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137aadd47545f6c334d6017a159c75cc9788190a

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H5N2

H5N2 H5N2 is a subtype of the species Influenzavirus A (avian influenza virus or bird flu virus). A highly pathogenic strain of H5N2 caused flu outbreaks with significant spread to numerous farms, resulting in great economic losses in 1983 in Pennsylvania, USA in chickens and turkeys, in 1994 in Mexico in chickens and a minor outbreak in 1997 in Italy in chickens. It was reported on November 12, 2005 that "One of 2 birds found infected with bird flu in Kuwait has the H5N1 strain of the virus, authorities said. The infected bird was a migrating flamingo found on a Kuwait beach. The other was an imported falcon found to have the milder H5N2 variant." In China, inactivated H5N2 has been used as a vaccine for H5N1. Japan's Health Ministry said May 11, 2006 that 93 poultry farm workers near Tokyo may have been exposed to H5N2 (which was not previously known to infect humans) in 2005. "Preliminary tests on the workers were positive for H5N2 antibodies, indicating they were previously exposed, Takimoto said. While exposure carries with it the possibility of infection and illness, he said none had tested positive for the virus itself or had developed flu symptoms. About 5.7 million birds have been destroyed in Ibaraki following the H5N2 outbreaks." In 2006, an H5N2 outbreak on a single farm in South Africa resulted in the destruction of all its sixty ostriches. The strain was similar to the one that caused outbreaks in South Africa 2004/2005. In 2007, a low-pathogenic strain of H5N2 was found in samples collected from 25,000 turkeys in Pendleton County, West Virginia in a routine testing prior to their slaughter. The birds showed no sign of illness or mortality. Measures were taken to prevent the virus from mutating and spreading. In late 2007 (December 21), an H5N2 outbreak was found in the Dominican Republic, in a Suburb of Higuey City, on the eastern side of the island. 15 roosters and 2 hens where eliminated even though they had no visible sign of infection. # Sources - ↑ WHO - ↑ article Kuwait: Avian influenza H5N1 confirmed case in flamingo November 12, 2005 - ↑ people.com.cn - ↑ article Japan workers may have been exposed to flu published May 12, 2006 - ↑ Mail&Guardian South African online news article Outbreak of avian flu in W Cape not H5N1 published 03 July 2006 - ↑ Regional News Service article Bird Flu Found in Pendleton County published April 3, 2007 - ↑ Listin Diario Article"Detectan virus gripe aviar en Higüey y Santo Domingo" In Spanish nl:H5N2

H5N2 Template:Flu H5N2 is a subtype of the species Influenzavirus A (avian influenza virus or bird flu virus). A highly pathogenic strain of H5N2 caused flu outbreaks with significant spread to numerous farms, resulting in great economic losses in 1983 in Pennsylvania, USA in chickens and turkeys, in 1994 in Mexico in chickens and a minor outbreak in 1997 in Italy in chickens. [1] It was reported on November 12, 2005 that "One of 2 birds found infected with bird flu in Kuwait has the H5N1 strain of the virus, authorities said. The infected bird was a migrating flamingo found on a Kuwait beach. The other was an imported falcon found to have the milder H5N2 variant."[2] In China, inactivated H5N2 has been used as a vaccine for H5N1. [3] Japan's Health Ministry said May 11, 2006 that 93 poultry farm workers near Tokyo may have been exposed to H5N2 (which was not previously known to infect humans) in 2005. "Preliminary tests on the workers were positive for H5N2 antibodies, indicating they were previously exposed, Takimoto said. While exposure carries with it the possibility of infection and illness, he said none had tested positive for the virus itself or had developed flu symptoms. [...] About 5.7 million birds have been destroyed in Ibaraki following the H5N2 outbreaks."[4] In 2006, an H5N2 outbreak on a single farm in South Africa resulted in the destruction of all its sixty ostriches. The strain was similar to the one that caused outbreaks in South Africa 2004/2005. [5] In 2007, a low-pathogenic strain of H5N2 was found in samples collected from 25,000 turkeys in Pendleton County, West Virginia in a routine testing prior to their slaughter. The birds showed no sign of illness or mortality. Measures were taken to prevent the virus from mutating and spreading.[6] In late 2007 (December 21), an H5N2 outbreak was found in the Dominican Republic, in a Suburb of Higuey City, on the eastern side of the island. 15 roosters and 2 hens where eliminated even though they had no visible sign of infection. [7] # Sources - ↑ WHO - ↑ [1] article Kuwait: Avian influenza H5N1 confirmed case in flamingo November 12, 2005 - ↑ people.com.cn - ↑ [2] article Japan workers may have been exposed to flu published May 12, 2006 - ↑ Mail&Guardian South African online news article Outbreak of avian flu in W Cape not H5N1 published 03 July 2006 - ↑ Regional News Service article Bird Flu Found in Pendleton County published April 3, 2007 - ↑ [3] Listin Diario Article"Detectan virus gripe aviar en Higüey y Santo Domingo" In Spanish nl:H5N2 Template:WikiDoc Sources

https://www.wikidoc.org/index.php/H5N2

c8710abf64c59bc2329f901b27d9b1359b8fc352

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H5N8

H5N8 H5N8 is a subtype of the species Influenza A virus (sometimes called bird flu virus). A highly pathogenic strain of it called A/turkey/Ireland/1378/83 caused a minor flu outbreak in 1983 in Ireland in turkeys. # Sources - ↑ "Avian influenza A(H5N1)- update 31: Situation (poultry) in Asia: need for a long-term response, comparison with previous outbreaks". Epidemic and Pandemic Alert and Response. World Health Organization. 2004-03-02. Retrieved 2007-11-04..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Scientific Committee on Animal Health and Animal Welfare (2006-06-27). "The Definition of Avian Influenza : The use of Vaccination against Avian Influenza" (pdf). European Commission, Health & Consumer Protection Directorate-General. Retrieved 2007-11-04. # Further reading - Walker JA, Kawaoka Y (1993). "Importance of conserved amino acids at the cleavage site of the haemagglutinin of a virulent avian influenza A virus". J. Gen. Virol. 74 ( Pt 2): 311–4. PMID 8429306. |access-date= requires |url= (help)

H5N8 Template:Flu H5N8 is a subtype of the species Influenza A virus (sometimes called bird flu virus). A highly pathogenic strain of it called A/turkey/Ireland/1378/83 caused a minor flu outbreak in 1983 in Ireland in turkeys.[1][2] # Sources - ↑ "Avian influenza A(H5N1)- update 31: Situation (poultry) in Asia: need for a long-term response, comparison with previous outbreaks". Epidemic and Pandemic Alert and Response. World Health Organization. 2004-03-02. Retrieved 2007-11-04..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Scientific Committee on Animal Health and Animal Welfare (2006-06-27). "The Definition of Avian Influenza : The use of Vaccination against Avian Influenza" (pdf). European Commission, Health & Consumer Protection Directorate-General. Retrieved 2007-11-04. # Further reading - Walker JA, Kawaoka Y (1993). "Importance of conserved amino acids at the cleavage site of the haemagglutinin of a virulent avian influenza A virus". J. Gen. Virol. 74 ( Pt 2): 311–4. PMID 8429306. |access-date= requires |url= (help) Template:WikiDoc Sources

https://www.wikidoc.org/index.php/H5N8

93d41ff2f94c5fd7724574ce0f244d9d59f3cc96

wikidoc

H7N2

H7N2 H7N2 is a subtype of the species Influenza A virus (sometimes called bird flu virus). # Outbreaks of H7N2 One person Virginia, US in 2002 and one person in New York, US, in 2003 were found to have serologic evidence of infection from H7N2; both fully recovered. In February 2004, an outbreak of low pathogenic avian influena (LPAI) A (H7N2) was reported on 2 chicken farms in Delaware and in four live bird markets in New Jersey supplied by the same farms. In March 2004, surveillance samples from a flock of chickens in Maryland tested positive for LPAI H7N2. It is likely that this was the same strain. A CDC study following the 2002 outbreaks of H7N2 in commercial poultry farms in western Virginia concluded: On 24 May 2007, an outbreak of H7N2 was confirmed at a poultry farm near Corwen, in Wales from tests on chickens that died from H7N2. The owners of the Conwy farm bought 15 Rhode Island Red chickens two weeks prior but all died from H7N2. The 32 other poultry at the site were slaughtered. A one kilometer exclusion zone was put in force around the property in which birds and bird products cannot be moved and bird gathering can only take place under licence. Nine people who were associated with the infected or dead poultry and reported flu-like symptoms were tested. Four tested positive for evidence of infection from H7N2 and were successfully treated for mild flu. In early June it was discovered that the virus had spread to a poultry farm 70 miles (113 km) away near St. Helens in north-west England. All the poultry at the farm were slaughtered and a 1 km exclusion zone imposed. # Sources - ↑ CDC - ↑ flu research - ↑ BBC physorg - ↑ Scotsman News article Mild bird flu virus spreads to north-west England June 8, 2007 - CDC avian flu information # Further reading - Research Update on H7n2 Avian Influenza Virus in Turkeys and Chickens - Epidemiology of an H7N2 Avian Influenza Outbreak in Broilers in Pennsylvania in November 2001- January 2002 - Avian influenza H7N2 in Wales and the Northwest of England - North Wales bird flu outbreak ends

H7N2 H7N2 is a subtype of the species Influenza A virus (sometimes called bird flu virus). # Outbreaks of H7N2 One person Virginia, US in 2002 and one person in New York, US, in 2003 were found to have serologic evidence of infection from H7N2; both fully recovered. In February 2004, an outbreak of low pathogenic avian influena (LPAI) A (H7N2) was reported on 2 chicken farms in Delaware and in four live bird markets in New Jersey supplied by the same farms. In March 2004, surveillance samples from a flock of chickens in Maryland tested positive for LPAI H7N2. It is likely that this was the same strain. [1] A CDC study following the 2002 outbreaks of H7N2 in commercial poultry farms in western Virginia concluded: On 24 May 2007, an outbreak of H7N2 was confirmed at a poultry farm near Corwen, in Wales from tests on chickens that died from H7N2. The owners of the Conwy farm bought 15 Rhode Island Red chickens two weeks prior but all died from H7N2. The 32 other poultry at the site were slaughtered. A one kilometer exclusion zone was put in force around the property in which birds and bird products cannot be moved and bird gathering can only take place under licence. Nine people who were associated with the infected or dead poultry and reported flu-like symptoms were tested. Four tested positive for evidence of infection from H7N2 and were successfully treated for mild flu.[3] In early June it was discovered that the virus had spread to a poultry farm 70 miles (113 km) away near St. Helens in north-west England. All the poultry at the farm were slaughtered and a 1 km exclusion zone imposed.[4] # Sources - ↑ CDC - ↑ flu research - ↑ BBC physorg - ↑ Scotsman News article Mild bird flu virus spreads to north-west England June 8, 2007 - CDC avian flu information # Further reading - Research Update on H7n2 Avian Influenza Virus in Turkeys and Chickens - Epidemiology of an H7N2 Avian Influenza Outbreak in Broilers in Pennsylvania in November 2001- January 2002 - Avian influenza H7N2 in Wales and the Northwest of England - North Wales bird flu outbreak ends Template:WikiDoc Sources

https://www.wikidoc.org/index.php/H7N2

7061362ff23a56cfb2f18791073b2cdb99ed5d17

wikidoc

H7N3

H7N3 H7N3 is a subtype of the species Influenza A virus (sometimes called bird flu virus). In North America, the presence of H7N3 was confirmed at several poultry farms in British Columbia in February 2004. As of April 2004, 18 farms had been quarantined to halt the spread of the virus. Two cases of humans infected with it have been confirmed in that region. Symptoms included conjunctivitis and mild influenza-like illness. Both fully recovered. "The H7N3 strain was first detected in turkeys in Britain in 1963 and made one of its last known appearances in poultry in Canada in April and May 2004, according to the WHO and World Organisation for Animal Health. An outbreak of the less virulent H5N2 strain of bird flu in Taiwan in 2004 led to the culling of hundreds of thousands of fowl." "Taiwan found a highly pathogenic strain of avian flu, H7N3, in droppings left by a migratory bird and is carrying out tests to see whether the virus has spread to nearby poultry farms, the agriculture department said 14 November 2005." For the first time since 1979, H7N3 was found in the UK in April 2006. It infected birds and one poultry worker (whose only symptom was conjunctivitis) in a Norfolk, England Witford Lodge Farm. "Antiviral Tamiflu was administered to poultry workers on the farm as a precautionary measure. 35,000 chickens will be culled in the infected farm and a 1 kilometre exclusion zone has been placed." In September 27, 2007 another outbreak of H7N3 was detected in a poultry operation in Saskatchewan, Canada. The Canadian Food Inspection Agency has requested the euthanization of the flock, and the disinfection of all building, materials and equipment in contact with the birds or their droppings. # Sources - ↑ Washington.edu - ↑ Washington.edu - ↑ Medical News Today article Norfolk Poultry Worker Contracts H7N3 Bird Flu Strain, UK published April 28, 2006 - CDC detailed analysis - CDC - Novel Avian Influenza H7N3 Strain Outbreak, British Columbia # Further reading - Comparative Pathobiology of Low and High Pathogenicity H7N3 Chilean Avian Influenza Viruses in Chickens de:Influenzavirus A/H7N3

H7N3 Template:Flu H7N3 is a subtype of the species Influenza A virus (sometimes called bird flu virus). In North America, the presence of H7N3 was confirmed at several poultry farms in British Columbia in February 2004. As of April 2004, 18 farms had been quarantined to halt the spread of the virus. Two cases of humans infected with it have been confirmed in that region. Symptoms included conjunctivitis and mild influenza-like illness. Both fully recovered. "The H7N3 strain was first detected in turkeys in Britain in 1963 and made one of its last known appearances in poultry in Canada in April and May 2004, according to the WHO and World Organisation for Animal Health. An outbreak of the less virulent H5N2 strain of bird flu in Taiwan in 2004 led to the culling of hundreds of thousands of fowl." [1] "Taiwan found a highly pathogenic strain of avian flu, H7N3, in droppings left by a migratory bird and is carrying out tests to see whether the virus has spread to nearby poultry farms, the agriculture department said 14 November 2005." [2] For the first time since 1979, H7N3 was found in the UK in April 2006. It infected birds and one poultry worker (whose only symptom was conjunctivitis) in a Norfolk, England Witford Lodge Farm. "Antiviral Tamiflu was administered to poultry workers on the farm as a precautionary measure. [...] 35,000 chickens will be culled in the infected farm and a 1 kilometre exclusion zone has been placed."[3] In September 27, 2007 another outbreak of H7N3 was detected in a poultry operation in Saskatchewan, Canada. The Canadian Food Inspection Agency has requested the euthanization of the flock, and the disinfection of all building, materials and equipment in contact with the birds or their droppings. # Sources - ↑ Washington.edu - ↑ Washington.edu - ↑ Medical News Today article Norfolk Poultry Worker Contracts H7N3 Bird Flu Strain, UK published April 28, 2006 - CDC detailed analysis - CDC - Novel Avian Influenza H7N3 Strain Outbreak, British Columbia # Further reading - Comparative Pathobiology of Low and High Pathogenicity H7N3 Chilean Avian Influenza Viruses in Chickens de:Influenzavirus A/H7N3 Template:WikiDoc Sources

https://www.wikidoc.org/index.php/H7N3

ee1a2f8c13c530b2bd593d7741478b56a17ef940

wikidoc

HARS

HARS Histidyl-tRNA synthetase (HARS) also known as histidine-tRNA ligase, is an enzyme which in humans is encoded by the HARS gene. # Function Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is a cytoplasmic enzyme which belongs to the class II family of aminoacyl tRNA synthetases. The enzyme is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. The gene is located in a head-to-head orientation with HARSL on chromosome five, where the homologous genes share a bidirectional promoter. # Clinical significance The gene product is a frequent target of autoantibodies in the human autoimmune disease polymyositis/dermatomyositis. # Interactions HARS has been shown to interact with EEF1B2 and EEF1G.

HARS Histidyl-tRNA synthetase (HARS) also known as histidine-tRNA ligase, is an enzyme which in humans is encoded by the HARS gene.[1][2] # Function Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is a cytoplasmic enzyme which belongs to the class II family of aminoacyl tRNA synthetases. The enzyme is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins.[3] The gene is located in a head-to-head orientation with HARSL on chromosome five, where the homologous genes share a bidirectional promoter.[1] # Clinical significance The gene product is a frequent target of autoantibodies in the human autoimmune disease polymyositis/dermatomyositis.[3] # Interactions HARS has been shown to interact with EEF1B2[4] and EEF1G.[4]

https://www.wikidoc.org/index.php/HARS

b3475c2d92b6a2dcb2607d3dd68ee525f0a21977

wikidoc

HAS1

HAS1 Hyaluronan synthase 1 is an enzyme that in humans is encoded by the HAS1 gene. # Structure Hyaluronan or hyaluronic acid (HA) is a high molecular weight unbranched polysaccharide synthesized by a wide variety of organisms from bacteria to mammals, and is a constituent of the extracellular matrix. It consists of alternating glucuronic acid and N-acetylglucosamine residues that are linked by beta-1-3 and beta-1-4 glycosidic bonds. HA is synthesized by membrane-bound synthase at the inner surface of the plasma membrane, and the chains are extruded via ABC-transporter into the extracellular space. # Function It serves a variety of functions, including space filling, lubrication of joints, and provision of a matrix through which cells can migrate. HA is actively produced during wound healing and tissue repair to provide a framework for ingrowth of blood vessels and fibroblasts. Changes in the serum concentration of HA are associated with inflammatory and degenerative arthropathies such as rheumatoid arthritis. In addition, the interaction of HA with the leukocyte receptor CD44 is important in tissue-specific homing by leukocytes, and overexpression of HA receptors has been correlated with tumor metastasis. HAS1 is a member of the newly identified vertebrate gene family encoding putative hyaluronan synthases, and its amino acid sequence shows significant homology to the hasA gene product of Streptococcus pyogenes, a glycosaminoglycan synthetase (DG42) from Xenopus laevis, and a recently described murine hyaluronan synthase.

HAS1 Hyaluronan synthase 1 is an enzyme that in humans is encoded by the HAS1 gene.[1][2] # Structure Hyaluronan or hyaluronic acid (HA) is a high molecular weight unbranched polysaccharide synthesized by a wide variety of organisms from bacteria to mammals, and is a constituent of the extracellular matrix. It consists of alternating glucuronic acid and N-acetylglucosamine residues that are linked by beta-1-3 and beta-1-4 glycosidic bonds. HA is synthesized by membrane-bound synthase at the inner surface of the plasma membrane, and the chains are extruded via ABC-transporter into the extracellular space.[3] # Function It serves a variety of functions, including space filling, lubrication of joints, and provision of a matrix through which cells can migrate. HA is actively produced during wound healing and tissue repair to provide a framework for ingrowth of blood vessels and fibroblasts. Changes in the serum concentration of HA are associated with inflammatory and degenerative arthropathies such as rheumatoid arthritis. In addition, the interaction of HA with the leukocyte receptor CD44 is important in tissue-specific homing by leukocytes, and overexpression of HA receptors has been correlated with tumor metastasis. HAS1 is a member of the newly identified vertebrate gene family encoding putative hyaluronan synthases, and its amino acid sequence shows significant homology to the hasA gene product of Streptococcus pyogenes, a glycosaminoglycan synthetase (DG42) from Xenopus laevis, and a recently described murine hyaluronan synthase.[2]

https://www.wikidoc.org/index.php/HAS1

1f0997b06e9bff578e8ee36fb4f62f9c44ed2ae7

wikidoc

HATS

HATS # Objective To assess the effects of lipid-lowering drugs and/or antioxidant vitamins on progression or regression of coronary heart disease as measured by quantitative angiography in patients with low high density lipoprotein (HDL) cholesterol. # Methods HDL-Atherosclerosis Treatment Study (HATS) was a randomized, 2 x 2 factorial study wherein 160 patients, both men and women with low HDL cholesterol, with at least one 50% stenotic coronary lesion or three 30% stenotic coronary lesions were enrolled. All the patients were randomized into four groups which were simvastatin (10-20g/day) plus niacin (2-4g/day), antioxidant vitamins (vitamins E, C, A and selenium), simvastatin-niacin plus antioxidants; or placebos. The primary end points were arteriographic evidence of a change in coronary stenosis and the occurrence of a first cardiovascular event (death, myocardial infarction, stroke, or revascularization). Coronary angiograms were done at baseline and at three years to assess the change. # Results - In the simvastatin-niacin group mean LDL-C was reduced by 42% and mean HDL-C was increased by 26% while levels of LDL-C and HDL-C in the antioxidants and placebo groups remained unaltered. - The rate of progression of coronary stenoses was lower in the simvastatin-niacin group compared to the other groups. - Patients receiving simvastatin and niacin sustained lower cardiovascular events. - Antioxidant vitamins alone had no benefit on progression or on clinical events. # Conclusion Addition of a drug that increases HDL-C levels to a statin proves to have additional protection over just statin alone.

HATS Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Objective To assess the effects of lipid-lowering drugs and/or antioxidant vitamins on progression or regression of coronary heart disease as measured by quantitative angiography in patients with low high density lipoprotein (HDL) cholesterol. # Methods HDL-Atherosclerosis Treatment Study (HATS) was a randomized, 2 x 2 factorial study wherein 160 patients, both men and women with low HDL cholesterol, with at least one 50% stenotic coronary lesion or three 30% stenotic coronary lesions were enrolled. All the patients were randomized into four groups which were simvastatin (10-20g/day) plus niacin (2-4g/day), antioxidant vitamins (vitamins E, C, A and selenium), simvastatin-niacin plus antioxidants; or placebos. The primary end points were arteriographic evidence of a change in coronary stenosis and the occurrence of a first cardiovascular event (death, myocardial infarction, stroke, or revascularization). Coronary angiograms were done at baseline and at three years to assess the change. # Results - In the simvastatin-niacin group mean LDL-C was reduced by 42% and mean HDL-C was increased by 26% while levels of LDL-C and HDL-C in the antioxidants and placebo groups remained unaltered. - The rate of progression of coronary stenoses was lower in the simvastatin-niacin group compared to the other groups. - Patients receiving simvastatin and niacin sustained lower cardiovascular events. - Antioxidant vitamins alone had no benefit on progression or on clinical events. # Conclusion Addition of a drug that increases HDL-C levels to a statin proves to have additional protection over just statin alone.[1]

https://www.wikidoc.org/index.php/HATS

a15b109db25438de54a06c50eb5e2292007d7ccb

wikidoc

HAX1

HAX1 HCLS1-associated protein X-1 is a protein that in humans is encoded by the HAX1 gene. The protein encoded by this gene is known to associate with HS1, a substrate of Src family tyrosine kinases. It also interacts with the product of PKD2 gene, mutations in which are associated with autosomal-dominant polycystic kidney disease, and with F-actin-binding protein, cortactin. It was earlier thought that this gene product is mainly localized in the mitochondria, however, recent studies indicate it to be localized in the cell body. Two transcript variants encoding different isoforms have been found for this gene. In 2015, localization of the protein to P-bodies was demonstrated. # Severe congenital neutropenia Homozygous mutations in HAX1 are associated with autosomal recessive severe congenital neutropenia, also known as Kostmann syndrome. # Interactions HAX1 has been shown to interact with IL1A. The protein has also been shown to interact with the 3' untranslated regions of vimentin and DNA polymerase B transcripts.

HAX1 HCLS1-associated protein X-1 is a protein that in humans is encoded by the HAX1 gene.[1][2][3] The protein encoded by this gene is known to associate with HS1, a substrate of Src family tyrosine kinases. It also interacts with the product of PKD2 gene, mutations in which are associated with autosomal-dominant polycystic kidney disease, and with F-actin-binding protein, cortactin. It was earlier thought that this gene product is mainly localized in the mitochondria, however, recent studies indicate it to be localized in the cell body. Two transcript variants encoding different isoforms have been found for this gene.[3] In 2015, localization of the protein to P-bodies was demonstrated.[4] # Severe congenital neutropenia Homozygous mutations in HAX1 are associated with autosomal recessive severe congenital neutropenia,[5] also known as Kostmann syndrome. # Interactions HAX1 has been shown to interact with IL1A.[6] The protein has also been shown to interact with the 3' untranslated regions of vimentin and DNA polymerase B transcripts.[4]

https://www.wikidoc.org/index.php/HAX1

e479265a90886412b0ffbe4bcb1ecbe4c15f77b6

wikidoc

HBA1

HBA1 Hemoglobin, alpha 1, also known as HBA1, is a human gene encoding the hemoglobin protein. "The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with HbF (fetal hemoglobin) makes up the remaining 3% of adult hemoglobin. Alpha thalassemias result from deletions of each of the alpha genes as well as deletions of both HBA2 and HBA1; some nondeletion alpha thalassemias have also been reported." # Gene ## Transcriptions "The 3' flanking area contained the highly conserved hexanucleotide sequence A-A-T-A-A-A found in eukaryotic messages between the terminator codon and the polyadenylylation site (44)."

HBA1 Associate Editor(s)-in-Chief: Henry A. Hoff Hemoglobin, alpha 1, also known as HBA1, is a human gene encoding the hemoglobin protein. "The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with HbF (fetal hemoglobin) makes up the remaining 3% of adult hemoglobin. Alpha thalassemias result from deletions of each of the alpha genes as well as deletions of both HBA2 and HBA1; some nondeletion alpha thalassemias have also been reported."[1] # Gene ## Transcriptions "The 3' flanking area contained the highly conserved hexanucleotide sequence A-A-T-A-A-A found in eukaryotic messages between the terminator codon and the polyadenylylation site (44)."[2]

https://www.wikidoc.org/index.php/HBA1

f4ba1938e805a118db1c90da174520b39aa6c4b0

wikidoc

HCN1

HCN1 Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 is a protein that in humans is encoded by the HCN1 gene. # Function Hyperpolarization-activated cation channels of the HCN gene family, such as HCN1, contribute to spontaneous rhythmic activity in both heart and brain. # Tissue distribution HCN1 channel expression is found in the sinoatrial node, the neocortex, hippocampus, cerebellar cortex, dorsal root ganglion, trigeminal ganglion and brainstem. # Interactions HCN1 has been shown to interact with HCN2. # Epilepsy De novo mutations in HCN1 cause epilepsy .

HCN1 Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 is a protein that in humans is encoded by the HCN1 gene.[1][2][3][4] # Function Hyperpolarization-activated cation channels of the HCN gene family, such as HCN1, contribute to spontaneous rhythmic activity in both heart and brain.[4] # Tissue distribution HCN1 channel expression is found in the sinoatrial node,[5][6] the neocortex, hippocampus, cerebellar cortex, dorsal root ganglion, trigeminal ganglion and brainstem.[7][8][9][10][11] # Interactions HCN1 has been shown to interact with HCN2.[12][13] # Epilepsy De novo mutations in HCN1 cause epilepsy .[14]

https://www.wikidoc.org/index.php/HCN1

2c88885ae15f8c4c23df5c45316d12607f608d2f

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HEPA

HEPA # Overview A high efficiency particulate air or HEPA (Template:IPAEng) filter is a type of high-efficiency air filter. # Function HEPA filters can remove at least 99.97% of airborne particles 0.3 micrometers (µm) in diameter. Particles of this size are the most difficult to filter and are thus considered the most penetrating particle size (MPPS). Particles that are larger or smaller are filtered with even higher efficiency. HEPA filters are composed of a mat of randomly arranged fibres. Key metrics affecting function are fibre density and diameter, and filter thickness. The air space between HEPA filter fibres is much greater than 0.3 μm. The common assumption that a HEPA filter acts like a sieve where particles smaller than the largest opening can pass through is incorrect. Just as for membrane filters, particles so large that they are as wide as the largest opening or distance between fibres cannot pass in between them at all. But HEPA filters are designed to target much smaller pollutants and particles are mainly trapped (they stick to a fibre) by one of the following three mechanisms: - Interception, where particles following a line of flow in the air stream come within one radius of a fibre and adhere to it. - Impaction, where larger particles are unable to avoid fibres by following the curving contours of the air stream and are forced to embed in one of them directly; this increases with diminishing fibre separation and higher air flow velocity. - Diffusion, an enhancing mechanism is a result of the collision with gas molecules by the smallest particles, especially those below 0.1 µm in diameter, which are thereby impeded and delayed in their path through the filter; this behaviour is similar to Brownian motion and raises the probability that a particle will be stopped by either of the two mechanisms above; it becomes dominant at lower air flow velocities. Diffusion predominates below the 0.1 μm diameter particle size. Impaction and interception predominate above 0.4 μm. In between, near the 0.3 μm MPPS, diffusion and interception predominate. The initial filter air flow resistance and final filter air flow resistance are typically measured as pressure drop across the filters. # History The original HEPA filter was designed in the 1940s and was used in the Manhattan Project to prevent the spread of airborne radioactive contaminants. It was commercialized in the 1950s, and the original term became a registered trademark and a generic term for highly efficient filters. Over the decades filters have evolved to satisfy the higher and higher demands for air quality in various high technology industries, such as aerospace, pharmaceutical processing, hospitals, health care, nuclear fuels, nuclear power, and electronic microcircuitry (computer chips). Today, a HEPA filter rating is applicable to any highly efficient air filter that can attain the same filter efficiency performance standards as a minimum and is equivalent to the more recent NIOSH N100 rating for respirator filters. The United States Department of Energy (DOE) has specific requirements for HEPA filters in DOE regulated applications. Products that claim to be "HEPA-type", "HEPA-like", or "99% HEPA" do not satisfy these requirements and may not be tested in independent laboratories. # Nuclear industry application HEPA filters must be correctly installed in a filter housing or frame to achieve proper results. In the Nuclear Fuels and Nuclear Power Generation industries, these housings are sometimes referred to as filter trains. Filter Housings are usually arranged in an array with 24 inch by 24 inch by 11½ inch deep filters (Size # 7, DOE-STD-3020-2005) having a nominal capacity of 1500 cfm (0.7 m³/s) each (see the DOE Nuclear Air Cleaning Handbook). A good general reference for Nuclear Facility HVAC design is Chapter 26 "Nuclear Facilities" found in the ASHRAE 2003 HVAC Applications Handbook. # Bio-medical applications HEPA filters are critical in the prevention of the spread of airborne bacterial and viral organisms and, therefore, infection. Typically, medical-use HEPA filtration systems also incorporate high-energy ultra-violet light units to kill off the live bacteria and viruses trapped by the filter media. Some of the best-rated HEPA units have an efficiency rating of 99.995%, which assures a very high level of protection against airborne disease transmission. # Vacuum cleaners Many vacuum cleaners also use HEPA filters as part of their filtration systems. This is beneficial for asthma and allergy sufferers, because the HEPA filter traps the fine particles (such as pollen and dust mite feces) which trigger allergy and asthma symptoms. For a HEPA filter in a vacuum cleaner to be effective, the vacuum cleaner must be designed so that all the air drawn into the machine is expelled through the filter, with none of the air leaking past it. Also, because of the extra density of a HEPA filter, the vacuum cleaner requires a more powerful motor to provide adequate cleaning power.

HEPA Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A high efficiency particulate air or HEPA[1] (Template:IPAEng) filter is a type of high-efficiency air filter. # Function HEPA filters can remove at least 99.97% of airborne particles 0.3 micrometers (µm) in diameter. Particles of this size are the most difficult to filter and are thus considered the most penetrating particle size (MPPS). Particles that are larger or smaller are filtered with even higher efficiency. HEPA filters are composed of a mat of randomly arranged fibres. Key metrics affecting function are fibre density and diameter, and filter thickness. The air space between HEPA filter fibres is much greater than 0.3 μm. The common assumption that a HEPA filter acts like a sieve where particles smaller than the largest opening can pass through is incorrect. Just as for membrane filters, particles so large that they are as wide as the largest opening or distance between fibres cannot pass in between them at all. But HEPA filters are designed to target much smaller pollutants and particles are mainly trapped (they stick to a fibre) by one of the following three mechanisms: - Interception, where particles following a line of flow in the air stream come within one radius of a fibre and adhere to it. - Impaction, where larger particles are unable to avoid fibres by following the curving contours of the air stream and are forced to embed in one of them directly; this increases with diminishing fibre separation and higher air flow velocity. - Diffusion, an enhancing mechanism is a result of the collision with gas molecules by the smallest particles, especially those below 0.1 µm in diameter, which are thereby impeded and delayed in their path through the filter; this behaviour is similar to Brownian motion and raises the probability that a particle will be stopped by either of the two mechanisms above; it becomes dominant at lower air flow velocities. Diffusion predominates below the 0.1 μm diameter particle size. Impaction and interception predominate above 0.4 μm. In between, near the 0.3 μm MPPS, diffusion and interception predominate. The initial filter air flow resistance and final filter air flow resistance are typically measured as pressure drop across the filters. # History The original HEPA filter was designed in the 1940s and was used in the Manhattan Project to prevent the spread of airborne radioactive contaminants. It was commercialized in the 1950s, and the original term became a registered trademark and a generic term for highly efficient filters. Over the decades filters have evolved to satisfy the higher and higher demands for air quality in various high technology industries, such as aerospace, pharmaceutical processing, hospitals, health care, nuclear fuels, nuclear power, and electronic microcircuitry (computer chips). Today, a HEPA filter rating is applicable to any highly efficient air filter that can attain the same filter efficiency performance standards as a minimum and is equivalent to the more recent NIOSH N100 rating for respirator filters. The United States Department of Energy (DOE) has specific requirements for HEPA filters in DOE regulated applications. Products that claim to be "HEPA-type", "HEPA-like", or "99% HEPA" do not satisfy these requirements and may not be tested in independent laboratories. # Nuclear industry application HEPA filters must be correctly installed in a filter housing or frame to achieve proper results. In the Nuclear Fuels and Nuclear Power Generation industries, these housings are sometimes referred to as filter trains. Filter Housings are usually arranged in an array with 24 inch by 24 inch by 11½ inch deep filters (Size # 7, DOE-STD-3020-2005) having a nominal capacity of 1500 cfm (0.7 m³/s) each (see the DOE Nuclear Air Cleaning Handbook). A good general reference for Nuclear Facility HVAC design is Chapter 26 "Nuclear Facilities" found in the ASHRAE 2003 HVAC Applications Handbook. # Bio-medical applications HEPA filters are critical in the prevention of the spread of airborne bacterial and viral organisms and, therefore, infection. Typically, medical-use HEPA filtration systems also incorporate high-energy ultra-violet light units to kill off the live bacteria and viruses trapped by the filter media. Some of the best-rated HEPA units have an efficiency rating of 99.995%, which assures a very high level of protection against airborne disease transmission. # Vacuum cleaners Many vacuum cleaners also use HEPA filters as part of their filtration systems. This is beneficial for asthma and allergy sufferers, because the HEPA filter traps the fine particles (such as pollen and dust mite feces) which trigger allergy and asthma symptoms. For a HEPA filter in a vacuum cleaner to be effective, the vacuum cleaner must be designed so that all the air drawn into the machine is expelled through the filter, with none of the air leaking past it. Also, because of the extra density of a HEPA filter, the vacuum cleaner requires a more powerful motor to provide adequate cleaning power.

https://www.wikidoc.org/index.php/HEPA

dd3717494c37042400b7551c4de17ad857b29032

wikidoc

hERG

hERG hERG (the human Ether-à-go-go-Related Gene) is a gene (KCNH2) that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to the electrical activity of the heart: the hERG channel mediates the repolarizing IKr current in the cardiac action potential, which helps coordinate the heart's beating. When this channel's ability to conduct electrical current across the cell membrane is inhibited or compromised, either by application of drugs or by rare mutations in some families, it can result in a potentially fatal disorder called long QT syndrome. Conversely, genetic mutations that increase the current through these channels can lead to the related inherited heart rhythm disorder Short QT syndrome. A number of clinically successful drugs in the market have had the tendency to inhibit hERG, lengthening the QT and potentially leading to a fatal irregularity of the heartbeat (a ventricular tachyarrhythmia called torsades de pointes). This has made hERG inhibition an important antitarget that must be avoided during drug development. hERG has also been associated with modulating the functions of some cells of the nervous system and with establishing and maintaining cancer-like features in leukemic cells. # Function hERG forms the major portion of one of the ion channel proteins (the 'rapid' delayed rectifier current (IKr)) that conducts potassium (K+) ions out of the muscle cells of the heart (cardiac myocytes), and this current is critical in correctly timing the return to the resting state (repolarization) of the cell membrane during the cardiac action potential. Sometimes, when referring to the pharmacological effects of drugs, the terms "hERG channels" and IKr are used interchangeably, but, in the technical sense, "hERG channels" can be made only by scientists in the laboratory; in formal terms, the naturally occurring channels in the body that include hERG are referred to by the name of the electrical current that has been measured in that cell type, so, for example, in the heart, the correct name is IKr. This difference in nomenclature becomes clearer in the controversy as to whether the channels conducting IKr include other subunits (e.g., beta subunits) or whether the channels include a mixture of different types (isoforms) of hERG, but, when the originally-discovered form of hERG is experimentally transferred into cells that previously lacked hERG (i.e., heterologous expression), a potassium ion channel is formed, and this channel has many signature features of the cardiac 'rapid' delayed rectifier current (IKr), including IKr's inward rectification that results in the channel producing a 'paradoxical resurgent current' in response to repolarization of the membrane. # Structure A detailed atomic structure for hERG based on X-ray crystallography is not yet available, but structures have recently been solved by electron microscopy. In the laboratory the heterologously expressed hERG potassium channel comprises 4 identical alpha subunits, which form the channel's pore through the plasma membrane. Each hERG subunit consists of 6 transmembrane alpha helices, numbered S1-S6, a pore helix situated between S5 and S6, and cytoplasmically located N- and C-termini. The S4 helix contains a positively charged arginine or lysine amino acid residue at every 3rd position and is thought to act as a voltage-sensitive sensor, which allows the channel to respond to voltage changes by changing conformations between conducting and non-conducting states (called 'gating'). Between the S5 and S6 helices, there is an extracellular loop (known as 'the turret') and 'the pore loop', which begins and ends extracellularly but loops into the plasma membrane; the pore loop for each of the hERG subunits in one channel face into the ion-conducting pore and are adjacent to the corresponding loops of the 3 other subunits, and together they form the selectivity filter region of the channel pore. The selectivity sequence, SVGFG, is very similar to that contained in bacterial KcsA channels. Although a full crystal structure for hERG is not yet available, a structure has been found for the cytoplasmic N-terminus, which was shown to contain a PAS domain (aminoacid 26-135) that slows the rate of deactivation. # Genetics Loss of function mutations in this channel may lead to long QT syndrome (LQT2), while gain of function mutations may lead to short QT syndrome. Both clinical disorders stem from ion channel dysfunction (so-called channelopathies) that can lead to the risk of potentially fatal cardiac arrhythmias (e.g., torsades de pointes), due to repolarization disturbances of the cardiac action potential. There are far more hERG mutations described for long QT syndrome than for short QT syndrome. # Drug interactions This channel is also sensitive to drug binding, as well as decreased extracellular potassium levels, both of which can result in decreased channel function and drug-induced (acquired) long QT syndrome. Among the drugs that can cause QT prolongation, the more common ones include antiarrhythmics (especially Class 1A and Class III), anti-psychotic agents, and certain antibiotics (including quinolones and macrolides). Although there exist other potential targets for cardiac adverse effects, the vast majority of drugs associated with acquired QT prolongation are known to interact with the hERG potassium channel. One of the main reasons for this phenomenon is the larger inner vestibule of the hERG channel, thus providing more space for many different drug classes to bind and block this potassium channel. # Drug development considerations Due to the documented potential of QT-interval-prolonging drugs, the United States Food and Drug Administration issued recommendations for the establishment of a cardiac safety profile during pre-clinical drug development: ICH S7B. The nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals, issued as CHMP/ICH/423/02, adopted by CHMP in May 2005. Preclinical hERG studies should be accomplished in GLP environment. # Naming The hERG gene was first named and described in a paper by Jeff Warmke and Barry Ganetzky, then both at the University of Wisconsin–Madison. The hERG gene is the human homolog of the Ether-à-go-go gene found in the Drosophila fly; Ether-à-go-go was named in the 1960s by William D. Kaplan, while at the City of Hope Hospital in Duarte, California. When flies with mutations in the Ether-à-go-go gene are anaesthetised with ether, their legs start to shake, like the dancing then popular at the Whisky A Go-Go nightclub in West Hollywood, California. # Interactions HERG has been shown to interact with the 14-3-3 epsilon protein, encoded by YWHAE.

hERG hERG (the human Ether-à-go-go-Related Gene) is a gene (KCNH2) that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to the electrical activity of the heart: the hERG channel mediates the repolarizing IKr current in the cardiac action potential, which helps coordinate the heart's beating. When this channel's ability to conduct electrical current across the cell membrane is inhibited or compromised, either by application of drugs or by rare mutations in some families,[1] it can result in a potentially fatal disorder called long QT syndrome. Conversely, genetic mutations that increase the current through these channels can lead to the related inherited heart rhythm disorder Short QT syndrome.[2] A number of clinically successful drugs in the market have had the tendency to inhibit hERG, lengthening the QT and potentially leading to a fatal irregularity of the heartbeat (a ventricular tachyarrhythmia called torsades de pointes).[3] This has made hERG inhibition an important antitarget that must be avoided during drug development.[4] hERG has also been associated with modulating the functions of some cells of the nervous system[5] and with establishing and maintaining cancer-like features in leukemic cells.[6] # Function hERG forms the major portion of one of the ion channel proteins (the 'rapid' delayed rectifier current (IKr)) that conducts potassium (K+) ions out of the muscle cells of the heart (cardiac myocytes), and this current is critical in correctly timing the return to the resting state (repolarization) of the cell membrane during the cardiac action potential.[4] Sometimes, when referring to the pharmacological effects of drugs, the terms "hERG channels" and IKr are used interchangeably, but, in the technical sense, "hERG channels" can be made only by scientists in the laboratory; in formal terms, the naturally occurring channels in the body that include hERG are referred to by the name of the electrical current that has been measured in that cell type, so, for example, in the heart, the correct name is IKr. This difference in nomenclature becomes clearer in the controversy as to whether the channels conducting IKr include other subunits (e.g., beta subunits[7]) or whether the channels include a mixture of different types (isoforms) of hERG,[8] but, when the originally-discovered form of hERG[9] is experimentally transferred into cells that previously lacked hERG (i.e., heterologous expression), a potassium ion channel is formed, and this channel has many signature features of the cardiac 'rapid' delayed rectifier current (IKr),[10][11][12] including IKr's inward rectification that results in the channel producing a 'paradoxical resurgent current' in response to repolarization of the membrane.[13] # Structure A detailed atomic structure for hERG based on X-ray crystallography is not yet available, but structures have recently been solved by electron microscopy.[14] In the laboratory the heterologously expressed hERG potassium channel comprises 4 identical alpha subunits, which form the channel's pore through the plasma membrane. Each hERG subunit consists of 6 transmembrane alpha helices, numbered S1-S6, a pore helix situated between S5 and S6, and cytoplasmically located N- and C-termini. The S4 helix contains a positively charged arginine or lysine amino acid residue at every 3rd position and is thought to act as a voltage-sensitive sensor, which allows the channel to respond to voltage changes by changing conformations between conducting and non-conducting states (called 'gating'). Between the S5 and S6 helices, there is an extracellular loop (known as 'the turret') and 'the pore loop', which begins and ends extracellularly but loops into the plasma membrane; the pore loop for each of the hERG subunits in one channel face into the ion-conducting pore and are adjacent to the corresponding loops of the 3 other subunits, and together they form the selectivity filter region of the channel pore. The selectivity sequence, SVGFG, is very similar to that contained in bacterial KcsA channels.[4] Although a full crystal structure for hERG is not yet available, a structure has been found for the cytoplasmic N-terminus, which was shown to contain a PAS domain (aminoacid 26-135) that slows the rate of deactivation.[15] # Genetics Loss of function mutations in this channel may lead to long QT syndrome (LQT2), while gain of function mutations may lead to short QT syndrome. Both clinical disorders stem from ion channel dysfunction (so-called channelopathies) that can lead to the risk of potentially fatal cardiac arrhythmias (e.g., torsades de pointes), due to repolarization disturbances of the cardiac action potential.[10][16] There are far more hERG mutations described for long QT syndrome than for short QT syndrome.[1] # Drug interactions This channel is also sensitive to drug binding, as well as decreased extracellular potassium levels, both of which can result in decreased channel function and drug-induced (acquired) long QT syndrome. Among the drugs that can cause QT prolongation, the more common ones include antiarrhythmics (especially Class 1A and Class III), anti-psychotic agents, and certain antibiotics (including quinolones and macrolides).[17] Although there exist other potential targets for cardiac adverse effects, the vast majority of drugs associated with acquired QT prolongation are known to interact with the hERG potassium channel. One of the main reasons for this phenomenon is the larger inner vestibule of the hERG channel, thus providing more space for many different drug classes to bind and block this potassium channel.[18] # Drug development considerations Due to the documented potential of QT-interval-prolonging drugs, the United States Food and Drug Administration issued recommendations for the establishment of a cardiac safety profile during pre-clinical drug development: ICH S7B.[19] The nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals, issued as CHMP/ICH/423/02, adopted by CHMP in May 2005. Preclinical hERG studies should be accomplished in GLP environment. # Naming The hERG gene was first named and described in a paper by Jeff Warmke and Barry Ganetzky, then both at the University of Wisconsin–Madison.[20] The hERG gene is the human homolog of the Ether-à-go-go gene found in the Drosophila fly; Ether-à-go-go was named in the 1960s by William D. Kaplan, while at the City of Hope Hospital in Duarte, California. When flies with mutations in the Ether-à-go-go gene are anaesthetised with ether, their legs start to shake, like the dancing then popular at the Whisky A Go-Go nightclub in West Hollywood, California. # Interactions HERG has been shown to interact with the 14-3-3 epsilon protein, encoded by YWHAE.[21]

https://www.wikidoc.org/index.php/HERG

1a3168eab00fbcdba228d046a7b784d623e65569

wikidoc

HES1

HES1 Transcription factor HES1 (hairy and enhancer of split-1) is a protein that is encoded by the Hes1 gene, and is the mammalian homolog of the hairy gene in Drosophila. HES1 is one of the seven members of the Hes gene family (HES1-7). Hes genes code nuclear proteins that suppress transcription. This protein belongs to the basic helix-loop-helix (bHLH) family of transcription factors. It is a transcriptional repressor of genes that require a bHLH protein for their transcription. The protein has a particular type of basic domain that contains a helix interrupting protein that binds to the N-box promoter region rather than the canonical enhancer box (E-box). As a member of the bHLH family, it is a transcriptional repressor that influences cell proliferation and differentiation in embryogenesis. HES1 regulates its own expression via a negative feedback loop, and oscillates with approximately 2-hour periodicity. # Structure There are three conserved domains in Hes genes that impart transcriptional functions: the bHLH domain, the Orange domain, and the WRPW motif. Hes genes differ from other bHLH factors in that they have a proline reside in the middle of the basic DNA binding region. This proline has been proposed to give Hes proteins unique DNA binding capacity. While most bHLH factors bind to the E-box consensus sequence (CANNTG) that is present in the promoter region of target genes, Hes factors bind more preferentially to the Class C site or N box (CACNAG). The Orange domain serves to regulate the choice of bHLH heterodimer partners. The C-terminal WRPW domain inhibits transcription. # Interactions Similarly to other HES proteins, Hes1 has been shown to interact with the co-repressors which Transducin-like E(spl) (TLE) genes and the Groucho-related gene (Grg), both homologs of the Drosophila groucho. Because Groucho in Drosophila inhibits transcription by recruiting histone deacetylase, it is likely that a Hes-Groucho complex actively blocks transcription by disabling chromatin. Hes proteins also heterodimerize with bHLH repressors such as Hey1 and Hey2, a process which also blocks transcription. Hes factors also heterodimerize with bHLH activators such as E47, also known as Tcfe2a, and Mash1, also known as Ascl1, both of which are the mammalian homologs to proneural genes in Drosophila. The E47-Hes and Mash1-Hes heterodimer complexes cannot bind DNA, and therefore repress transcription. Hes1 also interacts with TLE2 and Sirtuin 1. # HES1 and stem cells HES1 influences the maintenance of certain stem cells and progenitor cells. Specifically, HES1 influences the timing of differentiation by repressing bHLH activators, and determines binary cell fate. HES1 has been shown to play a large role in both the nervous, and digestive systems. HES1 has been shown to influence these two systems partially through the Notch signaling pathway. ## Neural development HES1 is expressed in both neuroepithelial cells and radial glial cells, both neural stem cells. Hes1 expression, along with that of Hes5, covers the majority of the developing embryo at embryonic day 10.5. After this point, expression of Hes1 is limited to the subventricular zone. In HES1 knockout (KO) mice, Mash1 is compensatorily upregulated, and neurogenesis is accelerated. Indeed, if the expression of Hes1, Hes3, and Hes5 genes is inhibited, the expression of proneural genes increases, and while neurogenesis is accelerated, neural stem cells become prematurely depleted. Contrariwise, if these HES genes are overexpressed, neurogenesis is inhibited. Thus HES1 genes are only involved in maintaining, not creating, neural stem cells. Additionally, HES1 can guide neural stem cells down one of two paths of differentiation. HES1 can maintain neural stem cells expressing Pax6, but leads cells that are Pax6-negative to an astrocyte differentiation fate. Epigenetic modifications such as DNA methylation also influence HES1's ability to direct differentiation. Demethylation of HES1 target sites in the promoter region of astrocyte-specific genes hastens astrocyte differentiation. The oscillatory nature of Hes1 expression has a role in determining differentiation fate as well. HES1-high embryonic stem cells that received a differentiation signal often adopted a mesodermal fate, while HES1-low cells that received a differentiation signal differentiated into neuronal cells. These results were confirmed using quantitative PCR which showed that HES1-high cells showed high levels of Brachyury and Fgf5 expression (both of which are expressed highly in mesodermal cell types) with comparatively low levels genes expressed in neural cells such as Nestin. By contrast, HES1-low cells showed high levels of expression of genes involved in neural induction and low levels of expression of genes involved in mesodermal differentiation. Cycling HES1 levels also contribute to the maintenance of neural progenitor cells by regulating Neurogenin2 (Ngn2) and Dll1 oscillations. Hes1 levels fluctuate at different frequencies in different parts of the central nervous system: HES1 is continuously expressed at high levels in the boundaries, but vacillates in the compartments. This suggests that alternating HES1 levels may prompt differences in characteristics between anatomical elements of the central nervous system. ## Interactions with the Notch pathway HES1 also plays an important role in the Notch signaling pathway. In the absence of Notch signaling, RBPJ inhibits the expression of HES1. After Notch signals have been processed within the cell, however, the plasma membrane releases the intracellular domain of Notch, which moves to the nucleus where it associates with RBPJ. The binding causes a conformational change which leads co-repressors to disassociate and allows co-activators to bind. The new activating complex then prompts HES1 expression. Notch signaling activates HES1 expression. HES1 has been shown to target at least Notch ligands: Dll1, Jagged1 (Jag1), and Neurogenin-2., Dll1, as with other Notch ligands, has been shown to induce neural differentiation, and HES1 binding of Dll1 blocks neural differentiation and leads to the maintenance of the neural stem cells and neural progenitor cells. Notch signaling also occurs in the intestinal crypt cells. Hyperactivated Notch causes a reduction in the number of secretory cell types (i.e. goblet cells, enteroendocrine cells, and Paneth cells). Deletion of the Notch pathway by removing the Notch expression controller, Rbpsuh, causes the production of nearly only goblet cells. ## Digestive system HES1 has been shown to influence the differentiation decision of cells in the gastrointestinal tract. In pancreatic progenitor cells, HES1 expression inhibits the expression of Ptf1a, which controls exocrine cell differentiation, and Ngn3, which drives differentiation of endocrine cell types that will form the islets of Langerhans. The absence of Hes1 in the developing intestine of mice promotes the increase of Math1 (a protein required for the production of intestinal secretory cell types), which leads to an increase of goblet, enteroendocrine, and Paneth cells. When Hes1 is deleted in mouse and zebrafish, surplus goblet cells and enteroendocrine cells are made while few enterocytes are made., Liver progenitor cells differentiate into two different cell types: hepatocytes and biliary epithelial cells. When Hes1 expression is low, hepatocytes form normally, but bile ducts are completely absent. This phenotype resembles Alagille syndrome, a hallmark of which is mutations in Jagged1. Therefore, Hes-Notch interactions also play a role in digestive organ development.

HES1 Transcription factor HES1 (hairy and enhancer of split-1) is a protein that is encoded by the Hes1 gene, and is the mammalian homolog of the hairy gene in Drosophila.[1][2] HES1 is one of the seven members of the Hes gene family (HES1-7). Hes genes code nuclear proteins that suppress transcription.[3] This protein belongs to the basic helix-loop-helix (bHLH) family of transcription factors. It is a transcriptional repressor of genes that require a bHLH protein for their transcription. The protein has a particular type of basic domain that contains a helix interrupting protein that binds to the N-box promoter region rather than the canonical enhancer box (E-box).[2] As a member of the bHLH family, it is a transcriptional repressor that influences cell proliferation and differentiation in embryogenesis.[3] HES1 regulates its own expression via a negative feedback loop, and oscillates with approximately 2-hour periodicity.[4] # Structure There are three conserved domains in Hes genes that impart transcriptional functions: the bHLH domain, the Orange domain, and the WRPW motif. Hes genes differ from other bHLH factors in that they have a proline reside in the middle of the basic DNA binding region. This proline has been proposed to give Hes proteins unique DNA binding capacity. While most bHLH factors bind to the E-box consensus sequence (CANNTG) that is present in the promoter region of target genes, Hes factors bind more preferentially to the Class C site or N box (CACNAG).[3] The Orange domain serves to regulate the choice of bHLH heterodimer partners.[5] The C-terminal WRPW domain inhibits transcription.[6] # Interactions Similarly to other HES proteins, Hes1 has been shown to interact with the co-repressors which Transducin-like E(spl) (TLE) genes and the Groucho-related gene (Grg), both homologs of the Drosophila groucho.[7] Because Groucho in Drosophila inhibits transcription by recruiting histone deacetylase, it is likely that a Hes-Groucho complex actively blocks transcription by disabling chromatin. Hes proteins also heterodimerize with bHLH repressors such as Hey1 and Hey2, a process which also blocks transcription. Hes factors also heterodimerize with bHLH activators such as E47, also known as Tcfe2a, and Mash1, also known as Ascl1, both of which are the mammalian homologs to proneural genes in Drosophila. The E47-Hes and Mash1-Hes heterodimer complexes cannot bind DNA, and therefore repress transcription.[3] Hes1 also interacts with TLE2[8] and Sirtuin 1.[9] # HES1 and stem cells HES1 influences the maintenance of certain stem cells and progenitor cells. Specifically, HES1 influences the timing of differentiation by repressing bHLH activators, and determines binary cell fate. HES1 has been shown to play a large role in both the nervous, and digestive systems. HES1 has been shown to influence these two systems partially through the Notch signaling pathway. ## Neural development HES1 is expressed in both neuroepithelial cells and radial glial cells, both neural stem cells. Hes1 expression, along with that of Hes5, covers the majority of the developing embryo at embryonic day 10.5.[10] After this point, expression of Hes1 is limited to the subventricular zone. In HES1 knockout (KO) mice, Mash1 is compensatorily upregulated, and neurogenesis is accelerated. Indeed, if the expression of Hes1, Hes3, and Hes5 genes is inhibited, the expression of proneural genes increases, and while neurogenesis is accelerated, neural stem cells become prematurely depleted. Contrariwise, if these HES genes are overexpressed, neurogenesis is inhibited.[11] Thus HES1 genes are only involved in maintaining, not creating, neural stem cells. Additionally, HES1 can guide neural stem cells down one of two paths of differentiation. HES1 can maintain neural stem cells expressing Pax6, but leads cells that are Pax6-negative to an astrocyte differentiation fate.[12] Epigenetic modifications such as DNA methylation also influence HES1's ability to direct differentiation. Demethylation of HES1 target sites in the promoter region of astrocyte-specific genes hastens astrocyte differentiation.[11] The oscillatory nature of Hes1 expression has a role in determining differentiation fate as well. HES1-high embryonic stem cells that received a differentiation signal often adopted a mesodermal fate, while HES1-low cells that received a differentiation signal differentiated into neuronal cells. These results were confirmed using quantitative PCR which showed that HES1-high cells showed high levels of Brachyury and Fgf5 expression (both of which are expressed highly in mesodermal cell types) with comparatively low levels genes expressed in neural cells such as Nestin. By contrast, HES1-low cells showed high levels of expression of genes involved in neural induction and low levels of expression of genes involved in mesodermal differentiation.[13] Cycling HES1 levels also contribute to the maintenance of neural progenitor cells by regulating Neurogenin2 (Ngn2) and Dll1 oscillations.[14] Hes1 levels fluctuate at different frequencies in different parts of the central nervous system: HES1 is continuously expressed at high levels in the boundaries, but vacillates in the compartments. This suggests that alternating HES1 levels may prompt differences in characteristics between anatomical elements of the central nervous system.[3] ## Interactions with the Notch pathway HES1 also plays an important role in the Notch signaling pathway.[15] In the absence of Notch signaling, RBPJ inhibits the expression of HES1. After Notch signals have been processed within the cell, however, the plasma membrane releases the intracellular domain of Notch, which moves to the nucleus where it associates with RBPJ. The binding causes a conformational change which leads co-repressors to disassociate and allows co-activators to bind. The new activating complex then prompts HES1 expression. Notch signaling activates HES1 expression. HES1 has been shown to target at least Notch ligands: Dll1, Jagged1 (Jag1), and Neurogenin-2.[11], [13] Dll1, as with other Notch ligands, has been shown to induce neural differentiation, and HES1 binding of Dll1 blocks neural differentiation and leads to the maintenance of the neural stem cells and neural progenitor cells.[16] Notch signaling also occurs in the intestinal crypt cells. Hyperactivated Notch causes a reduction in the number of secretory cell types (i.e. goblet cells, enteroendocrine cells, and Paneth cells). Deletion of the Notch pathway by removing the Notch expression controller, Rbpsuh, causes the production of nearly only goblet cells.[17] ## Digestive system HES1 has been shown to influence the differentiation decision of cells in the gastrointestinal tract. In pancreatic progenitor cells, HES1 expression inhibits the expression of Ptf1a, which controls exocrine cell differentiation, and Ngn3, which drives differentiation of endocrine cell types that will form the islets of Langerhans.[3] The absence of Hes1 in the developing intestine of mice promotes the increase of Math1 (a protein required for the production of intestinal secretory cell types), which leads to an increase of goblet, enteroendocrine, and Paneth cells. When Hes1 is deleted in mouse and zebrafish, surplus goblet cells and enteroendocrine cells are made while few enterocytes are made.[3], [17] Liver progenitor cells differentiate into two different cell types: hepatocytes and biliary epithelial cells. When Hes1 expression is low, hepatocytes form normally, but bile ducts are completely absent.[18] This phenotype resembles Alagille syndrome, a hallmark of which is mutations in Jagged1. Therefore, Hes-Notch interactions also play a role in digestive organ development.

https://www.wikidoc.org/index.php/HES1

2129815ac59a02b7867dcd585de4b29ae3256c7f

wikidoc

HEXA

HEXA Hexosaminidase A (alpha polypeptide), also known as HEXA, is an enzyme that in humans is encoded by the HEXA gene, located on the 15th chromosome. Hexosaminidase A and the cofactor GM2 activator protein catalyze the degradation of the GM2 gangliosides and other molecules containing terminal N-acetyl hexosamines. Hexosaminidase A is a heterodimer composed of an alpha subunit (this protein) and a beta subunit. The alpha subunit polypeptide is encoded by the HEXA gene while the beta subunit is encoded by the HEXB gene. Gene mutations in the gene encoding the beta subunit (HEXB) often result in Sandhoff disease; whereas, mutations in the gene encoding the alpha subunit (HEXA, this gene) decrease the hydrolysis of GM2 gangliosides, which is the main cause of Tay–Sachs disease. # Function Even though the alpha and beta subunits of hexosaminidase A can both cleave GalNAc residues, only the alpha subunit is able to hydrolyze GM2 gangliosides. The alpha subunit contains a key residue, Arg-424, which is essential for binding the N-acetyl-neuramanic residue of GM2 gangliosides. The alpha subunit can hydrolyze GM2 gangliosides because it contains a loop structure consisting of the amino acids: Gly-280, Ser-281, Glu-282, and Pro-283. The loop is absent in the beta subunit, but it serves as an ideal structure for the binding of the GM2 activator protein (GM2AP) in the alpha subunit. A combination of Arg-424 and the amino acids that cause the formation of the loop allow the alpha subunit to hydrolyze GM2 gangliosides into GM3 gangliosides by removing the N-acetylgalactosamine (GalNAc) residue from GM2 gangliosides. # Gene mutations resulting in Tay–Sachs disease There are numerous mutations that lead to hexosaminidase A deficiency including gene deletions, nonsense mutations, and missense mutations. Tay–Sachs disease occurs when hexosaminidase A loses its ability to function. People with Tay–Sachs disease are unable to remove the GalNAc residue from the GM2 ganglioside, and as a result, they end up storing 100 to 1000 times more GM2 gangliosides in the brain than the normal person. Over 100 different mutations have been discovered just in infantile cases of Tay–Sachs disease alone. The most common mutation, which occurs in over 80 percent of Tay–Sachs patients, results from a four base pair addition (TATC) in exon 11 of the Hex A gene. This insertion leads to an early stop codon, which causes the Hex A deficiency. Children born with Tay–Sachs usually die between two and six years of age from aspiration and pneumonia. Tay–Sachs causes cerebral degeneration and blindness. Patients also experience flaccid extremities and seizures. There is no cure for Tay–Sachs disease. # Gene Therapies for Tay-Sachs The HEXA gene is a protein encoding gene that codes for the lysosomal enzyme beta-hexosaminidase. This enzyme, combined with the GM2 activator protein, is responsible for the breakdown of ganglioside GM2 within the lysosome. Defects in the HEXA gene, however, prevent this degradation, leading to a buildup of toxins in brain and spinal cord cells. This fatal genetic disorder is called Tay-Sachs disease. Because the Tay-Sachs gene defect mainly affects neural cells, a patient with the HEXA mutation will experience a quick deterioration of motor and mental function before dying around the age of three or four. A “knockout” model, which is a mouse that has been genetically modified to observe the effects of inactivation of or damage to certain genes, found that the mice that were administered the HEXA gene experienced many of the same symptoms of Tay-Sachs, with one exception: GM2 buildup was distributed differently in the brains of the mice than in those of a typical human Tay-Sachs patient. This model has allowed scientists to research gene therapies for HEXA defects. One study, done on mice, successfully reestablished beta-hexoaminidase levels and removed the toxic cell buildup by using a non-replicated Herpes simplex vector to code for the missing gene.

HEXA Hexosaminidase A (alpha polypeptide), also known as HEXA, is an enzyme that in humans is encoded by the HEXA gene, located on the 15th chromosome.[1][2] Hexosaminidase A and the cofactor GM2 activator protein catalyze the degradation of the GM2 gangliosides and other molecules containing terminal N-acetyl hexosamines.[3] Hexosaminidase A is a heterodimer composed of an alpha subunit (this protein) and a beta subunit. The alpha subunit polypeptide is encoded by the HEXA gene while the beta subunit is encoded by the HEXB gene. Gene mutations in the gene encoding the beta subunit (HEXB) often result in Sandhoff disease; whereas, mutations in the gene encoding the alpha subunit (HEXA, this gene) decrease the hydrolysis of GM2 gangliosides, which is the main cause of Tay–Sachs disease.[4] # Function Even though the alpha and beta subunits of hexosaminidase A can both cleave GalNAc residues, only the alpha subunit is able to hydrolyze GM2 gangliosides. The alpha subunit contains a key residue, Arg-424, which is essential for binding the N-acetyl-neuramanic residue of GM2 gangliosides. The alpha subunit can hydrolyze GM2 gangliosides because it contains a loop structure consisting of the amino acids: Gly-280, Ser-281, Glu-282, and Pro-283. The loop is absent in the beta subunit, but it serves as an ideal structure for the binding of the GM2 activator protein (GM2AP) in the alpha subunit. A combination of Arg-424 and the amino acids that cause the formation of the loop allow the alpha subunit to hydrolyze GM2 gangliosides into GM3 gangliosides by removing the N-acetylgalactosamine (GalNAc) residue from GM2 gangliosides.[5] # Gene mutations resulting in Tay–Sachs disease There are numerous mutations that lead to hexosaminidase A deficiency including gene deletions, nonsense mutations, and missense mutations. Tay–Sachs disease occurs when hexosaminidase A loses its ability to function. People with Tay–Sachs disease are unable to remove the GalNAc residue from the GM2 ganglioside, and as a result, they end up storing 100 to 1000 times more GM2 gangliosides in the brain than the normal person. Over 100 different mutations have been discovered just in infantile cases of Tay–Sachs disease alone.[6] The most common mutation, which occurs in over 80 percent of Tay–Sachs patients, results from a four base pair addition (TATC) in exon 11 of the Hex A gene. This insertion leads to an early stop codon, which causes the Hex A deficiency.[7] Children born with Tay–Sachs usually die between two and six years of age from aspiration and pneumonia. Tay–Sachs causes cerebral degeneration and blindness. Patients also experience flaccid extremities and seizures. There is no cure for Tay–Sachs disease.[6] # Gene Therapies for Tay-Sachs The HEXA gene is a protein encoding gene that codes for the lysosomal enzyme beta-hexosaminidase. This enzyme, combined with the GM2 activator protein, is responsible for the breakdown of ganglioside GM2 within the lysosome. Defects in the HEXA gene, however, prevent this degradation, leading to a buildup of toxins in brain and spinal cord cells. This fatal genetic disorder is called Tay-Sachs disease. Because the Tay-Sachs gene defect mainly affects neural cells, a patient with the HEXA mutation will experience a quick deterioration of motor and mental function before dying around the age of three or four. [8] A “knockout” model, which is a mouse that has been genetically modified to observe the effects of inactivation of or damage to certain genes, found that the mice that were administered the HEXA gene experienced many of the same symptoms of Tay-Sachs, with one exception: GM2 buildup was distributed differently in the brains of the mice than in those of a typical human Tay-Sachs patient. [9] This model has allowed scientists to research gene therapies for HEXA defects. One study, done on mice, successfully reestablished beta-hexoaminidase levels and removed the toxic cell buildup by using a non-replicated Herpes simplex vector to code for the missing gene. [10]

https://www.wikidoc.org/index.php/HEXA

e2d239380c6407c32711feca16cafea22428ba04

wikidoc

HEXB

HEXB Beta-hexosaminidase subunit beta is an enzyme that in humans is encoded by the HEXB gene. Hexosaminidase B is the beta subunit of the lysosomal enzyme beta-hexosaminidase that, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Beta-hexosaminidase is composed of two subunits, alpha and beta, which are encoded by separate genes. Both beta-hexosaminidase alpha and beta subunits are members of family 20 of glycosyl hydrolases. Mutations in the alpha or beta subunit genes lead to an accumulation of GM2 ganglioside in neurons and neurodegenerative disorders termed the GM2 gangliosidoses. Beta subunit gene mutations lead to Sandhoff disease (GM2-gangliosidosis type II). # Structure ## Gene The HEXB gene lies on the chromosome location of 5q13.3 and consists of 15 exons, spanning 35-40Kb. ## Protein HEXB consists of 556 amino acid residues and weighs 63111Da. # Function HEXB is one of the two subunits forming β-hexosaminidase which functions as a glycosyl hydrolase that remove β-linked nonreducing-terminal GalNAc or GlcNAc residues in the lysosome. Inability of HEXB will lead toβ-hexosaminidase defect and result in a group of recessive disorders called GM2 gangliosidoses, characterized by the accumulation of GM2 ganglioside. # Clinical significance Genetic defects in HEXB can result in the accumulation of GM2 ganglioside in neural tissues and two of three lysosomal storage diseases collectively known as GM2 gangliosidosis, of which Sandhoff disease (defects in the β subunit) is the best studied one. Patients present with neurosomatic manifestations. Therapeutic effects of Hex subunit gene transduction have been examined on Sandhoff disease model mice. Intracerebroventricular administration of the modified β-hexosaminidase B to Sandhoff mode mice restored the β-hexosaminidase activity in the brains, and reduced the GM2 ganglioside storage in the parenchyma. # Interactions HEXB has been found to interact with HEXA and ganglioside.

HEXB Beta-hexosaminidase subunit beta is an enzyme that in humans is encoded by the HEXB gene.[1][2][3] Hexosaminidase B is the beta subunit of the lysosomal enzyme beta-hexosaminidase that, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Beta-hexosaminidase is composed of two subunits, alpha and beta, which are encoded by separate genes. Both beta-hexosaminidase alpha and beta subunits are members of family 20 of glycosyl hydrolases. Mutations in the alpha or beta subunit genes lead to an accumulation of GM2 ganglioside in neurons and neurodegenerative disorders termed the GM2 gangliosidoses. Beta subunit gene mutations lead to Sandhoff disease (GM2-gangliosidosis type II).[3] # Structure ## Gene The HEXB gene lies on the chromosome location of 5q13.3 and consists of 15 exons, spanning 35-40Kb. ## Protein HEXB consists of 556 amino acid residues and weighs 63111Da. # Function HEXB is one of the two subunits forming β-hexosaminidase which functions as a glycosyl hydrolase that remove β-linked nonreducing-terminal GalNAc or GlcNAc residues in the lysosome.[4] Inability of HEXB will lead toβ-hexosaminidase defect and result in a group of recessive disorders called GM2 gangliosidoses, characterized by the accumulation of GM2 ganglioside.[5] # Clinical significance Genetic defects in HEXB can result in the accumulation of GM2 ganglioside in neural tissues and two of three lysosomal storage diseases collectively known as GM2 gangliosidosis, of which Sandhoff disease (defects in the β subunit) is the best studied one.[4] Patients present with neurosomatic manifestations. Therapeutic effects of Hex subunit gene transduction have been examined on Sandhoff disease model mice.[6] Intracerebroventricular administration of the modified β-hexosaminidase B to Sandhoff mode mice restored the β-hexosaminidase activity in the brains, and reduced the GM2 ganglioside storage in the parenchyma.[7] # Interactions HEXB has been found to interact with HEXA[8] and ganglioside.[6]

https://www.wikidoc.org/index.php/HEXB

b9c411b7c652bade06f9a768de39ba725535dba5

wikidoc

HEY2

HEY2 Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2) also known as cardiovascular helix-loop-helix factor 1 (CHF1) is a protein that in humans is encoded by the HEY2 gene. # Function CHF1 is a member of the hairy and enhancer of split-related (HESR) family of basic helix-loop-helix (bHLH)-type transcription factors. The encoded protein forms homo- or hetero-dimers that localize to the nucleus and interact with a histone deacetylase complex to repress transcription. Expression of this gene is induced by the Notch signaling pathway. Two similar and redundant genes in mouse are required for embryonic cardiovascular development, and are also implicated in neurogenesis and somitogenesis. Alternatively spliced transcript variants have been found, but their biological validity has not been determined. # Clinical significance Common variants of SCN5A, SCN10A, and HEY2 (this gene) are associated with Brugada syndrome. # Interactions HEY2 has been shown to interact with Sirtuin 1 and Nuclear receptor co-repressor 1.

HEY2 Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2) also known as cardiovascular helix-loop-helix factor 1 (CHF1) is a protein that in humans is encoded by the HEY2 gene.[1][2] # Function CHF1 is a member of the hairy and enhancer of split-related (HESR) family of basic helix-loop-helix (bHLH)-type transcription factors. The encoded protein forms homo- or hetero-dimers that localize to the nucleus and interact with a histone deacetylase complex to repress transcription. Expression of this gene is induced by the Notch signaling pathway. Two similar and redundant genes in mouse are required for embryonic cardiovascular development, and are also implicated in neurogenesis and somitogenesis. Alternatively spliced transcript variants have been found, but their biological validity has not been determined.[2] # Clinical significance Common variants of SCN5A, SCN10A, and HEY2 (this gene) are associated with Brugada syndrome.[3] # Interactions HEY2 has been shown to interact with Sirtuin 1[4] and Nuclear receptor co-repressor 1.[5]

https://www.wikidoc.org/index.php/HEY2

d0237229cdc6462762f8943253ac83a2cc596534

wikidoc

HHEX

HHEX Hematopoietically-expressed homeobox protein HHEX is a protein that in humans is encoded by the HHEX gene. This gene encodes a member of the homeobox family of transcription factors, many of which are involved in developmental processes. Expression in specific hematopoietic lineages suggests that this protein may play a role in hematopoietic differentiation. # Function The HHEX transcription factor acts as a promoter in some instances and an inhibitor others. It interacts with a number of other signaling molecules to play an important role in the development of multiple organs, such as the liver, thyroid and forebrain. HHEX serves to repress VEGFA, another protein which is important in endothelial cell development. SCL, a significant transcription factor for blood and endothelial cell differentiation, is shown to interact with HHEX to promote the correct development of the hematopoiesis process. HHEX appears to work together with another molecule, β-catenin, for the development of the anterior organizer. It also contributes to developmental remodeling and stabilization of endothelial cells in an unborn organism. The importance of this transcription factor is illustrated by the inability of HHEX knockout mice embryos to survive gestation. Without the expression of HHEX, these mice embryos die in utero between Day 13 and Day 16. HHEX knockout mice display a range of abnormalities including forebrain abnormalities in various levels of severity, as well as a number of other defects including heart, vasculature, liver, monocyte, and thyroid abnormalities. # Interactions HHEX has been shown to interact with Promyelocytic leukemia protein.

HHEX Hematopoietically-expressed homeobox protein HHEX is a protein that in humans is encoded by the HHEX gene.[1][2][3] This gene encodes a member of the homeobox family of transcription factors, many of which are involved in developmental processes. Expression in specific hematopoietic lineages suggests that this protein may play a role in hematopoietic differentiation.[3] # Function The HHEX transcription factor acts as a promoter in some instances and an inhibitor others.[4][5] It interacts with a number of other signaling molecules to play an important role in the development of multiple organs, such as the liver, thyroid and forebrain.[6] HHEX serves to repress VEGFA, another protein which is important in endothelial cell development.[7] SCL, a significant transcription factor for blood and endothelial cell differentiation, is shown to interact with HHEX to promote the correct development of the hematopoiesis process.[8] HHEX appears to work together with another molecule, β-catenin, for the development of the anterior organizer.[9] It also contributes to developmental remodeling and stabilization of endothelial cells in an unborn organism.[7] The importance of this transcription factor is illustrated by the inability of HHEX knockout mice embryos to survive gestation. Without the expression of HHEX, these mice embryos die in utero between Day 13 and Day 16.[7] HHEX knockout mice display a range of abnormalities including forebrain abnormalities in various levels of severity, as well as a number of other defects including heart, vasculature, liver, monocyte, and thyroid abnormalities.[6][7] # Interactions HHEX has been shown to interact with Promyelocytic leukemia protein.[10]

https://www.wikidoc.org/index.php/HHEX

207462a1818d34d0ff72dfe8be7eb53942869b17

wikidoc

HICS

HICS # HICS- Hospital Incident Command System # Background HICS is a comprehensive incident management system intended for use in both emergent and non-emergent situations. It provides hospitals of all sizes with tools needed to advance their emergency preparedness and response capability—both individually and as a member of the broader response community. # Introduction to the Hospital Incident Command System HICS is based upon the Hospital Emergency Incident Command System (HEICS), which was created in the late 1980s as an important foundation for the more than 6,000 hospitals in the United States in their efforts to prepare for and respond to various types of disasters. In developing the fourth edition of HEICS, the value and importance of using an incident management system to assist as well with daily operations, preplanned events, and non-emergent situations became apparent. Thus, the HICS was created as a system for use in both emergent and non-emergent situations, such as moving the facility, dispensing medications to hospital staff, or planning for a large hospital or community event. HICS was developed by a National Work Group of twenty hospital subject-matter experts from across the United States. In addition to the contributions of the National Work Group, ex officio members were included to ensure consistency with governmental, industrial, and hospital accreditation planning efforts and requirements. # Overview of the Principles of the Incident Command System ICS is designed to: - Be usable for managing all routine or planned events, of any size or type, by establishing a clear chain of command - Allow personnel from different agencies or departments to be integrated into a common structure that can effectively address issues and delegate responsibilities - Provide needed logistical and administrative support to operational personnel - Ensure key functions are covered and eliminate duplication The incident planning process takes place regardless of the incident size or complexity. This planning involves six (6) essential steps: - Understanding the hospital’s policy and direction - Assessing the situation - Establishing incident objectives - Determining appropriate strategies to achieve the objectives - Giving tactical direction and ensuring that it is followed (e.g., correct resources assigned to complete a task and their performance monitored) - Providing necessary back-up (assigning more or fewer resources, changing tactics, et al.) # National Incident Management System Compliance for Hospitals The Homeland Security Presidential Directive-5 (HSPD-5), issued by President George W. Bush in February 2003, created the National Incident Management System (NIMS). Until NIMS, there had been no standard for domestic incident response that united all levels of government and all emergency response agencies. The NIMS is designed to provide a framework for interoperability and compatibility among the various members of the response community. The end result is a flexible framework that facilitates governmental and nongovernmental agencies working together at all levels during all phases of an incident, regardless of its size, complexity, or location. # The Hospital Emergency Management Program The Emergency Operations Plan (EOP) outlines the hospital’s strategy for responding to and recovering from a realized threat or hazard or other incident. The document is intended to provide overall direction and coordination of the response structure and processes to be used by the hospital. An effective EOP lays the groundwork for implementation of the Incident Command System and the needed communication and coordination between operating groups. The essence of the process includes the following steps: - Designating an Emergency Program Manager Program - Establishing the Emergency Management Committee - Developing the “all hazards ” Emergency Operations Plan - Conducting a Hazard Vulnerability Analysis - Developing incident-specific guidance (Incident Planning Guides) - Coordinating with external entities - Training key staff - Exercising the EOP and incident-specific guidance through an exercise program - Conducting program review and evaluation - Learning from the lessons that are identified (organizational learning) # The Hospital Incident Command System HICS incident management team charts depict the hospital command functions that have been identified and represent how authority and responsibility are distributed within the incident management team. The activities at the Hospital Command Center (HCC) are directed by the Incident Commander, who has overall responsibility for all activities within the Hospital Command Center (HCC). The Incident Commander may appoint other Command Staff personnel to assist. Many incidents that likely will occur involve injured or ill patients. The Operations Section will be responsible for managing the tactical objectives outlined by the Incident Commander. Branches of this section include: Department Level, Patient Care, Infrastructure, Business Continuity, Security, and HazMat. The Planning Section will “collect, evaluate, and disseminate incident situation information and intelligence to Incident Command” and includes a Resources Unit, Situation Unit, Documentation Unit, and Demobilization Unit. Support requirements will be coordinated by the Logistics Section, and the Finance/Administration account for the costs associated with the response. Also, several additional incident command principles and practices are covered in this section, including incident command staff identification, building incident command staff depth, job action sheets, and incident response guides. # Life Cycle of an Incident The life cycle of an incident includes the following steps: - Alert and notification - Situation assessment and monitoring - EOP Implementation - Establishing the HCC - Building the ICS structure - Incident action planning - Communications and coordination - Staff health and safety - Operational considerations - Legal and ethical considerations - Demobilization - System recovery - Response evaluation and organizational learning # Implementation

HICS Template:Wikify # HICS- Hospital Incident Command System # Background HICS[1][1] is a comprehensive incident management system intended for use in both emergent and non-emergent situations. It provides hospitals of all sizes with tools needed to advance their emergency preparedness and response capability—both individually and as a member of the broader response community. # Introduction to the Hospital Incident Command System HICS is based upon the Hospital Emergency Incident Command System (HEICS), which was created in the late 1980s as an important foundation for the more than 6,000 hospitals in the United States in their efforts to prepare for and respond to various types of disasters. In developing the fourth edition of HEICS, the value and importance of using an incident management system to assist as well with daily operations, preplanned events, and non-emergent situations became apparent. Thus, the HICS was created as a system for use in both emergent and non-emergent situations, such as moving the facility, dispensing medications to hospital staff, or planning for a large hospital or community event. HICS was developed by a National Work Group of twenty hospital subject-matter experts from across the United States. In addition to the contributions of the National Work Group, ex officio members were included to ensure consistency with governmental, industrial, and hospital accreditation planning efforts and requirements. # Overview of the Principles of the Incident Command System ICS is designed to: - Be usable for managing all routine or planned events, of any size or type, by establishing a clear chain of command - Allow personnel from different agencies or departments to be integrated into a common structure that can effectively address issues and delegate responsibilities - Provide needed logistical and administrative support to operational personnel - Ensure key functions are covered and eliminate duplication The incident planning process takes place regardless of the incident size or complexity. This planning involves six (6) essential steps: - Understanding the hospital’s policy and direction - Assessing the situation - Establishing incident objectives - Determining appropriate strategies to achieve the objectives - Giving tactical direction and ensuring that it is followed (e.g., correct resources assigned to complete a task and their performance monitored) - Providing necessary back-up (assigning more or fewer resources, changing tactics, et al.) # National Incident Management System Compliance for Hospitals The Homeland Security Presidential Directive-5 (HSPD-5), issued by President George W. Bush in February 2003, created the National Incident Management System (NIMS). Until NIMS, there had been no standard for domestic incident response that united all levels of government and all emergency response agencies. The NIMS is designed to provide a framework for interoperability and compatibility among the various members of the response community. The end result is a flexible framework that facilitates governmental and nongovernmental agencies working together at all levels during all phases of an incident, regardless of its size, complexity, or location. # The Hospital Emergency Management Program The Emergency Operations Plan (EOP) outlines the hospital’s strategy for responding to and recovering from a realized threat or hazard or other incident. The document is intended to provide overall direction and coordination of the response structure and processes to be used by the hospital. An effective EOP lays the groundwork for implementation of the Incident Command System and the needed communication and coordination between operating groups. The essence of the process includes the following steps: - Designating an Emergency Program Manager Program - Establishing the Emergency Management Committee - Developing the “all hazards ” Emergency Operations Plan - Conducting a Hazard Vulnerability Analysis - Developing incident-specific guidance (Incident Planning Guides) - Coordinating with external entities - Training key staff - Exercising the EOP and incident-specific guidance through an exercise program - Conducting program review and evaluation - Learning from the lessons that are identified (organizational learning) # The Hospital Incident Command System HICS incident management team charts depict the hospital command functions that have been identified and represent how authority and responsibility are distributed within the incident management team. The activities at the Hospital Command Center (HCC) are directed by the Incident Commander, who has overall responsibility for all activities within the Hospital Command Center (HCC). The Incident Commander may appoint other Command Staff personnel to assist. Many incidents that likely will occur involve injured or ill patients. The Operations Section will be responsible for managing the tactical objectives outlined by the Incident Commander. Branches of this section include: Department Level, Patient Care, Infrastructure, Business Continuity, Security, and HazMat. The Planning Section will “collect, evaluate, and disseminate incident situation information and intelligence to Incident Command” and includes a Resources Unit, Situation Unit, Documentation Unit, and Demobilization Unit. Support requirements will be coordinated by the Logistics Section, and the Finance/Administration account for the costs associated with the response. Also, several additional incident command principles and practices are covered in this section, including incident command staff identification, building incident command staff depth, job action sheets, and incident response guides. # Life Cycle of an Incident The life cycle of an incident includes the following steps: - Alert and notification - Situation assessment and monitoring - EOP Implementation - Establishing the HCC - Building the ICS structure - Incident action planning - Communications and coordination - Staff health and safety - Operational considerations - Legal and ethical considerations - Demobilization - System recovery - Response evaluation and organizational learning # Implementation

https://www.wikidoc.org/index.php/HICS

5560472778fc1765d7b5eb767ecdf2dfe11117ef

wikidoc

HIRA

HIRA Protein HIRA is a protein that in humans is encoded by the HIRA gene. This gene is mapped to 22q11.21, centromeric to COMT. # Function The specific function of this protein has yet to be determined; however, it has been speculated to play a role in transcriptional regulation and/or chromatin and histone metabolism. Research done by Salomé Adam, Sophie E. Polo, and Geneviève Almouzni indicate that HIRA proteins are involved in restarting transcription after UVC damage Function of HIRA gene can be effectively examined by siRNA knockdown based on an independent validation. # Clinical significance It is considered the primary candidate gene in some haploinsufficiency syndromes such as DiGeorge syndrome, and insufficient production of the gene may disrupt normal embryonic development. # Model organisms Model organisms have been used in the study of HIRA function. A conditional knockout mouse line, called Hiratm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty two tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant mice survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and a decreased leukocyte cell number was recorded in male animals. # Interactions HIRA has been shown to interact with HIST1H2BK.

HIRA Protein HIRA is a protein that in humans is encoded by the HIRA gene.[1][2][3][4] This gene is mapped to 22q11.21, centromeric to COMT.[4] # Function The specific function of this protein has yet to be determined; however, it has been speculated to play a role in transcriptional regulation and/or chromatin and histone metabolism.[4] Research done by Salomé Adam, Sophie E. Polo, and Geneviève Almouzni indicate that HIRA proteins are involved in restarting transcription after UVC damage[5] Function of HIRA gene can be effectively examined by siRNA knockdown based on an independent validation.[6] # Clinical significance It is considered the primary candidate gene in some haploinsufficiency syndromes such as DiGeorge syndrome, and insufficient production of the gene may disrupt normal embryonic development.[4] # Model organisms Model organisms have been used in the study of HIRA function. A conditional knockout mouse line, called Hiratm1a(EUCOMM)Wtsi[11][12] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[13][14][15] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[9][16] Twenty two tests were carried out on mutant mice and two significant abnormalities were observed.[9] No homozygous mutant mice survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and a decreased leukocyte cell number was recorded in male animals.[9] # Interactions HIRA has been shown to interact with HIST1H2BK.[17]

https://www.wikidoc.org/index.php/HIRA

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HLTF

HLTF Helicase-like transcription factor is an enzyme that in humans is encoded by the HLTF gene. # Function This gene encodes a member of the SWI/SNF family. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein contains a RING finger DNA binding motif. Two transcript variants encoding the same protein have been found for this gene. However, use of an alternative translation start site produces an isoform that is truncated at the N-terminus compared to the full-length protein. HLTF is a double-stranded DNA translocase, one of two human homologs of Saccharomyces cerevisiae RAD5 besides SHPRH (SNF2 histone linker PHD RING helicase), that is able to carry out fork regression, similarly to Rad5. # Interactions HLTF has been shown to interact with UBE2N,.

HLTF Helicase-like transcription factor is an enzyme that in humans is encoded by the HLTF gene.[1][2] # Function This gene encodes a member of the SWI/SNF family. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein contains a RING finger DNA binding motif. Two transcript variants encoding the same protein have been found for this gene. However, use of an alternative translation start site produces an isoform that is truncated at the N-terminus compared to the full-length protein.[2] HLTF is a double-stranded DNA translocase, one of two human homologs of Saccharomyces cerevisiae RAD5 besides SHPRH (SNF2 histone linker PHD RING helicase), that is able to carry out fork regression, similarly to Rad5.[3] # Interactions HLTF has been shown to interact with UBE2N,[4] RAD18[4] and UBE2V2 [4](see also STRING functional and physical associations network : under the option 'search by name' enter 'protein name' of interest, HLTF, klick on 'GO! ', choose 'organism ', klick on 'continue ->' ).

https://www.wikidoc.org/index.php/HLTF

aea2446ba9df33af2d4beb6c0f0bbc97dbb4eea3

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HM13

HM13 Minor histocompatibility antigen H13 is a protein that in humans is encoded by the HM13 gene. # Function The minor histocompatibility antigen 13 is a nonamer peptide that originates from a protein encoded by the H13 gene. The peptide is generated by the cytosol by the proteasome, enters the endoplasmic reticulum (ER) lumen by the transporter associated with antigen processing (TAP) and is presented on the cell surface on H2-Db major histocompatibility anigen I (MHC I) molecules. The alloreactivity, which leads to transplant rejection in mice, is conferred by Val/Ile polymorphism in the ‘SSV(V/I)GVWYL’ peptide. The orthologue gene in humans is called HM13. If a related polymorphism exists, and if the HM13 serves as a Minor histocompatibility antigen, however, remains to be addressed. The protein encoded by the M13/HM13 gene is the signal peptide peptidase (SPP), an ER-resident intramembrane protease. SPP localizes to the endoplasmic reticulum, catalyzes intramembrane proteolysis of some signal peptides after they have been cleaved from a preprotein. This activity is required to generate signal sequence-derived human lymphocyte antigen-E epitopes that are recognized by the immune system, and to process hepatitis C virus core protein. The encoded protein is an integral membrane protein with sequence motifs characteristic of the presenilin-type aspartic proteases. Multiple transcript variants encoding several different isoforms have been found for this gene.

HM13 Minor histocompatibility antigen H13 is a protein that in humans is encoded by the HM13 gene.[1][2][3] # Function The minor histocompatibility antigen 13 is a nonamer peptide that originates from a protein encoded by the H13 gene.[4][5] The peptide is generated by the cytosol by the proteasome, enters the endoplasmic reticulum (ER) lumen by the transporter associated with antigen processing (TAP) and is presented on the cell surface on H2-Db major histocompatibility anigen I (MHC I) molecules. The alloreactivity, which leads to transplant rejection in mice, is conferred by Val/Ile polymorphism in the ‘SSV(V/I)GVWYL’ peptide.[6] The orthologue gene in humans is called HM13. If a related polymorphism exists, and if the HM13 serves as a Minor histocompatibility antigen, however, remains to be addressed. The protein encoded by the M13/HM13 gene is the signal peptide peptidase (SPP), an ER-resident intramembrane protease.[1] SPP localizes to the endoplasmic reticulum, catalyzes intramembrane proteolysis of some signal peptides after they have been cleaved from a preprotein. This activity is required to generate signal sequence-derived human lymphocyte antigen-E epitopes that are recognized by the immune system, and to process hepatitis C virus core protein. The encoded protein is an integral membrane protein with sequence motifs characteristic of the presenilin-type aspartic proteases. Multiple transcript variants encoding several different isoforms have been found for this gene.[3]

https://www.wikidoc.org/index.php/HM13

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HPS4

HPS4 Hermansky-Pudlak syndrome 4 protein is a protein that in humans is encoded by the HPS4 gene. Hermansky-Pudlak syndrome is a disorder of organelle biogenesis in which oculocutaneous albinism, bleeding, and pulmonary fibrosis result from defects of melanosomes, platelet dense granules, and lysosomes. Mutations in this gene as well as several others can cause this syndrome. The protein encoded by this gene appears to be important in organelle biogenesis and is similar to the mouse 'light ear' protein. Five transcript variants encoding different isoforms have been found for this gene. In addition, transcript variants utilizing alternative polyadenylation signals exist. In melanocytic cells HPS4 gene expression may be regulated by MITF.

HPS4 Hermansky-Pudlak syndrome 4 protein is a protein that in humans is encoded by the HPS4 gene.[1][2][3] Hermansky-Pudlak syndrome is a disorder of organelle biogenesis in which oculocutaneous albinism, bleeding, and pulmonary fibrosis result from defects of melanosomes, platelet dense granules, and lysosomes. Mutations in this gene as well as several others can cause this syndrome. The protein encoded by this gene appears to be important in organelle biogenesis and is similar to the mouse 'light ear' protein. Five transcript variants encoding different isoforms have been found for this gene. In addition, transcript variants utilizing alternative polyadenylation signals exist.[3] In melanocytic cells HPS4 gene expression may be regulated by MITF.[4]

https://www.wikidoc.org/index.php/HPS4

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HPS6

HPS6 Hermansky-Pudlak syndrome 6 (HPS6) also known as ruby-eye protein homolog (Ru) is a protein that in humans is encoded by the HPS6 gene. # Function This intronless gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. HPS6 along with HPS3 and HPS5 form a stable protein complex named Biogenesis of Lysosome-related Organelles Complex-2 (BLOC-2). # Clinical significance Mutations in this gene are associated with Hermansky–Pudlak syndrome type 6 characterized by albinism and prolonged bleeding.

HPS6 Hermansky-Pudlak syndrome 6 (HPS6) also known as ruby-eye protein homolog (Ru) is a protein that in humans is encoded by the HPS6 gene.[1] # Function This intronless gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes.[2] HPS6 along with HPS3 and HPS5 form a stable protein complex named Biogenesis of Lysosome-related Organelles Complex-2 (BLOC-2).[3] # Clinical significance Mutations in this gene are associated with Hermansky–Pudlak syndrome type 6 characterized by albinism and prolonged bleeding.[1][4]

https://www.wikidoc.org/index.php/HPS6

ae1b949ce0c937f0be530df1bd4de6df36ab158d

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HRAS

HRAS GTPase HRas also known as transforming protein p21 is an enzyme that in humans is encoded by the HRAS gene. The HRAS gene is located on the short (p) arm of chromosome 11 at position 15.5, from base pair 522,241 to base pair 525,549. HRas is a small G protein in the Ras subfamily of the Ras superfamily of small GTPases. Once bound to Guanosine triphosphate, H-Ras will activate a Raf kinase like c-Raf, the next step in the MAPK/ERK pathway. # Function GTPase HRas is involved in regulating cell division in response to growth factor stimulation. Growth factors act by binding cell surface receptors that span the cell's plasma membrane. Once activated, receptors stimulate signal transduction events in the cytoplasm, a process by which proteins and second messengers relay signals from outside the cell to the cell nucleus and instructs the cell to grow or divide. The HRAS protein is a GTPase and is an early player in many signal transduction pathways and is usually associated with cell membranes due to the presence of an isoprenyl group on its C-terminus. HRAS acts as a molecular on/off switch, once it is turned on it recruits and activates proteins necessary for the propagation of the receptor's signal, such as c-Raf and PI 3-kinase. HRAS binds to GTP in the active state and possesses an intrinsic enzymatic activity that cleaves the terminal phosphate of this nucleotide converting it to GDP. Upon conversion of GTP to GDP, HRAS is turned off. The rate of conversion is usually slow but can be sped up dramatically by an accessory protein of the GTPase activating protein (GAP) class, for example RasGAP. In turn HRAS can bind to proteins of the Guanine Nucleotide Exchange Factor (GEF) class, for example SOS1, which forces the release of bound nucleotide. Subsequently, GTP present in the cytosol binds and HRAS-GTP dissociates from the GEF, resulting in HRAS activation. HRAS is in the Ras family, which also includes two other proto-oncogenes: KRAS and NRAS. These proteins all are regulated in the same manner and appear to differ largely in their sites of action within the cell. # Clinical significance ## Costello syndrome At least five inherited mutations in the HRAS gene have been identified in people with Costello syndrome. Each of these mutations changes an amino acid in a critical region of the HRAS protein. The most common mutation replaces the amino acid glycine with the amino acid serine at position 12 (written as Gly12Ser or G12S). The mutations responsible for Costello syndrome lead to the production of an HRAS protein that is permanently active. Instead of triggering cell growth in response to particular signals from outside the cell, the overactive protein directs cells to grow and divide constantly. This uncontrolled cell division can result in the formation of noncancerous and cancerous tumors. Researchers are uncertain how mutations in the HRAS gene cause the other features of Costello syndrome (such as mental retardation, distinctive facial features, and heart problems), but many of the signs and symptoms probably result from cell overgrowth and abnormal cell division. ## Bladder cancer HRAS has been shown to be a proto-oncogene. When mutated, proto-oncogenes have the potential to cause normal cells to become cancerous. Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. Somatic mutations in the HRAS gene in bladder cells have been associated with bladder cancer. One specific mutation has been identified in a significant percentage of bladder tumors; this mutation substitutes one protein building block (amino acid) for another amino acid in the HRAS protein. Specifically, the mutation replaces the amino acid glycine with the amino acid valine at position 12 (written as Gly12Val, G12V, or H-RasV12). The altered HRAS protein is permanently activated within the cell. This overactive protein directs the cell to grow and divide in the absence of outside signals, leading to uncontrolled cell division and the formation of a tumor. Mutations in the HRAS gene also have been associated with the progression of bladder cancer and an increased risk of tumor recurrence after treatment. ## Other cancers Somatic mutations in the HRAS gene are probably involved in the development of several other types of cancer. These mutations lead to an HRAS protein that is always active and can direct cells to grow and divide without control. Recent studies suggest that HRAS mutations are common in thyroid, salivary duct carcinoma, epithelial-myoepithelial carcinoma, and kidney cancers. DNA copy-number gain of a segment containing HRAS is included in a genome-wide pattern, which was found to be correlated with an astrocytoma patient’s outcome. The HRAS protein also may be produced at higher levels (overexpressed) in other types of cancer cells.

HRAS GTPase HRas also known as transforming protein p21 is an enzyme that in humans is encoded by the HRAS gene.[1][2] The HRAS gene is located on the short (p) arm of chromosome 11 at position 15.5, from base pair 522,241 to base pair 525,549.[3] HRas is a small G protein in the Ras subfamily of the Ras superfamily of small GTPases. Once bound to Guanosine triphosphate, H-Ras will activate a Raf kinase like c-Raf, the next step in the MAPK/ERK pathway. # Function GTPase HRas is involved in regulating cell division in response to growth factor stimulation. Growth factors act by binding cell surface receptors that span the cell's plasma membrane. Once activated, receptors stimulate signal transduction events in the cytoplasm, a process by which proteins and second messengers relay signals from outside the cell to the cell nucleus and instructs the cell to grow or divide. The HRAS protein is a GTPase and is an early player in many signal transduction pathways and is usually associated with cell membranes due to the presence of an isoprenyl group on its C-terminus. HRAS acts as a molecular on/off switch, once it is turned on it recruits and activates proteins necessary for the propagation of the receptor's signal, such as c-Raf and PI 3-kinase. HRAS binds to GTP in the active state and possesses an intrinsic enzymatic activity that cleaves the terminal phosphate of this nucleotide converting it to GDP. Upon conversion of GTP to GDP, HRAS is turned off. The rate of conversion is usually slow but can be sped up dramatically by an accessory protein of the GTPase activating protein (GAP) class, for example RasGAP. In turn HRAS can bind to proteins of the Guanine Nucleotide Exchange Factor (GEF) class, for example SOS1, which forces the release of bound nucleotide. Subsequently, GTP present in the cytosol binds and HRAS-GTP dissociates from the GEF, resulting in HRAS activation. HRAS is in the Ras family, which also includes two other proto-oncogenes: KRAS and NRAS. These proteins all are regulated in the same manner and appear to differ largely in their sites of action within the cell. # Clinical significance ## Costello syndrome At least five inherited mutations in the HRAS gene have been identified in people with Costello syndrome. Each of these mutations changes an amino acid in a critical region of the HRAS protein. The most common mutation replaces the amino acid glycine with the amino acid serine at position 12 (written as Gly12Ser or G12S). The mutations responsible for Costello syndrome lead to the production of an HRAS protein that is permanently active. Instead of triggering cell growth in response to particular signals from outside the cell, the overactive protein directs cells to grow and divide constantly. This uncontrolled cell division can result in the formation of noncancerous and cancerous tumors. Researchers are uncertain how mutations in the HRAS gene cause the other features of Costello syndrome (such as mental retardation, distinctive facial features, and heart problems), but many of the signs and symptoms probably result from cell overgrowth and abnormal cell division. ## Bladder cancer HRAS has been shown to be a proto-oncogene. When mutated, proto-oncogenes have the potential to cause normal cells to become cancerous. Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. Somatic mutations in the HRAS gene in bladder cells have been associated with bladder cancer. One specific mutation has been identified in a significant percentage of bladder tumors; this mutation substitutes one protein building block (amino acid) for another amino acid in the HRAS protein. Specifically, the mutation replaces the amino acid glycine with the amino acid valine at position 12 (written as Gly12Val, G12V, or H-RasV12). The altered HRAS protein is permanently activated within the cell. This overactive protein directs the cell to grow and divide in the absence of outside signals, leading to uncontrolled cell division and the formation of a tumor. Mutations in the HRAS gene also have been associated with the progression of bladder cancer and an increased risk of tumor recurrence after treatment. ## Other cancers Somatic mutations in the HRAS gene are probably involved in the development of several other types of cancer. These mutations lead to an HRAS protein that is always active and can direct cells to grow and divide without control. Recent studies suggest that HRAS mutations are common in thyroid, salivary duct carcinoma,[4] epithelial-myoepithelial carcinoma,[5] and kidney cancers. DNA copy-number gain of a segment containing HRAS is included in a genome-wide pattern, which was found to be correlated with an astrocytoma patient’s outcome.[6] [7] The HRAS protein also may be produced at higher levels (overexpressed) in other types of cancer cells.

https://www.wikidoc.org/index.php/HRAS

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HSF1

HSF1 Heat shock factor 1 (HSF1) is a protein that in humans is encoded by the HSF1 gene. HSF1 is highly conserved in eukaryotes and is the primary mediator of transcriptional responses to proteotoxic stress with important roles in non-stress regulation such as development and metabolism. # Structure Human HSF1 consists of several domains which regulate its binding and activity. File:HSF1 Domain Cartoon.jpg ## DNA-Binding Domain (DBD) This N-terminal domain of approximately 100 amino acids is the most highly conserved region in the HSF protein family and consists of a helix-turn-helix loop. The DBD of each HSF1 monomer recognizes the sequence nGAAn on target DNA. Repeated sequences of the nGAAn pentamer constitute heat shock elements (HSEs) for active HSF1 trimers to bind. ## Oligomerization Domain (Leucine Zipper Domains) The two regions responsible for oligomerization between HSF1 monomers are leucine zipper (LZ) domains 1-3 and 4 (these regions are also commonly referred to as HR-A/B and HR-C). LZ1-3 is situated just downstream of the DBD while LZ4 is located between the RD and the C-terminal TAD. Under non-stress conditions, spontaneous HSF1 activation is negatively regulated by the interaction between LZ1-3 and LZ4. When induced by stress, the LZ1-3 region breaks away from the LZ4 region and forms a trimer with other HSF1 LZ1-3 domains to form a triple coiled-coil. ## Regulatory Domain (RD) The structures of the C-terminal RD and TAD of HSF1 have not been clearly resolved due to their dynamic nature. However, it is known that the RD is situated between the two regions of the oligomerization domain. The RD has been shown to regulate the TAD through negative control by repressing TAD in the absence of stress, a role that is inducibly regulated through posttranslational modifications. ## Trans-Activation Domain (TAD) This C-terminal region spans the last 150 amino acids of the HSF1 protein and contains 2 TADs (TAD1 and TAD2). TAD1, which sits at amino acids 401-420, is largely hydrophobic and is predicted to take on an alpha-helical conformation. TAD1 has been shown to directly interact with target DNA to direct HSF1's transcriptional activation. The structure of TAD2, amino acids 431-529, is not expected to be helical as it contains proline residues in addition to hydrophobic and acidic ones. The function of the HSF1 TAD is still largely uncharacterized, but Hsp70 has been shown to bind with this domain, which could describe the mechanism by which Hsp70 negatively regulates HSF1. # Function The HSF1 protein regulates the heat shock response (HSR) pathway in humans by acting as the major transcription factor for heat shock proteins. The HSR plays a protective role by ensuring proper folding and distribution of proteins within cells. This pathway is induced by not only temperature stress, but also by a variety of other stressors such as hypoxic conditions and exposure to contaminants. HSF1 transactivates genes for many cytoprotective proteins involved in heat shock, DNA damage repair, and metabolism. This illustrates the versatile role of HSF1 in not only the heat shock response, but also in aging and diseases. # Mechanism of action Under non-stress conditions, HSF1 exists primarily as an inactive monomer located throughout the nucleus and the cytoplasm. In its monomeric form, HSF1 activation is repressed by interaction with chaperones such as heat shock proteins Hsp70 and Hsp90, and TRiC/CCT. In the event of proteotoxic stress such as heat shock, these chaperones are released from HSF1 to perform their protein-folding roles; simultaneously, the export of HSF1 to the cytoplasm is inhibited. These actions allow HSF1 to trimerize and accumulate in the nucleus to stimulate transcription of target genes. # Clinical significance HSF1 is a promising drug target in cancer and proteopathy. The genes activated by HSF1 under heat shock conditions have been recently shown to differ from those activated in malignant cancer cells, and this cancer-specific HSF1 panel of genes has indicated poor prognosis in breast cancer. The ability of cancer cells to use HSF1 in a unique manner gives this protein significant clinical implications for therapies and prognoses. In the case of protein-folding diseases such as Huntington's disease (HD), however, induction of the heat shock response pathway would prove beneficial. In recent years, using cells that express the poly-glutamine expansion found in HD, it has been shown that both the HSR and HSF1 levels are reduced after heat shock. This reduced ability of diseased cells to respond to stress helps to explain the toxicity associated with certain diseases. # Interactions HSF1 has been shown to interact with: CEBPB, HSF2, HSPA1A, HSPA4, Heat shock protein 90kDa alpha (cytosolic) member A1, NCOA6, RALBP1 and SYMPK.

HSF1 Heat shock factor 1 (HSF1) is a protein that in humans is encoded by the HSF1 gene.[1] HSF1 is highly conserved in eukaryotes and is the primary mediator of transcriptional responses to proteotoxic stress with important roles in non-stress regulation such as development and metabolism.[2] # Structure Human HSF1 consists of several domains which regulate its binding and activity. File:HSF1 Domain Cartoon.jpg ## DNA-Binding Domain (DBD) This N-terminal domain of approximately 100 amino acids is the most highly conserved region in the HSF protein family and consists of a helix-turn-helix loop. The DBD of each HSF1 monomer recognizes the sequence nGAAn on target DNA. Repeated sequences of the nGAAn pentamer constitute heat shock elements (HSEs) for active HSF1 trimers to bind.[3] ## Oligomerization Domain (Leucine Zipper Domains) The two regions responsible for oligomerization between HSF1 monomers are leucine zipper (LZ) domains 1-3 and 4[4] (these regions are also commonly referred to as HR-A/B and HR-C).[3] LZ1-3 is situated just downstream of the DBD while LZ4 is located between the RD and the C-terminal TAD. Under non-stress conditions, spontaneous HSF1 activation is negatively regulated by the interaction between LZ1-3 and LZ4. When induced by stress, the LZ1-3 region breaks away from the LZ4 region and forms a trimer with other HSF1 LZ1-3 domains to form a triple coiled-coil.[4] ## Regulatory Domain (RD) The structures of the C-terminal RD and TAD of HSF1 have not been clearly resolved due to their dynamic nature.[5] However, it is known that the RD is situated between the two regions of the oligomerization domain. The RD has been shown to regulate the TAD through negative control by repressing TAD in the absence of stress, a role that is inducibly regulated through posttranslational modifications.[3][4] ## Trans-Activation Domain (TAD) This C-terminal region spans the last 150 amino acids of the HSF1 protein and contains 2 TADs (TAD1 and TAD2). TAD1, which sits at amino acids 401-420, is largely hydrophobic and is predicted to take on an alpha-helical conformation. TAD1 has been shown to directly interact with target DNA to direct HSF1's transcriptional activation. The structure of TAD2, amino acids 431-529, is not expected to be helical as it contains proline residues in addition to hydrophobic and acidic ones.[3] The function of the HSF1 TAD is still largely uncharacterized, but Hsp70 has been shown to bind with this domain, which could describe the mechanism by which Hsp70 negatively regulates HSF1.[4] # Function The HSF1 protein regulates the heat shock response (HSR) pathway in humans by acting as the major transcription factor for heat shock proteins. The HSR plays a protective role by ensuring proper folding and distribution of proteins within cells. This pathway is induced by not only temperature stress, but also by a variety of other stressors such as hypoxic conditions and exposure to contaminants.[4] HSF1 transactivates genes for many cytoprotective proteins involved in heat shock, DNA damage repair, and metabolism. This illustrates the versatile role of HSF1 in not only the heat shock response, but also in aging and diseases.[4] # Mechanism of action Under non-stress conditions, HSF1 exists primarily as an inactive monomer located throughout the nucleus and the cytoplasm. In its monomeric form, HSF1 activation is repressed by interaction with chaperones such as heat shock proteins Hsp70 and Hsp90, and TRiC/CCT.[4][6] In the event of proteotoxic stress such as heat shock, these chaperones are released from HSF1 to perform their protein-folding roles; simultaneously, the export of HSF1 to the cytoplasm is inhibited. These actions allow HSF1 to trimerize and accumulate in the nucleus to stimulate transcription of target genes.[3][4][7] # Clinical significance HSF1 is a promising drug target in cancer and proteopathy.[8] The genes activated by HSF1 under heat shock conditions have been recently shown to differ from those activated in malignant cancer cells, and this cancer-specific HSF1 panel of genes has indicated poor prognosis in breast cancer. The ability of cancer cells to use HSF1 in a unique manner gives this protein significant clinical implications for therapies and prognoses.[9] In the case of protein-folding diseases such as Huntington's disease (HD), however, induction of the heat shock response pathway would prove beneficial. In recent years, using cells that express the poly-glutamine expansion found in HD, it has been shown that both the HSR and HSF1 levels are reduced after heat shock. This reduced ability of diseased cells to respond to stress helps to explain the toxicity associated with certain diseases.[10] # Interactions HSF1 has been shown to interact with: CEBPB,[11] HSF2,[12] HSPA1A,[13][14] HSPA4,[15][16] Heat shock protein 90kDa alpha (cytosolic) member A1,[17][15] NCOA6,[18] RALBP1[17] and SYMPK.[19]

https://www.wikidoc.org/index.php/HSF1

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HSF2

HSF2 Heat shock factor protein 2 is a protein that in humans is encoded by the HSF2 gene. # Function HSF2, as well as the related gene HSF1, encodes a protein that binds specifically to the heat-shock element and has homology to HSFs of other species. Heat shock transcription factors activate heat-shock response genes under conditions of heat or other stresses. Although the names HSF1 and HSF2 were chosen for historical reasons, these peptides should be referred to as heat-shock transcription factors. # Interactions HSF2 has been shown to interact with Nucleoporin 62 and HSF1.

HSF2 Heat shock factor protein 2 is a protein that in humans is encoded by the HSF2 gene.[1][2] # Function HSF2, as well as the related gene HSF1, encodes a protein that binds specifically to the heat-shock element and has homology to HSFs of other species. Heat shock transcription factors activate heat-shock response genes under conditions of heat or other stresses. Although the names HSF1 and HSF2 were chosen for historical reasons, these peptides should be referred to as heat-shock transcription factors.[2] # Interactions HSF2 has been shown to interact with Nucleoporin 62[3] and HSF1.[4]

https://www.wikidoc.org/index.php/HSF2

2e6b459e1cc7f17d5bd547e96ac8b974d55eb287

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Heme

Heme # Overview A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic subunit; these are known as hemoproteins. # Types ## Major hemes There are several biologically important kinds of heme: The most common type is heme B; other important types include heme A and heme C. Isolated hemes are commonly designated by capital letters while hemes bound to proteins are designated by lower case letters. Cytochrome a refers to the heme A in specific combination with membrane protein forming a portion of cytochrome c oxidase. ## Other hemes - Heme L is the derivative of heme B which is covalently attached to the protein of lactoperoxidase, eosinophil peroxidase and thyroid peroxidase. The addition of peroxide with the glutamyl-375 and aspartyl-225 of lactoperoxidase forms ester bonds between these amino acid residues and the heme 1- and 5-methyl groups, respectively. Similar ester bonds with these two methyl groups are thought to form in eosinophil and thyroid peroxidases. Heme L is one important characteristic of animal peroxidases; plant peroxidases incorporate heme B. Lactoperoxidase and eosinophil peroxidase are protective enzymes responsible for the destruction of invading bacteria and virus. Thyroid peroxidase is the enzyme catalyzing the biosynthesis of the important thyroid hormones. Because lactoperoxidase destroys invading organisms in excrement, it is thought to be an important protective enzyme. - Heme M is the derivative of heme B covalently bound at the active site of myeloperoxidase. Heme M also contains the two ester bonds at the heme 1- and 5-methyls, much as the other mammalian peroxidases. In addition, a unique sulfonium ion linkage between the sulfur of a methionyl aminoacid residue and the heme 2-vinyl group is formed, giving this enzyme the unique capability of easily oxidizing chloride and bromide ions. Myeloperoxidase is present in mammalian neutrophils and is responsible for the destruction of invading bacteria and virus. It also synthesizes hypobromite by "mistake" which is a known mutagenic compound. - Heme D is another derivative of heme B, but in which the propionic acid side chain at the carbon of position 6, ring III is bound to this carbon both via the usual C-C bond but also by the carboxyl oxygen, giving heme D a fifth ring and a lactone. Ring III is also hydroxylated at position 5, in a conformation trans to the new lactone group. Heme D is the site for oxygen reduction to water of many types of bacteria at low oxygen tension. - Heme S is related to heme B by the having a formyl group at position 2 in place of the 2-vinyl group. Heme S is found in the hemoglobin of marine worms. The correct structures of heme B and heme S were first elucidated by the great German chemist Hans Fischer. The names of cytochromes typically (but not always) reflect the kinds of hemes they contain: cytochrome a contains heme A, cytochrome c contains heme C, etc. # Function Hemoproteins have diverse biological functions including the transportation of diatomic gases, chemical catalysis, diatomic gas detection, and electron transfer. The heme iron serves as a source or sink of electrons during electron transfer or redox chemistry. In peroxidase reactions, the porphyrin molecule also serves as an electron source. In the transportation or detection of diatomic gases, the gas binds to the heme iron. During the detection of diatomic gases, the binding of the gas ligand to the heme iron induces conformational changes in the surrounding protein. It has been speculated that the original evolutionary function of hemoproteins was electron transfer in primitive sulfur-based photosynthesis pathways in ancestral cyanobacteria before the appearance of molecular oxygen. Hemoproteins achieve their remarkable functional diversity by modifying the environment of the heme macrocycle within the protein matrix. For example, the ability of hemoglobin to effectively deliver oxygen to tissues is due to specific amino acid residues located near the heme molecule. Hemoglobin binds oxygen in the pulmonary vasculature, where the pH is high and the pCO2 is low, and releases it in the tissues, where the situations are reversed. This phenomenon is known as the Bohr effect. The molecular mechanism behind this effect is the steric organisation of the globin chain; a histidine residue, located adjacent to the heme group, becomes positively charged under acid circumstances, sterically releasing oxygen from the heme group. # Synthesis Details of heme synthesis can be found in the article on porphyrin. The enzymatic process that produces heme is properly called porphyrin synthesis, as all the intermediates are tetrapyrroles that are chemically classified are porphyrins. The process is highly conserved across biology. In humans, this pathway serves almost exclusively to form heme. In other species, it also produces similar substances such as cobalamin (vitamin B12). The pathway is initiated by the synthesis of D-Aminolevulinic acid (dALA or δALA) from the amino acid glycine and succinyl-CoA from the citric acid cycle (Krebs cycle). The rate-limiting enzyme responsible for this reaction, ALA synthase, is strictly regulated by intracellular iron levels and heme concentration. A low-iron level, e.g., in iron deficiency, leads to decreased porphyrin synthesis, which prevents accumulation of the toxic intermediates. This mechanism is of therapeutic importance: infusion of heme arginate of hematin can abort attacks of porphyria in patients with an inborn error of metabolism of this process, by reducing transcription of ALA synthase. The organs mainly involved in heme synthesis are the liver and the bone marrow, although every cell requires heme to function properly. Heme is seen as an intermediate molecule in catabolism of haemoglobin in the process of bilirubin metabolism. # Degradation In the first step, heme is converted to biliverdin by the enzyme heme oxygenase (HOXG). NADPH is used as the reducing agent, molecular oxygen enters the reaction, carbon monoxide is produced and the iron is released from the molecule as the ferric ion (Fe3+). In the second reaction, biliverdin is converted to bilirubin by biliverdin reductase (BVR): Bilirubin is transported into the liver bound to a protein (serum albumin), where it is conjugated with glucuronic acid to become more water soluble. The reaction is catalyzed by the enzyme UDP-glucuronide transferase (UDPGUTF). This form of bilirubin is excreted from the liver in bile. The intestinal bacteria deconjugate bilirubin diglucuronide and convert bilirubin to urobilinogens. Some urobilinogen is absorbed by intestinal cells and transported into the kidneys and excreted with urine. The remainder travels down the digestive tract and is excreted as stercobilinogen, which is responsible for the color of feces. ## Genes The following genes are part of the chemical pathway for making heme: - ALAD: aminolevulinic acid, delta-, dehydratase - ALAS1: aminolevulinate, delta-, synthase 1 - ALAS2: aminolevulinate, delta-, synthase 2 (sideroblastic/hypochromic anemia) - CPOX: coproporphyrinogen oxidase - FECH: ferrochelatase (protoporphyria) - HMBS: hydroxymethylbilane synthase - PPOX: protoporphyrinogen oxidase - UROD: uroporphyrinogen decarboxylase - UROS: uroporphyrinogen III synthase (congenital erythropoietic porphyria)

Heme # Overview A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic subunit; these are known as hemoproteins. # Types ## Major hemes There are several biologically important kinds of heme: The most common type is heme B; other important types include heme A and heme C. Isolated hemes are commonly designated by capital letters while hemes bound to proteins are designated by lower case letters. Cytochrome a refers to the heme A in specific combination with membrane protein forming a portion of cytochrome c oxidase. ## Other hemes - Heme L is the derivative of heme B which is covalently attached to the protein of lactoperoxidase, eosinophil peroxidase and thyroid peroxidase. The addition of peroxide with the glutamyl-375 and aspartyl-225 of lactoperoxidase forms ester bonds between these amino acid residues and the heme 1- and 5-methyl groups, respectively. Similar ester bonds with these two methyl groups are thought to form in eosinophil and thyroid peroxidases. Heme L is one important characteristic of animal peroxidases; plant peroxidases incorporate heme B. Lactoperoxidase and eosinophil peroxidase are protective enzymes responsible for the destruction of invading bacteria and virus. Thyroid peroxidase is the enzyme catalyzing the biosynthesis of the important thyroid hormones. Because lactoperoxidase destroys invading organisms in excrement, it is thought to be an important protective enzyme. - Heme M is the derivative of heme B covalently bound at the active site of myeloperoxidase. Heme M also contains the two ester bonds at the heme 1- and 5-methyls, much as the other mammalian peroxidases. In addition, a unique sulfonium ion linkage between the sulfur of a methionyl aminoacid residue and the heme 2-vinyl group is formed, giving this enzyme the unique capability of easily oxidizing chloride and bromide ions. Myeloperoxidase is present in mammalian neutrophils and is responsible for the destruction of invading bacteria and virus. It also synthesizes hypobromite by "mistake" which is a known mutagenic compound. - Heme D is another derivative of heme B, but in which the propionic acid side chain at the carbon of position 6, ring III is bound to this carbon both via the usual C-C bond but also by the carboxyl oxygen, giving heme D a fifth ring and a lactone. Ring III is also hydroxylated at position 5, in a conformation trans to the new lactone group. [1] Heme D is the site for oxygen reduction to water of many types of bacteria at low oxygen tension. - Heme S is related to heme B by the having a formyl group at position 2 in place of the 2-vinyl group. Heme S is found in the hemoglobin of marine worms. The correct structures of heme B and heme S were first elucidated by the great German chemist Hans Fischer. The names of cytochromes typically (but not always) reflect the kinds of hemes they contain: cytochrome a contains heme A, cytochrome c contains heme C, etc. # Function Hemoproteins have diverse biological functions including the transportation of diatomic gases, chemical catalysis, diatomic gas detection, and electron transfer. The heme iron serves as a source or sink of electrons during electron transfer or redox chemistry. In peroxidase reactions, the porphyrin molecule also serves as an electron source. In the transportation or detection of diatomic gases, the gas binds to the heme iron. During the detection of diatomic gases, the binding of the gas ligand to the heme iron induces conformational changes in the surrounding protein. It has been speculated that the original evolutionary function of hemoproteins was electron transfer in primitive sulfur-based photosynthesis pathways in ancestral cyanobacteria before the appearance of molecular oxygen. [2] Hemoproteins achieve their remarkable functional diversity by modifying the environment of the heme macrocycle within the protein matrix. For example, the ability of hemoglobin to effectively deliver oxygen to tissues is due to specific amino acid residues located near the heme molecule. Hemoglobin binds oxygen in the pulmonary vasculature, where the pH is high and the pCO2 is low, and releases it in the tissues, where the situations are reversed. This phenomenon is known as the Bohr effect. The molecular mechanism behind this effect is the steric organisation of the globin chain; a histidine residue, located adjacent to the heme group, becomes positively charged under acid circumstances, sterically releasing oxygen from the heme group. # Synthesis Details of heme synthesis can be found in the article on porphyrin. The enzymatic process that produces heme is properly called porphyrin synthesis, as all the intermediates are tetrapyrroles that are chemically classified are porphyrins. The process is highly conserved across biology. In humans, this pathway serves almost exclusively to form heme. In other species, it also produces similar substances such as cobalamin (vitamin B12). The pathway is initiated by the synthesis of D-Aminolevulinic acid (dALA or δALA) from the amino acid glycine and succinyl-CoA from the citric acid cycle (Krebs cycle). The rate-limiting enzyme responsible for this reaction, ALA synthase, is strictly regulated by intracellular iron levels and heme concentration. A low-iron level, e.g., in iron deficiency, leads to decreased porphyrin synthesis, which prevents accumulation of the toxic intermediates. This mechanism is of therapeutic importance: infusion of heme arginate of hematin can abort attacks of porphyria in patients with an inborn error of metabolism of this process, by reducing transcription of ALA synthase. The organs mainly involved in heme synthesis are the liver and the bone marrow, although every cell requires heme to function properly. Heme is seen as an intermediate molecule in catabolism of haemoglobin in the process of bilirubin metabolism. # Degradation In the first step, heme is converted to biliverdin by the enzyme heme oxygenase (HOXG). NADPH is used as the reducing agent, molecular oxygen enters the reaction, carbon monoxide is produced and the iron is released from the molecule as the ferric ion (Fe3+). In the second reaction, biliverdin is converted to bilirubin by biliverdin reductase (BVR): Bilirubin is transported into the liver bound to a protein (serum albumin), where it is conjugated with glucuronic acid to become more water soluble. The reaction is catalyzed by the enzyme UDP-glucuronide transferase (UDPGUTF). This form of bilirubin is excreted from the liver in bile. The intestinal bacteria deconjugate bilirubin diglucuronide and convert bilirubin to urobilinogens. Some urobilinogen is absorbed by intestinal cells and transported into the kidneys and excreted with urine. The remainder travels down the digestive tract and is excreted as stercobilinogen, which is responsible for the color of feces. ## Genes The following genes are part of the chemical pathway for making heme: - ALAD: aminolevulinic acid, delta-, dehydratase - ALAS1: aminolevulinate, delta-, synthase 1 - ALAS2: aminolevulinate, delta-, synthase 2 (sideroblastic/hypochromic anemia) - CPOX: coproporphyrinogen oxidase - FECH: ferrochelatase (protoporphyria) - HMBS: hydroxymethylbilane synthase - PPOX: protoporphyrinogen oxidase - UROD: uroporphyrinogen decarboxylase - UROS: uroporphyrinogen III synthase (congenital erythropoietic porphyria)

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Hair

Hair # Overview Hair is a filamentous outgrowth of protein, found only on mammals. It projects from the epidermis, though it grows from hair follicles deep in the dermis. Although many other organisms, especially insects, show filamentous outgrowths, these are not considered "hair". So-called "hairs" (trichomes) are also found on plants. The projections on arthropods, such as insects and spiders are actually insect bristles. The hair of non-human mammal species is commonly referred to as fur. There are varieties of cats, dogs, and mice bred to have little or no visible fur. In some species, hair is absent at certain stages of life. The primary component of hair fiber is keratin. Keratins are proteins, long chains (polymers) of amino acids. # Human hair ## Body hair Historically, several ideas have been advanced to describe the reduction of human body hair. All were faced with the same problem that there is no fossil record of human hair to back up the conjectures nor to determine exactly when the feature evolved. However, recent research on the evolution of lice suggests that human ancestors lost their body hair approximately 3.3 million years ago. Savanna theory suggests that nature selected humans for shorter and thinner body hair as part of a set of adaptations to the warm plains of the savanna, including bipedal locomotion and an upright posture. There are several problems (including balding) with this theory, not least of which is that cursorial hunting is used by other animals that do not show any thinning of hair. Another theory for the thin body hair on humans proposes that Fisherian runaway sexual selection played a role here (as well as in the selection of long head hair). Possibly this occurred in conjunction with neoteny, with the more juvenile appearing females being selected by males as more desirable; see types of hair and vellus hair. The aquatic ape hypothesis posits that sparsity of hair is an adaptation to an aquatic environment, but it has little support amongst scientists and very few aquatic mammals are, in fact, hairless. In reality, there may be little to explain. Humans, like all primates, are part of a trend toward sparser hair in larger animals; the density of human hair follicles on the skin is actually about what one would expect for an animal of equivalent size. The outstanding question is why so much of human hair is short, underpigmented vellus hair rather than terminal hair. ## Head hair Head hair is a type of hair that is grown on the head (sometimes referring directly to the scalp) although it is not clear if these are applicable to both men and women. Average number of head hairs (Caucasian) ## Types of hair Humans have three different types of hair: - Lanugo, the fine hair that covers nearly the entire body of fetuses - Vellus hair, the short, fine, "peach fuzz" body hair that grows in most places on the human body in both sexes - Terminal hair, the fully developed hair, which is generally longer, coarser, thicker, and darker than vellus hair. ## Growth Different parts of the human body feature different types of hair. From childhood onward, vellus hair covers the entire human body regardless of sex or race except in the following locations: the lips, the palms of hands, the soles of feet, certain external genital areas, the navel and scar tissue. The density of the hairs (in hair follicles per square centimeter) varies from one person to another. The rising level of male hormones (androgens) during puberty causes a transformation process of vellus hair into terminal hair on several parts of the body. The hair follicles respond to androgens, primarily testosterone and its derivatives; the hair in these locations can be thus termed androgenic hair. The rate of hair growth and the weight of the hairs increase. However, different areas respond with different sensitivities. As testosterone levels increase, the sequence of appearance of androgenic hair reflects the gradations of androgen sensitivity. The pubic area is most sensitive, and heavier hair usually grows there first in response to androgens. Areas on the human body that develop terminal hair growth due to rising androgens in both sexes, men and women, are the underarms and the pubic area. In contrast, normally only men grow androgenic hair in other areas. There is a sexual dimorphism in the amount and distribution of androgenic hair, with males having more terminal hair (particularly facial hair, chest hair, abdominal hair and hair on legs and arms) and females having more vellus hair, which is less visible. The genetic disposition determines the sex-dependent and individual rising of androgens and therefore the development of androgenic hair. Increased body hair on women following the male pattern can be referred to as hirsutism. An excessive and abnormal hair growth on the body of males and females is defined as hypertrichosis. Considering an individual occurrence of body hair as abnormal does not implicitly depend on medical indications but also on cultural and social attitudes. Individual hairs alternate periods of growth and dormancy. During the growth portion of the cycle, hair follicles are long and bulbous, and the hair advances outward at about a third of a millimeter per day. After three to six months, body hair growth stops (the pubic and armpit areas having the longest growth period). The follicle shrinks and the root of the hair grows rigid. Following a period of dormancy, another growth cycle starts, and eventually a new hair pushes the old one out of the follicle from beneath. Head hair, by comparison, grows for a long duration and to a great length before being shed. The rate of growth is approximately 15 millimeters, or about ⅝ inch, per month. ## Texture Hair texture is measured by the degree of which one's hair is either fine or coarse, which in turn varies according to the diameter of each individual hair. There are usually four major types of hair texture: fine, medium, coarse and wiry. Within the four texture ranges hair can also be thin, medium or thick density and it can be straight, curly, wavy or kinky. Hair conditioner will also alter the ultimate equation and can be healthy, normal, oily, dry, damaged or a combination. Hair can also be textured if straighteners, crimpers, curlers, etc are used to style hair. Also, an expert hairdresser can change the hair texture with the use of special chemicals. Hair is genetically programmed to be straight, curly or wavy, and it tends to change over time. For many years, it was believed that the shape of a person’s hair was determined by the individual hair shafts, and that curly hair was curly because the cross-section of the hair shaft was flatter and had more intertwined layers than straight hair, which was round. But scientists have determined that whether your hair is curly or straight is determined by the shape of the follicle itself and the direction in which each strand grows out of its follicle. Curly hair is shaped like an elongated oval and grows at a sharp angle to the scalp. Curly hair has a different biological structure than straight hair. It tends to be much drier than straight hair because the oils secreted into the hair shaft by the sebaceous glands can more easily travel down the shaft of straight hair. People with very curly hair may find that this hair type can be dry, hard to manage, and often frizzy. Hair, whether it is curly or straight, is affected by the amount of humidity in the air. It serves as a "truth serum" for the hair, forcing water back into the hair fiber and forcing hair shaft to return to its original structure. This may be more noticeable in somebody with curly hair because it tends to get frizzy when the humidity rises. Hair texture variation is likely to have resulted from a significant event in human evolutionary history. Evolutionary biologists agree that the evidence suggests that genus Homo arose in East Africa approximately 2 million years ago. During this time body size increased in response to richer dietary intake. This increase was most likely a reflection of rapidly increasing brain size among members of this genus, which facilitated an increasing intellectual capacity that made more varied dietary access possible (i.e. via new hunting and scavenging techniques etc.). Jablonski et al (2004) postulate that as body size increase, it became evolutionarily necessary to expell heat from the body at a more rapid rate. As a result, humans developed the ability to sweat. They also lost body hair in order to facilitate sweat evaporation and hence cooling of the body. ## Aging Older people tend to develop grey hair because the pigment in the hair is lost and the hair becomes colorless. Grey hair is considered to be a characteristic of normal aging. The age at which this occurs varies from person to person, but in general nearly everyone 75 years or older has grey hair, and in general men tend to become grey at younger ages than women. It should be noted however, that grey hair in itself is not actually grey; the grey head of hair is a result of a combination of the dark and white/colorless hair forming an overall 'grey' appearance to the observer. As such, people starting out with very pale blond hair usually develop white hair instead of grey hair when aging. Red hair usually doesn't turn grey with age; rather it becomes a sandy color and afterward turns white. In fact, the grey or white appearance of individual hair fibers is a result of light scattering from air bubbles in the central medula of the hair fiber. Some degree of scalp hair loss or thinning generally accompanies aging in both males and females, and it's estimated that half of all men are affected by male pattern baldness by the time they are 50. The tendency toward baldness is a trait shared by a number of other primate species, and is thought to have evolutionary roots. It is commonly claimed that hair and nails will continue growing for several days after death. This is a myth; the appearance of growth is actually caused by the retraction of skin as the surrounding tissue dehydrates, making nails and hair more prominent. ## Pathological impacts on hair Drugs used in cancer chemotherapy frequently cause a temporary loss of hair, noticeable on the head and eyebrows, because they kill all rapidly dividing cells, not just the cancerous ones. Other diseases and traumas can cause temporary or permanent loss of hair, either generally or in patches. The hair shafts may also store certain poisons for years, even decades, after death. In the case of Col. Lafayette Baker, who died July 3, 1868, use of an atomic absorption spectrophotometer showed the man was killed by white arsenic. The prime suspect was Wally Pollack, Baker's brother-in-law. According to Dr. Ray A. Neff, Pollack had laced Baker's beer with it over a period of months, and a century or so later minute traces of arsenic showed up in the dead man's hair. Mrs. Baker's diary seems to confirm that it was indeed arsenic, as she writes of how she found some vials of it inside her brother's suitcoat one day. ## Width According to The Physics Factbook, the diameter of human hair ranges from 17 to 181 µm. # Cultural attitudes ## Head hair The remarkable head hair of humans has gained an important significance in nearly all present societies as well as any given historical period throughout the world. The haircut has always played a significant cultural and social role. In ancient Egypt head hair was often shaved, especially amongst children, as long hair was uncomfortable in the heat. Children were often left with a long lock of hair growing from one part of their heads, the practice being so common that it became the standard in Egyptian art for artists to depict children as always wearing this "sidelock". Many adult men and women kept their heads permanently shaved for comfort in the heat and to keep the head free of lice, while wearing a wig in public. In ancient Greece and ancient Rome men and women already differed from each other through their haircuts. The head hair of women was long and pulled back into a chignon. Many dyed their hair red with henna and sprinkled it with gold powder, often adorning it with fresh flowers. Men’s hair was short and even occasionally shaved. In Rome hairdressing became ever more popular and the upper classes were attended to by slaves or visited public barber shops. The traditional hair styling in some parts of Africa also gives interesting examples of how people dealt with their head hair. The Maasai warriors tied the front hair into sections of tiny braids while the back hair was allowed to grow to waist length. Women and non-warriors, however, shaved their heads. Many tribes dyed the hair with red earth and grease; some stiffened it with animal dung. Contemporary social and cultural conditions have constantly influenced popular hair styles. From the 17th century into the early 19th century it was the norm in Western culture for men to have long hair often tied back into a ponytail. Famous long-haired men include René Descartes, Giacomo Casanova, Oliver Cromwell and George Washington. During his younger years Napoleon Bonaparte had a long and flamboyant head of hair. Before World War I men generally had longer hair and beards. The trench warfare between 1914 and 1918 exposed men to lice and flea infestations, which prompted the order to cut hair short, establishing a norm that has persisted. It has also been advanced that short hair on men has been enforced as a means of control, as shown in the military and police and other forces that require obedience and discipline. Additionally, slaves and defeated armies were often required to shave their heads, in both pre-medieval Europe and China. Long hair was almost universal among women in Western culture until World War I. Many women in conservative Pentecostal groups abstain from trimming their hair after conversion (and some have never had their hair trimmed or cut at all since birth). The social revolution of the 1960s led to a renaissance of unchecked hair growth. Hair length is measured from the front scalp line on the forehead up over the top of the head and down the back to the floor. Standard milestones in this process of hair growing are waist length, hip length, classic length (midpoint on the body, where the buttocks meet the thighs), thigh length, knee length, ankle length and even beyond. It takes about seven years, including occasional trims, to grow one's hair to waist length. Terminal length varies from person to person according to genetics and overall health. A thriving salon culture in Detroit gave rise to the Detroit Hair Wars in 1991. Using the medium of human and synthetic hair, elaborate fantastical head pieces, such as spider webs, flowers and flying "hair-y copters", have been made by participants. ## Body hair The attitudes towards hair on the human body also vary between different cultures and times. In some cultures profuse chest hair on men is a symbol of virility and masculinity; other societies display a hairless body as a sign of youthfulness. In ancient Egypt, people regarded a completely smooth, hairless body as the standard of beauty. An upper class Egyptian woman took great pains to ensure that she did not have a single hair on her body, except for the top of her head (and even this was often replaced with a wig). The ancient Greeks later adopted this smooth ideal, considering a hairless body to be representative of youth and beauty. This is reflected in Greek female sculptures which do not display any pubic hair. Islam stipulates many tenets with respect to hair, such as the covering of hair by women and the removal of armpit and pubic hair (see five physical characteristics traits of fitrah). In Western societies it became a public trend during the late twentieth century, particularly for women, to reduce or to remove their body hair. The bikini and Brazilian waxing fashion as well as the sexual imagery in advertising and movies are major reasons for this development. This media trend began in the United States and is becoming ever more popular throughout other Western countries. It was also beginning to gain currency among men, among whom shaving or trimming one's body hair is sometimes jokingly called "manscaping". ## Hair as business factor Hair care for humans is a major world industry with specialized tools, chemicals and techniques. The business of various products connected with human hair has become an important industrial and financial factor in Western societies.

Hair Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Hair is a filamentous outgrowth of protein, found only on mammals. It projects from the epidermis, though it grows from hair follicles deep in the dermis. Although many other organisms, especially insects, show filamentous outgrowths, these are not considered "hair". So-called "hairs" (trichomes) are also found on plants. The projections on arthropods, such as insects and spiders are actually insect bristles. The hair of non-human mammal species is commonly referred to as fur. There are varieties of cats, dogs, and mice bred to have little or no visible fur. In some species, hair is absent at certain stages of life. The primary component of hair fiber is keratin. Keratins are proteins, long chains (polymers) of amino acids. # Human hair ## Body hair Historically, several ideas have been advanced to describe the reduction of human body hair. All were faced with the same problem that there is no fossil record of human hair to back up the conjectures nor to determine exactly when the feature evolved. However, recent research on the evolution of lice suggests that human ancestors lost their body hair approximately 3.3 million years ago.[1] Savanna theory suggests that nature selected humans for shorter and thinner body hair as part of a set of adaptations to the warm plains of the savanna, including bipedal locomotion and an upright posture. There are several problems (including balding) with this theory, not least of which is that cursorial hunting is used by other animals that do not show any thinning of hair. Another theory for the thin body hair on humans proposes that Fisherian runaway sexual selection played a role here (as well as in the selection of long head hair). Possibly this occurred in conjunction with neoteny, with the more juvenile appearing females being selected by males as more desirable; see types of hair and vellus hair. The aquatic ape hypothesis posits that sparsity of hair is an adaptation to an aquatic environment, but it has little support amongst scientists and very few aquatic mammals are, in fact, hairless. In reality, there may be little to explain. Humans, like all primates, are part of a trend toward sparser hair in larger animals; the density of human hair follicles on the skin is actually about what one would expect for an animal of equivalent size[2]. The outstanding question is why so much of human hair is short, underpigmented vellus hair rather than terminal hair. ## Head hair Head hair is a type of hair that is grown on the head (sometimes referring directly to the scalp)</ref> although it is not clear if these are applicable to both men and women. Average number of head hairs (Caucasian) [2] ## Types of hair Humans have three different types of hair: - Lanugo, the fine hair that covers nearly the entire body of fetuses - Vellus hair, the short, fine, "peach fuzz" body hair that grows in most places on the human body in both sexes - Terminal hair, the fully developed hair, which is generally longer, coarser, thicker, and darker than vellus hair. ## Growth Different parts of the human body feature different types of hair. From childhood onward, vellus hair covers the entire human body regardless of sex or race except in the following locations: the lips, the palms of hands, the soles of feet, certain external genital areas, the navel and scar tissue. The density of the hairs (in hair follicles per square centimeter) varies from one person to another. The rising level of male hormones (androgens) during puberty causes a transformation process of vellus hair into terminal hair on several parts of the body. The hair follicles respond to androgens, primarily testosterone and its derivatives; the hair in these locations can be thus termed androgenic hair. The rate of hair growth and the weight of the hairs increase. However, different areas respond with different sensitivities. As testosterone levels increase, the sequence of appearance of androgenic hair reflects the gradations of androgen sensitivity. The pubic area is most sensitive, and heavier hair usually grows there first in response to androgens. Areas on the human body that develop terminal hair growth due to rising androgens in both sexes, men and women, are the underarms and the pubic area. In contrast, normally only men grow androgenic hair in other areas. There is a sexual dimorphism in the amount and distribution of androgenic hair, with males having more terminal hair (particularly facial hair, chest hair, abdominal hair and hair on legs and arms) and females having more vellus hair, which is less visible. The genetic disposition determines the sex-dependent and individual rising of androgens and therefore the development of androgenic hair. Increased body hair on women following the male pattern can be referred to as hirsutism. An excessive and abnormal hair growth on the body of males and females is defined as hypertrichosis. Considering an individual occurrence of body hair as abnormal does not implicitly depend on medical indications but also on cultural and social attitudes. Individual hairs alternate periods of growth and dormancy. During the growth portion of the cycle, hair follicles are long and bulbous, and the hair advances outward at about a third of a millimeter per day. After three to six months, body hair growth stops (the pubic and armpit areas having the longest growth period). The follicle shrinks and the root of the hair grows rigid. Following a period of dormancy, another growth cycle starts, and eventually a new hair pushes the old one out of the follicle from beneath. Head hair, by comparison, grows for a long duration and to a great length before being shed. The rate of growth is approximately 15 millimeters, or about ⅝ inch, per month. ## Texture Hair texture is measured by the degree of which one's hair is either fine or coarse, which in turn varies according to the diameter of each individual hair. There are usually four major types of hair texture: fine, medium, coarse and wiry. Within the four texture ranges hair can also be thin, medium or thick density and it can be straight, curly, wavy or kinky. Hair conditioner will also alter the ultimate equation and can be healthy, normal, oily, dry, damaged or a combination. Hair can also be textured if straighteners, crimpers, curlers, etc are used to style hair. Also, an expert hairdresser can change the hair texture with the use of special chemicals. Hair is genetically programmed to be straight, curly or wavy, and it tends to change over time. For many years, it was believed that the shape of a person’s hair was determined by the individual hair shafts, and that curly hair was curly because the cross-section of the hair shaft was flatter and had more intertwined layers than straight hair, which was round. But scientists have determined that whether your hair is curly or straight is determined by the shape of the follicle itself and the direction in which each strand grows out of its follicle. Curly hair is shaped like an elongated oval and grows at a sharp angle to the scalp. Curly hair has a different biological structure than straight hair. It tends to be much drier than straight hair because the oils secreted into the hair shaft by the sebaceous glands can more easily travel down the shaft of straight hair. People with very curly hair may find that this hair type can be dry, hard to manage, and often frizzy. Hair, whether it is curly or straight, is affected by the amount of humidity in the air. It serves as a "truth serum" for the hair, forcing water back into the hair fiber and forcing hair shaft to return to its original structure. This may be more noticeable in somebody with curly hair because it tends to get frizzy when the humidity rises. Hair texture variation is likely to have resulted from a significant event in human evolutionary history. Evolutionary biologists agree that the evidence suggests that genus Homo arose in East Africa approximately 2 million years ago. During this time body size increased in response to richer dietary intake. This increase was most likely a reflection of rapidly increasing brain size among members of this genus, which facilitated an increasing intellectual capacity that made more varied dietary access possible (i.e. via new hunting and scavenging techniques etc.). Jablonski et al (2004) postulate that as body size increase, it became evolutionarily necessary to expell heat from the body at a more rapid rate. As a result, humans developed the ability to sweat. They also lost body hair in order to facilitate sweat evaporation and hence cooling of the body. ## Aging Older people tend to develop grey hair because the pigment in the hair is lost and the hair becomes colorless. Grey hair is considered to be a characteristic of normal aging. The age at which this occurs varies from person to person, but in general nearly everyone 75 years or older has grey hair, and in general men tend to become grey at younger ages than women. It should be noted however, that grey hair in itself is not actually grey; the grey head of hair is a result of a combination of the dark and white/colorless hair forming an overall 'grey' appearance to the observer. As such, people starting out with very pale blond hair usually develop white hair instead of grey hair when aging. Red hair usually doesn't turn grey with age; rather it becomes a sandy color and afterward turns white. In fact, the grey or white appearance of individual hair fibers is a result of light scattering from air bubbles in the central medula of the hair fiber. Some degree of scalp hair loss or thinning generally accompanies aging in both males and females, and it's estimated that half of all men are affected by male pattern baldness by the time they are 50[3]. The tendency toward baldness is a trait shared by a number of other primate species, and is thought to have evolutionary roots. It is commonly claimed that hair and nails will continue growing for several days after death. This is a myth; the appearance of growth is actually caused by the retraction of skin as the surrounding tissue dehydrates, making nails and hair more prominent. ## Pathological impacts on hair Drugs used in cancer chemotherapy frequently cause a temporary loss of hair, noticeable on the head and eyebrows, because they kill all rapidly dividing cells, not just the cancerous ones. Other diseases and traumas can cause temporary or permanent loss of hair, either generally or in patches. The hair shafts may also store certain poisons for years, even decades, after death. In the case of Col. Lafayette Baker, who died July 3, 1868, use of an atomic absorption spectrophotometer showed the man was killed by white arsenic. The prime suspect was Wally Pollack, Baker's brother-in-law. According to Dr. Ray A. Neff, Pollack had laced Baker's beer with it over a period of months, and a century or so later minute traces of arsenic showed up in the dead man's hair. Mrs. Baker's diary seems to confirm that it was indeed arsenic, as she writes of how she found some vials of it inside her brother's suitcoat one day. ## Width According to The Physics Factbook, the diameter of human hair ranges from 17 to 181 µm.[3] # Cultural attitudes ## Head hair The remarkable head hair of humans has gained an important significance in nearly all present societies as well as any given historical period throughout the world. The haircut has always played a significant cultural and social role. In ancient Egypt head hair was often shaved, especially amongst children, as long hair was uncomfortable in the heat. Children were often left with a long lock of hair growing from one part of their heads, the practice being so common that it became the standard in Egyptian art for artists to depict children as always wearing this "sidelock". Many adult men and women kept their heads permanently shaved for comfort in the heat and to keep the head free of lice, while wearing a wig in public. In ancient Greece and ancient Rome men and women already differed from each other through their haircuts. The head hair of women was long and pulled back into a chignon. Many dyed their hair red with henna and sprinkled it with gold powder, often adorning it with fresh flowers. Men’s hair was short and even occasionally shaved. In Rome hairdressing became ever more popular and the upper classes were attended to by slaves or visited public barber shops. The traditional hair styling in some parts of Africa also gives interesting examples of how people dealt with their head hair. The Maasai warriors tied the front hair into sections of tiny braids while the back hair was allowed to grow to waist length. Women and non-warriors, however, shaved their heads. Many tribes dyed the hair with red earth and grease; some stiffened it with animal dung. Contemporary social and cultural conditions have constantly influenced popular hair styles. From the 17th century into the early 19th century it was the norm in Western culture for men to have long hair often tied back into a ponytail. Famous long-haired men include René Descartes, Giacomo Casanova, Oliver Cromwell and George Washington. During his younger years Napoleon Bonaparte had a long and flamboyant head of hair. Before World War I men generally had longer hair and beards. The trench warfare between 1914 and 1918 exposed men to lice and flea infestations, which prompted the order to cut hair short, establishing a norm that has persisted. It has also been advanced that short hair on men has been enforced as a means of control, as shown in the military and police and other forces that require obedience and discipline. Additionally, slaves and defeated armies were often required to shave their heads, in both pre-medieval Europe and China. Long hair was almost universal among women in Western culture until World War I. Many women in conservative Pentecostal groups abstain from trimming their hair after conversion (and some have never had their hair trimmed or cut at all since birth). The social revolution of the 1960s led to a renaissance of unchecked hair growth. Hair length is measured from the front scalp line on the forehead up over the top of the head and down the back to the floor. Standard milestones in this process of hair growing are waist length, hip length, classic length (midpoint on the body, where the buttocks meet the thighs), thigh length, knee length, ankle length and even beyond. It takes about seven years, including occasional trims, to grow one's hair to waist length. Terminal length varies from person to person according to genetics and overall health. A thriving salon culture in Detroit gave rise to the Detroit Hair Wars in 1991. Using the medium of human and synthetic hair, elaborate fantastical head pieces, such as spider webs, flowers and flying "hair-y copters", have been made by participants.[4] ## Body hair The attitudes towards hair on the human body also vary between different cultures and times. In some cultures profuse chest hair on men is a symbol of virility and masculinity; other societies display a hairless body as a sign of youthfulness. In ancient Egypt, people regarded a completely smooth, hairless body as the standard of beauty. An upper class Egyptian woman took great pains to ensure that she did not have a single hair on her body, except for the top of her head (and even this was often replaced with a wig[4]). The ancient Greeks later adopted this smooth ideal, considering a hairless body to be representative of youth and beauty. This is reflected in Greek female sculptures which do not display any pubic hair. Islam stipulates many tenets with respect to hair, such as the covering of hair by women and the removal of armpit and pubic hair (see five physical characteristics traits of fitrah). In Western societies it became a public trend during the late twentieth century, particularly for women, to reduce or to remove their body hair. The bikini and Brazilian waxing fashion as well as the sexual imagery in advertising and movies are major reasons for this development. This media trend began in the United States and is becoming ever more popular throughout other Western countries. It was also beginning to gain currency among men, among whom shaving or trimming one's body hair is sometimes jokingly called "manscaping". ## Hair as business factor Hair care for humans is a major world industry with specialized tools, chemicals and techniques. The business of various products connected with human hair has become an important industrial and financial factor in Western societies. # External links - Discussion about shaving and cultures - Answers to several questions related to hair from curious kids

https://www.wikidoc.org/index.php/Hair

9e13992279055d5ff0b97e433998a5b3b2a42c3c

wikidoc

TSC1

TSC1 Tuberous sclerosis 1 (TSC1), also known as Hamartin, is a protein that in humans is encoded by the TSC1 gene. # Function TSC1 functions as a co-chaperone which inhibits the ATPase activity of the chaperone Hsp90 (heat shock protein-90) and decelerates its chaperone cycle. Tsc1 functions as a facilitator of Hsp90 in chaperoning the kinase and non-kinase clients including Tsc2, therefore preventing their ubiquitination and degradation in the proteasome. TSC1, TSC2 and TBC1D7 is a multi-protein complex also known as the TSC complex. This complex negatively regulates mTORC1 signaling by functioning as a GTPase-activating protein (GAP) for the small GTPase Rheb, an essential activator of mTORC1. The TSC complex has been implicated as a tumor suppressor. # Clinical significance Defects in this gene can cause tuberous sclerosis, due to a functional impairment of the TSC complex. Defects in TSC1 may also be a cause of focal cortical dysplasia. TSC1 may be involved in protecting brain neurons in the CA3 region of the hippocampus from the effects of stroke. # Interactions TSC1 has been shown to interact with: - AKT1, - HSP70 - HSP90 - NEFL, - PLK1, and - TSC2.

TSC1 Tuberous sclerosis 1 (TSC1), also known as Hamartin, is a protein that in humans is encoded by the TSC1 gene.[1] # Function TSC1 functions as a co-chaperone which inhibits the ATPase activity of the chaperone Hsp90 (heat shock protein-90) and decelerates its chaperone cycle. Tsc1 functions as a facilitator of Hsp90 in chaperoning the kinase and non-kinase clients including Tsc2, therefore preventing their ubiquitination and degradation in the proteasome.[2] TSC1, TSC2 and TBC1D7 is a multi-protein complex also known as the TSC complex. This complex negatively regulates mTORC1 signaling by functioning as a GTPase-activating protein (GAP) for the small GTPase Rheb, an essential activator of mTORC1. The TSC complex has been implicated as a tumor suppressor. # Clinical significance Defects in this gene can cause tuberous sclerosis, due to a functional impairment of the TSC complex.[citation needed] Defects in TSC1 may also be a cause of focal cortical dysplasia.[citation needed] TSC1 may be involved in protecting brain neurons in the CA3 region of the hippocampus from the effects of stroke.[3] # Interactions TSC1 has been shown to interact with: - AKT1,[4][5] - HSP70 [2] - HSP90 [2] - NEFL,[6] - PLK1,[7] and - TSC2.[5][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]

https://www.wikidoc.org/index.php/Hamartin

0714ec57430aeb2bee37484471df6e280397946e

wikidoc

Hand

Hand # Overview The hands (med./lat.: manus, pl. manūs) are the two intricate, prehensile, multi-fingered body parts normally located at the end of each arm of a human or other primate. They are the chief organs for physically manipulating the environment, using anywhere from the roughest motor skills (wielding a club) to the finest (threading a needle), and since the fingertips contain some of the densest areas of nerve endings on the human body, they are also the richest source of tactile feedback so that sense of touch is intimately associated with human hands. Like other paired organs (eyes, ears, legs), each hand is dominantly controlled by the opposing brain hemisphere, and thus handedness, or preferred hand choice for single-handed activities such as writing with a pen, reflects a significant individual trait. # What constitutes a hand? Many mammals and other animals have grasping appendages similar in form to a hand such as paws, claws, and talons, but these are not scientifically considered to be hands. The scientific use of the term hand to distinguish the terminations of the front paws from the hind ones is an example of anthropomorphism. The only true hands appear in the mammalian order of primates. Hands must also have opposable thumbs, as described later in the text. Humans have only two hands (except in cases of polymelia), which are attached to the arms. Apes and monkeys are sometimes described as having four hands, because the toes are long and the hallux is opposable and looks more like a thumb, thus enabling the feet to be used as hands. Also, some apes have toes that are longer than human fingers. # Anatomy of the human hand The human hand consists of a broad palm (metacarpus) with 5 digits, attached to the forearm by a joint called the wrist (carpus). The back of the hand is formally called the dorsum of the hand. ## Digits The four fingers on the hand are used for the outermost performance; these four digits can be folded over the palm which allows the grasping of objects. Each finger, starting with the one closest to the thumb, has a colloquial name to distinguish it from the others: - index finger (med./lat.:digitus secundus manus), pointer finger, or forefinger - middle finger (med./lat.:digitus me´dius) - ring finger (med./lat.:digitus annula´ris) - little finger (med./lat.:digitus mi´nimus ma´nus) or 'pinky' The thumb (connected to the trapezium) is located on one of the sides, parallel to the arm. The thumb can be easily rotated 90°, on a level perpendicular to the palm, unlike the other fingers which can only be rotated approximately 45°. A reliable way of identifying true hands is from the presence of opposable thumbs. Opposable thumbs are identified by the ability to be brought opposite to the fingers, a muscle action known as opposition. ## Bones The human hand has 27 bones: the carpus or wrist account for 8; the metacarpus or palm contains 5; the remaining 14 are digital bones, your fingers and thumb. The eight bones of the wrist are arranged in two rows of four. These bones fit into a shallow socket formed by the bones of the forearm. The bones of proximal row are (from lateral to medial): scaphoid, lunate, triquetral and pisiform. The bones of the distal row are (from lateral to medial): trapezium, trapezoid, capitate and hamate. The palm has 5 bones (metacarpals), one to each of the 5 digits. These metacarpals have a head and a shaft. Human hands contain 14 digital bones, also called phalanx bones: 2 in the thumb (the thumb has no middle phalanx) and 3 in each of the four fingers. These are: - the distal phalanx, carrying the nail, - the middle phalanx and - the proximal phalanx. Sesamoid bones are small ossified nodes embedded in the tendons to provide extra leverage and reduce pressure on the underlying tissue. Many exist around the palm at the bases of the digits; the exact number varies between different people. ## Articulations Also of note is that the articulation of the human hand is more complex and delicate than that of comparable organs in any other animals. Without this extra articulation, we would not be able to operate a wide variety of tools and devices. The hand can also form a fist, for example in combat, or as a gesture. The articulations are: - interphalangeal articulations of hand - metacarpophalangeal joints - intercarpal articulations - wrist (may also be viewed as belonging to the forearm.) ## Muscles and tendons The movements of the human hand are accomplished by two sets of each of these tissues. They can be subdivided into two groups: the extrinsic and intrinsic muscle groups. The extrinsic muscle groups are the long flexors and extensors. They are called extrinsic because the muscle belly is located on the forearm. The intrinsic muscle groups are the thenar and hypothenar muscles (thenar referring to the thumb, hypothenar to the small finger), the interosseus muscles (between the metacarpal bones, four dorsally and three volarly) and the lumbrical muscles. These muscles arise from the deep flexor (and are special because they have no bony origin) and insert on the dorsal extensor hood mechanism. The fingers have two long flexors, located on the underside of the forearm. They insert by tendons to the phalanges of the fingers. The deep flexor attaches to the distal phalanx, and the superficial flexor attaches to the middle phalanx. The flexors allow for the actual bending of the fingers. The thumb has one long flexor and a short flexor in the thenar muscle group. The human thumb also has other muscles in the thenar group (opponens- and abductor muscle), moving the thumb in opposition, making grasping possible. The extensors are located on the back of the forearm and are connected in a more complex way than the flexors to the dorsum of the fingers. The tendons unite with the interosseous and lumbrical muscles to form the extensorhood mechanism. The primary function of the extensors is to straighten out the digits. The thumb has two extensors in the forearm; the tendons of these form the anatomical snuff box. Also, the index finger and the little finger have an extra extensor, used for instance for pointing. The extensors are situated within 6 separate compartments. The 1st compartment contains abductor pollicis longus and extensor pollicis brevis. The 2nd compartment contains extensors carpi radialis longus and brevis. The 3rd compartment contains extensor pollicis longus. The extensor digitorum indicis and extensor digititorum communis are within the 4th compartment. Extensor digiti minimi is in the fifth, and extensor carpi ulnaris is in the 6th. ## Variation Some people have more than the usual number of fingers or toes, a condition called polydactyly. Others may have more than the typical number of metacarpal bones, a condition often caused by genetic disorders like Catel-Manzke syndrome. The average length of an adult male hand is 189 mm, while the average length of an adult female hand is 172 mm. The average hand breadth for adult males and females is 84 and 74 mm respectively.

Hand Template:Infobox Anatomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The hands (med./lat.: manus, pl. manūs) are the two intricate, prehensile, multi-fingered body parts normally located at the end of each arm of a human or other primate. They are the chief organs for physically manipulating the environment, using anywhere from the roughest motor skills (wielding a club) to the finest (threading a needle), and since the fingertips contain some of the densest areas of nerve endings on the human body, they are also the richest source of tactile feedback so that sense of touch is intimately associated with human hands. Like other paired organs (eyes, ears, legs), each hand is dominantly controlled by the opposing brain hemisphere, and thus handedness, or preferred hand choice for single-handed activities such as writing with a pen, reflects a significant individual trait. # What constitutes a hand? Many mammals and other animals have grasping appendages similar in form to a hand such as paws, claws, and talons, but these are not scientifically considered to be hands. The scientific use of the term hand to distinguish the terminations of the front paws from the hind ones is an example of anthropomorphism. The only true hands appear in the mammalian order of primates. Hands must also have opposable thumbs, as described later in the text. Humans have only two hands (except in cases of polymelia),[1] which are attached to the arms. Apes and monkeys are sometimes described as having four hands, because the toes are long and the hallux is opposable and looks more like a thumb, thus enabling the feet to be used as hands. Also, some apes have toes that are longer than human fingers[2]. # Anatomy of the human hand The human hand consists of a broad palm (metacarpus) with 5 digits, attached to the forearm by a joint called the wrist (carpus).[2][3] The back of the hand is formally called the dorsum of the hand. ## Digits The four fingers on the hand are used for the outermost performance; these four digits can be folded over the palm which allows the grasping of objects. Each finger, starting with the one closest to the thumb, has a colloquial name to distinguish it from the others: - index finger (med./lat.:digitus secundus manus), pointer finger, or forefinger - middle finger (med./lat.:digitus me´dius) - ring finger (med./lat.:digitus annula´ris) - little finger (med./lat.:digitus mi´nimus ma´nus) or 'pinky' The thumb (connected to the trapezium) is located on one of the sides, parallel to the arm. The thumb can be easily rotated 90°, on a level perpendicular to the palm, unlike the other fingers which can only be rotated approximately 45°. A reliable way of identifying true hands is from the presence of opposable thumbs. Opposable thumbs are identified by the ability to be brought opposite to the fingers, a muscle action known as opposition. ## Bones The human hand has 27 bones: the carpus or wrist account for 8; the metacarpus or palm contains 5; the remaining 14 are digital bones, your fingers and thumb. The eight bones of the wrist are arranged in two rows of four. These bones fit into a shallow socket formed by the bones of the forearm. The bones of proximal row are (from lateral to medial): scaphoid, lunate, triquetral and pisiform. The bones of the distal row are (from lateral to medial): trapezium, trapezoid, capitate and hamate. The palm has 5 bones (metacarpals), one to each of the 5 digits. These metacarpals have a head and a shaft. Human hands contain 14 digital bones, also called phalanx bones: 2 in the thumb (the thumb has no middle phalanx) and 3 in each of the four fingers. These are: - the distal phalanx, carrying the nail, - the middle phalanx and - the proximal phalanx. Sesamoid bones are small ossified nodes embedded in the tendons to provide extra leverage and reduce pressure on the underlying tissue. Many exist around the palm at the bases of the digits; the exact number varies between different people. ## Articulations Also of note is that the articulation of the human hand is more complex and delicate than that of comparable organs in any other animals. Without this extra articulation, we would not be able to operate a wide variety of tools and devices. The hand can also form a fist, for example in combat, or as a gesture. The articulations are: - interphalangeal articulations of hand - metacarpophalangeal joints - intercarpal articulations - wrist (may also be viewed as belonging to the forearm.) ## Muscles and tendons The movements of the human hand are accomplished by two sets of each of these tissues. They can be subdivided into two groups: the extrinsic and intrinsic muscle groups. The extrinsic muscle groups are the long flexors and extensors. They are called extrinsic because the muscle belly is located on the forearm. The intrinsic muscle groups are the thenar and hypothenar muscles (thenar referring to the thumb, hypothenar to the small finger), the interosseus muscles (between the metacarpal bones, four dorsally and three volarly) and the lumbrical muscles. These muscles arise from the deep flexor (and are special because they have no bony origin) and insert on the dorsal extensor hood mechanism. The fingers have two long flexors, located on the underside of the forearm. They insert by tendons to the phalanges of the fingers. The deep flexor attaches to the distal phalanx, and the superficial flexor attaches to the middle phalanx. The flexors allow for the actual bending of the fingers. The thumb has one long flexor and a short flexor in the thenar muscle group. The human thumb also has other muscles in the thenar group (opponens- and abductor muscle), moving the thumb in opposition, making grasping possible. The extensors are located on the back of the forearm and are connected in a more complex way than the flexors to the dorsum of the fingers. The tendons unite with the interosseous and lumbrical muscles to form the extensorhood mechanism. The primary function of the extensors is to straighten out the digits. The thumb has two extensors in the forearm; the tendons of these form the anatomical snuff box. Also, the index finger and the little finger have an extra extensor, used for instance for pointing. The extensors are situated within 6 separate compartments. The 1st compartment contains abductor pollicis longus and extensor pollicis brevis. The 2nd compartment contains extensors carpi radialis longus and brevis. The 3rd compartment contains extensor pollicis longus. The extensor digitorum indicis and extensor digititorum communis are within the 4th compartment. Extensor digiti minimi is in the fifth, and extensor carpi ulnaris is in the 6th. ## Variation Some people have more than the usual number of fingers or toes, a condition called polydactyly.[4] Others may have more than the typical number of metacarpal bones, a condition often caused by genetic disorders like Catel-Manzke syndrome. The average length of an adult male hand is 189 mm, while the average length of an adult female hand is 172 mm. The average hand breadth for adult males and females is 84 and 74 mm respectively.[5]

https://www.wikidoc.org/index.php/Hand

bc12b00191390f86d41a6f5a052da667e03291f1

wikidoc

HeLa

HeLa A HeLa cell (also Hela or hela cell) is an immortal cell line used in medical research. The cell line was derived from cervical cancer cells taken from Henrietta Lacks, who died from her cancer in 1951. # George Otto Gey and Henrietta Lacks The cells were propagated by George Otto Gey without Lacks' knowledge or permission and later commercialized, although never patented in their original form. There was then, as now, no requirement to inform a patient, or their relatives, about such matters because discarded material, or material obtained during surgery, diagnosis or therapy was the property of the physician and/or medical institution. This issue and Ms. Lacks' situation was brought up in the Supreme Court of California case of John Moore v. the Regents of the University of California. The court ruled that a person's discarded tissue and cells are not their property and can be commercialized. Initially, the cell line was said to be named after a "Helen Lane" or "Helen Larson", in order to preserve Lacks's anonymity. Despite this attempt, her real name was used by the press within a few years of her death. These cells are treated as cancer cells, as they are descended from a biopsy taken from a visible lesion on the cervix as part of Ms. Lacks' diagnosis of cancer, but a debate still continues on the classification of the cells. HeLa cells are termed "immortal" in that they can divide an unlimited number of times in a laboratory cell culture plate as long as basic cell survival conditions are met (i.e. being maintained and sustained in a suitable environment). There are many strains of HeLa cells as they continue to evolve by being grown in cell cultures, but all HeLa cells are descended from the same tumor cells removed from Ms. Lacks. It has been estimated that the total mass of HeLa cells that have been propogated in cell culture far exceeds the number of cells in Henrietta Lacks' body. # Telomerase The HeLa cell line was derived for use in cancer research. These cells proliferate abnormally rapidly, even compared to other cancer cells. HeLa cells have an active version of the enzyme telomerase during cell division, which prevents the incremental shortening of telomeres that is implicated in aging and eventual cell death. In this way, HeLa cells circumvent the Hayflick Limit, which is the limited number of cell divisions that most normal cells can undergo before dying out in cell culture. # Chromosome number Horizontal gene transfer from human papillomavirus 18 (HPV18) to human cervical cells created the HeLa genome which is different from either parent genome in various ways including its number of chromosomes. HeLa cells have a modal chromosome number of 82, with four copies of chromosome 12 and three copies of chromosomes 6, 8, and 17. Human papillomaviruses (HPVs) are frequently integrated into the cellular DNA in cervical cancers. We mapped by FISH five HPV18 integration sites: three on normal chromosomes 8 at 8q24 and two on derivative chromosomes, der(5)t(5;22;8)(q11;q11q13;q24) and der(22)t(8;22)(q24;q13), which have chromosome 8q24 material. An 8q24 copy number increase was detected by CGH. Dual-color FISH with a c-MYC probe mapping to 8q24 revealed colocalization with HPV18 at all integration sites, indicating that dispersion and amplification of the c-MYC gene sequences occurred after and was most likely triggered by the viral insertion at a single integration site. Numerical and structural chromosomal aberrations identified by SKY, genomic imbalances detected by CGH, as well as FISH localization of HPV18 integration at the c-MYC locus in HeLa cells are common and representative for advanced stage cervical cell carcinomas. The HeLa genome has been remarkably stable after years of continuous cultivation; therefore, the genetic alterations detected may have been present in the primary tumor and reflect events that are relevant to the development of cervical cancer. # Contamination Because of their avid adaptation to growth in tissue culture plates, HeLa cells are sometimes difficult to control. For example, they have proven to be a persistent laboratory "weed" and they can contaminate other cell cultures in the same laboratory, interfering with biological research. The degree of HeLa cell contamination among other cell types is unknown, because few researchers test the identity or purity of already-established cell lines. It has been demonstrated that a substantial fraction of in vitro cell lines - approximately 10%, maybe 20%, are actually HeLa cells, due to the fact that the original cells in the cell culture have been overwhelmed by a rapidly growing population derived from HeLa contaminant cells. Stanley Gartler in 1967 and Walter Nelson-Rees in 1975 were the first to publish on the contamination of various cell lines by HeLa. # Helacyton gartleri Due to their ability to replicate indefinitely, and their non-human number of chromosomes, Leigh Van Valen described HeLa as an example of the contemporary creation of a new species, Helacyton gartleri, named after Stanley M. Gartler, who Van Valen credits with discovering "the remarkable success of this species". His argument for speciation depends on three points: - The chromosomal incompatibility of HeLa cells with humans. - The ecological niche of HeLa cells. - Their ability to persist and expand well beyond the desires of human cultivators. As well as proposing a new species for HeLa cells, Van Valen proposes in the same paper that the new family Helacytidae and the genus Helacyton.

HeLa A HeLa cell (also Hela or hela cell) is an immortal cell line used in medical research. The cell line was derived from cervical cancer cells taken from Henrietta Lacks, who died from her cancer in 1951. # George Otto Gey and Henrietta Lacks The cells were propagated by George Otto Gey without Lacks' knowledge or permission and later commercialized, although never patented in their original form. There was then, as now, no requirement to inform a patient, or their relatives, about such matters because discarded material, or material obtained during surgery, diagnosis or therapy was the property of the physician and/or medical institution. This issue and Ms. Lacks' situation was brought up in the Supreme Court of California case of John Moore v. the Regents of the University of California. The court ruled that a person's discarded tissue and cells are not their property and can be commercialized. Initially, the cell line was said to be named after a "Helen Lane" or "Helen Larson", in order to preserve Lacks's anonymity. Despite this attempt, her real name was used by the press within a few years of her death. These cells are treated as cancer cells, as they are descended from a biopsy taken from a visible lesion on the cervix as part of Ms. Lacks' diagnosis of cancer, but a debate still continues on the classification of the cells. HeLa cells are termed "immortal" in that they can divide an unlimited number of times in a laboratory cell culture plate as long as basic cell survival conditions are met (i.e. being maintained and sustained in a suitable environment). There are many strains of HeLa cells as they continue to evolve by being grown in cell cultures, but all HeLa cells are descended from the same tumor cells removed from Ms. Lacks. It has been estimated that the total mass of HeLa cells that have been propogated in cell culture far exceeds the number of cells in Henrietta Lacks' body.[1] # Telomerase The HeLa cell line was derived for use in cancer research. These cells proliferate abnormally rapidly, even compared to other cancer cells. HeLa cells have an active version of the enzyme telomerase during cell division, which prevents the incremental shortening of telomeres that is implicated in aging and eventual cell death. In this way, HeLa cells circumvent the Hayflick Limit, which is the limited number of cell divisions that most normal cells can undergo before dying out in cell culture. # Chromosome number Horizontal gene transfer from human papillomavirus 18 (HPV18) to human cervical cells created the HeLa genome which is different from either parent genome in various ways including its number of chromosomes. HeLa cells have a modal chromosome number of 82, with four copies of chromosome 12 and three copies of chromosomes 6, 8, and 17. Human papillomaviruses (HPVs) are frequently integrated into the cellular DNA in cervical cancers. We mapped by FISH five HPV18 integration sites: three on normal chromosomes 8 at 8q24 and two on derivative chromosomes, der(5)t(5;22;8)(q11;q11q13;q24) and der(22)t(8;22)(q24;q13), which have chromosome 8q24 material. An 8q24 copy number increase was detected by CGH. Dual-color FISH with a c-MYC probe mapping to 8q24 revealed colocalization with HPV18 at all integration sites, indicating that dispersion and amplification of the c-MYC gene sequences occurred after and was most likely triggered by the viral insertion at a single integration site. Numerical and structural chromosomal aberrations identified by SKY, genomic imbalances detected by CGH, as well as FISH localization of HPV18 integration at the c-MYC locus in HeLa cells are common and representative for advanced stage cervical cell carcinomas. The HeLa genome has been remarkably stable after years of continuous cultivation; therefore, the genetic alterations detected may have been present in the primary tumor and reflect events that are relevant to the development of cervical cancer.[1] # Contamination Because of their avid adaptation to growth in tissue culture plates, HeLa cells are sometimes difficult to control. For example, they have proven to be a persistent laboratory "weed" and they can contaminate other cell cultures in the same laboratory, interfering with biological research. The degree of HeLa cell contamination among other cell types is unknown, because few researchers test the identity or purity of already-established cell lines. It has been demonstrated that a substantial fraction of in vitro cell lines - approximately 10%, maybe 20%, are actually HeLa cells, due to the fact that the original cells in the cell culture have been overwhelmed by a rapidly growing population derived from HeLa contaminant cells. Stanley Gartler in 1967 and Walter Nelson-Rees in 1975 were the first to publish on the contamination of various cell lines by HeLa. [2] # Helacyton gartleri Due to their ability to replicate indefinitely, and their non-human number of chromosomes, Leigh Van Valen described HeLa as an example of the contemporary creation of a new species, Helacyton gartleri, named after Stanley M. Gartler, who Van Valen credits with discovering "the remarkable success of this species". His argument for speciation depends on three points: - The chromosomal incompatibility of HeLa cells with humans. - The ecological niche of HeLa cells. - Their ability to persist and expand well beyond the desires of human cultivators. As well as proposing a new species for HeLa cells, Van Valen proposes in the same paper that the new family Helacytidae and the genus Helacyton. [3]

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Head

Head In anatomy, the head of an animal is the rostral part (from anatomical position) that usually comprises the brain, eyes, ears, nose, and mouth (all of which aid in various sensory functions, such as sight, hearing, smell, and taste). Some very simple animals may not have a head, but many bilaterally symmetric forms do. # Anatomy in humans ## Bones of the head The skull is divided into the cranium (all the skull bones except the mandible) and the mandible (or jawbone). One feature that distinguishes mammals and non-mammals is that there are also three ear bones (called ossicles): - malleus (hammer) - incus (anvil) - stapes (stirrup) These ossicles are important components in the sense of hearing in mammals. Other animals have a single bone that is usually called the columella. The cranium can be divided into a skull cap (or calvarium) and base. The cranium consists of several bones which fuse together at junctions called sutures. Several sutures join to form a pterion. This process of bone fusion occurs in utero to protect the most important organ in the body, the brain. Although most fusing is complete before birth, there are large areas of fibrous tissue (called fontanelles) where fusion is incomplete until puberty. The fontanelle above the forehead in newborns and young children is particularly easy to identify by touch. The adult cranium is separated into several bones, several of which are mirrored on the right and left sides of the skull. Descriptions of these bones often use terms of anatomical position to more accurately depict how the bones relate to each other: - two maxillae (one on each side of the head) that cover the inferior and medial to the eye socket (or orbit) - two zygomatic bones, inferior and lateral to the orbit - two temporal bones, covering an area where the ears are located - a single frontal bone, superior to the orbit - two parietal bones, posterior to the frontal bone and superior to the temporal bone - an occipital bone at the back of the head - several more internal bones which are not easily seen which are - a sphenoid bone - an ethmoid bone - two lacrimal bones - two nasal bones - two palatine bones - two nasal conchae - a vomer There are a total of 14 bones in the face. The rest of the skull is the mandible, a bone attached to the cranium at the temporomandibular joint (TMJ). This important joint allows the mandible to move, using the TMJ as a pivot to achieve actions such as chewing (mastication), eating, and speech. When viewed from below (inferiorly) the skull contains several holes (or foramina), the largest of which is the foramen magnum through which the spinal cord passes. Other holes allow for the passage of arteries, veins, and nerves (the cranial nerves). When the skull cap (or calvarium) is removed, the base of the skull is viewed from above, there are three clear impressions or fossa. The most anterior of these is the anterior cranial fossa, where, amongst other things, upon which the frontal lobe of the brain lies. The butterfly-shaped middle cranial fossa is the second most anterior depression, the wings of which serve as a base for the brain's temporal lobes. The body of the butterfly houses an important structure, the sella turcica (Latin for Turkish saddle), which encapsulates the pituitary gland, one of the major organs of the endocrine system. The posterior cranial fossa is where the foramen magnum is located and where the posterior lobe of the brain and the cerebellum lie. ## Anatomy of the face Anatomically, the face stretches from the point of the chin to the roots of hair. The skin of the face is quite pliable and loose. Owing to the face's lack of deep fascia, facial wounds tend to bleed rather freely. There are five orifices on the face: two for the eyes, two nostrils, and the mouth. The blood supply to the face and indeed the most of the scalp comes mainly from the external carotid artery. The sensory supply to the face comes solely from the trigeminal nerve (the fifth cranial nerve), so named because it branches into three divisions. The ophthalmic division covers an area above the eyes, including the forehead and most of the nose. The maxillary division covers an area below the eyes but above the mouth, including the cheeks and some of the nose. The mandibular division covers an area below the mouth and to the sides of the cheeks to the ears. This area does not cover the mandibular angle (the protrusion on the jawbone), which is innervated by the second cervical spinal nerve. The muscles in the face include the nasal muscles, zygomatic muscles, muscles of mastication (chewing), and those of facial expression. The frontal part of the large occipitofrontalis muscle contains two parts, the occipital part (or occipitalis) and the frontal part (or frontalis). Although the two muscles are separate and supplied by different nerves, they are connected by fibromuscular tissue (called the galea aponeurotica) that stretches across the top half of the head to form the scalp. This arrangement of two different muscles attached together constitutes a digastric muscle, the actions of which are to wrinkle the forehead and raise the eyebrow. The muscle is attached to the skin of the forehead and eyebrow in front (anteriorly) and to the superior nuchal line in back (posteriorly). The frontal belly of the digastric muscle is supplied by the temporal nerve, a branch of the facial nerve (the seventh cranial nerve) while the occipital belly is supplied by another branch of the facial nerve, the posterior auricular nerve. # Anatomy in non-humans ## Bilateral symmetry The very simplest animals do not have a head, but many bilaterally symmetric forms do. In vertebrates the contents of the head are protected by an enclosure of bone called the skull, which is attached to the spine. # Clothing In many cultures, covering the head is seen as a sign of respect. Often, some or all of the head must be covered and veiled when entering holy places, or places of prayer. For many centuries, women in Europe, the Middle East, and parts of Asia, have covered their hair as a sign of modesty. This trend has changed drastically in Europe in the 20th Century, although is still observed in other parts of the world. In addition, a number of religious paths require men to wear specific head clothing- such as the Jewish skullcap, or the sikh turban; or Muslim women, who cover their hair, ears and neck with a scarf. Different headpieces can also signify status, origin, religious/spiritual beliefs, social grouping, occupation, and fashion choices. # Pseudoscientific study of the human head Because the human head is the location of the thinking organ, it has been the subject of intense study. Some of the early modern research on the human head by German physician Franz Joseph Gall has resulted in the pseudoscience of phrenology, which reached its peak in the 19th century. It attributes character traits and mental abilities to the shape of the head. The measurement of the human head and skull, known as craniometry, gained popularity at the same time. Some, notably in Nazi Germany, have used these measurements and other comparative research as the underpinnings of racist, pseudoscientific theories. The procedure of trepanation has also been advocated and practiced for pseudoscientific reasons.

Head Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] In anatomy, the head of an animal is the rostral part (from anatomical position) that usually comprises the brain, eyes, ears, nose, and mouth (all of which aid in various sensory functions, such as sight, hearing, smell, and taste). Some very simple animals may not have a head, but many bilaterally symmetric forms do. # Anatomy in humans ## Bones of the head The skull is divided into the cranium (all the skull bones except the mandible) and the mandible (or jawbone). One feature that distinguishes mammals and non-mammals is that there are also three ear bones (called ossicles): - malleus (hammer) - incus (anvil) - stapes (stirrup) These ossicles are important components in the sense of hearing in mammals. Other animals have a single bone that is usually called the columella. The cranium can be divided into a skull cap (or calvarium) and base. The cranium consists of several bones which fuse together at junctions called sutures. Several sutures join to form a pterion. This process of bone fusion occurs in utero to protect the most important organ in the body, the brain. Although most fusing is complete before birth, there are large areas of fibrous tissue (called fontanelles) where fusion is incomplete until puberty. The fontanelle above the forehead in newborns and young children is particularly easy to identify by touch. The adult cranium is separated into several bones, several of which are mirrored on the right and left sides of the skull. Descriptions of these bones often use terms of anatomical position to more accurately depict how the bones relate to each other: - two maxillae (one on each side of the head) that cover the inferior and medial to the eye socket (or orbit) - two zygomatic bones, inferior and lateral to the orbit - two temporal bones, covering an area where the ears are located - a single frontal bone, superior to the orbit - two parietal bones, posterior to the frontal bone and superior to the temporal bone - an occipital bone at the back of the head - several more internal bones which are not easily seen which are - a sphenoid bone - an ethmoid bone - two lacrimal bones - two nasal bones - two palatine bones - two nasal conchae - a vomer There are a total of 14 bones in the face. The rest of the skull is the mandible, a bone attached to the cranium at the temporomandibular joint (TMJ). This important joint allows the mandible to move, using the TMJ as a pivot to achieve actions such as chewing (mastication), eating, and speech. When viewed from below (inferiorly) the skull contains several holes (or foramina), the largest of which is the foramen magnum through which the spinal cord passes. Other holes allow for the passage of arteries, veins, and nerves (the cranial nerves). When the skull cap (or calvarium) is removed, the base of the skull is viewed from above, there are three clear impressions or fossa. The most anterior of these is the anterior cranial fossa, where, amongst other things, upon which the frontal lobe of the brain lies. The butterfly-shaped middle cranial fossa is the second most anterior depression, the wings of which serve as a base for the brain's temporal lobes. The body of the butterfly houses an important structure, the sella turcica (Latin for Turkish saddle), which encapsulates the pituitary gland, one of the major organs of the endocrine system. The posterior cranial fossa is where the foramen magnum is located and where the posterior lobe of the brain and the cerebellum lie. ## Anatomy of the face Anatomically, the face stretches from the point of the chin to the roots of hair. The skin of the face is quite pliable and loose. Owing to the face's lack of deep fascia, facial wounds tend to bleed rather freely. There are five orifices on the face: two for the eyes, two nostrils, and the mouth. The blood supply to the face and indeed the most of the scalp comes mainly from the external carotid artery. The sensory supply to the face comes solely from the trigeminal nerve (the fifth cranial nerve), so named because it branches into three divisions. The ophthalmic division covers an area above the eyes, including the forehead and most of the nose. The maxillary division covers an area below the eyes but above the mouth, including the cheeks and some of the nose. The mandibular division covers an area below the mouth and to the sides of the cheeks to the ears. This area does not cover the mandibular angle (the protrusion on the jawbone), which is innervated by the second cervical spinal nerve. The muscles in the face include the nasal muscles, zygomatic muscles, muscles of mastication (chewing), and those of facial expression. The frontal part of the large occipitofrontalis muscle contains two parts, the occipital part (or occipitalis) and the frontal part (or frontalis). Although the two muscles are separate and supplied by different nerves, they are connected by fibromuscular tissue (called the galea aponeurotica) that stretches across the top half of the head to form the scalp. This arrangement of two different muscles attached together constitutes a digastric muscle, the actions of which are to wrinkle the forehead and raise the eyebrow. The muscle is attached to the skin of the forehead and eyebrow in front (anteriorly) and to the superior nuchal line in back (posteriorly). The frontal belly of the digastric muscle is supplied by the temporal nerve, a branch of the facial nerve (the seventh cranial nerve) while the occipital belly is supplied by another branch of the facial nerve, the posterior auricular nerve. # Anatomy in non-humans ## Bilateral symmetry The very simplest animals do not have a head, but many bilaterally symmetric forms do. In vertebrates the contents of the head are protected by an enclosure of bone called the skull, which is attached to the spine. # Clothing In many cultures, covering the head is seen as a sign of respect. Often, some or all of the head must be covered and veiled when entering holy places, or places of prayer. For many centuries, women in Europe, the Middle East, and parts of Asia, have covered their hair as a sign of modesty. This trend has changed drastically in Europe in the 20th Century, although is still observed in other parts of the world. In addition, a number of religious paths require men to wear specific head clothing- such as the Jewish skullcap, or the sikh turban; or Muslim women, who cover their hair, ears and neck with a scarf. Different headpieces can also signify status, origin, religious/spiritual beliefs, social grouping, occupation, and fashion choices. # Pseudoscientific study of the human head Because the human head is the location of the thinking organ, it has been the subject of intense study. Some of the early modern research on the human head by German physician Franz Joseph Gall has resulted in the pseudoscience of phrenology, which reached its peak in the 19th century. It attributes character traits and mental abilities to the shape of the head. The measurement of the human head and skull, known as craniometry, gained popularity at the same time. Some, notably in Nazi Germany, have used these measurements and other comparative research as the underpinnings of racist, pseudoscientific theories. The procedure of trepanation has also been advocated and practiced for pseudoscientific reasons.

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Heat

Heat In physics, heat, symbolized by Q, is energy transferred from one body or system to another due to a difference in temperature. In thermodynamics, the quantity TdS is used as a representative measure of heat, which is the absolute temperature of an object multiplied by the differential quantity of a system's entropy measured at the boundary of the object. Heat can flow spontaneously from an object with a high temperature to an object with a lower temperature. The transfer of heat from one object to another object with an equal or higher temperature can happen only with the aid of a heat pump. High temperature bodies, which often result in high rates of heat transfer, can be created by chemical reactions (such as burning), nuclear reactions (such as fusion taking place inside the Sun), electromagnetic dissipation (as in electric stoves), or mechanical dissipation (such as friction). Heat can be transferred between objects by radiation, conduction and convection. Temperature is used as a measure of the internal energy or enthalpy, that is the level of elementary motion giving rise to heat transfer. Heat can only be transferred between objects, or areas within an object, with different temperatures (as given by the zeroth law of thermodynamics), and then, in the absence of work, only in the direction of the colder body (as per the second law of thermodynamics). The temperature and phase of a substance subject to heat transfer are determined by latent heat and heat capacity. A related term is thermal energy, loosely defined as the energy of a body that increases with its temperature. # Overview The first law of thermodynamics states that the energy of a closed system is conserved. Therefore, to change the energy of a system, energy must be transferred to or from the system. Heat and work are the only two mechanisms by which energy can be transferred to or from a control mass. Heat is the transfer of energy caused by the temperature difference. The unit for the amount of energy transferred by heat in the International System of Units SI is the joule (J), though the British Thermal Unit and the calorie are still occasionally used in the United States. The unit for the rate of heat transfer is the watt (W = J/s). Heat transfer is a path function (process quantity), as opposed to a point function (state quantity). Heat flows between systems that are not in thermal equilibrium with each other; it spontaneously flows from the areas of high temperature to areas of low temperature. When two bodies of different temperature come into thermal contact, they will exchange internal energy until their temperatures are equalized; that is, until they reach thermal equilibrium. The adjective hot is used as a relative term to compare the object’s temperature to that of the surroundings (or that of the person using the term). The term heat is used to describe the flow of energy. In the absence of work interactions, the heat that is transferred to an object ends up getting stored in the object in the form of internal energy. Specific heat is defined as the amount of energy that has to be transferred to or from one unit of mass or mole of a substance to change its temperature by one degree. Specific heat is a property, which means that it depends on the substance under consideration and its state as specified by its properties. Fuels, when burned, release much of the energy in the chemical bonds of their molecules. Upon changing from one phase to another, a pure substance releases or absorbs heat without its temperature changing. The amount of heat transfer during a phase change is known as latent heat and depends primarily on the substance and its state. ## Thermal energy Thermal energy is a term often confused with that of heat. Loosely speaking, when heat is added to a thermodynamic system its thermal energy increases and when heat is withdrawn its thermal energy decreases. In this point of view, objects that are hot are referred to as being in possession of a large amount of thermal energy, whereas cold objects possess little thermal energy. Thermal energy then is often mistakenly defined as being synonym for the word heat. This, however, is not the case: an object cannot possess heat, but only energy. The term "thermal energy" when used in conversation is often not used in a strictly correct sense, but is more likely to be only used as a descriptive word. In physics and thermodynamics, the words “heat”, “internal energy”, “work”, "enthalpy" (heat content), "entropy", "external forces", etc., which can be defined exactly, i.e. without recourse to internal atomic motions and vibrations, tend to be preferred and used more often than the term "thermal energy", which is difficult to define. # History In the history of science, the history of heat traces its origins from the first hominids to make fire and to speculate on its operation and meaning to modern day particle physicists who study the sub-atomic nature of heat. In short, the phenomenon of heat and its definition evolved from mythological theories of fire, to heat, to terra pinguis, phlogiston, to fire air, to caloric, to the theory of heat, to the mechanical equivalent of heat, to thermo-dynamics (sometimes called energetics) to thermodynamics. The history of heat, then, is a precursor for developments and theories in the history of thermodynamics. # Notation The total amount of energy transferred through heat transfer is conventionally abbreviated as Q. The conventional sign convention is that when a body releases heat into its surroundings, Q  0 (+). Heat transfer rate, or heat flow per unit time, is denoted by: It is measured in watts. Heat flux is defined as rate of heat transfer per unit cross-sectional area, and is denoted q, resulting in units of watts per square metre, though slightly different notation conventions can be used. ## Entropy In 1854, German physicist Rudolf Clausius defined the second fundamental theorem (the second law of thermodynamics) in the mechanical theory of heat (thermodynamics): "if two transformations which, without necessitating any other permanent change, can mutually replace one another, be called equivalent, then the generations of the quantity of heat Q from work at the temperature T, has the equivalence-value:" In 1865, he came to define this ratio as entropy symbolized by S, such that, for a closed, stationary system: and thus, by reduction, quantities of heat δQ (an inexact differential) are defined as quantities of TdS (an exact differential): In other words, the entropy function S facilitates the quantification and measurement of heat flow through a thermodynamic boundary. # Definitions In modern terms, heat is concisely defined as energy in transit. Scottish physicist James Clerk Maxwell, in his 1871 classic Theory of Heat, was one of the first to enunciate a modern definition of “heat”. In short, Maxwell outlined four stipulations on the definition of heat. One, it is “something which may be transferred from one body to another”, as per the second law of thermodynamics. Two, it can be spoken of as a “measurable quantity”, and thus treated mathematically like other measurable quantities. Three, it “can not be treated as a substance”; for it may be transformed into something which is not a substance, e.g. mechanical work. Lastly, it is “one of the forms of energy”. Similar such modern, succinct definitions of heat are as follows: - In a thermodynamic sense, heat is never regarded as being stored within a body. Like work, it exists only as energy in transit from one body to another; in thermodynamic terminology, between a system and its surroundings. When energy in the form of heat is added to a system, it is stored not as heat, but as kinetic and potential energy of the atoms and molecules making up the system. - The noun heat is defined only during the process of energy transfer by conduction or radiation. - Heat is defined as any spontaneous flow of energy from one object to another, caused by a difference in temperature between two objects. - Heat may be defined as energy in transit from a high-temperature object to a lower-temperature object. - Heat as an interaction between two closed systems without exchange of work is a pure heat interaction when the two systems, initially isolated and in a stable equilibrium, are placed in contact. The energy exchanged between the two systems is then called heat. - Heat is a form of energy possessed by a substance by virtue of the vibrational movement, i.e. kinetic energy, of its molecules or atoms. - Heat is the transfer of energy between substances of different temperatures. # Thermodynamics ## Internal energy Heat is related to the internal energy U of the system and work W done by the system by the first law of thermodynamics: which means that the energy of the system can change either via work or via heat flows across the boundary of the thermodynamic system. In more detail, Internal energy is the sum of all microscopic forms of energy of a system. It is related to the molecular structure and the degree of molecular activity and may be viewed as the sum of kinetic and potential energies of the molecules; it comprises the following types of energies: The transfer of heat to an ideal gas at constant pressure increases the internal energy and performs boundary work (i.e. allows a control volume of gas to become larger or smaller), provided the volume is not constrained. Returning to the first law equation and separating the work term into two types, "boundary work" and "other" (e.g. shaft work performed by a compressor fan), yields the following: This combined quantity \Delta U + W_{boundary} is enthalpy, H, one of the thermodynamic potentials. Both enthalpy, H , and internal energy, U are state functions. State functions return to their initial values upon completion of each cycle in cyclic processes such as that of a heat engine. In contrast, neither Q nor W are properties of a system and need not sum to zero over the steps of a cycle. The infinitesimal expression for heat, \delta Q , forms an inexact differential for processes involving work. However, for processes involving no change in volume, applied magnetic field, or other external parameters, \delta Q , forms an exact differential. Likewise, for adiabatic processes (no heat transfer), the expression for work forms an exact differential, but for processes involving transfer of heat it forms an inexact differential. ## Heat capacity For a simple compressible system such as an ideal gas inside a piston, the changes in enthalpy and internal energy can be related to the heat capacity at constant pressure and volume, respectively. Constrained to have constant volume, the heat, Q, required to change its temperature from an initial temperature, T0, to a final temperature, Tf is given by: Removing the volume constraint and allowing the system to expand or contract at constant pressure: For incompressible substances, such as solids and liquids, the distinction between the two types of heat capacity disappears, as no work is performed. Heat capacity is an extensive quantity and as such is dependent on the number of molecules in the system. It can be represented as the product of mass, m , and specific heat capacity, c_s \,\! according to: -r is dependent on the number of moles and the molar heat capacity, c_n \,\! according to: The molar and specific heat capacities are dependent upon the internal degrees of freedom of the system and not on any external properties such as volume and number of molecules. The specific heats of monatomic gases (e.g., helium) are nearly constant with temperature. Diatomic gases such as hydrogen display some temperature dependence, and triatomic gases (e.g., carbon dioxide) still more. In liquids at sufficiently low temperatures, quantum effects become significant. An example is the behavior of bosons such as helium-4. For such substances, the behavior of heat capacity with temperature is discontinuous at the Bose-Einstein condensation point. The quantum behavior of solids is adequately characterized by the Debye model. At temperatures well below the characteristic Debye temperature of a solid lattice, its specific heat will be proportional to the cube of absolute temperature. For low-temperature metals, a second term is needed to account for the behavior of the conduction electrons, an example of Fermi-Dirac statistics. ## Changes of phase The boiling point of water, at sea level and normal atmospheric pressure and temperature, will always be at nearly 100 °C, no matter how much heat is added. The extra heat changes the phase of the water from liquid into water vapor. The heat added to change the phase of a substance in this way is said to be "hidden" and thus it is called latent heat (from the Latin latere meaning "to lie hidden"). Latent heat is the heat per unit mass necessary to change the state of a given substance, or: and Note that, as pressure increases, the L rises slightly. Here, M_o is the amount of mass initially in the new phase, and M is the amount of mass that ends up in the new phase. Also,L generally does not depend on the amount of mass that changes phase, so the equation can normally be written: Sometimes L can be time-dependent if pressure and volume are changing with time, so that the integral can be written as: # Heat transfer mechanisms Heat tends to move from a high-temperature region to a low-temperature region. This heat transfer may occur by the mechanisms of conduction and radiation. In engineering, the term convective heat transfer is used to describe the combined effects of conduction and fluid flow and is regarded as a third mechanism of heat transfer. ## Conduction Conduction is the most significant means of heat transfer in a solid. On a microscopic scale, conduction occurs as hot, rapidly moving or vibrating atoms and molecules interact with neighboring atoms and molecules, transferring some of their energy (heat) to these neighboring atoms. In insulators the heat flux is carried almost entirely by phonon vibrations. The "electron fluid" of a conductive metallic solid conducts nearly all of the heat flux through the solid. Phonon flux is still present, but carries less than 1% of the energy. Electrons also conduct electric current through conductive solids, and the thermal and electrical conductivities of most metals have about the same ratio. A good electrical conductor, such as copper, usually also conducts heat well. The Peltier-Seebeck effect exhibits the propensity of electrons to conduct heat through an electrically conductive solid. Thermoelectricity is caused by the relationship between electrons, heat fluxes and electrical currents. ## Convection Convection is usually the dominant form of heat transfer in liquids and gases. This is a term used to characterize the combined effects of conduction and fluid flow. In convection, enthalpy transfer occurs by the movement of hot or cold portions of the fluid together with heat transfer by conduction. Commonly an increase in temperature produces a reduction in density. Hence, when water is heated on a stove, hot water from the bottom of the pan rises, displacing the colder more dense liquid which falls. Mixing and conduction result eventually in a nearly homogenous density and even temperature. Two types of convection are commonly distinguished, free convection, in which gravity and buoyancy forces drive the fluid movement, and forced convection, where a fan, stirrer, or other means is used to move the fluid. Buoyant convection is due to the effects of gravity, and hence does not occur in microgravity environments. ## Radiation Radiation is the only form of heat transfer that can occur in the absence of any form of medium; thus it is the only means of heat transfer through a vacuum. Thermal radiation is a direct result of the movements of atoms and molecules in a material. Since these atoms and molecules are composed of charged particles (protons and electrons), their movements result in the emission of electromagnetic radiation, which carries energy away from the surface. At the same time, the surface is constantly bombarded by radiation from the surroundings, resulting in the transfer of energy to the surface. Since the amount of emitted radiation increases with increasing temperature, a net transfer of energy from higher temperatures to lower temperatures results. The power that a black body emits at various frequencies is described by Planck's law. There is a frequency fmax at which the power emitted is a maximum. Wien's displacement law, and the fact that the frequency of light is inversely proportional to its wavelength in vacuum, mean that the peak frequency fmax is proportional to the absolute temperature T of the black body. The photosphere of the Sun, at a temperature of approximately 6000 K, emits radiation principally in the visible portion of the spectrum. The earth's atmosphere is partly transparent to visible light, and the light reaching the earth's surface is absorbed or reflected. The earth's surface emits the absorbed radiation, approximating the behavior of a black body at 300 K with spectral peak at fmax. At these lower frequencies, the atmosphere is largely opaque and radiation from the earth's surface is absorbed or scattered by the atmosphere. Though some radiation escapes into space, it is absorbed and subsequently re-emitted by atmospheric gases. It is this spectral selectivity of the atmosphere that is responsible for the planetary greenhouse effect. The common household lightbulb has a spectrum overlapping the blackbody spectra of the sun and the earth. A portion of the photons emitted by a tungsten light bulb filament at 3000K are in the visible spectrum. However, most of the energy is associated with photons of longer wavelengths; these will not help a person see, but will still transfer heat to the environment, as can be deduced empirically by observing a household incandescent lightbulb. Whenever EM radiation is emitted and then absorbed, heat is transferred. This principle is used in microwave ovens, laser cutting, and RF hair removal. ## Other heat transfer mechanisms - Latent heat: Transfer of heat through a physical change in the medium such as water-to-ice or water-to-steam involves significant energy and is exploited in many ways: steam engine, refrigerator etc. (see latent heat of fusion) - Heat pipes: Using latent heat and capillary action to move heat, heat pipes can carry many times as much heat as a similar-sized copper rod. Originally invented for use in satellites, they are starting to have applications in personal computers. # Heat dissipation In cold climates, houses with their heating systems form dissipative systems. In spite of efforts to insulate such houses to reduce heat losses to their exteriors, considerable heat is lost, or dissipated, from them, which can make their interiors uncomfortably cool or cold. For the comfort of its inhabitants, the interior of a house must be maintained out of thermal equilibrium with its external surroundings. In effect, domestic residences are oases of warmth in a sea of cold and the thermal gradient between the inside and outside is often quite steep. This can lead to problems such as condensation and uncomfortable draughts (drafts) which, if left unaddressed, can cause structural damage to the property. This is why modern insulation techniques are required to reduce heat loss. In such a house, a thermostat is a device capable of starting the heating system when the house's interior falls below a set temperature, and of stopping that same system when another (higher) set temperature has been achieved. Thus the thermostat controls the flow of energy into the house, that energy eventually being dissipated to the exterior.

Heat Template:Pp-semi-vandalism In physics, heat, symbolized by Q, is energy transferred from one body or system to another due to a difference in temperature.[1][2] In thermodynamics, the quantity TdS is used as a representative measure of heat, which is the absolute temperature of an object multiplied by the differential quantity of a system's entropy measured at the boundary of the object. Heat can flow spontaneously from an object with a high temperature to an object with a lower temperature. The transfer of heat from one object to another object with an equal or higher temperature can happen only with the aid of a heat pump. High temperature bodies, which often result in high rates of heat transfer, can be created by chemical reactions (such as burning), nuclear reactions (such as fusion taking place inside the Sun), electromagnetic dissipation (as in electric stoves), or mechanical dissipation (such as friction). Heat can be transferred between objects by radiation, conduction and convection. Temperature is used as a measure of the internal energy or enthalpy, that is the level of elementary motion giving rise to heat transfer. Heat can only be transferred between objects, or areas within an object, with different temperatures (as given by the zeroth law of thermodynamics), and then, in the absence of work, only in the direction of the colder body (as per the second law of thermodynamics). The temperature and phase of a substance subject to heat transfer are determined by latent heat and heat capacity. A related term is thermal energy, loosely defined as the energy of a body that increases with its temperature. # Overview The first law of thermodynamics states that the energy of a closed system is conserved. Therefore, to change the energy of a system, energy must be transferred to or from the system. Heat and work are the only two mechanisms by which energy can be transferred to or from a control mass. Heat is the transfer of energy caused by the temperature difference. The unit for the amount of energy transferred by heat in the International System of Units SI is the joule (J), though the British Thermal Unit and the calorie are still occasionally used in the United States. The unit for the rate of heat transfer is the watt (W = J/s). Heat transfer is a path function (process quantity), as opposed to a point function (state quantity). Heat flows between systems that are not in thermal equilibrium with each other; it spontaneously flows from the areas of high temperature to areas of low temperature. When two bodies of different temperature come into thermal contact, they will exchange internal energy until their temperatures are equalized; that is, until they reach thermal equilibrium. The adjective hot is used as a relative term to compare the object’s temperature to that of the surroundings (or that of the person using the term). The term heat is used to describe the flow of energy. In the absence of work interactions, the heat that is transferred to an object ends up getting stored in the object in the form of internal energy. Specific heat is defined as the amount of energy that has to be transferred to or from one unit of mass or mole of a substance to change its temperature by one degree. Specific heat is a property, which means that it depends on the substance under consideration and its state as specified by its properties. Fuels, when burned, release much of the energy in the chemical bonds of their molecules. Upon changing from one phase to another, a pure substance releases or absorbs heat without its temperature changing. The amount of heat transfer during a phase change is known as latent heat and depends primarily on the substance and its state. ## Thermal energy Template:See main Thermal energy is a term often confused with that of heat. Loosely speaking, when heat is added to a thermodynamic system its thermal energy increases and when heat is withdrawn its thermal energy decreases. In this point of view, objects that are hot are referred to as being in possession of a large amount of thermal energy, whereas cold objects possess little thermal energy. Thermal energy then is often mistakenly defined as being synonym for the word heat. This, however, is not the case: an object cannot possess heat, but only energy. The term "thermal energy" when used in conversation is often not used in a strictly correct sense, but is more likely to be only used as a descriptive word. In physics and thermodynamics, the words “heat”, “internal energy”, “work”, "enthalpy" (heat content), "entropy", "external forces", etc., which can be defined exactly, i.e. without recourse to internal atomic motions and vibrations, tend to be preferred and used more often than the term "thermal energy", which is difficult to define. # History In the history of science, the history of heat traces its origins from the first hominids to make fire and to speculate on its operation and meaning to modern day particle physicists who study the sub-atomic nature of heat. In short, the phenomenon of heat and its definition evolved from mythological theories of fire, to heat, to terra pinguis, phlogiston, to fire air, to caloric, to the theory of heat, to the mechanical equivalent of heat, to thermo-dynamics (sometimes called energetics) to thermodynamics. The history of heat, then, is a precursor for developments and theories in the history of thermodynamics. # Notation The total amount of energy transferred through heat transfer is conventionally abbreviated as Q. The conventional sign convention is that when a body releases heat into its surroundings, Q < 0 (-); when a body absorbs heat from its surroundings, Q > 0 (+). Heat transfer rate, or heat flow per unit time, is denoted by: It is measured in watts. Heat flux is defined as rate of heat transfer per unit cross-sectional area, and is denoted q, resulting in units of watts per square metre, though slightly different notation conventions can be used. ## Entropy In 1854, German physicist Rudolf Clausius defined the second fundamental theorem (the second law of thermodynamics) in the mechanical theory of heat (thermodynamics): "if two transformations which, without necessitating any other permanent change, can mutually replace one another, be called equivalent, then the generations of the quantity of heat Q from work at the temperature T, has the equivalence-value:"[3][4] In 1865, he came to define this ratio as entropy symbolized by S, such that, for a closed, stationary system: and thus, by reduction, quantities of heat δQ (an inexact differential) are defined as quantities of TdS (an exact differential): In other words, the entropy function S facilitates the quantification and measurement of heat flow through a thermodynamic boundary. # Definitions In modern terms, heat is concisely defined as energy in transit. Scottish physicist James Clerk Maxwell, in his 1871 classic Theory of Heat, was one of the first to enunciate a modern definition of “heat”. In short, Maxwell outlined four stipulations on the definition of heat. One, it is “something which may be transferred from one body to another”, as per the second law of thermodynamics. Two, it can be spoken of as a “measurable quantity”, and thus treated mathematically like other measurable quantities. Three, it “can not be treated as a substance”; for it may be transformed into something which is not a substance, e.g. mechanical work. Lastly, it is “one of the forms of energy”. Similar such modern, succinct definitions of heat are as follows: - In a thermodynamic sense, heat is never regarded as being stored within a body. Like work, it exists only as energy in transit from one body to another; in thermodynamic terminology, between a system and its surroundings. When energy in the form of heat is added to a system, it is stored not as heat, but as kinetic and potential energy of the atoms and molecules making up the system.[2] - The noun heat is defined only during the process of energy transfer by conduction or radiation.[5] - Heat is defined as any spontaneous flow of energy from one object to another, caused by a difference in temperature between two objects.[6] - Heat may be defined as energy in transit from a high-temperature object to a lower-temperature object.[7] - Heat as an interaction between two closed systems without exchange of work is a pure heat interaction when the two systems, initially isolated and in a stable equilibrium, are placed in contact. The energy exchanged between the two systems is then called heat.[8] - Heat is a form of energy possessed by a substance by virtue of the vibrational movement, i.e. kinetic energy, of its molecules or atoms.[9] - Heat is the transfer of energy between substances of different temperatures. # Thermodynamics ## Internal energy Heat is related to the internal energy <math> U </math> of the system and work <math> W </math> done by the system by the first law of thermodynamics: which means that the energy of the system can change either via work or via heat flows across the boundary of the thermodynamic system. In more detail, Internal energy is the sum of all microscopic forms of energy of a system. It is related to the molecular structure and the degree of molecular activity and may be viewed as the sum of kinetic and potential energies of the molecules; it comprises the following types of energies:[10] The transfer of heat to an ideal gas at constant pressure increases the internal energy and performs boundary work (i.e. allows a control volume of gas to become larger or smaller), provided the volume is not constrained. Returning to the first law equation and separating the work term into two types, "boundary work" and "other" (e.g. shaft work performed by a compressor fan), yields the following: This combined quantity <math>\Delta U + W_{boundary}</math> is enthalpy, <math>H</math>, one of the thermodynamic potentials. Both enthalpy, <math> H </math>, and internal energy, <math> U </math> are state functions. State functions return to their initial values upon completion of each cycle in cyclic processes such as that of a heat engine. In contrast, neither <math>Q </math> nor <math> W </math> are properties of a system and need not sum to zero over the steps of a cycle. The infinitesimal expression for heat, <math>\delta Q </math>, forms an inexact differential for processes involving work. However, for processes involving no change in volume, applied magnetic field, or other external parameters, <math>\delta Q </math>, forms an exact differential. Likewise, for adiabatic processes (no heat transfer), the expression for work forms an exact differential, but for processes involving transfer of heat it forms an inexact differential. ## Heat capacity For a simple compressible system such as an ideal gas inside a piston, the changes in enthalpy and internal energy can be related to the heat capacity at constant pressure and volume, respectively. Constrained to have constant volume, the heat, <math>Q</math>, required to change its temperature from an initial temperature, T0, to a final temperature, Tf is given by: Removing the volume constraint and allowing the system to expand or contract at constant pressure: For incompressible substances, such as solids and liquids, the distinction between the two types of heat capacity disappears, as no work is performed. Heat capacity is an extensive quantity and as such is dependent on the number of molecules in the system. It can be represented as the product of mass, <math>m</math> , and specific heat capacity, <math>c_s \,\!</math> according to: or is dependent on the number of moles and the molar heat capacity, <math>c_n \,\!</math> according to: The molar and specific heat capacities are dependent upon the internal degrees of freedom of the system and not on any external properties such as volume and number of molecules. The specific heats of monatomic gases (e.g., helium) are nearly constant with temperature. Diatomic gases such as hydrogen display some temperature dependence, and triatomic gases (e.g., carbon dioxide) still more. In liquids at sufficiently low temperatures, quantum effects become significant. An example is the behavior of bosons such as helium-4. For such substances, the behavior of heat capacity with temperature is discontinuous at the Bose-Einstein condensation point. The quantum behavior of solids is adequately characterized by the Debye model. At temperatures well below the characteristic Debye temperature of a solid lattice, its specific heat will be proportional to the cube of absolute temperature. For low-temperature metals, a second term is needed to account for the behavior of the conduction electrons, an example of Fermi-Dirac statistics. ## Changes of phase The boiling point of water, at sea level and normal atmospheric pressure and temperature, will always be at nearly 100 °C, no matter how much heat is added. The extra heat changes the phase of the water from liquid into water vapor. The heat added to change the phase of a substance in this way is said to be "hidden" and thus it is called latent heat (from the Latin latere meaning "to lie hidden"). Latent heat is the heat per unit mass necessary to change the state of a given substance, or: and Note that, as pressure increases, the L rises slightly. Here, <math>M_o</math> is the amount of mass initially in the new phase, and M is the amount of mass that ends up in the new phase. Also,L generally does not depend on the amount of mass that changes phase, so the equation can normally be written: Sometimes L can be time-dependent if pressure and volume are changing with time, so that the integral can be written as: # Heat transfer mechanisms Heat tends to move from a high-temperature region to a low-temperature region. This heat transfer may occur by the mechanisms of conduction and radiation. In engineering, the term convective heat transfer is used to describe the combined effects of conduction and fluid flow and is regarded as a third mechanism of heat transfer. ## Conduction Conduction is the most significant means of heat transfer in a solid. On a microscopic scale, conduction occurs as hot, rapidly moving or vibrating atoms and molecules interact with neighboring atoms and molecules, transferring some of their energy (heat) to these neighboring atoms. In insulators the heat flux is carried almost entirely by phonon vibrations. The "electron fluid" of a conductive metallic solid conducts nearly all of the heat flux through the solid. Phonon flux is still present, but carries less than 1% of the energy. Electrons also conduct electric current through conductive solids, and the thermal and electrical conductivities of most metals have about the same ratio. A good electrical conductor, such as copper, usually also conducts heat well. The Peltier-Seebeck effect exhibits the propensity of electrons to conduct heat through an electrically conductive solid. Thermoelectricity is caused by the relationship between electrons, heat fluxes and electrical currents. ## Convection Convection is usually the dominant form of heat transfer in liquids and gases. This is a term used to characterize the combined effects of conduction and fluid flow. In convection, enthalpy transfer occurs by the movement of hot or cold portions of the fluid together with heat transfer by conduction. Commonly an increase in temperature produces a reduction in density. Hence, when water is heated on a stove, hot water from the bottom of the pan rises, displacing the colder more dense liquid which falls. Mixing and conduction result eventually in a nearly homogenous density and even temperature. Two types of convection are commonly distinguished, free convection, in which gravity and buoyancy forces drive the fluid movement, and forced convection, where a fan, stirrer, or other means is used to move the fluid. Buoyant convection is due to the effects of gravity, and hence does not occur in microgravity environments. ## Radiation Radiation is the only form of heat transfer that can occur in the absence of any form of medium; thus it is the only means of heat transfer through a vacuum. Thermal radiation is a direct result of the movements of atoms and molecules in a material. Since these atoms and molecules are composed of charged particles (protons and electrons), their movements result in the emission of electromagnetic radiation, which carries energy away from the surface. At the same time, the surface is constantly bombarded by radiation from the surroundings, resulting in the transfer of energy to the surface. Since the amount of emitted radiation increases with increasing temperature, a net transfer of energy from higher temperatures to lower temperatures results. The power that a black body emits at various frequencies is described by Planck's law. There is a frequency fmax at which the power emitted is a maximum. Wien's displacement law, and the fact that the frequency of light is inversely proportional to its wavelength in vacuum, mean that the peak frequency fmax is proportional to the absolute temperature T of the black body. The photosphere of the Sun, at a temperature of approximately 6000 K, emits radiation principally in the visible portion of the spectrum. The earth's atmosphere is partly transparent to visible light, and the light reaching the earth's surface is absorbed or reflected. The earth's surface emits the absorbed radiation, approximating the behavior of a black body at 300 K with spectral peak at fmax. At these lower frequencies, the atmosphere is largely opaque and radiation from the earth's surface is absorbed or scattered by the atmosphere. Though some radiation escapes into space, it is absorbed and subsequently re-emitted by atmospheric gases. It is this spectral selectivity of the atmosphere that is responsible for the planetary greenhouse effect. The common household lightbulb has a spectrum overlapping the blackbody spectra of the sun and the earth. A portion of the photons emitted by a tungsten light bulb filament at 3000K are in the visible spectrum. However, most of the energy is associated with photons of longer wavelengths; these will not help a person see, but will still transfer heat to the environment, as can be deduced empirically by observing a household incandescent lightbulb. Whenever EM radiation is emitted and then absorbed, heat is transferred. This principle is used in microwave ovens, laser cutting, and RF hair removal. ## Other heat transfer mechanisms - Latent heat: Transfer of heat through a physical change in the medium such as water-to-ice or water-to-steam involves significant energy and is exploited in many ways: steam engine, refrigerator etc. (see latent heat of fusion) - Heat pipes: Using latent heat and capillary action to move heat, heat pipes can carry many times as much heat as a similar-sized copper rod. Originally invented for use in satellites, they are starting to have applications in personal computers. # Heat dissipation In cold climates, houses with their heating systems form dissipative systems. In spite of efforts to insulate such houses to reduce heat losses to their exteriors, considerable heat is lost, or dissipated, from them, which can make their interiors uncomfortably cool or cold. For the comfort of its inhabitants, the interior of a house must be maintained out of thermal equilibrium with its external surroundings. In effect, domestic residences are oases of warmth in a sea of cold and the thermal gradient between the inside and outside is often quite steep. This can lead to problems such as condensation and uncomfortable draughts (drafts) which, if left unaddressed, can cause structural damage to the property. This is why modern insulation techniques are required to reduce heat loss. In such a house, a thermostat is a device capable of starting the heating system when the house's interior falls below a set temperature, and of stopping that same system when another (higher) set temperature has been achieved. Thus the thermostat controls the flow of energy into the house, that energy eventually being dissipated to the exterior.

https://www.wikidoc.org/index.php/Heat

70d372857dcbbafb341f3353cddf1b64efc82fc6

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Hoof

Hoof A hoof is the tip of a toe of an ungulate mammal, strengthened by a thick horny (keratin) covering. The hoof consists of a hard or rubbery sole, and a hard wall formed by a thick nail rolled around the tip of the toe. The weight of the animal is normally borne by both the sole and the edge of the hoof wall. Hooves grow continuously, and are constantly worn down by use. "Hoof" is Template:PronEng or Template:IPA; the plural is either hooves (Template:PronEng or Template:IPA), or hoofs (Template:IPA). Most even-toed ungulates (such as sheep, goats, deer, cattle, bison, and pigs) have two main hooves on each foot, together called a cloven hoof. Most cloven-hoofed animals also have two smaller hoofs called dew-claws a little further up the leg – these are not normally used for walking, but in some species with larger dew-claws (such as deer and pigs) they may touch the ground when running or jumping, or if the ground is soft. Other cloven-hoofed animals (such as giraffes and pronghorns) have no dew claws. In some so-called "cloven-hoofed" animals such as camels, there are no hooves proper – the toe is softer, and the hoof itself is reduced to little more than a nail. Some odd-toed ungulates (equids) have one hoof on each foot; others (including rhinoceroses, tapirs and many extinct species) have (or had) three hoofed or heavily nailed toes, or one hoof and two dew-claws. The tapir is a special case, with three toes on each hind foot and four toes on each front foot. The number of toes is considered in determining the kosher status of the animal's flesh.

Hoof A hoof is the tip of a toe of an ungulate mammal, strengthened by a thick horny (keratin) covering. The hoof consists of a hard or rubbery sole, and a hard wall formed by a thick nail rolled around the tip of the toe. The weight of the animal is normally borne by both the sole and the edge of the hoof wall. Hooves grow continuously, and are constantly worn down by use. "Hoof" is Template:PronEng or Template:IPA; the plural is either hooves (Template:PronEng or Template:IPA), or hoofs (Template:IPA). Most even-toed ungulates (such as sheep, goats, deer, cattle, bison, and pigs) have two main hooves on each foot, together called a cloven hoof. Most cloven-hoofed animals also have two smaller hoofs called dew-claws a little further up the leg – these are not normally used for walking, but in some species with larger dew-claws (such as deer and pigs) they may touch the ground when running or jumping, or if the ground is soft. Other cloven-hoofed animals (such as giraffes and pronghorns) have no dew claws. In some so-called "cloven-hoofed" animals such as camels, there are no hooves proper – the toe is softer, and the hoof itself is reduced to little more than a nail. Some odd-toed ungulates (equids) have one hoof on each foot; others (including rhinoceroses, tapirs and many extinct species) have (or had) three hoofed or heavily nailed toes, or one hoof and two dew-claws. The tapir is a special case, with three toes on each hind foot and four toes on each front foot. The number of toes is considered in determining the kosher status of the animal's flesh.

https://www.wikidoc.org/index.php/Hoof

e601649076d1b4463b6b2e352a90fba970342709

wikidoc

Hope

Hope # Overview Hope is a belief in a positive outcome related to events and circumstances in one's life. Hope implies a certain amount of despair, wanting, wishing, suffering or perseverance — i.e., believing that a better or positive outcome is possible even when there is some evidence to the contrary. Beyond the basic definition, usage of the term hope follows some basic patterns which distinguish its usage from related terms: - To wish for something with the expectation of the wish being fulfilled. - Hopefulness is somewhat different from optimism in that hope is an emotional state, whereas optimism is a conclusion reached through a deliberate thought pattern that leads to a positive attitude. But hope and optimism both can be based in unrealistic belief or fantasy. - When used in a religious context, hope carries a connotation of being aware of spiritual truth; see Hope (virtue). - In Catholic theology, hope is one of the three theological virtues (faith, hope, and charity), which are spiritual gifts of God. In contrast to the above, it is not a physical emotion but a spiritual grace. - Hope is distinct from positive thinking, which refers to a therapeutic or systematic process used in psychology for reversing pessimism. - The term false hope refers to a hope based entirely around a fantasy or an extremely unlikely outcome. # History Examples of hopes include hoping to get rich, hoping for someone to be cured of a disease, hoping to be done with a term paper, or hoping that a person has reciprocal feelings of love. Hope was personified in Greek mythology as Elpis. When Pandora opened Pandora's Box, she let out all the evils except one: hope. Apparently, the Greeks considered hope to be as dangerous as all the world's evils. But without hope to accompany all their troubles, humanity was filled with despair. It was a great relief when Pandora revisited her box and let out hope as well. It may be worthy to note that in the story, hope is represented as weakly leaving the box but is in effect far more potent than any of the major evils. In some faiths and religions of the world, hope plays a very important role. Buddhists and Muslims for instance, believe strongly in the concepts of free will and hope. Hope can be passive in the sense of a wish or prayer, or active as a plan or idea, often against popular belief, with persistent, personal action to execute the plan or prove the idea. Consider a prisoner of war who never gives up hope for escape and, against the odds, plans and accomplishes this. By contrast, consider another prisoner who simply wishes or prays for freedom, or another who gives up all hope of freedom. In Human, All Too Human, existential philosopher Friedrich Nietzsche had this to say about hope: It is also important to consider the relation between Hope and Utopia. Ernst Bloch in "Principle of Hope" (1986) traces the human search for a wide range of utopias. Bloch locates utopian projects not only in the social and political realms of the well-known utopian theorists (Marx, Hegel, Lenin) but also in a multiplicity of technical, architectural, geographical utopias, and in multiple works of art (opera, literature, music, dance, film). For Bloch hope permeates everyday life and it is present in countless aspects of popular culture phenomenon such as jokes, fairy tales, fashion or images of death. In his view Hope remains in the present as an open setting of latency and tendencies. Martin Seligman in his book Learned Optimism (1990) strongly criticizes the role of churches in the promotion of the idea that the individual has little chance or hope of affecting his or her life. He acknowledges that the social and cultural conditions, such as serfdom and the caste system weighed heavily against the freedom of individuals to change the social circumstances of their lives. Almost as if to avoid the criticism, in his book What You Can Change and What You Can't, he is careful to outline the extent that people can hold out hope for personal action to change some of the things that affect their lives. More recently, psychologist Anthony Scioli (2006) has developed an integrative theory of hope that consists of four elements: attachment, mastery, survival, and spirituality. This approach incorporates contributions from psychology, anthropology, philosophy and theology as well as classical and contemporary literature and the arts. # Socio-cognitive perspective From socio-cognitive viewpoint, hope is closely related to cognitive decision-making and can be considered its critical factor, such as risk dependent danger . In real situations, human agent's decision depends on the comparison of his/her danger perception and the hope indicator, which can be assessed as a value proportional to the probability of an event and its expected outcome/payoff/benefits There also is some evidence to suggest that in adverse situations, hope may be worse than hopelessness for overall well-being. For example, people sentenced to life imprisonment without the possibility of parole adjust better to their situation than prisoners who retain the possibility of parole. Similarly, patients who underwent a permanent colostomy showed higher life satisfaction 6 months after the operation than those who underwent a potentially reversible colostomy.

Hope Template:Emotion Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Hope is a belief in a positive outcome related to events and circumstances in one's life. Hope implies a certain amount of despair, wanting, wishing, suffering or perseverance — i.e., believing that a better or positive outcome is possible even when there is some evidence to the contrary. [1] Beyond the basic definition, usage of the term hope follows some basic patterns which distinguish its usage from related terms: - To wish for something with the expectation of the wish being fulfilled. [2] - Hopefulness is somewhat different from optimism in that hope is an emotional state, whereas optimism is a conclusion reached through a deliberate thought pattern that leads to a positive attitude. But hope and optimism both can be based in unrealistic belief or fantasy. - When used in a religious context, hope carries a connotation of being aware of spiritual truth; see Hope (virtue). - In Catholic theology, hope is one of the three theological virtues (faith, hope, and charity), which are spiritual gifts of God. In contrast to the above, it is not a physical emotion but a spiritual grace. - Hope is distinct from positive thinking, which refers to a therapeutic or systematic process used in psychology for reversing pessimism. - The term false hope refers to a hope based entirely around a fantasy or an extremely unlikely outcome. # History Examples of hopes include hoping to get rich, hoping for someone to be cured of a disease, hoping to be done with a term paper, or hoping that a person has reciprocal feelings of love. Hope was personified in Greek mythology as Elpis. When Pandora opened Pandora's Box, she let out all the evils except one: hope. Apparently, the Greeks considered hope to be as dangerous as all the world's evils. But without hope to accompany all their troubles, humanity was filled with despair. It was a great relief when Pandora revisited her box and let out hope as well. It may be worthy to note that in the story, hope is represented as weakly leaving the box but is in effect far more potent than any of the major evils. In some faiths and religions of the world, hope plays a very important role. Buddhists and Muslims for instance, believe strongly in the concepts of free will and hope. Hope can be passive in the sense of a wish or prayer, or active as a plan or idea, often against popular belief, with persistent, personal action to execute the plan or prove the idea. Consider a prisoner of war who never gives up hope for escape and, against the odds, plans and accomplishes this. By contrast, consider another prisoner who simply wishes or prays for freedom, or another who gives up all hope of freedom. In Human, All Too Human, existential philosopher Friedrich Nietzsche had this to say about hope: It is also important to consider the relation between Hope and Utopia. Ernst Bloch in "Principle of Hope" (1986) traces the human search for a wide range of utopias. Bloch locates utopian projects not only in the social and political realms of the well-known utopian theorists (Marx, Hegel, Lenin) but also in a multiplicity of technical, architectural, geographical utopias, and in multiple works of art (opera, literature, music, dance, film). For Bloch hope permeates everyday life and it is present in countless aspects of popular culture phenomenon such as jokes, fairy tales, fashion or images of death. In his view Hope remains in the present as an open setting of latency and tendencies. Martin Seligman in his book Learned Optimism (1990) strongly criticizes the role of churches in the promotion of the idea that the individual has little chance or hope of affecting his or her life. He acknowledges that the social and cultural conditions, such as serfdom and the caste system weighed heavily against the freedom of individuals to change the social circumstances of their lives. Almost as if to avoid the criticism, in his book What You Can Change and What You Can't, he is careful to outline the extent that people can hold out hope for personal action to change some of the things that affect their lives. More recently, psychologist Anthony Scioli (2006) has developed an integrative theory of hope that consists of four elements: attachment, mastery, survival, and spirituality. This approach incorporates contributions from psychology, anthropology, philosophy and theology as well as classical and contemporary literature and the arts.[3] # Socio-cognitive perspective From socio-cognitive viewpoint, hope is closely related to cognitive decision-making and can be considered its critical factor, such as risk dependent danger . In real situations, human agent's decision depends on the comparison of his/her danger perception and the hope indicator, which can be assessed as a value proportional to the probability of an event and its expected outcome/payoff/benefits [4] There also is some evidence to suggest that in adverse situations, hope may be worse than hopelessness for overall well-being. For example, people sentenced to life imprisonment without the possibility of parole adjust better to their situation than prisoners who retain the possibility of parole. Similarly, patients who underwent a permanent colostomy showed higher life satisfaction 6 months after the operation than those who underwent a potentially reversible colostomy.[5]

https://www.wikidoc.org/index.php/Hope

529731f4f70b28e191cb9bf2bf849a835d517311

wikidoc

Stye

Stye Synonyms and keywords: Hordeolum # Overview A stye (also known as a hordeolum) is a painful infection of the sebaceous glands at the base of the eyelashes on, inside, or under the eyelid.. The infection may be internal or external. In many cases, a hordeolum may resolve without treatment; however, the inflammation may spread to other ocular glands or recur. # Causes A stye is usually caused by Staphylococcus aureus. They can be triggered by stress, poor nutrition or lack of sleep. A stye may be secondary to blepharitis. # Differential Diagnosis A stye must be differentiated from: - Xanthelasma - Papilloma - Cyst - Pyogenic Granuloma - Amyloid Deposition # Risk Factors Common risk factors in the development of hordeola are: - Dry eyes - Chronic blepharitis # Epidemiology & Demographics Styes are particularly common in infants, though they may occur at any age. # Diagnosis ## History and Symptoms The first signs are tenderness and redness in the affected area. Symptoms of a stye include: - Swelling - Watering of the eye - Sensitivity to light - Discomfort during blinking ## Physical examination ### Eyes - A localized and tender area with a pointing eruption may be seen in the affected area. - A yellowish bump may be noted. ### Lymph Nodes - Adjacent lymph nodes may be palpable. ### Gallery - Hordeolum. With permission from Dermatology Atlas. - Hordeolum. With permission from Dermatology Atlas. # Treatment ## Medical Therapy Most cases of hordeolum resolve without treatment. Supportive therapy for hordeolum consists of warm compresses. Antimicrobial ophthalmic ointments may be administered. - Hordeolum - 1. External hordeolum, for a single lesion - Preferred regimen: Supportive therapy is sufficient. Application of warm compresses 4-6 times/day. - Note: Antibiotic therapy is questionable value for a single lesion and often not indicated. - 2. External hordeolum, for multiple/recurrent lesions - Preferred regimen (1): Bacitracin ophthalmic q8-24h - Preferred regimen (2): Erythromycin topical q4-6h - 3. Internal hordeolum - Preferred regimen: Warm compresses 4-6 times/day in conjugation with systemic antistaphylococcal antibiotics - Note: If the lesion do not respond to this regimen, incision and drainage are indicated.

Stye Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2]; Faizan Sheraz, M.D. [3] Synonyms and keywords: Hordeolum # Overview A stye (also known as a hordeolum) is a painful infection of the sebaceous glands at the base of the eyelashes on, inside, or under the eyelid.[1]. The infection may be internal or external. In many cases, a hordeolum may resolve without treatment; however, the inflammation may spread to other ocular glands or recur. [2] # Causes A stye is usually caused by Staphylococcus aureus.[3] They can be triggered by stress, poor nutrition or lack of sleep.[4] A stye may be secondary to blepharitis. # Differential Diagnosis A stye must be differentiated from:[5] - Xanthelasma - Papilloma - Cyst - Pyogenic Granuloma - Amyloid Deposition # Risk Factors Common risk factors in the development of hordeola are:[6] - Dry eyes - Chronic blepharitis # Epidemiology & Demographics Styes are particularly common in infants, though they may occur at any age.[3] # Diagnosis ## History and Symptoms The first signs are tenderness and redness in the affected area. Symptoms of a stye include: - Swelling - Watering of the eye - Sensitivity to light - Discomfort during blinking ## Physical examination ### Eyes - A localized and tender area with a pointing eruption may be seen in the affected area.[7] - A yellowish bump may be noted. ### Lymph Nodes - Adjacent lymph nodes may be palpable.[8] ### Gallery - Hordeolum. With permission from Dermatology Atlas.[9] - Hordeolum. With permission from Dermatology Atlas.[9] # Treatment ## Medical Therapy Most cases of hordeolum resolve without treatment. Supportive therapy for hordeolum consists of warm compresses. Antimicrobial ophthalmic ointments may be administered[3]. - Hordeolum[10] - 1. External hordeolum, for a single lesion - Preferred regimen: Supportive therapy is sufficient. Application of warm compresses 4-6 times/day. - Note: Antibiotic therapy is questionable value for a single lesion and often not indicated. - 2. External hordeolum, for multiple/recurrent lesions - Preferred regimen (1): Bacitracin ophthalmic q8-24h - Preferred regimen (2): Erythromycin topical q4-6h - 3. Internal hordeolum - Preferred regimen: Warm compresses 4-6 times/day in conjugation with systemic antistaphylococcal antibiotics - Note: If the lesion do not respond to this regimen, incision and drainage are indicated.

https://www.wikidoc.org/index.php/Hordeolum

f7ebcf2983d7159a8cd8f2c5a13c597b63b930da

wikidoc

IDH1

IDH1 Isocitrate dehydrogenase 1 (NADP+), soluble is an enzyme that in humans is encoded by the IDH1 gene on chromosome 2. Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which uses NAD+ as the electron acceptor and the other NADP+. Five isocitrate dehydrogenases have been reported: three NAD+-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP+-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP+-dependent isozyme is a homodimer. The protein encoded by this gene is the NADP+-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2,4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production. Alternatively spliced transcript variants encoding the same protein have been found for this gene. # Structure IDH1 is one of three isocitrate dehydrogenase isozymes, the other two being IDH2 and IDH3, and encoded by one of five isocitrate dehydrogenase genes, which are IDH1, IDH2, IDH3A, IDH3B, and IDH3G. IDH1 forms an asymmetric homodimer in the cytoplasm and carries out its function through two hydrophilic active sites formed by both protein subunits. Each subunit or monomer is composed of three domains: a large domain (residues 1–103 and 286–414), a small domain (residues 104–136 and 186–285), and a clasp domain (residues 137 to 185). The large domain contains a Rossmann fold, while the small domain forms an α/β sandwich structure, and the clasp domain folds as two stacked double-stranded anti-parallel β-sheets. A β-sheet joins the large and small domains and is flanked by two clefts on opposite sides. The deep cleft, also known as the active site, is formed by the large and small domains of one subunit and a small domain of the other subunit. This active site includes the NADP-binding site and the isocitrate-metal ion-binding site. The shallow cleft, also referred to as the back cleft, is formed by both domains of one subunit and participates in the conformational changes of homodimeric IDH1. Finally, the clasp domains of both subunits intertwine to form a double layer of four-stranded anti-parallel β-sheets linking together the two subunits and the two active sites. Furthermore, conformational changes to the subunits and a conserved structure at the active site affect the activity of the enzyme. In its open, inactive form, the active site structure forms a loop while one subunit adopts an asymmetric open conformation and the other adopts a quasi-open conformation. This conformation enables isocitrate to bind the active site, inducing a closed conformation that also activates IDH1. In its closed, inactive form, the active site structure becomes an α-helix that can chelate metal ions. An intermediate, semi-open form features this active site structure as a partially unraveled α-helix. There is also a type 1 peroxisomal targeting sequence at its C-terminal that targets the protein to the peroxisome. # Function As an isocitrate dehydrogenase, IDH1 catalyzes the reversible oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG) as part of the TCA cycle in glucose metabolism. This step also allows for the concomitant reduction of nicotinamide adenine dinucleotide phosphate (NADP+) to reduced nicotinamide adenine dinucleotide phosphate (NADPH). Since NADPH and α-KG function in cellular detoxification processes in response to oxidative stress, IDH1 also indirectly participates in mitigating oxidative damage. In addition, IDH1 is key to β-oxidation of unsaturated fatty acids in the peroxisomes of liver cells. IDH1 also participates in the regulation of glucose-induced insulin secretion. Notably, IDH1 is the primary producer of NADPH in most tissues, especially in brain. Within cells, IDH1 has been observed to localize to the cytoplasm, peroxisome, and endoplasmic reticulum. Under hypoxic conditions, IDH1 catalyzes the reverse reaction of α-KG to isocitrate, which contributes to citrate production via glutaminolysis. Isocitrate can also be converted into acetyl-CoA for lipid metabolism. ## Mutation IDH1 mutations are heterozygous, typically involving an amino acid substitution in the active site of the enzyme in codon 132. The mutation results in a loss of normal enzymatic function and the abnormal production of 2-hydroxyglutarate (2-HG). It has been proposed that this take place due to a change in the binding site of the enzyme. 2-HG has been found to inhibit enzymatic function of many alpha-ketoglutarate dependent dioxygenases, including histone and DNA demethylases, causing widespread changes in histone and DNA methylation and potentially promoting tumorigenesis. # Clinical Significance Mutations in this gene have been shown to cause metaphyseal chondromatosis with aciduria. Mutations in IDH1 are also implicated in cancer. Originally, mutations in IDH1 were detected in an integrated genomic analysis of human glioblastoma multiforme. Since then it has become clear that mutations in IDH1 and its homologue IDH2 are among the most frequent mutations in diffuse gliomas, including diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytoma, anaplastic oligoastrocytoma, and secondary glioblastoma. Mutations in IDH1 are often the first hit in the development of diffuse gliomas, suggesting IDH1 mutations as key events in the formation of these brain tumors. Glioblastomas with a wild-type IDH1 gene have a median overall survival of only 1 year, whereas IDH1-mutated glioblastoma patients have a median overall survival of over 2 years. In addition to being mutated in diffuse gliomas, IDH1 has also been shown to harbor mutations in human acute myeloid leukemia. The IDH1 mutation is considered a driver alteration and occurs early during tumorigenesis, in specific in glioma and glioblastoma multiforme, its possible use as a new tumour-specific antigen to induce antitumor immunity for the cancer treatment has recently been prompted. A tumour vaccine can stimulate the body’s immune system, upon exposure to a tumour-specific peptide antigen, by activation or amplification of a humoral and cytotoxic immune response targeted at the specific cancer cells. The study of Schumacher et al. has been shown that this attractive target (the mutation in the isocitrate dehydrogenase 1) from an immunological perspective represents a potential tumour-specific neoantigen with high uniformity and penetrance and could be exploited by immunotherapy through vaccination. Accordingly, some patients with IDH1-mutated gliomas demonstrated spontaneous peripheral CD4+ T-cell responses against the mutated IDH1 region with generation B-cell producing antibodies. Vaccination of MHC-humanized transgenic mice with mutant IDH1 peptide induced an IFN-γ CD4+ T-helper 1 cell response, indicating an endogenous processing through MHC class II, and production of antibodies targeting mutant IDH1. Tumour vaccination, both prophylactic and therapeutic, resulted in growth suppression of transplanted IDH1-expressing sarcomas in MHC-humanized mice. This in vivo data shows a specific and potent immunologic response in both transplanted and existing tumours. ## As a drug target Mutated and normal forms of IDH1 had been studied for drug inhibition both in silico and in vitro, and some drugs are being developed (e.g. Ivosidenib). Ivosidenib was approved by the FDA in July 2018 for relapsed or refractory acute myeloid leukemia (AML) with an IDH1 mutation.

IDH1 Isocitrate dehydrogenase 1 (NADP+), soluble is an enzyme that in humans is encoded by the IDH1 gene on chromosome 2. Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which uses NAD+ as the electron acceptor and the other NADP+. Five isocitrate dehydrogenases have been reported: three NAD+-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP+-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP+-dependent isozyme is a homodimer. The protein encoded by this gene is the NADP+-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2,4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013][1] # Structure IDH1 is one of three isocitrate dehydrogenase isozymes, the other two being IDH2 and IDH3, and encoded by one of five isocitrate dehydrogenase genes, which are IDH1, IDH2, IDH3A, IDH3B, and IDH3G.[2] IDH1 forms an asymmetric homodimer in the cytoplasm and carries out its function through two hydrophilic active sites formed by both protein subunits.[3][4][5][6][7] Each subunit or monomer is composed of three domains: a large domain (residues 1–103 and 286–414), a small domain (residues 104–136 and 186–285), and a clasp domain (residues 137 to 185). The large domain contains a Rossmann fold, while the small domain forms an α/β sandwich structure, and the clasp domain folds as two stacked double-stranded anti-parallel β-sheets. A β-sheet joins the large and small domains and is flanked by two clefts on opposite sides. The deep cleft, also known as the active site, is formed by the large and small domains of one subunit and a small domain of the other subunit. This active site includes the NADP-binding site and the isocitrate-metal ion-binding site. The shallow cleft, also referred to as the back cleft, is formed by both domains of one subunit and participates in the conformational changes of homodimeric IDH1. Finally, the clasp domains of both subunits intertwine to form a double layer of four-stranded anti-parallel β-sheets linking together the two subunits and the two active sites.[7] Furthermore, conformational changes to the subunits and a conserved structure at the active site affect the activity of the enzyme. In its open, inactive form, the active site structure forms a loop while one subunit adopts an asymmetric open conformation and the other adopts a quasi-open conformation.[5][7] This conformation enables isocitrate to bind the active site, inducing a closed conformation that also activates IDH1.[5] In its closed, inactive form, the active site structure becomes an α-helix that can chelate metal ions. An intermediate, semi-open form features this active site structure as a partially unraveled α-helix.[7] There is also a type 1 peroxisomal targeting sequence at its C-terminal that targets the protein to the peroxisome.[7] # Function As an isocitrate dehydrogenase, IDH1 catalyzes the reversible oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG) as part of the TCA cycle in glucose metabolism.[2][3][4][6][7] This step also allows for the concomitant reduction of nicotinamide adenine dinucleotide phosphate (NADP+) to reduced nicotinamide adenine dinucleotide phosphate (NADPH).[3][4][6] Since NADPH and α-KG function in cellular detoxification processes in response to oxidative stress, IDH1 also indirectly participates in mitigating oxidative damage.[2][3][7][8] In addition, IDH1 is key to β-oxidation of unsaturated fatty acids in the peroxisomes of liver cells.[7] IDH1 also participates in the regulation of glucose-induced insulin secretion.[2] Notably, IDH1 is the primary producer of NADPH in most tissues, especially in brain.[3] Within cells, IDH1 has been observed to localize to the cytoplasm, peroxisome, and endoplasmic reticulum.[6][8] Under hypoxic conditions, IDH1 catalyzes the reverse reaction of α-KG to isocitrate, which contributes to citrate production via glutaminolysis.[2][3] Isocitrate can also be converted into acetyl-CoA for lipid metabolism.[2] ## Mutation IDH1 mutations are heterozygous, typically involving an amino acid substitution in the active site of the enzyme in codon 132.[9][10] The mutation results in a loss of normal enzymatic function and the abnormal production of 2-hydroxyglutarate (2-HG).[9] It has been proposed that this take place due to a change in the binding site of the enzyme.[11] 2-HG has been found to inhibit enzymatic function of many alpha-ketoglutarate dependent dioxygenases, including histone and DNA demethylases, causing widespread changes in histone and DNA methylation and potentially promoting tumorigenesis.[10][12] # Clinical Significance Mutations in this gene have been shown to cause metaphyseal chondromatosis with aciduria.[13] Mutations in IDH1 are also implicated in cancer. Originally, mutations in IDH1 were detected in an integrated genomic analysis of human glioblastoma multiforme.[14] Since then it has become clear that mutations in IDH1 and its homologue IDH2 are among the most frequent mutations in diffuse gliomas, including diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytoma, anaplastic oligoastrocytoma, and secondary glioblastoma.[15] Mutations in IDH1 are often the first hit in the development of diffuse gliomas, suggesting IDH1 mutations as key events in the formation of these brain tumors.[16][17][18] Glioblastomas with a wild-type IDH1 gene have a median overall survival of only 1 year, whereas IDH1-mutated glioblastoma patients have a median overall survival of over 2 years.[19] In addition to being mutated in diffuse gliomas, IDH1 has also been shown to harbor mutations in human acute myeloid leukemia.[20][21] The IDH1 mutation is considered a driver alteration and occurs early during tumorigenesis, in specific in glioma and glioblastoma multiforme, its possible use as a new tumour-specific antigen to induce antitumor immunity for the cancer treatment has recently been prompted.[22] A tumour vaccine can stimulate the body’s immune system, upon exposure to a tumour-specific peptide antigen, by activation or amplification of a humoral and cytotoxic immune response targeted at the specific cancer cells. The study of Schumacher et al. has been shown that this attractive target (the mutation in the isocitrate dehydrogenase 1) from an immunological perspective represents a potential tumour-specific neoantigen with high uniformity and penetrance and could be exploited by immunotherapy through vaccination. Accordingly, some patients with IDH1-mutated gliomas demonstrated spontaneous peripheral CD4+ T-cell responses against the mutated IDH1 region with generation B-cell producing antibodies. Vaccination of MHC-humanized transgenic mice with mutant IDH1 peptide induced an IFN-γ CD4+ T-helper 1 cell response, indicating an endogenous processing through MHC class II, and production of antibodies targeting mutant IDH1. Tumour vaccination, both prophylactic and therapeutic, resulted in growth suppression of transplanted IDH1-expressing sarcomas in MHC-humanized mice. This in vivo data shows a specific and potent immunologic response in both transplanted and existing tumours.[22] ## As a drug target Mutated and normal forms of IDH1 had been studied for drug inhibition both in silico and in vitro[23][24][25][26], and some drugs are being developed (e.g. Ivosidenib). Ivosidenib was approved by the FDA in July 2018 for relapsed or refractory acute myeloid leukemia (AML) with an IDH1 mutation[27].

https://www.wikidoc.org/index.php/IDH1

f222e1319fa9ac9edde01d20cb127aaae36feae3

wikidoc

IDH2

IDH2 Isocitrate dehydrogenase , mitochondrial is an enzyme that in humans is encoded by the IDH2 gene. Isocitrate dehydrogenases are enzymes that catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer. The protein encoded by the IDH2 gene is the NADP(+)-dependent isocitrate dehydrogenase found in the mitochondria. It plays a role in intermediary metabolism and energy production. This protein may tightly associate or interact with the pyruvate dehydrogenase complex. Somatic mosaic mutations of this gene have also been found associated to Ollier disease and Maffucci syndrome. # Structure Isocitrate dehydrogenase is composed of 3 subunits, allosterically regulated, and requires an integrated Mg2+ or Mn2+ ion. The mitochondrial form of IDH, like most isoforms, is a homodimer, in which two identical monomer subunits form one unit. The structure of Mycobacterium tuberculosis IDH-1 bound with NADPH and Mn2+ has been solved by X-ray crystallography. It is a homodimer in which each subunit has a Rossmann fold, and a common top domain of interlocking β sheets. Mtb IDH-1 is most structurally similar to the R132H mutant human IDH found in certain glioblastomas. Similar to human R132H ICDH, Mtb ICDH-1 also catalyzes the formation of ;;alpha-Hydroxyglutaric acid|α-hydroxyglutarate]]. # Function Isocitrate dehydrogenase is a digestive enzyme that is used in the citric acid cycle. Its main function is to catalyze the oxidative decarboxylation of isocitrate into alpha-ketoglutarate. Human isocitrate dehydrogenase regulation is not fully understood however, it is known that NADP and Ca2+ bind in the active site to create three different conformations. These conformations form in the active site and are as follows: a loop is form in the inactive enzyme, a partially unraveled alpha helix in the semi open form, and an alpha helix in the active form. # Clinical significance The mitochondrial form of IDH2 is correlated with many diseases. Mutations in IDH2 are associated with 2-hydroxyglutaric aciduria, a condition that causes progressive damage to the brain. The major types of this disorder are called D-2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA). The main features of D-2-HGA are delayed development, seizures, weak muscle tone (hypotonia), and abnormalities in the largest part of the brain (the cerebrum), which controls many important functions such as muscle movement, speech, vision, thinking, emotion, and memory. Researchers have described two subtypes of D-2-HGA, type I and type II. The two subtypes are distinguished by their genetic cause and pattern of inheritance, although they also have some differences in signs and symptoms. Type II tends to begin earlier and often causes more severe health problems than type I. Type II may also be associated with a weakened and enlarged heart (cardiomyopathy), a feature that is typically not found with type I. L-2-HGA particularly affects a region of the brain called the cerebellum, which is involved in coordinating movements. As a result, many affected individuals have problems with balance and muscle coordination (ataxia). Additional features of L-2-HGA can include delayed development, seizures, speech difficulties, and an unusually large head (macrocephaly). Typically, signs and symptoms of this disorder begin during infancy or early childhood. The disorder worsens over time, usually leading to severe disability by early adulthood. Combined D,L-2-HGA causes severe brain abnormalities that become apparent in early infancy. Affected infants have severe seizures, weak muscle tone (hypotonia), and breathing and feeding problems. They usually survive only into infancy or early childhood. Mutations in the IDH2 gene, along with mutations in the IDH1 gene, are also strongly correlated with the development of glioma, acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma (ICC), and angioimmunoblastic T-cell lymphoma cancers. They also cause D-2-hydroxyglutaric aciduria and Ollier and Maffucci syndromes. IDH2 mutations may allow prolonged survival of glioma and ICC cancer cells, but not AML cells. The reason for this is unknown. Missense mutations in the active site of these IDH2 induce a neo-enzymatic reaction wherein NADPH reduces αKG to D-2-hydroxyglutarate, which accumulates and leads to hypoxia-inducible factor 1α (HIF1α) degradation, as well as changes in epigenetics and extracellular matrix homeostasis. Such mutations also imply less NADPH production capacity. Inhibitors of the neomorphic activity of mutant IDH1 and IDH2 are currently in Phase I/II clinical trials for both solid and blood tumors. As IDH1 and IDH2 represent key enzymes within the tricarboxylic acid (TCA) cycle, mutations have significant impact on intermediary metabolism. The loss of some wild-type metabolic activity is an important, potentially deleterious and therapeutically exploitable consequence of oncogenic IDH mutations and requires continued investigation in the future. # As a drug target Drugs that target mutated forms of IDH2 include : - Enasidenib for AML # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

IDH2 Isocitrate dehydrogenase [NADP], mitochondrial is an enzyme that in humans is encoded by the IDH2 gene.[1] Isocitrate dehydrogenases are enzymes that catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer. The protein encoded by the IDH2 gene is the NADP(+)-dependent isocitrate dehydrogenase found in the mitochondria. It plays a role in intermediary metabolism and energy production. This protein may tightly associate or interact with the pyruvate dehydrogenase complex.[1] Somatic mosaic mutations of this gene have also been found associated to Ollier disease and Maffucci syndrome.[2] # Structure Isocitrate dehydrogenase is composed of 3 subunits, allosterically regulated, and requires an integrated Mg2+ or Mn2+ ion. The mitochondrial form of IDH, like most isoforms, is a homodimer, in which two identical monomer subunits form one unit. The structure of Mycobacterium tuberculosis IDH-1 bound with NADPH and Mn2+ has been solved by X-ray crystallography. It is a homodimer in which each subunit has a Rossmann fold, and a common top domain of interlocking β sheets. Mtb IDH-1 is most structurally similar to the R132H mutant human IDH found in certain glioblastomas. Similar to human R132H ICDH, Mtb ICDH-1 also catalyzes the formation of ;;alpha-Hydroxyglutaric acid|α-hydroxyglutarate]].[3] # Function Isocitrate dehydrogenase is a digestive enzyme that is used in the citric acid cycle. Its main function is to catalyze the oxidative decarboxylation of isocitrate into alpha-ketoglutarate. Human isocitrate dehydrogenase regulation is not fully understood however, it is known that NADP and Ca2+ bind in the active site to create three different conformations. These conformations form in the active site and are as follows: a loop is form in the inactive enzyme, a partially unraveled alpha helix in the semi open form, and an alpha helix in the active form.[4] # Clinical significance The mitochondrial form of IDH2 is correlated with many diseases. Mutations in IDH2 are associated with 2-hydroxyglutaric aciduria, a condition that causes progressive damage to the brain. The major types of this disorder are called D-2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA). The main features of D-2-HGA are delayed development, seizures, weak muscle tone (hypotonia), and abnormalities in the largest part of the brain (the cerebrum), which controls many important functions such as muscle movement, speech, vision, thinking, emotion, and memory. Researchers have described two subtypes of D-2-HGA, type I and type II. The two subtypes are distinguished by their genetic cause and pattern of inheritance, although they also have some differences in signs and symptoms. Type II tends to begin earlier and often causes more severe health problems than type I. Type II may also be associated with a weakened and enlarged heart (cardiomyopathy), a feature that is typically not found with type I. L-2-HGA particularly affects a region of the brain called the cerebellum, which is involved in coordinating movements. As a result, many affected individuals have problems with balance and muscle coordination (ataxia). Additional features of L-2-HGA can include delayed development, seizures, speech difficulties, and an unusually large head (macrocephaly). Typically, signs and symptoms of this disorder begin during infancy or early childhood. The disorder worsens over time, usually leading to severe disability by early adulthood. Combined D,L-2-HGA causes severe brain abnormalities that become apparent in early infancy. Affected infants have severe seizures, weak muscle tone (hypotonia), and breathing and feeding problems. They usually survive only into infancy or early childhood.[1] Mutations in the IDH2 gene, along with mutations in the IDH1 gene, are also strongly correlated with the development of glioma, acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma (ICC), and angioimmunoblastic T-cell lymphoma cancers. They also cause D-2-hydroxyglutaric aciduria and Ollier and Maffucci syndromes. IDH2 mutations may allow prolonged survival of glioma and ICC cancer cells, but not AML cells. The reason for this is unknown. Missense mutations in the active site of these IDH2 induce a neo-enzymatic reaction wherein NADPH reduces αKG to D-2-hydroxyglutarate, which accumulates and leads to hypoxia-inducible factor 1α (HIF1α) degradation, as well as changes in epigenetics and extracellular matrix homeostasis. Such mutations also imply less NADPH production capacity.[5] Inhibitors of the neomorphic activity of mutant IDH1 and IDH2 are currently in Phase I/II clinical trials for both solid and blood tumors. As IDH1 and IDH2 represent key enzymes within the tricarboxylic acid (TCA) cycle, mutations have significant impact on intermediary metabolism. The loss of some wild-type metabolic activity is an important, potentially deleterious and therapeutically exploitable consequence of oncogenic IDH mutations and requires continued investigation in the future.[6] # As a drug target Drugs that target mutated forms of IDH2 include : - Enasidenib for AML # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. [§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

https://www.wikidoc.org/index.php/IDH2

889674b7a1935b4f77572438fb17bacff6932567

wikidoc

IGL@

IGL@ Immunoglobulin lambda locus, also known as IGL@, is a region on human chromosome 22 that contains genes for the lambda light chains of antibodies (or immunoglobulins). # Function Immunoglobulins recognize foreign antigens and initiate immune responses such as phagocytosis and the complement system. Each immunoglobulin molecule consists of two identical heavy chains and two identical light chains. There are two classes of light chains, kappa and lambda. This region represents the germline organization of the lambda light chain locus. The locus includes V (variable), J (joining), and C (constant) segments. During B cell development, a recombination event at the DNA level joins a single V segment with a J segment; the C segment is later joined by splicing at the RNA level. Recombination of many different V segments with several J segments provides a wide range of antigen recognition. Additional diversity is attained by junctional diversity, resulting from the random additional of nucleotides by terminal deoxynucleotidyltransferase, and by somatic hypermutation, which occurs during B cell maturation in the spleen and lymph nodes. Several V segments and three C segments are known to be incapable of encoding a protein and are considered pseudogenes. The locus also includes several non-immunoglobulin genes, many of which are pseudogenes or are predicted by automated computational analysis or homology to other species. # Genes The immunoglobulin lambda locus contains the following genes: - IGLC@ – constant group IGLC1 – immunoglobulin lambda constant 1 (Mcg marker) IGLC2 – immunoglobulin lambda constant 2 (Kern-Oz- marker) IGLC3 – immunoglobulin lambda constant 3 (Kern-Oz+ marker) IGLC7 – immunoglobulin lambda constant 7 - IGLC1 – immunoglobulin lambda constant 1 (Mcg marker) - IGLC2 – immunoglobulin lambda constant 2 (Kern-Oz- marker) - IGLC3 – immunoglobulin lambda constant 3 (Kern-Oz+ marker) - IGLC7 – immunoglobulin lambda constant 7 - IGLJ@ – joining group IGLJn – immunoglobulin lambda joining n IGLJ1, IGLJ2, IGLJ3, IGLJ6, IGLJ7 - IGLJn – immunoglobulin lambda joining n - IGLJ1, IGLJ2, IGLJ3, IGLJ6, IGLJ7 - IGLV@ – variable group IGLVm-n – immunoglobulin lambda variable n-m IGLV1-36, IGLV1-40, IGLV1-44, IGLV1-47, IGLV1-51, IGLV1-62 IGLV2-5, IGLV2-8, IGLV2-11, IGLV2-14, IGLV2-18, IGLV2-23 IGLV3-1, IGLV3-10, IGLV3-12, IGLV3-16, IGLV3-19, IGLV3-21, IGLV3-25, IGLV3-27 IGLV4-3, IGLV4-60, IGLV4-69 IGLV5-37, IGLV5-39, IGLV5-45, IGLV5-52 IGLV6-57 IGLV7-43 IGLV9-49 IGLV10-54 - IGLVm-n – immunoglobulin lambda variable n-m - IGLV1-36, IGLV1-40, IGLV1-44, IGLV1-47, IGLV1-51, IGLV1-62 - IGLV2-5, IGLV2-8, IGLV2-11, IGLV2-14, IGLV2-18, IGLV2-23 - IGLV3-1, IGLV3-10, IGLV3-12, IGLV3-16, IGLV3-19, IGLV3-21, IGLV3-25, IGLV3-27 - IGLV4-3, IGLV4-60, IGLV4-69 - IGLV5-37, IGLV5-39, IGLV5-45, IGLV5-52 - IGLV6-57 - IGLV7-43 - IGLV9-49 - IGLV10-54 Ig lambda chain C regions is a protein that in humans is encoded by the IGLC2 gene.

IGL@ Immunoglobulin lambda locus, also known as IGL@, is a region on human chromosome 22 that contains genes for the lambda light chains of antibodies (or immunoglobulins).[1] # Function Immunoglobulins recognize foreign antigens and initiate immune responses such as phagocytosis and the complement system. Each immunoglobulin molecule consists of two identical heavy chains and two identical light chains. There are two classes of light chains, kappa and lambda. This region represents the germline organization of the lambda light chain locus. The locus includes V (variable), J (joining), and C (constant) segments. During B cell development, a recombination event at the DNA level joins a single V segment with a J segment; the C segment is later joined by splicing at the RNA level. Recombination of many different V segments with several J segments provides a wide range of antigen recognition. Additional diversity is attained by junctional diversity, resulting from the random additional of nucleotides by terminal deoxynucleotidyltransferase, and by somatic hypermutation, which occurs during B cell maturation in the spleen and lymph nodes. Several V segments and three C segments are known to be incapable of encoding a protein and are considered pseudogenes. The locus also includes several non-immunoglobulin genes, many of which are pseudogenes or are predicted by automated computational analysis or homology to other species.[1] # Genes The immunoglobulin lambda locus contains the following genes: - IGLC@ – constant group IGLC1 – immunoglobulin lambda constant 1 (Mcg marker) IGLC2 – immunoglobulin lambda constant 2 (Kern-Oz- marker) IGLC3 – immunoglobulin lambda constant 3 (Kern-Oz+ marker) IGLC7 – immunoglobulin lambda constant 7 - IGLC1 – immunoglobulin lambda constant 1 (Mcg marker) - IGLC2 – immunoglobulin lambda constant 2 (Kern-Oz- marker) - IGLC3 – immunoglobulin lambda constant 3 (Kern-Oz+ marker) - IGLC7 – immunoglobulin lambda constant 7 - IGLJ@ – joining group IGLJn – immunoglobulin lambda joining n IGLJ1, IGLJ2, IGLJ3, IGLJ6, IGLJ7 - IGLJn – immunoglobulin lambda joining n - IGLJ1, IGLJ2, IGLJ3, IGLJ6, IGLJ7 - IGLV@ – variable group IGLVm-n – immunoglobulin lambda variable n-m IGLV1-36, IGLV1-40, IGLV1-44, IGLV1-47, IGLV1-51, IGLV1-62 IGLV2-5, IGLV2-8, IGLV2-11, IGLV2-14, IGLV2-18, IGLV2-23 IGLV3-1, IGLV3-10, IGLV3-12, IGLV3-16, IGLV3-19, IGLV3-21, IGLV3-25, IGLV3-27 IGLV4-3, IGLV4-60, IGLV4-69 IGLV5-37, IGLV5-39, IGLV5-45, IGLV5-52 IGLV6-57 IGLV7-43 IGLV9-49 IGLV10-54 - IGLVm-n – immunoglobulin lambda variable n-m - IGLV1-36, IGLV1-40, IGLV1-44, IGLV1-47, IGLV1-51, IGLV1-62 - IGLV2-5, IGLV2-8, IGLV2-11, IGLV2-14, IGLV2-18, IGLV2-23 - IGLV3-1, IGLV3-10, IGLV3-12, IGLV3-16, IGLV3-19, IGLV3-21, IGLV3-25, IGLV3-27 - IGLV4-3, IGLV4-60, IGLV4-69 - IGLV5-37, IGLV5-39, IGLV5-45, IGLV5-52 - IGLV6-57 - IGLV7-43 - IGLV9-49 - IGLV10-54 Ig lambda chain C regions is a protein that in humans is encoded by the IGLC2 gene.[1]

https://www.wikidoc.org/index.php/IGL@

6af4c7faad20d4c42a2659fdbb280989c183432b

wikidoc

IKK2

IKK2 IKK-β also known as inhibitor of nuclear factor kappa-B kinase subunit beta is a protein that in humans is encoded by the IKBKB (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta) gene. # Function IKK-β is an enzyme that serves as a protein subunit of IκB kinase, which is a component of the cytokine-activated intracellular signaling pathway involved in triggering immune responses. IKK's activity causes activation of a transcription factor known as Nuclear Transcription factor kappa-B or NF-κB. Activated IKK-β phosphorylates a protein called the inhibitor of NF-κB, IκB (IκBα), which binds NF-κB to inhibit its function. Phosphorylated IκB is degraded via the ubiquitination pathway, freeing NF-κB, and allowing its entry into the nucleus of the cell where it activates various genes involved in inflammation and other immune responses. # Clinical significance IKK-β plays a significant role in brain cells following a stroke. If NF-κB activation by IKK-β is blocked, damaged cells within the brain stay alive, and according to a study performed by the University of Heidelberg and the University of Ulm, the cells even appear to make some recovery. Inhibition of IKK and IKK-related kinases has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer. The small-molecule inhibitor of IKK2 SAR113945, developed by Sanofi-Aventis, was evaluated in patients with knee osteoarthritis. # Model organisms Model organisms have been used in the study of IKK-β function. The size of an infarct, or tissue killed or damaged by ischemia, is reduced in mice in which IKK-β has been blocked. Additionally, experimental mice with an overactive form of IKK-β experience loss of many more neurons than normal mice after a stroke-simulating event. Researchers found a molecule that could block the signaling of IKK-β for up to four and a half hours. In another study, researchers found that inhibiting IKK-β prevented kidney and wasting diseases in an animal model used to study wasting diseases of human AIDS sufferers. A conditional knockout mouse line, called Ikbkbtm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out and two phenotypes were reported. A reduced number of homozygous mutant embryos were identified during gestation, and none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice, and no significant abnormalities were observed in these animals. # Interactions IKK-β (IKBKB) has been shown to interact with - CDC37, - CHUK - CTNNB1, - FANCA, - IKBKG - IRAK1, - NFKBIA, - MAP3K14, - NFKB1, - NFKBIB, - NCOA3, - PPM1B, - TNFRSF1A, and - TRAF2.

IKK2 IKK-β also known as inhibitor of nuclear factor kappa-B kinase subunit beta is a protein that in humans is encoded by the IKBKB (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta) gene. # Function IKK-β is an enzyme that serves as a protein subunit of IκB kinase, which is a component of the cytokine-activated intracellular signaling pathway involved in triggering immune responses. IKK's activity causes activation of a transcription factor known as Nuclear Transcription factor kappa-B or NF-κB. Activated IKK-β phosphorylates a protein called the inhibitor of NF-κB, IκB (IκBα), which binds NF-κB to inhibit its function. Phosphorylated IκB is degraded via the ubiquitination pathway, freeing NF-κB, and allowing its entry into the nucleus of the cell where it activates various genes involved in inflammation and other immune responses. # Clinical significance IKK-β plays a significant role in brain cells following a stroke.[citation needed] If NF-κB activation by IKK-β is blocked, damaged cells within the brain stay alive, and according to a study performed by the University of Heidelberg and the University of Ulm, the cells even appear to make some recovery.[1] Inhibition of IKK and IKK-related kinases has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer.[2][2] The small-molecule inhibitor of IKK2 SAR113945, developed by Sanofi-Aventis, was evaluated in patients with knee osteoarthritis.[3] # Model organisms Model organisms have been used in the study of IKK-β function. The size of an infarct, or tissue killed or damaged by ischemia, is reduced in mice in which IKK-β has been blocked.[4] Additionally, experimental mice with an overactive form of IKK-β experience loss of many more neurons than normal mice after a stroke-simulating event.[1] Researchers found a molecule that could block the signaling of IKK-β for up to four and a half hours.[5] In another study, researchers found that inhibiting IKK-β prevented kidney and wasting diseases in an animal model used to study wasting diseases of human AIDS sufferers.[6] A conditional knockout mouse line, called Ikbkbtm1a(EUCOMM)Wtsi[11][12] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[13][14][15] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[9][16] Twenty six tests were carried out and two phenotypes were reported. A reduced number of homozygous mutant embryos were identified during gestation, and none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice, and no significant abnormalities were observed in these animals.[9] # Interactions IKK-β (IKBKB) has been shown to interact with - CDC37,[17] - CHUK[17][18][19][20][21][22][23] - CTNNB1,[24] - FANCA,[19] - IKBKG[17][22][25][26][27] - IRAK1,[28][29] - NFKBIA,[21][30][31] - MAP3K14,[21][32] - NFKB1,[33][34] - NFKBIB,[21] - NCOA3,[26] - PPM1B,[35] - TNFRSF1A,[36][37] and - TRAF2.[38][39]

https://www.wikidoc.org/index.php/IKK2

86959de5b3d09a92afd6cb10576e85e9fb7a1529

wikidoc

IL1A

IL1A Interleukin 1 alpha (IL-1α) also known as hematopoietin 1 is a cytokine of the interleukin 1 family that in humans is encoded by the IL1A gene. In general, Interleukin 1 is responsible for the production of inflammation, as well as the promotion of fever and sepsis. IL-1α inhibitors are being developed to interrupt those processes and treat diseases. IL-1α is produced mainly by activated macrophages, as well as neutrophils, epithelial cells, and endothelial cells. It possesses metabolic, physiological, haematopoietic activities, and plays one of the central roles in the regulation of the immune responses. It binds to the interleukin-1 receptor. It is on the pathway that activates tumor necrosis factor-alpha. # Discovery Interleukin 1 was discovered by Gery in 1972. He named it lymphocyte-activating factor (LAF) because it was a lymphocyte mitogen. It was not until 1985 that interleukin 1 was discovered to consist of two distinct proteins, now called interleukin-1 alpha and interleukin-1 beta. # Alternative names IL-1α is also known as fibroblast-activating factor (FAF), lymphocyte-activating factor (LAF), B-cell-activating factor (BAF), leukocyte endogenous mediator (LEM), epidermal cell-derived thymocyte-activating factor (ETAF), serum amyloid A inducer or hepatocyte-stimulating factor (HSP), catabolin, hemopoetin-1 (H-1), endogenous pyrogen (EP), and proteolysis-inducing factor (PIF). # Synthesis and structure IL-1α is a unique member in the cytokine family in the sense that the structure of its initially synthesized precursor does not contain a signal peptide fragment (same is known for IL-1β and IL-18). After processing by the removal of N-terminal amino acids by specific proteases, the resulting peptide is called "mature" form. Calpain, a calcium-activated cysteine protease, associated with the plasma membrane, is primarily responsible for the cleavage of the IL-1α precursor into a mature molecule. Both the 31kDa precursor form of IL-1α and its 18kDa mature form are biologically active. The 31 kDa IL-1α precursor is synthesized in association with cytoskeletal structures (microtubules), unlike most secreted proteins, which are translated on ribosomes associated with rough endoplasmic reticulum. The three-dimensional structure of the IL-1α contains an open-ended barrel composed entirely of beta-pleated strands. Crystal structure analysis of the mature form of IL-1α shows that it has two sites of binding to IL-1 receptor. There is a primary binding site located at the open top of its barrel, which is similar but not identical to that of IL-1β. # Production and cellular sources IL-1α is constitutively produced by epithelial cells. It is found in substantial amounts in normal human epidermis and is distributed in a 1:1 ratio between living epidermal cells and stratum corneum. The constitutive production of large amounts of IL-1α precursor by healthy epidermal keratinocytes interfere with the important role of IL-1α in immune responses, assuming skin as a barrier, which prevents the entry of pathogenic microorganisms into the body. The essential role of IL-1α in maintenance of skin barrier function, especially with increasing age, is an additional explanation of IL-1α constitutive production in epidermis. With the exception of skin keratinocytes, some epithelial cells and certain cells in central nervous system, the mRNA coding for IL-1α (and, thus, IL-1α itself) is not observed in health in most of cell types, tissues, and blood, in spite of wide physiological, metabolic, haematopoietic, and immunological IL-1α activities. A wide variety of other cells only upon stimulation can be induced to transcribe the IL-1α genes and produce the precursor form of IL-1α, Among them are fibroblasts, macrophages, granulocytes, eosinophils, mast cells and basophils, endothelial cells, platelets, monocytes and myeloid cell lines, blood T-lymphocytes and B-lymphocytes, astrocytes, kidney mesangial cells, Langerhans cells, dermal dendritic cells, natural killer cells, large granular lymphocytes, microglia, blood neutrophils, lymph node cells, maternal placental cells and several other cell types. These data suggest that IL-1α is as an epidermal cytokine. # Interactions IL1A has been shown to interact with HAX1, and NDN. Although there are many interactions of IL-1α with other cytokines, the most consistent and most clinically relevant is its synergism with TNF. IL-1α and TNF are both acute-phase cytokines that act to promote fever and inflammation. There are, in fact, few examples in which the synergism between IL-1α and TNFα has not been demonstrated. These include radioprotection, the Shwartzman reaction, PGE2 synthesis, sickness behavior, nitric oxide production, nerve growth factor synthesis, insulin resistance, loss of mean body mass, and IL-8 and chemokine synthesis. # Regulatory molecules The most important regulatory molecule for IL-1α activity is IL-1Ra, which is usually produced in a 10- to 100-fold molar excess. In addition, the soluble form of the IL-1R type I has a high affinity for IL-1α and is produced in a 5-10 molar excess. IL-10 also inhibits IL-1α synthesis. # Biological activity ## In vitro IL-1α possesses biological effect on cells in the picomolar to femtomolar range. In particular, IL-1α: - stimulates keratinocytes and macrophages for induced IL-1α secretion - induces pro-collagen type I and III synthesis - causes proliferation of fibroblasts, induces collagenase secretion, induces cytoskeletal rearrangements, induces IL-6 and GCSF secretion - induces cycloxygenase synthesis and prostaglandin PGE2 release - causes phosphorylation of heat shock protein - causes proliferation of smooth muscle cells, keratinocytes and stimulates release of other cytokines by keratinocytes - induces TNFα release by endothelial cells and Ca2+ release from osteoclasts. - stimulates hepatocytes for secretion of acute-phase proteins - induces proliferation of CD4+ cells, IL-2 production, co-stimulates CD8+/IL-1R+ cells, induces proliferation of mature B-cells and immunoglobulin secretion - kills a limited number of tumor cells types ## In vivo Shortly after an onset of an infection into organism, IL-1α activates a set of immune system response processes. In particular, IL-1α: - stimulates fibroblasts proliferation - induces synthesis of proteases, subsequent muscle proteolysis, release of all types of amino acids in blood and stimulates acute-phase proteins synthesis - changes the metallic ion content of blood plasma by increasing copper and decreasing zinc and iron concentration in blood - increases blood neutrophils - activates lymphocyte proliferation and induces fever Topically administered IL-1α also stimulates expression of FGF and EGF, and subsequent fibroblasts and keratinocytes proliferation. This, plus the presence of large depot of IL-1α precursor in keratinocytes, suggests that locally released IL-1α may play an important role and accelerate wound healing. IL-1α is known to protect against lethal doses of γ-irradiation in mice, possibly as a result of hemopoietin-1 activity. # Applications ## Pharmaceutical Clinical trials on IL-1α have been carried out that are specifically designed to mimic the protective studies in animals. IL-1α has been administered to patients during receiving autologous bone marrow transplantation. The treatment with 50 ng/kg IL-1α from day zero of autologous bone marrow or stem cells transfer resulted in an earlier recovery of thrombocytopenia compared with historical controls. IL-1α is currently being evaluated in clinical trials as a potential therapeutic in oncology indications. An anti-IL-1α therapeutic antibody, MABp1, is being tested in clinical trials for anti-neoplastic activity in solid tumors. Blocking the activity of IL-1α has the potential to treat skin diseases such as acne.

IL1A Interleukin 1 alpha (IL-1α) also known as hematopoietin 1 is a cytokine of the interleukin 1 family that in humans is encoded by the IL1A gene.[1][2] In general, Interleukin 1 is responsible for the production of inflammation, as well as the promotion of fever and sepsis. IL-1α inhibitors are being developed to interrupt those processes and treat diseases. IL-1α is produced mainly by activated macrophages, as well as neutrophils, epithelial cells, and endothelial cells. It possesses metabolic, physiological, haematopoietic activities, and plays one of the central roles in the regulation of the immune responses. It binds to the interleukin-1 receptor.[3][4] It is on the pathway that activates tumor necrosis factor-alpha. # Discovery Interleukin 1 was discovered by Gery in 1972.[5][6][7] He named it lymphocyte-activating factor (LAF) because it was a lymphocyte mitogen. It was not until 1985 that interleukin 1 was discovered to consist of two distinct proteins, now called interleukin-1 alpha and interleukin-1 beta.[2] # Alternative names IL-1α is also known as fibroblast-activating factor (FAF), lymphocyte-activating factor (LAF), B-cell-activating factor (BAF), leukocyte endogenous mediator (LEM), epidermal cell-derived thymocyte-activating factor (ETAF), serum amyloid A inducer or hepatocyte-stimulating factor (HSP), catabolin, hemopoetin-1 (H-1), endogenous pyrogen (EP), and proteolysis-inducing factor (PIF). # Synthesis and structure IL-1α is a unique member in the cytokine family in the sense that the structure of its initially synthesized precursor does not contain a signal peptide fragment (same is known for IL-1β and IL-18). After processing by the removal of N-terminal amino acids by specific proteases, the resulting peptide is called "mature" form. Calpain, a calcium-activated cysteine protease, associated with the plasma membrane, is primarily responsible for the cleavage of the IL-1α precursor into a mature molecule.[8] Both the 31kDa precursor form of IL-1α and its 18kDa mature form are biologically active. The 31 kDa IL-1α precursor is synthesized in association with cytoskeletal structures (microtubules), unlike most secreted proteins, which are translated on ribosomes associated with rough endoplasmic reticulum. The three-dimensional structure of the IL-1α contains an open-ended barrel composed entirely of beta-pleated strands. Crystal structure analysis of the mature form of IL-1α shows that it has two sites of binding to IL-1 receptor. There is a primary binding site[9] located at the open top of its barrel, which is similar but not identical to that of IL-1β. # Production and cellular sources IL-1α is constitutively produced by epithelial cells. It is found in substantial amounts in normal human epidermis and is distributed in a 1:1 ratio between living epidermal cells and stratum corneum.[9][10][11] The constitutive production of large amounts of IL-1α precursor by healthy epidermal keratinocytes interfere with the important role of IL-1α in immune responses, assuming skin as a barrier, which prevents the entry of pathogenic microorganisms into the body. The essential role of IL-1α in maintenance of skin barrier function, especially with increasing age,[12] is an additional explanation of IL-1α constitutive production in epidermis. With the exception of skin keratinocytes, some epithelial cells and certain cells in central nervous system, the mRNA coding for IL-1α (and, thus, IL-1α itself) is not observed in health in most of cell types, tissues, and blood, in spite of wide physiological, metabolic, haematopoietic, and immunological IL-1α activities. A wide variety of other cells only upon stimulation can be induced to transcribe the IL-1α genes and produce the precursor form of IL-1α,[13] Among them are fibroblasts, macrophages, granulocytes, eosinophils, mast cells and basophils, endothelial cells, platelets, monocytes and myeloid cell lines, blood T-lymphocytes and B-lymphocytes, astrocytes, kidney mesangial cells, Langerhans cells, dermal dendritic cells, natural killer cells, large granular lymphocytes, microglia, blood neutrophils, lymph node cells, maternal placental cells and several other cell types. These data suggest that IL-1α is as an epidermal cytokine. # Interactions IL1A has been shown to interact with HAX1,[14] and NDN.[15] Although there are many interactions of IL-1α with other cytokines, the most consistent and most clinically relevant is its synergism with TNF. IL-1α and TNF are both acute-phase cytokines that act to promote fever and inflammation. There are, in fact, few examples in which the synergism between IL-1α and TNFα has not been demonstrated. These include radioprotection, the Shwartzman reaction, PGE2 synthesis, sickness behavior, nitric oxide production, nerve growth factor synthesis, insulin resistance, loss of mean body mass, and IL-8 and chemokine synthesis.[16] # Regulatory molecules The most important regulatory molecule for IL-1α activity is IL-1Ra, which is usually produced in a 10- to 100-fold molar excess.[17] In addition, the soluble form of the IL-1R type I has a high affinity for IL-1α and is produced in a 5-10 molar excess. IL-10 also inhibits IL-1α synthesis.[18] # Biological activity ## In vitro IL-1α possesses biological effect on cells in the picomolar to femtomolar range. In particular, IL-1α: - stimulates keratinocytes and macrophages for induced IL-1α secretion - induces pro-collagen type I and III synthesis - causes proliferation of fibroblasts, induces collagenase secretion, induces cytoskeletal rearrangements, induces IL-6 and GCSF secretion - induces cycloxygenase synthesis and prostaglandin PGE2 release - causes phosphorylation of heat shock protein - causes proliferation of smooth muscle cells, keratinocytes and stimulates release of other cytokines by keratinocytes - induces TNFα release by endothelial cells and Ca2+ release from osteoclasts. - stimulates hepatocytes for secretion of acute-phase proteins - induces proliferation of CD4+ cells, IL-2 production, co-stimulates CD8+/IL-1R+ cells, induces proliferation of mature B-cells and immunoglobulin secretion - kills a limited number of tumor cells types ## In vivo Shortly after an onset of an infection into organism, IL-1α activates a set of immune system response processes. In particular, IL-1α: - stimulates fibroblasts proliferation - induces synthesis of proteases, subsequent muscle proteolysis, release of all types of amino acids in blood and stimulates acute-phase proteins synthesis - changes the metallic ion content of blood plasma by increasing copper and decreasing zinc and iron concentration in blood - increases blood neutrophils - activates lymphocyte proliferation and induces fever Topically administered IL-1α also stimulates expression of FGF and EGF, and subsequent fibroblasts and keratinocytes proliferation. This, plus the presence of large depot of IL-1α precursor in keratinocytes, suggests that locally released IL-1α may play an important role and accelerate wound healing. IL-1α is known to protect against lethal doses of γ-irradiation in mice,[19][20] possibly as a result of hemopoietin-1 activity.[21] # Applications ## Pharmaceutical Clinical trials on IL-1α have been carried out that are specifically designed to mimic the protective studies in animals.[16] IL-1α has been administered to patients during receiving autologous bone marrow transplantation.[22] The treatment with 50 ng/kg IL-1α from day zero of autologous bone marrow or stem cells transfer resulted in an earlier recovery of thrombocytopenia compared with historical controls. IL-1α is currently being evaluated in clinical trials as a potential therapeutic in oncology indications.[23] An anti-IL-1α therapeutic antibody, MABp1, is being tested in clinical trials for anti-neoplastic activity in solid tumors.[24] Blocking the activity of IL-1α has the potential to treat skin diseases such as acne.[25]

https://www.wikidoc.org/index.php/IL1A

06d7f1cec98cbbdf42a79ca2c6f3044768692408

wikidoc

ILF2

ILF2 Interleukin enhancer-binding factor 2 is a protein that in humans is encoded by the ILF2 gene. # Function Nuclear factor of activated T-cells (NFAT) is a transcription factor required for T-cell expression of the interleukin 2 gene. NFAT binds to a sequence in the interleukin 2 gene enhancer known as the antigen receptor response element 2. In addition, NFAT can bind RNA and is an essential component for encapsidation and protein priming of hepatitis B viral polymerase. NFAT is a heterodimer of 45 kDa and 90 kDa proteins, the smaller of which is the product of this gene. The encoded protein binds strongly to the 90 kDa protein and stimulates its ability to enhance gene expression. # Interactions ILF2 has been shown to interact with CDC5L and DNA-PKcs. ILF2 and ILF3 have been identified as autoantigens in mice with induced lupus, in canine systemic rheumatic autoimmune disease, and as a rare finding in humans with autoimmune disease.

ILF2 Interleukin enhancer-binding factor 2 is a protein that in humans is encoded by the ILF2 gene.[1][2] # Function Nuclear factor of activated T-cells (NFAT) is a transcription factor required for T-cell expression of the interleukin 2 gene. NFAT binds to a sequence in the interleukin 2 gene enhancer known as the antigen receptor response element 2. In addition, NFAT can bind RNA and is an essential component for encapsidation and protein priming of hepatitis B viral polymerase. NFAT is a heterodimer of 45 kDa and 90 kDa proteins, the smaller of which is the product of this gene. The encoded protein binds strongly to the 90 kDa protein and stimulates its ability to enhance gene expression.[2] # Interactions ILF2 has been shown to interact with CDC5L[3] and DNA-PKcs.[4] ILF2 and ILF3 have been identified as autoantigens in mice with induced lupus,[5][6] in canine systemic rheumatic autoimmune disease,[7][8] and as a rare finding in humans with autoimmune disease.[9]

https://www.wikidoc.org/index.php/ILF2

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ILF3

ILF3 Interleukin enhancer-binding factor 3 is a protein that in humans is encoded by the ILF3 gene. # Function Nuclear factor of activated T-cells (NFAT) is a transcription factor required for T-cell expression of interleukin 2. NFAT binds to a sequence in the IL2 enhancer known as the antigen receptor response element 2. In addition, NFAT can bind RNA and is an essential component for encapsidation and protein priming of hepatitis B viral polymerase. NFAT is a heterodimer of 45 kDa and 90 kDa proteins, the larger of which is the product of this gene. The encoded protein, which is primarily localized to ribosomes, probably regulates transcription at the level of mRNA elongation. At least three transcript variants encoding three different isoforms have been found for this gene. # Interactions ILF3 has been shown to interact with: - DNA-PKcs, - FUS, - PRMT1 - Protein kinase R, and - XPO5. - C5orf36 Small NF90/ILF3-associated RNAs (snaR) (~120 nucleotides long) and are known to interact with ILF3 double-stranded RNA-binding motifs. snaR-A is abundant in human testis and has been shown to associate with ribosomes in HeLa cells. snaR-A is present in human and gorilla but not in chimpanzee. Other snaR RNAs are found in African Great Apes (including chimpanzee and bonobo). ILF2 and ILF3 have been identified as autoantigens in mice with induced lupus, in canine systemic rheumatic autoimmune disease, and as a rare finding in humans with autoimmune disease.

ILF3 Interleukin enhancer-binding factor 3 is a protein that in humans is encoded by the ILF3 gene.[1][2] # Function Nuclear factor of activated T-cells (NFAT) is a transcription factor required for T-cell expression of interleukin 2. NFAT binds to a sequence in the IL2 enhancer known as the antigen receptor response element 2. In addition, NFAT can bind RNA and is an essential component for encapsidation and protein priming of hepatitis B viral polymerase. NFAT is a heterodimer of 45 kDa and 90 kDa proteins, the larger of which is the product of this gene. The encoded protein, which is primarily localized to ribosomes, probably regulates transcription at the level of mRNA elongation. At least three transcript variants encoding three different isoforms have been found for this gene.[3] # Interactions ILF3 has been shown to interact with: - DNA-PKcs,[4] - FUS,[5] - PRMT1[6][7] - Protein kinase R,[5][8][9][10] and - XPO5.[11] - C5orf36[12] Small NF90/ILF3-associated RNAs (snaR) (~120 nucleotides long) and are known to interact with ILF3 double-stranded RNA-binding motifs.[13] snaR-A is abundant in human testis and has been shown to associate with ribosomes in HeLa cells. snaR-A is present in human and gorilla but not in chimpanzee. Other snaR RNAs are found in African Great Apes (including chimpanzee and bonobo).[14] ILF2 and ILF3 have been identified as autoantigens in mice with induced lupus,[15][16] in canine systemic rheumatic autoimmune disease,[17] and as a rare finding in humans with autoimmune disease.[18]

https://www.wikidoc.org/index.php/ILF3

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wikidoc

ING4

ING4 Inhibitor of growth protein 4 is a protein that in humans is encoded by the ING4 gene. # Function The protein encoded by this gene is similar to ING1, a tumor suppressor protein that can interact with TP53, inhibit cell growth, and induce apoptosis. This protein contains a PHD-finger, which is a common motif in proteins involved in chromatin remodeling. This protein can bind TP53 and EP300/p300, a component of the histone acetyl transferase complex, suggesting its involvement in the TP53-dependent regulatory pathway. Alternatively spliced transcript variants have been observed, but the biological validity of them has not been determined. # Interactions ING4 has been shown to interact with EP300, RELA and P53.

ING4 Inhibitor of growth protein 4 is a protein that in humans is encoded by the ING4 gene.[1][2] # Function The protein encoded by this gene is similar to ING1, a tumor suppressor protein that can interact with TP53, inhibit cell growth, and induce apoptosis. This protein contains a PHD-finger, which is a common motif in proteins involved in chromatin remodeling. This protein can bind TP53 and EP300/p300, a component of the histone acetyl transferase complex, suggesting its involvement in the TP53-dependent regulatory pathway. Alternatively spliced transcript variants have been observed, but the biological validity of them has not been determined.[2] # Interactions ING4 has been shown to interact with EP300,[1] RELA[3] and P53.[1][4]

https://www.wikidoc.org/index.php/ING4

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wikidoc

INTJ

INTJ INTJ (Introverted iNtuitive Thinking Judging) is one of the sixteen personality types from the Myers-Briggs Type Indicator (MBTI), and the Keirsey Temperament Sorter. Referring to Keirsey, INTJs belong to the temperament of the rationals and are called Masterminds. The INTJ may also be referred to as "the scientist." # Myers-Briggs characteristics According to Myers-Briggs, INTJs are very analytical individuals. Like INTPs, they are more comfortable working alone than with other people, and are not usually as sociable as others, although they are prepared to take the lead if nobody else is up to the task, or they see a major weakness in the current leadership. They tend to be very pragmatic and logical individuals, often with an individualistic bent and a low tolerance for spin or rampant emotionalism. They are also commonly not succeptible to catchphrase and commonly do not recognize authority based on tradition, rank or title. Hallmark features of the INTJ personality type include independence of thought, strong individualism and creativity. Persons with this personality type work best given large amounts of autonomy and creative freedom. They harbor an innate desire to express themselves; that is to be creative by conceptualizing their own intellectual designs. Analyzing and formulating complex theories are among their greatest strengths. INTJs tend to be well-suited for occupations within academia, research, management, engineering and law. Differentiating the INTJ personality type from the related INTP type is their confidence. They tend to be acutely aware of their knowledge and abilities. Thus, they develop a strong confidence in their ability and talents, making them "natural leaders." It is this confidence that makes this personality type extremely rare. According to David Keirsey it is found in no more than 1% of the population. In forming relationships, INTJs tend to seek out others with similar character traits and ideologies. Agreement on theoretical concept is an important aspect of a relationship. By nature INTJs tend to be demanding in their expectations and approach relationships in a very rational manner. As a result, an INTJ may not always respond to a naturally occurring infatuation but wait for a mate who better fits his or her set criteria. Persons with this personality type are very stable, reliable and dedicated. Harmony in relationships and home life tends to be extremely important to the INTJ. He or she tends to withhold strong emotion and does not like to "waste" time with irrational social rituals. This, however, may cause non-INTJs to perceive him or her as distant and reserved. # Keirsey characteristics According to Keirsey, INTJs, or "Mastermind Rationals", are natural strategists, better than any other type at brainstorming approaches to situations. They are natural, but not eager, leaders, only stepping forward when it becomes obvious to them that they are the best for the job. Strong-willed and very self-assured, they may make this decision quickly, as they tend to make all decisions. But though they are decisive, they are always open-minded to new evidence and new ideas, flexible in their planning to accommodate changing situations. They are excellent at judging the usefulness of ideas and will apply whatever seems most efficient to them in accomplishing their clearly envisioned goals. To INTJs, what matters is getting it done, and they have a tendency to give little thought to personal cost in getting there. # Distinguished INTJs According to Marina Margaret Heiss at the University of Virginia, the following distinguished individuals have or had INTJ personalities: - Friedrich Nietzsche - Caesar Augustus (Gaius Julius Caesar Octavianus) - Hannibal (Carthaginian Military Leader) - Stephen Hawking - Niels Bohr - Peter the Great - John Maynard Keynes - Lise Meitner - Ayn Rand - Isaac Newton - Osama Bin Laden - Rudy Giuliani, ex-New York City mayor - Donald Rumsfeld, ex-U.S. Secretary of Defense - General Colin Powell, ex-U.S. Secretary of State - Arnold Schwarzenegger, Governor of California - Michael Dukakis, ex-Governor of Massachusetts, 1988 U.S. Democratic presidential candidate - Susan B. Anthony, civil rights pioneer Presidents: - Thomas Jefferson - James K. Polk - Ulysses S. Grant - Chester A. Arthur - Woodrow Wilson - Calvin Coolidge - Dwight D. Eisenhower - John F. Kennedy Fictional: - Cassius - Mr. Darcy - Batman - Gandalf the Grey - Hannibal Lecter - Professor Moriarty - Ensign Ro - Rosencrantz - George Smiley - Clarice Starling # MBTI cognitive functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality type's Achilles' heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity. - Dominant Introverted Intuition - Auxiliary Extroverted Thinking - Tertiary Introverted Feeling - inferior Extroverted Sensing

INTJ INTJ (Introverted iNtuitive Thinking Judging) is one of the sixteen personality types from the Myers-Briggs Type Indicator (MBTI), and the Keirsey Temperament Sorter. Referring to Keirsey, INTJs belong to the temperament of the rationals and are called Masterminds. The INTJ may also be referred to as "the scientist." # Myers-Briggs characteristics According to Myers-Briggs, INTJs are very analytical individuals. Like INTPs, they are more comfortable working alone than with other people, and are not usually as sociable as others, although they are prepared to take the lead if nobody else is up to the task, or they see a major weakness in the current leadership. They tend to be very pragmatic and logical individuals, often with an individualistic bent and a low tolerance for spin or rampant emotionalism. They are also commonly not succeptible to catchphrase and commonly do not recognize authority based on tradition, rank or title. Hallmark features of the INTJ personality type include independence of thought, strong individualism and creativity. Persons with this personality type work best given large amounts of autonomy and creative freedom. They harbor an innate desire to express themselves; that is to be creative by conceptualizing their own intellectual designs. Analyzing and formulating complex theories are among their greatest strengths. INTJs tend to be well-suited for occupations within academia, research, management, engineering and law. Differentiating the INTJ personality type from the related INTP type is their confidence. They tend to be acutely aware of their knowledge and abilities. Thus, they develop a strong confidence in their ability and talents, making them "natural leaders." It is this confidence that makes this personality type extremely rare. According to David Keirsey it is found in no more than 1% of the population. In forming relationships, INTJs tend to seek out others with similar character traits and ideologies. Agreement on theoretical concept is an important aspect of a relationship. By nature INTJs tend to be demanding in their expectations and approach relationships in a very rational manner. As a result, an INTJ may not always respond to a naturally occurring infatuation but wait for a mate who better fits his or her set criteria. Persons with this personality type are very stable, reliable and dedicated. Harmony in relationships and home life tends to be extremely important to the INTJ. He or she tends to withhold strong emotion and does not like to "waste" time with irrational social rituals. This, however, may cause non-INTJs to perceive him or her as distant and reserved. # Keirsey characteristics According to Keirsey, INTJs, or "Mastermind Rationals", are natural strategists, better than any other type at brainstorming approaches to situations. They are natural, but not eager, leaders, only stepping forward when it becomes obvious to them that they are the best for the job. Strong-willed and very self-assured, they may make this decision quickly, as they tend to make all decisions. But though they are decisive, they are always open-minded to new evidence and new ideas, flexible in their planning to accommodate changing situations. They are excellent at judging the usefulness of ideas and will apply whatever seems most efficient to them in accomplishing their clearly envisioned goals. To INTJs, what matters is getting it done, and they have a tendency to give little thought to personal cost in getting there. # Distinguished INTJs According to Marina Margaret Heiss at the University of Virginia, the following distinguished individuals have or had INTJ personalities: - Friedrich Nietzsche - Caesar Augustus (Gaius Julius Caesar Octavianus) - Hannibal (Carthaginian Military Leader) - Stephen Hawking - Niels Bohr - Peter the Great - John Maynard Keynes - Lise Meitner - Ayn Rand - Isaac Newton - Osama Bin Laden - Rudy Giuliani, ex-New York City mayor - Donald Rumsfeld, ex-U.S. Secretary of Defense - General Colin Powell, ex-U.S. Secretary of State - Arnold Schwarzenegger, Governor of California - Michael Dukakis, ex-Governor of Massachusetts, 1988 U.S. Democratic presidential candidate - Susan B. Anthony, civil rights pioneer Presidents: - Thomas Jefferson - James K. Polk - Ulysses S. Grant - Chester A. Arthur - Woodrow Wilson - Calvin Coolidge - Dwight D. Eisenhower - John F. Kennedy Fictional: - Cassius - Mr. Darcy - Batman - Gandalf the Grey - Hannibal Lecter - Professor Moriarty - Ensign Ro - Rosencrantz - George Smiley - Clarice Starling # MBTI cognitive functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality type's Achilles' heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity.[1] - Dominant Introverted Intuition - Auxiliary Extroverted Thinking - Tertiary Introverted Feeling - inferior Extroverted Sensing[1]

https://www.wikidoc.org/index.php/INTJ

958ab7d535cf3be0729184c56de6a969fea37de0

wikidoc

IPO5

IPO5 Importin-5 is a protein that in humans is encoded by the IPO5 gene. The protein encoded by this gene is a member of the importin beta family. # Function Nuclear transport, a signal- and energy-dependent process, takes place through nuclear pore complexes embedded in the nuclear envelope. The import of proteins containing a nuclear localization signal (NLS) requires the NLS import receptor, a heterodimer of importin alpha and beta subunits also known as karyopherins. Importin alpha binds the NLS-containing cargo in the cytoplasm and importin beta docks the complex at the cytoplasmic side of the nuclear pore complex. In the presence of nucleoside triphosphates and the small GTP binding protein Ran, the complex moves into the nuclear pore complex and the importin subunits dissociate. Importin alpha enters the nucleoplasm with its passenger protein and importin beta remains at the pore. Interactions between importin beta and the FG repeats of nucleoporins are essential in translocation through the pore complex. IPO5 facilitates cytoplasmic polyadenylation element-binding protein (CPEB)3 translocation by binding to RRM1 motif of CPEB3 in neurons. NMDAR signaling increases RanBP1 expression and reduces the level of cytoplasmic GTP-bound Ran. These changes enhance CPEB3–IPO5 interaction, which consequently accelerates the nuclear import of CPEB3 and promotes its nuclear function.

IPO5 Importin-5 is a protein that in humans is encoded by the IPO5 gene.[1][2][3] The protein encoded by this gene is a member of the importin beta family. # Function Nuclear transport, a signal- and energy-dependent process, takes place through nuclear pore complexes embedded in the nuclear envelope. The import of proteins containing a nuclear localization signal (NLS) requires the NLS import receptor, a heterodimer of importin alpha and beta subunits also known as karyopherins. Importin alpha binds the NLS-containing cargo in the cytoplasm and importin beta docks the complex at the cytoplasmic side of the nuclear pore complex. In the presence of nucleoside triphosphates and the small GTP binding protein Ran, the complex moves into the nuclear pore complex and the importin subunits dissociate. Importin alpha enters the nucleoplasm with its passenger protein and importin beta remains at the pore. Interactions between importin beta and the FG repeats of nucleoporins are essential in translocation through the pore complex.[4] IPO5 facilitates cytoplasmic polyadenylation element-binding protein (CPEB)3 translocation by binding to RRM1 motif of CPEB3 in neurons. NMDAR signaling increases RanBP1 expression and reduces the level of cytoplasmic GTP-bound Ran. These changes enhance CPEB3–IPO5 interaction, which consequently accelerates the nuclear import of CPEB3 and promotes its nuclear function.[5]

https://www.wikidoc.org/index.php/IPO5

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wikidoc

IRF3

IRF3 Interferon regulatory factor 3, also known as IRF3, is an interferon regulatory factor. # Function IRF3 is a member of the interferon regulatory transcription factor (IRF) family. IRF3 was originally discovered as a homolog of IRF1 and IRF2. IRF3 has been further characterized and shown to contain several functional domains including a nuclear export signal, a DNA-binding domain, a C-terminal IRF association domain and several regulatory phosphorylation sites. IRF3 is found in an inactive cytoplasmic form that upon serine/threonine phosphorylation forms a complex with CREBBP. This complex translocates to the nucleus and activates the transcription of interferons alpha and beta, as well as other interferon-induced genes. IRF3 plays an important role in the innate immune system's response to viral infection. Aggregated MAVS have been found to activate IRF3 dimerization. A recent study shows phosphorylation of innate immune adaptor proteins MAVS, STING and TRIF at a conserved pLxIS motif recruits and specifies IRF3 phosphorylation and activation by the Serine/threonine-protein kinase TBK1, thereby restricts the production of type-I interferons. Another study has shown that IRF3-/- knockouts protect from myocardial infarction. The same study identified IRF3 and the type I IFN response as a potential therapeutic target for post-myocardial infarction cardioprotection. # Interactions IRF3 has been shown to interact with IRF7.

IRF3 Interferon regulatory factor 3, also known as IRF3, is an interferon regulatory factor.[1] # Function IRF3 is a member of the interferon regulatory transcription factor (IRF) family.[1] IRF3 was originally discovered as a homolog of IRF1 and IRF2. IRF3 has been further characterized and shown to contain several functional domains including a nuclear export signal, a DNA-binding domain, a C-terminal IRF association domain and several regulatory phosphorylation sites.[2] IRF3 is found in an inactive cytoplasmic form that upon serine/threonine phosphorylation forms a complex with CREBBP.[3] This complex translocates to the nucleus and activates the transcription of interferons alpha and beta, as well as other interferon-induced genes.[4] IRF3 plays an important role in the innate immune system's response to viral infection.[5] Aggregated MAVS have been found to activate IRF3 dimerization.[6] A recent study shows phosphorylation of innate immune adaptor proteins MAVS, STING and TRIF at a conserved pLxIS motif recruits and specifies IRF3 phosphorylation and activation by the Serine/threonine-protein kinase TBK1, thereby restricts the production of type-I interferons.[7] Another study has shown that IRF3-/- knockouts protect from myocardial infarction.[8] The same study identified IRF3 and the type I IFN response as a potential therapeutic target for post-myocardial infarction cardioprotection.[8] # Interactions IRF3 has been shown to interact with IRF7.[9]

https://www.wikidoc.org/index.php/IRF3

4a89f3a69a29b6b75be2f7c3e8c58f4992f811d8

wikidoc

IRF4

IRF4 Interferon regulatory factor 4 also known as MUM1 is a protein that in humans is encoded by the IRF4 gene, located at 6p25-p23. The MUM1 symbol is polysemous; although it is an older synonym for IRF4 (HGNC:6119), it is also the current HGNC official symbol for melanoma associated antigen (mutated) 1 (HGNC:29641; located at 19p13.3). # Clinical significance In melanocytic cells the IRF4 gene may be regulated by MITF. IRF4 is a transcription factor that has been implicated in acute leukemia. This gene is strongly associated with pigmentation: sensitivity of skin to sun exposure, freckles, blue eyes, and brown hair color. A variant has been implicated in greying of hair. # Interactions IRF4 has been shown to interact with: - BCL6, - NFATC2, - SPI1, and - STAT6.

IRF4 Interferon regulatory factor 4 also known as MUM1 is a protein that in humans is encoded by the IRF4 gene,[1][2][3] located at 6p25-p23. The MUM1 symbol is polysemous; although it is an older synonym for IRF4 (HGNC:6119), it is also the current HGNC official symbol for melanoma associated antigen (mutated) 1 (HGNC:29641; located at 19p13.3). # Clinical significance In melanocytic cells the IRF4 gene may be regulated by MITF.[4] IRF4 is a transcription factor that has been implicated in acute leukemia.[5] This gene is strongly associated with pigmentation: sensitivity of skin to sun exposure, freckles, blue eyes, and brown hair color.[6] A variant has been implicated in greying of hair.[7] # Interactions IRF4 has been shown to interact with: - BCL6,[8] - NFATC2,[9] - SPI1,[10][11] and - STAT6.[8]

https://www.wikidoc.org/index.php/IRF4

492b5691052de2c9990500f82e81a3ea148a00e8

wikidoc

IRF5

IRF5 Interferon regulatory factor 5 is a protein that in humans is encoded by the IRF5 gene. # Function IRF5 is a member of the interferon regulatory factor (IRF) family, a group of transcription factors with diverse roles, including virus-mediated activation of interferon, and modulation of cell growth, differentiation, apoptosis, and immune system activity. Members of the IRF family are characterized by a conserved N-terminal DNA-binding domain containing tryptophan (W) repeats. Alternative splice variants encoding different isoforms exist. # Clinical significance IRF5 acts as a molecular switch that controls whether macrophages will promote or inhibit inflammation. Blocking the production of IRF5 in macrophages may help treat a wide range of autoimmune diseases, and that boosting IRF5 levels might help treat people whose immune systems are weak, compromised, or damaged. IRF5 seems to work "either by interacting with DNA directly, or by interacting with other proteins that themselves control which genes are switched on."

IRF5 Interferon regulatory factor 5 is a protein that in humans is encoded by the IRF5 gene.[1] # Function IRF5 is a member of the interferon regulatory factor (IRF) family, a group of transcription factors with diverse roles, including virus-mediated activation of interferon, and modulation of cell growth, differentiation, apoptosis, and immune system activity. Members of the IRF family are characterized by a conserved N-terminal DNA-binding domain containing tryptophan (W) repeats. Alternative splice variants encoding different isoforms exist.[1] # Clinical significance IRF5 acts as a molecular switch that controls whether macrophages will promote or inhibit inflammation. Blocking the production of IRF5 in macrophages may help treat a wide range of autoimmune diseases, and that boosting IRF5 levels might help treat people whose immune systems are weak, compromised, or damaged. IRF5 seems to work "either by interacting with DNA directly, or by interacting with other proteins that themselves control which genes are switched on."[2]

https://www.wikidoc.org/index.php/IRF5

25f511357e5af6b4a33795f8197ba876bbcd8fc8

wikidoc

IRF6

IRF6 Interferon regulatory factor 6 also known as IRF6 is a protein that in humans is encoded by the IRF6 gene. # Function This gene encodes a member of the interferon regulatory transcription factor (IRF) family. Family members share a highly conserved N-terminal helix-turn-helix DNA-binding domain and a less conserved C-terminal protein-binding domain. The function of IRF6 is related to the formation of connective tissue, for example that of the palate. This gene encodes a member of the interferon regulatory transcription factor (IRF) family. # Pathology A mutation of the IRF6 gene can lead to the autosomal dominant van der Woude syndrome (VWS) or the related popliteal pterygium syndrome (PPS). Van der Woude syndrome can include cleft lip and palate features along with dental anomalies and lip fistulas. In addition, common alleles in IRF6 have also been associated with non-syndromic cases of cleft lip and/or palate through genome-wide association studies and in many candidate gene studies. These disorders are caused by mutations in the IRF6 gene and some of the phenotypic heterogeneity is due to different types of IRF6 mutations. One explanation for this phenotypic variation between syndromes is based on a differential impact on the structure of the dimerized mutant proteins. VWS mutations appear to result in haploinsufficiency while PPS mutations may be dominant negative in nature. The spectrum of mutations in VWS and PPS has been recently summarized. IRF6 has been shown to play a critical role in keratinocyte development. A role for IRF6 in the common forms of cleft lip and palate has also been demonstrated and may explain ~20% of cases of cleft lip only. Variants in IRF6 have yielded consistent evidence of association with syndromic cleft and/or palate across multiple studies. A study by Birnbaum and colleagues in 2009 confirmed the impact of this gene on the etiology of cleft lip and/or palate, and the GENEVA Cleft Consortium study, which studied families from multiple populations, reconfirmed the findings that IRF6 mutations are strongly associated with cleft and/or palate. A role of IRF6 in causing cleft lip and/or palate is further supported by analysis of IRF6 mutant mice which exhibit a hyper-proliferative epidermis that fails to undergo terminal differentiation, leading to multiple epithelial adhesions that can occlude the oral cavity and result in cleft palate. Research on animal models indicate IRF6 determines keratinocyte proliferation and also has a key role in the formation of oral periderm. Recently, through utilization of mouse genetics, gene expression analyses, chromatin immunoprecipitation studies and luciferase reporter assays, it has been shown that IRF6 is a direct target of p63, which underlies several malformation syndromes that include cleft features, and p63 activates IRF6 transcription through the IRF6 enhancer element. Variation in the enhancer element increases susceptibility to cleft lip only. Both cleft lip with or without a cleft palate and cleft palate only features have been seen in families with an IRF6 mutation. In addition, different types of clefts can segregate within the same family.

IRF6 Interferon regulatory factor 6 also known as IRF6 is a protein that in humans is encoded by the IRF6 gene.[1] # Function This gene encodes a member of the interferon regulatory transcription factor (IRF) family. Family members share a highly conserved N-terminal helix-turn-helix DNA-binding domain and a less conserved C-terminal protein-binding domain.[2] The function of IRF6 is related to the formation of connective tissue, for example that of the palate.[3] This gene encodes a member of the interferon regulatory transcription factor (IRF) family. # Pathology A mutation of the IRF6 gene can lead to the autosomal dominant van der Woude syndrome (VWS) [4] or the related popliteal pterygium syndrome (PPS).[5] Van der Woude syndrome can include cleft lip and palate features along with dental anomalies and lip fistulas. In addition, common alleles in IRF6 have also been associated with non-syndromic cases of cleft lip and/or palate through genome-wide association studies and in many candidate gene studies.[6] These disorders are caused by mutations in the IRF6 gene and some of the phenotypic heterogeneity is due to different types of IRF6 mutations.[1] One explanation for this phenotypic variation between syndromes is based on a differential impact on the structure of the dimerized mutant proteins. VWS mutations appear to result in haploinsufficiency while PPS mutations may be dominant negative in nature.[7] The spectrum of mutations in VWS and PPS has been recently summarized.[8] IRF6 has been shown to play a critical role in keratinocyte development.[9][10] A role for IRF6 in the common forms of cleft lip and palate has also been demonstrated[11] and may explain ~20% of cases of cleft lip only.[12] Variants in IRF6 have yielded consistent evidence of association with syndromic cleft and/or palate across multiple studies. A study by Birnbaum and colleagues in 2009 confirmed the impact of this gene on the etiology of cleft lip and/or palate, and the GENEVA Cleft Consortium study, which studied families from multiple populations, reconfirmed the findings that IRF6 mutations are strongly associated with cleft and/or palate. A role of IRF6 in causing cleft lip and/or palate is further supported by analysis of IRF6 mutant mice which exhibit a hyper-proliferative epidermis that fails to undergo terminal differentiation, leading to multiple epithelial adhesions that can occlude the oral cavity and result in cleft palate. Research on animal models indicate IRF6 determines keratinocyte proliferation and also has a key role in the formation of oral periderm. Recently, through utilization of mouse genetics, gene expression analyses, chromatin immunoprecipitation studies and luciferase reporter assays, it has been shown that IRF6 is a direct target of p63, which underlies several malformation syndromes that include cleft features, and p63 activates IRF6 transcription through the IRF6 enhancer element. Variation in the enhancer element increases susceptibility to cleft lip only. Both cleft lip with or without a cleft palate and cleft palate only features have been seen in families with an IRF6 mutation. In addition, different types of clefts can segregate within the same family.[6]

https://www.wikidoc.org/index.php/IRF6

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wikidoc

IRF7

IRF7 Interferon regulatory factor 7, also known as IRF7, is a member of the interferon regulatory factor family of transcription factors. # Function IRF7 encodes interferon regulatory factor 7, a member of the interferon regulatory transcription factor (IRF) family. IRF7 has been shown to play a role in the transcriptional activation of virus-inducible cellular genes, including the type I interferon genes. In particular, IRF7 regulates many interferon-alpha genes. Constitutive expression of IRF7 is largely restricted to lymphoid tissue, largely plasmacytoid dendritic cells, whereas IRF7 is inducible in many tissues. Multiple IRF7 transcript variants have been identified, although the functional consequences of these have not yet been established. The IRF7 pathway was shown to be silenced in some metastatic breast cancer cell lines, which may help the cells avoid the host immune response. Restoring IRF7 to these cell lines reduced metastases and increased host survival time in animal models. The IRF7 gene and product were shown to be defective in a patient with severe susceptibility to H1N1 influenza, while susceptibility to other viral diseases such as CMV, RSV, and parainfluenza was unaffected. # Interactions IRF7 has been shown to interact with IRF3. Also, IRF7 has been shown to interact with Aryl Hydrocarbon Receptor Interacting Protein (AIP), which is a negative regulator for the antiviral pathway.

IRF7 Interferon regulatory factor 7, also known as IRF7, is a member of the interferon regulatory factor family of transcription factors. # Function IRF7 encodes interferon regulatory factor 7, a member of the interferon regulatory transcription factor (IRF) family. IRF7 has been shown to play a role in the transcriptional activation of virus-inducible cellular genes, including the type I interferon genes. In particular, IRF7 regulates many interferon-alpha genes.[1] Constitutive expression of IRF7 is largely restricted to lymphoid tissue, largely plasmacytoid dendritic cells, whereas IRF7 is inducible in many tissues. Multiple IRF7 transcript variants have been identified, although the functional consequences of these have not yet been established.[2] The IRF7 pathway was shown to be silenced in some metastatic breast cancer cell lines, which may help the cells avoid the host immune response.[3] Restoring IRF7 to these cell lines reduced metastases and increased host survival time in animal models. The IRF7 gene and product were shown to be defective in a patient with severe susceptibility to H1N1 influenza, while susceptibility to other viral diseases such as CMV, RSV, and parainfluenza was unaffected.[4] # Interactions IRF7 has been shown to interact with IRF3.[5] Also, IRF7 has been shown to interact with Aryl Hydrocarbon Receptor Interacting Protein (AIP), which is a negative regulator for the antiviral pathway.[6]

https://www.wikidoc.org/index.php/IRF7

52414a7e0c88c2cd5700584fd70c80df9489d588

wikidoc

IRF8

IRF8 Interferon regulatory factor 8 (IRF8) also known as interferon consensus sequence-binding protein (ICSBP), is a protein that in humans is encoded by the IRF8 gene. IRF8 is a transcription factor that plays critical roles in the regulation of lineage commitment and in myeloid cell maturation including the decision for a common myeloid progenitor (CMP) to differentiate into a monocyte precursor cell. # Function Interferon Consensus Sequence-binding protein (ICSBP) is a transcription factor of the interferon regulatory factor (IRF) family. Proteins of this family are composed of a conserved DNA-binding domain in the N-terminal region and a divergent C-terminal region that serves as the regulatory domain. The IRF family proteins bind to the IFN-stimulated response element (ISRE) and regulate expression of genes stimulated by type I IFNs, namely IFN-α and IFN-β. IRF family proteins also control expression of IFN-α and IFN-β-regulated genes that are induced by viral infection. # Knockout studies IFN-producing cells (mIPCs) were absent in all lymphoid organs from ICSBP knockout (KO) mice, as revealed by lack of CD11clowB220+Ly6C+CD11b− cells. In parallel, CD11c+ cells isolated from ICSBP KO spleens were unable to produce type I IFNs in response to viral stimulation. ICSBP KO mice also displayed a marked reduction of the DC subset expressing the CD8alpha marker (CD8alpha+ DCs) in spleen, lymph nodes, and thymus. Moreover, ICSBP-deficient CD8alpha+ DCs exhibited a markedly impaired phenotype when compared with WT DCs. They expressed very low levels of costimulatory molecules (intercellular adhesion molecule ICAM1, CD40, CD80, CD86) and of the T cell area-homing chemokine receptor CCR7. # Clinical significance In myeloid cells, IRF8 regulates the expression of Bax and Fas to regulate apoptosis. In chronic myelogenous leukemia (CML), IRF8 regulates acid ceramidase to mediate CML apoptosis. IRF8 is highly expressed in myeloid cells and was originally identified in as a critical lineage-specific transcription factor for myeloid cell differentiation, recent studies, however, have shown that IRF8 is also constitutively expressed in non-hematopoietic cancer cells, albeit at a lower level. Furthermore, IRF8 can also be up-regulated by IFN-γ in non-hemotopoietic cells. IRF8 mediates the expression of Fas, Bax, FLIP, Jak1 and STAT1 to mediate apoptosis in non-hemotopoietic cancer cells. Analysis of human cancer genomics database revealed that IRF8 is not significantly focally amplified across the entire dataset of 3131 tumors, but is significantly focally deleted across the entire dataset of 3131 tumors, suggesting that IRF8 is potentially a tumor suppressor in humans. Molecular analysis indicated that the IRF8 gene promoter is hypermethylated in human colon carcinoma cells, suggesting that these cells might use DNA methylation to silence IRF8 expression to advance the disease. # Interactions IRF8 has been shown to interact with IRF1 and COPS2.

IRF8 Interferon regulatory factor 8 (IRF8) also known as interferon consensus sequence-binding protein (ICSBP), is a protein that in humans is encoded by the IRF8 gene.[1][2][3] IRF8 is a transcription factor that plays critical roles in the regulation of lineage commitment and in myeloid cell maturation including the decision for a common myeloid progenitor (CMP) to differentiate into a monocyte precursor cell. # Function Interferon Consensus Sequence-binding protein (ICSBP) is a transcription factor of the interferon regulatory factor (IRF) family. Proteins of this family are composed of a conserved DNA-binding domain in the N-terminal region and a divergent C-terminal region that serves as the regulatory domain. The IRF family proteins bind to the IFN-stimulated response element (ISRE) and regulate expression of genes stimulated by type I IFNs, namely IFN-α and IFN-β. IRF family proteins also control expression of IFN-α and IFN-β-regulated genes that are induced by viral infection.[1] # Knockout studies IFN-producing cells (mIPCs) were absent in all lymphoid organs from ICSBP knockout (KO) mice, as revealed by lack of CD11clowB220+Ly6C+CD11b− cells. In parallel, CD11c+ cells isolated from ICSBP KO spleens were unable to produce type I IFNs in response to viral stimulation. ICSBP KO mice also displayed a marked reduction of the DC subset expressing the CD8alpha marker (CD8alpha+ DCs) in spleen, lymph nodes, and thymus. Moreover, ICSBP-deficient CD8alpha+ DCs exhibited a markedly impaired phenotype when compared with WT DCs. They expressed very low levels of costimulatory molecules (intercellular adhesion molecule ICAM1, CD40, CD80, CD86) and of the T cell area-homing chemokine receptor CCR7.[4] # Clinical significance In myeloid cells, IRF8 regulates the expression of Bax and Fas to regulate apoptosis.[5] In chronic myelogenous leukemia (CML), IRF8 regulates acid ceramidase to mediate CML apoptosis.[6] IRF8 is highly expressed in myeloid cells and was originally identified in as a critical lineage-specific transcription factor for myeloid cell differentiation,[7] recent studies, however, have shown that IRF8 is also constitutively expressed in non-hematopoietic cancer cells, albeit at a lower level. Furthermore, IRF8 can also be up-regulated by IFN-γ in non-hemotopoietic cells. IRF8 mediates the expression of Fas, Bax, FLIP, Jak1 and STAT1 to mediate apoptosis in non-hemotopoietic cancer cells.[8][9][10] Analysis of human cancer genomics database revealed that IRF8 is not significantly focally amplified across the entire dataset of 3131 tumors, but is significantly focally deleted across the entire dataset of 3131 tumors, suggesting that IRF8 is potentially a tumor suppressor in humans.[11] Molecular analysis indicated that the IRF8 gene promoter is hypermethylated in human colon carcinoma cells,[10][12] suggesting that these cells might use DNA methylation to silence IRF8 expression to advance the disease. # Interactions IRF8 has been shown to interact with IRF1[13][14] and COPS2.[15]

https://www.wikidoc.org/index.php/IRF8

0bd50dcee9c35b1e3b714a48979d6e9b3553d500

wikidoc

IRGM

IRGM Immunity-related GTPase family M protein (IRGM), also known as interferon-inducible protein 1 (IFI1), is an enzyme that in humans is IRGM gene. IRGM is a member of the interferon-inducible GTPase family. The encoded protein may play a role in the innate immune response by regulating autophagy formation in response to intracellular pathogens. # Clinical relevance Polymorphisms that affect the normal expression of this gene are associated with a susceptibility to Crohn's disease and tuberculosis.

IRGM Immunity-related GTPase family M protein (IRGM), also known as interferon-inducible protein 1 (IFI1), is an enzyme that in humans is IRGM gene.[1] IRGM is a member of the interferon-inducible GTPase family. The encoded protein may play a role in the innate immune response by regulating autophagy formation in response to intracellular pathogens. # Clinical relevance Polymorphisms that affect the normal expression of this gene are associated with a susceptibility to Crohn's disease and tuberculosis.[2]

https://www.wikidoc.org/index.php/IRGM

a55c8719c6cc0afe06f4f5103cfb351198af3f3d

wikidoc

IRS1

IRS1 Insulin receptor substrate 1 (IRS-1) is a signaling adapter protein that in humans is encoded by the IRS-1 gene. It is a 131 kDa protein with amino acid sequence of 1242 residues. It contains a single pleckstrin homology (PH) domain at the N-terminus and a PTB domain ca. 40 residues downstream of this, followed by a poorly conserved C-terminus tail. Together with IRS2, IRS3 (pseudogene) and IRS4, it is homologous to the Drosophila protein chico, whose disruption extends the median lifespan of flies up to 48%. Similarly, Irs1 mutant mice experience moderate life extension and delayed age-related pathologies. # Function Insulin receptor substrate 1 plays a key role in transmitting signals from the insulin and insulin-like growth factor-1 (IGF-1) receptors to intracellular pathways PI3K / Akt and Erk MAP kinase pathways. Tyrosine phosphorylation of IRS-1 by insulin receptor (IR) introduces multiple binding sites for proteins bearing SH2 homology domain, such as PI3K, Grb-2/Sos complex and SHP2. PI3K, involved in interaction with IRS-1, produces PIP3, which, in turn, recruits Akt kinase. Further, Akt kinase is activated via phosphorylation of its T308 residue and analogous sites in PKC by PDK1. This phosphorylation is absent in tissues lacking IRS-1. The cascade is followed by glucose uptake. Grb-2/Sos complex, also known as RAS, signaling results in ERK1/2 activation. IRS-1 signal transduction may be inhibited by SHP2 in some tissues. Tyrosine phosphorylation of the insulin receptors or IGF-1 receptors, upon extracellular ligand binding, induces the cytoplasmic binding of IRS-1 to these receptors, through its PTB domains. Multiple tyrosine residues of IRS-1 itself are then phosphorylated by these receptors. This enables IRS-1 to activate several signalling pathways, including the PI3K pathway and the MAP kinase pathway. An alternative multi-site phosphorylation of Serine/Tyrosine in IRS-1 regulates insulin signaling positively and negatively. C-terminal region contains most of the phosphorylation sites of the protein. The C-terminal tail is not structured, therefore the mechanisms of regulation of IRS-1 by phosphorylation still remain unclear. It has been shown that TNFα causes insulin resistance and multi-site S/T phosphorylation, which results in block of interaction between IRS-1 and juxtamembrane domain peptide, thus converting IRS-1 into an inactive state. IRS-1 plays important biological function for both metabolic and mitogenic (growth promoting) pathways: mice deficient of IRS1 have only a mild diabetic phenotype, but a pronounced growth impairment, i.e., IRS-1 knockout mice only reach 50% of the weight of normal mice. # Regulation The cellular protein levels of IRS-1 are regulated by the Cullin7 E3 ubiquitin ligase, which targets IRS-1 for ubiquitin mediated degradation by the proteasome. Different Serine phosphorylation of IRS-1, caused by various molecules, such as fatty acids, TNFα and AMPK, has different effects on the protein, but most of these effects include cellular re-localization, conformational and steric changes. These processes lead to decrease in Tyrosine phosphorylation by insulin receptors and diminished PI3K recruitment. Altogether, these mechanisms stimulate IRS-1 degradation and insulin resistance. Other inhibitory pathways include SOCS proteins and O-linked glycosylation of IRS-1. SOCS proteins act by binding to IR and by interfering with IR phosphorylation of IRS-1, therefore attenuating insulin signaling. They can also bind to JAK, causing a subsequent decrease in IRS-1 tyrosine phosphorylation. During insulin resistance induced by hyperglycemia, glucose accumulates in tissues as its hexosamine metabolite UDP-GlcNAc. This metabolite if present in high amounts leads to O-GlcNAc protein modifications. IRS-1 can undergo this modification, which results in its phosphorylation and functional suppression. # Interactions IRS1 has been shown to interact with: - Bcl-2, - Grb2, - INSR, - IGF1R, - JAK1, - JAK2, - MAPK8, - PIK3R1 - PIK3R3, - PTK2, - PTPN11, - PTPN1, and - YWHAE. # Role in cancer IRS-1, as a signalling adapter protein, is able to integrate different signalling cascades, which indicates its possible role in cancer progression. IRS-1 protein is known to be involved in various types of cancer, including colorectal, lung, prostate and breast cancer. IRS-1 integrates signalling from insulin receptor (InsR), insulin-like growth factor-1 receptor (IGF1R) and many other cytokine receptors and is elevated in β-catenin induced cells. Some evidence shows that TCF/LEF-β-catenin complexes directly regulate IRS-1. IRS-1 is required for maintenance of neoplasmic phenotype in adenomatous polyposis coli (APC) - mutated cells, it is also needed for transformation in ectopically expressing oncogenic β-catenin cells. IRS-1 dominant-negative mutant functions as tumor suppressor, whereas ectopic IRS-1 stimulates oncogenic transformation. IRS-1 is upregulated in colorectal cancers (CRC) with elevated levels of β-catenin, c-MYC, InsRβ and IGF1R. IRS-1 promotes CRC metastasis to the liver. Decreased apoptosis of crypt stem cells is associated with colon cancer risk. Reduced expression of IRS-1 in Apc (min/+) mutated mice showes increased irradiation-induced apoptosis in crypt. Deficiency in IRS-1 - partial (+/-) or absolute (-/-) - in Apc (min/+) mice demonstrates reduced amount of tumors comparing to IRS-1 (+/+)/ Apc (min/+) mice. In lung adenocarcinoma cell line A549 overexpression of IRS-1 leads to reduced growth. Tumor infiltrating neutrophils have recently been thought to adjust tumor growth and invasiveness. Neutrophil elastase is shown to degrade IRS-1 by gaining access to endosomal compartment of carcinoma cell. IRS-1 degradation induces cell proliferation in mouse and human adenocarcinomas. Ablation of IRS-1 alters downstream signalling through phosphatidylinositol-3 kinase (PI3K), causing an increased interaction of it with platelet-derived growth factor receptor (PDGFR). Therefore, IRS-1 acts as major regulator of PI3K in lung adenocarcinoma. Some evidence shows role of IRS-1 in hepatocellular carcinoma (HCC). In rat model, IRS-1 focal overexpression is associated with early events of hepatocarcinogenesis. During progression of preneoplastic foci into hepatocellular carcinomas expression of IRS-1 gradually decreases, which is characterises a metabolic shift heading towards malignant neoplastic phenotype. Transgenic mice, co-expressing IRS-1 and hepatitis Bx (HBx) protein, demonstrate higher rate of hepatocellular displasia that results in HCC development. Expressed alone, IRS-1 and HBx are not sufficient to induce neoplastic alterations in the liver, though their paired expression switches on IN/IRS-1/MAPK and Wnt/β-catenin cascades, causing HCC transformation. LNCaP prostate cancer cells increase cell adhesion and diminish cell motility via IGF-1 independent mechanism, when IRS-1 is ectopically expressed in the cells. These effects are mediated by PI3K. Uncanonical phosphorylation of Serine 612 by PI3K of IRS-1 protein is due to hyper-activation of Akt/PKB pathway in LNCaP. IRS-1 interacts with integrin α5β1, activating an alternative signalling cascade. This cascade results in decreased cell motility opposing to IGF-1 - dependent mechanism. Loss of IRS-1 expression and PTEN mutations in LNCaP cells could promote metastasis. Ex vivo studies of IRS-1 involvement in prostate cancer show ambiguous results. Down-regulation of IGF1R in bone marrow biopsies of metastatic prostate cancer goes along with down-regulation of IRS-1 and significant reduction of PTEN in 3 out of 12 cases. Most of the tumors still express IRS-1 and IGF1R during progression of the metastatic disease. IRS-1 has a functional role in breast cancer progression and metastasis. Overexpression of PTEN in MCF-7 epithelial breast cancer cells inhibits cell growth by inhibiting MAPK pathway. ERK phosphorylation through IRS-1/Grb-2/Sos pathway is inhibited by phosphatase activity of PTEN. PTEN does not have effect on IRS-1 independent MAPK activation. When treated with insulin, ectopic expression of PTEN in MCF-7 suppresses IRS-1/Grb-2/Sos complex formation due to differential phosphorylation of IRS-1. Overexpression of IRS-1 has been linked to antiestrogen resistance and hormone independence in breast cancer. Tamoxifen (TAM) inhibits IRS-1 function, therefore suppressing IRS-1/PI3K signalling cascade in estrogen receptor positive (ER+) MCF-7 cell line. IRS-1 siRNA is able to reduce IRS-1 transcript level, thereby reducing protein expression in MCF-7 ER+ cells. Reduction of IRS-1 leads to decreased survival of these cells. siRNA treatment effects are additive to effects of TAM treatment. IGFRs and estrogen coaction facilitates growth in different breast cancer cell lines, however amplification of IGF1R signalling can abrogate need of estrogen for transformation and growth of MCF-7 cells. IRS-1 overexpression in breast cancer cells decreased estrogen requirements. This decrease is dependent on IRS-1 levels in the cells. Estradiol enhances expression of IRS-1 and activity of ERK1/2 and PI3K/Akt pathways in MCF-7 and CHO cells transfected with mouse IRS-1 promoter. Estradiol acts directly on IRS-1 regulatory sequences and positively regulates IRS-1 mRNA production. Decreased anchorage- dependent/independent cell growth and initiation of cell death under low growth factor and estrogen conditions are observed in MCF-7 cells with down-regulated IRS-1. mir126 is underexpressed in breast cancer cells. mir126 targets IRS-1 at transcriptional level and inhibits transition from G1/G0 phase to S phase during cell cycle in HEK293 and MCF-7 cells. Transgenic mice overexpressing IRS-1 develop metastatic breast cancer.The tumors demonstrate squamous differentiation which is associated with β-catenin pathway. IRS-1 interacts with β-catenin both in vitro and in vivo. IRS-1 and its homologue IRS-2 play distinct roles in breast cancer progression and metastasis. Overexpression of either one is sufficient to cause tumorogenesis in vivo. Frequency of lung metastasis in IRS-1 deficient tumor is elevated opposing to IRS-2 deficient tumor, where it is decreased. Basically, IRS-2 has a positive impact on metastasis of breast cancer whereas a stronger metastatic potential is observed when IRS-1 is down-regulated. IRS-1 is strongly expressed in ductal carcinoma in situ, when IRS-2 is elevated in invasive tumors. Increased IRS-1 makes MCF-7 cells susceptible to specific chemotherapeutic agents, such as taxol, etoposide, and vincristine.Therefore, IRS-1 can be a good pointer of specific drug therapies effectiveness for breast cancer treatment.

IRS1 Insulin receptor substrate 1 (IRS-1) is a signaling adapter protein that in humans is encoded by the IRS-1 gene.[1] It is a 131 kDa protein with amino acid sequence of 1242 residues.[2] It contains a single pleckstrin homology (PH) domain at the N-terminus and a PTB domain ca. 40 residues downstream of this, followed by a poorly conserved C-terminus tail.[3] Together with IRS2, IRS3 (pseudogene) and IRS4, it is homologous to the Drosophila protein chico, whose disruption extends the median lifespan of flies up to 48%.[4] Similarly, Irs1 mutant mice experience moderate life extension and delayed age-related pathologies.[5] # Function Insulin receptor substrate 1 plays a key role in transmitting signals from the insulin and insulin-like growth factor-1 (IGF-1) receptors to intracellular pathways PI3K / Akt and Erk MAP kinase pathways. Tyrosine phosphorylation of IRS-1 by insulin receptor (IR) introduces multiple binding sites for proteins bearing SH2 homology domain, such as PI3K, Grb-2/Sos complex and SHP2. PI3K, involved in interaction with IRS-1, produces PIP3, which, in turn, recruits Akt kinase. Further, Akt kinase is activated via phosphorylation of its T308 residue and analogous sites in PKC by PDK1. This phosphorylation is absent in tissues lacking IRS-1. The cascade is followed by glucose uptake. Grb-2/Sos complex, also known as RAS, signaling results in ERK1/2 activation. IRS-1 signal transduction may be inhibited by SHP2 in some tissues.[3] Tyrosine phosphorylation of the insulin receptors or IGF-1 receptors, upon extracellular ligand binding, induces the cytoplasmic binding of IRS-1 to these receptors, through its PTB domains. Multiple tyrosine residues of IRS-1 itself are then phosphorylated by these receptors. This enables IRS-1 to activate several signalling pathways, including the PI3K pathway and the MAP kinase pathway. An alternative multi-site phosphorylation of Serine/Tyrosine in IRS-1 regulates insulin signaling positively and negatively. C-terminal region contains most of the phosphorylation sites of the protein. The C-terminal tail is not structured, therefore the mechanisms of regulation of IRS-1 by phosphorylation still remain unclear. It has been shown that TNFα causes insulin resistance and multi-site S/T phosphorylation, which results in block of interaction between IRS-1 and juxtamembrane domain peptide, thus converting IRS-1 into an inactive state.[3] IRS-1 plays important biological function for both metabolic and mitogenic (growth promoting) pathways: mice deficient of IRS1 have only a mild diabetic phenotype, but a pronounced growth impairment, i.e., IRS-1 knockout mice only reach 50% of the weight of normal mice. # Regulation The cellular protein levels of IRS-1 are regulated by the Cullin7 E3 ubiquitin ligase, which targets IRS-1 for ubiquitin mediated degradation by the proteasome.[6] Different Serine phosphorylation of IRS-1, caused by various molecules, such as fatty acids, TNFα and AMPK, has different effects on the protein, but most of these effects include cellular re-localization, conformational and steric changes. These processes lead to decrease in Tyrosine phosphorylation by insulin receptors and diminished PI3K recruitment. Altogether, these mechanisms stimulate IRS-1 degradation and insulin resistance. Other inhibitory pathways include SOCS proteins and O-linked glycosylation of IRS-1. SOCS proteins act by binding to IR and by interfering with IR phosphorylation of IRS-1, therefore attenuating insulin signaling. They can also bind to JAK, causing a subsequent decrease in IRS-1 tyrosine phosphorylation. During insulin resistance induced by hyperglycemia, glucose accumulates in tissues as its hexosamine metabolite UDP-GlcNAc. This metabolite if present in high amounts leads to O-GlcNAc protein modifications. IRS-1 can undergo this modification, which results in its phosphorylation and functional suppression.[7] # Interactions IRS1 has been shown to interact with: - Bcl-2,[8] - Grb2,[9][10][11] - INSR,[12][13] - IGF1R,[14][15][16] - JAK1,[17][18] - JAK2,[17][19] - MAPK8,[12][20] - PIK3R1[10][21][22][23] - PIK3R3,[24][25] - PTK2,[26] - PTPN11,[27][28] - PTPN1,[29][30] and - YWHAE.[31] # Role in cancer IRS-1, as a signalling adapter protein, is able to integrate different signalling cascades, which indicates its possible role in cancer progression.[32] IRS-1 protein is known to be involved in various types of cancer, including colorectal,[33] lung,[34] prostate and breast cancer.[35] IRS-1 integrates signalling from insulin receptor (InsR), insulin-like growth factor-1 receptor (IGF1R) and many other cytokine receptors and is elevated in β-catenin induced cells. Some evidence shows that TCF/LEF-β-catenin complexes directly regulate IRS-1. IRS-1 is required for maintenance of neoplasmic phenotype in adenomatous polyposis coli (APC) - mutated cells, it is also needed for transformation in ectopically expressing oncogenic β-catenin cells. IRS-1 dominant-negative mutant functions as tumor suppressor, whereas ectopic IRS-1 stimulates oncogenic transformation. IRS-1 is upregulated in colorectal cancers (CRC) with elevated levels of β-catenin, c-MYC, InsRβ and IGF1R. IRS-1 promotes CRC metastasis to the liver.[33] Decreased apoptosis of crypt stem cells is associated with colon cancer risk. Reduced expression of IRS-1 in Apc (min/+) mutated mice showes increased irradiation-induced apoptosis in crypt. Deficiency in IRS-1 - partial (+/-) or absolute (-/-) - in Apc (min/+) mice demonstrates reduced amount of tumors comparing to IRS-1 (+/+)/ Apc (min/+) mice.[36] In lung adenocarcinoma cell line A549 overexpression of IRS-1 leads to reduced growth. Tumor infiltrating neutrophils have recently been thought to adjust tumor growth and invasiveness. Neutrophil elastase is shown to degrade IRS-1 by gaining access to endosomal compartment of carcinoma cell. IRS-1 degradation induces cell proliferation in mouse and human adenocarcinomas. Ablation of IRS-1 alters downstream signalling through phosphatidylinositol-3 kinase (PI3K), causing an increased interaction of it with platelet-derived growth factor receptor (PDGFR). Therefore, IRS-1 acts as major regulator of PI3K in lung adenocarcinoma.[34] Some evidence shows role of IRS-1 in hepatocellular carcinoma (HCC). In rat model, IRS-1 focal overexpression is associated with early events of hepatocarcinogenesis. During progression of preneoplastic foci into hepatocellular carcinomas expression of IRS-1 gradually decreases, which is characterises a metabolic shift heading towards malignant neoplastic phenotype.[37] Transgenic mice, co-expressing IRS-1 and hepatitis Bx (HBx) protein, demonstrate higher rate of hepatocellular displasia that results in HCC development. Expressed alone, IRS-1 and HBx are not sufficient to induce neoplastic alterations in the liver, though their paired expression switches on IN/IRS-1/MAPK and Wnt/β-catenin cascades, causing HCC transformation.[38] LNCaP prostate cancer cells increase cell adhesion and diminish cell motility via IGF-1 independent mechanism, when IRS-1 is ectopically expressed in the cells. These effects are mediated by PI3K. Uncanonical phosphorylation of Serine 612 by PI3K of IRS-1 protein is due to hyper-activation of Akt/PKB pathway in LNCaP. IRS-1 interacts with integrin α5β1, activating an alternative signalling cascade. This cascade results in decreased cell motility opposing to IGF-1 - dependent mechanism. Loss of IRS-1 expression and PTEN mutations in LNCaP cells could promote metastasis.[39] Ex vivo studies of IRS-1 involvement in prostate cancer show ambiguous results. Down-regulation of IGF1R in bone marrow biopsies of metastatic prostate cancer goes along with down-regulation of IRS-1 and significant reduction of PTEN in 3 out of 12 cases. Most of the tumors still express IRS-1 and IGF1R during progression of the metastatic disease.[40] IRS-1 has a functional role in breast cancer progression and metastasis. Overexpression of PTEN in MCF-7 epithelial breast cancer cells inhibits cell growth by inhibiting MAPK pathway. ERK phosphorylation through IRS-1/Grb-2/Sos pathway is inhibited by phosphatase activity of PTEN. PTEN does not have effect on IRS-1 independent MAPK activation. When treated with insulin, ectopic expression of PTEN in MCF-7 suppresses IRS-1/Grb-2/Sos complex formation due to differential phosphorylation of IRS-1.[41] Overexpression of IRS-1 has been linked to antiestrogen resistance and hormone independence in breast cancer. Tamoxifen (TAM) inhibits IRS-1 function, therefore suppressing IRS-1/PI3K signalling cascade in estrogen receptor positive (ER+) MCF-7 cell line. IRS-1 siRNA is able to reduce IRS-1 transcript level, thereby reducing protein expression in MCF-7 ER+ cells. Reduction of IRS-1 leads to decreased survival of these cells. siRNA treatment effects are additive to effects of TAM treatment.[42] IGFRs and estrogen coaction facilitates growth in different breast cancer cell lines, however amplification of IGF1R signalling can abrogate need of estrogen for transformation and growth of MCF-7 cells. IRS-1 overexpression in breast cancer cells decreased estrogen requirements. This decrease is dependent on IRS-1 levels in the cells.[43] Estradiol enhances expression of IRS-1 and activity of ERK1/2 and PI3K/Akt pathways in MCF-7 and CHO cells transfected with mouse IRS-1 promoter. Estradiol acts directly on IRS-1 regulatory sequences and positively regulates IRS-1 mRNA production.[44] Decreased anchorage- dependent/independent cell growth and initiation of cell death under low growth factor and estrogen conditions are observed in MCF-7 cells with down-regulated IRS-1.[45] mir126 is underexpressed in breast cancer cells. mir126 targets IRS-1 at transcriptional level and inhibits transition from G1/G0 phase to S phase during cell cycle in HEK293 and MCF-7 cells.[46] Transgenic mice overexpressing IRS-1 develop metastatic breast cancer.The tumors demonstrate squamous differentiation which is associated with β-catenin pathway. IRS-1 interacts with β-catenin both in vitro and in vivo.[47] IRS-1 and its homologue IRS-2 play distinct roles in breast cancer progression and metastasis. Overexpression of either one is sufficient to cause tumorogenesis in vivo. Frequency of lung metastasis in IRS-1 deficient tumor is elevated opposing to IRS-2 deficient tumor, where it is decreased. Basically, IRS-2 has a positive impact on metastasis of breast cancer whereas a stronger metastatic potential is observed when IRS-1 is down-regulated.[citation needed] IRS-1 is strongly expressed in ductal carcinoma in situ, when IRS-2 is elevated in invasive tumors. Increased IRS-1 makes MCF-7 cells susceptible to specific chemotherapeutic agents, such as taxol, etoposide, and vincristine.Therefore, IRS-1 can be a good pointer of specific drug therapies effectiveness for breast cancer treatment.[48]

https://www.wikidoc.org/index.php/IRS-1

ab4c2e33f785a89ebd56fd83f51bdba6316e181e

wikidoc

IRS2

IRS2 Insulin receptor substrate 2 is a protein that in humans is encoded by the IRS2 gene. # Function This gene encodes the insulin receptor substrate 2, a cytoplasmic signaling molecule that mediates effects of insulin, insulin-like growth factor 1, and other cytokines by acting as a molecular adaptor between diverse receptor tyrosine kinases and downstream effectors. The product of this gene is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation, as well as by an interleukin 4 receptor-associated kinase in response to IL4 treatment. Mice lacking IRS2 have a diabetic phenotype as well as a 40% reduction in brain mass. # Interactions IRS2 has been shown to interact with: - PLCG1, - SOCS1, and - PIK3R1,

IRS2 Insulin receptor substrate 2 is a protein that in humans is encoded by the IRS2 gene.[1] # Function This gene encodes the insulin receptor substrate 2, a cytoplasmic signaling molecule that mediates effects of insulin, insulin-like growth factor 1, and other cytokines by acting as a molecular adaptor between diverse receptor tyrosine kinases and downstream effectors. The product of this gene is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation, as well as by an interleukin 4 receptor-associated kinase in response to IL4 treatment.[2] Mice lacking IRS2 have a diabetic phenotype[3] as well as a 40% reduction in brain mass.[4] # Interactions IRS2 has been shown to interact with: - PLCG1,[5] - SOCS1,[6] and - PIK3R1,[7][8][9][10]

https://www.wikidoc.org/index.php/IRS2

7b6c22acd395e8ed9d30ed75d6ed2d8168c3fd32

wikidoc

IRX1

IRX1 Iroquois-class homeodomain protein IRX-1, also known as Iroquois homeobox protein 1, is a protein that in humans is encoded by the IRX1 gene. All members of the Iroquois (IRO) family of proteins share two highly conserved features, encoding both a homeodomain and a characteristic IRO sequence motif. Members of this family are known to play numerous roles in early embryo patterning. IRX1 has also been shown to act as a tumor suppressor gene in several forms of cancer. # Role in development IRX1 is a member of the Iroquois homeobox gene family. Members of this family play multiple roles during pattern formation in embryos of numerous vertebrate and invertebrate species. IRO genes are thought to function early in development to define large territories, and again later in development for further patterning specification. Experimental data suggest roles for IRX1 in vertebrates may include development and patterning of lungs, limbs, heart, eyes, and nervous system. # Gene ## Overview IRX1 is located on the forward DNA strand (see Sense (molecular biology)) of chromosome 5, from position 3596054 - 3601403 at the 5p15.3 location. The human gene product is a 1858 base pair mRNA with 4 predicted exons in humans. Promoter analysis was performed using El Dorado through the Genomatix software page. The predicted promoter region spans 1040 base pairs from position 3595468 through 3595468 on the forward strand of chromosome 5. ## Gene neighborhood IRX1 is relatively isolated, with no other protein coding genes found from position 3177835 – 5070004. ## Expression Microarray and RNA seq data suggest that IRX1 is ubiquitously expressed at low levels in adult tissues, with the highest relative levels of expression occurring in the heart, adipose, kidney, and breast tissues. Moderate to high levels are also indicated in the lung, prostate and stomach. Promoter analysis with the El Dorado program from Genomatix predicted that IRX1 expression is regulated by factors that include E2F cell cycle regulators, NRF1, and ZF5, and brachyury. Expression data from human, mouse, and developing mouse brains are available though the Allen Brain Atlas. # Protein ## Properties & characteristics The mature IRX1 protein has 480 amino acid residues, with a molecular mass of 49,600 Daltons and an isoelectric point of 5.7. A BLAST search revealed that IRX1 contains two highly conserved domains: a homeodomain and a characteristic IRO motif of unknown function. The homeodomain belongs to the TALE (three amino acid loop extension) class of homeodomains, and is characterized by the addition of three extra amino acids between the first and second helix of three alpha helices that comprise the domain. The presence of this well characterized homeodomain strongly suggests that IRX1 acts as a transcription factor. This is further supported by the predicted localization of IRX1 to the nucleus. The IRO motif is a region downstream of the homeodomain that is found only in members of the Iroquois-class homeodomain proteins, though its function is poorly understood. However, its similarity to an internal region of the Notch receptor protein suggests that it may be involved with protein-protein interaction. In addition to these two characteristic domains, IRX1 contains a third domain from the HARE-HTH superfamily fused to the C-terminal end of the homeodomain. This domain adopts a winged helix-turn-helix fold predicted to bind DNA, and is thought to play a role in recruiting effector activities to DNA. Several forms of post-translational modification are predicted, including SUMOylation, C-mannosylation, and phosphorylation, using bioinformatics tools from ExPASy. Bioinformatic analysis of IRX1 with the NetPhos tool predicted 71 potential phosphorylation sites throughout the protein. ## Protein Interactions Potential protein interacting partners for IRX1 were found using computational tools. The STRING database lists nine putative interacting partners supported by text mining evidence, though closer analysis of the results shows little support for most of these predicted interactions. However, it is possible that one of these proteins, CDKN1A, is involved in the predicted regulation of IRX1 by E2F cell cycle regulators. # Conservation ## Orthologs IRX1 has a high degree of conservation across vertebrate and invertebrate species. The entire protein is more fully conserved through vertebrate species, while only the homeodomain and IRO motif are conserved in more distant homologs. Homologous sequences were found in species as distantly related to humans as the pig roundworm Ascaris suum, from the family Ascarididae, using BLAST and the ALIGN tool through the San Diego Super Computer Biology Workbench. The following is a table describing the evolutionary conservation of IRX1. ## Paralogs IRX1 is one of six members of the Iroquois-class homeodomain proteins found in humans: IRX2, IRX3, IRX4, IRX5, and IRX6. IRX1, IRX2, and IRX4 are found on human chromosome 5, and their orientation corresponds to that of IRX3, IRX5, and IRX6 found on human chromosome 16. It is thought that the genomic organization of IRO genes in conserved gene clusters allows for coregulation and enhancer sharing during development.

IRX1 Iroquois-class homeodomain protein IRX-1, also known as Iroquois homeobox protein 1, is a protein that in humans is encoded by the IRX1 gene.[1][2] All members of the Iroquois (IRO) family of proteins share two highly conserved features, encoding both a homeodomain and a characteristic IRO sequence motif.[3] Members of this family are known to play numerous roles in early embryo patterning.[1] IRX1 has also been shown to act as a tumor suppressor gene in several forms of cancer.[4][5][6][7] # Role in development IRX1 is a member of the Iroquois homeobox gene family. Members of this family play multiple roles during pattern formation in embryos of numerous vertebrate and invertebrate species.[1][8] IRO genes are thought to function early in development to define large territories, and again later in development for further patterning specification.[3] Experimental data suggest roles for IRX1 in vertebrates may include development and patterning of lungs, limbs, heart, eyes, and nervous system.[9][10][11][12][13][14] # Gene ## Overview IRX1 is located on the forward DNA strand (see Sense (molecular biology)) of chromosome 5, from position 3596054 - 3601403 at the 5p15.3 location.[1] The human gene product is a 1858 base pair mRNA with 4 predicted exons in humans.[15] Promoter analysis was performed using El Dorado through the Genomatix software page.[16] The predicted promoter region spans 1040 base pairs from position 3595468 through 3595468 on the forward strand of chromosome 5. ## Gene neighborhood IRX1 is relatively isolated, with no other protein coding genes found from position 3177835 – 5070004.[1] ## Expression Microarray and RNA seq data suggest that IRX1 is ubiquitously expressed at low levels in adult tissues, with the highest relative levels of expression occurring in the heart, adipose, kidney, and breast tissues.[17][18] Moderate to high levels are also indicated in the lung, prostate and stomach.[18][19] Promoter analysis with the El Dorado program from Genomatix predicted that IRX1 expression is regulated by factors that include E2F cell cycle regulators, NRF1, and ZF5,[20] and brachyury.[16] Expression data from human, mouse, and developing mouse brains are available though the Allen Brain Atlas.[21] # Protein ## Properties & characteristics The mature IRX1 protein has 480 amino acid residues, with a molecular mass of 49,600 Daltons and an isoelectric point of 5.7. A BLAST search revealed that IRX1 contains two highly conserved domains: a homeodomain and a characteristic IRO motif of unknown function.[22] The homeodomain belongs to the TALE (three amino acid loop extension) class of homeodomains, and is characterized by the addition of three extra amino acids between the first and second helix of three alpha helices that comprise the domain.[23] The presence of this well characterized homeodomain strongly suggests that IRX1 acts as a transcription factor. This is further supported by the predicted localization of IRX1 to the nucleus.[24] The IRO motif is a region downstream of the homeodomain that is found only in members of the Iroquois-class homeodomain proteins, though its function is poorly understood. However, its similarity to an internal region of the Notch receptor protein suggests that it may be involved with protein-protein interaction.[3] In addition to these two characteristic domains, IRX1 contains a third domain from the HARE-HTH superfamily[25] fused to the C-terminal end of the homeodomain.[26] This domain adopts a winged helix-turn-helix fold predicted to bind DNA, and is thought to play a role in recruiting effector activities to DNA.[25] Several forms of post-translational modification are predicted, including SUMOylation, C-mannosylation, and phosphorylation, using bioinformatics tools from ExPASy.[27] Bioinformatic analysis of IRX1 with the NetPhos tool predicted 71 potential phosphorylation sites throughout the protein.[28] ## Protein Interactions Potential protein interacting partners for IRX1 were found using computational tools. The STRING database lists nine putative interacting partners supported by text mining evidence, though closer analysis of the results shows little support for most of these predicted interactions.[29] However, it is possible that one of these proteins, CDKN1A, is involved in the predicted regulation of IRX1 by E2F cell cycle regulators.[16][29] # Conservation ## Orthologs IRX1 has a high degree of conservation across vertebrate and invertebrate species. The entire protein is more fully conserved through vertebrate species, while only the homeodomain and IRO motif are conserved in more distant homologs.[8] Homologous sequences were found in species as distantly related to humans as the pig roundworm Ascaris suum, from the family Ascarididae, using BLAST and the ALIGN tool through the San Diego Super Computer Biology Workbench.[22] The following is a table describing the evolutionary conservation of IRX1. ## Paralogs IRX1 is one of six members of the Iroquois-class homeodomain proteins found in humans: IRX2, IRX3, IRX4, IRX5, and IRX6. IRX1, IRX2, and IRX4 are found on human chromosome 5, and their orientation corresponds to that of IRX3, IRX5, and IRX6 found on human chromosome 16.[3] It is thought that the genomic organization of IRO genes in conserved gene clusters allows for coregulation and enhancer sharing during development.

https://www.wikidoc.org/index.php/IRX1

70d0c64bcfb6e0cb243e0808626a9287d76592bf

wikidoc

IRX3

IRX3 Iroquois-class homeodomain protein IRX-3, also known as Iroquois homeobox protein 3, is a protein that in humans is encoded by the IRX3 gene. # Function IRX3 is a member of the Iroquois homeobox gene family and plays a role in an early step of neural development. Members of this family appear to play multiple roles during pattern formation of vertebrate embryos. Specifically, IRX3 contributes to pattern formation in the spinal cord where it translates a morphogen gradient into transcriptional events, and is directly regulated by NKX2-2. # Clinical significance ## Association with obesity Obesity-associated noncoding sequences within FTO interact with the promoter of IRX3 and FTO in human, mouse, and zebrafish. Obesity-associated single nucleotide polymorphisms are related to the expression of IRX3 (not FTO) in the human brain. A direct connection between the expression of IRX3 and body mass and composition was shown through the decrease in body weight of 25-30% in IRX3-deficient mice. This suggests that IRX3 influences obesity. Manipulation of IRX3 and IRX5 pathways has also been shown to decrease obesity markers in human cell cultures. Genetic variants of FTO and IRX3 genes are in high linkage disequilibrium and are associated with obesity risk.

IRX3 Iroquois-class homeodomain protein IRX-3, also known as Iroquois homeobox protein 3, is a protein that in humans is encoded by the IRX3 gene.[1] # Function IRX3 is a member of the Iroquois homeobox gene family and plays a role in an early step of neural development.[2] Members of this family appear to play multiple roles during pattern formation of vertebrate embryos.[1][3] Specifically, IRX3 contributes to pattern formation in the spinal cord where it translates a morphogen gradient into transcriptional events, and is directly regulated by NKX2-2.[4] # Clinical significance ## Association with obesity Obesity-associated noncoding sequences within FTO interact with the promoter of IRX3 and FTO in human, mouse, and zebrafish. Obesity-associated single nucleotide polymorphisms are related to the expression of IRX3 (not FTO) in the human brain. A direct connection between the expression of IRX3 and body mass and composition was shown through the decrease in body weight of 25-30% in IRX3-deficient mice. This suggests that IRX3 influences obesity.[5] Manipulation of IRX3 and IRX5 pathways has also been shown to decrease obesity markers in human cell cultures.[6] Genetic variants of FTO and IRX3 genes are in high linkage disequilibrium and are associated with obesity risk.[7]

https://www.wikidoc.org/index.php/IRX3

eb77714aeb20fdbe8dba7d9597e4fd6b512b669c

wikidoc

ISCU

ISCU Iron-sulfur cluster assembly enzyme ISCU, mitochondrial is a protein that in humans is encoded by the ISCU gene. It encodes an iron-sulfur (Fe-S) cluster scaffold protein involved in and cluster synthesis and maturation. A deficiency of ISCU is associated with a mitochondrial myopathy with lifelong exercise intolerance where only minor exertion causes tachycardia, shortness of breath, muscle weakness and myalgia. # Structure ISCU is located on the q arm of chromosome 12 in position 23.3 and has 8 exons. ISCU, the protein encoded by this gene, is a member of the NifU family. It is an iron-sulfur transferase that contains binding sites for and clusters. ISCU contains a transit peptide, 4 beta strands, 4 alpha helixes, and 4 turns. Alternative splicing results in transcript variants encoding different protein isoforms that localize either to the cytosol or to the mitochondrion. A pseudogene of this gene is present on chromosome 1. # Function ISCU encodes a component of the iron-sulfur (Fe-S) cluster scaffold responsible for the synthesis and maturation of and clusters. Fe-S clusters are cofactors that play a role in the function of a diverse set of enzymes, including those that regulate metabolism, iron homeostasis, and oxidative stress response. In one process, the cluster transiently assembles on ISCU and is then transferred to GLRX5 in a cysteine desulfurase complex NFS1-LYRM4/ISD11 dependent process. ISCU has two isoforms, isoform 1, which is found in the mitochondrion and isoform 2, which is found in the nucleus and cytoplasm. # Clinical significance ISCU mutations have been found in patients with hereditary mitochondrial myopathy with exercise intolerance and lactic acidosis. This disease is a result of a deficiency of ISCU that corresponds to the deficiency of mitochondrial iron-sulfur proteins and impaired muscle oxidative metabolism. Characteristics of mitochondrial myopathy with deficiency of ISCU may include lifelong exercise intolerance in which exertion can cause tachycardia, dyspnoea, cardiac palpitations, shortness of breath, fatigue, pain of active muscles, rhabdomyolysis, myoglobinuria, elevated lactate and pyruvate, decreased oxygen utilization, large calves, and possibly weakness. ## Genetics This disorder has been associated with several different mutations and is inherited in an autosomal recessive manner. It was originally believed to affect only those of northern Swedish ancestry, however the disease has been found in those of Norwegian and Finnish decent as well. The carrier rate in northern Sweden has been estimated at 1:188. ISCU deficiency has been linked to pathogenic variants including intronic variants c.418+382G>C, g.7044G>C, and IVS5+382 G>C as well as a c.149G>A missense mutation in exon 3. The intronic mutations have been suggested to activate a cryptic splice site, resulting in the production of a splice variant that encodes a putatively non-functional protein. # Interactions ISCU has been shown to have 235 binary protein-protein interactions including 79 co-complex interactions. ISCU appears to interact with ISCS, NUP62, SDHB, HPRT1, CCDC172, GOLGA2, IKZF1, KRT40, AGTRAP, NECAB2, FAM9B, BANP, LNX1, MID2, GOLGA6L9, ccdc136, KRT34, SPERT, PICK1, YWHAB, SFN, mbl, E7, dnaX, hscB, MAPk-Ak2, hale, and cv-c.

ISCU Iron-sulfur cluster assembly enzyme ISCU, mitochondrial is a protein that in humans is encoded by the ISCU gene.[1] It encodes an iron-sulfur (Fe-S) cluster scaffold protein involved in [2Fe-2S] and [4Fe-4S] cluster synthesis and maturation.[2][3][4][5] A deficiency of ISCU is associated with a mitochondrial myopathy with lifelong exercise intolerance where only minor exertion causes tachycardia, shortness of breath, muscle weakness and myalgia.[6] # Structure ISCU is located on the q arm of chromosome 12 in position 23.3 and has 8 exons.[3] ISCU, the protein encoded by this gene, is a member of the NifU family. It is an iron-sulfur transferase that contains binding sites for [2Fe-2S] and [4Fe-4S] clusters. ISCU contains a transit peptide, 4 beta strands, 4 alpha helixes, and 4 turns.[4][5] Alternative splicing results in transcript variants encoding different protein isoforms that localize either to the cytosol or to the mitochondrion. A pseudogene of this gene is present on chromosome 1.[3] # Function ISCU encodes a component of the iron-sulfur (Fe-S) cluster scaffold responsible for the synthesis and maturation of [2Fe-2S] and [4Fe-4S] clusters. Fe-S clusters are cofactors that play a role in the function of a diverse set of enzymes, including those that regulate metabolism, iron homeostasis, and oxidative stress response. In one process, the [2Fe-2S] cluster transiently assembles on ISCU and is then transferred to GLRX5 in a cysteine desulfurase complex NFS1-LYRM4/ISD11 dependent process.[3][2][4][5] ISCU has two isoforms, isoform 1, which is found in the mitochondrion and isoform 2, which is found in the nucleus and cytoplasm.[4][5] # Clinical significance ISCU mutations have been found in patients with hereditary mitochondrial myopathy with exercise intolerance and lactic acidosis. This disease is a result of a deficiency of ISCU that corresponds to the deficiency of mitochondrial iron-sulfur proteins and impaired muscle oxidative metabolism.[3] Characteristics of mitochondrial myopathy with deficiency of ISCU may include lifelong exercise intolerance in which exertion can cause tachycardia, dyspnoea, cardiac palpitations, shortness of breath, fatigue, pain of active muscles, rhabdomyolysis, myoglobinuria, elevated lactate and pyruvate, decreased oxygen utilization, large calves, and possibly weakness.[7][4][5][6] ## Genetics This disorder has been associated with several different mutations and is inherited in an autosomal recessive manner. It was originally believed to affect only those of northern Swedish ancestry, however the disease has been found in those of Norwegian and Finnish decent as well. The carrier rate in northern Sweden has been estimated at 1:188.[7] ISCU deficiency has been linked to pathogenic variants including intronic variants c.418+382G>C, g.7044G>C,[8] and IVS5+382 G>C[9] as well as a c.149G>A missense mutation in exon 3.[10] The intronic mutations have been suggested to activate a cryptic splice site, resulting in the production of a splice variant that encodes a putatively non-functional protein.[6] # Interactions ISCU has been shown to have 235 binary protein-protein interactions including 79 co-complex interactions. ISCU appears to interact with ISCS, NUP62, SDHB, HPRT1, CCDC172, GOLGA2, IKZF1, KRT40, AGTRAP, NECAB2, FAM9B, BANP, LNX1, MID2, GOLGA6L9, ccdc136, KRT34, SPERT, PICK1, YWHAB, SFN, mbl, E7, dnaX, hscB, MAPk-Ak2, hale, and cv-c.[11]

https://www.wikidoc.org/index.php/ISCU

cee875a9ea6f7a0f9af472e30b4c142675558444

wikidoc

ISFJ

ISFJ ISFJ (Introverted Sensing Feeling Judging) is one of the sixteen personality types from the Myers-Briggs Type Indicator (MBTI), and the Keirsey Temperament Sorter. Referring to Keirsey, ISFJs belong to the Guardian temperament and are called Protectors. # Myers-Briggs Characteristics According to Myers-Briggs, ISFJs are interested in maintaining order and harmony in every aspect of their lives. They are steadfast and meticulous in handling their responsibilities. Although quiet, they are people-oriented and very observant. Not only do they remember details about others, but they observe and respect others’ feelings. Friends and family are likely to describe them as thoughtful and trustworthy. # Keirsey Characteristics According to Keirsey, ISFJs, or "Protector Guardians", are most concerned with taking care of people by keeping them safe and secure. They are modest caretakers who do not demand credit or thanks for their efforts. But while they are essentially very compassionate—and in fact exercise more patience in dealing with the disabled than perhaps any other type—their shyness with strangers can lead others to misread them as standoffish. Only among friends and family may this quiet type feel comfortable speaking freely. ISFJs are serious people with a strong work ethic, not inclined to self-indulgence. They believe in being meticulous and thrifty. They work well alone. While they may enjoy taking care of others, they do not enjoy giving orders. # MBTI cognitive functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality types Achille's heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity. - Dominant Introverted Sensing - Auxiliary Extroverted Feeling - Tertiary Introverted Thinking - inferior Extroverted iNtuition

ISFJ ISFJ (Introverted Sensing Feeling Judging) is one of the sixteen personality types from the Myers-Briggs Type Indicator (MBTI), and the Keirsey Temperament Sorter. Referring to Keirsey, ISFJs belong to the Guardian temperament and are called Protectors. # Myers-Briggs Characteristics According to Myers-Briggs, ISFJs are interested in maintaining order and harmony in every aspect of their lives. They are steadfast and meticulous in handling their responsibilities. Although quiet, they are people-oriented and very observant. Not only do they remember details about others, but they observe and respect others’ feelings. Friends and family are likely to describe them as thoughtful and trustworthy. # Keirsey Characteristics According to Keirsey, ISFJs, or "Protector Guardians", are most concerned with taking care of people by keeping them safe and secure. They are modest caretakers who do not demand credit or thanks for their efforts. But while they are essentially very compassionate—and in fact exercise more patience in dealing with the disabled than perhaps any other type—their shyness with strangers can lead others to misread them as standoffish. Only among friends and family may this quiet type feel comfortable speaking freely. ISFJs are serious people with a strong work ethic, not inclined to self-indulgence. They believe in being meticulous and thrifty. They work well alone. While they may enjoy taking care of others, they do not enjoy giving orders. # MBTI cognitive functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality types Achille's heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity.[1] - Dominant Introverted Sensing - Auxiliary Extroverted Feeling - Tertiary Introverted Thinking - inferior Extroverted iNtuition[1]

https://www.wikidoc.org/index.php/ISFJ

3c545d9eb583cddd90880840492a41c43b14b063

wikidoc

ISFP

ISFP ISFP (Introverted Sensing Feeling Perceiving) is one of the sixteen personality types from the Myers-Briggs Type Indicator (MBTI), and the Keirsey Temperament Sorter. Referring to Keirsey, ISFPs belong to the Artisan temperament and are called "Composers". # Myers-Briggs Characteristics According to Myers-Briggs, ISFPs are peaceful, easygoing people who adopt a "live and let live" approach to life. They enjoy taking things at their own pace and tend to live in the moment. Although quiet, they are pleasant, considerate and caring, devoted to the people in their lives. Though not inclined to debate or necessarily even air their views, their values are important to them. # Keirsey Characteristics According to Keirsey, ISFPs, or "Composer Artisans", are grounded in the here and now and are extremely sensitive to their environments. Like other "S" types, they are primarily concerned with what their five senses can tell them about their world, but they are extra attentive to those senses. They notice little variations in their environment or in the people around them. They are very sensitive to balance and understand well what does or does not fit, whether in a work of art or any other aspect of their lives. ISFPs are highly conscious of their companions, but they prefer to allow others to direct their own lives. # MBTI cognitive functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality types Achille's heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity. - Dominant Introverted Feeling - Auxiliary Extroverted Sensing - Tertiary Introverted iNtuition - inferior Extroverted Thinking

ISFP ISFP (Introverted Sensing Feeling Perceiving) is one of the sixteen personality types from the Myers-Briggs Type Indicator (MBTI), and the Keirsey Temperament Sorter. Referring to Keirsey, ISFPs belong to the Artisan temperament and are called "Composers". # Myers-Briggs Characteristics According to Myers-Briggs, ISFPs are peaceful, easygoing people who adopt a "live and let live" approach to life. They enjoy taking things at their own pace and tend to live in the moment. Although quiet, they are pleasant, considerate and caring, devoted to the people in their lives. Though not inclined to debate or necessarily even air their views, their values are important to them. # Keirsey Characteristics According to Keirsey, ISFPs, or "Composer Artisans", are grounded in the here and now and are extremely sensitive to their environments. Like other "S" types, they are primarily concerned with what their five senses can tell them about their world, but they are extra attentive to those senses. They notice little variations in their environment or in the people around them. They are very sensitive to balance and understand well what does or does not fit, whether in a work of art or any other aspect of their lives. ISFPs are highly conscious of their companions, but they prefer to allow others to direct their own lives. # MBTI cognitive functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality types Achille's heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity.[1] - Dominant Introverted Feeling - Auxiliary Extroverted Sensing - Tertiary Introverted iNtuition - inferior Extroverted Thinking[1]

https://www.wikidoc.org/index.php/ISFP

5080a72155f182718686d6a5b27b366b37036673

wikidoc

ISL1

ISL1 Insulin gene enhancer protein ISL-1 is a protein that in humans is encoded by the isl1 gene. # Function This gene encodes a transcription factor containing two N-terminal LIM domains and one C-terminal homeodomain. The encoded protein plays an important role in the embryogenesis of pancreatic islets of Langerhans. In mouse embryos, a deficiency of this gene fail to undergo neural tube motor neuron differentiation. # Interactions ISL1 has been shown to interact with Estrogen receptor alpha. # Role in cardiac development ISL1 is a marker for cardiac progenitors of the secondary heart field (SHF) which includes the right ventricle and the outflow tract. It also has a biological function as shown in Isl1 knockout mice which have a severely deformed heart. More recently it has been defined as a marker for a cardiac progenitor cell lineage that is capable of differentiating into all 3 major cell types of the heart: cardiomyocytes, smooth muscle and endothelial cell lineages. The validity of ISL1 as a marker for cardiac progenitor cells has been questioned since some groups have found no evidence that ISL1 cells serve as cardiac progenitors. Furthermore, ISL1 is not restricted to second heart field progenitors in the developing heart, but also labels cardiac neural crest. This paper supports work from the Vilquin group in 2011, which concluded that ISL1 can represent cells from both neural crest and cardiomyocyte lineages. While it has been demonstrated by multiple groups that ISL1-positive cells can indeed differentiate into all 3 major cell types of the heart, their significance in cardiovascular development is still unclear and their clinical relevance has been seriously questioned.

ISL1 Insulin gene enhancer protein ISL-1 is a protein that in humans is encoded by the isl1 gene.[1][2] # Function This gene encodes a transcription factor containing two N-terminal LIM domains and one C-terminal homeodomain. The encoded protein plays an important role in the embryogenesis of pancreatic islets of Langerhans. In mouse embryos, a deficiency of this gene fail to undergo neural tube motor neuron differentiation.[2] # Interactions ISL1 has been shown to interact with Estrogen receptor alpha.[3] # Role in cardiac development ISL1 is a marker for cardiac progenitors of the secondary heart field (SHF) which includes the right ventricle and the outflow tract. It also has a biological function as shown in Isl1 knockout mice which have a severely deformed heart.[4] More recently it has been defined as a marker for a cardiac progenitor cell lineage that is capable of differentiating into all 3 major cell types of the heart: cardiomyocytes, smooth muscle and endothelial cell lineages.[5][6][7] The validity of ISL1 as a marker for cardiac progenitor cells has been questioned since some groups have found no evidence that ISL1 cells serve as cardiac progenitors.[8] Furthermore, ISL1 is not restricted to second heart field progenitors in the developing heart, but also labels cardiac neural crest.[9] This paper supports work from the Vilquin group in 2011, which concluded that ISL1 can represent cells from both neural crest and cardiomyocyte lineages.[10] While it has been demonstrated by multiple groups that ISL1-positive cells can indeed differentiate into all 3 major cell types of the heart, their significance in cardiovascular development is still unclear and their clinical relevance has been seriously questioned.

https://www.wikidoc.org/index.php/ISL1

7f8758d49bff5ba4688cea2706f761c74eee9e7d

wikidoc

ITPA

ITPA Inosine triphosphate pyrophosphatase is an enzyme that in humans is encoded by the ITPA gene, by the rdgB gene in bacteria E.coli and the HAM1 gene in yeast S. cerevisiae. Two transcript variants encoding two different isoforms have been found for this gene. Also, at least two other transcript variants have been identified which are probably regulatory rather than protein-coding. # Function The protein encoded by this gene hydrolyzes inosine triphosphate and deoxyinosine triphosphate to the monophosphate nucleotide and diphosphate. The enzyme possesses a multiple substrate-specificity and acts on other nucleotides including xanthosine triphosphate and deoxyxanthosine triphosphate. The encoded protein, which is a member of the HAM1 NTPase protein family, is found in the cytoplasm and acts as a homodimer. # Clinical significance Defects in the encoded protein can result in inosine triphosphate pyrophosphorylase deficiency.

ITPA Inosine triphosphate pyrophosphatase is an enzyme that in humans is encoded by the ITPA gene,[1][2] by the rdgB gene in bacteria E.coli[3] and the HAM1 gene in yeast S. cerevisiae.[4] Two transcript variants encoding two different isoforms have been found for this gene. Also, at least two other transcript variants have been identified which are probably regulatory rather than protein-coding.[citation needed] # Function The protein encoded by this gene hydrolyzes inosine triphosphate and deoxyinosine triphosphate to the monophosphate nucleotide and diphosphate.[2] The enzyme possesses a multiple substrate-specificity and acts on other nucleotides including xanthosine triphosphate and deoxyxanthosine triphosphate.[4] The encoded protein, which is a member of the HAM1 NTPase protein family, is found in the cytoplasm and acts as a homodimer. # Clinical significance Defects in the encoded protein can result in inosine triphosphate pyrophosphorylase deficiency.[2]

https://www.wikidoc.org/index.php/ITPA

5916b482a00a4a6b8b0eb94df1d31f90796355fb

wikidoc

Idli

Idli The idli (IPA:Template:IPA), also romanized "idly" or "iddly", is a steamed rice cake popular throughout South India. It is made by steaming batter — traditionally made from pulses (specifically black lentils) and rice — into patties, usually two to three inches in diameter, using a mold. Most often eaten at breakfast or as a snack, idli are usually served in pairs with chutney, sambar, or other accompaniments. Mixtures of crushed dry spices such as milagai podi are the preferred condiment for idlis eaten on the go. It is recognized as one of the most healthiest foods in the world. The idli is a common fastfood available everywhere in India, especially in the states that make up South India. # History Although the precise history of the modern idli is unknown, it is a very old food in southern Indian cuisine. One mention of it in writings occurs in the Kannada writing of Shivakotiacharya in 920 AD, and it seems to have started as a dish made only of fermented black lentil. One description circa 1025 A.D. says the lentils were first soaked in buttermilk, and after grinding, seasoned with black pepper, coriander, cumin and asafoetida. The Kannada king and scholar Someshwara III, reigning in the area now called Karnataka, included an idli recipe in his encyclopedia, the Manasollasa, written in Sanskrit ca. 1130 A.D. There is no known record of rice being added until some time in the 17th century. It may have been found that the rice helped speed the fermentation process. Although the idli changed in ingredients, the preparation process and the name remained the same. # Preparation To prepare the classic idlis, two parts uncooked rice to one part split black lentil (Urad dal) are soaked until they can be ground to a paste in a heavy stone grinding vessel, the attu kal. This paste is allowed to ferment overnight, until about 2-1/2 times its original volume. In the morning, the idli batter is put into the ghee-greased molds of an idli tray or "tree" for steaming. This typically has several metal trays in tiers on a central support, with three or four round indentations per tray. These molds are perforated to allow the idlis to be cooked evenly. The tree holds the trays above the level of boiling water in a pot, and the pot is covered until the idlis are done, in 10-25 minutes, depending on size. The idli's pancake-like (or crepe-like) cousin is the dosa. # Contemporary Idlis and variations Southern Indians have brought the popular idli wherever they have settled throughout the world. Cooks have had to solve problems of hard-to-get ingredients, and climates that do not encourage overnight fermentation. One cook noted that idli batter, foaming within a few hours in India, might take several days to rise in Britain. The traditional heavy stones used to wet-grind the rice and dal are not easily transported. Access to Indian ingredients before the advent of Internet mail order could be virtually impossible in many places. Chlorinated water and iodized salt interfere with fermentation. Newer "quick" recipes for the idli can be rice- or wheat-based (rava idli). Parboiled rice, such as Uncle Ben's can reduce the soaking time considerably. Store-bought ground rice is available, or Cream of Rice may be used. Similarly, semolina or Cream of Wheat may be used for rava idli. Yoghurt may be added to provide the sour flavor for unfermented batters. Prepackaged mixes allow for almost instant idlis, for the truly desperate. Idli Burger is another variation that can be made easily. Besides the microwave steamer, electric idli steamers are available, with automatic steam release and shut-off for perfect cooking. Both types are non-stick, so a fat-free idli is possible. Table-mounted electric Wet grinders may take the place of floor-bound attu kal. With these appliances, even the classic idlis can be made more easily. The plain rice/black lentil idli continues to be the popular version, but it may also incorporate a variety of extra ingredients, savory or sweet. Mustard seeds, fresh chile peppers, black pepper, cumin, coriander seed and its fresh leaf form (cilantro), fenugreek seeds, curry leaves (neem), fresh ginger root, sesame seeds, nuts, garlic, scallions, coconut, and the unrefined sugar jaggery are all possibilities. Filled idlis contain small amounts of chutneys, sambars, or sauces placed inside before steaming. A variety of idlis are experimented these days, namely, standard idli, mini idlis soaked in sambar, rava idli, Kancheepuram idli, stuffed idli with a filling of potato, beans, carrot and masala, ragi idli, pudi idli with the sprinkling of chutney pudi that covers the bite-sized pieces of idlis, malli idli shallow-fried with coriander and curry leaves, and curd idli dipped in masala curds. # Picture gallery - Idli and Vada served with sambar and two type of chutneys (green and red) on banana leaf. Idli and Vada served with sambar and two type of chutneys (green and red) on banana leaf. - The South Indian staple breakfast item of idly, sambar, and vada served on a banana leaf. Note the stainless steel plates and cups; characteristics of south Indian dining tables. The South Indian staple breakfast item of idly, sambar, and vada served on a banana leaf. Note the stainless steel plates and cups; characteristics of south Indian dining tables. - Tatte Idli: variations from Karnataka Tatte Idli: variations from Karnataka - Sambar idly: Idly soaked in sambar. Chutney is the best companion for this dish. Sambar idly: Idly soaked in sambar. Chutney is the best companion for this dish. - MTR idly: Famous Mavalli Tiffin Room idly served with pure ghee and sambar. Pure Ghee is poured on seaming edli and relished with chutney or sambar. MTR idly: Famous Mavalli Tiffin Room idly served with pure ghee and sambar. Pure Ghee is poured on seaming edli and relished with chutney or sambar.

Idli The idli (IPA:Template:IPA), also romanized "idly" or "iddly", is a steamed rice cake popular throughout South India. It is made by steaming batter — traditionally made from pulses (specifically black lentils) and rice — into patties, usually two to three inches in diameter, using a mold. Most often eaten at breakfast or as a snack, idli are usually served in pairs with chutney, sambar, or other accompaniments. Mixtures of crushed dry spices such as milagai podi are the preferred condiment for idlis eaten on the go. It is recognized as one of the most healthiest foods in the world. The idli is a common fastfood available everywhere in India, especially in the states that make up South India. # History Although the precise history of the modern idli is unknown, it is a very old food in southern Indian cuisine. One mention of it in writings occurs in the Kannada writing of Shivakotiacharya in 920 AD,[1] and it seems to have started as a dish made only of fermented black lentil. One description circa 1025 A.D. says the lentils were first soaked in buttermilk, and after grinding, seasoned with black pepper, coriander, cumin and asafoetida. The Kannada king and scholar Someshwara III, reigning in the area now called Karnataka, included an idli recipe in his encyclopedia, the Manasollasa, written in Sanskrit ca. 1130 A.D. There is no known record of rice being added until some time in the 17th century. It may have been found that the rice helped speed the fermentation process. Although the idli changed in ingredients, the preparation process and the name remained the same. # Preparation To prepare the classic idlis, two parts uncooked rice to one part split black lentil (Urad dal) are soaked until they can be ground to a paste in a heavy stone grinding vessel, the attu kal. This paste is allowed to ferment overnight, until about 2-1/2 times its original volume. In the morning, the idli batter is put into the ghee-greased molds of an idli tray or "tree" for steaming. This typically has several metal trays in tiers on a central support, with three or four round indentations per tray. These molds are perforated to allow the idlis to be cooked evenly. The tree holds the trays above the level of boiling water in a pot, and the pot is covered until the idlis are done, in 10-25 minutes, depending on size. The idli's pancake-like (or crepe-like) cousin is the dosa. # Contemporary Idlis and variations Southern Indians have brought the popular idli wherever they have settled throughout the world. Cooks have had to solve problems of hard-to-get ingredients, and climates that do not encourage overnight fermentation. One cook noted that idli batter, foaming within a few hours in India, might take several days to rise in Britain. The traditional heavy stones used to wet-grind the rice and dal are not easily transported. Access to Indian ingredients before the advent of Internet mail order could be virtually impossible in many places. Chlorinated water and iodized salt interfere with fermentation. Newer "quick" recipes for the idli can be rice- or wheat-based (rava idli). Parboiled rice, such as Uncle Ben's can reduce the soaking time considerably. Store-bought ground rice is available, or Cream of Rice may be used. Similarly, semolina or Cream of Wheat may be used for rava idli. Yoghurt may be added to provide the sour flavor for unfermented batters. Prepackaged mixes allow for almost instant idlis, for the truly desperate. Idli Burger is another variation that can be made easily. Besides the microwave steamer, electric idli steamers are available, with automatic steam release and shut-off for perfect cooking. Both types are non-stick, so a fat-free idli is possible. Table-mounted electric Wet grinders may take the place of floor-bound attu kal. With these appliances, even the classic idlis can be made more easily. The plain rice/black lentil idli continues to be the popular version, but it may also incorporate a variety of extra ingredients, savory or sweet. Mustard seeds, fresh chile peppers, black pepper, cumin, coriander seed and its fresh leaf form (cilantro), fenugreek seeds, curry leaves (neem), fresh ginger root, sesame seeds, nuts, garlic, scallions, coconut, and the unrefined sugar jaggery are all possibilities. Filled idlis contain small amounts of chutneys, sambars, or sauces placed inside before steaming. A variety of idlis are experimented these days, namely, standard idli, mini idlis soaked in sambar, rava idli, Kancheepuram idli, stuffed idli with a filling of potato, beans, carrot and masala, ragi idli, pudi idli with the sprinkling of chutney pudi that covers the bite-sized pieces of idlis, malli idli shallow-fried with coriander and curry leaves, and curd idli dipped in masala curds. # Picture gallery - Idli and Vada served with sambar and two type of chutneys (green and red) on banana leaf. Idli and Vada served with sambar and two type of chutneys (green and red) on banana leaf. - The South Indian staple breakfast item of idly, sambar, and vada served on a banana leaf. Note the stainless steel plates and cups; characteristics of south Indian dining tables. The South Indian staple breakfast item of idly, sambar, and vada served on a banana leaf. Note the stainless steel plates and cups; characteristics of south Indian dining tables. - Tatte Idli: variations from Karnataka Tatte Idli: variations from Karnataka - Sambar idly: Idly soaked in sambar. Chutney is the best companion for this dish. Sambar idly: Idly soaked in sambar. Chutney is the best companion for this dish. - MTR idly: Famous Mavalli Tiffin Room idly served with pure ghee and sambar. Pure Ghee is poured on seaming edli and relished with chutney or sambar. MTR idly: Famous Mavalli Tiffin Room idly served with pure ghee and sambar. Pure Ghee is poured on seaming edli and relished with chutney or sambar.

https://www.wikidoc.org/index.php/Idli

c35b325f044c0f5a46f2681e70a0cd789bf80276

wikidoc

Inch

Inch An inch (plural: inches; symbol or abbreviation: in or, sometimes,  ″ — U+2033 - a double prime) is the name of a unit of length in a number of different systems, including English units, Imperial units, and United States customary units. Its size can vary from system to system. There are 36 inches in a yard and 12 inches in a foot. A corresponding unit of area is the square inch and a corresponding unit of volume is the cubic inch. The inch is one of the dominant units of measurement in the United States, and is commonly used in Canada. In the US and commonly in the UK and Canada, personal heights are expressed in feet and inches by people of all ages, and by people over the age of about 40 in Australia. In Australia, Canada and New Zealand, personal heights are shown in metric units on official documents. # International inch In 1959 the United States and countries of the Commonwealth of Nations defined the length of the international yard to be exactly 0.9144 meters. Consequently, the international inch is defined to be exactly 25.4 millimeters. The international standard symbol for inch is in (see ISO 31-1, Annex A). In some cases, the inch is denoted by a double prime, which is often approximated by double quotes, and the foot by a prime, which is often approximated by an apostrophe. For example, 6 feet 4 inches is denoted as 6′4″ (or approximated as 6'4").

Inch Template:Unit of length An inch (plural: inches; symbol or abbreviation: in or, sometimes,  ″ — U+2033 - a double prime) is the name of a unit of length in a number of different systems, including English units, Imperial units, and United States customary units. Its size can vary from system to system. There are 36 inches in a yard and 12 inches in a foot. A corresponding unit of area is the square inch and a corresponding unit of volume is the cubic inch. The inch is one of the dominant units of measurement in the United States, and is commonly used in Canada. In the US and commonly in the UK and Canada, personal heights are expressed in feet and inches by people of all ages, and by people over the age of about 40 in Australia. In Australia, Canada and New Zealand, personal heights are shown in metric units on official documents. # International inch In 1959 the United States and countries of the Commonwealth of Nations defined the length of the international yard to be exactly 0.9144 meters[1]. Consequently, the international inch is defined to be exactly 25.4 millimeters. The international standard symbol for inch is in (see ISO 31-1, Annex A). In some cases, the inch is denoted by a double prime, which is often approximated by double quotes, and the foot by a prime, which is often approximated by an apostrophe. For example, 6 feet 4 inches is denoted as 6′4″ (or approximated as 6'4").

https://www.wikidoc.org/index.php/Inch

4feea14d922598b68819273d2336e999073fbc39

wikidoc

JAG1

JAG1 Jagged1 (JAG1) is one of five cell surface proteins (ligands) that interact with 4 receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved pathway that functions to establish and regulate cell fate decisions in many organ systems. Once the JAG1-NOTCH (receptor-ligand) interactions take place, a cascade of proteolytic cleavages is triggered resulting in activation of the transcription for downstream target genes. Located on human chromosome 20, the JAG1 gene is expressed in multiple organ systems in the body and causes the autosomal dominant disorder Alagille syndrome (ALGS) resulting from loss of function mutations within the gene. JAG1 has also been designated as CD339 (cluster of differentiation 339). # Structure and function JAG1 was first identified as a ligand that was able to activate notch receptors when it was cloned in the mammalian rat in 1995. It is located at cytogenetic location 20p12.2 and genomic location (GRCh37) chr20:10,618,331-10,654,693 on the human chromosome 20. The structure of the JAG1 protein includes a small intracellular component, a transmembrane motif, proceeded by an extracellular region containing a cystine-rich region, 16 EGF-like repeats, a DSL domain, and finally a signal peptide totaling 1218 amino acids in length over 26 coding exons. The JAG1 protein encoded by JAG1 is the human homolog of the Drosophilia jagged protein. Human JAG1 is one of five ligands for receptors in the NOTCH signaling pathway which helps to determine cellular fate and is active during many developmental stages. The extracellular component of the JAG1 protein physically interacts with its respective Notch receptor. This interaction kicks off a cascade of proteolytic cleavages leading to the original NOTCH intracellular domain being trafficked into the nucleus of the cell leading to the activation of different target genes. # Expression profile and mouse studies In situ hybridization and conditional gene knockout studies have helped to demonstrate the role JAG1 plays in development and its effects on different organ systems. In humans, JAG1 has broad expression in many tissue types including the pancreas, heart, placenta, prostate, lung, kidney, thymus, testis, and leucocytes in the adult. In a developing embryo JAG1 expression is concentrated around the pulmonary artery, mesocardium, distal cardic outflow tract, major arteries, metanephros, branchial arches, pancreas, the portal vein, and otocyst. Generally, JAG1 expression patterns correlate with organ systems affected in ALGS, although it is important to note that not all tissues where JAG1 is expressed are affected in ALGS. More recently JAG1 expression has been found to be altered in breast cancer and adrenocortical carcinoma patients. Mouse models where the Jag1 gene is turned off in certain tissues (conditional knockout mouse models) have been used to study the role of Jag1 in many tissue specific areas. While homozygous deletions of Jag1 have been shown to be embryonic lethal in mice, and heterozygous deletions may show only a limited phenotype (involving the eye), mice haploinsufficient for both Jag1 and Notch2 present with the ALGS phenotype. Conditional gene knockout mouse models with Jag1 mutations targeted to the portal vein mesenchyme, endothelium, and cranial neural crest all exhibit features classic to those in individuals with ALGS, highlighting the role of this tissue type in disease origins # Disease phenotype ALGS is an autosomal dominant multi-system disorder affecting several body systems including the liver, heart, skeleton, eye, facial structure, kidneys and vascular system. The most clinically significant concerns stem from liver, heart, vascular or renal problems. Mutations in JAG1 were first discovered to be responsible for ALGS by researchers at The Children's Hospital of Philadelphia and the National Institutes of Health in 1997. Patients who are clinically consistent with the disorder usually have a mutation in JAG1 (94%), while a smaller 2% have a mutation in NOTCH2. Over half of individuals with mutations in the gene did not inherit it from either parent, and thus have a de novo mutation. JAG1 mutation types include protein truncating (splice site, frameshift, and nonsense), missense, and whole gene deletions accounting for 80%, 7%, and 12% respectively. Since all mutation types lead to a patient phenotype, it is thought that haploinsufficiency for JAG1 is the likely disease mechanism of action. Although individuals can have a range of mutation types in JAG1, all of the known mutations lead to loss of the function of one copy, and, there is no correlation between mutation type or location and disease severity. Though individuals with ALGS have several body systems affected, there is a subset of individuals with JAG1 mutations who present with tetralogy of fallot/pulmonary stenosis that do not show the other clinical signs of the syndrome. Given the variable expressivity of the disease, there may be other genetic or environmental modifiers present beyond the original JAG1 mutation. More recently, JAG1 expression changes have been implicated in many types of cancer. Specifically, up regulation of JAG1 has been correlated with both poor overall breast cancer survival rates and an enhancement of tumor proliferation in adrenocortical carcinoma patients.

JAG1 Jagged1 (JAG1) is one of five cell surface proteins (ligands) that interact with 4 receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved pathway that functions to establish and regulate cell fate decisions in many organ systems. Once the JAG1-NOTCH (receptor-ligand) interactions take place, a cascade of proteolytic cleavages is triggered resulting in activation of the transcription for downstream target genes. Located on human chromosome 20, the JAG1 gene is expressed in multiple organ systems in the body and causes the autosomal dominant disorder Alagille syndrome (ALGS) resulting from loss of function mutations within the gene. JAG1 has also been designated as CD339 (cluster of differentiation 339). # Structure and function JAG1 was first identified as a ligand that was able to activate notch receptors when it was cloned in the mammalian rat in 1995.[1] It is located at cytogenetic location 20p12.2 and genomic location (GRCh37) chr20:10,618,331-10,654,693 on the human chromosome 20.[2] The structure of the JAG1 protein includes a small intracellular component, a transmembrane motif, proceeded by an extracellular region containing a cystine-rich region, 16 EGF-like repeats, a DSL domain, and finally a signal peptide totaling 1218 amino acids in length over 26 coding exons.[3] The JAG1 protein encoded by JAG1 is the human homolog of the Drosophilia jagged protein.[1] Human JAG1 is one of five ligands for receptors in the NOTCH signaling pathway which helps to determine cellular fate and is active during many developmental stages. The extracellular component of the JAG1 protein physically interacts with its respective Notch receptor. This interaction kicks off a cascade of proteolytic cleavages leading to the original NOTCH intracellular domain being trafficked into the nucleus of the cell leading to the activation of different target genes.[4][5][6][7] # Expression profile and mouse studies In situ hybridization and conditional gene knockout studies have helped to demonstrate the role JAG1 plays in development and its effects on different organ systems. In humans, JAG1 has broad expression in many tissue types including the pancreas, heart, placenta, prostate, lung, kidney, thymus, testis, and leucocytes in the adult.[8] In a developing embryo JAG1 expression is concentrated around the pulmonary artery, mesocardium, distal cardic outflow tract, major arteries, metanephros, branchial arches, pancreas, the portal vein, and otocyst.[8] Generally, JAG1 expression patterns correlate with organ systems affected in ALGS, although it is important to note that not all tissues where JAG1 is expressed are affected in ALGS. More recently JAG1 expression has been found to be altered in breast cancer and adrenocortical carcinoma patients.[9][10] Mouse models where the Jag1 gene is turned off in certain tissues (conditional knockout mouse models) have been used to study the role of Jag1 in many tissue specific areas. While homozygous deletions of Jag1 have been shown to be embryonic lethal in mice, and heterozygous deletions may show only a limited phenotype (involving the eye), mice haploinsufficient for both Jag1 and Notch2 present with the ALGS phenotype.[11] Conditional gene knockout mouse models with Jag1 mutations targeted to the portal vein mesenchyme, endothelium, and cranial neural crest all exhibit features classic to those in individuals with ALGS, highlighting the role of this tissue type in disease origins[12][13][14][15][16] # Disease phenotype ALGS is an autosomal dominant multi-system disorder affecting several body systems including the liver, heart, skeleton, eye, facial structure, kidneys and vascular system. The most clinically significant concerns stem from liver, heart, vascular or renal problems. Mutations in JAG1 were first discovered to be responsible for ALGS by researchers at The Children's Hospital of Philadelphia and the National Institutes of Health in 1997.[2] Patients who are clinically consistent with the disorder usually have a mutation in JAG1 (94%), while a smaller 2% have a mutation in NOTCH2.[17] Over half of individuals with mutations in the gene did not inherit it from either parent, and thus have a de novo mutation.[17][18] JAG1 mutation types include protein truncating (splice site, frameshift, and nonsense), missense, and whole gene deletions accounting for 80%, 7%, and 12% respectively. Since all mutation types lead to a patient phenotype, it is thought that haploinsufficiency for JAG1 is the likely disease mechanism of action.[19][20][21] Although individuals can have a range of mutation types in JAG1, all of the known mutations lead to loss of the function of one copy, and, there is no correlation between mutation type or location and disease severity. Though individuals with ALGS have several body systems affected, there is a subset of individuals with JAG1 mutations who present with tetralogy of fallot/pulmonary stenosis that do not show the other clinical signs of the syndrome.[22] Given the variable expressivity of the disease, there may be other genetic or environmental modifiers present beyond the original JAG1 mutation. More recently, JAG1 expression changes have been implicated in many types of cancer. Specifically, up regulation of JAG1 has been correlated with both poor overall breast cancer survival rates and an enhancement of tumor proliferation in adrenocortical carcinoma patients.[9][23][24][25]

https://www.wikidoc.org/index.php/JAG1

3967d5cc9d422c83cb7f4018e7206cf1aea72e54

wikidoc

JAM2

JAM2 Junctional adhesion molecule B is a protein that in humans is encoded by the JAM2 gene. JAM2 has also been designated as CD322 (cluster of differentiation 322). # Function Tight junctions represent one mode of cell-to-cell adhesion in endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. The protein encoded by this immunoglobulin superfamily gene member is localized in the tight junctions between high endothelial cells. It acts as an adhesive ligand for interacting with a variety of immune cell types and may play a role in lymphocyte homing to secondary lymphoid organs. It is purported to promote lymphocyte transendothelial migration. It might also be involved with endothelial cell polarity, by associating to cell polarity protein PAR-3, together with JAM3. # Interactions JAM2 has been shown to interact with PARD3. It also interacts with the integrin dimer VLA-4 (also called α4β1).

JAM2 Junctional adhesion molecule B is a protein that in humans is encoded by the JAM2 gene.[1][2][3] JAM2 has also been designated as CD322 (cluster of differentiation 322). # Function Tight junctions represent one mode of cell-to-cell adhesion in endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. The protein encoded by this immunoglobulin superfamily gene member is localized in the tight junctions between high endothelial cells. It acts as an adhesive ligand for interacting with a variety of immune cell types and may play a role in lymphocyte homing to secondary lymphoid organs.[3] It is purported to promote lymphocyte transendothelial migration.[4] It might also be involved with endothelial cell polarity, by associating to cell polarity protein PAR-3, together with JAM3.[5] # Interactions JAM2 has been shown to interact with PARD3.[5] It also interacts with the integrin dimer VLA-4 (also called α4β1).[6]

https://www.wikidoc.org/index.php/JAM2

7a34852be28c96ef1b17734b20955ed166a93526

wikidoc

JAM3

JAM3 Junctional adhesion molecule C is a protein that in humans is encoded by the JAM3 gene. # Gene This gene is located on the long arm of chromosome 11 (11q25) on the Watson strand. It is 83,077 bases in length. The encoded protein is 310 amino acids long with a predicted molecular weight of 35.02 kiloDaltons. # Function Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. The protein encoded by this immunoglobulin superfamily gene member is localized in the tight junctions between high endothelial cells. Unlike other proteins in this family, this protein is unable to adhere to leukocyte cell lines and only forms weak homotypic interactions. The encoded protein is a member of the junctional adhesion molecule protein family and acts as a receptor for another member of this family. # Interactions JAM3 has been shown to interact with PARD3. # Clinical significance Mutations in this gene have been associated with a rare syndrome - autosomal recessive hemorrhagic destruction of the brain, subependymal calcification and congenital cataracts.

JAM3 Junctional adhesion molecule C is a protein that in humans is encoded by the JAM3 gene.[1] # Gene This gene is located on the long arm of chromosome 11 (11q25) on the Watson strand. It is 83,077 bases in length. The encoded protein is 310 amino acids long with a predicted molecular weight of 35.02 kiloDaltons. # Function Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. The protein encoded by this immunoglobulin superfamily gene member is localized in the tight junctions between high endothelial cells. Unlike other proteins in this family, this protein is unable to adhere to leukocyte cell lines and only forms weak homotypic interactions. The encoded protein is a member of the junctional adhesion molecule protein family and acts as a receptor for another member of this family.[1] # Interactions JAM3 has been shown to interact with PARD3.[2] # Clinical significance Mutations in this gene have been associated with a rare syndrome - autosomal recessive hemorrhagic destruction of the brain, subependymal calcification and congenital cataracts.[3]

https://www.wikidoc.org/index.php/JAM3

985d3212f84fe6af57fa63171afad6adcc8a376e

wikidoc

JP-8

JP-8 # Overview JP-8, or JP8 (for "Jet Propellant 8") is a jet fuel, specified and used widely by the US military. It is specified by MIL-DTL-83133 and British Defence Standard 91-87, and similar to commercial aviation's Jet-A. A kerosene-based fuel, JP-8 is projected to remain in use at least until 2025. It was first introduced at NATO bases in 1978. Its NATO code is F-34. # Usage It was specified in 1990 by the U.S. government as a replacement for government diesel fueled vehicles. The U.S. Air Force replaced JP-4 with JP-8 completely by the fall of 1996, to use a less flammable, less hazardous fuel for better safety and combat survivability. The U.S. Navy uses a similar formula, JP-5. JP-5 has an even higher flash point of > 60 °C (140 °F), but also a higher cost, limiting its use to aircraft carriers and other situations where the danger of fire is greatest. Outside of powering aircraft, JP-8 is used as a fuel for heaters, stoves, tanks, by the U.S. military as a replacement for diesel fuel in the engines of nearly all tactical ground vehicles and electrical generators, and as a coolant in engines and some other aircraft components. The use of a single fuel greatly simplifies logistics. JP-8 is formulated with icing inhibitor, corrosion inhibitors, lubricants, and antistatic agents, and less benzene (a carcinogen) and less n-hexane (a neurotoxin) than JP-4. However, it also smells stronger than JP-4. JP-8 has an oily feel to the touch, while JP-4 feels more like a solvent. # Problems When used in highly supercharged diesel engines with the corresponding low compression ratio of about only 14:1 or below, JP-8 causes troubles during cold start and idling due to low compression temperatures and following ignition delay because cetane index is not specified in MIL-DTL-83133G to 40 or higher. Because lubricity to the BOCLE method is not specified in MIL-DTL-83133G, modern common rail diesel engines can experience wear problems in high pressure fuel pumps and injectors. Another problem in diesel engines can be the increased wear in outlet valve seats in the cylinder heads, because a minimum content of sulfur is not specified in MIL-DTL-83133G. Sulfur in fuels contributes normally to build up damping soot layers in these valve seats. According to the notes in this standard it is intended to install a value for the cetane index in one of the next releases. Workers have complained of smelling and tasting JP-8 for hours after exposure. As JP-8 is less volatile, it remains on the contaminated surfaces for longer time, increasing the risk of exposure. # Variants JP-8+100 (F-37) is a version of JP-8 with an additive that increases its thermal stability by 56°C (a difference of 100°F). The additive is a combination of a surfactant, metal deactivator, and an antioxidant, and was introduced in 1994 to reduce choking and fouling in engine fuel systems. Commercially, this additive is used in Boeing aircraft operated by KLM, and in police helicopters in Tampa, Florida. JP-8+100 is also used for Canadian Forces CP-140 Aurora & CC-130 Hercules aircraft.

JP-8 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview JP-8, or JP8 (for "Jet Propellant 8") is a jet fuel, specified and used widely by the US military. It is specified by MIL-DTL-83133 and British Defence Standard 91-87, and similar to commercial aviation's Jet-A. A kerosene-based fuel, JP-8 is projected to remain in use at least until 2025. It was first introduced at NATO bases in 1978. Its NATO code is F-34. # Usage It was specified in 1990 by the U.S. government as a replacement for government diesel fueled vehicles. The U.S. Air Force replaced JP-4 with JP-8 completely by the fall of 1996, to use a less flammable, less hazardous fuel for better safety and combat survivability. The U.S. Navy uses a similar formula, JP-5. JP-5 has an even higher flash point of > 60 °C (140 °F), but also a higher cost, limiting its use to aircraft carriers and other situations where the danger of fire is greatest. Outside of powering aircraft, JP-8 is used as a fuel for heaters, stoves,[1] tanks,[2] by the U.S. military as a replacement for diesel fuel in the engines of nearly all tactical ground vehicles and electrical generators, and as a coolant in engines and some other aircraft components. The use of a single fuel greatly simplifies logistics. JP-8 is formulated with icing inhibitor, corrosion inhibitors, lubricants, and antistatic agents, and less benzene (a carcinogen) and less n-hexane (a neurotoxin) than JP-4. However, it also smells stronger than JP-4. JP-8 has an oily feel to the touch, while JP-4 feels more like a solvent. # Problems When used in highly supercharged diesel engines with the corresponding low compression ratio of about only 14:1 or below, JP-8 causes troubles during cold start and idling due to low compression temperatures and following ignition delay because cetane index is not specified in MIL-DTL-83133G to 40 or higher. Because lubricity to the BOCLE method is not specified in MIL-DTL-83133G, modern common rail diesel engines can experience wear problems in high pressure fuel pumps and injectors. Another problem in diesel engines can be the increased wear in outlet valve seats in the cylinder heads, because a minimum content of sulfur is not specified in MIL-DTL-83133G. Sulfur in fuels contributes normally to build up damping soot layers in these valve seats. According to the notes in this standard it is intended to install a value for the cetane index in one of the next releases. Workers have complained of smelling and tasting JP-8 for hours after exposure. As JP-8 is less volatile, it remains on the contaminated surfaces for longer time, increasing the risk of exposure.[3] # Variants JP-8+100 (F-37) is a version of JP-8 with an additive that increases its thermal stability by 56°C (a difference of 100°F). The additive is a combination of a surfactant, metal deactivator, and an antioxidant, and was introduced in 1994 to reduce choking and fouling in engine fuel systems. Commercially, this additive is used in Boeing aircraft operated by KLM, and in police helicopters in Tampa, Florida.[citation needed] JP-8+100 is also used for Canadian Forces CP-140 Aurora & CC-130 Hercules aircraft.

https://www.wikidoc.org/index.php/JP-8

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JPH2

JPH2 Junctophilin 2, also known as JPH2, is a protein which in humans is encoded by the JPH2 gene. Alternative splicing has been observed at this locus and two variants encoding distinct isoforms are described. # Function Junctional complexes between the plasma membrane and endoplasmic/sarcoplasmic reticulum are a common feature of all excitable cell types and mediate cross talk between cell surface and intracellular ion channels. The protein encoded by this gene is a component of junctional complexes and is composed of a C-terminal hydrophobic segment spanning the endoplasmic/sarcoplasmic reticulum membrane and a remaining cytoplasmic membrane occupation and recognition nexus (MORN) domain that shows specific affinity for the plasma membrane. JPH2 is a member of the junctophilin gene family (the other members of the family are JPH1, JPH3, and JPH4) and is the predominant isoform in cardiac tissue, but is also expressed with JPH1 in skeletal muscle. The JPH2 protein product plays a critical role in maintaining the spacing a geometry of the cardiac dyad - the space between the plasma membrane and sarcoplasmic reticulum. These cardiac dyads also known as junctional membrane complexes or calcium release units are thought to play a key role in calcium induced calcium release by approximating L-type calcium channels on the plasma membrane and ryanodine receptor type 2 on the sarcoplasmic reticulum. # Role in Disease Mutations in JPH2 were identified in a cohort of patients with hypertrophic cardiomyopathy who lacked the traditional mutations in sarcomere proteins. JPH2 has been shown to be downregulated in several animal models of heart failure. A JPH2 knock-out mouse model is lethal at embryonic day 10.5, which is around the time when cardiac contractility should initiate. These mice showed abnormal cardiac calcium handling, cardiomyopathy, and altered junctional membrane complex formation.

JPH2 Junctophilin 2, also known as JPH2, is a protein which in humans is encoded by the JPH2 gene.[1][2][3] Alternative splicing has been observed at this locus and two variants encoding distinct isoforms are described. # Function Junctional complexes between the plasma membrane and endoplasmic/sarcoplasmic reticulum are a common feature of all excitable cell types and mediate cross talk between cell surface and intracellular ion channels. The protein encoded by this gene is a component of junctional complexes and is composed of a C-terminal hydrophobic segment spanning the endoplasmic/sarcoplasmic reticulum membrane and a remaining cytoplasmic membrane occupation and recognition nexus (MORN) domain that shows specific affinity for the plasma membrane. JPH2 is a member of the junctophilin gene family (the other members of the family are JPH1, JPH3, and JPH4) and is the predominant isoform in cardiac tissue, but is also expressed with JPH1 in skeletal muscle.[4] The JPH2 protein product plays a critical role in maintaining the spacing a geometry of the cardiac dyad - the space between the plasma membrane and sarcoplasmic reticulum.[1] These cardiac dyads also known as junctional membrane complexes or calcium release units are thought to play a key role in calcium induced calcium release by approximating L-type calcium channels on the plasma membrane and ryanodine receptor type 2 on the sarcoplasmic reticulum. # Role in Disease Mutations in JPH2 were identified in a cohort of patients with hypertrophic cardiomyopathy who lacked the traditional mutations in sarcomere proteins.[5] JPH2 has been shown to be downregulated in several animal models of heart failure. A JPH2 knock-out mouse model is lethal at embryonic day 10.5, which is around the time when cardiac contractility should initiate. These mice showed abnormal cardiac calcium handling, cardiomyopathy, and altered junctional membrane complex formation.

https://www.wikidoc.org/index.php/JPH2

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JunD

JunD Transcription factor JunD is a protein that in humans is encoded by the JUND gene. # Function The protein encoded by this intronless gene is a member of the JUN family, and a functional component of the AP1 transcription factor complex. It has been proposed to protect cells from p53-dependent senescence and apoptosis. Alternate translation initiation site usage results in the production of different isoforms. # ΔJunD The dominant negative mutant variant of JunD, known as ΔJunD or Delta JunD, is a potent antagonist of the ΔFosB transcript, as well as other forms of AP-1-mediated transcriptional activity. In the nucleus accumbens, ΔJunD directly opposes many of the neurological changes that occur in addiction (i.e., those induced by ΔFosB). ΔFosB inhibitors (drugs that oppose its action) may be an effective treatment for addiction and addictive disorders. # Interactions JunD has been shown to interact with ATF3, MEN1, DNA damage-inducible transcript 3 and BRCA1.

JunD Transcription factor JunD is a protein that in humans is encoded by the JUND gene.[1][2] # Function The protein encoded by this intronless gene is a member of the JUN family, and a functional component of the AP1 transcription factor complex. It has been proposed to protect cells from p53-dependent senescence and apoptosis. Alternate translation initiation site usage results in the production of different isoforms.[3] # ΔJunD The dominant negative mutant variant of JunD, known as ΔJunD or Delta JunD, is a potent antagonist of the ΔFosB transcript, as well as other forms of AP-1-mediated transcriptional activity.[4][5][6] In the nucleus accumbens, ΔJunD directly opposes many of the neurological changes that occur in addiction (i.e., those induced by ΔFosB).[5][6] ΔFosB inhibitors (drugs that oppose its action) may be an effective treatment for addiction and addictive disorders.[7] # Interactions JunD has been shown to interact with ATF3,[8] MEN1,[9] DNA damage-inducible transcript 3[10] and BRCA1.[11]

https://www.wikidoc.org/index.php/JUND

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KAT5

KAT5 Histone acetyltransferase KAT5 is an enzyme that in humans is encoded by the KAT5 gene. It is also commonly identified as TIP60. The protein encoded by this gene belongs to the MYST family of histone acetyl transferases (HATs) and was originally isolated as an HIV-1 TAT-interactive protein. HATs play important roles in regulating chromatin remodeling, transcription and other nuclear processes by acetylating histone and nonhistone proteins. This protein is a histone acetylase that has a role in DNA repair and apoptosis and is thought to play an important role in signal transduction. Alternative splicing of this gene results in multiple transcript variants. # Structure The structure of KAT5 includes an acetyl CoA binding domain and a zinc finger in the MYST domain, and a CHROMO domain. Excess acetyl CoA is necessary for acetylation of histones. The zinc finger domain has been shown to aid in the acetylation process as well. The CHROMO domain aids in KAT5 ability to bind chromatin, which is important for DNA repair. # Function KAT5 enzyme is known for acetylating histones in the nucleosome, which alters binding with DNA. Acetylation neutralizes the positive charge on histones, decreasing binding affinity of negatively charged DNA. This in turn decreases steric hindrance of DNA and increases interaction of transcription factors and other proteins. Three key functions of KAT5 are its ability to regulate transcription, DNA repair, and apoptosis. ## Transcription Transcription factors such as E2F proteins and c-Myc can regulate the expression of proteins, particularly those involved with the cell cycle. KAT5 acetylates histones on genes of these transcription factors, which promote their activity. ## DNA repair KAT5 is an important enzyme for repairing DNA and returning cellular function to normal through its regulation of ataxia telangiectasia mutant (ATM) protein kinase. ATM protein kinase phosphorylates and therefore activates proteins involved in DNA repair. However, to be functional, ATM protein kinase must be acetylated by the KAT5 protein. Lack of KAT5 suppresses ATM protein kinase activity and reduces the ability of a cell to correct its DNA. KAT5 also works later in the DNA repair process, as it serves as a cofactor for TRRAP. TRRAP enhances DNA remodeling by binding to chromatin near broken double stranded DNA sequences. KAT5 aids this recognition. ## Apoptosis P53 is well known for causing cell apoptosis after DNA damage. Acetylation of p53 by KAT5 induces this cell death. Therefore, lack of KAT5 allows cells with damaged DNA to avoid apoptosis and continue dividing. # Regulation KAT5 catalytic activity is regulated by the phosphorylation of its histones during the G2/M phase of the cell cycle. Phosphorylation of KAT5 serines 86 and 90 reduces its activity. Therefore, cancer cells with uncontrolled growth and improper G2/M checkpoints lack KAT5 regulation by cyclin dependent kinase (CDK) phosphorylation. # Clinical relevance KAT5 has many clinically significant implications that make it a useful target for diagnostic or therapeutic approaches. Most notably, KAT5 helps to regulate cancers, HIV, and neurodegenerative diseases. ## Cancer As mentioned above, KAT5 helps to repair DNA and upregualte tumor suppressors such as p53. Therefore, many cancers are marked by a reduction of KAT5 mRNA. KAT5 also is linked to metastasis and malignancy. - Colon cancer - Lung cancer - Breast cancer - Pancreatic - Gastric cancer - Metastatic melanoma Studies have also shown that KAT5 augmented the ability of chemotherapy to stop tumor growth, demonstrating its potential for use in combination therapy. However, KAT5 isn’t always anti-cancer. It can enhance the activity of proteins for viruses that cause cancer such as human T-cell lymphotropic virus type-1 (HTLV), which may result in leukemia and lymphoma. Additionally, KAT5 reacts with human papillomavirus (HPV), the virus responsible for cervical cancer. Other proteins that KAT5 promotes may lead to cancer as well. For example, overexpressed E2F1, a transcriptional factor, is implicated in melanoma progression. More research needs to be performed to clearly elucidate the overall role KAT5 has in cancer. ## HIV KAT5 binds to HIV-1 Tat transactivator and helps to promote HIV replication. # Interactions HTATIP has been shown to interact with: - Androgen receptor, - BCL3, - CREB1, - ETV6, - EDNRA - FANCD2, - HDAC7A, - Mdm2, - Myc, and - PLA2G4A.

KAT5 Histone acetyltransferase KAT5 is an enzyme that in humans is encoded by the KAT5 gene.[1][2] It is also commonly identified as TIP60. The protein encoded by this gene belongs to the MYST family of histone acetyl transferases (HATs) and was originally isolated as an HIV-1 TAT-interactive protein. HATs play important roles in regulating chromatin remodeling, transcription and other nuclear processes by acetylating histone and nonhistone proteins. This protein is a histone acetylase that has a role in DNA repair and apoptosis and is thought to play an important role in signal transduction. Alternative splicing of this gene results in multiple transcript variants.[2] # Structure The structure of KAT5 includes an acetyl CoA binding domain and a zinc finger in the MYST domain, and a CHROMO domain.[3] Excess acetyl CoA is necessary for acetylation of histones. The zinc finger domain has been shown to aid in the acetylation process as well.[4] The CHROMO domain aids in KAT5 ability to bind chromatin, which is important for DNA repair.[5] # Function KAT5 enzyme is known for acetylating histones in the nucleosome, which alters binding with DNA. Acetylation neutralizes the positive charge on histones, decreasing binding affinity of negatively charged DNA.[6] This in turn decreases steric hindrance of DNA and increases interaction of transcription factors and other proteins. Three key functions of KAT5 are its ability to regulate transcription, DNA repair, and apoptosis. ## Transcription Transcription factors such as E2F proteins and c-Myc can regulate the expression of proteins, particularly those involved with the cell cycle.[7][8] KAT5 acetylates histones on genes of these transcription factors, which promote their activity. ## DNA repair KAT5 is an important enzyme for repairing DNA and returning cellular function to normal through its regulation of ataxia telangiectasia mutant (ATM) protein kinase.[9] ATM protein kinase phosphorylates and therefore activates proteins involved in DNA repair. However, to be functional, ATM protein kinase must be acetylated by the KAT5 protein. Lack of KAT5 suppresses ATM protein kinase activity and reduces the ability of a cell to correct its DNA. KAT5 also works later in the DNA repair process, as it serves as a cofactor for TRRAP.[10] TRRAP enhances DNA remodeling by binding to chromatin near broken double stranded DNA sequences. KAT5 aids this recognition. ## Apoptosis P53 is well known for causing cell apoptosis after DNA damage. Acetylation of p53 by KAT5 induces this cell death.[7] Therefore, lack of KAT5 allows cells with damaged DNA to avoid apoptosis and continue dividing. # Regulation KAT5 catalytic activity is regulated by the phosphorylation of its histones during the G2/M phase of the cell cycle.[11] Phosphorylation of KAT5 serines 86 and 90 reduces its activity. Therefore, cancer cells with uncontrolled growth and improper G2/M checkpoints lack KAT5 regulation by cyclin dependent kinase (CDK) phosphorylation. # Clinical relevance KAT5 has many clinically significant implications that make it a useful target for diagnostic or therapeutic approaches. Most notably, KAT5 helps to regulate cancers, HIV, and neurodegenerative diseases.[3] ## Cancer As mentioned above, KAT5 helps to repair DNA and upregualte tumor suppressors such as p53. Therefore, many cancers are marked by a reduction of KAT5 mRNA. KAT5 also is linked to metastasis and malignancy.[12] - Colon cancer[13] - Lung cancer[7] - Breast cancer[14] - Pancreatic[14] - Gastric cancer[15] - Metastatic melanoma[12] Studies have also shown that KAT5 augmented the ability of chemotherapy to stop tumor growth, demonstrating its potential for use in combination therapy.[14] However, KAT5 isn’t always anti-cancer. It can enhance the activity of proteins for viruses that cause cancer such as human T-cell lymphotropic virus type-1 (HTLV), which may result in leukemia and lymphoma.[16] Additionally, KAT5 reacts with human papillomavirus (HPV), the virus responsible for cervical cancer.[17] Other proteins that KAT5 promotes may lead to cancer as well. For example, overexpressed E2F1, a transcriptional factor, is implicated in melanoma progression.[18] More research needs to be performed to clearly elucidate the overall role KAT5 has in cancer. ## HIV KAT5 binds to HIV-1 Tat transactivator and helps to promote HIV replication.[19] # Interactions HTATIP has been shown to interact with: - Androgen receptor,[20] - BCL3,[21] - CREB1,[22] - ETV6,[23] - EDNRA[24] - FANCD2,[25] - HDAC7A,[26] - Mdm2,[27] - Myc,[28] and - PLA2G4A.[29]

https://www.wikidoc.org/index.php/KAT5

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wikidoc

KLC1

KLC1 Kinesin light chain 1 is a protein that in humans is encoded by the KLC1 gene. Conventional kinesin is a tetrameric molecule composed of two heavy chains and two light chains, and transports various cargos along microtubules toward their plus ends. The heavy chains provide the motor activity, while the light chains bind to various cargos. This gene encodes a member of the kinesin light chain family. It associates with kinesin heavy chain through an N-terminal domain, and six tetratricopeptide repeat (TPR) motifs are thought to be involved in binding of cargos such as vesicles, mitochondria, and the Golgi complex. Thus, kinesin light chains function as adapter molecules and not motors per se. Although previously named "kinesin 2", this gene is not a member of the kinesin-2 / kinesin heavy chain subfamily of kinesin motor proteins. Extensive alternative splicing produces isoforms with different C-termini that are proposed to bind to different cargos; however, the full-length nature of some of these variants has not been determined. # Interactions KLC1 has been shown to interact with MAPK8IP3, KIF5B and KIF5A.

KLC1 Kinesin light chain 1 is a protein that in humans is encoded by the KLC1 gene.[1][2][3] Conventional kinesin is a tetrameric molecule composed of two heavy chains and two light chains, and transports various cargos along microtubules toward their plus ends. The heavy chains provide the motor activity, while the light chains bind to various cargos. This gene encodes a member of the kinesin light chain family. It associates with kinesin heavy chain through an N-terminal domain, and six tetratricopeptide repeat (TPR) motifs are thought to be involved in binding of cargos such as vesicles, mitochondria, and the Golgi complex. Thus, kinesin light chains function as adapter molecules and not motors per se. Although previously named "kinesin 2", this gene is not a member of the kinesin-2 / kinesin heavy chain subfamily of kinesin motor proteins. Extensive alternative splicing produces isoforms with different C-termini that are proposed to bind to different cargos; however, the full-length nature of some of these variants has not been determined.[3] # Interactions KLC1 has been shown to interact with MAPK8IP3,[2] KIF5B[4][5][6] and KIF5A.[5][6]

https://www.wikidoc.org/index.php/KLC1

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KLF1

KLF1 Krueppel-like factor 1 is a protein that in humans is encoded by the KLF1 gene. The gene for KLF1 is on the human chromosome 19 and on mouse chromosome 8. Krueppel-like factor 1 is a transcription factor that is necessary for the proper maturation of erythroid (red blood) cells. # Structure The molecule has two domains; the transactivation domain and the chromatin-remodeling domain. The carboxyl (C) terminal is composed of three C2H2 zinc fingers that binds to DNA, and the amino (N) terminus is proline rich and acidic. # Function Studies in mice first demonstrated the critical function of KLF1 in hematopoietic development. KLF1 deficient (knockout) mouse embryos exhibit a lethal anemic phenotype, fail to promote the transcription of adult β-globin, and die by embryonic day 15. Over-expression of KLF1 results in a reduction of the number of circulating platelets and hastens the onset of the β-globin gene. KLF1 coordinates the regulation of six cellular pathways that are all essential to terminal erythroid differentiation: - Cell Membrane & Cytoskeleton - Apoptosis - Heme Synthesis & Transport - Cell Cycling - Iron Procurement - Globin Chain Production It has also been linked to three main processes that are all essential to transcription of the β globin gene: - Chromatin remodeling - Modulation of the gamma to beta globin switch - Transcriptional activation KLF1 binds specifically to the "CACCC" motif of the β-globin gene promoter. When natural mutations occur in the promoter, β+ thalassemia can arise in humans. Thalassemia's prevalence (2 million worldwide carry the trait) makes KLF1 clinically significant. # Clinical significance Next-Generation sequencing efforts have revealed a surprisingly high prevalence of mutations in human KLF1. The chance of a KLF1 null child being conceived is approximately 1:24,000 in Southern China. With pre-natal blood transfusions and bone marrow transplant, it is possible to be born without KLF1. Most mutations in KLF1 lead to a recessive loss-of-function phenotype, however semi-dominant mutations have been identified in humans and mice as the cause of a rare inherited anemia CDA type IV. Additional family studies and clinical research unveiled the molecular genetics of the HPFH KLF1-related condition and established KLF1 as a novel quantitative trait locus for HbF (HBFQTL6).

KLF1 Krueppel-like factor 1 is a protein that in humans is encoded by the KLF1 gene. The gene for KLF1 is on the human chromosome 19 and on mouse chromosome 8. Krueppel-like factor 1 is a transcription factor that is necessary for the proper maturation of erythroid (red blood) cells. # Structure The molecule has two domains; the transactivation domain and the chromatin-remodeling domain. The carboxyl (C) terminal is composed of three C2H2 zinc fingers that binds to DNA, and the amino (N) terminus is proline rich and acidic.[1] # Function Studies in mice first demonstrated the critical function of KLF1 in hematopoietic development. KLF1 deficient (knockout) mouse embryos exhibit a lethal anemic phenotype, fail to promote the transcription of adult β-globin, and die by embryonic day 15.[2] Over-expression of KLF1 results in a reduction of the number of circulating platelets and hastens the onset of the β-globin gene.[3] KLF1 coordinates the regulation of six cellular pathways that are all essential to terminal erythroid differentiation:[4] - Cell Membrane & Cytoskeleton - Apoptosis - Heme Synthesis & Transport - Cell Cycling - Iron Procurement - Globin Chain Production It has also been linked to three main processes that are all essential to transcription of the β globin gene: - Chromatin remodeling - Modulation of the gamma to beta globin switch - Transcriptional activation KLF1 binds specifically to the "CACCC" motif of the β-globin gene promoter.[2] When natural mutations occur in the promoter, β+ thalassemia can arise in humans. Thalassemia's prevalence (2 million worldwide carry the trait) makes KLF1 clinically significant. # Clinical significance Next-Generation sequencing efforts have revealed a surprisingly high prevalence of mutations in human KLF1.[5] The chance of a KLF1 null child being conceived is approximately 1:24,000 in Southern China.[6] With pre-natal blood transfusions and bone marrow transplant, it is possible to be born without KLF1.[7] Most mutations in KLF1 lead to a recessive loss-of-function phenotype,[6] however semi-dominant mutations have been identified in humans[8] and mice[9] as the cause of a rare inherited anemia CDA type IV. Additional family studies and clinical research[10] unveiled the molecular genetics of the HPFH KLF1-related condition and established KLF1 as a novel quantitative trait locus for HbF (HBFQTL6).[11]

https://www.wikidoc.org/index.php/KLF1

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wikidoc

KLF2

KLF2 Krüppel-like Factor 2 (KLF2), also known as lung Krüppel-like Factor (LKLF), is a protein that in humans is encoded by the KLF2 gene on chromosome 19. It is a member of the Krüppel-like factor family of zinc finger transcription factors, and it has been implicated in a variety of biochemical processes in the human body, including lung development, embryonic erythropoiesis, epithelial integrity, T-cell viability, and adipogenesis. # Discovery Erythroid Krüppel-like Factor (EKLF or KLF1) was the first Krüppel-like Factor discovered. It was found to be vitally important for embryonic erythropoiesis in promoting the switch from fetal hemoglobin (Hemoglobin F) to adult hemoglobin (Hemoglobin A) gene expression by binding to highly conserved CACCC domains. EKLF ablation in mouse embryos produces a lethal anemic phenotype, causing death by embryonic day 14, and natural mutations lead to β+ thalassemia in humans. However, expression of embryonic hemoglobin and fetal hemoglobin genes is normal in EKLF-deficient mice, and since all genes on the human β-globin locus exhibit the CACCC elements, researchers began searching for other Krüppel-like factors. KLF2, initially called lung Krüppel-like Factor due to its high expression in the adult mouse lung, was first isolated in 1995 by using the zinc finger domain of EKLF as a hybridization probe. By transactivation assay in mouse fibroblasts, KLF2 was also noticed to bind to the β-globin gene promoter containing the CACCC sequence shown to be the binding site for EKLF, confirming KLF2 as a member of the Krüppel-like Factor family. Since then, many other KLF proteins have been discovered. # Structure The main distinguishing feature of the KLF family is the presence of three highly conserved Cysteine2/Histidine2 zinc fingers of either 21 or 23 amino acid residues in length, located at the C-terminus of the protein. These amino acid sequences each chelate a single zinc ion, coordinated between the two cysteine and two histidine residues. These zinc fingers are joined by a conserved seven-amino acid sequence; TGEKP(Y/F)X. The zinc fingers enable all KLF proteins to bind to CACCC gene promoters, so although they may complete varied functions (due to lack of homology away from the zinc fingers), they all recognize similar binding domains. KLF2 also exhibits these structural features. The mRNA transcript is approximately 1.5 kilobases in length, and the 37.7 kDa protein contains 354 amino acids. KLF2 also shares some homology with EKLF at the N-terminus with a proline-rich region presumed to function as the transactivation domain. # Gene expression KLF2 was first discovered, and is highly expressed in, the adult mouse lung, but it is also expressed temporally during embryogenesis in erythroid cells, endothelium, lymphoid cells, the spleen, and white adipose tissue. It is expressed as early as embryonic day 9.5 in the endothelium. KLF2 has a particularly interesting expression profile in erythroid cells. It is minimally expressed in the primitive and fetal definitive erythroid cells, but is highly expressed in adult definitive erythroid cells, particularly in the proerythroblast and the polychromatic and orthochromatic normoblasts. # Mouse knockout Homologous recombination of embryonic stem cells was used to generate KLF2-deficient mouse embryos. Both vasculogenesis and angiogenesis were normal in the embryos, but they died by embryonic day 14.5 from severe hemorrhaging. The vasculature displayed defective morphology, with thin tunica media and aneurysmal dilation that led to rupturing. Aortic vascular smooth muscle cells failed to organize into a normal tunica media, and pericytes were low in number. These KLF2-deficient mice thus demonstrated the important role of KLF2 in blood vessel stabilization during embryogenesis. Due to embryonic lethality in KLF2-deficient embryos, it is difficult to examine the role of KLF2 in normal post-natal physiology, such as in lung development and function. # Function ## Lung development Lung buds removed from KLF2-deficient mouse embryos and cultured from normal tracheobronchial trees. In order to circumvent embryonic lethality usually observed in KLF2-deficient embryos, KLF2 homozygous null mouse embryonic stem cells were constructed and used to produce chimeric animals. These KLF2-deficient embryonic stem cells contribute significantly to development of skeletal muscle, spleen, heart, liver, kidney, stomach, brain, uterus, testis, and skin, but not to the development of the lung. These embryos had lungs arrested in the late canalicular stage of lung development, with undilated acinar tubules. In contrast, wild type embryos are born in the saccular stage of lung development with expanded alveoli. This suggests that KLF2 is an important transcription factor required in late gestation for lung development. ## Embryonic erythropoiesis KLF2 is now believed to play an important role in embryonic erythropoiesis, specifically in regulating embryonic and fetal β-like globin gene expression. In a murine KLF2-deficient embryo, expression of β-like globin genes normally expressed in primitive erythroid cells was significantly decreased, although adult β-globin gene expression was unaffected. The role of KLF2 in human β-like globin gene expression was further elucidated by transfection of a murine KLF2-deficient embryo with the human β-globin locus. It was found that KLF2 was important for ε-globin (found in embryonic hemoglobin) and γ-globin (found in fetal hemoglobin) gene expression. However, as before, KLF2 plays no role in adult β-globin gene expression; this is regulated by EKLF. However, KLF2 and EKLF have been found to interact in embryonic erythropoiesis. Deletion of both KLF2 and EKLF in mouse embryos results in fatal anemia earlier than in either single deletion at embryonic day 10.5. This indicates that KLF2 and EKLF interact in embryonic and fetal β-like globin gene expression. It has been shown using conditional knockout mice that both KLF2 and EKLF bind directly to β-like globin promoters. There is also evidence to suggest that KLF2 and EKLF synergistically bind to the Myc promoter, a transcription factor that is associated with gene expression of α-globin and β-globin in embryonic proerythroblasts. ## Endothelial physiology KLF2 expression is induced by fluid laminar flow shear stress, as is caused by blood flow in normal endothelium. This activates mechanosensitive channels, which in turn activates two pathways; the MEK5/ERK5 pathway, which activates MEF2, a transcription factor that upregulates KLF2 gene expression; and PI3K inhibition, which increases the stability of KLF2 mRNA. Binding of cytokines such as TNFα and IL-1β to their receptors activates transcription factor p65, which also induces KLF2 expression. KLF2 then has four key functions in endothelium: - By inhibiting activation of p65 by transcription coactivator p300, VCAM1 and SELE expression is downregulated, genes that encode endothelial cell adhesion molecules, causing decreased lymphocyte and leukocyte activation and hence decreasing inflammation - It upregulates THBD (thrombomodulin) and NOS3 (endothelial nitric oxide synthase) expression, having an anti-thrombotic effect - Through the upregulation of NOS3, as well as NPPC (natriuretic precursor peptide C), KLF2 has a vasodilatory effect - KLF2 also inhibits VEGFR2 (VEGF receptor 2) expression, having an anti-angiogenic effect Thus KLF2 has an important role in regulating normal endothelium physiology. It is hypothesized that myeloid-specific KLF2 plays a protective role in atherosclerosis. Gene expression changes in endothelial cells induced by KLF2 have been demonstrated to be atheroprotective. ## T-cell differentiation KLF2 has an important function in T-lymphocyte differentiation. T-cells are activated and more prone to apoptosis without KLF2, suggesting that KLF2 regulates T-cell quiescence and survival. KLF2-deficient thymocytes also do not express several receptors required for thymus emigration and differentiation into mature T-cells, such as sphingosine-1 phosphate receptor 1. ## Adipogenesis KLF2 is a negative regulator of adipocyte differentiation. KLF2 is expressed in preadipocytes, but not mature adipocytes, and it potently inhibits PPAR-γ (peroxisome proliferator-activated receptor-γ) expression by inhibiting promoter activity. This prevents differentiation of preadipocytes into adipocytes, and thus prevents adipogenesis.

KLF2 Krüppel-like Factor 2 (KLF2), also known as lung Krüppel-like Factor (LKLF), is a protein that in humans is encoded by the KLF2 gene on chromosome 19.[1][2] It is a member of the Krüppel-like factor family of zinc finger transcription factors, and it has been implicated in a variety of biochemical processes in the human body, including lung development, embryonic erythropoiesis, epithelial integrity, T-cell viability, and adipogenesis.[3] # Discovery Erythroid Krüppel-like Factor (EKLF or KLF1) was the first Krüppel-like Factor discovered. It was found to be vitally important for embryonic erythropoiesis in promoting the switch from fetal hemoglobin (Hemoglobin F) to adult hemoglobin (Hemoglobin A) gene expression by binding to highly conserved CACCC domains.[4] EKLF ablation in mouse embryos produces a lethal anemic phenotype, causing death by embryonic day 14, and natural mutations lead to β+ thalassemia in humans.[5] However, expression of embryonic hemoglobin and fetal hemoglobin genes is normal in EKLF-deficient mice, and since all genes on the human β-globin locus exhibit the CACCC elements, researchers began searching for other Krüppel-like factors.[6] KLF2, initially called lung Krüppel-like Factor due to its high expression in the adult mouse lung, was first isolated in 1995 by using the zinc finger domain of EKLF as a hybridization probe.[7] By transactivation assay in mouse fibroblasts, KLF2 was also noticed to bind to the β-globin gene promoter containing the CACCC sequence shown to be the binding site for EKLF, confirming KLF2 as a member of the Krüppel-like Factor family.[7] Since then, many other KLF proteins have been discovered. # Structure The main distinguishing feature of the KLF family is the presence of three highly conserved Cysteine2/Histidine2 zinc fingers of either 21 or 23 amino acid residues in length, located at the C-terminus of the protein. These amino acid sequences each chelate a single zinc ion, coordinated between the two cysteine and two histidine residues. These zinc fingers are joined by a conserved seven-amino acid sequence; TGEKP(Y/F)X. The zinc fingers enable all KLF proteins to bind to CACCC gene promoters, so although they may complete varied functions (due to lack of homology away from the zinc fingers), they all recognize similar binding domains.[3] KLF2 also exhibits these structural features. The mRNA transcript is approximately 1.5 kilobases in length, and the 37.7 kDa protein contains 354 amino acids.[7] KLF2 also shares some homology with EKLF at the N-terminus with a proline-rich region presumed to function as the transactivation domain.[7] # Gene expression KLF2 was first discovered, and is highly expressed in, the adult mouse lung, but it is also expressed temporally during embryogenesis in erythroid cells, endothelium, lymphoid cells, the spleen, and white adipose tissue.[3][7] It is expressed as early as embryonic day 9.5 in the endothelium. KLF2 has a particularly interesting expression profile in erythroid cells. It is minimally expressed in the primitive and fetal definitive erythroid cells, but is highly expressed in adult definitive erythroid cells, particularly in the proerythroblast and the polychromatic and orthochromatic normoblasts.[8] # Mouse knockout Homologous recombination of embryonic stem cells was used to generate KLF2-deficient mouse embryos. Both vasculogenesis and angiogenesis were normal in the embryos, but they died by embryonic day 14.5 from severe hemorrhaging. The vasculature displayed defective morphology, with thin tunica media and aneurysmal dilation that led to rupturing. Aortic vascular smooth muscle cells failed to organize into a normal tunica media, and pericytes were low in number. These KLF2-deficient mice thus demonstrated the important role of KLF2 in blood vessel stabilization during embryogenesis.[9] Due to embryonic lethality in KLF2-deficient embryos, it is difficult to examine the role of KLF2 in normal post-natal physiology, such as in lung development and function.[10] # Function ## Lung development Lung buds removed from KLF2-deficient mouse embryos and cultured from normal tracheobronchial trees. In order to circumvent embryonic lethality usually observed in KLF2-deficient embryos, KLF2 homozygous null mouse embryonic stem cells were constructed and used to produce chimeric animals. These KLF2-deficient embryonic stem cells contribute significantly to development of skeletal muscle, spleen, heart, liver, kidney, stomach, brain, uterus, testis, and skin, but not to the development of the lung. These embryos had lungs arrested in the late canalicular stage of lung development, with undilated acinar tubules. In contrast, wild type embryos are born in the saccular stage of lung development with expanded alveoli. This suggests that KLF2 is an important transcription factor required in late gestation for lung development.[3] ## Embryonic erythropoiesis KLF2 is now believed to play an important role in embryonic erythropoiesis, specifically in regulating embryonic and fetal β-like globin gene expression. In a murine KLF2-deficient embryo, expression of β-like globin genes normally expressed in primitive erythroid cells was significantly decreased, although adult β-globin gene expression was unaffected.[11] The role of KLF2 in human β-like globin gene expression was further elucidated by transfection of a murine KLF2-deficient embryo with the human β-globin locus. It was found that KLF2 was important for ε-globin (found in embryonic hemoglobin) and γ-globin (found in fetal hemoglobin) gene expression. However, as before, KLF2 plays no role in adult β-globin gene expression; this is regulated by EKLF.[11] However, KLF2 and EKLF have been found to interact in embryonic erythropoiesis. Deletion of both KLF2 and EKLF in mouse embryos results in fatal anemia earlier than in either single deletion at embryonic day 10.5. This indicates that KLF2 and EKLF interact in embryonic and fetal β-like globin gene expression.[12] It has been shown using conditional knockout mice that both KLF2 and EKLF bind directly to β-like globin promoters.[13] There is also evidence to suggest that KLF2 and EKLF synergistically bind to the Myc promoter, a transcription factor that is associated with gene expression of α-globin and β-globin in embryonic proerythroblasts.[14] ## Endothelial physiology KLF2 expression is induced by fluid laminar flow shear stress, as is caused by blood flow in normal endothelium.[15][16] This activates mechanosensitive channels, which in turn activates two pathways; the MEK5/ERK5 pathway, which activates MEF2, a transcription factor that upregulates KLF2 gene expression; and PI3K inhibition, which increases the stability of KLF2 mRNA. Binding of cytokines such as TNFα and IL-1β to their receptors activates transcription factor p65, which also induces KLF2 expression. KLF2 then has four key functions in endothelium: - By inhibiting activation of p65 by transcription coactivator p300, VCAM1 and SELE expression is downregulated, genes that encode endothelial cell adhesion molecules, causing decreased lymphocyte and leukocyte activation and hence decreasing inflammation - It upregulates THBD (thrombomodulin) and NOS3 (endothelial nitric oxide synthase) expression, having an anti-thrombotic effect - Through the upregulation of NOS3, as well as NPPC (natriuretic precursor peptide C), KLF2 has a vasodilatory effect - KLF2 also inhibits VEGFR2 (VEGF receptor 2) expression, having an anti-angiogenic effect[17] Thus KLF2 has an important role in regulating normal endothelium physiology. It is hypothesized that myeloid-specific KLF2 plays a protective role in atherosclerosis.[18] Gene expression changes in endothelial cells induced by KLF2 have been demonstrated to be atheroprotective.[16] ## T-cell differentiation KLF2 has an important function in T-lymphocyte differentiation. T-cells are activated and more prone to apoptosis without KLF2, suggesting that KLF2 regulates T-cell quiescence and survival.[3] KLF2-deficient thymocytes also do not express several receptors required for thymus emigration and differentiation into mature T-cells, such as sphingosine-1 phosphate receptor 1.[19] ## Adipogenesis KLF2 is a negative regulator of adipocyte differentiation. KLF2 is expressed in preadipocytes, but not mature adipocytes, and it potently inhibits PPAR-γ (peroxisome proliferator-activated receptor-γ) expression by inhibiting promoter activity. This prevents differentiation of preadipocytes into adipocytes, and thus prevents adipogenesis.[20]

https://www.wikidoc.org/index.php/KLF2

ff393ed73e2ccdec41db8d63e19aebe5703936c6

wikidoc

KLF3

KLF3 Krüppel-like factor 3 is a protein that in humans is encoded by the KLF3 gene. # Structure KLF3, originally termed Basic Krüppel-like Factor (BKLF), was the third member of the Krüppel-like factor family of zinc finger transcription factors to be discovered. Transcription factors in this family bind DNA by virtue of 3 characteristic three C2H2 zinc fingers at their C-termini. Since their DNA-binding domains are highly conserved within the family, all KLF proteins recognize CACCC or CGCCC boxes of the general form NCR CRC CCN, (where N is any base and R is a purine). # Function While the C-termini are similar in different KLFs, the N-termini vary and accordingly different KLFs can either activate or repress transcription or both. KLF3 appears to function predominantly as a repressor of transcription. It turns genes off. It does this by recruiting the C-terminal Binding Protein co-repressors CTBP1 and CTBP2. CtBP docks onto a short motif (residues 61-65) in the N-terminus of KLF3, of the general form Proline – Isoleucine – Aspartate – Leucine – Serine (the PIDLS motif). CtBP in turn recruits histone modifying enzymes to alter chromatin and repress gene expression. KLF3 is expressed highly in the red blood cell or erythroid lineage. Here it is driven by another KLF, Erythroid KLF or KLF1, and its expression increases as erythroid cells mature. Studies in knockout mice reveal a mild anemia in the absence of functional KLF3 and the de-repression of several target genes that contain CACCC boxes in their regulatory regions. Many of these genes are activated by KLF1, hence it appears that KLF3 operates in a negative feedback loop to balance the activating potential of KLF1. KLF3 also regulates another repressive KLF, KLF8. Thus KLF1, KLF3 and KLF8 operate in a tight regulatory network. KLF3 and KLF8 may have redundant functions, as mice lacking both KLF3 and KLF8 show defects that are more severe than in either single knockout. They die in utero around day 14 of gestation. As well as being expressed in erythroid cells, KLF3 is present in other cell types and analysis of the knockout mice has revealed defects affecting adipose tissue and B cells. KLF3 deficient mice have less adipose tissue and indications of metabolic health that may be attributable to de-repression of the adipokine hormone gene adipolin. The role of KLF3 in B lymphocytes is complex but it appears to operate in a network with KLF2 and KLF4 to influence the switch between spleen marginal zone and follicular B cells. # Interactions KLF3 has been shown to interact with: - CTBP2 and - FHL3.

KLF3 Krüppel-like factor 3 is a protein that in humans is encoded by the KLF3 gene. # Structure KLF3, originally termed Basic Krüppel-like Factor (BKLF), was the third member of the Krüppel-like factor family of zinc finger transcription factors to be discovered.[1] Transcription factors in this family bind DNA by virtue of 3 characteristic three C2H2 zinc fingers at their C-termini. Since their DNA-binding domains are highly conserved within the family, all KLF proteins recognize CACCC or CGCCC boxes of the general form NCR CRC CCN, (where N is any base and R is a purine). # Function While the C-termini are similar in different KLFs, the N-termini vary and accordingly different KLFs can either activate or repress transcription or both. KLF3 appears to function predominantly as a repressor of transcription. It turns genes off. It does this by recruiting the C-terminal Binding Protein co-repressors CTBP1 and CTBP2.[2][3] CtBP docks onto a short motif (residues 61-65) in the N-terminus of KLF3, of the general form Proline – Isoleucine – Aspartate – Leucine – Serine (the PIDLS motif).[2][3] CtBP in turn recruits histone modifying enzymes to alter chromatin and repress gene expression. KLF3 is expressed highly in the red blood cell or erythroid lineage. Here it is driven by another KLF, Erythroid KLF or KLF1, and its expression increases as erythroid cells mature. Studies in knockout mice reveal a mild anemia in the absence of functional KLF3 and the de-repression of several target genes that contain CACCC boxes in their regulatory regions.[4] Many of these genes are activated by KLF1, hence it appears that KLF3 operates in a negative feedback loop to balance the activating potential of KLF1. KLF3 also regulates another repressive KLF, KLF8.[5] Thus KLF1, KLF3 and KLF8 operate in a tight regulatory network. KLF3 and KLF8 may have redundant functions, as mice lacking both KLF3 and KLF8 show defects that are more severe than in either single knockout. They die in utero around day 14 of gestation.[6] As well as being expressed in erythroid cells, KLF3 is present in other cell types and analysis of the knockout mice has revealed defects affecting adipose tissue[7] and B cells.[8] KLF3 deficient mice have less adipose tissue and indications of metabolic health that may be attributable to de-repression of the adipokine hormone gene adipolin.[9] The role of KLF3 in B lymphocytes is complex but it appears to operate in a network with KLF2 and KLF4 to influence the switch between spleen marginal zone and follicular B cells.[10] # Interactions KLF3 has been shown to interact with: - CTBP2[2][3] and - FHL3.[2]

https://www.wikidoc.org/index.php/KLF3

279f294c95544f4689344129e48fa91215be43f3

wikidoc

KLF4

KLF4 Kruppel-like factor 4 (KLF4; gut-enriched Krüppel-like factor or GKLF) is a zinc-finger transcription factor, and it was first identified in 1996. KLF4 is a member of the KLF family of transcription factors, which belongs to the relatively large family of SP1-like transcription factors. KLF4 is involved in the regulation of proliferation, differentiation, apoptosis and somatic cell reprogramming. Evidence also suggests that KLF4 is a tumor suppressor in certain cancers, including Colorectal cancer. It has three C2H2-zinc fingers at its carboxyl terminus that are closely related to another KLF, KLF2. It has two nuclear localization sequences that signals it to localize to the nucleus. In embryonic stem cells (ESCs), KLF4 has been demonstrated to be a good indicator of stem-like capacity. It is suggested that the same is true in mesenchymal stem cells (MSCs). In humans, the protein is 513 amino acids with a predicted molecular weight of approximately 55kDa and is encoded by the KLF4 gene. The KLF4 gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog. # Interactions KLF4 can activate transcription by interacting via it N-terminus with specific transcriptional co-activators, such as p300-CBP coactivator family. Transcriptional repression by KLF4 is carried out by KLF4 competing with an activator for binding to a target DNA sequence (9-12). KLF4 has been shown to interact with CREB-binding protein. It was found that the transcription factor Klf4 present at the promoter of an enzymatic subunit of telomerase (TERT), where it formed a complex with β-catenin. Klf4 was required for accumulation of β-catenin at the Tert promoter but was unable to stimulate Tert expression in the absence of β-catenin. # Function KLF4 has diverse functions, and has been garnering attention in recent years because some of its functions are apparently contradicting, but mainly since the discovery of its integral role as one of four key factors that are essential for inducing pluripotent stem cells. KLF4 is highly expressed in non-dividing cells and its overexpression induces cell cycle arrest. KLF4 is particularly important in preventing cell division when the DNA is damaged. KLF4 is also important in regulating centrosome number and chromosome number (genetic stability), and in promoting cell survival. However, some studies have revealed that under certain conditions KLF4 may switch its role from pro-cell survival to pro-cell death. KLF4 is expressed in the cells that are non-dividing and are terminally differentiated in the intestinal epithelium, where KLF4 is important in the regulation of intestinal epithelium homeostasis (terminal cell differentiation and proper localization of the different intestinal epithelium cell types). In the intestinal epithelium, KLF4 is an important regulator of Wnt signaling pathway genes of genes regulating differentiation. KLF4 is expressed in a variety of tissues and organs such as: the cornea where it is required for epithelial barrier function and is a regulator of genes required for corneal homeostasis; the skin where it is required for the development of skin permeability barrier function; the bone and teeth tissues where it regulates normal skeletal development; epithelial cell of the mouse male and female reproductive tract where in the males it is important for proper spermatogenesis; vascular endothelial cells where it is critical in preventing vascular leakage in response to inflammatory stimuli; white blood cells where it mediates inflammatory responses cellular differentiation and proliferation; the kidneys where it is involved in the differentiation of embryonic stem cells and induced pluripotent stem (iPS) cells to renal lineage in vitro and its dysregulation has been linked to some renal pathologies. # Roles in diseases Several lines of evidence have shown that KLF4 role in disease is context dependent where under certain conditions it may play one role and under different conditions it may assume a complete opposite role. KLF4 is an anti-tumorigenic factor and its expression is often lost in various human cancer types, such as Colorectal cancer, gastric cancer, esophageal squamous cell carcinoma, intestinal cancer, prostate cancer, bladder cancer and lung cancer. However, in some cancer types KLF4 may act as a tumor promoter where increased KLF4 expression has been reported, such as in oral squamous cell carcinoma and in primary breast ductal carcinoma. Also, overexpression of KLF4 in skin resulted in hyperplasia and dysplasia, which lead to the development of squamous cell carcinoma. Similar finding in esophageal epithelium was observed, where overexpression of KLF4 resulted in increased inflammation that eventually lead to the development of esophageal squamous cell cancer in mice. The role of KLF4 in Epithelial–mesenchymal transition (EMT) is also controversial. It was shown to stimulate EMT in some systems by promoting/maintaining stemness of cancer cells, as is the case in pancreatic cancer, head and neck cancer, endometrial cancer, nasopharyngeal cancer, prostate cancer and non-small lung cancer. Under conditions of TGFβ-induced EMT KLF4 was shown to suppress EMT in the same systems where it was shown to promote EMT, such as prostate cancer and pancreatic cancer. Additionally, KLF4 was shown to suppress EMT in epidermal cancer, breast cancer, lung cancer, cisplatin-resistant nasopharyngeal carcinoma cells, and in hepatocellular carcinoma cells. KLF4 plays an important role in several vascular diseases where it was shown to regulate vascular inflammation by controlling macrophage polarization and plaque formation in atherosclerosis. It up-regulates Apolipoprotein E, which is an anti-atherosclerotic factor. It is also involved in the regulation of angiogenesis. It may suppress angiogenesis by regulating NOTCH1 activity, while in the central nervous system its overexpression leads to vascular dysplasia. KLF4 may promote inflammation by mediating NF-κB-dependent inflammatory pathway such as in macrophages, esophageal epithelium and in chemically-induced acute colitis in mice. However, KLF4 may also suppress the activation of inflammatory signaling such as in endothelial cells in response to pro-inflammatory stimuli. KLF4 is essential for the cellular response to DNA damage. It is required for preventing cell cycle entry into mitosis following γ-irradiation-induced DNA damage, in promoting DNA repair mechanisms (20) and in preventing the irradiated cell from undergoing programmed cell death (apoptosis) (23,25,26). In one study, the in vivo importance of KLF4 in response to γ-irradiation-induced DNA damage was revealed where deletion of KLF4 specifically from the intestinal epithelium in mice lead to inability of the intestinal epithelium to regenerate and resulting in increased mortality of these mice. # Importance in Stem cells Takahashi and Yamanaka were the first identify KLF4 as one of four factors that are required to induce mouse embryonic and adult fibroblasts into pluripotent stem cells (iPS). This was also found to be true for adult human fibroblasts. Since 2006 up to today, the work on clinically relevant research in stem cells and stem cell induction, has increased dramatically (more than 10,000 research articles, as compared to about 60 between years 1900 to 2005). In vivo functional studies on the role of KLF4 in stem cells are rare. Recently a group investigated the role of KLF4 in a particular population of intestinal stem cells, the Bmi1+ stem cells. This population of intestinal stem cells: are normally slow dividing, are known to be resistant to radiation injury, and are the ones responsible for intestinal epithelium regeneration following radiation injury. The study showed that in the intestine, following γ-irradiation-induced DNA damage, KLF4 may regulate epithelial regeneration by modulating the fate of Bmi1+ stem cells themselves, and consequently the development of BMI1+ intestinal stem cell-derived lineage.

KLF4 Kruppel-like factor 4 (KLF4; gut-enriched Krüppel-like factor or GKLF) is a zinc-finger transcription factor, and it was first identified in 1996.[1] KLF4 is a member of the KLF family of transcription factors, which belongs to the relatively large family of SP1-like transcription factors.[2][3][4] KLF4 is involved in the regulation of proliferation, differentiation, apoptosis and somatic cell reprogramming. Evidence also suggests that KLF4 is a tumor suppressor in certain cancers, including Colorectal cancer.[5] It has three C2H2-zinc fingers at its carboxyl terminus that are closely related to another KLF, KLF2.[3] It has two nuclear localization sequences that signals it to localize to the nucleus.[6] In embryonic stem cells (ESCs), KLF4 has been demonstrated to be a good indicator of stem-like capacity. It is suggested that the same is true in mesenchymal stem cells (MSCs). In humans, the protein is 513 amino acids with a predicted molecular weight of approximately 55kDa and is encoded by the KLF4 gene.[7] The KLF4 gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.[8] # Interactions KLF4 can activate transcription by interacting via it N-terminus with specific transcriptional co-activators, such as p300-CBP coactivator family.[9][10][11] Transcriptional repression by KLF4 is carried out by KLF4 competing with an activator for binding to a target DNA sequence (9-12).[12][13][14][15] KLF4 has been shown to interact with CREB-binding protein.[16] It was found that the transcription factor Klf4 present at the promoter of an enzymatic subunit of telomerase (TERT), where it formed a complex with β-catenin. Klf4 was required for accumulation of β-catenin at the Tert promoter but was unable to stimulate Tert expression in the absence of β-catenin.[17] # Function KLF4 has diverse functions, and has been garnering attention in recent years because some of its functions are apparently contradicting, but mainly since the discovery of its integral role as one of four key factors that are essential for inducing pluripotent stem cells.[18][19] KLF4 is highly expressed in non-dividing cells and its overexpression induces cell cycle arrest.[1][20][21][22][23] KLF4 is particularly important in preventing cell division when the DNA is damaged.[20][22][23][24] KLF4 is also important in regulating centrosome number and chromosome number (genetic stability),[25][26][27] and in promoting cell survival.[28][29][30][31][32][33] However, some studies have revealed that under certain conditions KLF4 may switch its role from pro-cell survival to pro-cell death.[32][34][35][36] KLF4 is expressed in the cells that are non-dividing and are terminally differentiated in the intestinal epithelium, where KLF4 is important in the regulation of intestinal epithelium homeostasis (terminal cell differentiation and proper localization of the different intestinal epithelium cell types).[37][38][39][40] In the intestinal epithelium, KLF4 is an important regulator of Wnt signaling pathway genes of genes regulating differentiation.[40] KLF4 is expressed in a variety of tissues and organs such as: the cornea where it is required for epithelial barrier function[41][42] and is a regulator of genes required for corneal homeostasis;[43] the skin where it is required for the development of skin permeability barrier function;[44][45][46] the bone and teeth tissues where it regulates normal skeletal development;[47][48][49][50] epithelial cell of the mouse male and female reproductive tract[51] where in the males it is important for proper spermatogenesis;[52][53][54] vascular endothelial cells[55] where it is critical in preventing vascular leakage in response to inflammatory stimuli;[56] white blood cells where it mediates inflammatory responses cellular differentiation[57][58][59][60] and proliferation;[60][61] the kidneys where it is involved in the differentiation of embryonic stem cells and induced pluripotent stem (iPS) cells to renal lineage in vitro[62] and its dysregulation has been linked to some renal pathologies.[63][64][65] # Roles in diseases Several lines of evidence have shown that KLF4 role in disease is context dependent where under certain conditions it may play one role and under different conditions it may assume a complete opposite role. KLF4 is an anti-tumorigenic factor and its expression is often lost in various human cancer types, such as Colorectal cancer,[66] gastric cancer,[67] esophageal squamous cell carcinoma,[29] intestinal cancer,[68] prostate cancer,[69] bladder cancer[70] and lung cancer.[71] However, in some cancer types KLF4 may act as a tumor promoter where increased KLF4 expression has been reported, such as in oral squamous cell carcinoma[72] and in primary breast ductal carcinoma.[73] Also, overexpression of KLF4 in skin resulted in hyperplasia and dysplasia,[74] which lead to the development of squamous cell carcinoma.[75] Similar finding in esophageal epithelium was observed, where overexpression of KLF4 resulted in increased inflammation that eventually lead to the development of esophageal squamous cell cancer in mice.[76] The role of KLF4 in Epithelial–mesenchymal transition (EMT) is also controversial. It was shown to stimulate EMT in some systems by promoting/maintaining stemness of cancer cells, as is the case in pancreatic cancer,[77][78][79] head and neck cancer,[80] endometrial cancer,[81] nasopharyngeal cancer,[82] prostate cancer[83] and non-small lung cancer.[84] Under conditions of TGFβ-induced EMT KLF4 was shown to suppress EMT in the same systems where it was shown to promote EMT, such as prostate cancer[85] and pancreatic cancer.[86] Additionally, KLF4 was shown to suppress EMT in epidermal cancer,[87] breast cancer,[32] lung cancer,[88] cisplatin-resistant nasopharyngeal carcinoma cells,[89] and in hepatocellular carcinoma cells.[90] KLF4 plays an important role in several vascular diseases where it was shown to regulate vascular inflammation by controlling macrophage polarization[91] and plaque formation in atherosclerosis.[92][93][94] It up-regulates Apolipoprotein E, which is an anti-atherosclerotic factor.[93] It is also involved in the regulation of angiogenesis. It may suppress angiogenesis by regulating NOTCH1 activity,[95] while in the central nervous system its overexpression leads to vascular dysplasia.[96] KLF4 may promote inflammation by mediating NF-κB-dependent inflammatory pathway such as in macrophages,[14] esophageal epithelium[76] and in chemically-induced acute colitis in mice.[97] However, KLF4 may also suppress the activation of inflammatory signaling such as in endothelial cells in response to pro-inflammatory stimuli.[98] KLF4 is essential for the cellular response to DNA damage. It is required for preventing cell cycle entry into mitosis following γ-irradiation-induced DNA damage,[22][23] in promoting DNA repair mechanisms (20) and in preventing the irradiated cell from undergoing programmed cell death (apoptosis) (23,25,26).[28][30][31] In one study, the in vivo importance of KLF4 in response to γ-irradiation-induced DNA damage was revealed where deletion of KLF4 specifically from the intestinal epithelium in mice lead to inability of the intestinal epithelium to regenerate and resulting in increased mortality of these mice.[31] # Importance in Stem cells Takahashi and Yamanaka were the first identify KLF4 as one of four factors that are required to induce mouse embryonic and adult fibroblasts into pluripotent stem cells (iPS).[19] This was also found to be true for adult human fibroblasts.[18] Since 2006 up to today, the work on clinically relevant research in stem cells and stem cell induction, has increased dramatically (more than 10,000 research articles, as compared to about 60 between years 1900 to 2005). In vivo functional studies on the role of KLF4 in stem cells are rare. Recently a group investigated the role of KLF4 in a particular population of intestinal stem cells, the Bmi1+ stem cells.[33] This population of intestinal stem cells: are normally slow dividing, are known to be resistant to radiation injury, and are the ones responsible for intestinal epithelium regeneration following radiation injury.[99] The study showed that in the intestine, following γ-irradiation-induced DNA damage, KLF4 may regulate epithelial regeneration by modulating the fate of Bmi1+ stem cells themselves, and consequently the development of BMI1+ intestinal stem cell-derived lineage.[33]

https://www.wikidoc.org/index.php/KLF4

127334eaab10d83ea66a6a4aed68eaa6049b42bc

wikidoc

KLF9

KLF9 Krueppel-like factor 9 is a protein that in humans is encoded by the KLF9 gene. Previously known as Basic Transcription Element Binding Protein 1 (BTEB Protein 1), Klf9 is part of the Sp1 C2H2-type zinc finger family of transcription factors. Several previous studies showed Klf9-related regulation of animal development, including cell differentiation of B cells, keratinocytes, and neurons. Klf9 is also a key transcriptional regulator for uterine endometrial cell proliferation, adhesion, and differentiation, all factors that are essential during the process of pregnancy and are turned off during tumorigenesis. # Function The protein encoded by this gene is a transcription factor that binds to GC box elements located in the promoter. Binding of the encoded protein to a single GC box inhibits mRNA expression while binding to tandemly repeated GC box elements activates transcription. Oxidative stress increases expression of Klf9 and overexpression of Klf9 gene sensitizes the cell to oxidative stress and reactive oxygen species (ROS)]. , Using a short hairpin RNA (shRNA) to silence expression of Klf9 provides resistance for the cell to oxidative stress and ROS-related cell death. Klf9 is upregulated by ROS and promotes ROS-related cell death. Klf9 exhibits similarities to other known oxidative stress genes like NQO1 and HMOX1. When exposed to the same amount of hydrogen peroxide, both mouse embryo cells and human cells produced similar amounts of Klf9 and NQO1/HMOX. The opposite of this effect also occurs; Klf9 overexpression within the cell leads to an increase in intracellular ROS. The end result of the increase in intracellular ROS and Klf9 is increase in cell death; with the overexpressed Klf9 gene, more cells die. Similar cell death was found in vivo when wild-type mice were exposed to oxidative stress agent paraquat intranasally, which validated the oxidative stress-dependent Klf9 expression found in just the cell lines. Regions around 10 kb upstream and 1 kb downstream of Klf9 transcription start site contain conserved antioxidant response elements (AREs), which are binding sites for Nrf2. Nrf2 is a major regulator of the antioxidant response to ROS within the cell. Klf9 is upregulated by Nrf2; when oxidative stress is high and concentration of intracellular ROS is high, Nrf2 binds to Klf9 promoter, which increases the amount of intracellular ROS, leading to cell death. When oxidative stress is low, Nrf2 goes through its normal pathway by increasing the amount of antioxidant species within the cell and decreasing the amount of intracellular ROS. # Animal studies A Klf9 deficiency suppresses bleomycin-induced fibrosis in the lungs of mice. By introducing bleomycin to lung tissue, the tissue will produce ROS and develop fibrotic lung tissue to combat the damage done by the bleomycin. When Klf9 was knocked out in these mice, not as much fibrotic lung tissue was formed. Because of this finding, the researchers proposed that manipulations of Klf9 levels within the body may be a valid treatment for other diseases as well, including certain types of cancer. # Interactions KLF9 has been shown to interact with progesterone receptor.

KLF9 Krueppel-like factor 9 is a protein that in humans is encoded by the KLF9 gene.[1][2] Previously known as Basic Transcription Element Binding Protein 1 (BTEB Protein 1), Klf9 is part of the Sp1 C2H2-type zinc finger family of transcription factors. Several previous studies showed Klf9-related regulation of animal development, including cell differentiation of B cells, keratinocytes, and neurons.[3] Klf9 is also a key transcriptional regulator for uterine endometrial cell proliferation, adhesion, and differentiation, all factors that are essential during the process of pregnancy and are turned off during tumorigenesis.[4] # Function The protein encoded by this gene is a transcription factor that binds to GC box elements located in the promoter. Binding of the encoded protein to a single GC box inhibits mRNA expression while binding to tandemly repeated GC box elements activates transcription.[2] Oxidative stress increases expression of Klf9 and overexpression of Klf9 gene sensitizes the cell to oxidative stress and reactive oxygen species (ROS)]. , Using a short hairpin RNA (shRNA) to silence expression of Klf9 provides resistance for the cell to oxidative stress and ROS-related cell death. Klf9 is upregulated by ROS and promotes ROS-related cell death.[3] Klf9 exhibits similarities to other known oxidative stress genes like NQO1 and HMOX1. When exposed to the same amount of hydrogen peroxide, both mouse embryo cells and human cells produced similar amounts of Klf9 and NQO1/HMOX.[3] The opposite of this effect also occurs; Klf9 overexpression within the cell leads to an increase in intracellular ROS. The end result of the increase in intracellular ROS and Klf9 is increase in cell death; with the overexpressed Klf9 gene, more cells die. Similar cell death was found in vivo when wild-type mice were exposed to oxidative stress agent paraquat intranasally, which validated the oxidative stress-dependent Klf9 expression found in just the cell lines.[3] Regions around 10 kb upstream and 1 kb downstream of Klf9 transcription start site contain conserved antioxidant response elements (AREs), which are binding sites for Nrf2.[3] Nrf2 is a major regulator of the antioxidant response to ROS within the cell. Klf9 is upregulated by Nrf2; when oxidative stress is high and concentration of intracellular ROS is high, Nrf2 binds to Klf9 promoter, which increases the amount of intracellular ROS, leading to cell death. When oxidative stress is low, Nrf2 goes through its normal pathway by increasing the amount of antioxidant species within the cell and decreasing the amount of intracellular ROS.[3] # Animal studies A Klf9 deficiency suppresses bleomycin-induced fibrosis in the lungs of mice. By introducing bleomycin to lung tissue, the tissue will produce ROS and develop fibrotic lung tissue to combat the damage done by the bleomycin. When Klf9 was knocked out in these mice, not as much fibrotic lung tissue was formed.[3] Because of this finding, the researchers proposed that manipulations of Klf9 levels within the body may be a valid treatment for other diseases as well, including certain types of cancer.[3] # Interactions KLF9 has been shown to interact with progesterone receptor.[5]

https://www.wikidoc.org/index.php/KLF9

a8874d2ad2b0717828adb14b3e864491e7475b08

wikidoc

KLK4

KLK4 Kallikrein-related peptidase 4 is a protein which in humans is encoded by the KLK4 gene. Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. In particular, they may serve as biomarkers for both prostate cancer and breast cancer. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. In some tissues its expression is hormonally regulated. The expression pattern of a similar mouse protein in murine developing teeth supports a role for the protein in the degradation of enamel proteins. Alternate splice variants for this gene have been described, but their biological validity has not been determined.

KLK4 Kallikrein-related peptidase 4 is a protein which in humans is encoded by the KLK4 gene.[1][2][3] Kallikreins are a subgroup of serine proteases having diverse physiological functions.[4] Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. In particular, they may serve as biomarkers for both prostate cancer and breast cancer. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. In some tissues its expression is hormonally regulated. The expression pattern of a similar mouse protein in murine developing teeth supports a role for the protein in the degradation of enamel proteins.[5] Alternate splice variants for this gene have been described, but their biological validity has not been determined.[6]

https://www.wikidoc.org/index.php/KLK-4

ff21586a7edff43bfc7f16b470f35631a3148707

wikidoc

KLK7

KLK7 Kallikrein-related peptidase 7 (KLK7) is a serine protease that in humans is encoded by the KLK7 gene. KLK7 was initially purified from the epidermis and characterised as stratum corneum chymotryptic enzyme (SCCE). It was later identified as the seventh member of the human kallikrein family, which includes fifteen homologous serine proteases located on chromosome 19 (19q13). # Gene Alternative splicing of the KLK7 gene results in two transcript variants encoding the same protein. # Function KLK7 is secreted as an inactive zymogen in the stratum granulosum layer of the epidermis, requiring proteolytic cleavage of the short N-terminal pro-region to liberate activated enzyme. This may be performed by KLK5 or matriptase, which are in vitro activators of KLK7. Once active, KLK7 is able to cleave desmocollin and corneodesmosin. These proteins constitute the extracellular component of corneodesmosomes, intercellular cohesive structures which link the intermediate filaments of adjacent cells in the stratum corneum. Proteolysis of corneodesmosomes is required for desquamation, the shedding of corneocytes from the outer layer of the epidermis. This indicates a role for KLK7 in maintaining skin homeostasis. Both KLK5 and KLK14, other skin-expressed proteases, also cleave corneodesmosomal proteins. KLK5 is able to undergo autoactivation, as well as activating KLK7 and KLK14, suggesting a KLK skin cascade is responsible for coordinating desquamation. KLK7 activity is regulated by a number of endogenous protein inhibitors including LEKTI, SPINK6, elafin and alpha-2-Macroglobulin-like 1. Both Zn2+ and Cu2+ ions are also able to inhibit KLK7. KLK7 is a chymotrypsin-like serine protease, preferring to cleave proteins at the residues tyrosine, phenylalanine or leucine. Analysis of peptide substrate hydrolysis indicates a strong preference for tyrosine at P1. # Clinical significance ## Skin disease Dysregulation of KLK7 has been linked to several skin disorders including atopic dermatitis, psoriasis and Netherton syndrome. These diseases are characterised by excessively dry, scaly and inflamed skin, due to a disruption of skin homeostasis and correct barrier function. ## Cancer Overexpression of KLK7 may provide a route for metastasis in ovarian, breast, pancreatic, cervix, and melanoma cancers by excessive cleavage of cell junction proteins. It may also be underexpressed in lung cancer.

KLK7 Kallikrein-related peptidase 7 (KLK7) is a serine protease that in humans is encoded by the KLK7 gene.[1][2][3][4] KLK7 was initially purified from the epidermis and characterised as stratum corneum chymotryptic enzyme (SCCE).[5] It was later identified as the seventh member of the human kallikrein family, which includes fifteen homologous serine proteases located on chromosome 19 (19q13).[6] # Gene Alternative splicing of the KLK7 gene results in two transcript variants encoding the same protein.[4] # Function KLK7 is secreted as an inactive zymogen in the stratum granulosum layer of the epidermis, requiring proteolytic cleavage of the short N-terminal pro-region to liberate activated enzyme. This may be performed by KLK5 or matriptase, which are in vitro activators of KLK7.[7][8] Once active, KLK7 is able to cleave desmocollin and corneodesmosin.[9] These proteins constitute the extracellular component of corneodesmosomes, intercellular cohesive structures which link the intermediate filaments of adjacent cells in the stratum corneum. Proteolysis of corneodesmosomes is required for desquamation, the shedding of corneocytes from the outer layer of the epidermis. This indicates a role for KLK7 in maintaining skin homeostasis. Both KLK5 and KLK14, other skin-expressed proteases, also cleave corneodesmosomal proteins.[9] KLK5 is able to undergo autoactivation, as well as activating KLK7 and KLK14, suggesting a KLK skin cascade is responsible for coordinating desquamation.[8] KLK7 activity is regulated by a number of endogenous protein inhibitors including LEKTI,[10][11] SPINK6,[12] elafin[13] and alpha-2-Macroglobulin-like 1.[14] Both Zn2+ and Cu2+ ions are also able to inhibit KLK7.[13] KLK7 is a chymotrypsin-like serine protease, preferring to cleave proteins at the residues tyrosine, phenylalanine or leucine.[15] Analysis of peptide substrate hydrolysis indicates a strong preference for tyrosine at P1.[16] # Clinical significance ## Skin disease Dysregulation of KLK7 has been linked to several skin disorders including atopic dermatitis,[17][18] psoriasis[19] and Netherton syndrome.[20][21] These diseases are characterised by excessively dry, scaly and inflamed skin, due to a disruption of skin homeostasis and correct barrier function. ## Cancer Overexpression of KLK7 may provide a route for metastasis in ovarian,[22] breast,[23] pancreatic,[24] cervix,[25] and melanoma[26] cancers by excessive cleavage of cell junction proteins. It may also be underexpressed in lung cancer.[27]

https://www.wikidoc.org/index.php/KLK7

469f15247d7c7650ca341e1bdc1e49c75bea321a

wikidoc

KLK9

KLK9 Kallikrein-related peptidase 9 also known as KLK9 is an enzyme which in humans is encoded by the KLK9 gene. # Function KLK9 belongs to the kallikrein subgroup of serine proteases, which have diverse physiologic functions in many tissues. KLK9 is primarily expressed in thymus, testis, spinal cord, cerebellum, trachea, mammary gland, prostate, brain, salivary gland, ovary, and skin. # Clinical significance KLK9 is under steroid hormone regulation in ovarian and breast cancer cell lines and is a potential prognostic marker for early-stage ovarian and breast cancer patients. Its excretion in urine has been associated with cardiac hypertrophy and aorta wall thickness, as well as some renal alterations.

KLK9 Kallikrein-related peptidase 9 also known as KLK9 is an enzyme which in humans is encoded by the KLK9 gene.[1] # Function KLK9 belongs to the kallikrein subgroup of serine proteases, which have diverse physiologic functions in many tissues.[2][3][4] KLK9 is primarily expressed in thymus, testis, spinal cord, cerebellum, trachea, mammary gland, prostate, brain, salivary gland, ovary, and skin.[1] # Clinical significance KLK9 is under steroid hormone regulation in ovarian and breast cancer cell lines and is a potential prognostic marker for early-stage ovarian[5] and breast cancer patients.[6] Its excretion in urine has been associated with cardiac hypertrophy and aorta wall thickness, as well as some renal alterations.[7]

https://www.wikidoc.org/index.php/KLK9

04fa552f46029ca54b5df5f830b67143463dbb90

wikidoc

KNL1

KNL1 KNL1 (kinetochore scaffold 1, aka CASC5) is a protein that is encoded by the KNL1 gene in humans. # Function KNL1 is part of the outer kinetochore. It is a part of KMN network of proteins together with MIS12, and NDC80. KNL1 is involved in microtubule attachment to chromosome centromeres and in the activation of the spindle checkpoint during mitosis. The CASC5 gene is upregulated in the areas of cell proliferation surrounding the ventricles during fetal brain development. # Interactions CASC5 has been shown to interact with MIS12, BUB1, BUBR1 and ZWINT-1. # Polymorphisms Homozygous polymorphisms in the CASC5 gene have been seen in patients with autosomal recessive primary microcephaly (MCPH). The mutation resulted in the skipping of exon 18 transcription, causing a frameshift and the production of a truncated protein. This truncation inhibits the binding ability of MIS12.

KNL1 KNL1 (kinetochore scaffold 1, aka CASC5) is a protein that is encoded by the KNL1 gene in humans.[1][2][3][4] # Function KNL1 is part of the outer kinetochore. It is a part of KMN network of proteins together with MIS12, and NDC80.[5] KNL1 is involved in microtubule attachment to chromosome centromeres and in the activation of the spindle checkpoint during mitosis. The CASC5 gene is upregulated in the areas of cell proliferation surrounding the ventricles during fetal brain development.[6] # Interactions CASC5 has been shown to interact with MIS12,[7][8] BUB1, BUBR1 and ZWINT-1.[6] # Polymorphisms Homozygous polymorphisms in the CASC5 gene have been seen in patients with autosomal recessive primary microcephaly (MCPH). The mutation resulted in the skipping of exon 18 transcription, causing a frameshift and the production of a truncated protein. This truncation inhibits the binding ability of MIS12.[6]

https://www.wikidoc.org/index.php/KNL1

bd1abae5b15bd18459d4fd0aee91b0560c97252d

wikidoc

KRAS

KRAS KRAS ( K-ras or Ki-ras) is a gene that acts as an on/off switch in cell signalling. When it functions normally, it controls cell proliferation. When it is mutated, negative signalling is disrupted. Thus, cells can continuously proliferate, and often develop into cancer. It is called KRAS because it was first identified as an oncogene in Kirsten RAt Sarcoma virus. The viral oncogene was derived from cellular genome. Thus, KRAS gene in cellular genome is called a proto-oncogene. The gene product was first found as a p21 GTPase. Like other members of the ras subfamily, the KRAS protein is a GTPase and is an early player in many signal transduction pathways. KRAS is usually tethered to cell membranes because of the presence of an isoprene group on its C-terminus. There are two protein products of the KRAS gene in mammalian cells that result from the use of alternative exon 4 (exon 4A and 4B respectively): K-Ras4A and K-Ras4B, these proteins have different structure in their C-terminal region and use different mechanisms to localize to cellular membranes including the plasma membrane. # Function KRAS acts as a molecular on/off switch, using protein dynamics. Once it is allosterically activated, it recruits and activates proteins necessary for the propagation of growth factors, as well as other cell signaling receptors like c-Raf and PI 3-kinase. KRAS upregulates the GLUT1 glucose transporter, thereby contributing to the Warburg effect in cancer cells. KRAS binds to GTP in its active state. It also possesses an intrinsic enzymatic activity which cleaves the terminal phosphate of the nucleotide, converting it to GDP. Upon conversion of GTP to GDP, KRAS is deactivated. The rate of conversion is usually slow, but can be increased dramatically by an accessory protein of the GTPase-activating protein (GAP) class, for example RasGAP. In turn, KRAS can bind to proteins of the Guanine Nucleotide Exchange Factor (GEF) class (such as SOS1), which forces the release of bound nucleotide (GDP). Subsequently, KRAS binds GTP present in the cytosol and the GEF is released from ras-GTP. Other members of the Ras family include: HRAS and NRAS. These proteins all are regulated in the same manner and appear to differ in their sites of action within the cell. # Clinical significance This proto-oncogene is a Kirsten ras oncogene homolog from the mammalian ras gene family. A single amino acid substitution, and in particular a single nucleotide substitution, is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal cancer. Several germline KRAS mutations have been found to be associated with Noonan syndrome and cardio-facio-cutaneous syndrome. Somatic KRAS mutations are found at high rates in leukemias, colorectal cancer, pancreatic cancer and lung cancer. ## Colorectal cancer The impact of KRAS mutations is heavily dependent on the order of mutations. Primary KRAS mutations generally lead to a self-limiting hyperplastic or borderline lesion, but if they occur after a previous APC mutation it often progresses to cancer. KRAS mutations are more commonly observed in cecal cancers than colorectal cancers located in any other places from ascending colon to rectum. KRAS mutation is predictive of a very poor response to panitumumab (Vectibix®) and cetuximab (Erbitux®) therapy in colorectal cancer. Currently, the most reliable way to predict whether a colorectal cancer patient will respond to one of the EGFR-inhibiting drugs is to test for certain “activating” mutations in the gene that encodes KRAS, which occurs in 30%–50% of colorectal cancers. Studies show patients whose tumors express the mutated version of the KRAS gene will not respond to cetuximab or panitumumab. Although presence of the wild-type (or normal) KRAS gene does not guarantee that these drugs will work, a number of large studies have shown that cetuximab has significant efficacy in mCRC patients with KRAS wild-type tumors. In the Phase III CRYSTAL study, published in 2009, patients with the wild-type KRAS gene treated with Erbitux plus chemotherapy showed a response rate of up to 59% compared to those treated with chemotherapy alone. Patients with the KRAS wild-type gene also showed a 32% decreased risk of disease progression compared to patients receiving chemotherapy alone. Emergence of KRAS mutations is a frequent driver of acquired resistance to cetuximab anti-EGFR therapy in colorectal cancers. The emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression. It suggests to perform an early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance. ### KRAS amplification KRAS gene can also be amplified in colorectal cancer. KRAS amplification is mutually exclusive with KRAS mutations. Tumors or cell lines harboring this genetic lesion are not responsive to EGFR inhibitors. Although KRAS amplification is an infrequent event in colorectal cancer, it might be responsible for precluding response to anti-EGFR treatment in some patients. Amplification of wild-type Kras has also been observed in ovarian, gastric, uterine, and lung cancers. ## Lung cancer Whether a patient is positive or negative for a mutation in the epidermal growth factor receptor (EGFR) will predict how patients will respond to certain EGFR antagonists such as erlotinib (Tarceva) or gefitinib (Iressa). Patients who harbor an EGFR mutation have a 60% response rate to erlotinib. However, the mutation of KRAS and EGFR are generally mutually exclusive. Lung cancer patients who are positive for KRAS mutation (and the EGFR status would be wild type) have a low response rate to erlotinib or gefitinib estimated at 5% or less. Different types of data including mutation status and gene expression did not have a significant prognostic power. No correlation to survival was observed in 72% of all studies with KRAS sequencing performed in non-small cell lung cancer (NSCLC). However, KRAS mutations can not only affect the gene itself and the expression of the corresponding protein, but can also influence the expression of other downstream genes involved in crucial pathways regulating cell growth, differentiation and apoptosis. The different expression of these genes in KRAS-mutant tumors might have a more prominent role in affecting patient’s clinical outcomes. A 2008 paper published in Cancer Research concluded that the in vivo administration of the compound oncrasin-1 "suppressed the growth of K-ras mutant human lung tumor xenografts by >70% and prolonged the survival of nude mice bearing these tumors, without causing detectable toxicity", and that the "results indicate that oncrasin-1 or its active analogues could be a novel class of anticancer agents which effectively kill K-Ras mutant cancer cells." # KRAS testing In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs (panitumumab (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations. In 2012, the FDA also cleared QIAGEN's therascreen KRAS test, which is a genetic test designed to detect the presence of seven mutations in the KRAS gene in colorectal cancer cells. This test is used to aid physicians in identifying patients with metastatic colorectal cancer for treatment with Erbitux. The presence of KRAS mutations in colorectal cancer tissue indicates that the patient may not benefit from treatment with Erbitux. If the test result indicates that the KRAS mutations are absent in the colorectal cancer cells, then the patient may be considered for treatment with Erbitux. # Interactions KRAS has been shown to interact with: - C-Raf, - PIK3CG, - RALGDS, and - RASSF2. - Calmodulin

KRAS KRAS ( K-ras or Ki-ras) is a gene that acts as an on/off switch in cell signalling. When it functions normally, it controls cell proliferation. When it is mutated, negative signalling is disrupted. Thus, cells can continuously proliferate, and often develop into cancer. It is called KRAS because it was first identified as an oncogene in Kirsten RAt Sarcoma virus.[1] The viral oncogene was derived from cellular genome. Thus, KRAS gene in cellular genome is called a proto-oncogene. The gene product was first found as a p21 GTPase.[2][3] Like other members of the ras subfamily, the KRAS protein is a GTPase and is an early player in many signal transduction pathways. KRAS is usually tethered to cell membranes because of the presence of an isoprene group on its C-terminus. There are two protein products of the KRAS gene in mammalian cells that result from the use of alternative exon 4 (exon 4A and 4B respectively): K-Ras4A and K-Ras4B, these proteins have different structure in their C-terminal region and use different mechanisms to localize to cellular membranes including the plasma membrane.[4] # Function KRAS acts as a molecular on/off switch, using protein dynamics. Once it is allosterically activated, it recruits and activates proteins necessary for the propagation of growth factors, as well as other cell signaling receptors like c-Raf and PI 3-kinase. KRAS upregulates the GLUT1 glucose transporter, thereby contributing to the Warburg effect in cancer cells.[5] KRAS binds to GTP in its active state. It also possesses an intrinsic enzymatic activity which cleaves the terminal phosphate of the nucleotide, converting it to GDP. Upon conversion of GTP to GDP, KRAS is deactivated. The rate of conversion is usually slow, but can be increased dramatically by an accessory protein of the GTPase-activating protein (GAP) class, for example RasGAP.[citation needed] In turn, KRAS can bind to proteins of the Guanine Nucleotide Exchange Factor (GEF) class (such as SOS1), which forces the release of bound nucleotide (GDP). Subsequently, KRAS binds GTP present in the cytosol and the GEF is released from ras-GTP. Other members of the Ras family include: HRAS and NRAS. These proteins all are regulated in the same manner and appear to differ in their sites of action within the cell.[citation needed] # Clinical significance This proto-oncogene is a Kirsten ras oncogene homolog from the mammalian ras gene family. A single amino acid substitution, and in particular a single nucleotide substitution, is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma,[6] mucinous adenoma, ductal carcinoma of the pancreas and colorectal cancer.[7][8] Several germline KRAS mutations have been found to be associated with Noonan syndrome[9] and cardio-facio-cutaneous syndrome.[10] Somatic KRAS mutations are found at high rates in leukemias, colorectal cancer,[11] pancreatic cancer[12] and lung cancer.[13] ## Colorectal cancer The impact of KRAS mutations is heavily dependent on the order of mutations. Primary KRAS mutations generally lead to a self-limiting hyperplastic or borderline lesion, but if they occur after a previous APC mutation it often progresses to cancer.[14] KRAS mutations are more commonly observed in cecal cancers than colorectal cancers located in any other places from ascending colon to rectum.[15][16] KRAS mutation is predictive of a very poor response to panitumumab (Vectibix®) and cetuximab (Erbitux®) therapy in colorectal cancer.[17] Currently, the most reliable way to predict whether a colorectal cancer patient will respond to one of the EGFR-inhibiting drugs is to test for certain “activating” mutations in the gene that encodes KRAS, which occurs in 30%–50% of colorectal cancers. Studies show patients whose tumors express the mutated version of the KRAS gene will not respond to cetuximab or panitumumab.[18] Although presence of the wild-type (or normal) KRAS gene does not guarantee that these drugs will work, a number of large studies[19][20] have shown that cetuximab has significant efficacy in mCRC patients with KRAS wild-type tumors. In the Phase III CRYSTAL study, published in 2009, patients with the wild-type KRAS gene treated with Erbitux plus chemotherapy showed a response rate of up to 59% compared to those treated with chemotherapy alone. Patients with the KRAS wild-type gene also showed a 32% decreased risk of disease progression compared to patients receiving chemotherapy alone.[20] Emergence of KRAS mutations is a frequent driver of acquired resistance to cetuximab anti-EGFR therapy in colorectal cancers. The emergence of KRAS mutant clones can be detected non-invasively[how?] months before radiographic progression. It suggests to perform an early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.[21] ### KRAS amplification KRAS gene can also be amplified in colorectal cancer. KRAS amplification is mutually exclusive with KRAS mutations. Tumors or cell lines harboring this genetic lesion are not responsive to EGFR inhibitors. Although KRAS amplification is an infrequent event in colorectal cancer, it might be responsible for precluding response to anti-EGFR treatment in some patients.[22] Amplification of wild-type Kras has also been observed in ovarian,[23] gastric, uterine, and lung cancers.[24] ## Lung cancer Whether a patient is positive or negative for a mutation in the epidermal growth factor receptor (EGFR) will predict how patients will respond to certain EGFR antagonists such as erlotinib (Tarceva) or gefitinib (Iressa). Patients who harbor an EGFR mutation have a 60% response rate to erlotinib. However, the mutation of KRAS and EGFR are generally mutually exclusive.[25][26][27] Lung cancer patients who are positive for KRAS mutation (and the EGFR status would be wild type) have a low response rate to erlotinib or gefitinib estimated at 5% or less.[25] Different types of data including mutation status and gene expression did not have a significant prognostic power.[28] No correlation to survival was observed in 72% of all studies with KRAS sequencing performed in non-small cell lung cancer (NSCLC).[28] However, KRAS mutations can not only affect the gene itself and the expression of the corresponding protein, but can also influence the expression of other downstream genes involved in crucial pathways regulating cell growth, differentiation and apoptosis. The different expression of these genes in KRAS-mutant tumors might have a more prominent role in affecting patient’s clinical outcomes.[28] A 2008 paper published in Cancer Research concluded that the in vivo administration of the compound oncrasin-1 "suppressed the growth of K-ras mutant human lung tumor xenografts by >70% and prolonged the survival of nude mice bearing these tumors, without causing detectable toxicity", and that the "results indicate that oncrasin-1 or its active analogues could be a novel class of anticancer agents which effectively kill K-Ras mutant cancer cells."[29] # KRAS testing In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs (panitumumab (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations.[30] In 2012, the FDA also cleared QIAGEN's therascreen KRAS test, which is a genetic test designed to detect the presence of seven mutations in the KRAS gene in colorectal cancer cells. This test is used to aid physicians in identifying patients with metastatic colorectal cancer for treatment with Erbitux. The presence of KRAS mutations in colorectal cancer tissue indicates that the patient may not benefit from treatment with Erbitux. If the test result indicates that the KRAS mutations are absent in the colorectal cancer cells, then the patient may be considered for treatment with Erbitux.[31] # Interactions KRAS has been shown to interact with: - C-Raf,[32][33] - PIK3CG,[34] - RALGDS,[32][35] and - RASSF2.[36] - Calmodulin[37]

https://www.wikidoc.org/index.php/KRAS

74ae681ffe10cfb07b782b20dbe6e5fe896831a9

wikidoc

KTN1

KTN1 Kinectin is a protein that in humans is encoded by the KTN1 gene. # Function Various cellular organelles and vesicles are transported along the microtubules in the cytoplasm. Likewise, membrane recycling of the endoplasmic reticulum (ER), Golgi assembly at the microtubule organizing center, and alignment of lysosomes along microtubules are all related processes. The transport of organelles requires a special class of microtubule-associated proteins (MAPs). One of these is the molecular motor kinesin (see MIM 148760 and MIM 600025), an ATPase that moves vesicles unidirectionally toward the plus end of the microtubule. Another such MAP is kinectin, a large integral ER membrane protein. Antibodies directed against kinectin have been shown to inhibit its binding to kinesin. # Interactions KTN1 has been shown to interact with EEF1D, RhoG and RHOA.

KTN1 Kinectin is a protein that in humans is encoded by the KTN1 gene.[1][2] # Function Various cellular organelles and vesicles are transported along the microtubules in the cytoplasm. Likewise, membrane recycling of the endoplasmic reticulum (ER), Golgi assembly at the microtubule organizing center, and alignment of lysosomes along microtubules are all related processes. The transport of organelles requires a special class of microtubule-associated proteins (MAPs). One of these is the molecular motor kinesin (see MIM 148760 and MIM 600025), an ATPase that moves vesicles unidirectionally toward the plus end of the microtubule. Another such MAP is kinectin, a large integral ER membrane protein. Antibodies directed against kinectin have been shown to inhibit its binding to kinesin.[supplied by OMIM][2] # Interactions KTN1 has been shown to interact with EEF1D,[3] RhoG[4][5] and RHOA.[4][5][6][7]

https://www.wikidoc.org/index.php/KTN1

a986849d29947f16e1383032845949ca437094ef

wikidoc

Kava

Kava Kava (Piper methysticum) (Piper Latin for "pepper", methysticum Greek for "intoxicating") is an ancient crop of the western Pacific. Other names for kava include Template:Okinaawa (Hawaii), 'ava (Samoa), yaqona (Fiji), and sakau (Pohnpei). The word kava is used to refer both to the plant and the beverage produced from it. In some parts of the Western World, kava extract is marketed as herbal medicine against stress and anxiety. # Preparation and consumption Kava is consumed in various ways throughout the Pacific Ocean cultures of Polynesia, Vanuatu, Melanesia and some parts of Micronesia and Australia. Traditionally it is prepared by either chewing, grinding or pounding. Chewing is followed by depositing into a bowl, mixing with water and straining through the cloth-like fiber of a coconut tree. Grinding is done by hand against a cone-shaped block of dead coral; the hand forms a mortar and the coral a pestle. The ground root is combined with only a little water, as the fresh root releases moisture during grinding. Pounding is done in a large stone with a small log. The product is then added to cold water and consumed as quickly as possible. The extract is an emulsion kavalactone droplets in starch. The taste is slightly pungent, while the distinctive aroma depends on whether it was prepared from dry or fresh plant, and on the variety. The colour is grey to tan to opaque greenish. Kava prepared as described above is much more potent than processed kava. Chewing produces the strongest effect because it produces the finest particles. Various sources incorrectly state that it is because saliva enzymes act on the plant. Fresh, undried kava produces a stronger beverage than old, dry kava. The strength also depends on the species and techniques of cultivation. Fijians commonly share a drink called "grog", made by pounding sun-dried kava root into a fine powder and mixing it with cold water. Traditionally, grog is drunk from the shorn half-shell of a coconut, called a "bilo." Despite tasting very much like dirty water, grog is very popular in Fiji, especially among young men, and often brings people together for storytelling and socializing. # Effects A moderately potent kava drink causes effects within 20-30 minutes that last for about two and a half hours, but can be felt for up to eight hours. The sensations, in order of appearance, are slight tongue and lip numbing caused by the contraction of the blood vessels in these areas (the lips and skin surrounding may appear unusually pale); mildly talkative and euphoric behavior; anxiolytic (calming) effects, sense of well-being, clear thinking; and relaxed muscles. Sleep is often restful and there are pronounced periods of sleepiness correlating to the amount and potency of kava consumed. In Vanuatu, a strong kava drink is normally followed by a hot meal or tea. The meal traditionally follows some time after the drink so that the psychoactives are absorbed into the bloodstream more quickly. A potent drink results in a faster onset with a lack of stimulation, somnolence, and then deep, dreamless sleep within 30 minutes. Unlike alcohol-induced sleep, after wakening the drinker does not experience any mental or physical after effects. It is reported that many people experience rather vivid dreams after drinking kava. # Kava culture Kava is used for medicinal, religious, political, cultural and social purposes throughout the Pacific. These cultures have a great respect for the plant and place a high importance on it. It is used primarily at social gatherings to increase amiability and to relax after work. It has great religious significance, being used to obtain inspiration. In some Westernized Pacific peoples, the drink has been demonized and seen as a vice, and youth there often reject its traditional use. However, it has gained a cult following among the youth culture of caucasian people living on Pacific islands. # Botany and agronomy There are several cultivars of kava, with varying concentrations of primary and secondary psychoactive substances. The largest number are grown in the Republic of Vanuatu, and so it is recognised as the "home" of kava. Kava was historically grown only in the Pacific islands of Hawaii, Federated States of Micronesia, Vanuatu, Fiji, the Samoas and Tonga. Some is grown in the Solomon Islands since World War II, but most is imported. Kava is a cash crop in Vanuatu and Fiji. The kava shrub thrives in loose, well-drained soils where plenty of air reaches the roots. It grows naturally where rainfall is plentiful (over 2,000mm/yr). Ideal growing conditions are 20-35 degrees Celsius (70-95 Fahrenheit), and 70-100% relative humidity. Too much sunlight is harmful, especially in early growth, so kava is an understory crop. Kava cannot reproduce sexually. Female flowers are especially rare and do not produce fruit even when hand-pollinated. Its propagation is entirely due to human efforts by the method of striking. Traditionally, plants are harvested around 4 years of age, as older plants have higher concentrations of kavalactones. But in the past two decades farmers have been harvesting younger and younger plants, as young as 18 months. After reaching about 2m height, plants grow a wider stalk and additional stalks, but not much taller. The roots can reach 60cm depth. # Composition Fresh kava root contains on average 80% water. Dried root contains approximately 43% starch, 20% fibers, 15% kavalactones, 12% water, 3.2% sugars, 3.6% proteins, and 3.2% minerals. Kavalactone content is greatest in the roots and decreases higher up the plant. Relative concentrations of 15%, 10% and 5% have been observed in the root, stump, and basal stems, respectively. # Basic research on anti-cancer potential On 15 February 2006, the Fiji Times and Fiji Live reported that researchers at the University of Aberdeen in Scotland and the Laboratoire de Biologie Moleculaire du Cancer in Luxembourg had discovered that kava may treat ovarian cancer and leukemia. Kava compounds inhibited the activation of a nuclear factor that led to the growth of cancer cells. The Aberdeen University researchers published in the journal The South Pacific Journal of Natural Science that kava methanol extracts had been shown to kill leukaemia and ovarian cancer cells in test tubes. The kava compounds were shown to target only cancerous cells but not healthy cells. Fiji Kava Council Chairman Ratu Josateki Nawalowalo welcomed the findings, saying that they would boost the kava industry. For his part, Agriculture Minister Ilaitia Tuisese called on the researchers to help persuade members of European Union to lift their ban on kava imports. # Pharmacology Kavas active principal ingredients are the kavalactones, of which at least 15 have been identified and are all considered psychoactive. Only six of them produce noticeable effects, and their concentrations in kava plants vary. Different ratios can produce different effects. Kava has been considered very safe. Yet, some kava herbal supplements have been accused of contributing to very rare but severe hepatotoxic reactions (see section on safety) such may have been due to their use of plant parts other than the root, such as stems or peelings that are known to have been exported to Europe manufacturers. Kava is considered to be not addictive. ## Pharmacodynamics Desmethoxyyangonin, one of the six major kavalactones, is a reversible MAO-B inhibitor (Ki 280 nM) and is able to increase dopamine levels in the nucleus accumbens. This finding might correspond to the slightly euphoric action of kava. Kavain in both enantiomeric forms inhibit the reuptake of noradrenalin at the transporter (NAT), but not of serotonin (SERT). An elevated extracellular NA level in the brain may account for the reported enhancement of attention and focus. # Safety ## Incidents and regulation In the year 2001 concerns were raised about the safety of commercial kava products. There have been allegations of severe liver toxicity, including liver failure in some people who had used dietary supplements containing kava extract. The possbility of liver damage consequently prompted action of many regulatory agencies in European countries where the legal precautionary principle so mandated. In the UK, the Medicines for Human Use (Kava-kava) (Prohibition) Order 2002 prohibits the sale, supply or import of most derivative medicinal products. Kava is banned in Switzerland, France and The Netherlands. The health agency of Canada issued a stop-sale order for kava in 2002. But legislation in 2004 made the legal status of kava uncertain. The United States CDC has released a report expressing reservations about the use of kava and its possibly adverse side effects (specifically severe liver toxicity), as has the Food and Drug Administration (FDA). The Australian Therapeutic Goods Administration has recommended that no more than 250 mg of kavalactones be taken in a 24 hour period. According to the Medicines Control Agency in the U.K., there is no safe dose of kava, as there is no way to predict which individuals would have adverse reactions. However, none of these regulatory actions and took into account the fact that when kava preparations are made with the peeled root of the plant no toxicity is found. ## Toxicology The legal intervention stimulated research, and hepatotoxic substances were found in the plant. Researchers from the University of Hawaii at Manoa found that an alkaloid called pipermethystine (formula 1), contained in stem peelings and leaves, had toxic effects on liver cells in vitro and in vivo. In rats fed with 10 mg/kg pipermethystine for two weeks, indications of hepatic toxicity were found. Comparable signs of toxicity were not detected with kava rhizome extracts (100 mg/kg, 2 weeks), (73 mg/kg, 3 months). Flavokavain B, found in the plant's rhizome, may also contribute to toxic effects. And, it is known that some of the kavapyrones block several subtypes of the enzyme cytochrome P450, which can result in adverse interactions with other drugs used concomitantly. The plant also contains glutathione. In extracts its concentration varies depending on the lipophilicity of the applied solvent; the amount is higher in aqueous extracts. Glutathione in kava preparations is able to provide a certain protection of liver cells. Before 2002, substantial amounts of aerial parts of the kava plant were being exported to North America and Europe and obviously used for the production of commercial prepartions. For traditional use in the South Pacific, stem peelings and leaves are discarded, and only the rhizomes are used and extracted with water. This may explain why native populations that make heavy use of kava experience side effects that are mild, temporary, and confined to the skin, whereas industrialized countries that have newly adopted kava occasionally show severe, acute responses. ## Outlook The issue has long been controversial and the debate fuelled by conflicting economic interests of monopoly-driven pharmaceutical companies, concerned with competition in anti-anxiety drug sales, and kava-exporting nations of the Pacific Islands as well as disagreements between the medical establishment and proponents of herbal and natural medicine. The German Federal Institute for Drugs and Medical Devices (BfArM), which in 2002 temporarily inactivated kava registrations, asked the producers to provide new clinical data by June 2007, in which case a reinstitution of the kava products on the market might again be possible. A New Zealand committee from the New Zealand Association of Medical Herbalists that considered the issue commented in its summary: "A comparison with paracetamol-associated hepatotoxicity, results in the conclusion that these potential risks for kava are dramatically less than that of a popular non prescription drug widely sold through grocery outlets." The NZ government is currently only considering requiring a suitable warning label standard to go on kava products.

Kava Kava (Piper methysticum) (Piper Latin for "pepper", methysticum Greek for "intoxicating") is an ancient crop of the western Pacific. Other names for kava include Template:Okinaawa (Hawaii), 'ava (Samoa), yaqona (Fiji), and sakau (Pohnpei). The word kava is used to refer both to the plant and the beverage produced from it. In some parts of the Western World, kava extract is marketed as herbal medicine against stress and anxiety. # Preparation and consumption Kava is consumed in various ways throughout the Pacific Ocean cultures of Polynesia, Vanuatu, Melanesia and some parts of Micronesia and Australia. Traditionally it is prepared by either chewing, grinding or pounding. Chewing is followed by depositing into a bowl, mixing with water and straining through the cloth-like fiber of a coconut tree. Grinding is done by hand against a cone-shaped block of dead coral; the hand forms a mortar and the coral a pestle. The ground root is combined with only a little water, as the fresh root releases moisture during grinding. Pounding is done in a large stone with a small log. The product is then added to cold water and consumed as quickly as possible. The extract is an emulsion kavalactone droplets in starch. The taste is slightly pungent, while the distinctive aroma depends on whether it was prepared from dry or fresh plant, and on the variety. The colour is grey to tan to opaque greenish. Kava prepared as described above is much more potent than processed kava. Chewing produces the strongest effect because it produces the finest particles. Various sources incorrectly state that it is because saliva enzymes act on the plant. Fresh, undried kava produces a stronger beverage than old, dry kava. The strength also depends on the species and techniques of cultivation. Fijians commonly share a drink called "grog", made by pounding sun-dried kava root into a fine powder and mixing it with cold water. Traditionally, grog is drunk from the shorn half-shell of a coconut, called a "bilo." Despite tasting very much like dirty water, grog is very popular in Fiji, especially among young men, and often brings people together for storytelling and socializing.[1] # Effects A moderately potent kava drink causes effects within 20-30 minutes that last for about two and a half hours, but can be felt for up to eight hours. The sensations, in order of appearance, are slight tongue and lip numbing caused by the contraction of the blood vessels in these areas (the lips and skin surrounding may appear unusually pale); mildly talkative and euphoric behavior; anxiolytic (calming) effects, sense of well-being, clear thinking; and relaxed muscles. Sleep is often restful and there are pronounced periods of sleepiness correlating to the amount and potency of kava consumed. In Vanuatu, a strong kava drink is normally followed by a hot meal or tea. The meal traditionally follows some time after the drink so that the psychoactives are absorbed into the bloodstream more quickly. A potent drink results in a faster onset with a lack of stimulation, somnolence, and then deep, dreamless sleep within 30 minutes. Unlike alcohol-induced sleep, after wakening the drinker does not experience any mental or physical after effects. It is reported that many people experience rather vivid dreams after drinking kava. [1] # Kava culture Kava is used for medicinal, religious, political, cultural and social purposes throughout the Pacific. These cultures have a great respect for the plant and place a high importance on it. It is used primarily at social gatherings to increase amiability and to relax after work. It has great religious significance, being used to obtain inspiration. In some Westernized Pacific peoples, the drink has been demonized and seen as a vice, and youth there often reject its traditional use. However, it has gained a cult following among the youth culture of caucasian people living on Pacific islands. # Botany and agronomy There are several cultivars of kava, with varying concentrations of primary and secondary psychoactive substances. The largest number are grown in the Republic of Vanuatu, and so it is recognised as the "home" of kava. Kava was historically grown only in the Pacific islands of Hawaii, Federated States of Micronesia, Vanuatu, Fiji, the Samoas and Tonga. Some is grown in the Solomon Islands since World War II, but most is imported. Kava is a cash crop in Vanuatu and Fiji. The kava shrub thrives in loose, well-drained soils where plenty of air reaches the roots. It grows naturally where rainfall is plentiful (over 2,000mm/yr). Ideal growing conditions are 20-35 degrees Celsius (70-95 Fahrenheit), and 70-100% relative humidity. Too much sunlight is harmful, especially in early growth, so kava is an understory crop. Kava cannot reproduce sexually. Female flowers are especially rare and do not produce fruit even when hand-pollinated. Its propagation is entirely due to human efforts by the method of striking. Traditionally, plants are harvested around 4 years of age, as older plants have higher concentrations of kavalactones. But in the past two decades farmers have been harvesting younger and younger plants, as young as 18 months. After reaching about 2m height, plants grow a wider stalk and additional stalks, but not much taller. The roots can reach 60cm depth. # Composition Fresh kava root contains on average 80% water. Dried root contains approximately 43% starch, 20% fibers, 15% kavalactones, 12% water, 3.2% sugars, 3.6% proteins, and 3.2% minerals. Kavalactone content is greatest in the roots and decreases higher up the plant. Relative concentrations of 15%, 10% and 5% have been observed in the root, stump, and basal stems, respectively. # Basic research on anti-cancer potential On 15 February 2006, the Fiji Times and Fiji Live reported that researchers at the University of Aberdeen in Scotland and the Laboratoire de Biologie Moleculaire du Cancer in Luxembourg had discovered that kava may treat ovarian cancer and leukemia. Kava compounds inhibited the activation of a nuclear factor that led to the growth of cancer cells. The Aberdeen University researchers published in the journal The South Pacific Journal of Natural Science that kava methanol extracts had been shown to kill leukaemia and ovarian cancer cells in test tubes. The kava compounds were shown to target only cancerous cells but not healthy cells. Fiji Kava Council Chairman Ratu Josateki Nawalowalo welcomed the findings, saying that they would boost the kava industry. For his part, Agriculture Minister Ilaitia Tuisese called on the researchers to help persuade members of European Union to lift their ban on kava imports. # Pharmacology Kavas active principal ingredients are the kavalactones, of which at least 15 have been identified and are all considered psychoactive. Only six of them produce noticeable effects, and their concentrations in kava plants vary. Different ratios can produce different effects. Kava has been considered very safe. Yet, some kava herbal supplements have been accused of contributing to very rare but severe hepatotoxic reactions (see section on safety) such may have been due to their use of plant parts other than the root, such as stems or peelings that are known to have been exported to Europe manufacturers. Kava is considered to be not addictive. ## Pharmacodynamics Desmethoxyyangonin, one of the six major kavalactones, is a reversible MAO-B inhibitor (Ki 280 nM)[2] and is able to increase dopamine levels in the nucleus accumbens. This finding might correspond to the slightly euphoric action of kava.[3] Kavain in both enantiomeric forms inhibit the reuptake of noradrenalin at the transporter (NAT), but not of serotonin (SERT).[4] An elevated extracellular NA level in the brain may account for the reported enhancement of attention and focus. # Safety ## Incidents and regulation In the year 2001 concerns were raised about the safety of commercial kava products.[5] There have been allegations of severe liver toxicity, including liver failure in some people who had used dietary supplements containing kava extract. The possbility of liver damage consequently prompted action of many regulatory agencies in European countries where the legal precautionary principle so mandated. In the UK, the Medicines for Human Use (Kava-kava) (Prohibition) Order 2002 prohibits the sale, supply or import of most derivative medicinal products. Kava is banned in Switzerland, France and The Netherlands[citation needed]. The health agency of Canada issued a stop-sale order for kava in 2002. But legislation in 2004 made the legal status of kava uncertain. The United States CDC has released a report[6] expressing reservations about the use of kava and its possibly adverse side effects (specifically severe liver toxicity), as has the Food and Drug Administration (FDA).[7] The Australian Therapeutic Goods Administration has recommended that no more than 250 mg of kavalactones be taken in a 24 hour period.[8] According to the Medicines Control Agency in the U.K., there is no safe dose of kava, as there is no way to predict which individuals would have adverse reactions.[9] However, none of these regulatory actions and took into account the fact that when kava preparations are made with the peeled root of the plant no toxicity is found.[10][citation needed] ## Toxicology The legal intervention stimulated research, and hepatotoxic substances were found in the plant. Researchers from the University of Hawaii at Manoa found that an alkaloid called pipermethystine (formula 1), contained in stem peelings and leaves, had toxic effects on liver cells in vitro[11] and in vivo.[12] In rats fed with 10 mg/kg pipermethystine for two weeks, indications of hepatic toxicity were found. Comparable signs of toxicity were not detected with kava rhizome extracts (100 mg/kg, 2 weeks)[12], (73 mg/kg, 3 months).[13] Flavokavain B, found in the plant's rhizome, may also contribute to toxic effects.[14] And, it is known that some of the kavapyrones block several subtypes of the enzyme cytochrome P450[15], which can result in adverse interactions with other drugs used concomitantly. The plant also contains glutathione. In extracts its concentration varies depending on the lipophilicity of the applied solvent; the amount is higher in aqueous extracts. Glutathione in kava preparations is able to provide a certain protection of liver cells.[16] Before 2002, substantial amounts of aerial parts of the kava plant were being exported to North America and Europe and obviously used for the production of commercial prepartions. For traditional use in the South Pacific, stem peelings and leaves are discarded, and only the rhizomes are used and extracted with water. This may explain why native populations that make heavy use of kava experience side effects that are mild, temporary, and confined to the skin, whereas industrialized countries that have newly adopted kava occasionally show severe, acute responses. ## Outlook The issue has long been controversial and the debate fuelled by conflicting economic interests of monopoly-driven pharmaceutical companies, concerned with competition in anti-anxiety drug sales, and kava-exporting nations of the Pacific Islands as well as disagreements between the medical establishment and proponents of herbal and natural medicine. The German Federal Institute for Drugs and Medical Devices (BfArM), which in 2002 temporarily inactivated kava registrations, asked the producers to provide new clinical data by June 2007, in which case a reinstitution of the kava products on the market might again be possible.[17] A New Zealand committee from the New Zealand Association of Medical Herbalists that considered the issue commented in its summary: "A comparison with paracetamol-associated hepatotoxicity, results in the conclusion that these potential risks for kava are dramatically less than that of a popular non prescription drug widely sold through grocery outlets."[18][19] The NZ government is currently only considering requiring a suitable warning label standard to go on kava products.

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Khat

Khat Khat (Catha edulis, family Celastraceae, Ge'ez ጫት č̣āt; Arabic: قات; Somali: Jaad; IPA: Template:IPA), and also known as qat, gat, chat, and miraa), is a flowering plant native to tropical East Africa and the Arabian Peninsula. Believed to have originated in Ethiopia, it is a shrub or small tree growing to 5–8 m tall, with evergreen leaves 5–10 cm long and 1–4 cm broad. The flowers are produced on short axillary cymes 4–8 cm long, each flower small, with five white petals. The fruit is an oblong three-valved capsule containing 1–3 seeds. Khat contains the alkaloid cathinone, an amphetamine-like stimulant which causes excitement and euphoria. In 1980 the World Health Organization classified khat as a drug of abuse that can produce mild to moderate psychological dependence, and the plant has been targeted by anti-drug organizations like the DEA. It is a controlled/illegal substance in many countries. # History The origins of khat are often argued. Many believe that they are Ethiopian in nature, from where it spread to the hillsides of East Africa and Yemen. Others believe that khat originated in Yemen before spreading to Ethiopia and nearby countries. Sir Richard Burton (First Footsteps in East Africa, 1856) explains that khat was introduced to the Yemen from Ethiopia in the 15th century. There is also evidence to suggest this may have occurred as early as the 13th century. Through botanical analysis, Revri (1983) supports Yemen origins of the plant. From Ethiopia and Yemen the trees spread to Kenya, Somalia, Malawi, Uganda, Tanzania, Arabia, the Congo, what are now Zimbabwe and Zambia, and South Africa. The earliest recorded use of khat medically is believed to be within the New Testament. The ancient Egyptians considered the khat plant a "divine food" which was capable of releasing humanity's divinity. The Egyptians used the plant for more than its stimulating effects. They used it as a metamorphic process and transcended into "apotheosis", intending to make the user god-like. In 1854, the Malay writer Abdullah bin Abdul Kadir noted that the custom of chewing Khat was prevalent in Al Hudaydah in Yemen: "I observed a new peculiarity in this city—everyone chewed leaves as goats chew the cud. There is a type of leaf, rather wide and about two fingers in length, which is widely sold, as people would consume these leaves just as they are; unlike betel leaves, which need certain condiments to go with them, these leaves were just stuffed fully into the mouth and munched. Thus when people gathered around, the remnants from these leaves would pile up in front of them. When they spat, their saliva was green. I then queried them on this matter: ‘What benefits are there to be gained from eating these leaves?’ To which they replied, ‘None whatsoever, it’s just another expense for us as we’ve grown accustomed to it’. Those who consume these leaves have to eat lots of ghee and honey, for they would fall ill otherwise. The leaves are known as Kad." In the town of Bohmensaka, South Africa the consumption of this product has been noted to date back as late as the 1500's. Tribes would chew on these at festivals and large gatherings. Khat was a delicacy to the natives and was customary to their nature. # Cultivation and uses Khat has been grown for use as a stimulant for centuries in the Horn of Africa and the Arabian Peninsula. There, chewing khat predates the use of coffee and is used in a similar social context. Its fresh leaves and tops are chewed or, less frequently, dried and consumed as tea, in order to achieve a state of euphoria and stimulation. Due to the availability of rapid, inexpensive air transportation, the drug has been reported in England, Rome, Amsterdam, Canada, Australia, New Zealand and the United States. The public has become more aware of this exotic drug through media reports pertaining to the United Nations mission in Somalia, where khat use is widespread, and its role in the Persian Gulf. The khat plant is known by a variety of names, such as qat and ghat in Yemen, chat in Ethiopia, jaad in Somalia and miraa in Kenya and Tanzania. Khat use has traditionally been confined to the regions where khat is grown, because only the fresh leaves have the desired stimulating effects. In recent years improved roads, off-road motor vehicles and air transport have increased the global distribution of this perishable commodity. Traditionally, khat has been used as a socializing drug, and this is still very much the case in Yemen where khat-chewing is a predominantly male habit. In other countries, khat is consumed largely by single individuals and at parties. It is mainly a recreational drug in the countries which grow khat, though it may also be used by farmers and laborers for reducing physical fatigue and by drivers and students for improving attention. Within the counter-culture segments of the Kenyan elite population, Khat (referred to as "veve") is used to counter the effects of a hangover or binge-drinking, similar to the use of the coca leaf in South America. Cheweing Khat is not primarily a male activity in Yemen, with women having their own saloons for the occasion and partaking in cheweing Khat with their husbands on weekends. In many places where grown, Khat has become mainstream enough for many children to start chewing the plant before puberty. Khat is used for its mild euphoric and stimulating effects, and also has anorectic side-effects. It use is generally not limited by religion, though the Ethiopian Orthodox Tewahedo Church (along with its Eritrean counterpart) has forbidden Christians from using it due to its stimulating effects. In Yemen it is so popular that 40% of the country's water supply goes towards irrigating it, with production increasing by about 10% to 15% every year. The water supply of Sanaa is so threatened by the crop that government officials have even proposed relocating large portions of the city's population to the coast of the Red Sea. In Somalia, the Supreme Islamic Courts Council, which took control of much of the country in 2006, banned khat during Ramadan, sparking street protests in Kismayo. In November 2006, Kenya banned all flights to Somalia, citing security concerns, prompting protests by Kenyan khat growers. The Kenyan MP from Ntonyiri, Meru North District stated that local land had been specialized in khat cultivation, that 20 tons worth $800,000 were shipped to Somalia daily and that a flight ban could devastate the local economy. With the victory of the Provisional Government backed by Ethiopian forces in the end of December 2006, khat has returned to the streets of Mogadishu, though Kenyan traders have noted demand has not yet returned to pre-ban levels. # Chemistry/pharmacology The stimulant effect of the plant was originally attributed to "katin", cathine, a phenethylamine-type substance isolated from the plant. However, the attribution was disputed by reports showing the plant extracts from fresh leaves contained another substance more behaviorally active than cathine. In 1975, the related alkaloid cathinone was isolated, and its absolute configuration was established in 1978. Cathinone is not very stable and breaks down to produce cathine and norephedrine. These chemicals belong to the PPA (phenylpropanolamine) family, a subset of the phenethylamines related to amphetamines and the catecholamines epinephrine and norepinephrine. Both of khat's major active ingredients -cathine and cathinone- are phenylalklamines, meaning they are in the same class of chemicals as amphetamines. In fact, cathinone and cathine have a very similar molecular structure to amphetamine. When khat leaves dry, the more potent chemical, cathinone, evaporates within 48 hours leaving behind the milder Schedule IV chemical, cathine. Thus, harvesters transport khat by packaging the leaves and stems in plastic bags or wrapping them in banana leaves to preserve their moisture and keep the cathinone potent. It is also common for them to frequently sprinkle the plant with water or use refrigeration during transportation. When the khat leaves are chewed, cathine and cathinone are released and absorbed through the mucous membranes of the mouth and the lining of the stomach. The action of cathine and cathinone on the reuptake of epinephrine and norepinephrine has been demonstrated in lab animals, showing that one or both of these chemicals cause the body to recycle these neurotransmitters more slowly, resulting in the wakefulness and insomnia associated with khat use. Receptors for serotonin show a high affinity for cathinone suggesting that this chemical is responsible for feelings of euphoria associated with chewing khat. In mice, cathinone produces the same types of nervous pacing or repetitive scratching behaviors associated with amphetamines. The effects of cathinone peak after 15 to 30 minutes with nearly 98% of the substance metabolized into norephedrine by the liver. Cathine is somewhat less understood, being believed to act upon the adrenergenic receptors causing the release of epinephrine and norepinephrine. It has a half-life of about 3 hours in humans. this is also used to stimulate vagina by tickling it with the smooth leaves. # Effects Khat consumption induces mild euphoria and excitement. Individuals become very talkative under the influence of the drug and may appear to be unrealistic and emotionally unstable. Khat can induce manic behaviors and hyperactivity. Khat is an effective anorectic and its use also results in constipation. Dilated pupils (mydriasis), which are prominent during khat consumption, reflect the sympathomimetic effects of the drug, which are also reflected in increased heart rate and blood pressure. A state of drowsy hallucinations (hypnagogic hallucinations) may result coming down from khat use as well. Withdrawal symptoms that may follow prolonged khat use include lethargy, mild depression, nightmares, and slight tremor. Long term use can precipitate the following effects: negative impact on liver function, permanent tooth darkening (of a greenish tinge), susceptibility to ulcers, and diminished sex drive. Khat is usually not an addictive drug, although those who are addicted generally cannot stay without it for more than 4-5 days, feeling tired and having difficulty concentrating. However, a recent British study found khat to be less dangerous than tobacco and alcohol. # User population It is estimated that several million people are frequent users of khat. Many of the users originate from countries between Sudan and Madagascar and in the southwestern part of the Arabian Peninsula, especially Yemen. In Yemen, 60% of the males and 35% of the females were found to be khat users who had chewed daily for long periods of their life. The traditional form of khat chewing in Yemen involves only male users; khat chewing by females is less formal and less frequent. In Saudi Arabia, the cultivation and consumption of khat are forbidden, and the ban is strictly enforced. The ban on khat is further supported by the clergy on the grounds that the Qur'an forbids anything that is harmful to the body. In Somalia, 61% of the population reported that they do use khat, 18% report habitual use, and 21% are occasional users. # Control status ## World In 1965, the World Health Organization Expert Committee on Dependence-producing Drugs' Fourteenth Report noted, "The Committee was pleased to note the resolution of the Economic and Social Council with respect to khat, confirming the view that the abuse of this substance is a regional problem and may best be controlled at that level" . For this reason, khat was not Scheduled under the Single Convention on Narcotic Drugs. In 1980 the World Health Organization classified khat as a drug of abuse that can produce mild to moderate psychological dependence. ## Australia In Australia, the importation of khat is controlled under the Customs (Prohibited Imports) Regulations. Individual users may apply for several required licenses to import up to 5 kg per month for personal use (primarily immigrants from the Horn of Africa). In 2003, the total number of khat annual permits was 294 and the total number of individual khat permits was 202. There are two types of import permits. The single use Permit to Import can be used only once and you must request a new permit for each time you wish to import khat. Annual Permits are labeled as such and consist of two pages. Annual Permits allow you to import up to 5 kg once a month for up to twelve months. ## Canada In Canada, khat is a controlled substance under Schedule IV of the Controlled Drugs and Substances Act (CDSA). Every person who seeks or obtains the substance without disclosing authorization to obtain such substances 30 days prior to obtaining another prescription from a practitioner is guilty of an indictable offence and liable to imprisonment for a term not exceeding eighteen months, where the subject-matter of the offence is a substance included in Schedule IV or is guilty of an offence punishable on summary conviction and liable for a first offence, to a fine not exceeding one thousand dollars or to imprisonment for a term not exceeding six months, or to both, and for a subsequent offence, to a fine not exceeding two thousand dollars or to imprisonment for a term not exceeding one year, or to both. ## Denmark Khat is a illegal and controlled substance from 1993. ## France Khat is prohibited in France as a stimulant. # =The Netherlands In the Netherlands(Holland) Khat is legal and is sold in a few places one of them is Uithoorn in the Province Noord Holland ## Germany In Germany, Cathine is a controlled substance, and ownership and sale of the plant is illegal. Similar levels of control exist throughout most other European countries. ## Hong Kong In Hong Kong, Cathine & Cathinone are regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10,000(HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time. ## Israel Khat is still used by some people of Yemeni origins. Traditionally, it is chewed on Saturday afternoons while reading the Zohar. The leaves are legal, but the cathonine extract pill called 'Hagiggat' (a joining of the Hebrew word Hagiga (party), and Gat (khat)), is currently illegal. Khat is also grown in backyards of many Yemenites, but is becoming more popular with other ethnics groups in Israel. The more potent strain from Ethiopia is flown in daily and is available for purchasing. ## New Zealand Khat plant is a Schedule 3 (Class C) drug in New Zealand, but is rarely encountered although occasional seizures at airports have been reported. Mature khat trees which were established before the plant became scheduled in 1998 do not have to be destroyed, but it is illegal to gather the leaves or otherwise prepare the plant for consumption. ## Norway Khat is classified as a narcotic drug and is illegal to use, sell and possess. Most users are Somali immigrants and khat is smuggled from the Netherlands and England. ## Somalia On November 17, 2006 the usage and distribution of khat was made illegal according to Somali Islamists in areas they control. In Somalia, the Supreme Islamic Courts Council, which took control of much of the country in 2006, banned khat during Ramadan, sparking street protests in Kismayo. In November 2006, Kenya banned all flights to Somalia, citing security concerns, prompting protests by Kenyan khat growers. The Kenyan MP from Ntonyiri, Meru North District stated that local land had been specialized in khat cultivation, that 20 tons worth US$800,000 were shipped to Somalia daily and that a flight ban could devastate the local economy. With the surprise victory of the Provisional Government backed by Ethiopian forces in the end of December 2006, khat has returned to the streets of Mogadishu, though Kenyan traders have noted demand has not yet returned to pre-ban levels. ## Sweden As in Norway, khat is classified as a narcotic drug in Sweden and is illegal to use, sell and possess. According to the police, most users are Somali immigrants and most khat is smuggled in from the Netherlands and England. For more information, see the Swedish police website on khat (text in Swedish). ## Switzerland Khat is prohibited in Switzerland as a stimulant. ## United Kingdom Khat is not a controlled substance in the United Kingdom. Because of this, and because of khat's short shelf life, the UK serves as a main gateway for khat being sent by air to North America. Khat is used by members of the Somali and Yemeni community (mainly men), which is concentrated in London, Birmingham, Bristol, Cardiff, Manchester and Sheffield. It is currently legal, although there are calls from some sections of the Somali community for it to be banned. In the UK, Cathine and Cathinone are Class C drugs. The plant Catha edulis is uncontrolled. ## United States In the United States, Cathine is in Schedule IV and cathinone is in Schedule I of the U.S. Controlled Substance Act. The 1993 DEA rule placing cathinone in Schedule I noted that it was effectively also banning khat: Cathinone is the major psychoactive component of the plant Catha edulis (khat). The young leaves of khat are chewed for a stimulant effect. Enactment of this rule results in the placement of any material which contains cathinone into Schedule I. Over 700 pounds of khat was seized by Philadelphia Police Officers in September, 2007. The khat was recovered after being shipped to Philadelphia in containers. KYW-TV reported the seizure is the first of its kind in Pennsylvania. Because the drug is cheaper than cocaine, sources said it has an economic appeal, a fact that also worries authorities.

Khat Template:Disputed Khat (Catha edulis, family Celastraceae, Ge'ez ጫት č̣āt; Arabic: قات; Somali: Jaad; IPA: Template:IPA), and also known as qat, gat, chat, and miraa), is a flowering plant native to tropical East Africa and the Arabian Peninsula. Believed to have originated in Ethiopia, it is a shrub or small tree growing to 5–8 m tall, with evergreen leaves 5–10 cm long and 1–4 cm broad. The flowers are produced on short axillary cymes 4–8 cm long, each flower small, with five white petals. The fruit is an oblong three-valved capsule containing 1–3 seeds. Khat contains the alkaloid cathinone, an amphetamine-like stimulant which causes excitement and euphoria. In 1980 the World Health Organization classified khat as a drug of abuse that can produce mild to moderate psychological dependence, and the plant has been targeted by anti-drug organizations like the DEA.[1] It is a controlled/illegal substance in many countries. # History The origins of khat are often argued. Many believe that they are Ethiopian in nature, from where it spread to the hillsides of East Africa and Yemen. Others believe that khat originated in Yemen before spreading to Ethiopia and nearby countries. Sir Richard Burton (First Footsteps in East Africa, 1856) explains that khat was introduced to the Yemen from Ethiopia in the 15th century. There is also evidence to suggest this may have occurred as early as the 13th century. Through botanical analysis, Revri (1983) supports Yemen origins of the plant.[2] From Ethiopia and Yemen the trees spread to Kenya, Somalia, Malawi, Uganda, Tanzania, Arabia, the Congo, what are now Zimbabwe and Zambia, and South Africa.[3] The earliest recorded use of khat medically is believed to be within the New Testament.[4] The ancient Egyptians considered the khat plant a "divine food" which was capable of releasing humanity's divinity. The Egyptians used the plant for more than its stimulating effects. They used it as a metamorphic process and transcended into "apotheosis", intending to make the user god-like.[5] In 1854, the Malay writer Abdullah bin Abdul Kadir noted that the custom of chewing Khat was prevalent in Al Hudaydah in Yemen: "I observed a new peculiarity in this city—everyone chewed leaves as goats chew the cud. There is a type of leaf, rather wide and about two fingers in length, which is widely sold, as people would consume these leaves just as they are; unlike betel leaves, which need certain condiments to go with them, these leaves were just stuffed fully into the mouth and munched. Thus when people gathered around, the remnants from these leaves would pile up in front of them. When they spat, their saliva was green. I then queried them on this matter: ‘What benefits are there to be gained from eating these leaves?’ To which they replied, ‘None whatsoever, it’s just another expense for us as we’ve grown accustomed to it’. Those who consume these leaves have to eat lots of ghee and honey, for they would fall ill otherwise. The leaves are known as Kad."[6] In the town of Bohmensaka, South Africa the consumption of this product has been noted to date back as late as the 1500's. Tribes would chew on these at festivals and large gatherings. Khat was a delicacy to the natives and was customary to their nature. # Cultivation and uses Khat has been grown for use as a stimulant for centuries in the Horn of Africa and the Arabian Peninsula. There, chewing khat predates the use of coffee and is used in a similar social context. Its fresh leaves and tops are chewed or, less frequently, dried and consumed as tea, in order to achieve a state of euphoria and stimulation. Due to the availability of rapid, inexpensive air transportation, the drug has been reported in England, Rome, Amsterdam, Canada, Australia, New Zealand[7] and the United States. The public has become more aware of this exotic drug through media reports pertaining to the United Nations mission in Somalia, where khat use is widespread, and its role in the Persian Gulf. The khat plant is known by a variety of names, such as qat and ghat in Yemen, chat in Ethiopia, jaad in Somalia and miraa in Kenya and Tanzania. Khat use has traditionally been confined to the regions where khat is grown, because only the fresh leaves have the desired stimulating effects. In recent years improved roads, off-road motor vehicles and air transport have increased the global distribution of this perishable commodity. Traditionally, khat has been used as a socializing drug, and this is still very much the case in Yemen where khat-chewing is a predominantly male habit.[8] In other countries, khat is consumed largely by single individuals and at parties. It is mainly a recreational drug in the countries which grow khat, though it may also be used by farmers and laborers for reducing physical fatigue and by drivers and students for improving attention. Within the counter-culture segments of the Kenyan elite population, Khat (referred to as "veve") is used to counter the effects of a hangover or binge-drinking, similar to the use of the coca leaf in South America. Cheweing Khat is not primarily a male activity in Yemen, with women having their own saloons for the occasion and partaking in cheweing Khat with their husbands on weekends. In many places where grown, Khat has become mainstream enough for many children to start chewing the plant before puberty. Khat is used for its mild euphoric and stimulating effects, and also has anorectic side-effects. It use is generally not limited by religion, though the Ethiopian Orthodox Tewahedo Church (along with its Eritrean counterpart) has forbidden Christians from using it due to its stimulating effects. In Yemen it is so popular that 40% of the country's water supply goes towards irrigating it, with production increasing by about 10% to 15% every year.[8] The water supply of Sanaa is so threatened by the crop that government officials have even proposed relocating large portions of the city's population to the coast of the Red Sea.[8] In Somalia, the Supreme Islamic Courts Council, which took control of much of the country in 2006, banned khat during Ramadan, sparking street protests in Kismayo. In November 2006, Kenya banned all flights to Somalia, citing security concerns, prompting protests by Kenyan khat growers. The Kenyan MP from Ntonyiri, Meru North District stated that local land had been specialized in khat cultivation, that 20 tons worth $800,000 were shipped to Somalia daily and that a flight ban could devastate the local economy.[9] With the victory of the Provisional Government backed by Ethiopian forces in the end of December 2006, khat has returned to the streets of Mogadishu, though Kenyan traders have noted demand has not yet returned to pre-ban levels.[10] # Chemistry/pharmacology The stimulant effect of the plant was originally attributed to "katin", cathine, a phenethylamine-type substance isolated from the plant. However, the attribution was disputed by reports showing the plant extracts from fresh leaves contained another substance more behaviorally active than cathine. In 1975, the related alkaloid cathinone was isolated, and its absolute configuration was established in 1978. Cathinone is not very stable and breaks down to produce cathine and norephedrine. These chemicals belong to the PPA (phenylpropanolamine) family, a subset of the phenethylamines related to amphetamines and the catecholamines epinephrine and norepinephrine.[11] Both of khat's major active ingredients -cathine and cathinone- are phenylalklamines, meaning they are in the same class of chemicals as amphetamines. In fact, cathinone and cathine have a very similar molecular structure to amphetamine.[12] When khat leaves dry, the more potent chemical, cathinone, evaporates within 48 hours leaving behind the milder Schedule IV chemical, cathine. Thus, harvesters transport khat by packaging the leaves and stems in plastic bags or wrapping them in banana leaves to preserve their moisture and keep the cathinone potent. It is also common for them to frequently sprinkle the plant with water or use refrigeration during transportation. When the khat leaves are chewed, cathine and cathinone are released and absorbed through the mucous membranes of the mouth and the lining of the stomach. The action of cathine and cathinone on the reuptake of epinephrine and norepinephrine has been demonstrated in lab animals, showing that one or both of these chemicals cause the body to recycle these neurotransmitters more slowly, resulting in the wakefulness and insomnia associated with khat use.[13] Receptors for serotonin show a high affinity for cathinone suggesting that this chemical is responsible for feelings of euphoria associated with chewing khat. In mice, cathinone produces the same types of nervous pacing or repetitive scratching behaviors associated with amphetamines.[14] The effects of cathinone peak after 15 to 30 minutes with nearly 98% of the substance metabolized into norephedrine by the liver.[15] Cathine is somewhat less understood, being believed to act upon the adrenergenic receptors causing the release of epinephrine and norepinephrine.[16] It has a half-life of about 3 hours in humans. this is also used to stimulate vagina by tickling it with the smooth leaves. # Effects Khat consumption induces mild euphoria and excitement. Individuals become very talkative under the influence of the drug and may appear to be unrealistic and emotionally unstable. Khat can induce manic behaviors and hyperactivity. Khat is an effective anorectic and its use also results in constipation. Dilated pupils (mydriasis), which are prominent during khat consumption, reflect the sympathomimetic effects of the drug, which are also reflected in increased heart rate and blood pressure. A state of drowsy hallucinations (hypnagogic hallucinations) may result coming down from khat use as well. Withdrawal symptoms that may follow prolonged khat use include lethargy, mild depression, nightmares, and slight tremor. Long term use can precipitate the following effects: negative impact on liver function, permanent tooth darkening (of a greenish tinge), susceptibility to ulcers, and diminished sex drive. Khat is usually not an addictive drug, although those who are addicted generally cannot stay without it for more than 4-5 days, feeling tired and having difficulty concentrating.[17] However, a recent British study found khat to be less dangerous than tobacco and alcohol.[18] # User population It is estimated that several million people are frequent users of khat. Many of the users originate from countries between Sudan and Madagascar and in the southwestern part of the Arabian Peninsula, especially Yemen. In Yemen, 60% of the males and 35% of the females were found to be khat users who had chewed daily for long periods of their life. The traditional form of khat chewing in Yemen involves only male users; khat chewing by females is less formal and less frequent. In Saudi Arabia, the cultivation and consumption of khat are forbidden, and the ban is strictly enforced. The ban on khat is further supported by the clergy on the grounds that the Qur'an forbids anything that is harmful to the body. In Somalia, 61% of the population reported that they do use khat, 18% report habitual use, and 21% are occasional users.[citation needed] # Control status ## World In 1965, the World Health Organization Expert Committee on Dependence-producing Drugs' Fourteenth Report noted, "The Committee was pleased to note the resolution of the Economic and Social Council with respect to khat, confirming the view that the abuse of this substance is a regional problem and may best be controlled at that level" [4]. For this reason, khat was not Scheduled under the Single Convention on Narcotic Drugs. In 1980 the World Health Organization classified khat as a drug of abuse that can produce mild to moderate psychological dependence. ## Australia In Australia, the importation of khat is controlled under the Customs (Prohibited Imports) Regulations. Individual users may apply for several required licenses to import up to 5 kg per month for personal use (primarily immigrants from the Horn of Africa). In 2003, the total number of khat annual permits was 294 and the total number of individual khat permits was 202. There are two types of import permits. The single use Permit to Import can be used only once and you must request a new permit for each time you wish to import khat. Annual Permits are labeled as such and consist of two pages. Annual Permits allow you to import up to 5 kg once a month for up to twelve months. ## Canada In Canada, khat is a controlled substance under Schedule IV of the Controlled Drugs and Substances Act (CDSA). Every person who seeks or obtains the substance without disclosing authorization to obtain such substances 30 days prior to obtaining another prescription from a practitioner is guilty of an indictable offence and liable to imprisonment for a term not exceeding eighteen months, where the subject-matter of the offence is a substance included in Schedule IV or is guilty of an offence punishable on summary conviction and liable for a first offence, to a fine not exceeding one thousand dollars or to imprisonment for a term not exceeding six months, or to both, and for a subsequent offence, to a fine not exceeding two thousand dollars or to imprisonment for a term not exceeding one year, or to both. [5] [6] ## Denmark Khat is a illegal and controlled substance from 1993. ## France Khat is prohibited in France as a stimulant.[19] # =The Netherlands In the Netherlands(Holland) Khat is legal and is sold in a few places one of them is Uithoorn in the Province Noord Holland ## Germany In Germany, Cathine is a controlled substance, and ownership and sale of the plant is illegal. Similar levels of control exist throughout most other European countries. ## Hong Kong In Hong Kong, Cathine & Cathinone are regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10,000(HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time. ## Israel Khat is still used by some people of Yemeni origins. Traditionally, it is chewed on Saturday afternoons while reading the Zohar. The leaves are legal, but the cathonine extract pill called 'Hagiggat' (a joining of the Hebrew word Hagiga (party), and Gat (khat)), is currently illegal. Khat is also grown in backyards of many Yemenites, but is becoming more popular with other ethnics groups in Israel. The more potent strain from Ethiopia is flown in daily and is available for purchasing. ## New Zealand Khat plant is a Schedule 3 (Class C) drug in New Zealand, but is rarely encountered although occasional seizures at airports have been reported. Mature khat trees which were established before the plant became scheduled in 1998 do not have to be destroyed, but it is illegal to gather the leaves or otherwise prepare the plant for consumption. ## Norway Khat is classified as a narcotic drug and is illegal to use, sell and possess. Most users are Somali immigrants and khat is smuggled from the Netherlands and England.[20] ## Somalia On November 17, 2006 the usage and distribution of khat was made illegal according to Somali Islamists in areas they control.[21] In Somalia, the Supreme Islamic Courts Council, which took control of much of the country in 2006, banned khat during Ramadan, sparking street protests in Kismayo. In November 2006, Kenya banned all flights to Somalia, citing security concerns, prompting protests by Kenyan khat growers. The Kenyan MP from Ntonyiri, Meru North District stated that local land had been specialized in khat cultivation, that 20 tons worth US$800,000 were shipped to Somalia daily and that a flight ban could devastate the local economy.[22] With the surprise victory of the Provisional Government backed by Ethiopian forces in the end of December 2006, khat has returned to the streets of Mogadishu, though Kenyan traders have noted demand has not yet returned to pre-ban levels.[23] ## Sweden As in Norway, khat is classified as a narcotic drug in Sweden and is illegal to use, sell and possess. According to the police, most users are Somali immigrants and most khat is smuggled in from the Netherlands and England. For more information, see the Swedish police website on khat (text in Swedish). ## Switzerland Khat is prohibited in Switzerland as a stimulant.[24] ## United Kingdom Khat is not a controlled substance in the United Kingdom. Because of this, and because of khat's short shelf life, the UK serves as a main gateway for khat being sent by air to North America.[7] Khat is used by members of the Somali and Yemeni community (mainly men), which is concentrated in London, Birmingham, Bristol, Cardiff, Manchester and Sheffield. It is currently legal, although there are calls from some sections of the Somali community for it to be banned. In the UK, Cathine and Cathinone are Class C drugs. The plant Catha edulis is uncontrolled. ## United States In the United States, Cathine is in Schedule IV and cathinone is in Schedule I of the U.S. Controlled Substance Act. The 1993 DEA rule placing cathinone in Schedule I noted that it was effectively also banning khat: Cathinone is the major psychoactive component of the plant Catha edulis (khat). The young leaves of khat are chewed for a stimulant effect. Enactment of this rule results in the placement of any material which contains cathinone into Schedule I. Over 700 pounds of khat was seized by Philadelphia Police Officers in September, 2007. The khat was recovered after being shipped to Philadelphia in containers[8]. KYW-TV reported the seizure is the first of its kind in Pennsylvania. Because the drug is cheaper than cocaine, sources said it has an economic appeal, a fact that also worries authorities.

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9472ede4c5c080d166c8133caa24eb0f93ecb943

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Knee

Knee # Overview In human anatomy, the knee is the lower extremity joint connecting the femur and the tibia. Since in humans the knee supports nearly the entire weight of the body, it is the joint most vulnerable both to acute injury and to the development of osteoarthritis. # Function of the knee The knee functions as a living, self-maintaining, biologic transmission, the purpose of which is to accept and transfer biomechanical loads between the femur, tibia, patella, and fibula. In this analogy the ligaments represent non-rigid adaptable sensate linkages within the biologic transmission. The articular cartilages act as bearing surfaces, and the menisci as mobile bearings. The muscles function as living cellular engines that in concentric contraction provide motive forces across the joint, and in eccentric contraction act as brakes and dampening systems, absorbing loads. # Human anatomy Upon birth, a baby will not have a conventional knee cap, but a knee cap formed of cartilege. In Human females this turns to a normal bone knee cap by the age of 3, in males the age of 5. The knee is a complex, compound, condyloid variety of a synovial joint which hovers. It actually comprises two separate joints. - The femoro-patellar joint consists of the patella, or "kneecap", a so-called sesamoid bone which sits within the tendon of the anterior thigh muscle (m. quadriceps femoris), and the patellar groove on the front of the femur through which it slides. - The femoro-tibial joint links the femur, or thigh bone, with the tibia, the main bone of the (lower) leg. The joint is bathed in a viscous (synovial) fluid which is contained inside the "synovial" membrane, or joint capsule. The recess behind the knee is called the popliteal fossa it can also be called a "knee pit." ## Ligaments ## Menisci These are cartilaginous elements within the knee joint which serve to protect the ends of the bones from rubbing on each other and to effectively deepen the tibial sockets into which the femur attaches. They also play a role in shock absorption. There are two menisci in each knee, the medial meniscus and the lateral meniscus. Either or both may be cracked, or torn, when the knee is forcefully rotated and/or bent. ## Movements The knee permits the following movements: flexion, extension, as well as slight medial and lateral rotation. Also, the knee has special locking and unlocking mechanisms, related to movement by the femoral condyles on the tibial plateau. The ligaments and menisci, along with the muscles which traverse the joint, prevent movement beyond the knee's intended range of motion. It is also classified as a hinge joint. The range of movement is as follows: Flexion is permitted up to 120º when the hip is extended, 140º when the hip is flexed and 160º when the knee is flexed passively. Medial rotation is limited to 10º and lateral rotation to 30º . # Blood Supply of Knee Joint The femoral artery and the popliteal artery help form the arterial network surrounding the knee joint (articular rete). There are 6 main branches: 1. Superior medial genicular artery 2. Superior lateral genicular artery 3. Inferior medial genicular artery 4. Inferior lateral genicular artery 5. Descending genicular artery 6. Recurrent branch of anterior tibial artery It is important to note that the medial genicular arteries penetrate the knee joint ## Injury In sports that place great stress on the knees, especially with twisting forces, it is common to tear one or more ligaments or cartilages. The anterior cruciate ligament is often torn as a result of a rapid direction change while running or as a result of some other type of violent twisting motion. It can also be torn by being extended forcefully beyond its normal range, or as a result of being forced sideways. In such cases, other structures will incur damage as well. Especially debilitating is the unfortunately common "unhappy triad" of torn medial collateral and anterior cruciate ligaments and a torn medial meniscus. This typically arises from a combination of inwards forcing and twisting. Before the advent of arthroscopy and arthroscopic surgery, patients having surgery for a torn ACL required at least nine months of rehabilitation. With current techniques, such patients may be walking without crutches in two weeks, and playing some sports in but a few months. In Australian rules football, knee injuries are among the most common, with a great deal of controversy caused in ruck contests, where the crashing of two knees during the leap has caused injuries to numerous players. This forced new rule changes in the Australian Football League for the 2005 season. In addition to developing new surgical procedures, ongoing research is looking into underlying problems which may increase the likelihood of an athlete suffering a severe knee injury. These findings may lead to effective preventive measures. Techniques to minimize the risk of an ACL injury while skiing are published by Vermont Safety Research

Knee Template:Infobox Anatomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In human anatomy, the knee is the lower extremity joint connecting the femur and the tibia. Since in humans the knee supports nearly the entire weight of the body, it is the joint most vulnerable both to acute injury and to the development of osteoarthritis. # Function of the knee The knee functions as a living, self-maintaining, biologic transmission, the purpose of which is to accept and transfer biomechanical loads between the femur, tibia, patella, and fibula. In this analogy the ligaments represent non-rigid adaptable sensate linkages within the biologic transmission. The articular cartilages act as bearing surfaces, and the menisci as mobile bearings. The muscles function as living cellular engines that in concentric contraction provide motive forces across the joint, and in eccentric contraction act as brakes and dampening systems, absorbing loads. # Human anatomy Upon birth, a baby will not have a conventional knee cap, but a knee cap formed of cartilege. In Human females this turns to a normal bone knee cap by the age of 3, in males the age of 5. The knee is a complex, compound, condyloid variety of a synovial joint which hovers. It actually comprises two separate joints. - The femoro-patellar joint consists of the patella, or "kneecap", a so-called sesamoid bone which sits within the tendon of the anterior thigh muscle (m. quadriceps femoris), and the patellar groove on the front of the femur through which it slides. - The femoro-tibial joint links the femur, or thigh bone, with the tibia, the main bone of the (lower) leg. The joint is bathed in a viscous (synovial) fluid which is contained inside the "synovial" membrane, or joint capsule. The recess behind the knee is called the popliteal fossa it can also be called a "knee pit." ## Ligaments ## Menisci These are cartilaginous elements within the knee joint which serve to protect the ends of the bones from rubbing on each other and to effectively deepen the tibial sockets into which the femur attaches. They also play a role in shock absorption. There are two menisci in each knee, the medial meniscus and the lateral meniscus. Either or both may be cracked, or torn, when the knee is forcefully rotated and/or bent. ## Movements The knee permits the following movements: flexion, extension, as well as slight medial and lateral rotation. Also, the knee has special locking and unlocking mechanisms, related to movement by the femoral condyles on the tibial plateau. The ligaments and menisci, along with the muscles which traverse the joint, prevent movement beyond the knee's intended range of motion. It is also classified as a hinge joint. The range of movement is as follows: Flexion is permitted up to 120º when the hip is extended, 140º when the hip is flexed and 160º when the knee is flexed passively. Medial rotation is limited to 10º and lateral rotation to 30º . # Blood Supply of Knee Joint The femoral artery and the popliteal artery help form the arterial network surrounding the knee joint (articular rete). There are 6 main branches: 1. Superior medial genicular artery 2. Superior lateral genicular artery 3. Inferior medial genicular artery 4. Inferior lateral genicular artery 5. Descending genicular artery 6. Recurrent branch of anterior tibial artery It is important to note that the medial genicular arteries penetrate the knee joint ## Injury In sports that place great stress on the knees, especially with twisting forces, it is common to tear one or more ligaments or cartilages. The anterior cruciate ligament is often torn as a result of a rapid direction change while running or as a result of some other type of violent twisting motion. It can also be torn by being extended forcefully beyond its normal range, or as a result of being forced sideways. In such cases, other structures will incur damage as well. Especially debilitating is the unfortunately common "unhappy triad" of torn medial collateral and anterior cruciate ligaments and a torn medial meniscus. This typically arises from a combination of inwards forcing and twisting. Before the advent of arthroscopy and arthroscopic surgery, patients having surgery for a torn ACL required at least nine months of rehabilitation. With current techniques, such patients may be walking without crutches in two weeks, and playing some sports in but a few months. In Australian rules football, knee injuries are among the most common, with a great deal of controversy caused in ruck contests, where the crashing of two knees during the leap has caused injuries to numerous players. This forced new rule changes in the Australian Football League for the 2005 season. In addition to developing new surgical procedures, ongoing research is looking into underlying problems which may increase the likelihood of an athlete suffering a severe knee injury. These findings may lead to effective preventive measures. Techniques to minimize the risk of an ACL injury while skiing are published by Vermont Safety Research

https://www.wikidoc.org/index.php/Knee

8e277edf2a4271564ff33e5ab35dbb35abbb90ae

wikidoc

Kt/V

Kt/V In medicine, Kt/V is a number used to quantify hemodialysis and peritoneal dialysis treatment adequacy. - K - dialyzer clearance of urea - t - dialysis time - V - patient's total body water In the context of hemodialysis, Kt/V is a bonafide dimensionless number that can be derived using the Buckingham π theorem. In peritoneal dialysis, it is dimensionless only by definition. It was developed by Frank Gotch and John Sargent as a way for measuring the dose of dialysis when they analyzed the data from the National Cooperative Dialysis Study. In hemodialysis the US National Kidney Foundation Kt/V target is 1.3, so that one can be sure that the delivered dose is at least 1.2. In peritoneal dialysis the target is 2.0/week. Despite the name, Kt/V is quite different from standardized Kt/V. # Rationale for Kt/V as a marker of dialysis adequacy K (clearance) multiplied by t (time) is a volume (since mL/min x min = mL, or L/hr x hr = L), and (K x t) can be thought of as the mL or L of fluid (blood in this case) cleared of urea (or any other solute) during the course of a single treatment. V also is a volume, expressed in mL or L. So the ratio of K x t / V is a so-called "dimensionless ratio" and can be thought of as a multiple of the volume of plasma cleared of urea divided by the distribution volume of urea. When Kt/V = 1.0, a volume of blood equal to the distribution volume of urea has been completely cleared of urea. The relationship between Kt/V and the concentration of urea C at the end of dialysis can be derived from the first-order differential equation that describes exponential decay and models the clearance of any substance from the body where the concentration of that substance decreases in an exponential fashion: where - C is the concentration - t is the time - K is the clearance - V is the volume of distribution From the above definitions it follows that \frac{dC}{dt} is the first derivative of concentration with respect to time, i.e. the change in concentration with time. This equation is separable and can be integrated as follows: After integration, where - const is the constant of integration If one takes the antilog of Equation 2b the result is: where - e is the base of the natural logarithm By integer exponentiation this can be written as: where - C0 is the concentration at the beginning of dialysis or . The above equation can also be written as Normally we measure postdialysis serum urea nitrogen concentration C and compare this with the initial or predialysis level C0. The session length or time is t and this is measured by the clock. The dialyzer clearance K is usually estimated, based on the urea transfer ability of the dialyzer (a function of its size and membrane permeability), the blood flow rate, and the dialysate flow rate. In some dialysis machines, the urea clearance during dialysis is estimated by testing the ability of the dialyzer to remove a small salt load that is added to the dialysate during dialysis. # Relation to URR The URR is simply the fractional reduction of urea during dialysis. So by definition, URR = 1 -C/C0. So 1-URR = C/C0. So by algebra, substituting into equation (4) above, since ln C/C0 = - ln C0/C, we get: ## Sample calculation Patient has a mass of 70 kg (154 lb) and gets a hemodialysis treatment that lasts 4 hours where the urea clearance 215 ml/min. - K = 215 mL/min - t = 4.0 hours = 240 min - V = 70 kg × 0.6 L of water/kg of body mass = 42 L = 42,000 mL Therefore: This means that if you dialyze a patient to a Kt/V of 1.23, and measure the postdialysis and predialysis urea nitrogen levels in the blood, then calculate the URR, then -ln (1-URR) should be about 1.23. The math does not quite work out, and more complicated relationships have been worked-out to account for the fluid removal (ultrafiltration) during dialysis as well as urea generation(see urea reduction ratio). Nevertheless, the URR and Kt/V are so closely related mathematically, that their predictive power has been shown to be no different in terms of prediction of patient outcomes in observational studies. ## Post-dialysis rebound The above analysis assumes that urea is removed from a single compartment during dialysis. In fact, this Kt/V is usually called the "single-pool" Kt/V. Due to the multiple compartments in the human body, a significant concentration rebound occurs following hemodialysis. Usually rebound lowers the Kt/V by about 15%. The amount of rebound depends on the rate of dialysis (K) in relation to the size of the patient (V). Equations have been devised to predict the amount of rebound based on the ratio of K/V, but usually this is not necessary in clinical practice. One can use such equations to calculate an "equilibrated Kt/V" or a "double-pool Kt/V", and some think that this should be used as a measure of dialysis adequacy, but this is not widely done in the United States, and the KDOQI guidelines (see below) recommend using the regular single pool Kt/V for simplicity. # Peritoneal dialysis In peritoneal dialysis calculation of Kt/V is easy, because the fluid drained is usually close to 100% saturated with urea. So the daily amount of plasma cleared is simply the drain volume divided by an estimate of the patient's volume of distribution. As an example, if someone is infusing four 2 liter exchanges a day, and drains out a total of 9 liters per day, then they drain 9 x 7 = 63 liters per week. If the patient has an estimated total body water volume V of about 35 liters, then the weekly Kt/V would be 63/35, or about 1.8. Calculation is a bit more complicated during Automated PD, when the serum concentration of urea is changing during dialysis. Usually blood samples are measured at some time point in the day thought to represent an average value, and the clearance is determined from this value. # Reason for adoption Kt/V has been widely adopted because it was correlated with survival. Before Kt/V nephrologists measured the serum urea concentration (specifically the time-averaged concentration of urea (TAC of urea)), which was found not to be correlated with survival (due to its strong dependence on protein intake) and thus deemed an unreliable marker of dialysis adequacy. # Criticisms/disadvantages of Kt/V - It is complex and tedious to calculate. Many nephrologists have difficulty understanding it. - Urea is not associated with toxicity. - Kt/V only measures a change in the concentration of urea and implicitly assumes the clearance of urea is comparable to other toxins. (It ignores molecules larger than urea having diffusion-limited transport - so called middle molecules). - Kt/V does not take into account the role of ultrafiltration. - It ignores the mass transfer between body compartments and across the plasma membrane (i.e. intracellular to extracellular transport), which has been shown to be important for the clearance of molecules such as phosphate. Practical use of Kt/V requires adjustment for rebound of the urea concentration due to the multi-compartmental nature of the body. - Kt/V may disadvantage women and smaller patients in terms of the amount of dialysis received. Normal kidney function is expressed as the Glomerular filtration rate or GFR. GFR is usually normalized in people to body surface area. A man and a woman of similar body surface areas will have markedly different levels of total body water (which corresponds to V). Also, smaller people of either sex will have markedly lower levels of V, but only slightly lower levels of body surface area. For this reason, any dialysis dosing system that is based on V may tend to underdose smaller patients and women. Some investigators have proposed dosing based on surface area (S) instead of V, but clinicians usually measure the URR and then calculate Kt/V. One can "adjust" the Kt/V, to calculate a "surface-area-normalized" or "SAN"-Kt/V as well as a "SAN"-standard Kt/V. This puts a wrapper around Kt/V and normalizes it to body surface area. ## Importance of total weekly dialysis time and frequency Kt/V has been criticized because quite high levels can be achieved, particularly in smaller patients, during relatively short dialysis sessions. This is especially true for small people, where "adequate" levels of Kt/V often can be achieved over 2 to 2.5 hours. One important part of dialysis adequacy has to do with adequate removal of salt and water, and also of solutes other than urea, especially larger molecular weight substances and phosphorus. A number of studies suggest that a longer amount of time on dialysis, or more frequent dialysis sessions, lead to better results. There have been various alternative methods of measuring dialysis adequacy, most of which have proposed some number based on Kt/V and number of dialysis sessions per week, e.g., the standardized Kt/V, or simply number of dialysis sessions per week squared multiplied by the hours on dialysis per session; e.g. the hemodialysis product by Scribner and Oreopoulos It is not practical to give long dialysis sessions (greater than 4.5 hours) 3x/week in a dialysis center during the day. Longer sessions can be practically delivered if dialysis is done at home. Most experience has been gained with such long dialysis sessions given at night. Some centers are offering every-other-night or 3x/week nocturnal dialysis. The benefits of giving more frequent dialysis sessions is also an area of active study, and new easy-to-use machines are permitting easier use of home dialysis, where 2-3+ hr sessions can be given 4-7 days per week. ## Kt/V minimums and targets for hemodialysis One question in terms of Kt/V is, how much is enough? The answer has been based on observational studies, and the NIH-funded HEMO trial done in the United States, and also, on kinetic analysis. For a US perspective, see the and for a United Kingdom perspective see According to the US guidelines, for 3x/week dialysis a Kt/V (without rebound) should be 1.2 at a minimum with a target value of 1.4 (15% above the minimum values). However, there is suggestive evidence that larger amounts may need to be given to women, smaller patients, malnourished patients, and patients with clinical problems. The recommended minimum Kt/V value changes depending on how many sessions per week are given, and is reduced for patients who have a substantial degree of residual renal function. ## Kt/V minimums and targets for peritoneal dialysis For a US perspective, see For the United States, the minimum weekly Kt/V target used to be 2.0. This was lowered to 1.7 in view of the results of a large randomized trial done in Mexico, the ADEMEX trial, and also from reanalysis of previous observational study results from the perspective of residual kidney function. For a United Kingdom perspective see: This is still in draft form.

Kt/V In medicine, Kt/V is a number used to quantify hemodialysis and peritoneal dialysis treatment adequacy. - K - dialyzer clearance of urea - t - dialysis time - V - patient's total body water In the context of hemodialysis, Kt/V is a bonafide dimensionless number that can be derived using the Buckingham π theorem. In peritoneal dialysis, it is dimensionless only by definition. It was developed by Frank Gotch and John Sargent as a way for measuring the dose of dialysis when they analyzed the data from the National Cooperative Dialysis Study.[1] In hemodialysis the US National Kidney Foundation Kt/V target is 1.3, so that one can be sure that the delivered dose is at least 1.2.[2] In peritoneal dialysis the target is 2.0/week.[2] Despite the name, Kt/V is quite different from standardized Kt/V. # Rationale for Kt/V as a marker of dialysis adequacy K (clearance) multiplied by t (time) is a volume (since mL/min x min = mL, or L/hr x hr = L), and (K x t) can be thought of as the mL or L of fluid (blood in this case) cleared of urea (or any other solute) during the course of a single treatment. V also is a volume, expressed in mL or L. So the ratio of K x t / V is a so-called "dimensionless ratio" and can be thought of as a multiple of the volume of plasma cleared of urea divided by the distribution volume of urea. When Kt/V = 1.0, a volume of blood equal to the distribution volume of urea has been completely cleared of urea. The relationship between Kt/V and the concentration of urea C at the end of dialysis can be derived from the first-order differential equation that describes exponential decay and models the clearance of any substance from the body where the concentration of that substance decreases in an exponential fashion: where - C is the concentration [mol/m3] - t is the time [s] - K is the clearance [m3/s] - V is the volume of distribution [m3] From the above definitions it follows that <math>\frac{dC}{dt}</math> is the first derivative of concentration with respect to time, i.e. the change in concentration with time. This equation is separable and can be integrated as follows: After integration, where - const is the constant of integration If one takes the antilog of Equation 2b the result is: where - e is the base of the natural logarithm By integer exponentiation this can be written as: where - C0 is the concentration at the beginning of dialysis [mmol/L] or [mol/m3]. The above equation can also be written as Normally we measure postdialysis serum urea nitrogen concentration C and compare this with the initial or predialysis level C0. The session length or time is t and this is measured by the clock. The dialyzer clearance K is usually estimated, based on the urea transfer ability of the dialyzer (a function of its size and membrane permeability), the blood flow rate, and the dialysate flow rate. [3] In some dialysis machines, the urea clearance during dialysis is estimated by testing the ability of the dialyzer to remove a small salt load that is added to the dialysate during dialysis. # Relation to URR The URR is simply the fractional reduction of urea during dialysis. So by definition, URR = 1 -C/C0. So 1-URR = C/C0. So by algebra, substituting into equation (4) above, since ln C/C0 = - ln C0/C, we get: ## Sample calculation Patient has a mass of 70 kg (154 lb) and gets a hemodialysis treatment that lasts 4 hours where the urea clearance 215 ml/min. - K = 215 mL/min - t = 4.0 hours = 240 min - V = 70 kg × 0.6 L of water/kg of body mass = 42 L = 42,000 mL Therefore: This means that if you dialyze a patient to a Kt/V of 1.23, and measure the postdialysis and predialysis urea nitrogen levels in the blood, then calculate the URR, then -ln (1-URR) should be about 1.23. The math does not quite work out, and more complicated relationships have been worked-out to account for the fluid removal (ultrafiltration) during dialysis as well as urea generation(see urea reduction ratio). Nevertheless, the URR and Kt/V are so closely related mathematically, that their predictive power has been shown to be no different in terms of prediction of patient outcomes in observational studies. ## Post-dialysis rebound The above analysis assumes that urea is removed from a single compartment during dialysis. In fact, this Kt/V is usually called the "single-pool" Kt/V. Due to the multiple compartments in the human body, a significant concentration rebound occurs following hemodialysis. Usually rebound lowers the Kt/V by about 15%. The amount of rebound depends on the rate of dialysis (K) in relation to the size of the patient (V). Equations have been devised to predict the amount of rebound based on the ratio of K/V, but usually this is not necessary in clinical practice. One can use such equations to calculate an "equilibrated Kt/V" or a "double-pool Kt/V", and some think that this should be used as a measure of dialysis adequacy, but this is not widely done in the United States, and the KDOQI guidelines (see below) recommend using the regular single pool Kt/V for simplicity. # Peritoneal dialysis In peritoneal dialysis calculation of Kt/V is easy, because the fluid drained is usually close to 100% saturated with urea. So the daily amount of plasma cleared is simply the drain volume divided by an estimate of the patient's volume of distribution. As an example, if someone is infusing four 2 liter exchanges a day, and drains out a total of 9 liters per day, then they drain 9 x 7 = 63 liters per week. If the patient has an estimated total body water volume V of about 35 liters, then the weekly Kt/V would be 63/35, or about 1.8. Calculation is a bit more complicated during Automated PD, when the serum concentration of urea is changing during dialysis. Usually blood samples are measured at some time point in the day thought to represent an average value, and the clearance is determined from this value. # Reason for adoption Kt/V has been widely adopted because it was correlated with survival. Before Kt/V nephrologists measured the serum urea concentration (specifically the time-averaged concentration of urea (TAC of urea)), which was found not to be correlated with survival (due to its strong dependence on protein intake) and thus deemed an unreliable marker of dialysis adequacy. # Criticisms/disadvantages of Kt/V - It is complex and tedious to calculate. Many nephrologists have difficulty understanding it. - Urea is not associated with toxicity.[4] - Kt/V only measures a change in the concentration of urea and implicitly assumes the clearance of urea is comparable to other toxins. (It ignores molecules larger than urea having diffusion-limited transport - so called middle molecules). - Kt/V does not take into account the role of ultrafiltration. - It ignores the mass transfer between body compartments and across the plasma membrane (i.e. intracellular to extracellular transport), which has been shown to be important for the clearance of molecules such as phosphate. Practical use of Kt/V requires adjustment for rebound of the urea concentration due to the multi-compartmental nature of the body. - Kt/V may disadvantage women and smaller patients in terms of the amount of dialysis received. Normal kidney function is expressed as the Glomerular filtration rate or GFR. GFR is usually normalized in people to body surface area. A man and a woman of similar body surface areas will have markedly different levels of total body water (which corresponds to V). Also, smaller people of either sex will have markedly lower levels of V, but only slightly lower levels of body surface area. For this reason, any dialysis dosing system that is based on V may tend to underdose smaller patients and women. Some investigators have proposed dosing based on surface area (S) instead of V, but clinicians usually measure the URR and then calculate Kt/V. One can "adjust" the Kt/V, to calculate a "surface-area-normalized" or "SAN"-Kt/V as well as a "SAN"-standard Kt/V. This puts a wrapper around Kt/V and normalizes it to body surface area. [5] ## Importance of total weekly dialysis time and frequency Kt/V has been criticized because quite high levels can be achieved, particularly in smaller patients, during relatively short dialysis sessions. This is especially true for small people, where "adequate" levels of Kt/V often can be achieved over 2 to 2.5 hours. One important part of dialysis adequacy has to do with adequate removal of salt and water, and also of solutes other than urea, especially larger molecular weight substances and phosphorus. A number of studies suggest that a longer amount of time on dialysis, or more frequent dialysis sessions, lead to better results. There have been various alternative methods of measuring dialysis adequacy, most of which have proposed some number based on Kt/V and number of dialysis sessions per week, e.g., the standardized Kt/V, or simply number of dialysis sessions per week squared multiplied by the hours on dialysis per session; e.g. the hemodialysis product by Scribner and Oreopoulos [6] It is not practical to give long dialysis sessions (greater than 4.5 hours) 3x/week in a dialysis center during the day. Longer sessions can be practically delivered if dialysis is done at home. Most experience has been gained with such long dialysis sessions given at night. Some centers are offering every-other-night or 3x/week nocturnal dialysis. The benefits of giving more frequent dialysis sessions is also an area of active study, and new easy-to-use machines are permitting easier use of home dialysis, where 2-3+ hr sessions can be given 4-7 days per week. ## Kt/V minimums and targets for hemodialysis One question in terms of Kt/V is, how much is enough? The answer has been based on observational studies, and the NIH-funded HEMO trial done in the United States, and also, on kinetic analysis. For a US perspective, see the [7] and for a United Kingdom perspective see [8] According to the US guidelines, for 3x/week dialysis a Kt/V (without rebound) should be 1.2 at a minimum with a target value of 1.4 (15% above the minimum values). However, there is suggestive evidence that larger amounts may need to be given to women, smaller patients, malnourished patients, and patients with clinical problems. The recommended minimum Kt/V value changes depending on how many sessions per week are given, and is reduced for patients who have a substantial degree of residual renal function. ## Kt/V minimums and targets for peritoneal dialysis For a US perspective, see [9] For the United States, the minimum weekly Kt/V target used to be 2.0. This was lowered to 1.7 in view of the results of a large randomized trial done in Mexico, the ADEMEX trial, [10] and also from reanalysis of previous observational study results from the perspective of residual kidney function. For a United Kingdom perspective see: [11] This is still in draft form.

https://www.wikidoc.org/index.php/Kt/V

c0ad3349ce06d62063fb1d66aa6750d581ed0a18

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Ku70

Ku70 Ku70 is a protein that, in humans, is encoded by the XRCC6 gene. # Function Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of DNA repair. It is also required for V(D)J recombination, which utilizes the NHEJ pathway to promote antigen diversity in the mammalian immune system. In addition to its role in NHEJ, Ku is also required for telomere length maintenance and subtelomeric gene silencing. Ku was originally identified when patients with systemic lupus erythematosus were found to have high levels of autoantibodies to the protein. # Aging Mouse embryonic stem cells with homozygous Ku70 mutations, that is Ku70−/− cells, have markedly increased sensitivity to ionizing radiation compared to heterozygous Ku70+/− or wild-type Ku70+/+ embryonic stem cells. Mutant mice deficient in Ku70 exhibit early aging. Using several specific criteria of aging, the mutant mice were found to display the same aging signs as control mice, but at a considerably earlier chronological age. These results suggest that reduced ability to repair DNA double-strand breaks causes early aging, and that the wild-type Ku70 gene plays an important role in longevity assurance. (Also see DNA damage theory of aging.) # Nomenclature Ku70 has been referred to by several names including: - Lupus Ku autoantigen protein p70 - ATP-dependent DNA helicase 2 subunit 1 - X-ray repair complementing defective repair in Chinese hamster cells 6 - X-ray repair cross-complementing 6 (XRCC6) # Interactions Ku70 has been shown to interact with: - CBX5, - CHEK1, - CREBBP, - GCN5L2, - HOXC4, - Ku80, - MRE11A, - NCOA6, - NCF4, - PCNA, - PTTG1, - RPA2, - TERF2, - TERT - VAV1, and - WRN.

Ku70 Ku70 is a protein that, in humans, is encoded by the XRCC6 gene.[1][2] # Function Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of DNA repair. It is also required for V(D)J recombination, which utilizes the NHEJ pathway to promote antigen diversity in the mammalian immune system. In addition to its role in NHEJ, Ku is also required for telomere length maintenance and subtelomeric gene silencing.[3] Ku was originally identified when patients with systemic lupus erythematosus were found to have high levels of autoantibodies to the protein.[1] # Aging Mouse embryonic stem cells with homozygous Ku70 mutations, that is Ku70−/− cells, have markedly increased sensitivity to ionizing radiation compared to heterozygous Ku70+/− or wild-type Ku70+/+ embryonic stem cells.[4] Mutant mice deficient in Ku70 exhibit early aging.[5] Using several specific criteria of aging, the mutant mice were found to display the same aging signs as control mice, but at a considerably earlier chronological age. These results suggest that reduced ability to repair DNA double-strand breaks causes early aging, and that the wild-type Ku70 gene plays an important role in longevity assurance.[6] (Also see DNA damage theory of aging.) # Nomenclature Ku70 has been referred to by several names including: - Lupus Ku autoantigen protein p70 - ATP-dependent DNA helicase 2 subunit 1 - X-ray repair complementing defective repair in Chinese hamster cells 6 - X-ray repair cross-complementing 6 (XRCC6) # Interactions Ku70 has been shown to interact with: - CBX5,[7] - CHEK1,[8] - CREBBP,[9] - GCN5L2,[9] - HOXC4,[10] - Ku80,[9][11][12][13][14] - MRE11A,[15] - NCOA6,[16][17] - NCF4,[18] - PCNA,[19][20] - PTTG1,[21] - RPA2,[22] - TERF2,[14] - TERT[23] - VAV1,[24] and - WRN.[25][26]

https://www.wikidoc.org/index.php/Ku70

d05f7a3cc65d83dcf7bdfa1bfe9bf989b6f575ab

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Ku80

Ku80 Ku80 is a protein that, in humans, is encoded by the XRCC5 gene. Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of DNA repair. It is also required for V(D)J recombination, which utilizes the NHEJ pathway to promote antigen diversity in the mammalian immune system. In addition to its role in NHEJ, Ku is required for telomere length maintenance and subtelomeric gene silencing. Ku was originally identified when patients with systemic lupus erythematosus were found to have high levels of autoantibodies to the protein. # Nomenclature Ku80 has been referred to by several names including: - Lupus Ku autoantigen protein p80 - ATP-dependent DNA helicase 2 subunit 2 - X-ray repair complementing defective repair in Chinese hamster cells 5 - X-ray repair cross-complementing 5 (XRCC5) # Epigenetic repression The protein expression level of Ku80 can be repressed by epigenetic hypermethylation of the promoter region of gene XRCC5 which encodes Ku80. In a study of 87 matched pairs of primary tumors of non-small-cell lung carcinoma and nearby normal lung tissue, 25% of the tumors had loss of heterozygosity at the XRCC5 locus and a similar percentage of tumors had hypermethylation of the promoter region of XRCC5. Low protein expression of Ku80 was significantly associated with low mRNA expression and with XRCC5 promoter hypermethylation but not with LOH of the gene. # Senescence Mouse mutants with homozygous defects in Ku80 experience an early onset of senescence. Ku80(-/-) mice exhibit aging-related pathology (osteopenia, atrophic skin, hepatocellular degeneration, hepatocellular inclusions, hepatic hyperplastic foci and age-specific mortality). Furthermore, Ku80(-/-) mice exhibit severely reduced lifespan and size. Loss of only a single Ku80 allele in Ku(-/+) heterozygous mice causes accelerated aging in skeletal muscle, although post natal growth is normal. An analysis of the level of Ku80 protein in human, cow, and mouse indicated that Ku80 levels vary dramatically between species, and that these levels are strongly correlated with species longevity. These results suggest that the NHEJ pathway of DNA repair mediated by Ku80 plays a significant role in repairing double-strand breaks that would otherwise cause early senescence (see DNA damage theory of aging). # Clinical significance A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity. ## Deficiency in cancer A deficiency in expression of a DNA repair gene increases the risk for cancer (see Deficient DNA repair in carcinogenesis). Ku80 protein expression was found to be deficient in melanoma. In addition, low expression of Ku80 was found in 15% of adenocarcinoma type and 32% of squamous cell type non-small cell lung cancers, and this was correlated with hypermethylation of the XRCC5 promoter. Ku80 appears to be one of 26 different DNA repair proteins that are epigenetically repressed in various cancers (see Cancer epigenetics). # Interactions Ku80 has been shown to interact with: - DNA-PKcs, - GCN5L2, - Ku70, - NCOA6, - PCNA, - POU2F1, - TERF2IP, - Telomerase reverse transcriptase, - Tyrosine kinase 2, and - Werner syndrome ATP-dependent helicase.

Ku80 Ku80 is a protein that, in humans, is encoded by the XRCC5 gene.[1] Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of DNA repair. It is also required for V(D)J recombination, which utilizes the NHEJ pathway to promote antigen diversity in the mammalian immune system. In addition to its role in NHEJ, Ku is required for telomere length maintenance and subtelomeric gene silencing.[2] Ku was originally identified when patients with systemic lupus erythematosus were found to have high levels of autoantibodies to the protein.[3] # Nomenclature Ku80 has been referred to by several names including: - Lupus Ku autoantigen protein p80 - ATP-dependent DNA helicase 2 subunit 2 - X-ray repair complementing defective repair in Chinese hamster cells 5 - X-ray repair cross-complementing 5 (XRCC5) # Epigenetic repression The protein expression level of Ku80 can be repressed by epigenetic hypermethylation of the promoter region of gene XRCC5 which encodes Ku80.[4] In a study of 87 matched pairs of primary tumors of non-small-cell lung carcinoma and nearby normal lung tissue, 25% of the tumors had loss of heterozygosity at the XRCC5 locus and a similar percentage of tumors had hypermethylation of the promoter region of XRCC5. Low protein expression of Ku80 was significantly associated with low mRNA expression and with XRCC5 promoter hypermethylation but not with LOH of the gene.[4] # Senescence Mouse mutants with homozygous defects in Ku80 experience an early onset of senescence.[5][6] Ku80(-/-) mice exhibit aging-related pathology (osteopenia, atrophic skin, hepatocellular degeneration, hepatocellular inclusions, hepatic hyperplastic foci and age-specific mortality). Furthermore, Ku80(-/-) mice exhibit severely reduced lifespan and size. Loss of only a single Ku80 allele in Ku(-/+) heterozygous mice causes accelerated aging in skeletal muscle, although post natal growth is normal.[7] An analysis of the level of Ku80 protein in human, cow, and mouse indicated that Ku80 levels vary dramatically between species, and that these levels are strongly correlated with species longevity.[8] These results suggest that the NHEJ pathway of DNA repair mediated by Ku80 plays a significant role in repairing double-strand breaks that would otherwise cause early senescence (see DNA damage theory of aging). # Clinical significance A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity.[1] ## Deficiency in cancer A deficiency in expression of a DNA repair gene increases the risk for cancer (see Deficient DNA repair in carcinogenesis). Ku80 protein expression was found to be deficient in melanoma.[9] In addition, low expression of Ku80 was found in 15% of adenocarcinoma type and 32% of squamous cell type non-small cell lung cancers, and this was correlated with hypermethylation of the XRCC5 promoter.[4] Ku80 appears to be one of 26 different DNA repair proteins that are epigenetically repressed in various cancers (see Cancer epigenetics). # Interactions Ku80 has been shown to interact with: - DNA-PKcs,[10][11][12] - GCN5L2,[13] - Ku70,[10][13][14][15][16] - NCOA6,[17][18] - PCNA,[12][19][20] - POU2F1,[12][21] - TERF2IP,[22] - Telomerase reverse transcriptase,[23] - Tyrosine kinase 2,[24] and - Werner syndrome ATP-dependent helicase.[25][26]

https://www.wikidoc.org/index.php/Ku80

ab980b7a9dc02fc5cfa7f3b42b7ae20ff4d1b04b

wikidoc

LAG3

LAG3 Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 (cluster of differentiation 223) after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biologic effects on T cell function. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right. # Gene The LAG3 gene contains 8 exons. The sequence data, exon/intron organization, and chromosomal localization all indicate a close relationship of LAG3 to CD4. The gene for LAG-3 lies adjacent to the gene for CD4 on human chromosome 12 (12p13) and is approximately 20% identical to the CD4 gene. # Protein The LAG3 protein, which belongs to immunoglobulin (Ig) superfamily, comprises a 503-amino acid type I transmembrane protein with four extracellular Ig-like domains, designated D1 to D4. When human LAG-3 was cloned in 1990 it was found to have approx. 70% homology with murine LAG3. The homology of pig LAG3 is 78%. # Tissue distribution LAG-3 is expressed on activated T cells, natural killer cells, B cells and plasmacytoid dendritic cells. # Function LAG3's main ligand is MHC class II, to which it binds with higher affinity than CD4. The protein negatively regulates cellular proliferation, activation, and homeostasis of T cells, in a similar fashion to CTLA-4 and PD-1 and has been reported to play a role in Treg suppressive function. LAG3 also helps maintain CD8+ T cells in a tolerogenic state and, working with PD-1, helps maintain CD8 exhaustion during chronic viral infection. LAG3 is known to be involved in the maturation and activation of dendritic cells. # Use as a pharmaceutical and as a drug target There are three approaches involving LAG3 that are in clinical development. - The first is IMP321, a soluble LAG3 which activates dendritic cells. - The second are antibodies to LAG3 which take the brakes off the anti-cancer immune response. An example is relatlimab, an anti-LAG3 monoclonal antibody that is currently in phase 1 clinical testing. A number of additional LAG3 antibodies are in preclinical development. LAG-3 may be a better checkpoint inhibitor target than CTLA-4 or PD-1 since antibodies to these two checkpoints only activate effector T cells, and do not inhibit Treg activity, whereas an antagonist LAG-3 antibody can both activate T effector cells (by downregulating the LAG-3 inhibiting signal into pre-activated LAG-3+ cells) and inhibit induced (i.e. antigen-specific) Treg suppressive activity. Combination therapies are also ongoing involving LAG-3 antibodies and CTLA-4 or PD-1 antibodies. - The third are agonist antibodies to LAG3 in order to blunt an autoimmune response. An example of this approach is GSK2831781 which has entered clinical testing (for plaque psoriasis). # History ## 1990 to 1999 LAG3 was discovered in 1990 by Frédéric Triebel (currently Chief Scientific Officer at Immutep) when he headed the cellular immunology group in the Department of Clinical Biology at the Institut Gustave Roussy. An initial characterization of the LAG-3 protein was reported in 1992 showing that it was a ligand for MHC class II antigens while a 1995 paper showed that it bound MHC Class II better than CD4. In 1996 INSERM scientists from Strasbourg showed, in knockout mice that were deficient in both CD4 and LAG-3, that the two proteins were not functionally equivalent. The first characterization of the MHC Class II binding sites on LAG-3 were reported by Triebel's group in 1997. The phenotype of LAG-3 knockout mice, as established by the INSERM Strasbourg group in 1996, demonstrated that LAG-3 was vital for the proper functioning of natural killer cells but in 1998 Triebel, working with LAG-3 antibodies and soluble protein, found that LAG-3 did not define a specific mode of natural killing. In May 1996 scientists at the University of Florence showed that CD4+ T cells that were LAG-3+ preferentially expressed IFN-γ, and this was up-regulated by IL-12 while in 1997 the same group showed that IFN-γ production was a driver of LAG-3 expression during the lineage commitment of human naive T cells. Subsequent work at the Sapienza University of Rome in 1998 showed that IFN-γ is not required for expression but rather for the up-regulation of LAG-3. The Triebel group in 1998 established that LAG-3 expression on activated human T cells is upregulated by IL-2, IL-7 and IL-12 and also showed that expression of LAG-3 may be controlled by some CD4 regulatory elements. In 1998 the Triebel group showed that, on T cells, LAG-3 down-modulates their proliferation and activation when LAG-3/MHC Class II co-caps with CD3/TCR complex. This relationship was confirmed in 1999 with co-capping experiments and with conventional fluorescence microscopy. In 1999 Triebel showed that LAG-3 could be used as a cancer vaccine, through cancer cell lines transfected with LAG-3. ## 2000 to 2009. In 2001 the Triebel group identified a LAG3-associated protein, called LAP, that seemed to participate in immune system down-regulation. Also in 2001 the Triebel group reported finding LAG3 expression on CD8+ tumor-infiltrating lymphocytes, with this LAG3 contributing to APC activation. In August 2002 the first phenotypic analysis of the murine LAG-3 was reported by a team at St. Jude Children's Research Hospital in Memphis. Molecular analysis reported by the St. Jude Children's Research Hospital team in November 2002 demonstrated that the inhibitory function of LAG-3 is performed via the protein's cytoplasmic domain. In 2003 the Triebel group was able to identify the MHC class II signal transduction pathways in human dendritic cells induced by LAG3. while the St. Jude Children's Research Hospital team showed that the absence of LAG3 caused no defect in T cell function. In May 2004 the St. Jude Children's Research Hospital team showed, through LAG3 knockout mice, that LAG-3 negatively regulates T cell expansion and controls the size of the memory T cell pool. This was in spite of earlier in vitro work that seemed to suggest that LAG-3 was necessary for T cell expansion. Work at Johns Hopkins University published in October 2004 identified LAG3's key role in regulatory T cells. The St. Jude Children's Research Hospital team reported in December 2004 that LAG-3 is cleaved within the D4 transmembrane domain into two fragments that remain membrane-associated: a 54-kDa fragment that contains all the extracellular domains and oligomerizes with full-length LAG-3 (70 kDa) on the cell surface via the D1 domain, and a 16-kDa peptide that contains the transmembrane and cytoplasmic domains and is subsequently released as soluble LAG-3. In January 2005 scientists at the D'Annunzio University of Chieti–Pescara showed that LAG-3 expression by tumour cells would recruit APCs into the tumour which would have Th1 commitment. Scientists working with AstraZeneca reported in March 2005 that SNPs on LAG3 conferred susceptibility to multiple sclerosis although later work at the Karolinska Institute showed no significant association. In June 2005 the Triebel group showed that antibodies to LAG-3 would result in T cell expansion, through increased rounds of cell division which LAG-3 signalling would otherwise block. In July 2005 scientists at the Institute for Research in Biomedicine in Bellinzona established that LAG3 expression on B cells is induced by T cells In 2006 scientists at the Istituto Superiore di Sanità in Rome showed that LAG could be used as a biomarker to assess the induction of Th-type responses in recipients of acellular pertussis vaccines. In April 2007 scientists working at Edward Jenner Institute for Vaccine Research in the UK demonstrated that LAG-3 participates in Treg-induced upregulation of CCR7 and CXCR4 on dendritic cells, resulting in semi-mature dendritic cells with the ability to migrate into lymphoid organs. Scientists at Sun Yat-sen University in China showed that LAG-3 played a role in immune privilege in the eye. In late 2007 the St. Jude Children's Research Hospital group showed that LAG-3 maintained tolerance to self and tumor antigens not just via CD4+ cells but also via CD8+ cells, independently of LAG-3's role on TReg cells. In 2009 the St. Jude Children's Research Hospital group reported that LAG3 appeared on plasmacytoid dendritic cells. Scientists at the University of Tokyo showed that LAG-3 was a marker of Tregs that secrete IL-10. ## 2010 to 2015. In 2010 scientists at Swiss Federal Institute of Technology in Zurich showed that LAG3 was an exhaustion marker for CD8+ T cells specific for Lymphocytic choriomeningitis virus, but alone did not significantly contribute to T-cell exhaustion. A team at the Roswell Park Cancer Institute showed that CD8+ Tumor-infiltrating lymphocytes that were specific for NY-ESO-1 were negatively regulated by LAG-3 and PD-1 in ovarian cancer. The St. Jude Children's Research Hospital group reported that most LAG3 was housed intracellularly in multiple domains before rapid translocation to the cell surface potentially facilitated by the microtubule organizing center and recycling endosomes during T-cell activation. Scientists at the Istituto Nazionale dei Tumori in Milan, collaborating with the Triebel group, showed that LAG3 defines a potent regulatory T cell subset that shows up more frequently in cancer patients and is expanded at tumor sites. Geneticists working at the National Cancer Institute reported that SNPs in the LAG3 gene were associated with higher risk of multiple myeloma. In 2011 scientists studying transplantation biology at Massachusetts General Hospital reported that when antibodies to CD40L induced tolerance in allogeneic bone marrow transplantation, LAG3 was part of the mechanism of action in CD8+ cells. Scientists at INSERM, working with the Triebel group, showed that the binding of MHC class II molecules on melanoma cells to LAG3 would increase resistance to apoptosis, providing evidence that antibodies to LAG3 would be relevant in melanoma. The St. Jude Children's Research Hospital group showed that LAG3 can play a modulating role in autoimmune diabetes. Microbiologists at the University of Iowa demonstrated that blockade of PD-L1 and LAG-3 was a valid therapeutic strategy for Plasmodium infection. In 2012 the St. Jude Children's Research Hospital group showed that LAG-3 and PD-1 synergistically regulate T-cell function in such a way as to allow an anti-tumoral immune response to be blunted. Scientists at Hanyang University in Seoul showed that tetravalent CTLA4-Ig and tetravalent LAG3-Ig could synergistically prevent acute graft-versus-host disease in animal models. In 2013 scientists at the San Raffaele Scientific Institute in Milan showed that LAG3 was a marker of type 1 Tregs. In 2014 scientists at Stanford University showed that LAG engagement could diminish alloreactive T cell responses after bone marrow transplantation. A group from the California Department of Public Health identified a subset of HIV-specific LAG3(+)CD8(+) T cells that negatively correlated with plasma viral load. The Istituto Nazionale dei Tumori group, collaborating with Triebel, found LAG3 expression on plasmacytoid dendritic cells is in part responsible for directing an immune-suppressive environment. A group at Korea University in Seoul demonstrated that LAG-3 translocates to the cell surface in activated T cells via the cytoplasmic domain through protein kinase C signaling. In 2015 scientists at the University of Tokyo showed how LAG3 on Tregs work with TGF beta 3 to suppress antibody production. At Tulane University bacteriologists working at the Tulane National Primate Research Center showed in rhesus macaques that Mycobacterium tuberculosis could work through LAG3 to modulate an anti-bacterial immune response. At National Taiwan University a group showed that LAG3 plays a role in the immunosuppressive capability of Tregs stimulated by Peyer's patch B cells.

LAG3 Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene.[1] LAG3, which was discovered in 1990[2] and was designated CD223 (cluster of differentiation 223) after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000,[3] is a cell surface molecule with diverse biologic effects on T cell function. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.[4] # Gene The LAG3 gene contains 8 exons. The sequence data, exon/intron organization, and chromosomal localization all indicate a close relationship of LAG3 to CD4.[1] The gene for LAG-3 lies adjacent to the gene for CD4 on human chromosome 12 (12p13) and is approximately 20% identical to the CD4 gene.[5] # Protein The LAG3 protein, which belongs to immunoglobulin (Ig) superfamily, comprises a 503-amino acid type I transmembrane protein with four extracellular Ig-like domains, designated D1 to D4. When human LAG-3 was cloned in 1990 it was found to have approx. 70% homology with murine LAG3.[2] The homology of pig LAG3 is 78%.[6] # Tissue distribution LAG-3 is expressed on activated T cells,[7] natural killer cells,[2] B cells[8] and plasmacytoid dendritic cells.[9] # Function LAG3's main ligand is MHC class II, to which it binds with higher affinity than CD4.[10] The protein negatively regulates cellular proliferation, activation,[11] and homeostasis of T cells, in a similar fashion to CTLA-4 and PD-1[12][13] and has been reported to play a role in Treg suppressive function.[14] LAG3 also helps maintain CD8+ T cells in a tolerogenic state[5] and, working with PD-1, helps maintain CD8 exhaustion during chronic viral infection.[15] LAG3 is known to be involved in the maturation and activation of dendritic cells.[16] # Use as a pharmaceutical and as a drug target There are three approaches involving LAG3 that are in clinical development. - The first is IMP321, a soluble LAG3 which activates dendritic cells.[17] - The second are antibodies to LAG3 which take the brakes off the anti-cancer immune response.[4] An example is relatlimab, an anti-LAG3 monoclonal antibody that is currently in phase 1 clinical testing.[18] A number of additional LAG3 antibodies are in preclinical development.[19] LAG-3 may be a better checkpoint inhibitor target than CTLA-4 or PD-1 since antibodies to these two checkpoints only activate effector T cells, and do not inhibit Treg activity, whereas an antagonist LAG-3 antibody can both activate T effector cells (by downregulating the LAG-3 inhibiting signal into pre-activated LAG-3+ cells) and inhibit induced (i.e. antigen-specific) Treg suppressive activity.[20] Combination therapies are also ongoing involving LAG-3 antibodies and CTLA-4 or PD-1 antibodies.[4] - The third are agonist antibodies to LAG3 in order to blunt an autoimmune response. An example of this approach is GSK2831781 which has entered clinical testing (for plaque psoriasis).[21] # History ## 1990 to 1999 LAG3 was discovered in 1990 by Frédéric Triebel (currently Chief Scientific Officer at Immutep) when he headed the cellular immunology group in the Department of Clinical Biology at the Institut Gustave Roussy.[22] An initial characterization of the LAG-3 protein was reported in 1992 showing that it was a ligand for MHC class II antigens[23] while a 1995 paper showed that it bound MHC Class II better than CD4.[10] In 1996 INSERM scientists from Strasbourg showed, in knockout mice that were deficient in both CD4 and LAG-3, that the two proteins were not functionally equivalent.[24] The first characterization of the MHC Class II binding sites on LAG-3 were reported by Triebel's group in 1997.[25] The phenotype of LAG-3 knockout mice, as established by the INSERM Strasbourg group in 1996, demonstrated that LAG-3 was vital for the proper functioning of natural killer cells[26] but in 1998 Triebel, working with LAG-3 antibodies and soluble protein, found that LAG-3 did not define a specific mode of natural killing.[27] In May 1996 scientists at the University of Florence showed that CD4+ T cells that were LAG-3+ preferentially expressed IFN-γ, and this was up-regulated by IL-12[28] while in 1997 the same group showed that IFN-γ production was a driver of LAG-3 expression during the lineage commitment of human naive T cells.[29] Subsequent work at the Sapienza University of Rome in 1998 showed that IFN-γ is not required for expression but rather for the up-regulation of LAG-3.[30] The Triebel group in 1998 established that LAG-3 expression on activated human T cells is upregulated by IL-2, IL-7 and IL-12 and also showed that expression of LAG-3 may be controlled by some CD4 regulatory elements.[31] In 1998 the Triebel group showed that, on T cells, LAG-3 down-modulates their proliferation and activation when LAG-3/MHC Class II co-caps with CD3/TCR complex.[32] This relationship was confirmed in 1999 with co-capping experiments and with conventional fluorescence microscopy.[33] In 1999 Triebel showed that LAG-3 could be used as a cancer vaccine, through cancer cell lines transfected with LAG-3.[34] ## 2000 to 2009. In 2001 the Triebel group identified a LAG3-associated protein, called LAP, that seemed to participate in immune system down-regulation.[35] Also in 2001 the Triebel group reported finding LAG3 expression on CD8+ tumor-infiltrating lymphocytes, with this LAG3 contributing to APC activation.[36] In August 2002 the first phenotypic analysis of the murine LAG-3 was reported by a team at St. Jude Children's Research Hospital in Memphis.[37] Molecular analysis reported by the St. Jude Children's Research Hospital team in November 2002 demonstrated that the inhibitory function of LAG-3 is performed via the protein's cytoplasmic domain.[38] In 2003 the Triebel group was able to identify the MHC class II signal transduction pathways in human dendritic cells induced by LAG3.[39] while the St. Jude Children's Research Hospital team showed that the absence of LAG3 caused no defect in T cell function.[12] In May 2004 the St. Jude Children's Research Hospital team showed, through LAG3 knockout mice, that LAG-3 negatively regulates T cell expansion and controls the size of the memory T cell pool.[13] This was in spite of earlier in vitro work that seemed to suggest that LAG-3 was necessary for T cell expansion.[12] Work at Johns Hopkins University published in October 2004 identified LAG3's key role in regulatory T cells.[14] The St. Jude Children's Research Hospital team reported in December 2004 that LAG-3 is cleaved within the D4 transmembrane domain into two fragments that remain membrane-associated: a 54-kDa fragment that contains all the extracellular domains and oligomerizes with full-length LAG-3 (70 kDa) on the cell surface via the D1 domain, and a 16-kDa peptide that contains the transmembrane and cytoplasmic domains and is subsequently released as soluble LAG-3.[40] In January 2005 scientists at the D'Annunzio University of Chieti–Pescara showed that LAG-3 expression by tumour cells would recruit APCs into the tumour which would have Th1 commitment.[41] Scientists working with AstraZeneca reported in March 2005 that SNPs on LAG3 conferred susceptibility to multiple sclerosis[42] although later work at the Karolinska Institute showed no significant association.[43] In June 2005 the Triebel group showed that antibodies to LAG-3 would result in T cell expansion, through increased rounds of cell division which LAG-3 signalling would otherwise block.[44] In July 2005 scientists at the Institute for Research in Biomedicine in Bellinzona established that LAG3 expression on B cells is induced by T cells[8] In 2006 scientists at the Istituto Superiore di Sanità in Rome showed that LAG could be used as a biomarker to assess the induction of Th-type responses in recipients of acellular pertussis vaccines.[45] In April 2007 scientists working at Edward Jenner Institute for Vaccine Research in the UK demonstrated that LAG-3 participates in Treg-induced upregulation of CCR7 and CXCR4 on dendritic cells, resulting in semi-mature dendritic cells with the ability to migrate into lymphoid organs.[46] Scientists at Sun Yat-sen University in China showed that LAG-3 played a role in immune privilege in the eye.[47] In late 2007 the St. Jude Children's Research Hospital group showed that LAG-3 maintained tolerance to self and tumor antigens not just via CD4+ cells but also via CD8+ cells, independently of LAG-3's role on TReg cells.[48] In 2009 the St. Jude Children's Research Hospital group reported that LAG3 appeared on plasmacytoid dendritic cells.[9] Scientists at the University of Tokyo showed that LAG-3 was a marker of Tregs that secrete IL-10.[49] ## 2010 to 2015. In 2010 scientists at Swiss Federal Institute of Technology in Zurich showed that LAG3 was an exhaustion marker for CD8+ T cells specific for Lymphocytic choriomeningitis virus, but alone did not significantly contribute to T-cell exhaustion.[50] A team at the Roswell Park Cancer Institute showed that CD8+ Tumor-infiltrating lymphocytes that were specific for NY-ESO-1 were negatively regulated by LAG-3 and PD-1 in ovarian cancer.[51] The St. Jude Children's Research Hospital group reported that most LAG3 was housed intracellularly in multiple domains before rapid translocation to the cell surface potentially facilitated by the microtubule organizing center and recycling endosomes during T-cell activation.[52] Scientists at the Istituto Nazionale dei Tumori in Milan, collaborating with the Triebel group, showed that LAG3 defines a potent regulatory T cell subset that shows up more frequently in cancer patients and is expanded at tumor sites.[53] Geneticists working at the National Cancer Institute reported that SNPs in the LAG3 gene were associated with higher risk of multiple myeloma.[54] In 2011 scientists studying transplantation biology at Massachusetts General Hospital reported that when antibodies to CD40L induced tolerance in allogeneic bone marrow transplantation, LAG3 was part of the mechanism of action in CD8+ cells.[55] Scientists at INSERM, working with the Triebel group, showed that the binding of MHC class II molecules on melanoma cells to LAG3 would increase resistance to apoptosis, providing evidence that antibodies to LAG3 would be relevant in melanoma.[56] The St. Jude Children's Research Hospital group showed that LAG3 can play a modulating role in autoimmune diabetes.[57] Microbiologists at the University of Iowa demonstrated that blockade of PD-L1 and LAG-3 was a valid therapeutic strategy for Plasmodium infection.[58] In 2012 the St. Jude Children's Research Hospital group showed that LAG-3 and PD-1 synergistically regulate T-cell function in such a way as to allow an anti-tumoral immune response to be blunted.[59] Scientists at Hanyang University in Seoul showed that tetravalent CTLA4-Ig and tetravalent LAG3-Ig could synergistically prevent acute graft-versus-host disease in animal models.[60] In 2013 scientists at the San Raffaele Scientific Institute in Milan showed that LAG3 was a marker of type 1 Tregs.[61] In 2014 scientists at Stanford University showed that LAG engagement could diminish alloreactive T cell responses after bone marrow transplantation.[62] A group from the California Department of Public Health identified a subset of HIV-specific LAG3(+)CD8(+) T cells that negatively correlated with plasma viral load.[63] The Istituto Nazionale dei Tumori group, collaborating with Triebel, found LAG3 expression on plasmacytoid dendritic cells is in part responsible for directing an immune-suppressive environment.[64] A group at Korea University in Seoul demonstrated that LAG-3 translocates to the cell surface in activated T cells via the cytoplasmic domain through protein kinase C signaling.[65] In 2015 scientists at the University of Tokyo showed how LAG3 on Tregs work with TGF beta 3 to suppress antibody production.[66] At Tulane University bacteriologists working at the Tulane National Primate Research Center showed in rhesus macaques that Mycobacterium tuberculosis could work through LAG3 to modulate an anti-bacterial immune response.[67] At National Taiwan University a group showed that LAG3 plays a role in the immunosuppressive capability of Tregs stimulated by Peyer's patch B cells.[68]

https://www.wikidoc.org/index.php/LAG3

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LCHN

LCHN LCHN is a protein that in humans is encoded by the KIAA1147 gene (NCBI Gene ID 57189) located on chromosome 7. It is likely part of the tripartite DENN domain family of proteins that often function as Rab-GEFs to regulate vesicular trafficking. Both the mRNA and protein have been shown to be upregulated following ischemic stroke, and to be produced at altered levels in patients with FTD-ALS, however the gene's contribution to these states is not well understood. # Gene KIAA1147 is located on the 7th chromosome in humans from bases 141652381-141702188 on the negative strand. Additional names for KIAA1147 include PRO25611, AI841796 in the mouse and RGD1563986 in the rat. Only one mRNA transcript of KIAA1147 has been reported in NCBI, and is composed of 9 exons. # Protein Human LCHN is a cytoplasmic protein composed of 455 amino acids predicted to be 51.4 kD before modifications with isoelectric point of 5.06. The majority of its 455 amino acids make up the tripartite DENN domains which are commonly found in proteins that act as Rab-GEFs and regulate vesicular trafficking. LCHN has several predicted phosphorylation sites and contains many motifs for kinase binding. The uDENN and cDENN domains of LCHN are predicted to be primarily coil, while the dDENN domain is predicted to be a combination of alpha helix and beta sheet. The cDENN domain is the most highly conserved domain within DENN family proteins, and is also primarily coil in protein DENND1B, which has been crystallized and confirmed to interact with the guanine nucleotide exchange domain of Rab-35. LCHN also contains a Stability of Polarity Axis (SPA) region. that may allow it to play a role in cell division. # Expression ## Tissues The Human Protein Atlas reports high levels of KIAA1147 transcription in several brain regions including cerebral cortex, cerebellum, and retina, as well as non-brain regions including spleen, thymus, stomach, prostate, lung, and ascending colon. Immunohistochemistry has shown LCHN to be localized to the cytoplasmic face of the Golgi apparatus in cell culture, and the brain in mouse fetal development. In the adult mouse and human brain, LCHN is expressed relatively ubiquitously. Expression of LCHN has been shown to increase in response to chronic alcoholism, immature and mature dendritic response to hypoxia, and ischemic stroke. ## Transcriptional regulation There are binding sites for two main groups of transcription factors in the predicted promoter of KIAA1147. The first group consists of elements related to the cell cycle and neuronal development and includes AP-2, NRF1, BRAC, E2F, NEUR, and NRSF. The second consists of elements related to brain insult, including HIFF (hypoxia inducible factor), CREB (cAMP responsive factor linked to ER stress response), GREF (glucocorticoid responsible factor), HEAT (heat shock responsive factor), and HDBP (Huntington's disease regulatory binding protein). In patients with FTD-ALS, there has been reported abnormal upstream CpG methylation of KIAA1147 # Interacting proteins ## SETBP1 Yeast two-hybrid assays have shown LCHN to physically interact with SETBP1, a protein that contains 3 nuclear localization signals. Despite the lack of a predicted nuclear localization signal in its own sequence, this interaction suggests that LCHN may be able to enter and have functional importance in the nucleus. ## TGOLN2 In affinity chromatography studies, LCHN has been reported to have a physical association with TGOLN2, a surface protein of the Golgi apparatus. This likely explains immunohistochemical finding of strong LCHN localization near the Golgi apparatus despite being a predicted cytoplasmic protein. ## Kallikreins Affinity chromatography studies have also reported a physical association between LCHN and kallikreins KLK5 and KLK11, serine proteases. It is possible that cleavage by these proteases may be relevant to LCHN's function. ## EFNB3 LCHN has been reported to be capable of a physical association with EFNB3, an ephrin receptor ligand with reported importance in neuronal development. This, coupled with the high expression of LCHN in the developing central nervous system, suggests that binding of LCHN to EFNB3 may modulate neuronal development. # Predicted function ## Neuronal insult LCHN expression has been reported to be unregulated following ischemic stroke, chronic alcoholism, and cell culture responses of immature and mature dendrites to prolonged hypoxia. Additionally, decreased expression as a result of CpG methylation has been implicated to be pathogenic in patients with FTD-ALS. Within the predicted promoter of KIAA1147, there are predicted binding sites for hypoxia response elements that would accompany ischemic stroke, heat shock proteins, factors related to the glucocorticoid mediated stress response, and cAMP responsive factors related to the ER stress response. Due to the reported evidence of LCHN upregulation following ischemic stroke, which often results in neuronal damage or death, as well presence of several binding sites for factors induced by rapid trauma to the brain, it is likely that KIAA1147 plays a role in the brain’s response to sudden stress and injury. ## Neuronal development The presence of the SPA domain within LCHN suggests that it may play a role in cell division. LCHN has been shown to physically associate with EFNB3, a protein with reported importance in neuronal development. A second reported association with SETBP1 may open up the possibility for LCHN to play a role in cell cycle regulation from within the nucleus. The predicted KIAA1147 promoter contains binding sites for cell-division related factors and factors known to have specific expression during neuronal development. RNA in situ hybrdization has shown KIAA1147 to be located at high levels in the developing brain. Together, these data suggest that LCHN plays a role in regulating cellular division during development of the brain. # Clinical significance LCHN has been shown to be upregulated following a number of insults to the brain including the response to chronic alcoholism, immature and mature dendritic response to hypoxia, and ischemic stroke. Recent studies have implicated abnormal CpG methylation of LCHN in FTD-ALS. No disease causing SNPs in LCHN have been reported with high frequency. # Homology There are no reported paralogs of LCHN in humans. LCHN homologs exist in animals dating back to the earliest sponges, with a notable lack of reported expression in Drosophila and C. elegans. There are also a number of LCHN homologs in protists including choanoflagellates, amoeba, and algae, as well as other unicellular eukaryotes including fungi.

LCHN LCHN is a protein that in humans is encoded by the KIAA1147 gene (NCBI Gene ID 57189) located on chromosome 7.[1] It is likely part of the tripartite DENN domain family of proteins that often function as Rab-GEFs[2][3] to regulate vesicular trafficking.[2] Both the mRNA and protein have been shown to be upregulated following ischemic stroke,[4] and to be produced at altered levels in patients with FTD-ALS,[5] however the gene's contribution to these states is not well understood. # Gene KIAA1147 is located on the 7th chromosome in humans from bases 141652381-141702188 on the negative strand.[6] Additional names for KIAA1147 include PRO25611,[7] AI841796 in the mouse[8] and RGD1563986 in the rat.[9] Only one mRNA transcript of KIAA1147 has been reported in NCBI, and is composed of 9 exons.[1] # Protein Human LCHN is a cytoplasmic protein composed of 455 amino acids predicted to be 51.4 kD before modifications with isoelectric point of 5.06.[10] The majority of its 455 amino acids make up the tripartite DENN domains which are commonly found in proteins that act as Rab-GEFs[2] and regulate vesicular trafficking.[2] LCHN has several predicted phosphorylation sites[11] and contains many motifs for kinase binding.[12] The uDENN and cDENN domains of LCHN are predicted to be primarily coil, while the dDENN domain is predicted to be a combination of alpha helix and beta sheet.[13][14][15] The cDENN domain is the most highly conserved domain within DENN family proteins,[2] and is also primarily coil in protein DENND1B,[16] which has been crystallized and confirmed to interact with the guanine nucleotide exchange domain of Rab-35.[16] LCHN also contains a Stability of Polarity Axis (SPA) region.[6] that may allow it to play a role in cell division.[17] # Expression ## Tissues The Human Protein Atlas reports high levels of KIAA1147 transcription in several brain regions including cerebral cortex, cerebellum, and retina, as well as non-brain regions including spleen, thymus, stomach, prostate, lung, and ascending colon.[18] Immunohistochemistry has shown LCHN to be localized to the cytoplasmic face of the Golgi apparatus in cell culture,[19] and the brain in mouse fetal development.[20] In the adult mouse and human brain, LCHN is expressed relatively ubiquitously.[21][22] Expression of LCHN has been shown to increase in response to chronic alcoholism,[23] immature and mature dendritic response to hypoxia, and ischemic stroke.[4] ## Transcriptional regulation There are binding sites for two main groups of transcription factors in the predicted promoter of KIAA1147. The first group consists of elements related to the cell cycle and neuronal development and includes AP-2, NRF1, BRAC, E2F, NEUR, and NRSF.[24] The second consists of elements related to brain insult, including HIFF (hypoxia inducible factor), CREB (cAMP responsive factor linked to ER stress response), GREF (glucocorticoid responsible factor), HEAT (heat shock responsive factor), and HDBP (Huntington's disease regulatory binding protein).[24] In patients with FTD-ALS, there has been reported abnormal upstream CpG methylation of KIAA1147[5] # Interacting proteins ## SETBP1 Yeast two-hybrid assays have shown LCHN to physically interact with SETBP1,[25] a protein that contains 3 nuclear localization signals.[26] Despite the lack of a predicted nuclear localization signal in its own sequence, this interaction suggests that LCHN may be able to enter and have functional importance in the nucleus. ## TGOLN2 In affinity chromatography studies, LCHN has been reported to have a physical association with TGOLN2,[27][28] a surface protein of the Golgi apparatus.[29] This likely explains immunohistochemical finding of strong LCHN localization near the Golgi apparatus [19] despite being a predicted cytoplasmic protein.[10] ## Kallikreins Affinity chromatography studies have also reported a physical association between LCHN and kallikreins KLK5 and KLK11,[27][28] serine proteases.[30] It is possible that cleavage by these proteases may be relevant to LCHN's function. ## EFNB3 LCHN has been reported to be capable of a physical association with EFNB3,[27] an ephrin receptor ligand with reported importance in neuronal development.[31] This, coupled with the high expression of LCHN in the developing central nervous system, suggests that binding of LCHN to EFNB3 may modulate neuronal development. # Predicted function ## Neuronal insult LCHN expression has been reported to be unregulated following ischemic stroke, chronic alcoholism, and cell culture responses of immature and mature dendrites to prolonged hypoxia.[4][23][4] Additionally, decreased expression as a result of CpG methylation has been implicated to be pathogenic in patients with FTD-ALS.[5] Within the predicted promoter of KIAA1147, there are predicted binding sites for hypoxia response elements that would accompany ischemic stroke, heat shock proteins, factors related to the glucocorticoid mediated stress response, and cAMP responsive factors related to the ER stress response.[32] Due to the reported evidence of LCHN upregulation following ischemic stroke, which often results in neuronal damage or death,[33] as well presence of several binding sites for factors induced by rapid trauma to the brain,[24] it is likely that KIAA1147 plays a role in the brain’s response to sudden stress and injury. ## Neuronal development The presence of the SPA domain within LCHN suggests that it may play a role in cell division.[6][17] LCHN has been shown to physically associate with EFNB3, a protein with reported importance in neuronal development.[27][31] A second reported association with SETBP1 may open up the possibility for LCHN to play a role in cell cycle regulation from within the nucleus.[25][26] The predicted KIAA1147 promoter contains binding sites for cell-division related factors and factors known to have specific expression during neuronal development. RNA in situ hybrdization has shown KIAA1147 to be located at high levels in the developing brain. Together, these data suggest that LCHN plays a role in regulating cellular division during development of the brain. # Clinical significance LCHN has been shown to be upregulated following a number of insults to the brain including the response to chronic alcoholism, immature and mature dendritic response to hypoxia, and ischemic stroke.[4][4][23] Recent studies have implicated abnormal CpG methylation of LCHN in FTD-ALS.[5] No disease causing SNPs in LCHN have been reported with high frequency.[34] # Homology There are no reported paralogs of LCHN in humans.[1] LCHN homologs exist in animals dating back to the earliest sponges, with a notable lack of reported expression in Drosophila and C. elegans.[1] There are also a number of LCHN homologs in protists including choanoflagellates, amoeba, and algae, as well as other unicellular eukaryotes including fungi.[1]

https://www.wikidoc.org/index.php/LCHN

da59672fbd60de66fd80ed93dc48524aa812c196

wikidoc

LDB3

LDB3 LIM domain binding 3 (LDB3), also known as Z-band alternatively spliced PDZ-motif (ZASP), is a protein which in humans is encoded by the LDB3 gene. ZASP belongs to the Enigma subfamily of proteins and stabilizes the sarcomere (the basic units of muscles) during contraction, through interactions with actin in cardiac and skeletal muscles. Mutations in the ZASP gene has been associated with several muscular diseases. # Structure ZASP is a PDZ domain-containing protein. PDZ motifs are modular protein-protein interaction domains consisting of 80-120 amino acid residues. PDZ domain-containing proteins interact with each other in cytoskeletal assembly or with other proteins involved in targeting and clustering of membrane proteins. ZASP interacts with alpha-actinin-2 through its N-terminal PDZ domain and with protein kinase C via its C-terminal LIM domains. The LIM domain is a cysteine-rich motif defined by 50-60 amino acids containing two zinc-binding modules. This protein also interacts with all three members of the myozenin family. Human ZASP can exist in cardiac and skeletal cells as six distinct isoforms, based on alternative splicing of 16 exons. There are 2 ZASP short forms (Uniprot ID: O75112-6, 31.0 kDa, 283 amino acids; and Uniprot ID: O75112-5, 35.6 kDa, 330 amino acids); and 4 ZASP long forms (Uniprot ID: O75112-4, 42.8 kDa, 398 amino acids; Uniprot ID: O75112-3, 50.6 kDa, 470 amino acids; Uniprot ID: O75112-2, 66.6 kDa, 617 amino acids; and Uniprot ID: O75112, 77.1 kDa, 727 amino acids). All ZASP isoforms have an N-terminal PDZ domain; internal, conserved sequences known as ZASP-like motifs (ZMs); and the four long isoforms have three C-terminal LIM domains. # Function ZASP functions to maintain structural integrity of sarcomeres during contraction, and has been shown to be involved in protein kinase A signaling. ZASP has also been shown to co-activate α5β1 integrins along with the protein TLN1. # Clinical significance Mutations in ZASP have been associated with myofibrillar myopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, noncompaction cardiomyopathy, and muscular dystrophy. # Interactions The PDZ domain of ZASP binds the C-terminus of alpha actinin-2 and ZMs bind the rod domain of alpha actinin-2. The LIM domains have been shown to interact with protein kinase C. The cardiac-specific region of ZASP encoded by exon 4 includes a ZP motif and binds a regulatory subunit of protein kinase A.

LDB3 LIM domain binding 3 (LDB3), also known as Z-band alternatively spliced PDZ-motif (ZASP), is a protein which in humans is encoded by the LDB3 gene.[1][2] ZASP belongs to the Enigma subfamily of proteins and stabilizes the sarcomere (the basic units of muscles) during contraction, through interactions with actin in cardiac and skeletal muscles. Mutations in the ZASP gene has been associated with several muscular diseases. # Structure ZASP is a PDZ domain-containing protein. PDZ motifs are modular protein-protein interaction domains consisting of 80-120 amino acid residues. PDZ domain-containing proteins interact with each other in cytoskeletal assembly or with other proteins involved in targeting and clustering of membrane proteins. ZASP interacts with alpha-actinin-2 through its N-terminal PDZ domain and with protein kinase C via its C-terminal LIM domains. The LIM domain is a cysteine-rich motif defined by 50-60 amino acids containing two zinc-binding modules. This protein also interacts with all three members of the myozenin family.[1] Human ZASP can exist in cardiac and skeletal cells as six distinct isoforms, based on alternative splicing of 16 exons.[3] There are 2 ZASP short forms (Uniprot ID: O75112-6, 31.0 kDa, 283 amino acids;[4] and Uniprot ID: O75112-5, 35.6 kDa, 330 amino acids);[5] and 4 ZASP long forms (Uniprot ID: O75112-4, 42.8 kDa, 398 amino acids;[6] Uniprot ID: O75112-3, 50.6 kDa, 470 amino acids;[7] Uniprot ID: O75112-2, 66.6 kDa, 617 amino acids;[8] and Uniprot ID: O75112, 77.1 kDa, 727 amino acids).[9][10] All ZASP isoforms have an N-terminal PDZ domain; internal, conserved sequences known as ZASP-like motifs (ZMs); and the four long isoforms have three C-terminal LIM domains.[3] # Function ZASP functions to maintain structural integrity of sarcomeres during contraction, and has been shown to be involved in protein kinase A signaling.[11] ZASP has also been shown to co-activate α5β1 integrins along with the protein TLN1.[12] # Clinical significance Mutations in ZASP have been associated with myofibrillar myopathy,[13] dilated cardiomyopathy,[14][15][16] arrhythmogenic right ventricular cardiomyopathy,[17] noncompaction cardiomyopathy,[16][18] and muscular dystrophy.[13] # Interactions The PDZ domain of ZASP binds the C-terminus of alpha actinin-2[19][20] and ZMs bind the rod domain of alpha actinin-2.[21] The LIM domains have been shown to interact with protein kinase C.[20][22] The cardiac-specific region of ZASP encoded by exon 4 includes a ZP motif and binds a regulatory subunit of protein kinase A.[11]

https://www.wikidoc.org/index.php/LDB3

697704d9d81a988b56ddc5b0ec826f55498306cb

wikidoc

LFNG

LFNG LFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase, also known as LFNG and Lunatic Fringe, is a human gene. This gene encodes a member of the glycosyltransferase superfamily. The encoded protein is a single-pass type II Golgi membrane protein that functions as a fucose-specific glycosyltransferase, adding an N-acetylglucosamine to the fucose residue of a group of signaling receptors involved in regulating cell fate decisions during development. Mutations in this gene have been associated with autosomal recessive spondylocostal dysostosis 3. Alternatively spliced transcript variants that encode different isoforms have been described, however, not all variants have been fully characterized. # Function Lunatic Fringe (Lfng) is a gene whose role in embryonic development is to establish the anterior boundary of somites, which will eventually develop in vertebrae, ribs, and dermis. Lunatic Fringe responds to certain threshold ratios of retinoic acid and FGF-8 in order to mark the anterior boundary of somites while another transcription factor, Hairy, responds to different threshold ratios of retinoic acid and FGF-8 to form the posterior boundaries of somites. # Clinical significance A defect associated with Lfng mutations is spondylocostal dysostosis. Spondylocostal dysostosis is characterized by segmentation problems in the developing vertebrae resulting in fusion or lack of vertebrae along with abnormalities in the ribs. Clinically, spondylocostal dysostosis presents as a shortened neck and trunk relative total height and a mild form of scoliosis. Respiratory problems are also common in spondylocostal dysostosis because of the shortened trunk. A knockout model for Lfng has been created in mice, and without Lfng, mice have shorter tails, and impaired rib, lung, and somite development. A deficiency of Lfng in male mice has also been associated with lack of spermatozoa in the epididymis of many mice; however, spermatogenesis was not impaired. Rather, the male mice were subfertile. In female mice, Lfng deficiency led to infertility because of abnormal folliculogenesis. Further examination showed that oocytes from these female mice did not complete meiotic maturation. However, there are other studies that contradict this stating that not all female mile deficient of Lfng are infertile. A possible explanation for this difference between these studies is that the Lfng alleles were functional different, however, this is unlikely. More likely is that this discrepancy results from differences in the genetic background of the mice or husbandry and colony conditions. # Impact of mutation Lunatic Fringe is a transcription factor that plays a crucial role in the development of the somites. Somites give rise to the skeletal muscle, the axial skeleton, the tendons, and the dorsal dermis. The somites are formed via the clock-wave front model, and as each somite is formed, each cell receives a burst of FGF8 (a signaling molecule). Somites are formed anterior to posterior, and since FGF8 has a short half-life, this leads to a greater concentration of FGF8 in the posterior, and a lesser concentration in the anterior. Lunatic fringe responds to the lower concentration of FGF8 in the anterior and leads these cells to their developmental fate. Mutation of the Lunatic Fringe gene can cause severe Spondylocostal Dysostosis, which involves vertebral segmentation defects and rib abnormalities. A mutation was discovered in which a conservative phenylalanine close to the active site of the enzyme mutates, leading to the enzymatic inactivation of Lunatic Fringe. A “knock-out” model has been created using mice. In mice, Lunatic Fringe plays a crucial role in the Notch signaling pathway during the formation of somites, and a mutation in this gene leads to somites with irregular shapes and a defect in the anterior-posterior formation.

LFNG LFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase, also known as LFNG and Lunatic Fringe,[1][2] is a human gene.[3] This gene encodes a member of the glycosyltransferase superfamily. The encoded protein is a single-pass type II Golgi membrane protein that functions as a fucose-specific glycosyltransferase, adding an N-acetylglucosamine to the fucose residue of a group of signaling receptors involved in regulating cell fate decisions during development. Mutations in this gene have been associated with autosomal recessive spondylocostal dysostosis 3. Alternatively spliced transcript variants that encode different isoforms have been described, however, not all variants have been fully characterized.[3] # Function Lunatic Fringe (Lfng) is a gene whose role in embryonic development is to establish the anterior boundary of somites, which will eventually develop in vertebrae, ribs, and dermis.[4] Lunatic Fringe responds to certain threshold ratios of retinoic acid and FGF-8 in order to mark the anterior boundary of somites while another transcription factor, Hairy, responds to different threshold ratios of retinoic acid and FGF-8 to form the posterior boundaries of somites.[5] # Clinical significance A defect associated with Lfng mutations is spondylocostal dysostosis. Spondylocostal dysostosis is characterized by segmentation problems in the developing vertebrae resulting in fusion or lack of vertebrae along with abnormalities in the ribs.[6] Clinically, spondylocostal dysostosis presents as a shortened neck and trunk relative total height and a mild form of scoliosis. Respiratory problems are also common in spondylocostal dysostosis because of the shortened trunk. A knockout model for Lfng has been created in mice, and without Lfng, mice have shorter tails, and impaired rib, lung, and somite development. A deficiency of Lfng in male mice has also been associated with lack of spermatozoa in the epididymis of many mice; however, spermatogenesis was not impaired. Rather, the male mice were subfertile.[7] In female mice, Lfng deficiency led to infertility because of abnormal folliculogenesis. Further examination showed that oocytes from these female mice did not complete meiotic maturation.[8] However, there are other studies that contradict this stating that not all female mile deficient of Lfng are infertile. A possible explanation for this difference between these studies is that the Lfng alleles were functional different, however, this is unlikely. More likely is that this discrepancy results from differences in the genetic background of the mice or husbandry and colony conditions.[9] # Impact of mutation Lunatic Fringe is a transcription factor that plays a crucial role in the development of the somites. Somites give rise to the skeletal muscle, the axial skeleton, the tendons, and the dorsal dermis. The somites are formed via the clock-wave front model, and as each somite is formed, each cell receives a burst of FGF8 (a signaling molecule). Somites are formed anterior to posterior, and since FGF8 has a short half-life, this leads to a greater concentration of FGF8 in the posterior, and a lesser concentration in the anterior. Lunatic fringe responds to the lower concentration of FGF8 in the anterior and leads these cells to their developmental fate. Mutation of the Lunatic Fringe gene can cause severe Spondylocostal Dysostosis, which involves vertebral segmentation defects and rib abnormalities. A mutation was discovered in which a conservative phenylalanine close to the active site of the enzyme mutates, leading to the enzymatic inactivation of Lunatic Fringe. A “knock-out” model has been created using mice. In mice, Lunatic Fringe plays a crucial role in the Notch signaling pathway during the formation of somites, and a mutation in this gene leads to somites with irregular shapes and a defect in the anterior-posterior formation. [6] [10]

https://www.wikidoc.org/index.php/LFNG

4cb38b643d00cb132c167ea295391a9cd0f06dca

wikidoc

LGI1

LGI1 Leucine-rich, glioma inactivated 1, also known as LGI1, is a protein which in humans is encoded by the LGI1 gene. It may be a metastasis suppressor. # Function The leucine-rich glioma inactivated -1 gene is rearranged as a result of translocations in glioblastoma cell lines. The protein contains a hydrophobic segment representing a putative transmembrane domain with the amino terminus located outside the cell. It also contains leucine-rich repeats with conserved cysteine-rich flanking sequences. This gene is predominantly expressed in neural tissues and its expression is reduced in low grade brain tumors and significantly reduced or absent in malignant gliomas. # Clinical significance Since its earliest discovery, the LGI1 gene has been implicated in the control of cancer metastasis and in a predisposition to epilepsy. Following genetic linkage studies placing the hereditary form of autosomal dominant partial epilepsy with auditory features (ADPEAF) on chromosome region 10q24 mutation analysis of affected members in these families demonstrated LGI1 was a major cause of the disease. More recently, LGI1 has been shown to be the major target of human autoantibodies which immunoprecipitate voltage-gated potassium channel complexes from mammalian brain tissue. LGI1 antibodies are found in patients with limbic encephalitis and in patients with faciobrachial dystonic seizures (FBDS). FBDS are a recently described form of epilepsy which is characterized by frequent, brief seizures which affect the arm and face. They appear to be preferentially responsive to immunotherapy over anti-epileptic drugs. # Interactions LGI1 has been shown to interact with ADAM22, and DLG4.

LGI1 Leucine-rich, glioma inactivated 1, also known as LGI1, is a protein which in humans is encoded by the LGI1 gene.[1] It may be a metastasis suppressor. # Function The leucine-rich glioma inactivated -1 gene is rearranged as a result of translocations in glioblastoma cell lines. The protein contains a hydrophobic segment representing a putative transmembrane domain with the amino terminus located outside the cell. It also contains leucine-rich repeats with conserved cysteine-rich flanking sequences. This gene is predominantly expressed in neural tissues and its expression is reduced in low grade brain tumors and significantly reduced or absent in malignant gliomas.[1] # Clinical significance Since its earliest discovery, the LGI1 gene has been implicated in the control of cancer metastasis and in a predisposition to epilepsy. Following genetic linkage studies placing the hereditary form of autosomal dominant partial epilepsy with auditory features (ADPEAF) on chromosome region 10q24[2][3] mutation analysis of affected members in these families[4][5][6] demonstrated LGI1 was a major cause of the disease. More recently, LGI1 has been shown to be the major target of human autoantibodies[7][8][9] which immunoprecipitate voltage-gated potassium channel complexes from mammalian brain tissue. LGI1 antibodies are found in patients with limbic encephalitis and in patients with faciobrachial dystonic seizures (FBDS). FBDS are a recently described form of epilepsy which is characterized by frequent, brief seizures which affect the arm and face. They appear to be preferentially responsive to immunotherapy over anti-epileptic drugs. # Interactions LGI1 has been shown to interact with ADAM22,[10] and DLG4.[10]

https://www.wikidoc.org/index.php/LGI1

ce73854f33b4d3f6b7f9dae4b8bad1dc130f9d5b

wikidoc

LGP2

LGP2 Probable ATP-dependent RNA helicase DHX58 also known as RIG-I-like receptor 3 (RLR-3) or RIG-I-like receptor LGP2 (RLR) is a RIG-I-like receptor dsRNA helicase enzyme that in humans is encoded by the DHX58 gene. The protein encoded by the gene DHX58 is known as LGP2 (Laboratory of Genetics and Physiology 2). # Structure and function LGP2 was first identified and characterized in the context of mammary tissue in 2001, but its function has been found to be more relevant to the field of innate antiviral immunity. LGP2 has been found to be essential for producing effective antiviral responses against many viruses that are recognized by RIG-I and MDA5. Since LGP2 lacks CARD domains, its effect on downstream antiviral signaling is likely due to interaction with dsRNA viral ligand or the other RLRs (RIG-I and MDA5). LGP2 has been shown to directly interact with RIG-I through its C-terminal repressor domain (RD). The primary contact sites in this interaction is likely between the RD of LGP2 and the CARD or helicase domain of RIG-I as it is seen with RIG-I self-association, but this has not been confirmed. The helicase activity of LGP2 has been found to be essential for its positive regulation of RIG-I signaling. Overexpression of LGP2 is able to inhibit RIG-I-mediated antiviral signaling both in the presence and absence of viral ligands. This inhibition of RIG-I signaling is not dependent upon the ability of LGP2 to bind viral ligands and is therefore not due to ligand competition. Although LGP2 binds to dsRNA with higher affinity, it is dispensable for RIG-I-mediated recognition of synthetic dsRNA ligands. RIG-I, when overexpressed and in LGP2 knock-down studies, has been shown to induce antiviral response in the absence of viral ligand.

LGP2 Probable ATP-dependent RNA helicase DHX58 also known as RIG-I-like receptor 3 (RLR-3) or RIG-I-like receptor LGP2 (RLR) is a RIG-I-like receptor dsRNA helicase enzyme that in humans is encoded by the DHX58 gene.[1][2] The protein encoded by the gene DHX58 is known as LGP2 (Laboratory of Genetics and Physiology 2).[1][3][4] # Structure and function LGP2 was first identified and characterized in the context of mammary tissue in 2001,[1] but its function has been found to be more relevant to the field of innate antiviral immunity. LGP2 has been found to be essential for producing effective antiviral responses against many viruses that are recognized by RIG-I and MDA5.[5] Since LGP2 lacks CARD domains, its effect on downstream antiviral signaling is likely due to interaction with dsRNA viral ligand or the other RLRs (RIG-I and MDA5).[6] LGP2 has been shown to directly interact[6] with RIG-I through its C-terminal repressor domain (RD). The primary contact sites in this interaction is likely between the RD of LGP2 and the CARD or helicase domain of RIG-I as it is seen with RIG-I self-association,[6] but this has not been confirmed. The helicase activity of LGP2 has been found to be essential for its positive regulation of RIG-I signaling.[5] Overexpression of LGP2 is able to inhibit RIG-I-mediated antiviral signaling both in the presence and absence of viral ligands.[6][7][8] This inhibition of RIG-I signaling is not dependent upon the ability of LGP2 to bind viral ligands and is therefore not due to ligand competition.[3][9] Although LGP2 binds to dsRNA with higher affinity,[8] it is dispensable for RIG-I-mediated recognition of synthetic dsRNA ligands.[5] RIG-I, when overexpressed[3] and in LGP2 knock-down studies,[10] has been shown to induce antiviral response in the absence of viral ligand.

https://www.wikidoc.org/index.php/LGP2

81d56521cca8e3a859e354e2d9e2a723c9b6e248

wikidoc

LGR5

LGR5 Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) also known as G-protein coupled receptor 49 (GPR49) or G-protein coupled receptor 67 (GPR67) is a protein that in humans is encoded by the LGR5 gene. It is a member of GPCR class A receptor proteins. R-spondin proteins are the biological ligands of LGR5. LGR5 is expressed across a diverse range of tissue such as in the muscle, placenta, spinal cord and brain and particularly as a biomarker of adult stem cells in certain tissues. # Gene Prior to its current naming designation, LGR5 was also known as FEX, HG38, GPR49, and GPR67. The Human LGR5 gene is 144,810 bases long and located at chromosome 12 at position 12q22-q23. Both human, rat and mouse homologs contain 907 amino acids and seven transmembrane domains. After translation, the signal peptide (amino acids 1-21) is cleaved off and the mature peptide (amino acids 22-907) inserts its transmembrane domain into the translocon membrane prior to packaging towards the plasma membrane. # Protein structure LGR5 is highly conserved within the mammalian clade. Sequence analyses showed that the transmembrane regions and cysteine-flanked junction between TM1 and the extracellular domain were highly conserved in sea anemone (Anthopleura elegantissima), fly (Drosophila melanogaster), worm (Caenorhabditis elegans), snail (Lymnaea stagnalis), rat (Rattus rattus) and human (Homo sapiens). Homology amongst the metazoan suggests that it has been conserved across animals and was hypothesised as a chimeric fusion of an ancestral GPCR and a leucine-rich repeat motif. Sheau Hsu, Shan Liang and Aaron Hsueh first identified LGR5, together with LGR4, in 1998 at the University Medical School Stanford, California using expression sequence tags based on putative glycoprotein hormone receptors in Drosophila. Experimental evidence show that the mature receptor protein contains up to 17 leucine-rich repeats, each composed of 24 amino acids spanning the extracellular domain flanked by the cysteine-rich N-terminal and C-terminal regions. In contrast, other glycoprotein hormone receptors such as Luteinizing hormone, Follicle-stimulating hormone and Thyroid-stimulating hormone contain only 9 repeats. Sequence alignment showed that the second N-glycosylation site in LGR5 (Asn 208) aligns with that on the sixth repeat of gonadotropin and TSH receptors. The cysteine residues flanking the ectodomain form stabilising disulfide bonds that support the secondary structure of the leucine-rich repeats. # Function LGR5 is a member of the Wnt signaling pathway. Although its ligand remains elusive, it has been shown that costimulation with R-spondin 1 and Wnt-3a induce increased internalization of LGR5. LGR5 also cointernalizes with LRP6 and FZD5 via a clathrin-dependent pathway to form a ternary complex upon Wnt ligand binding. Moreover, the rapid cointernalization of LRP6 by LGR5 induces faster rates of degradation for the former. It has been shown that the C-terminal region of LGR5 is crucial for both dynamic internalization and degradation to occur, although C-terminal truncation does not inhibit LRP6 interaction and internalization, but rather, heightens receptor activity. Thus, only the initial interaction with its unknown ligand and other membrane bound receptors is crucial in its role in Wnt signalling and not the internalization itself. LGR5 is crucial during embryogenesis as LGR null studies in mice incurred 100% neonatal mortality accompanied by several craniofacial distortions such as ankyloglossia and gastrointestinal dilation. ## Ligand LGR5 belongs to a class of class A GPCR orphan receptors. Thus its ligands remain elusive. However, it has been shown that Lgr2, the fly orthologue of mammalian LGR5, binds with "high affinity and specificity" with bursicon, an insect heterodimeric, neurohormone that belongs in the same class as FSH, LH and TSH, which in turn are homologous to mammalian bone morphogenetic factors (BMPs) such as gremlin and cerberus. Therefore, LGR5 might be a receptor for a member of the large family of bone morphogenetic protein antagonists. Moreover, R-spondin proteins were shown to interact with the extracellular domain of LRG5. The LGR5 / R-spondin complex acts by binding and subsequently internalizing RNF43 and ZNRF3. RNF43 and ZNRF3 are transmembrane E3 ligases that negatively regulate wnt signaling by ubiquitinating frizzled receptors. Thereby, R-spondin binding to LGR5 potentiates wnt signaling. # Clinical relevance LGR5 are well-established stem cell markers in certain types of tissue, wholly due to the fact that they are highly enriched in truly, multipotent stem cells compared to their immediate progeny, the transit-amplifying cells. ## Intestines Tracing has revealed that LGR5 is a marker of adult intestinal stem cells. The high turnover rate of the intestinal lining is due to a dedicated population of stem cells found at the base of the intestinal crypt. In the small intestines, these LGR5+ve crypt base columnar cells (CBC cells) have broad basal surfaces and very little cytoplasm and organelles and are located interspersed among the terminally differentiated Paneth cells. These CBC cells generate the plethora of functional cells in the intestinal tissue: Paneth cells, enteroendocrine cells, goblet cells, tuft cells, columnar cells and the M cells over an adult’s entire lifetime. Similarly, LGR5 expression in the colon resembles faithfully that of the small intestine. ## Kidney In vivo lineage tracing showed that LGR5 is expressed in nascent nephron cell cluster within the developing kidney. Specifically, the LGR5+ve stem cells contribute into the formation of the thick ascending limb of Henle’s loop and the distal convoluted tubule. However, expression is eventually truncated after postnatal day 7, a stark contrast to the facultative expression of LGR5 in actively renewing tissues such as in the intestines. ## Stomach The stomach lining also possess populations of LGR5+ve stem cells, although there are two conflicting theories: one is that LGR5+ve stem cells reside in the isthmus, the region between the pit cells and gland cells, where most cellular proliferation takes place. However, lineage tracing had revealed LGR5+ve stem cells at the bottom of the gland, architecture reminiscent to that of the intestinal arrangement. This suggests that LGR5 stem cells give rise to transit-amplifying cells, which migrate towards the isthmus where they proliferate and maintain the stomach epithelium. ## Ear LGR5+ve stem cells were pinpointed as the precursor for sensory hair cells that line the cochlea. ## Hair follicle Hair follicle renewal is governed by Wnt signalling that act upon hair follicle stem cells located in the follicle bulge. Although these cells are well characterised by CD34 and cytokeratin markers, there is a growing body of agreement that LGR5 is a putative hair follicle stem cell marker. LGR5 in conjunction with LRG6, is expressed in a remarkable fashion: LRG6+ve stem cells maintain the upper sebaceous gland whilst LRG5+ve stem cells fuel the actual hair follicle shaft upon migration of transit-amplifying cells into the dermal papilla. In between these two distinct populations of stem cells are the multipotent LRG5/6+ve stem cells that ultimately maintain the epidermal hair follicle in adults. # Cancer The cancer stem cell hypothesis states that a dedicated small population of cancerous stem cells that manages to evade anti-cancer therapy maintains benign and malignant tumours. This explains recurring malignancies even after surgical removal of the tumours. LGR5+ve stem cells were identified to fuel stem cell activity in murine intestinal adenomas via erroneous activation of the pro-cell cycle Wnt signalling pathway as a result of successive mutations, such as formation of adenoma via Adenomatous polyposis coli (APC) mutation. Studies on LGR5 in colorectal cancer revealed a rather perplexing mechanism: loss of LGR5 actually increased tumourigenicity and invasion whereas overexpression results a reduction in tumourigenicity and clonogenicity. This implies that LGR5 is not an oncogene but a tumor suppressor gene, and that its main role is delimiting stem cell expansion in their respective niches. Varying expression profile of LGR5 was also observed in different stages of gastrointestinal cancers, which suggests that the histoanatomical distribution of LGR5+ve stem cells determine how the cancer advances. Densitometry results of LGR5 expression by western blotting in the different cell lines showed that high LGR5 expression levels were apparent in BHK, AGS, VERO and NIH3T3 cell lines compared with the other cell lines.

LGR5 Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) also known as G-protein coupled receptor 49 (GPR49) or G-protein coupled receptor 67 (GPR67) is a protein that in humans is encoded by the LGR5 gene.[1][2] It is a member of GPCR class A receptor proteins. R-spondin proteins are the biological ligands of LGR5. LGR5 is expressed across a diverse range of tissue such as in the muscle, placenta, spinal cord and brain and particularly as a biomarker of adult stem cells in certain tissues.[3] # Gene Prior to its current naming designation, LGR5 was also known as FEX, HG38, GPR49, and GPR67.[4] The Human LGR5 gene is 144,810 bases long and located at chromosome 12 at position 12q22-q23.[4] Both human, rat and mouse homologs contain 907 amino acids and seven transmembrane domains.[5] After translation, the signal peptide (amino acids 1-21) is cleaved off and the mature peptide (amino acids 22-907) inserts its transmembrane domain into the translocon membrane prior to packaging towards the plasma membrane. # Protein structure LGR5 is highly conserved within the mammalian clade. Sequence analyses showed that the transmembrane regions and cysteine-flanked junction between TM1 and the extracellular domain were highly conserved in sea anemone (Anthopleura elegantissima), fly (Drosophila melanogaster), worm (Caenorhabditis elegans), snail (Lymnaea stagnalis), rat (Rattus rattus) and human (Homo sapiens).[3] Homology amongst the metazoan suggests that it has been conserved across animals and was hypothesised as a chimeric fusion of an ancestral GPCR and a leucine-rich repeat motif. Sheau Hsu, Shan Liang and Aaron Hsueh first identified LGR5, together with LGR4, in 1998 at the University Medical School Stanford, California using expression sequence tags based on putative glycoprotein hormone receptors in Drosophila.[3] Experimental evidence show that the mature receptor protein contains up to 17 leucine-rich repeats, each composed of 24 amino acids spanning the extracellular domain flanked by the cysteine-rich N-terminal and C-terminal regions. In contrast, other glycoprotein hormone receptors such as Luteinizing hormone, Follicle-stimulating hormone and Thyroid-stimulating hormone contain only 9 repeats.[3] Sequence alignment showed that the second N-glycosylation site in LGR5 (Asn 208) aligns with that on the sixth repeat of gonadotropin and TSH receptors. The cysteine residues flanking the ectodomain form stabilising disulfide bonds that support the secondary structure of the leucine-rich repeats. # Function LGR5 is a member of the Wnt signaling pathway. Although its ligand remains elusive, it has been shown that costimulation with R-spondin 1 and Wnt-3a induce increased internalization of LGR5. LGR5 also cointernalizes with LRP6 and FZD5 via a clathrin-dependent pathway to form a ternary complex upon Wnt ligand binding. Moreover, the rapid cointernalization of LRP6 by LGR5 induces faster rates of degradation for the former. It has been shown that the C-terminal region of LGR5 is crucial for both dynamic internalization and degradation to occur, although C-terminal truncation does not inhibit LRP6 interaction and internalization, but rather, heightens receptor activity. Thus, only the initial interaction with its unknown ligand and other membrane bound receptors is crucial in its role in Wnt signalling and not the internalization itself.[6] LGR5 is crucial during embryogenesis as LGR null studies in mice incurred 100% neonatal mortality accompanied by several craniofacial distortions such as ankyloglossia and gastrointestinal dilation.[7] ## Ligand LGR5 belongs to a class of class A GPCR orphan receptors. Thus its ligands remain elusive. However, it has been shown that Lgr2, the fly orthologue of mammalian LGR5, binds with "high affinity and specificity" with bursicon, an insect heterodimeric, neurohormone that belongs in the same class as FSH, LH and TSH, which in turn are homologous to mammalian bone morphogenetic factors (BMPs) such as gremlin and cerberus. Therefore, LGR5 might be a receptor for a member of the large family of bone morphogenetic protein antagonists.[8] Moreover, R-spondin proteins were shown to interact with the extracellular domain of LRG5.[9] The LGR5 / R-spondin complex acts by binding and subsequently internalizing RNF43 and ZNRF3. RNF43 and ZNRF3 are transmembrane E3 ligases that negatively regulate wnt signaling by ubiquitinating frizzled receptors.[10][11] Thereby, R-spondin binding to LGR5 potentiates wnt signaling.[12] # Clinical relevance LGR5 are well-established stem cell markers in certain types of tissue, wholly due to the fact that they are highly enriched in truly, multipotent stem cells compared to their immediate progeny, the transit-amplifying cells. ## Intestines Tracing has revealed that LGR5 is a marker of adult intestinal stem cells. The high turnover rate of the intestinal lining is due to a dedicated population of stem cells found at the base of the intestinal crypt. In the small intestines, these LGR5+ve crypt base columnar cells (CBC cells) have broad basal surfaces and very little cytoplasm and organelles and are located interspersed among the terminally differentiated Paneth cells.[8] These CBC cells generate the plethora of functional cells in the intestinal tissue: Paneth cells, enteroendocrine cells, goblet cells, tuft cells, columnar cells and the M cells over an adult’s entire lifetime. Similarly, LGR5 expression in the colon resembles faithfully that of the small intestine.[8] ## Kidney In vivo lineage tracing showed that LGR5 is expressed in nascent nephron cell cluster within the developing kidney. Specifically, the LGR5+ve stem cells contribute into the formation of the thick ascending limb of Henle’s loop and the distal convoluted tubule. However, expression is eventually truncated after postnatal day 7, a stark contrast to the facultative expression of LGR5 in actively renewing tissues such as in the intestines.[13] ## Stomach The stomach lining also possess populations of LGR5+ve stem cells, although there are two conflicting theories: one is that LGR5+ve stem cells reside in the isthmus, the region between the pit cells and gland cells, where most cellular proliferation takes place. However, lineage tracing had revealed LGR5+ve stem cells at the bottom of the gland,[14] architecture reminiscent to that of the intestinal arrangement. This suggests that LGR5 stem cells give rise to transit-amplifying cells, which migrate towards the isthmus where they proliferate and maintain the stomach epithelium.[8] ## Ear LGR5+ve stem cells were pinpointed as the precursor for sensory hair cells that line the cochlea.[9] ## Hair follicle Hair follicle renewal is governed by Wnt signalling that act upon hair follicle stem cells located in the follicle bulge. Although these cells are well characterised by CD34 and cytokeratin markers, there is a growing body of agreement that LGR5 is a putative hair follicle stem cell marker.[15] LGR5 in conjunction with LRG6, is expressed in a remarkable fashion: LRG6+ve stem cells maintain the upper sebaceous gland whilst LRG5+ve stem cells fuel the actual hair follicle shaft upon migration of transit-amplifying cells into the dermal papilla. In between these two distinct populations of stem cells are the multipotent LRG5/6+ve stem cells that ultimately maintain the epidermal hair follicle in adults.[8] # Cancer The cancer stem cell hypothesis states that a dedicated small population of cancerous stem cells[16] that manages to evade anti-cancer therapy maintains benign and malignant tumours. This explains recurring malignancies even after surgical removal of the tumours.[2] LGR5+ve stem cells were identified to fuel stem cell activity in murine intestinal adenomas via erroneous activation of the pro-cell cycle Wnt signalling pathway as a result of successive mutations, such as formation of adenoma via Adenomatous polyposis coli (APC) mutation.[17] Studies on LGR5 in colorectal cancer revealed a rather perplexing mechanism: loss of LGR5 actually increased tumourigenicity and invasion whereas overexpression results a reduction in tumourigenicity and clonogenicity. This implies that LGR5 is not an oncogene but a tumor suppressor gene, and that its main role is delimiting stem cell expansion in their respective niches.[18] Varying expression profile of LGR5 was also observed in different stages of gastrointestinal cancers, which suggests that the histoanatomical distribution of LGR5+ve stem cells determine how the cancer advances.[19] Densitometry results of LGR5 expression by western blotting in the different cell lines showed that high LGR5 expression levels were apparent in BHK, AGS, VERO and NIH3T3 cell lines compared with the other cell lines.[20]

https://www.wikidoc.org/index.php/LGR5

9bddef8a9a22ffe7d77cdad6c07c76205606d6f6

wikidoc

LHX1

LHX1 LIM homeobox 1 is a protein that in humans is encoded by the LHX1 gene. This gene encodes a member of a large protein family which contains the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor important for control of differentiation and development of neural and lymphoid cells. It is also key in development of renal and urogenital systems and is required for normal organogenesis. A similar protein in mice is an essential regulator of the vertebrate head organizer. # Function The Lim gene family is a subfamily of homeobox genes. The homeobox genes are essential in organizing the body plan of an organism and all contain the same conserved homeodomain of amino acids. Evidence that Lim-1 is essential to a developing organism is its conservation throughout evolution and presence in a variety of organisms. The Lim-1 gene encodes a transcription factor which binds to the DNA of specific genes and functions to produce the needed gene product for development of the organism. Lim-1 is important during early molecular development and is required in both primitive streak-derived tissue and visceral endoderm of the early embryo for development of a head. Studies done using mutant organisms without the Lim gene results in organisms that develop no head structure at all support the essential role of the Lim-1 gene in formation of the head. This gene has also been shown to play a crucial role in the formation of the female reproductive tract. The gene is expressed in the developing Müllerian duct of females, and when the gene is knocked out no reproductive tract forms. Recent studies have shown that Lim-1 mutations may be one cause of the Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. MRKH is characterized by defective development, or absence, of the uterus and upper part of the vagina in women with normal ovaries and karyotype. Lim-1’s expression is controlled in part by the sonic hedgehog-Gli signaling pathway. Recent studies in mice have shown that Lim-1 silencing halts tumor growth and impairs tumor cell movement via inhibition of protein expression involved in metastatic spread. Therefore, in tumor cells Lim-1 acts as an oncogene. Thus, targeting Lim-1 can be a potential cancer therapy. In addition, Lim-1 is important in rodent renal development. Lim-1 deficiency results in development of multicystic kidney, whereas, its expression can contribute to pathogenesis of nephroblastomas. Also, Lim-1 plays a role in embryonic retinal development. Lim-1 expression affects differentiation and maintenance of horizontal cells located in the retinal, thus, it could serve as a marker in studies of horizontal cell specification. Lim-1 (Lhx1) functions as a transcription factor necessary for regulating the production of coupling factors required for proper communication between the neurons located in the part of the brain responsible for regulation of circadian rhythms called the suprachiasmatic nucleus (SCN). In mouse studies where Lim-1 transcription was restricted at some point during development in utero, the individual units within the subject’s molecular clock functioned properly but were unable to work together. Communication of these units is required to match their release of clock proteins which begin a transcription cascade of many other proteins that produce functional responses in tissues. The cyclic pattern of these responses is due to the feedback of the clock proteins and consequent changes to this transcription cascade. Reduced Lim-1 expression leads to inadequate levels of proteins such as Vasoactive Intestinal Polypeptide (VIP) that work to produce the neuron coordination required for a regulated circadian rhythm. The lack of such coupling factors causes the circadian clock to not function properly because the units within the SCN cannot match their release of clock proteins, and therefore their transcriptional cascades of proteins that cause changes in arousal do not align.

LHX1 LIM homeobox 1 is a protein that in humans is encoded by the LHX1 gene.[1] This gene encodes a member of a large protein family which contains the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor important for control of differentiation and development of neural and lymphoid cells. It is also key in development of renal and urogenital systems and is required for normal organogenesis.[2] A similar protein in mice is an essential regulator of the vertebrate head organizer.[1] # Function The Lim gene family is a subfamily of homeobox genes.[3] The homeobox genes are essential in organizing the body plan of an organism and all contain the same conserved homeodomain of amino acids.[4] Evidence that Lim-1 is essential to a developing organism is its conservation throughout evolution and presence in a variety of organisms.[3] The Lim-1 gene encodes a transcription factor which binds to the DNA of specific genes and functions to produce the needed gene product for development of the organism.[5] Lim-1 is important during early molecular development and is required in both primitive streak-derived tissue and visceral endoderm of the early embryo for development of a head.[6] Studies done using mutant organisms without the Lim gene results in organisms that develop no head structure at all support the essential role of the Lim-1 gene in formation of the head.[7] This gene has also been shown to play a crucial role in the formation of the female reproductive tract.[5] The gene is expressed in the developing Müllerian duct of females, and when the gene is knocked out no reproductive tract forms.[5] Recent studies have shown that Lim-1 mutations may be one cause of the Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome.[8] MRKH is characterized by defective development, or absence, of the uterus and upper part of the vagina in women with normal ovaries and karyotype.[8] Lim-1’s expression is controlled in part by the sonic hedgehog-Gli signaling pathway.[2] Recent studies in mice have shown that Lim-1 silencing halts tumor growth and impairs tumor cell movement via inhibition of protein expression involved in metastatic spread.[2] Therefore, in tumor cells Lim-1 acts as an oncogene.[2] Thus, targeting Lim-1 can be a potential cancer therapy. In addition, Lim-1 is important in rodent renal development.[9] Lim-1 deficiency results in development of multicystic kidney, whereas, its expression can contribute to pathogenesis of nephroblastomas.[9] Also, Lim-1 plays a role in embryonic retinal development.[10] Lim-1 expression affects differentiation and maintenance of horizontal cells located in the retinal, thus, it could serve as a marker in studies of horizontal cell specification.[10] Lim-1 (Lhx1) functions as a transcription factor necessary for regulating the production of coupling factors required for proper communication between the neurons located in the part of the brain responsible for regulation of circadian rhythms called the suprachiasmatic nucleus (SCN).[11] In mouse studies where Lim-1 transcription was restricted at some point during development in utero, the individual units within the subject’s molecular clock functioned properly but were unable to work together.[11] Communication of these units is required to match their release of clock proteins which begin a transcription cascade of many other proteins that produce functional responses in tissues.[11] The cyclic pattern of these responses is due to the feedback of the clock proteins and consequent changes to this transcription cascade.[11] Reduced Lim-1 expression leads to inadequate levels of proteins such as Vasoactive Intestinal Polypeptide (VIP) that work to produce the neuron coordination required for a regulated circadian rhythm.[11] The lack of such coupling factors causes the circadian clock to not function properly because the units within the SCN cannot match their release of clock proteins, and therefore their transcriptional cascades of proteins that cause changes in arousal do not align.[11]

https://www.wikidoc.org/index.php/LHX1

0a3b78794b08076e3973e5cb7ff6394cb8580841

wikidoc

LHX3

LHX3 LIM/homeobox protein Lhx3 is a protein that in humans is encoded by the LHX3 gene. # Function LHX3 encodes a protein of a large protein family, members of which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor that is required for pituitary development and motor neuron specification. Two transcript variants encoding distinct isoforms have been identified for this gene. # Clinical significance Mutations in this gene have been associated with a syndrome of combined pituitary hormone deficiency and rigid cervical spine. # Interactions LHX3 has been shown to interact with Ldb1.

LHX3 LIM/homeobox protein Lhx3 is a protein that in humans is encoded by the LHX3 gene.[1][2][3] # Function LHX3 encodes a protein of a large protein family, members of which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor that is required for pituitary development and motor neuron specification. Two transcript variants encoding distinct isoforms have been identified for this gene.[3] # Clinical significance Mutations in this gene have been associated with a syndrome of combined pituitary hormone deficiency and rigid cervical spine.[3] # Interactions LHX3 has been shown to interact with Ldb1.[4]

https://www.wikidoc.org/index.php/LHX3

afd13482a2fa546290153b8a9b90065863a5c375

wikidoc

LIG1

LIG1 DNA ligase 1 is an enzyme that in humans is encoded by the LIG1 gene. DNA ligases are important tools for DNA replication and repair in living organisms. There are two families of DNA ligases, ATP-dependent DNA ligases and NAD+ dependent DNA ligases. Dependence upon ATP or NAD+ is conferred in the ligase-adenylate formation and which substrate is to be used. ATP dependent ligases are found in eukaryotes, while NAD+ dependent ligases are found in prokaryotes. DNA ligase I is found in eukaryotes and therefore is in the family of ATP-dependent DNA ligases. # Discovery Previously it had been known that DNA replication occurred through the breakage of the double DNA strand, but the mechanism of action and enzyme responsible for ligating the strands back together was unknown. In the 1960s Lehman laboratories investigated this mystery, discovering DNA ligase and its mechanism of action in 1967. The Gellert, Richardson, and Hurwitz laboratories are also credited for their help in the discovery of DNA ligases in the 1960s. Of the known eukaryotic DNA ligases, DNA ligase I is the only ligase involved in DNA replication making it the most studied of the ligases. # Recruitment and regulation The LIG1 gene encodes a, 120kDa enzyme, 919 residues long, known as DNA ligase I. The DNA ligase I polypeptide contains an N-terminal replication factory-targeting sequence (RFTS), followed by a nuclear localization sequence (NLS), and three functional domains. The three domains consist of an N-terminal DNA binding domain (DBD), and catalytic nucleotidyltransferase (NTase), and C-terminal oligonucleotide / oligosaccharide binding (OB) domains. Although the N-terminus of the peptide has no catalytic activity it is needed for activity within the cells. The N-terminus of the protein contains a replication factory-targeting sequence that is used to recruit it to sites of DNA replication known as replication factories. Activation and recruitment of DNA Ligase I seem to be associated with posttranslational modifications. N-terminal domain is completed through phosphorylation of four serine residues on this domain, Ser51, Ser76, and Ser91 by cyclin-dependent kinase (CDK) and Ser66 by casein kinase II (CKII). Phosphorylation of these residues (Ser66 in particular) has been shown to possibly regulate the interaction between the RFTS to the proliferating cell nuclear antigen (PCNA) when Ligase I is recruited to the replication factories during S-phase. Rossi et al. proposed that when Ser66 is dephosphorylated, the RFTS of Ligase I interact with PCNA, which was confirmed in vitro by Tom et al. Both data sets provide plausible evidence the N-terminal region of Ligase I plays a regulatory role in the enzymes in vivo function in the nucleus. Moreover, the identification of a cyclin binding (Cy) motif in the catalytic C-terminus domain was shown by mutational analysis to play a role in the phosphorylation of serines 91 and 76. Together, the N-terminal serines are substrates of the CDK and CKII, which appear to play an important regulatory role DNA ligase I recruitment to the replication factory during S-phase of the cell cycle. # Function and mechanism LIG1 encodes DNA ligase I, which functions in DNA replication and the base excision repair process. Eukaryotic DNA ligase 1 catalyzes a reaction that is chemically universal to all ligases. DNA ligase 1 utilizes adenosine triphosphate (ATP) to catalyze the energetically favorable ligation events in both DNA replication and repair. During the synthesis phase (S-phase) of the eukaryotic cell cycle, DNA replication occurs. DNA ligase 1 is responsible for joining Okazaki fragments formed during discontinuous DNA synthesis on the DNA’s lagging strand after DNA polymerase δ has replaced the RNA primer nucleotides with DNA nucleotides. If the Okazaki fragments are not properly ligated together, the unligated DNA (containing a ‘nick’) could easily degrade to a double strand break, a phenomenon known to cause genetic mutations. In order to ligate these fragments together, the ligase progresses through three steps: - Addition of an adenosine monophosphate (AMP) group to the enzyme, referred to as adenylylation, - Adenosine monophosphate transfer to the DNA and - Nick sealing, or phosphodiester bond formation. During adenylylation, there is a nucleophilic attack on the alpha phosphate of ATP from a catalytic lysine resulting in the production of inorganic pyrophosphate (PPi) and a covalently bound lysine-AMP intermediate in the active site of DNA ligase 1. During the AMP transfer step, the DNA ligase becomes associated with the DNA, locates a nick and catalyzes a reaction at the 5’ phosphate site of the DNA nick. An anionic oxygen on the 5’ phosphate of the DNA nick serves as the nucleophile, attacking the alpha phosphate of the covalently bound AMP causing the AMP to be covalently bound intermediate (DNA-AMP intermediate). In order for the phosphodiester bond to be formed, the DNA-AMP intermediate must be cleaved off. To accomplish this task, there is a nucleophilic attack on the 5’-phosphate from the upstream 3’-hydroxyl which results in the formation of the phosphodiester bond. During this nucleophilic attack, the AMP group is pushed off the 5’ phosphate as the leaving group allowing for the nick to seal and the AMP to be released, completing one cycle of DNA ligation. Under suboptimal conditions the ligase can disassociate from the DNA before the full reaction is complete. It has been shown that magnesium levels can slow the nick sealing process, causing the ligase to disassociate from the DNA, leaving an aborted adenylylated intermediate incapable of being fixed without the aid of a phosphodiesterase. Aprataxin (a phosphodiesterase) has been shown to act on aborted DNA intermediates via hydrolysis of the AMP-phosphate bond, restoring the DNA to its initial state before the ligase had reacted. # Role in damaged base repair DNA Ligase I functions to ligate single stranded DNA breaks in the final step of the base excision repair (BER) pathway. The nitrogenous bases of DNA are commonly damaged by environmental hazards such as reactive oxygen species, toxins, and ionizing radiation. BER is the major repair pathway responsible for excising and replacing damaged bases. Ligase I is involved in the LP-BER pathway, whereas ligase III is involved in the major SN-BER pathway(2). LP-BER proceeds in 4 catalytic steps. First, a DNA glycosylase cleaves the N-glycosidic bond, releasing the damaged base and creating an AP site– a site that lacks a purine or pyrimidine base. In the next step, an AP endonuclease creates a nick at the 5' end of the AP site, generating a hanging deoxyribose phosphate (dRP) residue in place of the AP site. DNA polymerase then synthesizes several new bases in the 5' to 3' direction, generating a hanging stretch of DNA with the dRP at its 5' end. It is at this step that SN-BER and LP-BER diverge in mechanism – in SNBER, only a single nucleotide is added and DNA Polymerase acts as a lyase to excise the AP site. In LP-BER, several bases are synthesized, generating a hanging flap of DNA, which is cleaved by a flap endonuclease. This leaves behind a nicked DNA strand that is sensed and ligated by DNA Ligase. The action of ligase I is stimulated by other LP-BER enzymes, particularly AP-endonuclease and DNA polymerase. # Clinical significance Mutations in LIG1 that lead to DNA ligase I deficiency result in immunodeficiency and increased sensitivity to DNA-damaging agents. There is only one confirmed case of a patient exhibiting Ligase I deficiency, which resulted from an inherited mutant allele. The symptoms of this deficiency manifested as stunted growth and development and an immunodeficiency. A mouse model was made based on cell lines derived from the patient, confirming that the mutant ligase confers replication errors leading to genomic instability. Notably the mutant mice also showed increases in tumorigenesis. Ligase I has also been found to be upregulated in proliferating tumor cells, as opposed to benign tumor cell lines and normal human cells. Furthermore, it has been shown that inhibiting Ligase I expression in these cells can have a cytotoxic effect, suggesting that Ligase I inhibitors may be viable chemotherapeutic agents. Deficiencies in aprataxin, a phosphodiesterase responsible for reconditioning the DNA (after DNA ligase I aborts the adenylylated DNA intermediate), has been linked to neurodegeneration. This suggests that DNA is incapable of reentering the repair pathway without additional back-up machinery to correct for Ligase errors. With the structure of DNA being well known and many of the components necessary for its manipulation, repair, and usage becoming identified and characterized, researchers are beginning to look into the development of nanoscopic machinery that would be incorporated into a living organism that would possess the ability to treat diseases, fight cancer, and release medications based on a biological stimulus provided by the organism to the nanosocpic machinery. DNA ligase would most likely have to be incorporated into such a machine.

LIG1 DNA ligase 1 is an enzyme that in humans is encoded by the LIG1 gene. DNA ligases are important tools for DNA replication and repair in living organisms. There are two families of DNA ligases, ATP-dependent DNA ligases and NAD+ dependent DNA ligases. Dependence upon ATP or NAD+ is conferred in the ligase-adenylate formation and which substrate is to be used. ATP dependent ligases are found in eukaryotes, while NAD+ dependent ligases are found in prokaryotes. DNA ligase I is found in eukaryotes and therefore is in the family of ATP-dependent DNA ligases. # Discovery Previously it had been known that DNA replication occurred through the breakage of the double DNA strand, but the mechanism of action and enzyme responsible for ligating the strands back together was unknown. In the 1960s Lehman laboratories investigated this mystery, discovering DNA ligase and its mechanism of action in 1967. The Gellert, Richardson, and Hurwitz laboratories are also credited for their help in the discovery of DNA ligases in the 1960s.[1] Of the known eukaryotic DNA ligases, DNA ligase I is the only ligase involved in DNA replication making it the most studied of the ligases. # Recruitment and regulation The LIG1 gene encodes a, 120kDa enzyme, 919 residues long, known as DNA ligase I. The DNA ligase I polypeptide contains an N-terminal replication factory-targeting sequence (RFTS), followed by a nuclear localization sequence (NLS), and three functional domains.[2] The three domains consist of an N-terminal DNA binding domain (DBD), and catalytic nucleotidyltransferase (NTase), and C-terminal oligonucleotide / oligosaccharide binding (OB) domains. Although the N-terminus of the peptide has no catalytic activity it is needed for activity within the cells. The N-terminus of the protein contains a replication factory-targeting sequence that is used to recruit it to sites of DNA replication known as replication factories. Activation and recruitment of DNA Ligase I seem to be associated with posttranslational modifications. N-terminal domain is completed through phosphorylation of four serine residues on this domain, Ser51, Ser76, and Ser91 by cyclin-dependent kinase (CDK) and Ser66 by casein kinase II (CKII). Phosphorylation of these residues (Ser66 in particular) has been shown to possibly regulate the interaction between the RFTS to the proliferating cell nuclear antigen (PCNA) when Ligase I is recruited to the replication factories during S-phase.[2][3] Rossi et al. proposed that when Ser66 is dephosphorylated, the RFTS of Ligase I interact with PCNA, which was confirmed in vitro by Tom et al. Both data sets provide plausible evidence the N-terminal region of Ligase I plays a regulatory role in the enzymes in vivo function in the nucleus.[3][4] Moreover, the identification of a cyclin binding (Cy) motif in the catalytic C-terminus domain was shown by mutational analysis to play a role in the phosphorylation of serines 91 and 76. Together, the N-terminal serines are substrates of the CDK and CKII, which appear to play an important regulatory role DNA ligase I recruitment to the replication factory during S-phase of the cell cycle.[2][5] # Function and mechanism LIG1 encodes DNA ligase I, which functions in DNA replication and the base excision repair process.[6] Eukaryotic DNA ligase 1 catalyzes a reaction that is chemically universal to all ligases. DNA ligase 1 utilizes adenosine triphosphate (ATP) to catalyze the energetically favorable ligation events in both DNA replication and repair. During the synthesis phase (S-phase) of the eukaryotic cell cycle, DNA replication occurs. DNA ligase 1 is responsible for joining Okazaki fragments formed during discontinuous DNA synthesis on the DNA’s lagging strand after DNA polymerase δ has replaced the RNA primer nucleotides with DNA nucleotides. If the Okazaki fragments are not properly ligated together, the unligated DNA (containing a ‘nick’) could easily degrade to a double strand break, a phenomenon known to cause genetic mutations. In order to ligate these fragments together, the ligase progresses through three steps: - Addition of an adenosine monophosphate (AMP) group to the enzyme, referred to as adenylylation, - Adenosine monophosphate transfer to the DNA and - Nick sealing, or phosphodiester bond formation.[4][7] During adenylylation, there is a nucleophilic attack on the alpha phosphate of ATP from a catalytic lysine resulting in the production of inorganic pyrophosphate (PPi) and a covalently bound lysine-AMP intermediate in the active site of DNA ligase 1. During the AMP transfer step, the DNA ligase becomes associated with the DNA, locates a nick and catalyzes a reaction at the 5’ phosphate site of the DNA nick. An anionic oxygen on the 5’ phosphate of the DNA nick serves as the nucleophile, attacking the alpha phosphate of the covalently bound AMP causing the AMP to be covalently bound intermediate (DNA-AMP intermediate). In order for the phosphodiester bond to be formed, the DNA-AMP intermediate must be cleaved off. To accomplish this task, there is a nucleophilic attack on the 5’-phosphate from the upstream 3’-hydroxyl which results in the formation of the phosphodiester bond. During this nucleophilic attack, the AMP group is pushed off the 5’ phosphate as the leaving group allowing for the nick to seal and the AMP to be released, completing one cycle of DNA ligation. Under suboptimal conditions the ligase can disassociate from the DNA before the full reaction is complete. It has been shown that magnesium levels can slow the nick sealing process, causing the ligase to disassociate from the DNA, leaving an aborted adenylylated intermediate incapable of being fixed without the aid of a phosphodiesterase. Aprataxin (a phosphodiesterase) has been shown to act on aborted DNA intermediates via hydrolysis of the AMP-phosphate bond, restoring the DNA to its initial state before the ligase had reacted.[8][9] # Role in damaged base repair DNA Ligase I functions to ligate single stranded DNA breaks in the final step of the base excision repair (BER) pathway.[10] The nitrogenous bases of DNA are commonly damaged by environmental hazards such as reactive oxygen species, toxins, and ionizing radiation. BER is the major repair pathway responsible for excising and replacing damaged bases. Ligase I is involved in the LP-BER pathway, whereas ligase III is involved in the major SN-BER pathway(2).[11] LP-BER proceeds in 4 catalytic steps. First, a DNA glycosylase cleaves the N-glycosidic bond, releasing the damaged base and creating an AP site– a site that lacks a purine or pyrimidine base. In the next step, an AP endonuclease creates a nick at the 5' end of the AP site, generating a hanging deoxyribose phosphate (dRP) residue in place of the AP site. DNA polymerase then synthesizes several new bases in the 5' to 3' direction, generating a hanging stretch of DNA with the dRP at its 5' end. It is at this step that SN-BER and LP-BER diverge in mechanism – in SNBER, only a single nucleotide is added and DNA Polymerase acts as a lyase to excise the AP site. In LP-BER, several bases are synthesized, generating a hanging flap of DNA, which is cleaved by a flap endonuclease. This leaves behind a nicked DNA strand that is sensed and ligated by DNA Ligase.[10][11][12] The action of ligase I is stimulated by other LP-BER enzymes, particularly AP-endonuclease and DNA polymerase.[12] # Clinical significance Mutations in LIG1 that lead to DNA ligase I deficiency result in immunodeficiency and increased sensitivity to DNA-damaging agents.[6] There is only one confirmed case of a patient exhibiting Ligase I deficiency, which resulted from an inherited mutant allele. The symptoms of this deficiency manifested as stunted growth and development and an immunodeficiency. A mouse model was made based on cell lines derived from the patient, confirming that the mutant ligase confers replication errors leading to genomic instability. Notably the mutant mice also showed increases in tumorigenesis.[4] Ligase I has also been found to be upregulated in proliferating tumor cells, as opposed to benign tumor cell lines and normal human cells. Furthermore, it has been shown that inhibiting Ligase I expression in these cells can have a cytotoxic effect, suggesting that Ligase I inhibitors may be viable chemotherapeutic agents.[13] Deficiencies in aprataxin, a phosphodiesterase responsible for reconditioning the DNA (after DNA ligase I aborts the adenylylated DNA intermediate), has been linked to neurodegeneration. This suggests that DNA is incapable of reentering the repair pathway without additional back-up machinery to correct for Ligase errors.[9] With the structure of DNA being well known and many of the components necessary for its manipulation, repair, and usage becoming identified and characterized, researchers are beginning to look into the development of nanoscopic machinery that would be incorporated into a living organism that would possess the ability to treat diseases, fight cancer, and release medications based on a biological stimulus provided by the organism to the nanosocpic machinery. DNA ligase would most likely have to be incorporated into such a machine.[14]

https://www.wikidoc.org/index.php/LIG1

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wikidoc

LIG3

LIG3 DNA ligase 3 is an enzyme that, in humans, is encoded by the LIG3 gene. The human LIG3 gene encodes ATP-dependent DNA ligases that seal interruptions in the phosphodiester backbone of duplex DNA. There are three families of ATP-dependent DNA ligases in eukaryotes. These enzymes utilize the same three step reaction mechanism; (i) formation of a covalent enzyme-adenylate intermediate; (ii) transfer of the adenylate group to the 5’ phosphate terminus of a DNA nick; (iii) phosphodiester bond formation. Unlike LIG1 and LIG4 family members that are found in almost all eukaryotes, LIG3 family members are less widely distributed. The LIG3 gene encodes several distinct DNA ligase species by alternative translation initiation and alternative splicing mechanisms that are described below. # Structure, DNA binding and catalytic activities Eukaryotic ATP-dependent DNA ligases have related catalytic region that contains three domains, a DNA binding domain, an adenylation domain and an oligonucleotide / oligosaccharide binding-fold domain. When these enzymes engage a nick in duplex DNA, these domains encircle the DNA duplex with each one making contact with the DNA. The structure of the catalytic region of DNA ligase III complexed with a nicked DNA has been determined by X-ray crystallography and is remarkably similar to that formed by the catalytic region of human DNA ligase I bound to nicked DNA. A unique feature of the DNA ligases encoded by the LIG3 gene is an N-terminal zinc finger that resembles the two zinc fingers at the N-terminus of poly (ADP-ribose) polymerase 1 (PARP1). As with the PARP1 zinc fingers, the DNA ligase III zinc finger is involved in binding to DNA strand breaks. Within the DNA ligase III polypeptide, the zinc finger co-operates with the DNA binding domain to form a DNA binding module. In addition, the adenylation domain and an oligonucleotide/oligosaccharide binding-fold domain form a second DNA binding module. In the jackknife model proposed by the Ellenberger laboratory, the zinc finger-DNA binding domain module serves as a strand break sensor that binds to DNA single strand interruptions irrespective of the nature of the strand break termini. If these breaks are ligatable, they are transferred to the adenylation domain-oligonucleotide/oligosaccharide binding-fold domain module that binds specifically to ligatable nicks. Compared with DNA ligases I and IV, DNA ligase III is the most active enzyme in the intermolecular joining of DNA duplexes. This activity is predominantly dependent upon the DNA ligase III zinc finger suggesting that the two DNA binding modules of DNA ligase III may be able to simultaneously engage duplex DNA ends. # Alternative splicing The alternative translation initiation and splicing mechanisms alter the amino- and carboxy-terminal sequences that flank the DNA ligase III catalytic region. In the alternative splicing mechanism, the exon encoding a C-terminal breast cancer susceptibility protein 1 C-terminal (BRCT) domain at the C-terminus of DNA ligase III-alpha is replaced by a short positively charged sequence that acts as a nuclear localization signal, generating DNA ligase III-beta. This alternatively spliced variant has, to date, only been detected in male germs cells. Based on its expression pattern during spermatogenesis, it appears likely that DNA ligase IIIbeta is involved in meiotic recombination and/or DNA repair in haploid sperm but this has not been definitively demonstrated. Although an internal ATG is the preferred site for translation initiation within the DNA ligase III open reading frame, translation initiations does also occur at the first ATG within the open reading frame, resulting in the synthesis of a polypeptide with an N-terminal mitochondrial targeting sequence. # Cellular function As mentioned above, DNA ligase III-alpha mRNA encodes nuclear and mitochondrial versions of DNA ligase III-alpha. Nuclear DNA ligase III-alpha exists and functions in a stable complex with the DNA repair protein XRCC1. These proteins interact via their C-terminal BRCT domains. XRCC1 has no enzymatic activity but instead appears to acts as a scaffold protein by interacting with a large number of proteins involved in base excision and single-strand break repair. The participation of XRCC1 in these pathways is consistent with the phenotype of xrcc1 cells. In contrast to nuclear DNA ligase III-alpha, mitochondrial DNA ligase III-alpha functions independently of XRCC1, which is not found in mitochondria. It appears that nuclear DNA ligase III-alpha forms a complex with XRCC1 in the cytoplasm and the subsequent nuclear targeting of the resultant complex is directed by the XRCC1 nuclear localization signal. While mitochondrial DNA ligase III-alpha also interacts with XRCC1, it is likely that the activity of the mitochondrial targeting sequence of DNA ligase III-alpha is greater than the activity of the XRCC1 nuclear localization signal and that the DNA ligase III-alpha/XRCC1 complex is disrupted when mitochondrial DNA ligase III-alpha passes through the mitochondrial membrane. Since the LIG3 gene encodes the only DNA ligase in mitochondria, inactivation of the LIG3 gene results in loss of mitochondrial DNA that in turn leads to loss of mitochondrial function. Fibroblasts with inactivated Lig3 gene can be propagated in the media supplemented with uridine and pyruvate. However, these cells lack mtDNA. Physiological levels of mitochondrial DNA ligase III appear excessive, and cells with 100-fold reduced mitochondrial content of mitochondrial DNA ligase III-alpha maintain normal mtDNA copy number. The essential role of DNA ligase III-alpha in mitochondrial DNA metabolism can be fulfilled by other DNA ligases, including the NAD-dependent DNA ligase of E. coli, if they are targeted to mitochondria. Thus, viable cells that lack nuclear DNA ligase III-alpha can be generated. While DNA ligase I is the predominant enzyme that joins Okazaki fragments during DNA replication, it is now evident that the DNA ligase III-alpha/XRCC1 complex enables cells that either lack or have reduced DNA ligase I activity to complete DNA replication. Given the biochemical and cell biology studies linking the DNA ligase III-alpha/XRCC1 complex with excision repair and the repair of DNA single strand breaks, it was surprising that the cells lacking nuclear DNA ligase III-alpha did not exhibit significantly increased sensitivity to DNA damaging agent. These studies suggest that there is significant functional redundancy between DNA ligase I and DNA ligase III-alpha in these nuclear DNA repair pathways. In mammalian cells, most DNA double strand breaks are repaired by DNA ligase IV-dependent non-homologous end joining (NHEJ). DNA ligase III-alpha participates in a minor alternative NHEJ pathway that generates chromosomal translocations. Unlike the other nuclear DNA repair functions, it appears that the role of DNA ligase III-alpha in alternative NHEJ is independent of XRCC1. # Clinical significance Unlike the LIG1 and LIG4 genes, inherited mutations in the LIG3 gene have not been identified in the human population. DNA ligase III-alpha has, however, been indirectly implicated in cancer and neurodegenerative diseases. In cancer, DNA ligase III-alpha is frequently overexpressed and this serves as a biomarker to identify cells that are more dependent upon the alternative NHEJ pathway for the repair of DNA double strand breaks. Although the increased activity of the alternative NHEJ pathway causes genomic instability that drives disease progression, it also constitutes a novel target for the development of cancer cell-specific therapeutic strategies. Several genes encoding proteins that interact directly with DNA ligase III-alpha or indirectly via interactions with XRCC1 have been identified as being mutated in inherited neurodegenerative diseases. Thus, it appears that DNA transactions involving DNA ligase III-alpha play an important role in maintaining the viability of neuronal cells. LIG3 has a role in microhomology-mediated end joining (MMEJ) repair of double strand breaks. It is one of 6 enzymes required for this error prone DNA repair pathway. LIG3 is upregulated in chronic myeloid leukemia, multiple myeloma, and breast cancer. Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes). (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers. (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, LIG3 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer. # Notes

LIG3 DNA ligase 3 is an enzyme that, in humans, is encoded by the LIG3 gene.[1][2] The human LIG3 gene encodes ATP-dependent DNA ligases that seal interruptions in the phosphodiester backbone of duplex DNA. There are three families of ATP-dependent DNA ligases in eukaryotes.[3] These enzymes utilize the same three step reaction mechanism; (i) formation of a covalent enzyme-adenylate intermediate; (ii) transfer of the adenylate group to the 5’ phosphate terminus of a DNA nick; (iii) phosphodiester bond formation. Unlike LIG1 and LIG4 family members that are found in almost all eukaryotes, LIG3 family members are less widely distributed.[4] The LIG3 gene encodes several distinct DNA ligase species by alternative translation initiation and alternative splicing mechanisms that are described below. # Structure, DNA binding and catalytic activities Eukaryotic ATP-dependent DNA ligases have related catalytic region that contains three domains, a DNA binding domain, an adenylation domain and an oligonucleotide / oligosaccharide binding-fold domain. When these enzymes engage a nick in duplex DNA, these domains encircle the DNA duplex with each one making contact with the DNA. The structure of the catalytic region of DNA ligase III complexed with a nicked DNA has been determined by X-ray crystallography and is remarkably similar to that formed by the catalytic region of human DNA ligase I bound to nicked DNA.[5] A unique feature of the DNA ligases encoded by the LIG3 gene is an N-terminal zinc finger that resembles the two zinc fingers at the N-terminus of poly (ADP-ribose) polymerase 1 (PARP1).[6] As with the PARP1 zinc fingers, the DNA ligase III zinc finger is involved in binding to DNA strand breaks.[6][7][8] Within the DNA ligase III polypeptide, the zinc finger co-operates with the DNA binding domain to form a DNA binding module.[9] In addition, the adenylation domain and an oligonucleotide/oligosaccharide binding-fold domain form a second DNA binding module.[9] In the jackknife model proposed by the Ellenberger laboratory,[9] the zinc finger-DNA binding domain module serves as a strand break sensor that binds to DNA single strand interruptions irrespective of the nature of the strand break termini. If these breaks are ligatable, they are transferred to the adenylation domain-oligonucleotide/oligosaccharide binding-fold domain module that binds specifically to ligatable nicks. Compared with DNA ligases I and IV, DNA ligase III is the most active enzyme in the intermolecular joining of DNA duplexes.[10] This activity is predominantly dependent upon the DNA ligase III zinc finger suggesting that the two DNA binding modules of DNA ligase III may be able to simultaneously engage duplex DNA ends.[5][9] # Alternative splicing The alternative translation initiation and splicing mechanisms alter the amino- and carboxy-terminal sequences that flank the DNA ligase III catalytic region.[11][12] In the alternative splicing mechanism, the exon encoding a C-terminal breast cancer susceptibility protein 1 C-terminal (BRCT) domain at the C-terminus of DNA ligase III-alpha is replaced by a short positively charged sequence that acts as a nuclear localization signal, generating DNA ligase III-beta. This alternatively spliced variant has, to date, only been detected in male germs cells.[12] Based on its expression pattern during spermatogenesis, it appears likely that DNA ligase IIIbeta is involved in meiotic recombination and/or DNA repair in haploid sperm but this has not been definitively demonstrated. Although an internal ATG is the preferred site for translation initiation within the DNA ligase III open reading frame, translation initiations does also occur at the first ATG within the open reading frame, resulting in the synthesis of a polypeptide with an N-terminal mitochondrial targeting sequence.[11][13][14] # Cellular function As mentioned above, DNA ligase III-alpha mRNA encodes nuclear and mitochondrial versions of DNA ligase III-alpha. Nuclear DNA ligase III-alpha exists and functions in a stable complex with the DNA repair protein XRCC1.[15][16] These proteins interact via their C-terminal BRCT domains.[12][17] XRCC1 has no enzymatic activity but instead appears to acts as a scaffold protein by interacting with a large number of proteins involved in base excision and single-strand break repair. The participation of XRCC1 in these pathways is consistent with the phenotype of xrcc1 cells.[15] In contrast to nuclear DNA ligase III-alpha, mitochondrial DNA ligase III-alpha functions independently of XRCC1, which is not found in mitochondria.[18] It appears that nuclear DNA ligase III-alpha forms a complex with XRCC1 in the cytoplasm and the subsequent nuclear targeting of the resultant complex is directed by the XRCC1 nuclear localization signal.[19] While mitochondrial DNA ligase III-alpha also interacts with XRCC1, it is likely that the activity of the mitochondrial targeting sequence of DNA ligase III-alpha is greater than the activity of the XRCC1 nuclear localization signal and that the DNA ligase III-alpha/XRCC1 complex is disrupted when mitochondrial DNA ligase III-alpha passes through the mitochondrial membrane. Since the LIG3 gene encodes the only DNA ligase in mitochondria, inactivation of the LIG3 gene results in loss of mitochondrial DNA that in turn leads to loss of mitochondrial function.[20][21][22] Fibroblasts with inactivated Lig3 gene can be propagated in the media supplemented with uridine and pyruvate. However, these cells lack mtDNA.[23] Physiological levels of mitochondrial DNA ligase III appear excessive, and cells with 100-fold reduced mitochondrial content of mitochondrial DNA ligase III-alpha maintain normal mtDNA copy number.[23] The essential role of DNA ligase III-alpha in mitochondrial DNA metabolism can be fulfilled by other DNA ligases, including the NAD-dependent DNA ligase of E. coli, if they are targeted to mitochondria.[20][22] Thus, viable cells that lack nuclear DNA ligase III-alpha can be generated. While DNA ligase I is the predominant enzyme that joins Okazaki fragments during DNA replication, it is now evident that the DNA ligase III-alpha/XRCC1 complex enables cells that either lack or have reduced DNA ligase I activity to complete DNA replication.[20][22][24][25] Given the biochemical and cell biology studies linking the DNA ligase III-alpha/XRCC1 complex with excision repair and the repair of DNA single strand breaks,[26][27][28][29] it was surprising that the cells lacking nuclear DNA ligase III-alpha did not exhibit significantly increased sensitivity to DNA damaging agent.[20][22] These studies suggest that there is significant functional redundancy between DNA ligase I and DNA ligase III-alpha in these nuclear DNA repair pathways. In mammalian cells, most DNA double strand breaks are repaired by DNA ligase IV-dependent non-homologous end joining (NHEJ).[30] DNA ligase III-alpha participates in a minor alternative NHEJ pathway that generates chromosomal translocations.[31][32] Unlike the other nuclear DNA repair functions, it appears that the role of DNA ligase III-alpha in alternative NHEJ is independent of XRCC1.[33] # Clinical significance Unlike the LIG1 and LIG4 genes,[34][35][36][37] inherited mutations in the LIG3 gene have not been identified in the human population. DNA ligase III-alpha has, however, been indirectly implicated in cancer and neurodegenerative diseases. In cancer, DNA ligase III-alpha is frequently overexpressed and this serves as a biomarker to identify cells that are more dependent upon the alternative NHEJ pathway for the repair of DNA double strand breaks.[38][39][40][41] Although the increased activity of the alternative NHEJ pathway causes genomic instability that drives disease progression, it also constitutes a novel target for the development of cancer cell-specific therapeutic strategies.[39][40] Several genes encoding proteins that interact directly with DNA ligase III-alpha or indirectly via interactions with XRCC1 have been identified as being mutated in inherited neurodegenerative diseases.[42][43][44][45][46] Thus, it appears that DNA transactions involving DNA ligase III-alpha play an important role in maintaining the viability of neuronal cells. LIG3 has a role in microhomology-mediated end joining (MMEJ) repair of double strand breaks. It is one of 6 enzymes required for this error prone DNA repair pathway.[47] LIG3 is upregulated in chronic myeloid leukemia,[41] multiple myeloma,[48] and breast cancer.[39] Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes).[49] (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers.[49] (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, LIG3 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer. # Notes

https://www.wikidoc.org/index.php/LIG3