs regulate the cell's progression through the phases of the cell cycle by modulating the activity of key substrates. Downstream targets of CDKs include transcription factor E2F and its regulator Rb. Precise activation and inactivation of CDKs at specific points in the cell cycle are required for orderly cell division. Cyclin-CDK inhibitors (CKIs), such as p16Ink4a, p15Ink4b, p27Kip1, and p21Cip1, are involved in the negative regulation of CDK activities, thus providing a pathway through which the cell cycle is negatively regulated.
The focus of this pathway is to illustrate the role of Polo-like Kinase 3 (Plk3 also known as Prk and Fnk) as part of the regulatory cascade leading to apoptosis and the arrest cell cycle progression prior to M phase. Phosphorylation of Cdc25C on serine-216 causes the arrest of the cell cycle at the G2/M phase border by preventing Cdc25C from activating cyclinB1/Cdk1. Xie et al. demonstrated that Plk3, like Chk1 and Chk2, also phosphorylates Cdc25C on serine-216 contributing to cell cycle arrest. Additionally they found that Plk3 also phosphorylates p53 on serine 20, a step that is stimulatory in the process leading up to p53-mediated apoptosis. Wang Q et al. found that Plk3 is closely associated with the centrosome and that this is dependent on the integrity of the microtubules. Expression of constitutively active or defective Plk3 kinase had significant defects on the shape and nature of the microtubule apparatus of the cell. In either case cell cycle progression was halted and apoptosis occurred. (This definition may be outdated - see the DesignNote.)
Regulation of cell cycle progression by Plk3
The cell cycle is regulated by the interplay of many molecules. Key among these are the cyclins which are expressed and then degraded in a concerted fashion to drive the stages of the cell cycle. Cyclins combine with cyclin dependent kinases (cdks) to form activated kinases that phosphorylate targets leading to cell cycle regulation. A breakdown in the regulation of this cycle can lead to out of control growth and contribute to tumor formation. Defects in many of the molecules that regulate the cell cycle have been implicated in cancer. Key among these are p53, the cdk inhibitors (p15, p16, p18, p19, p21, p27), and Rb, all of which act to keep the cell cycle from progressing until all repairs to damaged DNA have been completed. (This definition may be outdated - see the DesignNote.)
The estrogen-inducible RING finger protein Efp stimulates proliferation of breast cancer cells. 14-3-3 is p53-inducible protein that sequesters mitotic Cdks in the cytoplasm to inhibit entry into mitosis. To allow cell-cycle progression, estrogens stimulate production of Efp, which binds and ubiquinates 14-3-3s sigma. 14-3-3s marked with ubiquitin chains is recognized and destroyed by the proteasome. Released Cdks are now free to escape into the nucleus and promote mitotic entry. (This definition may be outdated - see the DesignNote.)
Estrogen-responsive protein Efp controls cell cycle and breast tumors growth
The cell cycle transition from G1 to S phase is a key regulatory point in the cell cycle. This transition is regulated by the checkpoint kinase cdk2 that activates the G1 to S transition when it is associated with cyclin E. Cdk2/Cyclin E causes the G1 to S transition through phosphorylation of the tumor suppressor Rb, releasing the transcription factor E2F-1. Other pathways acting through Rac, Ras, and Rho also regulate the G1 to S transition. Ras regulates cyclin D1 expression to affect the G1 to S transition. Transforming forms of Ras or Raf induce cyclin D1 expression and cause early entry into S phase. Signaling from Ras to Raf to MEK to ERKs induces Cyclin D1 expression, allowing Cyclin D1 to complex with Cdk4 and Cdk6 and phosphorylate Rb. Rac-1 and PAK appear to induce Cyclin D1 expression and induce the G1 to S transition primarily through activation of NF-kB to activate the Cyclin D1 promoter. Rho activates cdk2 and also inhibits p21 and p27 to induce cyclin D1 and stimulate the G1 to S transition. Rho represses p21 expression to block p21 induction by Ras and to allow Ras induced progression from G1 to S. Cells that lack p21 do not require Rho for Ras to induce cell cycle progression from G1 to S phase. The cooperative action of Ras, Rac and Rho to induce Cyclin D1 expression is a key component of oncogenic transformation. (This definition may be outdated - see the DesignNote.)
Influence of Ras and Rho proteins on G1 to S Transition
The G1/S cell cycle checkpoint controls the passage of eukaryotic cells from the first 'gap' phase (G1) into the DNA synthesis phase (S). Two cell cycle kinases, CDK4/6-cyclin D and CDK2-cyclin E, and the transcription complex that includes Rb and E2F are pivotal in controlling this checkpoint. During G1 phase, the Rb-HDAC repressor complex binds to the E2F-DP1 transcription factors, inhibiting downstream transcription. Phosphorylation of Rb by CDK4/6 and CDK2 dissociates the Rb-repressor complex, permitting transcription of S-phase genes encoding for proteins that amplify the G1 to S phase switch and that are required for DNA replication. Many different stimuli exert checkpoint control including TGFb, DNA damage, contact inhibition, replicative senescence, and growth factor withdrawal. The first four act by inducing members of the INK4 or Kip/Cip families of cell cycle kinase inhibitors. TGFb additionally inhibits the transcription of Cdc25A, a phosphatase that activates the cell cycle kinases. Growth factor withdrawal activates GSK3b, which phosphorylates cyclin D, leading to its rapid ubiquitination and proteasomal degradation. Ubiquitination, nuclear export, and degradation are mechanisms commonly used to rapidly reduce the concentration of cell-cycle control proteins. (This definition may be outdated - see the DesignNote.)
The G2/M DNA damage checkpoint prevents the cell from entering mitosis (M phase) if the genome is damaged. The Cdc2-cyclin B kinase is pivotal in regulating this transition. During G2 phase, Cdc2 is maintained in an inactive state by the kinases Wee1 and Mt1. As cells approach M phase, the phosphatase Cdc25 is activated, perhaps by the polo-kinase Pik1. Cdc25 then activates Cdc2, establishing a feedback amplification loop that efficiently drives the cell into mitosis. DNA damage activates the DNA-PK/ATM/ATR kinases, initiating two parallel cascades that inactivate Cdc2-cyclin B. The first cascade rapidly inhibits progression into mitosis: the CHK kinases phosphorylate and inactivate Cdc25, which can no longer activate Cdc2. The second cascade is slower. Phosphorylation of p53 dissociates it from MDM2, activating its DNA binding activity. Acetylation by p300/PCAF further activates its transcriptional activity. The genes that are turned on by p53 constitute effectors of this second cascade. They include 14-3-3s, which binds to the phosphorylated Cdc2-cyclin B kinase and exports it from the nucleus; GADD45, which apparently binds to and dissociates the Cdc2-cyclin B kinase; and p21Cip1, an inhibitor of a subset of the cyclin-dependent kinases including Cdc2 (CDK1). (This definition may be outdated - see the DesignNote.)
p27/Kip1 regulates the cell cycle by inhibiting the checkpoint kinase cdk2/cyclin E and blocking cell cycle progression through the G1-S transition. Cancer cells in some cases have reduced levels of p27, supporting the importance of p27 in cell cycle regulation. The activity of p27 is regulated by phosphorylation, synthesis and degradation. Phosphorylation of p27 at threonine-187 by cdk2 causes p27 to associate with an SCF complex that targets p27 for proteolytic degradation. The F box protein Skp2 binds specifically to threonine-187 phosphorylated p27, recruiting it to the SCF complex for degradation. Other components of the p27 ubiquitin ligase complex include Skp1, Cul1, and Roc1/Rbx-1. Cks-1 has also been identified in a reconstituted system as an essential component for recruitment of p27 for degradation by the SCF complex. Signaling by cytokines may modulate cell survival, proliferation, or apoptosis through modulation of p27 expression. Cytokine and AKT signaling pathways activate forkhead transcription factors that induce p27 expression at the transcriptional level. (This definition may be outdated - see the DesignNote.)
Regulation of p27 Phosphorylation during Cell Cycle Progression
p53 is a transcription factor who's activity is regulated by phosphorylation. The function is p53 is to keep the cell from progressing through the cell cycle if there is damage to DNA present. It may do this in multiple ways from holding the cell at a checkpoint until repairs can be made to causing the cell to enter apoptosis if the damage cannot be repaired. The critical role of p53 is evidenced by the fact that it is mutated in a very large fraction of tumors from nearly all sources. (This definition may be outdated - see the DesignNote.)
p53 activation is induced by a number of stress signals, including DNA damage, oxidative stress and activated oncogenes. The p53 protein is employed as a transcriptional activator of p53-regulated genes. This results in three major outputs; cell cycle arrest, cellular senescence or apoptosis. Other p53-regulated gene functions communicate with adjacent cells, repair the damaged DNA or set up positive and negative feedback loops that enhance or attenuate the functions of the p53 protein and integrate these stress responses with other signal transduction pathways.
Polo-like kinase signaling events in the cell cycle
Polo-like Kinase Signaling Pathway in the Cell Cycle
Sonic Hedgehog (Shh) is a secreted protein identified genetically as an important developmental factor. Shh provides a morphogenic signal in the developing CNS, organizing the spatial patterning of cells in the midbrain and inducing proliferation of neuronal precursor cells in the developing cerebellum, neural tube, and retina. Proliferative signaling by Shh is involved in the development of cancer, including specific brain and skin cancers such as basal cell carcinomas. Sonic hedgehog signaling may proceed by more than one mechanism. One signaling pathway is activated by Shh binding to Patched (Ptc-1) which releases inhibition of the GPCR Smoothened, activating the Shh signaling pathway and allowing progression through the G1 phase of the cell cycle. Shh can also affect progression through the G2/M transition. Patched binds to phosphorylated Cyclin B1, one component of the M-phase promoting factor (MPF), along with the kinase Cdc2. The interaction of Cyclin B1 with Patched blocks MPF activity, blocking progression through the G2/M transition. Shh binding leads to degradation of Ptc-1, release of Cyclin B1, and entry of the cyclin B1 into the nucleus. Patched acts as a tumor suppressor by blocking MPF activity. Blockade of the Hedgehog pathway by cyclopamine demonstrated the therapeutic potential of Hedgehog inhibition in the treatment of some cancers. (This definition may be outdated - see the DesignNote.)
Sonic Hedgehog (SHH) Receptor Ptc1 Regulates cell cycle
PTEN is a tumor suppressor gene. Recombinant PTEN is capable of dephosphorylating phosphatidylinositol 3,4,5-triphosphate[PI(3,4,5)P3], the product of phosphatidylinositol 3-kinase. Many of the cancer-related mutations have been mapped to the phosphatase catalytic domain; it has been suggested that the phosphatase activity of PTEN is required for its tumor suppressor function. The activation of PKB/AKT is regulated in a complex manner via phosphorylation of AKT on Thr308 and Ser473 by PDK1 and ILK (integrin-linked kinase) respectively. Inactivation of PTEN will constitutively activate PKB/AKT pathway. In addition to its role in regulating the PI 3-K/AKT cell survival pathway, PTEN also inhibits growth factor-induced Shc phosphorylation and suppresses the mitogen-activated protein (MAP) kinase signaling pathway. PTEN also interacts with FAK, a key molecule implicated in integrin signaling pathways, and it directly dephosphorylates tyrosine-phosphorylated FAK. PTEN down-regulation of p130CAS through FAK results in inhibition of cell migration and spreading. (This definition may be outdated - see the DesignNote.)
PTEN dependent cell cycle arrest and apoptosis
PTEN-Dependent Cell Cycle Arrest and Apoptosis Pathway
Regulation of Retinoblastoma Protein Pathway
Protein kinase A regulatory subunit RII-alpha (PKA-RIIa) is tightly bound to centrosomal structures during interphase through interaction with the A-kinase anchoring protein AKAP350 (also known as AKAP450 and CGNAP), MAP2 and Pericentrin. This diagram illustrates these three PKA-RII binding complexes. The cyclin B-p34(cdc2) kinase (CDK1) has been shown to phosphorylate PKA-RIIa on T54 and this has been proposed to alter the subcellular localization of PKA-RIIa at the onset of mitosis. It has been demonstrated that PKA-RIIa dissociates and redistributes from centrosomes at mitosis. The focal point of this illustration is the AKAP350 complex. In addition to binding PKA-RIIa, AKAP350 binds PKN (Takahashi et al 1999) and the phosphatases PP1 and PPA2 (Takahashi et al 1999). PKN is a serine/threonine protein kinase, having a catalytic domain homologous to the PKC family in the C-terminal region and a unique regulatory region in the N-terminal region. PKN is activated by a small GTPase RhoA and unsaturated fatty acids such as arachidonic acid. The binding of both kinases and phosphatases by the same scaffold protein provides a focal point where physiological events, such as cell cycle progression and intracellular membrane traffic, may be regulated by phosphorylation state of specific protein substrates. There are at least 4 isoforms of AKAP350 which lead to the possibility that they may behave differently at different subcellular locations. MAP2 is a member of a group of proteins that provide microtubule stabilization. MAP2 affinity appears to be dependent on PKA phosphorylation of MAP2. Pericentrin is also an AKAP (Diviani and Scott). Pericentrin binds Dynein which is also regulated by PKA leading to the possibility that pericentrin positions PKA to regulate dynein function (Diviani and Scott). (This definition may be outdated - see the DesignNote.)
The defects in cAMP-regulated chloride channel CTFR are believed to be the major cause for cystic fibrosis. Regulation of CFTR protein by the surface receptor beta adrenergic receptor is mediated through the ezrin/radixin/moesin binding phosphoprotein 50 (EBP50), which binds both the C-termini CFTR and b2AR through their PDZ binding motifs. In the resting state, CFTR, b2AR, and EBP50 exist as a macromolecular complex on the apical surface of epithelial cells. Upon agonist activation of the b2AR, the adenylate cyclase is stimulated through the G protein pathway, leading to an increase in cAMP. The elevated concentration of cAMP activates PKA, which is anchored near CFTR via interaction with Ezrin. The phosphorylation of CFTR by PKA disrupts the complex and leads to compartmentalized and specific signaling of the channel. (This definition may be outdated - see the DesignNote.)
Cystic fibrosis transmembrane conductance regulator (CFTR) and beta 2 adrenergic receptor (b2AR) pathway
Although insulin and glucagon play important roles in regulating the response of cells to nutrients, cells also respond to carbohydrates through transcriptional regulation by the glucose responsive transcription factor ChREBP. ChREBP, carbohydrate responsive element binding protein, is a transcription factor that is activated by high levels of carbohydrates and repressed by cAMP. The activation of ChREBP by elevated carbohydrate levels increases the activity of genes involved in glucose metabolism such as pyruvate kinase, a rate-limiting enzyme in glycolysis, increasing the overall rate of utilization of carbohydrates. Excess carbohydrates also increase the transcription of genes that convert carbohydrates to triglycerides in the liver for storage in adipose tissue. cAMP regulates ChREBP activity by activating PKA, which phosphorylates ChREBP. Phosphorylation of ChREBP at ser(196) inactivates nuclear import and phosphorylation at Thr(666) prevents DNA binding by ChREBP. A metabolite of glucose activates protein phosphatase PP2A that then dephosphorylates both sites on ChREBP in response to increased glucose levels and increases ChREBP activity. Other pathways also regulate ChREBP activity and response to nutrients. High fat diets repress ChREBP activation by increasing AMP in liver cells, activating the AMP kinase. Phosphorylation of ChREBP by AMP kinase inactivates ChREBP and blocks glucose induction of ChREBP, linking dietary fatty acids to the regulation of carbohydrate metabolism. (This definition may be outdated - see the DesignNote.)
ChREBP regulation by carbohydrates and cAMP
RXR and RAR are nuclear receptors that bind either all trans retinoic (tRA) or 9cis retinoic acid (9cisRA). In the absence of ligand corepressors with histone deacetylase activity are bound to the RAR/RXR heterodimer and suppress transcription. Once they bind retinoic acid a conformational change in the receptors cause the dissociation of the corepressors and the binding of coactivators with histone acetylase activity. Following ligand binding by the heterodimer the receptors and proteins in the basal transcription machinery (like TBP and TAF135) are degraded by the proteasome. (This definition may be outdated - see the DesignNote.)
Nuclear receptors coordinate the activities of chromatin remodeling complexes and coactivators to facilitate initiation of transcription in carcinoma cells
Chromatin Remodeling Complex and Coactivator Pathway
Cdk5 is a cyclin dependent protein kinase involved in dopaminergic signaling in the neostriatal region of the brain. The role of cdk5 in dopamine responses occurs through phosphorylation of DARPP-32. Casein kinase 1 (CK1) also regulates DARPP-32 phosphorylation and dopamine signaling. The phosphorylation of DARPP-32 by cdk5 reduced dopamine signaling. Depending on its phosphorylation state, DARPP-32 inhibits either protein phosphatase 1 (PP1) or PKA. The role of mGLUR1 in this process is supported by the induction of cdk5 and CK1 activity by the mGLUR1 agonist DHPG and the subsequent phosphorylation of DARPP-32 associated with DHPG treatment of nigrostriatal neurons. CK-1 and Ckd5 inhibitors block the DHPG induced DARPP-32 phosphorylation. Dopamine exerts a positive signal that increases dopamine response by reversing phosphorylation of DARPP-32 at threonine-75. Dopamine initiates this pathway through activation of the D1 dopamine receptor, a Gs coupled GPCR, elevating cAMP and activating PKA. PKA activates protein phosphatase 2A (PP2A) which dephosphorylates DARPP-32 and increases dopamine responsiveness. This also removes the inhibition of PKA by DARPP-32, forming a positive feedback loop for further DARPP-32 inactivation by PKA. Activation of the D2 dopamine receptor has the opposite effect, shifting the DARPP-32 population toward the threonine-75 phosphorylated form. (This definition may be outdated - see the DesignNote.)
Regulation of ck1/cdk5 by type 1 glutamate receptors
CTCF is central to signaling pathways in immature B cells elicited by cross-linking the Ig BCR and stimulation with TGF. Both stimuli result in induction of cell cycle arrest and apoptosis. BCR ligation stimulates a transient induction of MYC that leads to high level CTCF expression and feedback suppression of MYC transcription. BCR ligation also activates PTEN opposing PI3K activation of MYC. Pharmacologic inactivation of PI3K or mTOR/FRAP results in suppression of S6K resulting in activation of CTCF and suppression of MYC. CTCF activation induces transcriptional activation of p19ARF, with its downstream consequences, and of p27. Growth arrest is occasioned by co-expression of p21 and p27 and inhibition of MYC. CTCF, is a multivalent DNA-sequence binder whose specificity is mediated by different sets of zinc finger (ZF) proteins. (This definition may be outdated - see the DesignNote.)
Endothelial cells respond to treatment with the protease thrombin with increased secretion of the PDGF B-chain. This activation occurs at the transcriptional level and a thrombin response element was identified in the promoter of the PDGF B-chain gene. A transcription factor called the DNA-binding protein B (dbpB) mediates the activation of PDGF B-chain transcription in response to thrombin treatment. DbpB is a member of the Y box family of transcription factors and binds to both RNA and DNA. In the absence of thrombin, endothelial cells contain a 50 kD form of dbpB that binds RNA in the cytoplasm and may play a role as a chaperone for mRNA. The 50 kD version of dbpB also binds DNA to regulate genes containing Y box elements in their promoters. Thrombin activation results in the cleavage of dbpB to a 30 kD form. The proteolytic cleavage releases dbpB from RNA in the nucleus, allowing it to enter the nucleus and binds to a regulatory element distinct from the site recognized by the full length 50 kD dbpB. The genes activated by cleaved dbpB include the PDGF B chain. Dephosphorylation of dbpB also regulates nuclear entry and transcriptional activation. RNA digestion in vitro can release dbpB in its active form, suggesting that the protease responsible for dbpB may be closely associated in a complex. Identification of the protease that cleaves dbpB, the mechanisms of phosphorylation and dephosphorylation, and elucidation of the signaling path by which thrombin induces dbpB will provide greater understanding of this novel signaling pathway. (This definition may be outdated - see the DesignNote.)
Transcriptional activation of dbpb from mRNA
As with many cell-surface receptors, activation of the EGF receptor can result in receptor internalization through receptor-mediated endocytosis, desensitizing further receptor signaling. This process requires clathrin and occurs in clathrin-coated pits, which pinch off from the plasma membrane to form vesicles that move to the early endosome. From the early endosome, receptors can either be recycled back to the cell surface, or they can move through the late endosome to the lysosome for proteolytic degradation. The sorting of receptors in the early endosome for degradation requires the tyrosine kinase activity of activated growth factor receptor and involves ubiquitination of the receptor. Targeting of receptors for degradation requires members of the Cbl gene family. Cbl proteins bind to tyrosine phosphorylated EGF receptor, and are E3 ubiquitination ligases that label receptor for degradation. Cbl also recruits Cin85 to the receptor complex, and blocking Cin85 interaction blocks receptor internalization and degradation. Endophilins are also a member of this receptor-bound protein complex. In its role as a ubiquitin ligase and docking protein, Cbl desensitizes EGF signaling and also opposes cellular proliferation induced by EGF. EGF activation also appears to activate the tyrosine kinase Src, which phosphorylates Cbl, and helps to activate the ubiquitination and degradation of EGF receptor. PKC activation and threonine phosphorylation of the EGF receptor can induce heterologous receptor internalization, but opposes Cbl-mediated receptor degradation. PKC phosphorylated receptors are sorted for recycling to the cell surface, and directed away from the late endosome and proteasome. Other growth factor receptors are regulated in a similar manner, including the PDGF receptor, HGF receptor and the CSF-1 receptor, indicating that this is a fairly general regulatory mechanism. The importance of Cbl in the down-regulation of growth factor signaling means that it will have an important role in cellular transformation and the development and treatment of cancer. (This definition may be outdated - see the DesignNote.)
CBL mediated ligand-induced downregulation of EGF receptors
EGF Receptor Downregulation by CBL Pathway
Protein phosphorylation plays an important role in the control of translation by eukaryotic initiation factor-2 (eIF-2). eIF-2 binds GTP and Met-tRNAi and transfers the Met-tRNA to the 40S subunit, to form the 43S preinitiation complex. Later in the cycle, prior to elongation, the bound GTP is hydrolyzed, releasing eIF-2-GDP. For eIF-2 to promote another round of initiation, GDP must be exchanged for GTP, a reaction catalyzed by eIF-2B. Kinases activated by viral infection (PKR), endoplasmic reticulum stress (PERK/PEK), amino acid deprivation (GCN2), and hemin deficiency (HRI) can phosphorylate the a subunit of eIF-2. This phosphorylation stabilizes the eIF-2-GDP-eIF-2B complex, inhibiting the turnover of eIF-2B. eIF-2B is also inhibited by GSK-3b phosphorylation. These events result in a shut-down of cellular protein synthesis and can lead to apoptosis. (This definition may be outdated - see the DesignNote.)
eIF-4F and p70 S6 kinase play critical roles in translational regulation. eIF-4F is a complex whose functions include the recognition of the mRNA 5' cap structure (eIF-4E), delivery of an RNA helicase to the 5' region (eIF-4A), bridging of the mRNA and the ribosome (eIF-4G), and circularization of the mRNA via interaction between eIF-4G and the poly(A) binding protein (PABP). Several stimuli, including growth factors and cytokines, regulate the eIF-4 complex and p70 S6 kinase by initiating a phosphorylation cascade involving the sequential activation of PI3-K, PDK1/2, Akt/PKB, and FRAP/mTOR kinase. FRAP/mTOR, together with an unidentified kinase, phosphorylates 4E-BP, leading to its dissociation from and activation of eIF-4E. MNK1/2, activated by ERK and p38 MAPK, phosphorylates and activates eIF-4E. Both processes contribute to the association of eIF-4E and eIF-4G to form the active eIF-4F complex, a necessary component of the 48S initiation complex. Phosphorylation of ribosomal protein S6 by p70 S6 kinase stimulates the translation of mRNAs with a 5' oligopyrimidine tract which typically encode components of the protein synthesis. (This definition may be outdated - see the DesignNote.)
Several forms of post-translational modification regulate protein activities. Recently, protein methylation by CARM1 (coactivator-associated arginine methyltransferase 1) has been observed to play a key role in transcriptional regulation. CARM1 associates with the p160 class of transcriptional coactivators involved in gene activation by steroid hormone family receptors. CARM1 also interacts with CBP/p300 transcriptional coactivators involved in gene activation by a large variety of transcription factors, including steroid hormone receptors and CEBP. One target of CARM1 is the core histones H3 and H4, which are also targets of the histone acetylase activity of CBP/p300 coactivators. Recruitment of CARM1 to the promoter region by binding to coactivators increases histone methylation and makes promoter regions more accessible for transcription. Another target of CARM1 methylation is a coactivator it interacts with, CBP. Methylation of CBP by CARM1 blocks CBP from acting as a coactivator for CREB and redirects the limited CBP pool in the cell to be available for steroid hormone receptors. Other forms of post-translational protein modification such as phosphorylation are reversible in nature, but as of yet a protein demethylase is not known. The methylation activity of CARM1 modulates the activity of specific transcriptional regulators. CARM1 acts as a coactivator for the myogenic transcription factor Mef2c, and is necessary for normal muscle cell differentiation. The estrogen receptor is another transcription factor that uses CARM1 as one of several coactivators, acting synergistically with CBP through the Grip1 member of the p160 family of coactivators. The interaction of estrogen receptor with various ligand-dependent coactivators may produce the tissue selective response of some estrogen receptor ligands like tamoxifen. (This definition may be outdated - see the DesignNote.)
CARM1 and Regulation of the Estrogen Receptor
Estrogen Receptor Regulation by CARM1 Pathway
FOXA Transcription Factor Signaling Pathway
FOXA1 Transcription Factor Signaling Pathway
FOXA2 and FOXA3 transcription factor networks
FOXA2 and FOXA3 Transcription Factor Signaling Pathway
FOXM1 Transcription Factor Signaling Pathway
FOXO Transcription Factor Family Signaling Pathway
Gap junctions contain intercellular channels that allow direct communication between the cytosolic compartments of adjacent cells. Each gap junction channel is formed by docking of two 'hemichannels', each containing six connexins, contributed by each neighboring cell. These channels permit the direct transfer of small molecules including ions, amino acids, nucleotides, second messengers and other metabolites between adjacent cells. Gap junctional communication is essential for many physiological events, including embryonic development, electrical coupling, metabolic transport, apoptosis, and tissue homeostasis. Communication through Gap Junction is sensitive to a variety of stimuli, including changes in the level of intracellular Ca2+, pH, transjunctional applied voltage and phosphorylation/dephosphorylation processes. This figure represents the possible activation routes of different protein kinases involved in Cx43 and Cx36 phosphorylation.
A pathway that modulates the expression of genes involved in calcium homeostasis, bone formation, cellular differentiation, cell growth and apoptosis through the direct interaction between the nuclear receptor, vitamin D3 receptor (VDR), primarily as part of a heterodimeric complex with the retinoid X receptor (RXR), and vitamin D response elements (VDREs) found in the promoter regions of vitamin D regulated genes.
Control of Gene Expression by Vitamin D Receptor
Gene Expression Regulation by Vitamin D Receptor Pathway
An elaboration of the biological or biochemical events that are involved in the maintenance of the internal physiology of an organism.
Sodium transport across the tight epithelia of Na+ reabsorbing tissues such as the distal part of the kidney nephron and colon is the major factor determining total-body Na+ levels, and thus, long-term blood pressure. Aldosterone plays a major role in sodium and potassium metabolism by binding to epithelial mineralocorticoid receptors (MR) in the renal collecting duct cells localized in the distal nephron, promoting sodium resorption and potassium excretion. Aldosterone enters a target cell and binds MR, which translocates into the nucleus and regulates gene transcription. Activation of MR leads to increased expression of Sgk-1, which phosphorylates Nedd4-2, an ubiquitin-ligase which targets ENAC to proteasomal degradation. Phosphorylated Nedd4-2 dissociates from ENAC, increasing its apical membrane abundance. Activation of MR also leads to increased expression of Na+/K+-ATPase, thus causing a net increase in sodium uptake from the renal filtrate. The specificity of MR for aldosterone is provided by 11beta-HSD2 by the rapid conversion of cortisol to cortisone in renal cortical collecting duct cells. Recently, besides genomic effects mediated by activated MR, rapid aldosterone actions that are independent of translation and transcription have been documented.
Aldosterone-regulated sodium reabsorption
Aldosterone-Regulated Sodium Reabsorption Pathway
Cardiovascular diseases are predicted to be the most common cause of death worldwide by 2020. The major regulator of blood pressure homeostasis is the renin-angiotensin system. Angiotensinogen is digested by renin to produce angiotensin I (AGT I). AGT I is an inactive 10 amino-acid peptide that is further degraded to produce angiotensin II by the angiotensin-converting enzyme (ACE). Angiotensin II is the master regulator of blood pressure increase acting on the heart, kidneys and blood vessels. Angiotensin II causes direct constriction of the resistance vessels and stimulation of the adrenal thereby increasing blood volume and sodium absorption. In 2000, Tipnis et al. discovered ACE 2 a second carboxypeptidase that digests angiotensin. ACE is a di-peptidase, cleaving off 2 peptides from the c-terminal end of angiotensin. ACE 2 only cleaves 1 amino acid to produce angiotensin 1-9 (AGT 1-9) which has no identified function at this time. AGT 1-9 is not converted to angiotensin II but further degraded by ACE to AGT 1-7, a vasodilator. It would appear that ACE 2 inhibits the formation of angiotensin and reduces blood pressure increases. Crackower et al determined that ace2 -/- mice suffered significant heart defects at 6 months. Further deletion of ACE resulted in restored cardiac functions. (This definition may be outdated - see the DesignNote.)
Angiotensin-converting enzyme 2 regulates heart function
Osteoblasts mineralize bone matrix by promoting hydroxyapatite crystal formation and growth in the interior of membrane-limited matrix vesicles (MVs) and by propagating the crystals onto the collagenous extracellular matrix. Two osteoblast proteins, tissue-nonspecific alkaline phosphatase (TNAP) and plasma cell membrane glycoprotein-1 (PC-1) are involved in this process. In the bone matrix, PC-1 is the major producer of PPi, which in turn has an inhibitory effect on hydroxyapatite deposition. TNAP has a positive influence on mineralization primarily by controlling the size of the inhibitory pool of PPi through its inorganic pyrophosphatase activity. TNAP also generates Pi by using NTPs and PPi as substrates, but other more major sources of Pi e.g., intestinal absorption, are likely to contribute the bulk of the Pi needed for hydroxyapatite deposition. (This definition may be outdated - see the DesignNote.)
Contraction of the heart is a complex process initiated by the electrical excitation of cardiac myocytes (excitation-contraction coupling, ECC). In cardiac myocytes, Ca2+ influx induced by activation of voltage-dependent L-type Ca channels (DHP receptors) upon membrane depolarization triggers the release of Ca2+ via Ca2+ release channels (ryanodine receptors) of sarcoplasmic reticulum (SR) through a Ca2+ -induced Ca release (CICR) mechanism. Ca2+ ions released via the CICR mechanism diffuse through the cytosolic space to contractile proteins to bind to troponinC resulting in the release of inhibition induced by troponinI. The Ca2+ binding to troponinC thereby triggers the sliding of thin and thick filaments, that is, the activation of a crossbridge and subsequent cardiac force development and/or cell shortening. Recovery occurs as Ca2+ is pumped out of the cell by the Na+/Ca2+ exchanger (NCX) or is returned to the sarcoplasmic reticulum (SR) by sarco(endo)plasmic Ca2+ -ATPase (SERCA) pumps on the non-junctional region of the SR.
Organisms from flies to humans have daily circadian rhythms entrained with the 24-hour cycle of day and night that regulate many physiological systems. In mammals, there appears to be a master regulator of circadian rhythms in the hypothalamus, as well as additional peripheral mechanisms. The basic framework of the molecular pathways in the cell that produce and maintain these daily rhythms has been elucidated. The central feature of the circadian pathways are two transcription factors, Bmal1 and Clock, that are expressed in a 24 hour cycle and that act together as a heterodimer to regulate the expression of other genes involved in maintaining the circadian rhythm. Bmal1 and Clock activate transcription of multiple Period (per) and Cryptochrome (Cry) genes. When the activity of Bmal1 and Clock is maximal, Per and Cry genes are transcribed, and then translated in the cytoplasm. The translated Per and Cry genes form a complex in the cytoplasm that is transported back into the nucleus. In the nucleus, Per and Cry form a feedback loop that inhibits transcriptional activation by Bmal1 and Clock, lowering their own expression in the process. At the same time, Per and Cry increase transcription of Bmal1 and Clock genes, to initiate the next phase of the cycle once again. This cycle runs autonomously in the cell, causing jet lag during travel, but can be regulated to retrain to changes in the light cycle. Factors that regulate the cycle include casein kinase 1 epsilon (CK1e) that phosphorylates Per2 and induces its degradation. Mutation of PER2 in humans has been genetically linked to changes in human sleep patterns. Further exploration of the factors that regulate circadian rhythms may enable manipulation of the system in sleep disorders. (This definition may be outdated - see the DesignNote.)
One of the important roles of the collecting duct segment of the kidney nephron is acid secretion. As daily food intake loads acid into the body, urinary acid excretion is essential, and urine pH can drop as low as 4.5. The alpha-intercalated cell of collecting duct is the main responsible for hydrogen secretion into the urine. The carbon dioxide, which is generated in the cells and enters from the blood, is changed to carbonic acid. This carbonic acid is divided into hydrogen ion and bicarbonate ion. Intracellular CA II catalyses the formation of these ions. The hydrogen ion is secreted into the lumen by the luminal H(+)-ATPase. The bicarbonate ion is transported to the blood side by the anion exchanger type 1. Hydrogen ion in the lumen is trapped by urinary buffers. These include ammonium and phosphate.
Clot formation and fibrinolysis is a balance of plasmin activation/inhibition and thrombin-thrombomodulin activity that regulates fibrin polymer formation and degradation. Active thrombin is produced by the cleavage of prothrombin in the intrinsic thrombin activation pathway or the extrinsic thrombin activation pathway. Cleavage of fibrinogen by thrombin releases the fibrin monomers that auto-polymerize within seconds into fibrin threads or fibers. The coagulation cascade has many feedback loops. One example is the binding of thrombin to the fibrin polymers resulting in a reduction in soluble thrombin. The fibers form a more stable clot as a result of the covalent bonds formed by activated factor XIII enzyme (also known as Fibrin-stabilizing factor). These fibers form a mesh that traps platelets, blood cells and plasma to form a clot. The removal of the clot is caused by plasmin cleavage of the fibrin monomers into soluble fibrin degradation products. Plasmin is formed by the cleavage of plasminogen between Arg561 and Val562. Plasmin is a two-chain trypsin-like serine protease. Plasminogen activator inhibitor 1 (PAI1) and plasminogen activator inhibitor 2 (PAI2) inhibit cleavage of plasminogen by tissue-type plasminogen activator (tPA) or urokinase plasminogen activator (uPA). The presence of fibrin fibers and fibrin degradation products [(DD)E1 and (DD)E2] exert a two-fold stimulation of tPA and uPA. Plasmin activity is also inhibited by alpha2-antiplasmin. Thrombin activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B-like proenzyme activated by the thrombin-thrombomodulin dimer. TAFI cleaves (DD)E2 to separate DD and E fragments which do not enhance the activation of tPA or uPA and results in a reduced feedback signal. Overabundance or increased activity of the plasminogen activator inhibitors or reduced presence or function of tPA or uPA can result in atherosclerotic disease and venous thrombosis due to an increase in fibrin deposition or formation of a thrombus. Thrombosis can also result from plasminogen deficiency caused by a lack of protein or lack of functional protein. Reduced or depleted levels of alpha2-antiplamin can result in severe bleeding disorders. (This definition may be outdated - see the DesignNote.)
The synthesis and release of growth hormone (GH) from the pituitary are controlled by the hypothalamic hormones GH-releasing hormone (GHRH) and somatostatin (SRIF), which in turn are regulated by feedback from blood GH and insulin-like growth factor-I (IGF-I) concentrations. The recently discovered endogenous GH-releasing peptide, called ghrelin, also stimulates GH release. Circulating GH acts directly on many organs to stimulate IGF-I production, with IGF-I production in the liver providing the main source of blood IGF-I. Most of the IGF-I in the circulation is bound to IGF-binding protein-3 (IGFBP-3) in a ternary complex with acid-labile subunit (ALS); a smaller fraction is bound to the five other IGFBP. A small fraction of the total IGF-I in blood is in a bioactive-free fraction. In the kidney, IGF-I increases renal plasma flow and GFR, whereas on bone it acts on the epiphysial plate, which leads to longitudinal bone growth. GH also has direct effects on many organs, including kidney and cartilage, which can be independent of IGF-I action. The GH/IGF-I axis in chronic renal failure (CRF) is changed markedly compared with the normal axis. In CRF, the total concentrations of the hormones in the GH/IGF-I axis are not reduced, but there is reduced effectiveness of endogenous GH and IGF-I, which probably plays a major role in reducing linear bone growth. The reduced effectiveness of endogenous IGF-I likely is due to decreased levels of free, bioactive IGF-I as levels of circulating inhibitory IGFBP are increased. In addition, less IGF-I is circulating in the complex with ALS and IGFBP-3 as a result of increased proteolysis of IGFBP-3. Together, these lead to decreased IGF-I receptor activation and a decreased feedback to the hypothalamus and pituitary. Low free IGF-I and high IGFBP-1 and -2 levels probably contribute to a reduced renal function and lead to a reduced stature. The direct effects of GH on bone, which are poorly understood, also are blunted. (This definition may be outdated - see the DesignNote.)
Ghrelin: Regulation of Food Intake and Energy Homeostasis
Food Intake and Energy Homeostasis Pathway
Gastric acid is a key factor in normal upper gastrointestinal functions, including protein digestion and calcium and iron absorption, as well as providing some protection against bacterial infections. The principal stimulants of acid secretion at the level of the parietal cell are histamine (paracrine), gastrin (hormonal), and acetylcholine (ACh; neurocrine). Stimulation of acid secretion typically involves an initial elevation of intracellular calcium and cAMP, followed by activation of protein kinase cascades, which trigger the translocation of the proton pump, H+, K+-ATPase, from cytoplasmic tubulovesicles to the apical plasma membrane and H+ secretion into the stomach lumen.
The function of hemoglobin in oxygen transport by red blood cells requires precise assembly of a tetramer of two beta-subunits and two alpha-units. If too many beta-subunits are present, then all tetramers of beta-subunits are formed that bind oxygen but do not release it when needed. When alpha-subunits are in excess they form precipitates with oxidized heme that damage red blood cells. Red blood cells require a precise coregulation of alpha and beta subunit expression to maintain the proper ratio of the subunits and normal red blood cell function. Generally red blood cells express slightly more alpha than beta-subunits to avoid forming unproductive beta-tetramers (HbH). The slight excess of alpha units are blocked from precipitation by a molecular chaperone, AHSP, alpha-hemoglobin stabilizing protein. Expression of the AHSP gene is coordinately activated with the globin genes and heme biosynthesis genes by the GATA-1 gene involved in erythrocyte differentiation. AHSP blocks precipitation of alpha-units, and promotes the formation of normal productive alpha-beta tetramers (HbA). People with mutation or deletion of the beta-subunit gene have Beta-thalassemias resulting from an over-abundance of alpha subunits and their precipitation. The severity of the phenotype may depend on the AHSP genotype of these individuals and elevating AHSP levels through gene therapy may provide a treatment strategy for beta-thalassemia. (This definition may be outdated - see the DesignNote.)
Mammalian cells can respond to a variety of stresses such as heat, cold, oxidative stress, metabolic disturbance, and environmental toxins through necrotic or apoptotic cell death, while increased expression and phosphorylation of heat shock proteins such as Hsp27 can protect cells against cellular stress. Heat shock proteins commonly exhibit molecular chaperone activity and also interact with a wide variety of proteins to exert specific effects. The small heat shock protein Hsp27 exists as monomers, dimers, and oligomers in the cell, and each form has distinct activities. Oligomers are the main form of Hsp27 with molecular chaperone activity and are disrupted by phosphorylation of Hsp27 to form dimers and monomers. S-thiolation of Hsp27 on cysteine also dissociates oligomers and may provide another route of regulating the action of Hsp27 in stress. Map kinase cascades mediate Hsp27 phosphorylation. Heat stress activates the p38 kinase cascade and induces phosphorylation of Hsp27 by the downstream Map kinases Mapkapk2 and Mapkap3. Cytokines such as TNF and IL-1 can also induce Hsp27 phosphorylation through this Map kinase cascade, protecting cells in some settings against cytotoxic responses. In stressful conditions, dissociation of oligomeric Hsp27 by phosphorylation may allow lower molecular weight forms to perform other non-chaperone functions. One action of Hsp27 induced by stress is to protect cells against apoptosis and a common component of apoptotic pathways is the mitochondrial release of cytochrome c. One way that Hsp27 reduces apoptosis is by preventing the release of cytochrome c and by binding to cytochrome c in the cytosol. Downstream, Hsp27 also blocks caspase 9 activation and the subsequent activation of caspase 3, inhibiting the rest of the proteolytic caspase cascade. Yet a further role of Hsp27 in blocking apoptosis is through blocking Fas-induced apoptosis. Fas is a receptor in the TNF receptor gene family that induces apoptosis when stimulated by its cell-bound ligand, Fas-ligand. Fas induces apoptosis through two pathways, one mediated by the protein Daxx. Phosphorylated Hsp27 dimers block apoptosis by binding with Daxx and preventing downstream activation of the kinase Ask1. The interaction of Hsp27 with actin filaments may also prevent apoptosis triggered by some agents like staurosporine that damage actin. Unphosphorylated Hsp27 monomers regulate actin filament growth by binding to the end of fibers and capping them. Finally, Hsp27 appears to prevent damage to cells by reactive oxygen species (ROS), by altering the oxidative environment of the cell through induction of glutathione expression, as well as blocking apoptosis induced by ROS. Modulation of Hsp27 expression and phosphorylation may provide a useful means to alter cellular sensitivity to stress. (This definition may be outdated - see the DesignNote.)
Hypoxia (or low O2 levels) affects various pathologies. First, tissue ischemia, a variation in O2 tension caused by hypoxia/reoxygenation, can lead to endothelial cell changes. For example, long periods of ischemia result in endothelial changes, such as vascular leakage, resulting in varicose veins. In more severe situations, ischemia can lead to myocardial or cerebral infarction and retinal vessel occlusion. Of interest, HIF-1 is stabilized prior to induction of vascular endothelial growth factor (VEGF) expression during acute ischemia in the human heart. Second, pulmonary hypertension associated with chronic respiratory disorders results from persistent vasoconstriction and vascular remodeling. Third, hypoxic gradients created in enlarging solid tumors trigger expression of genes containing hypoxia response elements (HREs) such as those involved in angiogenesis. This allows subsequent delivery of O2, nutrients, and further tumor growth. Vascular remodeling is an important component to tumorigenesis; without proper blood supply, delivery of oxygen may occur by diffusion, but becomes inefficient in tumors greater than 1 mm in diameter. Short-term hypoxia can also elevate platelet numbers, while prolonged exposure may cause some degree of thrombocytopenia in response to increased levels of erythropoietin (EPO). Another disorder involving inadequate responses to hypoxia is preeclampsia, a pathology of pregnancy thought to be caused by improper differentiation of placental trophoblast cells due to poorly controlled O2 tension or improper hypoxia-inducible factor (HIF)-mediated responses. The primary molecular mechanism of gene activation during hypoxia is through HIF-1. Several genes involved in cellular differentiation are directly or indirectly regulated by hypoxia. These include EPO, LDH-A, ET-1, transferrin, transferrin receptor, VEGF, Flk-1, Flt-1, platelet-derived growth factor-beta (PDGF-b), basic fibroblast growth factor (bFGF), and others genes affecting glycolysis. HIF-1 is a member of the basic helix-loop-helix (bHLH)-PAS family of transcription factors known to induce gene expression by binding to a 50-bp HRE containing a core 5'-ACGTG-3' sequence. bHLH-PAS proteins heterodimerize to form transcription complexes that regulate O2 homeostasis, circadian rhythms, neurogenesis, and toxin metabolism. Three bHLH-PAS proteins in vertebrates respond to hypoxia: HIF-1, EPAS (HIF-2), and HIF-3. These dimerize with ARNT (aryl hydrocarbon receptor nuclear translocator protein), ARNT-2, or ARNT-3. HIF-1 is ubiquitinated and subsequently degraded in less than 5 minutes under normoxic conditions. Although several candidate O2-sensing molecules have emerged in the literature, the molecular basis of how cells sense O2 levels is poorly characterized. pVHL, the protein product of a tumor-suppressor gene responsible for von Hippel Lindau disease, is implicated in this O2-sensing system by its association with HIF-1, targeting it for ubiquitin-mediated degradation. Similarly, F-box-containing proteins recognize substrates of the ubiquitin ligases, targeting them for phosphorylation-dependent ubiquitination and proteasomal degradation. In addition to F-boxes, most of these proteins also contain a WD40 or a leucine-rich repeat (LLR) domain that presumably functions as a Ser/Thr binding module. A second family of proteins assisting the ubiquitin ligases share a region designated SOCS-box (originally from the suppressor of cytokine signaling proteins SOCS). Under low O2 (<5% O2) HIF-1 is stabilized leading to the formation of a functional transcription factor complex with ARNT. This complex is the master regulator of O2 homeostasis and induces a network of genes involved in angiogenesis, erythropoiesis, and glucose metabolism. (This definition may be outdated - see the DesignNote.)
Hypoxia-Inducible Factor in the Cardiovascular System
Endothelial cells (EC) form a multifunctional signal-transducing surface that performs different tasks dependent on its localization in the vessel tree. Arterial EC provide a pathway for delivery of oxygen from blood to tissue. They modulate the tone of vascular smooth muscle cells, which in turn controls blood pressure and blood flow by adjusting the caliber of arteries and arterioles. In the microvascular bed, EC regulate the permeation of various metabolites, macromolecules, and gases, as well as autocrine and paracrine factors and are involved in the regulation of cell nutrition. In all vessel types, EC are involved in blood coagulation, control of the transport between blood and tissue, movement of cells adhering to EC, wound healing, and angiogenesis. Other functions require an active response of EC to various signals of mechanical, chemical, or neuronal nature. This signal transduction is impaired during vessel disease (arteriosclerosis) and injury, inflammation, or hemodynamic disturbances (hypertension). The role of ion channels in the transduction of these signals into cellular responses is still a matter of debate and has received substantial attention only in the last few years. Our current knowledge is limited to effects of ion channels on fast endothelial responses, these channels being mainly essential for the regulation of Ca2+ signaling. Here we illustrate the negative feedback of cyclic nucleotides (CNG)-induced membrane depolarization on Ca2+ entry. Ca2+ entry via receptor-activated cation channels (RACC) and/or store-operated or capacitative (SOC) elevates [Ca2+]i and stimulates endothelial nitric oxide synthase (eNOS). The subsequent activation of soluble guanylate cyclase (sGC) increases cGMP. cGMP and cAMP, via agonist activation of G protein-coupled receptors (GPCRs), Gs, and adenylate cyclase (AC), activate CNG and/or nonselective cation channels (HCN) channels, which induce membrane depolarization. This depolarization exerts a negative feedback on Ca2+ entry via RACC/SOC. In addition, a feedback inhibition of Ca2+ entry channels via activation of PKG has been described. (This definition may be outdated - see the DesignNote.)
Ion Channels and Their Functional Role in Vascular Endothelium
Ion Channels in Vascular Endothelium Pathway
Cerebellar long-term depression (LTD), thought to be a molecular and cellular basis for cerebellar learning, is a process involving a decrease in the synaptic strength between parallel fiber (PF) and Purkinje cells (PCs) induced by the conjunctive activation of PFs and climbing fiber (CF). Multiple signal transduction pathways have been shown to be involved in this process. Activation of PFs terminating on spines in dendritic branchlets leads to glutamate release and activation of both AMPA and mGluRs. Activation of CFs, which make multiple synaptic contacts on proximal dendrites, also via AMPA receptors, opens voltage-gated calcium channels (VGCCs) and causes a generalized influx of calcium. These cellular signals, generated from two different synaptic origins, trigger a cascade of events culminating in a phosphorylation-dependent, long-term reduction in AMPA receptor sensitivity at the PF-PC synapse. This may take place either through receptor internalization and/or through receptor desensitization.
Hippocampal long-term potentiation (LTP), a long-lasting increase in synaptic efficacy, is the molecular basis for learning and memory. Tetanic stimulation of afferents in the CA1 region of the hippocampus induces glutamate release and activation of glutamate receptors in dendritic spines. A large increase in [Ca2+]i resulting from influx through NMDA receptors leads to constitutive activation of CaM kinase II (CaM KII). Constitutively active CaM kinase II phosphorylates AMPA receptors, resulting in potentiation of the ionic conductance of AMPA receptors. Early-phase LTP (E-LTP) expression is due, in part, to this phosphorylation of the AMPA receptor. It is hypothesized that postsynaptic Ca2+ increases generated through NMDA receptors activate several signal transduction pathways including the Erk/MAP kinase and cAMP regulatory pathways. The convergence of these pathways at the level of the CREB/CRE transcriptional pathway may increase expression of a family of genes required for late-phase LTP (L-LTP).
A demonstrated means to increase lifespan in a wide range of organisms is through the restriction of caloric intake. Reducing the consumption of calories increases the lifespan of many different organisms, including mice. Caloric restriction not only increases lifespan, but decreases age-related deterioration of systems and physiological responses, reducing age related diseases like cancer and neurodegenerative disease. Although caloric restriction has not been demonstrated experimentally to increase human lifespan, short-term changes in physiological measures like insulin responsiveness have been observed. Caloric restriction in animals reduces the levels of plasma glucose and insulin and reduces inflammatory responses and may reduce oxidative stress through reduced oxidative metabolism, further contributing to the health benefits of reduced calorie intake. The reduction in inflammation may be related to reduced plasma glucose and in humans could reduce an inflammation connection to cancer, heart disease, and Alzheimer's disease. Genetic analysis has indicated several genes that influence lifespan, particularly those that alter pituitary development, reduce growth hormone secretion, reduce food intake, and reduce apoptosis (p66 Shc). All of these appear to converge on an IGF-1 receptor pathway and to reproduce many of the effects of caloric restriction. Although dwarf mice with defective growth hormone or IGF-1 signaling also have significantly increased lifespan, humans with defects in growth hormone signaling tend to develop diseases that shorten their lifespan. One of the downstream actions of IGF-1 signaling is to repress stress resistance proteins including antioxidant enzymes like superoxide dismutase and heat shock proteins, so a reduction in IGF signaling may extend lifespan by increasing the expression of stress resistance genes. The link between caloric restriction and IGF signaling may be the increased expression of stress resistance proteins. In addition to the IGF-1R mutation, p66 Shc mutation also increases lifespan without significant aberration of other systems. Shc is a target of IGF-1R phosphorylation, and a major inducer of cellular responses to oxidative stress. Shc increases levels of intracellular reactive oxygen species, repressing the forkhead factor FKHRL1. Although FKHRL1 is also involved in apoptosis, in the absence of Shc, FKHRL1 mediates increased resistance to oxidative stress. Exploration of the genes that induce longevity in animal models may enlighten the role of these genes in human disease and lifespan. (This definition may be outdated - see the DesignNote.)
Maintaining the integrity of the gastrointestinal tract despite the continual presence of microbial flora and injurious agents is essential. Epithelial repair requires restitution and regeneration. During restitution, epithelial cells spread and migrate across the basement membrane to re-establish surface-cell continuity, a process that is independent of cell proliferation. Epithelial continuity depends on a family of small abundant secreted proteins, the trefoil factors (TFFs). The trefoil factor (TFF) family comprises the gastric peptides pS2/TFF1 and spasmolytic peptide (SP)/TFF2, and the intestinal trefoil factor (ITF)/TFF3. Their fundamental action is to promote epithelial-cell restitution within the gastrointestinal tract. TFFs are abundantly secreted onto the mucosal surface by mucus-secreting cells. Their expression is rapidly and coordinately upregulated at the margins of mucosal injury. Secreted TFF acts on adjacent mucosal cell populations either extracellularly (augmenting barrier function) or intracellularly (transcriptional and signaling events). TFF response elements in TFF gene promoters allow increases in TFF expression through auto-induction and cross-induction of other TFFs, in addition to mucin expression and possibly tumor suppression. Cell migration is the result of integrated disruption of cell-cell and cell-substratum adhesion and prevention of apoptosis through cell detachment. Epithelial movement therefore requires integration of motogenic and cell-survival signals. This is achieved by activation of several intracellular signaling pathways that converge on ERK/MAPK and possibly NF-B activation. Serine phosphorylation of the extracellular signal-regulated kinases (ERKs)/mitogen-activated protein kinases (MAPKs) 1 and 2 is central to trefoil factor-mediated signaling, lying downstream of EGFR activation and possibly FAK activation (through recruitment of GRB2 and SOS). Cell migration might result from cooperation between ERK/MAPKs and Rho proteins, FAK activation, beta-integrin clustering and beta-catenin activation. Abrogation of cell death has been shown to require both PI3K activation and ERK/MAPK activation; the former operates through serine/threonine phosphorylation of AKT/protein kinase B, serine phosphorylation of BAD (BCL-2 agonist of cell death) and inhibition of mitochondrial cytochrome c release and formation of the apoptosome (APAF1, caspase-9 (CASP9) and cytochrome c (CYT-c). Translocation of phosphorylated ERK/MAPK to the nucleus leads to amplification and de-restriction of TFF expression to ensure sustained action. (This definition may be outdated - see the DesignNote.)
Trefoil Factors Initiate Mucosal Healing
The phosphorylation of myosin affects its role in smooth muscle contraction, platelet formation, and possibly other processes. Phosphorylation by myosin light chain kinase (MLCK) increases myosin activity and dephosphorylation by myosin phosphatase decreases myosin activity. CPI, a factor that binds to and inhibits myosin phosphatase, is a target of phosphorylation by PKC and PKN. The inhibitory activity of CPI is regulated by its own phosphorylation state; when CPI is phosphorylated, its inhibitory activity is increased. The activation of signal transduction cascades such as GPCR pathways can lead to activation of PKC, phosphorylation of CPI, inhibition of myosin phosphatase, increased myosin phosphorylation, and increased smooth muscle contraction or platelet release. The action of histamine in vasoconstriction, for example, may be mediated by activation of PKC through the histamine receptor, resulting in phosphorylation of CPI-17, increased inhibition of myosin phosphatase, and increased smooth muscle contraction. (This definition may be outdated - see the DesignNote.)
PKC-catalyzed phosphorylation of inhibitory phosphoprotein of myosin phosphatase
Reactive oxygen species (ROS) are detrimental to cellular health and can damage biological macromolecules. Electrophilic compounds, xenobiotics and antioxidants are sources of reactive oxygen species, creating oxidative stress that can harm cells. Enzymes involved in the Phase II detoxification of xenobiotics to reduce cellular stress include glutathione transferases, quinone reductase, epoxide hydrolase, heme oxygenase, UDP-glucuronosyl transferases, and gamma-glutamylcysteine synthetase. Expression of these genes protects cells from oxidative damage and can prevent mutagenesis and cancer. Transcription of these enzymes is coordinately regulated through antioxidant response elements (AREs). Nrf2 (NF-E2-related factor 2) and Nrf1 are transcription factors that bind to AREs and activate these genes. Inactive Nrf2 is retained in the cytosol by association a complex with the cytoskeletal protein Keap1. Cytosolic Nrf2 is phosphorylated and translocates into the nucleus in response to protein kinase C activation and Map kinase pathways. In the nucleus, Nrf2 activate genes through AREs by interacting with transcription factors in the bZIP family, including CREB, ATF4 and fos or jun. Nrf2 activation of genes is opposed by small maf proteins, including MafG and MafK, maintaining a counterbalance to Nrf2 and balancing the oxidation level of the intracellular environment. (This definition may be outdated - see the DesignNote.)
Oxidative Stress Induced Gene Expression Via Nrf2
Eph kinases are a family of receptor tyrosine kinases with an extracellular domain that binds their ligand, the ephrins, and an intracellular kinase domain. The ephrins are also expressed on the cell surface, so that interaction between Eph kinases and ephrins occurs at the interface between neighboring cells. Binding of ephrins to Eph kinases stimulates signaling in both directions across the interface between cells, in both the receptor expressing and the ligand expressing cells. Eph kinases and ephrins are involved in several biological processes, and their role in neuronal development has been extensively examined. Both Eph kinases (EphA4 and EphB1) and ephrins (ephrinB1) are expressed on platelets, suggesting that activation of eph kinases by ephrins may play a role in clotting when platelets are brought into close proximity in the developing clot. Platelet activation progresses in stages with an early stage that is stimulated by soluble factors like ADP acting through GPCRs and is reversible and later stages with stronger interaction between platelets that may require interaction between Eph kinases and ephrins. One of the molecular targets of signaling by Eph kinases and ephrins is the actin cytoskeleton, which also plays a role in platelet activation. Clustering Eph kinases or ephrins in platelets stimulated cytoskeletal changes as well as other markers of platelet activation during clotting such as secretion of alpha-granules to release clotting factors. Clustering ephrins together activated Rap1b, a ras gene family member that may regulate integrins. Platelet activation caused Eph kinases to bind to src family members Fyn and Lyn and also with the cell adhesion molecule L1. Failure of the ephrins/Eph kinase pathway to function normally in platelets may result in loosely associated platelets and improper clot formation. Eph kinases and ephrins are also expressed on the vascular wall by endothelial cells, suggesting that signaling by these proteins may also play a role in the interaction of platelets with the vascular wall and clot formation in the vasculature. (This definition may be outdated - see the DesignNote.)
Eph Kinases and ephrins support platelet aggregation
The amyloid-beta peptide (Ab), a proteolytic fragment of amyloid precursor protein (APP), is the major component of senile plaques, the hallmark of Alzheimer's disease. Platelets contain both APP and Ab and probably contribute greater than 90% of circulating APP. The soluble APP is the major inhibitor of coagulation factors IXa and XIa, and platelet aggregation. Agonists such as ADP, thrombin, epinephrine and collagen activate the release of APP and plasminogen activator inhibitor I (an important regulator of coagulation) from platelet storage granules. These important molecules released from platelets are key regulators of hemostasis, the physiologic arrest of hemorrhage at site of vascular leakage. (This definition may be outdated - see the DesignNote.)
Platelet Amyloid Precursor Protein Pathway
One of the major tasks of the renal proximal tubule (PT) is to secrete acid into the tubule lumen, thereby reabsorbing approximately 80% of the filtered bicarbonate (HCO3(-)), as well as generating "new HCO3(-)" for regulating blood pH. In the tubular lumen, filtered HCO3(-) combines with H(+) in a reaction catalyzed by CA IV. The CO2 thus produced rapidly diffuses into the tubular cells and is combined with water to produce intracellular H(+) and HCO3(-), catalyzed by soluble cytoplasmic CA II. HCO3(-) is then cotransported with Na(+) into blood via the NBC-1. The intracellular H(+) produced by CA II is secreted into the tubular lumen predominantly via the NHE-3. The PT creates the "new HCO3(-)" by taking glutamine and metabolizing it to two molecules each of NH4(+) and HCO3(-). The NH4(+) is excreted into the tubular lumen, and the HCO3(-), which is "new HCO3(-)," is returned to the blood, where it replaces the HCO3(-) lost earlier in the titration of nonvolatile acids.
Proximal Tubule Bicarbonate Reclamation Pathway
Saliva has manifold functions in maintaining the integrity of the oral tissues, in protecting teeth from caries, in the tasting and ingestion of food, in speech and in the tolerance of tenures, for example. Salivary secretion occurs in response to stimulation by neurotransmitters released from autonomic nerve endings. There are two secretory pathways: protein exocytosis and fluid secretion. Sympathetic stimulation leads to the activation of adenylate cyclase and accumulation of intracellular cAMP. The elevation of cAMP causes the secretion of proteins such as amylase and mucin. In contrast, parasympathetic stimulation activates phospholipase C and causes the elevation of intracellular Ca2+, which leads to fluid secretion; that is, water and ion transport. Ca2+ also induces amylase secretion, but the amount is smaller than that induced by cAMP.
The vascular smooth muscle cell (VSMC) is a highly specialized cell whose principal function is contraction. On contraction, VSMCs shorten, thereby decreasing the diameter of a blood vessel to regulate the blood flow and pressure.
Vascular Smooth Muscle Contraction Pathway
In the kidney, the antidiuretic hormone vasopressin (AVP) is a critical regulator of water homeostasis by controlling the water movement from lumen to the interstitium for water reabsorption and adjusting the urinary water excretion. In normal physiology, AVP is secreted into the circulation by the posterior pituitary gland, in response to an increase in serum osmolality or a decrease in effective circulating volume. When reaching the kidney, AVP binds to V2 receptors on the basolateral surface of the collecting duct epithelium, triggering a G-protein-linked signaling cascade, which leads to water channel aquaporin-2 (AQP2) vesicle insertion into the apical plasma membrane. This results in higher water permeability in the collecting duct and, driven by an osmotic gradient, pro-urinary water then passes the membrane through AQP2 and leaves the cell on the basolateral side via AQP3 and AQP4 water channels, which are constitutively expressed on the basolateral side of these cells. When isotonicity is restored, reduced blood AVP levels results in AQP2 internalization, leaving the apical membrane watertight again.
Vasopressin-regulated water reabsorption
Vasopressin-Regulated Water Reabsorption Pathway
Vitamin C (ascorbic acid) was first identified by virtue of the essential role it plays in collagen modification, preventing the nutritional deficiency scurvy. Vitamin C acts as a cofactor for hydroxylase enzymes that post-translationally modify collagen to increase the strength and elasticity of tissues. Vitamin C reduces the metal ion prosthetic groups of many enzymes, maintaining activity of enzymes, and also acts as an anti-oxidant. Although the prevention of scurvy through modification of collagen may be the most obvious role for vitamin C, it is not necessarily the only role of vitamin C. Svct1 and Svct2 are ascorbate transporters for vitamin C import into tissues and into cells. Both of these transporters specifically transport reduced L-ascorbic acid against a concentration gradient using the intracellular sodium gradient to drive ascorbate transport. Svct1 is expressed in epithelial cells in the intestine, upregulated in cellular models for intestinal epithelium and appears to be responsible for the import of dietary vitamin C from the intestinal lumen. The vitamin C imported from the intestine is present in plasma at approximately 50 uM, almost exclusively in the reduced form, and is transported to tissues to play a variety of roles. Svct2 imports reduced ascorbate from the plasma into very active tissues like the brain. Deletion in mice of the gene for Svct2 revealed that ascorbate is required for normal development of the lungs and brain during pregnancy. A high concentration of vitamin C in neurons of the developing brain may help protect the developing brain from free radical damage. The oxidized form of ascorbate, dehydroascorbic acid, is transported into a variety of cells by the glucose transporter Glut-1. Glut-1, Glut-3, and Glut-4 can transport dehydroascorbate, but may not transport significant quantities of ascorbic acid in vivo. (This definition may be outdated - see the DesignNote.)
The eukaryotic genome is packaged by histone and nonhistone proteins to form chromatin. The assembly of nucleosomes, as well as compaction of nucleosomal arrays into higher-order chromatin structures, creates a highly restrictive environment for nuclear processes that require access to DNA. The packaging of eukaryotic DNA into nucleosomes inhibits the access of factors to DNA and thus results in the repression of transcription, replication, and recombination. To counterbalance the repressive nature of chromatin, a variety of chromatin remodeling factors use the energy of ATP hydrolysis to facilitate the interaction of proteins with nucleosomal DNA. ATP dependent chromatin remodeling complexes are characterized by the presence of an ATPase subunit from the SNF2-like family of the DEAD/H (SF2) DNA-stimulated ATPases. The highly conservative hSWI/SNF multisubunit complexes contain hBRM or BRG1 ATPases which alter the histone-DNA contacts enabling the access of general transcription factors to promoter regions. Remodeling complexes are targeted to promoters via interactions with sequence-specific transcription factors. Since chromatin constitutes a barrier for processes affecting DNA, such a transcription, replication, and repair, a mechanism is required that can open up or remodel chromatin to make it accessible to replication and transcription factors. Steroid receptors are a class of transcription factors that can interact with the repressive chromatin structure and remodel the chromatin to allow other transcription factors to bind. In addition to nuclear receptors, transcription activators as divergent as erythroid Kruppel-like factor, C/EBPs, c-Myc, MyoD, HSF1, and EBNA2 have also been found to recruit SWI/SNF to specific promoters. The role of steroid receptors in chromatin remodeling and transcription is exemplified by the glucocorticoid receptor (GR)-mediated transactivation of the mouse mammary tumor virus (MMTV) promoter. The MMTV promoter is organized into a phased array of six nucleosomes when stably integrated into mammalian cells. The second nucleosome (nucB) is positioned over the binding sites for the GR and nuclear factor 1 (NF1). Binding of NF1 is essential for GR-mediated transactivation of the MMTV promoter; in the absence of glucocorticoid, the chromatin structure of the promoter excludes the binding of NF1. Upon hormone administration, GR recruits an ATP-dependent remodeling hSWI/SNF complex (BRG1-BAF) to remodel the chromatin Individually, the GR makes direct interactions with BRG1-associated factor 60a (BAF60a) and BAF57. Further, BAF60a possesses at least two interaction surfaces, one for GR and BRG1 and a second for BAF155 and BAF170.The remodeling process converts the closed conformation of the MMTV promoter to an open one without altering the nucleosomal positioning. The remodeling of the promoter permits NF1 binding and the assembly of a transcription initiation complex. (This definition may be outdated - see the DesignNote.)
Chromatin Remodeling by hSWI/SNF ATP-dependent Complexes
Hypoxic and oxygen homeostasis regulation of HIF-1-alpha
Hypoxia and Oxygen Homeostasis Regulation of HIF-1-Alpha Pathway
HIF-1-alpha transcription factor network
HIF-1-Alpha Transcription Factor Pathway
The packaging of eukaryotic DNA into nucleosomes inhibits the access of factors to DNA and results in the repression of transcription, replication, and recombination. Local modification of histones on enhancers and promoters is required to activate gene expression. The transcription factors that bind to nucleosome-free regions of DNA or to DNA within nucleosomes recruit two types of enzymatic activities that modify the surrounding chromatin architecture. Chromatin remodeling machines, such as SWI/SNF complex, alter the structure of the pronucleosome in an ATP-dependent manner, and often cause nucleosome sliding. The second type of chromatin modifying complexes recruited by transcription factors covalently modify the N-terminal tails of histones by adding or removing phosphate, methyl, or acetyl groups. Virus-induced transcription of the human interferon-beta gene illustrates one of the best-characterized examples of the mechanisms by which the information contained in the DNA is transferred to the histone-N termini by generating novel adhesive surfaces required for the recruitment of transcription complexes. Upon virus infection, the gene is switched on by three transcription factors (NF-kB, IRFs, and ATF-2/c-Jun), and an architectural protein (HMG I(Y)), all of which bind cooperatively to the nucleosome-free enhancer DNA to form an enhanceosome. The enhanceosome targets the modification and repositioning of a nucleosome that blocks the formation of a transcriptional preinitiation complex on the IFN-beta promoter. This is accomplished by the ordered recruitment of HATs, SWI/SNF, and basal transcription factors. Initially, the PCAF HAT-containing complex is recruited, and it acetylates the nucleosome. This is followed by the recruitment of the CBP-PolII holoenzyme complex. The bromodomain containing transcription complexes SWI/SNF and TFIID are recruited to the promoter via bivalent interactions between the enhanceosome and specifically acetylated histone N termini. More specifically, acetylation of H4 lysine 8 is required for recruitment of the SWI/SNF complex, whereas acetylation of lysines 9 and 14 in histone H3 is critical for the recruitment of the general transcription factor TFIID. An unknown kinase recruited by the enhanceosome phosphorylates H3 Ser 10, a prerequisite for H3K14 acetylation by PCAF. The SWI/SNF remodeling machine arrives at the promoter via bivalent interactions with CBP and the acetylated histone N tails. SWI/SNF alters the structure of the nucleosome, thus allowing recruitment and DNA binding of TFIID to the TATA box. The DNA bending induced upon TFIID binding to the promoter causes sliding of the SWI/SNF-modified nucleosome to a new position 36 bp downstream, thus allowing the initiation of transcription. This cascade is obligatory for IFN-beta gene activation. (This definition may be outdated - see the DesignNote.)
The information-processing pathway at the IFN-beta enhancer
An elaboration of the sequence of events that play a role in organismal defense responses.
The activation of T cells requires a co-stimulatory signal with T cell receptor activation, provided in many cases by activation of CD28 in resting T cells. 4-1BB (CD137) is a member of the TNF receptor gene family that provides another T cell co-stimulatory signal. 4-1BB is expressed by activated cytotoxic and helper T cells and its expression is induced by a variety of T cell stimuli, including activation of the T cell receptor or stimulation with mitogens. The ligand for 4-1BB (4-1BBL) is induced on activated antigen-presenting cells including macrophages, activating T cells expressing 4-1BB. Mice lacking 4-1BB survive and have an altered though functional immune response. T cells of mice lacking 4-1BB proliferate more rapidly than normal T cells, but have reduced cytokine secretion. The costimulatory signal provided by 4-1BB may act in combination with CD28 activation to prolong the T cell response, and may also act independently of CD28. Stimulation of T cells with the 4-1BB ligand may provide a therapeutic immune response in the treatment of cancer or viral infection. 4-1BB in T cells activates several signaling pathways. Like other members of the TNF receptor family, the 4-1BB receptor does not have an intrinsic kinase activity. TRAF2 is a signaling adapter that mediates signaling by other members of the TNF receptor family and that also binds to the cytoplasmic domain of ligand activated 4-1BB to activate intracellular kinase cascades. TRAF1 also binds to the cytoplasmic domain of 4-1BB although with lower affinity than TRAF2. One downstream effector activated by 4-1BB through TRAF2 is the transcription factor NF-kB. 4-1BB also activates map kinase pathways, including p38 and JNK activation. ASK1 dependent pathways can activate both p38 and JNK, and dominant negative ASK1 blocks their activation. Other kinase pathways may also be involved in 4-1BB activation of p38 and JNK, such as activation of germinal center kinase (GCK) or related kinases involved in activation of JNK and p38 by TNF. Map kinase activation along with NF-kB activation results in transcriptional activation of cytokine genes involved in T cell activation and signaling. The co-stimulatory signaling provided by 4-1BB shares some features with CD28 signaling, providing an explanation for the ability of 4-1BB to replace the CD28 costimulatory signal in some settings. (This definition may be outdated - see the DesignNote.)
B cell and T cell lymphocytes interact with a variety of cells as part of their immune function, circulating and homing in on specific stimuli in tissues like inflammatory signals. The interaction of lymphocytes with other cell types like vascular endothelial cells requires transmembrane adhesion molecules like VLA-4, LFA-1, CD44, CD31 and L-selectin. Each of these lymphocyte adhesion molecules interacts with specific ligands expressed on cells like endothelial cells to moderate adhesion between cells. CD44 is an adhesion molecule with many roles, including interaction of leukocytes with endothelial cells in response to inflammation, with the most often studied ligand being hyaluronan, a component of the extracellular matrix. LFA-1, Leukocyte function-associated molecule 1, is an integrin composed of two subunits, CD11a and CD18. LFA-1 moderates adhesion of lymphocytes with other cells and also transduces signals into cells through interaction with ICAM-1 expressed on endothelial cells. Expression of ICAM-1 (CD54) is increased by inflammatory signals, increasing adhesion and permeation of lymphocytes into inflamed tissues. VLA-4 is another integrin expressed on lymphocytes that plays a role in adhesion through interaction with its adhesion partner on endothelial cells, VCAM-1. L-selectin appears to mediate adhesion through binding of a lectin-like domain to carbohydrates. PECAM-1 (CD31) is expressed on endothelial cells and is involved in angiogenesis as well as adhesion between cells. VAP-1 is an additional protein expressed by lymphocytes and involved in adhesion to vascular endothelial cells. (This definition may be outdated - see the DesignNote.)
Adhesion Molecules on Lymphocyte Pathway
The inflammatory response associated with asthma is characterized by the recruitment of eosinophils from the bronchial microcirculation in response to the regulated local production of chemoattractant molecules. Although several chemical mediators are active upon eosinophils in vitro, a central role in eosinophil accumulation in vivo is emerging for the C-C chemokine eotaxin, which was first identified in a guinea pig model of allergic airway inflammation using protein purification and microsequencing. Eotaxin is the dominant eosinophil-selective chemoattractant in this model, acting to cause both local eosinophil recruitment to the lung, and the release of a rapidly mobilizable pool of bone marrow eosinophils in cooperation with IL-5. Eotaxin and eotaxin-2 are potent stimulators of eosinophils, signaling exclusively via high affinity binding to the receptor CCR3. C-C chemokines, including MCP-3, MCP-4, and RANTES, also stimulate eosinophils via CCR3, although they show less leukocyte selectivity as they additionally signal via other chemokine receptors expressed on a range of leukocytes, including lymphocytes and monocytes. CCR3 is expressed in high numbers on eosinophils and is thought to be the major eosinophil chemokine receptor. Blockade of CCR3 in vivo inhibits eosinophil recruitment in response to eotaxin in both the guinea pig and mouse. More recently, CCR3 expression has been demonstrated on basophils and Th2-type T cells, suggesting possible roles for CCR3 in the genesis and maintenance of allergic inflammation. CCR3 is therefore a major target for anti-inflammatory drug development. (This definition may be outdated - see the DesignNote.)
The Role of Eosinophils in the Chemokine Network of Allergy
The complement system of plasma proteins is an important part of the immune system that forms a cascade of factors that lyses foreign cells. There are two branches of the complement system, the classical pathway that is initiated by antibody-antigen complexes on a cell and the alternative pathway that is antibody independent. The ultimate result in either pathway is the creation of the membrane attack complex, a large pore in the cell membrane that results in cell lysis. The alternative pathway starts with the spontaneous conversion of C3 to an active protease. C3 contains a thioester group that is spontaneously hydrolyzed at a slow rate to create C3(H2O). From there, binding of factor B (Fb) and activation by factor D (Fd) cleaves factor B to create the active protease C3 convertase (AP convertase). This enzyme cleaves C3 to form C3b, which can go on to form a C5 activating convertase. At this point the alternative pathway proceeds in the same manner as the classical pathway, recruiting additional complement factors (C6, C7, C8 and C9) to ultimately form the membrane attack complex and lyse the associated cell. One question about the alternative pathway is how the spontaneous activation of C3 in plasma leads to the lysis of specific cells in the absence of antibody on the cell surface. Active C3b binds to the cell surface, particularly to complement activators like cell wall components and lipopolysaccharide. A constant low level of spontaneous C3b formation ensures that C3b can bind to invading cells and trigger the rest of the alternative complement pathway to lyse the cells even in the absence of an antibody response. The constant low level of C3b activation and potential activation of the alternative pathway is kept in check by a natural damper, factor H and factor I. Factors H and I in plasma inactivate C3b enzyme in solution. Factors H and I cannot inactivate C3b on the cell surface due to protection by properdin, ensuring that the alternative pathway is primarily inactive in plasma and specifically activated on the surface of invading. (This definition may be outdated - see the DesignNote.)
Alternative Complement Activation Pathway
C76 COMPLEMENT ACTIVATION ALTERNATIVE PATHWAY
COMPLEMENT ACTIVATION ALTERNATIVE PATHWAY
Complement Activation Pathway, Alternative
Complement activation alternative pathway (function)
Complement activation alternative pathway, NOS
Complement activation alternative pathway, function
Complement activation alternative pathway, function (observable entity)
A key part of the immune system is the production of immunoglobulins (antibodies) by B cells to bind and inactivate specific foreign antigens. The body produces B cells with a wide range of antigen specificities in their immunoglobulin B cell receptor, but each cell only has a single specificity. When the B cell receptor immunoglobulin binds antigen, that cell is activated to proliferate and create plasma cells secreting immunoglobulins to bind that specific antigen. B cell activation also creates memory cells with the same antigen specificity that do not actively secrete immunoglobulin but provide for rapid future immune responses to the same antigen. B cells are not activated by antigen on their own, but require interaction with helper CD4+ T cells to become activated and proliferate. The B cell first expresses immunoglobulin on the cell surface as the B cell receptor. If the B cell receptor immunoglobulin binds specific antigen, then the cell internalizes the antigen and presents it to T cells in MHC II, where it is recognized by the T cell receptor. In addition to the interaction between the T cell receptor and the B cell MHC-antigen, T cell interaction with the B cell involves additional positive and negative regulatory signals. CD40 interaction with CD40L and CD28 interaction with CD80 provide positive costimulatory signals that stimulate B cell activation and proliferation. T cell receptor activation induces expression of molecules like the CD40 ligand that modulate the B cell-T cell interaction. The CD40-CD40L interaction induces cytokine production and expression of other genes and alters the fate of the B cell involved in the interaction. If the interaction between CD40 and CD40L is prolonged, the B cell can be induced to become a memory cell rather than a plasma cell. Fas ligand binding to Fas between B and T cells may negatively modulate B cell activation, inducing apoptosis that limits B cell proliferation and activation. Cytokines like IL-2, IL-4 and IL-10 also play an important role in B cell activation. (This definition may be outdated - see the DesignNote.)
Antigen Dependent B Cell Activation Pathway
Invariant chain (Ii) associates with newly synthesized class II molecules in the endoplasmic reticulum (ER), an interaction that has been shown to interfere with peptide binding to class II molecules. The class II-associated invariant chain peptide (CLIP) region (residues 81-104) of Ii is believed to mediate this inhibition by engaging the binding domain of class II like an antigenic peptide. Together, these findings have given rise to a model in which CLIP association with the class II groove acts to prevent inappropriate presentation of peptides imported into the ER for association with major histocompatibility complex class I molecules. (This definition may be outdated - see the DesignNote.)
Antigen Processing and Presentation Pathway
B cells produce immunoglobulins (Ig, antibodies) that specifically bind antigen molecules. B cells first produce a membrane-bound form of immunoglobulin, the B cell receptor, as part of B cell differentiation. Each B cell expresses one immunoglobulin but the population of B cells in each individual display a wide variety of antigen specificity, with each cell expressing Ig on its surface as part of the B cell receptor complex. When the B cell receptor binds to antigen, it initiates a signal through other proteins non-covalently associated with it in the B cell receptor complex, the Ig-alpha (CD79a) and Ig-beta (CD79b) chains. The signal initiated by binding of antigen to the B cell receptor complex causes growth and proliferation of the B cell and the creation of an amplified clone of effector cells that secrete the antigen-specific immunoglobulin. Activation of the B cell receptor by antigen also results in the production of memory cells that persist in circulation to produce a more rapid immune response after future challenges by the same antigen. (This definition may be outdated - see the DesignNote.)
B Cell Receptor Complex Signaling Pathway
B cells are an important component of adaptive immunity. They produce and secrete millions of different antibody molecules, each of which recognizes a different (foreign) antigen. The B cell receptor (BCR) is an integral membrane protein complex that is composed of two immunoglobulin (Ig) heavy chains, two Ig light chains and two heterodimers of Ig-alpha and Ig-beta. After BCR ligation by antigen, three main protein tyrosine kinases (PTKs) -the SRC-family kinase LYN, SYK and the TEC-family kinase BTK- are activated. Phosphatidylinositol 3-kinase (PI3K) and phospholipase C-gamma 2 (PLC-gamma 2) are important downstream effectors of BCR signalling. This signalling ultimately results in the expression of immediate early genes that further activate the expression of other genes involved in B cell proliferation, differentiation and Ig production as well as other processes.
B lymphocyte receptor signalling pathway
B-lymphocyte receptor signalling pathway
B cells must communicate with their environment to participate in the immune system as the source of antigen-specific immunoglobulins. Cell surface proteins on B cells receive signals from the exterior, adhere to other cells, and transmit signals to other cells. Antigen recognized by a B cell's immunoglobulin is presented in MHC Class II to T cells during B cell activation. Cell surface immunoglobulins are a key to B cell function, assisting in the response of B cells to specific antigen recognized by that cell's immunoglobulin. CD54 (ICAM-1) is an adhesion molecule involved in the binding of B cells to other cell types and LFA-1 is an integrin adhesion protein with two subunits that binds to ICAM. CD35 and CD21 are receptors for complement factors that stimulate the B cell response when complement is activated. CD80 and CD40 bind to T cell proteins (CD28 and CD40L, respectively) to provide costimulatory signals in the B cell-T cell interaction required for B cell activation. CD45 is a protein tyrosine phosphatase that regulates activation of B cells and T cells through dephosphorylation of signaling factors. CD32 is a receptor for IgG Fc, and is also called Fc gamma RII. The number of proteins on the surface of B cell proteins indicates the complexity of regulation of B cell activation. (This definition may be outdated - see the DesignNote.)
B Lymphocyte Cell Surface Molecule Pathway
APRIL and BAFF (also called TALL-I and BLyS) are TNF family members that act as ligands for the BCMA and TACI receptors. Both APRIL and BAFF bind to both the BCMA and TACI receptors to activate the humoral immune response, stimulating B cell immunoglobulin production and proliferation. BAFF is found as a membrane bound form in T cells and a soluble form that is released from the cell to stimulate B cell proliferation and differentiation. As members of the TNF receptor gene family, BCMA and TACI interact with TRAF family members to transduce signals downstream to NF-kappaB activation and MAP kinase pathways. Abnormally active BAFF or APRIL signaling may play a role in autoimmune disorders such as lupus. (This definition may be outdated - see the DesignNote.)
TACI and BCMA stimulation of B cell immune responses
Physical interactions between integrin alpha4beta1 heterodimer expressed on B cells and counter receptors on stroma cells are key mediators of the survival of normal and malignant B cells. Recent data indicate that integrin stimulation increases FBI-1, XIAP, survivin, and CCT4 expression but inhibits Requiem, c-Fos, and caspase 3 and 7 induction. (This definition may be outdated - see the DesignNote.)
Expression of Fas-Ligand by T cells can induce apoptosis through interaction with Fas on the target cell. A target of Fas-mediated apoptosis is the B cell. B cells that are not activated by antigen, bystander B cells, can interact through CD40 with the CD40 ligand on T cells. The CD40-CD40L interaction induces Fas expression by bystander B cells, and the interaction of Fas with the T cell Fas-Ligand, followed by B cell apoptosis. B cells that are activated by antigen binding and that interact with the T cell receptor through the B cell MHC II appear to become resistant to Fas-mediated apoptosis, survive and proliferate. IL-4 also appears to confer B cell resistance to Fas-mediated apoptosis. The induction of apoptosis in non-antigen stimulated B cells may prevent B cells from proliferating inappropriately and failure of this mechanism may be involved in autoimmune disorders and B cell lymphomas. (This definition may be outdated - see the DesignNote.)
Role of Calcineurin-dependent NFAT signaling in lymphocytes
Calcineurin-Dependent NFAT Signaling Pathway in Lymphocytes
Calcineurin-regulated NFAT-dependent transcription in lymphocytes
Lymphocyte NFAT-Dependent Transcription Pathway
Calcineurin-Regulated NFAT-Dependent Transcription Pathway
Inflammatory immune response requires the recruitment of leukocytes to the site of inflammation upon foreign insult. Chemokines are small chemoattractant peptides that provide directional cues for the cell trafficking and thus are vital for protective host response. In addition, chemokines regulate plethora of biological processes of hematopoietic cells to lead cellular activation, differentiation and survival.
The complement system is part of the defense against invading cells and is composed of about twenty different proteins found in the plasma. When activated, complement proteins form a pathway of proteolytic reactions that culminates in the lysis of foreign cells. The complement system also stimulates phagocytosis of foreign cells and an inflammatory response. There are two different complement systems, the classical complement pathway initiated by antibody complexes on the cell surface, and an alternative complement pathway that is initiated without antibodies. The complement system proteins are named with a capital C followed by a number. A small letter after the number indicates that the protein is a smaller protein resulting from the cleavage of a larger precursor by a protease. In the classical pathway, the first step is the initiation of the pathway triggered by recognition by complement factor C1 of antigen-antibody complexes on the cell surface. When C1 complex interacts with aggregates of IgG with antigen on a cell's surface, two C1-associated proteases, C1r and C1s, are activated. Other factors like lipopolysaccharide also activate C1s. Once C1s is activated, it cleaves C4 to form C4b that then binds to the cell membrane of the cell being attacked. The proteolytic complement cascade is then amplified on the cell membrane through sequential cleavage of complement factors and recruitment of new factors until a cell surface complex containing C5b, C6, C7, and C8 is formed. The addition of a multiple C9 proteins creates the membrane attack complex results in a large pore that spans the membrane of the cell being attacked, allowing ions to flow freely between the cellular interior and exterior. Ions flow out, but large molecules stay in, causing water to flood into the cell and ultimately burst the cell from osmotic pressure. (This definition may be outdated - see the DesignNote.)
Complement Activation Pathway, Classical
The complement system is a proteolytic cascade in blood plasma and a mediator of innate immunity, a nonspecific defense mechanism against pathogens. There are three pathways of complement activation: the classical pathway, the lectin pathway, and the alternative pathway. All of these pathways generate a crucial enzymatic activity that, in turn, generates the effector molecules of complement. The main consequences of complement activation are the opsinization of pathogens, the recruitment of inflammatory and immunocompetent cells, and the direct killing of pathogens. Blood coagulation is another series of proenzyme-to-serine protease conversions, culminating the formation of thrombin, the enzyme responsible for the conversion of soluble fibrinogen to the insoluble fibrin clot. Protease-activated receptors, such as those activated by thrombin, are members of G protein-coupled receptors and function as a mediator of innate immunity. The kallikrein-kinin system is an endogenous metabolic cascade, triggering of which results in the release of vasoactive kinins (bradykinin-related peptides). Kinin peptides are implicated in many physiological and pathological processes including the regulation of blood pressure and sodium homeostasis, inflammatory processes, and the cardioprotective effects of preconditioning.
The complement pathway consists of a series of over thirty proteins in plasma that are part of the immune response. Activation of the complement system lyses bacterial cells, forms chemotactic peptides (C3a and C5a) attracting immune cells, and increases phagocytotic clearance of infecting cells. Complement can also increase the permeability of vascular walls and cause inflammation. Most complement proteins exist in plasma as inactive precursors that cleave and activate each other in a proteolytic cascade in response to three different mechanisms by which the complement system is activated, the classical pathway, the alternative pathway and the lectin-induced pathway. These three systems are distinct in the initiation of the proteolytic cascade but share most of their components and all three converge in the creation of a C3 convertase that cleaves the C3 complement protein, leading ultimately to the formation of the membrane attack complex, MAC, a pore causing lysis of cells. The classical pathway is activated by the recognition of foreign cells by antibodies bound to the surface of the cells. The alternative and lectin-induced pathways are both antibody independent. Proteolysis is triggered in the alternative pathway by the spontaneous activation of C3 convertase from C3 and is triggered in the lectin-induced pathway by the recognition of carbohydrates on the bacterial cell surface by mannan-binding protein, Mbp. In addition to providing a key part of the response to bacterial infection, the complement system can be involved in the response to fungi, viruses and protists. While activation of the complement system is a key part of the immune system, it must also be kept in check to prevent inappropriate or exaggerated responses. Twelve different proteins have been identified that inhibit complement activation to control the system, including Factor H, Factor I and C1 inhibitor. Deficiencies in components of the complement system have been identified in humans that cause a variety of immune related disorders. C3 deficiency is associated with recurrent bacterial infections, while a lack of C2 can cause antibody-antigen complexes to accumulate and cause the autoimmune disorder systemic lupus erythematosus. People lacking C1 inhibitor have also been identified and found to be prone to uncontrolled complement activation and dangerous swelling through production of C3a and C5a anaphylatoxins. (This definition may be outdated - see the DesignNote.)
Interaction of T cell receptor with specific antigen in the context of MHC II activates a signal transduction pathway that leads to T cell activation. In the T cell receptor signaling pathway, the src family kinases Lck and Fyn are activated to phosphorylate proteins in the T cell receptor complex which recruit and activate the ZAP70 kinase. The activation of ZAP70 phosphorylates downstream targets that activate MAP kinase pathways and cause T cell activation. The CD45 phosphorylase also plays a role in T cell receptor signaling, dephosphorylated Lck and Fyn to activate them. Other factors modulate T cell receptor activation. Csk (COOH-terminal Src kinase) phosphorylates Lck and deactivates it, opposing the action of CD45. The phosphorylation of Lck by Csk inhibits T cell receptor signaling and inhibits T cell activation. Csk activity is regulated in T cells by PKA, the cAMP-dependent protein kinase activated by the second messenger cAMP. The activity of Csk also appears to depend on other factors such as CBP, which recruits Csk to the plasma membrane in lipid rafts where other signaling factors such the T cell receptor complex are localized. CBP also directly activates Csk. (This definition may be outdated - see the DesignNote.)
Activation of Csk by cAMP-dependent Protein Kinase Inhibits Signaling through the T Cell Receptor
Cytotoxic T lymphocytes (CTLs), also known as killer T cells, provide a cell-mediated response to specific foreign antigens associated with cells. CTLs only respond to foreign antigen when it is presented bound to the MHC-1 expressed on the surface of cells. CTLs do not respond to soluble antigen, but induce apoptosis in viral-infected cells and in cancer cells. When the complex of antigen bound to MHC-1 is bound to antigen-specific T cell receptor, the cytotoxic T cell induces apoptosis in the target cell primarily by two pathways, one involving perforin-mediated apoptosis and the other involving Fas/Fas-ligand interaction. When CTLs are activated by recognition of specific antigen on a cell, they release perforin proteins that integrate into the membrane of the target cell and organize to form a membrane pore. This allows the protease granzyme to enter the cell and activate the apoptotic caspase proteolytic cascade, and also allows other molecules to cross the cell membrane and trigger osmotic lysis of the membrane. The interaction of T-cell Fas ligand with the Fas receptor in the target cell can also activate the caspase cascade and other pathways involved in apoptosis. The interaction of a CTL with antigen-MHC I complex activates the CTL to proliferate and amplify the clone of T cells that respond to that antigen, amplifying the immune response against that specific antigen. (This definition may be outdated - see the DesignNote.)
CTL mediated immune response against target cells
Several different cell types coordinate their efforts as part of the immune system, including B cells, T cells, macrophages, neutrophils, basophils and eosinophils. Each of these cell types has a distinct role in the immune system, and each communicates with other immune cells using secreted factors called cytokines, including interleukins, TNF, and the interferons. Macrophages phagocytose foreign bodies and are antigen-presenting cells, using cytokines to stimulate specific antigen dependent responses by B and T cells and non-specific responses by other cell types. T cells secrete a variety of factors to coordinate and stimulate immune responses to specific antigen, such as the role of helper T cells in B cell activation in response to antigen. The proliferation and activation of eosinophils, neutrophils and basophils respond to cytokines as well. Cytokine communication is often local, within a tissue or between cells in close proximity. Each of the cytokines is secreted by one set of cells and provokes a response in another target set of cells, often including the cell that secretes the cytokine. Some cytokines, like IL-1, interferons and TNF, stimulate a broad inflammatory response in response to infection or injury. Other cytokines have more specific functions such the following examples. IL-2 stimulates the proliferation and activation of B and T cells. IL-4 plays a role in the differentiation of Th2 cells, in allergic responses, and in the switching of antibody types. IL-5 stimulates the production and maturation of eosinophils during inflammation. IL-8 is a chemokine, a chemotactic factor that attracts neutrophils, basophils and T cells to sites of inflammation. IL-12 and IL-18 are involved in helper T cell differentiation. IL-10 apparently acts to repress secretion of proinflammatory cytokines. The complex interplay of these different cytokine functions with immune cells is essential for correct immune function. (This definition may be outdated - see the DesignNote.)
Cytotoxic T cells are a key part of the cellular immune response, killing cells that display foreign antigen on their surface, primarily virus-infected cells. Transformed cells can also be detected and eliminated by cytotoxic T cells. There are two mechanisms by which activated cytotoxic T cells kill cells presenting specific antigen. One method involves the release of secretory granules containing perforin and granzyme to induce lysis of the targeted cell. Cytotoxic T cells also express Fas ligand to bind to Fas on target cells and induce apoptosis. Communication with and interaction with other cell types is essential for cytotoxic T cell function. Distinct types of T cells are characterized and their activities determined by the proteins they express on their cell surface. Cytotoxic T cells will only respond to antigen presented on the surface of cells bound to MHC I proteins, not antigens present in solution. The T cell receptor, with the multiprotein CD3 complex, is responsible for the recognition of specific antigens, triggering the activation and proliferation of cells. Cytotoxic T cell activation also requires additional signals provided by helper T cells in addition to signals provided by antigen-presenting cells. Thy1 provides a general marker of T cells, and the presence of CD8 protein that binds to MHC distinguishes cytotoxic T cells from CD4 positive helper T cells. CD28 expressed by T cells acts as a costimulatory signal with the T cell receptor when it binds its ligand, a B-7 coreceptor, on antigen-presenting cells (see The Co-Stimulatory Signal During T-cell Activation). Inappropriate regulation of the costimulatory signal can lead to too great or too small of an immune response. Interaction of activated cytotoxic T cells is aided by increased expression of LFA-1, a cell-adhesion molecule that binds to ICAM on target cells. CD2 is a T cell adhesion molecule. Mice with a disrupted CD2 gene are largely normal and appear to have a normal immune system, but CD2 on cytotoxic T cells may assist in interaction with target cells. (This definition may be outdated - see the DesignNote.)
T Cytotoxic Cell Surface Molecule Pathway
While T cells and B cells carry out the actions of antigen-specific immune responses, antigen-presenting cells called dendritic cells are required for this to happen. The name of dendritic cells is based on their shape, with activated dendritic cells displaying long processes on their surface. When immature dendritic cells found throughout the body internalize and present antigen, they express markers that stimulate the activation of lymphocytes, and migrate to lymphocyte rich tissues like the spleen and lymph nodes to initiate immune responses. In addition to stimulating responses against antigens, dendritic cells also produce tolerance to self antigens. Dendritic cells can be derived from either myeloid or lymphoid lineages. Monocyte (myeloid) derived lineages (pDC1) stimulate Th1 cell differentiation while plasmacytoid (lymphoid) dendritic cells (pDC2) induce Th2 cell differentiation. Factors that stimulate the maturation of monocytes derived dendritic cells include GM-CSF, and IL-4. IL-3 stimulates the differentiation of pDC2 cells into DC2 cells. A variety of factors are involved in antigen-recognition and processing by immature dendritic cells and in the maturation of these cells. The transition to mature dendritic cells down-regulates the factors involved in antigen internalization, and increases the expression of MHC, costimulatory molecules involved in lymphocyte activation, adhesion molecules, and specific cytokines and chemokines. Toll-like receptors on the surface of immature dendritic cells recognize microbial components to induce dendritic cell maturation. In addition to stimulating B cell responses, dendritic cells are potent activators of T cells. IL-12 secretion by dendritic cells stimulates T cell responses, particularly differentiation of Th1 cells that produce interferon-gamma and other pro-inflammatory cytokines. While IL-4 generally stimulates Th2 differentiation, the stimulation of Th2 cell formation by DC2 cells does not appear to involve IL-4. The stimulation of Th1 and Th2 cell formation by dendritic cells appears to be balanced by counter-regulation of each pathway by the other. Interferon-gamma produced by Th1 cells blocks the further stimulation of Th1 differentiation by DC1 cells. The IL-4 produced by Th2 cells kills dendritic cell precursors that contribute to Th2 cell creation. Direct interactions between T cells and dendritic cells are enhanced through the expression of adhesion molecules and costimulatory receptors CD80 and CD86 expressed by mature dendritic cells activate T cells in concert with the recognition of antigen/MHC by the T cell receptor. The central role of dendritic cells as modulators of immune responses makes them an important focus of studies about autoimmune disease, transplant rejection, allergies, responses to infections, and other alterations of the immune response. (This definition may be outdated - see the DesignNote.)
Dendritic cells in regulating TH1 and TH2 Development
One defense against viral infection is provided by PKR, double-stranded RNA activated protein kinase. When PKR interacts with dsRNA found in cells during viral infection, PKR phosphorylates itself and cellular proteins including the translation factor elF2a and the transcription factor NF-kB. The repression of translation caused by phosphorylation of elF2a prevents cells from producing viral proteins and creating infectious viral particles. PKR phosphorylation of I-kB kinase activates NF-kB to induce transcription of inflammatory factors and stimulate an immune response that impedes viral infection. The PKR kinase is induced by interferon and some of the anti-viral activity of interferon may be mediated by PKR. Some viruses have evolved mechanisms to inactivate PKR to promote successful infection. Another substrate of PKR, the tumor suppressor p53, may be involved in potential PKR regulation of the cell cycle and apoptosis. (This definition may be outdated - see the DesignNote.)
Double Stranded RNA Induced Gene Expression
The Fc Epsilon Receptor 1 signaling pathway in mast cells uses multiple core signal paths to achieve its necessary ends. Through the BTK protein and PKC Mast cells are able to degranulate, through the PKC and MAPK paths the cells are able to alter cytokine expression and arachidonic acid release. (This definition may be outdated - see the DesignNote.)
Fc Epsilon Receptor I Signaling in Mast Cells
Fc Epsilon Receptor I Signaling Pathway BioCarta
Fc epsilon RI-mediated signaling pathways in mast cells are initiated by the interaction of antigen (Ag) with IgE bound to the extracellular domain of the alpha chain of Fc epsilon RI. The activation pathways are regulated both positively and negatively by the interactions of numerous signaling molecules. Mast cells that are thus activated release preformed granules which contain biogenic amines (especially histamines) and proteoglycans (especially heparin). The activation of phospholipase A2 causes the release of membrane lipids followed by development of lipid mediators such as leukotrienes (LTC4, LTD4 and LTE4) and prostaglandins (especially PDG2). There is also secretion of cytokines, the most important of which are TNF-alpha, IL-4 and IL-5. These mediators and cytokines contribute to inflammatory responses.
Fc Epsilon Receptor I Signaling Pathway KEGG
Fc-epsilon receptor I signaling in mast cells
Fc-Epsilon Receptor I Signaling Pathway PID
Blood-cell development progresses from a hematopoietic stem cell (HSC), which can undergo either self-renewal or differentiation into a multilineage committed progenitor cell: a common lymphoid progenitor (CLP) or a common myeloid progenitor (CMP). A CLP gives rise to the lymphoid lineage of white blood cells or leukocytes-the natural killer (NK) cells and the T and B lymphocytes. A CMP gives rise to the myeloid lineage, which comprises the rest of the leukocytes, the erythrocytes (red blood cells), and the megakaryocytes that produce platelets important in blood clotting. Cells undergoing this differentiation process express a stage- and lineage-specific set of surface markers. Therefore cellular stages are identified by the specific expression patterns of these genes.
IL-10 is a cytokine with potent anti-inflammatory properties, repressing the expression of inflammatory cytokines such as TNF-alpha, IL-6 and IL-1 by activated macrophages. The IL-10 receptor is in the JAK/STAT class of receptors but activation of the JAK/STAT pathways by IL-10 does not appear on its own to be responsible for the anti-inflammatory properties of this cytokine. The anti-inflammatory actions of IL-10 appear to require induction of the enzyme heme oxygenase-1 (HO-1) through a map kinase pathway involving the p38 kinases. HO-1 is involved in the biosynthesis of heme, and catalyzes a reaction producing carbon monoxide, free iron, and the heme precursor biliverdin. HO-1 is induced by IL-10 and is also induced by oxidative stress. Blocking HO-1 with inhibitors or antisense blocks the anti-inflammatory actions of IL-10. The anti-inflammatory actions of HO-1 appear to be the result of signaling by the carbon monoxide it produces since removal of CO blocks the anti-inflammatory action of IL-10 and HO-1. The anti-inflammatory actions of IL-10 may be therapeutically useful either directly or through modulation of HO-1 activity. (This definition may be outdated - see the DesignNote.)
IL-10 Anti-inflammatory Signaling Pathway
IL10 Anti-inflammatory Signaling Pathway
The IL-2 receptor is a key component of immune signaling and is required for the activation, proliferation, and survival of T cells. This receptor is composed of three polypeptide chains, the alpha, beta, and gamma chains. The IL-2 receptor gamma chain is a common component for several other cytokine receptors, including IL-4, IL-7, IL-9 and IL-15. The IL-2 receptor beta chain is essential for IL-2 signaling and is also a component of the IL-15 receptor complex. The polypeptides of the IL-2 receptor do not themselves have intrinsic catalytic activity, but interact with cytoplasmic signaling proteins to transduce signals. Different regions of the cytoplasmic domain of the IL-2 receptor beta chain interact and couple with distinct signaling pathways and cellular responses. JAK1 associates with the beta chain and JAK3 with the gamma chain. Binding of IL-2 induces heterodimerization of receptor subunits, and activation of JAK kinase activity. Tyrosine residues in the beta chain cytoplasmic domain are phosphorylated during activation, recruiting other factors to the phosphorylated tyrosine residues through src homology 2 (SH2) domains. The adaptor protein Shc binds to phosphorylated tyrosine 338 of the beta chain. When bound, Shc is phosphorylated and couples through Grb2 and Sos-1 to activate Ras and stimulate T cell proliferation. Another key proliferative pathway activated by IL-2 is phosphorylation of STAT-5 by JAK kinases. STAT-5 is recruited to IL-2 beta phosphorylated tyrosines at multiple positions, including Y338, Y392 and Y510. Once phosphorylated, STAT-5 enters the nucleus to regulate the transcription of several genes, some proliferative, such as cyclin genes, and others that are involved in T cell immune function such as cytokine genes. The suppressors of cytokine activation, SOCS-3 and SOCS-1, oppose phosphorylation and activation of STAT-5 and JAK1 caused by IL-2. PI3 kinase is another protein recruited to IL-2 receptor beta chain tyrosines when phosphorylated. Activation of PI3 Kinase also contributes to the proliferative activity of IL-2 in T cells. The role of other tyrosines in the IL-2 receptor beta chain, Y355, Y358 and Y361, is not yet clear, but may be involved in signaling by the protein kinase p56lck. In addition to stimulating T cell activation and proliferation, IL-2 activation blocks T cell apoptosis through multiple pathways. Among the genes activated by STAT-5 are BCL-xL, an inhibitor of apoptosis, and fas-ligand, an activator of apoptosis in cells expressed the fas receptor. PI3 kinase also contributes to anti-apoptotic activity of IL-2 through AKT activation. T cell responses to IL-2 must be coordinated in part in the complex protein-protein interactions with the IL-2 receptor beta chain. (This definition may be outdated - see the DesignNote.)
IL-2 Receptor Beta Chain in T cell Activation
Inflammation is a protective response to infection by the immune system that requires communication between different classes of immune cells to coordinate their actions. Acute inflammation is an important part of the immune response, but chronic inappropriate inflammation can lead to destruction of tissues in autoimmune disorders and perhaps neurodegenerative or cardiovascular disease. Secreted cytokine proteins provide signals between immune cells to coordinate the inflammatory response. Some cytokines such as IL-1, IL-6, and TNF act to broadly provoke the inflammatory response while others act on specific types of immune cells. Macrophages and other phagocytotic cells provide a front-line defense against bacterial infection. Macrophages stimulate the inflammatory responses of neutrophils, fibroblasts, and endothelial cells in response to infection by secreting IL-1 and TNF. IL-1 and TNF cause fever through alteration of the body temperature set-point in the hypothalamus. Fibroblasts and endothelial cells respond to IL-1 and TNF by recruiting more immune cells to the site of inflammation. Secreted IL-8 is a chemokine that attracts neutrophils to sites of infection. Macrophages also present antigen to T helper cells that play a central role in coordinating immune responses. T helper cells induce clonal expansion of T cells that respond to antigen, with IL-2 as a key mediator of T cell proliferation and activation. TGF-beta is a negative regulator of proliferation in many cells, having anti-inflammatory actions in some settings. The cytotoxic activity of Natural Killer cells (NK cells) and lymphokine activated killer cells (LAK cells) toward viral infected or tumor cells is stimulated by IL-2 and other cytokines. T helpers secrete IL-3 and IL-5 to stimulate eosinophil proliferation and activation. Eosinophils are involved in the immune response to parasitic infection. T helper cells are required to stimulate B cell responses as well, with the cytokines IL-10, IL-4 and other cytokines regulating the clonal selection and differentiation of antigen-specific B cells to form antibody-secreting plasma B cells and memory cells. In addition to inducing activation and proliferation of specific differentiated immune cells, cytokines act on hematopoietic stem cells, causing their proliferation and differentiation into the full range of immune cells. (This definition may be outdated - see the DesignNote.)
The intestine is the largest lymphoid tissue in the body. One striking feature of intestinal immunity is its ability to generate great amounts of noninflammatory immunoglobulin A (IgA) antibodies that serve as the first line of defense against microorganisms. The basic map of IgA production includes induction of mucosal B cells in the Peyer's patches, circulation through the bloodstream and homing to intestinal mucosa of IgA-committed plasma cells, and local antibody production for export across the intestinal membranes. Multiple cytokines, including TGF-beta, IL-10, IL-4, IL-5, and IL-6, are required to promote IgA class switching and terminal differentiation process of the B cells. Secreted IgA promotes immune exclusion by entrapping dietary antigens and microorganisms in the mucus and functions for neutralization of toxins and pathogenic microbes.
Intestinal immune network for IgA production
The complement cascade of proteolytic factors involved in cellular lysis can be initiated by several different factors, including antibody-dependent and antibody-independent recognition of infectious organisms. In the lectin-induced complement cascade, carbohydrates on the surface of microbial cells activate the complement cascade by binding to mannan-binding lectin (also called the mannan-binding protein, Mbl/Mbp). Mbp is an acute phase serum protein whose expression is induced by microbial infection. The binding of Mbl to microbial ligands activates the Mbl associated serine proteases Masp1 and Masp2, triggering the cleavage of C2 and C4 to create C4bC2a, a C3 convertase that cleaves large numbers of C3. Masp1 and Masp2 are similar to the C1 protease in the classical complement pathway. Once formed the C3 convertase cleaves and activates the remaining complement factors leading ultimately to formation of a pore in the bacterial membrane by the membrane attack complex (MAC) that lyses the bacterial cell. The lectin-induced pathway also appears to play an important role of the activation of phagocytotic cells by infection. Although the initiating event activating the complement cascade is distinct in the lectin-induced pathway, from the C3 convertase onward the lectin induced complement pathway is the same as the classical complement pathway. Since antibodies are not required in the lectin-induced pathway, this aspect of the immune response is part of the innate immune response. The importance of this pathway to the immune response has been demonstrated by the identification of children and adults with little or no Mbl who lacked normal phagocytotic responses and are highly susceptible to infection. (This definition may be outdated - see the DesignNote.)
Leukocyte migration from the blood into tissues is vital for immune surveillance and inflammation. During this diapedesis of leukocytes, the leukocytes bind to endothelial cell adhesion molecules (CAM) and then migrate across the vascular endothelium. A leukocyte adherent to CAMs on the endothelial cells moves forward by leading-edge protrusion and retraction of its tail. In this process, alphaL/beta2 integrin activates through Vav1, RhoA, which subsequently activates the kinase p160ROCK. ROCK activation leads to MLC phosphorylation, resulting in retraction of the actin cytoskeleton. Moreover, leukocytes activate endothelial cell signals that stimulate endothelial cell retraction during localized dissociation of the endothelial cell junctions. ICAM-1-mediated signals activate an endothelial cell calcium flux and PKC, which are required for ICAM-1 dependent leukocyte migration. VCAM-1 is involved in the opening of the "endothelial passage" through which leukocytes can extravasate. In this regard, VCAM-1 ligation induces NADPH oxidase activation and the production of reactive oxygen species (ROS) in a Rac-mediated manner, with subsequent activation of matrix metalloproteinases and loss of VE-cadherin-mediated adhesion.
Leukocyte Transendothelial Migration Pathway
Inflammation has several distinct components, including the localized response at the site of tissue injury or infection. Tissue injury stimulates the release of inflammatory signaling molecules such as bradykinin. Bacterial infection stimulates an immune response in several ways. Bacteria that are phagocytosed can activate macrophages, causing the release of inflammatory cytokines such as IL-1, TNF, and IL-6. Bacteria can also activate the complement cascade through either the antibody-mediated pathway (classical pathway) or the alternative complement pathway. In extravascular tissues, cells that respond to infection or injury include macrophages and mast cells. Macrophages and other immune cells secrete chemokines that recruit leukocytes from the circulation to the site of inflammation. Mast cells release histamine, prostaglandins, and leukotrienes that act as chemokines, increase vascular permeability, and act on the vascular endothelium to increase tissue recruitment of leukocytes. Chemokines can recruit leukocytes or lymphocytes out of the blood stream into tissues and make blood vessels more permeable. Leukocytes are activated by inflammatory signals to express adhesion molecules that cause them to interact with the vascular endothelium, penetrate the endothelial wall and migrate into the extracellular space of tissues. The combined response of immune cells and signaling molecules at the site of inflammation induces swelling, activation of immune cells, and clearance of potential infectious agents. Chronic inflammation can however also lead to tissue damage in conditions such as arthritis, in which anti-inflammatory drugs act on various steps in inflammation to prevent disease. (This definition may be outdated - see the DesignNote.)
Local Acute Inflammatory Response Pathway
Monocytes are a class of phagocytes involved in non-specific immune defense that develop into macrophages. In plasma, monocytes ingest and destroy bacteria, and can form macrophages when they enter the extracellular space in tissues. In addition to the immune protection that monocytes provide, they may contribute to disease states such as arthritis and heart disease through an aberrant immune response. As with other immune cells, the immune function and differentiation of monocytes rely on communication with other cells through cell surface proteins. Cell surface proteins are involved in both interaction and adhesion with other cells and in transducing signals into the cellular interior. The LFA-1 integrin (Leukocyte function-associated molecule 1) is composed of two subunits, CD11a and CD18 and is involved in monocytes adhesion with ICAM-1 endothelial cells. Mac-1 is composed of the subunits CD11b and CD18 and is induced during inflammation as well. PECAM-1 mediates the migration of monocytes and other immune cells into inflamed tissues through interaction with vascular endothelial cells. CD44 interaction of leukocytes with hyaluronan in the extracellular matrix is induced by inflammation. VLA-4 is another integrin expressed on lymphocytes that plays a role in adhesion through interaction with its adhesion partner on endothelial cells, VCAM-1. (This definition may be outdated - see the DesignNote.)
Monocyte Phagocytosis and Adhesion Pathway
Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stress, such as infection with viruses, bacteria, or parasites or malignant transformation. Although NK cells do not express classical antigen receptors of the immunoglobulin gene family, such as the antibodies produced by B cells or the T cell receptor expressed by T cells, they are equipped with various receptors whose engagement allows them to discriminate between target and nontarget cells. Activating receptors bind ligands on the target cell surface and trigger NK cell activation and target cell lysis. However Inhibitory receptors recognize MHC class I molecules (HLA) and inhibit killing by NK cells by overruling the actions of the activating receptors. This inhibitory signal is lost when the target cells do not express MHC class I and perhaps also in cells infected with virus, which might inhibit MHC class I expression or alter its conformation. The mechanism of NK cell killing is the same as that used by the cytotoxic T cells generated in an adaptive immune response; cytotoxic granules are released onto the surface of the bound target cell, and the effector proteins they contain penetrate the cell membrane and induce programmed cell death.
Natural killer cell mediated cytotoxicity
Natural Killer Cell-Mediated Cytotoxicity Pathway
Neutrophils are important phagocytotic leukocytes (white blood cells) that internalize and destroy infectious bacteria by a respiratory burst of reactive oxygen species and by enzymatic digestion. Along with macrophages, neutrophils are crucial phagocytotic cells of the immune system and also contribute to anti-viral defenses, binding to and eliminating free virus or virus-infected cells. The presence of cytoplasmic granules in neutrophils leads to their classification as granulocytes, along with basophils and eosinophils. A lack of neutrophils or their normal function causes a variety of immune disorders and measuring neutrophil cell surface proteins can diagnose abnormal immune function. One such disorder is caused by a lack of normal expression of the adhesion molecules CD11 and CD18 by neutrophils, preventing them from interacting normally with adhesion molecules on endothelial cells and migrating into inflamed sites in tissues. CD11a and CD18 together form the LFA-1 receptor for ICAM-1 on endothelial cells and CD11b/CD18 form Mac-1. Deletion of the CD18 gene in mice produces a significant reduction in leukocyte emigration to sites of inflammation. CD44 is involved in the interaction of neutrophils with endothelial cells and the extracellular matrix during inflammation. The binding of selectins with their carbohydrate ligands also regulates adhesion of neutrophils with endothelial cells, with P- and L-selectins moderating initial interactions and E-selectin moderating subsequent interactions. Genetic disruption of the ability of neutrophils to kill internalized bacteria also impairs normal immune function, along with genetic or acquired lack of the normal number of neutrophils (neutropenia). CD11b binding to a complement component and CD16 binding to IgG Fc contribute to phagocytosis. Inflammatory cytokines activate neutrophils and chemotactic peptides attract them to sites of infection. Inflammatory molecules that activate neutrophils include IL-1, TNF, IL-6, C-reactive protein, C3a and C5a complement anaphylatoxins, leukotrienes, PAF, and histamine. Inappropriate recruitment and activation of neutrophils and the release of reactive oxygen species can damage surrounding tissues in inflammatory conditions including arthritis and reperfusion of heart tissue following myocardial infarction. (This definition may be outdated - see the DesignNote.)
Macrophages and NK cells help provide innate immunity against infection by intracellular parasites and communicate with each other to regulate this process. When stimulated, macrophages secrete the cytokine IL-12 which is essential for activation of the cytotoxic activity of natural killer (NK) cells. IL-12 stimulates this NK cell response through activation of a JAK/STAT signaling pathway. Binding of IL-12 to its receptor on NK cells causes tyrosine phosphorylation and activation of JAK2 and another JAK kinase, Tyk2. Tyk2 in turn phosphorylates the transcription factor STAT4, which can then translocate to the nucleus to activate genes, including the expression of interferon-gamma. IFN-gamma and IL-12 induce the differentiation of TH1 helper T cells that activate macrophages through interferon-gamma. A key modulator of NK cell activation by IL-12 is nitric oxide, NO, produced from arginine by the inducible nitric oxide synthase NOS2. Inactivation of the NOS2 gene in mice impairs the initial innate response to infection, including the activation of NK cells. This phenotype is similar to that of mice lacking interferon-gamma or IL-12 and a similar effect can be produced by inhibiting NOS2 with L-N6-iminoethyl-lysine (L-NIL) during infection, blocking the activation of NK cells by IL-12. NO production does not affect the activation of JAK2 by IL-12, but is required for Tyk2 activity, the downstream activation of STAT-4 and the production of interferon-gamma by NK cells. The role of NO in Tyk2 activation is not yet known, but does not seem to involve changing the phosphorylation status of Tyk2. Curiously, activation of T cells by IL-12 does not appear to involve NO production, indicating a distinct mechanism is involved in NK cells. NO also plays a role as a feedback inhibitor of IL-12 production by macrophages, helping to prevent over-activation of the Th1 cells by IL-12. NO appears to make an important contribution to the early innate response to infections before specific immunity is active. (This definition may be outdated - see the DesignNote.)
NK (natural killer) cells are lymphocytes distinct from B and T cells that induce perforin-mediated lysis of tumor cells and virus-infected cells. NK cell-mediated cytotoxicity is activated by glycoproteins on the cell surface (activating receptors) and inhibited by MHC-1 with self-peptide bound. The MHC-1 inhibitory signal through Ig-family or lectin receptors prevents NK cells from killing normal cells. Abnormal MHC-1 expression in infected or tumor cells results in the release of perforin, the lysis of the abnormal cell and the release of cytokines that stimulate the immune response. MAP kinase inhibitors, but not ras inhibitors, are able to block NK cell cytotoxicity, indicating that the pathway can function by a ras-independent manner that involves the MAP kinase pathway. This pathway includes phosphoinositide-3-kinase (PI3K) as a key component, followed by Rac1 and the exchange factor Vav. The tyrosine kinase SYK and LAT may provide an additional pathway for activation of MAP kinases leading to NK cell activation, and also Pyk-2 activation by integrins. The protein tyrosine phosphatase SHP-1 appears to mediate the cytotoxicity inhibitory signal that blocks lysis of normal cells. The balance of these positive and negative signaling pathways regulates the role of NK cells in the immune response. (This definition may be outdated - see the DesignNote.)
Ras-Independent pathway in NK cell-mediated cytotoxicity
Ras-Independent Cell-Mediated Cytotoxicity Pathway
The T cell receptor is a cell-surface receptor that recognizes specific antigen to stimulate the T cell response to that antigen. The T cell receptor complex of transmembrane proteins includes the T cell receptor that recognizes antigen and a set of proteins called CD3 involved in signal transduction. CD3 associated with the T cell receptor includes six polypeptides arranged in three dimers that recruit and activate protein kinases to signal the activation of T cell receptor by bound antigen through recruitment and activation of protein kinases (see T Cell Receptor Signaling Pathway). T cell receptors only recognize antigen on the surface of other cells, not antigen in solution, by requiring antigen to be bound to MHC proteins on the surface of other cells to be recognized. Cytotoxic T cells recognize antigen bound to MHC I on the surface of other cells and helper T cells recognize antigen bound to MHC II on antigen-presenting cells. CD4 (helper T cells) and CD8 (cytotoxic T cells) are cofactors in MHC recognition. Recombination in immature T cells of the genes for the alpha and beta T cell receptor subunits creates a huge variety of variable regions involved in antigen recognition resulting in many antigen specificities in the population of immature T cells. Some T cells called gamma/delta cells express T cell receptor composed of gamma and delta subunits rather than alpha/beta subunits. When the T cell receptor on a cell interacts with antigen in the proper context, that cell is stimulated to become activated and proliferate, in a process known as clonal selection. The recombination of T cell receptor genes and clonal selection of cells that bind specific antigen is very similar to the B cell process that creates immunoglobulins and clonal selection of B cells that bind antigen. (This definition may be outdated - see the DesignNote.)
T Cell Receptor and CD3 Complex Signaling Pathway
The T Cell Receptor plays a key role in the immune system. The specificity of the receptor is governed by the binding site formed from the mature alpha and beta chains or gamma and delta chains in gamma/delta T Cells. It is the ability of this receptor to bind a complex of foreign peptide in the groove of an MHC molecule that leads to T cell activation. Upon activation the T cell can assist in activating other cells or carry out cytolytic attacks depending on the particular T cell type. The CD3 complex and CD4 (Th cells) or CD8 (Tc cells) work to transmit the activation signal to the T cell's transcriptional machinery upon engagement of the receptor. (This definition may be outdated - see the DesignNote.)
T lymphocyte receptor signalling pathway
T-lymphocyte receptor signalling pathway
T Cell Receptor Signaling Pathway BioCarta
Activation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T-cell receptor (TCR) as well as costimulatory molecules such as CD28. Engagement of these receptors through the interaction with a foreign antigen associated with major histocompatibility complex molecules and CD28 counter-receptors B7.1/B7.2, respectively, results in a series of signaling cascades. These cascades comprise an array of protein-tyrosine kinases, phosphatases, GTP-binding proteins and adaptor proteins that regulate generic and specialised functions, leading to T-cell proliferation, cytokine production and differentiation into effector cells.
T helper cells play an essential role coordinating the activities of other parts of the immune system, including B cells, cytotoxic T cells, macrophages and other cells. The crucial nature of helper T cells in the normal immune response is demonstrated by the severe immune deficiency associated with the HIV-induced helper T cell depletion. To communicate with other cells, helper T cells express a range of cell surface molecules, a few of which are illustrated in this figure. Like all T cells, helper T cells express T cell receptors complexed with the CD3 proteins that are responsible for the recognition and response of the cell to specific antigens (see T Cell Receptor Signaling Pathway). CD4 is commonly used as a marker for helper T cells, in contrast to cytotoxic T cells, which express CD8. CD4 is used by HIV to gain cell entry, as well as the CCR5 chemokine receptor. Thy1 provides a more general cell surface antigen used to identify both T helper and cytotoxic T cells. CD28 provides a costimulatory signal in association with the activation of the T cell receptor complex by an antigen presenting cell that is required for the T cell to become activated (see The Co-Stimulatory Signal During T-cell Activation pathway). Adhesion molecules on the surface of T cells assist in their interaction with other cells. LFA-1 binds to its ligand ICAM-1 in a variety of cells and T cells themselves also express ICAM-1. The CD45 protein tyrosine phosphatase dephosphorylates factors in the pathways involved in B cells and T cells activation. Although CD45 is required for T cell receptor activation, exclusion of CD45 from the local membrane region near the T cell receptor appears important for efficient T cell activation. Helper T cells can be subdivided further into Th1 and Th2 cells, distinguished by their response to different antigens, differing cytokine expression and expression of different chemokine receptors (see Selective expression of chemokine receptors during T-cell polarization) CD2 is required for efficient helper T cell maturation and stimulates their differentiation, but does not select for a specific increase in Th1 or Th2 populations of cells. (This definition may be outdated - see the DesignNote.)
For a T cell to be activated by a specific antigen, the T cell receptor must recognize complexes of MHC-1 with the antigen on the surface of an antigen-presenting cell. T cells and the T cell receptor complex do not respond to antigen in solution, but even for the specific antigen they only respond to antigen-MHC-1 complexes on the cell surface. This interaction is necessary for T cell activation, but it is not sufficient. T cell activation also requires a co-stimulatory signal involving interaction of CD28 on the T cell with CD80 or CD86 (B7 family genes) on the antigen-presenting cell. CD28 activates a signal transduction pathway acting through PI-3K, Lck and Grb-2/ITK to provide its co-stimulatory signal for T cell activation. Another means to control T cell activation is by expressing factors that down-regulate T cell activation. Signaling by activated T cell receptors induces expression of CTLA-4, a receptor that opposes T cell activation. CTLA-4 has a higher affinity than CD28 for B7 proteins, terminating T cell activation. ICOS is a protein related to CD28 that is only expressed on activated T cells, and that provides another important co-stimulatory signal. The requirement for co-stimulatory signals provides additional control mechanisms that prevent inappropriate and hazardous T cell activation. (This definition may be outdated - see the DesignNote.)
The Co-Stimulatory Signal During T-cell Activation
T-Cell Activation Co-Stimulatory Signaling Pathway
Regulation of T cell activation is a crucial component of balanced functioning of the immune system. If the T cell response is too great and activation of self-responsive cells or unstimulated cells is not suppressed, then autoimmune disorders or tissue injury can result. Unstimulated T cells are maintained in a quiescent state and the activity of self-reactive T cells is maintained in an anergic state in which IL-2 expression is repressed. IL-2 is a cytokine with a key role in the activation and proliferation of T cells. The maintenance of T cells in the anergic or unstimulated state may not involve just an absence of activation, but an active repression of IL-2 expression, T cell proliferation, and activation. TGF beta may play a role in suppressing T cell activation. Tob is a member of a family of genes with anti-proliferative properties that represses T cell activation. Tob expression is highest in unstimulated and anergic T cells, and is reduced in activated T cells. Tob interacts with the TGF activated transcription factors SMAD2 and SMAD4, increasing their binding to the IL-2 promoter, and helping to repress IL-2 expression. This role of Tob suggests that interference in Tob's function may lead to autoimmune disease. (This definition may be outdated - see the DesignNote.)
Vasoactive intestinal peptide (VIP) and the structurally related pituitary adenylate cyclase-activating polypeptide (PACAP), two neuropeptides present in the lymphoid microenvironment, elicit a broad spectrum of biological functions, including the modulation of innate and adaptive immunity. Another important immunoregulatory function of VIP and PACAP is their inhibition effect on AICD in T cells. They inhibit the TCR-stimulated FasL expression and apoptosis of T cell through specific receptors and induction of intracellular cAMP. VIP down-regulate c-Myc synthesis, the NF-AT-dependent Egr2 and Egr3 expression, the NF-AT and NF-kB. (This definition may be outdated - see the DesignNote.)
Neuropeptides VIP and PACAP inhibit the apoptosis of activated T cells
Chemokine receptors expressed by T helper cells help recruit cells to specific locations based on their chemoattractant ligands. The polarization of T cells into Th1 and Th2 cells is associated with their expression of different subsets of chemokine receptors. Naive CD4 positive cells that have not been exposed to antigen express CXCR4 and CCR7. The most abundant chemokine receptors on Th1 cells involved in the cellular immune response to microbial agents include CXCR3, CCR1, CCR2 and CCR5, while Th2 cells express CCR2, CCR3 and CCR5. An additional class of T cells termed semi-naive cells may be induced by TGF-beta to express yet another class of chemokine receptors, CCR4 and CCR7. Although the expression of chemokine receptors in different cells is preferred in these cases, it is not absolute or exclusive, and there is overlap in expression between Th1 and Th2 cells. Although CCR7 positive cells have been reported to lack effector action, not be polarized, and to home only to lymphoid tissues, other studies have found CCR7 positive Th1 and Th2 cells and have identified CCR7 positive cells in non-lymphoid tissues. CCR4 appears associated with homing of lymphocytes to the skin, and CCR9 is associated with homing to the small intestine, while other chemokines like CXCR3 and CCR5 are associated with homing toward inflamed tissues more broadly. The expression of different chemokine receptors by subsets of T helper cells plays an important role in the migration and homing of these cells in tissues, and targeting of the immune response to specific cells. (This definition may be outdated - see the DesignNote.)
Selective expression of chemokine receptors during T-cell polarization
T-Cell Receptor Signaling Pathway in Naive CD4+ T Cells
Calcium signaling in the CD4+ TCR pathway
T-Cell Receptor Signaling Pathway in Naive CD8+ T Cells
Downstream signaling in naïve CD8+ T cells
Downstream Signaling Pathway in Naive CD8+ T Cells
T cell activation is initiated by recognition of antigen by the T cell receptor (TCR) in the context of Class II MHC on an antigen-presenting cell. The T cell receptor contains multiple subunits and interacts with several factors to transduce antigen-stimulated T cell activation. One of the key steps that initiates receptor activation is the tyrosine phosphorylation of TCR subunits by the src family protein kinases Lck and Fyn. T cell receptor phosphorylated by Lck and Fyn recruits the ZAP-70 protein kinase to the receptor complex, which becomes activated and stimulates downstream pathways like the Map kinase cascade. The CD45 protein tyrosine phosphatase activates Lck and Fyn by dephosphorylating these proteins and is required for TCR activation. Association of the CD4 coreceptor with Lck may also be involved in Lck activation. (This definition may be outdated - see the DesignNote.)
Lck and Fyn tyrosine kinases in initiation of TCR Activation
The innate immune response responds in a general manner to factors present in invading pathogens. Bacterial factors such as lipopolysaccharides (LPS, endotoxin), bacterial lipoproteins, peptidoglycans, and also CpG nucleic acids activate innate immunity as well as stimulating the antigen-specific immune response and triggering the inflammatory response. Members of the toll-like receptor (TLR) gene family convey signals stimulated by these factors, activating signal transduction pathways that result in transcriptional regulation and stimulate immune function. TLR2 is activated by bacterial lipoproteins, TLR4 is activated by LPS, and TLR9 is activated by CpG DNA; peptidoglycan recognition protein (PGRP) is activated by peptidoglycan (PGN). The downstream signaling pathways used by these receptors are similar to that used by the IL-1 receptor, activating the IL-1 receptor associated kinase (IRAK) through the MyD88 adaptor protein, and signaling through TRAF-6 and protein kinase cascades to activate NF-kB and Jun. NF-kB and c-Jun activate transcription of genes such as the proinflammatory cytokines IL-1 and IL-12. Several reports have suggested that the functional outcomes of signaling via TLR2, TLR4, and PGRP are not equivalent. For example, while the LPS-induced, p38-dependent response was dependent upon PU.1 binding, the PGN-induced, p38 response was not. The intracellular receptor for PGN, PGRP, is conserved from insects to mammals. In insects, PGRP activates prophenoloxidase cascade, a part of the insect antimicrobial defense system. Because mammals do not have the prophenoloxidase cascade, its function in mammals is unknown. However, it was suggested that an identical protein Tag7 was a tumor necrosis factor-like (TNF-like) cytokine. PGRP/Tag7 possesses cytotoxicity and triggers intranucleosomal DNA fragmentation in target cells in the same way as many known members of the TNF family. Fragmentation of DNA is one of the characteristics of apoptosis. The possibility that in another system, PGRP/Tag7 would induce NF-kB activation, as observed for TRAIL (TNF-related apoptosis-inducing ligand) receptors cannot be ruled out. (This definition may be outdated - see the DesignNote.)
Cellular transformation is accompanied by many cellular changes, including uncontrolled proliferation, loss of the differentiated cell morphology, and invasion of the extracellular matrix. Degradation of the extracellular matrix is a key component of tumor cell invasion into surrounding tissues. Matrix metalloproteinases (MMPs) are a class of proteases secreted by tumor cells, degrading the proteins of the extracellular matrix and allowing metastasis. Drug inhibitors of MMPs are one strategy to control cancer and block metastasis. In searching for genes that reverse the rounded morphology of transformed cells in culture, RECK was identified (reversion-inducing, cysteine-rich protein with Kazal motifs). RECK is a membrane-anchored inhibitor of matrix metalloproteinases, inhibiting MMP-2, MMP-9, and MT1-MMP. The processing of MMPs to their active form occurs at the plasma membrane, making the localization of RECK at the membrane a key to its potent activity as an inhibitor of MMP activity. Soluble secreted MMP inhibitors have also been identified, TIMPs, which appear to be less active at inhibiting MMPs and even perhaps to be essential for MMP maturation. The inhibition of MMPs by RECK inhibits invasion of tissues, metastasis, and tumor angiogenesis, and is essential for normal development. In addition to playing a role in tissue invasion in cancer, the activity of MMPs in angiogenesis, inflammation, and development is regulated by inhibitors such as RECK and TIMPs. RECK expression is inhibited by ras, suggesting one component by which ras induces transformation. High levels of RECK expression in tumors is correlated with cancer patient survival and overexpression of RECK may offer a therapeutic strategy for the control of cancer. (This definition may be outdated - see the DesignNote.)
Inhibition of Matrix Metalloproteinases Pathway
Map kinases transduce responses to extracellular signals by a variety of routes, and communicate with other pathways through extensive crosstalk networks. A closely studied Map kinase cascade originates with tyrosine kinase activation, and activation of Ras. Ras activates Raf, Raf activates the Map kinase kinases Mek1 and Mek2 and these kinases activate downstream Map kinases like Erk1 and Erk2. Erk1 and Erk2 in turn activate transgenes like p35 through the Map kinase activated transcription factor EGR-1. Mek1 plays a central role in many different Map kinase pathways. Factors that activate Mek1 include growth factors like NGF, cytokines, chemokines, and phorbol ester, resulting in cellular proliferation and survival. Mek1 activation may also play a role in differentiation in neuronal tissues. In cultured neuronal PC-12 cells, NGF induces neurite outgrowth via Mek1 and the map kinase pathway. Constitutive activation of Mek1 can transform cells and may play a role in cancer. The crucial role of Mek1 in a variety of pathways including cellular transformation suggests that the cell must tightly regulate its activity. Cdk5 is a kinase that regulates the activity of Mek1. Although Cdk5 is a member of the cyclin-dependent kinase gene family, the activity of Cdk5 does not appear to be regulated by cyclins, but is activated by association with p35. Cdk5 does not act as a checkpoint kinase to regulate cell cycle progression, but acts as a regulatory kinase involved in other post-mitotic processes such as neuronal activity such as neuronal migration during development and neurite outgrowth. Mice lacking Cdk5 exhibit defects in neuronal development. One target of Cdk5 is Mek1. Phosphorylation of Mek1 by Cdk5 represses Mek1 activity and blocks downstream cellular responses. The activation of p35 by Map kinase pathways followed by deactivation of Map kinase signaling by the Cdk5/p35 complex completes the loop of a feedback circuit to terminate Map kinase signaling. (This definition may be outdated - see the DesignNote.)
Phosphorylation of MEK1 by cdk5/p35 down regulates the MAP kinase pathway
Corepressors are coregulators that interact with transcriptional silencers in a variety of pathways such as cell proliferation, differentiation and apoptosis. Abnormal corepressor-silencer interactions have been implicated in a variety of human disease pathways including several types of leukemia. The regulation of the SMRT corepressor via the p38 and Mek-1 Kinase pathway is represented in this pathway. The EGF receptor represents one mechanism by which SMRT function is inhibited by the tyrosine kinase signaling pathway. The MEKK1 and p38 pathways are activated by EGF resulting in cross-regulation of SMRT. The induction of SMRT phosphorylation by either pathway causes SMRT to unbind from the transcription factor complexes represented by RXR, RAR, T3R and PLZF. (This definition may be outdated - see the DesignNote.)
Map Kinase Inactivation of SMRT Corepressor
Map Kinase Inactivation of SMRT Corepressor Pathway
Mitogen-activated protein (MAP) kinases are important players in signal transduction pathways activated by a range of stimuli and mediate a number of physiological and pathological changes in cell function. There are three major subgroups in the MAPK family: ERK, p38, and JNK/SAPK. ERK is activated mainly by mitogenic stimuli, whereas p38 and JNK/SAPK are activated mainly by stress stimuli or inflammatory cytokines. MAP kinases are part of a three-tiered phosphorylation cascade and MAP kinase phosphorylation on a threonine and tyrosine residue located within the activation loop of kinase subdomain VIII results in activation. However, this process is reversible even in the continued presence of activating stimuli, indicating that protein phosphatases provide an important mechanism for MAP kinase control. Dual specificity phosphatases (DSPs) from the tyrosine phosphatase (PTP) gene superfamily are selective for dephosphorylating the critical phosphothreonine and phosphotyrosine residues within MAP kinases. Ten members of dual specificity phosphatases specifically acting on MAPKs, termed MAPK phosphatases (MKPs), have been reported. They share sequence homology and are highly specific for MAPKs but differ in the substrate specificity, tissue distribution, subcellular localization, and inducibility by extracellular stimuli. MKPs have been shown to play important roles in regulating the function of the MAPK family. DSP gene expression is induced strongly by various growth factors and/or cellular stresses. Expression of some gene family members, including CL100/MKP-1, hVH-2/MKP-2, and PAC1, is dependent at least in part on MAP kinase activation providing negative feedback for the inducing MAP kinase or for regulatory cross talk between parallel MAP kinase pathways. DSPs are localized to different subcellular compartments and certain family members appear highly selective for inactivating distinct MAP kinase isoforms. This enzymatic specificity is due to catalytic activation of the DSP phosphatase after tight binding of its amino-terminal to the target MAP kinase. Thus, DSP phosphatases provide a sophisticated mechanism for targeted inactivation of selected MAP kinase activities. (This definition may be outdated - see the DesignNote.)
Regulation of MAP Kinase Pathways Through Dual Specificity Phosphatases
One of the central features of mitotic cell division is the formation of the spindle that segregates chromosomes into each daughter cell. Chromosomes are not just passengers along for a ride with the spindle, but active participants in the nucleation and stabilization of spindle microtubules in their near vicinity. The ras-like GTPase Ran that regulates nucleocytoplasmic transport through the nuclear pore complex (NPC) during interphase also regulates the formation of the mitotic spindle. Ran plays a similar role in each of these processes, regulating downstream signaling pathways in a differential manner based on whether GDP or GTP is bound. Like other GTPases, the inherent GTPase activity of Ran is regulated by GTPase activating proteins (GAPs) and by exchange factors. An exchange factor that stimulates nucleotide exchange by the Ran GTPase is RCC1, which binds to chromatin in both interphase and mitosis. While RCC1 helps RAN drive transport between the nucleus and cytoplasm during interphase, the localization of RCC1 on chromatin during mitosis localizes Ran-GTP near chromosomes, localizing microtubule formation in these regions. Ran-BP1 and Ran-GAP1 stimulate GTP hydrolysis by Ran, converting it back to Ran-GDP further away from chromosomes. Aster promoting activities (APA) and the importin-alpha and importin-beta proteins involved with Ran in nucleocytoplasmic transport are also involved in mitotic spindle formation. Aster promoting activities stabilize microtubules during spindle formation, but binding of importins to APA neutralizes their activity in forming microtubules. The importins bind to APA when far from the chromosomes, where Ran-GDP predominates, but Ran-GTP near chromosomes causes importins to release APA factors including Tpx2 and NuMa, allowing them to stimulate microtubule formation. Tpx2 interacts with the microtubule motor protein Xklp2 and also activates the Aurora A mitotic kinase, required for spindle formation. In addition to regulating spindle formation, Ran may also help reform the nuclear envelope after cell division and may use a similar mechanism to regulate other cellular processes. (This definition may be outdated - see the DesignNote.)
Role of Ran in mitotic spindle regulation
Nuclear hormone receptors are transcription factors that bind DNA and regulate transcription in a ligand-dependent manner. PPAR-gamma is a member of this gene family that is activated by fatty acids and thiazolidinedione drugs that plays a role in insulin sensitivity and adipogenesis. Like PPAR-alpha and other members of this gene family, PPAR-gamma activates transcription in concert with coactivators including Src-1 and Tif2. Although these coactivators act for multiple members of this gene family, coactivators may have specific functions in some settings. Deletion of the Src-1 gene or Tif2 gene in mice reduced the response to steroid hormones and development dependent on these hormones. Some PPAR-gamma ligands induce the specific recruitment of coactivators, and might evoke different functional responses based on the interactions they favor. The natural ligand 15-deoxy prostaglandin J2 stimulated PPAR-gamma interaction with SRC-1, TIF2, TRAP220, and p300, while the synthetic PPAR-gamma ligand troglitazone, an antidiabetic thiazolidinedione drug, did not promote these interactions, indicating that other distinct coactivators may mediate the response to PPAR-gamma when it binds this ligand. In normal rodents, a high-fat diet leads to high levels and free fatty acids and PPAR-gamma activation in white adipose tissue, stimulating fat uptake, adipogenesis and obesity. PPAR-gamma activation in brown adipose tissue depends mainly on Src-1 as a coactivator and Src-1 is essential for PGC-1 alpha to act as a coactivator to stimulate thermogenesis. Regulation of energy use by PGC-1 in other tissues such as muscle may contribute to weight loss associated with cancer and increased metabolism induced by exercise. High-fat feeding and high plasma free fatty acids reduce thermogenesis in brown fat due to the greater requirement of PPAR-gamma for Src-1 than Tif2 for activation in these cells. In white adipose cells, Tif2 predominates as the PPAR-gamma coactivator, stimulating fat uptake and adipogenesis in conditions of high-fat feeding. Trap220, a component of the TRAP coactivator complex, is also required for adipogenesis. Examining the metabolic consequences of coactivator deletion, Src-1 and Tif2 specifically alter PPAR-gamma signaling. Compared to normal rodents, Mice lacking the Tif2 coactivator are resistant to obesity when fed a high-fat diet, with increased lipolysis in adipocytes and decreased fatty acid uptake in adipose tissue. A high-fat diet increases the expression of Tif2 in both brown and white adipose cells, changing the Tif2 to Src-1 ratio. This change in the ratio of coactivators favors increased adipogenesis in white adipose while it blocks thermogenesis in brown adipose cells by opposing Src-1/PGC-1 alpha dependent signaling. (This definition may be outdated - see the DesignNote.)
Role of PPAR-gamma Coactivators in Obesity and Thermogenesis
During meiosis, a single round of DNA replication is followed by two rounds of chromosome segregation, called meiosis I and meiosis II. At meiosis I, homologous chromosomes recombine and then segregate to opposite poles, while the sister chromatids segregate from each other at meoisis II. In vertebrates, immature oocytes are arrested at the PI (prophase of meiosis I). The resumption of meiosis is stimulated by progesterone, which carries the oocyte through two consecutive M-phases (MI and MII) to a second arrest at MII. The key activity driving meiotic progression is the MPF (maturation-promoting factor), a heterodimer of CDC2 (cell division cycle 2 kinase) and cyclin B. In PI-arrested oocytes, MPF is initially inactive and is activated by the dual-specificity CDC25C phosphatase as the result of new synthesis of Mos induced by progesterone. MPF activation mediates the transition from the PI arrest to MI. The subsequent decrease in MPF levels, required to exit from MI into interkinesis, is induced by a negative feedback loop, where CDC2 brings about the activation of the APC (anaphase-promoting complex), which mediates destruction of cyclin B. Re-activation of MPF for MII requires re-accumulation of high levels of cyclin B as well as the inactivation of the APC by newly synthesized Emi2 and other components of the CSF (cytostatic factor), such as cyclin E or high levels of Mos. CSF antagonizes the ubiquitin ligase activity of the APC, preventing cyclin B destruction and meiotic exit until fertilization occurs. Fertilization triggers a transient increase in cytosolic free Ca2+, which leads to CSF inactivation and cyclin B destruction through the APC. Then eggs are released from MII into the first embryonic cell cycle.
p53 Pathway for Transcriptional Regulation
Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a) is a tissue-specific coactivator that enhances the activity of many nuclear receptors and coordinates transcriptional programs important for energy metabolism and energy homeostasis. Inappropriate increases in PGC-1a activity have been linked to a number of pathological conditions including heart failure and diabetes. PGC-1a is highly expressed in metabolically active tissues including brown fat, skeletal muscle and heart. PGC-1a has been implicated in mitochondrial biogenesis in the heart and increased mitochondrial respiration in brown fat. PGC-1a is a coactivator for many factors including, CBP, Scr-1, PPARa, glucocorticoid receptor, thyroid hormone receptor, several orphan receptors, and MEF2. This pathway illustrates two of the cofactor regulatory factors, MEF2 and PPARa, and an example orphan receptor feedback inhibition loop. Glut4 is used as an example of the downstream elements leading to changes in metabolism. Ichida et al discovered the ERRa repression of PGC-1a. Their results suggest a novel mechanism of transcriptional control wherein ERR-a can function as a specific molecular repressor of PGC-1a. This suggests that other co-activators might also have specific repressors, adding another layer of combinatorial complexity in transcriptional regulation. Czubryt et al identified PGC-1a as a key target of the MEF2/HDAC regulatory pathway and demonstrated this pathway's importance in maintenance of cardiac mitochondrial function. The linking of MEF2/HDAC provides a potential explanation for the increase in mitochondrial number observed in response to CaMK signaling. (This definition may be outdated - see the DesignNote.)
Nine currently identified phosphoinositide 3-kinases (PI 3-K) constitute a subfamily of lipid kinases that catalyze the addition of a phosphate molecule on the 3-position of the inositol ring of phosphoinositides. Phosphatidylinositol (PtdIns), the precursor of all phosphoinositides (PI), constitutes less than 10% of the total lipid in eukaryotic cell membranes. Approximately 5% of cellular PI is phosphorylated at the 4-position (PtdIns-4-P), and another 5% is phosphorylated at both the 4- and 5-positions (PtdIns-4, 5-P2). However, less than 0.25% of the total inositol-containing lipids are phosphorylated at the 3-position, consistent with the idea that these lipids exert specific regulatory functions inside the cell, as opposed to a structural function. Here we have chosen to highlight a group of the phosphoinositide targets of the PI3-Ks and their downstream targets. The downstream effects of these PI-3 targets are indicated, illustrating the important role the PI3Ks have in cell function and survival. (This definition may be outdated - see the DesignNote.)
Phosphoinositides and their downstream targets
Many transcription factors play essential roles in normal development by determining the proliferation and differentiation of cells. The coordinated transcriptional control of proliferation in specific developmental cell types is crucial in multiple developmental settings. One of a family of three bicoid-related transcription factors, Pitx2 acts downstream of the extracellular signaling protein Wnt to drive proliferation of cells with specific developmental fates, including cells in the pituitary, cardiac outflow region, and muscle. Wnt binds to Frizzled, a G-protein coupled receptor, activating homologs of the Drosophila Disheveled protein. Activation of Frizzled and Disheveled inhibits the kinase GSK-3 beta, part of a protein complex in the absence of Wnt signaling, causing beta-catenin protein to accumulate in the cytoplasm. Beta-catenin is known to alter the function of transcription factors like TCF/Lef. One result of Wnt signaling is activation of the transcription factor Lef by beta-catenin, inducing Pitx2 expression. Wnt activation also changes Pitx2 from a repressor to an activator by causing transcriptional corepressors like histone deacetylase 1 (HDAC1) bound to Pitx2 to be exchanged for coactivators. With coactivators bound, Pitx2 activates transcription of genes that regulate the cell cycle, such as Cyclin D2. Different coactivators are recruited by Pitx2 and other transcription factors like Myc to the Cyclin D2 promoter, with CBP/p300 recruited first, followed by NLI/Ldb/CLIM, Tip60/TRRAP, and PBP coactivators. Many of these coactivators help to alter histone acetylation and chromatin structure as part of transcriptional activation. The activation of cell cycle genes by Pitx2 ultimately stimulates the proliferation of specific cell types with the confluence of tissue-specific gene expression, growth factor signaling and coactivator recruitment. (This definition may be outdated - see the DesignNote.)
Multi-step Regulation of Transcription by Pitx2
The PML nuclear bodies are ring-shaped nuclear substructures associated with the regulation of transcription, transformation, cell growth, and apoptosis and are characterized by the presence of the protein PML. The activities of PML as a tumor suppressor and apoptosis inducing factor are exerted through the numerous proteins it interacts with in the PML-nuclear bodies including the tumor suppressor p53. DNA damage-induced activation of p53-dependent apoptosis requires PML. PML acts as a coactivator for p53 and increases acetylation of p53 by the transcriptional coactivator CBP. This acetylation of p53 is reversed by the deacetylase SirT1, the human homolog of the yeast gene Sir2, and this deacetylation opposes the transcriptional activation of p53. The tumor suppressor Rb also interacts with the PML nuclear body, increasing transcriptional repression of genes involved in cell cycle progression, suggesting that PML may affect cellular transformation through more than one mechanism. PML interacts directly with Ubc9, which modifies PML through the attachment of the ubiquitin-like peptide Sumo-1. Sumo-1 modification of PML is not necessary for the nuclear bodies to form, but may affect the recruitment of proteins that interact with PML. PML is involved in non-p53 mediated apoptotic pathways, such as DAXX-mediated apoptosis induced by Fas and TNF and regulates the transcriptional repressor activity of Daxx. The sequestration of Daxx by the PML nuclear bodies relieves the repression of other transcription factors like Pax3 by Daxx. Tumor suppression by PML may in general involve the formation of specific regulatory transcription complexes, including those with DAXX, p53 and CBP. Factors that affect the assembly of PML into the PML nuclear bodies affect the proliferation and transformation of cells. Viral early proteins can interact with PML to disrupt the nuclear bodies, allowing increased proliferation of cells and reduced apoptosis, good conditions for DNA virus infection. Another factor that disrupts the formation of PML nuclear bodies is a translocation between the PML and RAR-alpha genes found in acute promyelocytic leukemia (APL) patients. Binding of retinoic acid to the RAR-alpha steroid hormone receptor activates transcription of retinoic-acid responsive genes. The translocation found in APL patients creates two chimeric proteins, RARalpha-PML and PML-RARalpha. Retinoic acid given to APL patients causes the reappearance of nuclear bodies, and the reversal of cellular transformation, affecting a cure for these patients. (This definition may be outdated - see the DesignNote.)
Regulation of transcriptional activity by PML
The most recognized mechanism by which peroxisome proliferators regulate gene expression is through a PPAR/RXR heterodimeric complex binding to a peroxisome proliferator-response element (PPRE) (classical mechanism). However, there is the possibility of several variations on this theme: 1) the peroxisome proliferator interacts with PPAR that preexists as a DNA complex with associated corepressors proteins. The interaction with ligand causes release of the corepressor and association with a coactivator, resulting in the classical mechanism. 2) the peroxisome proliferator interacts with PPAR as a soluble member of the nucleus. The binding of ligand results in RXR heterodimerization, DNA binding and coactivator recruitment. 3) in this scenario, PPAR exists in the cytosol, perhaps complexed to heat shock protein 90 and/or other chaperones. Binding of peroxisome proliferator causes a conformational change and translocation into the nucleus. Scenarios 4 and 5 require regulation of gene expression via non-classical mechanisms: 4) PPAR is capable of interacting with, and forming DNA binding heterodimers with, several nuclear receptors including the thyroid hormone receptor. The binding site for this non-RXR heterodimer need not be the classic DR-1 motif found in the PPRE. 5) PPAR may participate in the regulation of gene expression without binding to DNA. By association with transcription factors such as c-jun or p65, PPAR diminishes the ability of AP1 or NFB to bind to their cognate DNA sequences, respectively. Also shown in this scheme are two means to modify the peroxisome proliferator response. Most importantly, growth factor signaling has a pronounced affect on PPAR via post-translational modification. PPAR is a phosphoprotein and its activity is affected by insulin. Several kinase pathways affect PPARa's activity, although the specific kinases and phosphorylation sites have not been conclusively determined. (This definition may be outdated - see the DesignNote.)
Mechanism of Gene Regulation by Peroxisome Proliferators via PPARa(alpha)
A sequence of biological or biochemical events that are involved in the manifestation of the activity of a protein.
Positive Regulation of Protein Activity Pathway
Blood coagulation takes place in 3 essential phases. The first phase is the activation of a prothrombin activator complex. The second phase is the activation of prothrombin. The third stage is clot formation as a result of fibrinogen cleavage by activated thrombin. The prothrombin activation complex is formed by two pathways each of which results in a different form of the prothrombin activator. The extrinsic mechanism of prothrombin activator formation begins with trauma to vascular walls or extravascular tissues. The damaged tissue releases tissue thromboplastin also known as tissue factor (TF). The formation of a clot by this mechanism usually takes as little as 15 seconds. This cascade is initiated by the activation of factor X by TF and factor VII. Activated factor X combined with factor V, factor VII and TF constitutes the prothrombin activator. Calcium (Ca++) is required for each of these steps. The prothrombin activator in the extrinsic pathway is very similar to the activator in the intrinsic pathway. Antithrombin III inhibits the activity of thrombin and also the step leading to the activation of factor X. Antithrombin III is a hundred to a thousand times more effective when bound by heparin. Protein C is activated by thrombin and with the Protein S cofactor provides a strong negative feedback in this phase of clot formation. (This definition may be outdated - see the DesignNote.)
Extrinsic Prothrombin Activation Pathway
Blood coagulation or clotting takes place in 3 essential phases. The first phase is the activation of a prothrombin activator complex. The second phase is the activation of prothrombin. The third stage is clot formation as a result of fibrinogen cleavage by activated thrombin. The prothrombin activation complex is formed by two pathways each of which results in a different form of the prothrombin activator. The intrinsic mechanism of prothrombin activator formation begins with trauma to the blood or exposure of blood to collagen in a traumatized vessel wall. This usually also results in damage to fragile platelets. The formation of a clot by this mechanism usually takes 1 to 6 minutes. This cascade begins with the activation of factor XII and the release of platelet factor 3 (PF3) from damaged platelets. Activated factor XII cleaves and actives factor XI and prekallikrein (PK). Factor XII is also activated by activated prekallikrein (aPK) in an internal amplification loop. Calcium (Ca++) is required for the initial three steps. The prothrombin activator in the intrinsic pathway is very similar to the activator in the extrinsic pathway. Antithrombin III inhibits the activity of thrombin and also two of the steps in the formation of the activator. Protein C is activated by thrombin and with the Protein S cofactor provides a strong negative feedback in this phase of clot formation. (This definition may be outdated - see the DesignNote.)
Intrinsic Prothrombin Activation Pathway
The binding of b-arrestins to agonist-occupied GPCRs triggers the assembly of a MAP kinase activation complex using b-arrestin as a scaffold, with subsequent activation of a b-arrestin-bound pool of ERK1/2. The receptor-b-arrestin-ERK complexes are localized to endosomal vesicles, and their formation does not result in nuclear translocation of activated ERK1/2 or stimulation of cell proliferation. The function of b-arrestin-bound ERK1/2 is presently unknown. Activation of ERK1/2 by b-arrestin scaffolds may favor the phosphorylation of plasma membrane, cytosolic, or cytoskeletal ERK1/2 substrates, or it may lead to transcriptional activation through the ERK-dependent activation of other kinases. The model depicts b-arrestin scaffolding of the ERK1/2 MAP kinase cascade, based upon data obtained with the protease-activated PAR2 and angiotensin AT1a receptors. A similar mechanism has been proposed for regulation of the JNK3 MAP kinase cascade by AT1a receptors. (This definition may be outdated - see the DesignNote.)
Role of beta-arrestins in the activation and targeting of MAP kinases
Similar to other nuclear hormone receptors, PPAR acts as a ligand activated transcription factor. Upon binding fatty acids or hypolipidemic drugs, PPARa interacts with RXR and regulates the expression of target genes. These genes are involved in the catabolism of fatty acids. Conversely, PPARg is activated by prostaglandins, leukotrienes, and anti-diabetic thiazolidinediones and affects the expression of genes involved in the storage of the fatty acids. PPARb is only weakly activated by fatty acids, prostaglandins, and leukotrienes and has no known physiologically relevant ligand. However, data from PPARb null mice suggest PPARb does serve a role in fatty acid metabolism and perhaps in skin proliferation and cancer. (This definition may be outdated - see the DesignNote.)
Basic mechanism of action of PPARa, PPARb(d) and PPARg and effects on gene expression
G-protein coupled receptors (GPCRs) comprise one of the largest gene families of signaling proteins. Residing in the plasma membrane with seven transmembrane domains, GPCRs respond to extracellular stimuli that include catecholamine neurotransmitters, neuropeptides, larger protein hormones, lipids, nucleotides and other biological molecules. When a GPCR binds its extracellular ligand, it interacts with a G-protein to transduce a signal across the membrane into the cellular interior. G-proteins are a heterotrimeric complex containing a Ga subunit with GTPase activity, as well as b and g subunits. Ga can exist in an active state and an inactive state. Ga in the off state has GDP bound and does not activate downstream signaling molecules. When a GPCR is activated by ligand, it stimulates Ga subunits to bind GTP instead of GDP and become active, dissociating from the receptor and from the b/g subunits to activate downstream signaling factors like the enzyme adenylyl cyclase that synthesizes cyclic-AMP (cAMP) from ATP. Ga turns itself back off again with its intrinsic GTPase activity, hydrolyzing GTP to GDP to become inactive. Activated G proteins interact with downstream signaling factors to alter the production of second messenger signaling molecules like inositolphosphates, calcium and cAMP. GPCRs that activate the Gi class of Ga subunits inhibit cAMP production and GPCRs that activate the Gs class of Ga subunits activate cAMP production. cAMP in turn activates the cAMP-dependent protein kinase, protein kinase A (PKA). PKA is a tetramer composed of catalytic subunits and regulatory subunits that repress the catalytic units when they are bound together. The regulatory subunits bind cAMP when it is present and release the catalytic units, releasing their inhibition of the catalytic subunits as well. The catalytic subunits of PKA when they are released and active phosphorylate target substrate proteins on serine and threonine residues, altering the activity of the modified protein and creating a cellular response to the extracellular stimulus acting on the GPCR. The PKA activation pathway is an example of a signal transduction cascade, in which tying several signaling events together amplifies the original signal in the cell. For each GPCR molecule that is activated, many G-proteins can be activated, and each active G protein can synthesize many cAMP molecules, continuing the cascade to PKA and further downstream. One of the roles of PKA that was first studied was the regulation of glycogen metabolism. When epinephrine binds to its receptor in liver, it activates cAMP production and PKA activation. One substrate of PKA is phosphorylase kinase, which is activated by phosphorylation and is part of the signaling cascade that mobilizes glycogen into glucose to provide energy that fuels the response to epinephrine. Another substrate of PKA is glycogen synthase, which is turned off by PKA phosphorylation. PKA also participates in many other signaling pathways, integrating the key signaling intermediary cAMP with a wide range of biological responses. (This definition may be outdated - see the DesignNote.)
Activation of cAMP-dependent protein kinase, PKA
G-protein coupled receptors (GPCRs) transduce a variety of signals from the extracellular environment across the plasma membrane. One of the common signaling systems utilized by GPCRs activates protein kinase C (PKC), a ubiquitous family of serine/threonine protein kinases. The pathway leading to PKC activation starts with a class of GPCRs that interact with and activate Gq G-proteins when the receptor has agonist ligand bound. GPCRs that act through Gq include some muscarinic acetylcholine receptors, many peptide receptors, and the 5-HT2 serotonin receptors. Activated Gq with GTP bound activates its downstream target phospholipase C (PLC) to hydrolyze the membrane lipid PIP2, producing IP3 and diacylglycerol (DAG). IP3 is water-soluble and diffuses through the cytoplasm to the ER, where it binds to and opens a calcium channel, releasing calcium stores from inside the ER into the cytoplasm. Calcium alters many cellular processes, in part by binding to regulatory proteins such as calmodulin and calcineurin. The interaction of both DAG and calcium with PKC activates its kinase activity and the phosphorylation of many different protein targets alters their activity. The involvement of PKC in cellular proliferation and the cell cycle is indicated by the activity of tumor promoters like phorbol esters as PKC activators. (This definition may be outdated - see the DesignNote.)
Activation of PKC through G protein coupled receptor
Progression through the cell cycle is accompanied by activation of the proto-oncogene c-Src, a protein tyrosine kinase. Overexpression of Src leads to tyrosine phosphorylation of multiple protein substrates and cellular transformation. During interphase the Src protein folds back upon itself to stay in the inactive state, with a phosphotyrosine residue in one domain at Tyrosine 529 bound by an SH2 domain in the same protein. Activation of c-Src involves protein-tyrosine phosphatase alpha (PTP-alpha, or RPTP-alpha), a transmembrane protein with a cytoplasmic phosphatase domain. A variety of evidence has indicated that PTP-alpha dephosphorylates c-Src at Tyr529, allowing Src to open up and become activated, and that this activation occurs in association with mitosis. To activate Src, PTP-alpha must first open up the folded Src through binding itself to the phosphorylated Src domain, a process blocked by binding of Grb-2 to PTP-alpha at phosphorylated Tyr789. PTP-alpha phosphorylated at Tyr789 also binds to the Src SH2 domain, causing the Src structure to open at Src Tyr529 to become available for dephosphorylation. During mitosis the mitotic kinase Cdc-2 phosphorylates Src, along with other cellular substrates, and in so doing makes Src more prone to PTP-alpha dephosphorylation and activation. The activity of PTP-alpha toward Src is also regulated by phosphorylation of PTP-alpha by protein kinase C at serines 180 and 204, releasing the inhibition of PTP-alpha by Grb-2. In the normal cell cycle, Src activity is down-regulated after cell division through dephosphorylation by protein phosphatases and phosphorylation by Csk (C-terminal src kinase) and PTP-alpha dephosphorylation returns the cycle to its interphase condition. The regulation of Src activity during mitosis demonstrates how protein phosphorylation can shift the delicate equilibrium of molecular interactions and cellular responses. (This definition may be outdated - see the DesignNote.)
Activation of Src by Protein-tyrosine phosphatase alpha
Serum response factor (SRF) is a transcription factor, which binds to a serum response element (SRE) associated with a variety of genes including immediate early genes such as c-fos, fosB, junB, egr-1 and -2, neuronal genes such as nurr1 and nur77, and muscle genes such as actins and myosins. By regulating expression of these genes, SRF controls cell growth and differentiation, neuronal transmission, as well as muscle development and function. SRF can be activated by serum, lysophosphatidic acid (LPA), lipopolysaccharide (LPS), 12-O-tetradecanoylphorbol-13-acetate (TPA), cytokines, tumor necrosis factor-alpha (TNFalpha), agents that increase intracellular Ca2+, T-cell virus1 activator protein, hepatitis B virus activator proteins pX, activated oncogenes and protooncogenes, and extracellular stimuli such as antioxidant and UV light. In serum-starved cells, MAL is predominantly cytoplasmic where it is sequestered by actin monomers. Upon serum stimulation, Rho becomes active and, through its interaction with ROCK and mDia1, causes an accumulation of F-actin and a commensurate decrease in the level of G-actin. As a consequence, MAL is no longer sequestered and is free to translocate to the nucleus where it associates with SRF and activates SRE-mediated gene expression. (This definition may be outdated - see the DesignNote.)
Role of MAL in Rho-Mediated Activation of SRF
Sumoylation by RanBP2 regulates transcriptional repression
RANBP2-Mediated Sumoylation Transcription Regulation Pathway
Regulation of cytoplasmic and nuclear SMAD2/3 signaling
Regulation of Cytoplasmic and Nuclear SMAD2/3 Signaling Pathway
Regulation of Nuclear SMAD2/3 Signaling Pathway
The rel/NF-kB family of transcription factors regulates the activity of genes involved in the immune response, hematopoiesis, and inflammation. NF-kB is a complex of two proteins, p65 (rel) and p50. NF-kB is held inactive in the cytoplasm by I-kB, until signals initiated by TNF or several other factors lead to the phosphorylation and degradation of I-kB and the subsequent release of NF-kB to bind DNA and activate genes. The activation of transcription by NF-kB requires transcriptional coactivators such as p300 and CBP to interact with the rest of the transcriptional apparatus. These coactivators posses enzyme activity, acting to catalyze the posttranslational acetylation of proteins on lysine groups. Acetylation of histones has been known for some time to occur in transcriptionally active chromatin regions. Histone deacetylase (HDAC) enzymes reverse the acetylation of histones. As with other signals, there an off-switch as well as an on-switch for NF-kB activation. The signal to terminate gene activation by NF-kB involves regulation of NF-kB acetylation. P300 and CBP recruited by NF-kB to the transcriptional complex acetylate RelA. Acetylated NF-kB proteins do not interact with I-kB and so continue stimulating transcription. To turn off NF-kB dependent transcription, the histone deacetylase HDAC3 binds to and deacetylates RelA, which then interacts strongly with I-kB once again and is inactivated. The reformed complex of NF-kB and I-kB is exported from the nucleus to the cytoplasm where it replenishes the pool of inactive NF-kB awaiting the next activation signal. The activity of other proteins may also be regulated by acetylation in a similar manner. (This definition may be outdated - see the DesignNote.)
Acetylation and Deacetylation of RelA in The Nucleus
The transcriptional regulator CREM plays a key role in spermatogenesis, acting as a central transcription factor triggering a cascade of transcriptional activation of post-meiotic genes involved in this process such as calspermin and testis angiotensin-converting enzyme. The key role of CREM in sperm formation is demonstrated by the male sterility of mice lacking CREM, the failure of spermatids to develop into mature sperm, and a lack of post-meiotic gene expression in these animals. Prior to meiosis, splice variants of CREM act as antagonists of cAMP-dependent transcriptional activation, but coordinate with spermatogenesis, the potent transcriptional activator CREM tau splice variant is highly expressed. In other tissues CREM activates genes in response to cAMP through phosphorylation and CBP association, but transcriptional activation by CREM in male germ cells is CBP independent. Stimulation of spermatids with follicle-stimulating hormone (FSH) induces cAMP formation, and the association of CREM with the coactivator ACT, although the mechanism regulating the interaction of CREM with ACT is not yet known. A two-hybrid screen looking for ACT interacting factors revealed another surprising component regulating CREM, the kinesin Kif17b. Kinesins are molecular motors that interact with microtubules to transport organelles and other material within the cell. Kif17b is actively exported from the nucleus in a Crm1-dependent manner, so when it is bound to ACT the export of Kif17b excludes CREM-ACT from the nucleus and blocks transcriptional activation by this complex. The mechanism regulating the interaction of Kif17b with ACT to drive CREM activation is not yet known. Although the regulation of transcription by a kinesin is surprising, a functional connection between cytoskeletal elements and transcriptional regulation is not unprecedented, as demonstrated by the transcription factor MIZ-1 that regulates transcription in response to changes in microtubule structure. (This definition may be outdated - see the DesignNote.)
Stathmin is a ubiquitous, cytosolic 19-kDa protein, that is phosphorylated on up to four sites in response to many regulatory signals within cells. Its molecular characterization indicates a functional organization including an N-terminal regulatory domain that bears the phosphorylation sites linked to a putative alpha-helical binding domain predicted to participate in coiled-coil, protein-protein interactions. In addition to the protein kinases that phosphorylate Stathmin such as CaMK, MAPK, p34cdc2, PKA, a few other proteins have been suggested to interact with stathmin in vivo. One of them was identified as BiP, a member of the hsp70 heat-shock protein family. Another is a previously unidentified, putative serine/threonine kinase, KIS, which might be regulated by stathmin or, more likely, be part of the kinases controlling its phosphorylation state. Finally, proteins CC1 and CC2, predicted to form alpha-helices participating in coiled-coil interacting structures. It has been suggest that the action of antimicrotubule drugs can be affected by stathmin in at least two ways: (a) altered drug binding; and (b) growth arrest at the G2 to M boundary. Mutant p53 breast cancers exhibiting high levels of stathmin may be resistant to antimicrotubule agents. (This definition may be outdated - see the DesignNote.)
Stathmin and breast cancer resistance to antimicrotubule agents
Covalent attachment of one eukaryotic protein to another is a prominent posttranslational modification and Ubiquitin is the most familiar of the protein modifiers. Recently a new group of ubiquitin-like (Ubl) proteins have come to light. One of the most intriguing of them is SUMO (small ubiquitin-like modifier, 12kDa) also known as Sentrin. SUMO family has been described in vertebrates: SUMO-1 and the closest homologs SUMO-2 and SUMO-3. SUMO have been shown to bind and regulate mammalian SP-RINGs (such as Mdm2, PIAS and PML), RanGAP1, RanBP2, p53, p73, HIPK2, TEL, c-Jun, CtBP, Fas, Daxx, TNFRI, Topo-I, Topo-II, WRN, Sp100, IkB-alpha, Androgen receptor (AR), GLUT1/4, Drosophila Ttk69, Dorsal, CaMK, yeast Septins, and viral CMV-IE1/2, EBV-BZLF1, HPV/BPV-E1. In the case of the transcription co-repressor CtBP, which can be recruited to the target promoter via interaction with a conserved PxDLS motif in the interacting repressor, CtBP SUMOylation profoundly affected its subcellular localization. SUMOylation occurred at a single Lys residue, Lys428, of CtBP1. Mutating Lys428 into Arg (K428R) shifted CtBP1 from the nucleus to the cytoplasm, while it had little effect on its interaction with the PxDLS motif. The K428R mutation also abolished the ability of CtBP1 to repress the E-cadherin promoter activity. Consistent with the known inhibitory effect of nNOS on the nuclear accumulation of CtBP1, PDZ domain of nNOS inhibits the SUMOylation of CtBP1. The current data indicates that SUMOylation can regulate CtBP1-dependent transcriptional repression. (This definition may be outdated - see the DesignNote.)
SUMOylation as a mechanism to modulate CtBP-dependent gene responses
Sumoylation in Modulation of CtBP-Dependent Gene Response Pathway
Like ubiquitin, SUMO (small ubiquitin-related modifier) proteins are small protein tags that are conjugated to proteins to modify their function. The ubiquitin system tags proteins for degradation by the proteasome but SUMO conjugation has a range of other functions, stabilizing some proteins and altering their subcellular localization. Sumoylation may also influence ubiquitination and protein stability indirectly. Three different SUMO proteins are conjugated to proteins, SUMO-1, SUMO-2 and SUMO-3. The SUMO-2 and SUMO-3 genes are closely related, with 86% sequence identity while SUMO-1 is less closely related with about 50% sequence identity with SUMO-2 and SUMO-3. These SUMO proteins also have distinct functions, with SUMO-1 conjugated to proteins as a monomer, while SUMO-2 and SUMO-3 are conjugated to proteins as higher molecular weight polymers with SUMO-1 terminating further SUMO addition. SUMO proteins are first activated by adenylation by one enzyme complex (SAE1/SAE2), then transferred to Ubc-9 and finally to the terminal amino group of a lysine side chain in target proteins. The same conjugation system appears to work for all three SUMO proteins. One target of SUMO modification is proteins involved in formation of the PML nuclear bodies, promoting the stability of these structures and perhaps altering their role in transcriptional regulation, cellular proliferation and anti-viral responses. Other targets of SUMO addition include DAXX, p53 and ran-Gap. The transcriptional activation by p53 is increased by SUMO addition. The localization of DAXX to the PML nuclear bodies and the localization of ran-Gap to the nuclear pores are also regulated by SUMO addition. The activity of several transcription factors is altered by sumoylation, including C/EBP proteins, c-Myb, glucocorticoid receptor, androgen receptor, and progesterone receptor. PIAS is a protein that modulates the activity of many different transcription factors perhaps by acting itself as a sumo ligase. Sumoylation of topoisomerase I alters its localization in the nucleus, and histone deacetylase enzymes are targets of this system. Viral proteins are targets of sumoylation, suggesting that infection and anti-viral cellular defenses may be affected by this system. Sumoylation may also alter the stability of proteins with polyglutamine repeats involved in neurodegenerative disorders, adding further to the important and diverse roles of this protein modification system. (This definition may be outdated - see the DesignNote.)
Current data indicates that nuclear pore complex (NPC) RanBP2 (SUMO E3 ligase) protein sumoylates Mdm2 and HDAC proteins during nuclear translocation. A sumoylation-deficient HDAC showed reduced deacetylation activity and suggests that sumoylation may be an important regulatory mechanism for the control of transcriptional repression. (This definition may be outdated - see the DesignNote.)
Sumoylation Regulation of Transcriptional Repression Pathway
Telomerase is an enzyme that replicates the terminal sequences of eukaryotic chromosomes, namely the telomeres. Cells that have an unlimited replicative capacity, such as male germ cells and the majority of human cancers, have high levels of telomerase activity. The level and frequency of telomerase activity in more than 85% of all cancers highlights the critical role telomerase plays in tumor progression. Telomerase activation is the most common general marker for a cancer cell to date making it an attractive target for new cancer diagnostics and therapeutics. Human telomerase activity can be reconstituted in vitro by the essential RNA subunit, hTERC, and the catalytic protein component coded for by the hTERT gene. Both the human telomerase reverse transcriptase gene (hTERT) and the telomerase RNA gene (hTERC) are controlled at least in part at the transcriptional level. The hTERC gene is expressed at high levels in cancer cells, and is absent or at low levels in some normal tissues. (This definition may be outdated - see the DesignNote.)
Overview of telomerase RNA component gene hTerc Transcriptional Regulation
Telomerase is an enzyme that replicates the terminal sequences of eukaryotic chromosomes, namely the telomeres. Cells that have an unlimited replicative capacity, such as male germ cells and the majority of human cancers, have high levels of telomerase activity. The level and frequency of telomerase activity in more than 85% of all cancers highlights the critical role telomerase plays in tumor progression. Telomerase activation is the most common general marker for a cancer cell to date making it an attractive target for new cancer diagnostics and therapeutics. Human telomerase activity can be reconstituted in vitro by the essential RNA subunit, hTERC, and the catalytic protein component coded for by the hTERT gene. Both the human telomerase reverse transcriptase gene (hTERT) and the telomerase RNA gene (hTERC) are controlled at least in part at the transcriptional level. The hTERT gene is expressed at low levels in cancer cells and is generally undetectable in normal cells. (This definition may be outdated - see the DesignNote.)
Overview of telomerase protein component gene hTert Transcriptional Regulation
CD4+ helper T cells differentiate into distinct subtypes, Th1 and Th2. Th2 cells are involved in the response to extracellular helminth parasites and allergic responses and secrete a distinct set of cytokines including IL-4, IL-5 and IL-13. The development and differentiation of T cells is influenced by many factors, including transcription factors such as GATA-3, a transcription factor associated with induction of Th2 cells. Factors that increase cAMP levels in Th2 cells activate p38 kinase, which phosphorylates and activates GATA-3 independently of PKA. Cells expressing GATA-3 develop the profile of Th2 cells, secreting IL-4, IL-5 and IL-13. These cytokines are found in a gene cluster together and are regulated coordinately by GATA-3. Binding of GATA-3 in the regulatory regions of these genes alters chromatin structure, increasing accessibility to other transcription factors. Activation of the T cell receptor through interaction with antigen on antigen presenting cells activates NFAT and other transcription factors that cooperate with GATA-3 in inducing Th2 cell differentiation. Dominant negative GATA-3 can repress the secretion of these cytokines and block the airway inflammation that causes asthma. Blocking GATA-3 action such as through antisense treatment has been suggested as a therapeutic strategy to treat asthma. GATA-3 has also been implicated in developmental processes such as the development of the inner ear. (This definition may be outdated - see the DesignNote.)
GATA3 participate in activating the Th2 cytokine genes expression
Epithelial tight junctions (TJs) are composed of at least three types of transmembrane protein -occludin, claudin and junctional adhesion molecules (JAMs)- and a cytoplasmic 'plaque' consisting of many different proteins that form large complexes. The transmembrane proteins mediate cell adhesion and are thought to constitute the intramembrane and paracellular diffusion barriers. The cytoplasmic 'plaque' contains three major multi-protein complexes consisting largely of scaffolding proteins, the ZO protein complex, the CRB3-Pals1-PATJ complex and the PAR-3-aPKC-PAR-6 complex. The ZO protein complex appears to organize the transmembrane proteins and couple them to other cytoplasmic proteins and to actin microfilaments. Two evolutionarily conserved protein complexes, the CRB3 and PAR complexes are involved in the establishment and maintenance of epithelial cell polarity. Besides these three protein complexes which seem to be constitutively associated at TJs, a number of proteins with different functions has been identified at TJs. These include additional scaffolding proteins like MUPP1 and MAGI-1, adaptor proteins, transcription regulators and RNA processing factors, regulatory proteins like small GTPases and G-proteins, kinases and phosphatases, and heat shock proteins. These are proposed to be involved in junction assembly, barrier regulation, gene transcription, and perhaps other, presently undefined pathways.
An elaboration of the sequence of biological or biochemical events that result in the transport of molecules from one physiological space to another.
The ATP-binding cassette (ABC) transporters form one of the largest known protein families and are widespread in bacteria, archaea, and eukaryotes. They couple ATP hydrolysis to active transport of a wide variety of substrates such as ions, sugars, lipids, sterols, peptides, proteins, and drugs. The structure of a prokaryotic ABC transporter usually consists of three components; typically two integral membrane proteins each having six transmembrane segments, two peripheral proteins that bind and hydrolyze ATP, and a periplasmic (or lipoprotein) substrate-binding protein. Many of the genes for the three components form operons as in fact observed in many bacterial and archaeal genomes. On the other hand, in a typical eukaryotic ABC transporter, the membrane spanning protein and the ATP-binding protein are fused, forming a multi-domain protein with the membrane-spanning domain (MSD) and the nucleotide-binding domain (NBD).
ATP-Binding Cassette Transporter Pathway
Gram-negative bacteria secrete a wide range of proteins whose functions include biogenesis of organelles, such as pilli and flagella, nutrient acquisition, virulence, and efflux of drugs and other toxins. Six distinct secretion systems have been shown to mediate protein export through the inner and outer membranes of Gram-negative bacteria. These pathways are highly conserved throughout the Gram-negative bacterial species. In Gram-positive bacteria, secreted proteins are commonly translocated across the single membrane by the Sec pathway or the two-arginine (Tat) pathway.
Phagocytosis plays an essential role in host-defense mechanisms through the uptake and destruction of infectious pathogens. Specialized cell types including macrophages, neutrophils, and monocytes take part in this process in higher organisms. After opsinization with antibodies (IgG), foreign extracellular materials are recognized by Fc gamma receptors. Cross-linking of Fc gamma receptors initiates a variety of signals mediated by tyrosine phosphorylation of multiple proteins, which lead through the actin cytoskeleton rearrangements and membrane remodeling to the formation of phagosomes. Nascent phagosomes undergo a process of maturation that involves fusion with lysosomes. The acquisition of lysosomal proteases and release of reactive oxygen species are crucial for digestion of engulfed materials in phagosomes.
Fc Gamma Receptor-Mediated Phagocytosis Pathway
Cancer cells resistant to a diverse set of hydrophobic drugs are known as MDR cells (multidrug-resistant). Large membrane proteins overproduced in MDR cells, belong to a family of transport P-glycoproteins known as ATP-binding cassette transporter proteins (ABC-ATPases). These proteins were initially thought to affect the permeability of cells to drugs, but they were later found to be pumps that remove drugs from cells at the cost of ATP hydrolysis. There are seven major families of ABC(ATP-binding cassette) proteins, two of them are shown on this pathway, MDR/TAP (Multi-Drug Resistance) and MRP (Multi-Drug Resistance Related Proteins). Members of the MDR/TAP subfamily are involved in multi-drug resistance as well as antigen presentation. Additional factors involved in detoxification are the P450 cytochromes (CYPs), glutathione-S-transferase (GST). Lack of MDR3 can cause a form of Progressive Familial Intrahepatic Cholestasis (PFIC), a heterogeneous group of autosomal recessive liver disorders, characterized by early onset of cholestasis that progresses to cirrhosis and liver failure before adulthood. (This definition may be outdated - see the DesignNote.)
Phagocytosis is the process of taking in relatively large particles by a cell, and is a central mechanism in the tissue remodeling, inflammation, and defense against infectious agents. A phagosome is formed when the specific receptors on the phagocyte surface recognize ligands on the particle surface. After formation, nascent phagosomes progressively acquire digestive characteristics. This maturation of phagosomes involves regulated interaction with the other membrane organelles, including recycling endosomes, late endosomes and lysosomes. The fusion of phagosomes and lysosomes releases toxic products that kill most bacteria and degrade them into fragments. However, some bacteria have strategies to escape the bactericidal mechanisms associated with phagocytosis and survive within host phagocytes.
A representation of the sequence of biological or biochemical events that occur as a protein is cycled between the plasma membrane and endosomal vesicles.
The neuregulins comprise a subfamily of at least four epidermal growth factor (EGF)-like growth factors that influence a variety of cellular events, including proliferation, differentiation, migration, survival, and fate. The most thoroughly examined neuregulin, neu differentiation factor NDF (AKA: neuregulin-1; NRG1; also heregulin, glial growth factor, or acetylcholine receptor-inducing activity), has been shown to play essential roles in the development of cardiac and neural tissues and also has been shown to play a role in the postsynaptic development of the neuromuscular junction. The neuregulins bind to ErbB3 or ErbB4 and can activate the ErbB2 receptor through a heterodimerization mechanism. Heterodimers of ErbB3 and ErbB2, which has no direct ligand, are potent in causing cell transformation. Controlled levels of signaling through ErbB and other growth factor receptors are maintained by keeping a relatively limited amount of receptors at the cell surface. Receptor overexpression can lead to disease states such as the genesis or progression of tumors. Hence, mechanisms must exist for localizing and maintaining a precise concentration of growth factor receptors at the site of signal reception. ErbB2, ErbB3, and ErbB4 are somewhat unique among studied receptor tyrosine kinases in that they exhibit impaired ligand-induced internalization, down-regulation, and degradation. In fact, the rate of degradation is dependent on factors that appear to act independent of ligand binding. Nrdp-1 (Neuregulin receptor degradation protein-1) is one such protein. Ndrp-1 is an E3 ubiquitin ligase that tags ErbB3 for degradation in non-lysosomal compartments. The cycling of ErbB1 is similar to that of EGF receptor and is included for contrast. (This definition may be outdated - see the DesignNote.)
Neuroregulin receptor degradation protein-1 Controls ErbB3 receptor recycling
Gamma-amino butyric acid (GABA) is an inhibitory neurotransmitter that acts at synapses through binding to ligand-gated ion channels, the GABA receptors. Clustering of the GABA-A receptor chloride channel alters receptor pharmacology on the cell surface and reduced clustering of the GABA receptor is associated with anxiety. GABA-A interacts with several proteins that modulate its clustering, endocytosis, and recycling or degradation. Plic-1 is a ubiquitin-like protein that binds to GABA-A receptors and causes them to accumulate at inhibitory synapses. Gephyrin interacts with the cytoplasmic domain of GABA-A, and with microtubules, bringing receptors together in plasma microdomains. Curiously, Gephyrin appears to be a bifunctional protein, with a domain involved in molybdenum metabolism. Another protein interacting with the GABA-A receptor is GABARAP, a microtubule-associated protein. Anchoring of the GABA-A receptor to GABARAP helps to cluster the receptor at the synaptic termini and to mediate fast synaptic transmission. GABARAP may mediate interaction of gephyrin with the GABA-A receptor and gephyrin may stabilize clusters by forming multimeric structures. GABARAP and gephyrin may play more of a role in receptor sorting and transport to the cell surface than in anchoring to the cytoplasm, since at inhibitory synapses GABARAP appears to associate with transport vesicles rather than the cell surface. The association of GABARAP with NSF (N-ethyl maleimide sensitive factor), a protein involved in intracellular vesicle transport, supports this hypothesis. (This definition may be outdated - see the DesignNote.)
Gamma-aminobutyric Acid Receptor Life Cycle
Homologous desensitization of GPCRs results from the binding of b-arrestins (b-arr) to agonist -occupied receptors following phosphorylation of the receptor by GRKs. b-arrestin binding sterically precludes coupling between the receptor and heterotrimeric G proteins, leading to termination of signaling by G proteins effectors. Receptor-bound b-arrestins also act as adapter proteins, binding to components of the clathrin endocytic machinery including clathrin, b2-adaptin (AP-2). Receptor sequestration reflects the dynamin (Dyn)-dependent endocytosis of GPCRs via clathrin-coated pits. Once internalized, GPCRs exhibit two distinct patterns of b-arrestin interaction. Class A GPCRs, for example the b2 adrenergic receptor, rapidly dissociate from b-arrestin upon internalization. These receptors are trafficked to an acidified endosomal compartment, wherein the ligand is dissociated and the receptor dephosphorylated by a GPCR-specific protein phosphatase PP2A isoform, and are subsequently recycled to the plasma membrane. Class B receptors, for example the angiotensin II AT1a receptor, form stable receptor-b-arrestin complexes. These receptors accumulate in endocytic vesicles and are either targeted for degradation or slowly recycled to the membrane via as yet poorly defined routes. (This definition may be outdated - see the DesignNote.)
Ran is a member of the Ras family of small GTPases. Ran is an important component of many crucial nucleocytoplasmic transport pathways. The cycling of Ran is controlled by the RanGTP-RanGDP gradient established by the Ran Guanine nucleotide exchange Factor (RanGEF) RCC1 and the Ran GTPase-activating Protein (RanGAP). These two proteins combine to create a Ran gradient where RanGDP is predominantly cytoplasmic. RCC1 binds to chromatin and so RanGTP is found associated with DNA. RCC1 dissociated GDP from Ran and allows GTP to be bound. As Ran leaves the nucleus the two Ran binding proteins, RanBP1 and RanBP2 cooperate with RanGAP to induce GTP hydrolysis of Ran. There are several nuclear import factors that use the Ran gradient as part of their translocation mechanism. (This definition may be outdated - see the DesignNote.)
Cycling of Ran in nucleocytoplasmic transport
Protein export is the active transport of proteins from the cytoplasm to the exterior of the cell, or to the periplasmic compartment in Gram-negative bacteria. The sec dependent pathway is the general protein export system that transports newly synthesized proteins into or across the cell membrane. The translocation channel is formed from a conserved trimeric membrane protein complex, called the Sec61/SecY complex. The twin-arginine translocation (Tat) pathway is another protein transport system that transports folded proteins in bacteria, archaea, and chloroplasts. Many Tat systems comprise three functionally different membrane proteins, TatA, TatB, and TatC, but TatA and TatE seem to have overlapping functions, with TatA having by far the more important role.
Nuclear pore complexes (NPCs) are large proteinaceous assemblies that provide the only known portals for exchanging macromolecules between the nucleus and cytoplasm. This includes the movement of small molecules and the selective, facilitated transport of large proteins and RNAs. Faithful, continuous NPC assembly is key for maintaining normal physiological function and is closely tied to proper cell division. One of the unexpected developments during the past decade was the realization that the NPC itself probably does not function primarily as a gating mechanism or by directly transporting cargo macromolecules between the nuclear and cytoplasmic compartments. Instead, nuclear trafficking relies on a range of soluble components. Transport factors bind their cargo in one compartment and then move through the NPCs to the other compartment, where the cargo is released. The transport factor then recycles back through the NPC to participate in another round of transport. In many instances, this process is orchestrated by the Ras-superfamily GTPase Ran. Bischoff et al. describe in detail how the nucleotide state of Ran is controlled by its nuclear guanine-nucleotide-exchange factor (RCC1) and cytoplasmic GTPase-activating protein (RanGAP). The nucleotide state of Ran is crucial to defining the interactions between transport factors, their cargoes and nucleoporins, and is fundamental to the sorting mechanism that defines the directionality of transport. (This definition may be outdated - see the DesignNote.)
Mechanism of Protein Import into the Nucleus
The eukaryotic cell contains compartments with distinct functions bounded by lipid bilayer membranes. The movement of membrane vesicles between these compartments allows proteins in the secretory pathway to move outward from the endoplasmic reticulum (ER) to the Golgi, trans Golgi network (TGN), secretory vesicles, and the plasma membrane and to be secreted into the extracellular environment. The trafficking of membrane vesicles is also essential for endocytosis and the movement of material from the extracellular environment into the early endosome (EE), late endosome (LE), and lysosome. The movement of vesicles and their contents between these compartments, and their secretion, are essential for a host of cellular functions, including the release of neurotransmitters and hormones. The movement of membrane vesicles between all of these compartments is regulated by members of the Rab family of GTPases, part of the ras superfamily of genes, regulated through binding of GTP and hydrolysis of bound GTP to GDP. At least eleven yeast genes in this family have been identified as Ypts, yeast transport proteins, and over sixty mammalian Rab genes have been identified in this highly conserved gene family. The products of the Rab genes regulate specific steps in vesicle transport. Rab1 is involved in the movement of membranes from the ER through the Golgi. Rab3 regulates secretory vesicle release and Rab27 is also involved in regulated release of secreted proteins. Rab5, 7 and 9 contribute to endocytosis while Rab4 and Rab11 mediate recycling from the endosome back to the plasma membrane. Rab11 is involved in both endocytosis and exocytosis. As with other Ras family GTPases, the activity of Rabs is regulated by guanine-nucleotide exchange factors (GEFs) and GAPs (GTPase activating proteins). Downstream effectors must also interact with Rabs to transmit their signals regulating each step of the membrane trafficking pathways including vesicle formation, movement of vesicles between compartments, vesicle docking, fusion, and membrane remodeling. Downstream effectors of the Rabs include Rabphilin-3 (vesicle movement effector for Rab3), Rabphilin-11 (vesicle formation effector for Rab11), and EEA1 (vesicle fusion and membrane remodeling). If Rabs are involved in more than one role and other components of Rab signaling also interact with more than one Rab this will further increase the complexity of the system. Elucidating the interaction of Rabs and regulation of vesicle trafficking by other signaling pathways will be a key area of research in the future. (This definition may be outdated - see the DesignNote.)
Rab GTPases Mark Targets in the Endocytotic Machinery
SNARE interactions in vesicular transport
SNARE Proteins Vesicular Transport Pathway
Reliable neurotransmitter release requires the presence of sufficient numbers of synaptic vesicles. The process of synaptic vesicle endocytosis (SVE) is coordinated by a group of proteins called dephosphins. The current set of seven known dephosphins are nerve terminal proteins with little or no structural homology but satisfy two essential criteria: they are essential for SVE and they are rapidly and coordinately dephosphorylated in response to a calcium influx through voltage-dependent calcium channels. The calcium signal is mediated by calmodulin (CaM) and calcineurin. Each dephosphin plays an essential role in overlapping phases or segments of the cycle. The four phases of SVE are nucleation, invagination, fission and uncoating. The nucleation phase initiates with the activation of CaM/Calcineurin and the subsequent dephosphorylation of AP180. AP180 and clathrin are then recruited to the membrane by AP2 and PtdIns(4,5)P2. Nucleation is completed by the addition of epsin and eps15. Invagination proceeds with the formation of the amphiphysin1/2 heterodimer and its addition to the maturing vesicle surface complexes. The final components, dynamin and synaptojanin, are recruited to the budding vesicle by the amphiphysin1/2 heterodimer. Dynamin forms a complete ring around the vesicle neck and completes fission via its PtdIns(4,5)P2 stimulated GTPase activity. After internalization the vesicle is quickly uncoated, in a process believed to be mediated by synaptojanin, and is accompanied by the disassembly of clathrin. (This definition may be outdated - see the DesignNote.)
Endocytotic role of NDK, Phosphins and Dynamin
Eukaryotic cells take up constituents of the extra-cellular environment and regulate the cell-surface level of membrane proteins via a recycling system of membrane vesicles called endosomes. When cells are taking up elements from the cell-surface it is called endocytosis, and when they are delivered to the cell-surface it is called exocytosis. The transferrin receptor (TfR) is often employed as a model protein for studying this process. The transferrin receptor mediates uptake of iron by binding diferrictransferrin (Tf-2Fe++) from the plasma. Endocytosis of the receptor is initiated by the formation of a clathrin-coated pit in the cell membrane, which subsequently forms the primary endosome and then fuses with the early endosome. The lumen of an early endosome has a slightly acidic pH, which enables the ions to be released. The ions move to the cytosol and the receptor-apotransferrin (Tf) complex is sorted for recycling back to the cell membrane in recycling endosomes. At the cell surface the apotransferrin is replaced with diferrictransferrin and the cycle repeats. Whether an endocytosed protein is recycled or not is determined by a sorting process initiated in the early endosome. The early endosome is the first organelle along the endo-lysosomal pathway and it is the major sorting station. Internalized membrane proteins can either be sorted for recycling from the early endosome by a fast route (e.g., TfR) or make it to the late endosome and recycle by a slow route (e.g., angiotensin receptor, AT1R) or be retained in the late endosome and directed to the lysosome for degradation (e.g., epidermal growth factor receptor, EGFR). The early endosome has been suggested to turn into a multi-vesicular late endosome through a maturation process that changes its biochemical composition and morphology. The late endosome is followed by the lysosome, which is the terminal organelle on the endocytic pathway and is devoid of recycling receptors. The lysosome has a very acidic environment and contains proteases. Vesicular trafficking and proper sorting of internalized proteins require the recruitment of cytosolic proteins to a specific endosomal membrane in a reversible and regulated manner. Many proteins become reversibly localized to membranes through interaction with specific lipid head groups. Phosphatidylinositol 3-phosphate (PI3P) is a minor PI3K product that is constitutively produced and specifically localize to early endosomes and several proteins bind specifically to its head group. These proteins all have a domain called a FYVE-finger which binds to PI3P. It is a cysteine-rich domain reminiscent of a zinc finger with eight conserved cysteines, which coordinate two Zinc ions, and several other conserved residues. Two FYVE finger proteins important in vesicle transport are illustrated in this pathway. The first and most well studied is the early endosomal autoantigen (EEA1). It is a protein involved in fusion of primary endosomes with early endosomes. EEA1 is a large coiled-coil protein that contains a C-terminal FYVE-finger and two domains that bind to the active, GTP-bound form of the early-endosomal GTPase Rab5. One of these domains is adjacent to the FYVE-finger, whereas the other, a C2H2-type zinc finger, is found at the N terminus. The C terminus of EEA1, containing one Rab5-binding domain and the FYVE-finger, is necessary and sufficient for specific targeting of EEA1 to early endosomes, and the membrane binding requires both PI3K activity and Rab5:GTP. The relatively low affinities of the C-terminal Rab5-binding domain for Rab5:GTP and of the FYVE-finger for PI3P secure that under physiological conditions, EEA1 is only recruited to membranes that contain both of these components and Rab5 is required on both membranes in order for the fusion to take place. The second FYVE finger protein in this pathway is HRS. It is also present in early endosomal membranes and is involved in sorting of endocytosed proteins. It binds ubiquitinated proteins and sorts them into clathrin-coated microdomains of the early endosomes. HRS has a domain structure with a FYVE domain, an N-terminal VHS-domain, an ubiquitin interacting motif (UIM), a proline-rich domain, two coiled-coil domains (the second binds to the SNARE protein SNAP-25), and a C-terminal clathrin interacting domain. There are two different forms of clathrin coats in endosomes with distinct localization, one that is involved in budding to form recycling vesicles and one with a flat morphology. HRS binds to the flat clathrin, which causes its specific localization in these parts of the early endosome. HRS prevents receptor recycling by recruiting and concentrating ubiquitinated proteins such as the EGFR in the early endosomes. The ubiquitinated proteins are retained in the late endosome and polyubiquitinated proteins are subsequently transported to the lysosome for degradation. (This definition may be outdated - see the DesignNote.)
The role of FYVE-finger proteins in vesicle transport
An elaboration of the known or inferred interactions involved in a signal transduction pathway.
Cell-cell adherens junctions (AJs), the most common type of intercellular adhesions, are important for maintaining tissue architecture and cell polarity and can limit cell movement and proliferation. At AJs, E-cadherin serves as an essential cell adhesion molecules (CAMs). The cytoplasmic tail binds beta-catenin, which in turn binds alpha-catenin. Alpha-catenin is associated with F-actin bundles directly and indirectly. The integrity of the cadherin-catenin complex is negatively regulated by phosphorylation of beta-catenin by receptor tyrosine kinases (RTKs) and cytoplasmic tyrosine kinases (Fer, Fyn, Yes, and Src), which leads to dissociation of the cadherin-catenin complex. Integrity of this complex is positively regulated by beta -catenin phosphorylation by casein kinase II, and dephosphorylation by protein tyrosine phosphatases. Changes in the phosphorylation state of beta-catenin affect cell-cell adhesion, cell migration and the level of signaling beta-catenin. Wnt signaling acts as a positive regulator of beta-catenin by inhibiting beta-catenin degradation, which stabilizes beta-catenin, and causes its accumulation. Cadherin may acts as a negative regulator of signaling beta-catenin as it binds beta-catenin at the cell surface and thereby sequesters it from the nucleus. Nectins also function as CAMs at AJs, but are more highly concentrated at AJs than E-cadherin. Nectins transduce signals through Cdc42 and Rac, which reorganize the actin cytoskeleton, regulate the formation of AJs, and strengthen cell-cell adhesion.
Increased adipocyte volume and number are positively correlated with leptin production, and negatively correlated with production of adiponectin.
ADP-ribosylation factors (ARFs) are 20-kDa guanine nucleotide-binding proteins, members of the Ras GTPase superfamily that were initially recognized and purified because of their ability to stimulate the ADP-ribosyltransferase activity of the cholera toxin A subunit. We now know that they are critical components of several different vesicular trafficking pathways in all eukaryotic cells and activators of specific phospholipase Ds (PLDs). ARF interacts with many proteins and other molecules that regulate its state of activation or are involved in its intracellular function. Arf proteins cycle between GDP-bound, inactive and GTP-bound, active forms, and the cycling is regulated by specific GEPs and GAPs. Members of the Arf GEP family can be grouped into two major subfamilies on the basis of their sequence similarities and functional differences. The high-molecular-weight Arf GEP subfamily includes yeast Sec7, Gea1, and Gea2, and mammalian BIG1/p200, BIG2, and GBF1, which all consist of 1,400-2,000 amino acid residues. Many Arf GAPs are multidomain proteins and have been found to interact with multiple signaling molecules. For instance, ASAP1 has a PH domain, ankyrin (ANK) repeats, proline-rich and Src-homology (SH) 3 domains and has been shown to bind PI, P2, Src, and Crk. PAPa/PAG3, with a similar domain structure, binds phosphoinositides, Src, Pyk, and paxillin. The GITs bind bARK, paxillin and the Rac/Cdc42 exchange factor PIX (also known as Cool). ASAP-related proteins, ARAP1, 2 and 3 have Arf GAP, Rho GAP, Ankyrin repeat, Ras-associating (RA), and five PH domains, and therefore have the potential of integrating four signaling pathways. (This definition may be outdated - see the DesignNote.)
The Ah receptor, bHLH/PAS transcription factor, upon binding of an agonist such as 2,3,7,8-tetrachlorodibenzo-p-dioxin translocates into the nucleus and heterodimerizes with the transcription factor ARNT. The Ah receptor/ARNT heterodimer binds to dioxin-responsive elements and alters expression of a number of genes including; CYP1A1, CYP1A2, CYP1B1, and NAD(P)H quinone oxidoreductase. The inactive form of the Ah receptor exists in the cytoplasm as a tetrameric complex composed of the ligand binding subunit, a dimer of the 90-kDa heat shock protein, and X-associated protein 2 (also referred to as AIP or ARA9). (This definition may be outdated - see the DesignNote.)
Many cell-surface receptors induce production of second messengers like PIP3, phosphatidylinositol 3,4,5-trisphosphate, that convey signals to the cytoplasm from the cell surface. PIP3 signals activate the kinase PDK1, 3-phosphoinositide-dependent protein kinase-1, which in turn activates the kinase AKT, also known as protein kinase B. Proteins phosphorylated by activated AKT promote cell survival. Phosphorylation of Ikappa-B kinase leads to activation of the transcription factor NF-kB to oppose apoptosis. Bad is a protein in the Bcl-2 gene family that opposes Bcl-2 to induce apoptosis. Phosphorylation of Bad by AKT blocks anti-apoptotic activity to promote cell survival. Similarly, phosphorylation of the protease caspase 9 or forkhead transcription factors by AKT block the induction of apoptosis by these factors. AKT promotes cell survival and opposes apoptosis by a variety of routes. (This definition may be outdated - see the DesignNote.)
Regulation of Androgen receptor activity
Coregulation of Androgen receptor activity
Coregulation Pathway for Androgen Receptor Activity
Nongenotropic Androgen Signaling Pathway
Angiopoietin receptor Tie2-mediated signaling
Angiopoietin-1 Receptor Signaling Pathway
Ang II binding to AT1-R triggers the activation of Ca2+ signaling and PKC. The signal is then transmitted to Pyk2 and to the small G protein Rac1 but not Cdc42. In turn, Rac1 activates a small G protein-activated kinase whose identity is still controversial, but which has been suggested to be PAK1. Finally, the JNK cascade, including MEKK1, SEK1, and JNK, is activated, causing induction of the c-Jun gene via binding of ATF2 and c-Jun heterodimer to the junTRE2 site. Ang II is closely involved in cardiac remodeling by stimulating synthesis of extracellular matrix proteins. It was recently found that expression of fibronectin by Ang II is transcriptionally regulated by AP-1 complex in cardiac fibroblasts. The collagenase gene, containing AP-1 sites, is also regulated by AP-1 components, including c-Jun. AP-1 activity is also enhanced in Ang II-induced cardiac hypertrophy. Expression of ANF is regulated by AP-1 components. (This definition may be outdated - see the DesignNote.)
Angiotensin II mediated activation of JNK Pathway via Pyk2 dependent signaling
The ataxia telangiectasia-mutated gene (ATM) encodes a protein kinase that acts as a tumor suppressor. ATM activation by ionizing radiation damage to DNA stimulates DNA repair and blocks progression through the cell cycle. Mutation of the ATM gene causes the disease ataxia telangiectasia which involves an inherited predisposition to some cancers. To play this role ATM interacts with a broad network of proteins, including checkpoint factors (chk1, chk2), tumor suppressors (p53 and BRCA), DNA repair factors (RAD50, RAD51, GADD45), and other signaling molecules (c-Abl and NF-kB). In addition to regulating DNA repair and the cell cycle, ATM can also trigger apoptosis in radiation treated cells. (This definition may be outdated - see the DesignNote.)
The G-protein coupled receptor (GPCR) family transduces extracellular signals across the plasma membrane, activating cellular responses through a variety of second messenger cascades (see PKA and PKC signaling pathways). These receptors provide rapid responses to a variety of stimuli, and are often rapidly attenuated in their signaling. Failure to attenuate GPCR signaling can have dramatic consequences. One method to attenuate GPCR signaling is by removal of the stimulus from the extracellular fluid. At the synapse, removal of neurotransmitter or peptide signaling molecules is accomplished by either reuptake or degradation. Acetylcholine is removed from synapses through degradation by the enzyme acetylcholinesterase. Inhibition of acetylcholinesterase results in prolonged signaling at the neuromuscular junction, and uncontrollable spasms in humans caused by nerve gas or in insects by some insecticides. Inhibition of acetylcholinesterase is also used therapeutically to treat Alzheimer's disease, compensating for the loss of cholinergic neurons. Transporters for serotonin, dopamine, GABA and noradrenaline remove these neurotransmitters from the synapse to terminate signaling. Antidepressants such as Prozac inhibit reuptake of serotonin and many drugs of abuse such as cocaine act by blocking reuptake of dopamine or adrenaline. Reuptake not only terminates signaling, but can also conserve neurotransmitter through recycling back into the presynaptic cell. The next step in the attenuation of GPCR signaling is receptor desensitization, in which receptors are modified to no longer transduce a signal even if the stimulus is still present. Desensitization of GPCRs occurs through protein kinases that phosphorylate the GPCR to turn off signaling. Downstream protein kinases such as PKA and PKC turned on by GPCR signaling can phosphorylate the activated GPCR and other GPCRs to prevent further signaling. G-protein receptor kinases (GRKs) are a family of kinases that specifically phosphorylate only agonist-occupied GPCRs. GRKs attenuate GPCR signaling in concert with arrestins, proteins that bind GRK-phosphorylated GPCRs to disrupt interaction with G-protein and to terminate signaling. Reducing the number of receptor expressed on the cell surface can also attenuate receptor signaling. Many GPCRs are removed from the cell surface by receptor-mediated endocytosis when they are activated. Endocytosis of activated GPCRs appears to be stimulated by GRKs and arrestins. Once internalized, receptors can either be degraded in lysosomes or they can be recycled back to the cell surface. (This definition may be outdated - see the DesignNote.)
Significant progress has been made towards delineation of the intrinsic molecular processes that regulate B lymphocyte immune function. Recent observations have provided a clearer picture of the interactive signaling pathways that emanate from the mature B cell antigen receptor (BCR) complex and the different precursor complexes that are expressed during development. Studies have also revealed that the net functional response to a given antigenic challenge is affected by the combined action of BCR-dependent signaling pathways, as well as those originating from various coreceptors expressed by B cells (e.g. CD19, CD22, FcgRIIb and PIR-B).It is now well established that reversible tyrosine phosphorylation plays an important role in regulating B cell biology. In particular, binding of antigen to the BCR promotes the activation of several protein tyrosine kinases (PTK) that, in conjunction with protein tyrosine phosphatases (PTP), alter the homeostasis of reversible tyrosine phosphorylation in the resting B cell. The net effect is a transient increase in protein tyrosine phosphorylation that facilitates the phosphotyrosine dependent formation of effector protein complexes, promotes targeting of effector proteins to specific microenvironments within the B cell and initiates the catalytic activation of downstream effector proteins. Studies have demonstrated that Src family PTKs are activated initially and serve to phosphorylate CD79a and CD79b thereby creating phosphotyrosine motifs that recruit downstream signaling proteins. In particular, phosphorylation of the BCR complex leads to the recruitment and activation of the PTK Syk, which in turn promotes phosphorylation of PLCg, Shc and Vav. Additionally, the Tec family member Btk is recruited to the plasma membrane where it is involved in activation of PLCg. Initiation of B lymphocyte activation is dependent on the tyrosine phosphorylation-dependent formation of multi-molecular effector protein complexes that activate downstream signaling pathways. The formation of such complexes was initially hypothesized to occur primarily via effector protein binding to the BCR complex itself. However, recent studies have demonstrated that productive signaling via the BCR is in fact dependent on tyrosine phosphorylation of one or more adapter proteins that play a crucial role in recruitment and organization of effector proteins at the plasma membrane. The SLP-65/BLNK adapter protein has recently been shown to play a crucial role in recruitment and activation of key signal transducing effector proteins in the B cell. After the BCR has been engaged by antigen and the activation response has been initiated, numerous second messengers and intermediate signal transducing proteins are activated. These include the production of lipid second messengers by phosphatidylinositol 3-kinase, and the PLC-dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate to yield diacylglycerol and 1,4,5-inositoltrisphosphate (IP3). DAG is important for activation of PKC whereas IP3 promote release of calcium from the endoplasmic reticulum and the subsequent influx Ca2+ from the extracellular space. Numerous intermediate signaling proteins are also activated including the Ras and Rap1, which are small molecular weight GTPases and these ultimately lead to the activation of MAP kinases including Erk, JNK and p38. The net effect of second messenger production and activation of intermediate signaling proteins is the concerted regulation of several transcription factors that mediate gene transcription in the B cell. (This definition may be outdated - see the DesignNote.)
Lipopolysaccharide (LPS) from XX bacteria induces a wide range of inflammatory responses, including the response of alveolar macrophages to bacteria in the lungs. CD14 and the Toll-like receptor TLR4 are activated by LPS, initiating a signaling cascade that activates PI3 kinase and increases synthesis of the inositol phosphate PIP3. PIP3 activates the inositol phosphate dependent protein kinase PDK1, which activates AKT (protein kinase B). One of the key actions of AKT is to block apoptosis. AKT phosphorylation of NF-kB promotes the survival and activation of macrophages responding to LPS. Another substrate of AKT is the protein kinase Gsk3-beta. AKT phosphorylates and deactivates Gsk3-beta. Non-phosphorylated Gsk3-beta is active and phosphorylates beta-catenin, leading to its degradation in the ubiquitin dependent proteasome pathway. Stimulation by LPS causes the accumulation of beta-catenin in the nucleus and the activation of genes in concert with the transcription factor LEF1. This pathway is probably not restricted to alveolar pathway, but leads to the activation of beta-catenin dependent genes by LPS in other cells as well. Other pathways regulate this pathway also, such as the modulation of PI3 kinase activity by ceramide and the inhibition of Gsk3-beta activity by the Wnt/frizzled/disheveled (DSH) pathway. (This definition may be outdated - see the DesignNote.)
Inactivation of Gsk3 by AKT causes accumulation of b-catenin in Alveolar Macrophages
Many different peptides act as signaling molecules, including the proinflammatory peptide bradykinin, the protease enzyme thrombin, and the blood pressure regulating peptide angiotensin. While these three proteins are distinct in their sequence and physiology, and act through different cell surface receptors, they share in a common class of cell surface receptors called G-protein coupled receptors (GPCRs). Other polypeptide ligands of GPCRs include vasopressin, oxytocin, somatostatin, neuropeptide Y, GnRH, luteinizing hormone, follicle stimulating hormone, parathyroid hormone, orexins, urotensin II, endorphins, enkephalins, and many others. GPCRs form a broad and diverse gene family that responds not only to peptide ligands but also small molecule neurotransmitters (acetylcholine, dopamine, serotonin and adrenaline), light, odorants, taste, lipids, nucleotides, and ions. The main signaling mechanism used by GPCRs is to interact with G-protein GTPase proteins coupled to downstream second messenger systems including intracellular calcium release and cAMP production. The intracellular signaling systems used by peptide GPCRs are similar to those used by all GPCRs, and are typically classified according to the G-protein they interact with and the second messenger system that is activated. For Gs-coupled GPCRs, activation of the G-protein Gs by receptor stimulates the downstream activation of adenylate cyclase and the production of cyclic AMP, while Gi-coupled receptors inhibit cAMP production. One of the key results of cAMP production is activation of protein kinase A. Gq-coupled receptors stimulate phospholipase C, releasing IP3 and diacylglycerol. IP3 binds to a receptor in the ER to cause the release of intracellular calcium, and the subsequent activation of protein kinase C, calmodulin-dependent pathways. In addition to these second messenger signaling systems for GPCRs, GPCR pathways exhibit crosstalk with other signaling pathways including tyrosine kinase growth factor receptors and map kinase pathways. Transactivation of either receptor tyrosine kinases like the EGF receptor or focal adhesion complexes can stimulate ras activation through the adaptor proteins Shc, Grb2 and Sos, and downstream Map kinases activating Erk1 and Erk2. Src kinases may also play an essential intermediary role in the activation of ras and map kinase pathways by GPCRs. (This definition may be outdated - see the DesignNote.)
Bioactive Peptide Induced Signaling Pathway
Bone Morphogenic Protein Receptor Family Signaling Pathway
bone morphogenetic protein signaling pathway
bone morphogenetic protein signalling pathway
Ca2+ that enters the cell from the outside is a principal source of signal Ca2+. Entry of Ca2+ is driven by the presence of a large electrochemical gradient across the plasma membrane. Cells use this external source of signal Ca2+ by activating various entry channels with widely different properties. The voltage-operated channels (VOCs) are found in excitable cells and generate the rapid Ca2+ fluxes that control fast cellular processes. There are many other Ca2+-entry channels, such as the receptor-operated channels (ROCs), for example the NMDA (N-methyl-D-aspartate) receptors (NMDARs) that respond to glutamate. There also are second-messenger-operated channels (SMOCs) and store-operated channels (SOCs).
Eosinophils are a key class of leukocytes involved in inflammatory responses, including allergic reactions in skin and airway. The eosinophil response in inflammation is absent in mice lacking CCR3, indicating the key role of this G protein coupled receptor in inflammation and allergic responses. Eotaxin is a chemokine ligand for CCR3 that recruits eosinophils to the site of inflammation and activates them. Other chemokine ligands of CCR3 include eotaxin-2, MCP-3, MCP-4, and RANTES. Multiple signaling pathways activated by CCR3 participate in the inflammatory response of eosinophils. Eotaxin stimulates intracellular calcium release, production of reactive oxygen species, and changes in actin polymerization through a pertussis sensitive pathway. Rho is a G protein that activates ROCK, a protein kinase. Rho and ROCK regulate actin stress fiber formation and are required for eosinophil chemotaxis. Map kinase pathways are also involved in chemotaxis. Another key action of activated eosinophils is the release of reactive oxygen species, causing tissue damage during chronic inflammatory responses. Blocking eosinophil activation and the signaling pathways that lead to chemotaxis, degranulation, and reactive oxygen release may alleviate inflammatory conditions and inflammation-associated tissue damage. (This definition may be outdated - see the DesignNote.)
The chemokine receptors CCR5 and CXCR4 in macrophages are activated by their peptide ligands and also by the HIV envelope protein GP120 during HIV infection. One mechanism of signaling by these GPCRs is through activation of Gi signaling. These chemokine receptors can also signal through a Gi-independent pertussis toxin-insensitive pathway. This pathway elevates calcium influx into the cell through CRAC channels, ion channels that are activated by calcium release. Elevated calcium from CRAC is required for downstream activation of Pyk2, a focal adhesion-associated protein kinase. Non Gi signaling by these chemokine receptors also involves the Jnk and p38 Map kinase pathways leading to AP-1 activation and activation of genes such as MIP-1 and MCP-1. This pathway may be involved in the role of macrophages in the pathogenesis of AIDS. (This definition may be outdated - see the DesignNote.)
Pertussis toxin-insensitive CCR5 Signaling in Macrophage
The CD40 receptor was first associated with expression in B cells and the role it plays through its ligand CD40L (CD154) in moderating T cell activation. Broader expression may indicate a broader role for CD40 and CD40L in immune function and disease states such as transplant rejection and HIV infection. Disruption and modulation of CD40 interaction with CD40L may prove therapeutic in the treatment of autoimmune disorders, heart disease, and cancer. As a member of the TNF receptor family, CD40 relies on interaction with TRAF proteins to mediate an intracellular signal in response to CD40L binding. The pathway downstream of TRAFs activates the transcription factor NF-kappaB through a kinase pathway involving map kinases, NIK (NF-kappaB inducing kinase) and I-kappa B kinases. Some CD40 responses like regulation of immunoglobulin expression might be mediated by NF-kappaB transcriptional activation. (This definition may be outdated - see the DesignNote.)
Cell adhesion molecules are (glyco)proteins expressed on the cell surface and play a critical role in a wide array of biologic processes that include hemostasis, the immune response, inflammation, embryogenesis, and development of neuronal tissue. There are four main groups: the integrin family, the immunoglobulin superfamily, selectins, and cadherins. Membrane proteins that mediate immune cell-cell interactions fall into different categories, namely those involved in antigen recognition, costimulation and cellular adhesion. Furthermore cell-cell adhesions are important for brain morphology and highly coordinated brain functions such as memory and learning. During early development of the nervous system, neurons elongate their axons towards their targets and establish and maintain synapses through formation of cell-cell adhesions. Cell-cell adhesions also underpin axon-axon contacts and link neurons with supporting schwann cells and oligodendrocytes.
Cell Adhesion Molecule Signaling Pathway
Interactions between cells, responsible for cell to cell adhesion, can communicate signals into the cellular interior. These signals often involve interactions with cytoskeletal elements to produce changes in cell motility, migration, proliferation and shape. The cadherins are cell surface adhesion molecules that help form tight junctions between cells, such as in formation of epithelial cell layers. E-cadherin inactivation has been implicated in cancer development. In addition to mediating adhesion with other cells, cadherins transduce signals into cells through interactions with the catenins. Catenins probably affect actin cytoskeletal function through interactions with proteins such as actinin and vinculin. Catenins also probably trigger changes in cell shape and motility by signals through the Rho small GTPases. Another important cell adhesion molecule is CD-31, or PECAM-1, involved in the formation of junctions between endothelial cells, cell migration, migration of lymphocytes, and regulation of lymphocyte activation. Src phosphorylates PECAM-1 on tyrosine residues causing SHP-2 association with PECAM-1. Paxillin acts as an adaptor protein between proteins involved in adhesion signaling like FAK and src and cytoskeletal elements. In addition to signals created by adhesion molecules to alter cellular responses, other signaling pathways can alter adhesion through components of the focal adhesion complex. (This definition may be outdated - see the DesignNote.)
Ceramide is a sphingosine-based lipid-signaling molecule involved in the regulation of cellular differentiation, proliferation, and apoptosis. This diagram represents some of the current understanding of the cascades that couple ceramide to specific signaling pathways. These cascades illustrate that ceramide can be a growth stimulus or proapoptotic signal. The ultimate ceramide action is determined within the context of other stimuli and by the subcellular topology of its production and is cell-type specific. There are 2 forms of sphingomyelinase, acid (acid-sphingomyelinase, A-SMase) and neutral (neutral-sphingomyelinase, N-SMase), that can produce ceramide. TNF-alpha can stimulate either form of sphingomyelinase as can other death receptors. Different domains of TNF-alpha stimulate the different SMases. N-SMase stimulation is enhanced by the receptor for activated-C kinase 1 (RACK1). The activity of each form is dependent on the local intracellular pH. In the illustration the forms are separated to reduce confusion however ceramide produced by either method can stimulate either cascade depending on the presence of specific co-factors and activators. A-SMase has been recognized as one of the required molecules to mediate proapoptotic signaling in cell death induced by a diverse array of stresses such as H2O2, Heat, UV exposure and Radiation. ROS generation in mitochondria activates caspase-3 via cooperation of cytochrome c, Aif and caspase-9 and stimulates or increases ceramide generation through A-SMase in a proapoptotic activation cycle. Caspase-3 further increases its own activation by proteolytically cleaving ceramide inhibited catalase which is an inhibitor of ROS generation. Ceramide-activated protein kinase(CARK) also known as Kinase Suppressor of RAS (KSR) activity is in some cases the switch point in the balance between proapoptotic and antiapoptotic signals and is also cell-type specific. In endothelial cells for example the activation of KSR is required for apoptosis. In contrast in epithelial cells activation of KSR is required for cell proliferation. An additional switch point is the availability of Bad in the cell. Activation of KSR leads to further mitochondrial stimulation or association with RAS and activation of the Raf1 cascade leading to proliferation or differentiation. (This definition may be outdated - see the DesignNote.)
Class I PI3K signaling events mediated by Akt
Cone Cell Visual Signal Transduction Pathway
The transcription factor CREB binds the cyclic AMP response element (CRE) and activates transcription in response to a variety of extracellular signals including neurotransmitters, hormones, membrane depolarization, and growth and neurotrophic factors. Protein kinase A and the calmodulin-dependent protein kinases CaMKII stimulate CREB phosphorylation at Ser133, a key regulatory site controlling transcriptional activity. Growth and neurotrophic factors also stimulate CREB phosphorylation at Ser133. Phosphorylation occurs at Ser133 via p44/42 MAP Kinase and p90RSK and also via p38 MAP Kinase and MSK1. CREB mutants exhibit deficiencies in spatial learning tasks, while flies overexpressing or lacking CREB show enhanced or diminished learning, respectively. (This definition may be outdated - see the DesignNote.)
Transcription factor CREB and its extracellular signals
CXCR4 is a chemokine receptor in the GPCR gene family, and is expressed by cells in the immune system and the central nervous system. In response to binding its ligand SDF-1 (stromal cell-derived factor-1), CXCR4 triggers the migration and recruitment of immune cells. This ligand-receptor pair may also play a role in development of the nervous system. In addition to acting as a chemokine receptor, CXCR4 is a co-receptor for entry of HIV into T cells and ligands of CXCR4, including SDF-1, may help to block HIV infection. Early in the infection of an individual, HIV viruses often are tropic for the CCR5 coreceptor that provides for macrophage entry, then later in infection are tropic for CXCR4 and T cell entry. Viruses that are tropic for CXCR4 are generally syncytium forming, causing T cells to aggregate and be destroyed at a rapid rate. CXCR4 induces downstream signaling by several different pathways. As a GPCR, CXCR4 binding of SDF-1 activates G-protein mediated signaling, including downstream pathways such as ras, and PI3 kinase. PI3 kinase activated by SDF-1 and CXCR4 plays a role in lymphocyte chemotaxis in response to these signals. One endpoint of CXCR4 signaling is the activation of transcription factors such as AP-1 and chemokine regulated genes. JAK/STAT signaling pathways also appear to play a role in SDF-1/CXCR4 signaling. Delineation of the signaling mechanisms utilized by CXCR4 may assist in determining the role of CXCR4 in HIV infection and in the immune response. (This definition may be outdated - see the DesignNote.)
C-X-C chemokine receptor CXCR4 signaling pathway
Cytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell growth, differentiation, cell death, angiogenesis, and development and repair processes aimed at the restoration of homeostasis. Cytokines are released by various cells in the body, usually in response to an activating stimulus, and they induce responses through binding to specific receptors on the cell surface of target cells. Cytokines can be grouped by structure into different families and their receptors can likewise be grouped.
Cytokine-Cytokine Receptor Signaling Pathway
Specific families of pattern recognition receptors are responsible for detecting foreign DNA from invading microbes or host cells and generating innate immune responses. DAI is the first identified sensor of cytosolic DNA which activates the IRF and NF-kappa B transcription factors, leading to production of type I interferon and other cytokines. The second type of cytoplasmic DNA sensor is AIM2. Upon sensing DNA, AIM2 triggers the assembly of the inflammasome, culminating in interleukin maturation. In addition to these receptors, there is a mechanism to sense foreign DNA, with the host RNA polymerase III converting the DNA into RNA for recognition by the RNA sensor RIG-I. These pathways provide various means to alert the cell.
D4-GDP dissociation inhibitor (D4-GDI) is a negative regulator of the ras related Rho Family of GTPases. Since the rho GTPases promote cytoskeletal and membrane changes associated with apoptotic cell death, the removal of the D4-GDI block through its cleavage is important for inducing apoptosis. Caspase-3 cleaves the 28 kDa mature form of D4-GDI to give a 5 kDa and 23 kDa size fragment. The 23 kDa fragment then translocates to the nucleus. The mechanisms involving cleavage of D4-GDI with apoptosis are not presently known. Activation of the Jun N-Terminal kinase, a regulator of apoptosis, may be one of the mechanisms. (This definition may be outdated - see the DesignNote.)
E-cadherin signaling in the nascent adherens junction
Stabilization and expansion of the E-cadherin adherens junction
E-Cadherin Signaling Pathway in Keratinocytes
The extracellular matrix (ECM) consists of a complex mixture of structural and functional macromolecules and serves an important role in tissue and organ morphogenesis and in the maintenance of cell and tissue structure and function. Specific interactions between cells and the ECM are mediated by transmembrane molecules, mainly integrins and perhaps also proteoglycans, CD36, or other cell-surface-associated components. These interactions lead to a direct or indirect control of cellular activities such as adhesion, migration, differentiation, proliferation, and apoptosis. In addition, integrins function as mechanoreceptors and provide a force-transmitting physical link between the ECM and the cytoskeleton. Integrins are a family of glycosylated, heterodimeric transmembrane adhesion receptors that consist of noncovalently bound alpha- and beta-subunits.
ECM-Receptor Interaction Signaling Pathway
The epidermal growth factor (EGF) peptide induces cellular proliferation through the EGF receptor. Inhibitors of the EGF receptor are being pursued as potential cancer therapies and EGF may stimulate wound healing. Mutation of the EGF receptor has been associated with cancer in humans. The proliferative effects of EGF are signaled through several pathways. Binding of EGF results in EGF receptor dimerization, autophosphorylation of the receptor, and tyrosine phosphorylation of other proteins. The EGF receptor activates ras and the MAP kinase pathway, ultimately causing phosphorylation of transcription factors such as c-Fos to create AP-1 and ELK-1 that contribute to proliferation. Activation of STAT-1 and STAT-3 transcription factors by JAK kinases in response to EGF contributes to proliferative signaling. Phosphatidylinositol signaling and calcium release induced by EGF activate protein kinase C, another component of EGF signaling. Crosstalk of EGF signaling with other pathways make the EGF receptor a junction point between signaling systems. (This definition may be outdated - see the DesignNote.)
EGFR-dependent Endothelin signaling events
EGFR-Dependent Endothelin Signaling Pathway
Epidermal Growth Factor Receptor Family Pathway
Epidermal Growth Factor Receptor Pathway
Epidermal Growth Factor Receptor Downstream Signaling Pathway
Internalization Pathway for Epidermal Growth Factor Receptor
Erythropoietin functions to increase the number of red blood cells. Thus, it has found utility as a drug for those needing to replenish erythrocytes for any number of reasons. The signaling mechanism includes multimerization of the receptor upon ligand binding, activation of MAPK cascade, and phosphorylation and activation of Stat5. (This definition may be outdated - see the DesignNote.)
The ErbB family of receptor tyrosine kinases (RTKs) couples binding of extracellular growth factor ligands to intracellular signaling pathways regulating diverse biologic responses, including proliferation, differentiation, cell motility, and survival. Ligand binding to the four closely related members of this RTK family-epidermal growth factor receptor (EGFR, also known as ErbB-1 or HER1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4)-induces the formation of receptor homo- and heterodimers and the activation of the intrinsic kinase domain, resulting in phosphorylation on specific tyrosine residues (pY) within the cytoplasmic tail. Signaling effectors containing binding pockets for pY-containing peptides are recruited to activated receptors and induce the various signaling pathways. The Shc- and/or Grb2-activated mitogen-activated protein kinase (MAPK) pathway is a common target downstream of all ErbB receptors. Similarly, the phosphatidylinositol-3-kinase (PI-3K) pathway is directly or indirectly activated by most ErbBs. Several cytoplasmic docking proteins appear to be recruited by specific ErbB receptors and less exploited by others. These include the adaptors Crk, Nck, the phospholipase C gamma (PLCgamma), the intracellular tyrosine kinase Src, or the Cbl E3 ubiquitin protein ligase.
Her2 or ERBB2 belongs to a class of proteins having high homology with epidermal growth factor receptor (EGFR or ERBB1). It encodes a protein with a molecular weight of 185 KDa. Unlike other members of the EGFR family, no ligand for Her2 has been found and it usually associates with members of ERBB1 family to form functional heterodimers. It has been shown that it can form dimers with ERBB (EGFR), ERBB3 and ERBB4 as well as gp130 subunits of IL-6 receptor. In at least some cell types, the association between gp130 and HRBB2 is essential for HRBB2-ERBB3 phosphorylation and subsequent MAP kinase signaling. Although ERBB1 can form homodimers, the signaling for ERBB1 is usually transient and the receptor undergoes internalization after ligand binding and activation. EGFR-HER2 complex increases the signaling capacity of EGFR by increasing the ligand affinity as well as the recycling of the heterodimer. Of all the ERBB heterodimers, ERBB2-ERBB3 heterodimers perhaps elicit the strongest signal. Removing ERBB3 from the cell has a drastic effect on ERBB2 mediated signaling and downstream effectors. The clinical importance of HER2 cannot be overstated. In addition, monoclonal antibody (Herceptin) against this receptor has been shown to be an effective treatment of breast cancer patients who have a high level of HER2 over expression. (This definition may be outdated - see the DesignNote.)
Role of ERBB2 in Signal Transduction and Oncology
receptor tyrosine-protein kinase erbB-2 signaling pathway
receptor tyrosine-protein kinase erbB-4 signaling pathway
The p44/42 MAP Kinase pathway consists of a protein kinase cascade linking growth and differentiation signals with transcription in the nucleus. Growth factor receptors and tyrosine kinases activate Ras which in turn activates c-Raf, MEK, and MAP kinase. Activated p44/42 MAP Kinase translocates to the nucleus and activates transcription by phosphorylation of kinases such as p90 RSK, MSK, and transcription factors such as ELK-1 and Stat3. The importance of this pathway in both growth control and development has been demonstrated via the transforming properties of various mutant forms of Ras, Raf, and MEK and by their effects on development. Signal amplification and the potential for crosstalk appear to be important features of this regulatory network. (This definition may be outdated - see the DesignNote.)
Receptors in the TNF receptor family are associated with the induction of apoptosis, as well as inflammatory signaling. The Fas receptor (CD95) mediates apoptotic signaling by Fas-ligand expressed on the surface of other cells. The Fas-FasL interaction plays an important role in the immune system and lack of this system leads to autoimmunity, indicating that Fas-mediated apoptosis removes self-reactive lymphocytes. Fas signaling is also involved in immune surveillance to remove transformed cells and virus infected cells. Binding of FAS to oligomerized FasL on another cell activates apoptotic signaling through a cytoplasmic domain termed the death domain that interacts with signaling adaptors including FAF, FADD and DAX to activate the caspase proteolytic cascade. Caspase-8 and caspase-10 are first activated and then cleave and activate downstream caspases, and a variety of cellular substrates, leading to cell death. Caspases cleave nuclear lamins, causing the nucleus to break down and lose its normal structure. They also cleave DFF, inducing cleavage and degradation of the genome. Other caspase substrates are involved in cytoskeletal structure, cell cycle regulation and signaling pathways. Activation of JNK kinase, activation of Jun, and production of ceramide may also play roles in Fas-mediated apoptosis. Activation of Fas-mediated apoptosis is opposed by I-FLICE and FAP. Viruses and tumors may escape immune surveillance in part through suppression of Fas-mediated apoptosis. (This definition may be outdated - see the DesignNote.)
Neutrophils respond to bacterial infection by releasing reactive oxygen species that kill bacteria and by expressing chemokines that attract other immune cells to the site of infection. The multisubunit enzyme NADPH oxidase, expressed by neutrophils, produces reactive oxygen species that are rapidly released in what is known as the respiratory burst. Activity of the NADPH oxidase is induced by fMLP receptor ligands, formylated peptides from bacteria. The fMLP receptor is a G-protein coupled receptor, FPR-1, that activates Map kinase pathways and phospholipase C. Phospholipase C activation releases IP3 and calcium, activating protein kinase C and also activating the transcription factor NFAT, which contributes to activation of chemokine genes. One of the components of the NADPH oxidase is p47phox. PKC activation phosphorylates p47phox to activate NADPH oxidase activity. Activation of Map kinase cascades leads to Erk1/Erk2 dependent p47phox phosphorylation as well as activation of the Elk-1 transcription factor and chemokine gene expression. Inhibition of p38 did not affect p47phox phosphorylation, indicating that p38 is not involved in Erk1/2 activation of the NADPH oxidase. Inhibition of p38 did inhibit NADPH oxidase though, indicating that other pathways contribute to activation of this enzyme. (This definition may be outdated - see the DesignNote.)
fMLP induced chemokine gene expression in HMC-1 cells
Formyl Peptide Receptor 1 Signaling Pathway
G-aS-coupled receptors stimulate adenylyl cyclase (AC), which synthesizes cAMP from ATP. In contrast Gai-coupled receptors inhibit AC and so reduce cAMP formation. The bg subunits from Gai and other G proteins are able to activate the MAP kinase pathways and PLCb. GPCRs coupled to the Gaq family of G proteins stimulate PLCb, which cleaves membrane phospholipids to produce IP3, which mobilizes intracellular calcium, and DAG, which activates PKC. Second messenger pathways then activate a range of effector systems to change cell behavior; in many cases this includes the regulation of gene transcription. (This definition may be outdated - see the DesignNote.)
Signaling Pathway from G-Protein Families
The HER4/erbB4 receptor tyrosine kinase is a member of the EGF1 receptor family. HER4 is a receptor for the neuregulins (NRGs), a family of growth and differentiation factors. HER4 can also bind and be activated by heparin-binding EGF growth factor, betacellulin, and epiregulin, members of the EGF family which, unlike the NRGs, are also ligands for the EGF receptor. HER4 mRNA is expressed in several tissues such as heart, brain, kidney, and skeletal muscle, suggesting that this receptor is involved in the development and maintenance of a variety of organs and cell types. It is likely that the control of expression and function of HER4 is important in normal development as well as in disease. (This definition may be outdated - see the DesignNote.)
g-Secretase mediated ErbB4 Signaling Pathway
Gamma-Secretase Mediated ErbB4 Signaling Pathway
glucocorticoid receptor signaling pathway
glucocorticoid receptor signalling pathway
Glucocorticoid receptor regulatory network
Gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. The GnRHR is coupled to Gq/11 proteins to activate phospholipase C which transmits its signal to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates the intracellular protein kinase C (PKC) pathway and IP3 stimulates release of intracellular calcium. In addition to the classical Gq/11, coupling of Gs is occasionally observed in a cell-specific fashion. Signaling downstream of protein kinase C (PKC) leads to transactivation of the epidermal growth factor (EGF) receptor and activation of mitogen-activated protein kinases (MAPKs), including extracellular-signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 MAPK. Active MAPKs translocate to the nucleus, resulting in activation of transcription factors and rapid induction of early genes.
Gonadotropin-Releasing Hormone Signaling Pathway
The binding of b-arrestins to agonist-occupied GPCRs coincides with the recruitment of Src family tyrosine kinases, including c-Src, Hck and c-Fgr (Src-TK), to the receptor-b-arrestin complex. Several signaling events have been reported to involve b-arrestin-dependent Src recruitment. These include the regulation of clathrin-dependent beta2-adrenergic receptor endocytosis by tyrosine phosphorylation of dynamin, Ras-dependent activation of the ERK1/2 MAP kinase cascade and stimulation of cell proliferation by beta2-adrenergic and neurokinin NK1 receptors, and stimulation of chemokine CXCR1 receptor-mediated neutrophil degranulation. (This definition may be outdated - see the DesignNote.)
G protein coupled receptor protein signaling pathway
G protein coupled receptor protein signalling pathway
G-protein coupled receptor protein signal transduction
G-protein coupled receptor protein signaling pathway
G-protein coupled receptor signaling pathway
G-protein coupled receptor signalling pathway
G-protein-coupled receptor protein signaling pathway
G-protein-coupled receptor protein signalling pathway
Growth hormone plays a major role in regulating growth during childhood and adolescence and also regulates metabolism. Defects in growth hormone signaling can result in dwarfism and decreases in growth hormone levels with age have been suggested to play a role in the reduced function of some physiological systems. Growth hormone signals a response in cells through the growth hormone receptor, a member of the cytokine receptor gene family. Growth hormone causes the receptor to dimerize, activating the JAK2 protein kinase. The activity of JAK2 mediates many of the downstream responses to growth hormone through phosphorylation of STAT transcription factors, MAP kinases, other kinase cascades and molecules involved in metabolism like IRS-1. Factors like SOCS and SHP-1 appear to play a role in the down regulation of signaling by growth hormone and cytokines. (This definition may be outdated - see the DesignNote.)
Signaling events mediated by HDAC Class I
Signaling events mediated by HDAC Class II
Signaling events mediated by HDAC Class III
Signaling events mediated by the Hedgehog family
Hedgehog Family-Mediated Signaling Pathway
Hedgehog signaling events mediated by Gli proteins
Hedgehog Signaling Events Mediated by Gli Family Proteins
The Hedgehog (Hh) family of secreted signaling proteins plays a crucial role in development of diverse animal phyla, from Drosophila to humans, regulating morphogenesis of a variety of tissues and organs. Hh signaling is also involved in control of stem cell proliferation in adult tissues and aberrant activation of the Hh pathway has been linked to multiple types of human cancer. Members of the Hh family bind to patched (ptc), thus releasing smoothened (smo) to transduce a signal. Transcriptional activation occurs through the GLI family of proteins resulting in activation of target genes.
The hepatocyte growth factor receptor, also called c-Met, is activated by HGF and stimulates proliferation of hepatocytes and other cell types. Mutated forms of the HGF receptor are associated with oncogenesis and metastasis, making the HGF receptor a potential therapeutic target for cancer drugs. Changes in cell motility, cell shape, adhesion, resistance to apoptosis, and anchorage independent growth all contribute to the role of c-Met in cancer. The HGF receptor is a heterodimer with tyrosine kinase activity and associates with a multiprotein complex involved in downstream signal transduction. The HGF receptor can associate with several different signaling systems, including src, Grb2/SOS, PI3 kinase and Gab1. One of the major substrates of the activated HGF receptor tyrosine kinase is the adaptor protein Gab1. Gab1 interacts with Crk and CrkL, two proteins with SH2 and SH3 protein interaction domains that couple to signaling further downstream. The actions of HGF on paxillin, DOCK180, and Rap1, mediated through GAB1 and other members of this complex, alter cell motility. Regulation of Rho, Rac1, and CDC42 pathways in response to HGF all contribute to changes in cellular motility. Another target of the HGF receptor kinase is the focal adhesion kinase, FAK. The activation of FAK induces the formation of focal adhesions, a preliminary step to increased cell motility and tissue invasion by transformed cells, and paxillin phosphorylation may also alter cell adhesion of Met transformed cells. Src and p130cas are required for the role of FAK in HGF induced cellular transformation. HGF also blocks anoikis, the induction of apoptosis through suspension of cells, by acting on Erk and AKT kinases. This activity may contribute to anchorage independent growth of Met transformed cells. Signaling by integrins also plays a key role in the activation of tissue invasive growth by HGF. The alpha6beta4 integrin acts as a cofactor along with Meta to participate in cell growth and proliferation. In addition to altering cell adhesion, proliferation, and cell motility, HGF alters cellular transcription through activation of STAT3. STAT3 activation by HGF is independent of PI3 kinase or map kinases and alters gene expression leading to changes in cellular shape. Although HGF is associated with cellular proliferation and survival, in rat liver epithelial cells HGF induces apoptosis and inhibits cell growth. (This definition may be outdated - see the DesignNote.)
Hepatocyte Growth Factor Receptor Signaling Pathway
Signaling of Hepatocyte Growth Factor Receptor
Hepatocyte Growth Factor Receptor Signaling Pathway BioCarta
Hepatocyte Growth Factor Receptor Signaling Pathway PID
HIF-2-alpha transcription factor network
HIF-2-Alpha Transcription Factor Pathway
Interferon alpha plays a role in viral infections. Signaling takes place through an IFN receptor complex consisting of two alpha chains (type I receptor) complexed with Jak1 and Tyk2. These kinases phosphorylate Stat1 and Stat2 respectively. (This definition may be outdated - see the DesignNote.)
Interferon gamma is secreted from CD4+ Th1 cells, CD8 cells, gamma/delta T cells, and activated NK cells. It plays a role in activating lymphocytes to enhance anti-microbial and anti-tumor effects. In addition it plays a role in regulating the proliferation, differentiation, and response of lymphocyte subsets. Signaling takes place through an IFN Receptor complex consisting of two alpha chains (type I receptor) and two beta chains (type 2 receptor). Upon phosphorylation by Jak1, Stat1 (alpha) transduces the signal into transcriptional events. (This definition may be outdated - see the DesignNote.)
Insulin like growth factor 1 (IGF-1) and its receptor (IGF-1R) provide a potent proliferative signaling system that stimulates growth in many different cell types and blocks apoptosis. In vivo IGF-1 acts as an intermediate of many growth hormone responses, and may stimulate the growth of some types of cancer. IGF-1 also provides a mitogenic signal to act as a growth factor for many tissue culture cells. One component of IGF-1 mitogenic signaling is association of the receptor tyrosine kinase with Shc, Grb2, and Sos-1 to activate ras and the Map kinase cascade (raf, Mek, Erk). An endpoint of the Map kinase pathway is modification of transcription factor activity, such as activation of ELK transcription factors. Serum response factor (SRF) and AP-1 contribute to mitogenic signaling by many factors. Phosphorylation of IRS-1 and PI3 kinase activation are also involved in IGF-1 signaling, similar to insulin signaling. (This definition may be outdated - see the DesignNote.)
Insulin-Like Growth Factor 1 Signaling Pathway
Interleukin-12 (IL-12) promotes cell-mediated immunity by inducing Th1 cell differentiation and activation of both T cells and NK cells. Dendritic cells and macrophages in peripheral tissues act as antigen presenting cells and secrete IL-12 as one component of the antigen response, Th1 differentiation. The role of IL-12 in cellular immunity is largely mediated by the STAT-4 transcription factor. STAT-4 is essential for IL-12 activity and the phenotype of mice lacking STAT-4 is very similar to the phenotype of mice lacking the IL-12 receptor or IL-12. The role of IL-12 in Th1 differentiation may not be to induce the Th1 cell fate, but to stimulate growth of cells determined for the Th1 cell fate by the T-bet transcription factor. Several signaling pathways contribute to IL-12 activation of STAT-4 to regulate cell-mediated immune responses. The JAK kinases such as JAK2 and TYK2 interact with the activated IL-12 receptor and tyrosine phosphorylate the IL-12 receptor and STAT-4. IL-12 also activates a map kinase pathway activating the map kinase kinase MKK6 and p38. Phosphorylation of STAT-4 on serine 721 by p38 contributes to the full transcriptional activation of genes by STAT-4. Some of the events downstream of IL-12 appear to include genes activated indirectly by STAT-4, such as genes activated by the transcription factor ERM. ERM is in the Ets family of transcription factors, is activated by IL-12 and activates IL-12 inducible genes such as Interferon-gamma that are not activated by STAT-4 itself. Interferon-gamma transcription in T cells is also activated by other signals such as from the T cell receptor. Other proteins activated transcriptionally downstream of IL-12 and STAT-4 include the chemokine receptor CCR5 and IL-18 and its receptor. Some viruses, including HIV, repress cell-mediated immunity by blocking IL-12 signaling. (This definition may be outdated - see the DesignNote.)
IL12 and Stat4 Dependent Signaling Pathway in Th1 Development
Inflammation is a complex response involving many different cells and signaling molecules, including the secretion of the cytokine IL-17 by activated T cells. IL-17 secretion is restricted to specific subsets of T cells but the receptor for IL-17 is widely expressed throughout the body, including fibroblasts and epithelial cells. Inflammatory responses involving IL-17 probably contribute to arthritis, asthma, skin immune reactions, and autoimmune disorders. Fibroblasts and other cells stimulated by IL-17 are induced themselves to secrete inflammatory and hematopoietic cytokines, including IL-6, IL-8, G-CSF, and Stem Cell Factor (SCF). These cytokines in turn provoke a range of activities, including the stimulation of neutrophil proliferation and differentiation. (This definition may be outdated - see the DesignNote.)
IL-18 is a pro-inflammatory cytokine similar in structure and mechanism of action to IL-1 beta. Formation of active IL-18 by macrophages requires cleavage of an inactive precursor by caspase-1 protease, also termed the IL-1 converting enzyme (ICE). One of the key biological responses induced by IL-18 is that, in combination with IL-12, it stimulates Th1 cell differentiation and involvement in immune responses. IL-18 was originally known as interferon-gamma-inducing factor, named after its induction of interferon-gamma production. Up-regulation of Fas ligand in Th1 cells by IL-18 may increase apoptosis of Fas receptor expressing cells that interact with the activated Th1 cells. This induction of apoptosis may allow IL-18 to have anti-tumor activity and may also play a role in chronic inflammatory and autoimmune conditions. (This definition may be outdated - see the DesignNote.)
Interleukin-1 (IL-1) is a pro-inflammatory cytokine that signals primarily through the type 1 IL-1 receptor (IL-1R1). The activities of IL-1 include induction of fever, expression of vascular adhesion molecules, and roles in arthritis and septic shock. The inflammatory activities of IL-1 are partially derived by transcriptionally inducing expression of cytokines such as TNF-alpha and interferons, as well as inducing the expression of other inflammation-related genes. There are two forms of IL-1 encoded by distinct genes, IL-1 alpha and IL-1 beta. IL-1 beta is produced as a 269 amino acid precursor that is cleaved by IL-1beta converting enzyme (ICE) to the active IL-1 beta form that is secreted. IL-1 signaling is opposed by the naturally occurring peptide IL-1 receptor antagonist which is a therapeutic agent for the treatment of arthritis. The type 1 IL-1 receptor protein binds IL-1 beta but requires the IL-1 receptor accessory protein (IL-1RAcP) to transduce a signal. IL-1 binding causes activation of two kinases, IRAK-1 and IRAK-2, associated with the IL-1 receptor complex. IRAK-1 (IL-1 Receptor Associated Kinase) activates and recruits TRAF6 to the IL-1 receptor complex. TRAF6 activates two pathways, one leading to NF-kB activation and another leading to c-jun activation. The TRAF associated protein ECSIT leads to c-Jun activation through the Map kinase/JNK signaling system. TRAF6 also signals through the TAB1/TAK1 kinases to trigger the degradation of I-kB, and activation of NF-kB. The IL-1 signaling cascade represents a highly conserved response to pathogens through evolution, with homologs in insects and even in plants. The signal transduction cascade utilized by IL-1 receptor is similar to that of TNF, resulting in NF-kB activation, and is most similar to that of the Toll-like receptors that also participate in inflammatory signaling responses to pathogen components like endotoxin (see Toll-like receptor pathway). (This definition may be outdated - see the DesignNote.)
Interleukin 2 (IL-2) is a potent cytokine that can lead to cellular activation and proliferation. IL-2 receptors are found on activated B-cells, LPS treated monocytes, and many T-cells. The receptor is formed from three chains, alpha (CD25), beta (CD122), and gamma (CD132). Primary signaling is through the JAK/Stat pathway and MAPKs. (This definition may be outdated - see the DesignNote.)
IL-22 is an inflammatory cytokine related to IL-10 that is produced by T cells and that induces a response in cells through a heterodimeric cell surface receptor composed of IL-22R1 and IL-10R2C. One of the actions of IL-22 appears to be the induction of acute phase inflammatory response in hepatocytes, acting through activation of STATs and transcriptional regulation. A gene with homology to the extracellular domain of the cell surface IL-22R1 receptor component was identified that lacked transmembrane and cytoplasmic domains. The protein derived from this gene was found to bind IL-22 and block its interaction with the cell surface receptor. The IL-22 soluble receptor (IL-22BP, IL-22 binding protein) also blocks some of the downstream effects of IL-22 such as STAT activation and the transcriptional induction of genes involved in the immune and inflammatory responses. The IL-22 soluble receptor may act as an anti-inflammatory agent. (This definition may be outdated - see the DesignNote.)
Interleukin-3 promotes the proliferation and differentiation of hematopoietic cells through binding to its receptor. The receptor for IL-3 is a heterodimer with a ligand-specific alpha chain (70 kD, CD123) and a common beta chain (shared with IL-5 and GM-CSF). Signaling is believed to be primarily through Stat5 and the MAPK pathways. (This definition may be outdated - see the DesignNote.)
Interleukin 4 (IL-4) is a cytokine that can lead to development of Th2 cells. The 140 kD IL-4 Receptor (CD124) is found on many cell types, even those of non-hematopoietic origin. The receptor is formed from two chains: IL-4R-alpha and the IL-2R gamma chain (CD132). Primary signaling is through the JAK/Stat6 pathway and MAPKs. (This definition may be outdated - see the DesignNote.)
IL-5 is an inflammatory signaling molecule that primarily stimulates eosinophil proliferation, maturation, and activation. Eosinophils are leukocytes involved in inflammatory responses that defend against parasites and cause some aspects of asthma, allergic reactions, and perhaps autoimmune disorders. The action of IL-5 begins with an immune response in tissues, such as activation of macrophages and T cells that secrete IL-1, IL-4, and IL-6. The immune response can lead to IL-5 secretion by T cells, eosinophils, and mast cells. Secreted IL-5 stimulates production and maturation of eosinophils in bone marrow that migrate to tissues in response to eotaxin and release factors that damage tissues, causing some of the undesirable consequences of inflammation. The receptor for IL-5 is a heterodimer of an alpha subunit that is required for IL-5 selective binding and a beta subunit that is also part of the IL-3 and GM-CSF receptors. Binding of IL-5 to the IL-5 receptor at the cell surface activates JAK/STAT signaling pathways that regulate transcription, proliferation, and differentiation. (This definition may be outdated - see the DesignNote.)
Interleukin-6 (IL-6) is a cytokine that provokes a broad range of cellular and physiological responses. In addition to playing a role in inflammation and hematopoiesis, IL-6 is involved in other processes such as neuronal differentiation and bone loss. To produce these effects IL-6 signals through a receptor composed of two different subunits, an alpha subunit that produces ligand specificity and gp130, a receptor subunit shared in common with other cytokines in the IL-6 family. Binding of IL-6 to its receptor initiates cellular events including activation of JAK kinases and activation of ras-mediated signaling. Activated JAK kinases phosphorylate and activate STAT transcription factors, particularly STAT3, that move into the nucleus to activate transcription of genes containing STAT3 response elements. The ras-mediated pathway, acting through Shc, Grb-2 and Sos-1 upstream and activating Map kinases downstream, activates transcription factors such as ELK-1 and NF-IL-6 (C/EBP-beta) that can act through their own cognate response elements in the genome. These factors and other transcription factors like AP-1 and SRF (serum response factor) that respond to many different signaling pathways come together to regulate a variety of complex promoters and enhancers that respond to IL-6 and other signaling factors. (This definition may be outdated - see the DesignNote.)
IL-7 is a key cytokine in the immune system, essential for normal development of B cells and T cells. Mice with the IL-7 receptor deleted lack B and T cells. Some humans with SCID (severe combined immunodeficiency disease) also have mutation of their IL-7 receptor gene leading to an absence of T cells and greatly impaired B cell production. The IL-7 receptor includes two polypeptides, a gamma chain and an alpha chain. The alpha-chain is unique to the IL-7 receptor while several other cytokines use the same gamma receptor chain as IL-7, including IL-2, IL-4, IL-9, IL-15 and IL-21. Binding of IL-7 to the alpha chain leads to dimerization of the alpha and gamma chains. JAK3 associated with the gamma chain tyrosine phosphorylates the alpha chain after dimerization. The importance of JAK3 in IL-7 signaling is supported by the similarity of the immune defects in JAK3 knockout mice and IL-7 knockout mice. The phosphorylated alpha chain serves as the site for recruiting other signaling molecules to the complex to be phosphorylated and activated, including STAT5, src kinases, PI3 kinase, Pyk2, and Bcl2 proteins. Some targets of IL-7 signaling contribute to cellular survival, including Bcl2 and Pyk2. Other targets contribute to cellular proliferation, including PI3 kinase, src family kinases (lck and fyn) and STAT5. The transcription factor STAT5 contributes to activation of multiple different downstream genes in B and T cells and may contribute to VDJ recombination through alteration of chromatin structure. The cell survival and cell proliferation signals induced by IL-7 combine to induce normal B and T cell development. (This definition may be outdated - see the DesignNote.)
Insulin-Mediated Glucose Transport Pathway
The appropriate signaling through the insulin pathway is critical for the regulation of glucose levels and the avoidance of diabetes. Insulin forms a complex with the insulin receptor (IR) and b chains to form the active signaling complex. Through recruitment of adaptor molecules and the activation of RAS, the activated IR can cause transcriptional activation. (This definition may be outdated - see the DesignNote.)
Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. Akt also leads to mTOR-mediated activation of protein synthesis by eIF4 and p70S6K. The translocation of GLUT4 protein is also elicited through the CAP/Cbl/TC10 pathway, once Cbl is phosphorylated by INSR.
Insulin/Insulin Receptor Signaling Pathway
Integrins are cell surface receptors that interact with the extracellular matrix and mediate intracellular signals in response to the extracellular matrix including cellular shape, mobility, and progression through the cell cycle. Integrins do not themselves possess a kinase domain or enzymatic activity but rely on association with other signaling molecules to transmit signals. Interactions between the extracellular matrix and the actin cytoskeleton commonly take place at focal adhesions on the cell surface that contain localized concentrations of integrins, signaling molecules, and cytoskeletal elements. Talin forms a direct interaction with the integrin cytoplasmic domain, and interacts with cytoskeletal elements (actin) and signaling factors. Paxillin and CAS also localize in focal adhesions and may serve as a scaffold for other integrin signaling components like FAK and src. Interaction of FAK, CAS and src may be required for integrin regulation of cell cycle progression. The CrkL adaptor protein may regulate downstream integrin signaling. Growth factor signaling pathways and the caveolin receptor exhibit important cross talk with integrin receptors in cellular responses like activation of map kinase, proliferation and motility. (This definition may be outdated - see the DesignNote.)
Signaling by interferon-gamma stimulates anti-viral responses and tumor suppression through the heterodimeric interferon-gamma receptor. Signaling is initiated by binding of interferon-gamma to its receptor, activating the receptor-associated JAK2 tyrosine kinase to phosphorylate STAT transcription factors that activate interferon responsive genes. Molecular chaperones that modulate or alter protein folding interact with different components of the interferon signaling pathway. One chaperone that modulates interferon signaling is hTid-1, a member of the DnaJ family of chaperones and a co-chaperone for the heat shock protein Hsp70, another molecular chaperone. hTid-1 was found in a two-hybrid screen to bind to JAK2 and also to interact with the interferon-gamma receptor. In addition, hTid-1 and JAK2 also interact with Hsp70. Overexpression of hTid-1 represses transcriptional activation by interferon-gamma and Hsp70 dissociates from these proteins when interferon is added to cells, suggesting that Hsp70 holds Jak2 in an inactive conformation prior to ligand activation, and is released in the presence of agonist to allow the activation of Jak-2 and downstream pathways. hTid-1 and Hsp-70 interact with other signaling proteins as well. One of these is Tax, a protein encoded by the HTLV-1 virus that binds to hTid-1. hTid-1 also represses NF-kB activation by blocking the phosphorylation and inactivation of I-kappaB by the IkappaB kinase beta. Hsp70 plays a significant role in protein unfolding for entry into mitochondria and also interacts with tumor suppressor gene products to produce their anti-proliferative activity. One of the actions of interferon is to induce apoptosis of infected target cells, in part through a mitochondrial dependent mechanism. An interaction between interferon signaling and Hsp70 may alter this mitochondrial apoptosis pathway, perhaps playing a role in interferon-mediated apoptosis of infected or transformed cells. The HTLV-1 Tax protein that interacts with Hsp70 blocks mitochondrial induced apoptosis, providing a protection against interferon-mediated cellular defenses. (This definition may be outdated - see the DesignNote.)
Chaperones modulate interferon Signaling Pathway
Molecules transmitting signals into cells often act through receptors in the plasma membrane that stimulate production of second messengers. When activated by a plasma membrane receptor, the enzyme phospholipase C (PLCg) hydrolyzes the membrane lipid phosphatidylinositol (PIP2) into the second messengers diacylglycerol (DAG) and IP3. IP3 releases calcium from intracellular stores into the cytoplasm where calcium alters many cellular activities, including activating protein kinase C. DAG also activates protein kinase C. Biologists often study signaling by artificially manipulating pathways using molecules like ionomycin and phorbol esters as research tools. Ionomycin is a molecule that carries calcium through the plasma membrane to increase the calcium concentration in the cytoplasm and activate protein kinase C without activating phospholipase C. Phorbol esters are molecules that mimic the action of DAG in the activation of protein kinase C, and were originally identified as tumor-promoting agents. The combination of ionomycin and phorbol esters is often used experimentally to study the effect of calcium and DAG signaling in cellular responses like T cell activation. (This definition may be outdated - see the DesignNote.)
Ion Channel and Phorbal Esters Signaling Pathway
The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in animals, from humans to flies. In mammals, the JAK/STAT pathway is the principal signaling mechanism for a wide array of cytokines and growth factors. Following the binding of cytokines to their cognate receptor, STATs are activated by members of the JAK family of tyrosine kinases. Once activated, they dimerize and translocate to the nucleus and modulate the expression of target genes. In addition to the activation of STATs, JAKs mediate the recruitment of other molecules such as the MAP kinases, PI3 kinase etc. These molecules process downstream signals via the Ras-Raf-MAP kinase and PI3 kinase pathways which results in the activation of additional transcription factors.
Lysophosphatidic Acid Receptor Signaling Pathway
Lysophosphatidic Acid Receptor 4 Signaling Pathway
MSP, macrophage-stimulating protein, acts through the transmembrane receptor kinase RON (Stk in mice) to play a role in inflammation and the response to tissue injury. MSP is secreted by the liver into the blood as pro-MSP, an inactive precursor form. MSP is related to clotting factors that are activated by proteolytic cleavage and pro-MSP is itself also activated by cleavage to MSP. Binding of activated MSP heterodimer to RON expressed on macrophages, monocytes and keratinocytes stimulates activation of the RON kinase and second messenger pathways, including PI-3 kinase. Macrophages respond to MSP with changes in cell shape and motility and keratinocytes respond by proliferating. Tissue injury leads to pro-MSP cleavage and activation, and macrophages and keratinocytes that respond to MSP are key cells in tissue injury response, supporting a role for MSP and RON in the response to tissue injury. The interaction of MSP and macrophages at sites of inflammation such as infection also depends on chemotactic factors such as MCP1 and inflammatory cytokines such as IL-1 and TNF that attract and activate immune cells in the affected tissue. (This definition may be outdated - see the DesignNote.)
Macrophage Stimulating 1 Receptor Signaling Pathway
The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli.
The ever evolving mitogen-activated protein kinase (MAP kinase) pathways consist of four major groupings and numerous related proteins which constitute interrelated signal transduction cascades activated by stimuli such as growth factors, stress, cytokines and inflammation. The four major groupings are the Erk, JNK or SAPK, p38, and the Big MAPK or ERK5 cascades. Signals from cell surface receptors such as GPCRs and growth factor receptors are transduced, directly or via small G proteins such as ras and rac, to multiple tiers of protein kinases that amplify these signals and/or regulate each other. In some cascades the first activation tier involves the MAPKKKKs, MAP kinase kinase kinase kinases or MAP4K proteins. The next tier are the serine/threonine MAPKKKs, MAP kinase kinase kinase or MAP3Ks such as RAF, TAK, ASK, and MEKK1. This level has the greatest amount of cross-communication currently known. The serine/threonine/tyrosine MAPKKs, MAP Kinase kinases or MAP2Ks, such as the MKK and MEK kinases, are one step up from the MAP kinase cascade, phosphorylating and activating these kinases. The focal tier, the MAPKs or MAP kinases includes JNK1, p38, and ERKs, and are the kinases that give each cascade its name. The endpoints of these cascades include the MAPK activated protein kinases (MAPKAPK) and some of the numerous transcription factors that regulate genes involved in apoptosis, inflammation, cell growth and differentiation. (This definition may be outdated - see the DesignNote.)
Signaling events mediated by Stem cell factor receptor (c-Kit)
stem cell factor receptor signaling pathway
Mast/Stem Cell Growth Factor Receptor Signaling Pathway
Mitochondria participate in apoptotic signaling pathways through the release of mitochondrial proteins into the cytoplasm. Cytochrome c, a key protein in electron transport, is released from mitochondria in response to apoptotic signals, and activates Apaf-1, a protease released from mitochondria. Activated Apaf-1 activates caspase-9 and the rest of the caspase pathway. Smac/DIABLO is released from mitochondria and inhibits IAP proteins that normally interact with caspase-9 to inhibit apoptosis. Apoptosis regulation by Bcl-2 family proteins occurs as family members form complexes that enter the mitochondrial membrane, regulating the release of cytochrome c and other proteins. TNF family receptors that cause apoptosis directly activate the caspase cascade, but can also activate Bid, a Bcl-2 family member, which activates mitochondria-mediated apoptosis. Bax, another Bcl-2 family member, is activated by this pathway to localize to the mitochondrial membrane and increase its permeability, releasing cytochrome c and other mitochondrial proteins. Bcl-2 and Bcl-xL prevent pore formation, blocking apoptosis. AIF (apoptosis inducing factor) is another mitochondrial factor that is released into the cytoplasm to induce apoptosis. AIF-induced apoptosis is important during development but is not caspase dependent. (This definition may be outdated - see the DesignNote.)
Role of Mitochondria in Apoptotic Signaling
Mitochondria in Apoptotic Signaling Pathway
mTOR (mammalian target of rapamycin) appears to play a central role in signaling caused by nutrients and mitogens such as growth factors to regulate translation. The drug rapamycin acts on mammalian cells through the mTOR protein kinase, also known as FRAP. When bound to the immunophilin binding protein FKBP12, rapamycin inhibits mTOR kinase activity and has immunosuppressant activity. Rapamycin and the mTOR inhibitor CCI-779 are being tested as anti-cancer agents, acting to block mitogenic signaling. Recently, mTOR was also found to act as an ATP sensor to regulate cell growth. Upstream activation of PI 3 kinase activity that leads to oncogenic transformation can be blocked by inhibition of mTOR by rapamycin. Growth factor receptors first stimulate PI 3 kinase, and through inositol phosphates activate PDK-1 and AKT (protein kinase B). AKT phosphorylates mTOR. The phosphorylation of p70S6K and 4EBP by mTOR and the phosphorylation downstream of RPS6 and EIF-4B stimulate translational initiation and contribute to cell growth. (This definition may be outdated - see the DesignNote.)
Nerve growth factor (NGF) is one of a family of neurotrophins that induce the survival and proliferation of neurons. In cell culture NGF induces the formation of neurite projections and in vivo may stimulate the innervation of tissues. NGF plays a role in the repair, regeneration, and protection of neurons, and as such could serve as a therapeutic agent in neurodegenerative conditions such as Alzheimer's disease. One potential method of NGF application would be through gene therapy or through implantation of cells that have been genetically modified ex vivo. NGF has also been suggested to play a role in other physiological systems and tissues such as the immune system. NGF has two receptors, TrkA and the p75(NTR). NGF may signal its neuroprotective actions through the tyrosine kinase TrkA receptor and trigger apoptosis in some cells through the p75 receptor. High-affinity binding of NGF requires both TrkA and p75(NTR). Binding of NGF to the TrkA receptor causes activation of the receptor tyrosine kinase and downstream signaling cascades. One of the downstream signaling pathways of NGF activates phospholipase C, releasing DAG and IP3 and activating associated downstream pathways such as protein kinase C. Another NGF-activated pathway is the ras-mediated activation of the map kinase pathway. This pathway is initiated through recruitment and activation of Shc, which leads to ras activation through Grb-2 and Sos-1. The Map kinase cascade includes raf, Mek and Erk. The downstream effectors of the ras pathway include activation of fos and jun to form AP-1, activating genes through this transcription factor. Other transcription factors involved in NGF responses include Egr and CREB. The Egr family of transcription factors, as well as the Mek/Erk pathway, contribute to NGF-induced neurite formation. The CREB family of transcription factors are involved in NGF-induced survival of sympathetic neurons. Further understanding of NGF signaling may be applied to the modulation of NGF responses in neurodegenerative conditions. (This definition may be outdated - see the DesignNote.)
Neuroactive Ligand-Receptor Signaling Pathway
High Affinity Nerve Growth Factor Receptor Signaling Pathway
Neurotrophic factor-mediated Trk receptor signaling
Neurotrophic Factor-Mediated NTRK1 Signaling Pathway
Trk receptor signaling mediated by the MAPK pathway
Trk receptor signaling mediated by PI3K and PLC-gamma
Nuclear factor kB (NF-kB) is a nuclear transcription factor that regulates expression of a large number of genes that are critical for the regulation of apoptosis, viral replication, tumorigenesis, inflammation, and various autoimmune diseases. The activation of NF-kB is thought to be part of a stress response as it is activated by a variety of stimuli that include growth factors, cytokines, lymphokines, UV, pharmacological agents, and stress. In its inactive form, NF-kB is sequestered in the cytoplasm, bound by members of the IkB family of inhibitor proteins, which include IkBa, IkBb, IkBg, and IkBe. The various stimuli that activate NF-kB cause phosphorylation of IkB, which is followed by its ubiquitination and subsequent degradation. This results in the exposure of the nuclear localization signals (NLS) on NF-kB subunits and the subsequent translocation of the molecule to the nucleus. In the nucleus, NF-kB binds with a consensus sequence (5'GGGACTTTCC-3') of various genes and thus activates their transcription. IkB proteins are phosphorylated by IkB kinase complex consisting of at least three proteins; IKK1/IKKa, IKK2/IKKb, and IKK3/IKKg. These enzymes phosphorylate IkB leading to its ubiquitination and degradation. Tumor necrosis factor (TNF) which is the best-studied activator binds to its receptor and recruits a protein called TNF receptor death domain (TRADD). TRADD binds to the TNF receptor-associated factor 2 (TRAF-2) that recruits NF-kB-inducible kinase (NIK). Both IKK1 and IKK2 have canonical sequences that can be phosphorylated by the MAP kinase NIK/MEKK1 and both kinases can independently phosphorylate IkBa or IkBb. TRAF-2 also interacts with A20, a zinc finger protein whose expression is induced by agents that activate NF-kB. A20 functions to block TRAF2-mediated NF-kB activation. A20 also inhibits TNF and IL-1 induced activation of NF-kB suggesting that it may act as a general inhibitor of NF-kB activation. (This definition may be outdated - see the DesignNote.)
Nitric oxide (NO) has a number of important physiological actions in the cardiovascular system. In the heart, NO plays a role in keeping the vessels open via vasodilation and prevention of platelet aggregation. It also plays an important role in regulating the force and rate of contraction. In vivo NO is released by shear stress of ligands that increase intracellular Ca2+ in endothelial cells. The increased intracellular Ca2+ activates nitric oxide synthase III (NOSIII) by promoting the binding of Ca/Calmodulin to the enzyme. NOSIII, which is resident in the Golgi complex, is transported together with caveolin-1 to the caveolae at the plasma membrane via vesicles. Shear stress signals via a potassium channel and the cytoskeleton, which results in tyrosine phosphorylation of specific proteins, activation of phosphatidylinositol 3-kinase, and subsequently in activation of Akt kinase. Akt activation by shear stress, but also by VEGF, activates NOSIII by serine phosphorylation, which increases the affinity of NOSIII for calmodulin. After agonist binding at the plasma membrane, NOSIII-activating receptors translocate to caveolae. VEGF receptor signals via its tyrosine kinase domain. Furthermore, agonist receptors activate calcium channels of the endoplasmic reticulum (ER) via phospholipase C and inositol 1,4,5-trisphosphate. This calcium flux induces binding of calmodulin to NOSIII, whereas the NOSIII-caveolin-1 interaction is disrupted. At the same time, NOSIII is translocated into the cytosol. On binding of calmodulin, NOSIII generates NO, is enhanced by the interaction with Hsp90. Once activated, NOSIII catabolizes L-arginine to NO, which diffuses out of the cell. NO stimulates guanylate (G-) cyclase and increases cGMP levels. cGMP activates cGMP-dependent protein kinase (PKG), cGMP-inhibited phosphodiesterase (PDEIII), and cGMP-stimulated phosphodiesterase (PDEII). PKG may reduce the force and rate of contraction, possibly by phosphorylating troponin I or by phosphorylating phospholamban. PDEIII is inhibited by the increases in cGMP brought about by NO. This may result in an increase in cAMP and cAMP-dependent protein kinase (PKA). PKA in turn activates Ca2+ channels, countering the effects of PKG. In contrast, cGMP may stimulate PDEII, reduce cAMP levels and PKA activity, and thereby reduce Ca2+ channel activity. (This definition may be outdated - see the DesignNote.)
Glutamatergic-mediated nitric oxide (NO) production occurs via the N-methyl-D-aspartic acid (NMDA) postsynaptic density protein 95 (PSD95)-neuronal nitric oxide synthase (NOS1) ternary complex. The increased intracellular Ca2+ stimulates the interaction of nNOS and calmodulin (CaM) and the translocation of nNOS from the plasma membrane to the cytoplasm. The dephosphorylation of nNOS by Calcineurin catalyzes the conversion of arginine to citrulline and nitric oxide (NO), which turns on guanylate cyclase and the various cGMP regulated signaling pathways. (This definition may be outdated - see the DesignNote.)
Specific families of pattern recognition receptors are responsible for detecting various pathogens and generating innate immune responses. The intracellular NOD-like receptor (NLR) family contains more than 20 members in mammals and plays a pivotal role in the recognition of intracellular ligands. NOD1 and NOD2, two prototypic NLRs, sense the cytosolic presence of the bacterial peptidoglycan fragments that escaped from endosomal compartments, driving the activation of NF-kappa-B and MAPK, cytokine production and apoptosis. On the other hand, a different set of NLRs induces caspase-1 activation through the assembly of multiprotein complexes called inflammasomes. These NLRs include NALP1, NALP3 and Ipaf. The inflammasomes are critical for generating mature proinflammatory cytokines in concert with Toll-like receptor signaling pathway.
Presenilin-1 (PS1) is associated with gamma secretase activity that cleaves amyloid precursor protein (APP) and is implicated in Alzheimer's disease. Presenilin-1 is also a component in gamma-secretase activity involved in signaling by the transmembrane protein Notch. Active gamma secretase requires PS-1 N-terminal fragment and a C-terminal fragment and is unique in catalyzing proteolysis within the transmembrane region of proteins. Other proteins such as nicastrin may also be components of the gamma-secretase. Binding of the ligand Delta by Notch appears to trigger two proteolytic cleavages of Notch. The first step cleaves an extracellular domain and is catalyzed by a metalloprotease termed alpha-secretase or TACE. The second cleavage step appears to occur within the transmembrane domain of Notch, and releases a Notch intracellular domain (NICD). Once released, NICD moves into the nucleus where it is involved in transcriptional regulation through CSL family transcription factors (CBF1, Su(H), Lag-1) or other transcriptional regulators such as LEF-1. Presenilin is also involved in the Wnt/frizzled signaling pathway through beta-catenin. Beta-catenin is a cytoskeletal component that enters the nucleus to act as a transcriptional cofactor. Binding of WNT to Frizzled causes disheveled (DSH) to inhibit Glycogen synthase kinase 3 beta (GSK-3b) activity. Phosphorylation of Beta-catenin induces the ubiquitination and proteolytic degradation of beta-catenin by the proteasome. Non-phosphorylated beta-catenin is stable and enters the nucleus to regulate transcription with TCF. The beta-catenin/TCF complex activates genes that promote cellular survival, proliferation and differentiation during development. Presenilin stimulates beta-catenin turnover, reducing its transcriptional activation. (This definition may be outdated - see the DesignNote.)
Presenilin action in Notch and Wnt signaling
Notch is a large cell-surface receptor that is activated by contact with membrane-bound ligands on neighboring cells. The ligands that activate Notch include Delta and Serrate, and Lag-2 is a Notch ligand in C. elegans. Activation of Notch by binding with its ligand on the surface of neighboring cells is involved in several developmental pathways, helping to determine cell fate. Much of the early insight into Notch signaling was derived from genetic studies in Drosophila and C. elegans models. Three different proteolytic steps process the 300 kD precursor of mature Notch. One protease is a furin-like enzyme that cleaves Notch constitutively adjacent to the amino acid sequence RQRR in the extracellular domain. Another proteolytic step in Notch processing is carried out by TACE, also known as ADAM17. Binding of extracellular ligand to Notch also induces cleavage at the transmembrane region by a gamma-secretase activity that is dependent on presenilin-1. The exact identity of the polypeptide that catalyzes the gamma-secretase enzyme activity has been debated. Labeling of presenilin with irreversible gamma-secretase transition state inhibitors indicates that is itself in fact the site of protease activity. It has also been argued that the gamma secretase is not presenilin-1 itself, but another polypeptide that requires Notch for its activity and is distinct from Presenilin-1. Cleavage of Notch in the extracellular domain releases the Notch intracellular domain (BIOCARTAD) which migrates into the nucleus where it associates with CSL transcription factors and acts as a transcriptional coactivator. The proteolytic processing of Notch resembles in several ways the proteolytic processing of amyloid precursor protein (APP) that is implicated in plaque formation in Alzheimer's disease, with TACE and Presenilin-1 implicated in proteolytic processing of both Notch and APP. (This definition may be outdated - see the DesignNote.)
Proteolysis and Signaling Pathway of Notch
The Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic development in all metazoan organisms in the Animal kingdom. The Notch proteins (Notch1-Notch4 in vertebrates) are single-pass receptors that are activated by the Delta (or Delta-like) and Jagged/Serrate families of membrane-bound ligands. They are transported to the plasma membrane as cleaved, but otherwise intact polypeptides. Interaction with ligand leads to two additional proteolytic cleavages that liberate the Notch intracellular domain (NICD) from the plasma membrane. The NICD translocates to the nucleus, where it forms a complex with the DNA binding protein CSL, displacing a histone deacetylase (HDAc)-co-repressor (CoR) complex from CSL. Components of an activation complex, such as MAML1 and histone acetyltransferases (HATs), are recruited to the NICD-CSL complex, leading to the transcriptional activation of Notch target genes.
Within the compact cilia of the olfactory receptor neurons (ORNs) a cascade of enzymatic activity transduces the binding of an odorant molecule to a receptor into an electrical signal that can be transmitted to the brain. Odorant molecules bind to a receptor protein (R) coupled to an olfactory specific Gs-protein (G) and activate a type III adenylyl cyclase (AC), increasing intracellular cAMP levels. cAMP targets an olfactory-specific cyclic-nucleotide gated ion channel (CNG), allowing cations, particularly Na and Ca, to flow down their electrochemical gradients into the cell, depolarizing the ORN. Furthermore, the Ca entering the cell is able to activate a Ca-activated Cl channel, which would allow Cl to flow out of the cell, thus further increasing the depolarization. Elevated intracellular Ca causes adaptation by at least two different molecular steps: inhibition of the activity of adenylyl cyclase via CAMKII-dependent phosphorylation and down-regulation of the affinity of the CNG channel to cAMP. Longer exposure to odorants can stimulate particulate guanylyl cyclase in cilia to produce cGMP and activate PKG, leading to a further increase in amount and duration of intracellular cAMP levels, which may serve to convert inactive forms of protein kinase A (PKA2) to active forms (PKA*). As part of a feedback loop, PKA can inhibit the activation of particulate guanylyl cyclase.
Two key features of the immune system are the clonal expansion of B cells and T cells in response to antigens, and the potentiation of future immune responses by long-lived memory cells. CD4-expressing T cells require costimulatory signals along with antigen stimulation to mount an effective immune response. CD28 has been widely characterized as a costimulatory receptor for CD4+ T cells. OX40, also called CD134, is another transmembrane receptor protein expressed by CD4 T cells that provides a costimulatory signal for T cell activation by antigen. The OX40L ligand for OX40 is expressed as a transmembrane protein by antigen-presenting cells, and is required for function of antigen-presenting cells. The T cell costimulatory signal provided by the OX40/OX40L interaction increases the clonal amplification of antigen-specific T cells and the survival of memory T cells that respond to this antigen. (This definition may be outdated - see the DesignNote.)
p38 MAPKs are members of the MAPK family that are activated by a variety of environmental stresses and inflammatory cytokines. Stress signals are delivered to this cascade by members of small GTPases of the Rho family (Rac, Rho, and Cdc42). As with other MAPK cascades, the membrane-proximal component is a MAPKKK, typically a MEKK or a mixed lineage kinase (MLK). The MAPKKK phosphorylates and activates MKK3/5. The p38 MAPK kinase. MKK3/6 can also be activated directly by ASK1, which is stimulated by apoptotic stimuli. P38 MAK is involved in regulation of Hsp27 and MAPKAP-2 and several transcription factors including ATF2, STAT1, Max/Myc complex, MEF-2, ELK-1, and indirectly CREB via activation of MSK1. (This definition may be outdated - see the DesignNote.)
p38 signaling mediated by MAPKAP kinases
Signaling mediated by p38-alpha and p38-beta
p38-alpha and p38-beta Signaling Pathway
Signaling mediated by p38-gamma and p38-delta
p38-gamma and p38-delta Signaling Pathway
Regulation of p38-alpha and p38-beta Pathway
The molecular events that lead to the perception of pain are a key research field in medicine and drug discovery. The opioid receptors modulate pain signaling in response to endogenous peptide ligands and opiate drugs such as morphine. The kappa opioid receptor plays a key role in the profound analgesia of opiates and is activated by the endogenous peptide ligand dynorphin, encoded by the prodynorphin gene. Production of prodynorphin is transcriptionally regulated by a downstream regulatory element (DRE) in the prodynorphin gene. A transcription factor called DREAM (DRE antagonistic modulator) binds to the DRE and represses prodynorphin transcription when bound. DREAM binds calcium with 4 EF-hand motifs and the binding of DREAM to DNA is repressed in the presence of calcium. Many transcription factors are regulated by calcium indirectly through calcium sensitive kinases and phosphatases, but DREAM is unique to date in being a transcription factor that directly binds calcium and is regulated by calcium binding. DREAM may also regulate other genes such as c-fos. DREAM is expressed in spinal cord neurons in regions involved in pain signaling. The regulation of prodynorphin expression by DREAM also leads to the hypothesis that DREAM is involved in pain signaling. Transgenic mice lacking the DREAM gene were unusually pain insensitive and had elevated spinal levels of dynorphin and tonic activation of the kappa opioid receptor, supporting this hypothesis. Other functions of DREAM may exist such as regulation of presenilins and potassium channel activity in the heart. DREAM is also known as calsenilin and KChIP3 through its association with these other proteins. These processes were not affected in mice lacking the DREAM gene however. (This definition may be outdated - see the DesignNote.)
Repression of Pain Sensation by the Transcriptional Regulator DREAM
Platelet Derived Growth Factor (PDGF) plays a critical role in cellular proliferation and development. The biologically active form is a dimer formed from the A and B chains. PDGF is active to a differing degree depending on which dimer is formed (AA, AB, or BB). The PDGF Receptor (PDGFR) is also a dimer and can form from the combination of the alpha and beta chains in any order (alpha-alpha, alpha-beta, beta-beta). The PDGFR dimer is only formed after ligand binding so the alpha/beta composition of the receptor can be influenced by the form of PDGF that is present. Upon binding of ligand the PDGFR is tyrosine phosphorylated and leads to the phosphorylation of several other cellular proteins. (This definition may be outdated - see the DesignNote.)
Alpha-Type Platelet-Derived Growth Factor Receptor Signaling Pathway
Beta-Type Platelet-Derived Growth Factor Receptor Signaling Pathway
platelet-derived growth factor receptor-beta signaling pathway
platelet-derived growth factor receptor-beta signalling pathway
Proline-, glutamic acid-, leucine-rich protein 1 (Pelp1 or modulator of nongenomic activity of estrogen, MNAR) is a recently discovered transmitter of estrogen signals. The receptors for estrogen (ER), progestin (PR), androgen (AR) and others are steroid hormone receptors, which are part of a large family of ligand-inducible transcription factors. It has been established that estrogen has at least two courses of action termed classical or genomic and nongenomic. The classical activation cascade is well known. The nongenomic or nontranscriptional activation cascade for the estrogen receptor was determined based on the rapid response times observed for the activation of the MAPK cascade and other cell proliferation effects. The mechanism was believed to involve a membrane bound ER but attempts to isolate such a protein have not been successful. A second possibility would involve a scaffold protein that interacts with ER. Pelp1 appears to fit the second scenario. Pelp1 was first isolated as a coactivator of transcription for ER-alpha. It was observed that Pelp1 was expressed at levels 3-5 times normal in breast tumors. Several breast cancer cell lines have been shown to express Pelp1. Like many nuclear hormone receptors Pelp1 also interacts with Cbp and p300. More recently it has been demonstrated that Pelp1 mediates the interaction of ER and Src leading to the activation of the Mitogen Activated Protein Kinases Erk1 and Erk2. (This definition may be outdated - see the DesignNote.)
Pelp1 Modulation of Estrogen Receptor Activity
Phosphatidylinositol Signaling System Pathway
Phospholipase C comes in multiple forms and plays a key role in the signal transduction process for many receptors. Its main function is to hydrolyze phosphatidylinositol diphosphate into diacylglycerol (DG) and inositol triphosphate (IP3). DG is necessary for further activation of Protein Kinase C while IP3 leads to the release of intracellular calcium. (This definition may be outdated - see the DesignNote.)
Proposed model for b2-AR- and prostanoid-receptor-mediated PLC and calcium signaling. Receptors coupling to Gs stimulate AC, resulting in elevated cAMP levels and activation of Epac1. Epac1 then catalyses GTP-loading on Rap2B, which leads to PLC-e activation. The proposed pathway may involve additional signaling components to attain PLC stimulation. The action of cAMP seems to be independent of PKA; instead, the cAMP-activated Rap-GEF Epac seems to serve as a cAMP effector, inducing GTP loading and, hence, activation of Rap2B, which then leads to specific activation of PLC-e, which has been shown to interact with Rap GTPases. It is an attractive hypothesis, therefore, that the Rap-dependent PLC and calcium signaling pathway reported here is not restricted to Gs-and AC-coupled receptors, such as the b2-AR and the prostanoid receptor, but could be used by other receptors as well. (This definition may be outdated - see the DesignNote.)
Phospholipase C-Epsilon Signaling Pathway
Phospholipase C (PLC) d1 is a member of the PLC family that produces two second messengers, diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) by hydrolyzing the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2). DAG in combination with Ca++ is necessary for further activation of Protein Kinase C, while IP3 diffuses into the cytoplasm and mediates the release of intracellular calcium. PLC d1 has a pleckstrin homology (PH) domain that binds to PIP2 in the membrane with an affinity of 1.7 mM. It has selectivity for PIP2 over other phosphatidylinositol lipids and provides a specific probe for activation of PIP2 metabolism to DG and IP3. Activation of PLC d1 results in its translocation from the membrane to the cytoplasm. PLC d1 activity is feedback-inhibited by IP3, which has an 8-fold higher affinity for PLC d1 than does PIP2. The members of the PLC family play a key role in the signal transduction cascade for many receptors. At basal Ca++ levels PLC d1 has been shown to be activated by the adrenoreceptor a1B, adrenoreceptor a1D, a-thromboxane receptor and oxytocin receptor. The G protein involved is the GTP-binding protein known as tissue transglutaminase (Gah or TGII). Gah is a bifunctional enzyme, having GTPase and transglutaminase (TGase) activity and is present in the plasma membrane, cytosol, and nucleus. Exchange of GDP to GTP by Gah is facilitated by activation of the receptors. However, a bimodal regulation of PLC d1 activity has been observed depending on Ca++ levels and occupancy of the guanine nucleotide binding site of Gah. In addition, the GTPase activating protein RhoGAP interacts with and stimulates PLC d1. The complex regulation of PLC d1 activity enables the protein to modulate intracellular signaling. (This definition may be outdated - see the DesignNote.)
Phospholipase C d1 in phospholipid associated cell signaling
Phospholipid Associated Cell Signaling Pathway
Sphingosine-1-phosphate (S1P) is an example of a lipid messenger with both intracellular and extracellular functions. Intracellularly S1P regulates proliferation and survival; extracellularly S1P is a ligand for EDG1 (also known as S1P1). Activation of sphingosine kinase (SPHK), the enzyme that catalyzes the phosphorylation of sphingosine, increases cellular levels of S1P. Inhibitors of SPHK block formation of S1P and inhibit cellular proliferation induced by a variety of factors, including platelet-derived growth factor (PDGF) and PMA. In a study using endothelial cells it was demonstrated that S1P induces activation of alpha-v and B3 integrins via RhoA. S1P also activates Akt via Gi and PI3K. The activated Akt phosphorylates the Edg1 receptor on threonine 236 leading to the activation of Rac1 and subsequent signals leading to actin assembly, chemotaxis and lamellipodia formation. Edg1 stimulation also leads to the activation of the ERK signaling cascade resulting in anti-apoptotic reversal, proliferation and cell survival. (This definition may be outdated - see the DesignNote.)
Phospholipids as signaling intermediaries
Phototransduction is a biochemical process by which the photoreceptor cells generate electrical signals in response to captured photons. The vertebrate cascade starts with the absorption of photons by the photoreceptive pigments, the rhodopsins, which consist of a membrane embedded chromophore, 11-cis-retinal, and a G-protein-coupled receptor, opsin. The photon isomerizes 11-cis-retinal to all-trans-retinal which induces a structural change that activates the opsin. This triggers hydrolysis of cGMP by activating a transducin-phosphodiesterase 6 (PDE6) cascade, which results in closure of the cGMP-gated cation channels (CNG) in the plasma membrane and membrane hyperpolarization. The hyperpolarization of the membrane potential of the photoreceptor cell modulates the release of neurotransmitters to downstream cells. Recovery from light involves the deactivation of the light-activated intermediates: photolyzed rhodopsin is phosphorylated by rhodopsin kinase (RK) and subsequently capped off by arrestin; GTP-binding transducin alpha subunit deactivates through a process that is stimulated by RGS9.
Plasma membrane estrogen receptor signaling
Plasma Membrane Estrogen Receptor Signaling Pathway
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that are activated by fatty acids and their derivatives. PPAR has three subtypes (PPARalpha, beta/delta, and gamma) showing different expression patterns in vertebrates. Each of them is encoded in a separate gene and binds fatty acids and eicosanoids. PPARalpha plays a role in the clearance of circulating or cellular lipids via the regulation of gene expression involved in lipid metabolism in liver and skeletal muscle. PPARbeta/delta is involved in lipid oxidation and cell proliferation. PPARgamma promotes adipocyte differentiation to enhance blood glucose uptake.
Peroxisome Proliferator-Activated Receptor Signaling Pathway
peroxisome proliferator activated receptor signaling pathway
peroxisome proliferator activated receptor signalling pathway
Signaling events regulated by Ret tyrosine kinase
Proto-Oncogene Tyrosine-Protein Kinase Receptor Ret Signaling Pathway
This pathway is a compilation of Pyk2 effort cascades; in specific cell types the receptor and effectors will vary. Binding of a transmembrane receptor triggers the activation of Ca2+ signaling and PKC. The signal is then transmitted to Pyk2 and further to the small G protein Rac1. In turn, Rac1 initiatives the JNK cascade, starting with PAK followed by MEKK1, SEK1, and JNK. JNK activation causes induction of c-Jun gene binding. Pyk2 stimulation has also been shown to activate MKK3 leading to activation of p38. The other major mitogen activated kinase cascade for ERK1/2 is stimulated via RAS, RAF and MEKK1/2. (This definition may be outdated - see the DesignNote.)
Rac-1 is a small G-protein in the Rho family that regulates cell motility in response to extracellular signals. Several changes in cytoskeletal structure and other aspects of cell structure are involved in cell motility. Rac-1 is activated by GEF factors, and repressed by GAPs. GEFs are guanine nucleotide exchange factors, including Trio and Vav. Sos-1 is involved in Ras signaling and also acts as a GEF for Rac to transduce signals between Ras and Rac. SWAP-70 is a Rac GEF that binds IP3 and transduces signals from tyrosine kinases to Rac to modulate the cytoskeleton and cause membrane ruffling. GAPs are GTPase- activating proteins. Rac stimulates the formation of actin-based structures such as filopodia and lamellipodia, while GAPs such as chimerin oppose the formation of these Rac dependent structures. Several different factors downstream of Rac act on cytoskeletal structure and other aspects of cell motility. Pak1 provides a direct link from Rac to cell motility through phosphorylation of the myosin light chain. Pak1 also phosphorylates and activates LIM kinase, which phosphorylates cofilin as one target. Cofilin stimulates actin depolymerization and changes in cell structure, and phosphorylation of cofilin by LIM kinase represses its activity. In neurons, Rac acts through the protein kinase cdk5 and p35 to phosphorylate and down regulate Pak1, increasing neuronal migration. Rac-1 also interacts with several other factors to regulate a variety of processes. Interaction of Por1 with Rac-1 is involved in membrane ruffling. WAVE is a member of the WASP family of proteins that regulate actin organization and that is involved in Rac signaling to cause membrane ruffling. Interaction of Rac-1 with MEKK1 integrates Rac signaling with pathways signaling through map kinases. (This definition may be outdated - see the DesignNote.)
Ras activates many signaling cascades. Here we illustrate some of the well-characterized cascades in a generic compilation of effector molecules. The effectors mediate Ras stimulation to a diverse set of cellular signals. Many of these signals are interpreted differently depending on the cell type or microenvironment receiving the stimulus. Not all of these effectors are activated in any given cell type. The primary method of activation is to promote the translocation of the molecule to the plasma membrane where additional interactions lead to the activation of the molecule. RalGDS is a Guanine Exchange Factor (GEF) for Ral but also has other independent functions. RalGDS activates RalA/B-related small GTPases. RalBP1 is a GTPase activating protein that leads to the inhibition of the Rac and CDC42 GTPases. Ral can also interact with phospholipase D1 (PLD1) that can also be activated by RhoA. Ras stimulation of the lipid kinase activity of PI3K occurs through an interaction with the p110 catalytic subunit. PI3K phosphorylates the D3 position of phosphatidylinositides. In this example Pip2 is converted to PIP3. PIP3 stimulates the AKT/PKB kinase and several of the Rac-GEFs such as Sos1 AND Vav. AKT activation inhibits apoptosis by inhibiting the actions of Bad, Caspase 9, and AFX. AKT further hinders apoptosis by phosphorylating the IkB repressor of NFkB. Stimulus of Rac causes, among other things, the activation of NFkB. Ras also stimulates the mitogen-activated kinases ERK1/2 via the Raf1 cascade. The Erk kinases translocate to the nucleus where they phosphorylate various transcription factors such as ELK1. (This definition may be outdated - see the DesignNote.)
Cell cycle checkpoint controls at the G1 to S transition and the G2 to M transition prevent the cell cycle from progressing when DNA is damaged. The ATM protein kinase detects DNA damage and, in response to this, activates DNA repair factors and inhibits cell cycle progression. Two of the proteins that ATM phosphorylates in response to DNA damage are the tumor suppressor p53 and the checkpoint kinase chk1. In turn, the tumor suppressor p53 interacts with p21 to block the activity of cdk2 (cyclin dependent kinase 2) preventing passage from G1 to S phase and harmful replication of damaged DNA. One of the targets of cdk2 is the Rb gene product, another tumor suppressor. When dephosphorylated, Rb interacts with E2F transcription factors and prevents transcription of genes required for progression through the cell cycle. When phosphorylated by cell cycle dependent kinases like cdk2 and cdk4, Rb no longer interacts with E2F and the cell cycle proceeds through the G1-S checkpoint. DNA damage also regulates the G2-M phase transition by acting on the cell cycle regulator cdc2. (This definition may be outdated - see the DesignNote.)
RB Tumor Suppressor/Checkpoint Signaling in response to DNA damage
Reelin is an extracellular protein secreted by neurons. Reeler mice with a defective Reelin gene exhibit neuronal abnormalities in development. Mice that are heterozygous for the Reelin knockout have neuroanatomical and behavioral traits similar to those of schizophrenia patients, suggesting that mice with a deficiency in Reelin may provide a useful model for schizophrenia. Reelin protein may be involved in cognitive function in adults as well as playing a role in the developmental organization of neurons in the cortex. Multiple cell surface receptors transduce Reelin signaling into neurons. One class of Reelin receptor includes the VLDL receptor and the ApoER2. The intracellular adaptor Dab1 binds to the VLDL receptor and ApoER2 receptor through an NPxY motif and is involved in transmission of Reelin signals through these lipoprotein receptors. Mutation of the mDab1 gene in mice creates a phenotype identical to Reeler mice, supporting the role of this cytoplasmic factor in signaling downstream from Reelin. Another class of receptor for Reelin is the cadherin-related neuronal receptors, CNR receptors. Reelin signaling through several different CNR receptors activates the Fyn tyrosine kinases. Reelin stimulates phosphorylation of Dab1 and Dab1 appears to link Reelin signaling with tyrosine kinases. Disruption of the p35 and Cdk5 genes in mice indicates that cdk5 is also involved in the role of Reelin in neuronal development. (This definition may be outdated - see the DesignNote.)
Retinoic acid receptors-mediated signaling
Retinoic Acid Receptor Family-Mediated Signaling Pathway
RXR and RAR heterodimerization with other nuclear receptor
RXR and RAR Heterodimerization with Other Nuclear Receptor Signaling Pathway
RhoA is a small G-protein in the Rho family that regulates cell morphology via actin cytoskeleton reorganization in response to extracellular signals. The majority of RhoA activations are due to disruption of intramolecular autoinhibitory interactions. Changes in cytoskeletal structure and other aspects of cell structure are involved in cell morphology. RhoA is activated by GEF factors, and repressed by GAPs. GEFs are guanine nucleotide exchange factors. GAPs are GTPase-activating proteins. The RhoGAP ARHGAP1 also acts as a GAP for Rac and CDC42. Active RhoA increases the stability of actin-based structures such as stress fibers and focal adhesions. Several different factors downstream of RhoA act on cytoskeletal structures to affect stability of these structures. Rock1 provides a direct link from RhoA to cell morphology through phosphorylation of the myosin light chain. Rock1 also phosphorylates and activates LIM kinase, which phosphorylates cofilin. Cofilin stimulates actin depolymerization and changes in cell structure, and phosphorylation of cofilin by LIM kinase represses this activity. According to Nimnual et al. Rho activity is reduced as a result of Rac-induced redox-dependent inhibition. (This definition may be outdated - see the DesignNote.)
Specific families of pattern recognition receptors are responsible for detecting viral pathogens and generating innate immune responses. Non-self RNA appearing in a cell as a result of intracellular viral replication is recognized by a family of cytosolic RNA helicases termed RIG-I-like receptors (RLRs). The RLR proteins include RIG-I, MDA5, and LGP2 and are expressed in both immune and nonimmune cells. Upon recognition of viral nucleic acids, RLRs recruit specific intracellular adaptor proteins to initiate signaling pathways that lead to the synthesis of type I interferon and other inflammatory cytokines, which are important for eliminating viruses.
Rod Cell Visual Signal Transduction Pathway
The tumor necrosis factor (TNF) receptor superfamily contains several members with homologous cytoplasmic domains known as death domains (DD). The intracellular DD are important in initiating apoptosis and other signaling pathways following ligand binding by the receptors. In the absence of ligand, DD-containing receptors are maintained in an inactive state. TNFR1 contains a cytoplasmic DD required for signaling pathways associated with apoptosis and NF-kB activation. Jiang et al. identified a widely expressed 60 kDa protein, named SODD (silencer of death domains), associated with the DD of TNFR1 and DR3. Overexpression of SODD suppresses TNF-induced cell death and NF-kB activation demonstrating its role as a negative regulatory protein for these signaling pathways. TNF-induced receptor trimerization aggregates the DD of TNFR1 and recruits the adapter protein TRADD. This in turn promotes the recruitment of the DD-containing cytoplasmic proteins FADD, TRAF2, and RIP to form an active TNFR1 signaling complex. In contrast, SODD acts as a silencer of TNFR1 signaling and does not interact with TRADD, FADD, or RIP. It is associated with the DD of TNFR1 and maintains TNFR1 in an inactive, monomeric state. TNF-induced aggregation of TNFR1 promotes the disruption of the SODD-TNFR1 complex. SODD does not interact with the DD of other TNF receptor superfamily members such as Fas, DR4, DR5, or TNFR2. SODD association with TNFR1 may represent a general model for the prevention of spontaneous TNF signaling by other DD-containing receptors. (This definition may be outdated - see the DesignNote.)
Sonic Hedgehog (Shh) is one of a family of three secreted proteins, including Indian Hedgehog (Ihh) and Desert Hedgehog (Dhh), that play distinct and crucial roles in development. The morphogenic signal Shh provides in the developing CNS induces proliferation of neuronal precursor cells in the developing cerebellum and other tissues. Proliferative signaling by Shh is involved in the development of cancer, including specific brain and skin cancers such as basal cell carcinomas, while activation of Shh signaling in neurons may also provide a means to induce neuronal regeneration. Mitogenic Shh signaling does not appear to involve Map kinase pathways, but may involve induction of Cyclin D1 expression to maintain Rb in the hyperphosphorylated state and allow progression through the G1 phase of the cell cycle. Activation of myc may be one mechanism by which Shh induces cell cycle progression. Activation of Shh proliferative signaling occurs through binding to a receptor complex including Patched (Ptc-1) and Smoothened, a G-protein coupled receptor. Patched is an integral membrane protein with twelve transmembrane domains that acts as an inhibitor of Smoothened activation. Patched has been classified as a tumor suppressor due to its inhibition of Smoothened and the presence of inactivated Ptc-1 mutations in some cancers. One possibility is that Ptc-1, which resembles transmembrane channels, may not directly associate with Smoothened but may repress Smoothened signaling by transporting an endogenous Smoothened inhibitor across the plasma membrane into the cytoplasm. Small non-peptide agonists and antagonists of the Shh pathway have been identified and appear to act at the level of the Smoothened receptor, providing pharmacological tools to study Shh signaling. The pathway downstream of the Smoothened receptor has remained somewhat unclear, but involves the Gli family of transcriptional activators, including Gli-1, Gli-2, and Gli-3, homologs of the drosophila gene cubitis interruptis. Kinases including GSK-3 and PKA oppose activation of the Shh pathway, perhaps by regulating the stability of Shh pathway intermediate signaling factors transcription factors. Suppressor of Fused (SUFU) interacts directly with Gli proteins, repressing Shh signaling while Dyrk1 is a kinase that acts by a distinct pathway to stimulate Gli1 activation of transcription. The multiplicity of factors involved in Shh signaling creates many opportunities for therapeutic intervention in the treatment of cancer and possibly neurodegenerative diseases. (This definition may be outdated - see the DesignNote.)
S1P-activated G-protein coupled receptor signaling pathway
S1P-stimulated signal transduction pathway
sphingosine-1-phosphate signal transduction
sphingosine-1-phosphate signaling pathway
Sphingosine 1-Phosphate Signaling Pathway
Sphingosine 1-Phosphate Receptor 1 Signaling Pathway
Sphingosine 1-Phosphate Receptor 2 Signaling Pathway
Sphingosine 1-Phosphate Receptor 3 Signaling Pathway
Sphingosine 1-Phosphate Receptor 4 Signaling Pathway
Sphingosine 1-Phosphate Receptor 5 Signaling Pathway
Four different members of the Sprouty protein family block the cellular proliferation and differentiation induced by several different growth factors, including EGF and FGF. One mechanism by which Sprouty proteins inhibit signaling is through binding to Grb-2, a signaling intermediary between the tyrosine kinase growth factors and the Ras/map kinase pathway. Binding of Sprouty to Grb-2 prevents Grb-2 and Sos-1 from interacting with downstream signaling factors that activate Ras and map kinases, including Ras, Raf-1, Mek1, Erk1/2, and downstream transcription factors. The action of Sprouty as an inhibitor of this pathway requires Sprouty phosphorylation and membrane localization at the site of the factors it interacts with. The inhibition of growth factor signaling by Sprouty is specific to the Ras pathway since the PI3 Kinase pathway responsible for cell survival signals from growth factor receptors is not inhibited by Sprouty. Tyrosine kinase activity of growth factor receptors is also not affected. The mechanism by which Sprouty inhibits Ras activation may be by blocking the nucleotide exchange activity of Sos. Sprouty expression is induced by growth factor receptor activation of Ras signaling, provided a self-regulatory feedback inhibition mechanism that regulates growth factor signaling through Ras. In addition to blocking the Ras pathway, Sprouty also induces protein tyrosine phosphatase 1B activity. Activation of PTP1B by Sprouty is responsible for the inhibition of cellular migration that Sprouty causes, but is not involved in regulation of cellular proliferation. While blocking receptor tyrosine kinase signaling, at least one member of the Sprouty family, Sprouty-2, also acts by one mechanism to stimulate EGF receptor signaling. Cbl targets the EGF receptor for tagging with ubiquitin and proteolytic destruction. Sprouty-2 binds to Cbl and blocks the ubiquitination and destruction of the EGF receptor, increasing EGF signaling. (This definition may be outdated - see the DesignNote.)
Sprouty regulation of tyrosine kinase signals
Sprouty Regulation of Tyrosine Kinase Signaling Pathway
STATs, Signal Transducers and Activators of Transcription, are transcription factors that are phosphorylated by JAK kinases in response to cytokine activation to dimerize and move into the nucleus to activate transcription of cytokine-responsive genes. There are at least 3 JAK kinases and at least six STATs, with different cytokines inducing different patterns of JAK and STAT activation. Cytokines that activate STAT3 include growth hormone, IL-6 family cytokines, and G-CSF. STAT3, as well as STAT5, induces progression through the cell cycle, prevents apoptosis, and may be associated with cancer development in some cases. STAT3 plays an important role in normal development, particularly hematopoiesis. The importance of STAT3 is underscored by the failure of mice lacking STAT3 to survive embryogenesis. Crosstalk from pathways other than JAK kinases also leads to phosphorylation and activation of STAT3 as indicated by a role of mTOR (mammalian target of rapamycin, or p70 S6 kinase) and mitogen-activated protein kinase (MAP kinase) pathways in STAT3 activation and signaling. (This definition may be outdated - see the DesignNote.)
The A-kinase anchor protein 13 (AKAP13, also known as AKAP-LBC) is one of a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. AKAP13 is a splice variant of the oncogene Lbc. Alternative splicing of the AKAP13 gene results in at least 3 transcript variants encoding different isoforms containing a Dbl oncogene homology (DH) domain and a pleckstrin homology (PH) domain. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. These splice variants contain a fragment that was originally identified as Ht31 (See Carr et al 1991) which acts as a scaffolding protein to regulate the Rho signaling pathway and as protein kinase A-anchoring protein creating a coordination of these two signaling pathways. Diviani et al. found that in HEK293 cells LPA induced stimulation preferentially activates AKAP13 via G-alpha12. As yet targets for the anchored PKA have not been identified. AKAP13 and Rho do not appear to be phosphorylated by PKA. Diviani et al also found that the Lbc oncogene and protooncogene splice variant show higher activation and stress fiber localization. This appears to be a result of the presence of N terminal inhibitory sequences. A similar model of regulation has been proposed for Dbl and Vav. (This definition may be outdated - see the DesignNote.)
Rho-Selective Guanine Exchange Factor AKAP13 Mediates Stress Fiber Formation
Proteogylcan syndecan-mediated signaling events
All taste pathways are proposed to converge on common elements that mediate a rise in intracellular Ca2+ followed by neurotransmitter release. Na+ salt depolarizes taste cells by passive influx of Na+ through the amiloride-sensitive Na+ channel (ENaC). Acids depolarize taste cells by a variety of mechanisms, including influx of protons (H+) through ENaC and a proton-gated cation channel (MDEG). Two putative umami receptors have been identified: a truncated variant of the metabotropic glutamate receptor mGluR4 and the heterodimer, T1R1 + T1R3. Umami receptors are coupled to a signaling pathway involving activation of PLCbeta2, production of IP3 and diacylglycerol, release of Ca2+ from intracellular stores and activation of a transient receptor potential channel, TRPM5. Bitter compounds, such as denatonium and PROP, activate particular T2R/TRB isoforms, which activate gustducin heterotrimers. Activated alpha-gustducin stimulates PDE to hydrolyze cAMP, whereas betagamma subunits activate PLCbeta2 to generate IP3, which leads to release of Ca2+ from internal stores. Artificial sweeteners activate GPCRs (T1R heterodimers) apparently linked via PLC to IP3 production and release of Ca2+ from intracellular stores. Sugars apparently activate GPCRs linked via AC to cAMP production which, in turn, may inhibit basolateral K+ channels through phosphorylation by cAMP-activated protein kinase A (PKA).
TGF-beta regulates growth and proliferation of cells, blocking growth of many cell types. The TGF-beta receptor includes type 1 and type 2 subunits that are serine-threonine kinases and that signal through the SMAD family of transcriptional regulators. Defects in TGF-beta signaling, including mutation in SMADs, have been associated with cancer in humans. Prior to activation, receptor regulated SMADs are anchored to the cell membrane by factors like SARA (SMAD Anchor for Receptor Activation) that brings the SMADs into proximity of the TGF receptor kinases. Binding of TGF induces phosphorylation and activation of the TGF-beta R1 receptor by the TGF-beta R2 receptor. The activated TGF-beta R1 phosphorylates SMAD2 and SMAD3, which bind to the SMAD4 mediator to move into the nucleus and form complexes that regulate transcription. SMADs regulate transcription in several ways, including binding to DNA, interacting with other transcription factors, and interacting with transcription corepressors and coactivators like p300 and CBP. SMAD-7 represses signaling by other SMADs to down-regulate the system. Other signaling pathways, like the MAP kinase-ERK cascade activated by TGF-beta signaling, modulate SMAD activation. SnoN also regulates TGF-beta signaling, by binding to SMADs to block transcriptional activation. TGF-beta signaling causes degradation of SnoN, releasing SMADs to regulate transcription, and also activates expression of SnoN, to down-regulate SMAD signaling at later times. (This definition may be outdated - see the DesignNote.)
Tumor Growth Factor-Beta Receptor Signaling Pathway
transforming growth factor beta receptor signaling pathway
transforming growth factor beta receptor signalling pathway
The transforming growth factor-beta (TGF-beta) family members, which include TGF-betas, activins and bone morphogenetic proteins (BMPs), are structurally related secreted cytokines found in species ranging from worms and insects to mammals. A wide spectrum of cellular functions such as proliferation, apoptosis, differentiation and migration are regulated by TGF-beta family members. TGF-beta family member binds to the Type II receptor and recruits Type I, whereby Type II receptor phosphorylates and activates Type I. The Type I receptor, in turn, phosphorylates receptor-activated Smads (R-Smads: Smad1, Smad2, Smad3, Smad5, and Smad8). Once phosphorylated, R-Smads associate with the co-mediator Smad, Smad4, and the heteromeric complex then translocates into the nucleus. In the nucleus, Smad complexes activate specific genes through cooperative interactions with other DNA-binding and coactivator (or co-repressor) proteins.
Thrombin is an extracellular protease that is involved in the clotting of blood and inflammation through its action on platelets and endothelial cells in the vasculature and that plays a role in thrombosis and myocardial infarction. The protease activated receptors PAR1 and PAR4 are cellular targets of thrombin signaling and members of the G-protein coupled receptor gene family. Both of these receptors are cleaved in their N-terminus by thrombin, unmasking a portion of the receptor sequence that acts itself as a tethered peptide ligand that activates the receptor. The tethered ligand that activates PAR1 is SFLLRN and the tethered ligand that activates PAR4 is GYPGQV. Other members of the family include PAR2 which is activated by trypsin rather than thrombin and PAR3 which seems to play a role in the activation of other PARs but does not itself transduce a signal directly. Addition of peptide agonist exogenously in solution can also activate PAR1, PAR2 and PAR4. PAR1 activation may be involved in the dilation of arteries during inflammation through the action of thrombin on endothelial cells and in platelet activation by thrombin during clotting. PAR1 and PAR2 activation cause bronchodilation in airway and may protect against asthma. PAR 4 activation by thrombin activates platelets during clotting and mice lacking PAR4 have impaired clotting and platelets that do not respond to thrombin signaling. The action of thrombin on PAR1 and PAR4 on platelets and endothelial cells may also contribute to vascular permeability and inflammation. Activated PARs appear to couple primarily through Gq-mediated stimulation of inositol phosphate metabolism and intracellular calcium levels to activate platelets. PAR1 and PAR4 also appear to couple to multiple G-proteins and transduce signals through more than one G-protein mediated pathway in some circumstances. Signaling by PAR1 and PAR4 through Galpha12 pathways couples to Rho signaling and changes in cytoskeletal structure and cell shape. Gi activation does not appear necessary for platelet activation by PAR1 or PAR4, and platelet activation by these receptors requires an ADP signal perhaps acting through the platelet-associated purinergic receptor P2Y12. Gi-coupled signaling may play a role in mitogenic PAR signaling in some settings through Map kinase activation. Activation of Rho by PAR1 can induce cellular transformation through a Galpha12 mediated mechanism and sustained rho-dependent phosphorylation of the myosin light chain by PAR1 contributes to cytoskeletal changes and activation of platelets. Since the activation of PARs by protease cleavage is irreversible the primary mechanism for down-regulation of the PAR signaling cascade appears to be internalization and degradation of PAR receptors. (This definition may be outdated - see the DesignNote.)
Thrombin signaling and protease-activated receptors
Thrombin/Protease-Activated Receptor Signaling Pathway
Thromboxane A2 Receptor Family Signaling Pathway
Tumor Necrosis Factor Receptor Signaling Pathway
TNF acts on several different signaling pathways through two cell surface receptors, TNFR1 and TNFR2 to regulate apoptotic pathways, NF-kB activation of inflammation, and activate stress-activated protein kinases (SAPKs). Interaction of TNFR1 with TRADD leads to activation of NF-kB and apoptosis pathways, while interaction with TRAF2 has generally been thought to be involved in stress kinase and NF-kB activation but is not required for TNF to induce apoptosis. Activation of NF-kB is mediated by TRAF2 through the NIK kinase and also by RIP but the observation that TNF activates NF-kB in mice lacking TRAF2 indicates that TRAF-2 does not play an essential role in this process. Stress-activated protein kinases, also called JNKs, are a family of map kinases activated by cellular stress and inflammatory signals. Binding of TNF to the TNFR1 receptor activates the germinal center kinase (GCK) through the TNF adaptor Traf2, activating the map kinase MEKK1. Both GCK and MEKK1 interact with Traf2, and GCK is required for MEKK1 activation by TNF, but GCK kinase activity does not appear to be required for MEKK1 activation. Instead, GCK activates MEKK1 by causing MEKK1 oligomerization and autophosphorylation. Tank increases the affinity of Traf2 for GCK to increase Map kinase activation by TNF. Once activated, MEKK1 stands at the top of a map kinase pathway leading to transcriptional regulation, including JNK phosphorylation of c-Jun to stimulate transcriptional activation by AP-1, a heterodimer of c-jun and fos or ATF proteins. The activation of the p38 Map kinase also contributes to AP-1 activation leading to the transcriptional activation of many stress and growth related genes. RIP has been suggested as a component of the p38 pathway in addition to playing a role in NF-kB activation. MEKK1 knockout mice support the role of MEKK1 in JNK activation in some cells but did not support MEKK1 dependent activation of NF-kB. Alternative redundant mechanisms may obscure the role of MEKK1 in NF-kB mechanisms. TNF activation of stress kinase pathways and downstream transcription factors may help to modulate the apoptotic pathways also activated by TNF. (This definition may be outdated - see the DesignNote.)
TNFR1 (p55, CD120a) is the receptor for TNF-alpha and also will bind TNF-beta. Upon binding TNF-alpha a TNFR1+ cell is triggered to undergo apoptosis. This critical regulatory process is accomplished by activating the proteolytic caspase cascade that results in the degradation of many critical cellular proteins. (This definition may be outdated - see the DesignNote.)
TNFR2 is the receptor for the 171 amino acid 19 kD TNF-beta (a.k.a. lymphotoxin). TNF-beta is produced by activated lymphocytes and can be cytotoxic to many tumor and other cells. In neutrophils, endothelial cells and osteoclasts TNF-beta can lead to activation while in many other cell types it can lead to increased expression of MHC and adhesion molecules. (This definition may be outdated - see the DesignNote.)
Specific families of pattern recognition receptors are responsible for detecting microbial pathogens and generating innate immune responses. Toll-like receptors (TLRs) are membrane-bound receptors identified as homologs of Toll in Drosophila. Mammalian TLRs are expressed on innate immune cells, such as macrophages and dendritic cells, and respond to the membrane components of Gram-positive or Gram-negative bacteria. Pathogen recognition by TLRs provokes rapid activation of innate immunity by inducing production of proinflammatory cytokines and upregulation of costimulatory molecules. TLR signaling pathways are separated into two groups: a MyD88-dependent pathway that leads to the production of proinflammatory cytokines with quick activation of NF-kappa B and MAPK, and a MyD88-independent pathway associated with the induction of IFN-beta and IFN-inducible genes, and maturation of dendritic cells with slow activation of NF-kappa B and MAPK.
Thrombopoietin (TPO) binds to its receptor, inducing aggregation and activation. TPO signals its growth regulating effects to the cell through several major pathways including MAPK (ERK and JNK), Protein Kinase C, and JAK/Stat. (This definition may be outdated - see the DesignNote.)
Nerve growth factor (NGF) is a neurotrophic factor that stimulates neuronal survival and growth through TrkA, a member of the trk family of tyrosine kinase receptors that also includes TrkB and TrkC. Some NGF responses are also mediated or modified by p75LNTR, a low affinity neurotrophin receptor. Binding of NGF to TrkA stimulates neuronal survival, and also proliferation. Pathways coupled to these responses are linked to TrkA through association of signaling factors with specific amino acids in the TrkA cytoplasmic domain. Cell survival through inhibition of apoptosis is signaled through activation of PI3-kinase and AKT. Ras-mediated signaling and phospholipase C both activate the MAP kinase pathway to stimulate proliferation. (This definition may be outdated - see the DesignNote.)
The tubby gene product is expressed in the brain and has been implicated by mouse genetics in obesity and other disorders such as blindness. Structural analysis predicts that this gene acts as a transcription factor, binding to DNA to regulate gene expression. More recently, it was reported that tubby binds to phosphoinositides in the plasma membrane, helping to localize this factor in the membrane region in the absence of pathway activation. Tubby also interacts with Gq-alpha g-protein subunits, localizing tubby to regions of g-protein activation. Activation of phosphatase C activity and hydrolysis of membrane phosphoinositides leads to release of tubby from the plasma membrane, allowing tubby to enter the nucleus to bind DNA and regulate transcription. Some G-protein coupled receptors such as 5-HT2c may signal in part through tubby in addition to calcium-mediated pathways and protein-kinase signaling pathways. The identity of genes regulated by tubby and the mechanism by which tubby affects obesity remain to be explored. (This definition may be outdated - see the DesignNote.)
G-Protein Signaling Through Tubby Proteins
There is now much evidence that VEGFR-2 is the major mediator of VEGF-driven responses in endothelial cells and it is considered to be a crucial signal transducer in both physiologic and pathologic angiogenesis. The binding of VEGF to VEGFR-2 leads to a cascade of different signaling pathways, resulting in the up-regulation of genes involved in mediating the proliferation and migration of endothelial cells and promoting their survival and vascular permeability. For example, the binding of VEGF to VEGFR-2 leads to dimerization of the receptor, followed by intracellular activation of the PLCgamma-PKC-Raf kinase-MEK-mitogen-activated protein kinase (MAPK) pathway and subsequent initiation of DNA synthesis and cell growth, whereas activation of the phosphatidylinositol 3'-kinase (PI3K)-Akt pathway leads to increased endothelial-cell survival. Activation of PI3K, FAK, and p38 MAPK is implicated in cell migration signaling.
Signaling events mediated by VEGFR1 and VEGFR2
Vascular Endothelial Growth Factor Receptor 1 Signaling Pathway
vascular endothelial growth factor receptor-1 signaling pathway
VEGFR3 signaling in lymphatic endothelium
Vascular Endothelial Growth Factor Receptor 3 Signaling Pathway
vascular endothelial growth factor receptor-3 signaling pathway
The signal transduction cascade responsible for sensing light in vertebrates is one of the best studied signal transduction processes, and is initiated by rhodopsin in rod cells, a member of the G-protein coupled receptor gene family. Rhodopsin remains the only GPCR whose structure has been resolved at high resolution. Rhodopsin in the discs of rod cells contains a bound 11-cis retinal chromophore, a small molecule derived from Vitamin A that acts as the light sensitive portion of the receptor molecule, absorbing light to initiate the signal transduction cascade. When light strikes 11-cis retinal and is absorbed, it isomerizes to all-trans retinal, changing the shape of the molecule and the receptor it is bound to. This change in rhodopsin's shape alters its interaction with transducin, the member of the G-protein gene family that is specific in its role in visual signal transduction. Activation of transducin causes its alpha subunit to dissociate from the trimer and exchange bound GDP for GTP, activating in turn a membrane-bound cyclic-GMP specific phosphodiesterase that hydrolyzes cGMP. In the resting rod cell, high levels of cGMP associate with a cyclic-GMP gated sodium channel in the plasma membrane, keeping the channels open and the membrane of the resting rod cells depolarized. This is distinct from synaptic generation of action potentials, in which stimulation induces opening of sodium channels and depolarization. When cGMP gated channels in rod cells open, both sodium and calcium ions enter the cell, hyperpolarizing the membrane and initiating the electrochemical impulse responsible for conveying the signal from the sensory neuron to the CNS. The rod cell in the resting state releases high levels of the inhibitory neurotransmitter glutamate, while the release of glutamate is repressed by the hyperpolarization in the presence of light to trigger a downstream action potential by ganglion cells that convey signals to the brain. The calcium which enters the cell also activates GCAP, which activates guanylate cyclase (GC-1 and GC-2) to rapidly produce more cGMP, ending the hyperpolarization and returning the cell to its resting depolarized state. A protein called recoverin helps mediate the inactivation of the signal transduction cascade, returning rhodopsin to its preactivated state, along with the rhodopsin kinase Grk1. Phosphorylation of rhodopsin by Grkl causes arrestin to bind, helping to terminate the receptor activation signal. Dissociation and reassociation of retinal, dephosphorylation of rhodopsin, and release of arrestin all return rhodopsin to its ready state, prepared once again to respond to light. (This definition may be outdated - see the DesignNote.)
Wnt family members are secreted glycoproteins that bind to cell surface receptors such as Frizzled. Wnt members can play a role in the expression of many genes by interacting with multiple disparate signaling pathways. (This definition may be outdated - see the DesignNote.)
Wnt proteins are secreted morphogens that are required for basic developmental processes, such as cell-fate specification, progenitor-cell proliferation and the control of asymmetric cell division, in many different species and organs. There are at least three different Wnt pathways: the canonical pathway, the planar cell polarity (PCP) pathway and the Wnt/Ca2+ pathway. In the canonical Wnt pathway, the major effect of Wnt ligand binding to its receptor is the stabilization of cytoplasmic beta-catenin through inhibition of the bea-catenin degradation complex. Beta-catenin is then free to enter the nucleus and activate Wnt-regulated genes through its interaction with TCF (T-cell factor) family transcription factors and concomitant recruitment of coactivators. Planar cell polarity (PCP) signaling leads to the activation of the small GTPases RHOA (RAS homologue gene-family member A) and RAC1, which activate the stress kinase JNK (Jun N-terminal kinase) and ROCK (RHO-associated coiled-coil-containing protein kinase 1) and leads to remodelling of the cytoskeleton and changes in cell adhesion and motility. WNT-Ca2+ signalling is mediated through G proteins and phospholipases and leads to transient increases in cytoplasmic free calcium that subsequently activate the kinase PKC (protein kinase C) and CAMKII (calcium calmodulin mediated kinase II) and the phosphatase calcineurin.
Wnt receptor signaling pathway through beta-catenin
Wnt receptor signaling pathway via beta-catenin
Wnt receptor signalling pathway through beta-catenin
canonical Wnt receptor signaling pathway
canonical Wnt-activated signaling pathway
Presenilin Action in Notch and Wnt Signaling Pathways
Wnt glycoproteins play a role in diverse processes during embryonic patterning in metazoa through interaction with frizzled-type seven-transmembrane-domain receptors (Frz) to stabilize b-catenin. LDL-receptor-related protein 6 (LRP6), a Wnt co-receptor, is required for this interaction. Dikkopf (dkk) proteins are both positive and negative modulators of this signaling. (This definition may be outdated - see the DesignNote.)
This pathway illustrates the opposing effects that Proepithelin (PEPI) and the elastase digest fragments, the epithelins (EPIa-g), have on epithelial growth and neutrophil activation. PEPI (also known as progranulin, PC-cell derived growth factor, and acrogranin) is comprised of seven full and one half EPI motif separated by a linker. NMR studies indicate that EPIs are compact globular structures leading to the current suggestion of a string of beads. The epithelins are highly homologous 6kDa peptides with significant conservation in plants, insects, worms and mammals. The EPIs stimulate epithelial cell secretion of IL-8, which in turn stimulates neutrophils to secrete elastase. PEPI also inhibits the inhibition of secretory leukocyte protease inhibitor (SLPI) and stimulates the growth of epithelial cells leading to wound closure. SLPI is secreted by epithelial cell, neutrophils and macrophages. SLPI inhibits elastase and cathepsinG and the inhibition of SLPI from free radicals produced by neutrophils in the blood stream as part of the balance between wound repair and wound cleaning. SLPI binds to PEPI and prevents elastase from cleaving the various linker regions between the EPIs. SLPI also binds and blocks the protease activities of elastase. Unchecked elastase leads to impaired wound healing. In summary PEPI and SLPI, normally prevalent epithelial cells, protect the epithelia from roving neutrophils. Injury causes a reduction in SLPI leading to the cleavage of PEPI into the individual EPIs. The individual EPIs activate the neutrophils and generate the wound cleaning response. As the level of SLPI returns the amount of PEPI is restored and the switch from inflammation to repair occurs. (This definition may be outdated - see the DesignNote.)
Proepithelin Conversion to Epithelin and Wound Repair Control
Inorganic Chemicals [Chemical/Ingredient]
Acids, Noncarboxylic [Chemical/Ingredient]
[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid
[(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid
Denti-Care Topical Fluoride Foam Bubble Gum
Denti-Care Topical Fluoride Foam Raspberry
Denti-Care Topical Sodium Fluoride Strawberry
Acidulated Phosphate Fluoride [Chemical/Ingredient]
Acidulated phosphate fluoride (substance)
Phosphoric acid, mixt. with sodium fluoride (NaF)
Calcium Phosphates [Chemical/Ingredient]
Calcium Pyrophosphate [Chemical/Ingredient]
Kit for the Preparation of Technetium Tc99m Pyrophosphate
Tin Polyphosphates [Chemical/Ingredient]
Phosphotungstic Acid [Chemical/Ingredient]
Magnesium Hydroxide [Chemical/Ingredient]
Ammonium Hydroxide [Chemical/Ingredient]
Prostaglandin Endoperoxides [Chemical/Ingredient]
(2R,2'R)-3,3'-disulfanediylbis(2-aminopropanoic acid)
(R,R)-3,3'-dithiobis(2-aminopropanoic acid)
(R-(R*,R*))-3,3'-Dithiobis(2-Aminopropanoic Acid)
3,3'-Dithiobis(2-Aminopropanoic Acid), (R-(R*,R*))-
Beta,Beta'-Diamino-Beta,Beta'-Dicarboxydiethyl Disulfide
Carbon Radioisotopes [Chemical/Ingredient]
Elements, Radioactive [Chemical/Ingredient]
Actinoid Series Elements [Chemical/Ingredient]
Carbon Monox, Helium, Oxygen, Nitrogen L.D.M.
Gaseous Inh Mixture 20% Oxygen 80% Helium
Xenon Radioisotopes [Chemical/Ingredient]
Alphadine Scrub Topical Microbiocidal Skin Cleanser
Basic Foley Cath Kit Iodophor Pvp Pad 1%
Foam Care Pvp Iodophor Surg Hand Scrub 0.75%
Iodine Radioisotopes [Chemical/Ingredient]
Cesium Radioisotopes [Chemical/Ingredient]
Buffered Vitamin C Powder With Ca Mg and K
Buffered Vitamin C Pwr W Cal-mag-potassium
Cal & Mag Hvp Chel Plus C Potass & Zinc Tab
Potassium Isotopes [Chemical/Ingredient]
Potassium Radioisotopes [Chemical/Ingredient]
Sodium Radioisotopes [Chemical/Ingredient]
Metals, Alkaline Earth [Chemical/Ingredient]
Actical Plus Calcium-magnesium-vitamin D3-silicon Chewable
Active Calcium Plus Magnesium, Vitamin D and Silicon
Calcium Radioisotopes [Chemical/Ingredient]
Acetabolan III Vitamin and Mineral Supplement
Acetabolan-II Vitamin and Mineral Supplement
Strontium Isotopes [Chemical/Ingredient]
Strontium Radioisotopes [Chemical/Ingredient]
Metals, Rare Earth [Chemical/Ingredient]
Yttrium Radioisotopes [Chemical/Ingredient]
Lanthanoid Series Elements [Chemical/Ingredient]
Cerium Radioisotopes [Chemical/Ingredient]
Nitrogen Radioisotopes [Chemical/Ingredient]
mineral supplements phosphorus preparations
Phosphorus Isotopes [Chemical/Ingredient]
Phosphorus Radioisotopes [Chemical/Ingredient]
Oxygen Radioisotopes [Chemical/Ingredient]
Complete Multivitamins and Minerals Tablets Timed Release
Acne Treatment Sulfur Wash Rodan and Field
Sulfur Radioisotopes [Chemical/Ingredient]
Calcium With Mg Zn Mn Cu CR Si and Vit. C & D
Chromium Radioisotopes [Chemical/Ingredient]
Cobalt Radioisotopes [Chemical/Ingredient]
Gallium Radioisotopes [Chemical/Ingredient]
Gold Radioisotopes [Chemical/Ingredient]
Gold Colloid, Radioactive [Chemical/Ingredient]
Iron Radioisotopes [Chemical/Ingredient]
Mercury Radioisotopes [Chemical/Ingredient]
Iron 25mg With Vit B-cmplx, Vit C, Cu & Mo
Zinc Radioisotopes [Chemical/Ingredient]
Transition Elements [Chemical/Ingredient]
Carbon Monoxide, Compressed Air Medical G.M.
Sulfur Hexafluoride [Chemical/Ingredient]
Barium Radioisotopes [Chemical/Ingredient]
Bromine Radioisotopes [Chemical/Ingredient]
Cadmium Radioisotopes [Chemical/Ingredient]
Copper Radioisotopes [Chemical/Ingredient]
Fluorine Radioisotopes [Chemical/Ingredient]
Indium Radioisotopes [Chemical/Ingredient]
Iridium Radioisotopes [Chemical/Ingredient]
Krypton Radioisotopes [Chemical/Ingredient]
Lead Radioisotopes [Chemical/Ingredient]
Radioactive Tracers [Chemical/Ingredient]
Rubidium Radioisotopes [Chemical/Ingredient]
Ruthenium Radioisotopes [Chemical/Ingredient]
Selenium Radioisotopes [Chemical/Ingredient]
Thallium Radioisotopes [Chemical/Ingredient]
Metal Ceramic Alloys [Chemical/Ingredient]
Alka-Seltzer Extra Strength Heartburn ReliefChews
Alka-Seltzer Heartburn Plus Gas ReliefChews Tropical Punch
Alka-Seltzer Heartburn ReliefChews Cool Mint
Diatomaceous Earth [Chemical/Ingredient]
Aluminum Silicates [Chemical/Ingredient]
Asbestos, Serpentine [Chemical/Ingredient]
Magnesium Silicates [Chemical/Ingredient]
Ferrosoferric Oxide [Chemical/Ingredient]
Magnetite Nanoparticles [Chemical/Ingredient]
Aurate(3-), bis(monothiosulfato(2-)-O,S)-, trisodium, (T-4)-
Bis(monothiosulfato(2-)-O,S)aurate(3-) Trisodium
Gold Sodium Thiosulfate [Chemical/Ingredient]
Gold sodium thiosulfate (in water) (product)
Gold sodium thiosulfate (in water) (substance)
Kit for the Prepartion of Technetium Tc99m Sulfur Colloid
Phosphorus Compounds [Chemical/Ingredient]
Phosphorus, Dietary [Chemical/Ingredient]
Carbon Compounds, Inorganic [Chemical/Ingredient]
Technetium Compounds [Chemical/Ingredient]
Sodium Pertechnetate Tc 99m [Chemical/Ingredient]
Sodium Hypochlorite [Chemical/Ingredient]
Aspirin Plus Stomach Guard Ext.stgth.caplet
Aspirin Plus Stomach Guard Extra Strength
Aspirin With Stomach Guard Extra Strength - Tab
Calcium Magnesium Avec Vitamine D Et Zinc
Chlorine Compounds [Chemical/Ingredient]
Chloramine (category, substance) (substance)
(40 Mmols/l) Potassium Chloride In Lactated Ringer's Injection USP
5% Dextrose In Lactated Ringer's Injection
(20 Mmol/l) Potassium Chloride In 3.3% Dextrose and 0.3% Sodium Chloride Injection USP
(20 Mmol/l) Potassium Chloride In 5% Dextrose Injection USP
(20 Mmol/l) Potassium Chloride In 5% Dextrose and 0.9% Sodium Chloride Injection USP
(20mmol/l) Potassium Chloride In 0.9% Sodium Chloride Injection USP
(20mmol/l) Potassium Chloride In 5% Dextrose and 0.2% Sodium Chloride Injection USP
(20mmol/l) Potassium Chloride In 5% Dextrose and 0.45% Sodium Chloride Injection USP
(40 Mmol/l) Potassium Chloride In 0.9% Sodium Chloride Injection USP
(40 Mmol/l) Potassium Chloride In 5% Dextrose Injection USP
(40mmol/l) Potassium Chloride In 3.3% Dextrose and 0.3% Sodium Chloride Injection USP
(40mmol/l)potassium Chloride In 5% Dextrose and 0.45% Sodium Chloride Injection USP
0.15% Potassium Chloride In 3.3% Dextrose and 0.30% Sodium Chloride Injection
2.5% Travasol Amino Acid Injection With Electrolytes In 10% Dextrose
2.5% Travasol Amino Acid Injection With Electrolytes In 10% Dextrose Clinimix
2.5%travasol Amino Acid InJ.W.eleC.W.25%dex
2.75% Travas. Amino Acid InJ.W.elecw.25%dex
2.75% Travasol Amino Acid Injection With Electrolytes In 25% Dextrose Quickmix
2.75% Travasol Amino Acid Injection With Electrolytes In 5% Dextrose Quickmix
2.75%travasol Amino Acid InJ.W.eleC.W.5%dex.
4.25% Travasol Amino Acid Injection With Electrolytes In 10% Dextrose
4.25% Travasol Amino Acid Injection With Electrolytes In 20% Dextrose
4.25% Travasol Amino Acid Injection With Electrolytes In 20% Dextrose Quickmix
Aluminum Compounds [Chemical/Ingredient]
Chromium Compounds [Chemical/Ingredient]
Chromic acid (H2Cr2O7), dipotassium salt
Potassium Dichromate [Chemical/Ingredient]
2-Hydroxy-1,2,3-propanetricarboxylic Acid, Calcium Salt (2:3)
Fluorine Compounds [Chemical/Ingredient]
Fluorides, Topical [Chemical/Ingredient]
1.1% Neutral Sodium Fluoride Topical Gel
2-Pyrrolidinone, 1-ethenyl-, homopolymer, compd. with iodine
Magnesium Compounds [Chemical/Ingredient]
Colgate Total Advanced Health Daily Repair
Platinum Compounds [Chemical/Ingredient]
Nitrogen Compounds [Chemical/Ingredient]
Peroxynitrous Acid [Chemical/Ingredient]
Reactive Nitrogen Species [Chemical/Ingredient]
Ammonium Compounds [Chemical/Ingredient]
Quaternary Ammonium Compounds [Chemical/Ingredient]
Quaternary ammonium compound (substance)
Potassium Compounds [Chemical/Ingredient]
Kali permanganicum / potassium permanganate
Permanganic acid (HMnO4), potassium salt
Potassium Permanganate [Chemical/Ingredient]
Potassium permanganate product (product)
Manganese Compounds [Chemical/Ingredient]
Vanadium Compounds [Chemical/Ingredient]
Tungsten Compounds [Chemical/Ingredient]
Ruthenium Compounds [Chemical/Ingredient]
Selenium Compounds [Chemical/Ingredient]
Coordination Complexes [Chemical/Ingredient]
Iron Carbonyl Compounds [Chemical/Ingredient]
Dioxins and Dioxin-like Compounds [Chemical/Ingredient]
Dibenzofurans, Polychlorinated [Chemical/Ingredient]
Dioxin (category, substance) (substance)
Polychlorinated Dibenzodioxins [Chemical/Ingredient]
Polychlorinated Biphenyls [Chemical/Ingredient]
1.8oz Hand Sanitizer With Clip -assorted
2 Pack Assured Instant Hand Sanitizer with moisturizers (Vitamin E and aloe)
2 Pack Assured Instant Hand Sanitizer with moisturizers (Vitamin E and aloe) lemon scented
Benzeneethanol, alpha-(4-(2-(diethylamino)ethoxy)phenyl)-4-methoxy-alpha-phenyl-
Mometasone Furoate Formoterol Fumarate Drug Combination
Mometasone Furoate, Formoterol Fumarate Drug Combination [Chemical/Ingredient]
Mometasone Furoate-Formoterol Fumarate Drug Combination
Mometasone Furoate, Formoterol Fumarate Drug Combination
Budesonide Formoterol Fumarate Drug Combination
Budesonide, Formoterol Fumarate Drug Combination [Chemical/Ingredient]
Budesonide-Formoterol Fumarate Drug Combination
Budesonide, Formoterol Fumarate Drug Combination
Combination, Fluticasone-Salmeterol Drug
Drug Combination, Fluticasone-Salmeterol
Albuterol, Ipratropium Drug Combination [Chemical/Ingredient]
American Eagle Energizer Plus Vitamin Supplement Drink
1 Alkyl 2 acetyl sn glycerophosphocholine
1,2-Benzenediol, 4-(1-hydroxy-2-(methylamino)ethyl)-, (R)-
2% Lidocaine and Epinephrine 1:100,000 Injection USP
1,2-Benzenediol, 4-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-
3,4-Dihydroxy-alpha-[(isopropylamino)methyl]benzyl alcohol
3-Carboxamido-4-hydroxy-alpha-((1-methyl-3-phenylpropylamino)methyl)benzyl alcohol
Benzamide, 2-hydroxy-5-(1-hydroxy-2-((1-methyl-3-phenylpropyl)amino)ethyl)-
(-)-alpha-(aminomethyl)-3,4-dihydroxybenzyl Alcohol
1,2-Benzenediol, 4-(2-amino-1-hydroxyethyl)-, (R)-
Benzenemethanol, alpha-(aminomethyl)-4-hydroxy-3-methoxy-
1,3-Benzenediol, 5-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-
1,2-Benzenediol, 4-(1-hydroxy-2-((1-methylethyl)amino)butyl)-
1-Propanone, 3-((2-hydroxy-1-methyl-2-phenylethyl)amino)-1-(3-methoxyphenyl)-, (R-(R*,S*))-
Brimonidine Tartrate Timolol Maleate Drug Combination
Brimonidine Tartrate, Timolol Maleate Drug Combination [Chemical/Ingredient]
Brimonidine Tartrate-Timolol Maleate Drug Combination
Brimonidine Tartrate, Timolol Maleate Drug Combination
2-Propanol, 1-((1-methylethyl)amino)-3-(1-naphthalenyloxy)-
beta-D-Galactopyranoside, 2-amino-3-hydroxy-4-octadecenyl, (R-(R*,S*-(E)))-
Dolichol Phosphates [Chemical/Ingredient]
2,6,10-Dodecatrien-1-ol, 3,7,11-trimethyl-
Dr.G Hydra Intensive Moist Cleansing gel
1-Tetradecanol, hydrogen sulfate, sodium salt
7-Ethyl-2-methyl-4-undecanol sulfate sodium salt
7-ethyl-2-methyl-4-undecanolsulfate, sodium salt
Sodium 2-methyl-7-ethylundecanol-4-sulfate
alpha-D-Glucofuranose, 1,2-O-(2,2,2-trichloroethylidene)-, (R)-
Poly(oxy-1,2-ethanediyl), alpha-hexadecyl-omega-hydroxy-
n Hexadecane Polyoxyethylene Glycol Monether
n-Hexadecane Polyoxyethylene Glycol Monether
Polyoxyethylene Polyoxypropylene Polyoxyethylene Polymer
2-Propenoic acid, 2-methyl-, 2-hydroxyethyl ester, homopolymer
Hydrogel, Polyethylene Glycol Dimethacrylate
alpha-Hydro-omega-hydroxypoly(oxyethylene)a-poly(oxopropylene)b-poly(oxyethylene)a block copolymer
Acetamide, 2,2-dichloro-N-(2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl)-, (R-(R*,R*))-
Chloramphenicol (class of antibiotic, substance)
Phospholipid Ethers [Chemical/Ingredient]
2,3-Butanediol, 1,4-dimercapto-, (R*,S*)-
2,3-Butanediol, 1,4-dimercapto-, (R*,R*)-
1,2,3,4-Butanetetrol, Tetranitrate, (R*,S*)-
Inositol Phosphates [Chemical/Ingredient]
Myo-Inositol Hexakis(Dihydrogen Phosphate)
D-myo-Inositol, 1,4,5-tris(dihydrogen phosphate)
Additive Solution Sodium Adenine Glucose Mannitol (sagm)
Mannitol Phosphates [Chemical/Ingredient]
50% Isopropyl Rubbing Alcohol with Wintergreen
Glyceraldehyde 3-Phosphate [Chemical/Ingredient]
Thiobarbituric Acid Reactive Substances [Chemical/Ingredient]
5-Heptenamide, 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((1E,3S)-3-hydroxy-5-phenyl-1-pentenyl)cyclopentyl)-N-ethyl-,(5Z)-
5-Heptenamide, 7-(3,5-dihydroxy-2-(3-hydrdoxy-5-phenyl-1-pentenyl)cyclopentyl)-N-ethyl-, (1R-(1alpha(Z),2beta(1E,3S*),3alpha,5alpha))-
Allylisopropylacetamide [Chemical/Ingredient]
2-Acetylaminofluorene [Chemical/Ingredient]
1-Cyclohexene-1-carboxylic acid, 4-(acetylamino)-5-amino-3-(1-ethylpropoxy)-, ethyl ester, (3R-(3alpha,4beta,5alpha))-
Ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate
1-Piperazineacetamide, N-(2,6-dimethylphenyl)-4-(2-hydroxy- 3-(2-methoxyphenoxy)propyl)-
Benzamide, N-(4-((aminoiminomethyl)amino)-1-(((4-nitrophenyl)amino)carbonyl)butyl)-, (+-)-
Benzoylarginine Nitroanilide [Chemical/Ingredient]
2-Piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-
Bupivacaine HCl 0.5% and Epinephrine 1:200,000 Injection
Urea, N,N'-bis(4-nitrophenyl)-, compd. with 4,6-dimethyl-2(1H)-pyrimidinone (1:1)
1,4-Oxathiin-3-carboxamide, 5,6-dihydro-2-methyl-N-phenyl-
4% Citanest Forte Dental With Epinephrine 1:200,000
Dentsply 4% Prilocaine Hydrochloride Dental Injection
Dentsply 4% Prilocaine and Epinephrine Injection 1:200,000
Propanamide, 2-amino-N-(2,6-dimethylphenyl)-
Benzamide, 4-methoxy-N-(2-(2-(1-methyl-2-piperidinyl)ethyl)phenyl)-, (+-)-
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide Monomethanesulfonate
2-(P-(2-(P-Chlorobenzamido)ethyl)phenoxy)-2-methylpropionic acid
Benzamide, N-(1-(2-(1H-indol-3-yl)ethyl)-4-piperidinyl)-
Benzamide, 4-amino-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxy-
Benzamide, 4-amino-N-(2-(diethylamino)ethyl)-
Benzamide, p-amino-N-(2-(diethylamino)ethyl)-
Benzamide, N-(1-methylethyl)-4-((2-methylhydrazino)methyl)-
Benzamide, 5-(Aminosulfonyl)-N-((1-Ethyl-2-Pyrrolidinyl)Methyl)-2-Methoxy-
Benzamide, 3-bromo-N-((1-ethyl-2-pyrrolidinyl)methyl)-2,6-dimethoxy-, (S)-
Benzamide, 4-amino-5-chloro-N-(1-(3-(4-fluorophenoxy)propyl)-3-methoxy -4-piperidinyl)-2-methoxy-, cis-
Benzamide, 3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl)-methyl)-2-hydroxy-6-methoxy-
Benzamide, 4-Chloro-N-(2-(4-Morpholinyl)Ethyl)-
Benzamide, N-(4-((aminoiminomethyl)amino)-1-((2-naphthalenylamino)carbonyl)butyl)-, (+-)-
Benzoylarginine-2-Naphthylamide [Chemical/Ingredient]
Trihexosylceramides [Chemical/Ingredient]
(2R,3S)-3-((4e,7e)-Nona-4,7-dienoyl)-oxirane-2-carboxylic acid amide
Oxiranecarboxamide, 3-(1-oxo-4,7-nonadienyl)-, (2R-(2alpha,3alpha(4E,7E)))-
2-Butoxy-quinoline-4-carboxylic acid (2-diethylamino-ethyl)-amide
2-Butoxyquinoline-4-carboxylic acid diethylaminoethylamide
4-Quinolinecarboxamide, 2-butoxy-N-(2-(diethylamino)ethyl)-
Lactams, Macrocyclic [Chemical/Ingredient]
Cephalosporin -class of antibiotic- (product)
Cephalosporin -class of antibiotic- (substance)
537 MISCELLANEOUS BETA-LACTAM ANTIBIOTICS
5-Oxa-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7-((carboxy(4-hydroxyphenyl)acetyl)amino)-7-methoxy-3-(((1-methyl-1H-tetrazol-5-yl)thio)methyl)-8-oxo-
7-((Carboxy(4-Hydroxyphenyl)Acetyl)Amino)-7-Methoxy-(3-((1-Methyl-1h-Tetrazol-5-Yl)Thio)Methyl)-8-Oxo-5-Oxa-1-Azabicyclo[4.2.0]Oct-2-Ene-2-Carboxylic Acid
Penicillin -class of antibiotic- (product)
Penicillin -class of antibiotic- (substance)
1-((3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo(4,3-d)pyrimidin-5-yl)-4-ethoxyphenyl)sulfonyl)-4-methylpiperazine citrate
Sildenafil Citrate [Chemical/Ingredient]
HMG-CoA reductase inhibitors rosuvastatin calcium
Rosuvastatin Calcium [Chemical/Ingredient]
(3-((4-aminobenzenesulfonyl)isobutylamino)-1-benzyl-2-hydroxypropyl)carbamic acid hexahydrofuro(2,3-b)furan-3-yl ester
(3R,3AS,6ar)-hexahydrofuro[2,3-b]furan-3-yl N-((1S,2R)-1-benzyl-2-hydroxy-3-(N(1)-isobutylsulfanilamido)propyl)carbamate
(3R,3AS,6ar)-tetrahydro-2H-furo[2,3-b]furan-3-yl (2S,3R)-4-(4-amino-N-isobutylphenylsulfonamido)-3-hydroxy-1-phenylbutan-2-ylcarbamate
(3R,3AS,6ar)-tetrahydro-2H-furo[2,3-b]furan-3-yl (2S,3R)-4-(4-amino-N-neopentylphenylsulfonamido)-3-hydroxy-1-phenylbutan-2-ylcarbamate
(3R,3aS,6aR)-Hexahydrofuro(2,3-b)furan-3-yl N-((1S,2R)-1-benzyl-2-hydroxy-3-(N1-isobutylsulfanilamido)propyl)carbamate
1,3,4-Thiadiazole-2-sulfonamide, 5-((phenylsulfonyl)amino)-
1,3,4-Thiadiazole-2-sulfonamide, 5-benzenesulfonamido- (6CI)
3-(Aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid
3-Butylamino-4-(phenoxy)-5-sulfamoylbenzoic acid
3-Butylamino-4-phenoxy-5-sulfamoyl-benzoic acid
3-Butylamino-4-phenoxy-5-sulfamoylbenzoic acid
Benzoic acid, 3-(aminosulfonyl)-5-(butylamino)-4-phenoxy-
Benzenesulfonamide, 2-Chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1-yl)-
Benzenesulfonamide, 2-chloro-5-(1-hydroxy-3-oxo-1-isoindolinyl)-
Benzamide, 3-(aminosulfonyl)-4-chloro-N-(2,6-dimethyl-1-piperidinyl)-, cis-
Clopamide [ingredient see bdek.] (product)
Clopamide [ingredient see bdek.] (substance)
4,5-Dichloro-benzene-1,3-disulfonic acid diamide
Benzamide, 3-(aminosulfonyl)-4-chloro-N-(2,3-dihydro-2-methyl-1H-indol-1-yl)-
1,3-Benzenedisulfonamide, 4-chloro-N1-methyl-N1-((tetrahydro-2-methyl-2-furanyl)methyl)-
6-Quinazolinesulfonamide, 7-chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-
Benzoic acid, 4-((dipropylamino)sulfonyl)-
2-Hydroxy-5-((4-((2-pyridinylamino)sulfonyl)phenyl)azo)benzoic acid
2-Hydroxy-5-[4-(pyridin-2-ylsulfamoyl)-phenylazo]-benzoic acid
2-Hydroxy-5-[[4-[(2-pyridinylamino)sulfonyl]phenyl]azo]benzoic Acid
5-((P-(2-Pyridylsulfamoyl)phenyl)azo)salicylic acid
5-(4-(2-Pyridylsulfamoyl)phenylazo)-2-hydroxybenzoic acid
5-(P-(2-Pyridylsulfamyl)phenylazo)salicylic acid
Benzenesulfonamide, 4-amino-N-(aminoiminomethyl)-
Benzenesulfonamide, 4-a)mino-N-(5-methyl-3-isoxazolyl)-, mixt. with 5-((3,4,5-trimethoxyphenyl)methyl-2,4-pyrimidinediamine
Trimethoprim, Sulfamethoxazole Drug Combination
Benzamide, 5-(Aminosulfonyl)-4-Chloro-N-(2,6-Dimethylphenyl)-2-Hydroxy-
1H-Indole-5-methanesulfonamide, 3-(2-(dimethylamino)ethyl)-N-methyl-
Polyunsaturated Alkamides [Chemical/Ingredient]
6-Nonenamide, N-((4-hydroxy-3-methoxyphenyl)methyl)-8-methyl-, (E)-
Benzenecarboximidamide, 4,4'-(1-triazene-1,3-diyl)bis-
Benzenecarboximidamide, 4,4'-(1,5-pentanediylbis(oxy))bis-
Methanimidamide, N'-(4-chloro-2-methylphenyl)-N,N-dimethyl-
Guanidine, N,N'-dimethyl-N''-(phenylmethyl)-
Sitagliptin Phosphate Metformin Hydrochloride Drug Combination
Sitagliptin Phosphate, Metformin Hydrochloride Drug Combination [Chemical/Ingredient]
Sitagliptin Phosphate-Metformin Hydrochloride Drug Combination
Sitagliptin Phosphate, Metformin Hydrochloride Drug Combination
((amino(Imino)methyl)(methyl)amino)acetic acid
Hydrazinecarboximidamide, 2-((2,6-dichlorophenyl)methylene)-
Hydrazinecarboximidamide, 2,2'-(1-methyl-1,2-ethanediylidene)bis-
Methylnitronitrosoguanidine [Chemical/Ingredient]
Carbonimidic dihydrazide, bis((4-chlorophenyl)methylene)-
Benzeneacetamide, N-(aminoiminomethyl)-2,6-dichloro-
Benzoic acid, 4-((6-((aminoiminomethyl)amino)-1-oxohexyl)oxy)-, ethyl ester
Ethyl p-hydroxybenzoate 6-guanidinohexanoate
Guanidine, N-(3-(1H-imidazol-4-yl)propyl)-N'-(2-(((5-methyl-1H-imidazol-4-yl)methyl)thio)ethyl)-
3-Iodobenzylguanidine [Chemical/Ingredient]
Guanidine, N''-cyano-N-4-pyridinyl-N'-(1,2,2-trimethylpropylmonohydrate), (+-)-
(2R,3R,4S)-3-(acetylamino)-4-Carbamimidamido-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid
2,3-Didehydro-2,4-Dideoxy-4-Guanidino-N-Acetyl-D-Neuraminic Acid
2,3-Didehydro-2,4-Dideoxy-4-Guanidinyl-N-Acetylneuraminic Acid
4 Guanidino 2 Deoxy 2,3 Didehydro N Acetylneuraminic Acid
4-Guanidino-2,4-Dideoxy-2,3-Didehydro-N-Acetylneuraminic Acid
4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic Acid
4-Guanidino-2-Deoxy-2,3-Didehydro-N-Acetylneuraminic Acid
1-Hexaminium, N,N,N-trimethyl-6-(2-propenylamino)-, Chloride, Polymer with (chloromethyl)oxirane, 2-propen-4-amine and N-2-propenyl-1-decanamine, Hydrochloride
Colesevelam Hydrochloride [Chemical/Ingredient]
3-Oxa-9-azoniatricyclo(3.3.1.02,4)nonane, 9-butyl-7-(3-hydroxy-1-oxo-2-phenylpropoxy)-9-methyl-, bromide, (7(S)-(1alpha,2beta,4beta,5alpha,7beta))-
Benzenepropanaminium, N-ethyl-N,N,alpha-trimethyl-gamma-phenyl-
Ethanaminium, 2,2',2''-(1,2,3-benzenetriyltris(oxy))tris(N,N,N-triethyl)-, triiodide
Gallamine Triethiodide [Chemical/Ingredient]
Gallamine triethiodide [dup] (substance)
Morpholinium, 2,2'-(1,1'-biphenyl)-4,4'-diylbis(2-hydroxy-4,4-dimethyl)-, dibromide
Lissamine Green Dyes [Chemical/Ingredient]
Bis-Trimethylammonium Compounds [Chemical/Ingredient]
Ethanaminium, 2-((cyclohexylhydroxyphenylacetyl)oxy)-N,N-diethyl-N-methyl-
2-Propanaminium, N-methyl-N-(1-methylethyl)-N-(2-((9H-xanthen-9-ylcarbonyl)oxy)ethyl)-
Tetraethylammonium Compounds [Chemical/Ingredient]
Toxiferine I, 2,2',16,16'-tetradehydro-16,16',17,17'-tetrahydro-
Tubocuraranium, 7',12'-dihydroxy-6,6'-dimethoxy-2,2',2'-trimethyl-
Trimethyl Ammonium Compounds [Chemical/Ingredient]
Bethanechol Compounds [Chemical/Ingredient]
Cetrimonium Compounds [Chemical/Ingredient]
1H-Isoindolium, 4,5,6,7-tetrachloro-2,3-dihydro-2-methyl-2-(2-(trimethylammonio)ethyl)-, dichloride
Ethanaminium, 2-mercapto-N,N,N-trimethyl-
Methacholine Compounds [Chemical/Ingredient]
2-Furanmethanaminium, tetrahydro-4-hydroxy-N,N,N,5-tetramethyl-, (2S-(2alpha,4beta,5alpha))-
Phenylammonium Compounds [Chemical/Ingredient]
Benzenaminium, N-ethyl-3-hydroxy-N,N-dimethyl-
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride [Chemical/Ingredient]
2-Butyn-1-aminium, 4-((((3-chlorophenyl)amino)carbonyl)oxy)-N,N,N-trimethyl-, chloride
CHLOROPHENYLCARBAMOYLOXY 2 BUTYNYL TRIMETHYLAMMONIUM CHLORIDE 4 M
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride
(m-Hydroxyphenyl)trimethylammonium dimethylcarbamate
3-Trimethylammoniumphenyl N,N-dimethylcarbamate
Benzenaminium, 3-(((dimethylamino)carbonyl)oxy)-N,N,N-trimethyl-
Neostigmine Methylsulfate Inj 0.5mg/ml USP
Neostigmine Methylsulfate Inj 1mg/ml USP
Benzylammonium Compounds [Chemical/Ingredient]
(Oxalylbis(iminoethylene))bis((o-chlorobenzyl)diethyl-ammonium), Dichloride
Ambenonium Chloride [Chemical/Ingredient]
Benzenemethanaminium, N,N'-((1,2-dioxo-1,2-ethanediyl)bis(imino-2,1-ethanediyl))bis(2-chloro-N,N-diethyl)-, dichloride
N,N'-((1,2-Dioxo-1,2-ethanediyl)bis(imino-2,1-ethanediyl))bis(2-chloro-N,N-diethyl-benzenemethanaminium), Dichloride
Benzalkonium Compounds [Chemical/Ingredient]
Benzenemethanaminium, N,N-Dimethyl-N-(2-(2-(4-(1,1,3,3-Tetramethylbutyl)Phenoxy)Ethoxy)Ethyl)
Benzenemethanaminium, N,N-dimethyl-N-(2-(2-(4-(1,1,3,3-tetramethylbutyl)phenoxy)ethoxy)ethyl)-, chloride
Bephenium Compounds [Chemical/Ingredient]
Anilino Naphthalenesulfonates [Chemical/Ingredient]
Benzenamine, 4,4'-carbonimidoylbis(N,N-dimethyl)-, monohydrochloride
Benzenemethanamine, 2-amino-3,5-dibromo-N-cyclohexyl-N-methyl-
BENZENAMINIUM 4 4 3 OXO 1 5 PENTANEDIYL BIS N N DIMETHYL N 2 PROPENYL DIBROMIDE
Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl)-, dibromide
Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide [Chemical/Ingredient]
Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide
Benzenamine, N,N-dimethyl-4-(phenylazo)-
Benzenaminium, 4-((4-(dimethylamino)phenyl)(4-(dimethyliminio)-2,5-cyclohexadien-1-ylidene)methyl)-N,N,N-trimethyl-, dichloride
Benzenamine, 4,4'-methylenebis(2-chloro)-
Benzenemethanamine, N-methyl-N-2-propynyl-
Ethanaminium, 2-(acetyloxy)-N,N,N-trimethyl-
Miochol E Acetylcholine Chloride Oph Soln
Biogenic Monoamines [Chemical/Ingredient]
Biogenic Polyamines [Chemical/Ingredient]
1,4-Butanediamine, N,N'-Bis(3-Aminopropyl)-
1,4-Butanediamine, N1,N4-Bis(3-Aminopropyl)-
1,4-Diaminobutane, N,N'-Bis(3-Aminopropyl)-
1,2-Benzenediol, 4-(2-((3-(4-hydroxyphenyl)-1-methylpropyl)amino)ethyl)-, (+-)-
Dihydroxyphenylalanine [Chemical/Ingredient]
(-)-L-alpha-Hydrazino-3,4-dihydroxy-alpha-methylhydrocinnamic Acid
(-)-L-alpha-Hydrazino-3,4-dihydroxy-alpha-methylhydrocinnamic acid monohydrate
(αS)-α-hydrazino-3,4-dihydroxy-α-methylbenzenepropanoic acid
Benzenemethanamine, N-(2-chloroethyl)-N-(phenylmethyl)-
Dibenzylchlorethamine [Chemical/Ingredient]
7 Select Night Time Severe Cold Cough and Flu
7 Select Night Time severe cold, cough and flu
(O-Benzhydryl(dimethylamino)ethanol) 8-chlorotheophyllinate
1H-Purine-2,6-dione, 8-chloro-3,7-dihydro-1,3-dimethyl-, compd. with 2-(diphenylmethoxy)-N,N-dimethylethanamine (1:1)
8-chloro-1,3-Dimethyl-3,7-dihydro-1H-purine-2,6-dione - 2-(diphenylmethoxy)-N,N-dimethylethanamine (1:1)
Benzhydryl-beta-dimethylaminoethylether 8-chlorotheophylline
Mercaptoethylamines [Chemical/Ingredient]
Ethanamine, N,N-dimethyl-2-((2-methylphenyl)phenylmethoxy)-
1,3-Dithiane-2-propanamine, 2-(3,4-dimethoxyphenyl)-N-(2-(3,4-dimethoxyphenyl)ethyl)-N-methyl-, 1,1,3,3-tetraoxide, hydrochloride
N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithian-2-propylamin-1,1,3,3-tetroxide hydrochloride
Tiapamil Hydrochloride [Chemical/Ingredient]
Benzenemethanamine, N-(2-chloroethyl)-N-(1-methyl-2-phenoxyethyl)-
N,N-Diethyl-2-((2-methoxy-5-(methylsulfonyl)benzoyl)amino)ethanaminium chloride
Tiapride Hydrochloride [Chemical/Ingredient]
Aminooxyacetic Acid [Chemical/Ingredient]
TECHNETIUM TC HEXAMETHYLPROPYLENEAMINE OXIME 099M
4-Hydroxyaminoquinoline-1-oxide [Chemical/Ingredient]
2-Propen-1-amine, Polymer with (Chloromethyl)oxirane
Allylamine Polymer with 1-Chloro-2,3-epoxypropane
Copolymer of bis(2-aminoethyl)amine and 2-(chloromethyl)oxirane
Epichlorohydrin-tetraethylenepentamine polymer
1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-, compd. with 1,2-ethanediamine (2:1)
1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-, compound with 1,2-Ethanediamine(2:1)
DTPA - Diethylenetriaminepentaacetic acid
Diethylenetriamine-N,N,N',N'',N''-pentaacetic Acid
99m-technetium Diethylenetriaminepentaacetic Acid
Diethylenetriaminepenta-acetic Acid, Gadolinium
Gadolinium Diethylenetriaminepenta acetic Acid
Gadolinium Diethylenetriaminepenta-acetic Acid
1,5-Dimethyl-1,5-Diazaundecamethylene Polymethobromide
1,6-Hexanediamine, N,N,N',N'-tetramethyl-, polymer with 1,3-dibromopropane
Hexadimethrine Bromide [Chemical/Ingredient]
Azo Urinary Tract Defense Antibacterial Protection
CVS Antibacterial Plus Urinary Pain Relief
(-)-N -Methyl-3-phenyl-3-(o-tolyloxy)-propylamine Hydrochloride
(-)-N-methyl-gamma(2-methylphenoxy)benzenepropamine Hydrochloride
Atomoxetine Hydrochloride [Chemical/Ingredient]
2-Propyn-1-amine, N-(3-(2,4-dichlorophenoxy)propyl)-N-methyl-
10H-Phenothiazine-10-ethanamine, N,N,alpha-trimethyl-
Cyclopropanamine, 2-phenyl-, trans-(+-)-
5-Isobenzofurancarbonitrile, 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydro-
1-Naphthalenamine,1,2,3,4-tetrahydro-4-(3,4-dichlorophenyl)-N-methyl-, (1S-cis)-
Citraconic Anhydrides [Chemical/Ingredient]
Phthalic Anhydrides [Chemical/Ingredient]
Succinic Anhydrides [Chemical/Ingredient]
1,3,5-Triazin-2(1H)-one, 4-amino-1-beta-D-ribofuranosyl-
7H-1,2,3-Triazolo(4,5-d)pyrimidin-7-one, 5-amino-1,4-dihydro-
1,2,4-Triazine-3,5(2H,4H)-dione, 2-Beta-D-ribofuranosyl-
1,2,4-triazine-3,5(2H,4H)-dione, 2-beta-D-ribofuranosyl
2-beta-D-ribofuranosyl-1,2,4-triazine-3,5(2H, 4H)-dione
3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine riboside
Azabicyclo Compounds [Chemical/Ingredient]
Atropine Derivatives [Chemical/Ingredient]
8-Azabicyclo(3.2.1)octane, 3-(diphenylmethoxy)-8-methyl-, endo-
2-Methyl-3beta-hydroxy-1alphah,5alphah-tropane-2beta-carboxylate benzoate (ester)
Scopolamine Derivatives [Chemical/Ingredient]
1H-Indazole-3-carboxamide, 1-methyl-N-(9-methyl-9-azabicyclo(3.3.1)non-3-yl)-, endo-
1-(4-sulfo-1-naphthylazo)-2-naphthol-3,6-disulfonic Acid Trisodium Salt
2,7-Naphthalenedisulfonic acid, 3-hydroxy-4-((4-sulfo-1-naphthalenyl)azo)-, trisodium salt
3-hydroxy-4-(2-(4-sulfo-1-naphthalenyl)diazenyl)-2,7-naphthalenedisulfonic Acid Sodium Salt (1:3)
2,7-Naphthalenedisulfonic acid, 4-amino-5-hydroxy-3-((4-nitrophenyl)azo)-6-(phenylazo)-, disodium salt
2,7-Naphthalenedisulfonic acid, 3,6-bis((2-arsonophenyl)azo)-4,5-dihydroxy-
(Methyl-ONN-azoxy)methyl beta-D-Glucopyranoside
beta-D-Glucopyranoside, (methyl-ONN-azoxy)methyl
Methanol, (methyl-ONN-azoxy)-, acetate (ester)
Methylazoxymethanol Acetate [Chemical/Ingredient]
Acid Bisdimethylamide, Diazodicarboxylic
Bisdimethylamide, Diazodicarboxylic Acid
Diazodicarboxylic Acid Bis(N,N-dimethyl)amide
Dizene Dicarboxylic Acid Bis(N,N-dimethylamide)
Dizenedicarboxylic Acid Bis(N,N-dimethylamide)
Diazonium Compounds [Chemical/Ingredient]
Diazooxonorleucine [Chemical/Ingredient]
Diazenecarbothioic acid, phenyl-, 2-phenylhydrazide
1,3-Naphthalenedisulfonic acid, 6,6'-((3,3'-dimethyl(1,1'-biphenyl)-4,4'-diyl)bis(azo))bis(4-amino-5-hydroxy)-, tetrasodium salt
Benzenamine, 2-methyl-4-((2-methylphenyl)azo)-
p-Azobenzenearsonate [Chemical/Ingredient]
1H-Pyrazole-3-carboxylic acid, 4,5-dihydro-5-oxo-1-(4-sulfophenyl)-4-((4-sulfophenyl)azo)-, trisodium salt
2,7-Naphthalenedisulfonic acid, 3,3'-((3,3'-dimethyl(1,1'-biphenyl)-4,4'-diyl)bis(azo))bis(5-amino-4-hydroxy-), tetrasodium salt
(2,3-Dichloro-4-(2-thenoyl)phenoxy)acetic acid
(2,3-Dichloro-4-(2-thienylcarbonyl)phenoxy)acetic acid
(2,3-Dichloro-4-(2-thiophenecarbonyl)phenoxy)acetic acid
4-(2-Thienylketo)-2,3-dichlorophenoxyacetic acid
Acetic acid, (2,3-dichloro-4-(2-thienylcarbonyl)phenoxy)-
Phosphonoacetic Acid [Chemical/Ingredient]
2-Propenoic acid, 2-cyano-, 2-methylpropyl ester
3-Hydroxybutyric Acid [Chemical/Ingredient]
Aminoisobutyric Acids [Chemical/Ingredient]
2 Phenoxy 2 Methylpropionic Acid Derivatives
2-Phenoxy-2-Methylpropionic Acid Derivatives
Methyl 2 Phenoxypropanoic Acid Derivatives
Methyl-2-Phenoxypropanoic Acid Derivatives
2-(4-(4-Chlorobenzoyl)phenoxy)-2-methylpropanoic acid 1-methylethyl ester
(e)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-5-phthalanyl)-4-methyl-4-hexenoic acid
-Hexenoic acid, 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-, (E)-
4-Hexenoic acid, 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-, (E)-
4-Hexenoic acid, 6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-5-phthalanyl)-4-methyl-, (E)-
2,5-Hexadienoic acid, 3-methoxy-5-methyl-4-oxo-
1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2-({[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)carbamoyl}amino)-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate
2,7,10,12-Tetraazatridecanoic acid, 12-methyl-13-(2-(1-methylethyl)-4-thiazolyl)-9-(2-(4-morpholinyl)ethyl)-8,11-dioxo-3,6-bis(phenylmethyl)-, 5-thiazolylmethyl ester, (3R,6R,9S)-
antiviral pharmacokinetic enhancers cobicistat
Elvitegravir Cobicistat Emtricitabine Tenofovir Disoproxil Fumarate Drug Combination
Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination [Chemical/Ingredient]
Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Disoproxil Fumarate
Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Disoproxil Fumarate Drug Combination
Elvitegravir-Cobicistat-Emtricitabine-Tenofovir Disoproxil Fumarate Drug Combination
Elvitegravir/ Cobicistat/ Emtricitabine/ Tenofovir disoproxil fumarate
elvitegravir + cobicistat + emtricitabine + tenofovir disoproxil fumarate
elvitegravir + cobicistat + emtricitabine + tenofovir disoproxil fumarate (medication)
Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Carbamic acid, monoanhydride with phosphoric acid
Carbamyl Phosphate [Chemical/Ingredient]
1-Piperazinecarboxamide, N,N-diethyl-4-methyl-
Ethanimidothioic acid, N-(((methylamino)carbonyl)oxy)-, methyl ester
Dimethyldithiocarbamate [Chemical/Ingredient]
Ethylenebis(dithiocarbamates) [Chemical/Ingredient]
Manganese, ((1,2-ethanediylbis(carbamodithioato))(2-))-
Zinc ethylenebis(dithiocarbamate) (product)
Zinc ethylenebis(dithiocarbamate) (substance)
Zinc, ((1,2-ethanediylbis(carbamodithioato))(2-))-
2-Naphthyl N-methyl-N-(3-tolyl)thionocarbamate
Carbamothioic acid, bis(1-methylethyl)-, S-(2,3,3-trichloro-2-propenyl) ester
Carbamic acid, methylnitroso-, ethyl ester
Nitrosomethylurethane [Chemical/Ingredient]
Pyrrolo(2,3-b)indol-5-ol, 1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethyl-, methylcarbamate (ester), (3aS-cis)-
Dicarboxylic Acids [Chemical/Ingredient]
Dimethyl Adipimidate [Chemical/Ingredient]
2-Aminoadipic Acid [Chemical/Ingredient]
Ketoglutaric Acids [Chemical/Ingredient]
Butanedioic acid, mercapto-, monogold(1+) sodium salt
Gold Sodium Thiomalate [Chemical/Ingredient]
Mercaptobutanedioic Acid Monogold(1+) Sodium Salt
Diaminopimelic Acid [Chemical/Ingredient]
Butanedioic Acid, 2,3-Dimercapto-, (2R,3S)-rel-
Butanedioic Acid, 2,3-Dimercapto-, (R*,S*)-Isomer
Butanedioic acid, 2,3-dimercapto-, (R*,S*)-
Technetium Tc 99m Dimercaptosuccinic Acid
Azetidinecarboxylic Acid [Chemical/Ingredient]
Technetium Tc 99m Diethyl-iminodiacetic Acid
Acid, Technetium-99m-Diisopropyliminodiacetic
Kit for the Preparation of Technetium Tc99m Disofenin
3-Mercaptopropionic Acid [Chemical/Ingredient]
Dehydroascorbic Acid [Chemical/Ingredient]
L-threo-2,3-Hexodiulosonic acid, gamma-lactone
L-threo-2,3-hexodiulosonic acid, γ-lactone
Antimony Sodium Gluconate [Chemical/Ingredient]
Diphosphoglyceric Acids [Chemical/Ingredient]
2,3-Diketogulonic Acid [Chemical/Ingredient]
Tricarboxylic Acids [Chemical/Ingredient]
Acids, Carbocyclic [Chemical/Ingredient]
Adapalene - Benzoyl Peroxide Drug Combination
Adapalene Benzoyl Peroxide Drug Combination
Adapalene, Benzoyl Peroxide Drug Combination [Chemical/Ingredient]
Adapalene-Benzoyl Peroxide Drug Combination
adapalene + benzoyl peroxide (medication)
Adapalene, Benzoyl Peroxide Drug Combination
D-Glucose, 2-((3-(acetylamino)-5-(acetylmethylamino)-2,4,6-triiodobenzoyl)amino)-2-deoxy-
3-Pyridinecarboxylic acid, 2-((3-(trifluoromethyl)phenyl)amino)-
Hydroxybenzoate Ethers [Chemical/Ingredient]
Adenosine, 3'-((2-amino-3-(4-methoxyphenyl)-1-oxopropyl)amino)-3'-deoxy-N,N-dimethyl-, (S)-
Adenosine, 3'-(alpha-amino-p-methoxyhydrocinnamamido)-3'-deoxy-N,N-dimethyl-, L-
Cyclohexanecarboxylic Acids [Chemical/Ingredient]
Cyclohexanecarboxylic acid, 1,3,4,5-tetrahydroxy-, (1R-(1alpha,3alpha,4alpha,5beta))-
1-Cyclohexene-1-carboxylic acid, 3,4,5-trihydroxy-, (3R-(3alpha,4alpha,5beta))-
Benzeneacetic acid, alpha-hydroxy-alpha-phenyl-, 1-azabicyclo(2.2.2)oct-3-yl ester
Quinuclidinyl Benzilate [Chemical/Ingredient]
2-Piperidineacetic acid, alpha-phenyl-, methyl ester
Phenylpyruvic Acids [Chemical/Ingredient]
2-Propenoic acid, 2-(phosphonooxy)-, ion(1-)
Phosphoenolpyruvate [Chemical/Ingredient]
1,2-Bis[2-(2, 3-epoxypropoxy)ethoxy]ethane
1,2:15,16-Diepoxy-4,7,10, 13-tetraoxahexadecane
Ethane, 1, 2-bis[2-(2,3-epoxypropoxy)ethoxy]-
9-[(E)-4-[(2S,3R,4R,5S)-3,4-dihydroxy-5-[[(2S,3S)-3- [(2S,3S)-3-hydroxybutan-2-yl]oxiran-2-yl]methyl] oxan-2-yl]-3-methylbut-2-enoyl]oxynonanoic acid
Ethane, 2,2-dichloro-1,1-difluoro-1-methoxy-
3H-1,2-Dithiole-3-thione, 5-(4-methoxyphenyl)-
Bis(Chloromethyl) Ether [Chemical/Ingredient]
2-Chloro-1,1,2-trifluoroethyl difluoromethyl Ether
1-Chloro-2,2,2-trifluoroethyl Difluoromethyl Ether
Ethane, 2-chloro-2-(difluoromethoxy)-1,1,1-trifluoro-
1% Triclosan Anti-microbial Foaming Skin Cleanser
1% Triclosan Anti-microbial Skin Cleanser
2,4,4'-Trichloro-2'-Hydroxydiphenyl Ether
2-Hydroxy-2',4,4'-trichlorodiphenyl Ether
AEROSCENT Milk and Honey Antibacterial Moisturizing
APRIL Bath and Shower Anti-bacterial Hand 3 Pack
Halogenated Diphenyl Ethers [Chemical/Ingredient]
1-Piperidinyloxy, 2,2,6,6-tetramethyl-4-oxo-
Triacetoneamine-N-Oxyl [Chemical/Ingredient]
DL-Serine 2-((2,3,4-trihydroxyphenyl)methyl)hydrazide
DL-Serine, 2-((2,3,4-trihydroxyphenyl)methyl)hydrazide
CARBONYL CYANIDE CHLOROPHENYL HYDRAZONE M
CARBONYL CYANIDE CHLOROPHENYL HYDRAZONE META
Carbonyl Cyanide m Chlorophenyl Hydrazone
Carbonyl Cyanide m-Chlorophenyl Hydrazone [Chemical/Ingredient]
Carbonyl Cyanide meta Chlorophenyl Hydrazone
Carbonyl Cyanide meta-Chlorophenyl Hydrazone
Propanedinitrile, ((3-chlorophenyl)hydrazono)-
Carbonyl Cyanide m-Chlorophenyl Hydrazone
CARBONYL CYANIDE TRIFLUOROMETHOXYPHENYLHYDRAZONE P
CARBONYL CYANIDE TRIFLUOROMETHOXYPHENYLHYDRAZONE PARA
Carbonyl Cyanide p Trifluoromethoxyphenylhydrazone
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone [Chemical/Ingredient]
Carbonyl Cyanide para Trifluoromethoxyphenylhydrazone
Carbonyl Cyanide para-Trifluoromethoxyphenylhydrazone
Cyanide p-Trifluoromethoxyphenylhydrazone, Carbonyl
Cyanide para-Trifluoromethoxyphenylhydrazone, Carbonyl
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
4-Pyridinecarboxylic acid, 2-(1-methylethyl)hydrazide
Dimethylhydrazines [Chemical/Ingredient]
Monomethylhydrazine [Chemical/Ingredient]
Hydrazinecarboxylic acid, 2-(1-phthalazinyl)-, ethyl ester, monohydrochloride
Hydrocarbons, Acyclic [Chemical/Ingredient]
2-Mercaptoethanesulfonic Acid Sodium Salt
Ethanesulfonic acid, 2-mercapto-, monosodium salt
1-Piperazineethanesulfonic acid, 4-(2-hydroxyethyl)-
HYDROXYETHYLPIPERAZINE ETHANESULFONIC ACID N N 02 02
N 2 Hydroxyethylpiperazine N' 2' ethanesulfonic Acid
N-2-Hydroxyethylpiperazine-N'-2'-ethanesulfonic Acid
Polyvinylpyridine N-Oxide [Chemical/Ingredient]
Pyridine, 2-ethenyl-, 1-oxide, homopolymer
Hydrocarbons, Cyclic [Chemical/Ingredient]
Bridged-Ring Compounds [Chemical/Ingredient]
Bridged Bicyclo Compounds [Chemical/Ingredient]
1-Piperidinepropanol, alpha-bicyclo(2.2.1)hept-5-en-2-yl-alpha-phenyl-
Hydrocarbons, Alicyclic [Chemical/Ingredient]
3,6-Methano-8H-1,5,7-trioxacyclopenta(ij)cycloprop(a)azulene-4,8(3H)-dione, hexahydro-2a-hydroxy-9-(1-hydroxy-1-methylethyl)-8b-methyl-, (1aR-(1aalpha,2abeta,3beta,6beta,6abeta,8aS*,8bbeta,9S*))-, compd. with (1aR-(1aalpha,2abeta,3beta,6beta,6abeta,8aS*,8
3,6-Methano-8H-1,5,7-trioxacyclopenta(ij)cycloprop(a)azulene-4,8(3H)-dione, hexahydro-2a-hydroxy-9-(1-hydroxy-1-methylethyl)-8b-methyl-, (1aR-(1aalpha,2abeta,3beta,6beta,6abeta,8aS*,8bbeta,9S*))-, compd. with (1aR-(1aalpha,2abeta,3beta,6beta,6abeta,8aS*,8bbeta,9R*))-hexahydro-2a-hydroxy-8b-methyl-9-(1-methylethenyl)-3,6-methano-8H-1,5,7-trioxacyclopenta(ij)cycloprop(a)azulene-4,8(3H)-dione (1:1)
Cyclohexanone, 2-(ethylamino)-2-(2-thienyl)-
Albumin-Bound Paclitaxel [Chemical/Ingredient]
Hydrocarbons, Aromatic [Chemical/Ingredient]
Benzenesulfonic acid, 4,4'-(3-(2-pyridinyl)-1,2,4-triazine-5,6-diyl)bis-, disodium salt
Benzene, 1-methoxy-4-(1-propenyl)-, (E)-, homopolymer, sulfonated, sodium salt
Polyanetholesulfonate [Chemical/Ingredient]
Less Drowsy Formula Motion Sickness Relief
1-Piperidinebutanol, alpha-(4-(1,1-dimethylethyl)phenyl)-4-(hydroxydiphenylmethyl)-
Pharmaplus Once A Day Allergy Caplet 120mg
2-Hydroxy-5-nitrobenzyl Bromide [Chemical/Ingredient]
4 Acetamido 4' isothiocyanatostilbene 2,2' disulfonic Acid
4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid [Chemical/Ingredient]
4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS)
ACETAMIDOISOTHIOCYANATOSTILBENEDISULFONIC ACID 04 04 02 02
Benzenesulfonic acid, 5-(acetylamino)-2-(2-(4-isothiocyanato-2-sulfophenyl)ethenyl)-
4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid
4,4'-Diisothiocyano-2,2'-Stilbene Disulfonic Acid
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid [Chemical/Ingredient]
Benzenesulfonic acid, 2,2'-(1,2-ethenediyl)bis(5-isothiocyanato)-
DIISOTHIOCYANOSTILBENEDISULFONIC ACID 04 04 02 02
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid
(1,1'-Biphenyl)-2,2'-diol, 5,5'-dichloro-3,3'-dinitro-
Benzeneacetic acid, 4-hydroxy-3-iodo-5-nitro-
1-Propanone, 3-(4-hydroxyphenyl)-1-(2,4,6-trihydroxyphenyl)-, phosphate, homopolymer
Polyphloretin Phosphate [Chemical/Ingredient]
1H-2-Benzoxacyclotetradecin-1,7(8H)-dione, 3,4,5,6,9,10-hexahydro-14,16-dihydroxy-3-methyl-, (S-(E))-
Aspirin, Dipyridamole Drug Combination [Chemical/Ingredient]
Phenylurea Compounds [Chemical/Ingredient]
Benzamide, N-(((4-chlorophenyl)amino)carbonyl)-2,6-difluoro-
Dichlorophenyl dimethyl urea (substance)
Urea, N'-(3,4-dichlorophenyl)-N,N-dimethyl-
Urea, N'-(3,4-dichlorophenyl)-N-methoxy-N-methyl-
Toluene 2,4-Diisocyanate [Chemical/Ingredient]
Benzenesulfonamide, N-(5-amino-1-(chloroacetyl)pentyl)-4-methyl-
Tosyllysine Chloromethyl Ketone [Chemical/Ingredient]
Benzenesulfonamide, N-(3-chloro-2-oxo-1-(phenylmethyl)propyl)-4-methyl-, (S)-
Tosylphenylalanyl Chloromethyl Ketone [Chemical/Ingredient]
Polycyclic Aromatic Hydrocarbons [Chemical/Ingredient]
2-Anthracenecarboxylic acid, 7-beta-D-glucopyranosyl-9,10-dihydro-3,5,6,8-tetrahydroxy-1-methyl-9,10-dioxo-
7-Glucopyranosyl-3,5,6,8-tetrahydroxyl-1-methyl-9,10-dioxoanthracene-2-carboxylic Acid
1,3-Dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9, 10-anthracenedione
1,4-Dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9, 10-anthroquinone
9,10-Anthracenedione, 1,4-dihydroxy-5,8-bis((2-((2-hydroxyethyl)amino)ethyl)amino)-
9,10-Ethanoanthracene-9(10H)-propanamine, N-methyl-
Benz(a)Anthracenes [Chemical/Ingredient]
9,10-Dimethyl-1,2-benzanthracene [Chemical/Ingredient]
Benzocycloheptenes [Chemical/Ingredient]
Dibenzocycloheptenes [Chemical/Ingredient]
9H-Fluoren-9-one, 2,7-bis(2-(diethylamino)ethoxy)-
1H-Indene-1,3(2h)-Dione, 5,6-Dimethyl-2-Nitro-, Ion(1-)
1H-Indene-2-Ethanamine, N,N-Dimethyl-3-(1-(2-Pyridinyl)Ethyl)-
(Z)-5-Fluoro-2-methyl-1-((P-(methylsulfinyl)phenyl)methylene)-1H-indene-3-acetic acid
(Z)-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetic acid
1H-Indene-3-acetic acid, 5-fluoro-2-methyl-1-((4-(methylsulfinyl)phenyl)methylene)-, (Z)-
6-(3-(1-Adamantyl)-4-methoxyphenyl)-2-naphthoic acid
6-(4-Methoxy-3-tricyclo(3.3.1.13,7)dec-1-ylphenyl)-2-naphthalenecarboxylic Acid
1-Naphthalenemethanamine, a-methyl-N-(3-(3-(trifluoromethyl)phenyl)propyl)-,(aR)-, Hydrochloride
Alpha-methyl-N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-naphthalenemethanamine, (alphaR)-hydrochloride
Cinacalcet Hydrochloride [Chemical/Ingredient]
1-Naphthalenecarboxamide, N-butyl-N-(2-(diethylamino)ethyl)-
Compounds, Dimethylaminonaphthalenesulfonyl
Dimethylaminonaphthalenesulfonyl Compounds
(1S,3R,7S,8S,8AR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-(2R,4R)-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl (S)-2-methyl-butyrate
(2S)-2-Methylbutanoic Acid, (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-Hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl Ester
2beta,6alpha-Dimethyl-8alpha-(2-methyl-1-oxobutoxy)-mevinic acid lactone
Butanoic Acid, 2,2-Dimethyl-, (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-((2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl Ester, Mixture with (3R,4S)-1-(4-Fluorophenyl)-3-((3S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)-2-azetidinone
Naphthaleneacetic Acids [Chemical/Ingredient]
Naphthalenesulfonates [Chemical/Ingredient]
1,4-Naphthalenedione, 2-methyl-3-(3,7,11,15-tetramethyl-2-hexadecenyl)-, (R-(R*,R*-(E)))-
Naphthylvinylpyridine [Chemical/Ingredient]
Pyridine, 4-(2-(1-naphthalenyl)ethenyl)-
Tetrahydronaphthalenes [Chemical/Ingredient]
4'-Demethylepipodophyllotoxin 9-(4,6-O-(R)-ethylidene-beta-D-glucopyranoside)
4'-Demethylepipodophyllotoxin 9-[4,6-O-ethylidene-beta-D-glucopyranoside
4'-Demethylepipodophyllotoxin 9-[4,6-O-ethylidene-beta-D-glucopyranoside]
4-Demethylepipodophyllotoxin beta-D-ethylideneglucoside
4-demethylepipodophyllotoxin β-D-ethylideneglucoside
1-Naphthylisothiocyanate [Chemical/Ingredient]
(+)-(3R,5R)-3,5-Dihydroxy-7-[(1S,2S,6S,8S,8ar)-6-hydroxy-2-methyl-8-{[(S)-2-methylbutyryl]oxy}-1,2,6,7,8,8a-hexahydro-1-naphthyl]heptanoic acid
1-Naphthaleneheptanoic acid, 1,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-, (1S-(1alpha(betaS*,deltaS*),2alpha,6alpha,8beta(R*),8aalpha))-
Aristolochic Acids [Chemical/Ingredient]
Diterpenes, Abietane [Chemical/Ingredient]
8-Azaspiro(4.5)decane-7,9-dione, 8-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-
Spiro(furan-2(3H),1'(3'H)-isobenzofuran)-3,3'-dione, 4-phenyl-
2',4',5',7'-Tetrabromofluorescein Disodium Salt
Fluorescein-5-isothiocyanate [Chemical/Ingredient]
Spiro(isobenzofuran-1(3H),9'-(9H)xanthen)-3-one, 3',6'-dihydroxy-5-isothiocyanato-
1,3,8-Triazaspiro(4.5)decan-4-one, 8-(4,4-bis(4-fluorophenyl)butyl)-1-phenyl-
1,3,8-Triazaspiro(4.5)decan-4-one, 8-(4-(4-fluorophenyl)-4-oxobutyl)-1-phenyl-
Hydrocarbons, Halogenated [Chemical/Ingredient]
Ethane, 2-bromo-2-chloro-1,1,1-trifluoro-
Hydrocarbons, Brominated [Chemical/Ingredient]
Hydrocarbons, Chlorinated [Chemical/Ingredient]
Hydrocarbons, Fluorinated [Chemical/Ingredient]
Hydrocarbons, Iodinated [Chemical/Ingredient]
2-oxo-N,3-bis-(2-chloroethyl) tetrahydro-2H-1,3,2-oxazaphosphorin- 2-amine
2H-1,3,2-Oxazaphosphorin-2-amine, N,3-bis(2-chloroethyl)tetrahydro-, 2-oxide
3-(2-Chloroethyl)-2-((2-chloroethyl)amino)tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide
Cannabinoid - non-pharmaceutical (substance)
(1Alpha,3Alpha,6Alpha,14Alpha,15Alpha,16Beta)-20-Ethyl-1,6,16-Trimethoxy-4-(Methoxymethyl)Aconitane-3,8,13,14,15-Pentol 8-Acetate 14-Benzoate
Aconitane-3,8,13,14,15-pentol, 20-ethyl-1,6,16-trimethoxy-4-(methoxymethyl)-, 8-acetate 14-benzoate, (1alpha,3alpha,6alpha,14alpha,15alpha,16beta)-
19-Norkaur-16-en-18-oic acid, 15-hydroxy-2-((2-O-(3-methyl-1-oxobutyl)-3,4-di-O-sulfo-beta-D-glucopyranosyl)oxy)-, (2beta,4alpha,15alpha)-
4,8,12-Tetradecatrienoic acid, 5,9,13-trimethyl-, 3,7-dimethyl-2,6-octadienyl ester, (E,E,E)-
Polyisoprenyl Phosphates [Chemical/Ingredient]
Polyisoprenyl Phosphate Sugars [Chemical/Ingredient]
Monosaccharides, Polyisoprenyl Phosphate
Phosphate Monosaccharides, Polyisoprenyl
Polyisoprenyl Phosphate Monosaccharides [Chemical/Ingredient]
Oligosaccharides, Polyisoprenyl Phosphate
Phosphate Oligosaccharides, Polyisoprenyl
Polyisoprenyl Phosphate Oligosaccharides [Chemical/Ingredient]
Polyisoprenyl Phosphate Oligosaccharides
Trichothec-9-en-4-ol, 12,13-epoxy-, acetate, (4beta)-
4,4,14 alpha-trimethyl-5 alpha-cholesta-8,24-dien-3 beta-ol
Picras-3-en-16-one, 11,20-epoxy-1,2,11,12-tetrahydroxy-15-(2-hydroxy-2-methyl-1-oxobutoxy)-, (1beta,2alpha,11beta,12alpha,15beta(S))-
701 Dieda Zhengtong Yaogao Medicated Plaster
Iridoid Glycosides [Chemical/Ingredient]
Iridoid Glucosides [Chemical/Ingredient]
Dimethyl Suberimidate [Chemical/Ingredient]
Morpholinium, 4-(2-((cyclohexylcarbonimidoyl)amino)ethyl)-4-methyl-, salt with 4-methylbenzenesulfonic acid (1:1)
Cyclohexanamine, N,N'-methanetetraylbis-
Dicyclohexylcarbodiimide [Chemical/Ingredient]
1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-
Ethyldimethylaminopropyl Carbodiimide [Chemical/Ingredient]
1-Deoxynojirimycin [Chemical/Ingredient]
3,4,5-Piperidinetriol, 2-(hydroxymethyl)-, (2R-(2alpha,3beta,4alpha,5beta))-
Benzoin Compound Tincture Professional Pack
1,3-Butanedione, 4,4,4-trifluoro-1-(2-thienyl)-
Thenoyltrifluoroacetone [Chemical/Ingredient]
1-Butanone, 1-(4-fluorophenyl)-4-(4-(2-pyridinyl)-1-piperazinyl)-
2H-Benzimidazol-2-one, 1-(1-(4-(4-fluorophenyl)-4-oxobutyl)-4-piperidinyl)-1,3-dihydro-
2H-Benzimidazol-2-one, 1-(1-(4-(4-fluorophenyl)-4-oxobutyl)-1,2,3,6-tetrahydro-4-pyridinyl)-1,3-dihydro-
1-Butanone, 4-(4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl)-1-(4-fluorophenyl)-
1-Butanone, 1-(4-fluorophenyl)-4-(4-hydroxy-4-(3-(trifluoromethyl)phenyl)-1-piperidinyl)-
3-Heptanone, 6-(dimethylamino)-4,4-diphenyl-
6-(Dimethylamino)-4,4-Diphenyl-3-Heptanol Acetate
Benzeneethanol, beta-(2-(dimethylamino)propyl)-alpha-ethyl-beta-phenyl-, acetate (ester)
1-Propanone, 1-phenyl-, monohydroxy deriv.
Hydroxypropiophenone [Chemical/Ingredient]
1-Propanone, 1-(2-(2-hydroxy-3-(propylamino)propoxy)phenyl)-3-phenyl-
1-Propanone, 2-methyl-1-(4-methylphenyl)-3-(1-piperidinyl)-
1-Propanone, 1-(3-Chlorophenyl)-2-((1,1-dimethylethyl)amino)-
17-Hydroxy-7alpha-mercapto-3-oxo-17alpha-pregn-4-ene-21-carboxylic Acid, gamma Lactone, Acetate
Alanine, N-acetyl-N-methyl-, 6-ester with 11-chloro-6, 21-dihydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-4,24-dioxa-9, 22-diazatetracyclo[19.3.1.1(10,24).0(3,5)]hexacosa-10,12,14[26], 16,18-pentaene-8,23-dione
alanine, N-acetyl-N-methyl-, 6-ester with 11-chloro-6, 21-dihydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-4,24-dioxa-9,22-diazatetracyclo[19.3.1.1(10,24).0(3,5)]hexacosa-10,12,14[26], 16,18-pentaene-8,23-dione
Candistatin Topical Powder - 100000 Unit/g
Leucomycin V, 3B,9-diacetate 3,4B-dipropanoate
[(2R,3R,4E,6E,9R,11R,12S,13S,14R) -12- {[3,6-dideoxy-4-O-(2,6-dideoxy-3-C-methyl-alpha-L-ribo-hexopyranosyl) -3- (dimethylamino)-beta-D-glucopyranosyl]oxy}-2-ethyl-14-hydroxy-5, 9,13-trimethyl-8, 16-dioxo-11-(2-oxoethyl)oxacyclohexadeca-4,6-dien-3-yl]methyl 6-deoxy-2,3-di-O-methyl-beta-D-allopyranoside
Acyl-Butyrolactones [Chemical/Ingredient]
3-Pyridinecarboxamide, N-(2-(Nitroxy)ethyl)-
Combination, Emtricitabine-Rilpivirine-Tenofovir Drug
Drug Combination, Emtricitabine-Rilpivirine-Tenofovir
Emtricitabine Rilpivirine Tenofovir Drug Combination
Emtricitabine, Rilpivirine, Tenofovir Drug Combination [Chemical/Ingredient]
Emtricitabine-Rilpivirine-Tenofovir Drug Combination
Emtricitabine, Rilpivirine, Tenofovir Drug Combination
Aminopropionitrile [Chemical/Ingredient]
Benzeneacetonitrile, alpha-((6-O-beta-D-glucopyranosyl-beta-D-glucopyranosyl)oxy)-, (R)-
Pregn-5-ene-16-carbonitrile, 3-hydroxy-20-oxo-, (3beta,16alpha)-
Pregnenolone Carbonitrile [Chemical/Ingredient]
Benzonitrile, 4-(5,6,7,8-tetrahydroimidazo(1,5-a)pyridin-5-yl)-
Amyl Nitrite Vitrellae Bpc Liq 0.33 Ml/cap
Formamide, N-(4-(5-nitro-2-furanyl)-2-thiazolyl)-
2,4-Imidazolidinedione, 1-((3-(5-nitro-2-furanyl)-2-propenylidene)amino)-
2-Oxazolidinone, 3-(((5-nitro-2-furanyl)methylene)amino)-
2-Furanacetamide, alpha-((5-nitro-2-furanyl)methylene)-
2-Oxazolidinone, 5-((methylthio)methyl)-3-(((5-nitro-2-furanyl)methylene)amino)-
4-Thiomorpholinamine, 3-methyl-N-((5-nitro-2-furanyl)methylene)-, 1,1-dioxide
2,4-Imidazolidinedione, 1-(((5-nitro-2-furanyl)methylene)amino)-
Hydrazinecarboxamide, 2-((5-nitro-2-furanyl)methylene)-
Hydrazinecarboximidamide, 2-(3-(5-nitro-2-furanyl)-1-(2-(5-nitro-2-furanyl)ethenyl)-2-propenylidene)-
1,2,4-Oxadiazol-5-amine, 3-(2-(5-nitro-2-furanyl)ethenyl)-, (E)-
5-Amino-3-((5-nitro-2-furyl)vinyl)-1,2,4-oxadiazole [Chemical/Ingredient]
AMINONITROFURYLVINYL OXADIAZOLE 05 03 05 02 01 02
1H-Imidazole, 1-methyl-2-(1-methylethyl)-5-nitro-
1H-Imidazole-1-ethanol, 2-methyl-5-nitro-
1-(alpha-methoxymethyl ethanol)-2-Nitroimidazole
1H-Imidazole-1-ethanol, alpha-(methoxymethyl)-2-nitro-
Morpholine, 4-(2-(5-nitro-1H-imidazol-1-yl)ethyl)-
1H-Imidazole-1-ethanol, alpha-(chloromethyl)-2-methyl-5-nitro-
1H-Imidazole-2-methanol, 1-methyl-5-nitro-, carbamate (ester)
1H-Imidazole, 1-(2-(ethylsulfonyl)ethyl)-2-methyl-5-nitro-
1H-Imidazole-1-acetamide, N-(2-hydroxyethyl)-2-nitro-
2-Nitroimidazole-1-acetamide, N-(2-hydroxyethyl)-
4-Nitroquinoline-1-oxide [Chemical/Ingredient]
Butylhydroxybutylnitrosamine [Chemical/Ingredient]
Diethylnitrosamine [Chemical/Ingredient]
Dimethylnitrosamine [Chemical/Ingredient]
N-Nitrosopyrrolidine [Chemical/Ingredient]
Nitrosourea Compounds [Chemical/Ingredient]
1-Nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-
D-Glucose, 2-deoxy-2-(((methylnitrosoamino)carbonyl)amino)-
Urea, N'-((4-amino-2-methyl-5-pyrimidinyl)methyl)-N-(2-chloroethyl)-N-nitroso-
Sulfonium Compounds [Chemical/Ingredient]
Antimonate(2-), bis(mu-(2,3-dihydroxybutanedioato(4-)-O1,O2:O3,O4))di-, dipotassium, trihydrate, stereoisomer
Antimony Potassium Tartrate [Chemical/Ingredient]
2,2'-(((4-(aminocarbonyl)phenyl)arsinidene)bis(thio))bisacetic Acid
4-carbamylphenyl bis(carboxymethylthio)arsenite
Acetic acid, 2,2'-(((4-(aminocarbonyl)phenyl)arsinidene)bis(thio))bis-
Phenol, 4,4'-(1,2-diarsenediyl)bis(2-amino)-, dihydrochloride
1,3,2-Dithiarsolane-4-methanol, 2-(4-((4,6-diamino-1,3,5-triazin-2-yl)amino)phenyl)-
Arsonic acid, (4-hydroxy-3-nitrophenyl)-
Organomercury Compounds [Chemical/Ingredient]
Alkylmercury Compounds [Chemical/Ingredient]
2,7-Dibromo-4-hydroxymercurifluoresceine disodium salt
Phenylmercury Compounds [Chemical/Ingredient]
Organoplatinum Compounds [Chemical/Ingredient]
1,1-cyclobutanedicarboxylic acid platinum complex
Organotin Compounds [Chemical/Ingredient]
Trialkyltin Compounds [Chemical/Ingredient]
Hexadeca-μ-hydroxytetracosahydroxy[μ8-[1,3,4,6-tetra-O-sulfo-β-Dfructofuranosyl-α-D-glucopyranoside tetrakis(hydrogen sulfato)8-)]]hexadecaaluminum
Organotechnetium Compounds [Chemical/Ingredient]
99m Mercaptoacetylglycyl-glycyl-glycine, Technetium
Disodium (N-(N-(N-(Mercaptoacetyl)Glycyl)Glycyl)Glycinato(5-)-N,N',N'',S)-Oxo((Sup 99m)Tc)
Mercaptoacetylglycyl-glycyl-glycine, Technetium 99m
Organogold Compounds [Chemical/Ingredient]
Organophosphorus Compounds [Chemical/Ingredient]
Organothiophosphorus Compounds [Chemical/Ingredient]
Organothiophosphonates [Chemical/Ingredient]
Organothiophosphates [Chemical/Ingredient]
(2S,4S)-4-Cyclohexyl-1-[2-[(2-methyl-1-propanoyloxypropoxy)-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid
(2S,4S)-4-Cyclohexyl-1-{2-[(2-methyl-1-propionyloxy-propoxy)-(4-phenyl-butyl)-phosphinoyl]-acetyl}-pyrrolidine-2-carboxylic acid
(S)-4-Cyclohexyl-1-{2-[(2-methyl-1-propionyloxy-propoxy)-(4-phenyl-butyl)-phosphinoyl]-acetyl}-pyrrolidine-2-carboxylic acid
Phosphoric acid, 2-chloro-1-(2,4-dichlorophenyl)ethenyl diethyl ester
0,0-Dimethyl 0-(2,2-dichlorovinyl) phosphate
0,0-Dimethyl 0-(2,2-dichlorvinyl) phosphate
2-Butenoic acid, 3-((dimethoxyphosphinyl)oxy)-, methyl ester
2-Methoxycarbonyl-1-methylvinyl dimethyl phosphate
Phosphoric acid, dimethyl 1-methyl-3-(methylamino)-3-oxo-1-propenyl ester, (E)-
Phosphoric acid, 1,2-dibromo-2,2-dichloroethyl dimethyl ester
Diethyl p-nitrophenyl phosphate (substance)
Phosphoric acid, 2-chloro-3-(diethylamino)-1-methyl-3-oxo-1-propenyl dimethyl ester
Phosphoric acid, 2-chloro-1-(2,4,5-trichlorophenyl)ethenyl dimethyl ester, (Z)-
Organophosphonates [Chemical/Ingredient]
(((1R)-2-(6-Amino-9H-purin-9-yl)-1-methylethoxy)methyl)phosphonic acid
Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination [Chemical/Ingredient]
Efavirenz/ Emtricitabine/ Tenofovir disoproxil fumarate
efavirenz + emtricitabine + tenofovir disoproxil fumarate
efavirenz + emtricitabine + tenofovir disoproxil fumarate (medication)
efavirenz / emtricitabine / tenofovir disoproxil
emtricitabine, tenofovir disoproxil and efavirenz
Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Emtricitabine Tenofovir Disoproxil Fumarate Drug Combination
Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination [Chemical/Ingredient]
Emtricitabine-Tenofovir Disoproxil Fumarate Drug Combination
Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Aminoethylphosphonic Acid [Chemical/Ingredient]
(-)-(1R,2S)-(1,2-Epoxypropyl)phosphonic acid
(2R-cis)-(3-Methyloxiranyl)phosphonic acid
Phosphonic acid, (2,2,2-trichloro-1-hydroxyethyl)-, dimethyl ester
Organofluorophosphonates [Chemical/Ingredient]
Diphosphoramide, N,N',N'',N'''-tetrakis(1-methylethyl)-
Tetraisopropylpyrophosphamide [Chemical/Ingredient]
Aziridine, 1,1',1''-phosphinothioylidynetris-
2,5-Cyclohexadiene-1,4-dione, 2-(2-((aminocarbonyl)oxy)-1-methoxyethyl)-3,6-bis(1-aziridinyl)-5-methyl-
2,5-Cyclohexadiene-1,4-dione, 2,3,5,6-tetrachloro-
Tetrachloro-1,4- benzoquinone (substance)
2,5 Dibromo 3 methyl 6 isopropyl p benzoquinone
2,5-Cyclohexadiene-1,4-dione, 2,5-dibromo-3-methyl-6-(1-methylethyl)-
Dibromothymoquinone [Chemical/Ingredient]
Pyrroloiminoquinones [Chemical/Ingredient]
Thiosemicarbazones [Chemical/Ingredient]
Hydrazinecarbothioamide, 2-(1,2-dihydro-1-methyl-2-oxo-3H-indol-3-ylidene)-
Isatin, 1-methyl-, 3-(thiosemicarbazone)
Acetamide, N-(4-(((aminothioxomethyl)hydrazono)methyl)phenyl)-
Amino Acids, Sulfur [Chemical/Ingredient]
2-Amino-4-(2-Amino-2-Carboxy-Ethyl) Thio-Butanoic Acid
2-Amino-4-[(2-Amino-2-Carboxyethyl)Sulfanyl]Butanoic Acid
Homocysteine, S-(2-Amino-2-Carboxyethyl)-
L-Homocysteine, S-(2-amino-2-carboxyethyl)-, (R)-
(L)-2-Amino-3-(carboxymethylthio)propionic acid
(2S)-2-amino-4-(Methylsulfanyl)butanoic acid
(S)-2-Amino-4-(methyl-sulfanyl)butanoic acid
2.5% Travasol Amino Acid Injection Without Electrolytes In 10% Dextrose Quickmix
L-Phenylalanine, N-(N-(N-formyl-L-methionyl)-L-leucyl)-
Leucyl-Phenylalanine, N-Formylmethionine
Butanoic acid, 2-amino-4-(methylseleno)-
(S)-2-amino-3-mercapto-3-methylbutanoic acid
Alpha-amino-beta-methyl-beta-mercaptobutyric Acid
Glycine, N-(2-(mercaptomethyl)-1-oxo-3-phenylpropyl)-, (+-)-
6,9-Methano-2,4,3-benzodioxathiepin, 6,7,8,9,10,10-hexachloro-1,5,5a,6,9,9a-hexahydro-, 3-oxide
10-(3-dimethylaminopropyl)phenothiazin-3-yl methyl ketone
10H-Phenothiazine-10-propanamine, 2-chloro-N,N-dimethyl-
1-Piperazineethanol, 4-(3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)propyl)-
1-Piperazineethanol, 4-(3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)propyl)-(9CI)
10-(2-(1-Methyl-2-piperidyl)ethyl)-2-methylsulfinyl phenothiazine
10H-Phenothiazine, 10-(2-(1-methyl-2-piperidinyl)ethyl)-2-(methylsulfinyl)-
10H-Phenothiazine-10-propanamine, 2-methoxy-N,N,beta-trimethyl-, (R)-
10H-Phenothiazine, 2-chloro-10-(3-(hexahydropyrrolo(1,2-a)pyrazin-2(1H)-yl)-1-oxopropyl)-, dihydrochloride
10H-Phenothiazine, 10-(3-(4-methyl-1-piperazinyl)propyl)-
1-Piperazineethanol, 4-(3-(2-chloro-10H-phenothiazin-10-yl)propyl)-
10H-Phenothiazine, 2-chloro-10-(3-(4-methyl-1-piperazinyl)propyl)-
Chloro-3 (N-methylpiperazinyl-3 propyl)-10 phenothiazine
10H-Phenothiazine-10-propanamine, N,N-dimethyl-
N-Dimethylamino-1-methylethyl thiodiphenylamine
10H-Phenothiazine, 2-(ethylthio)-10-(3-(4-methyl-1-piperazinyl)propyl)-
10H-Phenothiazine, 10-(2-(1-methyl-2-piperidinyl)ethyl)-2-(methylthio)-
Novo-ridazine (thioridazine Oral Suspension) - 2 mg/ml
3-Amino-7-Dimethylamino-2-Methylphenazathionium Chloride
Phenothiazin-5-ium, 3-amino-7-(dimethylamino)-2-methyl-, chloride
10H-Phenothiazine, 10-(3-(4-methyl-1-piperazinyl)propyl)-2-(trifluoromethyl)-
10H-Phenothiazine-10-propanamine, N,N-dimethyl-2-(trifluoromethyl)-
10H-Phenothiazine-10-propanamine, N,N,beta-trimethyl-
Carbamic acid, (10-(3-(4-morpholinyl)-1-oxopropyl)-10H-phenothiazin-2-yl)-, ethyl ester
Ethyl 10-(3-morpholinopropionyl)phenothiazine-2-carbamate
Ethyl 10-(beta-N-morpholinylpropionyl)phenothiazine-2-carbamate
Sulfhydryl Compounds [Chemical/Ingredient]
1H-Imidazole-4-ethanaminium, alpha-carboxy-2,3-dihydro-N,N,N-trimethyl-2-thioxo-, inner salt, (S)-
2H-Imidazole-2-thione, 1,3-dihydro-1-methyl-
Butanamide, 2,4-dihydroxy-N-(3-((2-mercaptoethyl)amino)-3-oxopropyl)-3,3-dimethyl-, (R)-
Phenylmethylsulfonyl Fluoride [Chemical/Ingredient]
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine [Chemical/Ingredient]
ISOQUINOLINESULFONYL METHYLPIPERAZINE 01 05 02
Sulfonylurea Compounds [Chemical/Ingredient]
1-[(4-acetylbenzene)sulfonyl]-3-cyclohexylurea 4-acetyl-N-(cyclohexylcarbamoyl)benzenesulfonamide
Benzenesulfonamide, 4-amino-N-((butylamino)carbonyl)-
Benzenesulfonamide, 4-chloro-N-((propylamino)carbonyl)-
Benzamide, 5-chloro-N-(2-(4-((((cyclohexylamino)carbonyl)amino)sulfonyl)phenyl)ethyl)-2-methoxy-
Benzenesulfonamide, N-(((hexahydrocyclopenta(c)pyrrol-2(1H)-yl)amino)carbonyl)-4-methyl-
Benzenesulfonamide, N-(((hexahydro-1H-azepin-1-yl)amino)carbonyl)-4-methyl-
Benzenesulfonamide, N-((butylamino)carbonyl)-4-methyl-
Dimethyl Sulfoxide [Chemical/Ingredient]
2-Pyridinylmethylsulfinylbenzimidazoles [Chemical/Ingredient]
Methylpyridine Sulfoxides, Benzimidazole
PYRIDINYLMETHYLSULFINYLBENZIMIDAZOLES 02
Sulfoxides, Benzimidazole Methylpyridine
Pentosan Sulfuric Polyester [Chemical/Ingredient]
2-(P-Chlorophenyl)tetrahydro-3-methyl-4H-1,3-thiazin-4-one 1,1-dioxide
4H-1,3-Thiazin-4-one, 2-(4-chlorophenyl)tetrahydro-3-methyl-, 1,1-dioxide
2H-1,2-Benzothiazine-3-carboxamide, 4-hydroxy-2-methyl-N-2-pyridinyl-, 1,1-dioxide
4H-1,3-Thiazin-2-amine, N-(2,6-dimethylphenyl)-5,6-dihydro-
Lurasidone Hydrochloride [Chemical/Ingredient]
2-(3-Cyano-4-(2-methylpropoxy)phenyl)-4-methylthiazole-5-carboxylic Acid
2-(3-cyano-4-isobutoxyphenyl)-4-methyl- 1,3-thiazole-5-carboxylic acid
5-Thiazolecarboxylic acid, 2-(3-cyano-4-(2-methylpropoxy)phenyl)-4-methyl-
Benzothiazolium, 3-ethyl-2-(5-(3-ethyl-2(3H)-benzothiazolylidene)-1,3-pentadienyl)-
Imidazo(2,1-b)thiazole, 2,3,5,6-tetrahydro-6-phenyl-, (S)-
2-Imidazolidinone, 1-(5-nitro-2-thiazolyl)-
Thiazolium, 3-((1,4-dihydro-2-methyl-4-oxo-5-pyrimidinyl)methyl)-5-(2-hydroxyethyl)-4-methyl-
1,2-Benzisothiazol-3(2H)-one, 1,1-dioxide
Imidazo(2,1-b)thiazole, 2,3,5,6-tetrahydro-6-phenyl-, (+-)-
Thiamine Pyrophosphate [Chemical/Ingredient]
3-(((2-((Diaminomethylene)amino)-4-thiazolyl)methyl)thio)-N(sup 2)-sulfamoylpropionamidine
1,1-Ethenediamine, N-(2-(((2-((dimethylamino)methyl)-4-thiazolyl)methyl)thio)ethyl)-N'-methyl-2-nitro-
Thiazolidinediones [Chemical/Ingredient]
Dibenzothiazepines [Chemical/Ingredient]
1H-Purine, 6-((1-methyl-4-nitro-1H-imidazol-5-yl)thio)-
Guanosine 5'-(trihydrogen diphosphate), P'-anhydride with phosphorothioic acid
Duloxetine Hydrochloride [Chemical/Ingredient]
Prasugrel Hydrochloride [Chemical/Ingredient]
5-Chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)- 1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide
2-Thiophenecarboxylic acid, 4-methyl-3-((1-oxo-2-(propylamino)propyl)amino)-, methyl ester
4% Astracaine Dental With Epinephrine 1:200,000 (0.005mg/ml)
4% Astracaine Dental With Epinephrine Forte 1:100,000 (0.01mg/ml)
10H-Benzo(4,5)cyclohepta(1,2-b)thiophen-10-one, 4,9-dihydro-4-(1-methyl-4-piperidinylidene)-
Allergy Eye Original Prescription Strength
Pyrimidine, 1,4,5,6-tetrahydro-1-methyl-2-(2-(3-methyl-2-thienyl)ethenyl)-, (E)-
Piperidine, 4-(9,10-Dihydro-4H-Benzo(4,5)Cyclohepta(1,2-b)Thien-4-Ylidene)-1-Methyl-
beta-Aminoethyl Isothiourea [Chemical/Ingredient]
Thiourea, N-(4-(1H-imidazol-4-yl)butyl)-N'-methyl-
Carbamimidothioic acid, 10-undecenyl ester, monohydriodide
1,2-Hydrazinedicarbothioamide, N-methyl-N'-(1-methyl-2-propenyl)-
Thiourea, N-methyl-N'-(2-(((5-methyl-1H-imidazol-4-yl)methyl)thio)ethyl)-
Carbamimidothioic acid, 3-(dimethylamino)propyl ester
1-Propanamine, 3-(2-chloro-9H-thioxanthen-9-ylidene)-N,N-dimethyl-, (Z)-
1-Piperazineethanol, 4-(3-(2-chloro-9H-thioxanthen-9-ylidene)propyl)-
1-Piperazineethanol, 4-(3-(2-(trifluoromethyl)-9H-thioxanthen-9-ylidene)propyl)-
9H-Thioxanthen-9-one, 1-((2-(diethylamino)ethyl)amino)-4-(hydroxymethyl)-
9H-Thioxanthen-9-one, 1-((2-(diethylamino)ethyl)amino)-4-methyl-
9H-Thioxanthene-2-sulfonamide, N,N-dimethyl-9-(3-(4-methyl-1-piperazinyl)propylidene)-
1H-Imidazole-4-carboxamide, 5-(3,3-dimethyl-1-triazenyl)-
5(or 4)-(dimethyltriazeno)imidazole-4(or 5)-carboxamide
Butanamide, N-(aminocarbonyl)-2-bromo-3-methyl-
Methylurea Compounds [Chemical/Ingredient]
Organoselenium Compounds [Chemical/Ingredient]
Organosilicon Compounds [Chemical/Ingredient]
Trimethylsilyl Compounds [Chemical/Ingredient]
Organically Modified Ceramics [Chemical/Ingredient]
Volatile Organic Compounds [Chemical/Ingredient]
Heterocyclic Compounds [Chemical/Ingredient]
Heterocyclic Compounds, Fused-Ring [Chemical/Ingredient]
Heterocyclic Compounds, 2-Ring [Chemical/Ingredient]
2-Propenamide, 3-(5,10,11,11a-tetrahydro-9,11-dihydroxy-8-methyl-5-oxo-1H-pyrrolo(2,1-c)(1,4)benzodiazepin-2-yl)-, (11R-(2(E),11alpha,11abeta))-
6H-Benzofuro(3a,3,2-ef)(2)benzazepin-6-ol, 4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-
2H-Benzimidazol-2-one, 5-chloro-1-(1-(3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl)-4-piperidinyl)-1,3-dihydro-
2-benzofurancarboxamide, 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)-1-piperazinyl)-, hydrochloride (1:1)
5-{4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl}benzofuran-2-carboxamide Hydrochloride
Vilazodone Hydrochloride [Chemical/Ingredient]
(1)Benzopyrano(3,4-b)furo(2,3-h)(1)benzopyran-6(6aH)-one, 1,2,12,12a-tetrahydro-8,9-dimethoxy-2-(1-methylethenyl)-, (2R-(2alpha,6aalpha,12aalpha))-
3H-2-Benzopyran-7-carboxylic acid, 4,6-dihydro-8-hydroxy-3,4,5-trimethyl-6-oxo-, (3R-trans)-
2H-1-Benzopyran-2-one, 6-(beta-D-glucopyranosyloxy)-7-hydroxy-
Benzamide, N-(7-((3-O-(aminocarbonyl)-6-deoxy-5-C-methyl-4-O-methyl-beta-L-lyxo-hexopyranosyl)oxy)-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl)-4-hydroxy-3-(3-methyl-2-butenyl)-
1H-Indole-5,6-dione, 2,3-dihydro-3-hydroxy-1-methyl-
8,12-Epoxy-1H,8H-2,7b,12a-triazadibenzo(a,g)cyclonona(cde)trinden-1-one, 2,3,9,10,11,12-hexahydro-9-methoxy-8-methyl-10-(methylamino)-, (8alpha,9beta,10beta,12alpha)-(+)-
10H-3,10a-Epidithiopyrazino(1,2-a)indole-1,4-dione, 2,3,5a,6-tetrahydro-6-hydroxy-3-(hydroxymethyl)-2-methyl-
Indoleacetic Acids [Chemical/Ingredient]
(+-)-1,8-Diethyl-1,3,4,9-tetrahydropyrano(3,4-b)indole-1-acetic acid
(1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid
1,3,4,9-Tetrahydro-1,8-diethylpyrano(3,4-b)indole-1-acetic Acid
1,8-Diethyl-1,3,4,9-tetrahydropyrano(3,4-b)indole-1-acetic acid
1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-ylacetic acid
1H-Indol-5-ol, 3-(2-(dimethylamino)ethyl)-
Acetamide, N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-
1H-Indol-4-ol, 3-(2-(dimethylamino)ethyl)-, dihydrogen phosphate (ester)
3-(2-(Dimethylamino)ethyl)-1H-indol-4-ol Dihydrogen Phosphate Ester
(N-[2-[4-[3-(1-Methylethylamino)pyridin-2-yl]piperazin-1-yl]carbonyl-1H-indol-5-yl] methanesulfonamide)
3H-Pyrido(3,4-b)indole, 4,9-dihydro-7-methoxy-1-methyl-
9H-Pyrido(3,4-b)indole, 7-methoxy-1-methyl-
Secologanin Tryptamine Alkaloids [Chemical/Ingredient]
1(3H)-Isobenzofuranone, 6,7-dimethoxy-3-(5,6,7,8-tetrahydro-4-methoxy-6-methyl-1,3-dioxolo(4,5-g)isoquinolin-5-yl)-, (S-(R*,S*))-
Quinuclidin-3'-yl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate
Solifenacin Succinate [Chemical/Ingredient]
Salsoline Alkaloids [Chemical/Ingredient]
Benzylisoquinolines [Chemical/Ingredient]
Furo(3,4-e)-1,3-benzodioxol-8(6H)-one, 6-(5,6,7,8-tetrahydro-6-methyl-1,3-dioxolo(4,5-g)isoquinolin-5-yl)-, (R-(R*,S*))-
Isoquinoline, 1-((3,4-dimethoxyphenyl)methyl)-6,7-dimethoxy-
Piperidine, 1-((2,3-dihydro-1,4-benzodioxin-2-yl)methyl)-
Flavin Mononucleotide [Chemical/Ingredient]
4(1H)-Pteridinone, 2-amino-6-(1,2-dihydroxypropyl)-, (S-(R*,S*))-
4(1H)-Pteridinone, 2-Amino-6-(1,2,3-Trihydroxypropyl)-
AMINOTRIHYDROXYPROPYL PTERIDINONE 002 006 001 001 003 004 003 H
Formyltetrahydrofolates [Chemical/Ingredient]
4,6-Pteridinedione, 2-amino-1,5-dihydro-
Purine Nucleosides [Chemical/Ingredient]
9-Beta-D-arabinofuranosyl-9H-purine-6-amine Monohydrate
9-Beta-D-arabinofuranosyladenine Monohydrate
4-Amino-7 beta-D-ribofuranosyl-7H-pyrrolo(2,3-d)pyrimidine
4-Amino-7-.beta.-D-ribofuranosyl-7H-pyrrolo[2, 3-d]pyrimidine
4-Amino-7.beta.-D-ribofuranosyl-7H-pyrrolo(2, 3-d)pyrimidine
7H-Pyrrolo(2,3-d)pyrimidin-4-amine, 7-beta-D-ribofuranosyl-
Purine Nucleotides [Chemical/Ingredient]
Adenine Nucleotides [Chemical/Ingredient]
Adenosine Cyclic 3',5'-(Hydrogen Phosphate)
9H-Purin-6-amine, 9-(5-O-phosphono-beta-D-arabinofuranosyl)-
Deoxyadenine Nucleotides [Chemical/Ingredient]
3-Carbamoyl-1-Beta-D-Ribofuranosylpyridinium Hydroxide 5'-5'-Ester with Adenosine 5'-(Trihydrogen Pyrophosphate) Inner Salt
3-Carbamoyl-1-Beta-D-Ribofuranosylpyridinium Hydroxide, 5'-Ester with Adenosine 5'-Pyrophosphate, Inner Salt
Adenine Dinucleotide, Dihydronicotinamide
Adenosine 5'-(Trihydrogen Diphosphate), 5'-5'-Ester with 3-(Aminocarbonyl)-1-Beta-D-Ribofuranosylpyridinium, Hydroxide, Inner Salt
Adenosine 5'-(trihydrogen diphosphate), P'-5'-ester with 3-(aminocarbonyl)-1-beta-D-ribofuranosylpyridinium, inner salt
Adenosine 5'-(trihydrogen diphosphate), 2'-(dihydrogen phosphate), P'-5'-ester with 3-(aminocarbonyl)-1-beta-D-ribofuranosylpyridinium, inner salt
Dinucleotide Phosphate, Nicotinamide-Adenine
Nicotinamide Adenine Dinucleotide Phosphate
Guanine Nucleotides [Chemical/Ingredient]
Deoxyguanine Nucleotides [Chemical/Ingredient]
Cyclic guanosine monophosphate (substance)
Inosine Nucleotides [Chemical/Ingredient]
(extra Strength) Acetaminophen, Caffeine & 8mg Codeine Phosphate Caplets
1H-Purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl-
1H-Purine-2,6-dione, 3,7-dihydro-3,7-dimethyl-
1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-
3-Pyridinecarboxylic acid, compd. with 3,7-dihydro-7-(2-hydroxy-3-((2-hydroxyethyl)methylamino)propyl)-1,3-dimethyl-1H-purine-2,6-dione (1:1)
Xanthinol Niacinate [Chemical/Ingredient]
1H-Purine-2,6,8(3H)-trione, 7,9-dihydro-
Pyrrolizidine Alkaloids [Chemical/Ingredient]
20-Norcrotalanan-11,15-dione, 14,19-dihydro-12,13-dihydroxy-, (13alpha,14alpha)-
2,4(1H,3H)-Quinazolinedione, 3-(2-(4-(4-fluorobenzoyl)-1-piperidinyl)ethyl)-
Cinchonan-9-ol, 6'-methoxy-, (8alpha,9R)-
2(1H)-Quinolinone, 7-(4-(4-(2,3-Dichlorophenyl)-1-piperazinyl)butoxy)-3,4-dihydro-
1H-pyrrolo(2,3-f)quinoline-2,7,9-tricarboxylic acid, 4,5-dihydro-4,5-dioxo-
2,7,9-Tricarboxypyrroloquinoline Quinone
4,5-Dihydro-4,5-Dioxo-1-H-Pyrrolo(2,3-f)Quinoline-2,7,9-Tricarboxylic Acid
1H-Pyrazolo(3,4-g)quinoline, 4,4a,5,6,7,8,8a,9-octahydro-5-propyl-, (4aR-trans)-
7,14-Methano-2H,6H-dipyrido(1,2-a:1',2'-e)(1,5)diazocine, dodecahydro-, (7S-(7alpha,7aalpha,14alpha,14abeta))-
Sparteine, (7S-(7alpha,7aalpha,14alpha,14abeta))-Isomer
Pyrazolo(3,4-e)(1,4)diazepin-7(1H)-one, 4-(2-fluorophenyl)-6,8-dihydro-1,3,8-trimethyl-
(2S-(1(R*(r*)),2alpha,3abeta,6abeta))-1-(2-((1-(ethoxycarbonyl)-3-phenylpropyl)amino)-1-oxopropyl)octahydrocyclopenta(b)pyrrole-2-carboxylic acid
Fused Heterocyclic Compounds, Three Ring
Fused Heterocyclic Compounds, Three-Ring
Heterocyclic Compounds, 3-Ring [Chemical/Ingredient]
7H-Pyrano(2,3-c)acridin-7-one, 3,12-dihydro-6-methoxy-3,3,12-trimethyl-
4H-Pyrano(2,3-b)(1,4)benzodioxin-4-one, decahydro-4a,7,9-trihydroxy-2-methyl-6,8-bis(methylamino)-, (2R-(2alpha,4abeta,5abeta,6beta,7beta,8beta,9alpha,9aalpha,10abeta))-
(1,3)Dioxolo(4,5-g)cinnoline-3-carboxylic acid, 1-ethyl-1,4-dihydro-4-oxo-
1-Ethyl-1,4-Dihydro-4-oxo [1,3] Dioxolo [4,5-g] Cinnoline-3-Carboxylic Acid
1-Ethyl-6,7-methylenedioxy-4(1H)-oxocinnoline-3-carboxylic acid
5-Ethyl-8-oxo-5,8-dihydro-1,3-dioxa-5,6-diaza-cyclopenta[b]naphthalene-7-carboxylic acid
2-bis[Cyclo(N-methyl-L-valyl-sarcosyl-L-prolyl-D-valyl-L-threonyl)]-1,9 dimethyl-4,6 3H-phenoxazinone-3
Benzophenanthridines [Chemical/Ingredient]
7H-Furo(3',2':4,5)furo(2,3-c)xanthen-7-one, 3a,12c-dihydro-8-hydroxy-6-methoxy-, (3aR-cis)-
HETEROCYCLIC COMPOUNDS A 4 OR MORE RINGS
Heterocyclic Compounds with 4 or More Rings
Heterocyclic Compounds with Four or More Rings
Heterocyclic Compounds, 4 or More Rings [Chemical/Ingredient]
Berberine Alkaloids [Chemical/Ingredient]
16(15H)-Oxaerythrinan-15-one, 1,6-didehydro-14,17-dihydro-3-methoxy-, (3beta)-
Dihydro-beta-Erythroidine [Chemical/Ingredient]
6,14-Ethenomorphinan-7-methanol, 17-(cyclopropylmethyl)-alpha-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-alpha-methyl-, (5alpha,7alpha(S))-
Buprenorphine, Naloxone Drug Combination [Chemical/Ingredient]
Buprenorphine, Naloxone Drug Combination
ACETAMINOPHEN DEXTROMETHORPHAN HYDROBROMIDE and DOXYLAMINE SUCCINATE
ACETAMINOPHEN DEXTROMETHORPHAN HYDROBROMIDE and PHENYLEPHRINE HYDROCHLORIDE
ACETAMINOPHEN, DEXTROMETHORPHAN HYDROBROMIDE, and DOXYLAMINE SUCCINATE
Morphinan-3-ol, 17-methyl-, (9alpha,13alpha,14alpha)-
6,14-Ethenomorphinan-7-methanol, 17-(cyclopropylmethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-alpha,alpha-dimethyl-, (5alpha,7alpha)-
6,14-Ethenomorphinan-7-methanol, 4,5-epoxy-3-hydroxy-6-methoxy-alpha,17-dimethyl-alpha-propyl-, (5alpha,7alpha(R))-
Morphine Derivatives [Chemical/Ingredient]
Morphinan-3,6,14-triol, 17-(cyclobutylmethyl)-4,5-epoxy-, (5alpha,6alpha)-
Morphinan-3,6-diol, 7,8-didehydro-4,5-epoxy-17-(2-propenyl)-, (5alpha,6alpha)-
Buprenorphine Hydrochloride and Naloxone Hydrochloride Dihydrate
Morphinan-6-one, 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)-, (5alpha)-
5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-2,7-(epoxypentadeca(1,11,13)trienimino)naphtho(2,1-B)furan-1,11(2h)-dione 21-Acetate
21H-Biline-8,12-dipropanoic acid, 2,17-diethenyl-1,10,19,22,23,24-hexahydro-3,7,13,18-tetramethyl-1,19-dioxo-
Bacteriochlorophylls [Chemical/Ingredient]
Metalloporphyrin preparation (substance)
Acids, Heterocyclic [Chemical/Ingredient]
Isonicotinic Acids [Chemical/Ingredient]
2-(2-(Benzylcarbamoyl)ethyl)hydrazide isonicotinic acid
2-(2-(Benzylcarbamoyl)ethyl)hydrazide, isonicotinic acid
2-(2-(Benzylcarbamyl)ethyl)hydrazide isonicotinic acid
2-[2-(Benzylcarbamoyl)ethyl]hydrazide isonicotinic acid
4-Pyridinecarboxylic acid, 2-(3-oxo-3-((phenylmethyl)amino)propyl)hydrazide
4-Pyridinecarboxylic acid, 3-hydroxy-5-(hydroxymethyl)-2-methyl-
Isonipecotic Acids [Chemical/Ingredient]
1-(3-Cyano-3,3-diphenylpropyl)-4-phenyl-isonipecotic acid ethyl ester
4-Piperidinecarboxylic acid, 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-, ethyl ester
4-Piperidinecarboxylic acid, 1-methyl-4-phenyl-, ethyl ester
Demerol 50 mg/ml (multiple Dose With Metacresol As Preservative)
Demerol 50 mg/ml (single Use, Preservative Free)
4-Piperidinecarboxylic acid, 1-(3-hydroxy-3-phenylpropyl)-4-phenyl-, ethyl ester
(1,4'-Bipiperidine)-4'-carboxamide, 1'-(3-Cyano-3,3-diphenylpropyl)
(1,4'-Bipiperidine)-4'-carboxamide, 1'-(3-cyano-3,3-diphenylpropyl)-
3-Pyridinecarboxylic acid, 1,2,5,6-tetrahydro-1-methyl-, methyl ester
3-Pyridinecarboxylic acid, 2-((3-chloro-2-methylphenyl)amino)-
1H-Pyrazolo(3,4-b)pyridine-5-carboxylic acid, 1-ethyl-4-((1-methylethylidene)hydrazino)-, ethyl ester
3-Pyridinecarboxylic acid, 2,2-bis(((3-pyridinylcarbonyl)oxy)methyl)-1,3-propanediyl ester
Pyrido(2,3-d)pyrimidine-6-carboxylic acid, 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)-
Pyrido(2,3-d)pyrimidine-6-carboxylic acid, 8-ethyl-5,8-dihydro-5-oxo-2-(1-pyrrolidinyl)-
4-Pyrimidinecarboxylic acid, 1,2,3,6-tetrahydro-2,6-dioxo-
2-Pyridinecarboxylic acid, 4-amino-3,5,6-trichloro-
2-Pyridinecarboxylic acid, 5-amino-6-(7-amino-5,8-dihydro-6-methoxy-5,8-dioxo-2-quinolinyl)-4-(2-hydroxy-3,4-dimethoxyphenyl)-3-methyl-
5-Amino-6-(7-amino-5,8-dihydro-6-methoxy-5,8-dioxo-2-quinolyl)-4-(2-hydroxy-3,4-dimethoxyphenyl)-3-methyl-2-pyridinecarboxylic Acid
5-Amino-6-(70-amino-5,8-dihydro-6-methoxy-5,8-dioxo-2-quinolyl)-4-(2-hydroxy-3,4-dimethoxyphenyl)-3-methylpicolinic Acid
1H-Pyrano(3',4':6,7)indolizino(1,2-b)quinoline-3,14(4H,12H)-dione, 4-ethyl-4-hydroxy-, (S)-
1H-Pyrano[3',3'.6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione, 4-ethyl-4hydroxy-(S)-(9CI)
9 Dimethylaminomethyl 10 hydroxycamptothecin
Mylan-topotecan Hydrochloride for Injection
Acetamide, N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo(a)heptalen-7-yl)-, (S)-
Benzo(a)heptalen-9(5H)-one, 6,7-dihydro-1,2,3,10-tetramethoxy-7-(methylamino)-, (S)-
Ethanone, 2-(6-(2-hydroxy-2-phenylethyl)-1-methyl-2-piperidinyl)-1-phenyl-, (2R-(2alpha,6alpha(S*)))-
2(3H)-Furanone, 3-ethyldihydro-4-((1-methyl-1H-imidazol-5-yl)methyl)-, (3S-cis)-
beta-D-Galactopyranoside, (3beta)-solanid-5-en-3-yl O-6-deoxy-alpha-L-mannopyranosyl-(1-2)-O-(beta-D-glucopyranosyl-(1-3))-
beta-D-Galactopyranoside, (3beta,5alpha,22beta,25S)-spirosolan-3-yl O-beta-D-glucopyranosyl-(1-2)-O-(beta-D-xylopyranosyl-(1-3))-O-beta-D-glucopyranosyl-(1-4)-
1,2,8-Indolizinetriol, octahydro-, (1S-(1alpha,2alpha,8beta,8abeta))-
Heterocyclic Compounds, Bridged-Ring [Chemical/Ingredient]
2,6-Methano-3-benzazocin-8-ol, 3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-
2,6-Methano-3-benzazocin-1(2H)-one, 3-(cyclopropylmethyl)-6-ethyl-3,4,5,6-tetrahydro-8-hydroxy-11-methyl-, (2alpha,6alpha,11S*)-(+-)-
Ethylketocyclazocine [Chemical/Ingredient]
Bridged Bicyclo Compounds, Heterocyclic [Chemical/Ingredient]
Heterocyclic Compounds, 1-Ring [Chemical/Ingredient]
Benzoic acid, 3,4,5-trimethoxy-, (tetrahydro-1H-1,4-diazepine-1,4(5H)-diyl)di-3,1-propanediyl ester
5H-Tetrazolo(1,5-a)azepine, 6,7,8,9-tetrahydro-
1,3,5-Triazine, 2,4,6-tris(1-aziridinyl)-
Triethylenemelamine [Chemical/Ingredient]
Amlodipine Besylate Olmesartan Medoxomil
Amlodipine Besylate Olmesartan Medoxomil Drug Combination
Amlodipine Besylate, Olmesartan Medoxomil
Amlodipine Besylate, Olmesartan Medoxomil Drug Combination [Chemical/Ingredient]
Amlodipine Besylate-Olmesartan Medoxomil
Amlodipine Besylate-Olmesartan Medoxomil Drug Combination
Amlodipine besylate and Olmesartan medoxomil
Besylate-Olmesartan Medoxomil, Amlodipine
Medoxomil, Amlodipine Besylate-Olmesartan
amlodipine besylate + olmesartan medoxomil
Amlodipine Besylate, Olmesartan Medoxomil Drug Combination
Vardenafil Dihydrochloride [Chemical/Ingredient]
(+)-cis-Hexahydro-2-oxo-1H-thieno[3,4]imidazole-4-valeric acid
(3AS,4S,6ar)-hexahydro-2-oxo-1H-thieno[3,4-D]imidazole-4-valeric acid
1H-Thieno(3,4-d)imidazole-4-pentanoic acid, hexahydro-2-oxo-, (3aS-(3aalpha,4beta,6aalpha))-
5-(2-Oxohexahydro-1H-thieno[3,4-D]imidazol-4-yl)pentanoic acid
5-(3-oxo-7-thia-2,4-diazabicyclo[3.3.0]oct-8-yl)pentanoic acid
Hexadecanoic Acid, 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)ethyl)-6,7,8,9-tetrahydro-2-methyl-4-oxo-4H-pyrido(1,2-a)pyrimidin-9-yl Ester
Paliperidone Palmitate [Chemical/Ingredient]
5-Isoxazoleacetic acid, alpha-amino-2,3-dihydro-3-oxo-
1,2,4-Oxadiazolidine-2-propanoic acid, alpha-amino-3,5-dioxo-, (S)-
Pyrimidine, 4-methoxy-2-(5-methoxy-3-methyl-1H-pyrazol-1-yl)-6-methyl-
Atorvastatin Calcium [Chemical/Ingredient]
2,2'-Bi-1H-pyrrole, 4-methoxy-5-((5-methyl-4-pentyl-2H-pyrrol-2-ylidene)methyl)-
Sitagliptin Phosphate [Chemical/Ingredient]
(1,2,4)Triazolo(1,5-a)pyrimidin-7-amine, N,N-diethyl-5-methyl-
(+-)-1-sec-Butyl-4-(p-(4-(p-(((2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)-1-piperazinyl)phenyl)-delta(sup 2)-1,2,4-triazolin-5-one
3H-1,2,4-Triazol-3-one, 4-(4-(4-(4-((2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)-1-piperazinyl)phenyl)-2,4-dihydro-2-(1-methylpropyl)-
(2R-(2alpha(2S*(3R*,4S*,5S*,7R*)3S*,5S*),5alpha,6beta))-6-(7-(5-Ethyl-5-(5-ethyltetrahydro-5-hydroxy-6-methyl-2H-pyran-2-yl)tetrahydro-3-methyl-2-furyl)-4-hydroxy-3,5-dimethyl-6-oxononyl)-3-methylsalicylic Acid
Benzoic acid, 6-(7-(5-ethyl-5-(5-ethyltetrahydro-5-hydroxy-6-methyl-2H-pyran-2-yl)tetrahydro-3-methyl-2-furanyl)-4-hydroxy-3,5-dimethyl-6-oxononyl)-2-hydroxy-3-methyl-, (2R-(2alpha(2S*(3R*,4S*,5S*,7R*),3S*,5S*),5alpha,6beta))-
4-{2-[2-Ethyl-3'-methyl-5'-(tetrahydro-6-hydroxy-6-hydroxymethyl-3,5-dimethylpyran-2-yl)perhydro-2,2'-bifuran-5-yl]-9-hydroxy-2,8-dimethyl-1,6-dioxaspiro[4.5]dec-7-yl}3-methoxy-2-methylpentanoic acid
2-(Diethylamino)Ethyl Tetrahydro-Alpha-(1-Naphthylmethyl)-2-Furanpropionate
2-Furanpropanoic Acid, Tetrahydro-A-(1-Naphthalenylmethyl)-, 2-(Diethylamino)Ethyl Ester
2-Furanpropanoic acid, tetrahydro-alpha-(1-naphthalenylmethyl)-, 2-(diethylamino)ethyl ester
1,1-Ethenediamine, N-(2-(((5-((dimethylamino)methyl)-2-furanyl)methyl)thio)ethyl)-N'-methyl-2-nitro-
Acid Reducer Maximum Strength Non-prescription
(+)-(5S)-6-(5-Chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazin-5-yl 4-methylpiperazine-1-carboxylate
(S)-6-(5-Chloro-2-pyridinyl)- 7-oxo- 6,7-dihydro- 5H-pyrrolo[3,4-b]pyrazin-5-yl- 4-methyl- 1-piperazinecarboxylate
1-Piperazinecarobxylic acid,4-methyl-,(5S)-6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl ester
Dimethylphenylpiperazinium Iodide [Chemical/Ingredient]
Piperazinium, 1,1-dimethyl-4-phenyl-, iodide
Ethanol, 2-(2-(4-((4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)-
1-Piperazineacetamide, 4-(4,4-bis(4-fluorophenyl)butyl)-N-(2,6-dimethylphenyl)-
Piperazine, 1,4-bis(3-bromo-1-oxopropyl)-
Pyrimidine, 2-(4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl)-
3,12-Bis(3-chloro-2-hydroxypropyl)-3,12-diaza-6,9- diazoniadispiro(5.2.5.2)hexadecane
1,2,4-Triazolo(4,3-a)pyridin-3(2H)-one, 2-(3-(4-(3-chlorophenyl)-1-piperazinyl)propyl)-
1-[2,3,4-trimethoxybenzyl] piperazine dihydrochloride
Piperazine, 1-((2,3,4-trimethoxyphenyl)methyl)-
1,3,5-Triazine-2,4-diamine, 6-(4-(bis(4-fluorophenyl)methyl)-1-piperazinyl)-N,N'-di-2-propenyl-
Piperazinium, 4,4'-((2beta,3alpha,5alpha,16beta,17beta)-3,17-bis(acetyloxy)androstane-2,16-diyl)bis(1,1-dimethyl)
4-Piperidinol, 1,3-dimethyl-4-phenyl-, propanoate (ester), cis-
Benzamide, N-(2-piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)-
1-Piperidinebutanamide, 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-alpha,alpha-diphenyl-
Care One anti diarrheal loperamide hydrochloride
2% Polocaine Dental With Levonordefrin 1:20,000
2-Piperidinecarboxamide, N-(2,6-dimethylphenyl)-1-methyl-
2,4-Diamino-6-piperidinopyrimidine 3-oxide
2,4-Pyrimidinediamine, 6-(1-Piperidinyl)-, 3-Oxide
6-Piperidin-1-ylpyrimidine-2,4-diamine 3-oxide
BOSLEY PROFESSIONAL STRENGTH HAIR REGROWTH TREATMENT Regular Strength For Men
BOSLEY PROFESSIONAL STRENGTH HAIR REGROWTH TREATMENT Regular Strength For Women
4-Piperidinol, 1-(4,4-bis(4-fluorophenyl)butyl)-4-(4-chloro-3-(trifluoromethyl)phenyl)-
1-Piperidinepropanol, alpha-cyclohexyl-alpha-phenyl-
5H-Thiazolo(3,2-a)Pyrimidin-5-One, 6-(2-(4-(Bis(4-Fluorophenyl)Methylene)-1-Piperidinyl)Ethyl)-7-Methyl-
4H-Furo(3,2-c)pyran-2(6H)-one, 4-hydroxy-
2,5-Furandione, polymer with 1,1'-oxybis(ethene)
Divinyl Ether Maleic Anhydride Copolymer
1,4-Phthalazinedione, 5-amino-2,3-dihydro-
(1S,9S)-9-(((S)-1-Carboxy-3-phenylpropyl)amino)octahydro-10-oxo-6H-pyridazino(1,2-a)(1,2)diazepine-1-carboxylic Acid 9-ethyl Ester Monohydrate
6H-Pyridazino(1,2-a)(1,2)diazepine-1-carboxylic acid, 9-((1-(ethoxycarbonyl)-3-phenylpropyl)amino)octahydro-10-oxo-, monohydrate, (1S-(1alpha,9alpha(R*)))-
Atazanavir Sulfate [Chemical/Ingredient]
2-Pyridineacetamide, alpha-(2-(bis(1-methylethyl)amino)ethyl)-alpha-phenyl-
Acetaminophen Dextromethorphan HBr Doxylamine succinate Phenylephrine HCl
Acetaminophen Dextromethorphan Hydrobromide Doxylamine Succinate Phenylephrine Hydrochloride
Alka-Seltzer Plus Day and Night Cold and Flu Formula
Alka-Seltzer Plus Day and Night Multi-Symptom Cold and Flu Formula
1-Propanone, 2-methyl-1,2-di-3-pyridinyl-
2-Pyridinepropanamine, N,N-dimethyl-gamma-phenyl-
CVS Pharmacy Cold and Sore Throat Lemon Flavor
3-hydroxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde 5-phosphate
4-Pyridinecarboxaldehyde, 3-hydroxy-2-methyl-5-((phosphonooxy)methyl)-
Pyridinium Compounds [Chemical/Ingredient]
Pyridinium, 4-(4-Amino-4-Carboxybutyl)-1-(5-Amino-5-Carboxypentyl)-3,5-Bis(3-Amino-3-Carboxypropyl)-
Pyridinium, 2-(4-amino-4-carboxybutyl)-1-(5-amino-5-carboxypentyl)-3,5-bis(3-amino-3-carboxypropyl)-
Pyridinium, 1-((4-amino-2-methyl-5-pyrimidinyl)methyl)-3-(2-hydroxyethyl)-2-methyl-, bromide, monohydrobromide
1(4H)-Pyridinepropanoic acid, alpha-amino-3-hydroxy-4-oxo-, (S)-
4-Pyridinemethanol, 3,3'-(dithiobis(methylene))bis(5-hydroxy-6-methyl- )
Pyridine, 2-(1-(4-methylphenyl)-3-(1-pyrrolidinyl)-1-propenyl)-, (E)-
Benzeneacetamide, N-ethyl-alpha-(hydroxymethyl)-N-(4-pyridinylmethyl)-
1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine [Chemical/Ingredient]
METHYLPHENYLTETRAHYDROPYRIDINE 01 04 01 02 03 06
Methylphenyltetrahydropyridine (substance)
Pyridine, 1,2,3,6-tetrahydro-1-methyl-4-phenyl-
6H-Dipyrido(3,2-b:2',3'-e)(1,4)diazepin-6-one, 11-cyclopropyl-5,11-dihydro-4-methyl-
Aspirin and Extended - Release Dipyridamole Capsules, 25 mg / 200 mg
5-Pyrimidinamine, 1,3-bis(2-ethylhexyl)hexahydro-5-methyl-
Ethanol, 2,2',2'',2'''-((4-(1-piperidinyl)pyrimido(5,4-d)pyrimidine-2,6-diyl)dinitrilo)tetrakis-
2,4-Pyrimidinediamine, 5-(4-chlorophenyl)-6-ethyl-
Pyrimidine Nucleosides [Chemical/Ingredient]
2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
(R)-3-(2-Deoxy-.beta.-D-erythro-pentofuranosyl)-3,6,7, 8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol
Imidazo(4,5-d)(1,3)diazepin-8-ol, 3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,4,7,8-tetrahydro-, (R)-
2,4(1H,3H)-Pyrimidinedione, 1-beta-D-arabinofuranosyl-
Arabinofuranosyluracil [Chemical/Ingredient]
(beta 1-(2-Deoxyribopyranosyl))thymidine
2,4(1H,3H)-Pyrimidinedione, 1-(2-Deoxy-Beta-D-Erythro-Ribofuranosyl)-
2,4(1H,3H)-Pyrimidinedione, 1-(2-Deoxy-Beta-D-Ribofuranosyl)-
Pyrimidine Nucleotides [Chemical/Ingredient]
Cytosine Nucleotides [Chemical/Ingredient]
2(1H)-Pyrimidinone, 4-amino-1-(5-O-(hydroxy((hydroxy(phosphonooxy)phosphinyl)oxy)phosphinyl)-beta-D-arabinofuranosyl)-
Arabinofuranosylcytosine Triphosphate [Chemical/Ingredient]
Deoxycytosine Nucleotides [Chemical/Ingredient]
Thymine Nucleotides [Chemical/Ingredient]
Uracil Nucleotides [Chemical/Ingredient]
Deoxyuracil Nucleotides [Chemical/Ingredient]
2,4-Pyrimidinediamine, 5-((3,4,5-trimethoxyphenyl)methyl)-
(2R,3S,4S)-2-(P-Methoxybenzyl)-3,4-Pyrrolidinediol 3-Acetate
3,4-Pyrrolidinediol, 2-((4-methoxyphenyl)methyl)-, 3-acetate, (2R-(2alpha,3alpha,4beta))-
2-Carboxy-4-isopropenyl-3-pyrrolidineacetic Acid
3-Pyrrolidineacetic acid, 2-carboxy-4-(1-methylethenyl)-, (2S-(2alpha,3beta,4beta))-
Pyrrolidine, 1-(2-(4-(3,4-dihydro-6-methoxy-2-phenyl-1-naphthalenyl)phenoxy)ethyl)-
Pyrrolidine, 1-(2-(4-(1-(4-methoxyphenyl)-2-nitro-2-phenylethenyl)phenoxy)ethyl)-
Pentolinium Tartrate [Chemical/Ingredient]
Pyrrolidinium, 1,1'-(1,5-pentanediyl)bis(1-methyl)-, salt with (R-(R*,R*))-2,3-dihydroxybutanedioic acid (1:2)
pentolinium tartrate (discontinued) (medication)
1-Pyrrolidinepropanol, alpha-cyclohexyl-alpha-phenyl-
1-cyclohexyl-1-phenyl-3-pyrrolidin-1-yl-propan-1-ol hydrochloride
2H-Pyrrol-2-one, 3-acetyl-1,5-dihydro-4-hydroxy-5-(1-methylpropyl)-, (S-(R*,R*))-
Pyrrolidine, 1,1'-(2-butyne-1,4-diyl)bis-
1-Pyrrolideneethanamine, Beta-((2-Methylpropoxy)Methyl)-N-Phenyl-N-(Phenylmethyl)-
1-Pyrrolidineethanamine, beta-((2-methylpropoxy)methyl)-N-phenyl-N-(phenylmethyl)-
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer [Chemical/Ingredient]
Benzeneacetamide, 3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)cyclohexyl)-, (trans)-Isomer
DICHLOROMETHYLPYRROLIDINYLCYCLOHEXYL BENZENEACETAMIDE 003 004 N N 002 001
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
D-erythro-alpha-D-galacto-Octopyranoside, methyl 6,8-dideoxy-6-(((1-methyl-4-propyl-2-pyrrolidinyl)carbonyl)amino)-1-thio-, (2S-trans)-
1H-Pyrazolo(1,2-a)(1,2,4)benzotriazine-1,3(2H)-dione, 5-(dimethylamino)-9-methyl-2-propyl-
1,3,5-Triazine-2,4-diamine, 6-chloro-N-ethyl-N'-(1-methylethyl)-
1,3,5-Triazine-2,4,6-triamine, N,N,N',N',N'',N''-hexamethyl-
1,3,5-Triazine-2-carboxylic acid, 1,4,5,6-tetrahydro-4,6-dioxo-
1,3,5-Triazine-2,4-diamine, N,N'-bis(1-methylethyl)-6-(methylthio)-
1,3,5-Triazine-2,4-diamine, 6-chloro-N,N'-diethyl-
Heterocyclic Oxides [Chemical/Ingredient]
Polycyclic Compounds [Chemical/Ingredient]
Fused-Ring Compounds [Chemical/Ingredient]
Bile Acids and Salts [Chemical/Ingredient]
Cardiac Glycosides [Chemical/Ingredient]
Bufa-4,20,22-trienolide, 3-((6-deoxy-alpha-L-mannopyranosyl)oxy)-14-hydroxy-, (3beta)-
29-Nordammara-17(20),24-dien-21-oic acid, 16-(acetyloxy)-3,11-dihydroxy-, (3alpha,4alpha,8alpha,9beta,11alpha,13alpha,14beta,16beta,17Z)-
19-Norcholest-5(10)-en-3-ol, 6-(iodomethyl)-, (3beta,6beta)-
Cholesterol, Dietary [Chemical/Ingredient]
HDL - High density lipoprotein cholesterol
HDLC - High density lipoprotein cholesterol
LDL - Low density lipoprotein cholesterol
VLDL - Very low density lipoprotein cholesterol
Steroids, Brominated [Chemical/Ingredient]
Steroids, Chlorinated [Chemical/Ingredient]
Steroids, Fluorinated [Chemical/Ingredient]
Steroids, Heterocyclic [Chemical/Ingredient]
Macrocyclic Compounds [Chemical/Ingredient]
alpha-Cyclodextrins [Chemical/Ingredient]
beta-Cyclodextrins [Chemical/Ingredient]
gamma-Cyclodextrins [Chemical/Ingredient]
Benzamide, N,N',N''-(2,6,10-trioxo-1,5,9-trioxacyclododecane-3,7,11-triyl)tris(2,3-dihydroxy-, (3S-(3R*,7R*,11R*)))-
D-Phenylalanyl-L-cysteinyl-L-phenyl-alanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl)propyl]-L-cysteinamide Cyclic (2->7)-Disulfide
D-Phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-L-cysteinyl-L-threoninol Cyclic (2->7)-Disulfide
D-Phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[(1R,2R)-2-hydroxy-1-(hyroxymethyl)propyl]-L-cysteinamide, Cyclic (2->7)-disulfide
L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-(2-hydroxy-1-(hydroxymethyl)propyl)-, cyclic (2-7)-disulfide, (R-(R*,R*))-
N-Decanoyl-L-tryptophyl-L-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine epsilon1-lactone
Macromolecular Substances [Chemical/Ingredient]
Fibroblast Intermediate Filament Proteins
Intermediate Filament Proteins [Chemical/Ingredient]
Neurofilament Proteins [Chemical/Ingredient]
Microfilament Proteins [Chemical/Ingredient]
Intracellular Signaling Peptides and Proteins
myristoylated alanine-rich C kinase substrate
Microtubule Proteins [Chemical/Ingredient]
Polyhydroxyalkanoates [Chemical/Ingredient]
Fluorocarbon Polymers [Chemical/Ingredient]
Propanoic acid, 2-hydroxy-, polymer with hydroxyacetic acid
Certolizumab Pegol [Chemical/Ingredient]
Silicone Elastomers [Chemical/Ingredient]
Multiprotein Complexes [Chemical/Ingredient]
Protein Translocation Systems [Chemical/Ingredient]
Twin-Arginine-Translocation System [Chemical/Ingredient]
SEC Translocation Channels [Chemical/Ingredient]
Bacterial Secretion Systems [Chemical/Ingredient]
FK506 binding protein 12-rapamycin associated protein 2
FK506-BINDING PROTEIN 12-RAPAMYCIN COMPLEX-ASSOCIATED PROTEIN 1
FKBP12-RAPAMYCIN COMPLEX-ASSOCIATED PROTEIN 1
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Rapamycin-Insensitive Companion of mTOR Protein
UDPgalactose-glucose galactosyltransferase
UDPgalactose:D-glucose 4-beta-D-galactosyltransferase
Multienzyme Complexes [Chemical/Ingredient]
2-Oxoglutarate:lipoamide 2-oxidoreductase (decarboxylating and acceptor-succinylating)
Complex, alpha-Ketoglutarate Dehydrogenase
Phosphoenolpyruvate Sugar Phosphotransferase System [Chemical/Ingredient]
Phosphoenolpyruvate Sugar Phosphotransferase System
Pyruvate Dehydrogenase Complex [Chemical/Ingredient]
Succinate Cytochrome c Oxidoreductase [Chemical/Ingredient]
Succinate cytochrome C reductase (substance)
Sucrase-Isomaltase Complex [Chemical/Ingredient]
Electron Transport Complex I [Chemical/Ingredient]
Photosynthetic Reaction Center Complex Proteins [Chemical/Ingredient]
Photosynthetic Reaction Center Complex Proteins
Oxidoreductase, Plastoquinol-Plastocyanin
Plastoquinol Plastocyanin Oxidoreductase
Plastoquinol-Plastocyanin Oxidoreductase
Plastoquinol-Plastocyanin Reductase [Chemical/Ingredient]
Plastoquinol-plastocyanin reductase (substance)
Glycine Decarboxylase Complex [Chemical/Ingredient]
Exosome Multienzyme Ribonuclease Complex [Chemical/Ingredient]
exosome (ribonucleasease complex location)
Exosome Multienzyme Ribonuclease Complex
Molecular Motor Proteins [Chemical/Ingredient]
Dystrophin-Associated Protein Complex [Chemical/Ingredient]
Endosomal Sorting Complex Required for Transport
Endosomal Sorting Complex Required for Transport Machinery
Endosomal Sorting Complexes Required for Transport [Chemical/Ingredient]
Endosomal Sorting Complexes Required for Transport
neuronal precursor cell-expressed developmentally down-regulated 4 ligase
Mediator of RNA Polymerase II Transcription Subunit CDK8
Activator-Recruited Cofactor 205 kDa Component
Mediator Complex Subunit 1 [Chemical/Ingredient]
Mediator of RNA Polymerase II Transcription Subunit 1
Calcifying Nanoparticles [Chemical/Ingredient]
APC-Axin-1-beta-catenin complex location
Axin Signaling Complex [Chemical/Ingredient]
Axin-APC-beta-catenin-GSK3B complex location
Adenomatous Polyposis Coli Protein [Chemical/Ingredient]
Glycogen Synthase Kinase 3 [Chemical/Ingredient]
Polycomb Repressive Complex 1 [Chemical/Ingredient]
Polycomb Repressive Complex 2 [Chemical/Ingredient]
Protein Aggregates [Chemical/Ingredient]
Hormones, Hormone Substitutes, and Hormone Antagonists [Chemical/Ingredient]
Hormones, Hormone Substitutes, and Hormone Antagonists
SERM - Selective estrogen receptor modulator
SERM - Selective oestrogen receptor modulator
Selective Estrogen Receptor Modifying Agents
Adrenal Cortex Hormones [Chemical/Ingredient]
Hydroxycorticosteroids [Chemical/Ingredient]
Gastrointestinal Hormones [Chemical/Ingredient]
Kinevac (sincalide) for Injection 5mcg/vial
Epidermal Growth Factor [Chemical/Ingredient]
Epidermal growth factor (substance) [Ambiguous]
GIP - Glucose dependent insulinotropic peptide
Gastric Inhibitory Polypeptide [Chemical/Ingredient]
L-Phenylalaninamide, N-((1,1-dimethylethoxy)carbonyl)-beta-alanyl-L-tryptophyl-L-methionyl-L-alpha-aspartyl-
Gastrin-Releasing Peptide [Chemical/Ingredient]
Thymic neuromuscular function blocking agent
Thymic neuromuscular function blocking agent (substance)
D-Tyrosine, O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-
Chorionic Gonadotropin [Chemical/Ingredient]
BHCG - Beta human chorionic gonadotrophin
BHCG - Beta human chorionic gonadotropin
Chorionic Gonadotropin, beta Subunit, Human
Gonadotropins, Equine [Chemical/Ingredient]
Human menopausal gonadotrophins (product)
Human menopausal gonadotrophins (substance)
Hormones, Hypothalamic Pituitary-Regulating
Hypothalamic Hormones [Chemical/Ingredient]
Hypothalamic Pituitary Regulating Hormones
Hypothalamic Pituitary Regulating Peptides
Hypothalamic Pituitary-Regulating Hormones
Hypothalamic Pituitary-Regulating Peptides
5-oxoPro-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 (human or pig)
Melanocyte stimulating hormone (substance)
Melanocyte-Stimulating Hormones [Chemical/Ingredient]
Pancreatic Hormones [Chemical/Ingredient]
Pancreatic hormone preparation (substance)
Pancreatic Polypeptide [Chemical/Ingredient]
Pituitary Hormones [Chemical/Ingredient]
Placental Hormones [Chemical/Ingredient]
Intercellular Signaling Peptides and Proteins
Natriuretic Peptides [Chemical/Ingredient]
1,2-Dithia-5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-hexadecaazacyclotripentacontane, Cyclic Peptide Derivative
Adipocyte Complement Related Protein 30 kDa
Adipocyte Complement-Related Protein 30-kDa
Adipocyte, C1q and Collagen Domain Containing Protein
Adipocyte Cysteine Rich Secreted Protein FIZZ3
Adipocyte Cysteine-Rich Secreted Protein FIZZ3
Corpus Luteum Hormones [Chemical/Ingredient]
Gonadal Steroid Hormones [Chemical/Ingredient]
Testicular Hormones [Chemical/Ingredient]
Enzymes and Coenzymes [Chemical/Ingredient]
Sphingolipid Activator Proteins [Chemical/Ingredient]
G(M2) Activator Protein [Chemical/Ingredient]
Cytochrome b Group [Chemical/Ingredient]
Cytochrome c Group [Chemical/Ingredient]
Cytochrome P450 Family 1 [Chemical/Ingredient]
Cytochrome P450 Family 2 [Chemical/Ingredient]
Cytochrome P450 Family 3 [Chemical/Ingredient]
Cytochrome P450 Family 4 [Chemical/Ingredient]
Cytochrome P450 Family 6 [Chemical/Ingredient]
Cytochrome P450 Family 7 [Chemical/Ingredient]
Cytochrome P450 Family 8 [Chemical/Ingredient]
Cytochrome P450 Family 11 [Chemical/Ingredient]
Cytochrome P450 Family 12 [Chemical/Ingredient]
Cytochrome P450 Family 19 [Chemical/Ingredient]
Cytochrome P450 Family 21 [Chemical/Ingredient]
Cytochrome P450 Family 24 [Chemical/Ingredient]
Cytochrome P450 Family 26 [Chemical/Ingredient]
Cytochrome P450 Family 27 [Chemical/Ingredient]
Cytochrome P450 Family 46 [Chemical/Ingredient]
Cytochrome P450 Family 51 [Chemical/Ingredient]
Aryl Hydrocarbon Hydroxylases [Chemical/Ingredient]
Microsomal P450 Flavoprotein-linked monooxygenase
Steroid Hydroxylases [Chemical/Ingredient]
Camphor 5-Monooxygenase [Chemical/Ingredient]
Cytochrome a Group [Chemical/Ingredient]
Cytochrome d Group [Chemical/Ingredient]
Complement Factor B [Chemical/Ingredient]
Complement Factor B, Alternative Pathway
Deubiquitinating Enzymes [Chemical/Ingredient]
Probable Ubiquitin Carboxyl-Terminal Hydrolase CYLD
Ubiquitin Carboxyl-Terminal Hydrolase CYLD
Ubiquitin-Specific-Processing Protease CYLD
Ubiquitin-Specific Proteases [Chemical/Ingredient]
Tumor Necrosis Factor Alpha-Induced Protein 3
Enzymes, Immobilized [Chemical/Ingredient]
Mi 2 Nucleosome Remodeling and Deacetylase Complex
Mi-2 Nucleosome Remodeling and Deacetylase Complex [Chemical/Ingredient]
Nucleosome Remodeling and Deacetylase Complex
Mi-2 Nucleosome Remodeling and Deacetylase Complex
Sin3 Histone Deacetylase and Corepressor Complex [Chemical/Ingredient]
Sin3-Histone Deacetylase (HDAC) Corepressor Complex
Sin3 Histone Deacetylase and Corepressor Complex
SILENT MATING TYPE INFORMATION REGULAT 2 LIKE PROTEINS
Silent Mating Type Information Regulator 2 like Proteins
Silent Mating Type Information Regulator 2-like Proteins
Silent Mating Type Information Regulation 2 Homolog 3
Complement Activating Enzymes [Chemical/Ingredient]
Epoxide Hydrolases [Chemical/Ingredient]
DNA Restriction Enzymes [Chemical/Ingredient]
Holliday Junction Resolvases [Chemical/Ingredient]
1 Phosphatidyl D myo Inositol 4,5 bisphosphate Inositoltrisphosphohydrolase
1 Phosphatidylinositol 4,5 Bisphosphate Phosphodiesterase
1-Phosphatidyl-D-myo-Inositol-4,5-bisphosphate Inositoltrisphosphohydrolase
1-Phosphatidylinositol-4,5-Bisphosphate Phosphodiesterase
1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase (substance)
Inositoltrisphosphohydrolase, 1-Phosphatidyl-D-myo-Inositol-4,5-bisphosphate
3',5' Cyclic Nucleotide Phosphodiesterase
3',5'-Cyclic Nucleotide Phosphodiesterase
3',5'-Cyclic-GMP Phosphodiesterases [Chemical/Ingredient]
3',5'-Cyclic-GMP phosphodiesterase (substance)
Dual-Specificity Phosphatases [Chemical/Ingredient]
cdc25 Phosphatases [Chemical/Ingredient]
Protein Phosphatase 2 [Chemical/Ingredient]
Protein Tyrosine Phosphatases, Receptor Like
Protein Tyrosine Phosphatases, Receptor-Like
Receptor Like Protein Tyrosine Phosphatases
Receptor-Like Protein Tyrosine Phosphatases [Chemical/Ingredient]
Receptor-Like Protein Tyrosine Phosphatases
Non Transmembrane Protein Tyrosine Phosphatases
Non-Receptor Protein Tyrosine Phosphatase
Non-Receptor Type Protein Tyrosine Phosphatase
Non-Transmembrane Protein Tyrosine Phosphatases
Protein Tyrosine Phosphatase Non-Receptor Type
Protein Tyrosine Phosphatases, Non Receptor
Protein Tyrosine Phosphatases, Non-Receptor [Chemical/Ingredient]
Tyrosine-Protein Phosphatase Non-Receptor Type
Protein Tyrosine Phosphatases, Non-Receptor
Domain-Containing Protein-Tyrosine-Phosphatases, SH2
Protein-Tyrosine-Phosphatases, SH2 Domain-Containing
SH2 Domain Containing Protein Tyrosine Phosphatase
SH2 Domain Containing Protein Tyrosine Phosphatases
SH2 Domain-Containing Protein Tyrosine Phosphatase
SH2 Domain-Containing Protein Tyrosine Phosphatases [Chemical/Ingredient]
SH2 Domain-Containing Protein-Tyrosine-Phosphatases
Src Homology-2 (SH2) Domain-Containing Phosphatase
Src Homology-2 (SH2) Domain-Containing Phosphatases
SH2 Domain-Containing Protein Tyrosine Phosphatases
ATP-D-Fructose-6-phosphate 2-phosphotransferase
Mutated In Multiple Advanced Cancers 1 Protein
PTEN Phosphohydrolase [Chemical/Ingredient]
Phosphatase and Tensin Homologue on Chromosome Ten Protein
Mitogen Activated Protein Kinase Phosphatases
Mitogen-Activated Protein Kinase Phosphatases [Chemical/Ingredient]
Mitogen-Activated Protein Kinase Phosphatases
Fatty Acid Synthase, Type I [Chemical/Ingredient]
Glycoside Hydrolases [Chemical/Ingredient]
Salivary alpha-Amylases [Chemical/Ingredient]
38-kDa heparin-binding glycoprotein, human
Lactase-Phlorizin Hydrolase [Chemical/Ingredient]
ribosomal ribonucleate N-glycosidase activity
Peptide Hydrolases [Chemical/Ingredient]
Insulin Like Growth Factor Binding Protein 4 Protease
Insulin Like Growth Factor Dependent IGF Binding Protein 4 Protease
Insulin-Like Growth Factor-Dependent IGF Binding Protein-4 Protease
Insulin-Like-Growth Factor Binding Protein-4 Protease
Antigens, Leukemia, Common Acute Lymphoblastic
CALLA - Common acute lymphoblastic leukaemia antigen
CALLA - Common acute lymphoblastic leukemia antigen
Matrix Metalloproteinases, Membrane Associated
Matrix Metalloproteinases, Membrane-Associated [Chemical/Ingredient]
Matrix Metalloproteinases, Membrane-Type
Membrane-Associated Matrix Metalloproteinases
Matrix Metalloproteinases, Membrane-Associated
Matrix Metalloproteinases, Secreted [Chemical/Ingredient]
Bone Morphogenetic Protein 1 [Chemical/Ingredient]
High-Temperature Requirement A Serine Peptidase 2
Tolloid-Like Metalloproteinases [Chemical/Ingredient]
A Disintegrin and Metalloprotease Proteins
ADAM (A Disintegrin and Metalloprotease) Proteins
Acid Anhydride Hydrolases [Chemical/Ingredient]
Replication Protein C [Chemical/Ingredient]
MutS DNA Mismatch-Binding Protein [Chemical/Ingredient]
Minichromosome Maintenance Proteins [Chemical/Ingredient]
Bacterial Proton-Translocating ATPases [Chemical/Ingredient]
Monomeric GTP-Binding Proteins [Chemical/Ingredient]
ran GTP-Binding Protein [Chemical/Ingredient]
Heterotrimeric GTP-Binding Proteins [Chemical/Ingredient]
Adenosylhomocysteinase [Chemical/Ingredient]
cis-trans-Isomerases [Chemical/Ingredient]
Peptidyl Prolyl Cis Trans Isomerase NIMA Interacting 4
Peptidyl Prolyl Cis Trans Isomerase Pin4
Peptidyl-Prolyl Cis-Trans Isomerase NIMA-Interacting 4 [Chemical/Ingredient]
Peptidyl-Prolyl Cis-Trans Isomerase Pin4
Peptidyl-Prolyl Cis-Trans Isomerase NIMA-Interacting 4
Intramolecular Oxidoreductases [Chemical/Ingredient]
2-Enoyl-CoA Hydratase, 3-Hydroxyacyl-CoA Dehydrogenase-delta 3, delta 2-Enoyl-CoA Isomerase
Dehydrogenase, Enoyl-CoA Hydratase-3-Hydroxyacyl-CoA
Enoyl CoA Hydratase 3 Hydroxyacyl CoA Dehydrogenase
Enoyl-CoA Hydratase-3-Hydroxyacyl-CoA Dehydrogenase
Hydratase-3-Hydroxyacyl-CoA Dehydrogenase, Enoyl-CoA
Hydratase-Dehydrogenase-Epimerase, Peroxisomal
Intramolecular Transferases [Chemical/Ingredient]
Intramolecular Lyases [Chemical/Ingredient]
Racemases and Epimerases [Chemical/Ingredient]
DNA Topoisomerases [Chemical/Ingredient]
DNA Topoisomerase IV [Chemical/Ingredient]
Polynucleotide Ligases [Chemical/Ingredient]
Carbon-Oxygen Ligases [Chemical/Ingredient]
Carbon-Sulfur Ligases [Chemical/Ingredient]
Carbon-Nitrogen Ligases [Chemical/Ingredient]
Carbon-Carbon Ligases [Chemical/Ingredient]
Acetyl-CoA Carboxylase [Chemical/Ingredient]
Acetyl-CoA:carbon-dioxide ligase (ADP-forming)
Acetyl-coenzyme A carboxylase (substance)
Polyketide Synthases [Chemical/Ingredient]
Ubiquitin-Protein Ligase Complexes [Chemical/Ingredient]
TRANSCRIPTIONAL INTERMEDIARY FACTOR 1-BETA
Baculoviral IAP Repeat-Containing Protein 1
Neuronal Apoptosis-Inhibitory Protein [Chemical/Ingredient]
Fanconi Anemia Complementation Group Proteins
Fanconi Anemia Complementation Group L Protein [Chemical/Ingredient]
Fanconi Anemia Group L Complementing Protein
Fanconi Anemia Complementation Group L Protein
Anaphase-Promoting Complex-Cyclosome [Chemical/Ingredient]
Carbon-Sulfur Lyases [Chemical/Ingredient]
Carbon-Carbon Lyases [Chemical/Ingredient]
Carbon-carbon lyase (biological function)
Carbon-carbon lyase (biological function) (substance)
Deoxyribocyclobutadipyrimidine pyrimidine-lyase
Deoxyribodipyrimidine Photo-Lyase [Chemical/Ingredient]
Deoxyribodipyrimidine photo-lyase (substance)
Anthranilate Synthase [Chemical/Ingredient]
Chorismate pyruvate-lyase (amino-accepting)
Carbon-Oxygen Lyases [Chemical/Ingredient]
Carbon-oxygen lyase (biological function)
Carbon-oxygen lyase (biological function) (substance)
Iron Regulatory Protein 1 [Chemical/Ingredient]
Iron Regulatory Protein 2 [Chemical/Ingredient]
Iron-Responsive-Element Binding Protein 2
Mitochondrial Fatty Acid beta Oxidation Trifunctional Protein
Mitochondrial Fatty Acid beta-Oxidation Trifunctional Protein
Mitochondrial Long Chain Enoyl CoA Hydratase 3 Hydroxyacyl CoA Dehydrogenase 3 Ketoacyl CoA Thiolase Trifunctional Protein
Mitochondrial Trifunctional Protein [Chemical/Ingredient]
L-Serine hydro-lyase (adding indoleglycerol-phosphate)
Tryptophan Synthase [Chemical/Ingredient]
3-alpha,7-alpha,12-alpha-Trihydroxy-5-beta-Cholest-24-enoyl-CoA Hydratase
Peroxisomal Multifunctional Enzyme Type 2
Peroxisomal Multifunctional Protein-2 [Chemical/Ingredient]
DNA-(Apurinic or Apyrimidinic Site) Lyase
Carbon-Nitrogen Lyases [Chemical/Ingredient]
Carbon-nitrogen lyase (biological function)
Carbon-nitrogen lyase (biological function) (substance)
Phosphorus-Oxygen Lyases [Chemical/Ingredient]
Phosphorus-oxygen lyase (biological function)
Phosphorus-oxygen lyase (biological function) (substance)
Anthranilate Phosphoribosyltransferase [Chemical/Ingredient]
Anthranilate phosphoribosyltransferase (substance)
N-(5-Phospho-D-ribosyl)-anthranilate:pyrophosphate phospho-alpha-D-ribosyltransferase
Phosphoribosyl-anthranilate pyrophosphorylase
Phosphoribosylanthranilate Pyrophosphorylase
Pyrophosphorylase, Phosphoribosylanthranilate
(5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenoate,hydrogen-donor:oxygen oxidoreductase
Electron Transport Chain Complex Proteins [Chemical/Ingredient]
Electron Transport Chain Complex Proteins
Electron transfer flavoprotein (substance)
Electron-Transferring Flavoproteins [Chemical/Ingredient]
Dehydrogenase (biological function) (substance)
Alcohol Oxidoreductases [Chemical/Ingredient]
Aspartokinase Homoserine Dehydrogenase [Chemical/Ingredient]
Aspartokinase-Homoserine Dehydrogenase, Bifunctional
Bifunctional Aspartokinase Homoserine Dehydrogenase
Bifunctional Aspartokinase-Homoserine Dehydrogenase
Dehydrogenase, Bifunctional Aspartokinase-Homoserine
Oxidoreductases Acting on CH NH Group Donors
Oxidoreductases Acting on CH-NH Group Donors [Chemical/Ingredient]
Oxidoreductases Acting on CH-NH Group Donors
Sarcosine-Oxygen Oxidoreductase (Demethylating)
5,10-Methylenetetrahydrofolate Reductase (NADPH)
5-methyltetrahydrofolate:NADP oxidoreductase
Methylenetetrahydrofolate Reductase (NADPH)
Methylenetetrahydrofolate Reductase (NADPH2)
Luciferases, Bacterial [Chemical/Ingredient]
NADH, NADPH Oxidoreductases [Chemical/Ingredient]
Cytochrome-B(5) Reductase [Chemical/Ingredient]
Cytochrome-b5 reductase (substance)
NADP Transhydrogenase, B-Specific [Chemical/Ingredient]
Pyridine Nucleotide Transhydrogenase, B Specific
Pyridine Nucleotide Transhydrogenase, B-Specific
NADH Dehydrogenase [Chemical/Ingredient]
Apoptosis Inducing Factor [Chemical/Ingredient]
Apoptosis-Inducing Factor, Mitochondrial
Reduced ferredoxin:dinitrogen oxidoreductase (ATP-hydrolysing)
Oxidoreductases Acting on other Nitrogenous Compounds as Donors
Assimilatory Nitrate Reductase, NADH Dependent
Assimilatory Nitrate Reductase, NADH-Dependent
Nitrate Reductase (NADH) [Chemical/Ingredient]
Nitrate Reductase (NAD(P)H) [Chemical/Ingredient]
Nitrate Reductase (Reduced Nicotinamide Adenine Dinucleotide (Phosphate))
Assimilatory Nitrate Reductase, NADPH Dependent
Assimilatory Nitrate Reductase, NADPH-Dependent
Assimilatory Reduced Nicotinamide Adenine Dinucleotide Phosphate Nitrate Reductase
Assimilatory Reduced Nicotinamide Adenine Dinucleotide Phosphate-Nitrate Reductase
Oxidoreductases, O-Demethylating [Chemical/Ingredient]
Alkylated DNA Repair Protein AlkB Homologs
Mitochondrial Thioredoxin Dependent Antioxidant Protein SP 22
Mitochondrial Thioredoxin-Dependent Antioxidant Protein SP-22
Thioredoxin Dependent Peroxide Reductase, Mitochondrial
Thioredoxin-Dependent Peroxide Reductase, Mitochondrial
Ribonucleotide Reductases [Chemical/Ingredient]
Superoxide Dismutase [Chemical/Ingredient]
Oxidoreductases Acting on CH CH Group Donors
Oxidoreductases Acting on CH-CH Group Donors [Chemical/Ingredient]
Oxidoreductases Acting on CH-CH Group Donors
Acyl-CoA Dehydrogenase [Chemical/Ingredient]
Butyryl-CoA Dehydrogenase [Chemical/Ingredient]
Acyl-CoA Dehydrogenase, Long-Chain [Chemical/Ingredient]
Dehydrogenase, Long-Chain-Acyl-Coenzyme A
Long Chain Acyl Coenzyme A Dehydrogenase
Protoporphyrinogen Oxidase [Chemical/Ingredient]
5,10-Methylenetetrahydrofolate Reductase (FADH)
5,10-Methylenetetrahydrofolate Reductase (FADH2) [Chemical/Ingredient]
5,10-Methylenetetrahydrofolate reductase
5,10-Methylenetetrahydrofolate reductase (FADH2)
5,10-Methylenetetrahydrofolate reductase (FADH2) (substance)
5,10-Methylenetetrahydrofolate reductase (FADH>2<)
5,10-Methylenetetrahydrofolate reductase (FADH>2<) (substance)
5,10-Methylenetetrahydrofolate reductase (reduced flavin adenine dinucleotide)
Oxidoreductases Acting on Aldehyde or Oxo Group Donors [Chemical/Ingredient]
Oxidoreductases Acting on Aldehyde or Oxo Group Donors
Aldehyde Dehydrogenase, Mitochondrial [Chemical/Ingredient]
Retinal Dehydrogenase [Chemical/Ingredient]
Oxidoreductases Acting on Sulfur Group Donors [Chemical/Ingredient]
Oxidoreductases Acting on Sulfur Group Donors
Oxidoreductases Acting on CH NH2 Group Donors
Oxidoreductases Acting on CH-NH2 Group Donors [Chemical/Ingredient]
Oxidoreductases Acting on CH-NH2 Group Donors
Glutamate Synthase (NADH) [Chemical/Ingredient]
Glutamate synthase (reduced nicotinamide adenine dinucleotide)
Glutamate synthase (reduced nicotinamide adenine dinucleotide) (substance)
Methionine Sulfoxide Reductases [Chemical/Ingredient]
Arsenate Reductases [Chemical/Ingredient]
p300-CBP Transcription Factors [Chemical/Ingredient]
Circadian Rhythm Signaling Peptides and Proteins
Circadian Locomotor Output Cycles Kaput Proteins
Blood Coagulation Factor XIII, Activated
Phosphotransferases [Chemical/Ingredient]
Rec A Recombinases [Chemical/Ingredient]
RNA Polymerase Sigma 54 [Chemical/Ingredient]
RNA, Ribosomal, Self-Splicing [Chemical/Ingredient]
Transposon Resolvases [Chemical/Ingredient]
Creatine Kinase, Mitochondrial Form [Chemical/Ingredient]
ATP:5'-dephosphopolynucleotide 5'-phosphotransferase
Proto-Oncogene Proteins c-fyn [Chemical/Ingredient]
ERBB RECEPTOR PROTEIN TYROSINE KINASE 002
Mitogen-Activated Protein Kinase Kinases
Focal Adhesion Protein Tyrosine Kinase Family
Focal Adhesion Protein-Tyrosine Kinase Family
Focal Adhesion Protein-Tyrosine Kinases [Chemical/Ingredient]
Focal Adhesion Associated Protein Tyrosine Kinase pp125FAK
Focal Adhesion Kinase 1 [Chemical/Ingredient]
Focal Adhesion-Associated Protein-Tyrosine Kinase pp125FAK
Leucine Rich Repeat Serine Threonine Protein Kinase 2
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 [Chemical/Ingredient]
Leucine-Rich Repeat Serine/Threonine-Protein Kinase 2
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Autophagy-Related Protein-1 Homolog [Chemical/Ingredient]
Unc 51 Like Autophagy Activating Kinase 1
Unc-51 Like Autophagy Activating Kinase 1
Cyclic Nucleotide Regulated Protein Kinases
Cyclic Nucleotide-Regulated Protein Kinases [Chemical/Ingredient]
Cyclic Nucleotide-Regulated Protein Kinases
CA 02 CALMODULIN DEPENDENT PROTEIN KINASE
Ca(2+)-Calmodulin Dependent Protein Kinase
Ca(2+)-Calmodulin Dependent Protein Kinase [Chemical/Ingredient]
Ca(2+)-Calmodulin-Dependent Protein Kinase
Calcium-Calmodulin Dependent Protein Kinases
Calcium-Calmodulin-Dependent Protein Kinases [Chemical/Ingredient]
Calcium-Calmodulin-Dependent Protein Kinases
Double Stranded RNA Dependent eIF 2 alpha Protein Kinase
Double Stranded RNA-Dependent Kinase (dsl)
Double Stranded RNA-Dependent eIF-2 alpha Protein Kinase
Eukaryotic Initiation Factor 2alpha Kinase
Ribosomal Protein S6 Kinases [Chemical/Ingredient]
Mitogen-Activated Protein Kinases [Chemical/Ingredient]
MAP Kinase Kinase Kinases [Chemical/Ingredient]
Mitogen Activated Protein Kinase Kinase Kinases
Mitogen-Activated Protein Kinase Kinase Kinases
Glycogen Synthase Kinases [Chemical/Ingredient]
Cyclin-Dependent Kinases [Chemical/Ingredient]
CDC2 Protein Kinase [Chemical/Ingredient]
Cyclin-Dependent Kinase 9 [Chemical/Ingredient]
Inhibitor of Nuclear Factor Kappa-B Kinase
INTERLEUKIN 001 RECEPTOR ASSOCIATED KINASES
Interleukin 1 Receptor Associated Kinase
Interleukin 1 Receptor Associated Kinases
Interleukin-1 Receptor-Associated Kinase
Interleukin-1 Receptor-Associated Kinases [Chemical/Ingredient]
Kinase, Interleukin-1 Receptor-Associated
Interleukin-1 Receptor-Associated Kinases
p21-Activated Kinases [Chemical/Ingredient]
G Protein-Coupled Receptor Kinase Family Protein
G-Protein-Coupled Receptor Kinases [Chemical/Ingredient]
G-Protein-Coupled Receptor Kinase 1 [Chemical/Ingredient]
5' Adenosine Monophosphate-Activated Protein Kinase
AMP-Activated Protein Kinases [Chemical/Ingredient]
Complex-Associated Protein, FKBP12-Rapamycin
FK506 Binding Protein 12 Rapamycin Associated Protein 1
FK506 Binding Protein 12-Rapamycin Associated Protein 1
FKBP12 Rapamycin Complex Associated Protein
FKBP12-Rapamycin Complex-Associated Protein
Class I Phosphatidylinositol 3-Kinases [Chemical/Ingredient]
Class II Phosphatidylinositol 3-Kinases [Chemical/Ingredient]
Class III Phosphatidylinositol 3 Kinases
Class III Phosphatidylinositol 3-Kinases [Chemical/Ingredient]
Phosphatidylinositol 3 Kinase, Class III
Phosphatidylinositol 3-Kinase, Class III
Class III Phosphatidylinositol 3-Kinases
Nucleoside Diphosphate Kinase D [Chemical/Ingredient]
Nucleoside Diphosphate Kinase, Mitochondrial
Glycosyltransferases [Chemical/Ingredient]
Galactosyltransferase, UDP Galactose-N-Acetylglucosamine
N-Acetyllactosamine Synthase [Chemical/Ingredient]
N-Acetyllactosamine synthase (substance)
One-Carbon Group Transferases [Chemical/Ingredient]
DNA Modification Methylases [Chemical/Ingredient]
Aspartate Carbamoyltransferase [Chemical/Ingredient]
Aspartate carbamoyltransferase (substance)
Carbamoyl-phosphate:L-aspartate carbamoyltransferase
Aldehyde-Ketone Transferases [Chemical/Ingredient]
Acetolactate Synthase [Chemical/Ingredient]
Acetolactate pyruvate-lyase (carboxylating)
Alkyl and Aryl Transferases [Chemical/Ingredient]
Nitrogenous Group Transferases [Chemical/Ingredient]
Sulfur Group Transferases [Chemical/Ingredient]
DNA Restriction-Modification Enzymes [Chemical/Ingredient]
DNA Repair Enzymes [Chemical/Ingredient]
Penicillin-Binding Proteins [Chemical/Ingredient]
Multifunctional Enzymes [Chemical/Ingredient]
4 O beta D Glucopyranosyl D glucopyranose
D-Fructose, 4-O-beta-D-galactopyranosyl-
D-Glucose, 6-O-alpha-D-galactopyranosyl-
alpha-D-Glucopyranoside, alpha-D-glucopyranosyl
Acetylmuramyl-Alanyl-Isoglutamine [Chemical/Ingredient]
D-alpha-Glutamine, N2-(N-(N-acetylmuramoyl)-L-alanyl)-
Dietary Carbohydrates [Chemical/Ingredient]
Hydroxyethyl Starch Derivatives [Chemical/Ingredient]
Glycosphingolipids [Chemical/Ingredient]
Neutral Glycosphingolipids [Chemical/Ingredient]
Acidic Glycosphingolipids [Chemical/Ingredient]
Glycosylphosphatidylinositols [Chemical/Ingredient]
Mylan-vancomycin Hydrochloride for Injection, USP
Cholesterol Ester Transfer Proteins [Chemical/Ingredient]
Cholesterol Ester Transport Protein, CETP
Cholesterol ester transfer protein (substance)
Lipopolysaccharides [Chemical/Ingredient]
Aminoglycosides [respiratory use] (product)
Aminoglycosides [respiratory use] (substance)
D-Streptamine, O-6-amino-6-deoxy-L-glycero-D-galacto-heptopyranosylidene-(1-2-3)-O-beta-D-talopyranosyl-(1-5)-2-deoxy-N3-methyl-
4,6-diamino-2-hydroxy-1,3-cyclohexane 3,6'diamino-3,6'-dideoxydi-α-D-glucoside
4,6-diamino-2-hydroxy-1,3-cyclohexylene 3,6'-diamino-3,6'-dideoxydi-D-glucopyranoside
D-Streptamine, O-3-amino-3-deoxy-alpha-D-glucopyranosyl-(1-6)-O-(6-amino-6-deoxy-alpha-D-glucopyranosyl-(1-4))-2-deoxy-
2,4-Diguanidino-3,5,6-trihydroxycyclohexyl 5-deoxy-2-O-(2-deoxy-2-methylamino-alpha-L-glucopyranosyl)-3-C-formyl-beta-L-lyxopentanofuranoside
D-Streptamine, O-2-deoxy-2-(methylamino)-alpha-L-glucopyranosyl-(1-2)-O-5-deoxy-3-C-formyl-alpha-L-lyxofuranosyl-(1-4)-N,N'-bis(aminoiminomethyl)-
Streptomycin Sulfate Injection USP 1g/2.5ml
3B-O-(4-O-Acetyl-2,6-dideoxy-3-C-methyl-alpha-L-arabino-hexopyranosyl)-7-methylolivomycin D
Olivomycin D, 3B-O-(4-O-Acetyl-2, 6-dideoxy-3-C-methyl-.alpha.-L-arabino-hexopyranosyl)-7-methyl- (9CI)
Olivomycin D, 3B-O-(4-O-Acetyl-2, 6-dideoxy-3-C-methyl-alpha-L-arabino-hexopyranosyl)-7-methyl- (9CI)
Olivomycin D, 3D-O-(4-O-acetyl-2,6-dideoxy-3-C-methyl-alpha-L-arabino-hexopyranosyl)-7-methyl-
Methylgalactosides [Chemical/Ingredient]
Nitrophenylgalactosides [Chemical/Ingredient]
4'-Demethylepipodophyllotoxin 9-(4,6-O-2-Thenylidene-beta-D-glucopyranoside)
4'-Demethylepipodophyllotoxin-beta-D-thenylidine Glucoside
4'-demethylepipodophyllotoxin 9-(4,6-O-(R)-2-thenylidene-beta-D-glucopyranoside)
Demethyl Epipodophyllotoxin Thenylidine Glucoside
Furo(3',4':6,7)naphtho(2,3-d)-1,3-dioxol-6(5aH)-one, 5,8,8a,9-tetrahydro-5-(4-hydroxy-3,5-dimethoxyphenyl)-9-((4,6-O-(2-thienylmethylene)-beta-D-glucopyranosyl)oxy)-, (5R-(5alpha,5abeta,8aalpha,9beta(R*)))-
Nucleic Acids, Nucleotides, and Nucleosides
Nucleoside Diphosphate Sugars [Chemical/Ingredient]
1-Propanone, 1-(2-(beta-D-glucopyranosyloxy)-4,6-dihydroxyphenyl)-3-(4-hydroxyphenyl)-
alpha-D-Glucopyranoside, beta-D-fructofuranosyl, homopolymer
Glycosaminoglycans [Chemical/Ingredient]
Heparan Sulfate Proteoglycans [Chemical/Ingredient]
Oligosaccharides, Branched-Chain [Chemical/Ingredient]
Polysaccharides, Bacterial [Chemical/Ingredient]
Small Leucine-Rich Proteoglycans [Chemical/Ingredient]
Chondroitin Sulfate Proteoglycans [Chemical/Ingredient]
Fungal Polysaccharides [Chemical/Ingredient]
1,3-Dihydroxy-2-propanone monodihydrogen phosphate
2-Propanone, 1-hydroxy-3-(phosphonooxy)-
Fructosephosphates [Chemical/Ingredient]
Galactosephosphates [Chemical/Ingredient]
Hexosediphosphates [Chemical/Ingredient]
Phosphoribosyl Pyrophosphate [Chemical/Ingredient]
Phosphoribosyl pyrophosphate (substance)
Ribosemonophosphates [Chemical/Ingredient]
Ribulosephosphates [Chemical/Ingredient]
Dietary Fats, Unsaturated [Chemical/Ingredient]
Fatty Acids, Omega-3 [Chemical/Ingredient]
9-Octadecenoic acid (Z)-, 1,2,3-propanetriyl ester
Fatty Acids, Nonesterified [Chemical/Ingredient]
Fatty Acids, Unsaturated [Chemical/Ingredient]
dietary supplements fatty acids (unsaturated)
Fatty Acids, Essential [Chemical/Ingredient]
Fatty Acids, Monounsaturated [Chemical/Ingredient]
Prostaglandin Endoperoxides, Synthetic [Chemical/Ingredient]
Prostaglandins A, Synthetic [Chemical/Ingredient]
Prostaglandins E, Synthetic [Chemical/Ingredient]
Prostaglandins F, Synthetic [Chemical/Ingredient]
(E)-(3aS,4R,5R,6aS)-Hexahydro-5-hydroxy-4-((E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-ynyl)-delta(sup 2(1H),delta)-pentalenevaleric Acid
Pentanoic Acid, 5-(hexahydro-5-hydroxy-4-(3-hydroxy-4-methyl-1-octen-6-ynyl)-2(1H)-pentalenylidene)
Pentanoic Acid, 5-(hexahydro-5-hydroxy-4-(3-hydroxy-4-methyl-1-octen-6-ynyl)-2(1H)-pentalenylidene)-
Fatty Acids, Omega-6 [Chemical/Ingredient]
Fatty Acids, Volatile [Chemical/Ingredient]
ATP Binding Cassette Transporter, Sub-Family G, Member 5 [Chemical/Ingredient]
ATP Binding Cassette Transporter, Sub-Family G, Member 5
ATP Binding Cassette Transporter, Sub-Family G, Member 8 [Chemical/Ingredient]
ATP Binding Cassette Transporter, Sub-Family G, Member 8
Chylomicron Remnants [Chemical/Ingredient]
HDL2 - High density lipoprotein subfraction 2
HDL3 - High density lipoprotein subfraction 3
High-Density Lipoproteins, Pre-beta [Chemical/Ingredient]
Lipoproteins, VLDL [Chemical/Ingredient]
Intermediate density lipoprotein (substance)
Myelin Proteolipid Protein [Chemical/Ingredient]
Myelin and Lymphocyte Associated Proteolipid Proteins
Myelin and Lymphocyte-Associated Proteolipid Proteins [Chemical/Ingredient]
Myelin and Lymphocyte-Associated Proteolipid Proteins
Chan Yat Hing She Kun Wool Lok Medicated Oil
Amino Acids, Peptides, and Proteins [Chemical/Ingredient]
Amino Acid Chloromethyl Ketones [Chemical/Ingredient]
Amino Acids, Branched-Chain [Chemical/Ingredient]
2-Amino-5-phosphonovalerate [Chemical/Ingredient]
Amino Acids, Cyclic [Chemical/Ingredient]
(S)-2-Amino-3-(1H-imidazol-4-yl)propanoic acid
(S)-a-Amino-1H-imidazole-4-propanoic acid
(S)-alpha-Amino-1H-imidazole-4-propionic acid
(S)-alpha-amino-1H-Imidazole-4-propanoic acid
(S)-α-amino-1H-Imidazole-4-propanoic acid
Amino Acids, Aromatic [Chemical/Ingredient]
(S)-alpha-Amino-beta-phenylpropionic acid
(2S)-2-amino-3-(1H-indol-3-yl)Propanoic acid
(S)-2-Amino-3-(1H-indol-3-yl)-propanoic acid
(S)-alpha-Amino-beta-(3-indolyl)-propionic acid
(S)-alpha-amino-1H-indole-3-propanoic acid
L-tyrosine, dihydrogen phosphate (ester)
Amino Acids, Diamino [Chemical/Ingredient]
(2S)-2-amino-5-(carbamimidamido)pentanoic acid
2-Amino-5-(carbamoylamino)pentanoic Acid
Earthlink Science Glutamine Chews Chocolate
Amino Acids, Dicarboxylic [Chemical/Ingredient]
Aminosyn II 7% M In 10% Dextrose(dual Chamber)
Amino Acids, Essential [Chemical/Ingredient]
L-Threonine, dihydrogen phosphate (ester)
L-Homoserine, O-((aminoiminomethyl)amino)-
Glycine, N-(imino(phosphonoamino)methyl)-N-methyl-
4.25% Amino Acid Injection Without Electrolytes In 20% Dextrose Quickmix
N-substituted Glycines [Chemical/Ingredient]
Benzenebutanoic acid, alpha,2-diamino-gamma-oxo-
RNA, Transfer, Amino Acyl [Chemical/Ingredient]
Excitatory Amino Acids [Chemical/Ingredient]
Phosphoamino Acids [Chemical/Ingredient]
2-Amino-3-(Oxyphosphinyloxyphosphinyl)Propanoic Acid
DL-2-Amino-3-Hydroxypropanoic Acid 3-Phosphate
Amino Acids, Neutral [Chemical/Ingredient]
(S)-alpha-Amino-beta-hydroxypropionic acid
Amino Acids, Acidic [Chemical/Ingredient]
Amino Acids, Basic [Chemical/Ingredient]
Glatiramer Acetate [Chemical/Ingredient]
L-Glutamic acid peptide with L-alanine, L-lysine and L-tyrosine, acetate (salt)
L-Tyrosine, L-tryptophyl-L-histidyl-L-tryptophyl-L-leucyl-L-glutaminyl-L-leucyl-L-lysyl-L-prolylglycyl-L-glutaminyl-L-prolyl-gamma-(methylsulfinyl)-L-alpha-aminobutyryl-
Sialoglycoproteins [Chemical/Ingredient]
Myocardial Depressant Factor [Chemical/Ingredient]
(2S)-2-[(3-Amino-1-Oxopropyl)Amino]-3-(3H-Imidazol-4-Yl)Propanoic Acid
Calcitonin Gene-Related Peptide [Chemical/Ingredient]
Calcitonin gene-related peptide (substance)
omega-Agatoxin IVA [Chemical/Ingredient]
Galanin-Like Peptide [Chemical/Ingredient]
Pituitary Adenylate Cyclase Activating Polypeptide
Pituitary Adenylate Cyclase-Activating Polypeptide [Chemical/Ingredient]
pituitary adenylate cyclase activating peptide
Pituitary Adenylate Cyclase-Activating Polypeptide
Angiotensinogen (protein renin substrate)
L-Valinamide, N2-(((1-carboxy-2-phenylethyl)amino)carbonyl)-L-arginyl-N-(4-((aminoiminomethyl)amino)-1-formylbutyl)-
Glycine, N-(N-L-gamma-glutamyl-L-cysteinyl)-
1H-Pyrrole-2-carboxamide, 4-((((aminoiminomethyl)amino)acetyl)amino)-N-(5-(((3-amino-3-iminopropyl)amino)carbonyl)-1-methyl-1H-pyrrol-3-yl)-1-methyl-
Bradykinin potentiator B, 2-L-tryptophan-3-de-L-leucine-4-de-L-proline-8-L-glutamine-
Enzyme Inhibitor, Nonapeptide-Converting
L-Arginine, N2-(1-(N2-L-threonyl-L-lysyl)-L-prolyl)-
L-Threonine, N-(N-(N2-(N-(N-(N-(N-D-alanyl-L-seryl)-L-threonyl)-L-threonyl)-L-threonyl)-L-asparaginyl)-L-tyrosyl)-
Immunoglobulin Fragments [Chemical/Ingredient]
Immunoglobulin Idiotypes [Chemical/Ingredient]
Nanotubes, Peptide [Chemical/Ingredient]
Salivary Proteins and Peptides [Chemical/Ingredient]
High Molecular Weight Salivary Mucin MG1
Salivary Proline-Rich Proteins [Chemical/Ingredient]
Salivary Cystatins [Chemical/Ingredient]
Complement C1 Inactivator Proteins [Chemical/Ingredient]
Complement Component 1 Inactivator Proteins
Food - Animal Products and Poultry Products, Egg, White Gallus sp.
Corticosteroid binding globulin (substance)
Corticosteroid binding globulin -RETIRED-
Plasminogen Inactivators [Chemical/Ingredient]
Plasminogen activator inhibitor (substance)
Plasminogen Activator Inhibitor 1 [Chemical/Ingredient]
Plasminogen activator inhibitor-1 (substance)
Plasminogen Activator Inhibitor 2 [Chemical/Ingredient]
Plasminogen activator inhibitor-2 (substance)
HSP47 Heat-Shock Proteins [Chemical/Ingredient]
Antithrombin Proteins [Chemical/Ingredient]
Antithrombin III preparation (substance)
Tissue Polypeptide Antigen [Chemical/Ingredient]
Protein Sorting Signals [Chemical/Ingredient]
Nuclear Localization Signals [Chemical/Ingredient]
Nuclear Export Signals [Chemical/Ingredient]
Antimicrobial Cationic Peptides [Chemical/Ingredient]
Diazepam Binding Inhibitor [Chemical/Ingredient]
INTERCELLULAR SIGNALING PEPTIDES PROTEINS
Intercellular Signaling Peptides and Proteins [Chemical/Ingredient]
Serrate-Jagged Proteins [Chemical/Ingredient]
Fibroblast Growth Factors [Chemical/Ingredient]
Fibroblast Growth Factor 1 [Chemical/Ingredient]
Fibroblast Growth Factor 4 [Chemical/Ingredient]
Heparin Secretory Transforming Protein 1
Heparin Secretory Transforming Protein-1
Kaposi's Sarcoma Fibroblast Growth Factor
Fibroblast Growth Factor 5 [Chemical/Ingredient]
Fibroblast Growth Factor 7 [Chemical/Ingredient]
Fibroblast Growth Factor 8 [Chemical/Ingredient]
Fibroblast Growth Factor 9 [Chemical/Ingredient]
Fibroblast Growth Factor 10 [Chemical/Ingredient]
Kininogen, Low-Molecular-Weight [Chemical/Ingredient]
Nerve Growth Factors [Chemical/Ingredient]
Brain-Derived Neurotrophic Factor [Chemical/Ingredient]
brain derived neurotrophic factor (BDNF)
Glia Maturation Factor [Chemical/Ingredient]
Nerve Growth Factor [Chemical/Ingredient]
HDNF (hippocampus derived neurotrophic factor)
Ciliary Neurotrophic Factor [Chemical/Ingredient]
Glial Cell Line Derived Neurotrophic Factors
Glial Cell Line-Derived Neurotrophic Factors [Chemical/Ingredient]
Glial Cell Line-Derived Neurotrophic Factors
Platelet-Derived Growth Factor [Chemical/Ingredient]
Platelet-derived growth factor (substance)
Proto-Oncogene Proteins c-sis [Chemical/Ingredient]
EPIDERMAL GROWTH FACTOR RELAT TRANSFORMING GROWTH FACTOR
Epidermal Growth Factor Related Transforming Growth Factor
Epidermal Growth Factor-Related Transforming Growth Factor
Transforming Growth Factor alpha [Chemical/Ingredient]
transforming growth factor alpha (TGF alpha)
Leukocyte Migration-Inhibitory Factors [Chemical/Ingredient]
Macrophage Migration-Inhibitory Factors [Chemical/Ingredient]
Macrophage inhibitory factor (substance)
Tumor Necrosis Factor Superfamily Protein
Hematopoietic Cell Growth Factors [Chemical/Ingredient]
Colony stimulating factor preparation (product)
Colony stimulating factor preparation (substance)
Hepatocyte Growth Factor [Chemical/Ingredient]
Lymphokines and Cytokines, scatter factor
beta-Thromboglobulin [Chemical/Ingredient]
Macrophage Inflammatory Proteins [Chemical/Ingredient]
Tumor Necrosis Factors [Chemical/Ingredient]
TUMOR NECROSIS FACTOR LIGAND SUPERFAMILY MEMBER 009
Tumor Necrosis Factor (Ligand) Superfamily, Member 9
Tumor Necrosis Factor Ligand Superfamily Member 9
INTERLEUKIN 001 RECEPTOR ANTAGONIST PROTEIN
Interleukin 1 Receptor Antagonist Protein [Chemical/Ingredient]
Interleukin 1 Receptor Antagonist Protein
Differentiation-Stimulating Factor, Myeloid
Leukemia Inhibitory Factor [Chemical/Ingredient]
Growth Differentiation Factor 15 [Chemical/Ingredient]
Endothelial Growth Factors [Chemical/Ingredient]
Endothelium-Derived Vasoconstrictor Factors
Vasoconstrictor Factors, Endothelium-Derived
Eph Family Receptor Interacting Protein B1
Angiogenic Proteins [Chemical/Ingredient]
Vascular Endothelial Growth Factors [Chemical/Ingredient]
Placenta Growth Factor [Chemical/Ingredient]
Angiostatic Proteins [Chemical/Ingredient]
Agouti Signaling Protein [Chemical/Ingredient]
Agouti-Related Protein [Chemical/Ingredient]
TGF-beta Superfamily Proteins [Chemical/Ingredient]
Transforming Growth Factor beta Superfamily Proteins
Bone Morphogenetic Proteins [Chemical/Ingredient]
Growth Differentiation Factors [Chemical/Ingredient]
Nodal Signaling Ligands [Chemical/Ingredient]
CCN Intercellular Signaling Proteins [Chemical/Ingredient]
Connective Tissue Growth Factor [Chemical/Ingredient]
Connective tissue growth factor (substance)
Hypertrophic Chondrocyte Specific Protein 24
Hypertrophic Chondrocyte-Specific Protein 24
Nephroblastoma Overexpressed Gene Product
Nephroblastoma Overexpressed Protein [Chemical/Ingredient]
Cysteine-Rich Heparin-Binding Protein 61
EGF Family of Proteins [Chemical/Ingredient]
Heparin-binding EGF-like Growth Factor [Chemical/Ingredient]
Intracellular Signaling Peptides and Proteins [Chemical/Ingredient]
Nucleotide binding Domain Leucine rich Repeat Proteins
Nucleotide-binding Domain Leucine-rich Repeat Proteins
Methyl-Accepting Chemotaxis Proteins [Chemical/Ingredient]
inhibitor of growth family, member 1 protein, human
GTP-Binding Protein Regulators [Chemical/Ingredient]
I-kappa B Proteins [Chemical/Ingredient]
Ewing Sarcoma Breakpointregion 1 Protein
RNA-Binding Protein EWS [Chemical/Ingredient]
Adaptor Proteins, Signal Transducing [Chemical/Ingredient]
Phosphotyrosine Independent Ligand For The Lck SH2 Domain Of 62 Kda
Phosphotyrosine-Independent Ligand For The Lck SH2 Domain Of 62 Kda
Sequestosome-1 Protein [Chemical/Ingredient]
Breast Cancer Anti Estrogen Resistance 1 Protein
Breast Cancer Anti-Estrogen Resistance 1 Protein
Crk-Associated Substrate Protein [Chemical/Ingredient]
STAT (Signal Transducers and Activators of Transcription) Proteins
STAT Transcription Factors [Chemical/Ingredient]
Interferon-Stimulated Gene Factor 3 [Chemical/Ingredient]
Interferon Regulatory Factors [Chemical/Ingredient]
Interferon Regulatory Factor-3 [Chemical/Ingredient]
Interferon Regulatory Factor-7 [Chemical/Ingredient]
Vesicular Integral Membrane Protein 21 kDa
Smad Proteins, Receptor-Regulated [Chemical/Ingredient]
Retinoblastoma Binding Proteins [Chemical/Ingredient]
Nuclear Receptor Coactivators [Chemical/Ingredient]
Hippocampal Cholinergic Neurostimulating Peptide Precursor
Phosphatidylethanolamine Binding Protein [Chemical/Ingredient]
Phosphatidylethanolamine-Binding Protein
Phosphatidylethanolamine Binding Protein
Cyclin Dependent Kinase Inhibitor Proteins
Cyclin-Dependent Kinase Inhibitor Protein
Cyclin-Dependent Kinase Inhibitor Proteins [Chemical/Ingredient]
Cyclin-Dependent Kinase Inhibitor Proteins
Apoptosis Regulatory Proteins [Chemical/Ingredient]
Coiled-Coil Myosin-Like BCL2-Interacting Protein
coiled-coil, myosin-like BCL2 interacting protein, human
Bcl 2 Interacting Mediator of Cell Death
Bcl-2-Interacting Mediator of Cell Death
Cyclic AMP-Dependent Transcription Factor ATF-6 Alpha
activating transcription factor 6, human
cAMP-Dependent Transcription Factor ATF-6 Alpha
Olfactory Marker Protein [Chemical/Ingredient]
Intracellular Calcium-Sensing Proteins [Chemical/Ingredient]
55 kDa High Affinity Calcium Binding Protein
55-kDa High-Affinity Calcium Binding Protein
Neuronal Calcium-Sensor Proteins [Chemical/Ingredient]
Guanylate Cyclase-Activating Proteins [Chemical/Ingredient]
Cold Shock Proteins and Peptides [Chemical/Ingredient]
Peptidase Inhibitory Proteins, Secretory
Proteinase Inhibitory Proteins, Secretory [Chemical/Ingredient]
Proteinase Inhibitory Proteins, Secretory
Leukocyte Peptidase Inhibitor, Secretory
Secretory Leukocyte Peptidase Inhibitor [Chemical/Ingredient]
Circadian Rhythm Signaling Peptides and Proteins [Chemical/Ingredient]
ARNTL Transcription Factors [Chemical/Ingredient]
Aryl Hydrocarbon Receptor Nuclear Translocator like Transcription Factors
Aryl Hydrocarbon Receptor Nuclear Translocator-like Transcription Factors
Period Circadian Proteins [Chemical/Ingredient]
Cystine-Knot Miniproteins [Chemical/Ingredient]
Cell-Penetrating Peptides [Chemical/Ingredient]
Parkinson Disease Associated Proteins [Chemical/Ingredient]
Promyelocytic Leukemia Protein [Chemical/Ingredient]
Huntingtin Protein [Chemical/Ingredient]
Autophagy-Related Proteins [Chemical/Ingredient]
Autophagy-Related Protein 8 Family [Chemical/Ingredient]
Autophagy-Related Protein 12 [Chemical/Ingredient]
Ubiquitin Activating Enzyme E1-Like Protein
Ubiquitin-Activating Enzyme E1-Like Protein
Ubiquitin-Like Modifier-Activating Enzyme ATG7
C-Reactive Protein [Chemical/Ingredient]
Amyloidogenic Proteins [Chemical/Ingredient]
Serum Amyloid P-Component [Chemical/Ingredient]
Amyloid beta-Protein Precursor [Chemical/Ingredient]
Transcription Activator-Like Effectors [Chemical/Ingredient]
Azurin (Pseudomonas fluorescens protein)
Bacterial Outer Membrane Proteins [Chemical/Ingredient]
Adhesins, Bacterial [Chemical/Ingredient]
Staphylococcal Protein A [Chemical/Ingredient]
Escherichia coli Proteins [Chemical/Ingredient]
Periplasmic Proteins [Chemical/Ingredient]
Periplasmic Binding Proteins [Chemical/Ingredient]
Integration Host Factors [Chemical/Ingredient]
Factor For Inversion Stimulation Protein [Chemical/Ingredient]
HIN Recombinational Enhancer Binding Protein
Factor For Inversion Stimulation Protein
AraC Transcription Factor [Chemical/Ingredient]
Acute-Phase Proteins [Chemical/Ingredient]
Fibrinogens, Abnormal [Chemical/Ingredient]
Blood Coagulation Factors [Chemical/Ingredient]
Blood Coagulation Factor VIII, Activated
Blood-coagulation factor VIIIa, procoagulant
Antigen-Antibody Complex [Chemical/Ingredient]
ANCA - Anti-neutrophil cytoplasmic antibody
Anti neutrophilic cytoplasm antibody (substance)
Antilymphocyte Serum [Chemical/Ingredient]
Antibodies, Immobilized [Chemical/Ingredient]
Retinol-Binding Proteins, Plasma [Chemical/Ingredient]
alpha-2-HS-Glycoprotein [Chemical/Ingredient]
Binding Globulin, Testosterone-Estradiol
Globulin, Testosterone-Estradiol Binding
Alpha-2 pregnancy associated glycoprotein
Alpha-2 pregnancy associated glycoprotein (substance)
Pregnancy Associated alpha 2 Glycoproteins
Pregnancy Associated alpha 2 Macroglobulins
Pregnancy-Associated alpha 2-Macroglobulins
Thyroxine-Binding Proteins [Chemical/Ingredient]
S protein complement component (substance)
Lipid Droplet Associated Proteins [Chemical/Ingredient]
X-ray repair cross complementing protein 1
Xeroderma Pigmentosum Group A Complementing Protein
Xeroderma Pigmentosum Group A Protein [Chemical/Ingredient]
Centromere Protein B [Chemical/Ingredient]
Acyl Carrier Protein [Chemical/Ingredient]
Androgen-Binding Protein [Chemical/Ingredient]
Calcium-Binding Proteins [Chemical/Ingredient]
Stromal Interaction Molecules [Chemical/Ingredient]
Secreted Protein Acidic and Rich in Cysteine 1
Calmodulin-Binding Proteins [Chemical/Ingredient]
Retinol-Binding Proteins [Chemical/Ingredient]
25 Hydroxycholecalciferol Binding Protein
25-Hydroxycholecalciferol-Binding Protein
RNA-Binding Proteins [Chemical/Ingredient]
Heterogeneous Nuclear Ribonucleoprotein K
Heterogeneous-Nuclear Ribonucleoprotein K [Chemical/Ingredient]
Ribonucleoprotein K, Heterogeneous-Nuclear
Heterogeneous-Nuclear Ribonucleoprotein K
Embryonic Lethal, Abnormal Vision Like Proteins
Embryonic Lethal, Abnormal Vision-Like Proteins
Hu Paraneoplastic Encephalomyelitis Antigens
DNA-Binding p52/p100 Complex, 100 kDa Subunit
PTB-Associated Splicing Factor [Chemical/Ingredient]
Polypyrimidine Tract Binding Protein Associated Splicing Factor
Polypyrimidine Tract-Binding Protein-Associated Splicing Factor
Small Nuclear Ribonucleoprotein Core Proteins
snRNP Core Proteins [Chemical/Ingredient]
NF90 Double Stranded RNA Binding Proteins
NF90 Double-Stranded RNA-Binding Proteins
Nuclear Factor 90 Proteins [Chemical/Ingredient]
Butyrate Response Factor 1 [Chemical/Ingredient]
Fragile X Mental Retardation Protein [Chemical/Ingredient]
SMN Complex Proteins [Chemical/Ingredient]
Survival of Motor Neuron Complex Proteins
IGF-BP - Insulin-like growth factor binding protein
IGFBP - Insulin-like growth factor binding protein
INSULIN LIKE GROWTH FACTOR 99 BINDING PROTEINS
Insulin-Like Growth Factor Binding Proteins
Membrane Transport Proteins [Chemical/Ingredient]
Glucose Transporter Type 3 [Chemical/Ingredient]
Solute Carrier Family 2, Facilitated Glucose Transporter, Member 3 Protein
INOSITOL TRIPHOSPHATE 01 04 05 RECEPTORS
INOSITOL TRISPHOSPHATE 01 04 05 RECEPTORS
Inositol 1,4,5-Trisphosphate Receptors [Chemical/Ingredient]
Sulfonylurea Receptors [Chemical/Ingredient]
Voltage-Gated Sodium Channels [Chemical/Ingredient]
Acid Sensing Ion Channels [Chemical/Ingredient]
Bacteriorhodopsins [Chemical/Ingredient]
Cellular Apoptosis Susceptibility Protein [Chemical/Ingredient]
Cellular Apoptosis Susceptibility Protein
Phosphate-Binding Proteins [Chemical/Ingredient]
Iron-Binding Proteins [Chemical/Ingredient]
Transferrin-Binding Proteins [Chemical/Ingredient]
Follistatin-Related Proteins [Chemical/Ingredient]
S-Phase Kinase-Associated Proteins [Chemical/Ingredient]
5-Lipoxygenase-Activating Proteins [Chemical/Ingredient]
Arachidonate 5 Lipoxygenase Activating Protein
Arachidonate 5 Lipoxygenase Activating Proteins
Arachidonate 5-Lipoxygenase Activating Protein
Arachidonate 5-Lipoxygenase Activating Proteins
Phospholipid Transfer Proteins [Chemical/Ingredient]
Fatty Acid-Binding Proteins [Chemical/Ingredient]
Fatty Acid-Binding Protein 7 [Chemical/Ingredient]
Mammary Derived Growth Inhibitor Related Protein
Mammary-Derived Growth Inhibitor Related Protein
Lymphocyte Antigen 96 [Chemical/Ingredient]
Endometrial Protein, Progestagen-Associated
Pregnancy Associated Endometrial Alpha 2 Globulin
Pregnancy-Associated Endometrial Alpha-2 Globulin
Progestagen Associated Endometrial Protein
Progestagen-Associated Endometrial Protein
Cerebrospinal Fluid Proteins [Chemical/Ingredient]
Contractile Proteins [Chemical/Ingredient]
dysferlin, limb girdle muscular dystrophy 2B (autosomal recessive) protein, human
Dystrophin-Associated Proteins [Chemical/Ingredient]
Cytoskeletal Proteins [Chemical/Ingredient]
Microtubule-Associated Proteins [Chemical/Ingredient]
Cadherin-Associated Protein, Beta 1 (88kD)
Cornified Envelope Proline Rich Proteins
Cornified Envelope Proline-Rich Proteins [Chemical/Ingredient]
Small Proline Rich Cornified Envelope Proteins
Small Proline-Rich Cornified Envelope Proteins
Cornified Envelope Proline-Rich Proteins
epididymis-specific protein BE-20, human
Dental Enamel Proteins [Chemical/Ingredient]
DNA-Binding Proteins [Chemical/Ingredient]
Swi Snf Related Matrix Associated Actin Dependent Regulator Of Chromatin Subfamily B Member 1
Swi-Snf-Related Matrix-Associated Actin-Dependent Regulator Of Chromatin Subfamily B Member 1
tumor protein p53 binding protein, 1, human
RNA Polymerase II Transcription Factor SIII
Repressor Proteins [Chemical/Ingredient]
Retinoblastoma Protein [Chemical/Ingredient]
Oncogene Protein p55(v-myc) [Chemical/Ingredient]
Enhancer-Binding Protein, Immunoglobulin
Adenovirus E2 Proteins [Chemical/Ingredient]
Homeodomain Proteins [Chemical/Ingredient]
Nanog Homeobox Protein [Chemical/Ingredient]
CDX2 Transcription Factor [Chemical/Ingredient]
Caudal Type Homeo Box Transcription Factor 2
Caudal Type Homeobox Transcription Factor 2
Homeobox Protein Nkx-2.5 [Chemical/Ingredient]
Homeobox Transcription Factor Csx Nkx2 5
Homeobox Transcription Factor Csx-Nkx2-5
thyroid-specific enhancer-binding protein
pre-B-cell leukemia homeobox 1 protein, human
Pre-B-Cell Leukemia Transcription Factor 1
myeloid ecotropic viral integration site 1 protein
MADS Domain Proteins [Chemical/Ingredient]
Onecut Transcription Factors [Chemical/Ingredient]
Fushi Tarazu Transcription Factors [Chemical/Ingredient]
Orthodenticle Homolog Homeodomain Proteins
Otx Transcription Factors [Chemical/Ingredient]
Antennapedia Homeodomain Protein [Chemical/Ingredient]
MSX1 Transcription Factor [Chemical/Ingredient]
Proto-Oncogene Proteins c-myb [Chemical/Ingredient]
T-Box Domain Proteins [Chemical/Ingredient]
Minichromosome Maintenance 1 Protein [Chemical/Ingredient]
Telomere-Binding Proteins [Chemical/Ingredient]
Transcription Factors, General [Chemical/Ingredient]
Matrix Attachment Region Binding Proteins [Chemical/Ingredient]
Matrix Attachment Region Binding Proteins
Proto-Oncogene Proteins c-ets [Chemical/Ingredient]
POU Domain Factors [Chemical/Ingredient]
Basic Leucine Zipper Transcription Factors
Basic-Leucine Zipper Transcription Factors [Chemical/Ingredient]
Basic-Leucine Zipper Transcription Factors
Proto-Oncogene Proteins c-jun [Chemical/Ingredient]
Proto-Oncogene Proteins c-fos [Chemical/Ingredient]
GATA Transcription Factors [Chemical/Ingredient]
Erythroid-Specific DNA-Binding Factors [Chemical/Ingredient]
Toll-Like Receptor 9 [Chemical/Ingredient]
Nuclear Respiratory Factors [Chemical/Ingredient]
Hepatocyte Nuclear Factors [Chemical/Ingredient]
Hepatocyte Nuclear Factor 4 [Chemical/Ingredient]
Hepatocyte Nuclear Factor Forkhead Homolog 4
Hepatocyte Nuclear Factor-Forkhead Homolog 4
Winged-Helix Transcription Factors [Chemical/Ingredient]
Replication Factor A Single Stranded DNA Binding Protein
Replication Factor A Single-Stranded DNA-Binding Protein
Replication Protein A [Chemical/Ingredient]
DNA Repair And Recombination Protein RAD52
RAD 052 DNA REPAIR AND RECOMBINATION PROTEIN
Rad52 DNA Repair and Recombination Protein [Chemical/Ingredient]
Rad52 DNA Repair and Recombination Protein
Origin Recognition Complex [Chemical/Ingredient]
Kruppel-Like Transcription Factors [Chemical/Ingredient]
Leucine-Responsive Regulatory Protein [Chemical/Ingredient]
Paired Box Transcription Factors [Chemical/Ingredient]
Early Growth Response Transcription Factors [Chemical/Ingredient]
Early Growth Response Transcription Factors
Methyl-CpG-Binding Protein 2 [Chemical/Ingredient]
Myeloid-Lymphoid Leukemia Protein [Chemical/Ingredient]
G-Box Binding Factors [Chemical/Ingredient]
Basic Helix Loop Helix Transcription Factors
Basic Helix-Loop-Helix Transcription Factors [Chemical/Ingredient]
Basic Helix-Loop-Helix Transcription Factors
BASIC HELIX-LOOP-HELIX PROTEIN, CLASS B, 1
OLIGODENDROCYTE LINEAGE TRANSCRIPTION FACTOR 2
Oligodendrocyte Lineage Transcription Factor 2 Gene
Class E Basic Helix-Loop-Helix Protein 39
Growth Factor-Inducible Nuclear Protein NUP475
IG J RECOMBINATION SIGNAL SEQUENCE BINDING PROTEIN
Immunoglobulin J Recombination Signal Sequence Binding Protein
Immunoglobulin J Recombination Signal Sequence-Binding Protein [Chemical/Ingredient]
Immunoglobulin J Recombination Signal Sequence-Binding Protein
TCF Transcription Factors [Chemical/Ingredient]
NFI Transcription Factors [Chemical/Ingredient]
SOX Transcription Factors [Chemical/Ingredient]
SRY (Sex Determining Region Y)-Box Proteins
Orphan Nuclear Receptors [Chemical/Ingredient]
Nuclear Receptor Subfamily 1 Group D Member 1
Nuclear Receptor Subfamily 1, Group D, Member 1 [Chemical/Ingredient]
Nuclear Receptor Subfamily 1, Group D, Member 1
Nuclear Receptor Subfamily 1, Group F, Member 1 [Chemical/Ingredient]
Nuclear Receptor Subfamily 1, Group F, Member 1
Nuclear Receptor Subfamily 1, Group F, Member 2 [Chemical/Ingredient]
Nuclear Receptor Subfamily 1, Group F, Member 2
LIM-Homeodomain Proteins [Chemical/Ingredient]
Zona Pellucida Glycoproteins [Chemical/Ingredient]
Saccharomyces cerevisiae Proteins [Chemical/Ingredient]
SILENT INFORMATION REGULAT PROTEINS SACCH CEREV
Silent Information Regulator Proteins, S cerevisiae
Silent Information Regulator Proteins, Saccharomyces cerevisiae [Chemical/Ingredient]
Silent Information Regulator Proteins, Saccharomyces cerevisiae
Schizosaccharomyces pombe Proteins [Chemical/Ingredient]
Killer Factors, Yeast [Chemical/Ingredient]
Asialoglycoproteins [Chemical/Ingredient]
Membrane Glycoproteins [Chemical/Ingredient]
Myelin-Oligodendrocyte Glycoprotein [Chemical/Ingredient]
Variant Surface Glycoproteins, Trypanosoma
Cell Adhesion Molecules [Chemical/Ingredient]
Cadherin Related Proteins [Chemical/Ingredient]
ECAM (epithelial cell adhesion molecule)
CD24 - Cluster of differentiation antigen 24
Integrin-Binding Sialoprotein [Chemical/Ingredient]
Luminescent Proteins [Chemical/Ingredient]
Green Fluorescent Proteins [Chemical/Ingredient]
Receptors, Cell Surface [Chemical/Ingredient]
LDL-Receptor Related Proteins [Chemical/Ingredient]
Low Density Lipoprotein Related Proteins
Low Density Lipoprotein-Related Proteins
Low Density Lipoprotein Receptor-Related Protein-1
Low Density Lipoprotein Receptor-Related Protein-2
Low Density Lipoprotein Receptor Related Protein 6
Low Density Lipoprotein Receptor-Related Protein 6
Low Density Lipoprotein Receptor-Related Protein-6 [Chemical/Ingredient]
Low Density Lipoprotein Receptor-Related Protein-6
Low Density Lipoprotein Receptor Related Protein 5
Low Density Lipoprotein Receptor-Related Protein 5
Low Density Lipoprotein Receptor-Related Protein-5 [Chemical/Ingredient]
Low-Density Lipoprotein Receptor-Related Protein 5
Low Density Lipoprotein Receptor-Related Protein-5
Receptors, Melatonin [Chemical/Ingredient]
Receptors, Artificial [Chemical/Ingredient]
ALPHA2 MACROGLOBULIN RECEPT ASSOC PROTEIN
LDL-Receptor Related Protein-Associated Protein
Membrane Transport Proteins, Mitochondrial
Mitochondrial Membrane Transport Proteins [Chemical/Ingredient]
Mitochondrial Membrane Transport Proteins
Vesicular Transport Proteins [Chemical/Ingredient]
Pulmonary Surfactant-Associated Proteins
Pulmonary Surfactant Associated Protein B
Pulmonary Surfactant Associated Protein SP B
Pulmonary Surfactant-Associated Protein B [Chemical/Ingredient]
Pulmonary Surfactant-Associated Protein SP-B
SP B Pulmonary Surfactant Associated Protein
Pulmonary Surfactant-Associated Protein B
Pulmonary Surfactant Associated Protein C
Pulmonary Surfactant Associated Protein SP C
Pulmonary Surfactant-Associated Protein C [Chemical/Ingredient]
Pulmonary Surfactant-Associated Protein SP-C
Pulmonary Surfactant-Associated Protein C
Membrane Fusion Proteins [Chemical/Ingredient]
Pore Forming Cytotoxic Proteins [Chemical/Ingredient]
Receptor Activity-Modifying Proteins [Chemical/Ingredient]
Lipid-Linked Proteins [Chemical/Ingredient]
Melanocyte Lineage Specific Antigen gp100
Melanocyte Lineage-Specific Antigen gp100
Thylakoid Membrane Proteins [Chemical/Ingredient]
V-set domain containing T cell activation inhibitor 1 protein, human
V-Set Domain-Containing T-Cell Activation Inhibitor 1
Programmed Cell Death 1 Ligand 2 Protein
Tight Junction Proteins [Chemical/Ingredient]
MARVEL Domain-Containing Proteins [Chemical/Ingredient]
Mal and Related Proteins for Vesicle Trafficking and Membrane Link Domain Proteins
Oncogene Proteins, Viral [Chemical/Ingredient]
Adenovirus Early Proteins [Chemical/Ingredient]
Adenovirus Early Region Transforming Proteins
Adenovirus E1 Proteins [Chemical/Ingredient]
Adenovirus E1A Proteins [Chemical/Ingredient]
Adenovirus E1B Proteins [Chemical/Ingredient]
Wingless Type MMTV Integration Site Family, Member 5A
Wingless-Type MMTV Integration Site Family, Member 5A
Receptors, Thyroid Hormone [Chemical/Ingredient]
Tumor Suppressor Proteins [Chemical/Ingredient]
Fanconi Anemia Complementation Group N Protein
Breast Cancer Type 1 Susceptibility Protein
Breast cancer type 1 susceptibility protein (substance)
Breast cancer type 2 susceptibility protein
Breast cancer type 2 susceptibility protein (substance)
FANCONI ANEMIA COMPLEMENTATION GROUP D 01 PROTEIN
Tumor Suppressor Protein p14ARF [Chemical/Ingredient]
Retinoblastoma-Like Protein p130 [Chemical/Ingredient]
107 kDa Retinoblastoma-Associated Protein
Retinoblastoma-Like Protein p107 [Chemical/Ingredient]
Melanoma-Specific Antigens [Chemical/Ingredient]
Nerve Tissue Proteins [Chemical/Ingredient]
NEUROENDOCRINE SECRETORY PROTEIN 007 B 002
Neuroendocrine Secretory Protein 7B2 [Chemical/Ingredient]
DOPAMINE AND CAMP REGULATED PHOSPHOPROTEIN 032
Dopamine and Adenosine 3',5' Monophosphate Regulated Phosphoprotein
Dopamine and Adenosine 3',5'-Monophosphate-Regulated Phosphoprotein
Dopamine and Cyclic AMP Regulated Phosphoprotein Mr 32,000
Dopamine and cAMP Regulated Phosphoprotein
Dopamine and cAMP Regulated Phosphoprotein 32
Dopamine and cAMP-Regulated Phosphoprotein
Dopamine and cAMP-Regulated Phosphoprotein 32
Chromosomal Proteins, Non-Histone [Chemical/Ingredient]
Proliferating Cell Nuclear Antigen [Chemical/Ingredient]
proliferating cell nuclear antigen (PCNA)
Nuclear Matrix-Associated Proteins [Chemical/Ingredient]
Antigen Identified by Monoclonal Antibody Ki-67
Host Cell Factor C1 [Chemical/Ingredient]
Fanconi Anemia Complementation Group A Protein [Chemical/Ingredient]
Fanconi Anemia Group A Complementing Protein
Fanconi Anemia Complementation Group A Protein
Fanconi Anemia Complementation Group F Protein [Chemical/Ingredient]
Fanconi Anemia Group F Complementing Protein
Fanconi Anemia Complementation Group F Protein
FANCONI ANEMIA COMPLEMENTATION GROUP D 02 PROTEIN
Fanconi Anemia Complementation Group D2 Protein [Chemical/Ingredient]
Fanconi Anemia Group D2 Complementing Protein
Fanconi Anemia Complementation Group D2 Protein
Fanconi Anemia Complementation Group E Protein [Chemical/Ingredient]
Fanconi Anemia Group E Complementing Protein
Fanconi Anemia Complementation Group E Protein
Mad2 Mitotic Arrest Deficient-like 1 Proteins
Deoxyribonucleoproteins [Chemical/Ingredient]
Oxidative Phosphorylation Coupling Factors [Chemical/Ingredient]
Oxidative Phosphorylation Coupling Factors
Fanconi Anemia Complementation Group G Protein
Seed Storage Proteins [Chemical/Ingredient]
Chloroplast Proteins [Chemical/Ingredient]
Chloroplast Thioredoxins [Chemical/Ingredient]
Pregnancy Proteins [Chemical/Ingredient]
1-Glycoproteins, Pregnancy-Specific beta
BETA GLYCOPROTEIN TROPHOBLAST SPECIFIC 01
PSBG - Pregnancy specific beta 1-glycoprotein
Protein Hydrolysates [Chemical/Ingredient]
protein hydrolysate (discontinued) (medication)
Protein Precursors [Chemical/Ingredient]
Imidazoline Receptors [Chemical/Ingredient]
Recombinant Proteins [Chemical/Ingredient]
Recombinant Fusion Proteins [Chemical/Ingredient]
Vaccines, Synthetic [Chemical/Ingredient]
Vaccines, Virosome [Chemical/Ingredient]
Vaccines, Virus-Like Particle [Chemical/Ingredient]
Ribosomal Proteins [Chemical/Ingredient]
Peptide Elongation Factors [Chemical/Ingredient]
Peptide Initiation Factors [Chemical/Ingredient]
Peptide Termination Factors [Chemical/Ingredient]
Ribosomal Protein S6 [Chemical/Ingredient]
Extracellular Matrix Proteins [Chemical/Ingredient]
Transcription Factors [Chemical/Ingredient]
Receptors, Steroid [Chemical/Ingredient]
Receptors, Retinoic Acid [Chemical/Ingredient]
Transcriptional Elongation Factors [Chemical/Ingredient]
PEROXISOME PROLIFERATOR ACTIVATED RECEPT
Peroxisome Proliferator Activated Receptors
Peroxisome Proliferator-Activated Receptors [Chemical/Ingredient]
Proliferator-Activated Receptors, Peroxisome
Receptors, Peroxisome Proliferator-Activated
peroxisome proliferator activated receptor
peroxisome proliferator activated receptor (PPAR)
Peroxisome Proliferator-Activated Receptors
Core Binding Factors [Chemical/Ingredient]
E2F Transcription Factors [Chemical/Ingredient]
NFATC Transcription Factors [Chemical/Ingredient]
Nuclear Factor of Activated T Cells, Cytoplasmic
Nuclear Factor of Activated T-Cells, Cytoplasmic
Inhibitor of Differentiation Proteins [Chemical/Ingredient]
Small Ubiquitin Related Modifier Proteins
Small Ubiquitin-Related Modifier Proteins [Chemical/Ingredient]
Ubiquitin Related Modifier Protein, Small
Ubiquitin-Related Modifier Protein, Small
Small Ubiquitin-Related Modifier Proteins
Retroviridae Proteins [Chemical/Ingredient]
Gene Products, gag [Chemical/Ingredient]
Gene Products, pol [Chemical/Ingredient]
Gene Products, env [Chemical/Ingredient]
Viral Structural Proteins [Chemical/Ingredient]
Hemagglutinins, Viral [Chemical/Ingredient]
Viral Regulatory and Accessory Proteins [Chemical/Ingredient]
Immediate-Early Proteins [Chemical/Ingredient]
Protozoan Proteins [Chemical/Ingredient]
Cell Cycle Proteins [Chemical/Ingredient]
geminin, DNA replication inhibitor protein, human
Pituitary Tumor-Transforming Gene 1 Protein
Molecular Chaperones [Chemical/Ingredient]
Heat-Shock Proteins [Chemical/Ingredient]
Histone Chaperones [Chemical/Ingredient]
Photoreceptors, Microbial [Chemical/Ingredient]
Rhodopsins, Microbial [Chemical/Ingredient]
Antifreeze Proteins [Chemical/Ingredient]
Antifreeze Proteins, Type IV [Chemical/Ingredient]
Antifreeze Proteins, Type I [Chemical/Ingredient]
Antifreeze Proteins, Type II [Chemical/Ingredient]
Antifreeze Proteins, Type III [Chemical/Ingredient]
Mitochondrial Proteins [Chemical/Ingredient]
Seminal Plasma Proteins [Chemical/Ingredient]
Prostatic Secretory Proteins [Chemical/Ingredient]
Seminal Vesicle Secretory Proteins [Chemical/Ingredient]
Epididymal Secretory Proteins [Chemical/Ingredient]
Iron-Regulatory Proteins [Chemical/Ingredient]
Wingless-Type MMTV Integration Site Family Member 4 Protein
wingless-type MMTV integration site family, member 4 protein, human
Pulmonary Surfactant Associated Protein A
Pulmonary Surfactant-Associated Protein A [Chemical/Ingredient]
Pulmonary Surfactant-Associated Protein A
Pulmonary Surfactant Associated Protein D
Pulmonary Surfactant-Associated Protein D [Chemical/Ingredient]
Surfactant pulmonary-associated protein D
Pulmonary Surfactant-Associated Protein D
Mannose-Binding Lectins [Chemical/Ingredient]
Sialic Acid Binding Immunoglobulin like Lectins
Sialic Acid Binding Immunoglobulin-like Lectins [Chemical/Ingredient]
Sialic Acid Binding Immunoglobulin-like Lectins
Pulmonary Surfactant Associated Proteins
Pulmonary Surfactant Associated Proteolipid
Mutant Chimeric Proteins [Chemical/Ingredient]
Selenium-Binding Proteins [Chemical/Ingredient]
Fanconi Anemia Complementation Group Protein
Fanconi Anemia Complementation Group Proteins [Chemical/Ingredient]
Fanconi Anemia Complementation Group C Protein [Chemical/Ingredient]
Fanconi Anemia Group C Complementing Protein
Fanconi Anemia Complementation Group C Protein
TISSUE INHIBITOR 99 OF METALLOPROTEINASES
Tissue Inhibitor of Metalloproteinases [Chemical/Ingredient]
tissue inhibitor of metalloproteinase (TIM)
Immobilized Proteins [Chemical/Ingredient]
Ubiquitinated Proteins [Chemical/Ingredient]
LIM Domain Proteins [Chemical/Ingredient]
Protein Degradation End Products [Chemical/Ingredient]
Glycosylation End Products, Advanced [Chemical/Ingredient]
Advanced Oxidation Protein Products [Chemical/Ingredient]
Advanced oxidation protein products (substance)
CRISPR-Associated Proteins [Chemical/Ingredient]
Intrinsically Disordered Proteins [Chemical/Ingredient]
Nucleic Acids, Nucleosides, and Nucleotides
Nucleic Acids, Nucleotides, and Nucleosides [Chemical/Ingredient]
Nucleic Acid Precursors [Chemical/Ingredient]
DNA Transposable Elements [Chemical/Ingredient]
DNA, Single-Stranded [Chemical/Ingredient]
Deoxyribonucleic acid, single stranded (substance)
Oligodeoxyribonucleotides, Antisense [Chemical/Ingredient]
Nucleic Acid Heteroduplexes [Chemical/Ingredient]
RNA, Double-Stranded [Chemical/Ingredient]
Ribonucleic acid, double stranded (substance)
RNA, Small Interfering [Chemical/Ingredient]
RNA, Complementary [Chemical/Ingredient]
Nucleic Acid Probes [Chemical/Ingredient]
Reagents, Molecular Assay, Nucleic Acid Probe
Reagents, Molecular Assay, Nucleic Acid Probe, DNA
Oligonucleotide Probes [Chemical/Ingredient]
Reagents, Molecular Assay, Nucleic Acid Probe, RNA
Antisense Elements (Genetics) [Chemical/Ingredient]
Oligonucleotides, Antisense [Chemical/Ingredient]
Immobilized Nucleic Acids [Chemical/Ingredient]
Arabinonucleosides [Chemical/Ingredient]
Deoxyribonucleosides [Chemical/Ingredient]
Dideoxynucleosides [Chemical/Ingredient]
1H-Benzimidazole, 5,6-dichloro-1-beta-D-ribofuranosyl-
5,6 Dichloro 1 beta D ribofuranosyl 1 H benzimidazol
5,6 Dichloro 1 beta ribofuranosylbenzimidazole
Dichlororibofuranosylbenzimidazole [Chemical/Ingredient]
1-.beta.-D-Ribofuranosyl-1H-1,2, 4-triazole-3-carboxamide
1H-1,2,4-Triazole-3-carboxamide, 1-beta-D-ribofuranosyl-
1H-Pyrrole-2,5-dione, 3-beta-D-ribofuranosyl-
7H-Pyrrolo(2,3-d)pyrimidine-5-carbonitrile, 4-amino-7-beta-D-ribofuranosyl-
Arabinonucleotides [Chemical/Ingredient]
Deoxyribonucleotides [Chemical/Ingredient]
Nucleotides, Cyclic [Chemical/Ingredient]
Polydeoxyribonucleotides [Chemical/Ingredient]
Polyribonucleotides [Chemical/Ingredient]
Nicotinamide Mononucleotide [Chemical/Ingredient]
Pyridinium, 3-(aminocarbonyl)-1-(5-O-phosphono-beta-D-ribofuranosyl)-, inner salt
Dinucleoside Phosphates [Chemical/Ingredient]
Dideoxynucleotides [Chemical/Ingredient]
Bacterial Vaccines [Chemical/Ingredient]
Vaccines, Attenuated [Chemical/Ingredient]
Vaccines, Conjugate [Chemical/Ingredient]
Vaccines, Inactivated [Chemical/Ingredient]
Protozoan Vaccines [Chemical/Ingredient]
Vaccines, Combined [Chemical/Ingredient]
Vaccines, Contraceptive [Chemical/Ingredient]
Alzheimer Vaccines [Chemical/Ingredient]
Vaccines, Live, Unattenuated [Chemical/Ingredient]
Biosimilar Pharmaceuticals [Chemical/Ingredient]
Pancreatic Extracts [Chemical/Ingredient]
Placental Extracts [Chemical/Ingredient]
Damage Associated Molecular Pattern Molecules
Damage-Associated Molecular Pattern Molecule
Damage-Associated Molecular Pattern Molecules
Molecules, Pathogen Associated Molecular Pattern
Molecules, Pathogen-Associated Molecular Pattern
Pathogen Associated Molecular Pattern Molecules
Pathogen-Associated Molecular Pattern Molecules [Chemical/Ingredient]
Pathogen-Associated Molecular Pattern Molecules
Antigens, Cancer-Associated Carbohydrate
Antigens, Carbohydrate, Tumor-Associated
Antigens, Tumor-Associated, Carbohydrate
Immunodominant Epitopes [Chemical/Ingredient]
Epitopes, T-Lymphocyte [Chemical/Ingredient]
Antigens, Bacterial [Chemical/Ingredient]
Mycobacterium tuberculosis purified protein derivative
Purified Protein Derivative of Tuberculin
Purified Protein Derivative of Tuberculin [Chemical/Ingredient]
Antigens, Neoplasm [Chemical/Ingredient]
Antigens, Viral, Tumor [Chemical/Ingredient]
Antigens, Protozoan [Chemical/Ingredient]
Antigens, Differentiation [Chemical/Ingredient]
Antigens, Differentiation, B-Lymphocyte [Chemical/Ingredient]
Antigens, Differentiation, T-Lymphocyte [Chemical/Ingredient]
Antigens, Differentiation, Myelomonocytic [Chemical/Ingredient]
Antigens, Myelomonocytic Differentiation
Antigens, Myelomonocytic, Differentiation
Differentiation Antigens, Myelomonocytic
Antigens, Differentiation, Myelomonocytic
CD - Cluster of differentiation antigen marker
Stage-Specific Embryonic Antigens [Chemical/Ingredient]
Blood Group Antigens [Chemical/Ingredient]
Histocompatibility Antigens [Chemical/Ingredient]
Determinants, Minor Lymphocyte-Stimulating
Antigens, T-Independent [Chemical/Ingredient]
Deltaretrovirus Antigens [Chemical/Ingredient]
Hepatitis Antigens [Chemical/Ingredient]
Epstein-Barr Virus Nuclear Antigens [Chemical/Ingredient]
Epstein-Barr virus nuclear antigen (substance)
Heymann Nephritis Antigenic Complex [Chemical/Ingredient]
RECEPT ASSOCIATED PROTEIN HEYMANN NEPHRITIS
Receptor Associated Protein, Heymann Nephritis
Receptor-Associated Protein, Heymann Nephritis
Antigens, Human Platelet [Chemical/Ingredient]
Antigens, Heterophile [Chemical/Ingredient]
Antigens, Archaeal [Chemical/Ingredient]
Chemotactic Factors [Chemical/Ingredient]
Chemotactic Factors, Eosinophil [Chemical/Ingredient]
Eosinophilic chemotactic factor (substance)
Pigments, Biological [Chemical/Ingredient]
Toxins, Biological [Chemical/Ingredient]
Virulence Factors, Bordetella [Chemical/Ingredient]
Biomarkers, Pharmacological [Chemical/Ingredient]
Inflammation Mediators [Chemical/Ingredient]
Blood Coagulation Factor Inhibitors [Chemical/Ingredient]
Host-Derived Cellular Factors [Chemical/Ingredient]
Biomedical and Dental Materials [Chemical/Ingredient]
Biocompatible Materials [Chemical/Ingredient]
Coated Materials, Biocompatible [Chemical/Ingredient]
Cariostatic Agents [Chemical/Ingredient]
Dental Casting Investment [Chemical/Ingredient]
Glass Ionomer Cements [Chemical/Ingredient]
Polycarboxylate Cement [Chemical/Ingredient]
Zinc Oxide-Eugenol Cement [Chemical/Ingredient]
Zinc oxide eugenol dental cement (substance)
Zinc Phosphate Cement [Chemical/Ingredient]
Zinc phosphate dental cement (substance)
Dentin-Bonding Agents [Chemical/Ingredient]
Dental Impression Materials [Chemical/Ingredient]
Dental impression material (physical object)
Dental materials and fillings, porcelain
Pit and Fissure Sealants [Chemical/Ingredient]
Root Canal Filling Materials [Chemical/Ingredient]
Pulp Capping and Pulpectomy Agents [Chemical/Ingredient]
Photoinitiators, Dental [Chemical/Ingredient]
Unilamellar Liposomes [Chemical/Ingredient]
Root Canal Irrigants [Chemical/Ingredient]
Pharmaceutical Preparations, Dental [Chemical/Ingredient]
Combined oral contraceptive product (product)
Combined oral contraceptive product (substance)
Cold, Flu, and Allergy Medications, Multi-Ingredient
Multi-Ingredient Cold, Flu, and Allergy Medications
Molecular Mechanisms of Pharmacological Action
Organ Preservative Organ preservation solution
Organ preservation solution (qualifier value)
CVS Long Lasting Lubricant Eye Twin Pack
Metabolic Side Effects of Drugs and Substances
Antidiuretic Hormone Receptor Antagonists
Endothelin receptor antagonist (product)
Endothelin receptor antagonist (substance)
Centrally acting muscle relaxant (product)
Centrally acting muscle relaxant (substance)
MUSCLE RELAXANTS, CENTRALLY ACTING AGENTS
840 MISCELLANEOUS GASTROINTESTINAL DRUGS
Drug groups primarily affecting the gastro-intestinal system
Metabolic Side Effects of Drugs and Substances [Disease/Finding]
Nerve agent - chemical warfare agent (substance)
Heterogeneous nuclear ribonucleic acid (substance)
RNA, Heterogeneous Nuclear [Chemical/Ingredient]
Mitochondrial ribonucleic acid (substance)
RNA, Small Nuclear [Chemical/Ingredient]
RNA, Small Nucleolar [Chemical/Ingredient]
Chromosome inversion (morphologic abnormality)
Chromosomal translocation (morphologic abnormality)