Datasets:

epfl-llm

/

guidelines

like 104

fd1b198a4bf4c7fd632f1facde5bcd7602a2de7e

wikidoc

TP63

TP63 Tumor protein p63, typically referred to as p63, also known as transformation-related protein 63 is a protein that in humans is encoded by the TP63 (also known as the p63) gene. The TP63 gene was discovered 20 years after the discovery of the p53 tumor suppressor gene and along with p73 constitutes the p53 gene family based on their structural similarity. Despite being discovered significantly later than p53, phylogenetic analysis of p53, p63 and p73, suggest that p63 was the original member of the family from which p53 and p73 evolved. # Function Tumor protein p63 is a member of the p53 family of transcription factors. p63 -/- mice have several developmental defects which include the lack of limbs and other tissues, such as teeth and mammary glands, which develop as a result of interactions between mesenchyme and epithelium. TP63 encodes for two main isoforms by alternative promoters (TAp63 and ΔNp63). ΔNp63 is involved in multiple functions during skin development and in adult stem/progenitor cell regulation. In contrast, TAp63 has been mostly restricted to its apoptotic function and more recently as the guardian of oocyte integrity. Recently, two new functions have been attributed to TAp63 in heart development and premature aging. # Clinical significance TP63 mutations underlie several malformation syndromes that include cleft lip and/or palate as a hallmark feature. Mutations in the TP63 gene are associated with ectrodactyly-ectodermal dysplasia-cleft syndrome in which a midline cleft lip is a common feature, cleft lip/palate syndrome 3 (EEC3); ectrodactyly (also known as split-hand/foot malformation 4 (SHFM4)); ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) or Hay–Wells syndrome in which a midline cleft lip is also a common feature, Acro–dermato–ungual–lacrimal–tooth syndrome (ADULT); limb-mammary syndrome; Rap-Hodgkin syndrome (RHS); and orofacial cleft 8. Both cleft lip with or without a cleft palate and cleft palate only features have been seen to segregate within the same family with a TP63 mutation. Recently, induced pluripotent stem cells have been produced from patients affected by EEC syndromes by cell reprogramming. The defective epithelial commitment could be partially rescued by a small therapeutic compound.< # Diagnostic utility p63 immunostaining has utility for head and neck squamous cell carcinomas, differentiating prostatic adenocarcinoma (the most common type of prostate cancer) and benign prostatic tissue; normal prostatic glands stain with p63 (as they have basal cells), while the malignant glands in prostatic adenocarcinoma (which lacks these cells) do not. P63 is also helpful in distinguishing poorly differentiated squamous cell carcinoma from small cell carcinoma or adenocarcinoma. P63 should be strongly stained in poorly differentiated squamous cell, but negative in small cell or adenocarcinoma. # Interactions TP63 has been shown to interact with HNRPAB. It also activates IRF6 transcription through the IRF6 enhancer element. # Regulation There is some evidence that the expression of p63 is regulated by the microRNA miR-203.

TP63 Tumor protein p63, typically referred to as p63, also known as transformation-related protein 63 is a protein that in humans is encoded by the TP63 (also known as the p63) gene.[1][2][3][4] The TP63 gene was discovered 20 years after the discovery of the p53 tumor suppressor gene and along with p73 constitutes the p53 gene family based on their structural similarity.[5] Despite being discovered significantly later than p53, phylogenetic analysis of p53, p63 and p73, suggest that p63 was the original member of the family from which p53 and p73 evolved.[6] # Function Tumor protein p63 is a member of the p53 family of transcription factors. p63 -/- mice have several developmental defects which include the lack of limbs and other tissues, such as teeth and mammary glands, which develop as a result of interactions between mesenchyme and epithelium. TP63 encodes for two main isoforms by alternative promoters (TAp63 and ΔNp63). ΔNp63 is involved in multiple functions during skin development and in adult stem/progenitor cell regulation.[7] In contrast, TAp63 has been mostly restricted to its apoptotic function and more recently as the guardian of oocyte integrity.[8] Recently, two new functions have been attributed to TAp63 in heart development[9] and premature aging.[10] # Clinical significance TP63 mutations underlie several malformation syndromes that include cleft lip and/or palate as a hallmark feature.[11] Mutations in the TP63 gene are associated with ectrodactyly-ectodermal dysplasia-cleft syndrome in which a midline cleft lip is a common feature,[11] cleft lip/palate syndrome 3 (EEC3); ectrodactyly (also known as split-hand/foot malformation 4 (SHFM4)); ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) or Hay–Wells syndrome in which a midline cleft lip is also a common feature,[11] Acro–dermato–ungual–lacrimal–tooth syndrome (ADULT); limb-mammary syndrome; Rap-Hodgkin syndrome (RHS); and orofacial cleft 8. Both cleft lip with or without a cleft palate and cleft palate only features have been seen to segregate within the same family with a TP63 mutation.[11] Recently, induced pluripotent stem cells have been produced from patients affected by EEC syndromes by cell reprogramming. The defective epithelial commitment could be partially rescued by a small therapeutic compound.<[12] # Diagnostic utility p63 immunostaining has utility for head and neck squamous cell carcinomas, differentiating prostatic adenocarcinoma (the most common type of prostate cancer) and benign prostatic tissue;[13] normal prostatic glands stain with p63 (as they have basal cells), while the malignant glands in prostatic adenocarcinoma (which lacks these cells) do not.[14] P63 is also helpful in distinguishing poorly differentiated squamous cell carcinoma from small cell carcinoma or adenocarcinoma. P63 should be strongly stained in poorly differentiated squamous cell, but negative in small cell or adenocarcinoma.[15] # Interactions TP63 has been shown to interact with HNRPAB.[16] It also activates IRF6 transcription through the IRF6 enhancer element.[11] # Regulation There is some evidence that the expression of p63 is regulated by the microRNA miR-203.[17][18]

https://www.wikidoc.org/index.php/TP63

a56bb286e16e49651192884ba13da93e73d755ea

wikidoc

TPBG

TPBG Trophoblast glycoprotein, also known as TPBG, 5T4, Wnt-Activated Inhibitory Factor 1 or WAIF1, is a human protein encoded by a TPBG gene. TPBG is an antagonist of Wnt/β-catenin signalling pathway. # Clinical significance 5T4 is an antigen expressed in a number of carcinomas. It is an N-glycosylated transmembrane 72 kDa glycoprotein containing eight leucine-rich repeats. 5T4 is often referred to as an oncofetal antigen due to its expression in foetal trophoblast (where it was first discovered) or trophoblast glycoprotein (TPBG). 5T4 is found in tumors including the colorectal, ovarian, and gastric. Its expression is used as a prognostic aid in these cases. It has very limited expression in normal tissue but is widespread in malignant tumours throughout their development. One study found that 5T4 was present in 85% of a cohort of 72 colorectal carcinomas and in 81% of a cohort of 27 gastric carcinomas. Its confined expression appears to give 5T4 the potential to be a target for T cells in cancer immunotherapy. There has been extensive research into its role in antibody-directed immunotherapy through the use of the high-affinity murine monoclonal antibody, mAb5T4, to deliver response modifiers (such as staphylococcus aureus superantigen) accurately to a tumor. 5T4 is also the target of the cancer vaccine TroVax which is in clinical trials for the treatment of a range of different solid tumour types. # Interactions TPBG has been shown to interact with GIPC1.

TPBG Trophoblast glycoprotein, also known as TPBG, 5T4, Wnt-Activated Inhibitory Factor 1 or WAIF1, is a human protein encoded by a TPBG gene.[1] TPBG is an antagonist of Wnt/β-catenin signalling pathway.[2] # Clinical significance 5T4 is an antigen expressed in a number of carcinomas.[3] It is an N-glycosylated transmembrane 72 kDa glycoprotein containing eight leucine-rich repeats.[2] 5T4 is often referred to as an oncofetal antigen due to its expression in foetal trophoblast (where it was first discovered) or trophoblast glycoprotein (TPBG). 5T4 is found in tumors including the colorectal, ovarian, and gastric. Its expression is used as a prognostic aid in these cases. It has very limited expression in normal tissue but is widespread in malignant tumours throughout their development. One study found that 5T4 was present in 85% of a cohort of 72 colorectal carcinomas and in 81% of a cohort of 27 gastric carcinomas.[4] Its confined expression appears to give 5T4 the potential to be a target for T cells in cancer immunotherapy. There has been extensive research into its role in antibody-directed immunotherapy through the use of the high-affinity murine monoclonal antibody, mAb5T4, to deliver response modifiers (such as staphylococcus aureus superantigen) accurately to a tumor. 5T4 is also the target of the cancer vaccine TroVax which is in clinical trials for the treatment of a range of different solid tumour types. # Interactions TPBG has been shown to interact with GIPC1.[5]

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

486b492af529048198c764149a0aed76954520ce

wikidoc

TPH1

TPH1 Tryptophan hydroxylase 1 (TPH1) is an isoenzyme of tryptophan hydroxylase which in humans is encoded by the TPH1 gene. TPH1 was first discovered to synthesize serotonin in 1988 and was thought that there only was a single TPH gene until 2003, while a second form was found in the mouse (Tph2), rat and human brain (TPH2) and the original TPH was then renamed to TPH1. # Function Tryptophan hydroxylases catalyze the biopterin-dependent monooxygenation of tryptophan to 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to form the neurotransmitter serotonin (5-hydroxytryptamine or 5-HT). It is the rate-limiting enzyme in the biosynthesis of serotonin. TPH expression is limited to a few specialized tissues: raphe neurons, pinealocytes, mast cells, mononuclear leukocytes, beta-cells of the islets of Langerhans, and intestinal and pancreatic enterochromaffin cells. # Clinical significance Tryptophan hydroxylase is important for synthesizing indoleamine neurotransmitters and related compounds in the body and brain, including serotonin, melatonin, tryptamine, N-methyltryptamine, and N,N-dimethyltryptamine. TPH1 is expressed in the body, but not the brain. Nevertheless, the effect of variations in the TPH1 gene on brain-related variables, such as personality traits and neuropsychiatric disorders, has been studied. For example, one study (1998) found an association between a polymorphism in the gene with impulsive-aggression measures, while a case-control study (2001) could find no association between polymorphisms and Alzheimer's Disease. One human mutant of TPH1, A218C found in intron 7, is highly associated with schizophrenia. Introns are regions of DNA that do not code for the amino acid sequence of a protein and were long considered to be 'junk DNA' lacking purpose. The correlation of an intron mutation with schizophrenia is significant because it suggests that introns have an important role in translation, transcription, or another, possibly unknown, aspect of the production of proteins from DNA.

TPH1 Tryptophan hydroxylase 1 (TPH1) is an isoenzyme of tryptophan hydroxylase which in humans is encoded by the TPH1 gene.[1] TPH1 was first discovered to synthesize serotonin in 1988[2] and was thought that there only was a single TPH gene until 2003, while a second form was found in the mouse (Tph2), rat and human brain (TPH2) and the original TPH was then renamed to TPH1.[3] # Function Tryptophan hydroxylases catalyze the biopterin-dependent monooxygenation of tryptophan to 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to form the neurotransmitter serotonin (5-hydroxytryptamine or 5-HT). It is the rate-limiting enzyme in the biosynthesis of serotonin. TPH expression is limited to a few specialized tissues: raphe neurons, pinealocytes, mast cells, mononuclear leukocytes, beta-cells of the islets of Langerhans, and intestinal and pancreatic enterochromaffin cells.[1][citation needed] # Clinical significance Tryptophan hydroxylase is important for synthesizing indoleamine neurotransmitters and related compounds in the body and brain, including serotonin, melatonin, tryptamine, N-methyltryptamine, and N,N-dimethyltryptamine. TPH1 is expressed in the body, but not the brain.[3] Nevertheless, the effect of variations in the TPH1 gene on brain-related variables, such as personality traits and neuropsychiatric disorders, has been studied. For example, one study (1998) found an association between a polymorphism in the gene with impulsive-aggression measures,[4] while a case-control study (2001) could find no association between polymorphisms and Alzheimer's Disease.[5] One human mutant of TPH1, A218C found in intron 7, is highly associated with schizophrenia.[6] Introns are regions of DNA that do not code for the amino acid sequence of a protein and were long considered to be 'junk DNA' lacking purpose. The correlation of an intron mutation with schizophrenia is significant because it suggests that introns have an important role in translation, transcription, or another, possibly unknown, aspect of the production of proteins from DNA.

https://www.wikidoc.org/index.php/TPH1

0aaf4697acb583b772757b586f9e0b05b0e6d342

wikidoc

TPI1

TPI1 Triosephosphate isomerase is an enzyme that in humans is encoded by the TPI1 gene. This gene encodes an enzyme, consisting of two identical proteins, which catalyzes the isomerization of glyceraldehydes 3-phosphate (G3P) and dihydroxy-acetone phosphate (DHAP) in glycolysis and gluconeogenesis. Mutations in this gene are associated with triosephosphate isomerase deficiency. Pseudogenes have been identified on chromosomes 1, 4, 6 and 7. Alternative splicing results in multiple transcript variants. # Structure Triose Phosphate Isomerase is a member of the alpha and beta (α/β) class of proteins; it is a homodimer, and each subunit contains 247 amino acids. Each TPI1 monomer contains the full set of catalytic residues, but the enzyme is only active in the oligomeric form. Therefore, the enzyme must be in a dimer in order to achieve full function of the enzyme, even though it is not believed that the two active sites participate in cooperativity with each other. Each subunit contains 8 exterior alpha helices surrounding 8 interior beta strands, which form a conserved structural domain called a closed alpha/beta barrel (αβ) or more specifically a TIM barrel. Characteristic of most all TIM barrel domains is the presence of the enzyme's active site in the lower loop regions created by the eight loops that connect the C-termini of the beta strands with the N-termini of the alpha helices. TIM barrel proteins also share a structurally conserved phosphate binding motif, with the phosphate group found in the substrate or cofactors. In each chain, nonpolar amino acids pointing inward from the beta strands contribute to the hydrophobic core of the structure. The alpha helices are amphipathic: their outer (water-contacting) surfaces are polar, while their inner surfaces are largely hydrophobic. # Function TPI catalyzes the transfer of a hydrogen atom from carbon 1 to carbon 2, an intramolecular oxidation-reduction reaction. This isomerization of a ketose to an aldose proceeds through an cis-enediol(ate) intermediate. This isomerization proceeds without any cofactors and the enzyme confers a 109 rate enhancement relative to the nonenzymatic reaction involving a chemical base (acetate ion). In addition to its role in glycolysis, TPI is also involved in several additional metabolic biological processes including gluconeogenesis, the pentose phosphate shunt, and fatty acid biosynthesis. # Clinical significance Triosephosphate isomerase deficiency is a disorder characterized by a shortage of red blood cells (anemia), movement problems, increased susceptibility to infection, and muscle weakness that can affect breathing and heart function. The anemia in this condition begins in infancy. Since the anemia results from the premature breakdown of red blood cells (hemolysis), it is known as hemolytic anemia. A shortage of red blood cells to carry oxygen throughout the body leads to extreme tiredness (fatigue), pale skin (pallor), and shortness of breath. When the red cells are broken down, iron and a molecule called bilirubin are released; individuals with triosephosphate isomerase deficiency have an excess of these substances circulating in the blood. Excess bilirubin in the blood causes jaundice, which is a yellowing of the skin and the whites of the eyes. Movement problems typically become apparent by age 2 in people with triosephosphate isomerase deficiency. The movement problems are caused by impairment of motor neurons, which are specialized nerve cells in the brain and spinal cord that control muscle movement. This impairment leads to muscle weakness and wasting (atrophy) and causes the movement problems typical of triosephosphate isomerase deficiency, including involuntary muscle tensing (dystonia), tremors, and weak muscle tone (hypotonia). Affected individuals may also develop seizures. Weakness of other muscles, such as the heart (a condition known as cardiomyopathy) and the muscle that separates the abdomen from the chest cavity (the diaphragm) can also occur in triosephosphate isomerase deficiency. Diaphragm weakness can cause breathing problems and ultimately leads to respiratory failure. Individuals with triosephosphate isomerase deficiency are at increased risk of developing infections because they have poorly functioning white blood cells. These immune system cells normally recognize and attack foreign invaders, such as viruses and bacteria, to prevent infection. The most common infections in people with triosephosphate isomerase deficiency are bacterial infections of the respiratory tract. People with triosephosphate isomerase deficiency often do not survive past childhood due to respiratory failure. In a few rare cases, affected individuals without severe nerve damage or muscle weakness have lived into adulthood. The deficiency is most commonly caused by mutations in TPI1, although mutations in other isoforms have been identified. A common marker for TPI deficiency is the increased accumulation of DHAP in erythrocyte extracts; this is because the defective enzyme no longer has the ability to catalyze the isomerization to GAP. The point mutation does not affect the catalysis rate, but rather, affects the assembly of the enzyme into a homodimer. Recent discoveries in Alzheimer's Disease research have indicated that amyloid beta peptide-induced nitro-oxidative damage promotes the nitrotyrosination of TPI in human neuroblastoma cells. Nitrosylated TPI was found to be present in brain slides from double transgenic mice over-expressing human amyloid precursor protein as well as in Alzheimer's disease patients. Specifically, the nitrotyrosination occurs on Tyr164 and Tyr208 within the protein, which are near the center of catalysis; this modification correlates with reduced isomerization activity. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..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} # Model organisms Model organisms have been used in the study of TPI1 function. A conditional knockout mouse line, called Tpi1tm1a(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 six tests were carried out on mutant mice and three significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and an increased susceptibility to bacterial infection was observed in male animals.

TPI1 Triosephosphate isomerase is an enzyme that in humans is encoded by the TPI1 gene. This gene encodes an enzyme, consisting of two identical proteins, which catalyzes the isomerization of glyceraldehydes 3-phosphate (G3P) and dihydroxy-acetone phosphate (DHAP) in glycolysis and gluconeogenesis. Mutations in this gene are associated with triosephosphate isomerase deficiency. Pseudogenes have been identified on chromosomes 1, 4, 6 and 7. Alternative splicing results in multiple transcript variants.[1] # Structure Triose Phosphate Isomerase is a member of the alpha and beta (α/β) class of proteins; it is a homodimer, and each subunit contains 247 amino acids. Each TPI1 monomer contains the full set of catalytic residues, but the enzyme is only active in the oligomeric form.[2] Therefore, the enzyme must be in a dimer in order to achieve full function of the enzyme, even though it is not believed that the two active sites participate in cooperativity with each other.[3] Each subunit contains 8 exterior alpha helices surrounding 8 interior beta strands, which form a conserved structural domain called a closed alpha/beta barrel (αβ) or more specifically a TIM barrel. Characteristic of most all TIM barrel domains is the presence of the enzyme's active site in the lower loop regions created by the eight loops that connect the C-termini of the beta strands with the N-termini of the alpha helices. TIM barrel proteins also share a structurally conserved phosphate binding motif, with the phosphate group found in the substrate or cofactors.[1] In each chain, nonpolar amino acids pointing inward from the beta strands contribute to the hydrophobic core of the structure. The alpha helices are amphipathic: their outer (water-contacting) surfaces are polar, while their inner surfaces are largely hydrophobic. # Function TPI catalyzes the transfer of a hydrogen atom from carbon 1 to carbon 2, an intramolecular oxidation-reduction reaction. This isomerization of a ketose to an aldose proceeds through an cis-enediol(ate) intermediate. This isomerization proceeds without any cofactors and the enzyme confers a 109 rate enhancement relative to the nonenzymatic reaction involving a chemical base (acetate ion).[4] In addition to its role in glycolysis, TPI is also involved in several additional metabolic biological processes including gluconeogenesis, the pentose phosphate shunt, and fatty acid biosynthesis. # Clinical significance Triosephosphate isomerase deficiency is a disorder characterized by a shortage of red blood cells (anemia), movement problems, increased susceptibility to infection, and muscle weakness that can affect breathing and heart function. The anemia in this condition begins in infancy. Since the anemia results from the premature breakdown of red blood cells (hemolysis), it is known as hemolytic anemia. A shortage of red blood cells to carry oxygen throughout the body leads to extreme tiredness (fatigue), pale skin (pallor), and shortness of breath. When the red cells are broken down, iron and a molecule called bilirubin are released; individuals with triosephosphate isomerase deficiency have an excess of these substances circulating in the blood. Excess bilirubin in the blood causes jaundice, which is a yellowing of the skin and the whites of the eyes. Movement problems typically become apparent by age 2 in people with triosephosphate isomerase deficiency. The movement problems are caused by impairment of motor neurons, which are specialized nerve cells in the brain and spinal cord that control muscle movement. This impairment leads to muscle weakness and wasting (atrophy) and causes the movement problems typical of triosephosphate isomerase deficiency, including involuntary muscle tensing (dystonia), tremors, and weak muscle tone (hypotonia). Affected individuals may also develop seizures. Weakness of other muscles, such as the heart (a condition known as cardiomyopathy) and the muscle that separates the abdomen from the chest cavity (the diaphragm) can also occur in triosephosphate isomerase deficiency. Diaphragm weakness can cause breathing problems and ultimately leads to respiratory failure. Individuals with triosephosphate isomerase deficiency are at increased risk of developing infections because they have poorly functioning white blood cells. These immune system cells normally recognize and attack foreign invaders, such as viruses and bacteria, to prevent infection. The most common infections in people with triosephosphate isomerase deficiency are bacterial infections of the respiratory tract. People with triosephosphate isomerase deficiency often do not survive past childhood due to respiratory failure. In a few rare cases, affected individuals without severe nerve damage or muscle weakness have lived into adulthood.[1] The deficiency is most commonly caused by mutations in TPI1, although mutations in other isoforms have been identified. A common marker for TPI deficiency is the increased accumulation of DHAP in erythrocyte extracts; this is because the defective enzyme no longer has the ability to catalyze the isomerization to GAP. The point mutation does not affect the catalysis rate, but rather, affects the assembly of the enzyme into a homodimer.[5][6] Recent discoveries in Alzheimer's Disease research have indicated that amyloid beta peptide-induced nitro-oxidative damage promotes the nitrotyrosination of TPI in human neuroblastoma cells.[7] Nitrosylated TPI was found to be present in brain slides from double transgenic mice over-expressing human amyloid precursor protein as well as in Alzheimer's disease patients. Specifically, the nitrotyrosination occurs on Tyr164 and Tyr208 within the protein, which are near the center of catalysis; this modification correlates with reduced isomerization activity. # 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: "GlycolysisGluconeogenesis_WP534"..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} # Model organisms Model organisms have been used in the study of TPI1 function. A conditional knockout mouse line, called Tpi1tm1a(EUCOMM)Wtsi[12][13] 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.[14][15][16] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[10][17] Twenty six tests were carried out on mutant mice and three significant abnormalities were observed.[10] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and an increased susceptibility to bacterial infection was observed in male animals.[10]

https://www.wikidoc.org/index.php/TPI1

228891f43341c0c327bf4f7fc8d1ab2ac561a056

wikidoc

TPM1

TPM1 Tropomyosin alpha-1 chain is a protein that in humans is encoded by the TPM1 gene. This gene is a member of the tropomyosin (Tm) family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. # Structure Tm is a 32.7 kDa protein composed of 284 amino acids. Tm is a flexible protein homodimer or heterodimer composed of two alpha-helical chains, which adopt a bent coiled coil conformation to wrap around the seven actin molecules in a functional unit of muscle. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. Human striated muscles express protein from the TPM1 (α-Tm), TPM2 (β-Tm) and TPM3 (γ-Tm) genes, with α-Tm being the predominant isoform in striated muscle. In human cardiac muscle the ratio of α-Tm to β-Tm is roughly 5:1. # Function Tm functions in association with the troponin complex to regulate the calcium-dependent interaction of actin and myosin during muscle contraction. Tm molecules are arranged head-to-tail along the actin thin filament, and are a key component in cooperative activation of muscle. A three state model has been proposed by McKillop and Geeves, which describes the positions of Tm during a cardiac cycle. The blocked (B) state occurs in diastole when intracellular calcium is low and Tm blocks the myosin binding site on actin. The closed (C) state is when Tm is positioned on the inner groove of actin; in this state myosin is in a "cocked" position where heads are weakly bound and not generating force. The myosin binding (M) state is when Tm is further displaced from actin by myosin crossbridges that are strongly-bound and actively generating force. In addition to actin, Tm binds troponin T (TnT). TnT tethers the region of head-to-tail overlap of subsequent Tm molecules to actin. # Clinical Significance Mutations in TPM1 have been associated with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy. HCM mutations tend to cluster around the N-terminal region and a primary actin binding region known as period 5.

TPM1 Tropomyosin alpha-1 chain is a protein that in humans is encoded by the TPM1 gene.[1] This gene is a member of the tropomyosin (Tm) family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. # Structure Tm is a 32.7 kDa protein composed of 284 amino acids.[2] Tm is a flexible protein homodimer or heterodimer composed of two alpha-helical chains, which adopt a bent coiled coil conformation to wrap around the seven actin molecules in a functional unit of muscle.[3] It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. Human striated muscles express protein from the TPM1 (α-Tm), TPM2 (β-Tm) and TPM3 (γ-Tm) genes, with α-Tm being the predominant isoform in striated muscle. In human cardiac muscle the ratio of α-Tm to β-Tm is roughly 5:1.[4] # Function Tm functions in association with the troponin complex to regulate the calcium-dependent interaction of actin and myosin during muscle contraction. Tm molecules are arranged head-to-tail along the actin thin filament, and are a key component in cooperative activation of muscle. A three state model has been proposed by McKillop and Geeves,[5] which describes the positions of Tm during a cardiac cycle. The blocked (B) state occurs in diastole when intracellular calcium is low and Tm blocks the myosin binding site on actin. The closed (C) state is when Tm is positioned on the inner groove of actin; in this state myosin is in a "cocked" position where heads are weakly bound and not generating force. The myosin binding (M) state is when Tm is further displaced from actin by myosin crossbridges that are strongly-bound and actively generating force. In addition to actin, Tm binds troponin T (TnT). TnT tethers the region of head-to-tail overlap of subsequent Tm molecules to actin. # Clinical Significance Mutations in TPM1 have been associated with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy. HCM mutations tend to cluster around the N-terminal region and a primary actin binding region known as period 5.[6]

https://www.wikidoc.org/index.php/TPM1

0214a9716a83ca1eb4d6eb29e2db3d7111dcba50

wikidoc

TPM2

TPM2 β-Tropomyosin, also known as tropomyosin beta chain is a protein that in humans is encoded by the TPM2 gene. β-tropomyosin is striated muscle-specific coiled coil dimer that functions to stabilize actin filaments and regulate muscle contraction. # Structure β-tropomyosin is roughly 32 kDa in molecular weight (284 amino acids), but multiple splice variants exist. Tropomysin is a flexible protein homodimer or heterodimer composed of two alpha-helical chains, which adopt a bent coiled coil conformation to wrap around the seven actin molecules in a functional unit of muscle. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. Tropomyosin dimers are composed of varying combinations of tropomyosin isoforms; human striated muscles express protein from the TPM1 (α-tropoomyosin), TPM2 (β-tropomyosin) and TPM3 (γ-tropomyosin) genes, with α-tropomyosin being the predominant isoform in striated muscle. Fast skeletal muscle and cardiac muscle contain more αα-homodimers, and slow skeletal muscle contains more ββ-homodimers. In human cardiac muscle the ratio of α-tropomyosin to β-tropomyosin is roughly 5:1. It has been shown that different combinations of tropomyosin isoforms bind troponin T with differing affinities, demonstrating that isoform combinations are used to impart a specific functional impact. # Function β-tropomyosin functions in association with α-tropomyosin and the troponin complex—composed of troponin I, troponin C and troponin T—to modulated the actin and myosin interaction. In diastole, the tropomyosin-troponin complex inhibits this interaction, and during systole the rise in intracellular calcium from sarcoplasmic reticulum binds to troponin C and induces a conformational change in the troponin-tropomyosin complex that disinhibits the actomyosin ATPase and permits contraction. Specific functional insights into the function of the β-tropomyosin isoform have come from studies employing transgenesis. A study overexpressing β-tropomyosin in adult cardiac muscle evoked a 34-fold increase in expression of β-tropomyosin, resulting in preferential formation of the αβ-tropomyosin heterodimer. Transgenic hearts showed a significant delay in relaxation time as well as a decrease in the maximum rate of left ventricular relaxation. A more aggressive overexpression of β-tropomyosin (to over 75% of total tropomyosin) in the heart causes death of mice 10–14 days old, along with cardiac abnormalities, suggesting that the normal distribution of tropomyosin isoforms is critical to normal cardiac function. In a disease model of cardiac hypertrophy, β-tropomyosin was shown to be reexpressed within two days following induction of pressure overload. Studies from mice, which express 98% α-tropomyosin, have shown that α-tropomyosin can be phosphorylated at Serine-283, which is one amino acid away from the C-terminus. β-tropomyosin also has a Serine residue at position 283, thus, it is likely that β-tropomyosin is also phosphorylated. Mouse transgenic studies in which the phosphorylation site in α-tropomyosin is mutated to Alanine have shown that phosphorylation may function to modulate tropomyosin polymerization, head-to-tail interactions between adjacent tropomyosin molecules, cooperativity, myosin ATPase activity, and the cardiac response to stress. # Clinical significance A decrease in β-tropomyosin in patients with heart failure was demonstrated, as failing ventricles expressed solely α-tropomyosin. Heterozygous mutations in TPM2 have been identified in patients with congenital cap myopathy, a rare disorder defined by cap-like structures in muscle fiber periphery. Mutations in TPM2 have also been associated with nemaline myopathy, a rare disorder characterized by muscle weakness and nemaline bodies, as well as distal arthrogryposis. The muscle weakness observed in these patients may be due to a change in mutated TPM2 affinity for actin or decreased calcium-induced activation of contractility. Moreover, studies unveiled alterations in cross-bridge attachment and detachment rates, as well as changes in ATPase rates. # Interactions TPM2 has been shown to interact with: - RRAD, - PDLIM7, - TNNT3, and - TPM1.

TPM2 β-Tropomyosin, also known as tropomyosin beta chain is a protein that in humans is encoded by the TPM2 gene.[1][2] β-tropomyosin is striated muscle-specific coiled coil dimer that functions to stabilize actin filaments and regulate muscle contraction. # Structure β-tropomyosin is roughly 32 kDa in molecular weight (284 amino acids), but multiple splice variants exist.[3][4][5][6] Tropomysin is a flexible protein homodimer or heterodimer composed of two alpha-helical chains, which adopt a bent coiled coil conformation to wrap around the seven actin molecules in a functional unit of muscle. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments.[7] Tropomyosin dimers are composed of varying combinations of tropomyosin isoforms; human striated muscles express protein from the TPM1 (α-tropoomyosin), TPM2 (β-tropomyosin) and TPM3 (γ-tropomyosin) genes, with α-tropomyosin being the predominant isoform in striated muscle. Fast skeletal muscle and cardiac muscle contain more αα-homodimers, and slow skeletal muscle contains more ββ-homodimers.[8] In human cardiac muscle the ratio of α-tropomyosin to β-tropomyosin is roughly 5:1.[9][10] It has been shown that different combinations of tropomyosin isoforms bind troponin T with differing affinities, demonstrating that isoform combinations are used to impart a specific functional impact.[8] # Function β-tropomyosin functions in association with α-tropomyosin and the troponin complex—composed of troponin I, troponin C and troponin T—to modulated the actin and myosin interaction. In diastole, the tropomyosin-troponin complex inhibits this interaction, and during systole the rise in intracellular calcium from sarcoplasmic reticulum binds to troponin C and induces a conformational change in the troponin-tropomyosin complex that disinhibits the actomyosin ATPase and permits contraction.[8] Specific functional insights into the function of the β-tropomyosin isoform have come from studies employing transgenesis. A study overexpressing β-tropomyosin in adult cardiac muscle evoked a 34-fold increase in expression of β-tropomyosin, resulting in preferential formation of the αβ-tropomyosin heterodimer. Transgenic hearts showed a significant delay in relaxation time as well as a decrease in the maximum rate of left ventricular relaxation.[8] A more aggressive overexpression of β-tropomyosin (to over 75% of total tropomyosin) in the heart causes death of mice 10–14 days old, along with cardiac abnormalities, suggesting that the normal distribution of tropomyosin isoforms is critical to normal cardiac function.[11] In a disease model of cardiac hypertrophy, β-tropomyosin was shown to be reexpressed within two days following induction of pressure overload.[12] Studies from mice, which express 98% α-tropomyosin, have shown that α-tropomyosin can be phosphorylated at Serine-283, which is one amino acid away from the C-terminus. β-tropomyosin also has a Serine residue at position 283,[13] thus, it is likely that β-tropomyosin is also phosphorylated. Mouse transgenic studies in which the phosphorylation site in α-tropomyosin is mutated to Alanine have shown that phosphorylation may function to modulate tropomyosin polymerization, head-to-tail interactions between adjacent tropomyosin molecules, cooperativity, myosin ATPase activity, and the cardiac response to stress.[14] # Clinical significance A decrease in β-tropomyosin in patients with heart failure was demonstrated, as failing ventricles expressed solely α-tropomyosin.[15] Heterozygous mutations in TPM2 have been identified in patients with congenital cap myopathy, a rare disorder defined by cap-like structures in muscle fiber periphery.[16][17][18][19] Mutations in TPM2 have also been associated with nemaline myopathy, a rare disorder characterized by muscle weakness and nemaline bodies,[20][21][22] as well as distal arthrogryposis.[23][24] The muscle weakness observed in these patients may be due to a change in mutated TPM2 affinity for actin or decreased calcium-induced activation of contractility.[25][26][27] Moreover, studies unveiled alterations in cross-bridge attachment and detachment rates,[28] as well as changes in ATPase rates.[26][29] # Interactions TPM2 has been shown to interact with: - RRAD,[30] - PDLIM7,[31] - TNNT3, and - TPM1.[32]

https://www.wikidoc.org/index.php/TPM2

5733aecf2c1b4ffdb583c1a11b75a8af42eab001

wikidoc

TPX2

TPX2 Targeting protein for Xklp2 is a protein that in humans is encoded by the TPX2 gene. It is one of the many spindle assembly factors that play a key role in inducing microtubule assembly and growth during M phase. # Key domains of TPX2 TPX2 has been reported to have two NLS-containing domains that mediate its localization to microtubules; one in the amino-terminal domain, and the other in the carboxy-terminal domain. In addition to an NLS, the carboxy-terminal domain of TPX2 consists of tandem repeats that cover over two-thirds of the protein and are computationally predicted to consist of predominantly alpha-helical content. This region can be further divided into five clusters of conserved residues separated by unstructured regions: α3-7. α3-6 all contain a central α-helical region that is followed by a characteristic "FKARP" motif. α7 is longer and exhibits a long α-helical stretch that is computationally predicted to form a coiled coil. Lastly, the final 35 amino acids of the carboxy-terminus of TPX2 are responsible for interacting with tetrameric kinesin Eg5. TPX2 contains one KEN box (K-E-N) motif at amino acid 87 and three D-box (R-X-X-L) motifs at amino acids 119, 341, and 708. Both motif types have been suspected to be important in regulation and degradation of TPX2 by the APC/C (see "Regulation of TPX2 in the Cell Cycle"), as typically mutations in these motifs render substrates resistant to ubiquitination by the APC/C. However, in vitro ubiquitination assays have shown that only the first 83 amino acids of the N-terminal region of TPX2 along with the KEN box are pertinent for recognition by Cdh1, an activator of the APC/C. # Role in microtubule assembly TPX2 has been shown in several biochemical assays to behave as a microtubule-associated protein (MAP) and co-localize with spindle microtubules during M-phase. It plays a role in microtubule nucleation and is regulated by importin proteins. TPX2 serves as a complement, depleting importin α affinity in order to allow RanGTP-induced microtubule nucleation. This has been demonstrated both in vitro in Xenopus laevis egg extracts, and with the human homologue in vivo in HeLa cells. TPX2 is also important in activating and recruiting Aurora A kinase, a kinase responsible for phosphorylating TPX2 and essential for cell proliferation. In the presence of nuclear import factor importin α, TPX2 is bound and prevented from binding Aurora A kinase, though it is still able to bind microtubules via its amino-terminal domain. This leads to inhibition of M phase microtubule nucleation. In contrast, TPX2 is freed from inhibition by displacement of importin α via RanGTP, though RanGTP is not required for free TPX2 activity, as TPX2 has been shown to induce microtubule assembly in the absence of exogenous and depletion of endogenous RanGTP. This suggests that TPX2 is downstream of RanGTP activity, but whether TPX2 is directly regulated by RanGTP still remains to be determined. The mechanism by which TPX2 promotes microtubule nucleation has yet to be determined. One proposed mechanism has been based on TPX2's role in directly suppressing tubulin subunit off-rates at the microtubule tip during microtubule assembly and disassembly, verified by fluorescence microscopy. This is made possible partially by TPX2's role in sequestering free tubulin subunits and nucleating small multi-subunit tubulin complexes, which inadvertently also slows the rate of growth by decreasing the effective free tubulin concentration. TPX2's stabilization of the microtubule in its polymer form therefore contributes to microtubule nucleation. Computational simulations speculate that TPX2 suppresses tubulin subunit kinetics at the microtubule tip by randomly increasing the bond stability between adjacent tubulin subunits. In addition, TPX2 has been shown to be important in chromatin-dependent spindle assembly. Even with duplicated centrosomes, TPX2 has been demonstrated to be required for formation of a stable bipolar spindle with overlapping antiparallel microtubule arrays. More specifically, TPX2 contributes to microtubule branching during spindle assembly by cooperating with augmin in order to amplify microtubule mass and preserve its polarity. Branching nucleation by TPX2 is observed without RanGTP, though more fan-shaped microtubule structures are formed when both RanGTP and TPX2 are present. The rate of branched formation is also enhanced in the presence of both components compared to Ran alone. The TPX2 region necessary for branching microtubule nucleation resides in its carboxy-terminal half (amino acids 319-716), with TPX2 domains α5-7 as the minimal necessary requirement and domains α3-4 serving as contributors to nucleation efficiency by enabling earlier induction at faster rates. The amino-terminal half of TPX2 also increases the efficiency of the reaction. TPX2 α5-7 is different from the remainder of the protein in that it contains conserved regions in its amino acid sequence that share sequence similarity with two known γ-TuRC nucleation activator motifs: SPM and γ-TuRC. The SPM-like motif is found within the α5 domain, while the γTuNA-like motif is found to start in the α5 domain and stretch into the SPM-like motif. Without these two motifs, no microtubule nucleation was observed in vitro, though microtubule binding ability was maintained. However, these two motifs are not the only essential ones in microtubule branching nucleation; the FKARP motifs of α5 and α6 are also essential for stimulating this process. Furthermore, the α-helical region stretch of domain α7 and the C-terminal residues that interact with Eg5 are critical for microtubule branching nucleation as well. While α5-7 domains are important in this process, none of them have intrinsic microtubule nucleation activity. In terms of binding to and bundling microtubules, at least any of the three domains α3-7 of TPX2 are necessary for significant binding and bundling in vitro. Furthermore, it is likely that the domains cooperatively mediate microtubule binding and bundling, as successive addition or subtraction of a domain does not result in a linear change in microtubule binding and bundling capacity. # Activation and reciprocation through Aurora A kinase TPX2 recruits and activates Aurora A kinase by utilizing its short 43 amino acid long amino-terminal sequence to bind the catalytic domain of Aurora A, locking the kinase into its active conformation. More specifically, this interaction positions the activation segment of the kinase into a more favorable conformation for substrate binding and swings the crucial phosphothreonine residue, a target usually exposed and accessible for deactivation of Aurora A kinase by PP1, into a buried position, thereby locking Aurora A into an active conformation. Notably, this recognition between TPX2 and Aurora A is analogous to that between the cAMP-dependent protein kinase (cAPK) catalytic core and its flanking region, suggesting a recurring theme in kinase regulation. Activated Aurora A in turn phosphorylates TPX2, but it is still unclear how Aurora A’s phosphorylation of TPX2 affects its activities. # Role in cleavage arrest and interaction with Eg5 When four-fold TPX2 over the endogenous level was injected into a blastomere with a two-cell embryo, cleavage arrest was induced. This arrest has been attributed to the amino acids 471-715 of the carboxy-terminus of the TPX2 protein, with the last 35 amino acids being absolutely necessary for inducing cleavage arrest. During cytokinesis failure, cycles of DNA synthesis and mitosis continue. Notably, spindle poles fail to segregate, leading to a failure to establish a bipolar spindle, a spindle midzone, and a central spindle complex. Because cleavage furrow ingression is primarily triggered by signals from the spindle midzone, these biological phenotypes could account for the failure of this event due to the inability to activate the spindle checkpoint. Instead of a bipolar spindle, both spindle poles are in apposition, with an impairment of pushing forces generated by interpolar microtubules. The mechanistic cause behind cleavage arrest is attributed to TPX2’s ability to directly bind motor protein Eg5, which requires the last 35 amino acids of the TPX2 carboxy-terminus for its interaction. When Eg5 was co-injected with TPX2 in vivo, cleavage furrow arrest was blocked and ingression was observed. This suggests that the carboxy-terminus of TPX2 regulates spindle pole movement via an Eg5-dependent mechanism. # Binding with Xlp2 When bound to microtubules, TPX2 recruits a plus-end directed motor protein, Xlp2, a protein that is required in early mitosis and localizes to spindle poles, to microtubule minus ends of asters. Like TPX2’s localization to microtubules, this recruitment is also RanGTP independent. # Regulation of TPX2 in the cell cycle Monitoring TPX2 gene mRNA expression during cell cycle progression in synchronized HeLa cells revealed that TPX2 expression is high in G2/M phase, decreases dramatically upon G1 phase entry, increases upon entry into S phase, and peaks again at the next G2/M phase. This is correlated by results showing an increased stability of TPX2 in S-phase extracts compared to that of TPX2 in mitotic extracts, indicated by a significant increase in TPX2 half-life. The drop in TPX2 is consistent with the drastic reorganization in structure and dynamics of the mitotic spindle. Overall, TPX2 has been shown through in vivo experiments to be regulated by the APC/CCdh1 pathway. The instability and drop in TPX2 at mitotic exit is dependent on both the anaphase-promoting complex/cyclosome (APC/C) and an ubiquitin ligase integral in mitotic progression, along with APC/C's activator protein, Cdh1. This is a result of TPX2 being bound directly by Cdh1, and not Cdc20 or any other substrate of APC/CCdh1, and designated for degradation by APC/C. Moreover, the Cdh1-TPX2 binding interaction produces the TPX2 stability seen during mitosis up until mitotic exit: The amino-terminal region of Cdh1 (amino acids 1-125) can act as a dominant negative mutant when expressed in mammalian cells, stabilizing APC/CCdh1 substrates such as TPX2 by competitive binding. # Role in the nucleus When the cell is in interphase, because of its ability to bind to importin α and β, TPX2 has been found localized in the nucleus. This has been proposed to be a physical mechanism by which proteins that operate in M phase are inactivated in interphase. TPX2 during M-phase accumulates at the poles of spindles in a “dynein-dynactin-dependent way.” The mechanism of this localization currently remains unclear, but it is not RanGTP dependent despite its downfield position from RanGTP activity, as TPX2 in Xenopus laevis egg extracts have been shown to accumulate at the center of microtubule asters (after the addition of centrosomes, taxol, or DMSO) and bind to pure microtubules in the presence of importins. Though nuclear import of TPX2 is thought to sequester TPX2 away from cytoplasmic tubulin in order to solely prevent premature spindle assembly, roles of nuclear TPX2 have recently been discovered. One of these roles is with the DNA damage response, where depletion of TPX2 in cells leads to a transient increase in γ-H2AX (the phosphorylated form of H2AX, the form that serves as a marker of DNA damage response amplification) levels in cells treated with ionizing radiation, and overexpression of TPX2 leads to a decrease in the number of ionizing radiation-induced MDC1 foci and γ-H2AX levels. This is supported by the discovery of TPX2 accumulation at DNA double strand breaks and association with the machinery of DNA damage response that controls the amplification of γ-H2AX. However, the exact molecular mechanisms by which TPX2 impacts the ionizing radiation-dependent γ-H2AX levels still remains to be discovered.  Note that TPX2’s function in the DNA damage response is independent of its mitotic function, and is therefore independent of apoptosis. When no ionizing radiation is present, TPX2 readily associates with the chromatin. Interestingly, overexpression of TPX2 in these conditions produces abnormal DAPI staining patterns, where DAPI staining is more structured and compartmentalized than the typical uniformly-distributed DAPI staining in wild type cells. Moreover, when TPX2 levels were depleted in unirradiated cells, no significant changes in γ-H2AX levels were found, but the levels of H4K16ac, the acetylated form of H4K16 (a histone post-translationally modified during DNA damage response), decreased. This decrease is unaffected by ionizing radiation, yet correlates with the decrease in γ-H2AX under such conditions. A result of this decrease is a defect in BP531 (p53 binding protein 1) recruitment to chromosomal breaks, as recruitment is dependent on the acetylation status of H4K16. As with TPX2 with regards to its impact on ionizing radiation-dependent γ-H2AX levels, the molecular mechanism by which TPX2 affects the acetylation status of H4K16 remains to be discovered. # Relevance in cancer Because of its integral role in microtubule assembly and therefore mitosis, TPX2 is found to be overexpressed in different types of human cancers including hepatocellular carcinoma (HCC), medullary thyroid cancer, bladder carcinoma, and estrogen receptor-positive metastatic breast cancer and contributes to tumor growth and metastasis. In HCC, TPX2 has been shown to be positively correlated with poor prognosis, metastasis, and recurrence. Studies on TPX2 in HCC have also showed that TPX2 promotes tumoriogenesis and liver cancer cell growth by increasing tumor spheroid and diminishing cell growth inhibition, demonstrated by knocking out endogenous expression of TPX2 using TPX2 si-RNA. As a result, TPX2 has recently been a topic of interest for learning more about the relationship between mitotic errors and tumorigenesis, along with novel cancer therapies. So far, research on depleting TPX2 via TPX2 si-RNA in HCC cells in vitro has shown significant effects in diminishing cell motility and invasion (i.e. metastasis), along with diminishing proteins involved in the G1 to S phase transition. Similar results have been shown with TPX2 depletion in esophageal cancer EC9706 cells, leading to reduced cancer cell growth and invasion ability, and in cervical and pancreatic cancer with regards to reduced tumor growth using TPX2 si-RNA transfection. In liver cancer cells, TPX2 depletion has been linked to increased genomic instability, resulting in multinucleation and DNA damage. While many tumor cells in general accumulate mutations in genomic instability that enable them to have a growth advantage in tumor promotion and transformation, high chromosomal instability can act as a tumor-suppressing mechanism by leading to cell death. Therefore, the significant aneuploidy and genomic instability at mitotic division via TPX2 depletion can serve as a potential therapeutic target for cancer patients by eliminating highly proliferating cells.

TPX2 Targeting protein for Xklp2 is a protein that in humans is encoded by the TPX2 gene. [1][2][3] It is one of the many spindle assembly factors that play a key role in inducing microtubule assembly and growth during M phase. # Key domains of TPX2 TPX2 has been reported to have two NLS-containing domains that mediate its localization to microtubules; one in the amino-terminal domain, and the other in the carboxy-terminal domain.[4][5] In addition to an NLS, the carboxy-terminal domain of TPX2 consists of tandem repeats that cover over two-thirds of the protein and are computationally predicted to consist of predominantly alpha-helical content.[6][7] This region can be further divided into five clusters of conserved residues separated by unstructured regions: α3-7.[7] α3-6 all contain a central α-helical region that is followed by a characteristic "FKARP" motif.[7] α7 is longer and exhibits a long α-helical stretch that is computationally predicted to form a coiled coil.[7] Lastly, the final 35 amino acids of the carboxy-terminus of TPX2 are responsible for interacting with tetrameric kinesin Eg5.[8][9] TPX2 contains one KEN box (K-E-N) motif at amino acid 87 and three D-box (R-X-X-L) motifs at amino acids 119, 341, and 708.[10] Both motif types have been suspected to be important in regulation and degradation of TPX2 by the APC/C (see "Regulation of TPX2 in the Cell Cycle"), as typically mutations in these motifs render substrates resistant to ubiquitination by the APC/C.[11][12] However, in vitro ubiquitination assays have shown that only the first 83 amino acids of the N-terminal region of TPX2 along with the KEN box are pertinent for recognition by Cdh1, an activator of the APC/C.[10] # Role in microtubule assembly TPX2 has been shown in several biochemical assays to behave as a microtubule-associated protein (MAP) and co-localize with spindle microtubules during M-phase.[1][13][14][5][15] It plays a role in microtubule nucleation and is regulated by importin proteins. TPX2 serves as a complement, depleting importin α affinity in order to allow RanGTP-induced microtubule nucleation. This has been demonstrated both in vitro in Xenopus laevis egg extracts, and with the human homologue in vivo in HeLa cells.[16] [14] TPX2 is also important in activating and recruiting Aurora A kinase, a kinase responsible for phosphorylating TPX2 and essential for cell proliferation.[5] In the presence of nuclear import factor importin α, TPX2 is bound and prevented from binding Aurora A kinase, though it is still able to bind microtubules via its amino-terminal domain.[5] This leads to inhibition of M phase microtubule nucleation. In contrast, TPX2 is freed from inhibition by displacement of importin α via RanGTP, though RanGTP is not required for free TPX2 activity, as TPX2 has been shown to induce microtubule assembly in the absence of exogenous and depletion of endogenous RanGTP.[16] This suggests that TPX2 is downstream of RanGTP activity, but whether TPX2 is directly regulated by RanGTP still remains to be determined. The mechanism by which TPX2 promotes microtubule nucleation has yet to be determined. One proposed mechanism has been based on TPX2's role in directly suppressing tubulin subunit off-rates at the microtubule tip during microtubule assembly and disassembly, verified by fluorescence microscopy.[17] This is made possible partially by TPX2's role in sequestering free tubulin subunits and nucleating small multi-subunit tubulin complexes, which inadvertently also slows the rate of growth by decreasing the effective free tubulin concentration.[17] TPX2's stabilization of the microtubule in its polymer form therefore contributes to microtubule nucleation. Computational simulations speculate that TPX2 suppresses tubulin subunit kinetics at the microtubule tip by randomly increasing the bond stability between adjacent tubulin subunits.[17] In addition, TPX2 has been shown to be important in chromatin-dependent spindle assembly. Even with duplicated centrosomes, TPX2 has been demonstrated to be required for formation of a stable bipolar spindle with overlapping antiparallel microtubule arrays.[14] More specifically, TPX2 contributes to microtubule branching during spindle assembly by cooperating with augmin in order to amplify microtubule mass and preserve its polarity.[18] Branching nucleation by TPX2 is observed without RanGTP, though more fan-shaped microtubule structures are formed when both RanGTP and TPX2 are present.[18] The rate of branched formation is also enhanced in the presence of both components compared to Ran alone.[18] The TPX2 region necessary for branching microtubule nucleation resides in its carboxy-terminal half (amino acids 319-716),[19] with TPX2 domains α5-7 as the minimal necessary requirement and domains α3-4 serving as contributors to nucleation efficiency by enabling earlier induction at faster rates. The amino-terminal half of TPX2 also increases the efficiency of the reaction.[7] TPX2 α5-7 is different from the remainder of the protein in that it contains conserved regions in its amino acid sequence that share sequence similarity with two known γ-TuRC nucleation activator motifs: SPM and γ-TuRC.[7] The SPM-like motif is found within the α5 domain, while the γTuNA-like motif is found to start in the α5 domain and stretch into the SPM-like motif. Without these two motifs, no microtubule nucleation was observed in vitro, though microtubule binding ability was maintained.[7] However, these two motifs are not the only essential ones in microtubule branching nucleation; the FKARP motifs of α5 and α6 are also essential for stimulating this process.[7] Furthermore, the α-helical region stretch of domain α7 and the C-terminal residues that interact with Eg5 are critical for microtubule branching nucleation as well.[7] While α5-7 domains are important in this process, none of them have intrinsic microtubule nucleation activity.[7] In terms of binding to and bundling microtubules, at least any of the three domains α3-7 of TPX2 are necessary for significant binding and bundling in vitro.[7] Furthermore, it is likely that the domains cooperatively mediate microtubule binding and bundling, as successive addition or subtraction of a domain does not result in a linear change in microtubule binding and bundling capacity.[7] # Activation and reciprocation through Aurora A kinase TPX2 recruits and activates Aurora A kinase by utilizing its short 43 amino acid long amino-terminal sequence to bind the catalytic domain of Aurora A, locking the kinase into its active conformation.[20][21] More specifically, this interaction positions the activation segment of the kinase into a more favorable conformation for substrate binding and swings the crucial phosphothreonine residue, a target usually exposed and accessible for deactivation of Aurora A kinase by PP1, into a buried position, thereby locking Aurora A into an active conformation.[20] Notably, this recognition between TPX2 and Aurora A is analogous to that between the cAMP-dependent protein kinase (cAPK) catalytic core and its flanking region, suggesting a recurring theme in kinase regulation.[20] Activated Aurora A in turn phosphorylates TPX2, but it is still unclear how Aurora A’s phosphorylation of TPX2 affects its activities. # Role in cleavage arrest and interaction with Eg5 When four-fold TPX2 over the endogenous level was injected into a blastomere with a two-cell embryo, cleavage arrest was induced.[8] This arrest has been attributed to the amino acids 471-715 of the carboxy-terminus of the TPX2 protein, with the last 35 amino acids being absolutely necessary for inducing cleavage arrest.[8] During cytokinesis failure, cycles of DNA synthesis and mitosis continue. Notably, spindle poles fail to segregate, leading to a failure to establish a bipolar spindle, a spindle midzone, and a central spindle complex.[8] Because cleavage furrow ingression is primarily triggered by signals from the spindle midzone,[22][23] these biological phenotypes could account for the failure of this event due to the inability to activate the spindle checkpoint.[8] Instead of a bipolar spindle, both spindle poles are in apposition, with an impairment of pushing forces generated by interpolar microtubules.[8] The mechanistic cause behind cleavage arrest is attributed to TPX2’s ability to directly bind motor protein Eg5, which requires the last 35 amino acids of the TPX2 carboxy-terminus for its interaction.[8] When Eg5 was co-injected with TPX2 in vivo, cleavage furrow arrest was blocked and ingression was observed. This suggests that the carboxy-terminus of TPX2 regulates spindle pole movement via an Eg5-dependent mechanism.[8] # Binding with Xlp2 When bound to microtubules, TPX2 recruits a plus-end directed motor protein, Xlp2, a protein that is required in early mitosis and localizes to spindle poles, to microtubule minus ends of asters.[13][24][25] Like TPX2’s localization to microtubules, this recruitment is also RanGTP independent.[13][26] # Regulation of TPX2 in the cell cycle Monitoring TPX2 gene mRNA expression during cell cycle progression in synchronized HeLa cells revealed that TPX2 expression is high in G2/M phase, decreases dramatically upon G1 phase entry, increases upon entry into S phase, and peaks again at the next G2/M phase.[27][10] This is correlated by results showing an increased stability of TPX2 in S-phase extracts compared to that of TPX2 in mitotic extracts, indicated by a significant increase in TPX2 half-life.[10] The drop in TPX2 is consistent with the drastic reorganization in structure and dynamics of the mitotic spindle.[28] Overall, TPX2 has been shown through in vivo experiments to be regulated by the APC/CCdh1 pathway.[10] The instability and drop in TPX2 at mitotic exit is dependent on both the anaphase-promoting complex/cyclosome (APC/C) and an ubiquitin ligase integral in mitotic progression, along with APC/C's activator protein, Cdh1.[10][29] This is a result of TPX2 being bound directly by Cdh1, and not Cdc20 or any other substrate of APC/CCdh1, and designated for degradation by APC/C.[10] Moreover, the Cdh1-TPX2 binding interaction produces the TPX2 stability seen during mitosis up until mitotic exit: The amino-terminal region of Cdh1 (amino acids 1-125) can act as a dominant negative mutant when expressed in mammalian cells, stabilizing APC/CCdh1 substrates such as TPX2 by competitive binding.[10] # Role in the nucleus When the cell is in interphase, because of its ability to bind to importin α and β, TPX2 has been found localized in the nucleus.[1][13] This has been proposed to be a physical mechanism by which proteins that operate in M phase are inactivated in interphase. TPX2 during M-phase accumulates at the poles of spindles in a “dynein-dynactin-dependent way.”[13][5] The mechanism of this localization currently remains unclear, but it is not RanGTP dependent despite its downfield position from RanGTP activity, as TPX2 in Xenopus laevis egg extracts have been shown to accumulate at the center of microtubule asters (after the addition of centrosomes, taxol, or DMSO) and bind to pure microtubules in the presence of importins.[15] Though nuclear import of TPX2 is thought to sequester TPX2 away from cytoplasmic tubulin in order to solely prevent premature spindle assembly,[30][31] roles of nuclear TPX2 have recently been discovered. One of these roles is with the DNA damage response, where depletion of TPX2 in cells leads to a transient increase in γ-H2AX (the phosphorylated form of H2AX, the form that serves as a marker of DNA damage response amplification) levels in cells treated with ionizing radiation,[32] and overexpression of TPX2 leads to a decrease in the number of ionizing radiation-induced MDC1 foci and γ-H2AX levels.[32] This is supported by the discovery of TPX2 accumulation at DNA double strand breaks and association with the machinery of DNA damage response that controls the amplification of γ-H2AX.[32] However, the exact molecular mechanisms by which TPX2 impacts the ionizing radiation-dependent γ-H2AX levels still remains to be discovered.  Note that TPX2’s function in the DNA damage response is independent of its mitotic function, and is therefore independent of apoptosis. When no ionizing radiation is present, TPX2 readily associates with the chromatin.[33] Interestingly, overexpression of TPX2 in these conditions produces abnormal DAPI staining patterns, where DAPI staining is more structured and compartmentalized than the typical uniformly-distributed DAPI staining in wild type cells.[33] Moreover, when TPX2 levels were depleted in unirradiated cells, no significant changes in γ-H2AX levels were found,[32] but the levels of H4K16ac, the acetylated form of H4K16 (a histone post-translationally modified during DNA damage response), decreased.[33] This decrease is unaffected by ionizing radiation, yet correlates with the decrease in γ-H2AX under such conditions. A result of this decrease is a defect in BP531 (p53 binding protein 1) recruitment to chromosomal breaks,[33] as recruitment is dependent on the acetylation status of H4K16.[34] As with TPX2 with regards to its impact on ionizing radiation-dependent γ-H2AX levels, the molecular mechanism by which TPX2 affects the acetylation status of H4K16 remains to be discovered. # Relevance in cancer Because of its integral role in microtubule assembly and therefore mitosis, TPX2 is found to be overexpressed in different types of human cancers including hepatocellular carcinoma (HCC),[27] medullary thyroid cancer,[35] bladder carcinoma,[36] and estrogen receptor-positive metastatic breast cancer[37] and contributes to tumor growth and metastasis.[27] In HCC, TPX2 has been shown to be positively correlated with poor prognosis, metastasis, and recurrence.[38][39][40] Studies on TPX2 in HCC have also showed that TPX2 promotes tumoriogenesis and liver cancer cell growth by increasing tumor spheroid and diminishing cell growth inhibition, demonstrated by knocking out endogenous expression of TPX2 using TPX2 si-RNA.[27] As a result, TPX2 has recently been a topic of interest for learning more about the relationship between mitotic errors and tumorigenesis, along with novel cancer therapies. So far, research on depleting TPX2 via TPX2 si-RNA in HCC cells in vitro has shown significant effects in diminishing cell motility and invasion (i.e. metastasis), along with diminishing proteins involved in the G1 to S phase transition.[27] Similar results have been shown with TPX2 depletion in esophageal cancer EC9706 cells, leading to reduced cancer cell growth and invasion ability,[41] and in cervical[42] and pancreatic cancer[43] with regards to reduced tumor growth using TPX2 si-RNA transfection. In liver cancer cells, TPX2 depletion has been linked to increased genomic instability, resulting in multinucleation and DNA damage.[27] While many tumor cells in general accumulate mutations in genomic instability that enable them to have a growth advantage in tumor promotion and transformation,[44] high chromosomal instability can act as a tumor-suppressing mechanism by leading to cell death.[45][46] Therefore, the significant aneuploidy and genomic instability at mitotic division via TPX2 depletion can serve as a potential therapeutic target for cancer patients by eliminating highly proliferating cells.

https://www.wikidoc.org/index.php/TPX2

ed13fa84fde92becd009d8ec45535de622df36cd

wikidoc

TRIF

TRIF TIR-domain-containing adapter-inducing interferon-β (TRIF) is an adapter in responding to activation of toll-like receptors (TLRs). It mediates the rather delayed cascade of two TLR-associated signaling cascades, where the other one is dependent upon a MyD88 adapter. Toll-like receptors (TLRs) recognize specific components of microbial invaders and activate an immune response to these pathogens. After these receptors recognize highly conserved pathogenic patterns, a downstream signaling cascade is activated in order to stimulate the release of inflammatory cytokines and chemokines as well as to upregulate the expression of immune cells. All TLRs have a TIR domain that initiates the signaling cascade through TIR adapters. Adapters are platforms that organize downstream signaling cascades leading to a specific cellular response after exposure to a given pathogen. # Structure TRIF is primarily active in the spleen and is often regulated when MyD88 is deficient in the liver, indicating organ-specific regulation of signaling pathways. Curiously, there is a lack of redundancy within the TLR4 signaling pathway that leads to microbial evasion of immune response in the host after mutations occur within intermediates of the pathway. Three TRAF-binding motifs present in the amino terminal region of TRIF are necessary for association with TRAF6. Destruction of these motifs reduced the activation of NF-κB, a transcription factor that is also activated by the carboxy-terminal domain of TRIF in the upregulation of cytokines and co-stimulatory immune molecules. This domain recruits receptor-interacting protein (RIP1) and RIP3 through the RIP homotypic interaction motif. Cells deficient for RIP1 gene display attenuated TLR3 activation of NF-κB, indicating the use of the RIP1 gene in downstream TRIF activation, in contrast to other TLRs that use IRAK protein for the activation of NF-κB. # Areas of research Investigations into the function of TRIF are of great significance to various fields of biomedical research. The pathogenesis of infectious disease, septic shock, tumor growth, and rheumatoid arthritis all have close ties with TLR signaling pathways, specifically to that of TRIF. Better understanding of the TRIF pathway will be therapeutically useful in the development of vaccines and treatments that can control associated inflammation and antiviral responses. Experiments involving wild-type and TRIF-deficient mice are critical for understanding the coordinated responses of TLR pathways. It is necessary to study the coordinated effects of these pathways in order to understand the complex responses initiated by TRIF.

TRIF TIR-domain-containing adapter-inducing interferon-β (TRIF) is an adapter in responding to activation of toll-like receptors (TLRs). It mediates the rather delayed cascade of two TLR-associated signaling cascades, where the other one is dependent upon a MyD88 adapter.[1] Toll-like receptors (TLRs) recognize specific components of microbial invaders and activate an immune response to these pathogens. After these receptors recognize highly conserved pathogenic patterns, a downstream signaling cascade is activated in order to stimulate the release of inflammatory cytokines and chemokines as well as to upregulate the expression of immune cells. All TLRs have a TIR domain that initiates the signaling cascade through TIR adapters. Adapters are platforms that organize downstream signaling cascades leading to a specific cellular response after exposure to a given pathogen.[2] # Structure TRIF is primarily active in the spleen and is often regulated when MyD88 is deficient in the liver, indicating organ-specific regulation of signaling pathways. Curiously, there is a lack of redundancy within the TLR4 signaling pathway that leads to microbial evasion of immune response in the host after mutations occur within intermediates of the pathway.[3] Three TRAF-binding motifs present in the amino terminal region of TRIF are necessary for association with TRAF6. Destruction of these motifs reduced the activation of NF-κB, a transcription factor that is also activated by the carboxy-terminal domain of TRIF in the upregulation of cytokines and co-stimulatory immune molecules. This domain recruits receptor-interacting protein (RIP1) and RIP3 through the RIP homotypic interaction motif. Cells deficient for RIP1 gene display attenuated TLR3 activation of NF-κB, indicating the use of the RIP1 gene in downstream TRIF activation, in contrast to other TLRs that use IRAK protein for the activation of NF-κB.[4] # Areas of research Investigations into the function of TRIF are of great significance to various fields of biomedical research. The pathogenesis of infectious disease, septic shock, tumor growth, and rheumatoid arthritis all have close ties with TLR signaling pathways, specifically to that of TRIF. Better understanding of the TRIF pathway will be therapeutically useful in the development of vaccines and treatments that can control associated inflammation and antiviral responses. Experiments involving wild-type and TRIF-deficient mice are critical for understanding the coordinated responses of TLR pathways. It is necessary to study the coordinated effects of these pathways in order to understand the complex responses initiated by TRIF.[5]

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

5af7ac3d773d2113661806f3015adc3e1da95179

wikidoc

TSC2

TSC2 Tuberous Sclerosis Complex 2 (TSC2), also known as Tuberin, is a protein that in humans is encoded by the TSC2 gene. # Function Mutations in this gene lead to tuberous sclerosis. Its gene product is believed to be a tumor suppressor and is able to stimulate specific GTPases. Hamartin coded by the gene TSC1 functions as a facilitator of Hsp90 in chaperoning of Tuberin, therefore preventing its ubiquitination and degradation in the proteasome. Alternative splicing results in multiple transcript variants encoding different isoforms of the protein. Mutations in TSC2 can cause Lymphangioleiomyomatosis, a disease caused by the enlargement of tissue in the lungs, creating cysts and tumours and causing difficulty breathing. Because Tuberin regulates cell size, along with the protein Hamartin, mutations to TSC1 and TSC2 genes may prevent the control of cell growth in the lungs of individuals. # Signaling Pathways Pharmacological inhibition of ERK1/2 restores GSK3β activity and protein synthesis levels in a model of tuberous sclerosis. # Interactions TSC2 functions within a multi-protein complex knowns as the TSC complex which consists of the core proteins TSC2, TSC1, and TBC1D7. TSC2 has been reported to interact with several other proteins that are not a part of the TSC complex including: - AKT1, - AXIN1, - FOXO1, - GSK3B, - Hsp70 - Hsp90 - MAPK1, - PTK2, - PAM, - PRKAA1, - RAP1A, - RHEB, - RPS6KA1, - UBE3A and - YWHAZ.

TSC2 Tuberous Sclerosis Complex 2 (TSC2), also known as Tuberin, is a protein that in humans is encoded by the TSC2 gene. # Function Mutations in this gene lead to tuberous sclerosis. Its gene product is believed to be a tumor suppressor and is able to stimulate specific GTPases. Hamartin coded by the gene TSC1 functions as a facilitator of Hsp90 in chaperoning of Tuberin, therefore preventing its ubiquitination and degradation in the proteasome.[1] Alternative splicing results in multiple transcript variants encoding different isoforms of the protein.[2] Mutations in TSC2 can cause Lymphangioleiomyomatosis, a disease caused by the enlargement of tissue in the lungs, creating cysts and tumours and causing difficulty breathing. Because Tuberin regulates cell size, along with the protein Hamartin, mutations to TSC1 and TSC2 genes may prevent the control of cell growth in the lungs of individuals.[1] # Signaling Pathways Pharmacological inhibition of ERK1/2 restores GSK3β activity and protein synthesis levels in a model of tuberous sclerosis.[3] # Interactions TSC2 functions within a multi-protein complex knowns as the TSC complex which consists of the core proteins TSC2, TSC1,[4][5] and TBC1D7. TSC2 has been reported to interact with several other proteins that are not a part of the TSC complex including: - AKT1,[6][7] - AXIN1,[8] - FOXO1,[9] - GSK3B,[8][10] - Hsp70[1] - Hsp90[1] - MAPK1,[11] - PTK2,[12] - PAM,[13] - PRKAA1,[14][15] - RAP1A,[16][17] - RHEB,[9][16][18][19][20][21] - RPS6KA1,[7][22] - UBE3A[23][24] and - YWHAZ.[25]

https://www.wikidoc.org/index.php/TSC2

a31362c9a4caebacabf4e8b93a4ca76ea3ad8dab

wikidoc

TTC8

TTC8 Tetratricopeptide repeat domain 8 (TTC8) also known as Bardet-Biedl syndrome 8 is a protein that in humans is encoded by the TTC8 gene. # Function TTC8 is associated with gamma-tubulin, BBS4, and PCM1 in the centrosome. PCM1 in turn is involved in centriolar replication during ciliogenesis. TTC8 is located in the cilia of spermatids, retina, and bronchial epithelium cells. # Clinical significance Mutations in the TTC8 gene is one of 14 genes identified as causal for Bardet-Biedl syndrome.

TTC8 Tetratricopeptide repeat domain 8 (TTC8) also known as Bardet-Biedl syndrome 8 is a protein that in humans is encoded by the TTC8 gene.[1] # Function TTC8 is associated with gamma-tubulin, BBS4, and PCM1 in the centrosome.[1] PCM1 in turn is involved in centriolar replication during ciliogenesis.[2] TTC8 is located in the cilia of spermatids, retina, and bronchial epithelium cells.[1] # Clinical significance Mutations in the TTC8 gene is one of 14 genes[3] identified as causal for Bardet-Biedl syndrome.[1][4]

https://www.wikidoc.org/index.php/TTC8

fea7b9e2abb956f9e203b3f6af5508852d0e1a90

wikidoc

TWF1

TWF1 Twinfilin-1 is a protein that in humans is encoded by the TWF1 gene. This gene encodes twinfilin, an actin monomer-binding protein conserved from yeast to mammals. Studies of the mouse counterpart suggest that this protein may be an actin monomer-binding protein, and its localization to cortical G-actin-rich structures may be regulated by the small GTPase RAC1. # Model organisms Model organisms have been used in the study of TWF1 function. A conditional knockout mouse line, called Twf1tm1a(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 three tests were carried out on mutant mice, but no significant abnormalities were observed.

TWF1 Twinfilin-1 is a protein that in humans is encoded by the TWF1 gene.[1][2] This gene encodes twinfilin, an actin monomer-binding protein conserved from yeast to mammals. Studies of the mouse counterpart suggest that this protein may be an actin monomer-binding protein, and its localization to cortical G-actin-rich structures may be regulated by the small GTPase RAC1.[2] # Model organisms Model organisms have been used in the study of TWF1 function. A conditional knockout mouse line, called Twf1tm1a(EUCOMM)Wtsi[9][10] 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.[11][12][13] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[7][14] Twenty three tests were carried out on mutant mice, but no significant abnormalities were observed.[7]

https://www.wikidoc.org/index.php/TWF1

2788ea01449d22ff4243f784e1a1a5e9aaedb573

wikidoc

TXN2

TXN2 Thioredoxin, mitochondrial also known as thioredoxin-2 is a protein that in humans is encoded by the TXN2 gene on chromosome 22. This nuclear gene encodes a mitochondrial member of the thioredoxin family, a group of small multifunctional redox-active proteins. The encoded protein may play important roles in the regulation of the mitochondrial membrane potential and in protection against oxidant-induced apoptosis. # Structure As a thioredoxin, TXN2 is a 12-kDa protein characterized by the redox active site Trp-Cys-Gly-Pro-Cys. In its oxidized (inactive) form, the two cysteines form a disulfide bond. This bond is then reduced by thioredoxin reductase and NADPH to a dithiol, which serves as a disulfide reductase. In contrast to TXN1, TXN2 contains a putative N-terminal mitochondrial targeting sequence, responsible for its mitochondria localization, and lacks structural cysteines. Two mRNA transcripts of the TXN2 gene differ by ~330 bp in the length of the 3′-untranslated region, and both are believed to exist in vivo. # Function This nuclear gene encodes a mitochondrial member of the thioredoxin family, a group of small multifunctional redox-active proteins. The encoded protein is ubiquitously expressed in all prokaryotic and eukaryotic organisms, but demonstrates especially high expression in tissues with heavy metabolic activity, including the stomach, testis, ovary, liver, heart, neurons, and adrenal gland. It may play important roles in the regulation of the mitochondrial membrane potential and in protection against oxidant-induced apoptosis. Specifically, the ability of TXN2 to reduce disulfide bonds enables the protein to regulate mitochondrial redox and, thus, the production of reactive oxygen species (ROS). By extension, downregulation of TXN2 can lead to increased ROS generation and cell death. The antiapoptotic function of TXN2 is attributed to its involvement in GSH-dependent mechanisms to scavenge ROS, or its interaction with, and thus regulation of, thiols in the mitochondrial permeability transition pore component adenine nucleotide translocator (ANT). Overexpression of TXN2 was shown to have attenuated hypoxia-induced HIF-1alpha accumulation, which is in direct opposition of the cytosolic TXN1, which enhanced HIF-1alpha levels. Moreover, although both TXN2 and TXN1 are able to reduce insulin, TXN2 does not depend on the oxidative status of the protein for this activity, a quality which may contribute to their difference in function. # Clinical Significance It has been demonstrated that genetic polymorphisms in the TXN2 gene may be associated with the risk of spina bifida. TXN2 is known to inhibit transforming growth factor (TGF)-β-stimulated ROS generation independent of Smad signaling. TGF-β is a pro-oncogenic cytokine that induces epithelial–mesenchymal transition (EMT), which is a crucial event in metastatic progression. In particular, TXN2 inhibits TGF-β-mediated induction of HMGA2, a central EMT mediator, and fibronectin, an EMT marker. # Interactions TXN2 is shown to interact with ANT.

TXN2 Thioredoxin, mitochondrial also known as thioredoxin-2 is a protein that in humans is encoded by the TXN2 gene on chromosome 22.[1][2][3] This nuclear gene encodes a mitochondrial member of the thioredoxin family, a group of small multifunctional redox-active proteins. The encoded protein may play important roles in the regulation of the mitochondrial membrane potential and in protection against oxidant-induced apoptosis.[1] # Structure As a thioredoxin, TXN2 is a 12-kDa protein characterized by the redox active site Trp-Cys-Gly-Pro-Cys. In its oxidized (inactive) form, the two cysteines form a disulfide bond. This bond is then reduced by thioredoxin reductase and NADPH to a dithiol, which serves as a disulfide reductase. In contrast to TXN1, TXN2 contains a putative N-terminal mitochondrial targeting sequence, responsible for its mitochondria localization, and lacks structural cysteines.[4][5] Two mRNA transcripts of the TXN2 gene differ by ~330 bp in the length of the 3′-untranslated region, and both are believed to exist in vivo.[5] # Function This nuclear gene encodes a mitochondrial member of the thioredoxin family, a group of small multifunctional redox-active proteins.[1] The encoded protein is ubiquitously expressed in all prokaryotic and eukaryotic organisms, but demonstrates especially high expression in tissues with heavy metabolic activity, including the stomach, testis, ovary, liver, heart, neurons, and adrenal gland.[4][5] It may play important roles in the regulation of the mitochondrial membrane potential and in protection against oxidant-induced apoptosis.[1][4] Specifically, the ability of TXN2 to reduce disulfide bonds enables the protein to regulate mitochondrial redox and, thus, the production of reactive oxygen species (ROS). By extension, downregulation of TXN2 can lead to increased ROS generation and cell death.[4] The antiapoptotic function of TXN2 is attributed to its involvement in GSH-dependent mechanisms to scavenge ROS, or its interaction with, and thus regulation of, thiols in the mitochondrial permeability transition pore component adenine nucleotide translocator (ANT).[5] Overexpression of TXN2 was shown to have attenuated hypoxia-induced HIF-1alpha accumulation, which is in direct opposition of the cytosolic TXN1, which enhanced HIF-1alpha levels.[6] Moreover, although both TXN2 and TXN1 are able to reduce insulin, TXN2 does not depend on the oxidative status of the protein for this activity, a quality which may contribute to their difference in function.[4] # Clinical Significance It has been demonstrated that genetic polymorphisms in the TXN2 gene may be associated with the risk of spina bifida.[7] TXN2 is known to inhibit transforming growth factor (TGF)-β-stimulated ROS generation independent of Smad signaling. TGF-β is a pro-oncogenic cytokine that induces epithelial–mesenchymal transition (EMT), which is a crucial event in metastatic progression. In particular, TXN2 inhibits TGF-β-mediated induction of HMGA2, a central EMT mediator, and fibronectin, an EMT marker.[8] # Interactions TXN2 is shown to interact with ANT.[5]

https://www.wikidoc.org/index.php/TXN2

0d51d61845b6d438cd682602fc70812b16e9675d

wikidoc

Taho

Taho Tahô is a Philippine snack food made of fresh soft/silken tofu, arnibal (brown sugar syrup), and sago "pearls" (similar to tapioca pearls). This staple comfort food is a signature sweet and can be found all over the country. # History The history of taho is debatable, but early records suggest it may trace its origin to China. Prior to the Spanish Occupation, Chinese were common traders with Filipinos, thus influencing Philippine cuisine. As douhua is fairly similar in consistency to the taho base, it is thought that early Filipinos adopted, sweetened and used it to create this delicacy. # Processing and preparation Most taho vendors prepare their goods before dawn. The main ingredient, fresh soft/silken tofu is processed to a consistency that is very similar to a very fine custard. Brown sugar is then heated and caramelized to create a viscous amber-colored syrup called arnibal. Sago "pearls," purchased from the local market or palengkê, are boiled to a gummy consistency until they are a transluscent white. # Marketing The Magtataho or taho vendors are a common sight in the Philippines. They are typically male and carry two large aluminum buckets that hang from each end of a long wooden plank or yoke. These buckets are made to fit the needs of a typical magtataho. One of the buckets has a hinged lid in the center and carries nothing but the tofu base, which comprises the bulk of the dessert; the other has a hinged lid that divides the bucket diagonally into two compartments, with one side containing the arnibal and the other containing sago "pearls". Often, this bucket also has another smaller compartment near the lid for keeping change. This contraption is carried on the shoulders, not unlike a yoke, as the vendors ply their route. Taho vendors peddle their product in a trademark manner, calling its name in a full, rising inflection as they walk at a leisurely pace either along the sidewalk or, in rural communities, in the middle of the road. As most magtataho keep a habitual route, it is not uncommon for vendors to call out "Tahoooooô!" to attract a customer's attention. Though vendors are most likely to ply their routes early in the morning, it is not uncommon for a magtataho to be spotted in the late afternoon or the evening as well. This is particularly common in the heart of Manila, most particularly by Manila Bay. # Eating Most magtataho carry plastic cups for their product, often in two sizes (though vendors in residential communities tend to use their customers' cups and price their product accordingly). Using a wide, shallow metal "sandok" or scoop, they skim the surface of the bean curd and toss out any excess water, subsequently scooping the bean curd itself into a cup. Then, using a long thin metal ladle, they scoop sago "pearls" and arnibal into the cup, loosely mixing it in. Taho is enjoyed either with a spoon or by simply "drinking" it from the cup. Though traditionally served warm, cold varieties exist in supermarkets and in food stalls in cafeterias which have the bean curd in a solid, unbroken state. These pre-packed cups tend to contain a firmer tofu which need to be broken up and is sold either with a plastic spoon or a wooden popsicle stick. Due to the increase in popularity of taho over the years, its traditional form may also be found in restaurants or at receptions with a native food theme. A nationwide chain, "Uncle Finn's Soya" is also known for setting up kiosks in mall openings or food courts, thus making the sweet treat available all day.

Taho Tahô is a Philippine snack food made of fresh soft/silken tofu, arnibal (brown sugar syrup), and sago "pearls" (similar to tapioca pearls).[1] This staple comfort food is a signature sweet and can be found all over the country. # History The history of taho is debatable, but early records suggest it may trace its origin to China. Prior to the Spanish Occupation, Chinese were common traders with Filipinos, thus influencing Philippine cuisine. As douhua is fairly similar in consistency to the taho base, it is thought that early Filipinos adopted, sweetened and used it to create this delicacy. # Processing and preparation Most taho vendors prepare their goods before dawn. The main ingredient, fresh soft/silken tofu is processed to a consistency that is very similar to a very fine custard. Brown sugar is then heated and caramelized to create a viscous amber-colored syrup called arnibal. Sago "pearls," purchased from the local market or palengkê, are boiled to a gummy consistency until they are a transluscent white. # Marketing The Magtataho or taho vendors are a common sight in the Philippines. They are typically male and carry two large aluminum buckets that hang from each end of a long wooden plank or yoke. These buckets are made to fit the needs of a typical magtataho. One of the buckets has a hinged lid in the center and carries nothing but the tofu base, which comprises the bulk of the dessert; the other has a hinged lid that divides the bucket diagonally into two compartments, with one side containing the arnibal and the other containing sago "pearls". Often, this bucket also has another smaller compartment near the lid for keeping change. This contraption is carried on the shoulders, not unlike a yoke, as the vendors ply their route. Taho vendors peddle their product in a trademark manner, calling its name in a full, rising inflection as they walk at a leisurely pace either along the sidewalk or, in rural communities, in the middle of the road. As most magtataho keep a habitual route, it is not uncommon for vendors to call out "Tahoooooô!" to attract a customer's attention. Though vendors are most likely to ply their routes early in the morning, it is not uncommon for a magtataho to be spotted in the late afternoon or the evening as well. This is particularly common in the heart of Manila, most particularly by Manila Bay. # Eating Most magtataho carry plastic cups for their product, often in two sizes (though vendors in residential communities tend to use their customers' cups and price their product accordingly). Using a wide, shallow metal "sandok" or scoop, they skim the surface of the bean curd and toss out any excess water, subsequently scooping the bean curd itself into a cup. Then, using a long thin metal ladle, they scoop sago "pearls" and arnibal into the cup, loosely mixing it in. Taho is enjoyed either with a spoon or by simply "drinking" it from the cup. Though traditionally served warm, cold varieties exist in supermarkets and in food stalls in cafeterias which have the bean curd in a solid, unbroken state. These pre-packed cups tend to contain a firmer tofu which need to be broken up and is sold either with a plastic spoon or a wooden popsicle stick. Due to the increase in popularity of taho over the years, its traditional form may also be found in restaurants or at receptions with a native food theme. A nationwide chain, "Uncle Finn's Soya" is also known for setting up kiosks in mall openings or food courts, thus making the sweet treat available all day.

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

5f0d2f296659ec6bc249059a9bb8c761809d4744

wikidoc

Watt

Watt The watt (symbol: W) is the SI derived unit of power, equal to one joule of energy per second. It measures a rate of energy use or production. A human climbing a flight of stairs is doing work at a rate of about 200 watts. A typical automobile engine produces mechanical energy at a rate of 25,000 watts (approximately 33.5 horsepower) while cruising. A typical household incandescent light bulb uses electrical energy at a rate of 25 to 100 watts, while compact fluorescent lights typically consume 5 to 30 watts. # Definition 1~\rm{W} = 1~\dfrac{\rm{J}}{\rm{s}} = 1~\dfrac{\rm{kg} \cdot \rm{m^2}}{\rm{s^3}} = 1~\dfrac{\rm{N\cdot m}}{\rm{s}} \, In electrical terms, it follows that: Or, in terms of volts and amperes: 1~\rm{W} = 1~\rm{V} \times 1~\rm{A} \, That is, if 1 volt of potential difference is applied to a resistive load, and a current of 1 ampere flows, then 1 watt of power is dissipated. More simply stated: watts is equal to amps times volts. Note that the electrical definitions are true instantaneously, and for DC voltage and current. The Volt-ampere article explains the consequences when the RMS voltage and current are measured separately. # Origin and adoption as an SI unit The watt is named after James Watt for his contributions to the development of the steam engine, and was adopted by the Second Congress of the British Association for the Advancement of Science in 1889 and by the 11th General Conference on Weights and Measures in 1960 as the unit of power incorporated in the International System of Units (or "SI"). # Derived and qualified units for power distribution ## Kilowatt The kilowatt (symbol: kW), equal to one thousand watts, is typically used to state the power output of engines and the power consumption of tools and machines. A kilowatt is roughly equivalent to 1.34 horsepower. An electric heater with one heating-element might use 1 kilowatt. ## Megawatt The megawatt (symbol: MW) is equal to one million (106) watts. Many things can sustain the transfer or consumption of energy on this scale; some of these events or entities include: lightning strikes, large electric motors, naval craft (such as aircraft carriers and submarines), engineering hardware, and some scientific research equipment (such as the supercollider and large lasers). A large residential or retail building may consume several megawatts in electric power and heating energy. The productive capacity of electrical generators operated by utility companies is often measured in MW. Modern high-powered diesel-electric railroad locomotives typically have a peak power output of 3 to 5 MW, whereas U.S. nuclear power plants have net summer capacities between about 500 and 1300 MW. According to the Oxford English Dictionary, the earliest citing for "megawatt" is a reference in the 1900 Webster's International Dictionary of English Language. The OED also says "megawatt" appeared in a 28 November, 1847, article in Science (506:2). ## Gigawatt The gigawatt (symbol: GW) is equal to one billion (109) watts. This unit is sometimes used with large power plants or power grids. ## Terawatt The terawatt (symbol: TW) is equal to one trillion (1012) watts. The average energy usage of the earth (about 15 TW) is commonly measured in these units. The most powerful lasers from the mid 1960s to the mid 1990s produced power in terawatts, but only for nanoseconds. ## Electrical and thermal Megawatt electrical (abbreviation: MWe or MWe) is a term that refers to electric power, while megawatt thermal (abbreviations: MWt, MWth, MWt, or MWth) refers to thermal power produced. Though 'megawatt electrical' and 'megawatt thermal' are not SI units, alternative SI prefixes are sometimes used, for example gigawatt electrical (GWe). The International Bureau of Weights and Measures states that unit symbols should not use subscripts to provide additional information about the quantity being measured, and regards these symbols as incorrect. These terms are used by engineers to disambiguate the electric output of a thermal power station versus the (larger) thermal output. For example, the Embalse nuclear power plant in Argentina uses a fission reactor to generate 2109 MWt of heat, which creates steam to drive a turbine, which generates 648 MWe of electricity. The difference is heat lost to the surroundings. # Confusion of watts and watt-hours Power and energy are frequently confused in the general media. A watt is one 1 joule of energy per second. So watts multiplied by a period of time equals energy. For example, if a 100 watt light bulb is turned on for one hour, then an amount of energy is used corresponding to 100 watts of power being generated for a time period of one hour, i.e. 100 watts times one hour, i.e. 0.1 kilowatt-hour. Since a joule as a quantity of energy does not have a readily imagined size to the layperson, the non-SI unit watt-hour, often in its multiples such the kilowatt-hour or higher prefixes, is frequently used as a unit of energy, especially by energy-supply companies (electricity and natural gas suppliers), which often quote charges by the kilowatt-hour. A kilowatt-hour is the amount of energy equivalent to a power of 1 kilowatt running for 1 hour:

Watt The watt (symbol: W) is the SI derived unit of power, equal to one joule of energy per second. It measures a rate of energy use or production. A human climbing a flight of stairs is doing work at a rate of about 200 watts. A typical automobile engine produces mechanical energy at a rate of 25,000 watts (approximately 33.5 horsepower) while cruising. A typical household incandescent light bulb uses electrical energy at a rate of 25 to 100 watts, while compact fluorescent lights typically consume 5 to 30 watts. # Definition 1~\rm{W} = 1~\dfrac{\rm{J}}{\rm{s}} = 1~\dfrac{\rm{kg} \cdot \rm{m^2}}{\rm{s^3}} = 1~\dfrac{\rm{N\cdot m}}{\rm{s}} \, </math>. In electrical terms, it follows that: Or, in terms of volts and amperes: 1~\rm{W} = 1~\rm{V} \times 1~\rm{A} \, </math> That is, if 1 volt of potential difference is applied to a resistive load, and a current of 1 ampere flows, then 1 watt of power is dissipated.[1] More simply stated: watts is equal to amps times volts. Note that the electrical definitions are true instantaneously, and for DC voltage and current. The Volt-ampere article explains the consequences when the RMS voltage and current are measured separately. # Origin and adoption as an SI unit The watt is named after James Watt for his contributions to the development of the steam engine, and was adopted by the Second Congress of the British Association for the Advancement of Science in 1889 and by the 11th General Conference on Weights and Measures in 1960 as the unit of power incorporated in the International System of Units (or "SI"). Template:SI unit lowercase # Derived and qualified units for power distribution ## Kilowatt The kilowatt (symbol: kW), equal to one thousand watts, is typically used to state the power output of engines and the power consumption of tools and machines. A kilowatt is roughly equivalent to 1.34 horsepower. An electric heater with one heating-element might use 1 kilowatt. ## Megawatt The megawatt (symbol: MW) is equal to one million (106) watts. Many things can sustain the transfer or consumption of energy on this scale; some of these events or entities include: lightning strikes, large electric motors, naval craft (such as aircraft carriers and submarines), engineering hardware, and some scientific research equipment (such as the supercollider and large lasers). A large residential or retail building may consume several megawatts in electric power and heating energy. The productive capacity of electrical generators operated by utility companies is often measured in MW. Modern high-powered diesel-electric railroad locomotives typically have a peak power output of 3 to 5 MW, whereas U.S. nuclear power plants have net summer capacities between about 500 and 1300 MW.[2] According to the Oxford English Dictionary, the earliest citing for "megawatt" is a reference in the 1900 Webster's International Dictionary of English Language. The OED also says "megawatt" appeared in a 28 November, 1847, article in Science (506:2). ## Gigawatt The gigawatt (symbol: GW) is equal to one billion (109) watts. This unit is sometimes used with large power plants or power grids. ## Terawatt The terawatt (symbol: TW) is equal to one trillion (1012) watts. The average energy usage of the earth (about 15 TW) is commonly measured in these units. The most powerful lasers from the mid 1960s to the mid 1990s produced power in terawatts, but only for nanoseconds. ## Electrical and thermal Megawatt electrical (abbreviation: MWe[citation needed] or MWe[3]) is a term that refers to electric power, while megawatt thermal (abbreviations: MWt, MWth, MWt, or MWth) refers to thermal power produced. Though 'megawatt electrical' and 'megawatt thermal' are not SI units,[4] alternative SI prefixes are sometimes used, for example gigawatt electrical (GWe). The International Bureau of Weights and Measures states that unit symbols should not use subscripts to provide additional information about the quantity being measured, and regards these symbols as incorrect.[5] These terms are used by engineers to disambiguate the electric output of a thermal power station versus the (larger) thermal output. For example, the Embalse nuclear power plant in Argentina uses a fission reactor to generate 2109 MWt of heat, which creates steam to drive a turbine, which generates 648 MWe of electricity. The difference is heat lost to the surroundings. # Confusion of watts and watt-hours Power and energy are frequently confused in the general media. A watt is one 1 joule of energy per second. So watts multiplied by a period of time equals energy. For example, if a 100 watt light bulb is turned on for one hour, then an amount of energy is used corresponding to 100 watts of power being generated for a time period of one hour, i.e. 100 watts times one hour, i.e. 0.1 kilowatt-hour. Since a joule as a quantity of energy does not have a readily imagined size to the layperson, the non-SI unit watt-hour, often in its multiples such the kilowatt-hour or higher prefixes, is frequently used as a unit of energy, especially by energy-supply companies (electricity and natural gas suppliers), which often quote charges by the kilowatt-hour. A kilowatt-hour is the amount of energy equivalent to a power of 1 kilowatt running for 1 hour:

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

72aa79d551da2ad7ac89f728e12b49d7ddf60b07

wikidoc

Test

Test # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Test is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) There is limited information regarding Test FDA-Labeled Indications and Dosage (Adult) in the drug label. ## Off-Label Use and Dosage (Adult) # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Test FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) # Contraindications There is limited information regarding Test Contraindications in the drug label. # Warnings There is limited information regarding Test Warnings' in the drug label. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Test Clinical Trials Experience in the drug label. ## Postmarketing Experience There is limited information regarding Test Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Test Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Test in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Test in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Test during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Test in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Test in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Test in geriatric settings. ### Gender There is no FDA guidance on the use of Test with respect to specific gender populations. ### Race There is no FDA guidance on the use of Test with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Test in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Test in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Test in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Test in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Test Administration in the drug label. ### Monitoring There is limited information regarding Test Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Test and IV administrations. # Overdosage There is limited information regarding Test overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action ## Structure ## Pharmacodynamics ## Pharmacokinetics ## Nonclinical Toxicology # Clinical Studies # How Supplied ## Storage # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol Alcohol-Test interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names # Look-Alike Drug Names There is limited information regarding Test Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

Test Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Test is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) There is limited information regarding Test FDA-Labeled Indications and Dosage (Adult) in the drug label. ## Off-Label Use and Dosage (Adult) # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Test FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) # Contraindications There is limited information regarding Test Contraindications in the drug label. # Warnings There is limited information regarding Test Warnings' in the drug label. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Test Clinical Trials Experience in the drug label. ## Postmarketing Experience There is limited information regarding Test Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Test Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Test in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Test in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Test during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Test in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Test in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Test in geriatric settings. ### Gender There is no FDA guidance on the use of Test with respect to specific gender populations. ### Race There is no FDA guidance on the use of Test with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Test in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Test in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Test in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Test in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Test Administration in the drug label. ### Monitoring There is limited information regarding Test Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Test and IV administrations. # Overdosage There is limited information regarding Test overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology 123 ## Mechanism of Action 123 ## Structure 123 ## Pharmacodynamics 123 ## Pharmacokinetics 123 ## Nonclinical Toxicology 123 # Clinical Studies 123 # How Supplied 123 ## Storage 123 # Images ## Drug Images ## Package and Label Display Panel 123 # Patient Counseling Information 123 # Precautions with Alcohol Alcohol-Test interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names 123 # Look-Alike Drug Names There is limited information regarding Test Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

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

9c6da52fdc9f0554d8cfb5337148d5ffed02155e

wikidoc

Tick

Tick Tick is the common name for the small arachnids that, along with other mites, constitute the order Acarina. Ticks are ectoparasites (external parasites), living by hematophagy on the blood of mammals, birds, and occasionally reptiles and amphibians. Ticks are important vectors of a number of diseases, including Lyme disease. # Characteristics The major families of ticks include the Ixodidae or hard ticks, which have thick outer shells made of chitin, and Argasidae or soft ticks, which have a membraneous outer surface. A third family, Nuttalliellidae, contains one rare African species, Nuttalliella namaqua. Soft ticks typically live in crevices and emerge briefly to feed, while hard ticks will attach themselves to the skin of a host for long periods of time. Ticks, like most other arachnids, typically have eight legs but may have six depending on their developmental stage. Tick bites look like mosquito bites, but can also sometimes bruise or resemble a bullseye. # Classification - Family: Ixodidae (hard ticks) Genus: Amblyomma Species: Amblyomma americanum - Lone Star Tick Genus: Anocentor Genus: Boophilus (5 species) Species: Boophilus annulatus Genus: Dermacentor (30 species) Species: Dermacentor albipictus Species: Dermacentor andersoni - Rocky Mountain wood tick Species: Dermacentor auratus Species: Dermacentor circumgutattus Species: Dermacentor halli Species: Dermacentor hunteri Species: Dermacentor marginatus Species: Dermacentor nitens Species: Dermacentor occidentali Species: Dermacentor parumapterus Species: Dermacentor reticulatus - Marsh tick; Ornate cow tick Species: Dermacentor silvarum Species: Dermacentor variabilis - American dog tick; Wood tick; Eastern Wood tick Genus: Ixodes Species: Ixodes dammini Species: Ixodes holocyclus Species: Ixodes ricinus Species: Ixodes scapularis Subfamily: Haemaphysalinae Genus: Haemaphysalis Species: Haemaphysalis punctata Subfamily: Hyalomminae Genus: Hyalomma Species: Hyalomma lusitanicum Subfamily: Rhipicephalinae (~75 species) Genus: Rhipicephalus Species: Rhipicephalus bursa Species: Rhipicephalus camicas Species: Rhipicephalus evertsi Species: Rhipicephalus pravus Species: Rhipicephalus pumilio Species: Rhipicephalus pusillus Species: Rhipicephalus rossicus Species: Rhipicephalus sanguineus Species: Rhipicephalus turanicus - Genus: Amblyomma Species: Amblyomma americanum - Lone Star Tick - Species: Amblyomma americanum - Lone Star Tick - Genus: Anocentor - Genus: Boophilus (5 species) Species: Boophilus annulatus - Species: Boophilus annulatus - Genus: Dermacentor (30 species) Species: Dermacentor albipictus Species: Dermacentor andersoni - Rocky Mountain wood tick Species: Dermacentor auratus Species: Dermacentor circumgutattus Species: Dermacentor halli Species: Dermacentor hunteri Species: Dermacentor marginatus Species: Dermacentor nitens Species: Dermacentor occidentali Species: Dermacentor parumapterus Species: Dermacentor reticulatus - Marsh tick; Ornate cow tick Species: Dermacentor silvarum Species: Dermacentor variabilis - American dog tick; Wood tick; Eastern Wood tick - Species: Dermacentor albipictus - Species: Dermacentor andersoni - Rocky Mountain wood tick - Species: Dermacentor auratus - Species: Dermacentor circumgutattus - Species: Dermacentor halli - Species: Dermacentor hunteri - Species: Dermacentor marginatus - Species: Dermacentor nitens - Species: Dermacentor occidentali - Species: Dermacentor parumapterus - Species: Dermacentor reticulatus - Marsh tick; Ornate cow tick - Species: Dermacentor silvarum - Species: Dermacentor variabilis - American dog tick; Wood tick; Eastern Wood tick - Genus: Ixodes Species: Ixodes dammini Species: Ixodes holocyclus Species: Ixodes ricinus Species: Ixodes scapularis - Species: Ixodes dammini - Species: Ixodes holocyclus - Species: Ixodes ricinus - Species: Ixodes scapularis - Subfamily: Haemaphysalinae Genus: Haemaphysalis Species: Haemaphysalis punctata - Genus: Haemaphysalis Species: Haemaphysalis punctata - Species: Haemaphysalis punctata - Subfamily: Hyalomminae Genus: Hyalomma Species: Hyalomma lusitanicum - Genus: Hyalomma Species: Hyalomma lusitanicum - Species: Hyalomma lusitanicum - Subfamily: Rhipicephalinae (~75 species) Genus: Rhipicephalus Species: Rhipicephalus bursa Species: Rhipicephalus camicas Species: Rhipicephalus evertsi Species: Rhipicephalus pravus Species: Rhipicephalus pumilio Species: Rhipicephalus pusillus Species: Rhipicephalus rossicus Species: Rhipicephalus sanguineus Species: Rhipicephalus turanicus - Genus: Rhipicephalus Species: Rhipicephalus bursa Species: Rhipicephalus camicas Species: Rhipicephalus evertsi Species: Rhipicephalus pravus Species: Rhipicephalus pumilio Species: Rhipicephalus pusillus Species: Rhipicephalus rossicus Species: Rhipicephalus sanguineus Species: Rhipicephalus turanicus - Species: Rhipicephalus bursa - Species: Rhipicephalus camicas - Species: Rhipicephalus evertsi - Species: Rhipicephalus pravus - Species: Rhipicephalus pumilio - Species: Rhipicephalus pusillus - Species: Rhipicephalus rossicus - Species: Rhipicephalus sanguineus - Species: Rhipicephalus turanicus - Family: Argasidae (soft ticks) Genus: Ornithodorinae Genus: Argasinae - Genus: Ornithodorinae - Genus: Argasinae - Family: Nuttalliellidae Genus: Nuttalliella Species: Nuttalliella namaqua - Genus: Nuttalliella Species: Nuttalliella namaqua - Species: Nuttalliella namaqua # Life cycle The life cycle of the hard tick requires one to three years to complete, and may require one, two or three different host animals. The following describes the three-host lifecycle - An adult female tick drops off her final host, lays her eggs and dies. - Tiny six-legged larvae congregate on grasses or other leaves and stems not far from ground level. Lucky individuals complete that stage after attaching to a host, feeding, and dropping off. The larval stage can cause intense itching on humans, but does not transmit disease. - Larvae molt and emerge as the nymph stage, about 1.5 mm long and again climb a grass stem to await a host. The nymph stage also causes intense itching in humans. - Engorged nymphs drop off, molt to the adult stage, approximately 3 mm long, mate, and again climb a stem to await a host. Adults are amazingly stealthy on humans in spite of their size, and may not be noticed until they have been attached for a considerable time. Ticks reproduce sexually, use internal fertilisation and are oviparous. Ticks produce a lot of young but the young have no nurturing. # Ticks as disease vectors Ticks are second only to mosquitoes as vectors of human disease, both infectious and toxic. Hard ticks can transmit human diseases such as Lyme disease, Rocky Mountain spotted fever, tularemia, equine encephalitis, Colorado tick fever, and several forms of ehrlichiosis. Additionally, they are responsible for transmitting livestock and pet diseases, including babesiosis, anaplasmosis and cytauxzoonosis. Soft ticks transmit tick-borne relapsing fever spirochetes such as Borrelia turicatae, Borrelia parkeri and Borrelia hermsii. Generally, tick-borne diseases correspond to a specific tick-host combination, and are limited in their geographical extent. For example, nearly 90% of all Lyme disease(caused by the Borrelia burgdorferi bacterium) cases have been reported in the Northeastern part of the US; only specific deer ticks carry that disease. According to the Rhode Island Department of Health, roughly 70% of people who develop Lyme disease in that part of North America catch it from ticks in their own yard. The West Coast, although originally identified by A.C.Steere as a focus of Lyme disease, has traditionally been viewed as having minimal tick infection rates. In the past, it was believed that the role of the Western Fence Lizard in the California tick life cycle produced adult tick infection rates of only 2-3%. However, a landmark study in 2003 published in The Journal of Medical Entomology by the San Jose State Entomology Department found that the minimum infection rates of the microbe Borrelia burgdorferi in the tick Ixodes pacifica were much higher in Santa Cruz County, up to 17.8% in The Forest of Nisene Marks State Park. This completely transformed traditionally held views of Lyme disease in California as a minimal risk and instead raised the specter of rampant misdiagnosis as the reason for the lower case numbers. Rick Vetter of UC Riverside has shown in published work that tick-induced Lyme disease rashes in California are often misidentified as brown recluse spider bites, when, in fact, brown recluse spiders have never been documented in California. # Habitats and behaviors Ticks are blood-feeding parasites that are often found in tall grass and shrubs where they will wait to attach to a passing host. Physical contact is the only method of transportation for ticks. Ticks do not jump or fly, although they may drop from their perch and fall onto a host. Changes in temperature and day length are some of the factors signaling a tick to seek a host. Ticks can detect heat emitted or carbon dioxide respired from a nearby host. They will generally drop off the animal when full, but this may take several days. Ticks have a harpoon-like structure in their mouth area, known as a hypostome, that allows them to anchor themselves firmly in place while feeding. The hypostome has a series of barbs angled back, which is why they are so difficult to remove once they have penetrated a host. # Population control The blacklegged or deer tick (Ixodes scapularis) is dependent on the white-tailed deer for successful reproduction. Larval and nymph stages (immature ticks that cannot reproduce) of the deer tick feed on birds and small mammals. The adult female tick needs a large 3 day blood meal from the deer before she can reproduce and lay her 2000 or more eggs. Deer are the primary host for the adult deer tick and are key to the reproductive success of the tick . By reducing the deer population back to healthy levels of 8 to 10 per square mile (from the current levels of 60 or more deer per square mile in the worst affected areas of the country) the tick numbers can be brought down to very low levels, perhaps too few to spread tick-borne diseases. See the Connecticut Agricultural Experiment Station and Connecticut Department of Public Health joint publication "Tick Management Handbook" for more details of the tick's life cycle and dependence on deer. Numerous studies have shown that abundance and distribution of deer ticks are correlated with deer densities. For example when the deer population was reduced by 74% at a 248-acre study site in Bridgeport, CT, the number of nymphal ticks collected at the site decreased by 92% . Furthermore, the relationship between deer abundance, tick abundance, and human cases of Lyme disease was well documented in the Mumford Cove Community in Groton, CT, from 1996 to 2004. The deer population in Mumford Cove was reduced from about 77 deer per square mile to about 10 deer per square mile after 2 years of controlled hunting. After the initial reduction the deer population was maintained at low levels. Reducing deer densities to 10 deer per square mile was adequate to reduce by more than 90% the risk of humans contracting Lyme disease in Mumford Cove. (DEP Wildlife Division: Managing Urban Deer in Connecticut 2nd edition June 2007) Deer population management must serve as the main tool in any long-term strategy to reduce human incidences of Lyme disease. A method of reducing deer tick (Ixodes scapularis/dammini) populations - Damminix - may be cited. It consists of biodegradable cardboard tubes stuffed with permethrin-treated cotton and works in the following way: Mice collect the cotton for lining their nests. The pesticide on the cotton kills any immature ticks that are feeding on the mice. It is important to put the tubes where mice will find them, such as in dense, dark brush or at the base of a log; mice are unlikely to gather the cotton from an open lawn. Best results are obtained with regular applications early in the spring and again in late summer. The more neighbors who also use Damminix, the better. Damminix appears to help control tick populations, particularly in the year following initial use. Note that it is not effective on the West Coast. See UMM Patient Education Link. A potential alternative to Damminix's permethrin is fipronil. It is used in the Maxforce Tick Management system, in which fipronil is painted onto rodents visiting the plastic baitboxes. see. This system is no longer generally available for sale by Bayer. In 2005, there were selective reports of grey squirrels "chewing" into some Maxforce TMS boxes in areas of the northeastern United States, compromising the child resistant box. Due to this problem, the Federal Environmental Protection Agency (EPA) asked that all similarly designed TMS boxes applied in 2006 be covered with a protective shroud capable of preventing squirrel damage. The Maxforce TMS system remains registered by the federal EPA for its continued use. A metal shroud has been developed and is reportedly in use to eliminate any potential squirrel damage to the plastic box. This shroud reportedly satisfies the EPA's mandate to protect the boxes from such damage and is recommended by Bayer Environmental Science. Availability however outside of Connecticut , New York, New Jersey and Rhode Island may be minimal. Also, the Centers for Disease Control and Prevention offers advice on reducing ticks around your home; see . The parasitic Ichneumon wasp Ixodiphagus hookeri has long been investigated for its potential to control tick populations. It lays its eggs into ticks; the hatching wasps kill its host. Another "natural" form of control for ticks is the Guineafowl. They consume mass quantities of ticks. Just 2 birds can clear 2 acres in a single year. However they can be quite noisy, and employers of this method should be prepared for complaints from neighbors. Topical (drops/dust) flea/tick medicines need to be used with care. Phenothrin (85.7%) in combination with Methopren was a popular topical flea/tick therapy for felines. Phenothrin kills adult fleas and ticks. Methoprene is an insect growth regulator that interrupts the insect's life cycle by killing the eggs. However, the US EPA has made at least one manufacturer of these products (Hartz Mountain Corp., Secaucus, New Jersey, USA), withdraw some products and include strong cautionary statements on others, warning of adverse reactions (). # Removal To remove a tick use a small set of tweezers: grab the head, pulling slowly and steadily.. There are a number of manufacturers that have produced tweezers specifically for tick removal. Crushing or irritating the tick (by heat or chemicals) should be avoided, because these methods may cause it to regurgitate its stomach contents into the skin, increasing the possibility of infection of the host. Tiny larval ticks can usually be removed by carefully scraping with a fingernail. Lyme disease found in deer ticks cannot be transmitted once the body is removed even if the mouthparts break off and are still in the skin. Prompt removal is important; infection generally takes an extended period of time, over 24 hours for Lyme disease. An effective method involves carving the end of a small stick into a flat blade resembling a screwdriver, but with a small notch in the end. This implement is especially useful removing ticks from dogs. An alternative method, used by fishermen and does not risk squeezing the tick's thorax, uses 18 inches of fine weight fishing line. The line is tied in a simple overhand knot that is tightened slowly around the tick's head. If the line is pressed against the skin while being gently pulled, the knot will tighten around the tick's head. Slowly pulling the ends of the line will then dislodge the tick from the bite site with a reduced chance of leaving the head attached. This method also works with sewing thread. It is commonly claimed that petroleum jelly placed on the tick will clogs the animal's breathing passages and cause it to de-attach itself. However, many medical authorities advise against this and other "smothering" approaches as ticks only breathe a few times per hour and feeding may thus continue for some time, and because these approaches may irritate the tick to the point of regurgitation of bacteria into the bloodstream.;;;; # Example species - Dermacentor variabilis, the American dog tick, is perhaps the most well-known of the North American hard ticks. This tick does not carry Lyme disease, but can carry Rocky Mountain spotted fever. - Ixodes scapularis (formerly Ixodes dammini), known as the black-legged tick or deer tick, is common to the eastern part of North America and is known for spreading Lyme disease. - Ixodes pacificus, the Western black-legged tick, lives in the western part of North America and is responsible for spreading Lyme disease and the more deadly Rocky Mountain spotted fever. It tends to prefer livestock as its adult host. - In some parts of Europe, tick-borne meningoencephalitis is a common viral infection. - Australian tick fauna consists of approximately 75 species, the majority of which fall into the Ixodidae, hard tick, family. The most medically important tick is the Paralysis tick, Ixodes holocyclus. It is found in a 20-kilometre band that follows the eastern coastline of Australia. As this is where much of the human population resides in New South Wales, encounters with these parasites are relatively common. Although most cases of tick bite are uneventful, some can result in life threatening illnesses including paralysis, tick typhus and severe allergic reactions.

Tick Template:Wikispecies Tick is the common name for the small arachnids that, along with other mites, constitute the order Acarina. Ticks are ectoparasites (external parasites), living by hematophagy on the blood of mammals, birds, and occasionally reptiles and amphibians. Ticks are important vectors of a number of diseases, including Lyme disease. # Characteristics The major families of ticks include the Ixodidae or hard ticks, which have thick outer shells made of chitin, and Argasidae or soft ticks, which have a membraneous outer surface. A third family, Nuttalliellidae, contains one rare African species, Nuttalliella namaqua. Soft ticks typically live in crevices and emerge briefly to feed, while hard ticks will attach themselves to the skin of a host for long periods of time. Ticks, like most other arachnids, typically have eight legs but may have six depending on their developmental stage. Tick bites look like mosquito bites, but can also sometimes bruise or resemble a bullseye. # Classification - Family: Ixodidae (hard ticks) Genus: Amblyomma Species: Amblyomma americanum - Lone Star Tick Genus: Anocentor Genus: Boophilus (5 species) Species: Boophilus annulatus Genus: Dermacentor (30 species) Species: Dermacentor albipictus Species: Dermacentor andersoni - Rocky Mountain wood tick Species: Dermacentor auratus Species: Dermacentor circumgutattus Species: Dermacentor halli Species: Dermacentor hunteri Species: Dermacentor marginatus Species: Dermacentor nitens Species: Dermacentor occidentali Species: Dermacentor parumapterus Species: Dermacentor reticulatus - Marsh tick; Ornate cow tick Species: Dermacentor silvarum Species: Dermacentor variabilis - American dog tick; Wood tick; Eastern Wood tick Genus: Ixodes Species: Ixodes dammini Species: Ixodes holocyclus Species: Ixodes ricinus Species: Ixodes scapularis Subfamily: Haemaphysalinae Genus: Haemaphysalis Species: Haemaphysalis punctata Subfamily: Hyalomminae Genus: Hyalomma Species: Hyalomma lusitanicum Subfamily: Rhipicephalinae (~75 species) Genus: Rhipicephalus Species: Rhipicephalus bursa Species: Rhipicephalus camicas Species: Rhipicephalus evertsi Species: Rhipicephalus pravus Species: Rhipicephalus pumilio Species: Rhipicephalus pusillus Species: Rhipicephalus rossicus Species: Rhipicephalus sanguineus Species: Rhipicephalus turanicus - Genus: Amblyomma Species: Amblyomma americanum - Lone Star Tick - Species: Amblyomma americanum - Lone Star Tick - Genus: Anocentor - Genus: Boophilus (5 species) Species: Boophilus annulatus - Species: Boophilus annulatus - Genus: Dermacentor (30 species) Species: Dermacentor albipictus Species: Dermacentor andersoni - Rocky Mountain wood tick Species: Dermacentor auratus Species: Dermacentor circumgutattus Species: Dermacentor halli Species: Dermacentor hunteri Species: Dermacentor marginatus Species: Dermacentor nitens Species: Dermacentor occidentali Species: Dermacentor parumapterus Species: Dermacentor reticulatus - Marsh tick; Ornate cow tick Species: Dermacentor silvarum Species: Dermacentor variabilis - American dog tick; Wood tick; Eastern Wood tick - Species: Dermacentor albipictus - Species: Dermacentor andersoni - Rocky Mountain wood tick - Species: Dermacentor auratus - Species: Dermacentor circumgutattus - Species: Dermacentor halli - Species: Dermacentor hunteri - Species: Dermacentor marginatus - Species: Dermacentor nitens - Species: Dermacentor occidentali - Species: Dermacentor parumapterus - Species: Dermacentor reticulatus - Marsh tick; Ornate cow tick - Species: Dermacentor silvarum - Species: Dermacentor variabilis - American dog tick; Wood tick; Eastern Wood tick - Genus: Ixodes Species: Ixodes dammini Species: Ixodes holocyclus Species: Ixodes ricinus Species: Ixodes scapularis - Species: Ixodes dammini - Species: Ixodes holocyclus - Species: Ixodes ricinus - Species: Ixodes scapularis - Subfamily: Haemaphysalinae Genus: Haemaphysalis Species: Haemaphysalis punctata - Genus: Haemaphysalis Species: Haemaphysalis punctata - Species: Haemaphysalis punctata - Subfamily: Hyalomminae Genus: Hyalomma Species: Hyalomma lusitanicum - Genus: Hyalomma Species: Hyalomma lusitanicum - Species: Hyalomma lusitanicum - Subfamily: Rhipicephalinae (~75 species) Genus: Rhipicephalus Species: Rhipicephalus bursa Species: Rhipicephalus camicas Species: Rhipicephalus evertsi Species: Rhipicephalus pravus Species: Rhipicephalus pumilio Species: Rhipicephalus pusillus Species: Rhipicephalus rossicus Species: Rhipicephalus sanguineus Species: Rhipicephalus turanicus - Genus: Rhipicephalus Species: Rhipicephalus bursa Species: Rhipicephalus camicas Species: Rhipicephalus evertsi Species: Rhipicephalus pravus Species: Rhipicephalus pumilio Species: Rhipicephalus pusillus Species: Rhipicephalus rossicus Species: Rhipicephalus sanguineus Species: Rhipicephalus turanicus - Species: Rhipicephalus bursa - Species: Rhipicephalus camicas - Species: Rhipicephalus evertsi - Species: Rhipicephalus pravus - Species: Rhipicephalus pumilio - Species: Rhipicephalus pusillus - Species: Rhipicephalus rossicus - Species: Rhipicephalus sanguineus - Species: Rhipicephalus turanicus - Family: Argasidae (soft ticks) Genus: Ornithodorinae Genus: Argasinae - Genus: Ornithodorinae - Genus: Argasinae - Family: Nuttalliellidae Genus: Nuttalliella Species: Nuttalliella namaqua - Genus: Nuttalliella Species: Nuttalliella namaqua - Species: Nuttalliella namaqua # Life cycle The life cycle of the hard tick requires one to three years to complete, and may require one, two or three different host animals. The following describes the three-host lifecycle - An adult female tick drops off her final host, lays her eggs and dies. - Tiny six-legged larvae congregate on grasses or other leaves and stems not far from ground level. Lucky individuals complete that stage after attaching to a host, feeding, and dropping off. The larval stage can cause intense itching on humans, but does not transmit disease. - Larvae molt and emerge as the nymph stage, about 1.5 mm long and again climb a grass stem to await a host. The nymph stage also causes intense itching in humans. - Engorged nymphs drop off, molt to the adult stage, approximately 3 mm long, mate, and again climb a stem to await a host. Adults are amazingly stealthy on humans in spite of their size, and may not be noticed until they have been attached for a considerable time. Ticks reproduce sexually, use internal fertilisation and are oviparous. Ticks produce a lot of young but the young have no nurturing. # Ticks as disease vectors Ticks are second only to mosquitoes as vectors of human disease, both infectious and toxic.[1] Hard ticks can transmit human diseases such as Lyme disease, Rocky Mountain spotted fever, tularemia, equine encephalitis, Colorado tick fever, and several forms of ehrlichiosis. Additionally, they are responsible for transmitting livestock and pet diseases, including babesiosis, anaplasmosis and cytauxzoonosis. Soft ticks transmit tick-borne relapsing fever spirochetes such as Borrelia turicatae, Borrelia parkeri and Borrelia hermsii. Generally, tick-borne diseases correspond to a specific tick-host combination, and are limited in their geographical extent. For example, nearly 90% of all Lyme disease(caused by the Borrelia burgdorferi bacterium) cases have been reported in the Northeastern part of the US; [2] only specific deer ticks carry that disease.[3] According to the Rhode Island Department of Health, roughly 70% of people who develop Lyme disease in that part of North America catch it from ticks in their own yard. [4] The West Coast, although originally identified by A.C.Steere as a focus of Lyme disease, has traditionally been viewed as having minimal tick infection rates. In the past, it was believed that the role of the Western Fence Lizard in the California tick life cycle produced adult tick infection rates of only 2-3%. However, a landmark study in 2003 published in The Journal of Medical Entomology by the San Jose State Entomology Department found that the minimum infection rates of the microbe Borrelia burgdorferi in the tick Ixodes pacifica were much higher in Santa Cruz County, up to 17.8% in The Forest of Nisene Marks State Park. This completely transformed traditionally held views of Lyme disease in California as a minimal risk and instead raised the specter of rampant misdiagnosis as the reason for the lower case numbers. Rick Vetter of UC Riverside has shown in published work that tick-induced Lyme disease rashes in California are often misidentified as brown recluse spider bites, when, in fact, brown recluse spiders have never been documented in California. # Habitats and behaviors Ticks are blood-feeding parasites that are often found in tall grass and shrubs where they will wait to attach to a passing host. Physical contact is the only method of transportation for ticks. Ticks do not jump or fly, although they may drop from their perch and fall onto a host. Changes in temperature and day length are some of the factors signaling a tick to seek a host. Ticks can detect heat emitted or carbon dioxide respired from a nearby host. They will generally drop off the animal when full, but this may take several days. Ticks have a harpoon-like structure in their mouth area, known as a hypostome, that allows them to anchor themselves firmly in place while feeding. The hypostome has a series of barbs angled back, which is why they are so difficult to remove once they have penetrated a host. # Population control The blacklegged or deer tick (Ixodes scapularis) is dependent on the white-tailed deer for successful reproduction. Larval and nymph stages (immature ticks that cannot reproduce) of the deer tick feed on birds and small mammals. The adult female tick needs a large 3 day blood meal from the deer before she can reproduce and lay her 2000 or more eggs. Deer are the primary host for the adult deer tick and are key to the reproductive success of the tick [5]. By reducing the deer population back to healthy levels of 8 to 10 per square mile (from the current levels of 60 or more deer per square mile in the worst affected areas of the country) the tick numbers can be brought down to very low levels, perhaps too few to spread tick-borne diseases. See the Connecticut Agricultural Experiment Station and Connecticut Department of Public Health joint publication "Tick Management Handbook" [6] for more details of the tick's life cycle and dependence on deer. Numerous studies have shown that abundance and distribution of deer ticks are correlated with deer densities. [5][7][8][9] For example when the deer population was reduced by 74% at a 248-acre study site in Bridgeport, CT, the number of nymphal ticks collected at the site decreased by 92% [5]. Furthermore, the relationship between deer abundance, tick abundance, and human cases of Lyme disease was well documented in the Mumford Cove Community in Groton, CT, from 1996 to 2004. The deer population in Mumford Cove was reduced from about 77 deer per square mile to about 10 deer per square mile after 2 years of controlled hunting. After the initial reduction the deer population was maintained at low levels. Reducing deer densities to 10 deer per square mile was adequate to reduce by more than 90% the risk of humans contracting Lyme disease in Mumford Cove. (DEP Wildlife Division: Managing Urban Deer in Connecticut 2nd edition June 2007) Deer population management must serve as the main tool in any long-term strategy to reduce human incidences of Lyme disease. [10] A method of reducing deer tick (Ixodes scapularis/dammini) populations - Damminix [2] - may be cited. It consists of biodegradable cardboard tubes stuffed with permethrin-treated cotton and works in the following way: Mice collect the cotton for lining their nests. The pesticide on the cotton kills any immature ticks that are feeding on the mice. It is important to put the tubes where mice will find them, such as in dense, dark brush or at the base of a log; mice are unlikely to gather the cotton from an open lawn. Best results are obtained with regular applications early in the spring and again in late summer. The more neighbors who also use Damminix, the better. Damminix appears to help control tick populations, particularly in the year following initial use. Note that it is not effective on the West Coast. See [3] UMM Patient Education Link. A potential alternative to Damminix's permethrin is fipronil. It is used in the Maxforce Tick Management system, in which fipronil is painted onto rodents visiting the plastic baitboxes. see[4]. This system is no longer generally available for sale by Bayer. In 2005, there were selective reports of grey squirrels "chewing" into some Maxforce TMS boxes in areas of the northeastern United States, compromising the child resistant box. Due to this problem, the Federal Environmental Protection Agency (EPA) asked that all similarly designed TMS boxes applied in 2006 be covered with a protective shroud capable of preventing squirrel damage. The Maxforce TMS system remains registered by the federal EPA for its continued use. A metal shroud has been developed and is reportedly in use to eliminate any potential squirrel damage to the plastic box. This shroud reportedly satisfies the EPA's mandate to protect the boxes from such damage and is recommended by Bayer Environmental Science. Availability however outside of Connecticut , New York, New Jersey and Rhode Island may be minimal. Also, the Centers for Disease Control and Prevention offers advice on reducing ticks around your home; see [5]. The parasitic Ichneumon wasp Ixodiphagus hookeri has long been investigated for its potential to control tick populations. It lays its eggs into ticks; the hatching wasps kill its host. Another "natural" form of control for ticks is the Guineafowl. They consume mass quantities of ticks. Just 2 birds can clear 2 acres in a single year. However they can be quite noisy, and employers of this method should be prepared for complaints from neighbors. Topical (drops/dust) flea/tick medicines need to be used with care. Phenothrin (85.7%) in combination with Methopren was a popular topical flea/tick therapy for felines. Phenothrin kills adult fleas and ticks. Methoprene is an insect growth regulator that interrupts the insect's life cycle by killing the eggs. However, the US EPA has made at least one manufacturer of these products (Hartz Mountain Corp., Secaucus, New Jersey, USA), withdraw some products and include strong cautionary statements on others, warning of adverse reactions (http://www.epa.gov/pesticides/factsheets/flea-tick-drops.htm). # Removal To remove a tick use a small set of tweezers: grab the head, pulling slowly and steadily.[6]. There are a number of manufacturers that have produced tweezers specifically for tick removal. Crushing or irritating the tick (by heat or chemicals) should be avoided, because these methods may cause it to regurgitate its stomach contents into the skin, increasing the possibility of infection of the host.[7] Tiny larval ticks can usually be removed by carefully scraping with a fingernail. Lyme disease found in deer ticks cannot be transmitted once the body is removed even if the mouthparts break off and are still in the skin. Prompt removal is important; infection generally takes an extended period of time, over 24 hours for Lyme disease. An effective method involves carving the end of a small stick into a flat blade resembling a screwdriver, but with a small notch in the end. This implement is especially useful removing ticks from dogs. An alternative method, used by fishermen and does not risk squeezing the tick's thorax, uses 18 inches of fine weight fishing line. The line is tied in a simple overhand knot that is tightened slowly around the tick's head. If the line is pressed against the skin while being gently pulled, the knot will tighten around the tick's head. Slowly pulling the ends of the line will then dislodge the tick from the bite site with a reduced chance of leaving the head attached. This method also works with sewing thread. It is commonly claimed that petroleum jelly placed on the tick will clogs the animal's breathing passages and cause it to de-attach itself. However, many medical authorities advise against this and other "smothering" approaches as ticks only breathe a few times per hour and feeding may thus continue for some time, and because these approaches may irritate the tick to the point of regurgitation of bacteria into the bloodstream.[8];[9];[10];[11];[12] # Example species - Dermacentor variabilis, the American dog tick, is perhaps the most well-known of the North American hard ticks. This tick does not carry Lyme disease, but can carry Rocky Mountain spotted fever. - Ixodes scapularis (formerly Ixodes dammini), known as the black-legged tick or deer tick, is common to the eastern part of North America and is known for spreading Lyme disease. - Ixodes pacificus, the Western black-legged tick, lives in the western part of North America and is responsible for spreading Lyme disease and the more deadly Rocky Mountain spotted fever. It tends to prefer livestock as its adult host. - In some parts of Europe, tick-borne meningoencephalitis is a common viral infection. - Australian tick fauna consists of approximately 75 species, the majority of which fall into the Ixodidae, hard tick, family. The most medically important tick is the Paralysis tick, Ixodes holocyclus. It is found in a 20-kilometre band that follows the eastern coastline of Australia. As this is where much of the human population resides in New South Wales, encounters with these parasites are relatively common. Although most cases of tick bite are uneventful, some can result in life threatening illnesses including paralysis, tick typhus and severe allergic reactions.[11]

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

3d7795ea6de7502f2f659bfff726d57ddee271a2

wikidoc

Tsix

Tsix Tsix is a non-coding RNA gene that is antisense to the Xist RNA. Tsix binds Xist during X chromosome inactivation. The name Tsix comes from the reverse of Xist, which stands for X-inactive specific transcript. # Background Female mammals have two X chromosomes and males have one X and one Y chromosome. The X chromosome has many active genes. This leads to dosage compensation problems: the two X chromosomes in the female will create twice as many gene products as the one X in the male. To mitigate this, one of the X chromosomes is inactivated in females, so that each sex only has one set of X chromosome genes. The inactive X chromosome in cells of females is visible as a Barr body under the microscope. Males do not have Barr bodies as they only have one X chromosome. Xist is only expressed from the future inactive X chromosome in females and is able to "coat" the chromosome from which it was produced. Many copies of Xist RNA bind the future inactivated X chromosome. Tsix prevents the accumulation of Xist on the future active female X chromosome to maintain the active euchromatin state of the chosen chromosome. # Function in mammals In the extra-embryonic lineage in mice and some other mammals, the maternal X chromosome is always active and the paternal X chromosome is always silenced, in a process called imprinted X-inactivation. Xist inactivates the paternal X chromosome in female mice by condensing the chromatin, via histone methylation among other mechanisms that are currently being studied. Tsix binds complementary Xist RNA and render it non-functional. After binding it, Xist is made inactive through dicer. Thus, Xist does not condense chromatin on the maternal chromosome, letting it remain active. This does not occur on the paternal chromosome, and Xist proceeds to inactivate that chromosome. Tsix also functions to silence transcription of Xist through epigenetic regulation. Tsix and Xist regulate X chromosome protein production in female mice to prevent early embryonic mortality. X inactivation allows for equal dosage of X-linked genes for both males and females by inactivating the extra X chromosome in the females. Mutation of the maternal Tsix gene can cause over accumulation of Xist on both X chromosomes, silencing both X chromosomes in females and the single X chromosome in male. This can cause early mortality. However, if the paternal Tsix allele is active, it can rescue female embryos from the over-accumulation of Xist. # Mutations When one allele of Tsix in mice is null, the inactivation is skewed toward the mutant X chromosome. This is due to an accumulation of Xist that is not countered by Tsix, and causes the mutant chromosome to be inactivated. When both alleles of Tsix are null (homozygous mutant), the results are low fertility, lower proportion of female births and a reversion to random X inactivation rather than gene imprinting. # Regulation in cell differentiation In development, X chromosome inactivation is a part of cellular differentiation. This is accomplished by normal Xist function. To confer pluripotency in an embryonic stem cell, factors inhibit Xist transcription. These factors also upregulate transcription of Tsix, which serves to inhibit Xist further. This cell is then able to remain pluripotent as X inactivation is not accomplished. The marker Rex1, as well as other members of the pluripotency network, are recruited to the Tsix promoter and transcription elongation of Tsix occurs. Along with Tsix and other proteins, factor PRDM14 has been shown to be necessary for the return to pluripotency. Assisted by Tsix, PRDM14 can associate with Xist and remove the inactivation of an X chromosome. # Tsix in humans X chromosome inactivation is random in human females, and imprinting does not occur. The deletion of a CpG island, a site involved in epigenetic regulation, in the human Tsix gene prevents Tsix from imprinting on the X chromosomes. Instead, the human Tsix chromosome is coexpressed with the human Xist gene on the inactivated X chromosome, indicating that it does not play an important role in random X chromosome inactivation. An autosome may be a more likely candidate for regulating this process in humans. The presence of Tsix in humans may be an evolutionary vestige, a sequence that no longer has a function in humans. Alternately, it may be necessary to study cells closer to the X inactivation stage rather than older cells in order to accurately locate Tsix expression and function.

Tsix Tsix is a non-coding RNA gene that is antisense to the Xist RNA. Tsix binds Xist during X chromosome inactivation. The name Tsix comes from the reverse of Xist, which stands for X-inactive specific transcript.[1] # Background Female mammals have two X chromosomes and males have one X and one Y chromosome. The X chromosome has many active genes. This leads to dosage compensation problems: the two X chromosomes in the female will create twice as many gene products as the one X in the male. To mitigate this, one of the X chromosomes is inactivated in females, so that each sex only has one set of X chromosome genes. The inactive X chromosome in cells of females is visible as a Barr body under the microscope. Males do not have Barr bodies as they only have one X chromosome.[1] Xist is only expressed from the future inactive X chromosome in females and is able to "coat" the chromosome from which it was produced. Many copies of Xist RNA bind the future inactivated X chromosome. Tsix prevents the accumulation of Xist on the future active female X chromosome to maintain the active euchromatin state of the chosen chromosome.[1][2] # Function in mammals In the extra-embryonic lineage in mice and some other mammals, the maternal X chromosome is always active and the paternal X chromosome is always silenced, in a process called imprinted X-inactivation. Xist inactivates the paternal X chromosome in female mice by condensing the chromatin, via histone methylation among other mechanisms that are currently being studied. Tsix binds complementary Xist RNA and render it non-functional. After binding it, Xist is made inactive through dicer.[2] Thus, Xist does not condense chromatin on the maternal chromosome, letting it remain active. This does not occur on the paternal chromosome, and Xist proceeds to inactivate that chromosome.[3] Tsix also functions to silence transcription of Xist through epigenetic regulation.[2] Tsix and Xist regulate X chromosome protein production in female mice to prevent early embryonic mortality.[4] X inactivation allows for equal dosage of X-linked genes for both males and females by inactivating the extra X chromosome in the females.[5] Mutation of the maternal Tsix gene can cause over accumulation of Xist on both X chromosomes, silencing both X chromosomes in females and the single X chromosome in male. This can cause early mortality. However, if the paternal Tsix allele is active, it can rescue female embryos from the over-accumulation of Xist.[6] # Mutations When one allele of Tsix in mice is null, the inactivation is skewed toward the mutant X chromosome. This is due to an accumulation of Xist that is not countered by Tsix, and causes the mutant chromosome to be inactivated. When both alleles of Tsix are null (homozygous mutant), the results are low fertility, lower proportion of female births and a reversion to random X inactivation rather than gene imprinting.[7] # Regulation in cell differentiation In development, X chromosome inactivation is a part of cellular differentiation. This is accomplished by normal Xist function. To confer pluripotency in an embryonic stem cell, factors inhibit Xist transcription. These factors also upregulate transcription of Tsix, which serves to inhibit Xist further. This cell is then able to remain pluripotent as X inactivation is not accomplished.[8] The marker Rex1, as well as other members of the pluripotency network, are recruited to the Tsix promoter and transcription elongation of Tsix occurs.[8] Along with Tsix and other proteins, factor PRDM14 has been shown to be necessary for the return to pluripotency. Assisted by Tsix, PRDM14 can associate with Xist and remove the inactivation of an X chromosome.[9] # Tsix in humans X chromosome inactivation is random in human females, and imprinting does not occur. The deletion of a CpG island, a site involved in epigenetic regulation, in the human Tsix gene prevents Tsix from imprinting on the X chromosomes. Instead, the human Tsix chromosome is coexpressed with the human Xist gene on the inactivated X chromosome, indicating that it does not play an important role in random X chromosome inactivation.[10] An autosome may be a more likely candidate for regulating this process in humans. The presence of Tsix in humans may be an evolutionary vestige, a sequence that no longer has a function in humans. Alternately, it may be necessary to study cells closer to the X inactivation stage rather than older cells in order to accurately locate Tsix expression and function.[3]

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

6e8ea7818b9d458466af70e9315a1a3377e4dab0

wikidoc

UBA1

UBA1 Ubiquitin-like modifier activating enzyme 1 (UBA1) is an enzyme which in humans is encoded by the UBA1 gene. UBA1 participates in ubiquitination and the NEDD8 pathway for protein folding and degradation, among many other biological processes. This protein has been linked to X-linked spinal muscular atrophy type 2, neurodegenerative diseases, and cancers. # Structure ## Gene The UBA1 gene is located in the chromosome band Xp11.23, consisting of 31 exons. ## Protein The UBA1 for ubiquitin (Ub) is a 110–120 kDa monomeric protein, and the UBA1 for the ubiquitin-like protein (Ubls) NEDD8 and SUMO are heterodimeric complexes with similar molecular weights. All eukaryotic UBA1 contain a two-fold repeat of a domain, derived from the bacterial MoeB and ThiF proteins, with one occurrence each in the N-terminal and C-terminal half of the UBA1 for Ub, or the separate subunits of the UBA1 for NEDD8 and SUMO. The UBA1 for Ub consists of four building blocks: First, the adenylation domains composed of two MoeB/ThiF-homology motifs, the latter of which binds ATP and Ub; second, the catalytic cysteine half-domains, which contain the E1 active site cysteine inserted into each of the adenylation domains; third, a four-helix bundle that represents a second insertion in the inactive adenylation domain and immediately follows the first catalytic cysteine half-domain; and fourth, the C-terminal ubiquitin-fold domain, which recruits specific E2s. # Function The protein encoded by this gene catalyzes the first step in ubiquitin conjugation, or ubiquitination, to mark cellular proteins for degradation. Specifically, UBA1 catalyzes the ATP-dependent adenylation of ubiquitin, thereby forming a thioester bond between the two. It also continues to participate in subsequent steps of ubiquination as a Ub carrier. There are only two human ubiquitin-activating enzymes, UBA1 and UBA6, and thus UBA1 is largely responsible for protein ubiquitination in humans. Through its central role in ubiquitination, UBA1 has been linked to cell cycle regulation, endocytosis, signal transduction, apoptosis, DNA damage repair, and transcriptional regulation. Additionally, UBA1 helps regulate the NEDD8 pathway, thus implicating it in protein folding, as well as mitigating the depletion of ubiquitin levels during stress. # Clinical significance Mutations in UBA1 are associated with X-linked spinal muscular atrophy type 2. UBA1 has also been implicated in other neurodegenerative diseases, including spinal muscular atrophy, as well as cancer and tumors. Since UBA1 is involved in multiple biological processes, there are concerns that inhibiting UBA1 would also damage normal cells. Nonetheless, preclinical testing of a UBA1 inhibitor in mice with leukemia revealed no additional toxic effects to normal cells, and the success of other drugs targeting pleiotropic targets likewise support the safety of using UBA1 inhibitor in cancer treatment Moreover, the UBA1 inhibitors Largazole, as well as its ketone and ester derivatives, preferentially targets cancer over normal cells by specifically blocking the ligation of Ub and UBA1 during the adenylation step of the E1 pathway. MLN4924, a NEDD8-activating enzyme inhibitor functioning according to similar mechanisms, is currently undergoing phase I clinical trials. # Interactions UBA1 has been shown to interact with: - UBC13 - PYR-41 - himeic acid A - hyrtioreticulines A–E

UBA1 Ubiquitin-like modifier activating enzyme 1 (UBA1) is an enzyme which in humans is encoded by the UBA1 gene.[1][2] UBA1 participates in ubiquitination and the NEDD8 pathway for protein folding and degradation, among many other biological processes.[1][3] This protein has been linked to X-linked spinal muscular atrophy type 2, neurodegenerative diseases, and cancers.[4][5] # Structure ## Gene The UBA1 gene is located in the chromosome band Xp11.23, consisting of 31 exons. ## Protein The UBA1 for ubiquitin (Ub) is a 110–120 kDa monomeric protein, and the UBA1 for the ubiquitin-like protein (Ubls) NEDD8 and SUMO are heterodimeric complexes with similar molecular weights. All eukaryotic UBA1 contain a two-fold repeat of a domain, derived from the bacterial MoeB and ThiF proteins,[6] with one occurrence each in the N-terminal and C-terminal half of the UBA1 for Ub, or the separate subunits of the UBA1 for NEDD8 and SUMO.[7] The UBA1 for Ub consists of four building blocks: First, the adenylation domains composed of two MoeB/ThiF-homology motifs, the latter of which binds ATP and Ub;[8][9][10] second, the catalytic cysteine half-domains, which contain the E1 active site cysteine inserted into each of the adenylation domains;[11] third, a four-helix bundle that represents a second insertion in the inactive adenylation domain and immediately follows the first catalytic cysteine half-domain; and fourth, the C-terminal ubiquitin-fold domain, which recruits specific E2s.[9][12][13] # Function The protein encoded by this gene catalyzes the first step in ubiquitin conjugation, or ubiquitination, to mark cellular proteins for degradation. Specifically, UBA1 catalyzes the ATP-dependent adenylation of ubiquitin, thereby forming a thioester bond between the two. It also continues to participate in subsequent steps of ubiquination as a Ub carrier.[4][5][14] There are only two human ubiquitin-activating enzymes, UBA1 and UBA6, and thus UBA1 is largely responsible for protein ubiquitination in humans.[4][5][14] Through its central role in ubiquitination, UBA1 has been linked to cell cycle regulation, endocytosis, signal transduction, apoptosis, DNA damage repair, and transcriptional regulation.[4][5] Additionally, UBA1 helps regulate the NEDD8 pathway, thus implicating it in protein folding, as well as mitigating the depletion of ubiquitin levels during stress.[3] # Clinical significance Mutations in UBA1 are associated with X-linked spinal muscular atrophy type 2.[1] UBA1 has also been implicated in other neurodegenerative diseases, including spinal muscular atrophy,[15] as well as cancer and tumors. Since UBA1 is involved in multiple biological processes, there are concerns that inhibiting UBA1 would also damage normal cells. Nonetheless, preclinical testing of a UBA1 inhibitor in mice with leukemia revealed no additional toxic effects to normal cells, and the success of other drugs targeting pleiotropic targets likewise support the safety of using UBA1 inhibitor in cancer treatment[4][5] Moreover, the UBA1 inhibitors Largazole, as well as its ketone and ester derivatives, preferentially targets cancer over normal cells by specifically blocking the ligation of Ub and UBA1 during the adenylation step of the E1 pathway. MLN4924, a NEDD8-activating enzyme inhibitor functioning according to similar mechanisms, is currently undergoing phase I clinical trials.[5] # Interactions UBA1 has been shown to interact with: - UBC13[4] - PYR-41[16] - himeic acid A[17] - hyrtioreticulines A–E[18]

https://www.wikidoc.org/index.php/UBA1

44845759f880b22ec2926ec7b5e0379f2aa8f7ca

wikidoc

UBA2

UBA2 Ubiquitin-like 1-activating enzyme E1B (UBLE1B) also known as SUMO-activating enzyme subunit 2 (SAE2) is an enzyme that in humans is encoded by the UBA2 gene. Posttranslational modification of proteins by the addition of the small protein SUMO (see SUMO1), or sumoylation, regulates protein structure and intracellular localization. SAE1 and UBA2 form a heterodimer that functions as a SUMO-activating enzyme for the sumoylation of proteins. # Structure ## DNA The UBA2 cDNA fragment 2683 bp long and encodes a peptide of 640 amino acids. The predicted protein sequence is more analogous to yeast UBA2 (35% identity) than human UBA3 or E1 (in ubiquitin pathway). The UBA gene is located on chromosome 19. ## Protein Uba2 subunit is 640 aa residues long with a molecular weight of 72 kDa. It consists of three domains: an adenylation domain (containing adenylation active site), a catalytic Cys domain (containing the catalytic Cys173 residue participated in thioester bond formation), and a ubiquitin-like domain. SUMO-1 binds on Uba2 between the catalytic Cys domain and UbL domain. # Mechanism SUMO activating enzyme (E1, heterodimer of SAE1 and UBA2) catalyzes the reaction of activating SUMO-1 and transferring it to Ubc9 (the only known E2 for SUMOylation). The reaction happens in three steps: adenylation, thioester bond formation, and SUMO transfer to E2. First, the carboxyl group of SUMO C-terminal glycine residue attacks ATP, forming SUMO-AMP and pyrophosphate. Next, the thiol group of a catalytic cysteine in the UBA2 active site attacks SUMO-AMP, forming a high energy thioester bond between UBA2 and the C-terminal glycine of SUMO and releasing AMP. Finally, SUMO is transferred to an E2 cysteine, forming another thioester bond. # Function Ubiquitin tag has a well understood role of directing protein towards degradation by proteasome. The role SUMO molecules play are more complicated and much less well understood. SUMOylation consequences include altering substrate affinity for other proteins or with DNA, changing substrate localization, and blocking ubiquitin binding (which prevents substrate degradation). For some proteins, SUMOylation doesn’t seem to have a function. ## NF-kB Transcription factor NF-kB in unstimulated cells is inactivated by IkBa inhibitor protein binding. The activation of NF-kB is achieved by ubiquitination and subsequent degradation of IkBa. SUMOylation of IkBa has a strong inhibitory effect on NF-kB-dependent transcription. This may be a mechanism for cell to regulate the number of NF-kB available for transcriptional activation. ## p53 Transcription factor p53 is a tumor suppressor acting by activating genes involved in cell cycle regulation and apoptosis. Its level is regulated by mdm2-dependent ubiquitination. SUMOylation of p53 (at a distinct lysine residue from ubiquitin modification sites) prevents proteasome degradation and acts as an additional regulator to p53 response. # Expression and regulation Studies of yeast budding and fission have revealed that SUMOylation may be important in cell cycle regulation. During a cell cycle, the UBA2 concentration doesn't undergo substantial change while SAE1 level shows dramatic fluctuation, suggesting regulation of SAE1 expression rather than UBA2 might be a way for cell to regulate SUMOylation. However, at time points when SAE1 levels are low, little evidence of UBA2-containing protein complexes are found other than SAE1-UBA2 heterodimer. One possible explanation would be that these complexes exist only for a short period of time, thus not obvious in cell extracts. UBA2 expression is found in most organs including the brain, lung and heart, indicating probable existence of SUMOylation pathway in these organs. An elevated level of UBA2 (as well as all other enzyme components of the pathway) is found in testis, suggesting possible role for UBA2 in meiosis or spermatogenesis. Inside the nucleus, UBA2 is distributed throughout nuclei but not found in nucleoli, suggesting SUMOylation may occur primarily in nuclei. Cytoplasmic existence of SAE 1 and UBA2 is also possible and is responsible for conjugation of cytoplasmic substrates. # Model organisms ## Mouse Model organisms have been used in the study of UBA2 function. A conditional knockout mouse line, called Uba2tm1a(KOMP)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 five tests were carried out on mutant mice and four significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice. Females were found to have a decreased body length by DEXA, while animals of both sex had a decreased number of lumbar and sacral vertebrae in X-rays. ## Drosophila The coding region of drosophila UBA2 homologue dUBA2 gene is 2.3 kb long and contains 2 introns (53 and 52 bp). The predicted protein has 766 amino acid residues and weighs 84 kDa. The protein has an overall identity of 47% to hUBA2 and 31% to yeast UBA2. There are also several regions of complete identity between the three homologous proteins. The C-terminal region of the coding sequence also contains a putative nuclear localization sequence. # Interactions SAE2 has been shown to interact with - SAE1, - Small ubiquitin-related modifier 1, and - UBE2I.

UBA2 Ubiquitin-like 1-activating enzyme E1B (UBLE1B) also known as SUMO-activating enzyme subunit 2 (SAE2) is an enzyme that in humans is encoded by the UBA2 gene.[1] Posttranslational modification of proteins by the addition of the small protein SUMO (see SUMO1), or sumoylation, regulates protein structure and intracellular localization. SAE1 and UBA2 form a heterodimer that functions as a SUMO-activating enzyme for the sumoylation of proteins.[1][2] # Structure ## DNA The UBA2 cDNA fragment 2683 bp long and encodes a peptide of 640 amino acids.[2] The predicted protein sequence is more analogous to yeast UBA2 (35% identity) than human UBA3 or E1 (in ubiquitin pathway). The UBA gene is located on chromosome 19.[3] ## Protein Uba2 subunit is 640 aa residues long with a molecular weight of 72 kDa.[4] It consists of three domains: an adenylation domain (containing adenylation active site), a catalytic Cys domain (containing the catalytic Cys173 residue participated in thioester bond formation), and a ubiquitin-like domain. SUMO-1 binds on Uba2 between the catalytic Cys domain and UbL domain.[5] # Mechanism SUMO activating enzyme (E1, heterodimer of SAE1 and UBA2) catalyzes the reaction of activating SUMO-1 and transferring it to Ubc9 (the only known E2 for SUMOylation). The reaction happens in three steps: adenylation, thioester bond formation, and SUMO transfer to E2. First, the carboxyl group of SUMO C-terminal glycine residue attacks ATP, forming SUMO-AMP and pyrophosphate. Next, the thiol group of a catalytic cysteine in the UBA2 active site attacks SUMO-AMP, forming a high energy thioester bond between UBA2 and the C-terminal glycine of SUMO and releasing AMP. Finally, SUMO is transferred to an E2 cysteine, forming another thioester bond.[5][6][7] # Function Ubiquitin tag has a well understood role of directing protein towards degradation by proteasome.[8] The role SUMO molecules play are more complicated and much less well understood. SUMOylation consequences include altering substrate affinity for other proteins or with DNA, changing substrate localization, and blocking ubiquitin binding (which prevents substrate degradation). For some proteins, SUMOylation doesn’t seem to have a function.[6][9] ## NF-kB Transcription factor NF-kB in unstimulated cells is inactivated by IkBa inhibitor protein binding. The activation of NF-kB is achieved by ubiquitination and subsequent degradation of IkBa. SUMOylation of IkBa has a strong inhibitory effect on NF-kB-dependent transcription. This may be a mechanism for cell to regulate the number of NF-kB available for transcriptional activation.[10] ## p53 Transcription factor p53 is a tumor suppressor acting by activating genes involved in cell cycle regulation and apoptosis. Its level is regulated by mdm2-dependent ubiquitination. SUMOylation of p53 (at a distinct lysine residue from ubiquitin modification sites) prevents proteasome degradation and acts as an additional regulator to p53 response.[11] # Expression and regulation Studies of yeast budding and fission have revealed that SUMOylation may be important in cell cycle regulation.[12] During a cell cycle, the UBA2 concentration doesn't undergo substantial change while SAE1 level shows dramatic fluctuation, suggesting regulation of SAE1 expression rather than UBA2 might be a way for cell to regulate SUMOylation. However, at time points when SAE1 levels are low, little evidence of UBA2-containing protein complexes are found other than SAE1-UBA2 heterodimer. One possible explanation would be that these complexes exist only for a short period of time, thus not obvious in cell extracts. UBA2 expression is found in most organs including the brain, lung and heart, indicating probable existence of SUMOylation pathway in these organs. An elevated level of UBA2 (as well as all other enzyme components of the pathway) is found in testis, suggesting possible role for UBA2 in meiosis or spermatogenesis. Inside the nucleus, UBA2 is distributed throughout nuclei but not found in nucleoli, suggesting SUMOylation may occur primarily in nuclei. Cytoplasmic existence of SAE 1 and UBA2 is also possible and is responsible for conjugation of cytoplasmic substrates.[13] # Model organisms ## Mouse Model organisms have been used in the study of UBA2 function. A conditional knockout mouse line, called Uba2tm1a(KOMP)Wtsi[20][21] 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.[22][23][24] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[18][25] Twenty five tests were carried out on mutant mice and four significant abnormalities were observed.[18] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice. Females were found to have a decreased body length by DEXA, while animals of both sex had a decreased number of lumbar and sacral vertebrae in X-rays.[18] ## Drosophila The coding region of drosophila UBA2 homologue dUBA2 gene is 2.3 kb long and contains 2 introns (53 and 52 bp). The predicted protein has 766 amino acid residues and weighs 84 kDa. The protein has an overall identity of 47% to hUBA2 and 31% to yeast UBA2. There are also several regions of complete identity between the three homologous proteins. The C-terminal region of the coding sequence also contains a putative nuclear localization sequence.[26] # Interactions SAE2 has been shown to interact with - SAE1,[3][4][27][28] - Small ubiquitin-related modifier 1,[3][29] and - UBE2I.[28][30]

https://www.wikidoc.org/index.php/UBA2

c26a68ef0253c1bdc622c79c9f35b98e1ea8c82c

wikidoc

UBL5

UBL5 Ubiquitin-like protein 5 is a protein that in humans is encoded by the UBL5 gene. It has been shown that in C. elegans mitochondria treated to lower expression of certain electron transport chain proteins during the L3/L4 stage, its expression levels is higher leading to increased lifespans. Ubiquitin-like proteins (UBLs) are thought to be reversible modulators of protein function rather than protein degraders like ubiquitin (MIM 191339).

UBL5 Ubiquitin-like protein 5 is a protein that in humans is encoded by the UBL5 gene.[1] It has been shown that in C. elegans mitochondria treated to lower expression of certain electron transport chain proteins during the L3/L4 stage, its expression levels is higher leading to increased lifespans.[2] Ubiquitin-like proteins (UBLs) are thought to be reversible modulators of protein function rather than protein degraders like ubiquitin (MIM 191339).[supplied by OMIM][1]

https://www.wikidoc.org/index.php/UBL5

99840acf3020c480641a9703f0acf33c358287bf

wikidoc

UCK2

UCK2 Uridine-cytidine kinase 2 (UCK2) is an enzyme that in humans is encoded by the UCK2 gene. The protein encoded by this gene catalyzes the phosphorylation of uridine and cytidine to uridine monophosphate (UMP) and cytidine monophosphate (CMP), respectively. This is the first step in the production of the pyrimidine nucleoside triphosphates required for RNA and DNA synthesis. In addition, an allele of this gene may play a role in mediating nonhumoral immunity to Hemophilus influenzae type B. # Structure and mechanism Uridine-cytidine kinase 2 is a tetramer with molecular mass of about 112 kDa. In the UCK2 monomer, the active site is composed of a five-stranded β-sheet, surrounded by five α-helices and a β-hairpin loop. The β-hairpin loop in particular forms a significant portion of a deep binding pocket for the uridine/cytidine substrate to moderate binding and release of substrate and products. Binding specificity for nucleosides is determined by the His-117 and Tyr-112 residues, which hydrogen bond with the 4-amino group or the 6-oxo group of cytidine and uridine, respectively. A magnesium ion is coordinated in the active site by Glu-135, Ser-34, and Asp-62. The Asp-62 residue is responsible for the catalytic activity in the enzyme active site; the acidic side chain of the Asp-62 residue deprotonates the 5’-hydroxyl group on the substrate and activates it to attack the γ-phosphorus of ATP. Structural analyses have shown that the side chain of the catalytic Asp-62 changes conformation before and after the reaction. It has been suggested that this conformational change occurs following phosphorylation, with the negatively charged Asp-62 moving away from the newly attached 5’-phosphate of the UMP/CMP product. # Substrate specificity Though uridine and cytidine are the physiologically preferred substrates for the enzyme, UCK2 has been shown to phosphorylate other nucleoside analogues. Examples of successfully phosphorylated substrates include 6-azauridine, 5-azacytidine, 4-thiouridine, 5-fluorocytidine, and 5-hydroxyuridine. Alternatively to ATP, GTP has been shown to act comparably as a phosphate donor. This promiscuity enables the important role for UCK2 as an in vivo activator of clinically active nucleoside prodrugs, such as cylcopentenylcytidine. Despite flexibility for different nucleoside analogs, UCK is unique among other nucleic acid kinsases in its specificity for ribose analogs over 2’-deoxyribose forms; whereas other proteins in the NMP kinase family will indiscriminately phosphorylate both deoxyribonucleosides and ribonucleosides, UCK2 only accepts ribonucleosides. This unique selectivity can be induced fit mechanisms and structural features that are unique to UCK2 among the NMP kinase family. Studies have shown that the binding of the cytidine/uridine sugar moiety results in the conformational change to reduce the distance between the His-117 and Arg-176 residues. Without the 2’-hydroxyl group on the sugar moiety, hydrogen bonding with Asp-84 and Arg-166 will be greatly reduced, resulting in diminished conformational change and weakened substrate binding. # Physiological role UCK2 is one of two human uridine-cytidine kinases. The other UCK protein is uridine-cytidine kinase 1, which shares about 70% sequence identity with UCK2. While UCK1 is expressed ubiquitously in a variety of healthy tissues including the liver, skeletal muscle, and heart, UCK2 has only been detected in placental tissue. UCK2, however, is of particular scientific interest due to its overexpression in tumor cell lines, which makes it a target in anti-cancer treatments. Studies determining the Michaelis-Menten kinetic parameters for these enzymes revealed that UCK2 had a four to sixfold higher binding affinity, faster maximal rates, and greater efficiencies for uridine and cytidine substrates than did UCK1. Both uridine-cytidine kinases, however, plays a crucial role in the biosynthesis of the pyrimidine nucleotides that compose RNA and DNA. Pyrimidine biosynthesis can occur through two pathways: de novo synthesis, which relies on L-glutamine as the pathway precursor, and salvage, which recycles cellular uridine and cytidine. UCK2 catalyzes the first step of pyrimidine salvage, and is the rate limiting enzyme in the pathway. # Disease relevance UCK1 is expressed ubiquitously in healthy tissue, but found in low levels in tumor tissues. Conversely, UCK2 has been detected mostly in cancerous cells and healthy placental tissue.The selective expression in target tissues has resulted in the identification of UCK2 as a target in anti-cancer therapies. One strategy for anti-cancer and anti-viral therapies involves using UCK2 to activate anti-tumor prodrugs through phosphorylation. As an example, 1-(3-C-ethynyl-β-D-ribopentofuranosyl)cytosine (ECyd) and 1-(3-C-ethynyl-β-D-ribopentofuranosyl)uridine (EUrd) are RNA polymerase inhibitors that are under investigation for use as anticancer drugs. The nucleoside, however, only gains its clinical activity after three phosphorylations; therefore, UCK2 plays a key role in initiating the activation of the drug. An alternate strategy involves inhibition of UCK2 to block pyrimidine salvage in cancerous cells. In certain cancer cell lines, pyrimidine biosynthesis primarily occurs through the salvage pathway. Blocking pyrimidine salvage can prevent DNA and RNA biosynthesis, resulting in reduced cell proliferation. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..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}

UCK2 Uridine-cytidine kinase 2 (UCK2) is an enzyme that in humans is encoded by the UCK2 gene.[1] The protein encoded by this gene catalyzes the phosphorylation of uridine and cytidine to uridine monophosphate (UMP) and cytidine monophosphate (CMP), respectively. This is the first step in the production of the pyrimidine nucleoside triphosphates required for RNA and DNA synthesis. In addition, an allele of this gene may play a role in mediating nonhumoral immunity to Hemophilus influenzae type B.[1] # Structure and mechanism Uridine-cytidine kinase 2 is a tetramer with molecular mass of about 112 kDa.[2] In the UCK2 monomer, the active site is composed of a five-stranded β-sheet, surrounded by five α-helices and a β-hairpin loop.[3] The β-hairpin loop in particular forms a significant portion of a deep binding pocket for the uridine/cytidine substrate to moderate binding and release of substrate and products. Binding specificity for nucleosides is determined by the His-117 and Tyr-112 residues, which hydrogen bond with the 4-amino group or the 6-oxo group of cytidine and uridine, respectively.[3] A magnesium ion is coordinated in the active site by Glu-135, Ser-34, and Asp-62. The Asp-62 residue is responsible for the catalytic activity in the enzyme active site;[4] the acidic side chain of the Asp-62 residue deprotonates the 5’-hydroxyl group on the substrate and activates it to attack the γ-phosphorus of ATP.[5] Structural analyses have shown that the side chain of the catalytic Asp-62 changes conformation before and after the reaction. It has been suggested that this conformational change occurs following phosphorylation, with the negatively charged Asp-62 moving away from the newly attached 5’-phosphate of the UMP/CMP product.[3] # Substrate specificity Though uridine and cytidine are the physiologically preferred substrates for the enzyme, UCK2 has been shown to phosphorylate other nucleoside analogues. Examples of successfully phosphorylated substrates include 6-azauridine, 5-azacytidine, 4-thiouridine, 5-fluorocytidine, and 5-hydroxyuridine.[6] Alternatively to ATP, GTP has been shown to act comparably as a phosphate donor.[7] This promiscuity enables the important role for UCK2 as an in vivo activator of clinically active nucleoside prodrugs, such as cylcopentenylcytidine.[8] Despite flexibility for different nucleoside analogs, UCK is unique among other nucleic acid kinsases in its specificity for ribose analogs over 2’-deoxyribose forms; whereas other proteins in the NMP kinase family will indiscriminately phosphorylate both deoxyribonucleosides and ribonucleosides, UCK2 only accepts ribonucleosides.[2] This unique selectivity can be induced fit mechanisms and structural features that are unique to UCK2 among the NMP kinase family. Studies have shown that the binding of the cytidine/uridine sugar moiety results in the conformational change to reduce the distance between the His-117 and Arg-176 residues. Without the 2’-hydroxyl group on the sugar moiety, hydrogen bonding with Asp-84 and Arg-166 will be greatly reduced, resulting in diminished conformational change and weakened substrate binding.[2] # Physiological role UCK2 is one of two human uridine-cytidine kinases. The other UCK protein is uridine-cytidine kinase 1, which shares about 70% sequence identity with UCK2.[3] While UCK1 is expressed ubiquitously in a variety of healthy tissues including the liver, skeletal muscle, and heart, UCK2 has only been detected in placental tissue.[6] UCK2, however, is of particular scientific interest due to its overexpression in tumor cell lines,[9] which makes it a target in anti-cancer treatments. Studies determining the Michaelis-Menten kinetic parameters for these enzymes revealed that UCK2 had a four to sixfold higher binding affinity, faster maximal rates, and greater efficiencies for uridine and cytidine substrates than did UCK1.[6] Both uridine-cytidine kinases, however, plays a crucial role in the biosynthesis of the pyrimidine nucleotides that compose RNA and DNA. Pyrimidine biosynthesis can occur through two pathways: de novo synthesis, which relies on L-glutamine as the pathway precursor, and salvage, which recycles cellular uridine and cytidine.[10] UCK2 catalyzes the first step of pyrimidine salvage, and is the rate limiting enzyme in the pathway.[11] # Disease relevance UCK1 is expressed ubiquitously in healthy tissue, but found in low levels in tumor tissues. Conversely, UCK2 has been detected mostly in cancerous cells and healthy placental tissue.The selective expression in target tissues has resulted in the identification of UCK2 as a target in anti-cancer therapies.[12] One strategy for anti-cancer and anti-viral therapies involves using UCK2 to activate anti-tumor prodrugs through phosphorylation.[13] As an example, 1-(3-C-ethynyl-β-D-ribopentofuranosyl)cytosine (ECyd) and 1-(3-C-ethynyl-β-D-ribopentofuranosyl)uridine (EUrd) are RNA polymerase inhibitors that are under investigation for use as anticancer drugs.[14] The nucleoside, however, only gains its clinical activity after three phosphorylations; therefore, UCK2 plays a key role in initiating the activation of the drug. An alternate strategy involves inhibition of UCK2 to block pyrimidine salvage in cancerous cells.[15] In certain cancer cell lines, pyrimidine biosynthesis primarily occurs through the salvage pathway.[16] Blocking pyrimidine salvage can prevent DNA and RNA biosynthesis, resulting in reduced cell proliferation. # 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: "FluoropyrimidineActivity_WP1601"..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/UCK2

c6faed9a1fd76598f698a8141db8b7551931eb25

wikidoc

UCP3

UCP3 Mitochondrial uncoupling protein 3 is a protein that in humans is encoded by the UCP3 gene. UCP3 is a mitochondrial uncoupling protein 3, which is encoded by UCP3. The gene is located in chromosome (11q13.4) with an exon count of 7 (HGNC et al., 2016). Uncoupling protein being a supreme family of mitochondrial anion carrier. Its functions is to separate the oxidative phosphorylation from synthesis of ATP as energy which is anticipated as heat. The uncoupling proteins involves in the transferring of anions from inner mitochondrial membrane to outer mitochondrial membrane, its protein is programmed in a way to protect mitochondria from induced oxidative stress. # Function Mitochondrial uncoupling proteins (UCP) are members of the larger family of mitochondrial anion carrier proteins (MACP).UCPs separate oxidative phosphorylation from ATP synthesis with energy dissipated as heat, also referred to as the mitochondrial proton leak. UCPs facilitate the transfer of anions from the inner to the outer mitochondrial membrane and there turn transfer of protons from the outer to the inner mitochondrial membrane. They also reduce the mitochondrial membrane potential in mammalian cells. Tissue specificity occurs for the different UCPs and the exact method so far how UCPs transfer H+/OH− are not known. # Protein expression Uncoupling proteins are transporters in mitochondrial membrane which deplete the proton gradient.UCP1 asseverate in brown adipocytes, But UCP2 is widely expressed. Molecular cloning of UCP3 (uncoupling protein homologue). At amino acid level the hUCP3 is 71% equivalent to hUCP2.Uncoupling protein3 is acclaimed from UCP1 and UCP2 because of its ample and preferred expression in skeletal muscle in humans and brown adipose tissue and skeletal muscle in rodents (Antonio et al., 1997). UCP3 is an important mediator of thermogenesis. # Associated SNPs UCP3 were confirmed containing four single nucleotide polymorphism rs1800849, rs11235972, rs1726745 and rs3781907. There was high impact score of rs11235972 GG genotype thus showing association of UCP3 gene polymorphism and nonalcoholic fatty liver disease in Chinese children (Xu YP et al., 2013) The research of counterfeits in two independent population there was a similarity between the -55CT mutation of UCP3 and lower BMI. This affiliation was being modulated by the energy intake, hence deriving the undefined effect of diet and partly association of inconsistencies of prior related studies. # Structure UCPs contain the three homologous protein domains of MACPs. # Gene regulation This gene has tissue-specific transcription initiation with other transcription initiation sites upstream of SM-1 (major skeletal muscle site). Chromosomal order is 5'-UCP3-UCP2-3'. Two splice variants have been found for this gene. # Disease association Mutations in the UCP3 gene are associated with obesity. UCP3 plays an essential role in obesity. A mutation in exon 3 (V102I) was diagnosed in an obese and diabetic. A mutation initializing a stop codon at exon 4 (R143X) and a mutation in the splice donor junction of exon 6 was analyzed in a compound heterozygote which was unnaturally obese and diabetic. Allele frequency of exon 3 and exon 6 splice at an alliance mutation were analyzed to be similar in African American and mende tribe and was absent in Caucasians. Exon 6–splice donor being heterozygotes, fat oxidation rates was reduced by 50%, initiating a role for UCP3 in metabolic fuel partitioning. UCP3 (uncoupling protein) deliberates the hypoxia resistance to the renal epithelial cells and its upregulation in renal cell carcinoma. The energy consumption of modulated and the association of -55CT polymorphism of UCP3 with the body weight and in type 2 diabetic patients. # Inhibitors Since protein UCP3 is affecting the long chain fatty acid metabolism and preventing cytosolic triglyceride storage. Telmisartan being an inhibitor by proven studies on rat skeletal muscle and improving the mutant protein activity and also its involvement in the dominant negative UCP3 mutants(C V Musa et al., 2012). Hence, novel UCP3 gene variants which associated to childhood obesity and even the effect of fatty acid oxidation prevention in triglyceride storage(C V Musa et al., 2012). # Interactions UCP3 has been shown to interact with YWHAQ. Uncoupling protein UPC2 and uncoupling protein UPC3 interaction with members of the 14.3.3 family (Benoit pierrat et al., 2000). Uncoupling protein (UCP3) modulating the process of Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) by declining the mitochondrial ATP fabrication (De Marchi U et al., 2011).

UCP3 Mitochondrial uncoupling protein 3 is a protein that in humans is encoded by the UCP3 gene.[1][2] UCP3 is a mitochondrial uncoupling protein 3, which is encoded by UCP3. The gene is located in chromosome (11q13.4) with an exon count of 7 (HGNC et al., 2016). Uncoupling protein being a supreme family of mitochondrial anion carrier. Its functions is to separate the oxidative phosphorylation from synthesis of ATP as energy which is anticipated as heat. The uncoupling proteins involves in the transferring of anions from inner mitochondrial membrane to outer mitochondrial membrane, its protein is programmed in a way to protect mitochondria from induced oxidative stress. # Function Mitochondrial uncoupling proteins (UCP) are members of the larger family of mitochondrial anion carrier proteins (MACP).UCPs separate oxidative phosphorylation from ATP synthesis with energy dissipated as heat, also referred to as the mitochondrial proton leak. UCPs facilitate the transfer of anions from the inner to the outer mitochondrial membrane and there turn transfer of protons from the outer to the inner mitochondrial membrane. They also reduce the mitochondrial membrane potential in mammalian cells. Tissue specificity occurs for the different UCPs and the exact method so far how UCPs transfer H+/OH− are not known.[3] # Protein expression Uncoupling proteins are transporters in mitochondrial membrane which deplete the proton gradient.UCP1 asseverate in brown adipocytes, But UCP2 is widely expressed. Molecular cloning of UCP3 (uncoupling protein homologue). At amino acid level the hUCP3 is 71% equivalent to hUCP2.Uncoupling protein3 is acclaimed from UCP1 and UCP2 because of its ample and preferred expression in skeletal muscle in humans and brown adipose tissue and skeletal muscle in rodents (Antonio et al., 1997). UCP3 is an important mediator of thermogenesis. # Associated SNPs UCP3 were confirmed containing four single nucleotide polymorphism rs1800849, rs11235972, rs1726745 and rs3781907. There was high impact score of rs11235972 GG genotype thus showing association of UCP3 gene polymorphism and nonalcoholic fatty liver disease in Chinese children (Xu YP et al., 2013) The research of counterfeits in two independent population there was a similarity between the -55CT mutation of UCP3 and lower BMI. This affiliation was being modulated by the energy intake, hence deriving the undefined effect of diet and partly association of inconsistencies of prior related studies. # Structure UCPs contain the three homologous protein domains of MACPs.[3] # Gene regulation This gene has tissue-specific transcription initiation with other transcription initiation sites upstream of SM-1 (major skeletal muscle site). Chromosomal order is 5'-UCP3-UCP2-3'. Two splice variants have been found for this gene.[3] # Disease association Mutations in the UCP3 gene are associated with obesity.[4][5] UCP3 plays an essential role in obesity. A mutation in exon 3 (V102I) was diagnosed in an obese and diabetic. A mutation initializing a stop codon at exon 4 (R143X) and a mutation in the splice donor junction of exon 6 was analyzed in a compound heterozygote which was unnaturally obese and diabetic.[4] Allele frequency of exon 3 and exon 6 splice at an alliance mutation were analyzed to be similar in African American and mende tribe and was absent in Caucasians.[4] Exon 6–splice donor being heterozygotes, fat oxidation rates was reduced by 50%, initiating a role for UCP3 in metabolic fuel partitioning.[4] UCP3 (uncoupling protein) deliberates the hypoxia resistance to the renal epithelial cells and its upregulation in renal cell carcinoma.[6] The energy consumption of modulated and the association of -55CT polymorphism of UCP3 with the body weight and in type 2 diabetic patients.[7] # Inhibitors Since protein UCP3 is affecting the long chain fatty acid metabolism and preventing cytosolic triglyceride storage. Telmisartan being an inhibitor by proven studies on rat skeletal muscle and improving the mutant protein activity and also its involvement in the dominant negative UCP3 mutants(C V Musa et al., 2012). Hence, novel UCP3 gene variants which associated to childhood obesity and even the effect of fatty acid oxidation prevention in triglyceride storage(C V Musa et al., 2012). # Interactions UCP3 has been shown to interact with YWHAQ.[8] Uncoupling protein UPC2 and uncoupling protein UPC3 interaction with members of the 14.3.3 family (Benoit pierrat et al., 2000). Uncoupling protein (UCP3) modulating the process of Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) by declining the mitochondrial ATP fabrication (De Marchi U et al., 2011).

https://www.wikidoc.org/index.php/UCP3

48157812d054a1c693a8892928685fc46b94f96e

wikidoc

UFM1

UFM1 Ubiquitin-fold modifier 1, also known as UFM1, is a protein which in humans is encoded by the UFM1 gene. UFM1 is a ubiquitin-like protein that is conjugated to target proteins by E1-like activating enzyme UBA5 (UBE1DC1) and E2-like conjugating enzyme UFC1 (see UBE2M). # Function UFM1 shares several common properties with ubiquitin (Ub) and the other ubiquitin-like proteins (UBLs). Ufm1 has similar tertiary structure to Ub but lacks any obvious sequence similarity. It is synthesized as an inactive precursor form (pro-Ufm1) which has 2 additional amino acids beyond the conserved glycine. The mechanism of Ufm1 conjugation is similar to that of ubiquitin. Mature Ufm1 has an exposed C-terminal glycine which is essential for subsequent activation by its cognate E1 protein (Uba5). This activation step results in the formation of a high-energy thiolester bond in the presence of ATP. The Ufm1 is subsequently transferred to its cognate E2-like enzyme (Ufc1) via a similar thioester linkage with a cysteine at the E2 active site. Ufm1 is conjugated to a variety of target proteins and forms complexes with as yet unidentified proteins. Thus, presumably there exist E3 ligases (none have been identified to date) to perform the final step in Ufm1 conjugation to relevant targets. The modification of proteins with Ufm1 is also reversible. Two novel cysteine proteases have been identified to date (UFSP1 and UFSP2) which cleave Ufm1-peptide C-terminal fusions and also removes Ufm1 from native intracellular conjugates. These proteases have no obvious homology to ubiquitin deconjugating enzymes. The proteins for Ufm1 conjugation (Uba5, Ufc1 and Ufm1) are all conserved in animals and plants (but not yeast) suggesting important roles in multicellular organisms. The exact role of Ufm1 modification in vivo is not yet known.

UFM1 Ubiquitin-fold modifier 1, also known as UFM1, is a protein which in humans is encoded by the UFM1 gene.[1][2] UFM1 is a ubiquitin-like protein that is conjugated to target proteins by E1-like activating enzyme UBA5 (UBE1DC1) and E2-like conjugating enzyme UFC1 (see UBE2M).[2] # Function UFM1 shares several common properties with ubiquitin (Ub) and the other ubiquitin-like proteins (UBLs). Ufm1 has similar tertiary structure to Ub but lacks any obvious sequence similarity. It is synthesized as an inactive precursor form (pro-Ufm1) which has 2 additional amino acids beyond the conserved glycine. The mechanism of Ufm1 conjugation is similar to that of ubiquitin. Mature Ufm1 has an exposed C-terminal glycine which is essential for subsequent activation by its cognate E1 protein (Uba5). This activation step results in the formation of a high-energy thiolester bond in the presence of ATP. The Ufm1 is subsequently transferred to its cognate E2-like enzyme (Ufc1) via a similar thioester linkage with a cysteine at the E2 active site. Ufm1 is conjugated to a variety of target proteins and forms complexes with as yet unidentified proteins. Thus, presumably there exist E3 ligases (none have been identified to date) to perform the final step in Ufm1 conjugation to relevant targets. The modification of proteins with Ufm1 is also reversible. Two novel cysteine proteases have been identified to date (UFSP1 and UFSP2) which cleave Ufm1-peptide C-terminal fusions and also removes Ufm1 from native intracellular conjugates. These proteases have no obvious homology to ubiquitin deconjugating enzymes. The proteins for Ufm1 conjugation (Uba5, Ufc1 and Ufm1) are all conserved in animals and plants (but not yeast) suggesting important roles in multicellular organisms. The exact role of Ufm1 modification in vivo is not yet known.[3]

https://www.wikidoc.org/index.php/UFM1

793fc195818759b7ce93a7eca59c2f0b1d988531

wikidoc

UGCG

UGCG Ceramide glucosyltransferase is an enzyme that in humans is encoded by the UGCG gene. Glycosphingolipids (GSLs) are a group of membrane components that contain lipid and sugar moieties. They are present in essentially all animal cells and are believed to have important roles in various cellular processes. UDP-glucose ceramide glucosyltransferase catalyzes the first glycosylation step in glycosphingolipid biosynthesis. The product, glucosylceramide, is the core structure of more than 300 GSLs. UGCG is widely expressed and transcription is upregulated during keratinocyte differentiation. # Interactions UGCG has been shown to interact with RTN1 .

UGCG Ceramide glucosyltransferase is an enzyme that in humans is encoded by the UGCG gene.[1][2][3] Glycosphingolipids (GSLs) are a group of membrane components that contain lipid and sugar moieties. They are present in essentially all animal cells and are believed to have important roles in various cellular processes. UDP-glucose ceramide glucosyltransferase catalyzes the first glycosylation step in glycosphingolipid biosynthesis. The product, glucosylceramide, is the core structure of more than 300 GSLs. UGCG is widely expressed and transcription is upregulated during keratinocyte differentiation.[3] # Interactions UGCG has been shown to interact with RTN1 .[4]

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

6bbfedca3c933d1b7fc03118b9780643ae63c660

wikidoc

UGGT

UGGT UGGT, or UDP-glucose:glycoprotein glucosyltransferase, is a soluble enzyme resident in the lumen of the endoplasmic reticulum (ER). The main function of UGGT is to recognize misfolded glycoproteins and transfer a glucose (Glc) monomer (monoglucosylate) to the terminal mannose of the A-branch of the glycan on the glycoprotein. It uses UDP-glucose (UDP-Glc) as the glucosyl donor and requires calcium ions for its activity: misfolded-glycoprotein-Asn-GlcNAc2Man9 + UDP-Glc => misfolded-glycoprotein-Asn-GlcNAc2Man9Glc1 + UDP UGGT is about 170 kDa and it consists of two structurally independent portions: a variable N-terminal portion of ~1200 amino acids, which in turn comprises 4 thioredoxin-like domains and two beta-sandwich domains, and senses glycoprotein misfolding; and a highly conserved C-terminal catalytic portion of ~300 amino acids, folding as a glucosyltransferase domain belonging to fold family GT24. Higher eukaryotes possess two isoforms, UGGT1 and UGGT2, but only the former has been conclusively shown to be active in misfolded glycoprotein recognition. UGGT is part of the ER quality control system of glycoprotein folding and its activity increases the potential for correctly folded glycoproteins. The main proteins involved in the ER quality control system are UGGT, the ER lectin chaperones (calnexin and calreticulin), and glucosidase II. UGGT first recognizes the incompletely folded glycoprotein and monoglucosylates it. The lectins, calnexin and calreticulin, have high affinities for monoglucosylated proteins and the ER chaperones that associate with these lectins assist the folding of the misfolded glycoprotein. Subsequently, glucosidase II will deglucosylate the glycoprotein. If the glycoprotein is still misfolded, UGGT will re-glucosylate it and allow it to go through the cycle again. Currently, it is unclear how UGGT recognizes misfolded glycoprotein. It has been proposed that UGGT may bind to exposed hydrophobic stretches, a characteristic feature of misfolded proteins. UGGT crystal structures suggest marked conformational mobility, which could explain the ability of the protein to recognise a wide variety of client glycoproteins of different shapes and forms. The same conformational mobility could account for the ability of the protein to re-glucosylate N-linked glycans at different distances from the misfold site. See for example the picture in which glycoproteins are symbolized by nuts and UGGT by an adjustable wrench.

UGGT UGGT, or UDP-glucose:glycoprotein glucosyltransferase, is a soluble enzyme resident in the lumen of the endoplasmic reticulum (ER).[1] The main function of UGGT is to recognize misfolded glycoproteins and transfer a glucose (Glc) monomer (monoglucosylate) to the terminal mannose of the A-branch of the glycan on the glycoprotein. It uses UDP-glucose (UDP-Glc) as the glucosyl donor and requires calcium ions for its activity: misfolded-glycoprotein-Asn-GlcNAc2Man9 + UDP-Glc => misfolded-glycoprotein-Asn-GlcNAc2Man9Glc1 + UDP UGGT is about 170 kDa and it consists of two structurally independent portions: a variable N-terminal portion of ~1200 amino acids, which in turn comprises 4 thioredoxin-like domains and two beta-sandwich domains, and senses glycoprotein misfolding; and a highly conserved C-terminal catalytic portion of ~300 amino acids, folding as a glucosyltransferase domain belonging to fold family GT24. Higher eukaryotes possess two isoforms, UGGT1 and UGGT2, but only the former has been conclusively shown to be active in misfolded glycoprotein recognition. UGGT is part of the ER quality control system of glycoprotein folding and its activity increases the potential for correctly folded glycoproteins.[2] The main proteins involved in the ER quality control system are UGGT, the ER lectin chaperones (calnexin and calreticulin), and glucosidase II. UGGT first recognizes the incompletely folded glycoprotein and monoglucosylates it. The lectins, calnexin and calreticulin, have high affinities for monoglucosylated proteins and the ER chaperones that associate with these lectins assist the folding of the misfolded glycoprotein. Subsequently, glucosidase II will deglucosylate the glycoprotein. If the glycoprotein is still misfolded, UGGT will re-glucosylate it and allow it to go through the cycle again. Currently, it is unclear how UGGT recognizes misfolded glycoprotein. It has been proposed that UGGT may bind to exposed hydrophobic stretches, a characteristic feature of misfolded proteins. UGGT crystal structures[3] suggest marked conformational mobility, which could explain the ability of the protein to recognise a wide variety of client glycoproteins of different shapes and forms. The same conformational mobility could account for the ability of the protein to re-glucosylate N-linked glycans at different distances from the misfold site. See for example the picture in which glycoproteins are symbolized by nuts and UGGT by an adjustable wrench.

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

0067f6373f58d1813d2c3aef349b9e13a0b941f6

wikidoc

ULK1

ULK1 ULK1 is an enzyme that in humans is encoded by the ULK1 gene. Unc-51 like autophagy activating kinase (ULK1/2) are two similar isoforms of an enzyme that in humans are encoded by the ULK1/2 genes. It is specifically a kinase that is involved with autophagy, particularly in response to amino acid withdrawal. Not many studies have been done comparing the two isoforms, but some differences have been recorded. # Function Ulk1/2 is an important protein in autophagy for mammalian cells, and is homologous to ATG1 in yeast. It is part of the ULK1-complex, which is needed in early steps of autophagosome biogenesis. The ULK1 complex also consists of the FAK family kinase interacting protein of 200 kDa (FIP200 or RB1CC1) and the HORMA (Hop/Rev7/Mad2) domain-containing proteins ATG13 and ATG101. ULK1, specifically, appears to be the most essential for autophagy and is activated under conditions of nutrient deprivation by several upstream signals which is followed by the initiation of autophagy. However, ULK1 and ULK2 show high functional redundancy; studies have shown that ULK2 can compensate for the loss of ULK1. Nutrient dependent autophagy is only fully inhibited if both ULK1 and ULK2 are knocked out. ULK1 has many downstream phosphorylation targets to aid in this induction of the isolation membrane/ autophagosome. Recently, a mechanism for autophagy has been elucidated. Models have proposed that the active ULK1 directly phosphorylates Beclin-1 at Ser 14 and activates the pro-autophagy class III phosphoinositide 3-kinase (PI(3)K), VPS34 complex, to promote autophagy induction and maturation. Ulk1/2 is negatively regulated by mTORC1 activity, which is active during anabolic-type environmental cues. In contrast, Ulk1/2 is activated by AMPK activity from starvation signals. Ulk1/2 may have critical roles beyond what ATG1 performs in yeast, including neural growth and development. # Interactions When active, mTORC1 inhibits autophagy by phosphorylating both ULK1 and ATG13, which reduces the kinase activity of ULK1. Under starvation conditions, mTORC1 is inhibited and dissociates from ULK1 allowing it to become active. AMPK is activated when intracellular AMP increases which occurs under starvation conditions, which inactivates mTORC1, and thus directly activates ULK1. AMPK also directly phosphorylates ULK1 at multiple sites in the linker region between the kinase and C-terminal domains. ULK1 can phosphorylate itself as well as ATG13 and RB1CC1, which are regulatory proteins; however, the direct substrate of ULK1 has not been identified although recent studies suggest it phosphorylates Beclin-1. Upon proteotoxic stresses, ULK1 has been found to phosphorylate the adaptor protein p62, which increases the binding affinity of p62 for ubiquitin. ULK1 has been shown interact with Raptor, Beclin1, Class-III-PI3K, GABARAPL2, GABARAP, SYNGAP1 and SDCBP. # Structure ULK1 is a 112-kDa protein. It contains a N-terminal kinase domain, a serine-proline rich region, and a C-terminal interacting domain. The serine-proline rich region has been shown experimentally to be the site of phosphorylation by mTORC1 and AMPK—a negative and positive regulator of ULK1 activity, respectively. The C-terminal domain contains two microtubule-interacting and transport (MIT) domains and acts as a scaffold which links ULK1, ATG13, and FIFP200 together to form a complex that is essential to initiate autophagy. Early autophagy targeting/tethering (EAT) domains in the C-terminus are arranged as MIT domains consisting of two three-helix bundles. MIT domains also mediate interactions with membranes. The N-terminus contains a serine-threonine kinase domain. ULK1 also contains a large activation loop between the N and C terminus that is positively charged. This region may regulate kinase activity and play a role in recognizing different substrates. ULK1 and ULK2 share significant homology in both the C-terminal and N-terminal domains. # Related Diseases Given ULK1’s role in autophagy, many diseases such as cancer, neurodegenerative disorders, neurodevelopment disorders, and Crohn’s disease could be attributed to any impairments in autophagy regulation. In cancer specifically, ULK1 has become an attractive therapeutic target. Since autophagy acts as a cell survival trait for cells, it enables tumors (once they are already formed) to survive energy deprivation and other stresses such as chemotherapeutics. For that reason, inhibiting autophagy may prove to be beneficial. Thus, inhibitors have been targeted towards ULK1.

ULK1 ULK1 is an enzyme that in humans is encoded by the ULK1 gene.[1][2] Unc-51 like autophagy activating kinase (ULK1/2) are two similar isoforms of an enzyme that in humans are encoded by the ULK1/2 genes.[5][6] It is specifically a kinase that is involved with autophagy, particularly in response to amino acid withdrawal. Not many studies have been done comparing the two isoforms, but some differences have been recorded.[3] # Function Ulk1/2 is an important protein in autophagy for mammalian cells, and is homologous to ATG1[4] in yeast. It is part of the ULK1-complex, which is needed in early steps of autophagosome biogenesis. The ULK1 complex also consists of the FAK family kinase interacting protein of 200 kDa (FIP200 or RB1CC1) and the HORMA (Hop/Rev7/Mad2) domain-containing proteins ATG13 and ATG101.[5] ULK1, specifically, appears to be the most essential for autophagy and is activated under conditions of nutrient deprivation by several upstream signals which is followed by the initiation of autophagy.[6] However, ULK1 and ULK2 show high functional redundancy; studies have shown that ULK2 can compensate for the loss of ULK1. Nutrient dependent autophagy is only fully inhibited if both ULK1 and ULK2 are knocked out. ULK1 has many downstream phosphorylation targets to aid in this induction of the isolation membrane/ autophagosome. Recently, a mechanism for autophagy has been elucidated. Models have proposed that the active ULK1 directly phosphorylates Beclin-1 at Ser 14 and activates the pro-autophagy class III phosphoinositide 3-kinase (PI(3)K), VPS34 complex, to promote autophagy induction and maturation.[7] Ulk1/2 is negatively regulated by mTORC1 activity, which is active during anabolic-type environmental cues. In contrast, Ulk1/2 is activated by AMPK activity from starvation signals.[8] Ulk1/2 may have critical roles beyond what ATG1 performs in yeast, including neural growth and development. # Interactions When active, mTORC1 inhibits autophagy by phosphorylating both ULK1 and ATG13, which reduces the kinase activity of ULK1. Under starvation conditions, mTORC1 is inhibited and dissociates from ULK1 allowing it to become active. AMPK is activated when intracellular AMP increases which occurs under starvation conditions, which inactivates mTORC1, and thus directly activates ULK1. AMPK also directly phosphorylates ULK1 at multiple sites in the linker region between the kinase and C-terminal domains.[5] ULK1 can phosphorylate itself as well as ATG13 and RB1CC1, which are regulatory proteins; however, the direct substrate of ULK1 has not been identified although recent studies suggest it phosphorylates Beclin-1. Upon proteotoxic stresses, ULK1 has been found to phosphorylate the adaptor protein p62, which increases the binding affinity of p62 for ubiquitin.[5][9] ULK1 has been shown interact with Raptor, Beclin1, Class-III-PI3K, GABARAPL2,[7] GABARAP,[7][8] SYNGAP1[9] and SDCBP.[9] # Structure ULK1 is a 112-kDa protein. It contains a N-terminal kinase domain, a serine-proline rich region, and a C-terminal interacting domain. The serine-proline rich region has been shown experimentally to be the site of phosphorylation by mTORC1 and AMPK—a negative and positive regulator of ULK1 activity, respectively. The C-terminal domain contains two microtubule-interacting and transport (MIT) domains and acts as a scaffold which links ULK1, ATG13, and FIFP200 together to form a complex that is essential to initiate autophagy. Early autophagy targeting/tethering (EAT) domains in the C-terminus are arranged as MIT domains consisting of two three-helix bundles. MIT domains also mediate interactions with membranes. The N-terminus contains a serine-threonine kinase domain. ULK1 also contains a large activation loop between the N and C terminus that is positively charged. This region may regulate kinase activity and play a role in recognizing different substrates. ULK1 and ULK2 share significant homology in both the C-terminal and N-terminal domains.[6] # Related Diseases Given ULK1’s role in autophagy, many diseases such as cancer,[10] neurodegenerative disorders, neurodevelopment disorders,[11] and Crohn’s disease[12] could be attributed to any impairments in autophagy regulation. In cancer specifically, ULK1 has become an attractive therapeutic target. Since autophagy acts as a cell survival trait for cells, it enables tumors (once they are already formed) to survive energy deprivation and other stresses such as chemotherapeutics. For that reason, inhibiting autophagy may prove to be beneficial. Thus, inhibitors have been targeted towards ULK1.[13]

https://www.wikidoc.org/index.php/ULK1

31f9ace693686b60826aac51dacd5c39bb71508a

wikidoc

UPB1

UPB1 Beta-ureidopropionase is an enzyme that in humans is encoded by the UPB1 gene. This gene encodes a protein that belongs to the CN hydrolase family. Beta-ureidopropionase catalyzes the last step in the pyrimidine degradation pathway. The pyrimidine bases uracil and thymine are degraded via the consecutive action of dihydropyrimidine dehydrogenase (DHPDH), dihydropyrimidinase (DHP) and beta-ureidopropionase (UP) to beta-alanine and beta-aminoisobutyric acid, respectively. UP deficiencies are associated with N-carbamyl-beta-amino aciduria and may lead to abnormalities in neurological activity. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..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}

UPB1 Beta-ureidopropionase is an enzyme that in humans is encoded by the UPB1 gene.[1][2] This gene encodes a protein that belongs to the CN hydrolase family. Beta-ureidopropionase catalyzes the last step in the pyrimidine degradation pathway. The pyrimidine bases uracil and thymine are degraded via the consecutive action of dihydropyrimidine dehydrogenase (DHPDH), dihydropyrimidinase (DHP) and beta-ureidopropionase (UP) to beta-alanine and beta-aminoisobutyric acid, respectively. UP deficiencies are associated with N-carbamyl-beta-amino aciduria and may lead to abnormalities in neurological activity.[2] # 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: "FluoropyrimidineActivity_WP1601"..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/UPB1

866e93d7fa253306424bdf026d3b2e1b8113043b

wikidoc

UPF2

UPF2 Regulator of nonsense transcripts 2 is a protein that in humans is encoded by the UPF2 gene. # Function This gene encodes a protein that is part of a post-splicing multiprotein complex, the exon junction complex, involved in both mRNA nuclear export and mRNA surveillance. mRNA surveillance detects exported mRNAs with truncated open reading frames and initiates nonsense-mediated mRNA decay (NMD). When translation ends upstream from the last exon-exon junction, this triggers NMD to degrade mRNAs containing premature stop codons. This protein is located in the perinuclear area. It interacts with translation release factors and the proteins that are functional homologs of yeast Upf1p and Upf3p. Two splice variants have been found for this gene; both variants encode the same protein. # Interactions UPF2 has been shown to interact with UPF1, UPF3A and UPF3B.

UPF2 Regulator of nonsense transcripts 2 is a protein that in humans is encoded by the UPF2 gene.[1][2][3] # Function This gene encodes a protein that is part of a post-splicing multiprotein complex, the exon junction complex, involved in both mRNA nuclear export and mRNA surveillance. mRNA surveillance detects exported mRNAs with truncated open reading frames and initiates nonsense-mediated mRNA decay (NMD). When translation ends upstream from the last exon-exon junction, this triggers NMD to degrade mRNAs containing premature stop codons. This protein is located in the perinuclear area. It interacts with translation release factors and the proteins that are functional homologs of yeast Upf1p and Upf3p. Two splice variants have been found for this gene; both variants encode the same protein.[3] # Interactions UPF2 has been shown to interact with UPF1,[1][4][5][6][7] UPF3A[4][7] and UPF3B.[4][7][8][9]

https://www.wikidoc.org/index.php/UPF2

261bb9687a0d923650b6e45bc6753c21044d3cb0

wikidoc

UPP1

UPP1 Uridine phosphorylase 1 is an enzyme that in humans is encoded by the UPP1 gene. # Interactions UPP1 has been shown to interact with Vimentin. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..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}

UPP1 Uridine phosphorylase 1 is an enzyme that in humans is encoded by the UPP1 gene.[1][2][3] # Interactions UPP1 has been shown to interact with Vimentin.[4] # 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: "FluoropyrimidineActivity_WP1601"..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/UPP1

82e1dcc33e73261da3d9b31ad5f8a8fb3a6ae0eb

wikidoc

URI1

URI1 Unconventional prefoldin RPB5 interactor, also called URI1, is a protein that in humans is encoded by the URI1 gene. # Function The protein encoded by this gene binds to RNA polymerase II subunit 5 (RPB5) and negatively modulates transcription through its binding to RPB5. The encoded protein seems to have inhibitory effects on various types of activated transcription, but it requires the RPB5-binding region. This protein acts as a corepressor. It is suggested that it may require signaling processes for its function or that it negatively modulates genes in the chromatin structure. Two alternatively spliced transcript variants encoding different isoforms have been described for this gene. # Interactions URI1 has been shown to interact with DMAP1 and STAP1. # Model organisms Model organisms have been used in the study of URI1 function. A conditional knockout mouse line called Uri1tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping

URI1 Unconventional prefoldin RPB5 interactor, also called URI1, is a protein that in humans is encoded by the URI1 gene.[1][2][3] # Function The protein encoded by this gene binds to RNA polymerase II subunit 5 (RPB5) and negatively modulates transcription through its binding to RPB5. The encoded protein seems to have inhibitory effects on various types of activated transcription, but it requires the RPB5-binding region. This protein acts as a corepressor. It is suggested that it may require signaling processes for its function or that it negatively modulates genes in the chromatin structure. Two alternatively spliced transcript variants encoding different isoforms have been described for this gene.[3] # Interactions URI1 has been shown to interact with DMAP1[4] and STAP1.[5] # Model organisms Model organisms have been used in the study of URI1 function. A conditional knockout mouse line called Uri1tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[6] Male and female animals underwent a standardized phenotypic screen[7] to determine the effects of deletion.[8][9][10][11] Additional screens performed: - In-depth immunological phenotyping[12]

https://www.wikidoc.org/index.php/URI1

68dfddb6261c154c7f9ac2ec5717f1d97799d9ff

wikidoc

USF1

USF1 Upstream stimulatory factor 1 is a protein that in humans is encoded by the USF1 gene. # Function This gene encodes a member of the basic helix-loop-helix leucine zipper family and can function as a cellular transcription factor. The encoded protein can activate transcription through pyrimidine-rich initiator (Inr) elements and E-box motifs. This gene has been linked to familial combined hyperlipidemia (FCHL). Two transcript variants encoding distinct isoforms have been identified for this gene. A study of mice suggested reduced USF1 levels increases metabolism in brown fat. # Interactions USF1 (human gene) has been shown to interact with USF2, FOSL1 and GTF2I.

USF1 Upstream stimulatory factor 1 is a protein that in humans is encoded by the USF1 gene.[1][2] # Function This gene encodes a member of the basic helix-loop-helix leucine zipper family and can function as a cellular transcription factor. The encoded protein can activate transcription through pyrimidine-rich initiator (Inr) elements and E-box motifs. This gene has been linked to familial combined hyperlipidemia (FCHL). Two transcript variants encoding distinct isoforms have been identified for this gene.[2] A study of mice suggested reduced USF1 levels increases metabolism in brown fat.[3] # Interactions USF1 (human gene) has been shown to interact with USF2,[4][5] FOSL1[6] and GTF2I.[7][8]

https://www.wikidoc.org/index.php/USF1

597d811b3058fe041e5d8468d8765c5137fdac83

wikidoc

USF2

USF2 Upstream stimulatory factor 2 is a protein that in humans is encoded by the USF2 gene. # Function This gene encodes a member of the basic helix-loop-helix leucine zipper family, and can function as a cellular transcription factor. The encoded protein can activate transcription through Pyridine-rich initiator (Inr) elements and E-box motifs. Two transcript variants encoding distinct isoforms have been identified for this gene. # Interactions USF2 has been shown to interact with USF1 (human gene), PPRC1 and BRCA1. # Regulation The USF2 gene is repressed by the microRNA miR-10a.

USF2 Upstream stimulatory factor 2 is a protein that in humans is encoded by the USF2 gene.[1][2] # Function This gene encodes a member of the basic helix-loop-helix leucine zipper family, and can function as a cellular transcription factor. The encoded protein can activate transcription through Pyridine-rich initiator (Inr) elements and E-box motifs. Two transcript variants encoding distinct isoforms have been identified for this gene.[2] # Interactions USF2 has been shown to interact with USF1 (human gene),[3][4] PPRC1[5] and BRCA1.[6] # Regulation The USF2 gene is repressed by the microRNA miR-10a.[7]

https://www.wikidoc.org/index.php/USF2

c5ced3f2bbcd6513519b7c9f517a5229fad74f9a

wikidoc

USP7

USP7 Ubiquitin-specific-processing protease 7 (USP7), also known as ubiquitin carboxyl-terminal hydrolase 7 or herpesvirus-associated ubiquitin-specific protease (HAUSP), is an enzyme that in humans is encoded by the USP7 gene. # Function ## Regulation of the p53 tumor suppressor USP7 or HAUSP is a ubiquitin specific protease or a deubiquitylating enzyme that cleaves ubiquitin from its substrates. Since ubiquitylation (polyubiquitination) is most commonly associated with the stability and degradation of cellular proteins, HAUSP activity generally stabilizes its substrate proteins. HAUSP is most popularly known as a direct antagonist of Mdm2, the E3 ubiquitin ligase for the tumor suppressor protein, p53. Normally, p53 levels are kept low in part due to Mdm2-mediated ubiquitylation and degradation of p53. In response to oncogenic insults, HAUSP can deubiquitinate p53 and protect p53 from Mdm2-mediated degradation, indicating that it may possess a tumor suppressor function for the immediate stabilization of p53 in response to stress. Another important role of HAUSP function involves the oncogenic stabilization of p53. Oncogenes such as Myc and E1A are thought to activate p53 through a p19 alternative reading frame (p19ARF, also called ARF)-dependent pathway, although some evidence suggests ARF is not essential in this process. A possibility is that HAUSP provides an alternative pathway for safeguarding the cell against oncogenic insults. ## Role in transcriptional regulation USP7 can deubiquitinate histone H2B and this activity is associated with gene silencing in Drosophila. USP7 associates with a metabolic enzyme, GMP synthetase (GMPS) and this association stimulates USP7 deubiquitinase activity towards H2B. The USP7-GMPS complex is recruited to the polycomb (Pc) region in Drosophila and contributes to epigenetic silecing of homeotic genes. # Association with herpesviruses USP7 was originally identified as a protein associated with the ICP0 protein of herpes simplex virus (HSV), hence the name Herpesvirus Associated USP (HAUSP). ICP0 is an E3-ubiquitin ligase that is involved in ubiquitination and subsequent degradation of itself and certain cellular proteins. USP7 has been shown to regulate the auto-ubiquitination and degradation of ICP0. More recently, an interaction between USP7 and the EBNA1 protein of Epstein-Barr virus (EBV) (another herpesvirus) was also discovered. This interaction is particularly interesting given the oncogenic potential (potential to cause cancer) of EBV, which is associated with several human cancers. EBNA1 can compete with p53 for binding USP7. Stabilization by USP7 is important for the tumor suppressor function of p53. In cells, EBNA1 can sequester USP7 from p53 and thus attenuate stabilization of p53, rendering the cells predisposed to turning cancerous. Compromising the function of p53 by sequestering USP7 is one way EBNA1 can contribute to the oncogenic potential of EBV. Additionally, human USP7 was also shown to form a complex with GMPS and this complex is recruited to EBV genome sequences. USP7 was shown to be important for histone H2B deubiquitination in human cells and for deubiquitination of histone H2B incorporated in the EBV genome. Thus USP7 may also be important for regulation of viral gene expression. The fact that viral proteins have evolved so as to target USP7, underscores the significance of USP7 in tumor suppression and other cellular processes. # Binding partners The following is a list of some of the known cellular binding partners of USP7/HAUSP: - p53 - Mdm2 - Mdm4/MdmX - FOXO4 - Daxx - PTEN - March7 - UVSSA # Interactions USP7 has been shown to interact with Ataxin 1, CLSPN and P53. A proteomic screen conducted to identify interacting partners of 75 human deubiquitinating enzymes (DUBs) has revealed several novel binding partners of USP7. # Clinical Significance Loss-of-function mutations of USP7 are associated with neurodevelopmental disorder whose symptoms include developmental delay/intellectual disability, autism spectrum disorder, increased prevalence of epilepsy, abnormal brain MRIs, and speech/motor impairments, with some patients being completely non-verbal,

USP7 Ubiquitin-specific-processing protease 7 (USP7), also known as ubiquitin carboxyl-terminal hydrolase 7 or herpesvirus-associated ubiquitin-specific protease (HAUSP), is an enzyme that in humans is encoded by the USP7 gene.[1][2][3][4] # Function ## Regulation of the p53 tumor suppressor USP7 or HAUSP is a ubiquitin specific protease or a deubiquitylating enzyme that cleaves ubiquitin from its substrates.[5] Since ubiquitylation (polyubiquitination) is most commonly associated with the stability and degradation of cellular proteins, HAUSP activity generally stabilizes its substrate proteins. HAUSP is most popularly known as a direct antagonist of Mdm2, the E3 ubiquitin ligase for the tumor suppressor protein, p53.[6] Normally, p53 levels are kept low in part due to Mdm2-mediated ubiquitylation and degradation of p53. In response to oncogenic insults, HAUSP can deubiquitinate p53 and protect p53 from Mdm2-mediated degradation, indicating that it may possess a tumor suppressor function for the immediate stabilization of p53 in response to stress. Another important role of HAUSP function involves the oncogenic stabilization of p53. Oncogenes such as Myc and E1A are thought to activate p53 through a p19 alternative reading frame (p19ARF, also called ARF)-dependent pathway, although some evidence suggests ARF is not essential in this process. A possibility is that HAUSP provides an alternative pathway for safeguarding the cell against oncogenic insults. ## Role in transcriptional regulation USP7 can deubiquitinate histone H2B and this activity is associated with gene silencing in Drosophila.[7] USP7 associates with a metabolic enzyme, GMP synthetase (GMPS) and this association stimulates USP7 deubiquitinase activity towards H2B.[7] The USP7-GMPS complex is recruited to the polycomb (Pc) region in Drosophila and contributes to epigenetic silecing of homeotic genes.[8] # Association with herpesviruses USP7 was originally identified as a protein associated with the ICP0 protein of herpes simplex virus (HSV), hence the name Herpesvirus Associated USP (HAUSP). ICP0 is an E3-ubiquitin ligase that is involved in ubiquitination and subsequent degradation of itself and certain cellular proteins. USP7 has been shown to regulate the auto-ubiquitination and degradation of ICP0. More recently, an interaction between USP7 and the EBNA1 protein of Epstein-Barr virus (EBV) (another herpesvirus) was also discovered.[9] This interaction is particularly interesting given the oncogenic potential (potential to cause cancer) of EBV, which is associated with several human cancers. EBNA1 can compete with p53 for binding USP7. Stabilization by USP7 is important for the tumor suppressor function of p53. In cells, EBNA1 can sequester USP7 from p53 and thus attenuate stabilization of p53, rendering the cells predisposed to turning cancerous. Compromising the function of p53 by sequestering USP7 is one way EBNA1 can contribute to the oncogenic potential of EBV. Additionally, human USP7 was also shown to form a complex with GMPS and this complex is recruited to EBV genome sequences.[10] USP7 was shown to be important for histone H2B deubiquitination in human cells and for deubiquitination of histone H2B incorporated in the EBV genome. Thus USP7 may also be important for regulation of viral gene expression. The fact that viral proteins have evolved so as to target USP7, underscores the significance of USP7 in tumor suppression and other cellular processes. # Binding partners The following is a list of some of the known cellular binding partners of USP7/HAUSP: - p53 - Mdm2 - Mdm4/MdmX - FOXO4 - Daxx - PTEN - March7 - UVSSA[11] # Interactions USP7 has been shown to interact with Ataxin 1,[12] CLSPN[13] and P53.[6] A proteomic screen conducted to identify interacting partners of 75 human deubiquitinating enzymes (DUBs) has revealed several novel binding partners of USP7.[14] # Clinical Significance Loss-of-function mutations of USP7 are associated with neurodevelopmental disorder whose symptoms include developmental delay/intellectual disability, autism spectrum disorder, increased prevalence of epilepsy, abnormal brain MRIs, and speech/motor impairments, with some patients being completely non-verbal,[15][16]

https://www.wikidoc.org/index.php/USP7

06355ac084687fdbe7047d1846394bd264d90647

wikidoc

UTF1

UTF1 Undifferentiated embryonic cell transcription factor 1 is a protein in humans that is encoded by the UTF1 gene. UTF1, first reported in 1998, is expressed in pluripotent cells including embryonic stem cells and embryonic carcinoma cells. Its expression is rapidly reduced upon differentiation. UTF1 protein is localized to the cell nucleus, where it functions to regulate the pluripotent chromatin state and buffer mRNA levels by promoting degradation of mRNA. Aberrant expression of UTF1 has also been reported in cervical cancer cells, where the UTF1 gene promoter loses methylation and becomes abnormally expressed compared to normal cervical cells.

UTF1 Undifferentiated embryonic cell transcription factor 1 is a protein in humans that is encoded by the UTF1 gene. [1] UTF1, first reported in 1998, is expressed in pluripotent cells including embryonic stem cells and embryonic carcinoma cells.[2] Its expression is rapidly reduced upon differentiation. UTF1 protein is localized to the cell nucleus, where it functions to regulate the pluripotent chromatin state and buffer mRNA levels by promoting degradation of mRNA.[3] Aberrant expression of UTF1 has also been reported in cervical cancer cells, where the UTF1 gene promoter loses methylation and becomes abnormally expressed compared to normal cervical cells.[4]

https://www.wikidoc.org/index.php/UTF1

2907481481ed0f5e012362ad328c329e50022357

wikidoc

Ulna

Ulna # Overview The ulna (elbow bone) is a long bone, prismatic in form, placed at the medial side of the forearm, parallel with the radius. # Articulations The ulna articulates with: - the humerus, at the right side elbow as a hinge joint. - the radius, near the elbow as a pivot joint, this allows the radius to cross over the ulna in pronation. - the distal radius, where it fits into the ulna notch. - the radius along its length via the interosseous membrane that forms a syndesmoses joint. # Proximal and distal aspects The ulna is broader proximally, and narrower distally. Proximally, the ulna has a bony process, the olecranon process, a hook-like structure that fits into the olecranon fossa of the humerus. This prevents hyperextension and forms a hinge joint with the trochlea of the humerus. There is also a radial notch for the head of the radius, and the ulnar tuberosity to which muscles can attach. Distally (near the hand), there is a styloid process. # Structure The long, narrow medullary cavity is enclosed in a strong wall of compact tissue which is thickest along the interosseous border and dorsal surface. At the extremities the compact layer thins. The compact layer is continued onto the back of the olecranon as a plate of close spongy bone with lamellæ parallel. From the inner surface of this plate and the compact layer below it trabeculæ arch forward toward the olecranon and coronoid and cross other trabeculæ, passing backward over the medullary cavity from the upper part of the shaft below the coronoid. Below the coronoid process there is a small area of compact bone from which trabeculæ curve upward to end obliquely to the surface of the semilunar notch which is coated with a thin layer of compact bone. The trabeculæ at the lower end have a more longitudinal direction.

Ulna Template:Infobox Bone # Overview The ulna (elbow bone) is a long bone, prismatic in form, placed at the medial side of the forearm, parallel with the radius. # Articulations The ulna articulates with: - the humerus, at the right side elbow as a hinge joint. - the radius, near the elbow as a pivot joint, this allows the radius to cross over the ulna in pronation. - the distal radius, where it fits into the ulna notch. - the radius along its length via the interosseous membrane that forms a syndesmoses joint. # Proximal and distal aspects The ulna is broader proximally, and narrower distally. Proximally, the ulna has a bony process, the olecranon process, a hook-like structure that fits into the olecranon fossa of the humerus. This prevents hyperextension and forms a hinge joint with the trochlea of the humerus. There is also a radial notch for the head of the radius, and the ulnar tuberosity to which muscles can attach. Distally (near the hand), there is a styloid process. # Structure The long, narrow medullary cavity is enclosed in a strong wall of compact tissue which is thickest along the interosseous border and dorsal surface. At the extremities the compact layer thins. The compact layer is continued onto the back of the olecranon as a plate of close spongy bone with lamellæ parallel. From the inner surface of this plate and the compact layer below it trabeculæ arch forward toward the olecranon and coronoid and cross other trabeculæ, passing backward over the medullary cavity from the upper part of the shaft below the coronoid. Below the coronoid process there is a small area of compact bone from which trabeculæ curve upward to end obliquely to the surface of the semilunar notch which is coated with a thin layer of compact bone. The trabeculæ at the lower end have a more longitudinal direction.

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

bceb9a8813c3a1abd62810760f718ebc20adf920

wikidoc

VAPA

VAPA VAMP-Associated Protein A ( or Vesicle-Associated Membrane Protein-Associated Protein A) is a protein that in humans is encoded by the VAPA gene. Together with VAPB and VAPC it forms the VAP protein family. They are integral endoplasmic reticulum membrane proteins of the type II and are ubiquitous among eukaryotes. VAPA is ubiquitously expressed in human tissues and is thought to be involved in membrane trafficking by interaction with SNAREs. in regulation of lipid transport and metabolism, and in the Unfolded Protein Response (UPR). # Protein structure The protein is divided in three different domains. First, an N-terminal beta-sheet with an immunoglobulin-like fold that shares homology with the Nematode major sperm protein (MSP). Secondly, a central coiled-coil domain. Then finally a C-terminal transmembrane domain (TMD) which is usually present in proteins of the t-SNARE superfamily and has been found in other proteins associated with vesicular transport. VAPA can form homo-dimers and also hetero dimers with VAPB by interactions through their (TMD). # Intracellular Localisation Because of its ubiquitous expression, the intracellular localisation and function of VAPA may vary between cell types. It is however mainly located in the ER, Golgi apparatus and the Vesicular Tubular Compartment or ER-Golgi Intermediate Compartment, an organelle of eukaryotic cells consisting in fused ER-derived vesicles that transports proteins from the ER to the Golgi apparatus. # Interactions VAPA has been documented to interact with three different groups of proteins: proteins associated with vesicle traffic and fusion, proteins containing the FFAT motif and viral proteins. ## Vesicle traffic and fusion VAPA is able to bind a range of SNARE proteins including syntaxin1A, rbet1 and rsec22. It also binds to proteins associated with membrane fusion machinery such as alphaSNAP and NSF.These interaction suggest that VAPA could have a general role in the regulation of the function of these proteins that are mainly involved in membrane fusion ## Viral Proteins VAP proteins have been found to be essential host factors for several viruses. VAP proteins binds with non-structural proteins of the hepatitis C virus NS5A and NS5B allowing the RNA replication machinery of the virus to set up on the lipid raft membrane of the host cell. VAPA also binds to several viral proteins from the Norovirus family and is important for the virus replication efficiency. The non-structural proteins NS1 and NS2 are able to bind VAPA thanks to sequence mimicry of the FFAT motif probably yielding the same advantage to viral replication as for hepatitis C virus. ## FFAT motif The N-terminal MSP-homologous part of VAPA is able to bind to the FFAT motif, a particular sequence motif shared by several lipid binding proteins including oxysterol-binding protein (OSBP). # Function One of its proposed functions is to slow down the lipid flow back towards the ER when protein misfolding occurs, in order to reduce the amount of stress triggered by the UPR. The VAP would regulate this process by inhibiting membrane contact. # Associated Diseases The P56S SNP in the MSP domain of VAPB is involved in the onset of Lou Gehrig's disease also called amyotrophic lateral sclerosis (ALS) where the patient loses muscle control and function. The degenerescence of motor neurons observed in such condition could to be due to the inability of VAPB to regulate the lipid function around the ER and the subsequent consequences on cell function.

VAPA VAMP-Associated Protein A ( or Vesicle-Associated Membrane Protein-Associated Protein A) is a protein that in humans is encoded by the VAPA gene.[1][2][3] Together with VAPB and VAPC it forms the VAP protein family. They are integral endoplasmic reticulum membrane proteins of the type II and are ubiquitous among eukaryotes.[4] VAPA is ubiquitously expressed in human tissues[1] and is thought to be involved in membrane trafficking by interaction with SNAREs.[5] in regulation of lipid transport and metabolism,[4] and in the Unfolded Protein Response (UPR).[4] # Protein structure The protein is divided in three different domains.[1] First, an N-terminal beta-sheet with an immunoglobulin-like fold that shares homology with the Nematode major sperm protein (MSP). Secondly, a central coiled-coil domain. Then finally a C-terminal transmembrane domain (TMD) which is usually present in proteins of the t-SNARE superfamily and has been found in other proteins associated with vesicular transport.[6] VAPA can form homo-dimers and also hetero dimers with VAPB by interactions through their (TMD).[1] # Intracellular Localisation Because of its ubiquitous expression[1], the intracellular localisation and function of VAPA may vary between cell types. It is however mainly located in the ER[7], Golgi apparatus and the Vesicular Tubular Compartment or ER-Golgi Intermediate Compartment,[5] an organelle of eukaryotic cells consisting in fused ER-derived vesicles that transports proteins from the ER to the Golgi apparatus.[8] # Interactions VAPA has been documented to interact with three different groups of proteins: proteins associated with vesicle traffic and fusion, proteins containing the FFAT motif and viral proteins.[4] ## Vesicle traffic and fusion VAPA is able to bind a range of SNARE proteins including syntaxin1A, rbet1 and rsec22. It also binds to proteins associated with membrane fusion machinery such as alphaSNAP and NSF.These interaction suggest that VAPA could have a general role in the regulation of the function of these proteins that are mainly involved in membrane fusion[5] ## Viral Proteins VAP proteins have been found to be essential host factors for several viruses.[9][10][11] VAP proteins binds with non-structural proteins of the hepatitis C virus NS5A and NS5B allowing the RNA replication machinery of the virus to set up on the lipid raft membrane of the host cell.[12] VAPA also binds to several viral proteins from the Norovirus family and is important for the virus replication efficiency.[9][10] The non-structural proteins NS1 and NS2 are able to bind VAPA thanks to sequence mimicry of the FFAT motif probably yielding the same advantage to viral replication as for hepatitis C virus.[10] ## FFAT motif The N-terminal MSP-homologous part of VAPA is able to bind to the FFAT motif, a particular sequence motif shared by several lipid binding proteins including oxysterol-binding protein (OSBP).[13][14] # Function One of its proposed functions is to slow down the lipid flow back towards the ER when protein misfolding occurs, in order to reduce the amount of stress triggered by the UPR. The VAP would regulate this process by inhibiting membrane contact.[15] # Associated Diseases The P56S SNP in the MSP domain of VAPB is involved in the onset of Lou Gehrig's disease also called amyotrophic lateral sclerosis (ALS) where the patient loses muscle control and function. The degenerescence of motor neurons observed in such condition could to be due to the inability of VAPB to regulate the lipid function around the ER and the subsequent consequences on cell function.[15]

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

224db746378b4ccd021d8f0e17bacaa36b302467

wikidoc

VAPB

VAPB Vesicle-associated membrane protein-associated protein B/C is a protein that in humans is encoded by the VAPB gene. The VAPB gene is found on the 20th human chromosome. Together with VAPA, it forms the VAP protein family. # Function The protein encoded by this gene is a type IV membrane protein found in plasma and intracellular vesicle membranes. The encoded protein is found as a homodimer and as a heterodimer with VAPA. This protein also can interact with VAMP1 and VAMP2 and may be involved in vesicle trafficking. Like VAPA, VAPB binds to proteins that contain a FFAT motif. Considerable interest in VAPB has arisen because mutations in this protein are associated with rare, familial forms of Motor Neurone Disease (also called Amyotrophic Lateral Sclerosis and Lou Gehrig's disease).

VAPB Vesicle-associated membrane protein-associated protein B/C is a protein that in humans is encoded by the VAPB gene.[1][2] The VAPB gene is found on the 20th human chromosome. Together with VAPA, it forms the VAP protein family. # Function The protein encoded by this gene is a type IV membrane protein found in plasma and intracellular vesicle membranes. The encoded protein is found as a homodimer and as a heterodimer with VAPA. This protein also can interact with VAMP1 and VAMP2 and may be involved in vesicle trafficking.[2] Like VAPA, VAPB binds to proteins that contain a FFAT motif.[3] Considerable interest in VAPB has arisen because mutations in this protein are associated with rare, familial forms of Motor Neurone Disease (also called Amyotrophic Lateral Sclerosis and Lou Gehrig's disease).[4]

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

9d779f09c5b5b2deee06de00a9365d894938795e

wikidoc

VAT1

VAT1 Synaptic vesicle membrane protein VAT-1 homolog is a protein that in humans is encoded by the VAT1 gene. Synaptic vesicles are responsible for regulating the storage and release of neurotransmitters in the nerve terminal. The protein encoded by this gene is an abundant integral membrane protein of cholinergic synaptic vesicles and is thought to be involved in vesicular transport. It belongs to the quinone oxidoreductase subfamily of zinc-containing alcohol dehydrogenase proteins. In melanocytic cells VAT1 gene expression may be regulated by MITF.

VAT1 Synaptic vesicle membrane protein VAT-1 homolog is a protein that in humans is encoded by the VAT1 gene.[1][2][3] Synaptic vesicles are responsible for regulating the storage and release of neurotransmitters in the nerve terminal. The protein encoded by this gene is an abundant integral membrane protein of cholinergic synaptic vesicles and is thought to be involved in vesicular transport. It belongs to the quinone oxidoreductase subfamily of zinc-containing alcohol dehydrogenase proteins.[3] In melanocytic cells VAT1 gene expression may be regulated by MITF.[4]

https://www.wikidoc.org/index.php/VAT1

e1071ddd06d809fc7f1bae8d8e5df469df760808

wikidoc

VAX1

VAX1 Ventral anterior homeobox 1 is a protein that in humans is encoded by the VAX1 gene. # Function This gene appears to influence the development in humans of the forebrain. It is also present in mice and xenopus frogs, which suggests a long evolutionary history, and in those organisms its expression is confined to the forebrain, optic and olfactory areas. VAX1 gene is a transcription factor that has a homeodomain located in the 100-159 amino acid position and an Ala–rich region located in 216-253 amino acid position of the gene. Expression studies in mice show that it is expressed in the palate, coloboma in the visual system, and the basal telencephalon, optic stalk, and visual eye fields where it is expressed along with the Shh and Bmp4 genes. # Clinical significance Mice with homozygous VAX1 mutations have been reported to display craniofacial malformations including cleft palate. Genome Wide Association Studies (GWAS) reported significant associations between non-syndromic clefts and SNPs in the VAX1 gene. Replication studies have confirmed these associations in different population groups

VAX1 Ventral anterior homeobox 1 is a protein that in humans is encoded by the VAX1 gene.[1][2][3] # Function This gene appears to influence the development in humans of the forebrain. It is also present in mice and xenopus frogs, which suggests a long evolutionary history, and in those organisms its expression is confined to the forebrain, optic and olfactory areas.[4] VAX1 gene is a transcription factor that has a homeodomain located in the 100-159 amino acid position and an Ala–rich region located in 216-253 amino acid position of the gene. Expression studies in mice show that it is expressed in the palate, coloboma in the visual system, and the basal telencephalon, optic stalk, and visual eye fields where it is expressed along with the Shh and Bmp4 genes.[4][5][6] # Clinical significance Mice with homozygous VAX1 mutations have been reported to display craniofacial malformations including cleft palate.[7] Genome Wide Association Studies (GWAS) reported significant associations between non-syndromic clefts and SNPs in the VAX1 gene.[8][9] Replication studies have confirmed these associations in different population groups[10][11]

https://www.wikidoc.org/index.php/VAX1

b11ef5cc939079b89dbdb118b66482d98907a87c

wikidoc

VWA2

VWA2 von Willebrand factor A domain-containing protein 2, also known as A domain-containing protein similar to matrilin and collagen (AMACO) is a protein that in humans is encoded by the VWA2 gene. AMACO is a member of the von Willebrand factor A-like (VWA) domain containing protein superfamily and consists of three VWA-like domains, two EGF-like domains, a cysteine-rich domain and a unique C-terminal domain. AMACO is an extracellular matrix protein and mostly deposited adjacent to basement membranes. AMACO binds directly to FRAS1 which is part of the Fraser complex important for epithelial-connective tissue interaction, the exact biological role of AMACO, however, is still unknown. In 2005 AMACO was found markedly induced in colon cancers ; indicating that it might be a good candidate as a biomarker for this type of cancer.

VWA2 von Willebrand factor A domain-containing protein 2, also known as A domain-containing protein similar to matrilin and collagen (AMACO) is a protein that in humans is encoded by the VWA2 gene.[1][2] AMACO is a member of the von Willebrand factor A-like (VWA) domain containing protein superfamily and consists of three VWA-like domains, two EGF-like domains, a cysteine-rich domain and a unique C-terminal domain.[2] AMACO is an extracellular matrix protein and mostly deposited adjacent to basement membranes.[3] AMACO binds directly to FRAS1 which is part of the Fraser complex important for epithelial-connective tissue interaction[4], the exact biological role of AMACO, however, is still unknown. In 2005 AMACO was found markedly induced in colon cancers [5]; indicating that it might be a good candidate as a biomarker for this type of cancer.

https://www.wikidoc.org/index.php/VWA2

615911ed5fd4bcb157dfad6c3d7ef2fbe4323ca3

wikidoc

Volt

Volt The volt (symbol: V) is the SI derived unit of electric potential difference or electromotive force. It is named in honor of the Lombard physicist Alessandro Volta (1745–1827), who invented the voltaic pile, the first modern chemical battery. # Definition The volt is defined as the potential difference across a conductor when a current of one ampere dissipates one watt of power. Hence, it is the base SI representation m2 · kg · s-3 · A-1, which can be equally represented as one joule of energy per coulomb of charge, J/C. ## Josephson junction definition Since 1990 the volt is maintained internationally for practical measurement using the Josephson effect, where a conventional value is used for the Josephson constant, fixed by the 18th General Conference on Weights and Measures as # Hydraulic analogy In the hydraulic analogy sometimes used to explain electric circuits by comparing them to water-filled pipes, voltage is likened to water pressure – it determines how fast the electrons will travel through the circuit. Current (in amperes), in the same analogy, is a measure of the volume of water that flows past a given point per unit time (volumetric flow rate). The flow rate is determined by the width of the pipe (analogous to electrical resistance) and the pressure difference between the front end of the pipe and the exit (potential difference or voltage). The analogy extends to power dissipation: the power given up by the water flow is equal to flow rate times pressure, just as the power dissipated in a resistor is equal to current times the voltage drop across the resistor (amperes x volts = watts). The relationship between voltage and current (in ohmic devices) is defined by Ohm's Law. # Common voltages Nominal voltages of familiar sources: - Nerve cell action potential: around 75 mV - Single-cell, rechargeable NiMH or NiCd battery: 1.2 V - Mercury battery: 1.355 V - Single-cell, non-rechargeable alkaline battery (e.g. AAA, AA, C and D cells): 1.5 V - Lithium polymer rechargeable battery: 3.75 V - Transistor-transistor logic/CMOS (TTL) power supply: 5 V - PP3 battery: 9 V - Automobile electrical system: "12 V", about 11.8 V discharged, 12.8 V charged, and 13.8-14.4 V while charging (vehicle running). - Household mains electricity: 240 V RMS in Australia, 230 V RMS in Europe, Asia and Africa, 120 V RMS in North America, 100 V RMS in Japan (see List of countries with mains power plugs, voltages and frequencies) - Rapid transit third rail: 600 to 750 V (see List of current systems for electric rail traction) - High speed train overhead power lines: 25 kV RMS at 50 Hz, but see the list of current systems for electric rail traction for exceptions. - High voltage electric power transmission lines: 110 kV RMS and up (1150 kV RMS was the record as of 2005) - Lightning: Varies greatly, often around 100 MV. Note: Where 'RMS' (root mean square) is stated above, the peak voltage is \sqrt{2} times greater than the RMS voltage for a sinusoidal signal centered around zero voltage. # History of the volt In 1800, as the result of a professional disagreement over the galvanic response advocated by Luigi Galvani, Alessandro Volta developed the so-called Voltaic pile, a forerunner of the battery, which produced a steady electric current. Volta had determined that the most effective pair of dissimilar metals to produce electricity was zinc and silver. In the 1880s, the International Electrical Congress, now the International Electrotechnical Commission (IEC), approved the volt for electromotive force. At that time, the volt was defined as the potential difference across a conductor when a current of one ampere dissipates one watt of power. Prior to the development of the Josephson junction voltage standard, the volt was maintained in national laboratories using specially constructed batteries called standard cells. The United States used a design called the Weston cell from 1905 to 1972.

Volt Template:Otheruses4 The volt (symbol: V) is the SI derived unit of electric potential difference or electromotive force.[1][2] It is named in honor of the Lombard physicist Alessandro Volta (1745–1827), who invented the voltaic pile, the first modern chemical battery. # Definition The volt is defined as the potential difference across a conductor when a current of one ampere dissipates one watt of power.[3] Hence, it is the base SI representation m2 · kg · s-3 · A-1, which can be equally represented as one joule of energy per coulomb of charge, J/C. ## Josephson junction definition Since 1990 the volt is maintained internationally for practical measurement using the Josephson effect, where a conventional value is used for the Josephson constant, fixed by the 18th General Conference on Weights and Measures as # Hydraulic analogy In the hydraulic analogy sometimes used to explain electric circuits by comparing them to water-filled pipes, voltage is likened to water pressure – it determines how fast the electrons will travel through the circuit. Current (in amperes), in the same analogy, is a measure of the volume of water that flows past a given point per unit time (volumetric flow rate). The flow rate is determined by the width of the pipe (analogous to electrical resistance) and the pressure difference between the front end of the pipe and the exit (potential difference or voltage). The analogy extends to power dissipation: the power given up by the water flow is equal to flow rate times pressure, just as the power dissipated in a resistor is equal to current times the voltage drop across the resistor (amperes x volts = watts). The relationship between voltage and current (in ohmic devices) is defined by Ohm's Law. # Common voltages Nominal voltages of familiar sources: - Nerve cell action potential: around 75 mV[4] - Single-cell, rechargeable NiMH or NiCd battery: 1.2 V - Mercury battery: 1.355 V - Single-cell, non-rechargeable alkaline battery (e.g. AAA, AA, C and D cells): 1.5 V - Lithium polymer rechargeable battery: 3.75 V - Transistor-transistor logic/CMOS (TTL) power supply: 5 V - PP3 battery: 9 V - Automobile electrical system: "12 V", about 11.8 V discharged, 12.8 V charged, and 13.8-14.4 V while charging (vehicle running). - Household mains electricity: 240 V RMS in Australia, 230 V RMS in Europe, Asia and Africa, 120 V RMS in North America, 100 V RMS in Japan (see List of countries with mains power plugs, voltages and frequencies) - Rapid transit third rail: 600 to 750 V (see List of current systems for electric rail traction) - High speed train overhead power lines: 25 kV RMS at 50 Hz, but see the list of current systems for electric rail traction for exceptions. - High voltage electric power transmission lines: 110 kV RMS and up (1150 kV RMS was the record as of 2005) - Lightning: Varies greatly, often around 100 MV. Note: Where 'RMS' (root mean square) is stated above, the peak voltage is <math>\sqrt{2}</math> times greater than the RMS voltage for a sinusoidal signal centered around zero voltage. # History of the volt In 1800, as the result of a professional disagreement over the galvanic response advocated by Luigi Galvani, Alessandro Volta developed the so-called Voltaic pile, a forerunner of the battery, which produced a steady electric current. Volta had determined that the most effective pair of dissimilar metals to produce electricity was zinc and silver. In the 1880s, the International Electrical Congress, now the International Electrotechnical Commission (IEC), approved the volt for electromotive force. At that time, the volt was defined as the potential difference across a conductor when a current of one ampere dissipates one watt of power. Prior to the development of the Josephson junction voltage standard, the volt was maintained in national laboratories using specially constructed batteries called standard cells. The United States used a design called the Weston cell from 1905 to 1972. Template:SI unit lowercase

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

60d4355369f0571e9fb5e1c41eeeb97540fc72ef

wikidoc

WBP2

WBP2 WW domain-binding protein 2 is a protein that in humans is encoded by the WBP2 gene. The globular WW domain is composed of 38 to 40 semiconserved amino acids shared by proteins of diverse functions including structural, regulatory, and signaling proteins. The domain is involved in mediating protein-protein interactions through the binding of polyproline ligands. This gene encodes a WW domain binding protein, which binds to the WW domain of Yes kinase-associated protein by its PY motifs. The function of this protein has not been determined. # Model organisms Model organisms have been used in the study of WBP2 function. A conditional knockout mouse line, called Wbp2tm1a(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 three tests were carried out on mutant mice and two significant abnormalities were observed. Homozygous mutant animals displayed an abnormal brainstem auditory evoked potential, while females also had decreased circulating amylase levels.

WBP2 WW domain-binding protein 2 is a protein that in humans is encoded by the WBP2 gene.[1][2] The globular WW domain is composed of 38 to 40 semiconserved amino acids shared by proteins of diverse functions including structural, regulatory, and signaling proteins. The domain is involved in mediating protein-protein interactions through the binding of polyproline ligands. This gene encodes a WW domain binding protein, which binds to the WW domain of Yes kinase-associated protein by its PY motifs. The function of this protein has not been determined.[2] # Model organisms Model organisms have been used in the study of WBP2 function. A conditional knockout mouse line, called Wbp2tm1a(EUCOMM)Wtsi[8][9] 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.[10][11][12] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty three tests were carried out on mutant mice and two significant abnormalities were observed.[6] Homozygous mutant animals displayed an abnormal brainstem auditory evoked potential, while females also had decreased circulating amylase levels.[6]

https://www.wikidoc.org/index.php/WBP2

fac5056c2487304ddeddde763c8c5ede048fa4ec

wikidoc

WDR3

WDR3 WD repeat-containing protein 3 is a protein that in humans is encoded by the WDR3 gene. This gene encodes a nuclear protein containing 10 WD repeats. WD repeats are approximately 30- to 40-amino acid domains containing several conserved residues, which usually include a trp-asp at the C-terminal end. Proteins belonging to the WD repeat family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. # Model organisms Model organisms have been used in the study of WDR3 function. A conditional knockout mouse line, called Wdr3tm1a(KOMP)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 four tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.

WDR3 WD repeat-containing protein 3 is a protein that in humans is encoded by the WDR3 gene.[1][2] This gene encodes a nuclear protein containing 10 WD repeats. WD repeats are approximately 30- to 40-amino acid domains containing several conserved residues, which usually include a trp-asp at the C-terminal end. Proteins belonging to the WD repeat family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation.[2] # Model organisms Model organisms have been used in the study of WDR3 function. A conditional knockout mouse line, called Wdr3tm1a(KOMP)Wtsi[7][8] 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.[9][10][11] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty four tests were carried out on mutant mice and two significant abnormalities were observed.[5] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.[5]

https://www.wikidoc.org/index.php/WDR3

5a549c768bf86eaf4fda808f17cfe8a1a761b0b4

wikidoc

WDR5

WDR5 WD repeat-containing protein 5 is a protein that in humans is encoded by the WDR5 gene. This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This protein contains 7 WD repeats. Alternatively spliced transcript variants encoding the same protein have been identified. # Interactions WDR5 has been shown to interact with Host cell factor C1 and MLL. It also interacts with the long non-coding RNA HOTTIP. WDR5 is a key determinant for MYC recruitment to chromatin

WDR5 WD repeat-containing protein 5 is a protein that in humans is encoded by the WDR5 gene.[1][2] This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This protein contains 7 WD repeats. Alternatively spliced transcript variants encoding the same protein have been identified.[2] # Interactions WDR5 has been shown to interact with Host cell factor C1[3][4] and MLL.[3] It also interacts with the long non-coding RNA HOTTIP.[5] WDR5 is a key determinant for MYC recruitment to chromatin[6]

https://www.wikidoc.org/index.php/WDR5

12f6c321b96b53e974ab7d29b96d7bfe46ac3fc8

wikidoc

WFS1

WFS1 Wolframin is a protein that in humans is encoded by the WFS1 gene. # Function Wolframin is a transmembrane protein. Wolframin appears to function as a cation-selective ion channel. # Clinical significance Mutations in this gene are associated with an autosomal recessive syndrome characterized by insulin-dependent diabetes mellitus and bilateral progressive optic atrophy, usually presenting in childhood or early adult life. Diverse neurologic symptoms, including a predisposition to psychiatric illness, may also be associated with this disorder. A large number and variety of mutations in this gene, particularly in exon 8, can be associated with this syndrome. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38. Mutations in this gene have also been associated with congenital cataracts.

WFS1 Wolframin is a protein that in humans is encoded by the WFS1 gene.[1][2][3] # Function Wolframin is a transmembrane protein.[3] Wolframin appears to function as a cation-selective ion channel.[4] # Clinical significance Mutations in this gene are associated with an autosomal recessive syndrome characterized by insulin-dependent diabetes mellitus and bilateral progressive optic atrophy, usually presenting in childhood or early adult life. Diverse neurologic symptoms, including a predisposition to psychiatric illness, may also be associated with this disorder. A large number and variety of mutations in this gene, particularly in exon 8, can be associated with this syndrome. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38.[3] Mutations in this gene have also been associated with congenital cataracts.[5]

https://www.wikidoc.org/index.php/WFS1

a33b60cddf04e9234321d98427a4e089a4fdb450

wikidoc

WNK1

WNK1 WNK (lysine deficient protein kinase 1), also known as WNK1, is an enzyme that is encoded by the WNK1 gene. WNK1 is serine-threonine kinase and part of the "with no lysine/K" kinase WNK family. The predominant role of WNK1 is the regulation of cation-Cl− cotransporters (CCCs) such as the sodium chloride cotransporter (NCC), basolateral Na-K-Cl symporter (NKCC1), and potassium chloride cotransporter (KCC1) located within the kidney. CCCs mediate ion homeostasis and modulate blood pressure by transporting ions in and out of the cell. WNK1 mutations as a result have been implicated in blood pressure disorders/diseases; a prime example being familial hyperkalemic hypertension (FHHt). # Structure The WNK1 protein is composed of 2382 amino acids (molecular weight 230 kDa). The protein contains a kinase domain located within its short N-terminaldomain and a long C-terminal tail. The kinase domain has some similarity to the MEKK protein kinase family. As a member of the WNK family, the kinase's catalytic lysine residue is uniquely located in beta strand 2 of the glycine loop. In order to have kinase activity, WNK1 must autophosphorylate the serine 382 residue found in its activation loop. Further, phosphorylation at another site (Ser378) increases WNK1 activity. An autoinhibitory domain is located within the C-terminal domain along with a HQ domain that is needed for WNK1 interactions with other WNKs. The interactions between WNKs play an important role in function; WNK1 mutants that lack an HQ domain also lack kinase activity. # Function The WNK1 gene encodes a cytoplasmic serine-threonine kinase expressed in the distal nephron. Studies have shown that WNK1 can activate multiple CCCs. WNK1 however, does not directly phosphorylate the CCCs themselves rather it phosphorylates other serine-threonine kinases: Sterile20 related proline-alanine-rich kinase (SPAK) and oxidative stress response kinase 1 (OXSR1). Phosphorylation of SPAK's T loop located in its catalytic domain will activate SPAK, which will go on to phosphorylation the CCC's N-terminaldomain. Hence, WNK1 activates CCCs indirectly as an upstream regulator of SPAK/OSR1. ## Sodium Reabsorption In the distal convoluted tubule (DCT), WNK1 is a potent activator of the NCC that results in an increase in sodium re absorption that drives an increase in blood pressure. The WNK1 mutant found in FHHt harbors a large deletion within intron 1 that causes an increase in the expression of full length WNK1. The boost in WNK1 leads to increases in NCC activation that promotes the high blood pressure/hypertension associated with FHHt. WNK1 activates the serum-and glucocorticoid-inducible protein kinase SGK1, leading to increased expression of the epithelial sodium channel (ENaC), which also promotes sodium re absorption. ## Potassium Secretion WNK1 regulates potassium channels found in the cortical collecting duct (CCD) and connecting tubule (CNT). Renal outer medullar potassium 1 (ROMK1) and large conductance calcium-activated potassium channel (BKCa) are the two primary channels for potassium secretion. WNK1 indirectly stimulates clathrin-dependent endocytosis of ROMK1 by a potential interaction with intersectin (ITSN1); thus, kinase activity is not needed. Another possible mechanism of ROMK1 regulation is via autosomal recessive hypercholeserolemia (ACH), which is a clathrin adaptor molecule. ACH phosphorylation by WNK1 promotes the translocation of ROMK1 to clathrin coated pits triggering endocytosis. WNK1 may indirectly activate BKCa by inhibiting the actions of extracellular signal–regulated kinases (ERK1 and ERK2) that lead to lysomal degradation. ## Cell Volume Regulation The NKCC1/2 cotransporters are regulated by intracellular Cl− concentration. Studies point to WNK1 as key effector that couples Cl− concentration to NKCC1/2 function. In hypertonic (high extracellular Cl− ) conditions that trigger cell shrinkage, an unknown mechanism upregulates WNK1 expression to counteract the volume loss. The increased WNK1 leads to activation of SPAK/OSR1 that activate NKCC1/2 via subsequent phosphorylation. NKCC1/2 will promote the influx of Na+, K+, and Cl− ions into the cell thereby causing the flow of water into the cell. In the reverse circumstances, where hypotonic (low extracellular Cl− ) conditions induce cell swelling, WNK1 is inhibited. Another cotransporter, KCC is inactive when phosphorylated; without activated WNK1, KCC does not undergo phosphorylation and can activate. The cotransporter will promote the efflux of K+ and Cl− ions and cause the flow of water out of the cell to combat swelling. ## WNK1 in the Brain In the mature brain, the GABA neurotransmitter represents the major inhibitory signal used in neuronal signaling. GABA activates the GABAA receptor which is a Cl− ion channel. Cl− ions will enter the neuron causing hyperpolarization and inhibition of signaling. During brain development however, GABAA activation will allow Cl− ions to leave the neuron causing the neuron to depolarize. Thus, GABA is an excitatory neurotransmitter during development. WNK1 has been implicated in the developmental switch from excitatory to inhibitory GABA signaling via interaction with NKCC1 and KCCs. WNK1 phosphorylates SPAK/OSR1 which then phosphorylates KCC2 inhibiting the flow of Cl− ions out of the cell during development. # Regulation of WNK1 The concentrations of Cl− ions and K+ ion play a major role in regulating WNK1 activity. In the DCT, the plasma concentration of K+ ion is thought to impact the concentration Cl− ions within the nephron. High plasma K+ concentration down regulates WNK1 activity and prevents Cl− ion from entering the nephron via the NCC. The opposite occurs when plasma K+ concentration is low; increased WNK1 activity boosts NCC activity promoting reabsorption of Cl− ions. When there is an abundance of Cl− ions within the nephron, WNK1 activity is inhibited by the binding of a Cl− ion to WNK1's catalytic domain. Furthermore, WNK1 and WNK4 may interact to form heterodimers that inhibit WNK1 function. WNK4 release from the heterodimer allows WNK1 monomer to bind another WNK1 monomer to promote activation. WNK1 function can also be inhibited if WNK1 is degraded. There are two enzymes responsible for WNK1 ubiquitination, kelch like 3 (KLHL3) and cullin 3 (CUL3). KLHL3 serves as an adaptor protein that promotes the interaction between WNK1 and Cullin3, which is in a complex containing an E3 ubquitin ligase that attaches the ubiquitin molecules to WNK1. The ubiquitinated WNK1 will subsequently undergo proteasomal degradation. # Clinical significance WNK1 has mutations associated with Gordon hyperkalemia-hypertension syndrome (pseudohypoaldosteronism Type II, featuring hypertension also called familial hyperkalemic hypertension (FHHt) ) and congenital sensory neuropathy (HSAN Type II, featuring loss of perception to pain, touch, and heat due to a loss of peripheral sensory nerves). See also: HSN2 gene. # Comparative genomics The gene belongs to a group of four related protein kinases (WNK1, WNK2, WNK3, WNK4). Homologs of this protein have been found in Arabidopsis thaliana, C. elegans, Chlamydomonas reinhardtii and Vitis viniferaas well as in vertebrates including Danio rerio and Taeniopygia guttata.

WNK1 WNK (lysine deficient protein kinase 1), also known as WNK1, is an enzyme that is encoded by the WNK1 gene.[1][2][3][4][5] WNK1 is serine-threonine kinase and part of the "with no lysine/K" kinase WNK family.[1][2][3][5] The predominant role of WNK1 is the regulation of cation-Cl− cotransporters (CCCs) such as the sodium chloride cotransporter (NCC), basolateral Na-K-Cl symporter (NKCC1), and potassium chloride cotransporter (KCC1) located within the kidney.[1][2][5] CCCs mediate ion homeostasis and modulate blood pressure by transporting ions in and out of the cell.[1] WNK1 mutations as a result have been implicated in blood pressure disorders/diseases; a prime example being familial hyperkalemic hypertension (FHHt).[1][2][3][4][5] # Structure The WNK1 protein is composed of 2382 amino acids (molecular weight 230 kDa).[4] The protein contains a kinase domain located within its short N-terminaldomain and a long C-terminal tail.[4] The kinase domain has some similarity to the MEKK protein kinase family.[4] As a member of the WNK family, the kinase's catalytic lysine residue is uniquely located in beta strand 2 of the glycine loop.[4] In order to have kinase activity, WNK1 must autophosphorylate the serine 382 residue found in its activation loop.[4][1] Further, phosphorylation at another site (Ser378) increases WNK1 activity.[1] An autoinhibitory domain is located within the C-terminal domain along with a HQ domain that is needed for WNK1 interactions with other WNKs.[1][2][3][4] The interactions between WNKs play an important role in function; WNK1 mutants that lack an HQ domain also lack kinase activity. # Function The WNK1 gene encodes a cytoplasmic serine-threonine kinase expressed in the distal nephron.[1][2][4] Studies have shown that WNK1 can activate multiple CCCs.[1][2] WNK1 however, does not directly phosphorylate the CCCs themselves rather it phosphorylates other serine-threonine kinases: Sterile20 related proline-alanine-rich kinase (SPAK) and oxidative stress response kinase 1 (OXSR1).[2][1][3] Phosphorylation of SPAK's T loop located in its catalytic domain will activate SPAK, which will go on to phosphorylation the CCC's N-terminaldomain.[1][2] Hence, WNK1 activates CCCs indirectly as an upstream regulator of SPAK/OSR1.[1][2][3] ## Sodium Reabsorption In the distal convoluted tubule (DCT), WNK1 is a potent activator of the NCC that results in an increase in sodium re absorption that drives an increase in blood pressure.[1][2][3] The WNK1 mutant found in FHHt harbors a large deletion within intron 1 that causes an increase in the expression of full length WNK1.[1][2][3][4] The boost in WNK1 leads to increases in NCC activation that promotes the high blood pressure/hypertension associated with FHHt.[1][2][3][4] WNK1 activates the serum-and glucocorticoid-inducible protein kinase SGK1, leading to increased expression of the epithelial sodium channel (ENaC), which also promotes sodium re absorption.[2] ## Potassium Secretion WNK1 regulates potassium channels found in the cortical collecting duct (CCD) and connecting tubule (CNT).[2] Renal outer medullar potassium 1 (ROMK1) and large conductance calcium-activated potassium channel (BKCa) are the two primary channels for potassium secretion.[2] WNK1 indirectly stimulates clathrin-dependent endocytosis of ROMK1 by a potential interaction with intersectin (ITSN1); thus, kinase activity is not needed.[2] Another possible mechanism of ROMK1 regulation is via autosomal recessive hypercholeserolemia (ACH), which is a clathrin adaptor molecule.[2] ACH phosphorylation by WNK1 promotes the translocation of ROMK1 to clathrin coated pits triggering endocytosis.[2] WNK1 may indirectly activate BKCa by inhibiting the actions of extracellular signal–regulated kinases (ERK1 and ERK2) that lead to lysomal degradation.[2] ## Cell Volume Regulation The NKCC1/2 cotransporters are regulated by intracellular Cl− concentration.[5] Studies point to WNK1 as key effector that couples Cl− concentration to NKCC1/2 function.[1][5] In hypertonic (high extracellular Cl− ) conditions that trigger cell shrinkage, an unknown mechanism upregulates WNK1 expression to counteract the volume loss.[1] The increased WNK1 leads to activation of SPAK/OSR1 that activate NKCC1/2 via subsequent phosphorylation.[1][5] NKCC1/2 will promote the influx of Na+, K+, and Cl− ions into the cell thereby causing the flow of water into the cell.[1] In the reverse circumstances, where hypotonic (low extracellular Cl− ) conditions induce cell swelling, WNK1 is inhibited.[1] Another cotransporter, KCC is inactive when phosphorylated; without activated WNK1, KCC does not undergo phosphorylation and can activate.[1] The cotransporter will promote the efflux of K+ and Cl− ions and cause the flow of water out of the cell to combat swelling.[1] ## WNK1 in the Brain In the mature brain, the GABA neurotransmitter represents the major inhibitory signal used in neuronal signaling.[1] GABA activates the GABAA receptor which is a Cl− ion channel.[1] Cl− ions will enter the neuron causing hyperpolarization and inhibition of signaling.[1] During brain development however, GABAA activation will allow Cl− ions to leave the neuron causing the neuron to depolarize.[1] Thus, GABA is an excitatory neurotransmitter during development.[1] WNK1 has been implicated in the developmental switch from excitatory to inhibitory GABA signaling via interaction with NKCC1 and KCCs.[1] WNK1 phosphorylates SPAK/OSR1 which then phosphorylates KCC2 inhibiting the flow of Cl− ions out of the cell during development.[1] # Regulation of WNK1 The concentrations of Cl− ions and K+ ion play a major role in regulating WNK1 activity.[1][5] In the DCT, the plasma concentration of K+ ion is thought to impact the concentration Cl− ions within the nephron.[1][5] High plasma K+ concentration down regulates WNK1 activity and prevents Cl− ion from entering the nephron via the NCC.[1][5] The opposite occurs when plasma K+ concentration is low; increased WNK1 activity boosts NCC activity promoting reabsorption of Cl− ions.[1][5] When there is an abundance of Cl− ions within the nephron, WNK1 activity is inhibited by the binding of a Cl− ion to WNK1's catalytic domain.[1][5] Furthermore, WNK1 and WNK4 may interact to form heterodimers that inhibit WNK1 function.[3][2] WNK4 release from the heterodimer allows WNK1 monomer to bind another WNK1 monomer to promote activation.[2][3] WNK1 function can also be inhibited if WNK1 is degraded. There are two enzymes responsible for WNK1 ubiquitination, kelch like 3 (KLHL3) and cullin 3 (CUL3).[3][2][6] KLHL3 serves as an adaptor protein that promotes the interaction between WNK1 and Cullin3, which is in a complex containing an E3 ubquitin ligase that attaches the ubiquitin molecules to WNK1.[3] The ubiquitinated WNK1 will subsequently undergo proteasomal degradation.[3][2][6] # Clinical significance WNK1 has mutations associated with Gordon hyperkalemia-hypertension syndrome (pseudohypoaldosteronism Type II, featuring hypertension also called familial hyperkalemic hypertension (FHHt) )[1][3][4] and congenital sensory neuropathy (HSAN Type II, featuring loss of perception to pain, touch, and heat due to a loss of peripheral sensory nerves).[1][7] See also: HSN2 gene. # Comparative genomics The gene belongs to a group of four related protein kinases (WNK1, WNK2, WNK3, WNK4).[1][3][4] Homologs of this protein have been found in Arabidopsis thaliana, C. elegans, Chlamydomonas reinhardtii and Vitis viniferaas well as in vertebrates including Danio rerio and Taeniopygia guttata.[3]

https://www.wikidoc.org/index.php/WNK1

46b6e8d34b7a77bcb3b14cc72c9c076e5c2af27b

wikidoc

WNK4

WNK4 Serine/threonine-protein kinase WNK4 also known as WNK lysine deficient protein kinase 4 or WNK4, is an enzyme that in humans is encoded by the WNK4 gene.. Missense mutations cause a genetic form of pseudohypoaldosteronism type 2, also called Gordon syndrome. # Function The WNK4 gene encodes a serine-threonine kinase expressed in distal nephron. Its primary role in renal physiology is as a molecular switch between the angiotensin II–aldosterone mediated volume retention and the aldosterone mediated potassium wasting. This is achieved by regulating the sodium-chloride symporter (NCC), that is uniquely expressed in the distal nephron and is sensitive to thiazide type diuretics. Under basal conditions (low circulating Ang II and low Aldosterone), WNK4 will inhibit NCC function. It has been proposed that in the event of hyperkalemia and an increased secretion of aldosterone (which will upregulate both ENac and ROMK), this inhibition of NCC, will allow an increase in the arrival of sodium to the distal nephron (rich in ENaC and ROMK) which will allow the exchange of sodium for potassium ions, thereby reducing plasma potassium levels, without increasing sodium chloride retention (which is always accompanied by volume expansion). Furthermore, it has been proposed that in the presence of AngII the WNK4 mediated NCC inhibition will be suppressed thereby increasing sodium-chloride reabsorption in the distal convoluted tubule. This along with the concomitant increase in passive water reabsortion due to the increased salt load in the distal convluted tubule cells will ultimately increase circulating volume.

WNK4 Serine/threonine-protein kinase WNK4 also known as WNK lysine deficient protein kinase 4 or WNK4, is an enzyme that in humans is encoded by the WNK4 gene.[1]. Missense mutations cause a genetic form of pseudohypoaldosteronism type 2, also called Gordon syndrome. # Function The WNK4 gene encodes a serine-threonine kinase expressed in distal nephron.[1] Its primary role in renal physiology is as a molecular switch between the angiotensin II–aldosterone mediated volume retention and the aldosterone mediated potassium wasting. This is achieved by regulating the sodium-chloride symporter (NCC), that is uniquely expressed in the distal nephron and is sensitive to thiazide type diuretics.[2] Under basal conditions (low circulating Ang II and low Aldosterone), WNK4 will inhibit NCC function. It has been proposed that in the event of hyperkalemia and an increased secretion of aldosterone (which will upregulate both ENac and ROMK), this inhibition of NCC, will allow an increase in the arrival of sodium to the distal nephron (rich in ENaC and ROMK) which will allow the exchange of sodium for potassium ions, thereby reducing plasma potassium levels, without increasing sodium chloride retention (which is always accompanied by volume expansion). Furthermore, it has been proposed that in the presence of AngII the WNK4 mediated NCC inhibition will be suppressed thereby increasing sodium-chloride reabsorption in the distal convoluted tubule. This along with the concomitant increase in passive water reabsortion due to the increased salt load in the distal convluted tubule cells will ultimately increase circulating volume.[3]

https://www.wikidoc.org/index.php/WNK4

2a3546cf7c1386e49bd025dfdb9b0aa153f437b1

wikidoc

WNT4

WNT4 WNT4 is a secreted protein that in humans is encoded by the Wnt4 gene, found on chromosome 1. It promotes female sex development and represses male sex development. Loss of function can have serious consequences, such as female to male sex reversal. # Function The WNT gene family consists of structurally related genes that encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and embryogenesis. ## Pregnancy WNT4 is involved in a couple features of pregnancy as a downstream target of BMP2. For example, it regulates endometrial stromal cell proliferation, survival, and differentiation. These processes are all necessary for the development of an embryo. Ablation in female mice results in subfertility, with defects in implantation and decidualization. For instance, there is a decrease in responsiveness to progesterone signaling. Furthermore, postnatal uterine differentiation is characterized by a reduction in gland numbers and the stratification of the luminal epithelium. ## Sexual development ### Early gonads Gonads arise from the thickening of coelomic epithelium, which at first appears as multiple cell layers. They later commit to sex determination, becoming either female or male under normal circumstances. Regardless of sex, though, WNT4 is needed for cell proliferation. In mouse gonads, it has been detected only eleven days after fertilization. If deficient in XY mice, there is a delay in Sertoli cell differentiation. Moreover, there is delay in sex cord formation. These issues are usually compensated for at birth. WNT4 also interacts with RSPO1 early in development. If both are deficient in XY mice, the outcome is less expression of SRY and downstream targets. Furthermore, the amount of SOX9 is reduced and defects in vascularization are found. These occurrences result in testicular hypoplasia. Male to female sex reversal, however, does not occur because Leydig cells remain normal. They are maintained by steroidogenic cells, now unrepressed. ### Ovaries WNT4 is required for female sex development. Upon secretion it binds to Frizzled receptors, activating a number of molecular pathways. One important example is the stabilization of β catenin, which increases the expression of target genes. For instance, TAFIIs 105 is now encoded, a subunit of the TATA binding protein for RNA polymerase in ovarian follicle cells. Without it, female mice have small ovaries with less mature follicles. In addition, the production of SOX9 is blocked. In humans, WNT4 also suppresses 5-α reductase activity, which converts testosterone into dihydrotestosterone. External male genitalia are therefore not formed. Moreover, it contributes to the formation of the Müllerian duct, a precursor to female reproductive organs. ### Male sexual development The absence of WNT4 is required for male sex development. FGF signaling suppresses WNT4, acting in a feed forward loop triggered by SOX9. If this signaling is deficient in XY mice, female genes are unrepressed. With no FGF2, there is a partial sex reversal. With no FGF9, there is a full sex reversal. Both cases are rescued, though, by a WNT4 deletion. In these double mutants, the resulting somatic cells are normal. ## Kidneys WNT4 is essential for nephrogenesis. It regulates kidney tubule induction and the mesenchymal to epithelial transformation in the cortical region. In addition, it influences the fate of the medullary stroma during development. Without it, smooth muscle α actin is markedly reduced. This occurrence causes pericyte deficiency around the vessels, leading to a defect in maturation. WNT4 probably functions by activating BMP4, a known smooth muscle differentiation factor. ## Muscles WNT4 contributes to the formation of the neuromuscular junction in vertebrates. Expression is high during the creation of first synaptic contacts, but subsequently downregulated. Moreover, loss of function causes a 35 percent decrease in the number of acetylcholine receptors. Overexpression, however, causes an increase. These events alter fiber type composition with the production of more slow fibers. Lastly, MuSK is the receptor for WNT4, activated through tyrosine phosphorylation. It contains a CRD domain similar to Frizzled receptors. ## Lungs WNT4 is also associated with lung formation and has a role in the formation of the respiratory system. When WNT4 is knocked out, there are many problems that occur in lung development. It has been shown that when WNT4 is knocked out, the lung buds formed are reduced in size and proliferation has greatly diminished which cause underdeveloped or incomplete development of the lungs. It also causes tracheal abnormalities because it affects the tracheal cartilage ring formation. Lastly, the absence of WNT4 also affects the expression of other genes that function in lung development such as Sox9 and FGF9. # Clinical significance ## Deficiency Several mutations are known to cause loss of function in WNT4. One example is a heterozygous C to T transition in exon 2. This causes an arginine to cysteine substitution at amino acid position 83, a conserved location. The formation of illegitimate sulfide bonds creates a misfolded protein, resulting in loss of function. In XX humans, WNT4 now cannot stabilize β-catenin. Furthermore, steroidogenic enzymes like CYP17A1 and HSD3B2 are not suppressed, leading to an increase in testosterone production. Along with this androgen excess, patients have no uteruses. Other Müllerian abnormalities, however, are not found. This disorder is therefore distinct from classic Mayer-Rokitansky-Kuster-Hauser syndrome. ## SERKAL syndrome A disruption of WNT4 synthesis in XX humans produces SERKAL syndrome. The genetic mutation is a homozygous C to T transition at cDNA position 341. This causes an alanine to valine residue substitution at amino acid position 114, a location highly conserved in all organisms, including zebrafish and Drosophila. The result is loss of function, which affects mRNA stability. Ultimately it causes female to male sex reversal. ## Mayer-Rokitansky-Kuster-Hauser Syndrome WNT4 has been clearly implicated in the atypical version of Mayer-Rokitansky-Kuster-Hauser Syndromefound in XX humans. A genetic mutation causes a leucine to proline residue substitution at amino acid position 12. This occurrence reduces the intranuclear levels of β-catenin. In addition, it removes the inhibition of steroidogenic enzymes like 3β-hydroxysteriod dehydrogenase and 17α-hydroxylase. Patients usually have uterine hypoplasia, which is associated with biological symptoms of androgen excess. Furthermore, Müllerian abnormalities are often found.

WNT4 WNT4 is a secreted protein that in humans is encoded by the Wnt4 gene, found on chromosome 1.[1][2] It promotes female sex development and represses male sex development. Loss of function can have serious consequences, such as female to male sex reversal. # Function The WNT gene family consists of structurally related genes that encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and embryogenesis.[1] ## Pregnancy WNT4 is involved in a couple features of pregnancy as a downstream target of BMP2. For example, it regulates endometrial stromal cell proliferation, survival, and differentiation.[3] These processes are all necessary for the development of an embryo. Ablation in female mice results in subfertility, with defects in implantation and decidualization. For instance, there is a decrease in responsiveness to progesterone signaling. Furthermore, postnatal uterine differentiation is characterized by a reduction in gland numbers and the stratification of the luminal epithelium.[3] ## Sexual development ### Early gonads Gonads arise from the thickening of coelomic epithelium, which at first appears as multiple cell layers. They later commit to sex determination, becoming either female or male under normal circumstances. Regardless of sex, though, WNT4 is needed for cell proliferation.[4] In mouse gonads, it has been detected only eleven days after fertilization. If deficient in XY mice, there is a delay in Sertoli cell differentiation. Moreover, there is delay in sex cord formation. These issues are usually compensated for at birth.[4] WNT4 also interacts with RSPO1 early in development. If both are deficient in XY mice, the outcome is less expression of SRY and downstream targets.[4] Furthermore, the amount of SOX9 is reduced and defects in vascularization are found. These occurrences result in testicular hypoplasia. Male to female sex reversal, however, does not occur because Leydig cells remain normal. They are maintained by steroidogenic cells, now unrepressed.[4] ### Ovaries WNT4 is required for female sex development. Upon secretion it binds to Frizzled receptors, activating a number of molecular pathways. One important example is the stabilization of β catenin, which increases the expression of target genes.[5] For instance, TAFIIs 105 is now encoded, a subunit of the TATA binding protein for RNA polymerase in ovarian follicle cells. Without it, female mice have small ovaries with less mature follicles. In addition, the production of SOX9 is blocked.[6] In humans, WNT4 also suppresses 5-α reductase activity, which converts testosterone into dihydrotestosterone. External male genitalia are therefore not formed. Moreover, it contributes to the formation of the Müllerian duct, a precursor to female reproductive organs.[5] ### Male sexual development The absence of WNT4 is required for male sex development. FGF signaling suppresses WNT4, acting in a feed forward loop triggered by SOX9. If this signaling is deficient in XY mice, female genes are unrepressed.[7] With no FGF2, there is a partial sex reversal. With no FGF9, there is a full sex reversal. Both cases are rescued, though, by a WNT4 deletion. In these double mutants, the resulting somatic cells are normal.[7] ## Kidneys WNT4 is essential for nephrogenesis. It regulates kidney tubule induction and the mesenchymal to epithelial transformation in the cortical region. In addition, it influences the fate of the medullary stroma during development. Without it, smooth muscle α actin is markedly reduced. This occurrence causes pericyte deficiency around the vessels, leading to a defect in maturation. WNT4 probably functions by activating BMP4, a known smooth muscle differentiation factor.[8] ## Muscles WNT4 contributes to the formation of the neuromuscular junction in vertebrates. Expression is high during the creation of first synaptic contacts, but subsequently downregulated.[9] Moreover, loss of function causes a 35 percent decrease in the number of acetylcholine receptors. Overexpression, however, causes an increase. These events alter fiber type composition with the production of more slow fibers. Lastly, MuSK is the receptor for WNT4, activated through tyrosine phosphorylation. It contains a CRD domain similar to Frizzled receptors.[9] ## Lungs WNT4 is also associated with lung formation and has a role in the formation of the respiratory system. When WNT4 is knocked out, there are many problems that occur in lung development. It has been shown that when WNT4 is knocked out, the lung buds formed are reduced in size and proliferation has greatly diminished which cause underdeveloped or incomplete development of the lungs. It also causes tracheal abnormalities because it affects the tracheal cartilage ring formation. Lastly, the absence of WNT4 also affects the expression of other genes that function in lung development such as Sox9 and FGF9.[10] # Clinical significance ## Deficiency Several mutations are known to cause loss of function in WNT4. One example is a heterozygous C to T transition in exon 2.[11] This causes an arginine to cysteine substitution at amino acid position 83, a conserved location. The formation of illegitimate sulfide bonds creates a misfolded protein, resulting in loss of function. In XX humans, WNT4 now cannot stabilize β-catenin.[11] Furthermore, steroidogenic enzymes like CYP17A1 and HSD3B2 are not suppressed, leading to an increase in testosterone production. Along with this androgen excess, patients have no uteruses. Other Müllerian abnormalities, however, are not found. This disorder is therefore distinct from classic Mayer-Rokitansky-Kuster-Hauser syndrome.[11] ## SERKAL syndrome A disruption of WNT4 synthesis in XX humans produces SERKAL syndrome. The genetic mutation is a homozygous C to T transition at cDNA position 341.[5] This causes an alanine to valine residue substitution at amino acid position 114, a location highly conserved in all organisms, including zebrafish and Drosophila. The result is loss of function, which affects mRNA stability. Ultimately it causes female to male sex reversal.[5] ## Mayer-Rokitansky-Kuster-Hauser Syndrome WNT4 has been clearly implicated in the atypical version of Mayer-Rokitansky-Kuster-Hauser Syndromefound in XX humans. A genetic mutation causes a leucine to proline residue substitution at amino acid position 12.[12] This occurrence reduces the intranuclear levels of β-catenin. In addition, it removes the inhibition of steroidogenic enzymes like 3β-hydroxysteriod dehydrogenase and 17α-hydroxylase. Patients usually have uterine hypoplasia, which is associated with biological symptoms of androgen excess. Furthermore, Müllerian abnormalities are often found.[12]

https://www.wikidoc.org/index.php/WNT4

0ba2a0f1558375c18cbd9d78a74d822ecf447924

wikidoc

WNT6

WNT6 Wingless-type MMTV integration site family, member 6, also known as WNT6, is a human gene. The WNT gene family consists of structurally related genes that encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is a member of the WNT gene family, which are involved in the Wnt signaling pathway. It is overexpressed in cervical cancer cell line and strongly coexpressed with another family member, WNT10A, in colorectal cancer cell line. The gene overexpression may play key roles in carcinogenesis. This gene and the WNT10A gene are clustered in the chromosome 2q35 region. The protein encoded by this gene is 97% identical to the mouse Wnt6 protein at the amino acid level. Role in Development Wnt6 plays a role in the formation and maturation of different embryonic structures, namely the fetal heart, ventral body wall, and somite derived structures. Wnt6, through the canonical Wnt signaling pathway, inhibits the induction of cardiogenic mesoderm. For this reason, Wnt6 inhibitors like Cerberus must be present to allow the cells to be induced. Knockout models show that without Wnt6 the fetus develops an enlarged heart, while upregulating Wnt6 results in the heart being underdeveloped. Several Wnts, including Wnt6, have shown to be involved in the formation of the ventral body wall and when inhibited result in birth defects such as failure of the wall to close, hypoplasia of the musculature, and other defects. Following the formation of the somites from the Paraxial Mesoderm, the outermost cells of the somites undergo a mesenchymal to epithelial transition. Wnt6 is expressed by the overlying ectoderm and promotes the production of Paraxis, which facilitates the transition. While many structures will still form if Wnt6 is knocked out, the structures (ribs, vertebra, and muscles) are fused and not organized properly. On the other hand, if Wnt6 is upregulated, muscle in the limbs and surrounding areas are decreased as the mesenchymal progenitor cells that migrate and become the muscle are locked in the somite as epithelial cells.

WNT6 Wingless-type MMTV integration site family, member 6, also known as WNT6, is a human gene.[1][2] The WNT gene family consists of structurally related genes that encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is a member of the WNT gene family, which are involved in the Wnt signaling pathway. It is overexpressed in cervical cancer cell line and strongly coexpressed with another family member, WNT10A, in colorectal cancer cell line.[3] The gene overexpression may play key roles in carcinogenesis. This gene and the WNT10A gene are clustered in the chromosome 2q35 region. The protein encoded by this gene is 97% identical to the mouse Wnt6 protein at the amino acid level.[1] Role in Development Wnt6 plays a role in the formation and maturation of different embryonic structures, namely the fetal heart, ventral body wall, and somite derived structures. Wnt6, through the canonical Wnt signaling pathway, inhibits the induction of cardiogenic mesoderm.[4] For this reason, Wnt6 inhibitors like Cerberus must be present to allow the cells to be induced.[4] Knockout models show that without Wnt6 the fetus develops an enlarged heart, while upregulating Wnt6 results in the heart being underdeveloped.[4] Several Wnts, including Wnt6, have shown to be involved in the formation of the ventral body wall and when inhibited result in birth defects such as failure of the wall to close, hypoplasia of the musculature, and other defects.[5] Following the formation of the somites from the Paraxial Mesoderm, the outermost cells of the somites undergo a mesenchymal to epithelial transition.[6] Wnt6 is expressed by the overlying ectoderm and promotes the production of Paraxis, which facilitates the transition.[6] While many structures will still form if Wnt6 is knocked out, the structures (ribs, vertebra, and muscles) are fused and not organized properly.[6] On the other hand, if Wnt6 is upregulated, muscle in the limbs and surrounding areas are decreased as the mesenchymal progenitor cells that migrate and become the muscle are locked in the somite as epithelial cells.[6]

https://www.wikidoc.org/index.php/WNT6

906cc276861004e1f510d11957fa750f87e81a96

wikidoc

WWC1

WWC1 Protein KIBRA also known as kidney and brain expressed protein (KIBRA) or WW domain-containing protein 1 (WWC1) is a protein that in humans is encoded by the WWC1 gene. # Research on human memory A single nucleotide polymorphism (rs17070145) in the gene has been associated with human memory performance in one 2006 study. While no significant support for KIBRA's association with memory was found in a 2008 study with 584 subjects, the original 2006 study was replicated in a smaller sample of an elderly population in 2008. A subsequent study in 2009 in two large UK samples indicated that KIBRA is specifically associated with forgetting of non-semantic material. Studies have also begun to investigate the role of KIBRA in Alzheimer's disease. # Interactions KIBRA has at least 10 interaction partners, including synaptopodin, PKCζ and Dendrin, most of which modify synaptic plasticity. For instance, Dendrin is a post-synaptic protein with expression regulated by sleep deprivation. KIBRA has been shown to interact with Protein kinase Mζ.

WWC1 Protein KIBRA also known as kidney and brain expressed protein (KIBRA) or WW domain-containing protein 1 (WWC1) is a protein that in humans is encoded by the WWC1 gene.[1][2][3] # Research on human memory A single nucleotide polymorphism (rs17070145) [4] in the gene has been associated with human memory performance in one 2006 study.[5] While no significant support for KIBRA's association with memory was found in a 2008 study with 584 subjects,[6] the original 2006 study was replicated in a smaller sample of an elderly population in 2008.[7] A subsequent study in 2009 in two large UK samples indicated that KIBRA is specifically associated with forgetting of non-semantic material.[8] Studies have also begun to investigate the role of KIBRA in Alzheimer's disease.[9] # Interactions KIBRA has at least 10 interaction partners, including synaptopodin, PKCζ and Dendrin, most of which modify synaptic plasticity. For instance, Dendrin is a post-synaptic protein with expression regulated by sleep deprivation.[10] KIBRA has been shown to interact with Protein kinase Mζ.[11]

https://www.wikidoc.org/index.php/WWC1

1a8c2996b59645e5046e6d611b0247d7ce1849ed

wikidoc

WWC2

WWC2 WW and C2 domain containing 2 (WWC2) is a protein that in humans is encoded by the WWC2 gene (4q35.1). Though function of WWC2 remains unknown, it has been predicted that WWC2 may play a role in cancer. # Gene Locus The human gene WWC2 is found on chromosome 4 at band 4q35.1. The gene is found on the plus strand of the chromosome and is 8,822 base pairs long. The gene contains 23 exons. The WWC2 locus is quite complex and appears to produce several proteins with no sequence overlap Aliases A common alias of the gene is BH3-Only Member B (BOMB) # Homology Paralogs There are two paralogs of WWC2 found in humans, WWC1 and WWC3. WWC1 is located on chromosome 5 and is a probable regulator of the Hippo signaling pathway that plays a role in tumor suppression by restricting proliferation and promoting apoptosis. WWC3 is located on chromosome X and not much is known about its function. Orthologs WWC2 is highly conserved in Mammalia, Aves, Reptilia, and Amphibia, as well as the rare coelacanth, which is more closely related to lungfish, reptiles, and mammals than ray finned fish. WWC2 is conserved in some Actinopterygii, Gastropoda, and Bivalvia. However, WWC2 is not well conserved in Insecta. # Protein Primary sequence The gene encodes a protein also called WWC2 which is 1,192 amino acids long. The molecular weight of the protein is 133.9 kilodaltons. The protein is serine rich with no charge clusters, hydrophobic segments or transmembrane domains. The isoelectric point is 5.23800 Domains and motifs WWC2 is a member of the WWC protein family which consists of a WW domain and a C2 domain. WWC2 contains two WW domains and one C2 domain. WWC2 also contains two domains of unknown function, DUF342 and DUF444. A leucine zipper is located at position 854. Post translational modifications The WWC2 protein is predicted to be highly phosphorylated. There are 89 predicted sites of serine phosphorylation, 17 predicted sites of threonine phosphorylation, and 11 predicted sites of tyrosine phosphorylation. These numbers were relatively consistent in orthologous proteins. It is also predicted that p38 mitogen-activated protein kinases and glycogen synthase kinase 3 bind at position T3, and casein kinase 2 binds at positions S13 and T50. # Expression Expression WWC2 is expressed at a low level, and is tissue specific to the uterus, thyroid, lung, and liver. WWC2 expression is found to be elevated in the blastocyst and fetal stages of development. Transcript variants Many transcript variants exist for WWC2. Those that change a highly conserved amino acid residue, or surround a highly conserved amino acid residue are listed below: # Interacting proteins Transcription factors Transcription factors with highest matrix scores that bind to sequences within the promoter (ID GXP_1499160) are shown below: - STAT (signal transducer and activator of transcription) - Muscle TATA box - NOLF (neuron-specific olfactory factor) - XCPE (X gene core promoter element 1) - CTCF (CCCTC-binding factor) - HDBP (Huntington's disease gene regulatory region) - OCT1 (octamer binding protein) - E2FF (E2F-myc activator cell cycle regulator) - ZF57 (KRAB domain zinc finger protein 57) - ZF07 (C2H2 zinc finger transcription factor 7) - EGRF (EGR/nerve growth factor induced protein) - CDEF (cell cycle dependent element - CDF-1 binding site) - AP2F (activator protein 2) Proteins Potential interacting proteins include: YWHAZ, YWHAQ, RUVBL1, and REPS1. # Clinical significance and Current bioinformation While the exact function of WWC2 remains unknown, several mutations and variants of WWC2 have been researched in disease. A novel missense mutation in WWC2 was analyzed in Restless Leg Syndrome, but was not identified as a candidate gene. One study examined the role of Drosophila KIBRA (WWC1) in the Expanded-Hippo-Warts signaling cascade, which is involved with tumor suppression. The study stated that copy number aberration, translocation, and point mutations of WWC2, as well as other genes, should be further investigated in human cancers. WWC2 alias, BOMB, was researched in a grant suggesting that BOMB, along with two other genes (APOL6 and APOL1) promoted cell death in p53-null HCT116 cells.

WWC2 WW and C2 domain containing 2 (WWC2) is a protein that in humans is encoded by the WWC2 gene (4q35.1). Though function of WWC2 remains unknown, it has been predicted that WWC2 may play a role in cancer. # Gene Locus The human gene WWC2 is found on chromosome 4 at band 4q35.1. The gene is found on the plus strand of the chromosome and is 8,822 base pairs long. The gene contains 23 exons. The WWC2 locus is quite complex and appears to produce several proteins with no sequence overlap[1] Aliases A common alias of the gene is BH3-Only Member B (BOMB)[2] # Homology Paralogs There are two paralogs of WWC2 found in humans, WWC1 and WWC3. WWC1 is located on chromosome 5 and is a probable regulator of the Hippo signaling pathway that plays a role in tumor suppression by restricting proliferation and promoting apoptosis.[3] WWC3 is located on chromosome X and not much is known about its function. Orthologs WWC2 is highly conserved in Mammalia, Aves, Reptilia, and Amphibia, as well as the rare coelacanth, which is more closely related to lungfish, reptiles, and mammals than ray finned fish. WWC2 is conserved in some Actinopterygii, Gastropoda, and Bivalvia. However, WWC2 is not well conserved in Insecta. # Protein Primary sequence The gene encodes a protein also called WWC2 which is 1,192 amino acids long. The molecular weight of the protein is 133.9 kilodaltons.[4] The protein is serine rich with no charge clusters, hydrophobic segments or transmembrane domains. The isoelectric point is 5.23800[5] Domains and motifs WWC2 is a member of the WWC protein family[6] which consists of a WW domain and a C2 domain. WWC2 contains two WW domains and one C2 domain. WWC2 also contains two domains of unknown function, DUF342 and DUF444. A leucine zipper is located at position 854. Post translational modifications The WWC2 protein is predicted to be highly phosphorylated.[7] There are 89 predicted sites of serine phosphorylation, 17 predicted sites of threonine phosphorylation, and 11 predicted sites of tyrosine phosphorylation. These numbers were relatively consistent in orthologous proteins. It is also predicted that p38 mitogen-activated protein kinases and glycogen synthase kinase 3 bind at position T3, and casein kinase 2 binds at positions S13 and T50.[8] # Expression Expression WWC2 is expressed at a low level, and is tissue specific to the uterus, thyroid, lung, and liver. WWC2 expression is found to be elevated in the blastocyst and fetal stages of development. Transcript variants Many transcript variants exist for WWC2. Those that change a highly conserved amino acid residue, or surround a highly conserved amino acid residue are listed below: # Interacting proteins Transcription factors Transcription factors with highest matrix scores that bind to sequences within the promoter (ID GXP_1499160) are shown below: - STAT (signal transducer and activator of transcription) - Muscle TATA box - NOLF (neuron-specific olfactory factor) - XCPE (X gene core promoter element 1) - CTCF (CCCTC-binding factor) - HDBP (Huntington's disease gene regulatory region) - OCT1 (octamer binding protein) - E2FF (E2F-myc activator cell cycle regulator) - ZF57 (KRAB domain zinc finger protein 57) - ZF07 (C2H2 zinc finger transcription factor 7) - EGRF (EGR/nerve growth factor induced protein) - CDEF (cell cycle dependent element - CDF-1 binding site) - AP2F (activator protein 2) Proteins Potential interacting proteins include: YWHAZ, YWHAQ, RUVBL1, and REPS1. # Clinical significance and Current bioinformation While the exact function of WWC2 remains unknown, several mutations and variants of WWC2 have been researched in disease. A novel missense mutation in WWC2 was analyzed in Restless Leg Syndrome, but was not identified as a candidate gene.[9] One study examined the role of Drosophila KIBRA (WWC1) in the Expanded-Hippo-Warts signaling cascade, which is involved with tumor suppression. The study stated that copy number aberration, translocation, and point mutations of WWC2, as well as other genes, should be further investigated in human cancers.[10] WWC2 alias, BOMB, was researched in a grant suggesting that BOMB, along with two other genes (APOL6 and APOL1) promoted cell death in p53-null HCT116 cells.

https://www.wikidoc.org/index.php/WWC2

9479169df57f8a405ef0032a9b7ca2afebdacd21

wikidoc

WWOX

WWOX WW domain-containing oxidoreductase is an enzyme that in humans is encoded by the WWOX gene. # Function WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellular functions such as protein degradation, transcription, and RNA splicing. This gene encodes a protein which contains 2 WW domains and a short-chain dehydrogenase/reductase domain (SRD). The highest normal expression of this gene is detected in hormonally regulated tissues such as testis, ovary, and prostate. This expression pattern and the presence of an SRD domain suggest a role for this gene in steroid metabolism. The encoded protein is more than 90% identical to the mouse protein, which is an essential mediator of tumor necrosis factor-alpha-induced apoptosis, suggesting a similar, important role in apoptosis for the human protein. In addition, there is evidence that this gene behaves as a suppressor of tumor growth. Alternative splicing of this gene generates transcript variants that encode different isoforms. WWOX is also known as human accelerated region 6. It may, therefore, have played a key role in differentiating humans from apes. # Interactions WWOX has been shown to interact with P53 and ACK1.

WWOX WW domain-containing oxidoreductase is an enzyme that in humans is encoded by the WWOX gene.[1][2][3][4] # Function WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellular functions such as protein degradation, transcription, and RNA splicing. This gene encodes a protein which contains 2 WW domains and a short-chain dehydrogenase/reductase domain (SRD). The highest normal expression of this gene is detected in hormonally regulated tissues such as testis, ovary, and prostate. This expression pattern and the presence of an SRD domain suggest a role for this gene in steroid metabolism. The encoded protein is more than 90% identical to the mouse protein, which is an essential mediator of tumor necrosis factor-alpha-induced apoptosis, suggesting a similar, important role in apoptosis for the human protein. In addition, there is evidence that this gene behaves as a suppressor of tumor growth. Alternative splicing of this gene generates transcript variants that encode different isoforms.[4] WWOX is also known as human accelerated region 6. It may, therefore, have played a key role in differentiating humans from apes.[5] # Interactions WWOX has been shown to interact with P53 and ACK1.[6][7]

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

1496d1646358c1da7071cd13c85aa4ed5d86158c

wikidoc

WWP2

WWP2 NEDD4-like E3 ubiquitin-protein ligase WWP2 also known as atrophin-1-interacting protein 2 (AIP2) or WW domain-containing protein 2 (WWP2) is an enzyme that in humans is encoded by the WWP2 gene. # Function This gene encodes a member of the NEDD4-like protein family. The family of proteins is known to possess ubiquitin-protein ligase activity. The encoded protein contains 4 tandem WW domains. The WW domain is a protein motif consisting of 35 to 40 amino acids and is characterized by 4 conserved aromatic residues. The WW domain may mediate specific protein–protein interactions. Three alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. # Interactions WWP2 has been shown to interact with SCNN1B and ATN1. # Clinical significance Full-length WWP2 (WWP2-FL), together with N-terminal, (WWP2-N); C-terminal (WWP2-C) isoforms bind to SMAD proteins. WWP2-FL interacts with SMAD2, SMAD3 and SMAD7 in the TGF-β pathway. The WWP2-N isoform interacts with SMAD2 and SMAD3, whereas WWP2-C interacts only with SMAD7. Disruption of interactions between WWP2 and SMAD7 can stabilize SMAD7 protein levels and prevent TGF-β induced Epithelial-mesenchymal transition. Hence inhibiting WWP2 may in turn lead to the disabling of an inhibitor that normally controls cell growth and tumorogenesis. In tissue cultures lacking the inhibitor SMAD7, cancer cells spread rapidly, so that silencing WWP2 prevented the spread.

WWP2 NEDD4-like E3 ubiquitin-protein ligase WWP2 also known as atrophin-1-interacting protein 2 (AIP2) or WW domain-containing protein 2 (WWP2) is an enzyme that in humans is encoded by the WWP2 gene.[1][2][3] # Function This gene encodes a member of the NEDD4-like protein family. The family of proteins is known to possess ubiquitin-protein ligase activity. The encoded protein contains 4 tandem WW domains. The WW domain is a protein motif consisting of 35 to 40 amino acids and is characterized by 4 conserved aromatic residues. The WW domain may mediate specific protein–protein interactions. Three alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[3] # Interactions WWP2 has been shown to interact with SCNN1B[2][4] and ATN1.[5] # Clinical significance Full-length WWP2 (WWP2-FL), together with N-terminal, (WWP2-N); C-terminal (WWP2-C) isoforms bind to SMAD proteins. WWP2-FL interacts with SMAD2, SMAD3 and SMAD7 in the TGF-β pathway. The WWP2-N isoform interacts with SMAD2 and SMAD3, whereas WWP2-C interacts only with SMAD7. Disruption of interactions between WWP2 and SMAD7 can stabilize SMAD7 protein levels and prevent TGF-β induced Epithelial-mesenchymal transition. Hence inhibiting WWP2 may in turn lead to the disabling of an inhibitor that normally controls cell growth and tumorogenesis. In tissue cultures lacking the inhibitor SMAD7, cancer cells spread rapidly, so that silencing WWP2 prevented the spread.[6]

https://www.wikidoc.org/index.php/WWP2

f7200da887048ba271cfeaad2ff26f9fc419fcef

wikidoc

Wee1

Wee1 Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe (S. pombe). Wee1 has a molecular mass of 96 kDa and it is a key regulator of cell cycle progression. It influences cell size by inhibiting the entry into mitosis, through inhibiting Cdk1. It has homologues in many other organisms, including mammals. # Introduction The regulation of cell size is critical to ensure functionality of a cell. Besides environmental factors such as nutrients, growth factors and functional load, cell size is also controlled by a cellular cell size checkpoint. Wee1 is a component of this checkpoint. It is a kinase determining the timepoint of entry into mitosis, thus influencing the size of the daughter cells. Loss of Wee1 function will produce smaller than normal daughter cell, because cell division occurs prematurely. Its name is derived from the Scottish dialect word wee, meaning small - its discoverer Paul Nurse was working at the University of Edinburgh in Scotland at the time of discovery. # Function Wee1 inhibits Cdk1 by phosphorylating it on two different sites, Tyr15 and Thr14. Cdk1 is crucial for the cyclin-dependent passage of the various cell cycle checkpoints. At least three checkpoints exist for which the inhibition of Cdk1 by Wee1 is important: - G2/M checkpoint: Wee1 phosphorylates the amino acids Tyr15 and Thr14 of Cdk1, which keeps the kinase activity of Cdk1 low and prevents entry into mitosis; in S. pombe further cell growth can occur. Wee1 mediated inactivation of Cdk1 has been shown to be ultrasensitive as a result of substrate competition. During mitotic entry the activity of Wee1 is decreased by several regulators and thus Cdk1 activity is increased. In S. pombe, Pom1, a protein kinase, localizes to the cell poles. This activates a pathway in which Cdr2 inhibits Wee1 through Cdr1. Cdk1 itself negatively regulates Wee1 by phosphorylation, which leads to a positive feedback loop. The decreased Wee1 activity alone is not sufficient for mitotic entry: Synthesis of cyclins and an activating phosphorylation by a Cdk activating kinase (CAK) are also required. - Cell size checkpoint: There is evidence for the existence of a cell size checkpoint, which prevents small cells from entering mitosis. Wee1 plays a role in this checkpoint by coordinating cell size and cell cycle progression. - DNA damage checkpoint: This checkpoint also controls the G2/M transition. In S. pombe this checkpoint delays the mitosis entry of cells with DNA damage (for example induced by gamma radiation). The lengthening of the G2 phase depends on Wee1; wee1 mutants have no prolonged G2 phase after gamma irradiation. Epigenetic function of Wee1 kinase has also been reported. Wee1 was shown to phosphorylate histone H2B at tyrosine 37 residue which regulated global expression of histones. # Homologues The WEE1 gene has two known homologues in humans, WEE1 (also known as WEE1A) and WEE2 (WEE1B). The corresponding proteins are Wee1-like protein kinase and Wee1-like protein kinase 2 which act on the human Cdk1 homologue Cdk1. The homologue to Wee1 in budding yeast Saccharomyces cerevisiae is called Swe1. # Regulation In S. pombe, Wee1 is phosphorylated Cdk1 and cyclin B make up the maturation promoting factor (MPF) which promotes the entry into mitosis. It is inactivated by phosphorylation through Wee1 and activated by the phosphatase Cdc25C. Cdc25C in turn is activated by Polo kinase and inactivated by Chk1. Thus in S. pombe Wee1 regulation is mainly under the control of phosphorylation through the polarity kinase, Pom1's, pathway including Cdr2 and Cdr1. At the G2/M transition, Cdk1 is activated by Cdc25 through dephosphorylation of Tyr15. At the same time, Wee1 is inactivated through phosphorylation at its C-terminal catalytic domain by Nim1/Cdr1. Also, the active MPF will promote its own activity by activating Cdc25 and inactivating Wee1, creating a positive feedback loop, though this is not yet understood in detail. Higher eukaryotes regulate Wee1 via phosphorylation and degradation In higher eukaryotes, Wee1 inactivation occurs both by phosphorylation and degradation. The protein complex SCFβ-TrCP1/2 is an E3 ubiquitin ligase that functions in Wee1A ubiquitination. The M-phase kinases Polo-like kinase (Plk1) and Cdc2 phosphorylate two serine residues in Wee1A which are recognized by SCFβ-TrCP1/2. S. cerevisiae homologue Swe1 In S. cerevisiae, cyclin-dependent kinase Cdc28 (Cdk1 homologue) is phosphorylated by Swe1 (Wee1 homologue) and dephosphorylated by Mih1 (Cdc25 homologue). Nim1/Cdr1 homologue in S. cerevisiae, Hsl1, together with its related kinases Gin4 and Kcc4 localize Swe1 to the bud-neck. Bud-neck associating kinases Cla4 and Cdc5 (polo kinase homologue) phosphorylate Swe1 at different stages of the cell cycle. Swe1 is also phosphorylated by Clb2-Cdc28 which serves as a recognition for further phosphorylation by Cdc5. The S. cerevisiae protein Swe1 is also regulated by degradation. Swe1 is hyperphosphorylated by Clb2-Cdc28 and Cdc5 which may be a signal for ubiquitination and degradation by SCF E3 ubiquitin ligase complex as in higher eukaryotes. # Role in cancer The mitosis promoting factor MPF also regulates DNA-damage induced apoptosis. Negative regulation of MPF by WEE1 causes aberrant mitosis and thus resistance to DNA-damage induced apoptosis. Kruppel-like factor 2 (KLF2) negatively regulates human WEE1, thus increasing sensitivity to DNA-damage induced apoptosis in cancer cells. # Mutant phenotype Wee1 acts as a dosage-dependent inhibitor of mitosis. Thus, the amount of Wee1 protein correlates with the size of the cells: The fission yeast mutant wee1, also called wee1−, divides at a significantly smaller cell size than wildtype cells. Since Wee1 inhibits entry into mitosis, its absence will lead to division at a premature stage and sub-normal cell size. Conversely, when Wee1 expression is increased, mitosis is delayed and cells grow to a large size before dividing.

Wee1 Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe (S. pombe). Wee1 has a molecular mass of 96 kDa and it is a key regulator of cell cycle progression. It influences cell size by inhibiting the entry into mitosis, through inhibiting Cdk1. It has homologues in many other organisms, including mammals. # Introduction The regulation of cell size is critical to ensure functionality of a cell. Besides environmental factors such as nutrients, growth factors and functional load, cell size is also controlled by a cellular cell size checkpoint. Wee1 is a component of this checkpoint. It is a kinase determining the timepoint of entry into mitosis, thus influencing the size of the daughter cells. Loss of Wee1 function will produce smaller than normal daughter cell, because cell division occurs prematurely. Its name is derived from the Scottish dialect word wee, meaning small - its discoverer Paul Nurse was working at the University of Edinburgh in Scotland at the time of discovery.[1][2] # Function Wee1 inhibits Cdk1 by phosphorylating it on two different sites, Tyr15 and Thr14.[3] Cdk1 is crucial for the cyclin-dependent passage of the various cell cycle checkpoints. At least three checkpoints exist for which the inhibition of Cdk1 by Wee1 is important: - G2/M checkpoint: Wee1 phosphorylates the amino acids Tyr15 and Thr14 of Cdk1, which keeps the kinase activity of Cdk1 low and prevents entry into mitosis; in S. pombe further cell growth can occur. Wee1 mediated inactivation of Cdk1 has been shown to be ultrasensitive as a result of substrate competition.[4] During mitotic entry the activity of Wee1 is decreased by several regulators and thus Cdk1 activity is increased. In S. pombe, Pom1, a protein kinase, localizes to the cell poles. This activates a pathway in which Cdr2 inhibits Wee1 through Cdr1. Cdk1 itself negatively regulates Wee1 by phosphorylation, which leads to a positive feedback loop. The decreased Wee1 activity alone is not sufficient for mitotic entry: Synthesis of cyclins and an activating phosphorylation by a Cdk activating kinase (CAK) are also required.[5] - Cell size checkpoint: There is evidence for the existence of a cell size checkpoint, which prevents small cells from entering mitosis. Wee1 plays a role in this checkpoint by coordinating cell size and cell cycle progression.[6] - DNA damage checkpoint: This checkpoint also controls the G2/M transition. In S. pombe this checkpoint delays the mitosis entry of cells with DNA damage (for example induced by gamma radiation). The lengthening of the G2 phase depends on Wee1; wee1 mutants have no prolonged G2 phase after gamma irradiation.[7] Epigenetic function of Wee1 kinase has also been reported. Wee1 was shown to phosphorylate histone H2B at tyrosine 37 residue which regulated global expression of histones.[8] [9] # Homologues The WEE1 gene has two known homologues in humans, WEE1 (also known as WEE1A) and WEE2 (WEE1B). The corresponding proteins are Wee1-like protein kinase and Wee1-like protein kinase 2 which act on the human Cdk1 homologue Cdk1. The homologue to Wee1 in budding yeast Saccharomyces cerevisiae is called Swe1. # Regulation In S. pombe, Wee1 is phosphorylated Cdk1 and cyclin B make up the maturation promoting factor (MPF) which promotes the entry into mitosis. It is inactivated by phosphorylation through Wee1 and activated by the phosphatase Cdc25C. Cdc25C in turn is activated by Polo kinase and inactivated by Chk1.[6] Thus in S. pombe Wee1 regulation is mainly under the control of phosphorylation through the polarity kinase, Pom1's, pathway including Cdr2 and Cdr1.[10][11][12][13] At the G2/M transition, Cdk1 is activated by Cdc25 through dephosphorylation of Tyr15. At the same time, Wee1 is inactivated through phosphorylation at its C-terminal catalytic domain by Nim1/Cdr1.[12] Also, the active MPF will promote its own activity by activating Cdc25 and inactivating Wee1, creating a positive feedback loop, though this is not yet understood in detail.[6] Higher eukaryotes regulate Wee1 via phosphorylation and degradation In higher eukaryotes, Wee1 inactivation occurs both by phosphorylation and degradation.[14] The protein complex[nb 1] SCFβ-TrCP1/2 is an E3 ubiquitin ligase that functions in Wee1A ubiquitination. The M-phase kinases Polo-like kinase (Plk1) and Cdc2 phosphorylate two serine residues in Wee1A which are recognized by SCFβ-TrCP1/2.[15] S. cerevisiae homologue Swe1 In S. cerevisiae, cyclin-dependent kinase Cdc28 (Cdk1 homologue) is phosphorylated by Swe1 (Wee1 homologue) and dephosphorylated by Mih1 (Cdc25 homologue). Nim1/Cdr1 homologue in S. cerevisiae, Hsl1, together with its related kinases Gin4 and Kcc4 localize Swe1 to the bud-neck. Bud-neck associating kinases Cla4 and Cdc5 (polo kinase homologue) phosphorylate Swe1 at different stages of the cell cycle. Swe1 is also phosphorylated by Clb2-Cdc28 which serves as a recognition for further phosphorylation by Cdc5. The S. cerevisiae protein Swe1 is also regulated by degradation. Swe1 is hyperphosphorylated by Clb2-Cdc28 and Cdc5 which may be a signal for ubiquitination and degradation by SCF E3 ubiquitin ligase complex as in higher eukaryotes.[16] # Role in cancer The mitosis promoting factor MPF also regulates DNA-damage induced apoptosis. Negative regulation of MPF by WEE1 causes aberrant mitosis and thus resistance to DNA-damage induced apoptosis. Kruppel-like factor 2 (KLF2) negatively regulates human WEE1, thus increasing sensitivity to DNA-damage induced apoptosis in cancer cells.[17] # Mutant phenotype Wee1 acts as a dosage-dependent inhibitor of mitosis.[18] Thus, the amount of Wee1 protein correlates with the size of the cells: The fission yeast mutant wee1, also called wee1−, divides at a significantly smaller cell size than wildtype cells. Since Wee1 inhibits entry into mitosis, its absence will lead to division at a premature stage and sub-normal cell size. Conversely, when Wee1 expression is increased, mitosis is delayed and cells grow to a large size before dividing.

https://www.wikidoc.org/index.php/Wee1

1e4ac83ed35b287fc10a0cf85f91db52c1615638

wikidoc

Wiki

Wiki # Overview A wiki is a collection of web pages designed to enable anyone who accesses it to contribute or modify content, using a simplified markup language. Wikis are often used to create collaborative websites and to power community websites. For example, the collaborative encyclopedia Wikipedia is one of the best-known wikis. Wikis are used in businesses to provide affordable and effective intranets and for Knowledge Management. Ward Cunningham, developer of the first wiki software, WikiWikiWeb, originally described it as "the simplest online database that could possibly work". "Wiki Wiki" (Template:IPA) is a reduplication of "wiki", a Hawaiian word for "fast". It has been suggested that "wiki" means "What I Know Is". However, this is a backronym. # History WikiWikiWeb was the first site to be called a wiki. Ward Cunningham started developing WikiWikiWeb in 1994, and installed it on the Internet domain c2.com on March 25, 1995. It was named by Cunningham, who remembered a Honolulu International Airport counter employee telling him to take the "Wiki Wiki" shuttle bus that runs between the airport's terminals. According to Cunningham, "I chose wiki-wiki as an alliterative substitute for 'quick' and thereby avoided naming this stuff quick-web." Cunningham was in part inspired by Apple's HyperCard. Apple had designed a system allowing users to create virtual "card stacks" supporting links among the various cards. Cunningham developed Vannevar Bush's ideas by allowing users to "comment on and change one another's text". In the early 2000s, wikis were increasingly adopted in enterprise as collaborative software. Common uses included project communication, intranets, and documentation, initially for technical users. Today some companies use wikis as their only collaborative software and as a replacement for static intranets. There may be greater use of wikis behind firewalls than on the public Internet. On March 15, 2007, wiki entered the Oxford English Dictionary Online. # Characteristics Ward Cunningham, and co-author Bo Leuf, in their book The Wiki Way: Quick Collaboration on the Web described the essence of the Wiki concept as follows: - A wiki invites all users to edit any page or to create new pages within the wiki Web site, using only a plain-vanilla Web browser without any extra add-ons. - Wiki promotes meaningful topic associations between different pages by making page link creation almost intuitively easy and showing whether an intended target page exists or not. - A wiki is not a carefully-crafted site for casual visitors. Instead, it seeks to involve the visitor in an ongoing process of creation and collaboration that constantly changes the Web site landscape. A wiki enables documents to be written collaboratively, in a simple markup language using a Web browser. A single page in a wiki website is referred to as a "wiki page", while the entire collection of pages, which are usually well interconnected by hyperlinks, is "the wiki". A wiki is essentially a database for creating, browsing, and searching through information. A defining characteristic of wiki technology is the ease with which pages can be created and updated. Generally, there is no review before modifications are accepted. Many wikis are open to alteration by the general public without requiring them to register user accounts. Sometimes logging in for a session is recommended, to create a "wiki-signature" cookie for signing edits automatically. Many edits, however, can be made in real-time and appear almost instantly online. This can facilitate abuse of the system. Private wiki servers require user authentication to edit pages, and sometimes even to read them. ## Editing wiki pages Ordinarily, the structure and formatting of wiki pages are specified with a simplified markup language, sometimes known as "wikitext". For example, starting a line of text with an asterisk ("*") is often used to enter it in a bulleted list. The style and syntax of wikitexts can vary greatly among wiki implementations, some of which also allow HTML tags. The reason for taking this approach is that HTML, with its many cryptic tags, is not very legible, making it hard to edit. Wikis therefore favour plain text editing, with fewer and simpler conventions than HTML, for indicating style and structure. (Quotation above from Alice's Adventures in Wonderland by Lewis Carroll) Although limiting access to HTML and Cascading Style Sheets (CSS) of wikis limits user ability to alter the structure and formatting of wiki content, there are some benefits. Limited access to CSS promotes consistency in the look and feel and having JavaScript disabled prevents a user from implementing code, which may limit access for other users. Increasingly, wikis are making "WYSIWYG" ("What You See Is What You Get") editing available to users, usually by means of JavaScript or an ActiveX control that translates graphically-entered formatting instructions, such as "bold" and "italics", into the corresponding HTML tags or wikitext. In those implementations, the markup of a newly edited, marked-up version of the page is generated and submitted to the server transparently, and the user is shielded from this technical detail. However, WYSIWYG controls do not always provide all of the features available in wikitext. Many implementations (for example MediaWiki) allow users to supply an "edit summary" when they edit a page. This is a short piece of text (usually one line) summarizing the changes. It is not inserted into the article, but is stored along with that revision of the page, allowing users to explain what has been done and why; this is similar to a log message when committing changes to a revision control system. Most wikis keep a record of changes made to wiki pages; often every version of the page is stored. This means that authors can revert to an older version of the page, should it be necessary because a mistake has been made or the page has been vandalised. ## Navigation Within the text of most pages there are usually a large number of hypertext links to other pages. This form of non-linear navigation is more "native" to wiki than structured/formalized navigation schemes. That said, users can also create any number of index or table of contents pages, with hierarchical categorization or whatever form of organization they like. These may be challenging to maintain by hand, as multiple authors create and delete pages in an ad hoc manner. Wikis generally provide one or more ways to categorize or tag pages, to support the maintenance of such index pages. Most wikis have a backlink feature, an easy way to see what pages link to the page you're currently on. It is typical in a wiki to create links to pages that do not yet exist, as a way to invite others to share what they know about a subject new to the wiki. ## Linking and creating pages Links are created using a specific syntax, the so-called "link pattern" (also see CURIE). Originally, most wikis used CamelCase to name pages and create links. These are produced by capitalizing words in a phrase and removing the spaces between them (the word "CamelCase" is itself an example). While CamelCase makes linking very easy, it also leads to links which are written in a form that deviates from the standard spelling. CamelCase-based wikis are instantly recognizable because they have many links with names such as "TableOfContents" and "BeginnerQuestions". It is possible for a wiki to render the visible anchor for such links "pretty" by reinserting spaces, and possibly also reverting to lower case. However, this reprocessing of the link to improve the readability of the anchor is limited by the loss of capitalization information caused by CamelCase reversal. For example, "RichardWagner" should be rendered as "Richard Wagner", whereas "PopularMusic" should be rendered as "popular music". There is no easy way to determine which capital letters should remain capitalized. As a result, many wikis now have "free linking" using brackets, and some disable CamelCase by default. ## Searching Most wikis offer at least a title search, and sometimes a full-text search. The scalability of the search depends on whether the wiki engine uses a database. Indexed database access is necessary for high speed searches on large wikis. Alternatively, external search engines such as Google can sometimes be used on wikis with limited searching functions in order to obtain more precise results. However, a search engine's indexes can be very out of date (days, weeks or months) for many websites. ## Software architecture Wiki software is a type of collaborative software that runs a wiki system, allowing web pages to be created and edited using a common web browser. It is usually implemented as a software engine that runs on one or more web servers. The content is stored in a file system, and changes to the content are stored in a relational database management system. Alternatively, Personal wikis run as a standalone application on a single computer. Examples: WikidPad and VoodooPad. # Trust and security ## Controlling changes Wikis are generally designed with the philosophy of making it easy to correct mistakes, rather than making it difficult to make them. Thus, while wikis are very open, they provide a means to verify the validity of recent additions to the body of pages. The most prominent, on almost every wiki, is the "Recent Changes" page—a specific list numbering recent edits, or a list of edits made within a given time frame. Some wikis can filter the list to remove minor edits and edits made by automatic importing scripts ("bots"). From the change log, other functions are accessible in most wikis: the Revision History showing previous page versions; and the diff feature, highlighting the changes between two revisions. Using the Revision History, an editor can view and restore a previous version of the article. The diff feature can be used to decide whether or not this is necessary. A regular wiki user can view the diff of an edit listed on the "Recent Changes" page and, if it is an unacceptable edit, consult the history, restoring a previous revision; this process is more or less streamlined, depending on the wiki software used. In case unacceptable edits are missed on the "Recent Changes" page, some wiki engines provide additional content control. It can be monitored to ensure that a page, or a set of pages, keeps its quality. A person willing to maintain pages will be warned of modifications to the pages, allowing him or her to verify the validity of new editions quickly. ## Trustworthiness Critics of publicly-editable wiki systems argue that these systems could be easily tampered with, while proponents argue that the community of users can catch malicious content and correct it. Lars Aronsson, a data systems specialist, summarizes the controversy as follows: ## Security The open philosophy of most wikis, allowing anyone to edit content, does not ensure that every editor is well-meaning. Vandalism can be a major problem. In larger wiki sites, such as those run by the WikiDoc Foundation, vandalism can go unnoticed for a period of time. Wikis by their very nature are susceptible to intentional disruption, known as "trolling". Wikis tend to take a soft security approach to the problem of vandalism; making damage easy to undo rather than attempting to prevent damage. Larger wikis often employ sophisticated methods, such as bots that automatically identify and revert vandalism and JavaScript enhancements that show characters that have been added in each edit. In this way vandalism can be limited to just "minor vandalism" or "sneaky vandalism", where the characters added/eliminated are so few that bots do not identify them and users do not pay much attention to them. The amount of vandalism a wiki receives depends on how open the wiki is. For instance, some wikis allow unregistered users, identified by their IP addresses, to edit content, whilst others limit this function to just registered users. Most wikis allow anonymous editing without an account, but give registered users additional editing functions; on most wikis, becoming a registered user is a short and simple process. Some wikis require an additional waiting period before gaining access to certain tools. For example, on the English WikiDoc, registered users can only rename pages if their account is at least four days old. Other wikis such as the Spanish WikiDoc use an editing requirement instead of a time requirement, granting extra tools after the user has made a certain number of edits to prove their trustworthiness and usefulness as an editor. Basically, "closed up" wikis are more secure and reliable but grow slowly, whilst more open wikis grow at a steady rate but result in being an easy target for vandalism. A clear example of this would be that of WikiDoc and Citizendium. The first is extremely open, allowing anyone with a computer and internet access to edit it, making it grow rapidly, whilst the latter requires the users' real name and a biography of themselves, affecting the growth of the wiki but creating an almost "vandalism-free" ambiance. # Communities Many wiki communities are private, particularly within enterprises. They are often used as internal documentation for in-house systems and applications. The "open to everyone", all-encompassing nature of Wikipedia is a significant factor in its growth, while there are other wikis which are highly specialized. There also exist WikiNodes which are pages on wikis that describe related wikis. They are usually organized as neighbors and delegates. A neighbor wiki is simply a wiki that may discuss similar content or may otherwise be of interest. A delegate wiki is a wiki that agrees to have certain content delegated to that wiki. One way of finding a wiki on a specific subject is to follow the wiki-node network from wiki to wiki; another is to take a Wiki "bus tour", for example: WikiDoc Tour. Domain names containing "wiki" are growing in popularity to support specific niches. For those interested in creating their own wiki, there are publicly-available "wiki farms", some of which can also make private, password-protected wikis. PeanutButterWiki, Socialtext, Wetpaint, and Wikia are popular examples of such services. For more information, see List of wiki farms. Note that free wiki farms generally contain advertising on every page. The English-language Wikipedia has the largest user base among wikis on the World Wide Web and ranks in the top 10 among all Web sites in terms of traffic. Other large wikis include the WikiWikiWeb, Memory Alpha, Wikitravel, World66 and Susning.nu, a Swedish-language knowledge base. The English-language based WikiDoc (the original medical wiki) is the largest physician driven textbook of medicine. In WikiDoc, only registered users are allowed to contribute.

Wiki Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A wiki is a collection of web pages designed to enable anyone who accesses it to contribute or modify content, using a simplified markup language[1][2]. Wikis are often used to create collaborative websites and to power community websites. For example, the collaborative encyclopedia Wikipedia is one of the best-known wikis.[2] Wikis are used in businesses to provide affordable and effective intranets and for Knowledge Management. Ward Cunningham, developer of the first wiki software, WikiWikiWeb, originally described it as "the simplest online database that could possibly work".[3] "Wiki Wiki" (Template:IPA) is a reduplication of "wiki", a Hawaiian word for "fast". It has been suggested that "wiki" means "What I Know Is". However, this is a backronym. # History WikiWikiWeb was the first site to be called a wiki.[4] Ward Cunningham started developing WikiWikiWeb in 1994, and installed it on the Internet domain c2.com on March 25, 1995. It was named by Cunningham, who remembered a Honolulu International Airport counter employee telling him to take the "Wiki Wiki" shuttle bus that runs between the airport's terminals. According to Cunningham, "I chose wiki-wiki as an alliterative substitute for 'quick' and thereby avoided naming this stuff quick-web."[5][6] Cunningham was in part inspired by Apple's HyperCard. Apple had designed a system allowing users to create virtual "card stacks" supporting links among the various cards. Cunningham developed Vannevar Bush's ideas by allowing users to "comment on and change one another's text".[2][7] In the early 2000s, wikis were increasingly adopted in enterprise as collaborative software. Common uses included project communication, intranets, and documentation, initially for technical users. Today some companies use wikis as their only collaborative software and as a replacement for static intranets. There may be greater use of wikis behind firewalls than on the public Internet. On March 15, 2007, wiki entered the Oxford English Dictionary Online.[8] # Characteristics Ward Cunningham, and co-author Bo Leuf, in their book The Wiki Way: Quick Collaboration on the Web described the essence of the Wiki concept as follows: - A wiki invites all users to edit any page or to create new pages within the wiki Web site, using only a plain-vanilla Web browser without any extra add-ons. - Wiki promotes meaningful topic associations between different pages by making page link creation almost intuitively easy and showing whether an intended target page exists or not. - A wiki is not a carefully-crafted site for casual visitors. Instead, it seeks to involve the visitor in an ongoing process of creation and collaboration that constantly changes the Web site landscape. A wiki enables documents to be written collaboratively, in a simple markup language using a Web browser. A single page in a wiki website is referred to as a "wiki page", while the entire collection of pages, which are usually well interconnected by hyperlinks, is "the wiki". A wiki is essentially a database for creating, browsing, and searching through information. A defining characteristic of wiki technology is the ease with which pages can be created and updated. Generally, there is no review before modifications are accepted. Many wikis are open to alteration by the general public without requiring them to register user accounts. Sometimes logging in for a session is recommended, to create a "wiki-signature" cookie for signing edits automatically. Many edits, however, can be made in real-time and appear almost instantly online. This can facilitate abuse of the system. Private wiki servers require user authentication to edit pages, and sometimes even to read them. ## Editing wiki pages Ordinarily, the structure and formatting of wiki pages are specified with a simplified markup language, sometimes known as "wikitext". For example, starting a line of text with an asterisk ("*") is often used to enter it in a bulleted list. The style and syntax of wikitexts can vary greatly among wiki implementations, some of which also allow HTML tags. The reason for taking this approach is that HTML, with its many cryptic tags, is not very legible, making it hard to edit. Wikis therefore favour plain text editing, with fewer and simpler conventions than HTML, for indicating style and structure. (Quotation above from Alice's Adventures in Wonderland by Lewis Carroll) Although limiting access to HTML and Cascading Style Sheets (CSS) of wikis limits user ability to alter the structure and formatting of wiki content, there are some benefits. Limited access to CSS promotes consistency in the look and feel and having JavaScript disabled prevents a user from implementing code, which may limit access for other users. Increasingly, wikis are making "WYSIWYG" ("What You See Is What You Get") editing available to users, usually by means of JavaScript or an ActiveX control that translates graphically-entered formatting instructions, such as "bold" and "italics", into the corresponding HTML tags or wikitext. In those implementations, the markup of a newly edited, marked-up version of the page is generated and submitted to the server transparently, and the user is shielded from this technical detail. However, WYSIWYG controls do not always provide all of the features available in wikitext. Many implementations (for example MediaWiki) allow users to supply an "edit summary" when they edit a page. This is a short piece of text (usually one line) summarizing the changes. It is not inserted into the article, but is stored along with that revision of the page, allowing users to explain what has been done and why; this is similar to a log message when committing changes to a revision control system. Most wikis keep a record of changes made to wiki pages; often every version of the page is stored. This means that authors can revert to an older version of the page, should it be necessary because a mistake has been made or the page has been vandalised. ## Navigation Within the text of most pages there are usually a large number of hypertext links to other pages. This form of non-linear navigation is more "native" to wiki than structured/formalized navigation schemes. That said, users can also create any number of index or table of contents pages, with hierarchical categorization or whatever form of organization they like. These may be challenging to maintain by hand, as multiple authors create and delete pages in an ad hoc manner. Wikis generally provide one or more ways to categorize or tag pages, to support the maintenance of such index pages. Most wikis have a backlink feature, an easy way to see what pages link to the page you're currently on. It is typical in a wiki to create links to pages that do not yet exist, as a way to invite others to share what they know about a subject new to the wiki. ## Linking and creating pages Links are created using a specific syntax, the so-called "link pattern" (also see CURIE). Originally, most wikis used CamelCase to name pages and create links. These are produced by capitalizing words in a phrase and removing the spaces between them (the word "CamelCase" is itself an example). While CamelCase makes linking very easy, it also leads to links which are written in a form that deviates from the standard spelling. CamelCase-based wikis are instantly recognizable because they have many links with names such as "TableOfContents" and "BeginnerQuestions". It is possible for a wiki to render the visible anchor for such links "pretty" by reinserting spaces, and possibly also reverting to lower case. However, this reprocessing of the link to improve the readability of the anchor is limited by the loss of capitalization information caused by CamelCase reversal. For example, "RichardWagner" should be rendered as "Richard Wagner", whereas "PopularMusic" should be rendered as "popular music". There is no easy way to determine which capital letters should remain capitalized. As a result, many wikis now have "free linking" using brackets, and some disable CamelCase by default. ## Searching Most wikis offer at least a title search, and sometimes a full-text search. The scalability of the search depends on whether the wiki engine uses a database. Indexed database access is necessary for high speed searches on large wikis. Alternatively, external search engines such as Google can sometimes be used on wikis with limited searching functions in order to obtain more precise results. However, a search engine's indexes can be very out of date (days, weeks or months) for many websites. ## Software architecture Wiki software is a type of collaborative software that runs a wiki system, allowing web pages to be created and edited using a common web browser. It is usually implemented as a software engine that runs on one or more web servers. The content is stored in a file system, and changes to the content are stored in a relational database management system. Alternatively, Personal wikis run as a standalone application on a single computer. Examples: WikidPad and VoodooPad. # Trust and security ## Controlling changes Wikis are generally designed with the philosophy of making it easy to correct mistakes, rather than making it difficult to make them. Thus, while wikis are very open, they provide a means to verify the validity of recent additions to the body of pages. The most prominent, on almost every wiki, is the "Recent Changes" page—a specific list numbering recent edits, or a list of edits made within a given time frame.[9] Some wikis can filter the list to remove minor edits and edits made by automatic importing scripts ("bots").[10] From the change log, other functions are accessible in most wikis: the Revision History showing previous page versions; and the diff feature, highlighting the changes between two revisions. Using the Revision History, an editor can view and restore a previous version of the article. The diff feature can be used to decide whether or not this is necessary. A regular wiki user can view the diff of an edit listed on the "Recent Changes" page and, if it is an unacceptable edit, consult the history, restoring a previous revision; this process is more or less streamlined, depending on the wiki software used.[11] In case unacceptable edits are missed on the "Recent Changes" page, some wiki engines provide additional content control. It can be monitored to ensure that a page, or a set of pages, keeps its quality. A person willing to maintain pages will be warned of modifications to the pages, allowing him or her to verify the validity of new editions quickly.[12] ## Trustworthiness Critics of publicly-editable wiki systems argue that these systems could be easily tampered with, while proponents argue that the community of users can catch malicious content and correct it.[2] Lars Aronsson, a data systems specialist, summarizes the controversy as follows: ## Security The open philosophy of most wikis, allowing anyone to edit content, does not ensure that every editor is well-meaning. Vandalism can be a major problem. In larger wiki sites, such as those run by the WikiDoc Foundation, vandalism can go unnoticed for a period of time. Wikis by their very nature are susceptible to intentional disruption, known as "trolling". Wikis tend to take a soft security[14] approach to the problem of vandalism; making damage easy to undo rather than attempting to prevent damage. Larger wikis often employ sophisticated methods, such as bots that automatically identify and revert vandalism and JavaScript enhancements that show characters that have been added in each edit. In this way vandalism can be limited to just "minor vandalism" or "sneaky vandalism", where the characters added/eliminated are so few that bots do not identify them and users do not pay much attention to them. The amount of vandalism a wiki receives depends on how open the wiki is. For instance, some wikis allow unregistered users, identified by their IP addresses, to edit content, whilst others limit this function to just registered users. Most wikis allow anonymous editing without an account,[15] but give registered users additional editing functions; on most wikis, becoming a registered user is a short and simple process. Some wikis require an additional waiting period before gaining access to certain tools. For example, on the English WikiDoc, registered users can only rename pages if their account is at least four days old. Other wikis such as the Spanish WikiDoc use an editing requirement instead of a time requirement, granting extra tools after the user has made a certain number of edits to prove their trustworthiness and usefulness as an editor. Basically, "closed up" wikis are more secure and reliable but grow slowly, whilst more open wikis grow at a steady rate but result in being an easy target for vandalism. A clear example of this would be that of WikiDoc and Citizendium. The first is extremely open, allowing anyone with a computer and internet access to edit it, making it grow rapidly, whilst the latter requires the users' real name and a biography of themselves, affecting the growth of the wiki but creating an almost "vandalism-free" ambiance. # Communities Many wiki communities are private, particularly within enterprises. They are often used as internal documentation for in-house systems and applications. The "open to everyone", all-encompassing nature of Wikipedia is a significant factor in its growth, while there are other wikis which are highly specialized. There also exist WikiNodes which are pages on wikis that describe related wikis. They are usually organized as neighbors and delegates. A neighbor wiki is simply a wiki that may discuss similar content or may otherwise be of interest. A delegate wiki is a wiki that agrees to have certain content delegated to that wiki. One way of finding a wiki on a specific subject is to follow the wiki-node network from wiki to wiki; another is to take a Wiki "bus tour", for example: WikiDoc Tour. Domain names containing "wiki" are growing in popularity to support specific niches. For those interested in creating their own wiki, there are publicly-available "wiki farms", some of which can also make private, password-protected wikis. PeanutButterWiki, Socialtext, Wetpaint, and Wikia are popular examples of such services. For more information, see List of wiki farms. Note that free wiki farms generally contain advertising on every page. The English-language Wikipedia has the largest user base among wikis on the World Wide Web[16] and ranks in the top 10 among all Web sites in terms of traffic.[17] Other large wikis include the WikiWikiWeb, Memory Alpha, Wikitravel, World66 and Susning.nu, a Swedish-language knowledge base. The English-language based WikiDoc (the original medical wiki) is the largest physician driven textbook of medicine. In WikiDoc, only registered users are allowed to contribute.

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

ef4d62ec09f3d47d573133d0f6e5da86f4b7e939

wikidoc

Wood

Wood Wood is hard, fibrous, lignified structural tissue produced as secondary xylem in the stems of woody plants, notably trees but also shrubs. This tissue conducts water to the leaves and other growing tissues and has a support function, enabling plants to reach large sizes. Wood may also refer to other plant materials and tissues with comparable properties. Wood is a heterogeneous, hygroscopic, cellular and anisotropic material. Wood is composed of fibers of cellulose (40% – 50%) and hemicellulose (15% – 25%) impregnated with lignin (15% – 30%). Wood has been used for millennia for many purposes. One of its primary uses is as fuel. It is also used as for making artworks, furniture, tools, and weapons, and as a construction material. Wood has been an important construction material since humans began building shelters, houses and boats. Nearly all boats were made out of wood till the late 1800s, and wood remains in common use today in boat construction. New domestic housing in many parts of the world today is commonly of timber-framed construction. In buildings made of other materials, wood will still be found as a supporting material, especially in roof construction and interior doors and their frames and exterior cladding. Wood to be used for construction work is commonly known as lumber in North America. Elsewhere, lumber will usually refer to felled trees, and the word for sawn planks ready for use is timber. Wood unsuitable for construction in its native form may be broken down mechanically (into fibres or chips) or chemically (into cellulose) and used as a raw material for other building materials such as chipboard, engineered wood, hardboard, medium-density fiberboard (MDF), oriented strand board (OSB). Such wood derivatives are widely used: wood fibers are an important component of most paper, and cellulose is used as a component of some synthetic materials. Wood derivatives can also be used for kinds of flooring, for example laminate flooring. Wood is also used for cutlery, such as chopsticks, toothpicks, and other utensils, like the wooden spoon. # Formation A tree increases in diameter by the formation, between the old wood and the inner bark, of new woody layers which envelop the entire stem, living branches, and roots. Where there are clear seasons, this can happen in a discrete pattern, leading to what is known as growth rings, as can be seen on the end of a log. If these seasons are annual these growth rings are annual rings. Where there is no seasonal difference growth rings are likely to be indistinct or absent. Within a growth ring it may be possible to see two parts. The part nearest the center of the tree is more open textured and almost invariably lighter in colour than that near the outer portion of the ring. The inner portion is formed early in the season, when growth is comparatively rapid; it is known as early wood or spring wood. The outer portion is the late wood or summer wood, being produced in the summer. In white pines there is not much contrast in the different parts of the ring, and as a result the wood is very uniform in texture and is easy to work. In hard pines, on the other hand, the late wood is very dense and is deep-colored, presenting a very decided contrast to the soft, straw-colored early wood. In ring-porous woods each season's growth is always well defined, because the large pores of the spring abut on the denser tissue of the fall before. In the diffuse-porous woods, the demarcation between rings is not always so clear and in some cases is almost (if not entirely) invisible to the unaided eye. ## Knots A knot is a particular type of imperfection in a piece of timber, which reduces its strength, but which may be exploited for artistic effect. In a longitudinally-sawn plank, a knot will appear as a roughly circular "solid" (usually darker) piece of wood around which the roughly parallel fibres (grain) of the rest of the "flows" (parts and rejoins). A knot is actually a portion of a side branch (or a dormant bud) included in the wood of the stem or larger branch. The included portion is irregularly conical in shape (hence the roughly circular cross-section) with the tip at the point in stem diameter at which the plant's cambium was located when the branch formed as a bud. Within a knot, the fibre direction (grain) is up to 90 degrees different from the fibres of the stem, thus producing local cross grain. During the development of a tree, the lower limbs often die, but may persist for a time, sometimes years. Subsequent layers of growth of the attaching stem are no longer intimately joined with the dead limb, but are grown around it. Hence, dead branches produce knots which are not attached, and likely to drop out after the tree has been sawn into boards. In grading lumber and structural timber, knots are classified according to their form, size, soundness, and the firmness with which they are held in place. This firmness is affected by, among other factors, the length of time for which the branch was dead while the attaching stem continued to grow. Knots materially affect cracking (known in the industry as checking) and warping, ease in working, and cleavability of timber. They are defects which weaken timber and lower its value for structural purposes where strength is an important consideration. The weakening effect is much more serious when timber is subjected to forces perpendicular to the grain and/or tension than where under load along the grain and/or compression. The extent to which knots affect the strength of a beam depends upon their position, size, number, direction of fiber, and condition. A knot on the upper side is compressed, while one on the lower side is subjected to tension. If there is a season check in the knot, as is often the case, it will offer little resistance to this tensile stress. Small knots, however, may be located along the neutral plane of a beam and increase the strength by preventing longitudinal shearing. Knots in a board or plank are least injurious when they extend through it at right angles to its broadest surface. Knots which occur near the ends of a beam do not weaken it. Sound knots which occur in the central portion one-fourth the height of the beam from either edge are not serious defects. Knots do not necessarily influence the stiffness of structural timber. Only defects of the most serious character affect the elastic limit of beams. Stiffness and elastic strength are more dependent upon the quality of the wood fiber than upon defects in the beam. The effect of knots is to reduce the difference between the fiber stress at elastic limit and the modulus of rupture of beams. The breaking strength is very susceptible to defects. Sound knots do not weaken wood when subject to compression parallel to the grain. For purposes for which appearance is more important than strength, such as wall panelling, knots are considered a benefit, as they add visual texture to the wood, giving it a more interesting appearance. The traditional style of playing the Basque xylophon txalaparta involves hitting the right knots to obtain different tones. ## Heartwood and sapwood Heartwood is wood that has died and become resistant to decay as a result of genetically programmed processes. It appears in a cross-section as a discolored circle, following annual rings in shape. Heartwood is usually much darker than living wood, and forms with age. Many woody plants do not form heartwood, but other processes, such as decay, can discolor wood in similar ways, leading to confusion. Some uncertainty still exists as to whether heartwood is truly dead, as it can still chemically react to decay organisms, but only once (Shigo 1986, 54). Sapwood is living wood in the growing tree. All wood in a tree is first formed as sapwood. Its principal functions are to conduct water from the roots to the leaves and to store up and give back according to the season the food prepared in the leaves. The more leaves a tree bears and the more vigorous its growth, the larger the volume of sapwood required. Hence trees making rapid growth in the open have thicker sapwood for their size than trees of the same species growing in dense forests. Sometimes trees grown in the open may become of considerable size, 30 cm or more in diameter, before any heartwood begins to form, for example, in second-growth hickory, or open-grown pines. The term heartwood derives solely from its position and not from any vital importance to the tree. This is evidenced by the fact that a tree can thrive with its heart completely decayed. Some species begin to form heartwood very early in life, so having only a thin layer of live sapwood, while in others the change comes slowly. Thin sapwood is characteristic of such trees as chestnut, black locust, mulberry, osage-orange, and sassafras, while in maple, ash, hickory, hackberry, beech, and pine, thick sapwood is the rule. There is no definite relation between the annual rings of growth and the amount of sapwood. Within the same species the cross-sectional area of the sapwood is very roughly proportional to the size of the crown of the tree. If the rings are narrow, more of them are required than where they are wide. As the tree gets larger, the sapwood must necessarily become thinner or increase materially in volume. Sapwood is thicker in the upper portion of the trunk of a tree than near the base, because the age and the diameter of the upper sections are less. When a tree is very young it is covered with limbs almost, if not entirely, to the ground, but as it grows older some or all of them will eventually die and are either broken off or fall off. Subsequent growth of wood may completely conceal the stubs which will however remain as knots. No matter how smooth and clear a log is on the outside, it is more or less knotty near the middle. Consequently the sapwood of an old tree, and particularly of a forest-grown tree, will be freer from knots than the heartwood. Since in most uses of wood, knots are defects that weaken the timber and interfere with its ease of working and other properties, it follows that sapwood, because of its position in the tree, may have certain advantages over heartwood. It is remarkable that the inner heartwood of old trees remains as sound as it usually does, since in many cases it is hundreds of years, and in a few instances thousands of years, old. Every broken limb or root, or deep wound from fire, insects, or falling timber, may afford an entrance for decay, which, once started, may penetrate to all parts of the trunk. The larvae of many insects bore into the trees and their tunnels remain indefinitely as sources of weakness. Whatever advantages, however, that sapwood may have in this connection are due solely to its relative age and position. If a tree grows all its life in the open and the conditions of soil and site remain unchanged, it will make its most rapid growth in youth, and gradually decline. The annual rings of growth are for many years quite wide, but later they become narrower and narrower. Since each succeeding ring is laid down on the outside of the wood previously formed, it follows that unless a tree materially increases its production of wood from year to year, the rings must necessarily become thinner as the trunk gets wider. As a tree reaches maturity its crown becomes more open and the annual wood production is lessened, thereby reducing still more the width of the growth rings. In the case of forest-grown trees so much depends upon the competition of the trees in their struggle for light and nourishment that periods of rapid and slow growth may alternate. Some trees, such as southern oaks, maintain the same width of ring for hundreds of years. Upon the whole, however, as a tree gets larger in diameter the width of the growth rings decreases. There may be decided differences in the grain of heartwood and sapwood cut from a large tree, particularly one that is mature. In some trees, the wood laid on late in the life of a tree is softer, lighter, weaker, and more even-textured than that produced earlier, but in other species, the reverse applies. In a large log the sapwood, because of the time in the life of the tree when it was grown, may be inferior in hardness, strength, and toughness to equally sound heartwood from the same log. # Different woods There is a strong relationship between the properties of wood and the properties of the particular tree that yielded it. For every tree species there is a range of density for the wood it yields. There is a rough correlation between density of a wood and its strength (mechanical properties). For example, while mahogany is a medium-dense hardwood which is excellent for fine furniture crafting, balsa is light, making it useful for model building. The densest wood may be black ironwood. Wood is commonly classified as either softwood or hardwood. The wood from conifers (e.g. pine) is called softwood, and the wood from broad-leaved trees (e.g. oak) is called hardwood. These names are a bit misleading, as hardwoods are not necessarily hard, and softwoods are not necessarily soft. The well-known balsa (a hardwood) is actually softer than any commercial softwood. Conversely, some softwoods (e.g. yew) are harder than most hardwoods. Wood products such as plywood are typically classified as engineered wood and not considered raw wood. ## Color In species which show a distinct difference between heartwood and sapwood the natural color of heartwood is usually darker than that of the sapwood, and very frequently the contrast is conspicuous. This is produced by deposits in the heartwood of various materials resulting from the process of growth, increased possibly by oxidation and other chemical changes, which usually have little or no appreciable effect on the mechanical properties of the wood. Some experiments on very resinous Longleaf Pine specimens, however, indicate an increase in strength. This is due to the resin which increases the strength when dry. Such resin-saturated heartwood is called "fat lighter". Structures built of fat lighter are almost impervious to rot and termites; however they are very flammable. Stumps of old longleaf pines are often dug, split into small pieces and sold as kindling for fires. Stumps thus dug may actually remain a century or more since being cut. Spruce impregnated with crude resin and dried is also greatly increased in strength thereby. Since the late wood of a growth ring is usually darker in color than the early wood, this fact may be used in judging the density, and therefore the hardness and strength of the material. This is particularly the case with coniferous woods. In ring-porous woods the vessels of the early wood not infrequently appear on a finished surface as darker than the denser late wood, though on cross sections of heartwood the reverse is commonly true. Except in the manner just stated the color of wood is no indication of strength. Abnormal discoloration of wood often denotes a diseased condition, indicating unsoundness. The black check in western hemlock is the result of insect attacks. The reddish-brown streaks so common in hickory and certain other woods are mostly the result of injury by birds. The discoloration is merely an indication of an injury, and in all probability does not of itself affect the properties of the wood. Certain rot-producing fungi impart to wood characteristic colors which thus become symptomatic of weakness; however an attractive effect known as spalting produced by this process is often considered a desirable characteristic. Ordinary sap-staining is due to fungous growth, but does not necessarily produce a weakening effect. ## Structure "In coniferous or softwood species the wood cells are mostly of one kind, tracheids, and as a result the material is much more uniform in structure than that of most hardwoods. There are no vessels ("pores") in coniferous wood such as one sees so prominently in oak and ash, for example. The structure of the hardwoods is more complex. They are more or less filled with vessels: in some cases (oak, chestnut, ash) quite large and distinct, in others (buckeye, poplar, willow) too small to be seen plainly without a small hand lens. In discussing such woods it is customary to divide them into two large classes, ring-porous and diffuse-porous. In ring-porous species, such as ash, black locust, catalpa, chestnut, elm, hickory, mulberry, and oak, the larger vessels or pores (as cross sections of vessels are called) are localized in the part of the growth ring formed in spring, thus forming a region of more or less open and porous tissue. The rest of the ring, produced in summer, is made up of smaller vessels and a much greater proportion of wood fibres. These fibres are the elements which give strength and toughness to wood, while the vessels are a source of weakness. In diffuse-porous woods the pores are scattered throughout the growth ring instead of being collected in a band or row. Examples of this kind of wood are basswood, birch, buckeye, maple, poplar, and willow. Some species, such as walnut and cherry, are on the border between the two classes, forming an intermediate group. If a heavy piece of pine is compared with a light specimen it will be seen at once that the heavier one contains a larger proportion of late wood than the other, and is therefore considerably darker. The late wood of all species is denser than that formed early in the season, hence the greater the proportion of late wood the greater the density and strength. When examined under a microscope the cells of the late wood are seen to be very thick-walled and with very small cavities, while those formed first in the season have thin walls and large cavities. The strength is in the walls, not the cavities. In choosing a piece of pine where strength or stiffness is the important consideration, the principal thing to observe is the comparative amounts of early and late wood. The width of ring is not nearly so important as the proportion of the late wood in the ring. It is not only the proportion of late wood, but also its quality, that counts. In specimens that show a very large proportion of late wood it may be noticeably more porous and weigh considerably less than the late wood in pieces that contain but little. One can judge comparative density, and therefore to some extent weight and strength, by visual inspection. No satisfactory explanation can as yet be given for the real causes underlying the formation of early and late wood. Several factors may be involved. In conifers, at least, rate of growth alone does not determine the proportion of the two portions of the ring, for in some cases the wood of slow growth is very hard and heavy, while in others the opposite is true. The quality of the site where the tree grows undoubtedly affects the character of the wood formed, though it is not possible to formulate a rule governing it. In general, however, it may be said that where strength or ease of working is essential, woods of moderate to slow growth should be chosen. But in choosing a particular specimen it is not the width of ring, but the proportion and character of the late wood which should govern. In the case of the ring-porous hardwoods there seems to exist a pretty definite relation between the rate of growth of timber and its properties. This may be briefly summed up in the general statement that the more rapid the growth or the wider the rings of growth, the heavier, harder, stronger, and stiffer the wood. This, it must be remembered, applies only to ring-porous woods such as oak, ash, hickory, and others of the same group, and is, of course, subject to some exceptions and limitations. In ring-porous woods of good growth it is usually the middle portion of the ring in which the thick-walled, strength-giving fibers are most abundant. As the breadth of ring diminishes, this middle portion is reduced so that very slow growth produces comparatively light, porous wood composed of thin-walled vessels and wood parenchyma. In good oak these large vessels of the early wood occupy from 6 to 10 per cent of the volume of the log, while in inferior material they may make up 25 per cent or more. The late wood of good oak, except for radial grayish patches of small pores, is dark colored and firm, and consists of thick-walled fibers which form one-half or more of the wood. In inferior oak, such fiber areas are much reduced both in quantity and quality. Such variation is very largely the result of rate of growth. Wide-ringed wood is often called "second-growth", because the growth of the young timber in open stands after the old trees have been removed is more rapid than in trees in the forest, and in the manufacture of articles where strength is an important consideration such "second-growth" hardwood material is preferred. This is particularly the case in the choice of hickory for handles and spokes. Here not only strength, but toughness and resilience are important. The results of a series of tests on hickory by the U.S. Forest Service show that: The effect of rate of growth on the qualities of chestnut wood is summarized by the same authority as follows: In diffuse-porous woods, as has been stated, the vessels or pores are scattered throughout the ring instead of collected in the early wood. The effect of rate of growth is, therefore, not the same as in the ring-porous woods, approaching more nearly the conditions in the conifers. In general it may be stated that such woods of medium growth afford stronger material than when very rapidly or very slowly grown. In many uses of wood, strength is not the main consideration. If ease of working is prized, wood should be chosen with regard to its uniformity of texture and straightness of grain, which will in most cases occur when there is little contrast between the late wood of one season's growth and the early wood of the next. ## Monocot wood Structural tissue resembling ordinary 'dicot' wood is produced by a number of monocot plants, and these are also usually called wood. Of these, the wood of the grass bamboo has considerable economic importance, larger culms being used in the manufacture of engineered flooring, panels and veneer. Other plant groups that produce woody tissue are palms, and members of the Liliales, such as Dracaena and Cordyline. With all these woods, the structure and composition of the structural tissue is quite different from ordinary wood. # Water content Water occurs in living wood in three conditions, namely: (1) in the cell walls, (2) in the protoplasmic contents of the cells, and (3) as free water in the cell cavities and spaces. In heartwood it occurs only in the first and last forms. Wood that is thoroughly air-dried retains from 8-16% of water in the cell walls, and none, or practically none, in the other forms. Even oven-dried wood retains a small percentage of moisture, but for all except chemical purposes, may be considered absolutely dry. The general effect of the water content upon the wood substance is to render it softer and more pliable. A similar effect of common observation is in the softening action of water on paper or cloth. Within certain limits the greater the water content the greater its softening effect. Drying produces a decided increase in the strength of wood, particularly in small specimens. An extreme example is the case of a completely dry spruce block 5 cm in section, which will sustain a permanent load four times as great as that which a green block of the same size will support. The greatest increase due to drying is in the ultimate crushing strength, and strength at elastic limit in endwise compression; these are followed by the modulus of rupture, and stress at elastic limit in cross-bending, while the modulus of elasticity is least affected. # Wood as fuel Wood is burned as a fuel mostly in rural areas of the world. Hard wood is preferred over softwood because it creates less smoke and burns longer. Adding a woodstove or fireplace to a home adds ambiance and warmth.

Wood Wood is hard, fibrous, lignified structural tissue produced as secondary xylem in the stems of woody plants, notably trees but also shrubs. This tissue conducts water to the leaves and other growing tissues and has a support function, enabling plants to reach large sizes. Wood may also refer to other plant materials and tissues with comparable properties. Wood is a heterogeneous, hygroscopic, cellular and anisotropic material. Wood is composed of fibers of cellulose (40% – 50%) and hemicellulose (15% – 25%) impregnated with lignin (15% – 30%).[1] Wood has been used for millennia for many purposes. One of its primary uses is as fuel. It is also used as for making artworks, furniture, tools, and weapons, and as a construction material. Wood has been an important construction material since humans began building shelters, houses and boats. Nearly all boats were made out of wood till the late 1800s, and wood remains in common use today in boat construction. New domestic housing in many parts of the world today is commonly of timber-framed construction. In buildings made of other materials, wood will still be found as a supporting material, especially in roof construction and interior doors and their frames and exterior cladding. Wood to be used for construction work is commonly known as lumber in North America. Elsewhere, lumber will usually refer to felled trees, and the word for sawn planks ready for use is timber. Wood unsuitable for construction in its native form may be broken down mechanically (into fibres or chips) or chemically (into cellulose) and used as a raw material for other building materials such as chipboard, engineered wood, hardboard, medium-density fiberboard (MDF), oriented strand board (OSB). Such wood derivatives are widely used: wood fibers are an important component of most paper, and cellulose is used as a component of some synthetic materials. Wood derivatives can also be used for kinds of flooring, for example laminate flooring. Wood is also used for cutlery, such as chopsticks, toothpicks, and other utensils, like the wooden spoon. # Formation A tree increases in diameter by the formation, between the old wood and the inner bark, of new woody layers which envelop the entire stem, living branches, and roots. Where there are clear seasons, this can happen in a discrete pattern, leading to what is known as growth rings, as can be seen on the end of a log. If these seasons are annual these growth rings are annual rings. Where there is no seasonal difference growth rings are likely to be indistinct or absent. Within a growth ring it may be possible to see two parts. The part nearest the center of the tree is more open textured and almost invariably lighter in colour than that near the outer portion of the ring. The inner portion is formed early in the season, when growth is comparatively rapid; it is known as early wood or spring wood. The outer portion is the late wood or summer wood, being produced in the summer.[2] In white pines there is not much contrast in the different parts of the ring, and as a result the wood is very uniform in texture and is easy to work. In hard pines, on the other hand, the late wood is very dense and is deep-colored, presenting a very decided contrast to the soft, straw-colored early wood. In ring-porous woods each season's growth is always well defined, because the large pores of the spring abut on the denser tissue of the fall before. In the diffuse-porous woods, the demarcation between rings is not always so clear and in some cases is almost (if not entirely) invisible to the unaided eye. ## Knots A knot is a particular type of imperfection in a piece of timber, which reduces its strength, but which may be exploited for artistic effect. In a longitudinally-sawn plank, a knot will appear as a roughly circular "solid" (usually darker) piece of wood around which the roughly parallel fibres (grain) of the rest of the "flows" (parts and rejoins). A knot is actually a portion of a side branch (or a dormant bud) included in the wood of the stem or larger branch. The included portion is irregularly conical in shape (hence the roughly circular cross-section) with the tip at the point in stem diameter at which the plant's cambium was located when the branch formed as a bud. Within a knot, the fibre direction (grain) is up to 90 degrees different from the fibres of the stem, thus producing local cross grain. During the development of a tree, the lower limbs often die, but may persist for a time, sometimes years. Subsequent layers of growth of the attaching stem are no longer intimately joined with the dead limb, but are grown around it. Hence, dead branches produce knots which are not attached, and likely to drop out after the tree has been sawn into boards. In grading lumber and structural timber, knots are classified according to their form, size, soundness, and the firmness with which they are held in place. This firmness is affected by, among other factors, the length of time for which the branch was dead while the attaching stem continued to grow. Knots materially affect cracking (known in the industry as checking) and warping, ease in working, and cleavability of timber. They are defects which weaken timber and lower its value for structural purposes where strength is an important consideration. The weakening effect is much more serious when timber is subjected to forces perpendicular to the grain and/or tension than where under load along the grain and/or compression. The extent to which knots affect the strength of a beam depends upon their position, size, number, direction of fiber, and condition. A knot on the upper side is compressed, while one on the lower side is subjected to tension. If there is a season check in the knot, as is often the case, it will offer little resistance to this tensile stress. Small knots, however, may be located along the neutral plane of a beam and increase the strength by preventing longitudinal shearing. Knots in a board or plank are least injurious when they extend through it at right angles to its broadest surface. Knots which occur near the ends of a beam do not weaken it. Sound knots which occur in the central portion one-fourth the height of the beam from either edge are not serious defects. Knots do not necessarily influence the stiffness of structural timber. Only defects of the most serious character affect the elastic limit of beams. Stiffness and elastic strength are more dependent upon the quality of the wood fiber than upon defects in the beam. The effect of knots is to reduce the difference between the fiber stress at elastic limit and the modulus of rupture of beams. The breaking strength is very susceptible to defects. Sound knots do not weaken wood when subject to compression parallel to the grain. For purposes for which appearance is more important than strength, such as wall panelling, knots are considered a benefit, as they add visual texture to the wood, giving it a more interesting appearance. The traditional style of playing the Basque xylophon txalaparta involves hitting the right knots to obtain different tones. ## Heartwood and sapwood Heartwood is wood that has died and become resistant to decay as a result of genetically programmed processes. It appears in a cross-section as a discolored circle, following annual rings in shape. Heartwood is usually much darker than living wood, and forms with age. Many woody plants do not form heartwood, but other processes, such as decay, can discolor wood in similar ways, leading to confusion. Some uncertainty still exists as to whether heartwood is truly dead, as it can still chemically react to decay organisms, but only once (Shigo 1986, 54). Sapwood is living wood in the growing tree. All wood in a tree is first formed as sapwood. Its principal functions are to conduct water from the roots to the leaves and to store up and give back according to the season the food prepared in the leaves. The more leaves a tree bears and the more vigorous its growth, the larger the volume of sapwood required. Hence trees making rapid growth in the open have thicker sapwood for their size than trees of the same species growing in dense forests. Sometimes trees grown in the open may become of considerable size, 30 cm or more in diameter, before any heartwood begins to form, for example, in second-growth hickory, or open-grown pines. The term heartwood derives solely from its position and not from any vital importance to the tree. This is evidenced by the fact that a tree can thrive with its heart completely decayed. Some species begin to form heartwood very early in life, so having only a thin layer of live sapwood, while in others the change comes slowly. Thin sapwood is characteristic of such trees as chestnut, black locust, mulberry, osage-orange, and sassafras, while in maple, ash, hickory, hackberry, beech, and pine, thick sapwood is the rule. There is no definite relation between the annual rings of growth and the amount of sapwood. Within the same species the cross-sectional area of the sapwood is very roughly proportional to the size of the crown of the tree. If the rings are narrow, more of them are required than where they are wide. As the tree gets larger, the sapwood must necessarily become thinner or increase materially in volume. Sapwood is thicker in the upper portion of the trunk of a tree than near the base, because the age and the diameter of the upper sections are less. When a tree is very young it is covered with limbs almost, if not entirely, to the ground, but as it grows older some or all of them will eventually die and are either broken off or fall off. Subsequent growth of wood may completely conceal the stubs which will however remain as knots. No matter how smooth and clear a log is on the outside, it is more or less knotty near the middle. Consequently the sapwood of an old tree, and particularly of a forest-grown tree, will be freer from knots than the heartwood. Since in most uses of wood, knots are defects that weaken the timber and interfere with its ease of working and other properties, it follows that sapwood, because of its position in the tree, may have certain advantages over heartwood. It is remarkable that the inner heartwood of old trees remains as sound as it usually does, since in many cases it is hundreds of years, and in a few instances thousands of years, old. Every broken limb or root, or deep wound from fire, insects, or falling timber, may afford an entrance for decay, which, once started, may penetrate to all parts of the trunk. The larvae of many insects bore into the trees and their tunnels remain indefinitely as sources of weakness. Whatever advantages, however, that sapwood may have in this connection are due solely to its relative age and position. If a tree grows all its life in the open and the conditions of soil and site remain unchanged, it will make its most rapid growth in youth, and gradually decline. The annual rings of growth are for many years quite wide, but later they become narrower and narrower. Since each succeeding ring is laid down on the outside of the wood previously formed, it follows that unless a tree materially increases its production of wood from year to year, the rings must necessarily become thinner as the trunk gets wider. As a tree reaches maturity its crown becomes more open and the annual wood production is lessened, thereby reducing still more the width of the growth rings. In the case of forest-grown trees so much depends upon the competition of the trees in their struggle for light and nourishment that periods of rapid and slow growth may alternate. Some trees, such as southern oaks, maintain the same width of ring for hundreds of years. Upon the whole, however, as a tree gets larger in diameter the width of the growth rings decreases. There may be decided differences in the grain of heartwood and sapwood cut from a large tree, particularly one that is mature. In some trees, the wood laid on late in the life of a tree is softer, lighter, weaker, and more even-textured than that produced earlier, but in other species, the reverse applies. In a large log the sapwood, because of the time in the life of the tree when it was grown, may be inferior in hardness, strength, and toughness to equally sound heartwood from the same log. # Different woods There is a strong relationship between the properties of wood and the properties of the particular tree that yielded it. For every tree species there is a range of density for the wood it yields. There is a rough correlation between density of a wood and its strength (mechanical properties). For example, while mahogany is a medium-dense hardwood which is excellent for fine furniture crafting, balsa is light, making it useful for model building. The densest wood may be black ironwood. Wood is commonly classified as either softwood or hardwood. The wood from conifers (e.g. pine) is called softwood, and the wood from broad-leaved trees (e.g. oak) is called hardwood. These names are a bit misleading, as hardwoods are not necessarily hard, and softwoods are not necessarily soft. The well-known balsa (a hardwood) is actually softer than any commercial softwood. Conversely, some softwoods (e.g. yew) are harder than most hardwoods. Wood products such as plywood are typically classified as engineered wood and not considered raw wood. ## Color In species which show a distinct difference between heartwood and sapwood the natural color of heartwood is usually darker than that of the sapwood, and very frequently the contrast is conspicuous. This is produced by deposits in the heartwood of various materials resulting from the process of growth, increased possibly by oxidation and other chemical changes, which usually have little or no appreciable effect on the mechanical properties of the wood. Some experiments on very resinous Longleaf Pine specimens, however, indicate an increase in strength. This is due to the resin which increases the strength when dry. Such resin-saturated heartwood is called "fat lighter". Structures built of fat lighter are almost impervious to rot and termites; however they are very flammable. Stumps of old longleaf pines are often dug, split into small pieces and sold as kindling for fires. Stumps thus dug may actually remain a century or more since being cut. Spruce impregnated with crude resin and dried is also greatly increased in strength thereby. Since the late wood of a growth ring is usually darker in color than the early wood, this fact may be used in judging the density, and therefore the hardness and strength of the material. This is particularly the case with coniferous woods. In ring-porous woods the vessels of the early wood not infrequently appear on a finished surface as darker than the denser late wood, though on cross sections of heartwood the reverse is commonly true. Except in the manner just stated the color of wood is no indication of strength. Abnormal discoloration of wood often denotes a diseased condition, indicating unsoundness. The black check in western hemlock is the result of insect attacks. The reddish-brown streaks so common in hickory and certain other woods are mostly the result of injury by birds. The discoloration is merely an indication of an injury, and in all probability does not of itself affect the properties of the wood. Certain rot-producing fungi impart to wood characteristic colors which thus become symptomatic of weakness; however an attractive effect known as spalting produced by this process is often considered a desirable characteristic. Ordinary sap-staining is due to fungous growth, but does not necessarily produce a weakening effect. ## Structure "In coniferous or softwood species the wood cells are mostly of one kind, tracheids, and as a result the material is much more uniform in structure than that of most hardwoods. There are no vessels ("pores") in coniferous wood such as one sees so prominently in oak and ash, for example. The structure of the hardwoods is more complex.[3] They are more or less filled with vessels: in some cases (oak, chestnut, ash) quite large and distinct, in others (buckeye, poplar, willow) too small to be seen plainly without a small hand lens. In discussing such woods it is customary to divide them into two large classes, ring-porous and diffuse-porous. In ring-porous species, such as ash, black locust, catalpa, chestnut, elm, hickory, mulberry, and oak, the larger vessels or pores (as cross sections of vessels are called) are localized in the part of the growth ring formed in spring, thus forming a region of more or less open and porous tissue. The rest of the ring, produced in summer, is made up of smaller vessels and a much greater proportion of wood fibres. These fibres are the elements which give strength and toughness to wood, while the vessels are a source of weakness. In diffuse-porous woods the pores are scattered throughout the growth ring instead of being collected in a band or row. Examples of this kind of wood are basswood, birch, buckeye, maple, poplar, and willow. Some species, such as walnut and cherry, are on the border between the two classes, forming an intermediate group. If a heavy piece of pine is compared with a light specimen it will be seen at once that the heavier one contains a larger proportion of late wood than the other, and is therefore considerably darker. The late wood of all species is denser than that formed early in the season, hence the greater the proportion of late wood the greater the density and strength. When examined under a microscope the cells of the late wood are seen to be very thick-walled and with very small cavities, while those formed first in the season have thin walls and large cavities. The strength is in the walls, not the cavities. In choosing a piece of pine where strength or stiffness is the important consideration, the principal thing to observe is the comparative amounts of early and late wood. The width of ring is not nearly so important as the proportion of the late wood in the ring. It is not only the proportion of late wood, but also its quality, that counts. In specimens that show a very large proportion of late wood it may be noticeably more porous and weigh considerably less than the late wood in pieces that contain but little. One can judge comparative density, and therefore to some extent weight and strength, by visual inspection. No satisfactory explanation can as yet be given for the real causes underlying the formation of early and late wood. Several factors may be involved. In conifers, at least, rate of growth alone does not determine the proportion of the two portions of the ring, for in some cases the wood of slow growth is very hard and heavy, while in others the opposite is true. The quality of the site where the tree grows undoubtedly affects the character of the wood formed, though it is not possible to formulate a rule governing it. In general, however, it may be said that where strength or ease of working is essential, woods of moderate to slow growth should be chosen. But in choosing a particular specimen it is not the width of ring, but the proportion and character of the late wood which should govern. In the case of the ring-porous hardwoods there seems to exist a pretty definite relation between the rate of growth of timber and its properties. This may be briefly summed up in the general statement that the more rapid the growth or the wider the rings of growth, the heavier, harder, stronger, and stiffer the wood. This, it must be remembered, applies only to ring-porous woods such as oak, ash, hickory, and others of the same group, and is, of course, subject to some exceptions and limitations. In ring-porous woods of good growth it is usually the middle portion of the ring in which the thick-walled, strength-giving fibers are most abundant. As the breadth of ring diminishes, this middle portion is reduced so that very slow growth produces comparatively light, porous wood composed of thin-walled vessels and wood parenchyma. In good oak these large vessels of the early wood occupy from 6 to 10 per cent of the volume of the log, while in inferior material they may make up 25 per cent or more. The late wood of good oak, except for radial grayish patches of small pores, is dark colored and firm, and consists of thick-walled fibers which form one-half or more of the wood. In inferior oak, such fiber areas are much reduced both in quantity and quality. Such variation is very largely the result of rate of growth. Wide-ringed wood is often called "second-growth", because the growth of the young timber in open stands after the old trees have been removed is more rapid than in trees in the forest, and in the manufacture of articles where strength is an important consideration such "second-growth" hardwood material is preferred. This is particularly the case in the choice of hickory for handles and spokes. Here not only strength, but toughness and resilience are important. The results of a series of tests on hickory by the U.S. Forest Service show that: The effect of rate of growth on the qualities of chestnut wood is summarized by the same authority as follows: In diffuse-porous woods, as has been stated, the vessels or pores are scattered throughout the ring instead of collected in the early wood. The effect of rate of growth is, therefore, not the same as in the ring-porous woods, approaching more nearly the conditions in the conifers. In general it may be stated that such woods of medium growth afford stronger material than when very rapidly or very slowly grown. In many uses of wood, strength is not the main consideration. If ease of working is prized, wood should be chosen with regard to its uniformity of texture and straightness of grain, which will in most cases occur when there is little contrast between the late wood of one season's growth and the early wood of the next. ## Monocot wood Structural tissue resembling ordinary 'dicot' wood is produced by a number of monocot plants, and these are also usually called wood. Of these, the wood of the grass bamboo has considerable economic importance, larger culms being used in the manufacture of engineered flooring, panels and veneer. Other plant groups that produce woody tissue are palms, and members of the Liliales, such as Dracaena and Cordyline. With all these woods, the structure and composition of the structural tissue is quite different from ordinary wood. # Water content Water occurs in living wood in three conditions, namely: (1) in the cell walls, (2) in the protoplasmic contents of the cells, and (3) as free water in the cell cavities and spaces. In heartwood it occurs only in the first and last forms. Wood that is thoroughly air-dried retains from 8-16% of water in the cell walls, and none, or practically none, in the other forms. Even oven-dried wood retains a small percentage of moisture, but for all except chemical purposes, may be considered absolutely dry. The general effect of the water content upon the wood substance is to render it softer and more pliable. A similar effect of common observation is in the softening action of water on paper or cloth. Within certain limits the greater the water content the greater its softening effect. Drying produces a decided increase in the strength of wood, particularly in small specimens. An extreme example is the case of a completely dry spruce block 5 cm in section, which will sustain a permanent load four times as great as that which a green block of the same size will support. The greatest increase due to drying is in the ultimate crushing strength, and strength at elastic limit in endwise compression; these are followed by the modulus of rupture, and stress at elastic limit in cross-bending, while the modulus of elasticity is least affected. # Wood as fuel Wood is burned as a fuel mostly in rural areas of the world. Hard wood is preferred over softwood because it creates less smoke and burns longer. Adding a woodstove or fireplace to a home adds ambiance and warmth.[5]

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

6f40a2044d90c3c0d55555fa90384141fed6437e

wikidoc

XBP1

XBP1 X-box binding protein 1, also known as XBP1, is a protein which in humans is encoded by the XBP1 gene. The XBP1 gene is located on chromosome 22 while a closely related pseudogene has been identified and localized to chromosome 5. The XBP1 protein is a transcription factor that regulates the expression of genes important to the proper functioning of the immune system and in the cellular stress response. # Discovery The X-box binding protein 1 (XBP1) is a transcription factor containing a bZIP domain. It was first identified by its ability to bind to the Xbox, a conserved transcriptional element in the promoter of the human leukocyte antigen (HLA) DR alpha. # Function ## MHC class II gene regulation The expression of this protein is required for the transcription of a subset of class II major histocompatibility genes. Furthermore, XBP1 heterodimerizes with other bZIP transcription factors such as c-fos. XBP1 expression is controlled by the cytokine IL-4 and the antibody IGHM. XBP1 in turn controls the expression of IL-6 which promotes plasma cell growth and of immunoglobulins in B lymphocytes. ## Plasma cell differentiation XBP1 is also essential for differentiation of plasma cells (a type of antibody secreting immune cell). This differentiation requires not only the expression of XBP1 but the expression of the spliced isoform of XBP1s. XBP1 regulates plasma cell differentiation independent of its known functions in the endoplasmic reticulum stress response (see below). Without normal expression of XBP1, two important plasma cell differentiation-related genes, IRF4 and Blimp1, are misregulated, and XBP1-lacking plasma cells fail to colonize their long-lived niches in the bone marrow and to sustain antibody secretion. ## Eosinophil differentiation XBP1 is required for eosinophil differentiation. Eosinophils lacking XBP1 exhibit defects in granule proteins. ## Angiogenesis XBP1 acts to regulate endothelial cell proliferation through growth factor pathways, leading to angiogenesis. Additionally, XBP1 protects endothelial cells from oxidative stress by interacting with HDAC3. ## Viral replication This protein has also been identified as a cellular transcription factor that binds to an enhancer in the promoter of the Human T-lymphotropic virus 1. The generation of XBP1s during plasma cell differentiation also seems to be the cue for Kaposi's sarcoma-associated herpesvirus and Epstein Barr virus reactivation from latency. ## Endoplasmic reticulum stress response XBP1 is part of the endoplasmic reticulum (ER) stress response, the unfolded protein response (UPR). Conditions that exceed capacity of the ER provoke ER stress and trigger the unfolded protein response (UPR). As a result, GRP78 is released from IRE1 to support protein folding. IRE1 oligomerises and activates its ribonuclease domain through auto (self) phosphorylation. Activated IRE1 catalyses the excision of a 26 nucleotide unconventional intron from ubiquitously expressed XBP1u mRNA, in a manner mechanistically similar to pre-tRNA splicing. Removal of this intron causes a frame shift in the XBP1 coding sequence resulting in the translation of a 376 amino acid, 40 kDa, XBP-1s isoform rather than the 261 amino acid, 33 kDa, XBP1u isoform. Moreover, the XBP1u/XBP1s ratio (XBP1-unspliced/XBP1-spliced ratio) correlates with the expression level of expressed proteins in order to adapt the folding capacity of the ER to the respective requirements. # Clinical significance Abnormalities in XBP1 lead to a heightened ER stress and subsequently causes a heightened susceptibility for inflammatory processes that may contribute to Alzheimer's disease. In the colon, XBP1 anomalies have been linked to Crohn's disease. A single nucleotide polymorphism, C116G, in the promoter region of XBP1 has been examined for possible associations with personality traits. None were found. # Interactions XBP1 has been shown to interact with estrogen receptor alpha.

XBP1 X-box binding protein 1, also known as XBP1, is a protein which in humans is encoded by the XBP1 gene.[1][2] The XBP1 gene is located on chromosome 22 while a closely related pseudogene has been identified and localized to chromosome 5.[3] The XBP1 protein is a transcription factor that regulates the expression of genes important to the proper functioning of the immune system and in the cellular stress response.[4] # Discovery The X-box binding protein 1 (XBP1) is a transcription factor containing a bZIP domain. It was first identified by its ability to bind to the Xbox, a conserved transcriptional element in the promoter of the human leukocyte antigen (HLA) DR alpha.[2] # Function ## MHC class II gene regulation The expression of this protein is required for the transcription of a subset of class II major histocompatibility genes.[5] Furthermore, XBP1 heterodimerizes with other bZIP transcription factors such as c-fos.[5] XBP1 expression is controlled by the cytokine IL-4 and the antibody IGHM.[6] XBP1 in turn controls the expression of IL-6 which promotes plasma cell growth and of immunoglobulins in B lymphocytes.[6] ## Plasma cell differentiation XBP1 is also essential for differentiation of plasma cells (a type of antibody secreting immune cell).[6] This differentiation requires not only the expression of XBP1 but the expression of the spliced isoform of XBP1s. XBP1 regulates plasma cell differentiation independent of its known functions in the endoplasmic reticulum stress response (see below).[7] Without normal expression of XBP1, two important plasma cell differentiation-related genes, IRF4 and Blimp1, are misregulated, and XBP1-lacking plasma cells fail to colonize their long-lived niches in the bone marrow and to sustain antibody secretion.[7] ## Eosinophil differentiation XBP1 is required for eosinophil differentiation. Eosinophils lacking XBP1 exhibit defects in granule proteins.[8] ## Angiogenesis XBP1 acts to regulate endothelial cell proliferation through growth factor pathways,[9] leading to angiogenesis. Additionally, XBP1 protects endothelial cells from oxidative stress by interacting with HDAC3.[10] ## Viral replication This protein has also been identified as a cellular transcription factor that binds to an enhancer in the promoter of the Human T-lymphotropic virus 1.[11] The generation of XBP1s during plasma cell differentiation also seems to be the cue for Kaposi's sarcoma-associated herpesvirus and Epstein Barr virus reactivation from latency. ## Endoplasmic reticulum stress response XBP1 is part of the endoplasmic reticulum (ER) stress response, the unfolded protein response (UPR).[6] Conditions that exceed capacity of the ER provoke ER stress and trigger the unfolded protein response (UPR). As a result, GRP78 is released from IRE1 to support protein folding.[12] IRE1 oligomerises and activates its ribonuclease domain through auto (self) phosphorylation. Activated IRE1 catalyses the excision of a 26 nucleotide unconventional intron from ubiquitously expressed XBP1u mRNA, in a manner mechanistically similar to pre-tRNA splicing. Removal of this intron causes a frame shift in the XBP1 coding sequence resulting in the translation of a 376 amino acid, 40 kDa, XBP-1s isoform rather than the 261 amino acid, 33 kDa, XBP1u isoform. Moreover, the XBP1u/XBP1s ratio (XBP1-unspliced/XBP1-spliced ratio) correlates with the expression level of expressed proteins in order to adapt the folding capacity of the ER to the respective requirements.[13] # Clinical significance Abnormalities in XBP1 lead to a heightened ER stress and subsequently causes a heightened susceptibility for inflammatory processes that may contribute to Alzheimer's disease.[14] In the colon, XBP1 anomalies have been linked to Crohn's disease.[15] A single nucleotide polymorphism, C116G, in the promoter region of XBP1 has been examined for possible associations with personality traits. None were found.[16] # Interactions XBP1 has been shown to interact with estrogen receptor alpha.[17]

https://www.wikidoc.org/index.php/XBP1

e98aa41f87c6c4ced883deaf05f2b373446a84d7

wikidoc

XCL1

XCL1 Chemokine (C motif) ligand (XCL1) is a small cytokine belonging to the C chemokine family that is also known as lymphotactin. Chemokines are known for their function in inflammatory and immunological responses. This family C chemokines differs in structure and function from most chemokines. There are only two chemokines in this family and what separated them from other chemokines is that they only have two cysteines; one N-terminal cysteine and one cysteine downstream. These both are called Lymphotactin, alpha and beta form, and claim special characteristics only found between the two. Lymphotactins can go through a reversible conformational change which changes its binding shifts. In normal tissues, XCL1 is found in high levels in spleen, thymus, small intestine and peripheral blood leukocytes, and at lower levels in lung, prostate gland and ovary. Secretion of XCL1 is responsible for the increase of intracellular calcium in peripheral blood lymphocytes. Cellular sources for XCL1 include activated thymic and peripheral blood CD8+ T cells. XCL1 is also expressed by dendritic cells (DC). NK cells also secrete XCL1 along with other chemokines early in infections. In humans, XCL1 is closely related to another chemokine called XCL2, whose gene is found at the same locus on chromosome 1. Both of these chemokines share many genetic and functional similarities; however XCL2 has only been known to be observed in humans and not in mice. XCL1 induces it chemotactic function by binding to a chemokine receptor called XCR1. XCL1 is expressed on macrophages, fibroblasts, and specific lymphocytes. LTN, is found in two states: a monomer at 10 °C, LTN10, and a dimer at 40 °C, LTN40. # Genomics XCL1's gene is found on the long arm of chromosome 1, located on cytogenetic band q24.2 as seen in the infobox. The encoding gene is made of 6,017 DNA bases to encode for the protein XCL1. This gene contains three exons and two introns as well as several transcription initiation sites. This gene encodes for the 114-amino acid protein called XCL1 which is similar to other chemokines except that it lacks the first and third cysteine characteristics. This means that XCL1 only contains one cysteine creating a disulfide bond instead of two or three like the other chemokines. The genetic differences between XCL1 and XCL2 are very small. Both proteins are from the same family containing the C motif structure containing one disulfide bond and have almost identical tertiary structures. These C chemokines also have the same flanking regions, meaning regions of the gene including the promoter and other places of protein binging that do not contribute to the RNA transcribed gene. Gene mapping of this chemokine family shows similarities in their intron and exon locations with only one distinct difference. XCL1 has only one difference in its first intron that encodes for a large ribosomal subunit called L7a. In XCL2 have of the region encoding for L7a is cut off. The only other genetic difference between the two mature proteins is the different amino acid in positions 7 and 8. This amino acid difference may account for some biological differences. Some difficulties with comparing these two chemokines is that XCL2 has never been observed in a mouse. # Structure One thing that sets XCL1 apart from other cytokines is its structure. While most chemokines have two disulfide bonds that connect the N-terminus to the core of the structure, XCL1 only has one. This simple difference in disulfide bonds changes the overall tertiary structure of XCL1 from other chemokines. There are two parts of the lymphotactin protein, structures Ltn10 and Ltn40, that folds into each other, which make it biologically active. This conformational change alters the binding structures on the chemokine. This understanding of the interfolding provides more of a basis to understanding to the lymphotactin kinetics. # Biological Significance Most of the secreted XCL1 comes from a specific kind of dendritic cell that is involved in antigen cross-presentation. This means that XCL1 is involved in the activation of cytotoxic T cells by a dendritic cell. XCL1 can also be secreted by NK cells along with other chemokines in the beginning of infection. This has been associated with the T helper cell type 1 defense. This secretion has also been observed to facilitate the NK cells to communicate with DC containing XCR1 on their surface. In the same way, secretion of XCL1 encourages Cytotoxic T cells to also communicate with DC containing SCR1. The pair of XCL1 and XCR1 are known to be involved in cross-presentation, antigen uptake, and induction of innate as well as adaptive cytotoxic immunity. XCL1 is also known to increate T cells in joints that are effected with rheumatoid arthritis. They are also expressed on RA synovial lymphocytes.

XCL1 Chemokine (C motif) ligand (XCL1) is a small cytokine belonging to the C chemokine family that is also known as lymphotactin. Chemokines are known for their function in inflammatory and immunological responses. This family C chemokines differs in structure and function from most chemokines.[1][2] There are only two chemokines in this family and what separated them from other chemokines is that they only have two cysteines; one N-terminal cysteine and one cysteine downstream. These both are called Lymphotactin, alpha and beta form, and claim special characteristics only found between the two. Lymphotactins can go through a reversible conformational change which changes its binding shifts.[3] In normal tissues, XCL1 is found in high levels in spleen, thymus, small intestine and peripheral blood leukocytes, and at lower levels in lung, prostate gland and ovary. Secretion of XCL1 is responsible for the increase of intracellular calcium in peripheral blood lymphocytes.[4] Cellular sources for XCL1 include activated thymic and peripheral blood CD8+ T cells.[5][6][7] XCL1 is also expressed by dendritic cells (DC).[8] NK cells also secrete XCL1 along with other chemokines early in infections.[8] In humans, XCL1 is closely related to another chemokine called XCL2, whose gene is found at the same locus on chromosome 1.[7] Both of these chemokines share many genetic and functional similarities; however XCL2 has only been known to be observed in humans and not in mice.[8] XCL1 induces it chemotactic function by binding to a chemokine receptor called XCR1.[9] XCL1 is expressed on macrophages, fibroblasts, and specific lymphocytes.[2] LTN, is found in two states: a monomer at 10 °C, LTN10, and a dimer at 40 °C, LTN40.[10] # Genomics XCL1's gene is found on the long arm of chromosome 1, located on cytogenetic band q24.2 as seen in the infobox. The encoding gene is made of 6,017 DNA bases to encode for the protein XCL1.[11] This gene contains three exons and two introns as well as several transcription initiation sites.[4] This gene encodes for the 114-amino acid protein called XCL1 which is similar to other chemokines except that it lacks the first and third cysteine characteristics. This means that XCL1 only contains one cysteine creating a disulfide bond instead of two or three like the other chemokines.[1] The genetic differences between XCL1 and XCL2 are very small. Both proteins are from the same family containing the C motif structure containing one disulfide bond and have almost identical tertiary structures.[4] These C chemokines also have the same flanking regions, meaning regions of the gene including the promoter and other places of protein binging that do not contribute to the RNA transcribed gene.[4] Gene mapping of this chemokine family shows similarities in their intron and exon locations with only one distinct difference. XCL1 has only one difference in its first intron that encodes for a large ribosomal subunit called L7a. In XCL2 have of the region encoding for L7a is cut off.[4] The only other genetic difference between the two mature proteins is the different amino acid in positions 7 and 8.[4][8] This amino acid difference may account for some biological differences. Some difficulties with comparing these two chemokines is that XCL2 has never been observed in a mouse.[8] # Structure One thing that sets XCL1 apart from other cytokines is its structure.[3] While most chemokines have two disulfide bonds that connect the N-terminus to the core of the structure, XCL1 only has one.[1] This simple difference in disulfide bonds changes the overall tertiary structure of XCL1 from other chemokines. There are two parts of the lymphotactin protein, structures Ltn10 and Ltn40, that folds into each other, which make it biologically active.[3] This conformational change alters the binding structures on the chemokine. This understanding of the interfolding provides more of a basis to understanding to the lymphotactin kinetics.[3] # Biological Significance Most of the secreted XCL1 comes from a specific kind of dendritic cell that is involved in antigen cross-presentation.[8] This means that XCL1 is involved in the activation of cytotoxic T cells by a dendritic cell. XCL1 can also be secreted by NK cells along with other chemokines in the beginning of infection. This has been associated with the T helper cell type 1 defense.[8] This secretion has also been observed to facilitate the NK cells to communicate with DC containing XCR1 on their surface. In the same way, secretion of XCL1 encourages Cytotoxic T cells to also communicate with DC containing SCR1.[8] The pair of XCL1 and XCR1 are known to be involved in cross-presentation, antigen uptake, and induction of innate as well as adaptive cytotoxic immunity.[8] XCL1 is also known to increate T cells in joints that are effected with rheumatoid arthritis.[2] They are also expressed on RA synovial lymphocytes.[2]

https://www.wikidoc.org/index.php/XCL1

85c8bb58cd733093923f965ded27254645f5f868

wikidoc

XCR1

XCR1 The "C" sub-family of chemokine receptors contains only one member: XCR1, the receptor for XCL1 and XCL2 (or lymphotactin-1 and -2). XCR1 is also known as GPR5. # Function The protein encoded by this gene is a chemokine receptor belonging to the G protein-coupled receptor superfamily. The family members are characterized by the presence of 7 transmembrane domains and numerous conserved amino acids. This receptor is most closely related to RBS11 and the MIP1-alpha/RANTES receptor. It transduces a signal by increasing the intracellular calcium ions level. The viral macrophage inflammatory protein-II is an antagonist of this receptor and blocks signaling. Two alternatively spliced transcript variants encoding the same protein have been found for this gene. Cross-presenting dendritic cells (DCs) in the spleen develop into XCR1+ DCs in the small intestine, T cell zones of Peyer’s patches, and T cell zones and sinuses of mesenteric lymph nodes. XCR1+ DCs specialize in cross-presentations of orally applied antigens. The integrin SIRPα is also a differentiating factor for the XCR1+ DCs. The development transcription factor Batf3 helps develop the differences between XCR1+ DCs and CD103+ CD11b- DCs. XCL1 contributes to chemotaxis only in CD8+ murine cells, but not other DC types, B cells, T cells, or NK cells. Only some of these CD8+ murine cells expressed XCR1 receptors. NK cells release XCL1 along with IFN-γ and some other chemokines upon encountering certain bacteria such as Listeria or MCMV. XCR1+ and CD8+cells work together to cross-present antigen and communicate CD8+ activation. Cross presentation of XCR1+ CD8+ and XCR1+ CD8- cells was strongest, as is expected since they have XCR1 receptors. CD4+ and CD8+ may become outdated terms, since the activity of the cell appears to be primarily dependent upon the expression of XCR1, which will make a population far more similar than the expression of CD4 or CD8. XCR1+ cells are dependent on the growth factor Ftl3 ligand and are nonexistent in Batf3- deficient mice. Also, XCR1+ DCs are related to CD103+CD11b- DCs. XCL1 is expressed by medullary thymic epithelial T cells (mTECs) while XCR1 is expressed by thymic dendritic cells (tDCs). This communication helps with the destruction of cells that are not self-tolerant. When mice lose the ability to express XCL1, they are deficient in accumulation of tDCs and producing naturally occurring regulatory T cells (nT reg cells). The displaying of XCL1 by mTECs, tDC chemotaxis, and nT reg cell production are all decreased in mice that lack Aire, demonstrating it as a important regulator of XCL1 production. Naive CD8+ T cells are prepared when tumors form by cross-presentation via XCR1+ DCs and as a result will require a lower threshold to respond to antigen. Memory CD8+ T lymphocytes (mCTLs) are activated first after infection and then are signaled by CXCR3, IL-12, and CXCL9 by other XCR1+ DCs. In order to make a powerful secondary infection response, cytokine and chemokine signaling between XCR1+ DCs and NK cells must occur.

XCR1 The "C" sub-family of chemokine receptors contains only one member: XCR1, the receptor for XCL1 and XCL2 (or lymphotactin-1 and -2). XCR1 is also known as GPR5. # Function The protein encoded by this gene is a chemokine receptor belonging to the G protein-coupled receptor superfamily. The family members are characterized by the presence of 7 transmembrane domains and numerous conserved amino acids. This receptor is most closely related to RBS11 and the MIP1-alpha/RANTES receptor. It transduces a signal by increasing the intracellular calcium ions level. The viral macrophage inflammatory protein-II is an antagonist of this receptor and blocks signaling. Two alternatively spliced transcript variants encoding the same protein have been found for this gene.[1] Cross-presenting dendritic cells (DCs) in the spleen develop into XCR1+ DCs in the small intestine, T cell zones of Peyer’s patches, and T cell zones and sinuses of mesenteric lymph nodes. XCR1+ DCs specialize in cross-presentations of orally applied antigens. The integrin SIRPα is also a differentiating factor for the XCR1+ DCs. The development transcription factor Batf3 helps develop the differences between XCR1+ DCs and CD103+ CD11b- DCs.[2] XCL1 contributes to chemotaxis only in CD8+ murine cells, but not other DC types, B cells, T cells, or NK cells. Only some of these CD8+ murine cells expressed XCR1 receptors. NK cells release XCL1 along with IFN-γ and some other chemokines upon encountering certain bacteria such as Listeria or MCMV. XCR1+ and CD8+cells work together to cross-present antigen and communicate CD8+ activation. Cross presentation of XCR1+ CD8+ and XCR1+ CD8- cells was strongest, as is expected since they have XCR1 receptors. CD4+ and CD8+ may become outdated terms, since the activity of the cell appears to be primarily dependent upon the expression of XCR1, which will make a population far more similar than the expression of CD4 or CD8.[3] XCR1+ cells are dependent on the growth factor Ftl3 ligand and are nonexistent in Batf3- deficient mice. Also, XCR1+ DCs are related to CD103+CD11b- DCs.[4] XCL1 is expressed by medullary thymic epithelial T cells (mTECs) while XCR1 is expressed by thymic dendritic cells (tDCs). This communication helps with the destruction of cells that are not self-tolerant. When mice lose the ability to express XCL1, they are deficient in accumulation of tDCs and producing naturally occurring regulatory T cells (nT reg cells). The displaying of XCL1 by mTECs, tDC chemotaxis, and nT reg cell production are all decreased in mice that lack Aire, demonstrating it as a important regulator of XCL1 production.[5] Naive CD8+ T cells are prepared when tumors form by cross-presentation via XCR1+ DCs and as a result will require a lower threshold to respond to antigen. Memory CD8+ T lymphocytes (mCTLs) are activated first after infection and then are signaled by CXCR3, IL-12, and CXCL9 by other XCR1+ DCs. In order to make a powerful secondary infection response, cytokine and chemokine signaling between XCR1+ DCs and NK cells must occur. [6]

https://www.wikidoc.org/index.php/XCR1

17092cb8c5244a06b1a796b5acfb9d563baf57ab

wikidoc

XIAP

XIAP X-linked Inhibitor of Apoptosis Protein (XIAP) is a member of the Inhibitor of apoptosis family of proteins (IAP). IAPs were initially identified in baculoviruses, but XIAP is one of the homologous proteins found in mammals. It is so called because it was first discovered by a 273 base pair site on the X chromosome. The protein is also called human IAP-like Protein (hILP), because it is not as well conserved as the human IAPS: hIAP-1 and hIAP-2. XIAP is the most potent human IAP protein currently identified. # Discovery Neuronal apoptosis inhibitor protein (NAIP) was the first homolog to baculoviral IAPs that was identified in humans. With the sequencing data of NIAP, the gene sequence for a RING zinc-finger domain was discovered at site Xq24-25. Using PCR and cloning, three BIR domains and a RING finger were found on the protein, which became known as X-linked Inhibitor of Apoptosis Protein. The transcript size of Xiap is 9.0kb, with an open reading frame of 1.8kb. Xiap mRNA has been observed in all human adult and fetal tissues "except peripheral blood leukocytes". The XIAP sequences led to the discovery of other members of the IAP family. # Structure XIAP, like the rest of the IAP family, has two major structural elements. Firstly, there is the baculoviral IAP repeat (BIR) domain consisting of approximately 70 amino acids. Secondly, there is a zinc-binding domain, or a “carboxy-terminal RING Finger”. XIAP has been characterized with three amino-terminal BIR domains and one RING domain. Between the BIR-1 and BIR-2 domains, there is a linker-BIR-2 region that is thought to contain the only element that comes into contact with the caspase molecule to form the XIAP/Caspase-7 complex. # Function XIAP stops apoptotic cell death induced either by viral infection or by overproduction of caspases, the enzymes primarily responsible for cell death. XIAP binds to and inhibits caspase 3, 7 and 9. Recent studies have pinpointed the structural location of these inhibiting properties: the region immediately following the terminal end of BIR2 inhibits caspase 3 and 7, while BIR3 binds to and inhibits caspase 9. The RING domain utilizes E3 ubiquitin ligase activity and enables IAPs to catalyze ubiquination of self, caspase-3, or caspase-7 by degradation via proteasome activity. However, mutations affecting the RING Finger do not significantly affect apoptosis, indicating that the BIR domain is sufficient for the protein’s function. When inhibiting caspase-3 and caspase-7 activity, the BIR2 domain of XIAP binds to the active-site substrate groove, blocking access of the normal protein substrate that would result in apoptosis. Caspases are activated by cytochrome c, which is released into the cytosol by dysfunctioning mitochondria. Studies show that XIAP does not directly affect cytochrome c. XIAP distinguishes itself from the other human IAPs because it is able to effectively prevent cell death due to "TNF-α, Fas, UV light, and genotoxic agents". The second BIR domain of XIAP can be shown binding to caspase 3 where a protein substrate would normally bind during aptosis. By blocking this binding, XIAP inhibits apoptosis. # Inhibiting XIAP XIAP is inhibited by Smac/DIABLO and Omi/HtrA2, two death-signaling proteins released into the cytoplasm by the mitochondria. Smac/ DIABLO, a mitochondrial protein and negative regulator of XIAP, can enhance apoptosis by binding to XIAP and preventing it from binding to caspases. This allows normal caspase activity to proceed. The binding process of Smac/DIABLO to XIAP and caspase release requires a conserved tetrapeptide motif. # Significance Deregulation of XIAP can result in “cancer, neurodegenerative disorders, and autoimmunity”. High proportions of XIAP may function as a tumor marker. In the development of lung cancer NCI-H460, the overexpression of XIAP not only inhibits caspase, but also stops the activity of cytochrome c (Apoptosis). In developing prostate cancer, XIAP is one of four IAPs overexpressed in the prostatic epithelium, indicating that a molecule that inhibits all IAPs may be necessary for effective treatment. Apoptotic regulation is an extremely important biological function, as evidenced by "the conservation of the IAPs from humans to Drosophila".

XIAP X-linked Inhibitor of Apoptosis Protein (XIAP) is a member of the Inhibitor of apoptosis family of proteins (IAP). IAPs were initially identified in baculoviruses, but XIAP is one of the homologous proteins found in mammals.[1] It is so called because it was first discovered by a 273 base pair site on the X chromosome.[2] The protein is also called human IAP-like Protein (hILP), because it is not as well conserved as the human IAPS: hIAP-1 and hIAP-2.[2][3] XIAP is the most potent human IAP protein currently identified.[4] # Discovery Neuronal apoptosis inhibitor protein (NAIP) was the first homolog to baculoviral IAPs that was identified in humans.[2] With the sequencing data of NIAP, the gene sequence for a RING zinc-finger domain was discovered at site Xq24-25.[2] Using PCR and cloning, three BIR domains and a RING finger were found on the protein, which became known as X-linked Inhibitor of Apoptosis Protein. The transcript size of Xiap is 9.0kb, with an open reading frame of 1.8kb.[2] Xiap mRNA has been observed in all human adult and fetal tissues "except peripheral blood leukocytes".[2] The XIAP sequences led to the discovery of other members of the IAP family. # Structure XIAP, like the rest of the IAP family, has two major structural elements. Firstly, there is the baculoviral IAP repeat (BIR) domain consisting of approximately 70 amino acids.[4] Secondly, there is a zinc-binding domain, or a “carboxy-terminal RING Finger”.[3] XIAP has been characterized with three amino-terminal BIR domains and one RING domain.[5] Between the BIR-1 and BIR-2 domains, there is a linker-BIR-2 region that is thought to contain the only element that comes into contact with the caspase molecule to form the XIAP/Caspase-7 complex.[6] # Function XIAP stops apoptotic cell death induced either by viral infection or by overproduction of caspases, the enzymes primarily responsible for cell death[3]. XIAP binds to and inhibits caspase 3, 7 and 9.[1][5][7] Recent studies have pinpointed the structural location of these inhibiting properties: the region immediately following the terminal end of BIR2 inhibits caspase 3 and 7, while BIR3 binds to and inhibits caspase 9.[5] The RING domain utilizes E3 ubiquitin ligase activity and enables IAPs to catalyze ubiquination of self, caspase-3, or caspase-7 by degradation via proteasome activity.[8] However, mutations affecting the RING Finger do not significantly affect apoptosis, indicating that the BIR domain is sufficient for the protein’s function.[3] When inhibiting caspase-3 and caspase-7 activity, the BIR2 domain of XIAP binds to the active-site substrate groove, blocking access of the normal protein substrate that would result in apoptosis.[8] Caspases are activated by cytochrome c, which is released into the cytosol by dysfunctioning mitochondria.[3] Studies show that XIAP does not directly affect cytochrome c.[3] XIAP distinguishes itself from the other human IAPs because it is able to effectively prevent cell death due to "TNF-α, Fas, UV light, and genotoxic agents".[3] The second BIR domain of XIAP can be shown binding to caspase 3 where a protein substrate would normally bind during aptosis. By blocking this binding, XIAP inhibits apoptosis. # Inhibiting XIAP XIAP is inhibited by Smac/DIABLO and Omi/HtrA2, two death-signaling proteins released into the cytoplasm by the mitochondria.[5] Smac/ DIABLO, a mitochondrial protein and negative regulator of XIAP, can enhance apoptosis by binding to XIAP and preventing it from binding to caspases. This allows normal caspase activity to proceed. The binding process of Smac/DIABLO to XIAP and caspase release requires a conserved tetrapeptide motif.[8] # Significance Deregulation of XIAP can result in “cancer, neurodegenerative disorders, and autoimmunity”.[5] High proportions of XIAP may function as a tumor marker.[4] In the development of lung cancer NCI-H460, the overexpression of XIAP not only inhibits caspase, but also stops the activity of cytochrome c (Apoptosis). In developing prostate cancer, XIAP is one of four IAPs overexpressed in the prostatic epithelium, indicating that a molecule that inhibits all IAPs may be necessary for effective treatment.[9] Apoptotic regulation is an extremely important biological function, as evidenced by "the conservation of the IAPs from humans to Drosophila".[2]

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

d1bf7223524465faf7e2457b2325d746453e682e

wikidoc

XIST

XIST Xist (X-inactive specific transcript) is an RNA gene on the X chromosome of the placental mammals that acts as a major effector of the X inactivation process. It is a component of the Xic – X-chromosome inactivation centre – along with two other RNA genes (Jpx and Ftx) and two protein genes (Tsx and Cnbp2). The Xist RNA, a large (17 kb in humans) transcript, is expressed on the inactive chromosome and not on the active one. It is processed in a similar way to mRNAs, through splicing and polyadenylation. However, it remains untranslated. It has been suggested that this RNA gene evolved at least partly from a protein coding gene that became a pseudogene. The inactive X chromosome is coated with this transcript, which is essential for the inactivation. X chromosomes lacking Xist will not be inactivated, while duplication of the Xist gene on another chromosome causes inactivation of that chromosome. # Function X inactivation is an early developmental process in mammalian females that transcriptionally silences one of the pair of X chromosomes, thus providing dosage equivalence between males and females (see dosage compensation). The process is regulated by several factors, including a region of chromosome X called the X inactivation center (XIC). The XIST gene is expressed exclusively from the XIC of the inactive X chromosome. The transcript is spliced but apparently does not encode a protein. The transcript remains in the nucleus where it coats the inactive X chromosome. Alternatively spliced transcript variants have been identified, but their full length sequences have not been determined. The functional role of the Xist transcript was definitively demonstrated in mouse female ES cells using a novel antisense technology, called peptide nucleic acid (PNA) interference mapping. In the reported experiments, a single 19-bp antisense cell-permeating PNA targeted against a particular region of Xist RNA prevented the formation of Xi and inhibited cis-silencing of X-linked genes. The association of the Xi with macro-histone H2A is also disturbed by PNA interference mapping. X-inactivation process occurs in mice even in the absence of this gene via epigenetic regulation, but Xist is required to stabilize this silencing. # Gene location The human Xist RNA gene is located on the long (q) arm of the X chromosome. The Xist RNA gene consists of conserved repeats within its structure and is also largely localized in the nucleus. The Xist RNA gene consists of an A region, which contains 8 repeats separated by U-rich spacers. The A region appears to contain two long stem-loop structures that each include four repeats. An ortholog of the Xist RNA gene in humans has been identified in mice. This ortholog is a 15 kb Xist RNA gene that is also localized in the nucleus. However, the ortholog does not consist of conserved repeats. The gene also consists of an Xist Inactivation Center (XIC), which plays a major role in X inactivation. # Transcript organization ## A region The Xist RNA contains a region of conservation called the repeat A (repA) region that contains up to nine repeated elements. It was initially suggested that repA repeats could fold back on themselves to form local intra-repeat stem-loop structures. Later work using in vitro biochemical structure probing proposed several inter-repeat stem-loop structures. A recent study using in vivo biochemical probing and comparative sequence analysis proposed a revision of the repA structure model that includes both intra-repeat and inter-repeat folding found in previous models as well as novel features (see Figure). In addition to its agreement with the in vivo data, this revised model is highly conserved in rodents and mammals (including humans) suggesting functional importance for repA structure. Although the exact function of the repA region is uncertain, it was shown that the entire region is needed for efficient binding to the Suz12 protein. ## C region The Xist RNA directly binds to the inactive X-chromosome through a chromatin binding region of the RNA transcript. The Xist chromatin binding region was first elucidated in female mouse fibroblastic cells. The primary chromatin binding region was shown to localize to the C-repeat region. The chromatin-binding region was functionally mapped and evaluated by using an approach for studying noncoding RNA function in living cells called peptide nucleic acid (PNA) interference mapping. In the reported experiments, a single 19-bp antisense cell-permeating PNA targeted against a particular region of Xist RNA caused the disruption of the Xi. The association of the Xi with macro-histone H2A is also disturbed by PNA interference mapping. # X Inactivation Centre (XIC) The Xist RNA gene lies within the X-Inactivation Centre (XIC), which plays a major role in Xist expression and X inactivation. The XIC is located on the q arm of the X chromosome (Xq13). XIC regulates Xist in cis X inactivation, where Tsix, an antisense of Xist, downregulates the expression of Xist. The Xist promoter of XIC is the master regulator of X inactivation. X inactivation plays a key role in dosage compensation. ## Tsix antisense transcript The Tsix antisense gene is a transcript of the Xist gene at the XIC center. The Tsix antisense transcript acts in cis to repress the transcription of Xist, which negatively regulates its expression. The mechanism behind how Tsix modulates Xist activity in cis is poorly understood; however, there are a few theories on its mechanism. One theory is that Tsix is involved in chromatin modification at the Xist locus and another is that transcription factors of pluripotent cells play a role in Xist repression. # Regulation of the Xist promoter ## Methylation The Tsix antisense is believed to activate DNA methyl transferases that methylate the Xist promoter, in return resulting in inhibition of the Xist promoter and thus the expression of the Xist gene. Methylation of histone 3 lysine 4 (H3K4) produces an active chromatin structure, which recruits transcription factors and thus allows for transcription to occur, therefore in this case the transcription of Xist. ## dsRNA and RNAi A dsRNA and RNAi pathway have been also proposed to play a role in regulation of the Xist Promoter. Dicer is an RNAi enzyme and it is believed to cleave the duplex of Xist and Tsix at the beginning of X inactivation, to small ~30 nucleotide RNAs, which have been termed xiRNAs, These xiRNAs are believed to be involved in repressing Xist on the probable active X chromosome based upon studies. A study was conducted where normal endogenous Dicer levels were decreased to 5%, which led to an increase in Xist expression in undifferentiated cells, thus supporting the role of xiRNAs in Xist repression. The role and mechanism of xiRNAs is still under examination and debate. ## Tsix independent mechanisms ### Pluripotent cell transcriptional factors Pluripotent stem cells express transcription factors Nanog, Oct4 and Sox2 that seem to play a role in repressing Xist. In the absence of Tsix in pluripotent cells, Xist is repressed, where a mechanism has been proposed that these transcription factors cause splicing to occur at intron 1 at the binding site of these factors on the Xist gene, which inhibits Xist expression A study was conducted where Nanog or Oct4 transcription factors were depleted in pluripotent cells, which resulted in the upregulation of Xist. From this study, it is proposed that Nanog and Oct4 are involved in the repression of Xist expression. ### Polycomb repressive complex Polycomb repressive complex 2 (PRC2) consist of a class of polycomb group proteins that are involved in catalyzing the trimethylation of histone H3 on lysine 27 (K27), which results in chromatin repression, and thus leads to transcriptional silencing. Xist RNA recruits polycomb complexes to the inactive X chromosome at the onset of XCI. SUZ12 is a component of the PRC2 and contains a zinc finger domain. The zinc finger domain is believed to bind to the RNA molecule. The PRC2 has been observed to repress Xist expression independent of the Tsix antisense transcript, although the definite mechanism is still not known. # Dosage compensation X inactivation plays a key role in dosage compensation mechanisms that allow for equal expression of the X and autosomal chromosomes. Different species have different dosage compensation methods, with all of the methods involving the regulation of an X chromosome from one of the either sexes. Some methods involved in dosage compensation to inactivate one of the X chromosomes from one of the sexes are Tsix antisense gene, DNA methylation and DNA acetylation; however, the definite mechanism of X inactivation is still poorly understood. If one of the X chromosomes is not inactivated or is partially expressed, it could lead to over expression of the X chromosome and it could be lethal in some cases. Turner's Syndrome is one example of where dosage compensation does not equally express the X chromosome, and in females one of the X chromosomes is missing or has abnormalities, which leads to physical abnormalities and also gonadal dysfunction in females due to the one missing or abnormal X chromosome. Turner's syndrome is also referred to as a monosomy X condition. # X inactivation cycle Xist expression and X inactivation change throughout embryonic development. In early embryogenesis, the oocyte and sperm do not express Xist and the X chromosome remains active. After fertilization, when the cells are in the 2 to 4 cell stage, Xist transcripts are expressed from parent X chromosome(Xp) in every cell, causing that X chromosome to become imprinted and inactivated. Some cells develop into pluripotent cells (the inner cell mass) when the blastocyte forms. There, the imprint is removed, leading to the downregulation of Xist and thus reactivation of the inactive X chromosome. Recent data suggests that Xist activity is regulated by an anti-sense transcript. The epiblast cells are then formed and they begin to be differentiated, and the Xist is upregulated from either of the two X chromosomes and at random in ICM, but the Xist is maintained in epiblast, an X is inactivated and the Xist allele is turned off in the active X chromosome. In maturing XX primordial germ cells, Xist is downregulated and X reactivation occurs once again. # Disease linkage Mutations in the XIST promoter cause familial skewed X inactivation. # Interactions XIST (gene) has been shown to interact with BRCA1.

XIST Xist (X-inactive specific transcript) is an RNA gene on the X chromosome of the placental mammals that acts as a major effector of the X inactivation process.[1] It is a component of the Xic – X-chromosome inactivation centre[2] – along with two other RNA genes (Jpx and Ftx) and two protein genes (Tsx and Cnbp2).[3] The Xist RNA, a large (17 kb in humans)[4] transcript, is expressed on the inactive chromosome and not on the active one. It is processed in a similar way to mRNAs, through splicing and polyadenylation. However, it remains untranslated. It has been suggested that this RNA gene evolved at least partly from a protein coding gene that became a pseudogene.[5] The inactive X chromosome is coated with this transcript, which is essential for the inactivation.[6] X chromosomes lacking Xist will not be inactivated, while duplication of the Xist gene on another chromosome causes inactivation of that chromosome.[7] # Function X inactivation is an early developmental process in mammalian females that transcriptionally silences one of the pair of X chromosomes, thus providing dosage equivalence between males and females (see dosage compensation). The process is regulated by several factors, including a region of chromosome X called the X inactivation center (XIC). The XIST gene is expressed exclusively from the XIC of the inactive X chromosome. The transcript is spliced but apparently does not encode a protein. The transcript remains in the nucleus where it coats the inactive X chromosome. Alternatively spliced transcript variants have been identified, but their full length sequences have not been determined.[1] The functional role of the Xist transcript was definitively demonstrated in mouse female ES cells using a novel antisense technology, called peptide nucleic acid (PNA) interference mapping. In the reported experiments, a single 19-bp antisense cell-permeating PNA targeted against a particular region of Xist RNA prevented the formation of Xi and inhibited cis-silencing of X-linked genes. The association of the Xi with macro-histone H2A is also disturbed by PNA interference mapping.[8] X-inactivation process occurs in mice even in the absence of this gene via epigenetic regulation, but Xist is required to stabilize this silencing.[9] # Gene location The human Xist RNA gene is located on the long (q) arm of the X chromosome. The Xist RNA gene consists of conserved repeats within its structure and is also largely localized in the nucleus.[4] The Xist RNA gene consists of an A region, which contains 8 repeats separated by U-rich spacers. The A region appears to contain two long stem-loop structures that each include four repeats.[10] An ortholog of the Xist RNA gene in humans has been identified in mice. This ortholog is a 15 kb Xist RNA gene that is also localized in the nucleus. However, the ortholog does not consist of conserved repeats.[11] The gene also consists of an Xist Inactivation Center (XIC), which plays a major role in X inactivation.[12] # Transcript organization ## A region The Xist RNA contains a region of conservation called the repeat A (repA) region that contains up to nine repeated elements.[10] It was initially suggested that repA repeats could fold back on themselves to form local intra-repeat stem-loop structures. Later work using in vitro biochemical structure probing proposed several inter-repeat stem-loop structures.[4][10] A recent study using in vivo biochemical probing and comparative sequence analysis proposed a revision of the repA structure model that includes both intra-repeat and inter-repeat folding found in previous models as well as novel features (see Figure). In addition to its agreement with the in vivo data, this revised model is highly conserved in rodents and mammals (including humans) suggesting functional importance for repA structure. Although the exact function of the repA region is uncertain, it was shown that the entire region is needed for efficient binding to the Suz12 protein.[10] ## C region The Xist RNA directly binds to the inactive X-chromosome through a chromatin binding region of the RNA transcript. The Xist chromatin binding region was first elucidated in female mouse fibroblastic cells. The primary chromatin binding region was shown to localize to the C-repeat region. The chromatin-binding region was functionally mapped and evaluated by using an approach for studying noncoding RNA function in living cells called peptide nucleic acid (PNA) interference mapping. In the reported experiments, a single 19-bp antisense cell-permeating PNA targeted against a particular region of Xist RNA caused the disruption of the Xi. The association of the Xi with macro-histone H2A is also disturbed by PNA interference mapping.[8] # X Inactivation Centre (XIC) The Xist RNA gene lies within the X-Inactivation Centre (XIC), which plays a major role in Xist expression and X inactivation.[13] The XIC is located on the q arm of the X chromosome (Xq13). XIC regulates Xist in cis X inactivation, where Tsix, an antisense of Xist, downregulates the expression of Xist. The Xist promoter of XIC is the master regulator of X inactivation.[12] X inactivation plays a key role in dosage compensation. ## Tsix antisense transcript The Tsix antisense gene is a transcript of the Xist gene at the XIC center.[14] The Tsix antisense transcript acts in cis to repress the transcription of Xist, which negatively regulates its expression. The mechanism behind how Tsix modulates Xist activity in cis is poorly understood; however, there are a few theories on its mechanism. One theory is that Tsix is involved in chromatin modification at the Xist locus and another is that transcription factors of pluripotent cells play a role in Xist repression.[15] # Regulation of the Xist promoter ## Methylation The Tsix antisense is believed to activate DNA methyl transferases that methylate the Xist promoter, in return resulting in inhibition of the Xist promoter and thus the expression of the Xist gene.[16] Methylation of histone 3 lysine 4 (H3K4) produces an active chromatin structure, which recruits transcription factors and thus allows for transcription to occur, therefore in this case the transcription of Xist.[17] ## dsRNA and RNAi A dsRNA and RNAi pathway have been also proposed to play a role in regulation of the Xist Promoter. Dicer is an RNAi enzyme and it is believed to cleave the duplex of Xist and Tsix at the beginning of X inactivation, to small ~30 nucleotide RNAs, which have been termed xiRNAs, These xiRNAs are believed to be involved in repressing Xist on the probable active X chromosome based upon studies. A study was conducted where normal endogenous Dicer levels were decreased to 5%, which led to an increase in Xist expression in undifferentiated cells, thus supporting the role of xiRNAs in Xist repression.[18] The role and mechanism of xiRNAs is still under examination and debate.[citation needed] ## Tsix independent mechanisms ### Pluripotent cell transcriptional factors Pluripotent stem cells express transcription factors Nanog, Oct4 and Sox2 that seem to play a role in repressing Xist. In the absence of Tsix in pluripotent cells, Xist is repressed, where a mechanism has been proposed that these transcription factors cause splicing to occur at intron 1 at the binding site of these factors on the Xist gene, which inhibits Xist expression[15] A study was conducted where Nanog or Oct4 transcription factors were depleted in pluripotent cells, which resulted in the upregulation of Xist. From this study, it is proposed that Nanog and Oct4 are involved in the repression of Xist expression.[19] ### Polycomb repressive complex Polycomb repressive complex 2 (PRC2) consist of a class of polycomb group proteins that are involved in catalyzing the trimethylation of histone H3 on lysine 27 (K27), which results in chromatin repression, and thus leads to transcriptional silencing. Xist RNA recruits polycomb complexes to the inactive X chromosome at the onset of XCI.[20] SUZ12 is a component of the PRC2 and contains a zinc finger domain. The zinc finger domain is believed to bind to the RNA molecule.[21] The PRC2 has been observed to repress Xist expression independent of the Tsix antisense transcript, although the definite mechanism is still not known. # Dosage compensation X inactivation plays a key role in dosage compensation mechanisms that allow for equal expression of the X and autosomal chromosomes.[22] Different species have different dosage compensation methods, with all of the methods involving the regulation of an X chromosome from one of the either sexes.[22] Some methods involved in dosage compensation to inactivate one of the X chromosomes from one of the sexes are Tsix antisense gene, DNA methylation and DNA acetylation;[23] however, the definite mechanism of X inactivation is still poorly understood. If one of the X chromosomes is not inactivated or is partially expressed, it could lead to over expression of the X chromosome and it could be lethal in some cases. Turner's Syndrome is one example of where dosage compensation does not equally express the X chromosome, and in females one of the X chromosomes is missing or has abnormalities, which leads to physical abnormalities and also gonadal dysfunction in females due to the one missing or abnormal X chromosome. Turner's syndrome is also referred to as a monosomy X condition.[24] # X inactivation cycle Xist expression and X inactivation change throughout embryonic development. In early embryogenesis, the oocyte and sperm do not express Xist and the X chromosome remains active. After fertilization, when the cells are in the 2 to 4 cell stage, Xist transcripts are expressed from parent X chromosome(Xp) in every cell, causing that X chromosome to become imprinted and inactivated. Some cells develop into pluripotent cells (the inner cell mass) when the blastocyte forms. There, the imprint is removed, leading to the downregulation of Xist and thus reactivation of the inactive X chromosome. Recent data suggests that Xist activity is regulated by an anti-sense transcript.[25] The epiblast cells are then formed and they begin to be differentiated, and the Xist is upregulated from either of the two X chromosomes and at random in ICM, but the Xist is maintained in epiblast, an X is inactivated and the Xist allele is turned off in the active X chromosome. In maturing XX primordial germ cells, Xist is downregulated and X reactivation occurs once again.[26] # Disease linkage Mutations in the XIST promoter cause familial skewed X inactivation.[1] # Interactions XIST (gene) has been shown to interact with BRCA1.[27][28]

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

3083a48797c58594fcbbc87f1cf8aa0530b52cae

wikidoc

XPO1

XPO1 Exportin 1 (XPO1), also known as chromosomal maintenance 1 (CRM1), is an eukaryotic protein that mediates the nuclear export of proteins, rRNA, snRNA, and some mRNA. # History XPO1 (CRM1) originally was identified in the fission yeast Schizosaccharomyces pombe in a genetic screen, and investigators determined that it was involved in control of the chromosome structure # Function Exportin 1 mediates leucine-rich nuclear export signal (NES)-dependent protein transport. Exportin 1 specifically mediates the nuclear export of Rev and U snRNAs. It is involved in the control of several cellular processes by controlling the localization of cyclin B, MAPK, and MAPKAP kinase 2. This protein also regulates NFAT and AP-1. # Interactions XPO1 has been shown to interact with: - APC, - CDKN1B, - CIITA, - NMD3, - Nucleoporin 62, - RANBP1, - RANBP3, - Ran, - SMARCB1, and - p53.

XPO1 Exportin 1 (XPO1), also known as chromosomal maintenance 1 (CRM1), is an eukaryotic protein that mediates the nuclear export of proteins, rRNA, snRNA, and some mRNA.[1][2][3][4] # History XPO1 (CRM1) originally was identified in the fission yeast Schizosaccharomyces pombe in a genetic screen, and investigators determined that it was involved in control of the chromosome structure[5] # Function Exportin 1 mediates leucine-rich nuclear export signal (NES)-dependent protein transport. Exportin 1 specifically mediates the nuclear export of Rev and U snRNAs. It is involved in the control of several cellular processes by controlling the localization of cyclin B, MAPK, and MAPKAP kinase 2. This protein also regulates NFAT and AP-1.[6] # Interactions XPO1 has been shown to interact with: - APC,[7] - CDKN1B,[8][9] - CIITA,[10][11] - NMD3,[12] - Nucleoporin 62,[13][14] - RANBP1,[15][16] - RANBP3,[13][17] - Ran,[7][15][18] - SMARCB1,[19] and - p53.[20][21]

https://www.wikidoc.org/index.php/XPO1

be78ecb845a5a01eff67a336d6f7dbeb6b010cd8

wikidoc

XPO5

XPO5 Exportin-5 (XPO5) is a protein that, in humans, is encoded by the XPO5 gene. In eukaryotic cells, the primary purpose of XPO5 is to export pre-microRNA (also known as pre-miRNA) out of the nucleus and into the cytoplasm, for further processing by the Dicer enzyme. Once in the cytoplasm, the microRNA (also known as miRNA) can act as a gene silencer by regulating translation of mRNA. Although XPO5 is primarily involved in the transport of pre-miRNA, it has also been reported to transport tRNA. Much research on XPO5 is ongoing. miRNA is a prominent research topic due to its potential use as a therapeutic, with several miRNA-based drugs already in use. # Mechanism ## Binding to pre-miRNA After RanGTP binds to XPO5, the XPO5-RanGTP complex forms a U-like structure to hold the pre-miRNA. The XPO5-RanGTP complex recognizes pre-miRNA by its two-nucleotide 3’ overhang—a sequence consisting of two bases at the 3’ end of the pre-miRNA that are not paired with other bases. This motif is unique to pre-miRNA, and by recognizing it XPO5 ensures specificity for transporting only pre-miRNA. On its own, pre-miRNA is in a “closed” conformation, with the 3’ overhang flipped up toward the RNA minor groove. However, upon binding to XPO5, the 3’ overhang is flipped downwards away from the rest of the pre-miRNA molecule into an “open” conformation. This helps the backbone phosphates of these two nucleotides form hydrogen bonds with many XPO5 residues, allowing XPO5 to recognize the RNA as pre-miRNA. Because these interactions involve only the RNA phosphate backbone, they are nonspecific and allow XPO5 to recognize and transport any pre-miRNA. The rest of the pre-miRNA stem binds to XPO5 via interactions between the negatively-charged phosphate backbone and several positively-charged interior XPO5 residues. ## XPO5 Ternary Complex Transport Mechanism The combined structure of XPO5, RanGTP, and pre-miRNA is known as the ternary complex. Once the ternary complex is formed, it diffuses through a nuclear pore complex into the cytoplasm, transporting pre-miRNA into the cytoplasm in the process. Once in the cytoplasm, RanGAP hydrolyzes GTP to GDP, causing a conformational change that releases the pre-miRNA into the cytoplasm. ## Export out of the Nucleus It has been suggested, through evidence provided by contour maps of water density, that the interior of XPO5 is hydrophilic, while the exterior of XPO5 is hydrophobic. Therefore, this enhances the binding capabilities of XPO5 to the nuclear pore complex, allowing for transport of the ternary complex out of the nucleus. # Additional interactions XPO5 has been shown to interact with ILF3 and Ran. # Potential oncogenic role Recent evidence has shown higher levels of XPO5 in prostate cancer cell lines in-vitro, suggesting that altered XPO5 expression levels may have a role in cancer development. Suppressing XPO5 has also been found to be therapeutic in-vitro.

XPO5 Exportin-5 (XPO5) is a protein that, in humans, is encoded by the XPO5 gene.[1][2][3] In eukaryotic cells, the primary purpose of XPO5 is to export pre-microRNA (also known as pre-miRNA) out of the nucleus and into the cytoplasm, for further processing by the Dicer enzyme.[4][5][6][7] Once in the cytoplasm, the microRNA (also known as miRNA) can act as a gene silencer by regulating translation of mRNA. Although XPO5 is primarily involved in the transport of pre-miRNA, it has also been reported to transport tRNA.[8] Much research on XPO5 is ongoing. miRNA is a prominent research topic due to its potential use as a therapeutic, with several miRNA-based drugs already in use.[9] # Mechanism ## Binding to pre-miRNA After RanGTP binds to XPO5, the XPO5-RanGTP complex forms a U-like structure to hold the pre-miRNA. The XPO5-RanGTP complex recognizes pre-miRNA by its two-nucleotide 3’ overhang—a sequence consisting of two bases at the 3’ end of the pre-miRNA that are not paired with other bases. This motif is unique to pre-miRNA, and by recognizing it XPO5 ensures specificity for transporting only pre-miRNA. On its own, pre-miRNA is in a “closed” conformation, with the 3’ overhang flipped up toward the RNA minor groove. However, upon binding to XPO5, the 3’ overhang is flipped downwards away from the rest of the pre-miRNA molecule into an “open” conformation. This helps the backbone phosphates of these two nucleotides form hydrogen bonds with many XPO5 residues, allowing XPO5 to recognize the RNA as pre-miRNA. Because these interactions involve only the RNA phosphate backbone, they are nonspecific and allow XPO5 to recognize and transport any pre-miRNA. The rest of the pre-miRNA stem binds to XPO5 via interactions between the negatively-charged phosphate backbone and several positively-charged interior XPO5 residues.[11] ## XPO5 Ternary Complex Transport Mechanism The combined structure of XPO5, RanGTP, and pre-miRNA is known as the ternary complex. Once the ternary complex is formed, it diffuses through a nuclear pore complex into the cytoplasm, transporting pre-miRNA into the cytoplasm in the process. Once in the cytoplasm, RanGAP hydrolyzes GTP to GDP, causing a conformational change that releases the pre-miRNA into the cytoplasm.[11] ## Export out of the Nucleus It has been suggested, through evidence provided by contour maps of water density, that the interior of XPO5 is hydrophilic, while the exterior of XPO5 is hydrophobic.[11] Therefore, this enhances the binding capabilities of XPO5 to the nuclear pore complex, allowing for transport of the ternary complex out of the nucleus.[11] # Additional interactions XPO5 has been shown to interact with ILF3[1] and Ran.[1] # Potential oncogenic role Recent evidence has shown higher levels of XPO5 in prostate cancer cell lines in-vitro, suggesting that altered XPO5 expression levels may have a role in cancer development. Suppressing XPO5 has also been found to be therapeutic in-vitro.[12]

https://www.wikidoc.org/index.php/XPO5

1dcd9235c13ed09f47356a6115d9708a81985fe4

wikidoc

Xist

Xist # Overview Xist is an RNA gene on the X chromosome of the placental mammals that acts as major effector of the X inactivation process. The Xist RNA, a large (18 kb) transcript, is expressed on the inactive chromosome and not on the active one. It is processed similarly to mRNAs, through splicing and polyadenylation, however, it remains untranslated. It has been suggested that this RNA gene evolved at least partly from a protein coding gene that became a pseudogene. The inactive X is coated with this transcript, which is essential for the inactivation. X lacking Xist will not be inactivated, while duplication of the Xist gene on another chromosome causes inactivation of that chromosome.

Xist # Overview Xist is an RNA gene on the X chromosome of the placental mammals that acts as major effector of the X inactivation process. The Xist RNA, a large (18 kb) transcript, is expressed on the inactive chromosome and not on the active one. It is processed similarly to mRNAs, through splicing and polyadenylation, however, it remains untranslated. It has been suggested that this RNA gene evolved at least partly from a protein coding gene that became a pseudogene.[1] The inactive X is coated with this transcript, which is essential for the inactivation. X lacking Xist will not be inactivated, while duplication of the Xist gene on another chromosome causes inactivation of that chromosome.

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

6fd7a6cfb0e68e9835154eae3c4e095a7feecbb4

wikidoc

Xq28

Xq28 Xq28 is a chromosome band and genetic marker situated at the tip of the X chromosome which has been studied since at least 1980. The band contains three distinct regions, totaling about 8 Mbp of genetic information. The marker came to the public eye in 1993 when studies by Dean Hamer and others indicated a link between the Xq28 marker and male sexual orientation. # Initial linkage The 1993 study by Hamer et al. examined 114 families of gay men in the United States and found increased rates of homosexuality among maternal uncles and cousins, but not among paternal relatives. This pattern of inheritance suggested that there might be linked genes on the X chromosome, since males always inherit their copy of the X chromosome from their mothers. Polymorphisms of genetic markers of the X chromosome were analyzed for 40 families to see if a specific marker was shared by a disproportionate amount of brothers who were both gay. The results showed that among gay brothers, the concordance rate for markers from the Xq28 region were significantly greater than expected for random Mendelian segregation, indicating that a link did exist in that small sample. It was concluded that at least one form of male homosexuality is preferentially transmitted through the maternal side and is genetically linked to the Xq28 region. A follow-up study, Hu et al. (1995), conducted by the Hamer lab in collaboration with two groups of statistical experts in 1995, corroborated the original results for males with homosexual brothers sharing Xq28 at significantly elevated rates. This study also included heterosexual brothers, who showed significantly less than expected sharing of the Xq28 region, as expected for a genetic locus that in one form is associated with same-sex attraction and in another form is associated with opposite-sex attraction. In this study no link to Xq28 was found among homosexual females, indicating a different genetic pathway as for most sex-specific phenotypes. Hamer's findings were highlighted in scientific journals including Science, Nature and the topic of a mini-symposium in Scientific American. ## Controversy In June 1994, an article in the Chicago Tribune by John Crewdson stated that an anonymous junior researcher in Hamer's laboratory alleged that Hamer selectively presented the data in his 1993 paper in the journal Science. The junior researcher had assisted in the gene mapping in Hamer's 1993 study. Shortly after voicing her questions, she was summarily dismissed from her post-doctoral fellowship in Hamer's lab; who dismissed her could not be determined. Later, she was given another position in a different lab. Hamer stated that Crewdson's article was "seriously in error" and denied the allegations made against him. An official inquiry launched by the Office of Research Integrity (ORI) to investigate the allegations of selective presentation of the data ended in December 1996. It determined that Hamer had not committed any scientific misconduct in his study. # Subsequent studies Two further studies in the 1990s gave mixed results. One was an X chromosome linkage analysis of 54 pairs of gay brothers carried out by the independent research group of Sanders et al. in 1998. The results of the study were indistinguishable from the results of the study by Hu et al.: both reported that the chromosomal location of maximum sharing was locus DXS1108 and both reported similar degrees of allele sharing (66% versus 67%). The second study by Rice et al. in 1999 studied 52 pairs of Canadian gay brothers and found no statistically significant linkage in alleles and haplotypes. Consequently, they concluded against the possibility of any gene in the Xq28 region having a large genetic influence on male sexual orientation (though they could not rule out the possibility of a gene in this region having a small influence). Rice et al. also asserted that their results do not exclude the possibility of finding male homosexuality genes elsewhere in the genome. Hamer criticized the study for not selecting families for their study population based on maternal transmission as selecting only families that show an excess of maternal gay relatives is necessary to detect the Xq28 linkage. A meta-analysis of all data available at that time (i.e., Hamer et al. (1993), Hu et al. (1995), Rice et al. (1999), and the unpublished 1998 study by Sanders et al. indicated that Xq28 has a significant but not exclusive role in male sexual orientation. The authors of the meta-analysis (which included three authors of the Rice et al. study, Rice, Risch and Ebers) presented several methodological reasons due to which Rice et al. (1999) may have been unable to detect statistically significant linkage between Xq28 and male sexual orientation: the families genotyped by Rice et al. were non-representative as they had an excess of paternal instead of maternal gay relatives thus obscuring the display of any X-chromosome linkage; the statistical power of their sample was insufficient to adequately detect linkage and they lacked definite criteria for what constituted as homosexuality (the researchers depended on their own judgement and sometimes based their judgement on a single question to the subject). They also lacked criteria "to select appropriate families for the study of a putative X-linked locus" — as they did not select families based on the presence of maternal transmission of homosexuality, the Xq28 contribution to male sexual orientation may have been hidden. In addition, the meta-analysis revealed that the family pedigree data of Rice et al. (1999), in contrast to the genotyping data, seemed to support X chromosome linkage for homosexuality. In 2012, a large, comprehensive genome-wide linkage study of male sexual orientation was conducted by several independent groups of researchers. The study population included 409 independent pairs of gay brothers from 384 families, who were analyzed with over 300,000 single-nucleotide polymorphism markers. The study confirmed the Xq28 linkage to homosexuality by two-point and multipoint (MERLIN) LOD score mapping. Significant linkage was also detected in the region near the centromere of chromosome 8, overlapping with one of the regions detected in a previous genomewide linkage study by the Hamer lab. The authors concluded that "our findings, taken in context with previous work, suggest that genetic variation in each of these regions contributes to development of the important psychological trait of male sexual orientation." It was the largest study of the genetic basis of homosexuality to date and was published online in November 2014. # Other contents Xq28 is a large, complex, and gene dense region. Among its various genes are the 12 genes of the melanoma-associated antigen (MAGE) family, of which MAGEA11 has been identified as a coregulator for the androgen receptor. Mutations involving the production of extra copies of the MECP2 and IRAK1 genes within Xq28 have been associated with phenotypes including anxiety and autism in mice.

Xq28 Xq28 is a chromosome band and genetic marker situated at the tip of the X chromosome which has been studied since at least 1980.[1] The band contains three distinct regions, totaling about 8 Mbp of genetic information.[2] The marker came to the public eye in 1993 when studies by Dean Hamer and others indicated a link between the Xq28 marker and male sexual orientation.[3] # Initial linkage The 1993 study by Hamer et al. examined 114 families of gay men in the United States and found increased rates of homosexuality among maternal uncles and cousins, but not among paternal relatives. This pattern of inheritance suggested that there might be linked genes on the X chromosome, since males always inherit their copy of the X chromosome from their mothers. Polymorphisms of genetic markers of the X chromosome were analyzed for 40 families to see if a specific marker was shared by a disproportionate amount of brothers who were both gay. The results showed that among gay brothers, the concordance rate for markers from the Xq28 region were significantly greater than expected for random Mendelian segregation, indicating that a link did exist in that small sample. It was concluded that at least one form of male homosexuality is preferentially transmitted through the maternal side and is genetically linked to the Xq28 region.[3] A follow-up study, Hu et al. (1995), conducted by the Hamer lab in collaboration with two groups of statistical experts in 1995, corroborated the original results for males with homosexual brothers sharing Xq28 at significantly elevated rates. This study also included heterosexual brothers, who showed significantly less than expected sharing of the Xq28 region, as expected for a genetic locus that in one form is associated with same-sex attraction and in another form is associated with opposite-sex attraction. In this study no link to Xq28 was found among homosexual females, indicating a different genetic pathway as for most sex-specific phenotypes.[4] Hamer's findings were highlighted in scientific journals including Science,[5] Nature[6] and the topic of a mini-symposium in Scientific American.[7][8] ## Controversy In June 1994, an article in the Chicago Tribune by John Crewdson stated that an anonymous junior researcher in Hamer's laboratory alleged that Hamer selectively presented the data in his 1993 paper in the journal Science. The junior researcher had assisted in the gene mapping in Hamer's 1993 study. Shortly after voicing her questions, she was summarily dismissed from her post-doctoral fellowship in Hamer's lab; who dismissed her could not be determined. Later, she was given another position in a different lab.[9] Hamer stated that Crewdson's article was "seriously in error" and denied the allegations made against him.[10][11] An official inquiry launched by the Office of Research Integrity (ORI) to investigate the allegations of selective presentation of the data ended in December 1996. It determined that Hamer had not committed any scientific misconduct in his study.[10] # Subsequent studies Two further studies in the 1990s gave mixed results. One was an X chromosome linkage analysis of 54 pairs of gay brothers carried out by the independent research group of Sanders et al. in 1998. The results of the study were indistinguishable from the results of the study by Hu et al.: both reported that the chromosomal location of maximum sharing was locus DXS1108 and both reported similar degrees of allele sharing (66% versus 67%).[12] The second study by Rice et al. in 1999 studied 52 pairs of Canadian gay brothers and found no statistically significant[note 1] linkage in alleles and haplotypes. Consequently, they concluded against the possibility of any gene in the Xq28 region having a large genetic influence on male sexual orientation (though they could not rule out the possibility of a gene in this region having a small influence).[13] Rice et al. also asserted that their results do not exclude the possibility of finding male homosexuality genes elsewhere in the genome.[14] Hamer criticized the study for not selecting families for their study population based on maternal transmission as selecting only families that show an excess of maternal gay relatives is necessary to detect the Xq28 linkage.[13] A meta-analysis of all data available at that time (i.e., Hamer et al. (1993), Hu et al. (1995), Rice et al. (1999), and the unpublished 1998 study by Sanders et al. indicated that Xq28 has a significant but not exclusive role in male sexual orientation.[12] The authors of the meta-analysis (which included three authors of the Rice et al. study, Rice, Risch and Ebers) presented several methodological reasons due to which Rice et al. (1999) may have been unable to detect statistically significant linkage between Xq28 and male sexual orientation: the families genotyped by Rice et al. were non-representative as they had an excess of paternal instead of maternal gay relatives thus obscuring the display of any X-chromosome linkage; the statistical power of their sample was insufficient to adequately detect linkage[note 2] and they lacked definite criteria for what constituted as homosexuality (the researchers depended on their own judgement and sometimes based their judgement on a single question to the subject).[12] They also lacked criteria "to select appropriate families for the study of a putative X-linked locus"[12] — as they did not select families based on the presence of maternal transmission of homosexuality, the Xq28 contribution to male sexual orientation may have been hidden.[13] In addition, the meta-analysis revealed that the family pedigree data of Rice et al. (1999), in contrast to the genotyping data, seemed to support X chromosome linkage for homosexuality.[12][note 3] In 2012, a large, comprehensive genome-wide linkage study of male sexual orientation was conducted by several independent groups of researchers.[15] The study population included 409 independent pairs of gay brothers from 384 families, who were analyzed with over 300,000 single-nucleotide polymorphism markers. The study confirmed the Xq28 linkage to homosexuality by two-point and multipoint (MERLIN) LOD score mapping. Significant linkage was also detected in the region near the centromere of chromosome 8, overlapping with one of the regions detected in a previous genomewide linkage study by the Hamer lab. The authors concluded that "our findings, taken in context with previous work, suggest that genetic variation in each of these regions contributes to development of the important psychological trait of male sexual orientation." It was the largest study of the genetic basis of homosexuality to date and was published online in November 2014.[16] # Other contents Xq28 is a large, complex, and gene dense region.[17] Among its various genes are the 12 genes of the melanoma-associated antigen (MAGE) family,[18] of which MAGEA11 has been identified as a coregulator for the androgen receptor.[19] Mutations involving the production of extra copies of the MECP2 and IRAK1 genes within Xq28 have been associated with phenotypes including anxiety and autism in mice.[20]

https://www.wikidoc.org/index.php/Xq28

4f4de3e9b6f40a1fe1fc5493c997ddc2a64c8d50

wikidoc

YAP1

YAP1 YAP1 (yes-associated protein 1), also known as YAP or YAP65, is a protein that acts as a transcriptional regulator by activating the transcription of genes involved in cell proliferation and suppressing apoptotic genes. YAP1 is inhibited in the Hippo signaling pathway which allows the cellular control of organ size and tumor suppression. YAP1 was first identified by virtue of its ability to associate with the SH3 domain of Yes and Src protein tyrosine kinases. YAP1 is a potent oncogene, which is amplified in various human cancers. # Structure Cloning of the YAP1 gene facilitated the identification of a modular protein domain, known as the WW domain. Two splice isoforms of the YAP1 gene product were initially identified, named YAP1-1 and YAP1-2, which differed by the presence of an extra 38 amino acids that encoded the WW domain. Apart from the WW domain, the modular structure of YAP1 contains a proline-rich region at the very amino terminus, which is followed by a TID (TEAD transcription factor interacting domain). Next, following a single WW domain, which is present in the YAP1-1 isoform, and two WW domains, which are present in the YAP1-2 isoform, there is the SH3-BM (Src Homology 3 binding motif). Following the SH3-BM is a TAD (transcription activation domain) and a PDZ domain-binding motif (PDZ-BM) (Figure 1). # Function YAP1 is a transcriptional co-activator and its proliferative and oncogenic activity is driven by its association with the TEAD family of transcription factors, which up-regulate genes that promote cell growth and inhibit apoptosis. Several other functional partners of YAP1 were identified, including RUNX, SMADs, p73, ErbB4, TP53BP, LATS1/2, PTPN14, AMOTs, and ZO1/2. YAP1 and its close paralog, TAZ (WWTR1), are the main effectors of the Hippo tumor suppressor pathway. When the pathway is activated, YAP1 and TAZ are phosphorylated on a serine residue and sequestered in the cytoplasm by 14-3-3 proteins. When the Hippo pathway is not activated, YAP1/TAZ enter the nucleus and regulate gene expression. It is reported that several genes are regulated by YAP1, including Birc2, Birc5, connective tissue growth factor (CTGF), amphiregulin (AREG), Cyr61, Hoxa1 and Hoxc13. YAP/TAZ have also been shown to act as stiffness sensors, regulating mechanotransduction independently of the Hippo signalling cascade. # Clinical significance Heterozygous loss-of-function mutations in the YAP1 gene have been identified in two families with major eye malformations with or without extra-ocular features such as hearing loss, cleft lip, intellectual disability and renal disease. The YAP1 oncogene serves as a target for the development of new cancer drugs. Small compounds have been identified that disrupt the YAP1-TEAD complex or block the binding function of WW domains. These small molecules represent lead compounds for the development of therapies for cancer patients, who harbor amplified or overexpressed YAP oncogene. The Hippo/YAP signaling pathway may exert neuroprotective effects through mitigating blood-brain barrier disruption after cerebral ischemia/reperfusion injury.

YAP1 YAP1 (yes-associated protein 1), also known as YAP or YAP65, is a protein that acts as a transcriptional regulator by activating the transcription of genes involved in cell proliferation and suppressing apoptotic genes. YAP1 is inhibited in the Hippo signaling pathway which allows the cellular control of organ size and tumor suppression. YAP1 was first identified by virtue of its ability to associate with the SH3 domain of Yes and Src protein tyrosine kinases.[1] YAP1 is a potent oncogene, which is amplified in various human cancers.[2][3] # Structure Cloning of the YAP1 gene facilitated the identification of a modular protein domain, known as the WW domain.[4][5][6] Two splice isoforms of the YAP1 gene product were initially identified, named YAP1-1 and YAP1-2, which differed by the presence of an extra 38 amino acids that encoded the WW domain.[7][8] Apart from the WW domain, the modular structure of YAP1 contains a proline-rich region at the very amino terminus, which is followed by a TID (TEAD transcription factor interacting domain).[9] Next, following a single WW domain, which is present in the YAP1-1 isoform, and two WW domains, which are present in the YAP1-2 isoform, there is the SH3-BM (Src Homology 3 binding motif).[1][10] Following the SH3-BM is a TAD (transcription activation domain) and a PDZ domain-binding motif (PDZ-BM) (Figure 1).[11][12] # Function YAP1 is a transcriptional co-activator[13] and its proliferative and oncogenic activity is driven by its association with the TEAD family of transcription factors,[9] which up-regulate genes that promote cell growth and inhibit apoptosis.[14] Several other functional partners of YAP1 were identified, including RUNX,[13] SMADs,[15][16] p73,[17] ErbB4,[18][19] TP53BP,[20] LATS1/2,[21] PTPN14,[22] AMOTs,[23][24][25][26] and ZO1/2.[27] YAP1 and its close paralog, TAZ (WWTR1), are the main effectors of the Hippo tumor suppressor pathway.[28] When the pathway is activated, YAP1 and TAZ are phosphorylated on a serine residue and sequestered in the cytoplasm by 14-3-3 proteins.[28] When the Hippo pathway is not activated, YAP1/TAZ enter the nucleus and regulate gene expression.[28] It is reported that several genes are regulated by YAP1, including Birc2, Birc5, connective tissue growth factor (CTGF), amphiregulin (AREG), Cyr61, Hoxa1 and Hoxc13. YAP/TAZ have also been shown to act as stiffness sensors, regulating mechanotransduction independently of the Hippo signalling cascade.[29] # Clinical significance Heterozygous loss-of-function mutations in the YAP1 gene have been identified in two families with major eye malformations with or without extra-ocular features such as hearing loss, cleft lip, intellectual disability and renal disease.[30] The YAP1 oncogene serves as a target for the development of new cancer drugs.[31] Small compounds have been identified that disrupt the YAP1-TEAD complex or block the binding function of WW domains.[32][33] These small molecules represent lead compounds for the development of therapies for cancer patients, who harbor amplified or overexpressed YAP oncogene. The Hippo/YAP signaling pathway may exert neuroprotective effects through mitigating blood-brain barrier disruption after cerebral ischemia/reperfusion injury.[34]

https://www.wikidoc.org/index.php/YAP1

973bbe5bc349a04c5f8a0e75170019674ca96499

wikidoc

YARS

YARS Tyrosyl-tRNA synthetase, cytoplasmic, also known as Tyrosine-tRNA ligase, is an enzyme that in humans is encoded by the YARS gene. Living cells translate DNA sequences into RNA sequences and then into protein sequences. Proteins are chains of amino acids, such as tyrosine. As the protein grows, each amino acid is added to the end by an enzyme called transfer RNA (tRNA). Each amino acid has its own tRNA, and tyrosyl-tRNA synthetase is the tRNA that adds tyrosine to the end of a growing protein. Aminoacyl-tRNA synthetases catalyze the aminoacylation of transfer RNA (tRNA) by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Tyrosyl-tRNA synthetase belongs to the class I tRNA synthetase family. Cytokine activities have also been observed for the human tyrosyl-tRNA synthetase, after it is split into two parts, an N-terminal fragment that harbors the catalytic site and a C-terminal fragment found only in the mammalian enzyme. The N-terminal fragment is an interleukin-8-like cytokine, whereas the released C-terminal fragment is an EMAP II-like cytokine. Recently, tyrosyl-tRNA synthetase has been demonstrated as the biologically and functionally significant target for resveratrol. For a comparison of cytoplasmic human tyrosyl-tRNA synthetase with its mitochondrial counterpart and with tyrosyl-tRNA synthetases of other biological kingdoms and organisms, see the Wikipedia page on Tyrosine-tRNA ligase and a general review on their structures and functions.

YARS Tyrosyl-tRNA synthetase, cytoplasmic, also known as Tyrosine-tRNA ligase, is an enzyme that in humans is encoded by the YARS gene.[1][2][3] Living cells translate DNA sequences into RNA sequences and then into protein sequences. Proteins are chains of amino acids, such as tyrosine. As the protein grows, each amino acid is added to the end by an enzyme called transfer RNA (tRNA). Each amino acid has its own tRNA, and tyrosyl-tRNA synthetase is the tRNA that adds tyrosine to the end of a growing protein. Aminoacyl-tRNA synthetases catalyze the aminoacylation of transfer RNA (tRNA) by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Tyrosyl-tRNA synthetase belongs to the class I tRNA synthetase family. Cytokine activities have also been observed for the human tyrosyl-tRNA synthetase, after it is split into two parts, an N-terminal fragment that harbors the catalytic site and a C-terminal fragment found only in the mammalian enzyme. The N-terminal fragment is an interleukin-8-like cytokine, whereas the released C-terminal fragment is an EMAP II-like cytokine.[3] Recently, tyrosyl-tRNA synthetase has been demonstrated as the biologically and functionally significant target for resveratrol.[4] For a comparison of cytoplasmic human tyrosyl-tRNA synthetase with its mitochondrial counterpart and with tyrosyl-tRNA synthetases of other biological kingdoms and organisms, see the Wikipedia page on Tyrosine-tRNA ligase and a general review on their structures and functions.[5]

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

f9ec65d0334f6300d7f03b2bcdc6282b39b27847

wikidoc

YES1

YES1 Proto-oncogene tyrosine-protein kinase Yes is an enzyme that in humans is encoded by the YES1 gene. This gene is the cellular homolog of the Yamaguchi sarcoma virus oncogene. The encoded protein has tyrosine kinase activity and belongs to the src family of proteins. This gene lies in close proximity to thymidylate synthase gene on chromosome 18, and a corresponding pseudogene has been found on chromosome 22. # Interactions YES1 has been shown to interact with Janus kinase 2, CTNND1, RPL10 and Occludin.

YES1 Proto-oncogene tyrosine-protein kinase Yes is an enzyme that in humans is encoded by the YES1 gene.[1][2] This gene is the cellular homolog of the Yamaguchi sarcoma virus oncogene. The encoded protein has tyrosine kinase activity and belongs to the src family of proteins. This gene lies in close proximity to thymidylate synthase gene on chromosome 18, and a corresponding pseudogene has been found on chromosome 22.[2] # Interactions YES1 has been shown to interact with Janus kinase 2,[3] CTNND1,[4] RPL10[5] and Occludin.[6]

https://www.wikidoc.org/index.php/YES1

06e921b255c1c6a90291298e0e6cfb7c16f7e293

wikidoc

Yawn

Yawn A yawn (synonyms chasma, pandiculation, oscitation from the Latin verb oscitare, to open the mouth wide ) is a reflex of deep inhalation and exhalation associated with tiredness, stress, over-work, lack of stimulation, or boredom. Pandiculation is the term for the act of stretching and yawning. Yawning is a powerful non-verbal message with several possible meanings, depending on the circumstances. Another speculated reason for yawning is nervousness and is also claimed to help increase the state of alertness of a person - paratroopers were noted yawning right before their first jump. The exact causes of yawning are still undetermined. Some claim that yawning is not caused by lack of oxygen, for the reason that yawning allegedly reduces oxygen intake compared to normal respiration. However, both of these are as controversial as a debate over yawning can be. The word "yawn" has evolved from the Middle English word yanen, an alteration of yonen or yenen, which in turn comes from the Old English geonian. # Hypothesized causes of yawning - A means of cooling the brain. - An action used as an unconscious communication of psychological decompression after a state of high alert. - A means of expressing powerful emotions like anger, apathy, apprehension, remorse or boredom. - An excess of carbon dioxide and lack of oxygen in the blood. - A way of displaying (or indicative of) empathy. - Tiredness A recent(2007) hypothesis by Andrew C. Gallup and Gordon Gallup of the University of Albany states that yawning may be a means to keep the brain cool. Mammalian brains operate best when they are cool. In an experiment, he showed several groups of people videos of other people yawning. When the subjects held heat packs up to their foreheads while viewing the videos, they yawned often. But when they held cold packs up to their foreheads or breathed through their noses (another means of brain cooling), they did not yawn at all. Another recent hypothesis is that yawning is used for regulation of body temperature. Another hypothesis is that yawns are caused by the same chemicals (neurotransmitters) in the brain that affect emotions, mood, appetite and other phenomena. These chemicals include serotonin, dopamine, glutamic acid and nitric oxide. As more (or less) of these compounds are activated in the brain, the frequency of yawning increases. Conversely, a greater presence in the brain of opiate neurotransmitters such as endorphins reduces the frequency of yawning. Patients taking the serotonin reuptake inhibitor Paxil (Paroxetine HCl) or Citalopram, another SSRI, have been observed yawning abnormally often. Anecdotal reports by users of psilocybin mushrooms often describe a marked stimulation of yawning while intoxicated, often associated with excess lacrimation and nasal mucosal stimulation, especially while "peaking" (i.e. undergoing the most intense portion of the psilocybin experience). While opioids have been demonstrated to reduce this yawning and lacrimation provoked by psilocybin, it is not clear that the same pathways that induce yawning as a symptom of opioid abstinence in habituated users are the mode of action in psilocybin induced yawning. While even opioid dependent users of psilocybin on stable opioid therapy often report yawning and excess lacrimation while undergoing this entheogenic mushroom experience, there are no known reports in the literature that suggest psilocybin acts as any sort of general opioid antagonist. Psilocybin induced yawning in opioid habituated users does not appear to produce other typical opioid withdrawal symptoms such as cramping, physical pain, anxiety, gooseflesh etc. Recent research carried out at by Catriona Morrison, a lecturer in psychology at the University of Leeds, involving monitoring the yawning behaviour of students kept waiting in a reception area, indicates a connection (supported by neuro-imaging research) between empathic ability and yawning. "We believe that contagious yawning indicates empathy. It indicates an appreciation of other people's behavioural and physiological state," said Morrison. Another theory is that yawning is similar to stretching. Stretching, like yawning, increases blood pressure and heart rate while also flexing many muscles and joints. It is also theorized that yawning helps redistribute surfactant, an oil-like substance which coats the lungs and aids breathing. Some have observed that if one tries to stifle or prevent a yawn by clenching one's jaws shut, the yawn is unsatisfying. As such, the stretching of jaw and face muscles seems to be necessary for a satisfactory yawn. Yet another theory is that yawning occurs to stabilize pressure on either side of the ear drums. The deep intake of air can sometimes cause a popping sound that only the yawner can hear; this is the pressure on the inner ear stabilizing. This commonly occurs in environments where pressure is changing relatively rapidly, such as inside an airplane and when travelling up and down hills, which cause the eardrums to be bent instead of flat. Some people yawn when storms approach, which is a sure sign that changes in pressure affect them. Some movements in psychotherapy, such as Re-evaluation Counseling or co-counselling treatments, believe that yawning, along with laughter and crying, are means of "discharging" painful emotion, and therefore can be encouraged in order to promote physical and emotional healing. # Yawning as a medical sign Excessive yawning has been associated with several medical conditions and may be considered as a medical sign for some diseases. These conditions include: - Multiple sclerosis - Amyotrophic lateral sclerosis (ALS) - Migraine headache (rare) - Radiation poisoning, including radiation therapy Yawning may occur less frequently in persons with schizophrenia. Certain medications may also induce yawning. These include: - Apomorphine hydrochloride - Selective serotonin reuptake inhibitors - Levodopa - Dopamine agonists - Monoamine oxidase inhibitors of the MAO-B isoform (such as selegiline) - Ayahuasca, the psychoactive Amazonian tea that contains MAO-inhibiting harmala alkaloids - Opioids, such as morphine, methadone, buprenorphine, dextromethorphan - Benzodiazepines - Lidocaine - Flecainide - Psilocybin # Contagiousness The yawn reflex is often described as contagious: if one person yawns, this will cause another person to "sympathetically" yawn. Observing another person's yawning face (especially his/her eyes), or even reading about or thinking about yawning, can cause a person to yawn. However, only about 55% of people in a given audience will respond to such a stimulus; fewer if only the mouth is shown in a visual stimulus.The proximate cause for contagious yawning may lie with mirror neurons, i.e. neurons in the frontal cortex of certain vertebrates, which upon being exposed to a stimulus from conspecific (same species) and occasionally interspecific organisms, activates the same regions in the brain. Mirror neurons have been proposed as a driving force for imitation which lies at the root of much human learning, e.g. language acquisition. Yawning may be an offshoot of the same imitative impulse. A 2007 study found that children with autism spectrum disorders, unlike typical children, did not yawn after seeing videos of other people yawning; this supports the claim that contagious yawning is based on the capacity for empathy. To look at the issue in terms of evolutionary advantage, if there is one at all, yawning might be a herd instinct. Other theories suggest that the yawn serves to synchronize mood behavior among gregarious animals, similar to the howling of the wolf pack. It signals tiredness to other members of the group in order to synchronize sleeping patterns and periods of activity. This phenomenon has been observed among various primates. The threat gesture is a way of maintaining order in the primates' social structure. Specific studies were conducted on chimpanzees and stumptail macaques. A group of these animals was shown a video of other conspecifics yawning, and both chimpanzees and stumptail macaques yawned also. This helps to partly confirm a yawn's "contagiousness". Gordon Gallup, who hypothesizes that yawning may be a means of keeping the brain cool, also hypothesizes that "contagious" yawning may be a survival instinct inherited from our evolutionary past. "During human evolutionary history when we were subject to predation and attacks by other groups, if everybody yawns in response to seeing someone yawn, the whole group becomes much more vigilant, and much better at being able to detect danger." # Other uses for yawning In non-human animals, yawning can serve as a warning signal. For example, Charles Darwin, in his book The Expression of the Emotions in Man and Animals, mentioned that baboons use yawn to threaten their enemies, possibly by displaying large, canine teeth. Similarly, Siamese Fighting Fish yawn only when they see a conspecific (same species) or their own mirror-image, and their yawn often accompanies aggressive attack. Adelie Penguins employ yawning as part of their courtship ritual. Penguin couples face off and the males engage in what is described as an "ecstatic display," their beaks open wide and their faces pointed skyward. This trait has also been seen among Emperor Penguins. Researchers have been attempting to discover why these two different species share this trait, despite not sharing a habitat.. # Superstitions Certain superstitions surround the act of yawning. The most common of these is the belief that it is necessary to cover one's mouth when one is yawning in order to prevent one's soul from escaping the body. The Ancient Greeks believed that yawning was not a sign of boredom, but that a person's soul was trying to escape from its body, so that it may rest with the gods in the skies. This belief was also shared by the Maya. Other superstitions include: - A yawn is a sign that danger is near. - Counting a person's teeth robs them of one year of life for every tooth counted. This is why some people cover their mouths when they laugh, smile, or yawn. - If two persons are seen to yawn one after the other, it is said that the one who yawned last bears no malice towards the one who yawned first. - The one who yawns first shows no malice towards those he or she yawns around. - If you don't cover your mouth while yawning, then the devil will come and steal your soul (Estonia). - In Ancient Mayan civilization, yawning was thought to indicate subconscious sexual desires. - In some Latin American, East Asian and Central African countries yawning is said to be caused by someone else talking about you. - A yawn may be a sign that one is afflicted by the evil eye (Greece). - When one person yawns, it is said that anybody watching will instantly yawn as well These superstitions may not only have arisen to prevent people from committing the faux pas of yawning loudly in another's presence — one of Mason Cooley's aphorisms is "A yawn is more disconcerting than a contradiction" — but may also have arisen from concerns over public health. Polydore Vergil (c. 1470–1555), in his De Rerum Inventoribus, writes that it was customary to make the sign of the cross over one's mouth, since "alike deadly plague was sometime in yawning, wherefore men used to fence themselves with the sign of the cross...which custom we retain at this day." # Notes and references - ↑ Jump up to: 1.0 1.1 MedOnline.net term pandiculate - ↑ A. Price Heusner. YAWNING AND ASSOCIATED PHENOMENA. Physiological Review 1946: 25; 156–168. Online pdf-version - ↑ Jump up to: 3.0 3.1 3.2 Provine RR (2005). "Yawning". American Scientist. 93 (6): 532. doi:10.1511/2005.6.532. Text "pages 532–539 " ignored (help).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} - ↑ Template:Citeweb - ↑ Jump up to: 5.0 5.1 5.2 Gordon G. Gallup (2007). Good Morning America - The Science of Yawning (July 30, 2007) (TV-Series). USA: ABC. External link in |title= (help) - ↑ Gallup AC & Gallup GG Jr (2007). "Yawning as a brain cooling mechanism: Nasal breathing and forehead cooling diminish the incidence of contagious yawning" (pdf). Evolutionary Psychology. 5 (1). - ↑ BBC News, Monday 10 September 2007, "Contagious yawn 'sign of empathy'" - ↑ Robert H. Shmerling. "Medical Myths: What Are You Yawning About?" Published by Aetna InteliHealth. Last reviewed on January 9, 2006. Last retrieved on June 22, 2007. - ↑ Sommet A, Desplas M, Lapeyre-Mestre M, Montastruc JL (2007). "Drug-induced yawning: a review of the French pharmacovigilance database". Drug safety : an international journal of medical toxicology and drug experience. 30 (4): 327–31. PMID 17408309.CS1 maint: Multiple names: authors list (link) - ↑ The website by Émilie attempts to prove this. - ↑ Provine RR (1986). "Yawning as a stereotyped action pattern and releasing stimulus". Ethology. 72: 109–122. - ↑ V.S. Ramachandran, "Mirror Neurons and imitation learning as the driving force behind "the great leap forward" in human evolution". Retrieved 2006-11-16. - ↑ Senju A, Maeda M, Kikuchi Y, Hasegawa T, Tojo Y, Osanai H (2007). "Absence of contagious yawning in children with autism spectrum disorder". Biol Lett. doi:10.1098/rsbl.2007.0337. PMID 17698452.CS1 maint: Multiple names: authors list (link) - ↑ Schürmann; et al. (2005). "Yearning to yawn: the neural basis of contagious yawning". NeuroImage. 24 (4): 1260–1264. PMID 15670705.CS1 maint: Explicit use of et al. (link) (see also Platek; et al. (2005). "Contagious Yawning and The Brain". Cognitive Brain Research. 23 (2–3): 448–52. PMID 15820652.CS1 maint: Explicit use of et al. (link) ) - ↑ Anderson JR, Myowa-Yamakoshi M & Matsuzawa T (2004). "Contagious yawning in chimpanzees". Proceedings of the Royal Society of London B: Biological Sciences: S468–S470. PMID 15801606. Unknown parameter |volune= ignored (help) - ↑ Paukner A & Anderson JR (2006). "Video-induced yawning in stumptail macaques (Macaca arctoides)". Biology Letters. 2 (1): 36–38. PMID 17148320. - ↑ Baenninger R (1987). "Some comparative aspects of yawning in Betta sleepnes, Homo Sapiens, Pantera leo and Papio sphinx". Journal of Comparative Psychology. 101 (4): 349–354. - ↑ Iona Opie and Moira Tatem, A Dictionary of Superstitions (Oxford: Oxford University Press, 1992), 454.

Yawn A yawn (synonyms chasma, pandiculation[1], oscitation from the Latin verb oscitare, to open the mouth wide [2] ) is a reflex of deep inhalation and exhalation associated with tiredness, stress, over-work, lack of stimulation, or boredom. Pandiculation is the term for the act of stretching and yawning.[1] Yawning is a powerful non-verbal message with several possible meanings, depending on the circumstances. Another speculated reason for yawning is nervousness and is also claimed to help increase the state of alertness of a person - paratroopers were noted yawning right before their first jump.[citation needed] The exact causes of yawning are still undetermined. Some claim that yawning is not caused by lack of oxygen, for the reason that yawning allegedly reduces oxygen intake compared to normal respiration. [3] However, both of these are as controversial as a debate over yawning can be. The word "yawn" has evolved from the Middle English word yanen, an alteration of yonen or yenen, which in turn comes from the Old English geonian.[4] # Hypothesized causes of yawning - A means of cooling the brain.[5] - An action used as an unconscious communication of psychological decompression after a state of high alert. - A means of expressing powerful emotions like anger, apathy, apprehension, remorse or boredom.[citation needed] - An excess of carbon dioxide and lack of oxygen in the blood. [1] - A way of displaying (or indicative of) empathy. - Tiredness A recent(2007) hypothesis by Andrew C. Gallup and Gordon Gallup of the University of Albany states that yawning may be a means to keep the brain cool. Mammalian brains operate best when they are cool. In an experiment, he showed several groups of people videos of other people yawning. When the subjects held heat packs up to their foreheads while viewing the videos, they yawned often. But when they held cold packs up to their foreheads or breathed through their noses (another means of brain cooling), they did not yawn at all. [5] [6] Another recent hypothesis is that yawning is used for regulation of body temperature. Another hypothesis is that yawns are caused by the same chemicals (neurotransmitters) in the brain that affect emotions, mood, appetite and other phenomena. These chemicals include serotonin, dopamine, glutamic acid and nitric oxide. As more (or less) of these compounds are activated in the brain, the frequency of yawning increases. Conversely, a greater presence in the brain of opiate neurotransmitters such as endorphins reduces the frequency of yawning. Patients taking the serotonin reuptake inhibitor Paxil (Paroxetine HCl) or Citalopram, another SSRI, have been observed yawning abnormally often. Anecdotal reports by users of psilocybin mushrooms often describe a marked stimulation of yawning while intoxicated, often associated with excess lacrimation and nasal mucosal stimulation, especially while "peaking" (i.e. undergoing the most intense portion of the psilocybin experience). While opioids have been demonstrated to reduce this yawning and lacrimation provoked by psilocybin, it is not clear that the same pathways that induce yawning as a symptom of opioid abstinence in habituated users are the mode of action in psilocybin induced yawning. While even opioid dependent users of psilocybin on stable opioid therapy often report yawning and excess lacrimation while undergoing this entheogenic mushroom experience, there are no known reports in the literature that suggest psilocybin acts as any sort of general opioid antagonist. Psilocybin induced yawning in opioid habituated users does not appear to produce other typical opioid withdrawal symptoms such as cramping, physical pain, anxiety, gooseflesh etc. Recent research carried out at by Catriona Morrison, a lecturer in psychology at the University of Leeds, involving monitoring the yawning behaviour of students kept waiting in a reception area, indicates a connection (supported by neuro-imaging research) between empathic ability and yawning. "We believe that contagious yawning indicates empathy. It indicates an appreciation of other people's behavioural and physiological state," said Morrison.[7] Another theory is that yawning is similar to stretching. Stretching, like yawning, increases blood pressure and heart rate while also flexing many muscles and joints. It is also theorized that yawning helps redistribute surfactant, an oil-like substance which coats the lungs and aids breathing. Some have observed that if one tries to stifle or prevent a yawn by clenching one's jaws shut, the yawn is unsatisfying. As such, the stretching of jaw and face muscles seems to be necessary for a satisfactory yawn. Yet another theory is that yawning occurs to stabilize pressure on either side of the ear drums. The deep intake of air can sometimes cause a popping sound that only the yawner can hear; this is the pressure on the inner ear stabilizing. This commonly occurs in environments where pressure is changing relatively rapidly, such as inside an airplane and when travelling up and down hills, which cause the eardrums to be bent instead of flat. Some people yawn when storms approach, which is a sure sign that changes in pressure affect them. Some movements in psychotherapy, such as Re-evaluation Counseling or co-counselling treatments, believe that yawning, along with laughter and crying, are means of "discharging" painful emotion, and therefore can be encouraged in order to promote physical and emotional healing. # Yawning as a medical sign Excessive yawning has been associated with several medical conditions and may be considered as a medical sign for some diseases. These conditions include:[8] - Multiple sclerosis - Amyotrophic lateral sclerosis (ALS) - Migraine headache (rare) - Radiation poisoning, including radiation therapy Yawning may occur less frequently in persons with schizophrenia. Certain medications may also induce yawning. These include:[9] - Apomorphine hydrochloride - Selective serotonin reuptake inhibitors - Levodopa - Dopamine agonists - Monoamine oxidase inhibitors of the MAO-B isoform (such as selegiline) - Ayahuasca, the psychoactive Amazonian tea that contains MAO-inhibiting harmala alkaloids - Opioids, such as morphine, methadone, buprenorphine, dextromethorphan - Benzodiazepines - Lidocaine - Flecainide - Psilocybin # Contagiousness The yawn reflex is often described as contagious: if one person yawns, this will cause another person to "sympathetically" yawn.[3][10] Observing another person's yawning face (especially his/her eyes), or even reading about or thinking about yawning, can cause a person to yawn.[3][11] However, only about 55% of people in a given audience will respond to such a stimulus; fewer if only the mouth is shown in a visual stimulus.[12]The proximate cause for contagious yawning may lie with mirror neurons, i.e. neurons in the frontal cortex of certain vertebrates, which upon being exposed to a stimulus from conspecific (same species) and occasionally interspecific organisms, activates the same regions in the brain.[13] Mirror neurons have been proposed as a driving force for imitation which lies at the root of much human learning, e.g. language acquisition. Yawning may be an offshoot of the same imitative impulse. A 2007 study found that children with autism spectrum disorders, unlike typical children, did not yawn after seeing videos of other people yawning; this supports the claim that contagious yawning is based on the capacity for empathy.[14] To look at the issue in terms of evolutionary advantage, if there is one at all, yawning might be a herd instinct.[15] Other theories suggest that the yawn serves to synchronize mood behavior among gregarious animals, similar to the howling of the wolf pack. It signals tiredness to other members of the group in order to synchronize sleeping patterns and periods of activity. This phenomenon has been observed among various primates. The threat gesture is a way of maintaining order in the primates' social structure. Specific studies were conducted on chimpanzees[16] and stumptail macaques[17]. A group of these animals was shown a video of other conspecifics yawning, and both chimpanzees and stumptail macaques yawned also. This helps to partly confirm a yawn's "contagiousness". Gordon Gallup, who hypothesizes that yawning may be a means of keeping the brain cool, also hypothesizes that "contagious" yawning may be a survival instinct inherited from our evolutionary past. "During human evolutionary history when we were subject to predation and attacks by other groups, if everybody yawns in response to seeing someone yawn, the whole group becomes much more vigilant, and much better at being able to detect danger."[5] # Other uses for yawning In non-human animals, yawning can serve as a warning signal. For example, Charles Darwin, in his book The Expression of the Emotions in Man and Animals, mentioned that baboons use yawn to threaten their enemies, possibly by displaying large, canine teeth. Similarly, Siamese Fighting Fish yawn only when they see a conspecific (same species) or their own mirror-image, and their yawn often accompanies aggressive attack. [18] Adelie Penguins employ yawning as part of their courtship ritual. Penguin couples face off and the males engage in what is described as an "ecstatic display," their beaks open wide and their faces pointed skyward. This trait has also been seen among Emperor Penguins. Researchers have been attempting to discover why these two different species share this trait, despite not sharing a habitat.[citation needed]. # Superstitions Certain superstitions surround the act of yawning. The most common of these is the belief that it is necessary to cover one's mouth when one is yawning in order to prevent one's soul from escaping the body. The Ancient Greeks believed that yawning was not a sign of boredom, but that a person's soul was trying to escape from its body, so that it may rest with the gods in the skies. This belief was also shared by the Maya.[citation needed] Other superstitions include: - A yawn is a sign that danger is near. - Counting a person's teeth robs them of one year of life for every tooth counted. This is why some people cover their mouths when they laugh, smile, or yawn. - If two persons are seen to yawn one after the other, it is said that the one who yawned last bears no malice towards the one who yawned first. - The one who yawns first shows no malice towards those he or she yawns around. - If you don't cover your mouth while yawning, then the devil will come and steal your soul (Estonia). - In Ancient Mayan civilization, yawning was thought to indicate subconscious sexual desires. - In some Latin American, East Asian and Central African countries yawning is said to be caused by someone else talking about you. - A yawn may be a sign that one is afflicted by the evil eye (Greece). - When one person yawns, it is said that anybody watching will instantly yawn as well These superstitions may not only have arisen to prevent people from committing the faux pas of yawning loudly in another's presence — one of Mason Cooley's aphorisms is "A yawn is more disconcerting than a contradiction" — but may also have arisen from concerns over public health. Polydore Vergil (c. 1470–1555), in his De Rerum Inventoribus, writes that it was customary to make the sign of the cross over one's mouth, since "alike deadly plague was sometime in yawning, wherefore men used to fence themselves with the sign of the cross...which custom we retain at this day."[19] # Notes and references - ↑ Jump up to: 1.0 1.1 MedOnline.net term pandiculate - ↑ A. Price Heusner. YAWNING AND ASSOCIATED PHENOMENA. Physiological Review 1946: 25; 156–168. Online pdf-version - ↑ Jump up to: 3.0 3.1 3.2 Provine RR (2005). "Yawning". American Scientist. 93 (6): 532. doi:10.1511/2005.6.532. Text "pages 532–539 " ignored (help).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} - ↑ Template:Citeweb - ↑ Jump up to: 5.0 5.1 5.2 Gordon G. Gallup (2007). Good Morning America - The Science of Yawning (July 30, 2007) (TV-Series). USA: ABC. External link in |title= (help) - ↑ Gallup AC & Gallup GG Jr (2007). "Yawning as a brain cooling mechanism: Nasal breathing and forehead cooling diminish the incidence of contagious yawning" (pdf). Evolutionary Psychology. 5 (1). - ↑ BBC News, Monday 10 September 2007, "Contagious yawn 'sign of empathy'" - ↑ Robert H. Shmerling. "Medical Myths: What Are You Yawning About?" Published by Aetna InteliHealth. Last reviewed on January 9, 2006. Last retrieved on June 22, 2007. - ↑ Sommet A, Desplas M, Lapeyre-Mestre M, Montastruc JL (2007). "Drug-induced yawning: a review of the French pharmacovigilance database". Drug safety : an international journal of medical toxicology and drug experience. 30 (4): 327–31. PMID 17408309.CS1 maint: Multiple names: authors list (link) - ↑ The website by Émilie attempts to prove this. - ↑ Provine RR (1986). "Yawning as a stereotyped action pattern and releasing stimulus". Ethology. 72: 109–122. - ↑ http://www.npr.org/templates/story/story.php?storyId=14654608 - ↑ V.S. Ramachandran, "Mirror Neurons and imitation learning as the driving force behind "the great leap forward" in human evolution". Retrieved 2006-11-16. - ↑ Senju A, Maeda M, Kikuchi Y, Hasegawa T, Tojo Y, Osanai H (2007). "Absence of contagious yawning in children with autism spectrum disorder". Biol Lett. doi:10.1098/rsbl.2007.0337. PMID 17698452.CS1 maint: Multiple names: authors list (link) - ↑ Schürmann; et al. (2005). "Yearning to yawn: the neural basis of contagious yawning". NeuroImage. 24 (4): 1260–1264. PMID 15670705.CS1 maint: Explicit use of et al. (link) (see also Platek; et al. (2005). "Contagious Yawning and The Brain". Cognitive Brain Research. 23 (2–3): 448–52. PMID 15820652.CS1 maint: Explicit use of et al. (link) ) - ↑ Anderson JR, Myowa-Yamakoshi M & Matsuzawa T (2004). "Contagious yawning in chimpanzees". Proceedings of the Royal Society of London B: Biological Sciences: S468–S470. PMID 15801606. Unknown parameter |volune= ignored (help) - ↑ Paukner A & Anderson JR (2006). "Video-induced yawning in stumptail macaques (Macaca arctoides)". Biology Letters. 2 (1): 36–38. PMID 17148320. - ↑ Baenninger R (1987). "Some comparative aspects of yawning in Betta sleepnes, Homo Sapiens, Pantera leo and Papio sphinx". Journal of Comparative Psychology. 101 (4): 349–354. - ↑ Iona Opie and Moira Tatem, A Dictionary of Superstitions (Oxford: Oxford University Press, 1992), 454. # External links - Video: Good Morning America (July 30, 2007) - The Science of Yawning - Causes, Concerns and Communications of the Yawn - "What makes us yawn?" - Dr. Steven Platek - Yawn Researcher at the University of Liverpool - Archive of animal yawn pictures - The hidden sexuality of the human yawn - Yawns, and why do we yawn? - From a February issue of the research journal Neuroimage - Old Superstitions.com - Why are yawns contagious? - All you want to know about yawning (French and English) - Yawning as Brain Cooling Mechanism, Evolutionary Psychology, 2007, 5(1). - Dr Karl Kruszelnicki 'Yawning & Oxygen' from Great Moments in Science - Can You Catch a Yawn? (article) de:Gähnen id:Kuap he:פיהוק ka:მთქნარება lt:Žiovulys ml:കോട്ടുവായ് nl:Geeuwreflex no:Gjesping qu:Surkay simple:Yawn fi:Haukottelu sv:Gäspning uk:Позіхання Template:WikiDoc Sources

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

d2448ea259db90f765f65db437df85d920ca9454

wikidoc

Yoga

Yoga Yoga (Sanskrit: योग Yoga, Template:IPA2) is a group of ancient spiritual practices originating in India. According to Gavin Flood, Academic Director of the Oxford Centre for Hindu Studies it has been defined as referring to "technologies or disciplines of asceticism and meditation which are thought to lead to spiritual experience and profound understanding or insight into the nature of existence." Yoga is also intimately connected to the religious beliefs and practices of the other Indian religions. Outside India, Yoga is mostly associated with the practice of asanas (postures) of Hatha Yoga or as a form of exercise, although it has influenced the entire Indian religions family and other spiritual practices throughout the world. Hindu texts discussing different aspects of yoga include the Upanishads, the Bhagavad Gita, the Yoga Sutras of Patanjali, the Hatha Yoga Pradipika, the Shiva Samhita, and many others. Major branches of Yoga include: Hatha Yoga, Karma Yoga, Jnana Yoga, Bhakti Yoga, and Raja Yoga. Raja Yoga, established by the Yoga Sutras of Patanjali, and known simply as Yoga in the context of Hindu philosophy, is one of the six orthodox (āstika) schools of thought. # Etymology The Sanskrit term yoga has a wide range of different meanings. It is derived from the Sanskrit root yuj, "to control", "to yoke", or "to unite". Common meanings include "joining" or "uniting", and related ideas such as "union" and "conjunction". Another conceptual definition is that of "mode, manner, means" or "expedient, means in general". # History of Yoga ## Indus Valley seals Several seals discovered at Indus Valley Civilization (c. 3300–1700 BC) sites depict figures in a yoga or meditation like posture. There is considerable evidence to support the idea that the images show "a form of ritual discipline, suggesting a precursor of yoga" according to archaeologist Gregory Possehl. He points to sixteen other specific "yogi glyptics" in the corpus of Mature Harappan artifacts as pointing to Harappan devotion to "ritual discipline and concentration." These images show that the yoga pose "may have been used by deities and humans alike." Possehl suggests that yoga goes back to the Indus Valley Civilization. The most widely known of these images was named the "Pashupati seal" by its discoverer, John Marshall, who believed that it represented a "proto-Shiva" figure. Many modern authorities discount the idea that this "Pashupati" (Lord of Animals, Sanskrit Template:IAST) represents a Shiva or Rudra figure. Gavin Flood also characterizes these views as "speculative", saying that it is not clear from the 'Pashupati' seal that the figure is seated in a yoga posture, or that the shape is intended to represent a human figure. Authorities who support the idea that the 'Pashupati' figure shows a figure in a yoga or meditation posture include Archaeologist Jonathan Mark Kenoyer, current Co-director of the Harappa Archaeological Research Project in Pakistan and Indologist Heinrich Zimmer. In 2007, terracotta seals were discovered in the Cholistan Desert in Pakistan. Punjab University Archaeology Department Chairman Dr. Farzand Masih described one of the seals as similar to the previously discovered Mohenjodaro seals, with three pictographs on one side and a "yogi" on the other side. ## Literary sources Ascetic practices (tapas) are referenced in the ] (900 BCE and 500 BCE), early commentaries on the vedas. In the Upanishads, an early reference to meditation is made in Brihadaranyaka Upanishad, one of the earliest Upanishads (approx. 900 BCE). The main textual sources for the evolving concept of Yoga are the middle Upanishads, (ca. 400 BCE), the Mahabharata (5th c. BCE) including the Bhagavad Gita (ca. 200 BCE), and the Yoga Sutras of Patanjali (200 BCE-300 CE). ### Bhagavad Gita The Bhagavad Gita ('Song of the Lord'), uses the term yoga extensively in a variety of senses. Of many possible meanings given to the term in the Gita, most emphasis is given to these three: - Karma yoga: The yoga of action - Bhakti yoga: The yoga of devotion - Jnana yoga: The yoga of knowledge The influential commentator Madhusudana Sarasvati (b. circa 1490) divided the Gita's eighteen chapters into three sections, each of six chapters. According to his method of division the first six chapters deal with Karma yoga, the middle six deal with Bhakti yoga, and the last six deal with Jnana (knowledge). This interpretation has been adopted by some later commentators and rejected by others. ### Yoga Sutras of Patanjali In Indian philosophy, Yoga is the name of one of the six orthodox philosophical schools. The Yoga philosophical system is closely allied with the Samkhya school. The Yoga school as expounded by Patanjali accepts the Samkhya psychology and metaphysics, but is more theistic than the Samkhya, as evidenced by the addition of a divine entity to the Samkhya's twenty-five elements of reality. The parallels between Yoga and Samkhya were so close that Max Müller says that "the two philosophies were in popular parlance distinguished from each other as Samkhya with and Samkhya without a Lord...." The intimate relationship between Samkhya and Yoga is explained by Heinrich Zimmer: These two are regarded in India as twins, the two aspects of a single discipline. Template:IAST provides a basic theoretical exposition of human nature, enumerating and defining its elements, analyzing their manner of co-operation in a state of bondage (bandha), and describing their state of disentanglement or separation in release (Template:IAST), while Yoga treats specifically of the dynamics of the process for the disentanglement, and outlines practical techniques for the gaining of release, or 'isolation-integration' (kaivalya). The sage Patanjali is regarded as the founder of the formal Yoga philosophy. The Yoga Sutras of Patanjali are ascribed to Patanjali, who, may have been, as Max Müller explains, "the author or representative of the Yoga-philosophy without being necessarily the author of the Sutras." Indologist Axel Michaels is dismissive of claims that the work was written by Patanjali, characterizing it instead as a collection of fragments and traditions of texts stemming from the second or third century. Gavin Flood cites a wider period of uncertainty for the composition, between 100 BCE and 500 CE. Patanjali's yoga is known as Raja yoga, which is a system for control of the mind. Patanjali defines the word "yoga" in his second sutra, which is the definitional sutra for his entire work: This terse definition hinges on the meaning of three Sanskrit terms. I. K. Taimni translates it as "Yoga is the inhibition (Template:IAST) of the modifications (Template:IAST) of the mind (Template:IAST)". Swami Vivekananda translates the sutra as "Yoga is restraining the mind-stuff (Citta) from taking various forms (Vrittis)." Gavin Flood translates the sutra as "yoga is the cessation of mental fluctuations". Patanjali's writing also became the basis for a system referred to it as "Ashtanga Yoga" ("Eight-Limbed Yoga"). This eight-limbed concept derived from the 29th Sutra of the 2nd book became a feature of Raja yoga, and is a core characteristic of practically every Raja yoga variation taught today.The Eight Limbs of yoga practice are: They are sometimes divided into the lower and the upper four limbs, the lower ones being parallel to the lower limbs of Hatha Yoga, while the upper ones being specific for the Raja yoga. The upper three limbs practiced simultaneously constitute the Samyama. It details every aspect of the meditative process, and the preparation for it. The book is available in as many as 40 English translations, both in-print and on-line. ### Yoga Sámkhya History The Primordial Yoga, more than 6.000 years old when only one form of Yoga was recognised - at the beginning Yoga was called Sámkhya – (without compromised power or modern simplifications), preserved over the last millennia in the Indian Himalayas and with older vestiges in the Indus Valley, taught by Manu/Rudra/Shiva, (it is assumed that it dates from between 9.500 and 11.500 years ago, according to the recent underwater discoveries in the Cambaia Gulf, the mythical city of Duarka, victim of the thaws and floods of the 2º phase of the last Ice Age). Three great aspects of Yoga 1 – a strong self-demand base, of “Service”, work up to ego reduction, and Fraternity (Yama and Niyama); 2 – an Exceptional Development of the Human being in its all positive aspects, integrally and always in harmony, through the constant work, in each Class - Mahá Sádhaná (with 12 Anga or parts) with its 12 Technique Disciplines: 1 - Dhyána/Samyama - Meditation through the control of the frequency of brain waves; 2 - Pránáyáma - energetic and neuro-vegetative influence through respiratory Exercises; 3 - Ásana – psycho-bio-physical Positions; 4 - Yoganidrá - Physical, emotional and mental Relaxation Techniques; 5- Kriyá- Organic Cleaning and Strengthening; 6 - Mantra/Kírtana - Domain of external sounds and Harmony; 7 - Jápa - Concentrative Sounds; 8 - Bandha – Muscular enlivening and neuro-endocrinal; 9 - Yantra - concentrative Symbols for psychosomatic effect; 10 - Pujá - Energetic Repayments; 11 - Mudrá - Reflexive and energetic Gestures made with the hands; 12 - Mánasika - Mind process, will strengthening and projection of the Conscience. - and with its 6 secondary disciplines (total of 18) and complementary subjects (Sámkhya, Samskrta/Sanskrit, Chakra, Sat Sanga, Sat Chakra, Sháshtra, Great World Masters, Mauna, Nyása, Shákta, Nutrition, etc.), where the practical Philosopher will apply constantly in his daily life what he has learned in the Áshrama (place of practice), and where in the long run – the path – must be always in tune with the Grand goal, 3 - to reach the Samádhi (enlightenment) – Human and Cosmic Intellective Supreme Consciousness. ### Hatha Yoga Pradipika Hatha Yoga is a particular system of Yoga described by Yogi Swatmarama, a yogic sage of the 15th century in India, and compiler of the Hatha Yoga Pradipika. Hatha Yoga is a development of — but also differs substantially from — the Raja Yoga of Patanjali, in that it focuses on shatkarma, the purification of the physical as leading to the purification of the mind (ha), and prana, or vital energy (tha). In contrast, the Raja Yoga posited by Patanjali begins with a purification of the mind (yamas) and spirit (niyamas), then comes to the body via asana (body postures) and pranayama (breath). Hatha yoga contains substantial tantric influence, and marks the first point at which chakras and kundalini were introduced into the yogic canon. Compared to the seated asanas of Patanjali's Raja yoga which were seen largely as a means of preparing for meditation, it also marks the development of asanas as full body 'postures' in the modern sense. Hatha Yoga in its many modern variations is the style that most people actually associate with the word "Yoga" today. Because its emphasis is on the body through asana and pranayama practice, many western students are satisfied with the physical health and vitality it develops and are not interested in the other six limbs of the complete Hatha yoga teaching, or with the even older Raja Yoga tradition it is based on. # Yoga in other traditions ## Yoga and Buddhism Yoga is intimately connected to the religious beliefs and practices of the Indian religions. The influence of Yoga is also visible in Buddhism, which is distinguished by its austerities, spiritual exercises, and trance states. ### Yogacara Buddhism Yogacara (Sanskrit: "Practice of Yoga " ), also spelled yogāchāra, is a school of philosophy and psychology that developed in India during the 4th to 5th centuries. Yogacara received the name as it provided a yoga, a framework for engaging in the practices that lead to the path of the bodhisattva. The Yogacara sect teaches yoga in order to reach enlightenment. ### Ch`an (Zen) Buddhism Zen (the name of which derives from the Sanskrit "dhyana" via the Chinese "ch'an") is a form of Mahayana Buddhism. The Mahayana school of Buddhism is noted for its proximity with Yoga. In the west, Zen is often set alongside Yoga; the two schools of meditation display obvious family resemblances. This phenomenon merits special attention since the Zen Buddhist school of meditation has some of its roots in yogic practices. Certain essential elements of Yoga are important both for Buddhism in general and for Zen in particular. ### Tibetan Buddhism Yoga is central to Tibetan Buddhism. In the Nyingma tradition, practitioners progress to increasingly profound levels of yoga, starting with Mahā yoga, continuing to Anu yoga and ultimately undertaking the highest practice, Ati yoga. In the Sarma traditions, the Anuttara yoga class is equivalent. Other tantra yoga practices include a system of 108 bodily postures practiced with breath and heart rhythm. Timing in movement exercises is known as Trul khor or union of moon and sun (channel) prajna energies. The body postures of Tibetan ancient yogis are depicted on the walls of the Dalai Lama's summer temple of Lukhang. ## Yoga and Tantra Tantrism is a practice that is supposed to alter the relation of its practitioners to the ordinary social, religious, and logical reality in which they live. Through Tantric practice an individual perceives reality as maya, illusion, and the individual achieves liberation from it. This particular path to salvation among the several offered by Hinduism, links Tantrism to those practices of Indian religions, such as yoga, meditation, and social renunciation, which are based on temporary or permanent withdrawal from social relationships and modes. During tantric practices and studies, the student is instructed further in meditation technique, particularly chakra meditation. This is often in a limited form in comparison with the way this kind of meditation is known and used by Tantric practitioners and yogis elsewhere, but is more elaborate than the initiate's previous meditation. It is considered to be a kind of Kundalini Yoga for the purpose of moving the Goddess into the chakra located in the "heart," for meditation and worship. # Goal of Yoga There are numerous opinions on what the goal of Yoga may be. Goals can range from improving health and fitness, to reaching Moksha. Within the monist schools of Advaita Vedanta and Shaivism this perfection takes the form of Moksha, which is a liberation from all worldly suffering and the cycle of birth and death (Samsara) at which point there is a realisation of identity with the Supreme Brahman. For the dualistic bhakti schools of Vaishnavism, bhakti itself is the ultimate goal of the yoga process, wherein perfection culminates in an eternal relationship with Vishnu or one of his associated avatars such as Krishna or Rama.

Yoga Yoga (Sanskrit: योग Yoga, Template:IPA2) is a group of ancient spiritual practices originating in India. According to Gavin Flood, Academic Director of the Oxford Centre for Hindu Studies[1] it has been defined as referring to "technologies or disciplines of asceticism and meditation which are thought to lead to spiritual experience and profound understanding or insight into the nature of existence."[2] Yoga is also intimately connected to the religious beliefs and practices of the other Indian religions. Outside India, Yoga is mostly associated with the practice of asanas (postures) of Hatha Yoga or as a form of exercise, although it has influenced the entire Indian religions family and other spiritual practices throughout the world.[3] Hindu texts discussing different aspects of yoga include the Upanishads, the Bhagavad Gita, the Yoga Sutras of Patanjali, the Hatha Yoga Pradipika, the Shiva Samhita, and many others.[3][4] Major branches of Yoga include: Hatha Yoga, Karma Yoga, Jnana Yoga, Bhakti Yoga, and Raja Yoga.[5] [6] [7] Raja Yoga, established by the Yoga Sutras of Patanjali, and known simply as Yoga in the context of Hindu philosophy, is one of the six orthodox (āstika) schools of thought. # Etymology The Sanskrit term yoga has a wide range of different meanings.[8] It is derived from the Sanskrit root yuj, "to control", "to yoke", or "to unite".[9] Common meanings include "joining" or "uniting", and related ideas such as "union" and "conjunction".[10] Another conceptual definition is that of "mode, manner, means"[11] or "expedient, means in general".[12] # History of Yoga ## Indus Valley seals Several seals discovered at Indus Valley Civilization (c. 3300–1700 BC) sites depict figures in a yoga or meditation like posture. There is considerable evidence to support the idea that the images show "a form of ritual discipline, suggesting a precursor of yoga"[13] according to archaeologist Gregory Possehl. He points to sixteen other specific "yogi glyptics"[14] in the corpus of Mature Harappan artifacts as pointing to Harappan devotion to "ritual discipline and concentration." These images show that the yoga pose "may have been used by deities and humans alike." Possehl suggests that yoga goes back to the Indus Valley Civilization.[15] The most widely known of these images was named the "Pashupati seal"[16] by its discoverer, John Marshall, who believed that it represented a "proto-Shiva" figure.[17] Many modern authorities discount the idea that this "Pashupati" (Lord of Animals, Sanskrit Template:IAST)[18] represents a Shiva or Rudra figure.[19][20] Gavin Flood also characterizes these views as "speculative", saying that it is not clear from the 'Pashupati' seal that the figure is seated in a yoga posture, or that the shape is intended to represent a human figure.[21][22] Authorities who support the idea that the 'Pashupati' figure shows a figure in a yoga or meditation posture include Archaeologist Jonathan Mark Kenoyer, current Co-director of the Harappa Archaeological Research Project in Pakistan[23][24] and Indologist Heinrich Zimmer.[25] In 2007, terracotta seals were discovered in the Cholistan Desert in Pakistan. Punjab University Archaeology Department Chairman Dr. Farzand Masih described one of the seals as similar to the previously discovered Mohenjodaro seals, with three pictographs on one side and a "yogi" on the other side.[26][27] ## Literary sources Ascetic practices (tapas) are referenced in the [[Brahmana|Template:IAST]] (900 BCE and 500 BCE),[28] early commentaries on the vedas. In the Upanishads, an early reference to meditation is made in Brihadaranyaka Upanishad,[29] one of the earliest Upanishads (approx. 900 BCE). The main textual sources for the evolving concept of Yoga are the middle Upanishads, (ca. 400 BCE), the Mahabharata (5th c. BCE) including the Bhagavad Gita (ca. 200 BCE), and the Yoga Sutras of Patanjali (200 BCE-300 CE). ### Bhagavad Gita The Bhagavad Gita ('Song of the Lord'), uses the term yoga extensively in a variety of senses. Of many possible meanings given to the term in the Gita, most emphasis is given to these three:[30] - Karma yoga: The yoga of action - Bhakti yoga: The yoga of devotion - Jnana yoga: The yoga of knowledge The influential commentator Madhusudana Sarasvati (b. circa 1490) divided the Gita's eighteen chapters into three sections, each of six chapters. According to his method of division the first six chapters deal with Karma yoga, the middle six deal with Bhakti yoga, and the last six deal with Jnana (knowledge).[31] This interpretation has been adopted by some later commentators and rejected by others. ### Yoga Sutras of Patanjali In Indian philosophy, Yoga is the name of one of the six orthodox philosophical schools.[32][33] The Yoga philosophical system is closely allied with the Samkhya school.[34] The Yoga school as expounded by Patanjali accepts the Samkhya psychology and metaphysics, but is more theistic than the Samkhya, as evidenced by the addition of a divine entity to the Samkhya's twenty-five elements of reality.[35][36] The parallels between Yoga and Samkhya were so close that Max Müller says that "the two philosophies were in popular parlance distinguished from each other as Samkhya with and Samkhya without a Lord...."[37] The intimate relationship between Samkhya and Yoga is explained by Heinrich Zimmer: These two are regarded in India as twins, the two aspects of a single discipline. Template:IAST provides a basic theoretical exposition of human nature, enumerating and defining its elements, analyzing their manner of co-operation in a state of bondage (bandha), and describing their state of disentanglement or separation in release (Template:IAST), while Yoga treats specifically of the dynamics of the process for the disentanglement, and outlines practical techniques for the gaining of release, or 'isolation-integration' (kaivalya).[38] The sage Patanjali is regarded as the founder of the formal Yoga philosophy.[39] The Yoga Sutras of Patanjali are ascribed to Patanjali, who, may have been, as Max Müller explains, "the author or representative of the Yoga-philosophy without being necessarily the author of the Sutras."[40] Indologist Axel Michaels is dismissive of claims that the work was written by Patanjali, characterizing it instead as a collection of fragments and traditions of texts stemming from the second or third century.[41] Gavin Flood cites a wider period of uncertainty for the composition, between 100 BCE and 500 CE.[42] Patanjali's yoga is known as Raja yoga, which is a system for control of the mind.[43] Patanjali defines the word "yoga" in his second sutra, which is the definitional sutra for his entire work: Template:IAST- Yoga Sutras 1.2 This terse definition hinges on the meaning of three Sanskrit terms. I. K. Taimni translates it as "Yoga is the inhibition (Template:IAST) of the modifications (Template:IAST) of the mind (Template:IAST)".[44] Swami Vivekananda translates the sutra as "Yoga is restraining the mind-stuff (Citta) from taking various forms (Vrittis)."[45] Gavin Flood translates the sutra as "yoga is the cessation of mental fluctuations".[46] Patanjali's writing also became the basis for a system referred to it as "Ashtanga Yoga" ("Eight-Limbed Yoga"). This eight-limbed concept derived from the 29th Sutra of the 2nd book became a feature of Raja yoga, and is a core characteristic of practically every Raja yoga variation taught today.[1]The Eight Limbs of yoga practice are: They are sometimes divided into the lower and the upper four limbs, the lower ones being parallel to the lower limbs of Hatha Yoga, while the upper ones being specific for the Raja yoga. The upper three limbs practiced simultaneously constitute the Samyama. It details every aspect of the meditative process, and the preparation for it. The book is available in as many as 40 English translations, both in-print and on-line.[2][3][4][5][6][7][8] [9] ### Yoga Sámkhya History The Primordial Yoga, more than 6.000 years old when only one form of Yoga was recognised - at the beginning Yoga was called Sámkhya – (without compromised power or modern simplifications), preserved over the last millennia in the Indian Himalayas and with older vestiges in the Indus Valley, taught by Manu/Rudra/Shiva, (it is assumed that it dates from between 9.500 and 11.500 years ago, according to the recent underwater discoveries in the Cambaia Gulf, the mythical city of Duarka, victim of the thaws and floods of the 2º phase of the last Ice Age). Three great aspects of Yoga 1 – a strong self-demand base, of “Service”, work up to ego reduction, and Fraternity (Yama and Niyama); 2 – an Exceptional Development of the Human being in its all positive aspects, integrally and always in harmony, through the constant work, in each Class - Mahá Sádhaná (with 12 Anga or parts) with its 12 Technique Disciplines: 1 - Dhyána/Samyama - Meditation through the control of the frequency of brain waves; 2 - Pránáyáma - energetic and neuro-vegetative influence through respiratory Exercises; 3 - Ásana – psycho-bio-physical Positions; 4 - Yoganidrá - Physical, emotional and mental Relaxation Techniques; 5- Kriyá- Organic Cleaning and Strengthening; 6 - Mantra/Kírtana - Domain of external sounds and Harmony; 7 - Jápa - Concentrative Sounds; 8 - Bandha – Muscular enlivening and neuro-endocrinal; 9 - Yantra - concentrative Symbols for psychosomatic effect; 10 - Pujá - Energetic Repayments; 11 - Mudrá - Reflexive and energetic Gestures made with the hands; 12 - Mánasika - Mind process, will strengthening and projection of the Conscience. - and with its 6 secondary disciplines (total of 18) and complementary subjects (Sámkhya, Samskrta/Sanskrit, Chakra, Sat Sanga, Sat Chakra, Sháshtra, Great World Masters, Mauna, Nyása, Shákta, Nutrition, etc.), where the practical Philosopher will apply constantly in his daily life what he has learned in the Áshrama (place of practice), and where in the long run – the path – must be always in tune with the Grand goal, 3 - to reach the Samádhi (enlightenment) – Human and Cosmic Intellective Supreme Consciousness. ### Hatha Yoga Pradipika Hatha Yoga is a particular system of Yoga described by Yogi Swatmarama, a yogic sage of the 15th century in India, and compiler of the Hatha Yoga Pradipika. Hatha Yoga is a development of — but also differs substantially from — the Raja Yoga of Patanjali, in that it focuses on shatkarma, the purification of the physical as leading to the purification of the mind (ha), and prana, or vital energy (tha).[47][48] In contrast, the Raja Yoga posited by Patanjali begins with a purification of the mind (yamas) and spirit (niyamas), then comes to the body via asana (body postures) and pranayama (breath). Hatha yoga contains substantial tantric influence,[49][50] and marks the first point at which chakras and kundalini were introduced into the yogic canon. Compared to the seated asanas of Patanjali's Raja yoga which were seen largely as a means of preparing for meditation, it also marks the development of asanas as full body 'postures' in the modern sense.[51] Hatha Yoga in its many modern variations is the style that most people actually associate with the word "Yoga" today.[52] Because its emphasis is on the body through asana and pranayama practice, many western students are satisfied with the physical health and vitality it develops and are not interested in the other six limbs of the complete Hatha yoga teaching, or with the even older Raja Yoga tradition it is based on. # Yoga in other traditions ## Yoga and Buddhism Yoga is intimately connected to the religious beliefs and practices of the Indian religions.[53] The influence of Yoga is also visible in Buddhism, which is distinguished by its austerities, spiritual exercises, and trance states.[54][55] ### Yogacara Buddhism Yogacara (Sanskrit: "Practice of Yoga [Union]"[56] ), also spelled yogāchāra, is a school of philosophy and psychology that developed in India during the 4th to 5th centuries. Yogacara received the name as it provided a yoga, a framework for engaging in the practices that lead to the path of the bodhisattva.[57] The Yogacara sect teaches yoga in order to reach enlightenment.[58] ### Ch`an (Zen) Buddhism Zen (the name of which derives from the Sanskrit "dhyana" via the Chinese "ch'an"[59]) is a form of Mahayana Buddhism. The Mahayana school of Buddhism is noted for its proximity with Yoga.[55] In the west, Zen is often set alongside Yoga; the two schools of meditation display obvious family resemblances.[60] This phenomenon merits special attention since the Zen Buddhist school of meditation has some of its roots in yogic practices.[61] Certain essential elements of Yoga are important both for Buddhism in general and for Zen in particular.[3] ### Tibetan Buddhism Yoga is central to Tibetan Buddhism. In the Nyingma tradition, practitioners progress to increasingly profound levels of yoga, starting with Mahā yoga, continuing to Anu yoga and ultimately undertaking the highest practice, Ati yoga. In the Sarma traditions, the Anuttara yoga class is equivalent. Other tantra yoga practices include a system of 108 bodily postures practiced with breath and heart rhythm. Timing in movement exercises is known as Trul khor or union of moon and sun (channel) prajna energies. The body postures of Tibetan ancient yogis are depicted on the walls of the Dalai Lama's summer temple of Lukhang. ## Yoga and Tantra Tantrism is a practice that is supposed to alter the relation of its practitioners to the ordinary social, religious, and logical reality in which they live. Through Tantric practice an individual perceives reality as maya, illusion, and the individual achieves liberation from it.[62] This particular path to salvation among the several offered by Hinduism, links Tantrism to those practices of Indian religions, such as yoga, meditation, and social renunciation, which are based on temporary or permanent withdrawal from social relationships and modes.[62] During tantric practices and studies, the student is instructed further in meditation technique, particularly chakra meditation. This is often in a limited form in comparison with the way this kind of meditation is known and used by Tantric practitioners and yogis elsewhere, but is more elaborate than the initiate's previous meditation. It is considered to be a kind of Kundalini Yoga for the purpose of moving the Goddess into the chakra located in the "heart," for meditation and worship.[63] # Goal of Yoga There are numerous opinions on what the goal of Yoga may be. Goals can range from improving health and fitness, to reaching Moksha. Within the monist schools of Advaita Vedanta and Shaivism this perfection takes the form of Moksha, which is a liberation from all worldly suffering and the cycle of birth and death (Samsara) at which point there is a realisation of identity with the Supreme Brahman. For the dualistic bhakti schools of Vaishnavism, bhakti itself is the ultimate goal of the yoga process[64], wherein perfection culminates in an eternal relationship with Vishnu or one of his associated avatars such as Krishna or Rama.[65]

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

64c4415d2c449d7e72e5eccd2df5abaa5f57d489

wikidoc

ZBP1

ZBP1 Z-DNA-binding protein 1, also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1, is a protein that in humans is encoded by the ZBP1 gene. ZBP1 is also an abbreviation for chicken or rat β-actin zipcode-binding protein 1, a homolog of the human insulin-like growth factor 2 mRNA-binding protein 1 (IMP-1) and murine CRD-BP, the proteins involved in mRNA transport (RNA-binding proteins, RBPs). # Function DLM1 encodes a Z-DNA binding protein. Z-DNA formation is a dynamic process, largely controlled by the amount of supercoiling. ZBP1 recognizes DNA in the cytoplasm as an antiviral mechanism. Viral life cycles often include steps where DNA is exposed in the cytoplasm. DNA is normally contained in the nucleus of a cell, and therefore cells use proteins like ZBP1 as an indicator of a viral infection. Once ZBP1 is activated, it increases the production of antiviral cytokines such as interferon beta. DLM1 then binds to cytosolic Viral DNA using two Z-DNA-binding domains (Zα and Zβ) at its N-terminus along with a DNA binding domain (D3). The role of ZBP1 in DNA sensing has been questioned. It has been found to sense Influenza A Virus (IAV) infection and induce cell death. Since DNA is not synthesized in any stage of IAV life cycle, DNA sensing playing a role in this context is unlikely. A follow up study identified that ZBP1 senses the IAV ribonucleoprotein complex to induce cell death. A more recent study has identified transcription factor IRF1 as the upstream regulator of ZBP1 expression. Zipcode binding protein 1 (ZBP1) was shown to regulate dendritogenesis (dendrite formation) in hippocampal neurons. This protein is different from the nucleic acid sensor ZBP1.

ZBP1 Z-DNA-binding protein 1, also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1, is a protein that in humans is encoded by the ZBP1 gene.[1][2] ZBP1 is also an abbreviation for chicken or rat β-actin zipcode-binding protein 1, a homolog of the human insulin-like growth factor 2 mRNA-binding protein 1 (IMP-1) and murine CRD-BP, the proteins involved in mRNA transport (RNA-binding proteins, RBPs). # Function DLM1 encodes a Z-DNA binding protein. Z-DNA formation is a dynamic process, largely controlled by the amount of supercoiling.[2] ZBP1 recognizes DNA in the cytoplasm as an antiviral mechanism. Viral life cycles often include steps where DNA is exposed in the cytoplasm. DNA is normally contained in the nucleus of a cell, and therefore cells use proteins like ZBP1 as an indicator of a viral infection. Once ZBP1 is activated, it increases the production of antiviral cytokines such as interferon beta.[3] DLM1 then binds to cytosolic Viral DNA using two Z-DNA-binding domains (Zα and Zβ) at its N-terminus along with a DNA binding domain (D3).[4] The role of ZBP1 in DNA sensing has been questioned. It has been found to sense Influenza A Virus (IAV) infection and induce cell death. Since DNA is not synthesized in any stage of IAV life cycle, DNA sensing playing a role in this context is unlikely.[5][6] A follow up study identified that ZBP1 senses the IAV ribonucleoprotein complex to induce cell death.[6] A more recent study has identified transcription factor IRF1 as the upstream regulator of ZBP1 expression.[7] Zipcode binding protein 1 (ZBP1) was shown to regulate dendritogenesis (dendrite formation) in hippocampal neurons.[8] This protein is different from the nucleic acid sensor ZBP1.

https://www.wikidoc.org/index.php/ZBP1

df53cd5694bc00a9435ffbd013e616aa70ce0128

wikidoc

ZEB1

ZEB1 Zinc finger E-box-binding homeobox 1 is a protein that in humans is encoded by the ZEB1 gene. ZEB1 (previously known as TCF8) encodes a zinc finger and homeodomain transcription factor that represses T-lymphocyte-specific IL2 gene expression by binding to a negative regulatory domain 100 nucleotides 5-prime of the IL2 transcription start site. ZEB1 and its mammalian paralog ZEB2 belongs to the Zeb family within the ZF (zinc finger) class of homeodomain transcription factors. ZEB1 protein has 7 zinc fingers and 1 homeodomain. The structure of the homeodomain shown on the right. # Clinical significance Mutations of the gene are linked to posterior polymorphous corneal dystrophy 3. A recent study suggested its contributing role in lung cancer invasiveness and metastasis development.

ZEB1 Zinc finger E-box-binding homeobox 1 is a protein that in humans is encoded by the ZEB1 gene.[1][2][3] ZEB1 (previously known as TCF8) encodes a zinc finger and homeodomain transcription factor that represses T-lymphocyte-specific IL2 gene expression by binding to a negative regulatory domain 100 nucleotides 5-prime of the IL2 transcription start site.[3][4] ZEB1 and its mammalian paralog ZEB2 belongs to the Zeb family within the ZF (zinc finger) class of homeodomain transcription factors. ZEB1 protein has 7 zinc fingers and 1 homeodomain.[5] The structure of the homeodomain shown on the right. # Clinical significance Mutations of the gene are linked to posterior polymorphous corneal dystrophy 3. A recent study suggested its contributing role in lung cancer invasiveness and metastasis development.[6]

https://www.wikidoc.org/index.php/ZEB1

7769fad04981258f5c7386d8909632ae5b498fe8

wikidoc

ZEB2

ZEB2 Zinc finger E-box-binding homeobox 2 is a protein that in humans is encoded by the ZEB2 gene. The ZEB2 protein is a transcription factor that plays a role in the transforming growth factor β (TGFβ) signaling pathways that are essential during early fetal development. # Function ZEB2 (previously also known as SMADIP1, SIP1) and its mammalian paralog ZEB1 belongs to the Zeb family within the ZF (zinc finger) class of homeodomain transcription factors. ZEB2 protein has 8 zinc fingers and 1 homeodomain.The structure of the homeodomain shown on the right. ZEB2 interacts with receptor-mediated, activated full-length SMADs. The activation of TGFβ receptors brings about the phosphorylation of intracellular effector molecules, R-SMADs. ZEB2 is an R-SMAD-binding protein and acts as a transcriptional corepressor. ZEB2 transcripts are found in tissues differentiated from the neural crest such as the cranial nerve ganglia, dorsal root ganglia, sympathetic ganglionic chains, the enteric nervous system and melanocytes. ZEB2 is also found in tissues that are not derived from the neural crest, including the wall of the digestive tract, kidneys, and skeletal muscles. # Clinical significance Mutations in the ZEB2 gene are associated with the Mowat–Wilson syndrome. This disease exhibits mutations and even complete deletions of the ZEB2 gene. Mutations of the gene can cause the gene to produce nonfunctional ZEB2 proteins or inactivate the function gene as a whole. These deficits of ZEB2 protein interferes with the development of many organs. Many of the symptoms can be explained by the irregular development of the structures from the neural crest. Hirschsprung's disease also has many symptoms that can be explained by lack of ZEB2 during development of the digestive tract nerves. This disease causes severe constipation and enlargement of the colon.

ZEB2 Zinc finger E-box-binding homeobox 2 is a protein that in humans is encoded by the ZEB2 gene.[1] The ZEB2 protein is a transcription factor that plays a role in the transforming growth factor β (TGFβ) signaling pathways that are essential during early fetal development.[2] # Function ZEB2 (previously also known as SMADIP1, SIP1) and its mammalian paralog ZEB1 belongs to the Zeb family within the ZF (zinc finger) class of homeodomain transcription factors. ZEB2 protein has 8 zinc fingers and 1 homeodomain.[3]The structure of the homeodomain shown on the right. ZEB2 interacts with receptor-mediated, activated full-length SMADs.[1] The activation of TGFβ receptors brings about the phosphorylation of intracellular effector molecules, R-SMADs. ZEB2 is an R-SMAD-binding protein and acts as a transcriptional corepressor. ZEB2 transcripts are found in tissues differentiated from the neural crest such as the cranial nerve ganglia, dorsal root ganglia, sympathetic ganglionic chains, the enteric nervous system and melanocytes. ZEB2 is also found in tissues that are not derived from the neural crest, including the wall of the digestive tract, kidneys, and skeletal muscles. # Clinical significance Mutations in the ZEB2 gene are associated with the Mowat–Wilson syndrome. This disease exhibits mutations and even complete deletions of the ZEB2 gene. Mutations of the gene can cause the gene to produce nonfunctional ZEB2 proteins or inactivate the function gene as a whole. These deficits of ZEB2 protein interferes with the development of many organs. Many of the symptoms can be explained by the irregular development of the structures from the neural crest.[4] Hirschsprung's disease also has many symptoms that can be explained by lack of ZEB2 during development of the digestive tract nerves. This disease causes severe constipation and enlargement of the colon.[5]

https://www.wikidoc.org/index.php/ZEB2

5ef3e6e114f281734cda1f4d194cfebe5249e4f8

wikidoc

ZIC2

ZIC2 Zinc finger protein ZIC2 is a protein that in humans is encoded by the ZIC2 gene. ZIC2 is a member of the Zinc finger of the cerebellum (ZIC) protein family. # Function ZIC2 is classified as a ZIC protein due to conservation of the five C2H2 zinc fingers, which enables the protein to interact with DNA and proteins. # Clinical significance Correct function of these proteins is critical for early development, and as such mutations of the genes encoding these proteins is known to result in various congenital defects. For example, mutation of ZIC2 is known to result in holoprosencephaly due to defect in the function of the organizer region (node), which leads to a defective anterior notochord (ANC). The ANC provides a maintenance signal to the Prechordal plate (PCP), thus a defective ANC results in degradation of the PCP, which is normally responsible for sending a shh signal to the developing forebrain resulting in the formation of the two hemispheres. Holoprosencephaly is the most common structural anomaly of the human forebrain. Recently ZIC2 has also been shown to be critical for establishment of the left-right axis, thus loss of ZIC2 function can result in defects in heart formation. Another member of the ZIC family, ZIC3, has previously been linked to establishment of the left-right axis. A polyhistidine tract polymorphism in this gene may be associated with increased risk of neural tube defects (spina bifida). This gene is closely linked to a gene encoding ZIC5, a related family member on chromosome 13. # Interactions ZIC2 has recently been found to interact with TCF7L2, enabling it to act as a Wnt/β-catenin signalling inhibitor. Such a role is of critical importance, as not only is correct Wnt signalling critical for early development, Wnt signalling has also been found to be upregulated to several cancers. ZIC2 has also been shown to interact with GLI3.

ZIC2 Zinc finger protein ZIC2 is a protein that in humans is encoded by the ZIC2 gene.[1][2] ZIC2 is a member of the Zinc finger of the cerebellum (ZIC) protein family.[3] # Function ZIC2 is classified as a ZIC protein due to conservation of the five C2H2 zinc fingers, which enables the protein to interact with DNA and proteins.[2] # Clinical significance Correct function of these proteins is critical for early development, and as such mutations of the genes encoding these proteins is known to result in various congenital defects. For example, mutation of ZIC2 is known to result in holoprosencephaly due to defect in the function of the organizer region (node), which leads to a defective anterior notochord (ANC). The ANC provides a maintenance signal to the Prechordal plate (PCP), thus a defective ANC results in degradation of the PCP, which is normally responsible for sending a shh signal to the developing forebrain resulting in the formation of the two hemispheres.[4] Holoprosencephaly is the most common structural anomaly of the human forebrain. Recently ZIC2 has also been shown to be critical for establishment of the left-right axis, thus loss of ZIC2 function can result in defects in heart formation.[5] Another member of the ZIC family, ZIC3, has previously been linked to establishment of the left-right axis. A polyhistidine tract polymorphism in this gene may be associated with increased risk of neural tube defects (spina bifida). This gene is closely linked to a gene encoding ZIC5, a related family member on chromosome 13.[2] # Interactions ZIC2 has recently been found to interact with TCF7L2, enabling it to act as a Wnt/β-catenin signalling inhibitor.[6] Such a role is of critical importance, as not only is correct Wnt signalling critical for early development,[7] Wnt signalling has also been found to be upregulated to several cancers. ZIC2 has also been shown to interact with GLI3.[8]

https://www.wikidoc.org/index.php/ZIC2

63a92482651c231ee30e07157532a42113d85941

wikidoc

ZIC3

ZIC3 ZIC3 is a member of the Zinc finger of the cerebellum (ZIC) protein family. ZIC3 is classified as a ZIC protein due to conservation of the five C2H2 zinc fingers, which enables the protein to interact with DNA and proteins. Correct function of this protein family in critical for early development, and as such mutations of the genes encoding these proteins is known to result in various congenital defects. For example, mutation of ZIC3 is associated with heterotaxy, that is thought to occur due to the role of ZIC3 in initial left-right symmetry formation, which involves the maintaining redistributed Nodal after the asymmetry of the embryo is initially broken. Mutation of ZIC3 is also associated with various heart defects, such as heart looping, however these are thought to represent a mild form of heterotaxy. Mouse based studies have linked defective ZIC3 with neural tube defects (spina bifida) and skeletal defects. ZIC3 is also of particular interest as it has been shown to be required for maintenance of embryonic stem cell pluripotency. # Involvement in Wnt signalling ZIC2, another member of the ZIC family, has recently been found to interact with TCF7L2, enabling it to act as a Wnt/β-catenin signalling inhibitor. Further experiments have indicated that human ZIC3 is also able to inhibit Wnt signalling and that the Zinc finger domains are absolutely critical for this role. Such a role is of critical importance, as not only is correct Wnt signalling critical for early development, Wnt signalling has also been found to be upregulated to several cancers.

ZIC3 ZIC3 is a member of the Zinc finger of the cerebellum (ZIC) protein family.[1][2] ZIC3 is classified as a ZIC protein due to conservation of the five C2H2 zinc fingers, which enables the protein to interact with DNA and proteins. Correct function of this protein family in critical for early development, and as such mutations of the genes encoding these proteins is known to result in various congenital defects. For example, mutation of ZIC3 is associated with heterotaxy,[3] that is thought to occur due to the role of ZIC3 in initial left-right symmetry formation, which involves the maintaining redistributed Nodal after the asymmetry of the embryo is initially broken.[4] Mutation of ZIC3 is also associated with various heart defects, such as heart looping, however these are thought to represent a mild form of heterotaxy. Mouse based studies have linked defective ZIC3 with neural tube defects (spina bifida) and skeletal defects.[5] ZIC3 is also of particular interest as it has been shown to be required for maintenance of embryonic stem cell pluripotency.[6] # Involvement in Wnt signalling ZIC2, another member of the ZIC family, has recently been found to interact with TCF7L2, enabling it to act as a Wnt/β-catenin signalling inhibitor.[7] Further experiments have indicated that human ZIC3 is also able to inhibit Wnt signalling and that the Zinc finger domains are absolutely critical for this role.[8] Such a role is of critical importance, as not only is correct Wnt signalling critical for early development,[9] Wnt signalling has also been found to be upregulated to several cancers.

https://www.wikidoc.org/index.php/ZIC3

145312959d554f7ea1369eb105daeb8ba311036b

wikidoc

ZIP9

ZIP9 Zinc transporter ZIP9 also known as Zrt- and Irt-like protein 9 (ZIP9) and solute carrier family 39 member 9 (SLC39A9) is a protein that in humans is encoded by the SLC39A9 gene. This protein is the 9th member out of 14 ZIP family proteins, which is a membrane androgen receptor (mAR) coupled to G proteins, and also classified as a zinc transporter protein. ZIP family proteins transport zinc metal from the extracellular environment into cells through cell membrane. # Classification and nomenclature Mammalian cells have two major groups of zinc transporter proteins; the ones that export zinc from the cytoplasm to the extracellular space (efflux), which are called ZnT (SLC30 family) , and ZIP (SLC39 family) proteins whose functions are in the opposite direction (influx). ZIP family proteins are named as Zrt- and Irt-like proteins because of their similarities to Zrt and Irt proteins which are respectively zinc and iron -regulated transporter proteins in yeast and Arabidopsis that were discovered earlier than ZIP and ZnT proteins. ZIP family is consisted of four subfamilies (I, II, LIV-1, and gufA), and ZIP9 is the only member of subfamily I. # Isoforms ZIP9 can be present as 3 different isoforms in human cells. The canonical isoform of this protein has a length of 307 amino acids, with a molecular mass of 32,251Da. In the second isoform, amino acids 135-157 are missing, so its length and molecular weight are respectively reduced to 284 amino acids and 29,931Da. In the third isoform the amino acids 233-307 are missing, so the isoform only has 232 amino acids and its molecular mass is 24,626 Da. Additionally, the last amino acid of isoform 3, which is usually serine, is replaced with aspartic acid. # Discovery ZIP9 membrane androgen receptor was first discovered in Atlantic croaker (Micropogonias undulatus) brain, ovary and testicular tissues and named "AR2" in 1999, together with another androgen receptor which was found only in brain tissue, and it was named "AR1" in that time. AR1 and AR2 were first thought to be nuclear androgen receptors (nAR), however, further studies on their biochemical and functional features in 2003 illustrated that they were involved in non-genomic mechanisms in the plasma membrane of the cells and were membrane androgen receptors. In 2005, the similarities between the nucleotide and amino acid sequences of AR2 and ZIP family proteins were discovered in other vertebrates, suggesting that AR2 is from this family of proteins. A study in 2014 utilised the latest research technologies to clone and express a particular cDNA of the female Atlantic croaker ovaries, which encoded a protein showing the characteristics of the canonical isoform of ZIP9, as a novel membrane androgen receptor(mAR). # Structure Unlike other ZIP subfamilies that are consisted of 8 transmembrane (TM) domains with an extracellular C-terminal, ZIP9 is consisted of a 7 TM structure with an intracellular C-terminus. ZIP9 is shorter than other ZIP proteins, and only has about 307 amino acids within its structure, however, like other ZIP proteins, between its domains III and IV, within the intracellular loop, it contains histidine-rich clusters. ZIP9 and other ZIP proteins have polar or charged amino acids in their TM domains which probably play important roles in making ion transfer channels and therefore in importing zinc ions into cytoplasm. # Location, expression and function ZIP9 influxes zinc ions into the cytosol and its gene is expressed almost in every tissue of human body. The sub-cellular location of ZIP9 is in plasma, nucleus, endoplasmic reticulum and mitochondrial membrane. One of the responsibilities of ZIP9 is the homeostasis of zinc in the secretory pathway, during which this protein stays within the Trans Golgi Network regardless of the change in the concentrations of zinc. ZIP9 is the only ZIP protein that signals through G protein binding, and pharmaceutical agents decrease its ligand binding once ZIP9 is uncoupled from G proteins. ZIP9 is also the only member of ZIP family with mAR characteristics. # Ligands Testosterone has high affinity for ZIP9 with a Kd of 14 nM and acts as an agonist of the receptor. In contrast, the other endogenous androgens dihydrotestosterone (DHT) and androstenedione show low affinity for the receptor with less than 1% of that of testosterone, although DHT is still effective in activating the receptor at sufficiently high concentrations. Moreover, the synthetic androgens mibolerone and metribolone (R-1881), the endogenous androgen 11-ketotestoterone, and the other steroid hormones estradiol and cortisol are all ineffective competitors for the receptor. Since mibolerone and metribolone bind to and activate the nuclear androgen receptor (AR) but not ZIP9, they could potentially be employed to differentiate between AR- and ZIP9-mediated responses of testosterone. The nonsteroidal antiandrogen bicalutamide has been identified as an antagonist of ZIP9. # Clinical significance Zinc homeostasis is very important in human health, because zinc is present in the structure of some proteins like zinc-dependent metalloenzymes and zinc-finger-containing transcriptional factors. In addition, zinc is involved in signalling for cell growth, proliferation, division and apoptosis. As a result, any dysfunction of zinc transporter proteins can be harmful for the cells, and some of them are associated with different cancers, diabetes and inflammation. For instance, through activation of ZIP9, testosterone has been found to increase intracellular zinc levels in breast cancer, prostate cancer, and ovarian follicle cells and to induce apoptosis in these cells, an action which may be mediated partially or fully by increased zinc concentrations. ## Gene mutations Mutations in the SLC39A9 gene can occur due to genetic deletion of the q24.1-24.3 band of base pairs within the human chromosome 14. This interstitial deletion mutation deletes the SLC39A9 gene along with 18 other genes found close to the SLC39A9 gene on chromosome 14 Although specific gene associated diseases have not been determined, the deletion of this band causes diseases such as congenital heart defects, mild intellectual disability, brachydactyly, and all patients with band deletion had hypertelorism and a broad nasal bridge. Patient specific clinical issues included ectopic organs, undescended testes, also called cryptorchidism, and malrotation of the small intestine. Deletion mutation involving the SLC39A9 gene has also been reported in 23 cases of patients with circulation related cancers such as B-cell lymphoma and B-cell chronic lymphocytic leukaemia (CLL). Chimeric genes are a result of faulty DNA replication, and arise when two or more coding sequences of the same or different chromosome combine in order to produce a single new gene. SLC39A9 forms a chimeric gene product with a gene called PLEKHD1, that codes for an intracellular protein found within the cerebellum. A study done in Seattle, USA, established the presence of the fusion protein product of the SLC39A9-PLEKHD1 gene to be present in 124 cases of schizophrenia and was closely related to the pathophysiology of disease. The fusion protein had features from both the parent genes and also possessed the ability to interact with cellular signalling pathways involving kinases such as Akt and Erk, leading to their increased phosphorylation within the brain and a consequent onset of schizophrenia. SLC39A9 gene also forms a fusion transcript with another gene called MAP3K9, that encodes for MAP3 kinase enzyme. This SLC39A9-MAP3K9 fusion gene has a repetitive occurrence in breast cancers, demonstrated by a study done on 120 primary breast cancer samples from Korean women in 2015. ## Cancer ### Breast and prostate A study in 2014, elucidated the intermediary role of ZIP9 in causing human breast and prostate cancer, as it induced the apoptosis of testosterone in breast and prostate cancerous cells. unlike ZIP1, 2 and 3, ZIP9 mRNA expression was increased in human prostate and breast malignant biopsy cancer cells, which probably was because cells that divide rapidly require more zinc. ### Brain Treatment of glioblastoma cells with TPEN showed that upregulation of ZIP9 in glioblastoma cells enhances cell migration in brain cancer by influencing P53 and GSK-3ß, and also ERK and AKT signalling pathways in phosphorylation after activation of B-cell receptors. ## Diabetes Zinc must be constantly supplied to Pancreatic β-cells to function normally and maintain glycaemic control. The insulin secretory pathway in humans is highly dependent on zinc activities. The cells lose many zinc ions during the secretion of insulin, and need to receive more zinc, and expression of ZIP9 mRNA during this process increases. As a result, ZIP9, which is involved in importing zinc into the cells, is potentially a target for therapeutic studies in the future regarding diabetes type2.

ZIP9 Zinc transporter ZIP9 also known as Zrt- and Irt-like protein 9 (ZIP9) and solute carrier family 39 member 9 (SLC39A9) is a protein that in humans is encoded by the SLC39A9 gene.[1] This protein is the 9th member out of 14 ZIP family proteins, which is a membrane androgen receptor (mAR) coupled to G proteins, and also classified as a zinc transporter protein.[1][2][3][4] ZIP family proteins transport zinc metal from the extracellular environment into cells through cell membrane.[2] # Classification and nomenclature Mammalian cells have two major groups of zinc transporter proteins; the ones that export zinc from the cytoplasm to the extracellular space (efflux), which are called ZnT (SLC30 family) , and ZIP (SLC39 family) proteins[5] whose functions are in the opposite direction (influx).[6] ZIP family proteins are named as Zrt- and Irt-like proteins because of their similarities to Zrt and Irt proteins which are respectively zinc and iron -regulated transporter proteins in yeast and Arabidopsis that were discovered earlier than ZIP and ZnT proteins.[6] ZIP family is consisted of four subfamilies (I, II, LIV-1, and gufA), and ZIP9 is the only member of subfamily I.[7] # Isoforms ZIP9 can be present as 3 different isoforms in human cells. The canonical isoform of this protein has a length of 307 amino acids, with a molecular mass of 32,251Da. In the second isoform, amino acids 135-157 are missing, so its length and molecular weight are respectively reduced to 284 amino acids and 29,931Da. In the third isoform the amino acids 233-307 are missing, so the isoform only has 232 amino acids and its molecular mass is 24,626 Da. Additionally, the last amino acid of isoform 3, which is usually serine, is replaced with aspartic acid.[8] # Discovery ZIP9 membrane androgen receptor was first discovered in Atlantic croaker (Micropogonias undulatus) brain, ovary and testicular tissues and named "AR2" in 1999, together with another androgen receptor which was found only in brain tissue, and it was named "AR1" in that time.[9] AR1 and AR2 were first thought to be nuclear androgen receptors (nAR), however, further studies on their biochemical and functional features in 2003 illustrated that they were involved in non-genomic mechanisms in the plasma membrane of the cells and were membrane androgen receptors.[10] In 2005, the similarities between the nucleotide and amino acid sequences of AR2 and ZIP family proteins were discovered in other vertebrates, suggesting that AR2 is from this family of proteins.[11] A study in 2014 utilised the latest research technologies to clone and express a particular cDNA of the female Atlantic croaker ovaries, which encoded a protein showing the characteristics of the canonical isoform of ZIP9, as a novel membrane androgen receptor(mAR).[3] # Structure Unlike other ZIP subfamilies that are consisted of 8 transmembrane (TM) domains with an extracellular C-terminal, ZIP9 is consisted of a 7 TM structure with an intracellular C-terminus.[3] ZIP9 is shorter than other ZIP proteins, and only has about 307 amino acids within its structure, however, like other ZIP proteins, between its domains III and IV, within the intracellular loop, it contains histidine-rich clusters.[3] ZIP9 and other ZIP proteins have polar or charged amino acids in their TM domains which probably play important roles in making ion transfer channels and therefore in importing zinc ions into cytoplasm.[11] # Location, expression and function ZIP9 influxes zinc ions into the cytosol and its gene is expressed almost in every tissue of human body.[4] The sub-cellular location of ZIP9 is in plasma, nucleus, endoplasmic reticulum and mitochondrial membrane.[4] One of the responsibilities of ZIP9 is the homeostasis of zinc in the secretory pathway, during which this protein stays within the Trans Golgi Network regardless of the change in the concentrations of zinc.[7] ZIP9 is the only ZIP protein that signals through G protein binding, and pharmaceutical agents decrease its ligand binding once ZIP9 is uncoupled from G proteins.[1] ZIP9 is also the only member of ZIP family with mAR characteristics.[1] # Ligands Testosterone has high affinity for ZIP9 with a Kd of 14 nM and acts as an agonist of the receptor.[1] In contrast, the other endogenous androgens dihydrotestosterone (DHT) and androstenedione show low affinity for the receptor with less than 1% of that of testosterone, although DHT is still effective in activating the receptor at sufficiently high concentrations.[1] Moreover, the synthetic androgens mibolerone and metribolone (R-1881), the endogenous androgen 11-ketotestoterone, and the other steroid hormones estradiol and cortisol are all ineffective competitors for the receptor.[1] Since mibolerone and metribolone bind to and activate the nuclear androgen receptor (AR) but not ZIP9, they could potentially be employed to differentiate between AR- and ZIP9-mediated responses of testosterone.[1] The nonsteroidal antiandrogen bicalutamide has been identified as an antagonist of ZIP9.[13] # Clinical significance Zinc homeostasis is very important in human health, because zinc is present in the structure of some proteins like zinc-dependent metalloenzymes and zinc-finger-containing transcriptional factors.[14] In addition, zinc is involved in signalling for cell growth, proliferation, division and apoptosis.[14][15] As a result, any dysfunction of zinc transporter proteins can be harmful for the cells, and some of them are associated with different cancers, diabetes and inflammation.[14] For instance, through activation of ZIP9, testosterone has been found to increase intracellular zinc levels in breast cancer, prostate cancer, and ovarian follicle cells and to induce apoptosis in these cells, an action which may be mediated partially or fully by increased zinc concentrations.[1][16] ## Gene mutations Mutations in the SLC39A9 gene can occur due to genetic deletion of the q24.1-24.3 band of base pairs within the human chromosome 14. This interstitial deletion mutation deletes the SLC39A9 gene along with 18 other genes found close to the SLC39A9 gene on chromosome 14 Although specific gene associated diseases have not been determined, the deletion of this band causes diseases such as congenital heart defects, mild intellectual disability, brachydactyly, and all patients with band deletion had hypertelorism and a broad nasal bridge. Patient specific clinical issues included ectopic organs, undescended testes, also called cryptorchidism, and malrotation of the small intestine. Deletion mutation involving the SLC39A9 gene has also been reported in 23 cases of patients with circulation related cancers such as B-cell lymphoma and B-cell chronic lymphocytic leukaemia (CLL).[17][18] Chimeric genes are a result of faulty DNA replication, and arise when two or more coding sequences of the same or different chromosome combine in order to produce a single new gene. SLC39A9 forms a chimeric gene product with a gene called PLEKHD1, that codes for an intracellular protein found within the cerebellum. A study done in Seattle, USA, established the presence of the fusion protein product of the SLC39A9-PLEKHD1 gene to be present in 124 cases of schizophrenia and was closely related to the pathophysiology of disease.[19][20] The fusion protein had features from both the parent genes and also possessed the ability to interact with cellular signalling pathways involving kinases such as Akt and Erk, leading to their increased phosphorylation within the brain and a consequent onset of schizophrenia.[19][20] SLC39A9 gene also forms a fusion transcript with another gene called MAP3K9, that encodes for MAP3 kinase enzyme. This SLC39A9-MAP3K9 fusion gene has a repetitive occurrence in breast cancers, demonstrated by a study done on 120 primary breast cancer samples from Korean women in 2015.[21][22] ## Cancer ### Breast and prostate A study in 2014, elucidated the intermediary role of ZIP9 in causing human breast and prostate cancer, as it induced the apoptosis of testosterone in breast and prostate cancerous cells.[4] unlike ZIP1, 2 and 3, ZIP9 mRNA expression was increased in human prostate and breast malignant biopsy cancer cells, which probably was because cells that divide rapidly require more zinc.[4] ### Brain Treatment of glioblastoma cells with TPEN showed that upregulation of ZIP9 in glioblastoma cells enhances cell migration in brain cancer by influencing P53 and GSK-3ß, and also ERK and AKT signalling pathways in phosphorylation after activation of B-cell receptors.[14][23] ## Diabetes Zinc must be constantly supplied to Pancreatic β-cells to function normally and maintain glycaemic control.[15] The insulin secretory pathway in humans is highly dependent on zinc activities.[24] The cells lose many zinc ions during the secretion of insulin, and need to receive more zinc, and expression of ZIP9 mRNA during this process increases.[25] As a result, ZIP9, which is involved in importing zinc into the cells, is potentially a target for therapeutic studies in the future regarding diabetes type2.[25]

https://www.wikidoc.org/index.php/ZIP9

bdeb56e8d91f8bd1405c5f8910ce78d76248adcf

wikidoc

ZW10

ZW10 Centromere/kinetochore protein zw10 homolog is a protein that in humans is encoded by the ZW10 gene. This gene encodes a protein that is one of many involved in mechanisms to ensure proper chromosome segregation during cell division. The encoded protein binds to centromeres during the prophase, metaphase, and early anaphase cell division stages and to kinetochore microtubules during metaphase. # Function Zeste white 10 (ZW10) was initially identified as a mitotic checkpoint protein involved in chromosome segregation, and then implicated in targeting cytoplasmic dynein and dynactin to mitotic kinetochores, but it is also important in non-dividing cells. These include cytoplasmic dynein targeting to Golgi and other membranes, and SNARE-mediated ER-Golgi trafficking. Dominant-negative ZW10, anti-ZW10 antibody, and ZW10 RNA interference (RNAi) cause Golgi dispersal. ZW10 RNAi also disperse endosomes and lysosomes. Drosophila kinetochore components Rough deal (Rod) and Zw10 are required for the proper functioning of the metaphase checkpoint in flies. The eukaryotic spindle assembly checkpoint (SAC) monitors microtubule attachment to kinetochores and prevents anaphase onset until all kinetochores are aligned on the metaphase plate. It is an essential surveillance mechanism that ensures high fidelity chromosome segregation during mitosis. In higher eukaryotes, cytoplasmic dynein is involved in silencing the SAC by removing the checkpoint proteins Mad2 and the Rod-Zw10-Zwilch complex (RZZ) from aligned kinetochores. # Interactions ZW10 has been shown to interact with RINT1

ZW10 Centromere/kinetochore protein zw10 homolog is a protein that in humans is encoded by the ZW10 gene.[1][2] This gene encodes a protein that is one of many involved in mechanisms to ensure proper chromosome segregation during cell division. The encoded protein binds to centromeres during the prophase, metaphase, and early anaphase cell division stages and to kinetochore microtubules during metaphase.[2] # Function Zeste white 10 (ZW10) was initially identified as a mitotic checkpoint protein involved in chromosome segregation, and then implicated in targeting cytoplasmic dynein and dynactin to mitotic kinetochores, but it is also important in non-dividing cells. These include cytoplasmic dynein targeting to Golgi and other membranes, and SNARE-mediated ER-Golgi trafficking.[3][4] Dominant-negative ZW10, anti-ZW10 antibody, and ZW10 RNA interference (RNAi) cause Golgi dispersal. ZW10 RNAi also disperse endosomes and lysosomes.[4] Drosophila kinetochore components Rough deal (Rod) and Zw10 are required for the proper functioning of the metaphase checkpoint in flies.[5] The eukaryotic spindle assembly checkpoint (SAC) monitors microtubule attachment to kinetochores and prevents anaphase onset until all kinetochores are aligned on the metaphase plate. It is an essential surveillance mechanism that ensures high fidelity chromosome segregation during mitosis. In higher eukaryotes, cytoplasmic dynein is involved in silencing the SAC by removing the checkpoint proteins Mad2 and the Rod-Zw10-Zwilch complex (RZZ) from aligned kinetochores.[6][7][8] # Interactions ZW10 has been shown to interact with RINT1[9]

https://www.wikidoc.org/index.php/ZW10

afaa1903e08f9aa91d9be36b6ab325ba3244d37c

wikidoc

ZZZ3

ZZZ3 ZZ-type zinc finger-containing protein 3 is a protein that in humans is encoded by the ZZZ3 gene. # Model organisms Model organisms have been used in the study of ZZZ3 function. A conditional knockout mouse line, called Zzz3tm1a(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 four tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and no further abnormal phenotypes were identified.

ZZZ3 ZZ-type zinc finger-containing protein 3 is a protein that in humans is encoded by the ZZZ3 gene.[1] # Model organisms Model organisms have been used in the study of ZZZ3 function. A conditional knockout mouse line, called Zzz3tm1a(EUCOMM)Wtsi[5][6] 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.[7][8][9] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[3][10] Twenty four tests were carried out on mutant mice and two significant abnormalities were observed.[3] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and no further abnormal phenotypes were identified.[3]

https://www.wikidoc.org/index.php/ZZZ3

af842e775fc78267d8c52ad5742d22d757f042e8

wikidoc

Ziac

Ziac Synonyms / Brand Names: Bisoprolol Fumarate, Bisoprolol fumerate, Bisoprolol Hemifumarate, Cardicor, Concor, Condyline, Detensiel, Emconcor, Emcor, Euradal, Isoten, Monocor, Soloc, Soprol, Zebeta # Dosing and Administration Bisoprolol is an effective treatment of hypertension in once-daily doses of 2.5 to 40 mg, while hydrochlorothiazide is effective in doses of 12.5 to 50 mg. In clinical trials of bisoprolol/hydrochlorothiazide combination therapy using bisoprolol doses of 2.5 to 20 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects increased with increasing doses of either component. FDA Package Insert Resources Indications, Contraindications, Side Effects, Drug Interactions, etc. Calculate Creatine Clearance On line calculator of your patients Cr Cl by a variety of formulas. Convert pounds to Kilograms On line calculator of your patients weight in pounds to Kg for dosing estimates. Publication Resources Recent articles, WikiDoc State of the Art Review, Textbook Information Trial Resources Ongoing Trials, Trial Results Guidelines & Evidence Based Medicine Resources US National Guidelines, Cochrane Collaboration, etc. Media Resources Slides, Video, Images, MP3, Podcasts, etc. Patient Resources Discussion Groups, Handouts, Blogs, News, etc. International Resources en Español # FDA Package Insert Resources Indications Contraindications Side Effects Drug Interactions Precautions Overdose Instructions for Administration How Supplied Pharmacokinetics and Molecular Data FDA label FDA on Ziac Return to top # Publication Resources Most Recent Articles on Ziac Review Articles on Ziac Articles on Ziac in N Eng J Med, Lancet, BMJ WikiDoc State of the Art Review Textbook Information on Ziac Return to top # Trial Resources Ongoing Trials with Ziac at Clinical Trials.gov Trial Results with Ziac Return to top # Guidelines & Evidence Based Medicine Resources US National Guidelines Clearinghouse on Ziac Cochrane Collaboration on Ziac Cost Effectiveness of Ziac Return to top # Media Resources Powerpoint Slides on Ziac Images of Ziac Podcasts & MP3s on Ziac Videos on Ziac Return to top # Patient Resources Patient Information from National Library of Medicine Patient Resources on Ziac Discussion Groups on Ziac Patient Handouts on Ziac Blogs on Ziac Ziac in the News Ziac in the Marketplace Return to top # International Resources Ziac en Español Return to top Adapted from the FDA Package Insert.

Ziac Synonyms / Brand Names: Bisoprolol Fumarate, Bisoprolol fumerate, Bisoprolol Hemifumarate, Cardicor, Concor, Condyline, Detensiel, Emconcor, Emcor, Euradal, Isoten, Monocor, Soloc, Soprol, Zebeta Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Dosing and Administration Bisoprolol is an effective treatment of hypertension in once-daily doses of 2.5 to 40 mg, while hydrochlorothiazide is effective in doses of 12.5 to 50 mg. In clinical trials of bisoprolol/hydrochlorothiazide combination therapy using bisoprolol doses of 2.5 to 20 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects increased with increasing doses of either component. FDA Package Insert Resources Indications, Contraindications, Side Effects, Drug Interactions, etc. Calculate Creatine Clearance On line calculator of your patients Cr Cl by a variety of formulas. Convert pounds to Kilograms On line calculator of your patients weight in pounds to Kg for dosing estimates. Publication Resources Recent articles, WikiDoc State of the Art Review, Textbook Information Trial Resources Ongoing Trials, Trial Results Guidelines & Evidence Based Medicine Resources US National Guidelines, Cochrane Collaboration, etc. Media Resources Slides, Video, Images, MP3, Podcasts, etc. Patient Resources Discussion Groups, Handouts, Blogs, News, etc. International Resources en Español # FDA Package Insert Resources Indications Contraindications Side Effects Drug Interactions Precautions Overdose Instructions for Administration How Supplied Pharmacokinetics and Molecular Data FDA label FDA on Ziac Return to top # Publication Resources Most Recent Articles on Ziac Review Articles on Ziac Articles on Ziac in N Eng J Med, Lancet, BMJ WikiDoc State of the Art Review Textbook Information on Ziac Return to top # Trial Resources Ongoing Trials with Ziac at Clinical Trials.gov Trial Results with Ziac Return to top # Guidelines & Evidence Based Medicine Resources US National Guidelines Clearinghouse on Ziac Cochrane Collaboration on Ziac Cost Effectiveness of Ziac Return to top # Media Resources Powerpoint Slides on Ziac Images of Ziac Podcasts & MP3s on Ziac Videos on Ziac Return to top # Patient Resources Patient Information from National Library of Medicine Patient Resources on Ziac Discussion Groups on Ziac Patient Handouts on Ziac Blogs on Ziac Ziac in the News Ziac in the Marketplace Return to top # International Resources Ziac en Español Return to top Adapted from the FDA Package Insert.

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

be45abaa5d95b84e5622411c9c1c6160b8bc6c50

wikidoc

Élan

Élan Élan Corporation plc (Template:Nyse, Template:Lse) is a major drugs firm based in Athlone, County Westmeath, Ireland which has major interests in the United States. In the late 1990's its value on the Irish Stock Exchange reached over €20bn. It has secondary listings on the London Stock Exchange and the New York Stock Exchange. It was one of Ireland's major business success stories. However in the early years of 2000's an accounting scandal and investor reactions to the global slump, caused a major devaluation resulting in a share price slump of over 90%. Since then the company has regained its growth path under the reign of a new American CEO Kelly Martin. Élan employs over 2,000 people worldwide. It is listed on the New York Stock Exchange as ELN, the Irish Stock Exchange as ELN.I, and the London Stock Exchange as ELN.L. Reformulations for client-based projects has contributed to more than $9 billion in in-market sales for these clients. Currently more than 2.5 million patients take Élan's products worldwide. # Products in development In neurology, Élan is focused on building upon its breakthrough research and extensive experience in the area of neuropathology-related disorders such as Alzheimer’s disease, where the company’s efforts include programs focused on small molecule inhibitors of beta secretase and gamma secretase, enzymes whose actions are thought to affect the accumulation of the amyloid plaques found in the brains of patients with Alzheimer’s disease. Élan is also studying other neurodegenerative diseases, such as Parkinson's disease. Élan, in collaboration with Wyeth, initiated a Phase II clinical trial for an experimental humanized monoclonal antibody with a targeted indication of immunotherapeutic treatment of mild to moderate Alzheimer’s disease. The humanized monoclonal antibody is designed and engineered to clear the neurotoxic beta-amyloid peptide that accumulates in the brains of patients with Alzheimer’s disease. Élan is hopeful that its drug "aab-001" (now known as bapineuzumab) is doing well in trials as the first results are due in 2006. In autoimmune diseases, Élan’s primary emphasis is studying cell trafficking to discover ways to provide disease-modifying therapies for autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Research efforts are also focused on physiological and neuropathic pain. ## Natalizumab/Tysabri Previously named Antegren, Natalizumab is a drug co-marketed by Biogen Idec and Élan as "Tysabri". Tysabri is a monoclonal antibody that inhibits immune cells from crossing blood vessel walls to reach various tissues, including the brain. It has proven efficacy in the treatment of two serious autoimmune disorders: multiple sclerosis, and Crohn's disease. In multiple sclerosis, Tysabri was shown to reduce relapses by 67% vs. a placebo in double-blind studies. It slowed the progression of disability by 42%. While it is impossible to compare results across different clinical trials, the older generation drugs, i.e. interferons and Copaxone, are generally acknowledged as demonstrating about a 30-35% decrease in relapse rate vs. placebo; and only two drugs have been shown to decrease the progression of disability, but again only by around 20-40%. ## NanoCrystal Technology For poorly water soluble compounds, Élan's proprietary NanoCrystal technology can enable formulation and improve compound activity and final product characteristics. The NanoCrystal technology can be incorporated into all dosage forms both parenteral and oral, including solid, liquid, fast-melt, pulsed release and controlled release dosage forms. # Drugs Products and drugs that Élan has developed include: - Avinza – once-daily, novel dual release morphine sulphate - Emend – oral table form of aprepitant, a poorly water soluble compound - Focalin XR – once-daily dexmethylphenidate marketed in US and other territories - Herbesser R – once-daily, high-potency, sustained release diltiazem for Japanese and other Asian markets - Megace ES – concentrated oral suspension utilizing NanoCrystal Technology, marketed in the U.S. - NaprÉlan - once-daily, sustained-release naproxen sodium - Rapamune - oral tablet form of poorly water soluble compound - Ritalin LA – once-daily, pulsatile release of methylphenidate - Theo-Dur - twice-daily, sustained-release theophylline - TriCor - new formulation of Abbott’s fenofibrate, which can be taken without regard to food, launched in the U.S. - VerÉlan - once-daily, sustained-release verapamil - VerÉlan PM – modified release, chronotherapeutic verapamil

Élan Élan Corporation plc (Template:Nyse, Template:Lse) is a major drugs firm based in Athlone, County Westmeath, Ireland which has major interests in the United States. In the late 1990's its value on the Irish Stock Exchange reached over €20bn. It has secondary listings on the London Stock Exchange and the New York Stock Exchange. It was one of Ireland's major business success stories. However in the early years of 2000's an accounting scandal and investor reactions to the global slump, caused a major devaluation resulting in a share price slump of over 90%. Since then the company has regained its growth path under the reign of a new American CEO Kelly Martin. Élan employs over 2,000 people worldwide. It is listed on the New York Stock Exchange as ELN, the Irish Stock Exchange as ELN.I, and the London Stock Exchange as ELN.L. Reformulations for client-based projects has contributed to more than $9 billion in in-market sales for these clients. Currently more than 2.5 million patients take Élan's products worldwide. # Products in development In neurology, Élan is focused on building upon its breakthrough research and extensive experience in the area of neuropathology-related disorders such as Alzheimer’s disease, where the company’s efforts include programs focused on small molecule inhibitors of beta secretase and gamma secretase, enzymes whose actions are thought to affect the accumulation of the amyloid plaques found in the brains of patients with Alzheimer’s disease. Élan is also studying other neurodegenerative diseases, such as Parkinson's disease. Élan, in collaboration with Wyeth, initiated a Phase II clinical trial for an experimental humanized monoclonal antibody with a targeted indication of immunotherapeutic treatment of mild to moderate Alzheimer’s disease. The humanized monoclonal antibody is designed and engineered to clear the neurotoxic beta-amyloid peptide that accumulates in the brains of patients with Alzheimer’s disease. Élan is hopeful that its drug "aab-001" (now known as bapineuzumab) is doing well in trials as the first results are due in 2006. In autoimmune diseases, Élan’s primary emphasis is studying cell trafficking to discover ways to provide disease-modifying therapies for autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Research efforts are also focused on physiological and neuropathic pain. ## Natalizumab/Tysabri Previously named Antegren, Natalizumab is a drug co-marketed by Biogen Idec and Élan as "Tysabri". Tysabri is a monoclonal antibody that inhibits immune cells from crossing blood vessel walls to reach various tissues, including the brain. It has proven efficacy in the treatment of two serious autoimmune disorders: multiple sclerosis, and Crohn's disease. In multiple sclerosis, Tysabri was shown to reduce relapses by 67% vs. a placebo in double-blind studies. It slowed the progression of disability by 42%. While it is impossible to compare results across different clinical trials, the older generation drugs, i.e. interferons and Copaxone, are generally acknowledged as demonstrating about a 30-35% decrease in relapse rate vs. placebo; and only two drugs have been shown to decrease the progression of disability, but again only by around 20-40%. ## NanoCrystal Technology For poorly water soluble compounds, Élan's proprietary NanoCrystal technology can enable formulation and improve compound activity and final product characteristics. The NanoCrystal technology can be incorporated into all dosage forms both parenteral and oral, including solid, liquid, fast-melt, pulsed release and controlled release dosage forms. # Drugs Products and drugs that Élan has developed include: - Avinza – once-daily, novel dual release morphine sulphate - Emend – oral table form of aprepitant, a poorly water soluble compound - Focalin XR – once-daily dexmethylphenidate marketed in US and other territories - Herbesser R – once-daily, high-potency, sustained release diltiazem for Japanese and other Asian markets - Megace ES – concentrated oral suspension utilizing NanoCrystal Technology, marketed in the U.S. - NaprÉlan - once-daily, sustained-release naproxen sodium - Rapamune - oral tablet form of poorly water soluble compound - Ritalin LA – once-daily, pulsatile release of methylphenidate - Theo-Dur - twice-daily, sustained-release theophylline - TriCor - new formulation of Abbott’s fenofibrate, which can be taken without regard to food, launched in the U.S. - VerÉlan - once-daily, sustained-release verapamil - VerÉlan PM – modified release, chronotherapeutic verapamil

https://www.wikidoc.org/index.php/%C3%89lan

12686f1e85cc328282196b47c23d5005cca94d47

wikidoc

PMA

PMA # Overview PMA (paramethoxyamphetamine, p-methoxyamphetamine or 4-methoxyamphetamine) is a synthetic phenethylamine drug, psychostimulant and hallucinogen. It is commonly sold as "Ecstasy" and both dealers and users are likely to be unaware that a particular batch of pills contains PMA rather than MDMA. Notable batches of pills containing PMA have included Mitsubishi Turbo or Red/Blue Mitsubishi and Yellow Euro pills. PMA is often synthesized from anethole, the flavor compound of anise and fennel, mainly because the starting material for MDMA, safrole has become less available due to law enforcement action, causing illicit drug manufacturers to use anethole as an alternative. Once thought to be a human invention , recent research suggests PMA occurs as a trace alkaloid in plants including certain Acacia species. . It is classified as a Schedule I hallucinogen under the Controlled Substances Act in the United States. Internationally, PMA is a Schedule I drug under the Convention on Psychotropic Substances . PMA has been associated with numerous adverse reactions including death. Effects of PMA ingestion include many effects of the hallucinogenic amphetamines including accelerated and irregular heartbeat, blurred vision, and a strong feeling of intoxication which is often unpleasant. While PMA can reportedly be euphoric at low doses, the dose-response curve is much steeper than that of MDMA, and at higher doses unpleasant effects such as nausea and vomiting, severe hyperthermia and hallucinations quickly overpower any pleasurable effects. The effects of PMA also seem to be much more unpredictable and variable between individuals than those of MDMA, and sensitive individuals may die from a dose of PMA that a less susceptible person might only be mildly affected by. There are approximately twice as many deaths caused by PMA as by MDMA, even though the actual proportion of PMA on the market is only a fraction of that of MDMA. While PMA alone may cause significant toxicity, the combination of PMA with MDMA has a synergistic effect which seems to be particularly hazardous. Since PMA has a slow onset of effects, several deaths have occurred where individuals have taken a pill containing PMA, followed by a pill containing MDMA some time afterwards due to thinking that the first pill was not active. It appears that PMA elevates body temperatures dramatically; the cause of this property is suspected to be related to its ability to inhibit monoamine oxidase A and at the same time releasing large amounts of serotonin, effectively causing serotonin syndrome . Amphetamines, especially serotonergic analogues such as MDMA, are strongly contraindicated to take with MAOIs. Many amphetamines and adrenergic compounds raise body temperatures; whereas some tend to produce more euphoric activity, or peripheral vasoconstriction, or tend to favor one effect over another, it appears that PMA activates the hypothalamus much more strongly than MDMA and other drugs like ephedrine, thereby causing rapid increases in body temperature (which is the major cause of death in PMA mortalities). Many people taking PMA try to get rid of the heat by taking off their clothes, taking cold showers or wrapping themselves in wet towels, and even sometimes by shaving off their hair. Because PMA is given out through the same venues and distribution channels that "Ecstasy" tablets are, the risk of being severely injured, hospitalized or even killed from use of Ecstasy increases significantly when a batch of "Ecstasy" pills containing PMA starts to be sold in a particular area. PMA pills could be a variety of colours or logos, and there is no way of knowing just from the appearance of a pill what drugs it might contain. . Due to the variations in street "Ecstasy" pills, the only way to reduce the risk of ingestion of PMA is to test any "Ecstasy" pill that is bought with a pill testing kit before it is consumed, and to monitor reported results from police or government drug testing laboratories and avoid any pills that are reported to contain PMA. Four analogues of PMA have been reported to be sold on the black market: PMMA, PMEA , 4-ETA and 4-MTA. These are the N-methyl, N-ethyl, 4-ethoxy and 4-methylthio analogues of PMA, respectively. PMMA and PMEA are reportedly weaker, more "ecstasy-like" and somewhat less dangerous than PMA itself, but can still produce nausea and hyperthermia similar to that produced by PMA, albeit at slightly higher doses. 4-ETA was briefly sold in Canada in the 1970s but little is known about it. 4-MTA however is more dangerous even than PMA and produces strong stimulant effects and intense hyperthermia, but with little euphoria, and was implicated in several deaths in the late 1990s.

PMA Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview PMA (paramethoxyamphetamine, p-methoxyamphetamine or 4-methoxyamphetamine) is a synthetic phenethylamine drug, psychostimulant and hallucinogen. It is commonly sold as "Ecstasy" and both dealers and users are likely to be unaware that a particular batch of pills contains PMA rather than MDMA.[1][2] Notable batches of pills containing PMA have included Mitsubishi Turbo or Red/Blue Mitsubishi and Yellow Euro pills.[3] PMA is often synthesized from anethole, the flavor compound of anise and fennel, mainly because the starting material for MDMA, safrole has become less available due to law enforcement action, causing illicit drug manufacturers to use anethole as an alternative.[4] Once thought to be a human invention [3], recent research suggests PMA occurs as a trace alkaloid in plants including certain Acacia species. [5]. It is classified as a Schedule I hallucinogen under the Controlled Substances Act in the United States. Internationally, PMA is a Schedule I drug under the Convention on Psychotropic Substances [4]. PMA has been associated with numerous adverse reactions including death.[6][7] Effects of PMA ingestion include many effects of the hallucinogenic amphetamines including accelerated and irregular heartbeat, blurred vision, and a strong feeling of intoxication which is often unpleasant. While PMA can reportedly be euphoric at low doses, the dose-response curve is much steeper than that of MDMA, and at higher doses unpleasant effects such as nausea and vomiting, severe hyperthermia and hallucinations quickly overpower any pleasurable effects.[8][9][10][11][12] The effects of PMA also seem to be much more unpredictable and variable between individuals than those of MDMA, and sensitive individuals may die from a dose of PMA that a less susceptible person might only be mildly affected by.[13] There are approximately twice as many deaths caused by PMA as by MDMA, even though the actual proportion of PMA on the market is only a fraction of that of MDMA. While PMA alone may cause significant toxicity, the combination of PMA with MDMA has a synergistic effect which seems to be particularly hazardous.[14] Since PMA has a slow onset of effects, several deaths have occurred where individuals have taken a pill containing PMA, followed by a pill containing MDMA some time afterwards due to thinking that the first pill was not active.[15] It appears that PMA elevates body temperatures dramatically; the cause of this property is suspected to be related to its ability to inhibit monoamine oxidase A and at the same time releasing large amounts of serotonin,[16] effectively causing serotonin syndrome [5]. Amphetamines, especially serotonergic analogues such as MDMA, are strongly contraindicated to take with MAOIs. Many amphetamines and adrenergic compounds raise body temperatures; whereas some tend to produce more euphoric activity, or peripheral vasoconstriction, or tend to favor one effect over another, it appears that PMA activates the hypothalamus much more strongly than MDMA and other drugs like ephedrine, thereby causing rapid increases in body temperature (which is the major cause of death in PMA mortalities).[17][18][19] Many people taking PMA try to get rid of the heat by taking off their clothes, taking cold showers or wrapping themselves in wet towels, and even sometimes by shaving off their hair.[20] Because PMA is given out through the same venues and distribution channels that "Ecstasy" tablets are, the risk of being severely injured, hospitalized or even killed from use of Ecstasy increases significantly when a batch of "Ecstasy" pills containing PMA starts to be sold in a particular area.[21] PMA pills could be a variety of colours or logos, and there is no way of knowing just from the appearance of a pill what drugs it might contain. [6][7]. Due to the variations in street "Ecstasy" pills, the only way to reduce the risk of ingestion of PMA is to test any "Ecstasy" pill that is bought with a pill testing kit before it is consumed, and to monitor reported results from police or government drug testing laboratories and avoid any pills that are reported to contain PMA. Four analogues of PMA have been reported to be sold on the black market: PMMA, PMEA[22] , 4-ETA and 4-MTA. These are the N-methyl, N-ethyl, 4-ethoxy and 4-methylthio analogues of PMA, respectively. PMMA and PMEA are reportedly weaker, more "ecstasy-like" and somewhat less dangerous than PMA itself, but can still produce nausea and hyperthermia similar to that produced by PMA, albeit at slightly higher doses. 4-ETA was briefly sold in Canada in the 1970s but little is known about it. [23] 4-MTA however is more dangerous even than PMA and produces strong stimulant effects and intense hyperthermia, but with little euphoria, and was implicated in several deaths in the late 1990s.

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

6944b232594d59669be40d8d942e4dc4d0b367b7

wikidoc

68W

68W # Overview 68W (often pronounced as 6 8 Whiskey using the phonetic alphabet) is the Military Occupational Specialty (MOS) for the United States Army's healthcare specialist, also known as the combat medic. # Description The main role of the 68W in the United States Army is to provide medical treatment to wounded soldiers. Whiskeys are staples in the functionality of the US Army, as every squad is required to have a whiskey in attendance when going on any hazardous mission. They are found in every stage of medical treatment in a combat zone. Whiskeys initiate medical treatment at the accident or injury location, maintain medical treatment during evacuation to healthcare facilities, and provide medical tratment in the medical facilities themselves. 68W10s are highly trained to perform medical duties in hazardous and challenging atmospheres. 68Ws work alongside Army PAs, or doctors under their respective jurisdiction and licensure. Their work can range from the administration of immunizations and collection of fluid samples to obtaining vitals and initial information from patients/casualties and treating trauma to surgical assistance and suturing. The 68W, oft times, must work in the absence of medical professionals or healthcare providers through BLS (Basic Life Support) monitoring and maintenance. The 68W health care specialist will and can also work as the senior enlisted person in a clinical setting, as well as the Platoon Sergeant of a medical platoon in field units. As senior personnel, the 68W will have various collateral assignments that must be performed, such as daily, monthly, annual training and counseling sessions for soldiers to better help them in assisting with the treatment and education of patients who visit the clinic along with self improvement. There are constant expansions initiated to the 68W MOS in order to improve the capabilities of the healthcare specialist. Currently, the only civilian equivalent for 68Ws is Emergency Medical Technician - Basic, or upon completion of courses prescribed through MSU (Mountain State University), they may receive an Associate's Degree in medical assisting. There are educational programs at some universities which offer a technical degree in the Emergency Medical Sciences, and allow the 68W to grow in the medical field. Many 68Ws go on to become Physician Assistants, Nurse Practitioners, Registered Nurses, Doctors, and Healthcare Administrators with extra training through continuing their education. # Skill Levels - 1 is the basic entry level Combat medic (e.g. 68W10) - 2 is a combat medic with the rank of Sergeant (E-5) - 3 is a combat medic with the rank of Staff Sergeant (E-6) - 4 is a combat medic with the rank of Sergeant First Class (E-7) - 5 is a combat medic with the rank of Master Sergeant/First Sergeant (E-8) or Sergeant Major (E-9) # Skill Identifiers - F6 is an Army Flight Medic - M6 is the Army's Licensed Practical Nurse - P6 is an orthopedics specialist (clinical) - Y8 is an immunization-allergy specialist (clinical, lab) - N3 is the Army's Occupational Therapy Assistant (clinical) - N9 is a physical therapy technician (clinical) - Y2 is the code used to identify those who have not finished the upgrade classes. - W1 is a special operations combat medic (SOCM) - P3 is an optometry specialist (clinical) - Y6 is a cardiovascular specialist (Cardiac Catheterization Technologist and Echocardiographer) # History Recently known as 91W, the MOS was changed effective October 1, 2006. Formerly known by the MOS codes 91B (9 1 Bravo) and 91A (91 Alpha). The Department of the Army Deputy Chief of Staff for Personnel issued a notice for future change for the MOS 91B&C in September 1999. This notice established the transition to 91W to begin on 1 October 2001 and end on 30 September 2007. During this period all 91B&C will be given the identifier of Y2 until they complete the transition to 68W. To complete their transition to 68W many 91B&C must complete EMT-B which was offered but never required for any medic until now. Failure to conform to these standards has resulted in some medics having to reclassify into another MOS. # Training Upon the completion of their basic training, future 68W10s are shipped to Fort Sam Houston where they undergo Advanced Individual Training (AIT) for 16 to 68 weeks, depending on their identifier training time. During these weeks, soldiers will attend many courses that teach them the various medical tasks that they require in their military career. To maintain their MOS they must also obtain and maintain an EMT, and CPR certification. To provide the necessary hours for their re-certification many medics go through extensive ongoing training for the rest of their military career. As with any medical career or profession, the medical personnel must be willing to be educated throughout their career which may consist of many hours of research. In addition to skills taught at the AIT level, 68W's may, at the request of their unit's Physician's Assistant (PA), attend any number of requested advanced topics. These topic are generally prescribed per each units functional role. For example a front line combat medic (aka "line medic") may learn about advanced trauma treatments including venous cutdowns, placement of chest tubes, or use of specialty hemorrhage control methods such as Chitosan patches or "Quikclot". In the case of those attached to medical units, they may learn and administer medications which result in more definitive treatment than their civilian counterparts are allowed to. Unknown to most, field hospital units don't usually have a large amount if any 68WM6 (LPN) so they use the combat medic who is readily available and partially trained. Hopefully the future will allow for an independent duty medical team or personnel to conduct operations in the absence of qualified health care providers. In order to take their training to the next level many medics opt to become EMT-I or EMT-P certified. The Army also has a IPAP which is oriented toward helping medics become PAs through a two year school program. And yet fewer medics choose to become 18D which is the Special Forces Medical Sergeant, these medics are required to become EMT-P. Some medics choose to enter special operations through the Special Operations Combat Medic (SOCM) course and are awarded additional skill identifier "W1". SOCM-qualified 68W personnel serve in the 75th Ranger Regiment (Ranger Medic), 160th Special Operations Aviation Regiment (SOAR Flight Medic), 96th Civil Affairs Battalion (CA-Med SGT), Special Operations Support Command, and in support positions of the special forces groups. The SOCM 68W is currently the most independent-duty enlisted medical personnel in the CMF 68 field. SOCM medics work relatively independent through specific protocols in a limited scope of practice that may be enhanced during the complete absence of a medical officer. SOCM medics assigned to special operations units attend unique advanced medical and military training to enhance their interoperability with other special operations soldiers. - EMT Basic - ATLS - BTLS/PHTLS - Trauma-AIMS # Responsibilities - Provide cover fire to incapacitate an enemy - Accompany every patrol to provide immediate medical coverage for all soldiers in combat - Initial stabilizing treatment and triage - Plan and conduct Evacuation from the field of battle and en route life support - Preventive medicine - Field sanitation - Clinical medicine - Supportive Care in the event of delayed transport - Plan and Provide instructions for unit Combat Lifesaver programs ## Plan and conduct Combat Lifesaver training CLS (combat lifesaver) trained soldiers are non medic soldiers in their unit (such as infantrymen or engineers) who receive moderate amounts of extra emergency medical training in order to provide point of wounding care and to act as a link between "buddy aid" and the standard Combat Medic. The 68W trains the Combat Lifesaver. Combat lifesaver skills are exactly that, for use in combat conditions. However, skills may be applied in non-combat conditions where soldiers are concerned. The combat lifesaver is instructed in various techniques to treat and stabilize injuries related to combat. To include, but not limited to, blast injury, amputation, severe bleeding, penetrating chest injuries, simple airway management, and evacuation techniques. The combat lifesaver doctrine was developed as an effort to increase survivability in combat environments where the combat medic may not be readily available. The combat lifesaver is a bridge between self aid or buddy aid and the combat medic. The combat lifesaver can augment the combat medic as the situation necessitates. ## Skills of the Combat Lifesaver - Basic casualty evaluation - Airway management - Chest injury and tension pneumothorax management - Controlling Bleeding - Intravenous Drip therapy - Requesting medical evacuation

68W # Overview 68W (often pronounced as 6 8 Whiskey using the phonetic alphabet) is the Military Occupational Specialty (MOS) for the United States Army's healthcare specialist, also known as the combat medic. # Description The main role of the 68W in the United States Army is to provide medical treatment to wounded soldiers. Whiskeys are staples in the functionality of the US Army, as every squad is required to have a whiskey in attendance when going on any hazardous mission. They are found in every stage of medical treatment in a combat zone. Whiskeys initiate medical treatment at the accident or injury location, maintain medical treatment during evacuation to healthcare facilities, and provide medical tratment in the medical facilities themselves. 68W10s are highly trained to perform medical duties in hazardous and challenging atmospheres. 68Ws work alongside Army PAs, or doctors under their respective jurisdiction and licensure. Their work can range from the administration of immunizations and collection of fluid samples to obtaining vitals and initial information from patients/casualties and treating trauma to surgical assistance and suturing. The 68W, oft times, must work in the absence of medical professionals or healthcare providers through BLS (Basic Life Support) monitoring and maintenance. The 68W health care specialist will and can also work as the senior enlisted person in a clinical setting, as well as the Platoon Sergeant of a medical platoon in field units. As senior personnel, the 68W will have various collateral assignments that must be performed, such as daily, monthly, annual training and counseling sessions for soldiers to better help them in assisting with the treatment and education of patients who visit the clinic along with self improvement. There are constant expansions initiated to the 68W MOS in order to improve the capabilities of the healthcare specialist. Currently, the only civilian equivalent for 68Ws is Emergency Medical Technician - Basic, or upon completion of courses prescribed through MSU (Mountain State University), they may receive an Associate's Degree in medical assisting. There are educational programs at some universities which offer a technical degree in the Emergency Medical Sciences, and allow the 68W to grow in the medical field. Many 68Ws go on to become Physician Assistants, Nurse Practitioners, Registered Nurses, Doctors, and Healthcare Administrators with extra training through continuing their education. # Skill Levels - 1 is the basic entry level Combat medic (e.g. 68W10) - 2 is a combat medic with the rank of Sergeant (E-5) - 3 is a combat medic with the rank of Staff Sergeant (E-6) - 4 is a combat medic with the rank of Sergeant First Class (E-7) - 5 is a combat medic with the rank of Master Sergeant/First Sergeant (E-8) or Sergeant Major (E-9) # Skill Identifiers - F6 is an Army Flight Medic - M6 is the Army's Licensed Practical Nurse - P6 is an orthopedics specialist (clinical) - Y8 is an immunization-allergy specialist (clinical, lab) - N3 is the Army's Occupational Therapy Assistant (clinical) - N9 is a physical therapy technician (clinical) - Y2 is the code used to identify those who have not finished the upgrade classes. - W1 is a special operations combat medic (SOCM) - P3 is an optometry specialist (clinical) - Y6 is a cardiovascular specialist (Cardiac Catheterization Technologist and Echocardiographer) # History Recently known as 91W, the MOS was changed effective October 1, 2006. Formerly known by the MOS codes 91B (9 1 Bravo) and 91A (91 Alpha). The Department of the Army Deputy Chief of Staff for Personnel issued a notice for future change for the MOS 91B&C in September 1999. This notice established the transition to 91W to begin on 1 October 2001 and end on 30 September 2007. During this period all 91B&C will be given the identifier of Y2 until they complete the transition to 68W. To complete their transition to 68W many 91B&C must complete EMT-B which was offered but never required for any medic until now. Failure to conform to these standards has resulted in some medics having to reclassify into another MOS. # Training Upon the completion of their basic training, future 68W10s are shipped to Fort Sam Houston where they undergo Advanced Individual Training (AIT) for 16 to 68 weeks, depending on their identifier training time. During these weeks, soldiers will attend many courses that teach them the various medical tasks that they require in their military career. To maintain their MOS they must also obtain and maintain an EMT, and CPR certification. To provide the necessary hours for their re-certification many medics go through extensive ongoing training for the rest of their military career. As with any medical career or profession, the medical personnel must be willing to be educated throughout their career which may consist of many hours of research. In addition to skills taught at the AIT level, 68W's may, at the request of their unit's Physician's Assistant (PA), attend any number of requested advanced topics. These topic are generally prescribed per each units functional role. For example a front line combat medic (aka "line medic") may learn about advanced trauma treatments including venous cutdowns, placement of chest tubes, or use of specialty hemorrhage control methods such as Chitosan patches or "Quikclot". In the case of those attached to medical units, they may learn and administer medications which result in more definitive treatment than their civilian counterparts are allowed to. Unknown to most, field hospital units don't usually have a large amount if any 68WM6 (LPN) so they use the combat medic who is readily available and partially trained. Hopefully the future will allow for an independent duty medical team or personnel to conduct operations in the absence of qualified health care providers. In order to take their training to the next level many medics opt to become EMT-I or EMT-P certified. The Army also has a IPAP which is oriented toward helping medics become PAs through a two year school program. And yet fewer medics choose to become 18D which is the Special Forces Medical Sergeant, these medics are required to become EMT-P. Some medics choose to enter special operations through the Special Operations Combat Medic (SOCM) course and are awarded additional skill identifier "W1". SOCM-qualified 68W personnel serve in the 75th Ranger Regiment (Ranger Medic), 160th Special Operations Aviation Regiment (SOAR Flight Medic), 96th Civil Affairs Battalion (CA-Med SGT), Special Operations Support Command, and in support positions of the special forces groups. The SOCM 68W is currently the most independent-duty enlisted medical personnel in the CMF 68 field. SOCM medics work relatively independent through specific protocols in a limited scope of practice that may be enhanced during the complete absence of a medical officer. SOCM medics assigned to special operations units attend unique advanced medical and military training to enhance their interoperability with other special operations soldiers. - EMT Basic - ATLS - BTLS/PHTLS - Trauma-AIMS # Responsibilities - Provide cover fire to incapacitate an enemy - Accompany every patrol to provide immediate medical coverage for all soldiers in combat - Initial stabilizing treatment and triage - Plan and conduct Evacuation from the field of battle and en route life support - Preventive medicine - Field sanitation - Clinical medicine - Supportive Care in the event of delayed transport - Plan and Provide instructions for unit Combat Lifesaver programs ## Plan and conduct Combat Lifesaver training CLS (combat lifesaver) trained soldiers are non medic soldiers in their unit (such as infantrymen or engineers) who receive moderate amounts of extra emergency medical training in order to provide point of wounding care and to act as a link between "buddy aid" and the standard Combat Medic. The 68W trains the Combat Lifesaver. Combat lifesaver skills are exactly that, for use in combat conditions. However, skills may be applied in non-combat conditions where soldiers are concerned. The combat lifesaver is instructed in various techniques to treat and stabilize injuries related to combat. To include, but not limited to, blast injury, amputation, severe bleeding, penetrating chest injuries, simple airway management, and evacuation techniques. The combat lifesaver doctrine was developed as an effort to increase survivability in combat environments where the combat medic may not be readily available. The combat lifesaver is a bridge between self aid or buddy aid and the combat medic. The combat lifesaver can augment the combat medic as the situation necessitates. ## Skills of the Combat Lifesaver - Basic casualty evaluation - Airway management - Chest injury and tension pneumothorax management - Controlling Bleeding - Intravenous Drip therapy - Requesting medical evacuation

https://www.wikidoc.org/index.php/68W

3dfdf72fd0182b424daebda9cd25b9f8374e9fa3

wikidoc

AK2

AK2 Adenylate kinase 2 is an enzyme that is encoded in humans by the AK2 gene. The AK2 protein is found in the intermembrane space of the mitochondrion. # Function Adenylate kinases are involved in regulating the adenine nucleotide composition within a cell by catalyzing the reversible transfer of phosphate groups among adenine nucleotides. Three isozymes of adenylate kinase, namely 1, 2, and 3, have been identified in vertebrates; this gene encodes isozyme 2. Expression of these isozymes is tissue-specific and developmentally regulated. Isozyme 2 is localized in the mitochondrial intermembrane space and may play a role in apoptosis. Two transcript variants encoding distinct isoforms have been identified for this gene. ## AK2 deficiency Adenylate Kinase 2 (AK2) deficiency in humans causes hematopoietic defects associated with sensorineural deafness. Recticular dysgenesis is an autosomal recessive form of human combined immunodeficiency. It is also characterized by an impaired lymphoid maturation and early differentiation arrest in the myeloid lineage. AK2 deficiency results in absent or a large decrease in the expression of proteins. AK2 is specifically expressed in the stria vascularis of the inner ear which indicates why individuals with an AK2 deficiency will have sensorineural deafness.

AK2 Adenylate kinase 2 is an enzyme that is encoded in humans by the AK2 gene.[1][2][3] The AK2 protein is found in the intermembrane space of the mitochondrion.[4][5] # Function Adenylate kinases are involved in regulating the adenine nucleotide composition within a cell by catalyzing the reversible transfer of phosphate groups among adenine nucleotides. Three isozymes of adenylate kinase, namely 1, 2, and 3, have been identified in vertebrates; this gene encodes isozyme 2. Expression of these isozymes is tissue-specific and developmentally regulated. Isozyme 2 is localized in the mitochondrial intermembrane space and may play a role in apoptosis. Two transcript variants encoding distinct isoforms have been identified for this gene.[3] ## AK2 deficiency Adenylate Kinase 2 (AK2) deficiency in humans causes hematopoietic defects associated with sensorineural deafness.[6][7] Recticular dysgenesis is an autosomal recessive form of human combined immunodeficiency. It is also characterized by an impaired lymphoid maturation and early differentiation arrest in the myeloid lineage. AK2 deficiency results in absent or a large decrease in the expression of proteins. AK2 is specifically expressed in the stria vascularis of the inner ear which indicates why individuals with an AK2 deficiency will have sensorineural deafness.[7]

https://www.wikidoc.org/index.php/AK2

e42aed4837996ec2dda00f03441d6c0779d29191

wikidoc

AKT

AKT # Overview Akt1, also known as "Akt" or protein kinase B (PKB) is an important molecule in mammalian cellular signaling. # AKT family: AKT1, AKT2, AKT3 In humans, there are three genes in the "Akt family": Akt1, Akt2, and Akt3. These enzymes are members of the serine/threonine-specific protein kinase family (EC 2.7.11.1). Akt1 is involved in cellular survival pathways, by inhibiting apoptotic processes. Akt1 is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Akt1 has been implicated as a major factor in many types of cancer. Akt (now also called Akt1) was originally identified as the oncogene in the transforming retrovirus, AKT8 by Dr. Philip Tsichlis at Fox Chase Cancer Center in the 1990's. Akt2 is an important signaling molecule in the Insulin signaling pathway. It is required to induce glucose transport. These separate roles for Akt1 and Akt2 were demonstrated by studying mice in which either the Akt1 or the Akt2 gene was deleted, or "knocked out". In a mouse which is null for Akt1 but normal for Akt2, glucose homeostasis is unperturbed, but the animals are smaller, consistent with a role for Akt1 in growth. In contrast, mice which do not have Akt2, but have normal Akt1, have mild growth deficiency and display a diabetic phenotype (insulin resistance), again consistent with the idea that Akt2 is more specific for the insulin receptor signaling pathway . The role of Akt3 is less clear, though it appears to be predominantly expressed in brain. It has been reported that mice lacking Akt3 have small brains . The name Akt does not refer to its function. Presumably, the "Ak" in Akt was a temporary classification name for a mouse strain developing spontaneous thymic lymphomas. The "t" stands for 'transforming', the letter was added when a transforming retrovirus was isolated from the Ak strain, which was termed "Akt-8". When the oncogene encoded in this virus was discovered, it was termed v-Akt. Thus, the later identified human analogues were named accordingly. # Regulation: Activation and Inactivation of Akt ## Binding phospho-lipids in the membrane Akt possesses a protein domain known as a PH domain, or Pleckstrin Homology domain, named after Pleckstrin, the protein in which it was first discovered. This domain binds to phosphoinositides with high affinity. In the case of the PH domain of Akt, it binds either phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3 aka PIP3) or phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)P2 aka PI(3,4)P2). This is useful for control of cellular signaling because the di-phosphorylated phosphoinositide PtdIns(4,5)P2 is only phosphorylated by the family of enzymes, PI 3-kinases (phosphoinositide 3-kinase or PI3K), and only upon receipt of chemical messengers which tell the cell to begin the growth process. For example, PI 3-kinases may be activated by a G protein coupled receptor or receptor tyrosine kinase such as the insulin receptor. Once activated, PI 3-kinases phosphorylates PtdIns(4,5)P2 to form PtdIns(3,4,5)P3. ## Phosphorylation by PDK1 and PDK2 Once correctly positioned in the membrane via binding of PIP3, Akt can then be phosphorylated by its activating kinases, phosphoinositide dependent kinase 1 (PDK1) and mTORC2. First, the mammalian target of rapamycin complex 2 (mTORC2) phosphorylates Akt; mTORC2 therefore functionally acts as the long-sought PDK2 molecule, although other molecules, including Integrin-Linked Kinase (ILK) and Mitogen-Activated Protein Kinase Activated Kinase-2 (MAPKAPK2) can also serve as PDK2. Phosphorylation by mTORC2 stimulates the subsequent phosphorylation of Akt by PDK1. Activated Akt can then go on to activate or deactivate its myriad substrates via its kinase activity. See this link for a more thorough and detailed image of the Akt signaling pathway. Besides being a downstream effector of PI 3-kinases, Akt may also be activated in a PI 3-kinase-independent manner. Studies have suggested that cAMP-elevating agents could activate Akt through protein kinase A (PKA), although these studies are disputed and the mechanism of action is unclear. ## Lipid phosphatases control the amount of PIP3, thereby modulating the ability of Akt to be activated PI3K dependent Akt activation can be regulated through the tumor suppressor PTEN, which works essentially as the opposite of PI3K mentioned above (PTEN and PI3K). PTEN acts as a phosphatase to dephosphorylate PtdIns(3,4,5)P3 back to PtdIns(4,5)P2. This removes the membrane-localization factor from the Akt signaling pathway. Without this localization, the rate of Akt activation decreases significantly, as do the all the downstream pathways that depend on Akt for activation. PIP3 can also be de-phosphorylated at the "5" position by the SHIP family of inositol phosphatases, SHIP1 and SHIP2. These poly-phosphate inositil phosphatases dephosphorylate PtdIns(3,4,5)P3 to form PtdIns(3,4)P2. ## Protein phosphatases control the amount of phosphorylated Akt The phosphatases in the PHLPP family, PHLPP1 and PHLPP2 have been shown to directly de-phosphorylate, and therefore inactivate, distinct Akt isoforms. PHLPP2 dephosphorylates Akt1 and Akt3, whereas PHLPP1 is specific for Akt 2 and Akt3. # Functions Akt regulate the cellular survival and metabolism by binding and regulating many downstream effectors, e.g. Nuclear Factor-κB, Bcl-2 family proteins and murine double minute 2 (MDM2). Akt could promote growth factor-mediated cell survival both directly and indirectly. BAD is a pro-apoptotic protein of the Bcl-2 family. Akt could phosphorylate BAD on Ser136 (BAD phosphorylation by Akt), which makes BAD dissociate from the Bcl-2/Bcl-X complex and lose the pro-apoptotic function (BAD interaction with Bcl-2). Akt could also activate NF-κB via regulating IκB kinase (IKK), thus result in transcription of pro-survival genes (regulation of NF-kB). Akt is required for the insulin-induced translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Glycogen synthase kinase 3 (GSK-3) could be inhibited upon phosphorylation by Akt, which results in promotion of glycogen synthesis. It's worthy to note that GSK3 is also involved in Wnt signaling cascade, so Akt might be also implicated in the Wnt pathway. Still unknown role in HCV induced steatosis. Akt1 has also been implicated in angiogenesis and tumor development. Deficiency of Akt1 in mice although inhibited physiological angiogenesis, it enhanced pathological angiogenesis and tumor growth associated with matrix abnormalities in skin and blood vessels ,

AKT # Overview Akt1, also known as "Akt" or protein kinase B (PKB) is an important molecule in mammalian cellular signaling. # AKT family: AKT1, AKT2, AKT3 In humans, there are three genes in the "Akt family": Akt1, Akt2, and Akt3. These enzymes are members of the serine/threonine-specific protein kinase family (EC 2.7.11.1). Akt1 is involved in cellular survival pathways, by inhibiting apoptotic processes. Akt1 is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Akt1 has been implicated as a major factor in many types of cancer. Akt (now also called Akt1) was originally identified as the oncogene in the transforming retrovirus, AKT8 by Dr. Philip Tsichlis at Fox Chase Cancer Center in the 1990's. Akt2 is an important signaling molecule in the Insulin signaling pathway. It is required to induce glucose transport. These separate roles for Akt1 and Akt2 were demonstrated by studying mice in which either the Akt1 or the Akt2 gene was deleted, or "knocked out". In a mouse which is null for Akt1 but normal for Akt2, glucose homeostasis is unperturbed, but the animals are smaller, consistent with a role for Akt1 in growth. In contrast, mice which do not have Akt2, but have normal Akt1, have mild growth deficiency and display a diabetic phenotype (insulin resistance), again consistent with the idea that Akt2 is more specific for the insulin receptor signaling pathway [1]. The role of Akt3 is less clear, though it appears to be predominantly expressed in brain. It has been reported that mice lacking Akt3 have small brains [2]. The name Akt does not refer to its function. Presumably, the "Ak" in Akt was a temporary classification name for a mouse strain developing spontaneous thymic lymphomas. The "t" stands for 'transforming', the letter was added when a transforming retrovirus was isolated from the Ak strain, which was termed "Akt-8". When the oncogene encoded in this virus was discovered, it was termed v-Akt. Thus, the later identified human analogues were named accordingly. # Regulation: Activation and Inactivation of Akt ## Binding phospho-lipids in the membrane Akt possesses a protein domain known as a PH domain, or Pleckstrin Homology domain, named after Pleckstrin, the protein in which it was first discovered. This domain binds to phosphoinositides with high affinity. In the case of the PH domain of Akt, it binds either phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3 aka PIP3) or phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)P2 aka PI(3,4)P2). This is useful for control of cellular signaling because the di-phosphorylated phosphoinositide PtdIns(4,5)P2 is only phosphorylated by the family of enzymes, PI 3-kinases (phosphoinositide 3-kinase or PI3K), and only upon receipt of chemical messengers which tell the cell to begin the growth process. For example, PI 3-kinases may be activated by a G protein coupled receptor or receptor tyrosine kinase such as the insulin receptor. Once activated, PI 3-kinases phosphorylates PtdIns(4,5)P2 to form PtdIns(3,4,5)P3. ## Phosphorylation by PDK1 and PDK2 Once correctly positioned in the membrane via binding of PIP3, Akt can then be phosphorylated by its activating kinases, phosphoinositide dependent kinase 1 (PDK1) and mTORC2. First, the mammalian target of rapamycin complex 2 (mTORC2) phosphorylates Akt; mTORC2 therefore functionally acts as the long-sought PDK2 molecule, although other molecules, including Integrin-Linked Kinase (ILK) and Mitogen-Activated Protein Kinase Activated Kinase-2 (MAPKAPK2) can also serve as PDK2. Phosphorylation by mTORC2 stimulates the subsequent phosphorylation of Akt by PDK1. Activated Akt can then go on to activate or deactivate its myriad substrates via its kinase activity. See this link for a more thorough and detailed image of the Akt signaling pathway. Besides being a downstream effector of PI 3-kinases, Akt may also be activated in a PI 3-kinase-independent manner. Studies have suggested that cAMP-elevating agents could activate Akt through protein kinase A (PKA), although these studies are disputed and the mechanism of action is unclear. ## Lipid phosphatases control the amount of PIP3, thereby modulating the ability of Akt to be activated PI3K dependent Akt activation can be regulated through the tumor suppressor PTEN, which works essentially as the opposite of PI3K mentioned above (PTEN and PI3K). PTEN acts as a phosphatase to dephosphorylate PtdIns(3,4,5)P3 back to PtdIns(4,5)P2. This removes the membrane-localization factor from the Akt signaling pathway. Without this localization, the rate of Akt activation decreases significantly, as do the all the downstream pathways that depend on Akt for activation. PIP3 can also be de-phosphorylated at the "5" position by the SHIP family of inositol phosphatases, SHIP1 and SHIP2. These poly-phosphate inositil phosphatases dephosphorylate PtdIns(3,4,5)P3 to form PtdIns(3,4)P2. ## Protein phosphatases control the amount of phosphorylated Akt The phosphatases in the PHLPP family, PHLPP1 and PHLPP2 have been shown to directly de-phosphorylate, and therefore inactivate, distinct Akt isoforms. PHLPP2 dephosphorylates Akt1 and Akt3, whereas PHLPP1 is specific for Akt 2 and Akt3. # Functions Akt regulate the cellular survival [3] and metabolism by binding and regulating many downstream effectors, e.g. Nuclear Factor-κB, Bcl-2 family proteins and murine double minute 2 (MDM2). Akt could promote growth factor-mediated cell survival both directly and indirectly. BAD is a pro-apoptotic protein of the Bcl-2 family. Akt could phosphorylate BAD on Ser136 (BAD phosphorylation by Akt), which makes BAD dissociate from the Bcl-2/Bcl-X complex and lose the pro-apoptotic function (BAD interaction with Bcl-2). Akt could also activate NF-κB via regulating IκB kinase (IKK), thus result in transcription of pro-survival genes (regulation of NF-kB). Akt is required for the insulin-induced translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Glycogen synthase kinase 3 (GSK-3) could be inhibited upon phosphorylation by Akt, which results in promotion of glycogen synthesis. It's worthy to note that GSK3 is also involved in Wnt signaling cascade, so Akt might be also implicated in the Wnt pathway. Still unknown role in HCV induced steatosis. Akt1 has also been implicated in angiogenesis and tumor development. Deficiency of Akt1 in mice although inhibited physiological angiogenesis, it enhanced pathological angiogenesis and tumor growth associated with matrix abnormalities in skin and blood vessels [4],[5]

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

f3cc4a384a213d9efcae75b1b297cb49db379e05

wikidoc

APC

APC Apc may refer to: - Apc, Hungary, a village in the Heves county of Hungary APC may also refer to: - APC (gene), a human gene that is classified as a tumor suppressor gene - Activated protein C, a protein involved in blood coagulation - Allophycocyanin, a protein from the light-harvesting phycobiliprotein family - Allylpalladium chloride dimer, a chemical compound - Anaphase-promoting complex, a complex of several proteins which is activated during mitosis to initiate anaphase - Antigen-presenting cell, a cell that displays foreign antigen complexed with MHC on its surface # Clinical Trials - Adenoma Prevention With Celecoxib - A Perfect Circle, an alternative rock band - American Presbyterian Church, a small Reformed Christian denomination in the United States formed in 1979 - Associated Presbyterian Churches, a small Scottish Christian denomination - Armour-piercing capped, a category of anti-tank shell that has a soft metal cap on the penetrating nose - Armoured personnel carrier, an armoured fighting vehicle developed to transport infantry on the battlefield - Average propensity to consume, the proportion of income spent. - All People's Congress, a political party of Sierra Leone - Alternate Playing Cost, a cost to play a spell in the game Magic: The Gathering that is an alternative to the mana cost in the upper right hand corner of the card - American Pie Council, the only organization committed to preserving America's pie heritage - American Plastics Council, a major trade association for the U.S. plastics industry - Animal Procedures Committee, a public body and task force of the United Kingdom government - Anti-Poverty Committee, a direct action organization in Vancouver, Canada. - Arab Potash Company in Jordan - Archaeogeophysical Pseudotechnical Consultant, a consultant who utilizes archaeogeophysical pseudotechnical "black box" methods in geoarchaeological site investigations - Arrangers' Publishing Company, a sheet music publishing company in the United States. - Asia Pacific College, a non-profit joint-venture between IBM Philippines and the SM Foundation - Association for Progressive Communications, an international network of organizations that was founded in 1990 to provide communication infrastructure - Attoparsec, an unusual unit of measurement - Australian Press Council, the self-regulatory body of the Australian print media - Australian Provincial Championship, a rugby union competition in Australia - Napa County Airport, California, United States, from its IATA airport code - Armed Proletarians for Communism, an Italian far-left terrorist group of the 1970s. - Argon plasma coagulation, an endoscopic technique for controlling hemorrhage - Adaptive predictive coding, a narrowband analog-to-digital conversion that uses a one-level or multilevel sampling system - Advanced process control, a broad term within the control theory - Alternative PHP Cache, a PHP accelerator program - American Power Conversion, a company with a worldwide presence based in West Kingston, Rhode Island - APC-7 connector, a high grade sexless, 7 mm, coaxial connector used for high frequency applications up to 18 GHz - Application Program Command, a control code; see C0 and C1 control codes - aPOCALYPSE pRODUCTION cREW, a major MP3 warez organization founded by two individuals known under the pseudonyms acid^rain and Viper in May of 1997 - Australian Personal Computer, a computer magazine in Australia - Automatic Performance Control, a system that was introduced on turbo charged Saab H engines in 1982 de:APC ko:APC it:APC nl:APC sv:APC

APC Template:TOCright Apc may refer to: - Apc, Hungary, a village in the Heves county of Hungary APC may also refer to: - APC (gene), a human gene that is classified as a tumor suppressor gene - Activated protein C, a protein involved in blood coagulation - Allophycocyanin, a protein from the light-harvesting phycobiliprotein family - Allylpalladium chloride dimer, a chemical compound - Anaphase-promoting complex, a complex of several proteins which is activated during mitosis to initiate anaphase - Antigen-presenting cell, a cell that displays foreign antigen complexed with MHC on its surface ### Clinical Trials - Adenoma Prevention With Celecoxib - A Perfect Circle, an alternative rock band - American Presbyterian Church, a small Reformed Christian denomination in the United States formed in 1979 - Associated Presbyterian Churches, a small Scottish Christian denomination - Armour-piercing capped, a category of anti-tank shell that has a soft metal cap on the penetrating nose - Armoured personnel carrier, an armoured fighting vehicle developed to transport infantry on the battlefield - Average propensity to consume, the proportion of income spent. - All People's Congress, a political party of Sierra Leone - Alternate Playing Cost, a cost to play a spell in the game Magic: The Gathering that is an alternative to the mana cost in the upper right hand corner of the card - American Pie Council, the only organization committed to preserving America's pie heritage - American Plastics Council, a major trade association for the U.S. plastics industry - Animal Procedures Committee, a public body and task force of the United Kingdom government - Anti-Poverty Committee, a direct action organization in Vancouver, Canada. - Arab Potash Company in Jordan - Archaeogeophysical Pseudotechnical Consultant, a consultant who utilizes archaeogeophysical pseudotechnical "black box" methods in geoarchaeological site investigations - Arrangers' Publishing Company, a sheet music publishing company in the United States. - Asia Pacific College, a non-profit joint-venture between IBM Philippines and the SM Foundation - Association for Progressive Communications, an international network of organizations that was founded in 1990 to provide communication infrastructure - Attoparsec, an unusual unit of measurement - Australian Press Council, the self-regulatory body of the Australian print media - Australian Provincial Championship, a rugby union competition in Australia - Napa County Airport, California, United States, from its IATA airport code - Armed Proletarians for Communism, an Italian far-left terrorist group of the 1970s. - Argon plasma coagulation, an endoscopic technique for controlling hemorrhage - Adaptive predictive coding, a narrowband analog-to-digital conversion that uses a one-level or multilevel sampling system - Advanced process control, a broad term within the control theory - Alternative PHP Cache, a PHP accelerator program - American Power Conversion, a company with a worldwide presence based in West Kingston, Rhode Island - APC-7 connector, a high grade sexless, 7 mm, coaxial connector used for high frequency applications up to 18 GHz - Application Program Command, a control code; see C0 and C1 control codes - aPOCALYPSE pRODUCTION cREW, a major MP3 warez organization founded by two individuals known under the pseudonyms acid^rain and Viper in May of 1997 - Australian Personal Computer, a computer magazine in Australia - Automatic Performance Control, a system that was introduced on turbo charged Saab H engines in 1982 Template:Disambig de:APC ko:APC it:APC nl:APC sv:APC Template:WikiDoc Sources

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

19fdb6622e4951606dc94b0ab584684725c1c313

wikidoc

Abc

Abc Synonyms and keywords: # Special consideration when adding information from observational studies # Overview # Historical Perspective was first discovered by , a , in /during/following . The association between and was made in/during . In , was the first to discover the association between and the development of . In , mutations were first implicated in the pathogenesis of . There have been several outbreaks of , including -----. In , was developed by to treat/diagnose . # Classification There is no established system for the classification of . OR may be classified according to into subtypes/groups: , , , and . OR may be classified into subtypes based on , , and . may be classified into several subtypes based on , , and . OR Based on the duration of symptoms, may be classified as either acute or chronic. OR If the staging system involves specific and characteristic findings and features: According to the , there are stages of based on the , , and . Each stage is assigned a and a that designate the and . OR The staging of is based on the . OR There is no established system for the staging of . # Pathophysiology The exact pathogenesis of is not fully understood. OR It is thought that is the result of / is mediated by / is produced by / is caused by either , , or . OR is usually transmitted via the route to the human host. OR Following transmission/ingestion, the uses the to invade the cell. OR arises from s, which are cells that are normally involved in . OR The progression to usually involves the . OR The pathophysiology of depends on the histological subtype. # Causes Disease name] may be caused by , , or . OR Common causes of include , , and . OR The most common cause of is . Less common causes of include , , and . OR The cause of has not been identified. To review risk factors for the development of , click here. # Differentiating ((Page name)) from other Diseases must be differentiated from other diseases that cause , , and , such as , , and . OR must be differentiated from , , and . # Epidemiology and Demographics The incidence/prevalence of is approximately per 100,000 individuals worldwide. OR In , the incidence/prevalence of was estimated to be cases per 100,000 individuals worldwide. OR In , the incidence of is approximately per 100,000 individuals with a case-fatality rate of %. Patients of all age groups may develop . OR The incidence of increases with age; the median age at diagnosis is years. OR commonly affects individuals younger than/older than years of age. OR is usually first diagnosed among . OR commonly affects . There is no racial predilection to . OR usually affects individuals of the race. individuals are less likely to develop . affects men and women equally. OR are more commonly affected by than . The to ratio is approximately to 1. The majority of cases are reported in . OR is a common/rare disease that tends to affect and . # Risk Factors There are no established risk factors for . OR The most potent risk factor in the development of is . Other risk factors include , , and . OR Common risk factors in the development of include , , , and . OR Common risk factors in the development of may be occupational, environmental, genetic, and viral. # Screening There is insufficient evidence to recommend routine screening for . OR According to the , screening for is not recommended. OR According to the , screening for by is recommended every among patients with , , and . # Natural History, Complications, and Prognosis If left untreated, % of patients with may progress to develop , , and . OR Common complications of include , , and . OR Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with is approximately %. # Diagnosis ## Diagnostic Study of Choice The diagnosis of is made when at least of the following diagnostic criteria are met: , , , and . OR The diagnosis of is based on the criteria, which include , , and . OR The diagnosis of is based on the definition, which includes , , and . OR There are no established criteria for the diagnosis of . ## History and Symptoms The majority of patients with are asymptomatic. OR The hallmark of is . A positive history of and is suggestive of . The most common symptoms of include , , and . Common symptoms of include , , and . Less common symptoms of include , , and . ## Physical Examination Patients with usually appear . Physical examination of patients with is usually remarkable for , , and . OR Common physical examination findings of include , , and . OR The presence of on physical examination is diagnostic of . OR The presence of on physical examination is highly suggestive of . ## Laboratory Findings An elevated/reduced concentration of serum/blood/urinary/CSF/other is diagnostic of . OR Laboratory findings consistent with the diagnosis of include , , and . OR is usually normal among patients with . OR Some patients with may have elevated/reduced concentration of , which is usually suggestive of . OR There are no diagnostic laboratory findings associated with . ## Electrocardiogram There are no ECG findings associated with . OR An ECG may be helpful in the diagnosis of . Findings on an ECG suggestive of/diagnostic of include , , and . ## X-ray There are no x-ray findings associated with . OR An x-ray may be helpful in the diagnosis of . Findings on an x-ray suggestive of/diagnostic of include , , and . OR There are no x-ray findings associated with . However, an x-ray may be helpful in the diagnosis of complications of , which include , , and . ## Echocardiography or Ultrasound There are no echocardiography/ultrasound findings associated with . OR Echocardiography/ultrasound may be helpful in the diagnosis of . Findings on an echocardiography/ultrasound suggestive of/diagnostic of include , , and . OR There are no echocardiography/ultrasound findings associated with . However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of , which include , , and . ## CT scan There are no CT scan findings associated with . OR CT scan may be helpful in the diagnosis of . Findings on CT scan suggestive of/diagnostic of include , , and . OR There are no CT scan findings associated with . However, a CT scan may be helpful in the diagnosis of complications of , which include , , and . ## MRI There are no MRI findings associated with . OR MRI may be helpful in the diagnosis of . Findings on MRI suggestive of/diagnostic of include , , and . OR There are no MRI findings associated with . However, a MRI may be helpful in the diagnosis of complications of , which include , , and . ## Other Imaging Findings There are no other imaging findings associated with . OR may be helpful in the diagnosis of . Findings on an suggestive of/diagnostic of include , , and . ## Other Diagnostic Studies There are no other diagnostic studies associated with . OR may be helpful in the diagnosis of . Findings suggestive of/diagnostic of include , , and . OR Other diagnostic studies for include , which demonstrates , , and , and , which demonstrates , , and . # Treatment ## Medical Therapy There is no treatment for ; the mainstay of therapy is supportive care. OR Supportive therapy for includes , , and . OR The majority of cases of are self-limited and require only supportive care. OR is a medical emergency and requires prompt treatment. OR The mainstay of treatment for is . OR The optimal therapy for depends on the stage at diagnosis. OR is recommended among all patients who develop . OR Pharmacologic medical therapy is recommended among patients with , , and . OR Pharmacologic medical therapies for include (either) , , and/or . OR Empiric therapy for depends on and . OR Patients with are treated with , whereas patients with are treated with . ## Surgery Surgical intervention is not recommended for the management of . OR Surgery is not the first-line treatment option for patients with . Surgery is usually reserved for patients with either , , and OR The mainstay of treatment for is medical therapy. Surgery is usually reserved for patients with either , , and/or . OR The feasibility of surgery depends on the stage of at diagnosis. OR Surgery is the mainstay of treatment for . ## Primary Prevention There are no established measures for the primary prevention of . OR There are no available vaccines against . OR Effective measures for the primary prevention of include , , and . OR vaccine is recommended for to prevent . Other primary prevention strategies include , , and . ## Secondary Prevention There are no established measures for the secondary prevention of . OR Effective measures for the secondary prevention of include , , and .

Abc Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Synonyms and keywords: # Special consideration when adding information from observational studies # Overview # Historical Perspective [Disease name] was first discovered by [name of scientist], a [nationality + occupation], in [year]/during/following [event]. The association between [important risk factor/cause] and [disease name] was made in/during [year/event]. In [year], [scientist] was the first to discover the association between [risk factor] and the development of [disease name]. In [year], [gene] mutations were first implicated in the pathogenesis of [disease name]. There have been several outbreaks of [disease name], including -----. In [year], [diagnostic test/therapy] was developed by [scientist] to treat/diagnose [disease name]. # Classification There is no established system for the classification of [disease name]. OR [Disease name] may be classified according to [classification method] into [number] subtypes/groups: [group1], [group2], [group3], and [group4]. OR [Disease name] may be classified into [large number > 6] subtypes based on [classification method 1], [classification method 2], and [classification method 3]. [Disease name] may be classified into several subtypes based on [classification method 1], [classification method 2], and [classification method 3]. OR Based on the duration of symptoms, [disease name] may be classified as either acute or chronic. OR If the staging system involves specific and characteristic findings and features: According to the [staging system + reference], there are [number] stages of [malignancy name] based on the [finding1], [finding2], and [finding3]. Each stage is assigned a [letter/number1] and a [letter/number2] that designate the [feature1] and [feature2]. OR The staging of [malignancy name] is based on the [staging system]. OR There is no established system for the staging of [malignancy name]. # Pathophysiology The exact pathogenesis of [disease name] is not fully understood. OR It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3]. OR [Pathogen name] is usually transmitted via the [transmission route] route to the human host. OR Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell. OR [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells]. OR The progression to [disease name] usually involves the [molecular pathway]. OR The pathophysiology of [disease/malignancy] depends on the histological subtype. # Causes Disease name] may be caused by [cause1], [cause2], or [cause3]. OR Common causes of [disease] include [cause1], [cause2], and [cause3]. OR The most common cause of [disease name] is [cause 1]. Less common causes of [disease name] include [cause 2], [cause 3], and [cause 4]. OR The cause of [disease name] has not been identified. To review risk factors for the development of [disease name], click here. # Differentiating ((Page name)) from other Diseases [Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3]. OR [Disease name] must be differentiated from [[differential dx1], [differential dx2], and [differential dx3]. # Epidemiology and Demographics The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide. OR In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide. OR In [year], the incidence of [disease name] is approximately [number range] per 100,000 individuals with a case-fatality rate of [number range]%. Patients of all age groups may develop [disease name]. OR The incidence of [disease name] increases with age; the median age at diagnosis is [#] years. OR [Disease name] commonly affects individuals younger than/older than [number of years] years of age. OR [Chronic disease name] is usually first diagnosed among [age group]. OR [Acute disease name] commonly affects [age group]. There is no racial predilection to [disease name]. OR [Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name]. [Disease name] affects men and women equally. OR [Gender 1] are more commonly affected by [disease name] than [gender 2]. The [gender 1] to [gender 2] ratio is approximately [number > 1] to 1. The majority of [disease name] cases are reported in [geographical region]. OR [Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2]. # Risk Factors There are no established risk factors for [disease name]. OR The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4]. OR Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4]. OR Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral. # Screening There is insufficient evidence to recommend routine screening for [disease/malignancy]. OR According to the [guideline name], screening for [disease name] is not recommended. OR According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3]. # Natural History, Complications, and Prognosis If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3]. OR Common complications of [disease name] include [complication 1], [complication 2], and [complication 3]. OR Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%. # Diagnosis ## Diagnostic Study of Choice The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: [criterion 1], [criterion 2], [criterion 3], and [criterion 4]. OR The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3]. OR The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3]. OR There are no established criteria for the diagnosis of [disease name]. ## History and Symptoms The majority of patients with [disease name] are asymptomatic. OR The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. ## Physical Examination Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3]. OR Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3]. OR The presence of [finding(s)] on physical examination is diagnostic of [disease name]. OR The presence of [finding(s)] on physical examination is highly suggestive of [disease name]. ## Laboratory Findings An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name]. OR Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3]. OR [Test] is usually normal among patients with [disease name]. OR Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication]. OR There are no diagnostic laboratory findings associated with [disease name]. ## Electrocardiogram There are no ECG findings associated with [disease name]. OR An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3]. ## X-ray There are no x-ray findings associated with [disease name]. OR An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3]. OR There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3]. ## Echocardiography or Ultrasound There are no echocardiography/ultrasound findings associated with [disease name]. OR Echocardiography/ultrasound may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3]. OR There are no echocardiography/ultrasound findings associated with [disease name]. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3]. ## CT scan There are no CT scan findings associated with [disease name]. OR [Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3]. OR There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3]. ## MRI There are no MRI findings associated with [disease name]. OR [Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3]. OR There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3]. ## Other Imaging Findings There are no other imaging findings associated with [disease name]. OR [Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3]. ## Other Diagnostic Studies There are no other diagnostic studies associated with [disease name]. OR [Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3]. OR Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3]. # Treatment ## Medical Therapy There is no treatment for [disease name]; the mainstay of therapy is supportive care. OR Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3]. OR The majority of cases of [disease name] are self-limited and require only supportive care. OR [Disease name] is a medical emergency and requires prompt treatment. OR The mainstay of treatment for [disease name] is [therapy]. OR The optimal therapy for [malignancy name] depends on the stage at diagnosis. OR [Therapy] is recommended among all patients who develop [disease name]. OR Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3]. OR Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3]. OR Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2]. OR Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2]. ## Surgery Surgical intervention is not recommended for the management of [disease name]. OR Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3] OR The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3]. OR The feasibility of surgery depends on the stage of [malignancy] at diagnosis. OR Surgery is the mainstay of treatment for [disease or malignancy]. ## Primary Prevention There are no established measures for the primary prevention of [disease name]. OR There are no available vaccines against [disease name]. OR Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3]. OR [Vaccine name] vaccine is recommended for [patient population] to prevent [disease name]. Other primary prevention strategies include [strategy 1], [strategy 2], and [strategy 3]. ## Secondary Prevention There are no established measures for the secondary prevention of [disease name]. OR Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and [strategy 3].

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

8a3813c8f9084e6149fc0f9198e9030a6a8911bb

wikidoc

Ion

Ion An ion is an atom or molecule which has lost or gained one or more valence electrons, giving it a positive or negative electrical charge. A negatively charged ion, which has more electrons in its electron shells than it has protons in its nuclei, is known as an anion (Template:PronEng; an-eye-on). Conversely, a positively-charged ion, which has fewer electrons than protons, is known as a cation (Template:PronEng; cat-eye-on). An ion consisting of a single atom is called a monatomic ion, but if it consists of two or more atoms, it is a polyatomic ion. Polyatomic ions containing oxygen, such as carbonate and sulfate, are called oxyanions. Ions are denoted in the same way as electrically neutral atoms and molecules except for the presence of a superscript indicating the sign of the net electric charge and the number of electrons lost or gained, if more than one. For example: H+ and SO42−. # Formation ## Formation of polyatomic and molecular ions Polyatomic and molecular ions are often formed by the combination of elemental ions such as H+ with neutral molecules or by the gain of such elemental ions from neutral molecules. A simple example of this is the ammonium ion NH4+ which can be formed by ammonia NH3 accepting a proton, H+. Ammonia and ammonium have the same number of electrons in essentially the same electronic configuration but differ in protons. The charge has been added by the addition of a proton (H+) not the addition or removal of electrons. The distinction between this and the removal of an electron from the whole molecule is important in large systems because it usually results in much more stable ions with complete electron shells. For example NH3·+ is not stable because of an incomplete valence shell around nitrogen and is in fact a radical ion. ## Ionization potential The energy required to detach an electron in its lowest energy state from an atom or molecule of a gas with less net electric charge is called the ionization potential, or ionization energy. The nth ionization energy of an atom is the energy required to detach its nth electron after the first n − 1 electrons have already been detached. Each successive ionization energy is markedly greater than the last. Particularly great increases occur after any given block of atomic orbitals is exhausted of electrons. For this reason, ions tend to form in ways that leave them with full orbital blocks. For example, sodium has one valence electron, in its outermost shell, so in ionized form it is commonly found with one lost electron, as Na+. On the other side of the periodic table, chlorine has seven valence electrons, so in ionized form it is commonly found with one gained electron, as Cl−. Francium has the lowest ionization energy of all the elements and fluorine has the greatest. The ionization energy of metals is generally much lower than the ionization energy of nonmetals, which is why metals will generally lose electrons to form positively-charged ions while nonmetals will generally gain electrons to form negatively-charged ions. A neutral atom contains an equal number of Z protons in the nucleus and Z electrons in the electron shell. The electrons' negative charges thus exactly cancel the protons' positive charges. In the simple view of the Free electron model, a passing electron is therefore not attracted to a neutral atom and cannot bind to it. In reality, however, the atomic electrons form a cloud into which the additional electron penetrates, thus being exposed to a net positive charge part of the time. Furthermore, the additional charge displaces the original electrons and all of the Z + 1 electrons rearrange into a new configuration. # Ions - Anions (see pronunciation above) are negatively charged ions, formed when an atom gains electrons in a reaction. Anions are negatively charged because there are more electrons associated with them than there are protons in their nuclei. - Cations (see pronunciation above) are positively charged ions, formed when an atom loses electrons in a reaction. Cations are the opposite of anions, since cations have fewer electrons than protons. - Dianion: a dianion is a species which has two negative charges on it; for example, the aromatic dianion pentalene. - Radical ions: radical ions are ions that contain an odd number of electrons and are mostly very reactive and unstable. ## Plasma A collection of non-aqueous gas-like ions, or even a gas containing a proportion of charged particles, is called a plasma, often called the fourth state of matter because its properties are quite different from solids, liquids, and gases. Astrophysical plasmas containing predominantly a mixture of electrons and protons, may make up as much as 99.9% of visible matter in the universe. # Applications Ions are essential to life. Sodium, potassium, calcium and other ions play an important role in the cells of living organisms, particularly in cell membranes. They have many practical, everyday applications in items such as smoke detectors, and are also finding use in unconventional technologies such as ion engines. Inorganic dissolved ions are a component of total dissolved solids, an indicator of water quality in the world. # Negative 'Ions' and Air Ionisers Many manufacturers sell devices that release 'negative ions' into the air, claiming that a higher concentration of negative ions will make a room feel less 'stuffy'. Some also claim health benefits such as relieving asthma and depression. The 'ions' referred to are in fact charged oxygen or nitrogen molecules surrounded by a cluster of water molecules, rather than ions. Scientific studies have shown no particular benefit from a greater concentration of negative ions. Negative air ionization can reduce the concentration of bioaerosols and dust particles in the air by causing them to bond, forming larger particles and thus falling out of the air onto horizontal surfaces. This may help reduce infection due to airborne contamination. Ionization was shown to reduce transmission of the Newcastle Disease Virus in an experiment with chickens. # Common ions

Ion Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] An ion is an atom or molecule which has lost or gained one or more valence electrons, giving it a positive or negative electrical charge. A negatively charged ion, which has more electrons in its electron shells than it has protons in its nuclei, is known as an anion (Template:PronEng; an-eye-on). Conversely, a positively-charged ion, which has fewer electrons than protons, is known as a cation (Template:PronEng; cat-eye-on). An ion consisting of a single atom is called a monatomic ion, but if it consists of two or more atoms, it is a polyatomic ion. Polyatomic ions containing oxygen, such as carbonate and sulfate, are called oxyanions. Ions are denoted in the same way as electrically neutral atoms and molecules except for the presence of a superscript indicating the sign of the net electric charge and the number of electrons lost or gained, if more than one. For example: H+ and SO42−. # Formation ## Formation of polyatomic and molecular ions Polyatomic and molecular ions are often formed by the combination of elemental ions such as H+ with neutral molecules or by the gain of such elemental ions from neutral molecules. A simple example of this is the ammonium ion NH4+ which can be formed by ammonia NH3 accepting a proton, H+. Ammonia and ammonium have the same number of electrons in essentially the same electronic configuration but differ in protons. The charge has been added by the addition of a proton (H+) not the addition or removal of electrons. The distinction between this and the removal of an electron from the whole molecule is important in large systems because it usually results in much more stable ions with complete electron shells. For example NH3·+ is not stable because of an incomplete valence shell around nitrogen and is in fact a radical ion. ## Ionization potential The energy required to detach an electron in its lowest energy state from an atom or molecule of a gas with less net electric charge is called the ionization potential, or ionization energy. The nth ionization energy of an atom is the energy required to detach its nth electron after the first n − 1 electrons have already been detached. Each successive ionization energy is markedly greater than the last. Particularly great increases occur after any given block of atomic orbitals is exhausted of electrons. For this reason, ions tend to form in ways that leave them with full orbital blocks. For example, sodium has one valence electron, in its outermost shell, so in ionized form it is commonly found with one lost electron, as Na+. On the other side of the periodic table, chlorine has seven valence electrons, so in ionized form it is commonly found with one gained electron, as Cl−. Francium has the lowest ionization energy of all the elements and fluorine has the greatest. The ionization energy of metals is generally much lower than the ionization energy of nonmetals, which is why metals will generally lose electrons to form positively-charged ions while nonmetals will generally gain electrons to form negatively-charged ions. A neutral atom contains an equal number of Z protons in the nucleus and Z electrons in the electron shell. The electrons' negative charges thus exactly cancel the protons' positive charges. In the simple view of the Free electron model, a passing electron is therefore not attracted to a neutral atom and cannot bind to it. In reality, however, the atomic electrons form a cloud into which the additional electron penetrates, thus being exposed to a net positive charge part of the time. Furthermore, the additional charge displaces the original electrons and all of the Z + 1 electrons rearrange into a new configuration. # Ions - Anions (see pronunciation above) are negatively charged ions, formed when an atom gains electrons in a reaction. Anions are negatively charged because there are more electrons associated with them than there are protons in their nuclei. - Cations (see pronunciation above) are positively charged ions, formed when an atom loses electrons in a reaction. Cations are the opposite of anions, since cations have fewer electrons than protons. - Dianion: a dianion is a species which has two negative charges on it; for example, the aromatic dianion pentalene. - Radical ions: radical ions are ions that contain an odd number of electrons and are mostly very reactive and unstable. ## Plasma A collection of non-aqueous gas-like ions, or even a gas containing a proportion of charged particles, is called a plasma, often called the fourth state of matter because its properties are quite different from solids, liquids, and gases. Astrophysical plasmas containing predominantly a mixture of electrons and protons, may make up as much as 99.9% of visible matter in the universe.[1] # Applications Ions are essential to life. Sodium, potassium, calcium and other ions play an important role in the cells of living organisms, particularly in cell membranes. They have many practical, everyday applications in items such as smoke detectors, and are also finding use in unconventional technologies such as ion engines. Inorganic dissolved ions are a component of total dissolved solids, an indicator of water quality in the world. # Negative 'Ions' and Air Ionisers Many manufacturers sell devices that release 'negative ions' into the air, claiming that a higher concentration of negative ions will make a room feel less 'stuffy'. Some also claim health benefits such as relieving asthma and depression. The 'ions' referred to are in fact charged oxygen or nitrogen molecules surrounded by a cluster of water molecules, rather than ions. Scientific studies have shown no particular benefit from a greater concentration of negative ions.[2] Negative air ionization can reduce the concentration of bioaerosols and dust particles in the air by causing them to bond, forming larger particles and thus falling out of the air onto horizontal surfaces. This may help reduce infection due to airborne contamination[3]. Ionization was shown to reduce transmission of the Newcastle Disease Virus in an experiment with chickens[4]. # Common ions

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

641ed90b43088b29e9707650eb1990eea4c69c8f

wikidoc

Arm

Arm # Overview In anatomy, an arm is one of the upper limbs of an animal. The term arm can also be used for analogous structures, such as one of the paired upper limbs of a four-legged animal, or the arms of an octopus. Anatomically, the term arm refers specifically to the segment between the shoulder and the elbow. The segment between the elbow and wrist is the forearm. However, in colloquial speech the term arm often refers to the entire upper limb from shoulder to wrist. In primates the arms are richly adapted for both climbing and for more skilled, manipulative tasks. The ball and socket shoulder joint allows for movement of the arms in a wide circular plane, while the presence of two forearm bones which can rotate around each other allows for additional range of motion at this level. # Anatomy of the human arm The human arm contains bones, joints, muscles, nerves, and blood vessels. Many of these muscles are used for everyday tasks. ## Bony structure and joints The humerus is the (upper) arm bone. It joins with the scapula above at the shoulder joint (or glenohumeral joint) and with the ulna and radius below at the elbow joint. ### Elbow joint The elbow joint is the hinge joint between the distal end of the humerus and the proximal ends of the radius and ulna. The upper arm bone is not easily broken. It is built to handle pressure of up to 300lbs. ## Osteofascial compartments The arm is divided by a fascial layer (known as lateral and medial intermuscular septa) separating the muscles into two osteofascial compartments: - Anterior compartment of the arm - Posterior compartment of the arm The fascia merges with the periosteum (outer bone layer) of the humerus. The compartments contain muscles which are innervated by the same nerve and perform the same action. Two other muscles are considered to be partially in the arm: - The large deltoid muscle is considered to have part of its body in the anterior compartment. This muscle is the main abductor muscle of the upper limb and extends over the shoulder. - The brachioradialis muscle originates in the arm but inserts into the forearm. This muscle is responsible for rotating the hand so its palm faces forward (supination). ## Cubital fossa The cubital fossa is clinically important for venepuncture and for blood pressure measurement. It is an imaginary triangle with borders being: - Laterally, the medial border of brachioradialis muscle - Medially, the lateral border of pronator teres muscle - Superiorly, the intercondylar line, an imaginary line between the two condyles of the humerus - The floor is the brachialis muscle - The roof is the skin and fascia of the arm and forearm The structures which smell through the cubital fossa are vital. The order from which they pass into the forearm are as follows, from medial to lateral: - Median nerve, which starts to branch - Brachial artery - Tendon of the biceps brachii muscle - Radial nerve - Median cubital vein - this important vein is where venepuncture occurs. It connects the basilic and cephalic veins. - lymph nodes ## Nervous supply The musculocutaneous nerve, from C5, C6, C7, is the main supplier of muscles of the anterior compartment. It originates from the lateral cord of the brachial plexus of nerves. It pierces the coracobrachialis muscle and gives off branches to the muscle, as well as to brachialis and biceps brachii. It terminates as the anterior cutaneous nerve of the forearm. The radial nerve, which is from the fifth cervical spinal nerve to the first thoracic spinal nerve, originates as the continuation of the posterior cord of the brachial plexus. This nerve enters the lower triangular space (an imaginary space bounded by, amongst others, the shaft of the humerus and the triceps brachii) of the arm and lies deep to the triceps brachii. Here it travels with a deep artery of the arm (the profunda brachii), which sits in the radial groove of the humerus. This fact is very important clinically as a fracture of the bone at the shaft of the bone here can cause lesions or even transections in the nerve. Other nerves passing through give no supply to the arm. These include: - The median nerve, nerve origin C5-T1, which is a branch of the lateral and medial cords of the brachial plexus. This nerve continues in the arm, travelling in a plane between the biceps and triceps muscles. At the cubital fossa, this nerve is deep to the pronator teres muscle and is the most medial structure in the fossa. The nerve passes into the forearm. - The ulnar nerve, origin C7-T1, is a continuation of the medial cord of the brachial plexus. This nerve passes in the same plane as the median nerve, between the biceps and triceps muscles. At the elbow, this nerve travels posterior to the medial epicondyle of the humerus. This means that condylar fractures can cause lesion to this nerve. ## Blood supply and venous drainage ### Arteries The main artery in the arm is the brachial artery. This artery is a continuation of the axillary artery. The point at which the axillary becomes the brachial is distal to the lower border of teres major. The brachial artery gives off an important branch, the profunda brachii (deep artery of the arm). This branching occurs just below the lower border of teres major. The brachial artery continues to the cubital fossa in the anterior compartment of the arm. It travels in a plane between the biceps and triceps muscles, the same as the median nerve and basilic vein. It is accompanied by venae comitantes (accompanying veins). It gives branches to the muscles of the anterior compartment. The artery is in between the median nerve and the tendon of the biceps muscle in the cubital fossa. It then continues into the forearm. The profunda brachii travels through the lower triangular space with the radial nerve. From here onwards it has an intimate relationship with the radial nerve. They are both found deep to the triceps muscle and are located on the spiral groove of the humerus. Therefore fracture of the bone may not only lead to lesion of the radial nerve, but also haematoma of the internal structures of the arm. The artery then continues on to anastamose with the recurrent radial branch of the brachial artery, providing a diffuse blood supply for the elbow joint. ### Veins The veins of the arm carry blood from the extremities of the limb, as well as drain the arm itself. The two main veins are the basilic and the cephalic veins. There is a connecting vein between the two, the median cubital vein, which passes through the cubital fossa and is clinically important for venepuncture (withdrawing blood). The basilic vein travels on the medial side of the arm and terminates at the level of the seventh rib. The cephalic vein travels on the lateral side of the arm and terminates as the axillary vein. It passes through the deltopectoral triangle, a space between the deltoid and the pectoralis major muscles.

Arm Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In anatomy, an arm is one of the upper limbs of an animal. The term arm can also be used for analogous structures, such as one of the paired upper limbs of a four-legged animal, or the arms of an octopus. Anatomically, the term arm refers specifically to the segment between the shoulder and the elbow. The segment between the elbow and wrist is the forearm. However, in colloquial speech the term arm often refers to the entire upper limb from shoulder to wrist. In primates the arms are richly adapted for both climbing and for more skilled, manipulative tasks. The ball and socket shoulder joint allows for movement of the arms in a wide circular plane, while the presence of two forearm bones which can rotate around each other allows for additional range of motion at this level. # Anatomy of the human arm The human arm contains bones, joints, muscles, nerves, and blood vessels. Many of these muscles are used for everyday tasks. ## Bony structure and joints The humerus is the (upper) arm bone. It joins with the scapula above at the shoulder joint (or glenohumeral joint) and with the ulna and radius below at the elbow joint. ### Elbow joint The elbow joint is the hinge joint between the distal end of the humerus and the proximal ends of the radius and ulna. The upper arm bone is not easily broken. It is built to handle pressure of up to 300lbs. ## Osteofascial compartments The arm is divided by a fascial layer (known as lateral and medial intermuscular septa) separating the muscles into two osteofascial compartments: - Anterior compartment of the arm - Posterior compartment of the arm The fascia merges with the periosteum (outer bone layer) of the humerus. The compartments contain muscles which are innervated by the same nerve and perform the same action. Two other muscles are considered to be partially in the arm: - The large deltoid muscle is considered to have part of its body in the anterior compartment. This muscle is the main abductor muscle of the upper limb and extends over the shoulder. - The brachioradialis muscle originates in the arm but inserts into the forearm. This muscle is responsible for rotating the hand so its palm faces forward (supination). ## Cubital fossa The cubital fossa is clinically important for venepuncture and for blood pressure measurement. It is an imaginary triangle with borders being: - Laterally, the medial border of brachioradialis muscle - Medially, the lateral border of pronator teres muscle - Superiorly, the intercondylar line, an imaginary line between the two condyles of the humerus - The floor is the brachialis muscle - The roof is the skin and fascia of the arm and forearm The structures which smell through the cubital fossa are vital. The order from which they pass into the forearm are as follows, from medial to lateral: - Median nerve, which starts to branch - Brachial artery - Tendon of the biceps brachii muscle - Radial nerve - Median cubital vein - this important vein is where venepuncture occurs. It connects the basilic and cephalic veins. - lymph nodes ## Nervous supply The musculocutaneous nerve, from C5, C6, C7, is the main supplier of muscles of the anterior compartment. It originates from the lateral cord of the brachial plexus of nerves. It pierces the coracobrachialis muscle and gives off branches to the muscle, as well as to brachialis and biceps brachii. It terminates as the anterior cutaneous nerve of the forearm. The radial nerve, which is from the fifth cervical spinal nerve to the first thoracic spinal nerve, originates as the continuation of the posterior cord of the brachial plexus. This nerve enters the lower triangular space (an imaginary space bounded by, amongst others, the shaft of the humerus and the triceps brachii) of the arm and lies deep to the triceps brachii. Here it travels with a deep artery of the arm (the profunda brachii), which sits in the radial groove of the humerus. This fact is very important clinically as a fracture of the bone at the shaft of the bone here can cause lesions or even transections in the nerve. Other nerves passing through give no supply to the arm. These include: - The median nerve, nerve origin C5-T1, which is a branch of the lateral and medial cords of the brachial plexus. This nerve continues in the arm, travelling in a plane between the biceps and triceps muscles. At the cubital fossa, this nerve is deep to the pronator teres muscle and is the most medial structure in the fossa. The nerve passes into the forearm. - The ulnar nerve, origin C7-T1, is a continuation of the medial cord of the brachial plexus. This nerve passes in the same plane as the median nerve, between the biceps and triceps muscles. At the elbow, this nerve travels posterior to the medial epicondyle of the humerus. This means that condylar fractures can cause lesion to this nerve. ## Blood supply and venous drainage ### Arteries The main artery in the arm is the brachial artery. This artery is a continuation of the axillary artery. The point at which the axillary becomes the brachial is distal to the lower border of teres major. The brachial artery gives off an important branch, the profunda brachii (deep artery of the arm). This branching occurs just below the lower border of teres major. The brachial artery continues to the cubital fossa in the anterior compartment of the arm. It travels in a plane between the biceps and triceps muscles, the same as the median nerve and basilic vein. It is accompanied by venae comitantes (accompanying veins). It gives branches to the muscles of the anterior compartment. The artery is in between the median nerve and the tendon of the biceps muscle in the cubital fossa. It then continues into the forearm. The profunda brachii travels through the lower triangular space with the radial nerve. From here onwards it has an intimate relationship with the radial nerve. They are both found deep to the triceps muscle and are located on the spiral groove of the humerus. Therefore fracture of the bone may not only lead to lesion of the radial nerve, but also haematoma of the internal structures of the arm. The artery then continues on to anastamose with the recurrent radial branch of the brachial artery, providing a diffuse blood supply for the elbow joint. ### Veins The veins of the arm carry blood from the extremities of the limb, as well as drain the arm itself. The two main veins are the basilic and the cephalic veins. There is a connecting vein between the two, the median cubital vein, which passes through the cubital fossa and is clinically important for venepuncture (withdrawing blood). The basilic vein travels on the medial side of the arm and terminates at the level of the seventh rib. The cephalic vein travels on the lateral side of the arm and terminates as the axillary vein. It passes through the deltopectoral triangle, a space between the deltoid and the pectoralis major muscles.

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

81c20f0a04e961e6423e2e3768ae5417843d30e9

wikidoc

BSc

BSc A Bachelor of Science (B.S., B.Sc. or less commonly, S.B. or Sc.B. from the Latin Scientiæ Baccalaureus) is an undergraduate academic degree awarded for completed courses that generally last three to five years (see below). In the United States, a Bachelor of Science degree may be a more specialized version of B.A., with more focus on the subject and less on a broad liberal arts background; for example, a B.S. in economics may require several more advanced economics courses than a B.A. in economics, and possibly more support courses (such as statistics). The B.S. is also frequently used for professional areas of study such as engineering, journalism, accounting, and advertising. At least two American schools (Caltech, MIT) and four of the service academies (United States Military Academy, United States Naval Academy, United States Air Force Academy and United States Coast Guard Academy) award the BS for all subjects, including, e.g., Literature. In the UK and Canada, which subjects are considered science subjects varies, e.g. economics degrees may be B.A. in one university but B.Sc. in another. In addition, some universities, like the London School of Economics, offer the B.Sc. in practically all subject areas even when they are normally associated with arts degrees, while others award arts qualifications almost exclusively, namely the Oxbridge universities. In both instances, this is generally for historical and traditional reasons. A Bachelor of Science receives the designation B.Sc. or B.S. for a major/pass degree and B.Sc. (Hons) or B.S. (Hon) for an honours degree. The B.Sc. from Germany was equivalent to a B.Sc. (Hons). Note that many universities in German speaking countries are changing their systems into the Ba/Ma system, thus of course also offering the full equivalent of a B.Sc. Formerly at the University of Oxford, the degree of B.Sc. was a postgraduate degree. This former degree, still actively granted, has since been renamed M.Sc. In Brazil, a Bachelor of Science degree is a graduation degree and is also more specific, usually containing a one-year mandatory probation time by the end of the course followed by relatively elaborate written and oral evaluations (Monografia). # Typical completion period ## Three years Australia, Austria, Barbados, Belgium, Cameroon, Cote d'Ivoire, Slovak Republic, Czech Republic, Denmark, England (three or four years with a one-year placement in industry), Estonia, Finland, France, Germany (mostly three years, but can be up to four years), Hong Kong, Hungary, Iceland, India, Italy, Jamaica, Latvia, Malaysia, The Netherlands, New Zealand, Northern Ireland, Norway, Poland, Portugal, Romania, Quebec, Scotland (non-Honour),Singapore, South Africa, Spain, Sweden, Switzerland, Trinidad and Tobago, Wales and Zimbabwe. ## Four years Afghanistan, Albania, Bangladesh (three or four years), Bahrain, Brunei, Bulgaria, Canada (except Quebec), Croatia (four or five years), Guatemala, Greece, Indonesia, Iran, Iraq, Ireland, Israel, Japan, Jordan, Kazakhstan, Korea, Malta, Mexico, Myanmar, Pakistan, People's Republic of China, the Philippines, Russia, Saudi Arabia, Scotland (Honour Degree), Slovenia, Taiwan, Turkey, Sri Lanka,Haiti (three or four years), United States, Zambia (four or five years). ## Five years Peru, Argentina, Brazil, Colombia, Mexico (4.5 years), Chile (usually four years dedicated to coursework plus one year of research thesis), Egypt, Haiti (four or five years), Syria, and Serbia.

BSc A Bachelor of Science (B.S., B.Sc. or less commonly, S.B. or Sc.B. from the Latin Scientiæ Baccalaureus) is an undergraduate academic degree awarded for completed courses that generally last three to five years (see below). In the United States, a Bachelor of Science degree may be a more specialized version of B.A., with more focus on the subject and less on a broad liberal arts background; for example, a B.S. in economics may require several more advanced economics courses than a B.A. in economics, and possibly more support courses (such as statistics). The B.S. is also frequently used for professional areas of study such as engineering, journalism, accounting, and advertising. At least two American schools (Caltech, MIT) and four of the service academies (United States Military Academy, United States Naval Academy, United States Air Force Academy and United States Coast Guard Academy) award the BS for all subjects, including, e.g., Literature. In the UK and Canada, which subjects are considered science subjects varies, e.g. economics degrees may be B.A. in one university but B.Sc. in another. In addition, some universities, like the London School of Economics, offer the B.Sc. in practically all subject areas even when they are normally associated with arts degrees, while others award arts qualifications almost exclusively, namely the Oxbridge universities. In both instances, this is generally for historical and traditional reasons. A Bachelor of Science receives the designation B.Sc. or B.S. for a major/pass degree and B.Sc. (Hons) or B.S. (Hon) for an honours degree. The B.Sc. from Germany was equivalent to a B.Sc. (Hons). Note that many universities in German speaking countries are changing their systems into the Ba/Ma system, thus of course also offering the full equivalent of a B.Sc. Formerly at the University of Oxford, the degree of B.Sc. was a postgraduate degree. This former degree, still actively granted, has since been renamed M.Sc. In Brazil, a Bachelor of Science degree is a graduation degree and is also more specific, usually containing a one-year mandatory probation time by the end of the course followed by relatively elaborate written and oral evaluations (Monografia). # Typical completion period ## Three years Australia, Austria, Barbados, Belgium, Cameroon, Cote d'Ivoire, Slovak Republic, Czech Republic, Denmark, England (three or four years with a one-year placement in industry), Estonia, Finland, France, Germany (mostly three years, but can be up to four years), Hong Kong, Hungary, Iceland, India, Italy, Jamaica, Latvia, Malaysia, The Netherlands, New Zealand, Northern Ireland, Norway, Poland, Portugal, Romania, Quebec, Scotland (non-Honour),Singapore, South Africa, Spain, Sweden, Switzerland, Trinidad and Tobago, Wales and Zimbabwe. ## Four years Afghanistan, Albania, Bangladesh (three or four years), Bahrain, Brunei, Bulgaria, Canada (except Quebec), Croatia (four or five years), Guatemala, Greece, Indonesia, Iran, Iraq, Ireland, Israel, Japan, Jordan, Kazakhstan, Korea, Malta, Mexico, Myanmar, Pakistan, People's Republic of China, the Philippines, Russia, Saudi Arabia, Scotland (Honour Degree), Slovenia, Taiwan, Turkey, Sri Lanka,Haiti (three or four years), United States, Zambia (four or five years). ## Five years Peru, Argentina, Brazil, Colombia, Mexico (4.5 years), Chile (usually four years dedicated to coursework plus one year of research thesis), Egypt, Haiti (four or five years), Syria, and Serbia.

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

72c133d81260f3e412dda954a3217dec6fde6f4b

wikidoc

Bee

Bee Bees are flying insects closely related to wasps and ants. Bees are a monophyletic lineage within the superfamily Apoidea, presently classified by the unranked taxon name Anthophila. There are slightly fewer than 20,000 known species of bee, in 9 recognized families, though many are undescribed and the actual number is probably higher. They are found on every continent except Antarctica, in every habitat on the planet that contains flowering dicotyledons. # Introduction Bees are adapted for feeding on nectar and pollen, the former primarily as an energy source, and the latter primarily for protein and other nutrients. Most pollen is used as food for larvae. Bees have a long proboscis (a complex "tongue") that enables them to obtain the nectar from flowers. They have antennae almost universally made up of thirteen segments in males and twelve in females, as is typical for the superfamily. Bees all have two pairs of wings, the hind pair being the smaller of the two; in a very few species, one sex or caste has relatively short wings that make flight difficult or impossible, but none are wingless. The smallest bee is the dwarf bee (Trigona minima), about 2.1 mm (5/64") long. The largest bee in the world is Megachile pluto, which can grow to a size of 39 mm (1.5"). Member of the family Halictidae, or sweat bees, are the most common type of bee in the Northern Hemisphere, though they are small and often mistaken for wasps or flies. The best-known bee species is the Western honey bee, which, as its name suggests, produces honey, as do a few other types of bee. Human management of this species is known as beekeeping or apiculture. # Pollination Bees play an important role in pollinating flowering plants, and are the major type of pollinators in ecosystems that contain flowering plants. Bees may focus on gathering nectar or on gathering pollen, depending on their greater need at the time, especially in social species. Bees gathering nectar may accomplish pollination, but bees that are deliberately gathering pollen are more efficient pollinators. It is estimated that one third of the human food supply depends on insect pollination, most of this accomplished by bees. Bees are extremely important as pollinators in agriculture, especially the domesticated Western honey bee, with contract pollination having overtaken the role of honey production for beekeepers in many countries. Monoculture and pollinator decline (of many bee species) have increasingly caused honey bee keepers to become migratory so that bees can be concentrated in areas of pollination need at the appropriate season. Recently, many such migratory beekeepers have experienced substantial losses, prompting the announcement of investigation into the phenomenon, dubbed "Colony Collapse Disorder," amidst great concern over the nature and extent of the losses. Many other species of bees such as mason bees are increasingly cultured and used to meet the agricultural pollination need. Bees also play a major, though not always understood, role in providing food for birds and wildlife. Many of these bees survive in refuge in wild areas away from agricultural spraying, only to be poisoned in massive spray programs for mosquitoes, gypsy moths, or other insect pests. Most bees are fuzzy and carry an electrostatic charge, thus aiding in the adherence of pollen. Female bees periodically stop foraging and groom themselves to pack the pollen into the scopa, which is on the legs in most bees, and on the ventral abdomen on others, and modified into specialized pollen baskets on the legs of honey bees and their relatives. Many bees are opportunistic foragers, and will gather pollen from a variety of plants, but many others are oligolectic, gathering pollen from only one or a few types of plant. A small number of plants produce nutritious floral oils rather than pollen, which are gathered and used by oligolectic bees. One small subgroup of stingless bees (called "vulture bees") is specialized to feed on carrion, and these are the only bees that do not use plant products as food. Pollen and nectar are usually combined together to form a "provision mass", which is often soupy, but can be firm. It is formed into various shapes (typically spheroid), and stored in a small chamber (a "cell"), with the egg deposited on the mass. The cell is typically sealed after the egg is laid, and the adult and larva never interact directly (a system called "mass provisioning"). Visiting flowers can be a dangerous occupation. Many assassin bugs and crab spiders hide in flowers to capture unwary bees. Others are lost to birds in flight. Insecticides used on blooming plants can kill large numbers of bees, both by direct poisoning and by contamination of their food supply. A honey bee queen may lay 2000 eggs per day during spring buildup, but she also must lay 1000 to 1500 eggs per day during the foraging season, mostly to replace daily casualties - note, however, that most casualties are workers simply dying of old age rather than predation. Among solitary and primitively social bees, however, lifetime reproduction is among the lowest of all insects, as it is not uncommon for females of such species to produce fewer than 25 offspring. The population value of bees depends partly on the individual efficiency of the bees, but also on the population itself. Thus, while bumblebees have been found to be about ten times more efficient pollinators on cucurbits, the total efficiency of a colony of honey bees is much greater, due to greater numbers. Likewise, during early spring orchard blossoms, bumblebee populations are limited to only a few queens, and thus are not significant pollinators of early fruit. See also List of plants pollinated by bees # Evolution Bees, like ants, are essentially a highly specialized form of wasp. The ancestors of bees were wasps in the family Crabronidae, and therefore predators of other insects. The switch from insect prey to pollen may have resulted from the consumption of prey insects that were flower visitors and were partially covered with pollen when they were fed to the wasp larvae. This same evolutionary scenario has also occurred within the vespoid wasps, where the group known as "pollen wasps" also evolved from predatory ancestors. Up until recently the oldest non-compression bee fossil had been Cretotrigona prisca in New Jersey amber and of Cretaceous age, a meliponine. A recently reported bee fossil, of the genus Melittosphex, is considered "an extinct lineage of pollen-collecting Apoidea sister to the modern bees", and dates from the early Cretaceous (~100 mya). Derived features of its morphology ("apomorphies") place it clearly within the bees, but it retains two unmodified ancestral traits ("plesiomorphies") of the legs (two mid-tibial spurs, and a slender hind basitarsus), indicative of its transitional status. The earliest animal-pollinated flowers were pollinated by insects such as beetles, so the syndrome of insect pollination was well established before bees first appeared. The novelty is that bees are specialized as pollination agents, with behavioral and physical modifications that specifically enhance pollination, and are much more efficient at the task than beetles, flies, butterflies, pollen wasps, or any other pollinating insect. The appearance of such floral specialists is believed to have driven the adaptive radiation of the angiosperms, and, in turn, the bees themselves. Among living bee groups, the Dasypodaidae are now considered to be the most "primitive", and sister taxon to the remainder of the bees, contrary to earlier hypotheses that the "short-tongued" bee family Colletidae was the basal group of bees; the short, wasp-like mouthparts of colletids are apparently the result of convergent evolution, rather than indicative of a plesiomorphic condition. # Eusocial and semisocial bees Bees may be solitary or may live in various types of communities. The most advanced of these are eusocial colonies found among the honey bees, bumblebees, and stingless bees. Sociality, of several different types, is believed to have evolved separately many times within the bees. In some species, groups of cohabiting females may be sisters, and if there is a division of labor within the group, then they are considered semisocial. If, in addition to a division of labor, the group consists of a mother and her daughters, then the group is called eusocial. The mother is considered the "queen" and the daughters are "workers". These castes may be purely behavioral alternatives, in which case the system is considered "primitively eusocial" (similar to many paper wasps), and if the castes are morphologically discrete, then the system is "highly eusocial". There are many more species of primitively eusocial bees than highly eusocial bees, but they have been rarely studied. The biology of most such species is almost completely unknown. The vast majority are in the family Halictidae, or "sweat bees". Colonies are typically small, with a dozen or fewer workers, on average. The only physical difference between queens and workers is average size, if they differ at all. Most species have a single season colony cycle, even in the tropics, and only mated females (future queens, or "gynes") hibernate (called diapause). A few species have long active seasons and attain colony sizes in the hundreds. The orchid bees include a number of primitively eusocial species with similar biology. Certain species of allodapine bees (relatives of carpenter bees) also have primitively eusocial colonies, with unusual levels of interaction between the adult bees and the developing brood. This is "progressive provisioning"; a larva's food is supplied gradually as it develops. This system is also seen in honey bees and some bumblebees. Highly eusocial bees live in colonies. Each colony has a single queen, together with workers and, at certain stages in the colony cycle, drones. When humans provide a home for a colony, the structure is called a hive. A honey bee hive can contain up to 40,000 bees at their annual peak, which occurs in the spring, but usually have fewer. ## Bumblebees Bumblebees (Bombus terrestris, B. pratorum, et al.) are eusocial in a manner quite similar to the eusocial Vespidae such as hornets. The queen initiates a nest on her own (unlike queens of honey bees and stingless bees which start nests via swarms in the company of a large worker force). Bumblebee colonies typically have from 50 to 200 bees at peak population, which occurs in mid to late summer. Nest architecture is simple, limited by the size of the nest cavity (pre-existing), and colonies are rarely perennial. Bumblebee queens sometimes seek winter safety in honey bee hives, where they are sometimes found dead in the spring by beekeepers, presumably stung to death by the honey bees. It is unknown whether any survive winter in such an environment. ## Stingless bees Stingless bees are very diverse in behavior, but all are highly eusocial. They practice mass provisioning, complex nest architecture, and perennial colonies. ## Honey bees The true honey bees (genus Apis) have arguably the most complex social behavior among the bees. The Western (or European) honey bee, Apis mellifera, is the best known bee species and one of the best known of all insects. ## Africanized honey bee Africanized bees, also called killer bees, are a hybrid strain of Apis mellifera derived from experiments to cross European and African honey bees by Warwick Estevam Kerr. Several queen bees escaped his laboratory in South America and have spread throughout the Americas. Africanized honey bees are more defensive than European honey bees. # Solitary and communal bees Most other bees, including familiar species of bee such as the Eastern carpenter bee (Xylocopa virginica), alfalfa leafcutter bee (Megachile rotundata), orchard mason bee (Osmia lignaria) and the hornfaced bee (Osmia cornifrons) are solitary in the sense that every female is fertile, and typically inhabits a nest she constructs herself. There are no worker bees for these species. Solitary bees typically produce neither honey nor beeswax. They are immune from acarine and Varroa mites (see diseases of the honey bee), but have their own unique parasites, pests and diseases. Solitary bees are important pollinators, and pollen is gathered for provisioning the nest with food for their brood. Often it is mixed with nectar to form a paste-like consistency. Some solitary bees have very advanced types of pollen carrying structures on their bodies. A very few species of solitary bees are being increasingly cultured for commercial pollination. Solitary bees are often oligoleges, in that they only gather pollen from one or a few species/genera of plants (unlike honey bees and bumblebees which are generalists). No known bees are nectar specialists; many oligolectic bees will visit multiple plants for nectar, but there are no bees which visit only one plant for nectar while also gathering pollen from many different sources. Specialist pollinators also include bee species that gather floral oils instead of pollen, and male orchid bees, which gather aromatic compounds from orchids (one of the only cases where male bees are effective pollinators). In a very few cases only one species of bee can effectively pollinate a plant species, and some plants are endangered at least in part because their pollinator is dying off. There is, however, a pronounced tendency for oligolectic bees to be associated with common, widespread plants which are visited by multiple pollinators (e.g., there are some 40 oligoleges associated with creosotebush in the US desert southwest, and a similar pattern is seen in sunflowers, asters, mesquite, etc.) Solitary bees create nests in hollow reeds or twigs, holes in wood, or, most commonly, in tunnels in the ground. The female typically creates a compartment (a "cell") with an egg and some provisions for the resulting larva, then seals it off. A nest may consist of numerous cells. When the nest is in wood, usually the last (those closer to the entrance) contain eggs that will become males. The adult does not provide care for the brood once the egg is laid, and usually dies after making one or more nests. The males typically emerge first and are ready for mating when the females emerge. Providing nest boxes for solitary bees is increasingly popular for gardeners. Solitary bees are either stingless or very unlikely to sting (only in self defense, if ever). While solitary females each make individual nests, some species are gregarious, preferring to make nests near others of the same species, giving the appearance to the casual observer that they are social. Large groups of solitary bee nests are called aggregations, to distinguish them from colonies. In some species, multiple females share a common nest, but each makes and provisions her own cells independently. This type of group is called "communal" and is not uncommon. The primary advantage appears to be that a nest entrance is easier to defend from predators and parasites when there are multiple females using that same entrance on a regular basis. # Cleptoparasitic bees Cleptoparasitic bees, commonly called "cuckoo bees" because their behavior is similar to cuckoo birds, occur in several bee families, though the name is technically best applied to the apid subfamily Nomadinae. Females of these bees lack pollen collecting structures (the scopa) and do not construct their own nests. They typically enter the nests of pollen collecting species, and lay their eggs in cells provisioned by the host bee. When the cuckoo bee larva hatches it consumes the host larva's pollen ball, and if the female cleptoparasite has not already done so, kills and eats the host larva. In a few cases where the hosts are social species, the cleptoparasite remains in the host nest and lays many eggs, sometimes even killing the host queen and replacing her. Many cleptoparasitic bees are closely related to, and resemble, their hosts in looks and size, (i.e., the Bombus subgenus Psithyrus, which are parasitic bumble bees that infiltrate nests of species in other subgenera of Bombus). This common pattern gave rise to the ecological principle known as "Emery's Rule". Others parasitize bees in different families, like Townsendiella, a nomadine apid, one species of which is a cleptoparasite of the dasypodaid genus Hesperapis, while the other species in the same genus attack halictid bees. # "Nocturnal" bees Four bee families (Andrenidae, Colletidae, Halictidae, and Apidae) contain some species that are crepuscular (these may be either the "vespertine" or "matinal" type). These bees have greatly enlarged ocelli, which are extremely sensitive to light and dark, though incapable of forming images. Many are pollinators of flowers that themselves are crepuscular, such as evening primroses, and some live in desert habitats where daytime temperatures are extremely high. # Bee flight There is a reference in the 1934 French book Le vol des insectes by M. Magnan, in which it is written that he and a Mr. Saint-Lague had applied the equations of air resistance to bumblebees and found that their flight was impossible, but that "One shouldn't be surprised that the results of the calculations don't square with reality". In 1996 Charlie Ellington at Cambridge University, UK, showed that vortices created by many insects’ wings and non-linear effects were a vital source of lift—vortices and non-linear phenomena are notoriously difficult areas of hydrodynamics, which has made for slow progress in theoretical understanding of insect flight. In 2005 Michael Dickinson and colleagues at Caltech studied honey bee flight with the assistance of high-speed cinematography and a giant robotic mock-up of a bee wing, which "proves bees can fly, thank God”. # Miscellaneous Bees figure prominently in mythology. See Bee (mythology). Bees are the favorite meal of Merops apiaster, a bird. Other common predators are kingbirds, mockingbirds, bee wolves, and dragonflies. In North America, yellowjackets and hornets, especially when encountered as flying pests, are often misidentified as bees, despite numerous differences between them. Bees are often affected or even harmed by encounters with toxic chemicals in the environment (see Bees and toxic chemicals). Despite the honey bee's painful sting and the stereotype of insects as pests, bees are generally held in high regard. This is most likely due to their usefulness as pollinators and as producers of honey, their social nature and their reputation for diligence. Bees are one of the few insects used on advertisements, being used to illustrate honey and foods made with honey. Although a bee sting can be deadly to those with allergies, virtually all bee species are non-aggressive if undisturbed and many cannot sting at all. Bee Wilson states that a community of honey bees have often been employed historically by political theorists as a model of human society: This image occurs from ancient to modern times, in Aristotle and Plato; in Virgil and Seneca; in Erasmus and Shakespeare; Tolstoy, as well as by social theorists Bernard Mandeville and Karl Marx. # Gallery - two species together two species together - Western honey bee, Poland Western honey bee, Poland - Western honey bee on a Sphaeralcea flower. Mesa, Az Western honey bee on a Sphaeralcea flower. Mesa, Az - Western honey bee in a Sphaeralcea flower. Mesa, Az Western honey bee in a Sphaeralcea flower. Mesa, Az - Sweat bee, Agapostemon virescens (female) on a Coreopsis flower. Madison, Wi Sweat bee, Agapostemon virescens (female) on a Coreopsis flower. Madison, Wi - Bumblebee, Bombus sp. startles Agapostemon virescens. Madison, Wi Bumblebee, Bombus sp. startles Agapostemon virescens. Madison, Wi - Western honey bee on lavender Western honey bee on lavender - Western honey bee, Kaunakakai, HI Western honey bee, Kaunakakai, HI - Western honey bees, Lebanon. Western honey bees, Lebanon. - Western honey bee, Lebanon. Western honey bee, Lebanon. - Western honey bee collecting pollen from a rose. Western honey bee collecting pollen from a rose. - Western honey bee collecting nectar from small flowers. Location: McKinney, Texas. Western honey bee collecting nectar from small flowers. Location: McKinney, Texas. - Hovering bumblebee at lupine Hovering bumblebee at lupine - Western honey bee on Apple blossom Western honey bee on Apple blossom

Bee Template:Otheruses6 Template:For2 Bees are flying insects closely related to wasps and ants. Bees are a monophyletic lineage within the superfamily Apoidea, presently classified by the unranked taxon name Anthophila. There are slightly fewer than 20,000 known species of bee, in 9 recognized families,[1] though many are undescribed and the actual number is probably higher. They are found on every continent except Antarctica, in every habitat on the planet that contains flowering dicotyledons. # Introduction Bees are adapted for feeding on nectar and pollen, the former primarily as an energy source, and the latter primarily for protein and other nutrients. Most pollen is used as food for larvae. Bees have a long proboscis (a complex "tongue") that enables them to obtain the nectar from flowers. They have antennae almost universally made up of thirteen segments in males and twelve in females, as is typical for the superfamily. Bees all have two pairs of wings, the hind pair being the smaller of the two; in a very few species, one sex or caste has relatively short wings that make flight difficult or impossible, but none are wingless. The smallest bee is the dwarf bee (Trigona minima), about 2.1 mm (5/64") long. The largest bee in the world is Megachile pluto, which can grow to a size of 39 mm (1.5"). Member of the family Halictidae, or sweat bees, are the most common type of bee in the Northern Hemisphere, though they are small and often mistaken for wasps or flies. The best-known bee species is the Western honey bee, which, as its name suggests, produces honey, as do a few other types of bee. Human management of this species is known as beekeeping or apiculture. # Pollination Bees play an important role in pollinating flowering plants, and are the major type of pollinators in ecosystems that contain flowering plants. Bees may focus on gathering nectar or on gathering pollen, depending on their greater need at the time, especially in social species. Bees gathering nectar may accomplish pollination, but bees that are deliberately gathering pollen are more efficient pollinators. It is estimated that one third of the human food supply depends on insect pollination, most of this accomplished by bees. Bees are extremely important as pollinators in agriculture, especially the domesticated Western honey bee, with contract pollination having overtaken the role of honey production for beekeepers in many countries. Monoculture and pollinator decline (of many bee species) have increasingly caused honey bee keepers to become migratory so that bees can be concentrated in areas of pollination need at the appropriate season. Recently, many such migratory beekeepers have experienced substantial losses, prompting the announcement of investigation into the phenomenon, dubbed "Colony Collapse Disorder," amidst great concern over the nature and extent of the losses. Many other species of bees such as mason bees are increasingly cultured and used to meet the agricultural pollination need. Bees also play a major, though not always understood, role in providing food for birds and wildlife. Many of these bees survive in refuge in wild areas away from agricultural spraying, only to be poisoned in massive spray programs for mosquitoes, gypsy moths, or other insect pests. Most bees are fuzzy and carry an electrostatic charge, thus aiding in the adherence of pollen. Female bees periodically stop foraging and groom themselves to pack the pollen into the scopa, which is on the legs in most bees, and on the ventral abdomen on others, and modified into specialized pollen baskets on the legs of honey bees and their relatives. Many bees are opportunistic foragers, and will gather pollen from a variety of plants, but many others are oligolectic, gathering pollen from only one or a few types of plant. A small number of plants produce nutritious floral oils rather than pollen, which are gathered and used by oligolectic bees. One small subgroup of stingless bees (called "vulture bees") is specialized to feed on carrion, and these are the only bees that do not use plant products as food. Pollen and nectar are usually combined together to form a "provision mass", which is often soupy, but can be firm. It is formed into various shapes (typically spheroid), and stored in a small chamber (a "cell"), with the egg deposited on the mass. The cell is typically sealed after the egg is laid, and the adult and larva never interact directly (a system called "mass provisioning"). Visiting flowers can be a dangerous occupation. Many assassin bugs and crab spiders hide in flowers to capture unwary bees. Others are lost to birds in flight. Insecticides used on blooming plants can kill large numbers of bees, both by direct poisoning and by contamination of their food supply. A honey bee queen may lay 2000 eggs per day during spring buildup, but she also must lay 1000 to 1500 eggs per day during the foraging season, mostly to replace daily casualties - note, however, that most casualties are workers simply dying of old age rather than predation. Among solitary and primitively social bees, however, lifetime reproduction is among the lowest of all insects, as it is not uncommon for females of such species to produce fewer than 25 offspring. The population value of bees depends partly on the individual efficiency of the bees, but also on the population itself. Thus, while bumblebees have been found to be about ten times more efficient pollinators on cucurbits, the total efficiency of a colony of honey bees is much greater, due to greater numbers. Likewise, during early spring orchard blossoms, bumblebee populations are limited to only a few queens, and thus are not significant pollinators of early fruit. See also List of plants pollinated by bees # Evolution Bees, like ants, are essentially a highly specialized form of wasp. The ancestors of bees were wasps in the family Crabronidae, and therefore predators of other insects. The switch from insect prey to pollen may have resulted from the consumption of prey insects that were flower visitors and were partially covered with pollen when they were fed to the wasp larvae. This same evolutionary scenario has also occurred within the vespoid wasps, where the group known as "pollen wasps" also evolved from predatory ancestors. Up until recently the oldest non-compression bee fossil had been Cretotrigona prisca in New Jersey amber and of Cretaceous age, a meliponine. A recently reported bee fossil, of the genus Melittosphex, is considered "an extinct lineage of pollen-collecting Apoidea sister to the modern bees", and dates from the early Cretaceous (~100 mya).[2] Derived features of its morphology ("apomorphies") place it clearly within the bees, but it retains two unmodified ancestral traits ("plesiomorphies") of the legs (two mid-tibial spurs, and a slender hind basitarsus), indicative of its transitional status. The earliest animal-pollinated flowers were pollinated by insects such as beetles, so the syndrome of insect pollination was well established before bees first appeared. The novelty is that bees are specialized as pollination agents, with behavioral and physical modifications that specifically enhance pollination, and are much more efficient at the task than beetles, flies, butterflies, pollen wasps, or any other pollinating insect. The appearance of such floral specialists is believed to have driven the adaptive radiation of the angiosperms, and, in turn, the bees themselves. Among living bee groups, the Dasypodaidae are now considered to be the most "primitive", and sister taxon to the remainder of the bees, contrary to earlier hypotheses that the "short-tongued" bee family Colletidae was the basal group of bees; the short, wasp-like mouthparts of colletids are apparently the result of convergent evolution, rather than indicative of a plesiomorphic condition.[1] # Eusocial and semisocial bees Bees may be solitary or may live in various types of communities. The most advanced of these are eusocial colonies found among the honey bees, bumblebees, and stingless bees. Sociality, of several different types, is believed to have evolved separately many times within the bees. In some species, groups of cohabiting females may be sisters, and if there is a division of labor within the group, then they are considered semisocial. If, in addition to a division of labor, the group consists of a mother and her daughters, then the group is called eusocial. The mother is considered the "queen" and the daughters are "workers". These castes may be purely behavioral alternatives, in which case the system is considered "primitively eusocial" (similar to many paper wasps), and if the castes are morphologically discrete, then the system is "highly eusocial". There are many more species of primitively eusocial bees than highly eusocial bees, but they have been rarely studied. The biology of most such species is almost completely unknown. The vast majority are in the family Halictidae, or "sweat bees". Colonies are typically small, with a dozen or fewer workers, on average. The only physical difference between queens and workers is average size, if they differ at all. Most species have a single season colony cycle, even in the tropics, and only mated females (future queens, or "gynes") hibernate (called diapause). A few species have long active seasons and attain colony sizes in the hundreds. The orchid bees include a number of primitively eusocial species with similar biology. Certain species of allodapine bees (relatives of carpenter bees) also have primitively eusocial colonies, with unusual levels of interaction between the adult bees and the developing brood. This is "progressive provisioning"; a larva's food is supplied gradually as it develops. This system is also seen in honey bees and some bumblebees. Highly eusocial bees live in colonies. Each colony has a single queen, together with workers and, at certain stages in the colony cycle, drones. When humans provide a home for a colony, the structure is called a hive. A honey bee hive can contain up to 40,000 bees at their annual peak, which occurs in the spring, but usually have fewer. ## Bumblebees Bumblebees (Bombus terrestris, B. pratorum, et al.) are eusocial in a manner quite similar to the eusocial Vespidae such as hornets. The queen initiates a nest on her own (unlike queens of honey bees and stingless bees which start nests via swarms in the company of a large worker force). Bumblebee colonies typically have from 50 to 200 bees at peak population, which occurs in mid to late summer. Nest architecture is simple, limited by the size of the nest cavity (pre-existing), and colonies are rarely perennial. Bumblebee queens sometimes seek winter safety in honey bee hives, where they are sometimes found dead in the spring by beekeepers, presumably stung to death by the honey bees. It is unknown whether any survive winter in such an environment. ## Stingless bees Stingless bees are very diverse in behavior, but all are highly eusocial. They practice mass provisioning, complex nest architecture, and perennial colonies. ## Honey bees The true honey bees (genus Apis) have arguably the most complex social behavior among the bees. The Western (or European) honey bee, Apis mellifera, is the best known bee species and one of the best known of all insects. ## Africanized honey bee Africanized bees, also called killer bees, are a hybrid strain of Apis mellifera derived from experiments to cross European and African honey bees by Warwick Estevam Kerr. Several queen bees escaped his laboratory in South America and have spread throughout the Americas. Africanized honey bees are more defensive than European honey bees. # Solitary and communal bees Most other bees, including familiar species of bee such as the Eastern carpenter bee (Xylocopa virginica), alfalfa leafcutter bee (Megachile rotundata), orchard mason bee (Osmia lignaria) and the hornfaced bee (Osmia cornifrons) are solitary in the sense that every female is fertile, and typically inhabits a nest she constructs herself. There are no worker bees for these species. Solitary bees typically produce neither honey nor beeswax. They are immune from acarine and Varroa mites (see diseases of the honey bee), but have their own unique parasites, pests and diseases. Solitary bees are important pollinators, and pollen is gathered for provisioning the nest with food for their brood. Often it is mixed with nectar to form a paste-like consistency. Some solitary bees have very advanced types of pollen carrying structures on their bodies. A very few species of solitary bees are being increasingly cultured for commercial pollination. Solitary bees are often oligoleges, in that they only gather pollen from one or a few species/genera of plants (unlike honey bees and bumblebees which are generalists). No known bees are nectar specialists; many oligolectic bees will visit multiple plants for nectar, but there are no bees which visit only one plant for nectar while also gathering pollen from many different sources. Specialist pollinators also include bee species that gather floral oils instead of pollen, and male orchid bees, which gather aromatic compounds from orchids (one of the only cases where male bees are effective pollinators). In a very few cases only one species of bee can effectively pollinate a plant species, and some plants are endangered at least in part because their pollinator is dying off. There is, however, a pronounced tendency for oligolectic bees to be associated with common, widespread plants which are visited by multiple pollinators (e.g., there are some 40 oligoleges associated with creosotebush in the US desert southwest[3], and a similar pattern is seen in sunflowers, asters, mesquite, etc.) Solitary bees create nests in hollow reeds or twigs, holes in wood, or, most commonly, in tunnels in the ground. The female typically creates a compartment (a "cell") with an egg and some provisions for the resulting larva, then seals it off. A nest may consist of numerous cells. When the nest is in wood, usually the last (those closer to the entrance) contain eggs that will become males. The adult does not provide care for the brood once the egg is laid, and usually dies after making one or more nests. The males typically emerge first and are ready for mating when the females emerge. Providing nest boxes for solitary bees is increasingly popular for gardeners. Solitary bees are either stingless or very unlikely to sting (only in self defense, if ever). While solitary females each make individual nests, some species are gregarious, preferring to make nests near others of the same species, giving the appearance to the casual observer that they are social. Large groups of solitary bee nests are called aggregations, to distinguish them from colonies. In some species, multiple females share a common nest, but each makes and provisions her own cells independently. This type of group is called "communal" and is not uncommon. The primary advantage appears to be that a nest entrance is easier to defend from predators and parasites when there are multiple females using that same entrance on a regular basis. # Cleptoparasitic bees Cleptoparasitic bees, commonly called "cuckoo bees" because their behavior is similar to cuckoo birds, occur in several bee families, though the name is technically best applied to the apid subfamily Nomadinae. Females of these bees lack pollen collecting structures (the scopa) and do not construct their own nests. They typically enter the nests of pollen collecting species, and lay their eggs in cells provisioned by the host bee. When the cuckoo bee larva hatches it consumes the host larva's pollen ball, and if the female cleptoparasite has not already done so, kills and eats the host larva. In a few cases where the hosts are social species, the cleptoparasite remains in the host nest and lays many eggs, sometimes even killing the host queen and replacing her. Many cleptoparasitic bees are closely related to, and resemble, their hosts in looks and size, (i.e., the Bombus subgenus Psithyrus, which are parasitic bumble bees that infiltrate nests of species in other subgenera of Bombus). This common pattern gave rise to the ecological principle known as "Emery's Rule". Others parasitize bees in different families, like Townsendiella, a nomadine apid, one species of which is a cleptoparasite of the dasypodaid genus Hesperapis, while the other species in the same genus attack halictid bees. # "Nocturnal" bees Four bee families (Andrenidae, Colletidae, Halictidae, and Apidae) contain some species that are crepuscular (these may be either the "vespertine" or "matinal" type). These bees have greatly enlarged ocelli, which are extremely sensitive to light and dark, though incapable of forming images. Many are pollinators of flowers that themselves are crepuscular, such as evening primroses, and some live in desert habitats where daytime temperatures are extremely high. # Bee flight There is a reference in the 1934 French book Le vol des insectes by M. Magnan, in which it is written that he and a Mr. Saint-Lague had applied the equations of air resistance to bumblebees and found that their flight was impossible, but that "One shouldn't be surprised that the results of the calculations don't square with reality".[4] In 1996 Charlie Ellington at Cambridge University, UK, showed that vortices created by many insects’ wings and non-linear effects were a vital source of lift[1]—vortices and non-linear phenomena are notoriously difficult areas of hydrodynamics, which has made for slow progress in theoretical understanding of insect flight. In 2005 Michael Dickinson and colleagues at Caltech studied honey bee flight with the assistance of high-speed cinematography[2] and a giant robotic mock-up of a bee wing[5], which "proves bees can fly, thank God”. # Miscellaneous Bees figure prominently in mythology. See Bee (mythology). Bees are the favorite meal of Merops apiaster, a bird. Other common predators are kingbirds, mockingbirds, bee wolves, and dragonflies. In North America, yellowjackets and hornets, especially when encountered as flying pests, are often misidentified as bees, despite numerous differences between them. Bees are often affected or even harmed by encounters with toxic chemicals in the environment (see Bees and toxic chemicals). Despite the honey bee's painful sting and the stereotype of insects as pests, bees are generally held in high regard. This is most likely due to their usefulness as pollinators and as producers of honey, their social nature and their reputation for diligence. Bees are one of the few insects used on advertisements, being used to illustrate honey and foods made with honey. Although a bee sting can be deadly to those with allergies, virtually all bee species are non-aggressive if undisturbed and many cannot sting at all. Bee Wilson states that a community of honey bees have often been employed historically by political theorists as a model of human society: This image occurs from ancient to modern times, in Aristotle and Plato; in Virgil and Seneca; in Erasmus and Shakespeare; Tolstoy, as well as by social theorists Bernard Mandeville and Karl Marx.[6] # Gallery - two species together two species together - Western honey bee, Poland Western honey bee, Poland - Western honey bee on a Sphaeralcea flower. Mesa, Az Western honey bee on a Sphaeralcea flower. Mesa, Az - Western honey bee in a Sphaeralcea flower. Mesa, Az Western honey bee in a Sphaeralcea flower. Mesa, Az - Sweat bee, Agapostemon virescens (female) on a Coreopsis flower. Madison, Wi Sweat bee, Agapostemon virescens (female) on a Coreopsis flower. Madison, Wi - Bumblebee, Bombus sp. startles Agapostemon virescens. Madison, Wi Bumblebee, Bombus sp. startles Agapostemon virescens. Madison, Wi - Western honey bee on lavender Western honey bee on lavender - Western honey bee, Kaunakakai, HI Western honey bee, Kaunakakai, HI - Western honey bees, Lebanon. Western honey bees, Lebanon. - Western honey bee, Lebanon. Western honey bee, Lebanon. - Western honey bee collecting pollen from a rose. Western honey bee collecting pollen from a rose. - Western honey bee collecting nectar from small flowers. Location: McKinney, Texas. Western honey bee collecting nectar from small flowers. Location: McKinney, Texas. - Hovering bumblebee at lupine Hovering bumblebee at lupine - Western honey bee on Apple blossom Western honey bee on Apple blossom

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

fbd648696fdcd7aa73be55dd44da45aa2cfead6a

wikidoc

HBB

HBB Beta globin (also referred to as HBB, β-globin, haemoglobin beta, hemoglobin beta, or preferably haemoglobin subunit beta) is a globin protein, which along with alpha globin (HBA), makes up the most common form of haemoglobin in adult humans, the HbA. It is 146 amino acids long and has a molecular weight of 15,867 Da. Normal adult human HbA is a heterotetramer consisting of two alpha chains and two beta chains. HBB is encoded by the HBB gene on human chromosome 11. Mutations in the gene produce several variants of the proteins which are implicated with genetic disorders such as sickle-cell disease and beta thalassemia, as well as beneficial traits such as genetic resistance to malaria. # Gene locus HBB protein is produced by the gene HBB which is located in the multigene locus of β-globin locus on chromosome 11, specifically on the short arm position 15.5. Expression of beta globin and the neighbouring globins in the β-globin locus is controlled by single locus control region (LCR), the most important regulatory element in the locus located upstream of the globin genes. The normal allelic variant is 1600 base pairs (bp) long and contains three exons. The order of the genes in the beta-globin cluster is 5' - epsilon – gamma-G – gamma-A – delta – beta - 3'. # Transcriptions "DNA sequence analysis of a cloned β-globin gene from a Chinese patient with β-thalassemia revealed a single nucleotide substitution (A→ G) within the ATA box homology and 28 base pairs upstream from the cap site." "Comparison of the level of β-globin transcripts in a variety of deletion mutants shows that for efficient transcription, both the ATA or Goldberg–Hogness box, and a region between 100 and 58 base pairs in front of the site at which transcription is initiated, are required. Deletion of either of these regions results in a decrease in the level of β-globin transcripts by an order of magnitude; deletion of the ATA box causes an additional loss in the specificity of the site of initiation of RNA synthesis. The DNA sequences downstream from the ATA box, including the natural β-globin mRNA cap site, are dispensable for transcription in vivo." "The first is a sequence rich in the nucleic acids adenine and thymine (the Goldberg-Hogness, "TATA," or "ATA" box) which is located 20-30 base pairs upstream from the RNA initiation site (the cap site which is the transcriptional start site for the mRNA) and is characterized by a concensus sequence (5'-TATAA-ATA-3')." # Function GeneID: 3043 HBB hemoglobin subunit beta, "The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'." # Interactions HBB interacts with Hemoglobin, alpha 1 (HBA1) to form haemoglobin A, the major haemoglobin in adult humans. The interaction is two-fold. First, one HBB and one HBA1 combine, non-covalently, to form a dimer. Secondly, two dimers combine to form the four-chain tetramer, and this becomes the functional haemolglobin. # Associated genetic disorders ## Beta thalassemia Total or partial absence of HBB causes a genetic disease called beta thalassemia. Total loss called, thalassemia major or beta-0-thalassemia, is due to mutation in both alleles, and this results in failure to form beta chain of haemoglobin. It prevents oxygen supply in the tissues. It is highly lethal. Symptoms, such as severe anaemia and heart attack, appear within two years after birth. They can be treated only by lifelong blood transfusion and bone marrow transplantation. Reduced HBB function called thalassemia minor or beta+ thalassemia is due to mutation in one of the alleles. It is less severe but patients are prone to other diseases such as asthma and liver problems. According to a recent study, the stop gain mutation Gln40stop in HBB gene is a common cause of autosomal recessive Beta- thalassemia in Sardinian people (almost exclusive in Sardinia). Carriers of this mutation show an enhanced red blood cell count. As a curiosity, the same mutation was also associated to a decrease in serum LDL levels in carriers, so the authors suggest that is due to the need of cholesterol to regenerate cell membranes. ## Sickle cell disease More than a thousand naturally occurring HBB variants have been discovered. The most common is HbS, which causes sickle cell disease. HbS is produced by a point mutation in HBB in which the codon GAG is replaced by GTG. This results in the replacement of hydrophilic amino acid glutamic acid with the hydrophobic amino acid valine at the sixth position (β6Glu→Val). This substitution creates a hydrophobic spot on the outside of the protein that sticks to the hydrophobic region of an adjacent haemoglobin molecule's beta chain. This further causes clumping of HbS molecules into rigid fibers, causing "sickling" of the entire red blood cells in the homozygous (HbS/HbS) condition. The homozygous allele has become one of the deadliest genetic factors. Whereas, people heterozygous for the mutant allele (HbS/HbA) are resistant to malaria and develop minimal effects of the anaemia. ## Haemoglobin C Sickle cell disease is closely related to another mutant haemoglobin called haemoglobin C (HbC), because they can be inherited together. HbC mutation is at the same position in HbS, but glutamic acid is replaced by lysine (β6Glu→Lys). The mutation is particularly prevalent in West African populations. HbC provides near full protection against Plasmodium falciparum in homozygous (CC) individuals and intermediate protection in heterozygous (AC) individuals. This indicates that HbC has stronger influence than HbS, and is predicted to replace HbS in malaria-endemic regions. ## Haemoglobin E Another point mutation in HBB, in which glutamic acid is replaced with lysine at position 26 (β26Glu→Lys), leads to the formation of haemoglobin E (HbE). HbE has a very unstable α- and β-globin association. Even though the unstable protein itself has mild effect, inherited with HbS and thalassemia traits, it turns into a life-threatening form of β-thalassemia. The mutation is of relatively recent origin suggesting that it resulted from selective pressure against severe falciparum malaria, as heterozygous allele prevents the development of malaria. # Human evolution Malaria due to Plasmodium falciparum is a major selective factor in human evolution. It has influenced mutations in HBB in various degrees resulting in the existence of numerous HBB variants. Some of these mutations are not directly lethal and instead confer resistance to malaria, particularly in Africa where malaria is epidemic. People of African descent have evolved to have higher rates of the mutant HBB because the heterozygous individuals have a misshaped red blood cell that prevent attacks from malarial parasites. Thus, HBB mutants are the sources of positive selection in these regions and are important for their long-term survival. Such selection markers are important for tracing human ancestry and diversification from Africa.

HBB Associate Editor(s)-in-Chief: Henry A. Hoff Beta globin (also referred to as HBB, β-globin, haemoglobin beta, hemoglobin beta, or preferably haemoglobin subunit beta) is a globin protein, which along with alpha globin (HBA), makes up the most common form of haemoglobin in adult humans, the HbA.[1] It is 146 amino acids long and has a molecular weight of 15,867 Da. Normal adult human HbA is a heterotetramer consisting of two alpha chains and two beta chains. HBB is encoded by the HBB gene on human chromosome 11. Mutations in the gene produce several variants of the proteins which are implicated with genetic disorders such as sickle-cell disease and beta thalassemia, as well as beneficial traits such as genetic resistance to malaria.[2][3] # Gene locus HBB protein is produced by the gene HBB which is located in the multigene locus of β-globin locus on chromosome 11, specifically on the short arm position 15.5. Expression of beta globin and the neighbouring globins in the β-globin locus is controlled by single locus control region (LCR), the most important regulatory element in the locus located upstream of the globin genes.[4] The normal allelic variant is 1600 base pairs (bp) long and contains three exons. The order of the genes in the beta-globin cluster is 5' - epsilon – gamma-G – gamma-A – delta – beta - 3'.[1] # Transcriptions "DNA sequence analysis of a cloned β-globin gene from a Chinese patient with β-thalassemia revealed a single nucleotide substitution (A→ G) within the ATA box homology and 28 base pairs upstream from the cap site."[5] "Comparison of the level of β-globin transcripts in a variety of deletion mutants shows that for efficient transcription, both the ATA or Goldberg–Hogness box, and a region between 100 and 58 base pairs in front of the site at which transcription is initiated, are required. Deletion of either of these regions results in a decrease in the level of β-globin transcripts by an order of magnitude; deletion of the ATA box causes an additional loss in the specificity of the site of initiation of RNA synthesis. The DNA sequences downstream from the ATA box, including the natural β-globin mRNA cap site, are dispensable for transcription in vivo."[6] "The first is a sequence rich in the nucleic acids adenine and thymine (the Goldberg-Hogness, "TATA," or "ATA" box) which is located 20-30 base pairs upstream from the RNA initiation site (the cap site which is the transcriptional start site for the mRNA) and is characterized by a concensus sequence (5'-TATAA-ATA-3')."[7] # Function GeneID: 3043 HBB hemoglobin subunit beta, "The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'."[8] # Interactions HBB interacts with Hemoglobin, alpha 1 (HBA1) to form haemoglobin A, the major haemoglobin in adult humans.[9][10] The interaction is two-fold. First, one HBB and one HBA1 combine, non-covalently, to form a dimer. Secondly, two dimers combine to form the four-chain tetramer, and this becomes the functional haemolglobin.[11] # Associated genetic disorders ## Beta thalassemia Total or partial absence of HBB causes a genetic disease called beta thalassemia. Total loss called, thalassemia major or beta-0-thalassemia, is due to mutation in both alleles, and this results in failure to form beta chain of haemoglobin. It prevents oxygen supply in the tissues. It is highly lethal. Symptoms, such as severe anaemia and heart attack, appear within two years after birth. They can be treated only by lifelong blood transfusion and bone marrow transplantation.[12][13] Reduced HBB function called thalassemia minor or beta+ thalassemia is due to mutation in one of the alleles. It is less severe but patients are prone to other diseases such as asthma and liver problems.[14] According to a recent study, the stop gain mutation Gln40stop in HBB gene is a common cause of autosomal recessive Beta- thalassemia in Sardinian people (almost exclusive in Sardinia). Carriers of this mutation show an enhanced red blood cell count. As a curiosity, the same mutation was also associated to a decrease in serum LDL levels in carriers, so the authors suggest that is due to the need of cholesterol to regenerate cell membranes.[15] ## Sickle cell disease More than a thousand naturally occurring HBB variants have been discovered. The most common is HbS, which causes sickle cell disease. HbS is produced by a point mutation in HBB in which the codon GAG is replaced by GTG. This results in the replacement of hydrophilic amino acid glutamic acid with the hydrophobic amino acid valine at the sixth position (β6Glu→Val). This substitution creates a hydrophobic spot on the outside of the protein that sticks to the hydrophobic region of an adjacent haemoglobin molecule's beta chain. This further causes clumping of HbS molecules into rigid fibers, causing "sickling" of the entire red blood cells in the homozygous (HbS/HbS) condition.[16] The homozygous allele has become one of the deadliest genetic factors.[17] Whereas, people heterozygous for the mutant allele (HbS/HbA) are resistant to malaria and develop minimal effects of the anaemia.[18] ## Haemoglobin C Sickle cell disease is closely related to another mutant haemoglobin called haemoglobin C (HbC), because they can be inherited together.[19] HbC mutation is at the same position in HbS, but glutamic acid is replaced by lysine (β6Glu→Lys). The mutation is particularly prevalent in West African populations. HbC provides near full protection against Plasmodium falciparum in homozygous (CC) individuals and intermediate protection in heterozygous (AC) individuals.[20] This indicates that HbC has stronger influence than HbS, and is predicted to replace HbS in malaria-endemic regions.[21] ## Haemoglobin E Another point mutation in HBB, in which glutamic acid is replaced with lysine at position 26 (β26Glu→Lys), leads to the formation of haemoglobin E (HbE).[22] HbE has a very unstable α- and β-globin association. Even though the unstable protein itself has mild effect, inherited with HbS and thalassemia traits, it turns into a life-threatening form of β-thalassemia. The mutation is of relatively recent origin suggesting that it resulted from selective pressure against severe falciparum malaria, as heterozygous allele prevents the development of malaria.[23] # Human evolution Malaria due to Plasmodium falciparum is a major selective factor in human evolution.[3][24] It has influenced mutations in HBB in various degrees resulting in the existence of numerous HBB variants. Some of these mutations are not directly lethal and instead confer resistance to malaria, particularly in Africa where malaria is epidemic.[25] People of African descent have evolved to have higher rates of the mutant HBB because the heterozygous individuals have a misshaped red blood cell that prevent attacks from malarial parasites. Thus, HBB mutants are the sources of positive selection in these regions and are important for their long-term survival.[2][26] Such selection markers are important for tracing human ancestry and diversification from Africa.[27]

https://www.wikidoc.org/index.php/Beta-globin

18edafebc8848bc1a5615ecbe428b8558b00a0c2

wikidoc

Myc

Myc Myc is a family of regulator genes and proto-oncogenes that code for transcription factors. The Myc family consists of three related human genes: c-myc, l-myc, and n-myc. c-myc (also sometimes referred to as MYC) was the first gene to be discovered in this family, due to homology with the viral gene v-myc. In cancer, c-myc is often constitutively (persistently) expressed. This leads to the increased expression of many genes, some of which are involved in cell proliferation, contributing to the formation of cancer. A common human translocation involving c-myc is critical to the development of most cases of Burkitt lymphoma. Constitutive upregulation of Myc genes have also been observed in carcinoma of the cervix, colon, breast, lung and stomach. Myc is thus viewed as a promising target for anti-cancer drugs. In the human genome, C-myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes through binding on enhancer box sequences (E-boxes). In addition to its role as a classical transcription factor, N-myc may recruit histone acetyltransferases (HATs). This allows it to regulate global chromatin structure via histone acetylation. # Discovery The Myc family was first established after discovery of homology between an oncogene carried by the Avian virus, Myelocytomatosis (v-myc) and a human gene over-expressed in various cancers (c-Myc). Later, discovery of further homologous genes in humans led to the addition of n-Myc and l-Myc to the family of genes. The most frequently discussed example of c-Myc as an oncogene is its implication in Burkitt lymphoma. In Burkitt lymphoma, cancer cells show chromosomal translocations, most commonly between chromosome 8 and chromosome 14 . This causes c-Myc to be placed downstream of the highly active immunoglobulin (Ig) promoter region, leading to overexpression of c-Myc. # Structure The protein product of Myc family genes all belong to the Myc family of transcription factors, which contain bHLH (basic helix-loop-helix) and LZ (leucine zipper) structural motifs. The bHLH motif, allows Myc proteins to bind with DNA, while the leucine zipper TF-binding motif allows dimerization with Max, another bHLH transcription factor. Myc mRNA contains an IRES (internal ribosome entry site) that allows the RNA to be translated into protein when 5' cap-dependent translation is inhibited, such as during viral infection. # Function Myc proteins are transcription factors that activate expression of many pro-proliferative genes through binding enhancer box sequences (E-boxes) and recruiting histone acetyltransferases (HATs). Myc is thought to function by upregulating transcript elongation of actively transcribed genes through the recruitment of elongation factors. It can also act as a transcriptional repressor. By binding Miz-1 transcription factor and displacing the p300 co-activator, it inhibits expression of Miz-1 target genes. In addition, myc has a direct role in the control of DNA replication. Myc is activated upon various mitogenic signals such as serum stimulation or by Wnt, Shh and EGF (via the MAPK/ERK pathway). By modifying the expression of its target genes, Myc activation results in numerous biological effects. The first to be discovered was its capability to drive cell proliferation (upregulates cyclins, downregulates p21), but it also plays a very important role in regulating cell growth (upregulates ribosomal RNA and proteins), apoptosis (downregulates Bcl-2), differentiation, and stem cell self-renewal. Nucleotide metabolism genes are upregulated by Myc, which are necessary for Myc induced proliferation or cell growth. There have been several studies that have clearly indicated Myc's role in cell competition. A major effect of c-myc is B cell proliferation. c-Myc induces MTDH(AEG-1) gene expression and in turn itself requires AEG-1 oncogene for its expression. # Myc-nick Myc-nick is a cytoplasmic form of Myc produced by a partial proteolytic cleavage of full-length c-Myc and N-Myc. Myc cleavage is mediated by the calpain family of calcium-dependent cytosolic proteases. The cleavage of Myc by calpains is a constitutive process but is enhanced under conditions that require rapid downregulation of Myc levels, such as during terminal differentiation. Upon cleavage, the C-terminus of Myc (containing the DNA binding domain) is degraded, while Myc-nick, the N-terminal segment 298-residue segment remains in the cytoplasm. Myc-nick contains binding domains for histone acetyltransferases and for ubiquitin ligases. The functions of Myc-nick are currently under investigation, but this new Myc family member was found to regulate cell morphology, at least in part, by interacting with acetyl transferases to promote the acetylation of α-tubulin. Ectopic expression of Myc-nick accelerates the differentiation of committed myoblasts into muscle cells. Myc-Nick # Clinical significance Except for early response genes, Myc universally upregulates gene expression. Furthermore, the upregulation is nonlinear. Genes whose expression is already significantly upregulated in the absence of Myc are strongly boosted in the presence of Myc, whereas genes whose expression is low in the absence Myc get only a small boost when Myc is present. Inactivation of SUMO-activating enzyme (SAE1 / SAE2) in the presence of Myc hyperactivation results in mitotic catastrophe and cell death in cancer cells. Hence inhibitors of SUMOylation may be a possible treatment for cancer. Amplification of the MYC gene was found in a significant number of epithelial ovarian cancer cases. In TCGA datasets, the amplification of Myc occurs in several cancer types, including breast, colorectal, pancreatic, gastric, and uterine cancers. In the experimental transformation process of normal cells into cancer cells, the MYC gene can cooperate with the RAS gene. Expression of Myc is highly dependent on BRD4 function in some cancers. BET inhibitors have been used to successfully block Myc function in pre-clinical cancer models and are currently being evaluated in clinical trials. # Animal models In Drosophila Myc is encoded by the diminutive locus, (which was known to geneticists prior to 1935). Calssical diminutive alleles resulted in a viable animal with small body size. Drosophila has subsequently been used to implicate Myc in cell competition, endoreplication, and cell growth. During the discovery of Myc gene, it was realized that chromosomes that reciprocally translocate to chromosome 8 contained immunoglobulin genes at the break-point. Enhancers that normally drive expression of immunoglobin genes now lead to overexpression of Myc proto-oncogene in lymphoma cells. To study the mechanism of tumorigenesis in Burkitt lymphoma by mimicking expression pattern of Myc in these cancer cells, transgenic mouse models were developed. Myc gene placed under the control of IgM heavy chain enhancer in transgenic mice gives rise to mainly lymphomas. Later on, in order to study effects of Myc in other types of cancer, transgenic mice that overexpress Myc in different tissues (liver, breast) were also made. In all these mouse models overexpression of Myc causes tumorigenesis, illustrating the potency of Myc oncogene. In a study with mice, reduced expression of Myc was shown to induce longevity, with significantly extended median and maximum lifespans in both sexes and a reduced mortality rate across all ages, better health, cancer progression was slower, better metabolism and they had smaller bodies. Also, Less TOR, AKT, S6K and other changes in energy and metabolic pathways (such as AMPK, more oxygen consumption, more body movements, etc.). The study by John M. Sedivy and others used Cre-Loxp -recombinase to knockout one copy of Myc and this resulted in a "Haplo-insufficient" genotype noted as Myc+/-. The phenotypes seen oppose the effects of normal aging and are shared with many other long-lived mouse models such as CR (calorie restriction) ames dwarf, rapamycin, metformin and resveratrol. One study found that Myc and p53 genes were key to the survival of Chronic Myeloid Leukaemia (CML) cells. Targeting Myc and p53 proteins with drugs gave positive results on mice with CML. # Relationship to Stem Cells c-Myc plays a major role in the generation of induced pluripotent stem cells (iPSCs). It one of the original factors discovered by Yamanaka et al. to encourage cells to return to a 'stem-like' state alongside transcription factors Oct4, Sox2 and Klf4). It has since been shown that it is possible to generate iPSCs without c-Myc. # Interactions Myc has been shown to interact with: - ACTL6A - BRCA1 - Bcl-2 - Cyclin T1 - CHD8 - DNMT3A - EP400 - GTF2I - HTATIP - let-7 - MAPK1 - MAPK8 - MAX - MLH1 - MYCBP2 - MYCBP - NMI - NFYB - NFYC - P73 - PCAF - PFDN5 - RuvB-like 1 - SAP130 - SMAD2 - SMAD3 - SMARCA4 - SMARCB1 - SUPT3H - TIAM1 - TADA2L - TAF9 - TFAP2A - TRRAP - WDR5 - YY1 and - ZBTB17.

Myc Myc is a family of regulator genes and proto-oncogenes that code for transcription factors. The Myc family consists of three related human genes: c-myc, l-myc, and n-myc. c-myc (also sometimes referred to as MYC) was the first gene to be discovered in this family, due to homology with the viral gene v-myc. In cancer, c-myc is often constitutively (persistently) expressed. This leads to the increased expression of many genes, some of which are involved in cell proliferation, contributing to the formation of cancer.[1] A common human translocation involving c-myc is critical to the development of most cases of Burkitt lymphoma.[2] Constitutive upregulation of Myc genes have also been observed in carcinoma of the cervix, colon, breast, lung and stomach.[1] Myc is thus viewed as a promising target for anti-cancer drugs.[3] In the human genome, C-myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes[4] through binding on enhancer box sequences (E-boxes).[5] In addition to its role as a classical transcription factor, N-myc may recruit histone acetyltransferases (HATs). This allows it to regulate global chromatin structure via histone acetylation.[6] # Discovery The Myc family was first established after discovery of homology between an oncogene carried by the Avian virus, Myelocytomatosis (v-myc) and a human gene over-expressed in various cancers (c-Myc). Later, discovery of further homologous genes in humans led to the addition of n-Myc and l-Myc to the family of genes. The most frequently discussed example of c-Myc as an oncogene is its implication in Burkitt lymphoma. In Burkitt lymphoma, cancer cells show chromosomal translocations, most commonly between chromosome 8 and chromosome 14 [t(8;14)]. This causes c-Myc to be placed downstream of the highly active immunoglobulin (Ig) promoter region, leading to overexpression of c-Myc. # Structure The protein product of Myc family genes all belong to the Myc family of transcription factors, which contain bHLH (basic helix-loop-helix) and LZ (leucine zipper) structural motifs. The bHLH motif, allows Myc proteins to bind with DNA, while the leucine zipper TF-binding motif allows dimerization with Max, another bHLH transcription factor. Myc mRNA contains an IRES (internal ribosome entry site) that allows the RNA to be translated into protein when 5' cap-dependent translation is inhibited, such as during viral infection. # Function Myc proteins are transcription factors that activate expression of many pro-proliferative genes through binding enhancer box sequences (E-boxes) and recruiting histone acetyltransferases (HATs). Myc is thought to function by upregulating transcript elongation of actively transcribed genes through the recruitment of elongation factors.[7] It can also act as a transcriptional repressor. By binding Miz-1 transcription factor and displacing the p300 co-activator, it inhibits expression of Miz-1 target genes. In addition, myc has a direct role in the control of DNA replication.[8] Myc is activated upon various mitogenic signals such as serum stimulation or by Wnt, Shh and EGF (via the MAPK/ERK pathway).[9] By modifying the expression of its target genes, Myc activation results in numerous biological effects. The first to be discovered was its capability to drive cell proliferation (upregulates cyclins, downregulates p21), but it also plays a very important role in regulating cell growth (upregulates ribosomal RNA and proteins), apoptosis (downregulates Bcl-2), differentiation, and stem cell self-renewal. Nucleotide metabolism genes are upregulated by Myc,[10] which are necessary for Myc induced proliferation[11] or cell growth.[12] There have been several studies that have clearly indicated Myc's role in cell competition.[13] A major effect of c-myc is B cell proliferation.[14] c-Myc induces MTDH(AEG-1) gene expression and in turn itself requires AEG-1 oncogene for its expression. # Myc-nick Myc-nick is a cytoplasmic form of Myc produced by a partial proteolytic cleavage of full-length c-Myc and N-Myc.[15] Myc cleavage is mediated by the calpain family of calcium-dependent cytosolic proteases. The cleavage of Myc by calpains is a constitutive process but is enhanced under conditions that require rapid downregulation of Myc levels, such as during terminal differentiation. Upon cleavage, the C-terminus of Myc (containing the DNA binding domain) is degraded, while Myc-nick, the N-terminal segment 298-residue segment remains in the cytoplasm. Myc-nick contains binding domains for histone acetyltransferases and for ubiquitin ligases. The functions of Myc-nick are currently under investigation, but this new Myc family member was found to regulate cell morphology, at least in part, by interacting with acetyl transferases to promote the acetylation of α-tubulin. Ectopic expression of Myc-nick accelerates the differentiation of committed myoblasts into muscle cells. Myc-Nick # Clinical significance Except for early response genes, Myc universally upregulates gene expression. Furthermore, the upregulation is nonlinear. Genes whose expression is already significantly upregulated in the absence of Myc are strongly boosted in the presence of Myc, whereas genes whose expression is low in the absence Myc get only a small boost when Myc is present.[16] Inactivation of SUMO-activating enzyme (SAE1 / SAE2) in the presence of Myc hyperactivation results in mitotic catastrophe and cell death in cancer cells. Hence inhibitors of SUMOylation may be a possible treatment for cancer.[17] Amplification of the MYC gene was found in a significant number of epithelial ovarian cancer cases.[18] In TCGA datasets, the amplification of Myc occurs in several cancer types, including breast, colorectal, pancreatic, gastric, and uterine cancers.[19] In the experimental transformation process of normal cells into cancer cells, the MYC gene can cooperate with the RAS gene.[20][21] Expression of Myc is highly dependent on BRD4 function in some cancers.[22][23] BET inhibitors have been used to successfully block Myc function in pre-clinical cancer models and are currently being evaluated in clinical trials.[24][25] # Animal models In Drosophila Myc is encoded by the diminutive locus, (which was known to geneticists prior to 1935).[26] Calssical diminutive alleles resulted in a viable animal with small body size. Drosophila has subsequently been used to implicate Myc in cell competition,[27] endoreplication,[28] and cell growth.[29] During the discovery of Myc gene, it was realized that chromosomes that reciprocally translocate to chromosome 8 contained immunoglobulin genes at the break-point. Enhancers that normally drive expression of immunoglobin genes now lead to overexpression of Myc proto-oncogene in lymphoma cells. To study the mechanism of tumorigenesis in Burkitt lymphoma by mimicking expression pattern of Myc in these cancer cells, transgenic mouse models were developed. Myc gene placed under the control of IgM heavy chain enhancer in transgenic mice gives rise to mainly lymphomas. Later on, in order to study effects of Myc in other types of cancer, transgenic mice that overexpress Myc in different tissues (liver, breast) were also made. In all these mouse models overexpression of Myc causes tumorigenesis, illustrating the potency of Myc oncogene. In a study with mice, reduced expression of Myc was shown to induce longevity, with significantly extended median and maximum lifespans in both sexes and a reduced mortality rate across all ages, better health, cancer progression was slower, better metabolism and they had smaller bodies. Also, Less TOR, AKT, S6K and other changes in energy and metabolic pathways (such as AMPK, more oxygen consumption, more body movements, etc.). The study by John M. Sedivy and others used Cre-Loxp -recombinase to knockout one copy of Myc and this resulted in a "Haplo-insufficient" genotype noted as Myc+/-. The phenotypes seen oppose the effects of normal aging and are shared with many other long-lived mouse models such as CR (calorie restriction) ames dwarf, rapamycin, metformin and resveratrol. One study found that Myc and p53 genes were key to the survival of Chronic Myeloid Leukaemia (CML) cells. Targeting Myc and p53 proteins with drugs gave positive results on mice with CML.[30][31] # Relationship to Stem Cells c-Myc plays a major role in the generation of induced pluripotent stem cells (iPSCs). It one of the original factors discovered by Yamanaka et al. to encourage cells to return to a 'stem-like' state alongside transcription factors Oct4, Sox2 and Klf4). It has since been shown that it is possible to generate iPSCs without c-Myc. # Interactions Myc has been shown to interact with: - ACTL6A[32] - BRCA1[33][34][35][36] - Bcl-2[37] - Cyclin T1[38] - CHD8[39] - DNMT3A[40] - EP400[41] - GTF2I[42] - HTATIP[43] - let-7[44][45][46] - MAPK1[37][47][48] - MAPK8[49] - MAX[50][51][52][53][54][55][56][57][58][59][60][61][62] - MLH1[54] - MYCBP2[63] - MYCBP[64] - NMI[33] - NFYB[65] - NFYC[66] - P73[67] - PCAF[68] - PFDN5[69][70] - RuvB-like 1[32][41] - SAP130[68] - SMAD2[71] - SMAD3[71] - SMARCA4[32][50] - SMARCB1[53] - SUPT3H[68] - TIAM1[72] - TADA2L[68] - TAF9[68] - TFAP2A[73] - TRRAP[32][51][52][68] - WDR5[74] - YY1[75] and - ZBTB17.[76][77]

https://www.wikidoc.org/index.php/C-myc

3d0a8e7a952ac1a50f8fcabd6de31fd53d2f7482

wikidoc

C3b

C3b C3b is a one of the elements formed by the cleavage of complement component 3. C3b may bind to microbial cell surfaces within an organism's body. This can lead to the production of surface-bound C3 convertase and thus more C3b components. Also known as C3bBb, this convertase is similar to soluble C3-convertase except that it is membrane bound. Alternatively, bound C3b may aid in opsonization of the microbe by macrophages. Complement receptor 1 or CR1 on macrophages allows the engaging of C3b covered microbes. C3b is cleaved into C3c and C3d.

C3b Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] C3b is a one of the elements formed by the cleavage of complement component 3. C3b may bind to microbial cell surfaces within an organism's body. This can lead to the production of surface-bound C3 convertase and thus more C3b components. Also known as C3bBb, this convertase is similar to soluble C3-convertase except that it is membrane bound. Alternatively, bound C3b may aid in opsonization of the microbe by macrophages.[1] Complement receptor 1 or CR1 on macrophages allows the engaging of C3b covered microbes. C3b is cleaved into C3c and C3d. # External links - http://www.merck.com/mmpe/sec13/ch163/ch163d.html Template:WH Template:WS - ↑

https://www.wikidoc.org/index.php/C3b

23f50ed6dee9c6894fd30f0b90db6a4d8f8aeb9f

wikidoc

CD1

CD1 CD1 (cluster of differentiation 1) is a family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are related to the class I MHC molecules, and are involved in the presentation of lipid antigens to T cells. However their precise function is unknown. # Types CD1 glycoproteins can be classified primarily into two groups which differ in their lipid anchoring. - CD1a, CD1b and CD1c (group 1 CD1 molecules) are expressed on cells specialized for antigen presentation. - CD1d (group 2 CD1) is expressed in a wider variety of cells. CD1e is an intermediate form, expressed intracellularly, the role of which is currently unclear. # In humans ## Group 1 Group 1 CD1 molecules have been shown to present foreign lipid antigens, and specifically a number of mycobacterial cell wall components, to CD1-specific T cells. ## Group 2 The natural antigens of group 2 CD1 are not well characterized, but a synthetic glycolipid, alpha-galactosylceramide, originally isolated from a compound found in a marine sponge, has strong biologic activity. Group 2 CD1 molecules activate a group of T cells, known as Natural killer T cells because of their expression of NK surface markers such as CD161. Natural Killer T (NKT) cells are activated by CD1d-presented antigens, and rapidly produce Th1 and Th2 cytokines, typically represented by interferon-gamma and IL-4 production. The group 2 (CD1d) ligand alpha-galactosylceramide is currently in phase I clinical trials for the treatment of advanced non-hematologic cancers. ## Diagnostic relevance CD1 antigens are expressed on cortical thymocytes, but not on mature T cells. This often remains true in neoplastic cells from these populations, so that the presence of CD1 antigens can be used in diagnostic immunohistochemistry to identify some thymomas and malignancies arising from T cell precursors. CD1a, in particular, is a specific marker for Langerhans cells, and can therefore also be used in the diagnosis of Langerhans cell histiocytosis. Other conditions that may show CD1 positivity include myeloid leukaemia and some B cell lymphomas. # In cows and mice Mice lack the group 1 CD1 molecules, and instead have 2 copies of CD1d. Thus, mice have been used extensively to characterize the role of CD1d and CD1d-dependent NKT cells in a variety of disease models. It has recently been shown that cows lack the group 2 CD1 molecules, and have an expanded set of group 1 CD1 molecules. Because of this and the fact that cows are a natural host of Mycobacterium bovis, a pathogen in humans as well, it is hoped that studying cows will yield insights into the group 1 CD1 antigen-presenting system.

CD1 CD1 (cluster of differentiation 1) is a family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are related to the class I MHC molecules, and are involved in the presentation of lipid antigens to T cells. However their precise function is unknown.[1] # Types CD1 glycoproteins can be classified primarily into two groups which differ in their lipid anchoring.[2] - CD1a, CD1b and CD1c (group 1 CD1 molecules) are expressed on cells specialized for antigen presentation.[3] - CD1d (group 2 CD1) is expressed in a wider variety of cells. CD1e is an intermediate form, expressed intracellularly, the role of which is currently unclear.[4] # In humans ## Group 1 Group 1 CD1 molecules have been shown to present foreign lipid antigens, and specifically a number of mycobacterial cell wall components, to CD1-specific T cells. ## Group 2 The natural antigens of group 2 CD1 are not well characterized, but a synthetic glycolipid, alpha-galactosylceramide, originally isolated from a compound found in a marine sponge, has strong biologic activity. Group 2 CD1 molecules activate a group of T cells, known as Natural killer T cells because of their expression of NK surface markers such as CD161. Natural Killer T (NKT) cells are activated by CD1d-presented antigens, and rapidly produce Th1 and Th2 cytokines, typically represented by interferon-gamma and IL-4 production. The group 2 (CD1d) ligand alpha-galactosylceramide is currently in phase I clinical trials for the treatment of advanced non-hematologic cancers. ## Diagnostic relevance CD1 antigens are expressed on cortical thymocytes, but not on mature T cells. This often remains true in neoplastic cells from these populations, so that the presence of CD1 antigens can be used in diagnostic immunohistochemistry to identify some thymomas and malignancies arising from T cell precursors. CD1a, in particular, is a specific marker for Langerhans cells, and can therefore also be used in the diagnosis of Langerhans cell histiocytosis. Other conditions that may show CD1 positivity include myeloid leukaemia and some B cell lymphomas.[5] # In cows and mice Mice lack the group 1 CD1 molecules, and instead have 2 copies of CD1d. Thus, mice have been used extensively to characterize the role of CD1d and CD1d-dependent NKT cells in a variety of disease models. It has recently been shown that cows lack the group 2 CD1 molecules, and have an expanded set of group 1 CD1 molecules.[6] Because of this and the fact that cows are a natural host of Mycobacterium bovis, a pathogen in humans as well, it is hoped that studying cows will yield insights into the group 1 CD1 antigen-presenting system.

https://www.wikidoc.org/index.php/CD1

31bdda805b04f21365220f750d354aa13d598227

wikidoc

CD2

CD2 CD2 (cluster of differentiation 2) is a cell adhesion molecule found on the surface of T cells and natural killer (NK) cells. It has also been called T-cell surface antigen T11/Leu-5, LFA-2, LFA-3 receptor, erythrocyte receptor and rosette receptor. # Function It interacts with other adhesion molecules, such as lymphocyte function-associated antigen-3 (LFA-3/CD58) in humans, or CD48 in rodents, which are expressed on the surfaces of other cells. In addition to its adhesive properties, CD2 also acts as a co-stimulatory molecule on T and NK cells. ## Diagnostic relevance CD2 is a specific marker for T cells and NK cells, and can therefore be used in immunohistochemistry to identify the presence of such cells in tissue sections. The great majority of T cell lymphomas and leukaemias also express CD2, making it possible to use the presence of the antigen to distinguish these conditions from B cell neoplasms. # Classification Due to its structural characteristics, CD2 is a member of the immunoglobulin superfamily; it possesses two immunoglobulin-like domains in its extracellular portion. # Interactions CD2 has been shown to interact with CD2BP2, Lck and PSTPIP1.

CD2 CD2 (cluster of differentiation 2) is a cell adhesion molecule found on the surface of T cells and natural killer (NK) cells. It has also been called T-cell surface antigen T11/Leu-5, LFA-2,[1] LFA-3 receptor, erythrocyte receptor and rosette receptor.[2] # Function It interacts with other adhesion molecules, such as lymphocyte function-associated antigen-3 (LFA-3/CD58) in humans, or CD48 in rodents, which are expressed on the surfaces of other cells.[3] In addition to its adhesive properties, CD2 also acts as a co-stimulatory molecule on T and NK cells.[4] ## Diagnostic relevance CD2 is a specific marker for T cells and NK cells, and can therefore be used in immunohistochemistry to identify the presence of such cells in tissue sections. The great majority of T cell lymphomas and leukaemias also express CD2, making it possible to use the presence of the antigen to distinguish these conditions from B cell neoplasms.[5] # Classification Due to its structural characteristics, CD2 is a member of the immunoglobulin superfamily; it possesses two immunoglobulin-like domains in its extracellular portion.[4] # Interactions CD2 has been shown to interact with CD2BP2,[6] Lck[7] and PSTPIP1.[8]

https://www.wikidoc.org/index.php/CD2

70b2f2334cf80927c6d76404433ed6c8da7ae66a

wikidoc

CD4

CD4 In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 (after the OKT4 monoclonal antibody that reacted with it) before being named CD4 in 1984. In humans, the CD4 protein is encoded by the CD4 gene. CD4+ T helper cells are white blood cells that are an essential part of the human immune system. They are often referred to as CD4 cells, T-helper cells or T4 cells. They are called helper cells because one of their main roles is to send signals to other types of immune cells, including CD8 killer cells, which then destroy the infectious particle. If CD4 cells become depleted, for example in untreated HIV infection, or following immune suppression prior to a transplant, the body is left vulnerable to a wide range of infections that it would otherwise have been able to fight. # Structure Like many cell surface receptors/markers, CD4 is a member of the immunoglobulin superfamily. It has four immunoglobulin domains (D1 to D4) that are exposed on the extracellular surface of the cell: - D1 and D3 resemble immunoglobulin variable (IgV) domains. - D2 and D4 resemble immunoglobulin constant (IgC) domains. The immunoglobulin variable (IgV) domain of D1 adopts an immunoglobulin-like β-sandwich fold with seven β-strands in 2 β-sheets, in a Greek key topology. CD4 interacts with the β2-domain of MHC class II molecules through its D1 domain. T cells displaying CD4 molecules (and not CD8) on their surface, therefore, are specific for antigens presented by MHC II and not by MHC class I (they are MHC class II-restricted). MHC class I contains Beta-2 microglobulin. The short cytoplasmic/intracellular tail (C) of CD4 contains a special sequence of amino acids that allow it to recruit and interact with the tyrosine kinase Lck. # Function CD4 is a co-receptor of the T cell receptor (TCR) and assists the latter in communicating with antigen-presenting cells. The TCR complex and CD4 each bind to distinct regions of the antigen-presenting MHCII molecule - α1/β1 and β2, respectively. In CD4 the interaction involves its extracellular D1 domain. The resulting close proximity between the TCR complex and CD4 (extracellular and intracellular) allows the tyrosine kinase Lck bound to the cytoplasmic tail of CD4 to tyrosine-phosphorylate the Immunoreceptor tyrosine activation motifs (ITAM) on the cytoplasmic domains of CD3 to amplify the signal generated by the TCR. Lck is essential for the activation of many molecular components of the signaling cascade of an activated T cell. Depending on the signal, different types of T helper cells result. Phosphorylated ITAM motifs on CD3 recruit and activate SH2 domain-containing protein tyrosine kinases (PTK) such as Zap70 to further mediate downstream signalling through tyrosine phosphorylation, leading to transcription factor activation including NF-κB and consequent T cell activation. ## Other interactions CD4 has also been shown to interact with SPG21, Lck and Protein unc-119 homolog. # Disease ## HIV infection HIV-1 uses CD4 to gain entry into host T-cells and achieves this through its viral envelope protein known as gp120. The binding to CD4 creates a shift in the conformation of gp120 allowing HIV-1 to bind to a co-receptor expressed on the host cell. These co-receptors are chemokine receptors CCR5 or CXCR4. Following a structural change in another viral protein (gp41), HIV inserts a fusion peptide into the host cell that allows the outer membrane of the virus to fuse with the cell membrane. ## HIV pathology HIV infection leads to a progressive reduction in the number of T cells expressing CD4. Medical professionals refer to the CD4 count to decide when to begin treatment during HIV infection, although recent medical guidelines have changed to recommend treatment at all CD4 counts as soon as HIV is diagnosed. A CD4 count measures the number of T cells expressing CD4. While CD4 counts are not a direct HIV test—e.g. they do not check the presence of viral DNA, or specific antibodies against HIV—they are used to assess the immune system of a patient. National Institutes of Health guidelines recommend treatment of any HIV-positive individuals, regardless of CD4 count Normal blood values are usually expressed as the number of cells per microliter (μL, or equivalently, cubic millimeter, mm3) of blood, with normal values for CD4 cells being 500–1200 cells/mm3. Patients often undergo treatments when the CD4 counts reach a level of 350 cells per microliter in Europe but usually around 500/μL in the US; people with less than 200 cells per microliter are at high risk of contracting AIDS defined illnesses. Medical professionals also refer to CD4 tests to determine efficacy of treatment. Viral load testing provides more information about the efficacy for therapy than CD4 counts. For the first 2 years of HIV therapy, CD4 counts may be done every 3–6 months. If a patient's viral load becomes undetectable after 2 years then CD4 counts might not be needed if they are consistently above 500/mm3. If the count remains at 300–500/mm3, then the tests can be done annually. It is not necessary to schedule CD4 counts with viral load tests and the two should be done independently when each is indicated. ## Other diseases CD4 continues to be expressed in most neoplasms derived from T helper cells. It is therefore possible to use CD4 immunohistochemistry on tissue biopsy samples to identify most forms of peripheral T cell lymphoma and related malignant conditions. The antigen has also been associated with a number of autoimmune diseases such as vitiligo and type I diabetes mellitus. T-cells play a large part in autoinflammatory diseases. When testing a drug's efficacy or studying diseases, it is helpful to quantify the amount of T-cells. -n fresh-frozen tissue with CD4+, CD8+, and CD3+ T-cell markers (which stain different markers on a T-cell - giving different results).

CD4 In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 (after the OKT4 monoclonal antibody that reacted with it) before being named CD4 in 1984.[1] In humans, the CD4 protein is encoded by the CD4 gene.[2][3] CD4+ T helper cells are white blood cells that are an essential part of the human immune system. They are often referred to as CD4 cells, T-helper cells or T4 cells. They are called helper cells because one of their main roles is to send signals to other types of immune cells, including CD8 killer cells, which then destroy the infectious particle. If CD4 cells become depleted, for example in untreated HIV infection, or following immune suppression prior to a transplant, the body is left vulnerable to a wide range of infections that it would otherwise have been able to fight. # Structure Like many cell surface receptors/markers, CD4 is a member of the immunoglobulin superfamily. It has four immunoglobulin domains (D1 to D4) that are exposed on the extracellular surface of the cell: - D1 and D3 resemble immunoglobulin variable (IgV) domains. - D2 and D4 resemble immunoglobulin constant (IgC) domains. The immunoglobulin variable (IgV) domain of D1 adopts an immunoglobulin-like β-sandwich fold with seven β-strands in 2 β-sheets, in a Greek key topology.[4] CD4 interacts with the β2-domain of MHC class II molecules through its D1 domain. T cells displaying CD4 molecules (and not CD8) on their surface, therefore, are specific for antigens presented by MHC II and not by MHC class I (they are MHC class II-restricted). MHC class I contains Beta-2 microglobulin. The short cytoplasmic/intracellular tail (C) of CD4 contains a special sequence of amino acids that allow it to recruit and interact with the tyrosine kinase Lck. # Function CD4 is a co-receptor of the T cell receptor (TCR) and assists the latter in communicating with antigen-presenting cells. The TCR complex and CD4 each bind to distinct regions of the antigen-presenting MHCII molecule - α1/β1 and β2, respectively. In CD4 the interaction involves its extracellular D1 domain. The resulting close proximity between the TCR complex and CD4 (extracellular and intracellular) allows the tyrosine kinase Lck bound to the cytoplasmic tail of CD4 to tyrosine-phosphorylate the Immunoreceptor tyrosine activation motifs (ITAM) on the cytoplasmic domains of CD3 to amplify the signal generated by the TCR. Lck is essential for the activation of many molecular components of the signaling cascade of an activated T cell. Depending on the signal, different types of T helper cells result. Phosphorylated ITAM motifs on CD3 recruit and activate SH2 domain-containing protein tyrosine kinases (PTK) such as Zap70 to further mediate downstream signalling through tyrosine phosphorylation, leading to transcription factor activation including NF-κB and consequent T cell activation.[citation needed] ## Other interactions CD4 has also been shown to interact with SPG21,[5] Lck[6][7][8][9][10] and Protein unc-119 homolog.[11] # Disease ## HIV infection HIV-1 uses CD4 to gain entry into host T-cells and achieves this through its viral envelope protein known as gp120.[12] The binding to CD4 creates a shift in the conformation of gp120 allowing HIV-1 to bind to a co-receptor expressed on the host cell. These co-receptors are chemokine receptors CCR5 or CXCR4. Following a structural change in another viral protein (gp41), HIV inserts a fusion peptide into the host cell that allows the outer membrane of the virus to fuse with the cell membrane. ## HIV pathology HIV infection leads to a progressive reduction in the number of T cells expressing CD4. Medical professionals refer to the CD4 count to decide when to begin treatment during HIV infection, although recent medical guidelines have changed to recommend treatment at all CD4 counts as soon as HIV is diagnosed. A CD4 count measures the number of T cells expressing CD4. While CD4 counts are not a direct HIV test—e.g. they do not check the presence of viral DNA, or specific antibodies against HIV—they are used to assess the immune system of a patient.[citation needed] National Institutes of Health guidelines recommend treatment of any HIV-positive individuals, regardless of CD4 count[13] Normal blood values are usually expressed as the number of cells per microliter (μL, or equivalently, cubic millimeter, mm3) of blood, with normal values for CD4 cells being 500–1200 cells/mm3.[14] Patients often undergo treatments when the CD4 counts reach a level of 350 cells per microliter in Europe but usually around 500/μL in the US; people with less than 200 cells per microliter are at high risk of contracting AIDS defined illnesses. Medical professionals also refer to CD4 tests to determine efficacy of treatment.[citation needed] Viral load testing provides more information about the efficacy for therapy than CD4 counts.[15] For the first 2 years of HIV therapy, CD4 counts may be done every 3–6 months.[15] If a patient's viral load becomes undetectable after 2 years then CD4 counts might not be needed if they are consistently above 500/mm3.[15] If the count remains at 300–500/mm3, then the tests can be done annually.[15] It is not necessary to schedule CD4 counts with viral load tests and the two should be done independently when each is indicated.[15] ## Other diseases CD4 continues to be expressed in most neoplasms derived from T helper cells. It is therefore possible to use CD4 immunohistochemistry on tissue biopsy samples to identify most forms of peripheral T cell lymphoma and related malignant conditions.[16] The antigen has also been associated with a number of autoimmune diseases such as vitiligo and type I diabetes mellitus.[17] T-cells play a large part in autoinflammatory diseases.[18] When testing a drug's efficacy or studying diseases, it is helpful to quantify the amount of T-cells. on fresh-frozen tissue with CD4+, CD8+, and CD3+ T-cell markers (which stain different markers on a T-cell - giving different results).[19]

https://www.wikidoc.org/index.php/CD4

6f22b6f2b9d054a4cc560183a4833a7a9374aebe

wikidoc

CD6

CD6 CD6 (Cluster of Differentiation 6) is a human protein encoded by the CD6 gene. # Function This gene encodes a protein found on the outer membrane of T-lymphocytes as well as some other immune cells. The encoded protein contains three scavenger receptor cysteine-rich (SRCR) domains and a binding site for an activated leukocyte cell adhesion molecule. The gene product is important for continuation of T cell activation. # Clinical significance Certain alleles of this gene may be associated with susceptibility to multiple sclerosis.

CD6 CD6 (Cluster of Differentiation 6) is a human protein encoded by the CD6 gene.[1][2] # Function This gene encodes a protein found on the outer membrane of T-lymphocytes as well as some other immune cells. The encoded protein contains three scavenger receptor cysteine-rich (SRCR) domains and a binding site for an activated leukocyte cell adhesion molecule. The gene product is important for continuation of T cell activation.[1] # Clinical significance Certain alleles of this gene may be associated with susceptibility to multiple sclerosis.[3][4]

https://www.wikidoc.org/index.php/CD6

ba28d083eb52916cacbb528fc74f1e01e72079b3

wikidoc

CD8

CD8 CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor (TCR). Like the TCR, CD8 binds to a major histocompatibility complex (MHC) molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene. In humans, both genes are located on chromosome 2 in position 2p12. # Tissue distribution The CD8 co-receptor is predominantly expressed on the surface of cytotoxic T cells, but can also be found on natural killer cells, cortical thymocytes, and dendritic cells.The CD8 molecule is a marker for cytotoxic T cell population. It is expressed in T cell lymphoblastic lymphoma and hypo-pigmented mycosis fungoides. # Structure To function, CD8 forms a dimer, consisting of a pair of CD8 chains. The most common form of CD8 is composed of a CD8-α and CD8-β chain, both members of the immunoglobulin superfamily with an immunoglobulin variable (IgV)-like extracellular domain connected to the membrane by a thin stalk, and an intracellular tail. Less-common homodimers of the CD8-α chain are also expressed on some cells. The molecular weight of each CD8 chain is about 34 kDa. The structure of the CD8 molecule was determined by Leahy, D.J., Axel, R., and Hendrickson, W.A. by X-ray Diffraction at a 2.6A resolution. The structure was determined to have an immunoglobulin-like beta-sandwich folding and 114 amino acid residues. 2% of the protein is wound into α-helices and 46% into β-sheets, with the remaining 52% of the molecules remaining in the loop portions. # Function The extracellular IgV-like domain of CD8-α interacts with the α3 portion of the Class I MHC molecule. This affinity keeps the T cell receptor of the cytotoxic T cell and the target cell bound closely together during antigen-specific activation. Cytotoxic T cells with CD8 surface protein are called CD8+ T cells. The main recognition site is a flexible loop at the α3 domain of an MHC molecule. This was discovered by doing mutational analyses. The flexible α3 domain is located between residues 223 and 229 in the genome. In addition to aiding with cytotoxic T cell antigen interactions the CD8 co-receptor also plays a role in T cell signaling. The cytoplasmic tails of the CD8 co-receptor interact with Lck (lymphocyte-specific protein tyrosine kinase). Once the T cell receptor binds its specific antigen Lck phosphorylates the cytoplasmic CD3 and ζ-chains of the TCR complex which initiates a cascade of phosphorylation eventually leading to activation of transcription factors like NFAT, NF-κB, and AP-1 which affect the expression of certain genes.

CD8 CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor (TCR). Like the TCR, CD8 binds to a major histocompatibility complex (MHC) molecule, but is specific for the class I MHC protein.[2] There are two isoforms of the protein, alpha and beta, each encoded by a different gene. In humans, both genes are located on chromosome 2 in position 2p12. # Tissue distribution The CD8 co-receptor is predominantly expressed on the surface of cytotoxic T cells, but can also be found on natural killer cells, cortical thymocytes, and dendritic cells.The CD8 molecule is a marker for cytotoxic T cell population. It is expressed in T cell lymphoblastic lymphoma and hypo-pigmented mycosis fungoides.[3] # Structure To function, CD8 forms a dimer, consisting of a pair of CD8 chains. The most common form of CD8 is composed of a CD8-α and CD8-β chain, both members of the immunoglobulin superfamily with an immunoglobulin variable (IgV)-like extracellular domain connected to the membrane by a thin stalk, and an intracellular tail. Less-common homodimers of the CD8-α chain are also expressed on some cells. The molecular weight of each CD8 chain is about 34 kDa.[4] The structure of the CD8 molecule was determined by Leahy, D.J., Axel, R., and Hendrickson, W.A. by X-ray Diffraction at a 2.6A resolution.[1] The structure was determined to have an immunoglobulin-like beta-sandwich folding and 114 amino acid residues. 2% of the protein is wound into α-helices and 46% into β-sheets, with the remaining 52% of the molecules remaining in the loop portions. # Function The extracellular IgV-like domain of CD8-α interacts with the α3 portion of the Class I MHC molecule.[5] This affinity keeps the T cell receptor of the cytotoxic T cell and the target cell bound closely together during antigen-specific activation. Cytotoxic T cells with CD8 surface protein are called CD8+ T cells. The main recognition site is a flexible loop at the α3 domain of an MHC molecule. This was discovered by doing mutational analyses. The flexible α3 domain is located between residues 223 and 229 in the genome.[1] In addition to aiding with cytotoxic T cell antigen interactions the CD8 co-receptor also plays a role in T cell signaling. The cytoplasmic tails of the CD8 co-receptor interact with Lck (lymphocyte-specific protein tyrosine kinase). Once the T cell receptor binds its specific antigen Lck phosphorylates the cytoplasmic CD3 and ζ-chains of the TCR complex which initiates a cascade of phosphorylation eventually leading to activation of transcription factors like NFAT, NF-κB, and AP-1 which affect the expression of certain genes.[6]

https://www.wikidoc.org/index.php/CD8

fe1f9f56cca7053b65b690b28a468181e7a3d866

wikidoc

CD9

CD9 CD9 antigen is a protein that in humans is encoded by the CD9 gene. # Function The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. CD9 is a cell surface glycoprotein that is known to complex with integrins and other transmembrane 4 superfamily proteins. CD9 is found on the surface of exosomes and it can modulate cell adhesion and migration and also trigger platelet activation and aggregation. In addition, the protein appears to promote muscle cell fusion and support myotube maintenance. This protein also seems to be a key part in the egg-sperm fusion during mammalian fertilization. While oocytes are ovulated, CD9-deficient oocytes are not properly fused with sperm upon fertilization. CD9 is located in the microvillar membrane of the oocytes and also appears to intervene in maintaining the normal shape of oocyte microvilli. # Interactions CD9 has been shown to interact with: - CD117, - CD29 - CD46, - CD49c, - CD81, - PTGFRN, and - TSPAN4.

CD9 CD9 antigen is a protein that in humans is encoded by the CD9 gene.[1] # Function The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. CD9 is a cell surface glycoprotein that is known to complex with integrins and other transmembrane 4 superfamily proteins. CD9 is found on the surface of exosomes[2][3] and it can modulate cell adhesion and migration and also trigger platelet activation and aggregation. In addition, the protein appears to promote muscle cell fusion and support myotube maintenance.[4] This protein also seems to be a key part in the egg-sperm fusion during mammalian fertilization. While oocytes are ovulated, CD9-deficient oocytes are not properly fused with sperm upon fertilization.[5] CD9 is located in the microvillar membrane of the oocytes and also appears to intervene in maintaining the normal shape of oocyte microvilli.[6] # Interactions CD9 has been shown to interact with: - CD117,[7] - CD29[8][9] - CD46,[10] - CD49c,[11][12] - CD81,[8][13] - PTGFRN,[14][15] and - TSPAN4.[16]

https://www.wikidoc.org/index.php/CD9

7b5e49308e399782f49bfb5ede4d801c061af1cb

wikidoc

CLS

CLS CLS may refer to: # Education and society ## Academic fields - Critical legal studies, a contentious school of legal philosophy, that emerged from Harvard Law School in the 1980s. - Critical language studies - the study of language that evolved into critical discourse analysis ## Educational institutions - City of London School (an all-boys school; see also City of London School for Girls. - Covington Latin School, a high school in Covington, Kentucky ## Academic associations, divisions, programs and facilities - Columbia Law School at Columbia University - Coalition of Latin@ Scholars at Teachers College, Columbia University - Canadian Light Source - a synchrotron research facility located at the University of Saskatchewan, in Saskatoon, Saskatchewan ## Societies and associations - Chicago Linguistic Society - Christian Legal Society # Software - Common Language Specification an open specification developed by Microsoft that describes the executable code and runtime environment. It defines an environment that allows multiple high-level languages to be used on different computer platforms without being rewritten for specific architectures. - cls is a command in some operating systems, including MS-DOS, and programming languages, such as BASIC, that clears the screen. - Call logging system, a transaction logging system or interface. # Occupational terms - Clinical laboratory scientist, another term for medical technician, a type of healthcare professional. - Combat lifesaver (or combat medic) US Military Occupational Specialty 68W # Music - CLS Records, a record label. - Cory Lee Senn, rapper, leader of The M.O.B. # Medicine - Capillary leak syndrome - Coffin-Lowry syndrome, a genetic disorder associated with mental retardation - Clinical laboratory scientist, another term for medical technician, a type of healthcare professional # Aerospace - Capsule launch system for space capsules # Business and finance - Continuous linked settlement, a financial clearing system - CLS Group of Companies (headquartered in France, but with various divisions, including CLS America) - Celestica Inc. (New York Stock Exhchange symbol: CLS). # Miscellaneous products - The Mercedes-Benz CLS-Class, a series of automobile models. - Canadian lumber sizes - a surfaced timber widely used in building for studding. It has 3mm radius eased edges and consistent dimensions. - Nikon's Creative Lighting System, a complete lighting solution for Nikon's camera bodies and external light units. de:CLS it:CLS ksh:CLS (Watt ėßß datt?)

CLS CLS may refer to: # Education and society ## Academic fields - Critical legal studies, a contentious school of legal philosophy, that emerged from Harvard Law School in the 1980s. - Critical language studies - the study of language that evolved into critical discourse analysis ## Educational institutions - City of London School (an all-boys school; see also City of London School for Girls. - Covington Latin School, a high school in Covington, Kentucky ## Academic associations, divisions, programs and facilities - Columbia Law School at Columbia University - Coalition of Latin@ Scholars at Teachers College, Columbia University - Canadian Light Source - a synchrotron research facility located at the University of Saskatchewan, in Saskatoon, Saskatchewan ## Societies and associations - Chicago Linguistic Society - Christian Legal Society # Software - Common Language Specification an open specification developed by Microsoft that describes the executable code and runtime environment. It defines an environment that allows multiple high-level languages to be used on different computer platforms without being rewritten for specific architectures. - cls is a command in some operating systems, including MS-DOS, and programming languages, such as BASIC, that clears the screen. - Call logging system, a transaction logging system or interface. # Occupational terms - Clinical laboratory scientist, another term for medical technician, a type of healthcare professional. - Combat lifesaver (or combat medic) US Military Occupational Specialty 68W # Music - CLS Records, a record label. - Cory Lee Senn, rapper, leader of The M.O.B. # Medicine - Capillary leak syndrome - Coffin-Lowry syndrome, a genetic disorder associated with mental retardation - Clinical laboratory scientist, another term for medical technician, a type of healthcare professional # Aerospace - Capsule launch system for space capsules # Business and finance - Continuous linked settlement, a financial clearing system - CLS Group of Companies (headquartered in France, but with various divisions, including CLS America) - Celestica Inc. (New York Stock Exhchange symbol: CLS). # Miscellaneous products - The Mercedes-Benz CLS-Class, a series of automobile models. - Canadian lumber sizes - a surfaced timber widely used in building for studding. It has 3mm radius eased edges and consistent dimensions. - Nikon's Creative Lighting System, a complete lighting solution for Nikon's camera bodies and external light units. Template:Disambig de:CLS it:CLS ksh:CLS (Watt ėßß datt?) Template:WikiDoc Sources

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