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93da28f7330e7fc3b0b67a94b1f24c05bf42d3d1 | wikidoc | ACP1 | ACP1
Low molecular weight phosphotyrosine protein phosphatase is an enzyme that in humans is encoded by the ACP1 gene.
The product of this gene belongs to the phosphotyrosine protein phosphatase family of proteins. It functions as an acid phosphatase and a protein tyrosine phosphatase by hydrolyzing protein tyrosine phosphate to protein tyrosine and orthophosphate. This enzyme also hydrolyzes orthophosphoric monoesters to alcohol and orthophosphate. This gene is genetically polymorphic, and three common alleles segregating at the corresponding locus give rise to six phenotypes. Each allele appears to encode at least two electrophoretically different isozymes, Bf and Bs, which are produced in allele-specific ratios. Three transcript variants encoding distinct isoforms have been identified for this gene.
# Interactions
ACP1 has been shown to interact with EPH receptor A2 and EPH receptor B1. | ACP1
Low molecular weight phosphotyrosine protein phosphatase is an enzyme that in humans is encoded by the ACP1 gene.
The product of this gene belongs to the phosphotyrosine protein phosphatase family of proteins. It functions as an acid phosphatase and a protein tyrosine phosphatase by hydrolyzing protein tyrosine phosphate to protein tyrosine and orthophosphate. This enzyme also hydrolyzes orthophosphoric monoesters to alcohol and orthophosphate. This gene is genetically polymorphic, and three common alleles segregating at the corresponding locus give rise to six phenotypes. Each allele appears to encode at least two electrophoretically different isozymes, Bf and Bs, which are produced in allele-specific ratios. Three transcript variants encoding distinct isoforms have been identified for this gene.[1]
# Interactions
ACP1 has been shown to interact with EPH receptor A2[2] and EPH receptor B1.[3] | https://www.wikidoc.org/index.php/ACP1 | |
15c46939f4797fe3ce0e54cdf0a033c515249d98 | wikidoc | ADAR | ADAR
Double-stranded RNA-specific adenosine deaminase is an enzyme that in humans is encoded by the ADAR gene (which stands for adenosine deaminase acting on RNA).
Adenosine deaminases acting on RNA (ADAR) are enzymes responsible for binding to double stranded RNA (dsRNA) and converting adenosine (A) to inosine (I) by deamination. ADAR protein is a RNA-binding protein, which functions in RNA-editing through post-transcriptional modification of mRNA transcripts by changing the nucleotide content of the RNA. The conversion from A to I in the RNA disrupt the normal A:U pairing which makes the RNA unstable. Inosine is structurally similar to that of guanine (G) which leads to I to cytosine (C) binding. Inosine typically mimicks guanosine during translation. Codon changes can arise from editing which may lead to changes in the coding sequences for proteins and their functions. Most editing sites are found in noncoding regions of RNA such as untranslated regions (UTRs), Alu elements, and long interspersed nuclear element (LINEs). Mutations in this gene have been associated with dyschromatosis symmetrica hereditaria, as well as Aicardi–Goutières syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. ADAR also impacts the transcriptome in editing-independent ways, likely by interfering with other RNA-binding proteins.
# Discovery
Adenosine Deaminase Acting on RNA (ADAR) and its gene were first discovered accidentally in 1987 as a result of research by Brenda Bass and Harold Weintraub. These researchers were using antisense RNA inhibition to determine which genes play a key role in the development of Xenopus leavis embryos. Previous research on Xenopus oocytes had been successful. However, when Bass and Weintraub applied identical protocols to Xenopus embryos, they were unable to determine the embryo’s developmental genes. In an attempt to understand why the method was unsuccessful, they began comparing duplex RNA in both oocytes and embryos. This lead them to discover that a developmentally regulated activity denatures RNA:RNA hybrids in embryos.
In 1988, Richard Wagner et al. further studied the activity occurring on Xenopus embryos. They determined that a protein was responsible for the unwinding of RNA due to the absence of activity after proteinase treatment. It was also shown that this protein is specific for double stranded RNA, or dsRNA, and does not require ATP. Additionally, it became evident that the protein’s activity on dsRNA modifies it beyond a point of rehybridization, but does not fully denature it. Finally, the researchers determined that this unwinding is due to the deamination of adenosine residues to inosine. This modification results in mismatched base-pairing between inosine and uridine, leading to the destabilization and unwinding of dsRNA.
# Function and origin
Adenosine Deaminase Acting on RNA is one of the most common forms of RNA editing, and has both selective and non-selective activity. ADAR is able to both modify and regulate the output of gene product, as inosine is interpreted by the cell to be guanosine. ADAR has also been determined to change the functionality of small RNA molecules. It is believed that ADAR evolved from ADAT (Adenosine Deaminase Acting on tRNA), a critical protein present in all eukaryotes, early in the metazoan period through the addition of a dsRNA binding domain. This likely occurred in the lineage which leads to the crown Metazoa when a duplicate ADAT gene was coupled to a gene encoding at least one double stranded RNA binding. The ADAR family of genes has been largely conserved over the history of its existence. This, along with its presence in the majority of modern phyla, indicates that RNA editing is an essential regulatory gene for metazoan organisms. ADAR has not been discovered in a variety of non-metazoan eukaryotes, such as plants, fungi and choanoflagellates.
# Types
In mammals, there are three types of ADARs, 1, 2 and 3. ADAR1 and ADAR2 are found in many tissues in the body while ADAR3 is only found in the brain. ADAR1 and ADAR2 are known to be catalytically active while ADAR3 is thought to be inactive. ADAR1 has two known isoforms known as ADAR1p150 and ADAR1p110. ADAR1p110 is only found in the nucleus and ADAR1p150 goes from the nucleus to the cytoplasm. Although ADAR1 and ADAR2 share many common functional domains as well as commonality in terms of expression pattern, structure of protein and requirements of substrates having double stranded RNA structures, they differ in their editing activity.
# Catalytic activity
## Biochemical reaction
ADARs catalyze the reaction from A to I by hydrolytic deamination. It does this by the use of an activated water molecule for a nucelophilic attack. It is done by the addition of water to carbon 6 and removal of ammonia with a hydrated intermediate.
File:ADAR1 mechanism.png
- scheme of adenosine conversion to inosine via ADAR
scheme of adenosine conversion to inosine via ADAR
## Active site
In humans, the enzyme's active site has 2-3 amino-terminal dsRNA binding domains (dsRBDs) and one carboxy terminal catalytic deaminase domain. In the dsRBD domain there is a conserved α-β-β-β-α configuration present. ADAR1 contains two areas for binding Z-DNA known as Zα and Zβ. ADAR2 and ADAR3 have an arginine rich single stranded RNA (ssRNA) binding domain. A crystal structure of ADAR2 has been solved. In the enzyme active site, there is a glutamic acid residue(E396) that hydrogen bonds to a water. There is a histidine (H394) and two cysteine restudies (C451 and C516) that coordinates a zinc ion. The zinc activates the water molecule for the nucelophilic hydrolytic deamination. Within the catalytic core there is an inositol hexakisphosphate (IP6), which stabilizes arginine and lysine residues.
ADAR1 active site
## Dimerization
It has been found in mammals that the conversion from A to I requires homodimerization of ADAR1 and ADAR2, but not ADAR3. In vivo studies have not yet been conclusive if RNA binding is required for dimerization. A study with ADAR1 and 2 mutants which were not able to bind to dsRNA were still able to dimerize, showing they may bind based on protein-protein interactions
# Model organisms
Model organisms have been used in the study of ADAR function. A conditional knockout mouse line, called Adartm1a(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 five tests were carried out on mutant mice and two significant abnormalities were observed. Few homozygous mutant embryos were identified during gestation, and none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and no abnormalities were observed in these animals.
# Role in disease
## Aicardi–Goutières syndrome
ADAR1 is one of multiple genes which can contribute to Aicardi–Goutières syndrome when mutated. This is a genetic inflammatory disease primarily affecting the skin and the brain. The inflammation is caused by incorrect activation of interferon inducible genes such as those activated to fight off viral infections. Mutation and loss of function of ADAR1 prevents destabilization of double stranded RNA (dsRNA) and the body mistakes this for viral RNA resulting in an autoimmune response.
## HIV
Research has shown that ADAR1 can be both beneficial and a hindrance in a cells ability to fight off HIV infection. Expression levels of the ADAR1 protein have shown to be elevated during HIV infection and it has been suggested that it is responsible for A to G mutations in the HIV genome, inhibiting replication. The authors of this study also suggest that mutation of the HIV genome by ADAR1 might in some cases lead to beneficial viral mutations which could contribute to drug resistance.
## Hepatocellular carcinoma
Studies of samples from patients with hepatocellular carcinoma (HCC) have shown that ADAR1 is frequently upregulated and ADAR2 is frequently downregulated in the disease. It has been suggested that this is responsible for the disrupted A to I editing pattern seen in HCC and that ADAR1 acts as an oncogene in this context whilst ADAR2 has tumor suppressor activities. The imbalance of ADAR expression could change the frequency of A to I transitions in the protein coding region of genes, resulting in mutated proteins which drive the disease. The dysregulation of ADAR1 and ADAR2 could be used as a possible poor prognostic marker.
## Melanoma
In contrast to hepatocellular carcinoma, several research studies have indicated that loss of ADAR1 contributes to melanoma growth and metastasis. It is known that ADAR can act on microRNA and affect its biogenesis, stability and/or its binding target. It has been suggested that ADAR1 is downregulated by cAMP- response element binding protein (CREB), limiting its ability to act on miRNA. One such example is miR-455-5p which is edited by ADAR1. When ADAR is downregulated by CREB the unedited miR-455-5p downregulates a tumor suppressor protein called CPEB1, contributing to melanoma progression in an in vivo model.
## Dyschromatosis symmetrica hereditaria (DSH1)
A Gly1007Arg mutation in ADAR1, as well as other truncated versions, have been implicated as a cause in some cases of DSH1. This is a disease characterized by hyperpigmentation in the hands and feet and can occur in Japanese and Chinese families.
# Viral activity
## Antiviral
ADAR1 is an interferon ( IFN )-inducible protein (one released by a cell in response to a pathogen or virus), so it would make sense that it would assist with a cell’s immune pathway. This seems to be true for the HCV replicon, Lymphocytic choriomeningitis LCMV, and polyomavirus
## Proviral
ADAR1 is known to be proviral in other circumstances. ADAR1’s A to I editing has been found in many viruses including measles virus, influenza virus, lymphocytic choriomeningitis virus, polyomavirus, hepatitis delta virus, and hepatitis C virus. Although ADAR1 has been seen in other viruses, it has only been studied extensively in a few; one of those is measles virus (MV). Research done on MV has shown that ADAR1 enhances viral replication. This is done through two different mechanisms: RNA editing and inhibition of dsRNA-activated protein kinase (PKR). Specifically, viruses are thought to use ADAR1 as a positive replication factor by selectively suppressing dsRNA-dependent and antiviral pathways. | ADAR
Double-stranded RNA-specific adenosine deaminase is an enzyme that in humans is encoded by the ADAR gene (which stands for adenosine deaminase acting on RNA).[1][2]
Adenosine deaminases acting on RNA (ADAR) are enzymes responsible for binding to double stranded RNA (dsRNA) and converting adenosine (A) to inosine (I) by deamination.[3] ADAR protein is a RNA-binding protein, which functions in RNA-editing through post-transcriptional modification of mRNA transcripts by changing the nucleotide content of the RNA.[4] The conversion from A to I in the RNA disrupt the normal A:U pairing which makes the RNA unstable. Inosine is structurally similar to that of guanine (G) which leads to I to cytosine (C) binding. Inosine typically mimicks guanosine during translation.[5] Codon changes can arise from editing which may lead to changes in the coding sequences for proteins and their functions.[6] Most editing sites are found in noncoding regions of RNA such as untranslated regions (UTRs), Alu elements, and long interspersed nuclear element (LINEs).[7] Mutations in this gene have been associated with dyschromatosis symmetrica hereditaria, as well as Aicardi–Goutières syndrome.[8] Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[4] ADAR also impacts the transcriptome in editing-independent ways, likely by interfering with other RNA-binding proteins.[9]
# Discovery
Adenosine Deaminase Acting on RNA (ADAR) and its gene were first discovered accidentally in 1987 as a result of research by Brenda Bass and Harold Weintraub.[10] These researchers were using antisense RNA inhibition to determine which genes play a key role in the development of Xenopus leavis embryos. Previous research on Xenopus oocytes had been successful. However, when Bass and Weintraub applied identical protocols to Xenopus embryos, they were unable to determine the embryo’s developmental genes. In an attempt to understand why the method was unsuccessful, they began comparing duplex RNA in both oocytes and embryos. This lead them to discover that a developmentally regulated activity denatures RNA:RNA hybrids in embryos.
In 1988, Richard Wagner et al. further studied the activity occurring on Xenopus embryos.[11] They determined that a protein was responsible for the unwinding of RNA due to the absence of activity after proteinase treatment. It was also shown that this protein is specific for double stranded RNA, or dsRNA, and does not require ATP. Additionally, it became evident that the protein’s activity on dsRNA modifies it beyond a point of rehybridization, but does not fully denature it. Finally, the researchers determined that this unwinding is due to the deamination of adenosine residues to inosine. This modification results in mismatched base-pairing between inosine and uridine, leading to the destabilization and unwinding of dsRNA.
# Function and origin
Adenosine Deaminase Acting on RNA is one of the most common forms of RNA editing, and has both selective and non-selective activity.[12] ADAR is able to both modify and regulate the output of gene product, as inosine is interpreted by the cell to be guanosine. ADAR has also been determined to change the functionality of small RNA molecules. It is believed that ADAR evolved from ADAT (Adenosine Deaminase Acting on tRNA), a critical protein present in all eukaryotes, early in the metazoan period through the addition of a dsRNA binding domain. This likely occurred in the lineage which leads to the crown Metazoa when a duplicate ADAT gene was coupled to a gene encoding at least one double stranded RNA binding. The ADAR family of genes has been largely conserved over the history of its existence. This, along with its presence in the majority of modern phyla, indicates that RNA editing is an essential regulatory gene for metazoan organisms. ADAR has not been discovered in a variety of non-metazoan eukaryotes, such as plants, fungi and choanoflagellates.
# Types
In mammals, there are three types of ADARs, 1, 2 and 3.[13] ADAR1 and ADAR2 are found in many tissues in the body while ADAR3 is only found in the brain.[6] ADAR1 and ADAR2 are known to be catalytically active while ADAR3 is thought to be inactive.[6] ADAR1 has two known isoforms known as ADAR1p150 and ADAR1p110. ADAR1p110 is only found in the nucleus and ADAR1p150 goes from the nucleus to the cytoplasm.[13] Although ADAR1 and ADAR2 share many common functional domains as well as commonality in terms of expression pattern, structure of protein and requirements of substrates having double stranded RNA structures, they differ in their editing activity.[14]
# Catalytic activity
## Biochemical reaction
ADARs catalyze the reaction from A to I by hydrolytic deamination.[3] It does this by the use of an activated water molecule for a nucelophilic attack. It is done by the addition of water to carbon 6 and removal of ammonia with a hydrated intermediate.
File:ADAR1 mechanism.png
- scheme of adenosine conversion to inosine via ADAR
scheme of adenosine conversion to inosine via ADAR
## Active site
In humans, the enzyme's active site has 2-3 amino-terminal dsRNA binding domains (dsRBDs) and one carboxy terminal catalytic deaminase domain.[13] In the dsRBD domain there is a conserved α-β-β-β-α configuration present.[6] ADAR1 contains two areas for binding Z-DNA known as Zα and Zβ. ADAR2 and ADAR3 have an arginine rich single stranded RNA (ssRNA) binding domain. A crystal structure of ADAR2 has been solved.[13] In the enzyme active site, there is a glutamic acid residue(E396) that hydrogen bonds to a water. There is a histidine (H394) and two cysteine restudies (C451 and C516) that coordinates a zinc ion. The zinc activates the water molecule for the nucelophilic hydrolytic deamination. Within the catalytic core there is an inositol hexakisphosphate (IP6), which stabilizes arginine and lysine residues.
ADAR1 active site
## Dimerization
It has been found in mammals that the conversion from A to I requires homodimerization of ADAR1 and ADAR2, but not ADAR3.[6] In vivo studies have not yet been conclusive if RNA binding is required for dimerization. A study with ADAR1 and 2 mutants which were not able to bind to dsRNA were still able to dimerize, showing they may bind based on protein-protein interactions[6][15]
# Model organisms
Model organisms have been used in the study of ADAR function. A conditional knockout mouse line, called Adartm1a(EUCOMM)Wtsi[16][17] 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[18][19][20] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[21][22] Twenty five tests were carried out on mutant mice and two significant abnormalities were observed.[6] Few homozygous mutant embryos were identified during gestation, and none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and no abnormalities were observed in these animals.[21]
# Role in disease
## Aicardi–Goutières syndrome
ADAR1 is one of multiple genes which can contribute to Aicardi–Goutières syndrome when mutated.[8] This is a genetic inflammatory disease primarily affecting the skin and the brain. The inflammation is caused by incorrect activation of interferon inducible genes such as those activated to fight off viral infections. Mutation and loss of function of ADAR1 prevents destabilization of double stranded RNA (dsRNA) and the body mistakes this for viral RNA resulting in an autoimmune response.[23]
## HIV
Research has shown that ADAR1 can be both beneficial and a hindrance in a cells ability to fight off HIV infection. Expression levels of the ADAR1 protein have shown to be elevated during HIV infection and it has been suggested that it is responsible for A to G mutations in the HIV genome, inhibiting replication.[24] The authors of this study also suggest that mutation of the HIV genome by ADAR1 might in some cases lead to beneficial viral mutations which could contribute to drug resistance.
## Hepatocellular carcinoma
Studies of samples from patients with hepatocellular carcinoma (HCC) have shown that ADAR1 is frequently upregulated and ADAR2 is frequently downregulated in the disease. It has been suggested that this is responsible for the disrupted A to I editing pattern seen in HCC and that ADAR1 acts as an oncogene in this context whilst ADAR2 has tumor suppressor activities.[25] The imbalance of ADAR expression could change the frequency of A to I transitions in the protein coding region of genes, resulting in mutated proteins which drive the disease. The dysregulation of ADAR1 and ADAR2 could be used as a possible poor prognostic marker.
## Melanoma
In contrast to hepatocellular carcinoma, several research studies have indicated that loss of ADAR1 contributes to melanoma growth and metastasis. It is known that ADAR can act on microRNA and affect its biogenesis, stability and/or its binding target.[26] It has been suggested that ADAR1 is downregulated by cAMP- response element binding protein (CREB), limiting its ability to act on miRNA.[27] One such example is miR-455-5p which is edited by ADAR1. When ADAR is downregulated by CREB the unedited miR-455-5p downregulates a tumor suppressor protein called CPEB1, contributing to melanoma progression in an in vivo model.[27]
## Dyschromatosis symmetrica hereditaria (DSH1)
A Gly1007Arg mutation in ADAR1, as well as other truncated versions, have been implicated as a cause in some cases of DSH1.[28] This is a disease characterized by hyperpigmentation in the hands and feet and can occur in Japanese and Chinese families.
# Viral activity
## Antiviral
ADAR1 is an interferon ( IFN )-inducible protein (one released by a cell in response to a pathogen or virus), so it would make sense that it would assist with a cell’s immune pathway. This seems to be true for the HCV replicon, Lymphocytic choriomeningitis LCMV, and polyomavirus[29]
## Proviral
ADAR1 is known to be proviral in other circumstances. ADAR1’s A to I editing has been found in many viruses including measles virus,[30][31] influenza virus,[32] lymphocytic choriomeningitis virus,[33] polyomavirus,[34] hepatitis delta virus,[35] and hepatitis C virus.[36] Although ADAR1 has been seen in other viruses, it has only been studied extensively in a few; one of those is measles virus (MV). Research done on MV has shown that ADAR1 enhances viral replication. This is done through two different mechanisms: RNA editing and inhibition of dsRNA-activated protein kinase (PKR).[29] Specifically, viruses are thought to use ADAR1 as a positive replication factor by selectively suppressing dsRNA-dependent and antiviral pathways.[37] | https://www.wikidoc.org/index.php/ADAR | |
5d7301abb2e9b5b7c5ea30caa3496f55f64a7e3b | wikidoc | ADD2 | ADD2
Beta-adducin is a protein that in humans is encoded by the ADD2 gene.
# Function
Adducins are heteromeric proteins composed of different subunits referred to as adducin alpha, beta, and gamma. The three subunits are encoded by distinct genes and belong to a family of membrane skeletal proteins involved in the assembly of spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues.
While adducins alpha and gamma are ubiquitously expressed, the expression of adducin beta is restricted to brain and hematopoietic tissues. Adducin, originally purified from human erythrocytes, was found to be a heterodimer of adducins alpha and beta. Polymorphisms resulting in amino acid substitutions in these two subunits have been associated with the regulation of blood pressure in an animal model of hypertension. Heterodimers consisting of alpha and gamma subunits have also been described. Structurally, each subunit is composed of two distinct domains.
The amino-terminal region is protease resistant and globular in shape, while the carboxy-terminal region is protease sensitive. The latter contains multiple phosphorylation sites for protein kinase C, the binding site for calmodulin, and is required for association with spectrin and actin. Various adducin beta mRNAs, alternatively spliced at 3'end and/or internally spliced and encoding different isoforms, have been described. The functions of all the different isoforms are not known.
# Interactions
ADD2 has been shown to interact with FYN. | ADD2
Beta-adducin is a protein that in humans is encoded by the ADD2 gene.[1][2]
# Function
Adducins are heteromeric proteins composed of different subunits referred to as adducin alpha, beta, and gamma. The three subunits are encoded by distinct genes and belong to a family of membrane skeletal proteins involved in the assembly of spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues.
While adducins alpha and gamma are ubiquitously expressed, the expression of adducin beta is restricted to brain and hematopoietic tissues. Adducin, originally purified from human erythrocytes, was found to be a heterodimer of adducins alpha and beta. Polymorphisms resulting in amino acid substitutions in these two subunits have been associated with the regulation of blood pressure in an animal model of hypertension. Heterodimers consisting of alpha and gamma subunits have also been described. Structurally, each subunit is composed of two distinct domains.
The amino-terminal region is protease resistant and globular in shape, while the carboxy-terminal region is protease sensitive. The latter contains multiple phosphorylation sites for protein kinase C, the binding site for calmodulin, and is required for association with spectrin and actin. Various adducin beta mRNAs, alternatively spliced at 3'end and/or internally spliced and encoding different isoforms, have been described. The functions of all the different isoforms are not known.[2]
# Interactions
ADD2 has been shown to interact with FYN.[3] | https://www.wikidoc.org/index.php/ADD2 | |
97817428e6ffc30935578c163632208363a831c4 | wikidoc | ADH5 | ADH5
Alcohol dehydrogenase class-3 is an enzyme that in humans is encoded by the ADH5 gene.
This gene encodes glutathione-dependent formaldehyde dehydrogenase or the class III alcohol dehydrogenase chi subunit, which is a member of the alcohol dehydrogenase family. Members of this family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. Class III alcohol dehydrogenase is a homodimer composed of 2 chi subunits. It has virtually no activity for ethanol oxidation, but exhibits high activity for oxidation of long-chain primary alcohols and for oxidation of S-hydroxymethyl-glutathione, a spontaneous adduct between formaldehyde and glutathione.
This enzyme is an important component of cellular metabolism for the elimination of formaldehyde, a potent irritant and sensitizing agent that causes lacrymation, rhinitis, pharyngitis, and contact dermatitis. | ADH5
Alcohol dehydrogenase class-3 is an enzyme that in humans is encoded by the ADH5 gene.[1][2][3]
This gene encodes glutathione-dependent formaldehyde dehydrogenase or the class III alcohol dehydrogenase chi subunit, which is a member of the alcohol dehydrogenase family. Members of this family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. Class III alcohol dehydrogenase is a homodimer composed of 2 chi subunits. It has virtually no activity for ethanol oxidation, but exhibits high activity for oxidation of long-chain primary alcohols and for oxidation of S-hydroxymethyl-glutathione, a spontaneous adduct between formaldehyde and glutathione.
This enzyme is an important component of cellular metabolism for the elimination of formaldehyde, a potent irritant and sensitizing agent that causes lacrymation, rhinitis, pharyngitis, and contact dermatitis.[3] | https://www.wikidoc.org/index.php/ADH5 | |
2f1bb0ea44005489cad974d406166c7043d7ebbb | wikidoc | ADME | ADME
# Overview
ADME is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism. The four criteria all influence the drug levels and kinetics of drug exposure to the tissues and hence influence the performance and pharmacological activity of the compound as a drug:
## Absorption
## Distribution
## Metabolism
## Excretion/Elimination
- Glomerular filtration of unbound drug.
- Active secretion of (free & protein-bound) drug by transporters e.g. anions such as urate, penicillin, glucuronide, sulphate conjugates) or cations such as choline, histamine.
- Filtrate 100-fold concentrated in tubules for a favourable concentration gradient so that it may be reabsorbed by passive diffusion and passed out through the urine.
Sometimes, the potential or real toxicity of the compound is taken into account (ADME-Tox or ADMET). When the Liberation of the substance (from protective coating, or other excipients) is considered, we speak of LADME.
Computational chemists try to predict the ADME-Tox qualities of compounds through methods like QSPR or QSAR.
The route of administration critically influences ADME. | ADME
# Overview
ADME is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism. The four criteria all influence the drug levels and kinetics of drug exposure to the tissues and hence influence the performance and pharmacological activity of the compound as a drug:
## Absorption
## Distribution
## Metabolism
## Excretion/Elimination
- Glomerular filtration of unbound drug.
- Active secretion of (free & protein-bound) drug by transporters e.g. anions such as urate, penicillin, glucuronide, sulphate conjugates) or cations such as choline, histamine.
- Filtrate 100-fold concentrated in tubules for a favourable concentration gradient so that it may be reabsorbed by passive diffusion and passed out through the urine.
Sometimes, the potential or real toxicity of the compound is taken into account (ADME-Tox or ADMET). When the Liberation of the substance (from protective coating, or other excipients) is considered, we speak of LADME.
Computational chemists try to predict the ADME-Tox qualities of compounds through methods like QSPR or QSAR.
The route of administration critically influences ADME. | https://www.wikidoc.org/index.php/ADME | |
1471c2dd4b75cd7d3e85d97987d7f3a0dae6c399 | wikidoc | AGR2 | AGR2
Anterior gradient protein 2 homolog (AGR-2), also known as secreted cement gland protein XAG-2 homolog, is a protein that in humans is encoded by the AGR2 gene. Anterior gradient homolog 2 was originally discovered in Xenopus laevis. In Xenopus AGR2 plays a role in cement gland differentiation, but in human cancer cell lines high levels of AGR2 correlate with downregulation of the p53 response, cell migration, and cell transformation. However, there have been other observations that AGR2 can repress growth and proliferation.
# Discovery in Xenopus laevis
The Xenopus laevis anterior gradient genes - XAG-1, XAG-2, and XAG-3 - were discovered through dissection of different-aged embryos. They become expressed in the anterior region of the dorsal ectoderm in late gastrula embryos. XAG-2 expression gathers at the anterior region of the dorsal ectoderm, and this region corresponds to the cement gland anlage. Many other homologous proteins have been discovered afterwards in Xenopus.
# Tissue distribution
AGR2 is the human homolog of XAG-2. It is expressed strongly in tissues that secrete mucus or function as endocrine organs, including the lungs, stomach, colon, prostate and small intestine. Its protein expression has been shown to be regulated by both androgens and estrogens.
# Structure and function
AGR2 is a protein disulfide isomerase, with a single CXXS active domain motif for oxidation and reduction reactions. AGR2 forms mixed disulfides in substrates, such as intestinal mucin. AGR2 interacts with Mucin 2 through its thioredoxin-like domain forming a heterodisulfide bond with cysteine residues in MUC2. AGR2 is suggested to play a role in protein folding, and it has a KTEL C-terminal motif similar to KDEL and KVEL endoplasmic reticulum retention sequences.
# Clinical significance
Agr2 is located on chromosome 7p21, a region that has frequent genetic alterations. It was first identified in estrogen receptor-positive breast cancer cells. Later studies showed elevated levels of AGR2 in adenocarcinomas of the esophagus, pancreas, and prostate. In Barrett's esophagus, Agr2 expression is elevated by over 70 times compared to normal esophageal epithelia. Thus, this protein alone is enough to distinguish Barrett's esophagus, which is linked to esophageal adenocarcinoma, from a normal esophagus.
Varying AGR2 levels exist in different cancers. In breast cancer, high AGR2 expression is correlated with low survival rate. AGR2 levels are elevated in the preneoplastic tissue Barrett's oesophagus. AGR2 is also associated with prostate cancer, though lower levels are associated with higher Gleason grades.
In contrast to upregulation of AGR2 in various cancers, downregulation of AGR2 is linked with inflammatory bowel disease and increases in the risk of Crohn's disease and ulcerative colitis. This implies the importance of AGR2 in maintaining epithelial barrier function, which is supported by FOXA1 and FOXA2 molecules (transcription factors for epithelial goblet cells) which can activate the AGR2 promoter.
## Breast cancer
In breast cancer, AGR2 and estrogen (ER) expression are positively correlated. Approximately 70% of breast cancer patients have breast cancer cells that heavily express ER and progesterone receptors (PgR). These patients are normally treated with endocrine therapy. Tamoxifen, which blocks the binding of estradiol to its receptor, is the standard treatment for ER-positive breast cancer. However, about one third of patients do not respond to this therapy, and increased AGR2 may be one reason.
There is a positive correlation for a higher level of AGR2 expression with poor therapeutic results in ERα-positive breast cancer patients. Agr2 mRNA expression is elevated in in vitro and in vivo studies responding to tamoxifen adjuvant therapy, so AGR2 is likely provides an agonistic effect on tamoxifen. Therefore, AGR2 is a possible predictive biomarker when selecting patients with ER-positive breast cancer to participate this therapy.
Although Agr2 mRNA levels are correlated with the tamoxifen therapy response, AGR2 protein levels have yet to be statistically associated with the therapy. A combinatorial therapy using the anastrozole and fulvestrant has been shown to prevent binding of the ER to the Agr2 promoter, and there has been improved prognosis in the patients receiving it, possibly because AGR2 expression in the tumors have been reduced.
What AGR2 does in cancers is poorly understood. In breast cancer, HSP90 is a molecular chaperone expressed in tumor cells when there exists an excess of unfolded protein, and its co-chaperone has been reported to induce expression of AGR2, so AGR2 may be used by the endoplasmic reticulum to assist with protein folding to alleviate proteotoxic stress. AGR2 may help regulate the protein and mRNA levels in a cell overall as well. During late pregnancy and lactation, AGR2 levels peak when milk proteins are produced, and mammary-specific Agr2 knockout mice had downregulated milk protein mRNA expression.
## Prostate cancer
AGR2 is expressed in relatively high levels for prostate cancer patients. Urine sediment tests determined Agr2 transcript levels to be elevated. AGR2 expression was increased in metastatic prostate cancer cells cultured in a bone marrow microenvironment, where intense levels of Agr2 mRNA were detected, suggesting AGR2 is required for bone metastasis of prostate cancer cells. AGR2 transcript levels were lower in metastatic lesions compared to the primary tumor, however. A greater chance of prostate cancer recurrence is linked to relatively lower levels of AGR2.
AGR2 depletion through gene knockdown was shown to result in accumulation of prostate cancer cell lines at the G0/G1 phase of the cell cycle, while forced expression of AGR led to an increase in cell proliferation. AGR2 was determined to be involved in cell adhesion. Agr2-silenced prostate cancer cells had a large decrease in association with fibronectin, lost expression of integrin, and reduced tumor cell migration.
## Pancreatic cancer
AGR2 mRNA was discovered to be increased in precancerous lesions and neoplastic cells of pancreatic tumors and cancer cell lines. Transient silencing of AGR2 by small interfering RNA and short hairpin RNA significantly reduces cell proliferation and invasion while increasing the effectiveness of gemcitabine treatment in pancreatic cancer cell lines in vitro, indicating that AGR2 can help pancreatic cancer cells survive and protect tumors from chemotherapeutic treatments for pancreatic cancer. This is critical because pancreatic cancer is well recognized as being highly resistant to therapeutics, and five-year survival rates for pancreatic cancer are extremely low.
# Protein interactions
AGR2 protein has been demonstrated to interact with C4.4A and DAG-1 proteins which are associated with metastasis formation since these transmembrane proteins are involved in cell and matrix interactions between cancer and normal cells. AGR2 is able to suppress p53 activity by preventing phosphorylation after DNA damage. AGR2 has been shown to bind to Reptin, a tumor repressor, in the nucleus. | AGR2
Anterior gradient protein 2 homolog (AGR-2), also known as secreted cement gland protein XAG-2 homolog, is a protein that in humans is encoded by the AGR2 gene. Anterior gradient homolog 2 was originally discovered in Xenopus laevis.[1] In Xenopus AGR2 plays a role in cement gland differentiation,[2] but in human cancer cell lines high levels of AGR2 correlate with downregulation of the p53 response,[3] cell migration, and cell transformation.[4] However, there have been other observations that AGR2 can repress growth and proliferation.[5]
# Discovery in Xenopus laevis
The Xenopus laevis anterior gradient genes - XAG-1, XAG-2, and XAG-3 - were discovered through dissection of different-aged embryos.[6] They become expressed in the anterior region of the dorsal ectoderm in late gastrula embryos.[6][7] XAG-2 expression gathers at the anterior region of the dorsal ectoderm, and this region corresponds to the cement gland anlage.[8] Many other homologous proteins have been discovered afterwards in Xenopus.
# Tissue distribution
AGR2 is the human homolog of XAG-2. It is expressed strongly in tissues that secrete mucus or function as endocrine organs, including the lungs, stomach, colon, prostate and small intestine.[9][10] Its protein expression has been shown to be regulated by both androgens and estrogens.[5][11]
# Structure and function
AGR2 is a protein disulfide isomerase, with a single CXXS active domain motif for oxidation and reduction reactions.[12][13] AGR2 forms mixed disulfides in substrates, such as intestinal mucin. AGR2 interacts with Mucin 2 through its thioredoxin-like domain forming a heterodisulfide bond with cysteine residues in MUC2.[14] AGR2 is suggested to play a role in protein folding, and it has a KTEL C-terminal motif similar to KDEL and KVEL endoplasmic reticulum retention sequences.[15]
# Clinical significance
Agr2 is located on chromosome 7p21, a region that has frequent genetic alterations.[16] It was first identified in estrogen receptor-positive breast cancer cells.[10] Later studies showed elevated levels of AGR2 in adenocarcinomas of the esophagus, pancreas, and prostate. In Barrett's esophagus, Agr2 expression is elevated by over 70 times compared to normal esophageal epithelia.[17] Thus, this protein alone is enough to distinguish Barrett's esophagus, which is linked to esophageal adenocarcinoma, from a normal esophagus.[18]
Varying AGR2 levels exist in different cancers. In breast cancer, high AGR2 expression is correlated with low survival rate.[19] AGR2 levels are elevated in the preneoplastic tissue Barrett's oesophagus. AGR2 is also associated with prostate cancer, though lower levels are associated with higher Gleason grades.[20]
In contrast to upregulation of AGR2 in various cancers, downregulation of AGR2 is linked with inflammatory bowel disease and increases in the risk of Crohn's disease and ulcerative colitis. This implies the importance of AGR2 in maintaining epithelial barrier function, which is supported by FOXA1 and FOXA2 molecules (transcription factors for epithelial goblet cells) which can activate the AGR2 promoter.[21]
## Breast cancer
In breast cancer, AGR2 and estrogen (ER) expression are positively correlated. Approximately 70% of breast cancer patients have breast cancer cells that heavily express ER and progesterone receptors (PgR). These patients are normally treated with endocrine therapy. Tamoxifen, which blocks the binding of estradiol to its receptor, is the standard treatment for ER-positive breast cancer. However, about one third of patients do not respond to this therapy,[22] and increased AGR2 may be one reason.
There is a positive correlation for a higher level of AGR2 expression with poor therapeutic results in ERα-positive breast cancer patients.[23][24] Agr2 mRNA expression is elevated in in vitro and in vivo studies responding to tamoxifen adjuvant therapy, so AGR2 is likely provides an agonistic effect on tamoxifen.[23][25] Therefore, AGR2 is a possible predictive biomarker when selecting patients with ER-positive breast cancer to participate this therapy.[26]
Although Agr2 mRNA levels are correlated with the tamoxifen therapy response, AGR2 protein levels have yet to be statistically associated with the therapy. A combinatorial therapy using the anastrozole and fulvestrant has been shown to prevent binding of the ER to the Agr2 promoter, and there has been improved prognosis in the patients receiving it, possibly because AGR2 expression in the tumors have been reduced.[27][unreliable medical source]
What AGR2 does in cancers is poorly understood. In breast cancer, HSP90 is a molecular chaperone expressed in tumor cells when there exists an excess of unfolded protein, and its co-chaperone has been reported to induce expression of AGR2,[28][29] so AGR2 may be used by the endoplasmic reticulum to assist with protein folding to alleviate proteotoxic stress. AGR2 may help regulate the protein and mRNA levels in a cell overall as well. During late pregnancy and lactation, AGR2 levels peak when milk proteins are produced, and mammary-specific Agr2 knockout mice had downregulated milk protein mRNA expression.[30]
## Prostate cancer
AGR2 is expressed in relatively high levels for prostate cancer patients. Urine sediment tests determined Agr2 transcript levels to be elevated.[5] AGR2 expression was increased in metastatic prostate cancer cells cultured in a bone marrow microenvironment, where intense levels of Agr2 mRNA were detected, suggesting AGR2 is required for bone metastasis of prostate cancer cells.[31] AGR2 transcript levels were lower in metastatic lesions compared to the primary tumor, however.[20] A greater chance of prostate cancer recurrence is linked to relatively lower levels of AGR2.[20]
AGR2 depletion through gene knockdown was shown to result in accumulation of prostate cancer cell lines at the G0/G1 phase of the cell cycle, while forced expression of AGR led to an increase in cell proliferation.[32] AGR2 was determined to be involved in cell adhesion. Agr2-silenced prostate cancer cells had a large decrease in association with fibronectin, lost expression of integrin, and reduced tumor cell migration.[31]
## Pancreatic cancer
AGR2 mRNA was discovered to be increased in precancerous lesions and neoplastic cells of pancreatic tumors and cancer cell lines.[33] Transient silencing of AGR2 by small interfering RNA and short hairpin RNA significantly reduces cell proliferation and invasion while increasing the effectiveness of gemcitabine treatment in pancreatic cancer cell lines in vitro,[33][34] indicating that AGR2 can help pancreatic cancer cells survive and protect tumors from chemotherapeutic treatments for pancreatic cancer. This is critical because pancreatic cancer is well recognized as being highly resistant to therapeutics, and five-year survival rates for pancreatic cancer are extremely low.
# Protein interactions
AGR2 protein has been demonstrated to interact with C4.4A and DAG-1 proteins which are associated with metastasis formation since these transmembrane proteins are involved in cell and matrix interactions between cancer and normal cells.[35] AGR2 is able to suppress p53 activity by preventing phosphorylation after DNA damage.[3] AGR2 has been shown to bind to Reptin, a tumor repressor, in the nucleus.[36] | https://www.wikidoc.org/index.php/AGR2 | |
cfa3ee102692843305a1eb32f1224983d8e03c57 | wikidoc | AIM2 | AIM2
Interferon-inducible protein AIM2 also known as absent in melanoma 2 or simply AIM2 is a protein that in humans is encoded by the AIM2 gene. Recent research has shown that AIM2 is part of the inflammasome and contributes to the defence against bacterial and viral DNA.
# Structure
AIM2 is a 343 amino acid protein with a N-terminal DAPIN (or pyrin) domain (amino acids 1-87) and a C-terminal HIN-200 domain (amino acids 138-337), which is known to have two oligonucleotide-binding folds.
# Function
AIM2 is a member of the Ifi202/IFI16 family. It plays a putative role in tumorigenic reversion and may control cell proliferation. Interferon-gamma induces expression of AIM2.
Though there has been virtually no biochemistry performed, a model based on cell-based or in vivo experiments has led to the current model of how AIM2 triggers the inflammasome. The C-terminal HIN domain binds double stranded DNA (either viral, bacterial, or even host) and acts as a cytosolic dsDNA sensor. This leads to the oligomerization of the inflammasome complex. The N-terminal pyrin domain of AIM2 interacts with the pyrin domain of another protein ASC (or Apoptosis-associated Speck-like protein containing a caspase activation and recruitment domain). ASC also contains a CARD domain (caspase activation and recruitment domain), that recruits procaspase-1 to the complex. This leads to the autoactivation of caspase-1, an enzyme that processes proinflammatory cytokines (IL-1b and IL-18).
AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity.
# Clinical relevance
Elevated levels of AIM2 expression are found in skin cells from people with psoriasis. In systemic lupus erythematosus, lysosome dysfunction allows DNA to gain access to the cytosol and activate AIM2 resulting in increased type 1 interferon production. | AIM2
Interferon-inducible protein AIM2 also known as absent in melanoma 2 or simply AIM2 is a protein that in humans is encoded by the AIM2 gene.[1][2] Recent research has shown that AIM2 is part of the inflammasome and contributes to the defence against bacterial and viral DNA.[3]
# Structure
AIM2 is a 343 amino acid protein with a N-terminal DAPIN (or pyrin) domain (amino acids 1-87) and a C-terminal HIN-200 domain (amino acids 138-337), which is known to have two oligonucleotide-binding folds.[4]
# Function
AIM2 is a member of the Ifi202/IFI16 family. It plays a putative role in tumorigenic reversion and may control cell proliferation. Interferon-gamma induces expression of AIM2.[2]
Though there has been virtually no biochemistry performed, a model based on cell-based or in vivo experiments has led to the current model of how AIM2 triggers the inflammasome. The C-terminal HIN domain binds double stranded DNA (either viral, bacterial, or even host) and acts as a cytosolic dsDNA sensor. This leads to the oligomerization of the inflammasome complex. The N-terminal pyrin domain of AIM2 interacts with the pyrin domain of another protein ASC (or Apoptosis-associated Speck-like protein containing a caspase activation and recruitment domain). ASC also contains a CARD domain (caspase activation and recruitment domain), that recruits procaspase-1 to the complex. This leads to the autoactivation of caspase-1, an enzyme that processes proinflammatory cytokines (IL-1b and IL-18).[3]
AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity.[5]
# Clinical relevance
Elevated levels of AIM2 expression are found in skin cells from people with psoriasis.[6] In systemic lupus erythematosus, lysosome dysfunction allows DNA to gain access to the cytosol and activate AIM2 resulting in increased type 1 interferon production.[7] | https://www.wikidoc.org/index.php/AIM2 | |
5f2ee58fa8bd2d588001967e2c97883203281579 | wikidoc | AKT1 | AKT1
RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 (Src homology 2-like) domains. It is commonly referred to as PKB, or by both names as "Akt/PKB".
# Function
The serine-threonine protein kinase AKT1 is catalytically inactive in serum-starved primary and immortalized fibroblasts. AKT1 and the related AKT2 are activated by platelet-derived growth factor. The activation is rapid and specific, and it is abrogated by mutations in the pleckstrin homology domain of AKT1. It was shown that the activation occurs through phosphatidylinositol 3-kinase. In the developing nervous system AKT is a critical mediator of growth factor-induced neuronal survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/threonine kinase AKT1, which then phosphorylates and inactivates components of the apoptotic machinery. Mice lacking Akt1 display a 25% reduction in body mass, indicating that Akt1 is critical for transmitting growth-promoting signals, most likely via the IGF1 receptor. Mice lacking Akt1 are also resistant to cancer: They experience considerable delay in tumor growth initiated by the large T antigen or the Neu oncogene. A single-nucleotide polymorphism in this gene causes Proteus syndrome.
# History
AKT (now also called AKT1) was originally identified as the oncogene in the transforming retrovirus, AKT8. AKT8 was isolated from a spontaneous thymoma cell line derived from AKR mice by cocultivation with an indicator mink cell line. The transforming cellular sequences, v-akt, were cloned from a transformed mink cell clone and these sequences were used to identify Akt1 and Akt2 in a human clone library. AKT8 was isolated by Stephen Staal in the laboratory of Wallace P. Rowe; he subsequently cloned v-akt and human AKT1 and AKT2 while on staff at the Johns Hopkins Oncology Center.
In 2011, a mutation in AKT1 was strongly associated with Proteus syndrome, the disease that probably affected the Elephant Man.
The name Akt stands for Ak strain transforming. The origins of the Akt name date back to 1928, where J. Furth performed experimental studies on mice that developed spontaneous thymic lymphomas. Mice from three different stocks were studied, and the stocks were designated A, R, and S. Stock A was noted to yield many cancers, and inbred families were subsequently designated by a second small letter (Aa, Ab, Ac, etc.), and thus came the Ak strain of mice. Further inbreeding was undertaken with Ak mice at the Rockefeller Institute in 1936, leading to the designation of the AKR mouse strain. In 1977, a transforming retrovirus was isolated from the AKR mouse. This virus was named Akt-8, the "t" representing its transforming capabilities.
# Interactions
AKT1 has been shown to interact with:
- AKTIP,
- BRAF,
- BRCA1,
- C-Raf,
- CDKN1B,
- CHUK
- GAB2,
- HSP90AA1,
- ILK,
- KRT10,
- MAP2K4,
- MAP3K11,
- MAP3K8,
- MAPK14,
- MAPKAPK2,
- MARK2,
- MTCP1,
- MTOR,
- NPM1,
- NR4A1,
- NR3C4,
- PKN2,
- PRKCQ,
- PDPK1,
- PLXNA1,
- TCL1A,
- TRIB3,
- TSC1,
- TSC2, and
- YWHAZ. | AKT1
RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 (Src homology 2-like) domains.[1] It is commonly referred to as PKB, or by both names as "Akt/PKB".
# Function
The serine-threonine protein kinase AKT1 is catalytically inactive in serum-starved primary and immortalized fibroblasts. AKT1 and the related AKT2 are activated by platelet-derived growth factor. The activation is rapid and specific, and it is abrogated by mutations in the pleckstrin homology domain of AKT1. It was shown that the activation occurs through phosphatidylinositol 3-kinase. In the developing nervous system AKT is a critical mediator of growth factor-induced neuronal survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/threonine kinase AKT1, which then phosphorylates and inactivates components of the apoptotic machinery. Mice lacking Akt1 display a 25% reduction in body mass, indicating that Akt1 is critical for transmitting growth-promoting signals, most likely via the IGF1 receptor. Mice lacking Akt1 are also resistant to cancer: They experience considerable delay in tumor growth initiated by the large T antigen or the Neu oncogene. A single-nucleotide polymorphism in this gene causes Proteus syndrome.[2][3]
# History
AKT (now also called AKT1) was originally identified as the oncogene in the transforming retrovirus, AKT8.[4] AKT8 was isolated from a spontaneous thymoma cell line derived from AKR mice by cocultivation with an indicator mink cell line. The transforming cellular sequences, v-akt, were cloned from a transformed mink cell clone and these sequences were used to identify Akt1 and Akt2 in a human clone library. AKT8 was isolated by Stephen Staal in the laboratory of Wallace P. Rowe; he subsequently cloned v-akt and human AKT1 and AKT2 while on staff at the Johns Hopkins Oncology Center.[5]
In 2011, a mutation in AKT1 was strongly associated with Proteus syndrome, the disease that probably affected the Elephant Man.[6]
The name Akt stands for Ak strain transforming. The origins of the Akt name date back to 1928, where J. Furth performed experimental studies on mice that developed spontaneous thymic lymphomas. Mice from three different stocks were studied, and the stocks were designated A, R, and S. Stock A was noted to yield many cancers, and inbred families were subsequently designated by a second small letter (Aa, Ab, Ac, etc.), and thus came the Ak strain of mice. Further inbreeding was undertaken with Ak mice at the Rockefeller Institute in 1936, leading to the designation of the AKR mouse strain. In 1977, a transforming retrovirus was isolated from the AKR mouse. This virus was named Akt-8, the "t" representing its transforming capabilities.
# Interactions
AKT1 has been shown to interact with:
- AKTIP,[7]
- BRAF,[8]
- BRCA1,[9][10]
- C-Raf,[11]
- CDKN1B,[12]
- CHUK[13][14]
- GAB2,[15]
- HSP90AA1,[16][17][18]
- ILK,[19][20][21]
- KRT10,[22]
- MAP2K4,[23]
- MAP3K11,[24]
- MAP3K8,[25]
- MAPK14,[26]
- MAPKAPK2,[26]
- MARK2,[27]
- MTCP1,[28][29]
- MTOR,[30][31][32]
- NPM1,[33]
- NR4A1,[34]
- NR3C4,[35]
- PKN2,[36]
- PRKCQ,[37]
- PDPK1,[19][20]
- PLXNA1,[38]
- TCL1A,[28][29][39]
- TRIB3,[40]
- TSC1,[41][42]
- TSC2,[41][42] and
- YWHAZ.[43] | https://www.wikidoc.org/index.php/AKT1 | |
e16d594251491ffdb1219f95ad0e46ae37c76266 | wikidoc | AKT2 | AKT2
RAC-beta serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT2 gene.
# Function
This gene is a putative oncogene encoding a protein belonging to the AKT subfamily of serine/threonine kinases that contain SH2-like (Src homology 2-like) domains. The encoded protein is a general protein kinase capable of phosphorylating several known proteins.
# Clinical significance
The gene was shown to be amplified and overexpressed in 2 of 8 ovarian carcinoma cell lines and 2 of 15 primary ovarian tumors. Overexpression contributes to the malignant phenotype of a subset of human ductal pancreatic cancers.
Mice lacking Akt2 have a normal body mass, but display a profound diabetic phenotype, indicating that Akt2 plays a key role in signal transduction downstream of the insulin receptor. Mice lacking Akt2 show worse outcome in breast cancer initiated by the large T antigen as well as the neu oncogene.
# Interactions
AKT2 has been shown to interact with:
- APPL1,
- CHUK,
- SH3RF1 and
- TCL1A. | AKT2
RAC-beta serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT2 gene.[1]
# Function
This gene is a putative oncogene encoding a protein belonging to the AKT subfamily of serine/threonine kinases that contain SH2-like (Src homology 2-like) domains. The encoded protein is a general protein kinase capable of phosphorylating several known proteins.[2]
# Clinical significance
The gene was shown to be amplified and overexpressed in 2 of 8 ovarian carcinoma cell lines and 2 of 15 primary ovarian tumors. Overexpression contributes to the malignant phenotype of a subset of human ductal pancreatic cancers.[2]
Mice lacking Akt2 have a normal body mass, but display a profound diabetic phenotype, indicating that Akt2 plays a key role in signal transduction downstream of the insulin receptor. Mice lacking Akt2 show worse outcome in breast cancer initiated by the large T antigen as well as the neu oncogene.[3]
# Interactions
AKT2 has been shown to interact with:
- APPL1,[4]
- CHUK,[5]
- SH3RF1[6] and
- TCL1A.[7][8] | https://www.wikidoc.org/index.php/AKT2 | |
ce7bd5bb4d1fd99f6fcd2a583675268fd478da81 | wikidoc | ALG2 | ALG2
Alpha-1,3-mannosyltransferase ALG2 is an enzyme that is encoded by the ALG2 gene. Mutations in the human gene are associated with congenital defects in glycosylation
# Function
This gene encodes a member of the glycosyltransferase 1 family. The encoded protein acts as an alpha 1,3 mannosyltransferase, mannosylating Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)-dolichol diphosphate. Defects in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ii).
# Interactions
ALG2 has been shown to interact with ANXA7 and ANXA11. | ALG2
Alpha-1,3-mannosyltransferase ALG2 is an enzyme that is encoded by the ALG2 gene.[1] Mutations in the human gene are associated with congenital defects in glycosylation [2][3]
# Function
This gene encodes a member of the glycosyltransferase 1 family. The encoded protein acts as an alpha 1,3 mannosyltransferase, mannosylating Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)-dolichol diphosphate. Defects in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ii).[3]
# Interactions
ALG2 has been shown to interact with ANXA7[4] and ANXA11.[4] | https://www.wikidoc.org/index.php/ALG2 | |
3f7fc6cbe74dad179d9d36bc24e3923c47ae94f4 | wikidoc | ALPL | ALPL
Alkaline phosphatase, tissue-nonspecific isozyme is an enzyme that in humans is encoded by the ALPL gene.
# Function
There are at least four distinct but related alkaline phosphatases: intestinal, placental, placental-like, and liver/bone/kidney (tissue-nonspecific). The first three are located together on chromosome 2, whereas the tissue-nonspecific form is located on chromosome 1. The product of this gene is a membrane-bound glycosylated enzyme that is not expressed in any particular tissue and is, therefore, referred to as the tissue-nonspecific form of the enzyme. The exact physiological function of the alkaline phosphatases is not known. A proposed function of this form of the enzyme is matrix mineralization. However, mice that lack a functional form of this enzyme show normal skeletal development.
# Clinical significance
This enzyme has been linked directly to a disorder known as hypophosphatasia, a disorder that is characterized by hypercalcemia and includes skeletal defects. The character of this disorder can vary, however, depending on the specific mutation, since this determines age of onset and severity of symptoms.
The severity of symptoms ranges from premature loss of deciduous teeth with no bone abnormalities to stillbirth depending upon which amino acid
is changed in the ALPL gene. Mutations in the ALPL gene lead to varying low activity of the enzyme tissue-nonspecific alkaline phosphatase (TNSALP) resulting in hypophosphatasia (HPP). There are different clinical forms of HPP which can be inherited by an autosomal recessive trait or autosomal dominant trait, the former causing more severe forms of the disease. Alkaline phosphatase allows for mineralization of calcium and phosphorus by bones and teeth. ALPL gene mutation leads to insufficient TNSALP enzyme and allows for an accumulation of chemicals such as inorganic pyrophosphate to indirectly cause elevated calcium levels in the body and lack of bone calcification.
The mutation E174K, where a glycine is converted to an alanine amino acid at the 571st position of its respective polypeptide chain, is a result of an ancestral mutation that occurred in Caucasians and shows a mild form of HPP. | ALPL
Alkaline phosphatase, tissue-nonspecific isozyme is an enzyme that in humans is encoded by the ALPL gene.[1][2]
# Function
There are at least four distinct but related alkaline phosphatases: intestinal, placental, placental-like, and liver/bone/kidney (tissue-nonspecific). The first three are located together on chromosome 2, whereas the tissue-nonspecific form is located on chromosome 1. The product of this gene is a membrane-bound glycosylated enzyme that is not expressed in any particular tissue and is, therefore, referred to as the tissue-nonspecific form of the enzyme. The exact physiological function of the alkaline phosphatases is not known. A proposed function of this form of the enzyme is matrix mineralization. However, mice that lack a functional form of this enzyme show normal skeletal development.[3]
# Clinical significance
This enzyme has been linked directly to a disorder known as hypophosphatasia, a disorder that is characterized by hypercalcemia and includes skeletal defects. The character of this disorder can vary, however, depending on the specific mutation, since this determines age of onset and severity of symptoms.
The severity of symptoms ranges from premature loss of deciduous teeth with no bone abnormalities to stillbirth[4] depending upon which amino acid[5][6]
is changed in the ALPL gene. Mutations in the ALPL gene lead to varying low activity of the enzyme tissue-nonspecific alkaline phosphatase (TNSALP) resulting in hypophosphatasia (HPP).[7] There are different clinical forms of HPP which can be inherited by an autosomal recessive trait or autosomal dominant trait,[4] the former causing more severe forms of the disease. Alkaline phosphatase allows for mineralization of calcium and phosphorus by bones and teeth.[7] ALPL gene mutation leads to insufficient TNSALP enzyme and allows for an accumulation of chemicals such as inorganic pyrophosphate[7] to indirectly cause elevated calcium levels in the body and lack of bone calcification.
The mutation E174K, where a glycine is converted to an alanine amino acid at the 571st position of its respective polypeptide chain, is a result of an ancestral mutation that occurred in Caucasians and shows a mild form of HPP.[4] | https://www.wikidoc.org/index.php/ALPL | |
e32ec78adc7a80e10c865e234cf1b5366e192508 | wikidoc | ALX1 | ALX1
ALX homeobox protein 1 is a protein that in humans is encoded by the ALX1 gene.
# Function
The specific function of this gene has yet to be determined in humans; however, in rodents, it is necessary for survival of the forebrain mesenchyme and may also be involved in development of the cervix. Mutations in the mouse gene lead to neural tube defects such as acrania and meroanencephaly.
In Darwin's finches, inhabiting the Galapagos islands, ALX1 has been linked to the diversity of beak shapes.
# Interactions
ALX1 has been shown to interact with IPO13. | ALX1
ALX homeobox protein 1 is a protein that in humans is encoded by the ALX1 gene.[1][2][3]
# Function
The specific function of this gene has yet to be determined in humans; however, in rodents, it is necessary for survival of the forebrain mesenchyme and may also be involved in development of the cervix. Mutations in the mouse gene lead to neural tube defects such as acrania and meroanencephaly.[3]
In Darwin's finches, inhabiting the Galapagos islands, ALX1 has been linked to the diversity of beak shapes.[4]
# Interactions
ALX1 has been shown to interact with IPO13.[5] | https://www.wikidoc.org/index.php/ALX1 | |
2d33488eb8caa08773073288e767f8232e8135e7 | wikidoc | ALX3 | ALX3
The ALX3 gene, also known as aristaless-like homeobox 3, is a protein coding gene that provides instructions to build a protein which is a member of the homeobox protein family. This grouping regulates patterns of anatomical development. The gene encodes a nuclear protein that functions as a transcription regulator involved in cell-type differentiation and development.
The ALX3 protein, encoded by the gene, is a transcription factor, meaning that it binds to DNA and obtains control over the action of other genes. The ALX3 protein specifically controls genes that regulate cell growth, proliferation, and migration. This protein is essential for the development of the head and face, specifically the nose. This event begins around the fourth week of development.
At least 7 mutations in the ALX3 gene are known to cause frontonasal dysplasia. The mutations eliminate the function of the ALX3 protein, resulting in decreased ability to bind to DNA. The loss of regulatory function results in uncontrolled cell proliferation and migration during fetal development. One particular form of the disorder, called frontonasal dysplasia type 1, presents with abnormal development of structures in the middle of the face. The most common malformation of this defect is a cleft in the nose, lip, and palate.
ALX3 was first discovered by a group of scientists, led by Hopi Hoekstra, a biologist from Harvard University, that investigated how stripe patterns form in animals. They investigated the Rhabdomys pumiliom, commonly known as the African striped mouse because of the alternating colored stripes observed on its back. One of the members of the team, Ricardo Mallarino, discovered that the stripes were formed during embryogenesis in the mice. Melanocytes, the specialized cells that produce the pigments in the skin, were not active in areas where the lighter stripes were observed. They then researched the genes active in those areas using RNA sequencing. They discovered that ALX3 was expressed in the light hair areas but not in the dark hair areas. They found that all mice expressed the gene on their abdomen but only the African striped mouse expressed it on its back, hence why the strips appear. Protein-DNA binding was then performed to determine where the ALX3 protein binds on the DNA. ALX3 binds to the promoter and represses MITF, which allows transcription to take place when making melanocytes. More tests were performed to confirm the function of ALX3 within the African striped mice. The gene was observed in other rodents such as the North American chipmunks and deemed responsible for the similar outcomes. The differences in evolution amongst the species did not hinder the similarities in the expression of the gene. This lead the team to believe that ALX3 may have the same effect in mammals. However, further studies must be completed to confirm that ALX3 is responsible for the same in other mammals. | ALX3
The ALX3 gene, also known as aristaless-like homeobox 3, is a protein coding gene that provides instructions to build a protein which is a member of the homeobox protein family.[1] This grouping regulates patterns of anatomical development. The gene encodes a nuclear protein that functions as a transcription regulator involved in cell-type differentiation and development.
The ALX3 protein, encoded by the gene, is a transcription factor, meaning that it binds to DNA and obtains control over the action of other genes. The ALX3 protein specifically controls genes that regulate cell growth, proliferation, and migration. This protein is essential for the development of the head and face, specifically the nose. This event begins around the fourth week of development.
At least 7 mutations in the ALX3 gene are known to cause frontonasal dysplasia. The mutations eliminate the function of the ALX3 protein, resulting in decreased ability to bind to DNA. The loss of regulatory function results in uncontrolled cell proliferation and migration during fetal development. One particular form of the disorder, called frontonasal dysplasia type 1, presents with abnormal development of structures in the middle of the face. The most common malformation of this defect is a cleft in the nose, lip, and palate.[2]
ALX3 was first discovered by a group of scientists, led by Hopi Hoekstra, a biologist from Harvard University, that investigated how stripe patterns form in animals. They investigated the Rhabdomys pumiliom, commonly known as the African striped mouse because of the alternating colored stripes observed on its back. One of the members of the team, Ricardo Mallarino, discovered that the stripes were formed during embryogenesis in the mice. Melanocytes, the specialized cells that produce the pigments in the skin, were not active in areas where the lighter stripes were observed. They then researched the genes active in those areas using RNA sequencing. They discovered that ALX3 was expressed in the light hair areas but not in the dark hair areas. They found that all mice expressed the gene on their abdomen but only the African striped mouse expressed it on its back, hence why the strips appear. Protein-DNA binding was then performed to determine where the ALX3 protein binds on the DNA. ALX3 binds to the promoter and represses MITF, which allows transcription to take place when making melanocytes. More tests were performed to confirm the function of ALX3 within the African striped mice. The gene was observed in other rodents such as the North American chipmunks and deemed responsible for the similar outcomes. The differences in evolution amongst the species did not hinder the similarities in the expression of the gene. This lead the team to believe that ALX3 may have the same effect in mammals. However, further studies must be completed to confirm that ALX3 is responsible for the same in other mammals. | https://www.wikidoc.org/index.php/ALX3 | |
c95b09063c92124d8e79de35a324088db34d7199 | wikidoc | AMBN | AMBN
Ameloblastin (enamel matrix protein) is a protein that in humans is encoded by the AMBN gene.
# Function
Ameloblastin, also known as amelin, is a gene-specific protein found in tooth enamel. Although less than 5% of enamel consists of protein, ameloblastins comprise 5–10% of all enamel protein. This protein is formed by ameloblasts during the early secretory to late maturation stages of amelogenesis. Although not completely understood, the function of ameloblastins is believed to be in controlling the elongation of enamel crystals and generally directing enamel mineralization during tooth development.
Other significant proteins in enamel are amelogenins, enamelins, and tuftelins.
This gene encodes the nonamelogenin enamel matrix protein ameloblastin. The encoded protein may be important in enamel matrix formation and mineralization. This gene is located in the calcium-binding phosphoprotein gene cluster on chromosome 4. Mutations in this gene may be associated with dentinogenesis imperfecta and autosomal dominant amelogenesis imperfecta. .
# Clinical significance
Mutations in AMBN cause amelogenesis imperfecta. | AMBN
Ameloblastin (enamel matrix protein) is a protein that in humans is encoded by the AMBN gene.[1]
# Function
Ameloblastin, also known as amelin, is a gene-specific protein found in tooth enamel. Although less than 5% of enamel consists of protein, ameloblastins comprise 5–10% of all enamel protein. This protein is formed by ameloblasts during the early secretory to late maturation stages of amelogenesis. Although not completely understood, the function of ameloblastins is believed to be in controlling the elongation of enamel crystals and generally directing enamel mineralization during tooth development.
Other significant proteins in enamel are amelogenins, enamelins, and tuftelins.
This gene encodes the nonamelogenin enamel matrix protein ameloblastin. The encoded protein may be important in enamel matrix formation and mineralization. This gene is located in the calcium-binding phosphoprotein gene cluster on chromosome 4. Mutations in this gene may be associated with dentinogenesis imperfecta and autosomal dominant amelogenesis imperfecta. [provided by RefSeq, Aug 2011].
# Clinical significance
Mutations in AMBN cause amelogenesis imperfecta.[2] | https://www.wikidoc.org/index.php/AMBN | |
4cb78fcc46a69a3b18c4e248b19497616f2ebe26 | wikidoc | AMFR | AMFR
Autocrine motility factor receptor, isoform 2 is a protein that in humans is encoded by the AMFR gene.
Autocrine motility factor is a tumor motility-stimulating protein secreted by tumor cells. The protein encoded by this gene is a glycosylated transmembrane protein and a receptor for autocrine motility factor. The receptor, which shows some sequence similarity to tumor protein p53, is localized to the leading and trailing edges of carcinoma cells.
# Model organisms
Model organisms have been used in the study of AMFR function. A conditional knockout mouse line, called Amfrtm1a(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 six tests were carried out on mutant mice and one significant abnormality was observed: Fewer than expected homozygous mutant mice survived until weaning.
# Interactions
AMFR has been shown to interact with Valosin-containing protein. | AMFR
Autocrine motility factor receptor, isoform 2 is a protein that in humans is encoded by the AMFR gene.[1][2]
Autocrine motility factor is a tumor motility-stimulating protein secreted by tumor cells. The protein encoded by this gene is a glycosylated transmembrane protein and a receptor for autocrine motility factor. The receptor, which shows some sequence similarity to tumor protein p53, is localized to the leading and trailing edges of carcinoma cells.[2]
# Model organisms
Model organisms have been used in the study of AMFR function. A conditional knockout mouse line, called Amfrtm1a(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 six tests were carried out on mutant mice and one significant abnormality was observed: Fewer than expected homozygous mutant mice survived until weaning.[5]
# Interactions
AMFR has been shown to interact with Valosin-containing protein.[13][14] | https://www.wikidoc.org/index.php/AMFR | |
4928f84a275fe9bec65145e3ae0aa7ee9877cda0 | wikidoc | ANK1 | ANK1
Ankyrin 1, erythrocytic, also known as ANK1, is a protein that in humans is encoded by the ANK1 gene.
# Tissue distribution
The protein encoded by this gene, Ankyrin 1, is the prototype of the ankyrin family, was first discovered in erythrocytes, but since has also been found in brain and muscles.
# Genetics
Complex patterns of alternative splicing in the regulatory domain, giving rise to different isoforms of ankyrin 1 have been described, however, the precise functions of the various isoforms are not known. Alternative polyadenylation accounting for the different sized erythrocytic ankyrin 1 mRNAs, has also been reported. Truncated muscle-specific isoforms of ankyrin 1 resulting from usage of an alternate promoter have also been identified.
# Disease linkage
Mutations in erythrocytic ankyrin 1 have been associated in approximately half of all patients with hereditary spherocytosis.
ANK1 shows altered methylation and expression in Alzheimer's disease. A gene expression study of postmortem brains has suggested ANK1 interacts with interferon-γ signalling.
# Function
The ANK1 protein belongs to the ankyrin family that are believed to link the integral membrane proteins to the underlying spectrin-actin cytoskeleton and play key roles in activities such as cell motility, activation, proliferation, contact, and maintenance of specialized membrane domains. Multiple isoforms of ankyrin with different affinities for various target proteins are expressed in a tissue-specific, developmentally regulated manner. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin-binding domain; and a carboxy-terminal regulatory domain, which is the least conserved and subject to variation.
The small ANK1 (sAnk1) protein splice variants makes contacts with obscurin, a giant protein surrounding the contractile apparatus in striated muscle.
# Interactions
ANK1 has been shown to interact with T-cell lymphoma invasion and metastasis-inducing protein 1, Titin, RHAG and OBSCN. | ANK1
Ankyrin 1, erythrocytic, also known as ANK1, is a protein that in humans is encoded by the ANK1 gene.[1][2]
# Tissue distribution
The protein encoded by this gene, Ankyrin 1, is the prototype of the ankyrin family, was first discovered in erythrocytes, but since has also been found in brain and muscles.[2]
# Genetics
Complex patterns of alternative splicing in the regulatory domain, giving rise to different isoforms of ankyrin 1 have been described, however, the precise functions of the various isoforms are not known. Alternative polyadenylation accounting for the different sized erythrocytic ankyrin 1 mRNAs, has also been reported. Truncated muscle-specific isoforms of ankyrin 1 resulting from usage of an alternate promoter have also been identified.[2]
# Disease linkage
Mutations in erythrocytic ankyrin 1 have been associated in approximately half of all patients with hereditary spherocytosis.[2]
ANK1 shows altered methylation and expression in Alzheimer's disease.[3][4] A gene expression study of postmortem brains has suggested ANK1 interacts with interferon-γ signalling.[5]
# Function
The ANK1 protein belongs to the ankyrin family that are believed to link the integral membrane proteins to the underlying spectrin-actin cytoskeleton and play key roles in activities such as cell motility, activation, proliferation, contact, and maintenance of specialized membrane domains. Multiple isoforms of ankyrin with different affinities for various target proteins are expressed in a tissue-specific, developmentally regulated manner. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin-binding domain; and a carboxy-terminal regulatory domain, which is the least conserved and subject to variation.[2]
The small ANK1 (sAnk1) protein splice variants makes contacts with obscurin, a giant protein surrounding the contractile apparatus in striated muscle.[6]
# Interactions
ANK1 has been shown to interact with T-cell lymphoma invasion and metastasis-inducing protein 1,[7] Titin,[8] RHAG[9] and OBSCN.[10] | https://www.wikidoc.org/index.php/ANK1 | |
598379008b945dcec460621e2df5e23a17dd32dd | wikidoc | ANK2 | ANK2
Ankyrin-B, also known as Ankyrin-2, is a protein which in humans is encoded by the ANK2 gene. Ankyrin-B is ubiquitously expressed, but shows high expression in cardiac muscle. Ankyrin-B plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in cardiomyocytes, as well as in costamere structures. Mutations in ankyrin-B cause a dominantly-inherited, cardiac arrhythmia syndrome known as ankyrin-B syndrome as well as sick sinus syndrome; mutations have also been associated to a lesser degree with hypertrophic cardiomyopathy. Alterations in ankyrin-B expression levels are observed in human heart failure.
# Structure
Ankyrin-B protein is around 220 kDa, with several isoforms. The ANK2 gene is approximately 560 kb in size and consists of 53 exons on human chromosome 4; ANK2 is also transcriptionally regulated via over 30 alternative splicing events with variable expression of isoforms in cardiac muscle. Ankyrin-B is a member of the ankyrin family of proteins, and is a modular protein which is composed of three structural domains: an N-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain and death domain; and a C-terminal regulatory domain which is the least conserved and subject to variation, and determines ankyrin-B activity. The membrane-binding region of ankyrin-B is composed of 24 consecutive ankyrin repeats, and it is the membrane-binding domain of ankyrins that confer functional differences among ankyrin isoforms. Though ubiquitously expressed, ankyrin-B shows high expression levels in cardiac muscle, and is expressed 10-fold lower levels in skeletal muscle, suggesting that ankyrin-B plays a specifically adapted functional role in cardiac muscle.
# Function
Ankyrin-B is a member of the ankyrin family of proteins. ankyrin-1 has shown to be essential in normal function of erythrocytes; however, ankyrin-B and ankyrin-3 play essential roles in the localization and membrane stabilization of ion transporters and ion channels in cardiomyocytes.
Functional insights into ankyrin-B function have come from studies employing ankyrin-B chimeric proteins. One study showed that the death/C-terminal domain of ankyrin-B determines both the subcellular localization as well as activity in restoring normal inositol trisphosphate receptor and ryanodine receptor localization and cardiomyocyte contractility. Further studies have shown that the beta-hairpin loops within the ankyrin repeat domain of ankyrin-B are required for the interaction with the inositol trisphosphate receptor, and a reduction of ankyrin-B in neonatal cardiomyocytes reduces the half-life of the inositol trisphosphate receptor by 3-fold and destabilizes its proper localization; all of these effects were rescued by reintroducing ankyrin-B. Moreover, a specific sequence in ankyrin-B (absent in other ankyrin isoforms) folds as an amphipathic alpha helix is required for normal levels of sodium-calcium exchanger, sodium potassium ATPase and inositol triphosphate receptor in cardiomyocytes, and is regulated by HDJ1/HSP40 binding to this region.
Additional insights into ankyrin-B function have come from studies employing ankyrin-B transgenic animals. Cardiomyocytes from ankyrin-B (-/+) mice exhibited irregular spatial patterns and periodicity of calcium release, as well as abnormal distribution of the sarcomplasmic reticular calcium ATPase, SERCA2, and ryanodine receptors; effects that were rescued by transfection of ankyrin-B. Effects on ryanodine receptors specifically were also rescued by a potent Ca2+/calmodulin-dependent protein kinase II inhibitor, suggesting that inhibition of Ca2+/calmodulin-dependent protein kinase II may also be a potential treatment strategy. These mice also display several electrophysiological abnormalities, including bradycardia, variable heart rate, long QT intervals, catecholaminergic polymorphic ventricular tachycardia, syncope, and sudden cardiac death. Mechanistic explanations underlying these effects were explained in a later study conducted in the ankyrin-B (-/+) mice, which showed that reduction of ankyrin-B alters the transport of sodium and calcium and enhances the coupled openings of ryanodine receptors, which results in a higher frequency of calcium sparks and waves of calcium.
It is now becoming clear that ankyrin-B exists in a biomolecular complex with the sodium potassium ATPase, sodium calcium exchanger and inositol triphosphate receptor which is localized in T-tubules within discrete microdomains of cardiomyocytes that are distinct from dyads formed by dihydropyridine receptors complexed to ryanodine receptors. The human ankyrin-B arrhythmogenic mutation (Glu1425Gly) blocks the formation of this complex, which provides a mechanism behind cardiac arrhythmias in patients. Studies from other labs have shed light on the requirement of ankyrin-B in the targeting and post-translational stability of the sodium calcium exchanger in cardiomyocytes, which is clinically important because elevated expression of the sodium calcium exchanger is a factor related to arrhythmia and heart failure. Ankyrin-B forms a membrane complex with ATP-sensitive potassium channels, which is necessary for normal channel trafficking and targeting the channel to sarcolemmal membranes; this interaction is also important in the response of cardiomyocytes to cardiac ischemia and metabolic regulation.
Ankyrin-B has also been identified to associate at sarcomeric M-lines and costameres in cardiac muscle and skeletal muscle, respectively. Exon 43′ in ankyrin-B is specifically and predominantly expressed in cardiac muscle and harbors key residues for modulating the interaction between ankyrin-B and obscurin. This interaction is also key for targeting protein phosphatase 2A to cardiac M-lines to propagate phosphorylation signaling paradigms. In skeletal muscle, ankyrin-B interacts with dynactin-4 and with β2-spectrin, which is required for proper localization and functioning of the dystrophin complex and costamere structures, as well as protection from exercise-induced injury.
# Clinical Significance
Mutations in the ANK2 gene have been associated with a dominantly-inherited, cardiac arrhythmia syndrome known as ankyrin-B syndrome, previously referred to as long QT syndrome, type 4, which can be described as an atypical arrhythmia syndrome with bradycardia, atrial fibrillation, conduction block, arrhythmia and risk of sudden cardiac death. Intense investigation is currently ongoing regarding linking ANK2 mutations to the range of severity of cardiac phenotypes, and initial evidence suggests that the varying degrees of loss of function of ankyrin-B protein may explain the effect of any particular mutation.
Initially, a Glu1425Gly mutation in ANK2 was found to cause dominantly-inherited long QT syndrome, type 4, cardiac arrhythmia. The mechanistic underpinnings of this mutation include abnormal expression and targeting of the sodium pump, the sodium-calcium exchanger, and inositol-1,4,5-trisphosphate receptors to transverse tubules, as well as calcium handling resulting in extrasystoles. Further analysis in ANK2 mutations localized in the regulatory domain of ankyrin-2, which is specific to the ankyrin-2 isoform, indicated that long QT syndrome was not a consistent clinical manifestation of ANK2 mutations; however, the effect on Ca(2+) dynamics and localization/expression of the sodium calcium exchanger, sodium potassium ATPase and inositol triphosphate receptor in cardiomyocytes were consistent observations. This study demonstrated that common pathogenic features of all ANK2 mutations was the abnormal coordination of a panel of related ion channels and transporters. Additional mechanistic studies have shown that atrial cardiomyocytes lacking ankyrin-B have shortened action potentials, which can be explained by decreased voltage-dependent calcium channel expression, specifically Ca(v)1.3, which is responsible for low voltage-activated L-type Ca(2+) currents. Ankyrin-B directly associates with and is required for targeting Ca(v)1.3 to membranes.
ANK2 mutations have also been identified in patients with sinus node dysfunction. Mechanistic studies on effects of these mutations in mice showed severe bradycardia and variability in heart rate, as well as dysfunction in ankyrin-B-based trafficking pathways in primary and subsidiary pacemaker cells. In a large genotype-phenotype study of 874 patients with hypertrophic cardiomyopathy, patients with ANK2 variants exhibited greater maximum left ventricular wall thickness.
In patients with both ischemic and non-ischemic heart failure, ankyrin-B levels are altered. Further mechanistic study showed that reactive oxygen species, intracellular calcium and calpain regulate cardiac ankyrin-B levels, and ankyrin-B is required for normal cardioprotection following ischemia reperfusion injury.
# Interactions
- ITPR1
- HDJ1/HSP40
- SPTBN1
- OBSCN
- DMD
- DCTN4
- tubulin | ANK2
Ankyrin-B, also known as Ankyrin-2, is a protein which in humans is encoded by the ANK2 gene.[1][2] Ankyrin-B is ubiquitously expressed, but shows high expression in cardiac muscle. Ankyrin-B plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in cardiomyocytes, as well as in costamere structures. Mutations in ankyrin-B cause a dominantly-inherited, cardiac arrhythmia syndrome known as ankyrin-B syndrome as well as sick sinus syndrome; mutations have also been associated to a lesser degree with hypertrophic cardiomyopathy. Alterations in ankyrin-B expression levels are observed in human heart failure.
# Structure
Ankyrin-B protein is around 220 kDa, with several isoforms.[3] The ANK2 gene is approximately 560 kb in size and consists of 53 exons on human chromosome 4; ANK2 is also transcriptionally regulated via over 30 alternative splicing events with variable expression of isoforms in cardiac muscle.[4][5][6] Ankyrin-B is a member of the ankyrin family of proteins, and is a modular protein which is composed of three structural domains: an N-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain and death domain; and a C-terminal regulatory domain which is the least conserved and subject to variation, and determines ankyrin-B activity.[1][7][8] The membrane-binding region of ankyrin-B is composed of 24 consecutive ankyrin repeats, and it is the membrane-binding domain of ankyrins that confer functional differences among ankyrin isoforms.[8] Though ubiquitously expressed, ankyrin-B shows high expression levels in cardiac muscle, and is expressed 10-fold lower levels in skeletal muscle, suggesting that ankyrin-B plays a specifically adapted functional role in cardiac muscle.[9]
# Function
Ankyrin-B is a member of the ankyrin family of proteins. ankyrin-1 has shown to be essential in normal function of erythrocytes;[10] however, ankyrin-B and ankyrin-3 play essential roles in the localization and membrane stabilization of ion transporters and ion channels in cardiomyocytes.[9][11]
Functional insights into ankyrin-B function have come from studies employing ankyrin-B chimeric proteins. One study showed that the death/C-terminal domain of ankyrin-B determines both the subcellular localization as well as activity in restoring normal inositol trisphosphate receptor and ryanodine receptor localization and cardiomyocyte contractility.[8] Further studies have shown that the beta-hairpin loops within the ankyrin repeat domain of ankyrin-B are required for the interaction with the inositol trisphosphate receptor, and a reduction of ankyrin-B in neonatal cardiomyocytes reduces the half-life of the inositol trisphosphate receptor by 3-fold and destabilizes its proper localization; all of these effects were rescued by reintroducing ankyrin-B.[12] Moreover, a specific sequence in ankyrin-B (absent in other ankyrin isoforms) folds as an amphipathic alpha helix is required for normal levels of sodium-calcium exchanger, sodium potassium ATPase and inositol triphosphate receptor in cardiomyocytes, and is regulated by HDJ1/HSP40 binding to this region.[13]
Additional insights into ankyrin-B function have come from studies employing ankyrin-B transgenic animals. Cardiomyocytes from ankyrin-B (-/+) mice exhibited irregular spatial patterns and periodicity of calcium release, as well as abnormal distribution of the sarcomplasmic reticular calcium ATPase, SERCA2, and ryanodine receptors; effects that were rescued by transfection of ankyrin-B.[14] Effects on ryanodine receptors specifically were also rescued by a potent Ca2+/calmodulin-dependent protein kinase II inhibitor, suggesting that inhibition of Ca2+/calmodulin-dependent protein kinase II may also be a potential treatment strategy.[15][16] These mice also display several electrophysiological abnormalities, including bradycardia, variable heart rate, long QT intervals, catecholaminergic polymorphic ventricular tachycardia, syncope, and sudden cardiac death.[17] Mechanistic explanations underlying these effects were explained in a later study conducted in the ankyrin-B (-/+) mice, which showed that reduction of ankyrin-B alters the transport of sodium and calcium and enhances the coupled openings of ryanodine receptors, which results in a higher frequency of calcium sparks and waves of calcium.[18]
It is now becoming clear that ankyrin-B exists in a biomolecular complex with the sodium potassium ATPase, sodium calcium exchanger and inositol triphosphate receptor which is localized in T-tubules within discrete microdomains of cardiomyocytes that are distinct from dyads formed by dihydropyridine receptors complexed to ryanodine receptors. The human ankyrin-B arrhythmogenic mutation (Glu1425Gly) blocks the formation of this complex, which provides a mechanism behind cardiac arrhythmias in patients.[9] Studies from other labs have shed light on the requirement of ankyrin-B in the targeting and post-translational stability of the sodium calcium exchanger in cardiomyocytes, which is clinically important because elevated expression of the sodium calcium exchanger is a factor related to arrhythmia and heart failure.[19] Ankyrin-B forms a membrane complex with ATP-sensitive potassium channels, which is necessary for normal channel trafficking and targeting the channel to sarcolemmal membranes; this interaction is also important in the response of cardiomyocytes to cardiac ischemia and metabolic regulation.[20][21]
Ankyrin-B has also been identified to associate at sarcomeric M-lines and costameres in cardiac muscle and skeletal muscle, respectively. Exon 43′ in ankyrin-B is specifically and predominantly expressed in cardiac muscle and harbors key residues for modulating the interaction between ankyrin-B and obscurin. This interaction is also key for targeting protein phosphatase 2A to cardiac M-lines to propagate phosphorylation signaling paradigms.[22] In skeletal muscle, ankyrin-B interacts with dynactin-4 and with β2-spectrin, which is required for proper localization and functioning of the dystrophin complex and costamere structures, as well as protection from exercise-induced injury.[23]
# Clinical Significance
Mutations in the ANK2 gene have been associated with a dominantly-inherited, cardiac arrhythmia syndrome known as ankyrin-B syndrome, previously referred to as long QT syndrome, type 4, which can be described as an atypical arrhythmia syndrome with bradycardia, atrial fibrillation, conduction block, arrhythmia and risk of sudden cardiac death.[24][25][26] Intense investigation is currently ongoing regarding linking ANK2 mutations to the range of severity of cardiac phenotypes, and initial evidence suggests that the varying degrees of loss of function of ankyrin-B protein may explain the effect of any particular mutation.[27][28][29][30][31][32][33][34][35][36]
Initially, a Glu1425Gly mutation in ANK2 was found to cause dominantly-inherited long QT syndrome, type 4, cardiac arrhythmia. The mechanistic underpinnings of this mutation include abnormal expression and targeting of the sodium pump, the sodium-calcium exchanger, and inositol-1,4,5-trisphosphate receptors to transverse tubules, as well as calcium handling resulting in extrasystoles.[37] Further analysis in ANK2 mutations localized in the regulatory domain of ankyrin-2, which is specific to the ankyrin-2 isoform, indicated that long QT syndrome was not a consistent clinical manifestation of ANK2 mutations;[38] however, the effect on Ca(2+) dynamics and localization/expression of the sodium calcium exchanger, sodium potassium ATPase and inositol triphosphate receptor in cardiomyocytes were consistent observations. This study demonstrated that common pathogenic features of all ANK2 mutations was the abnormal coordination of a panel of related ion channels and transporters.[39] Additional mechanistic studies have shown that atrial cardiomyocytes lacking ankyrin-B have shortened action potentials, which can be explained by decreased voltage-dependent calcium channel expression, specifically Ca(v)1.3, which is responsible for low voltage-activated L-type Ca(2+) currents. Ankyrin-B directly associates with and is required for targeting Ca(v)1.3 to membranes.[40]
ANK2 mutations have also been identified in patients with sinus node dysfunction. Mechanistic studies on effects of these mutations in mice showed severe bradycardia and variability in heart rate, as well as dysfunction in ankyrin-B-based trafficking pathways in primary and subsidiary pacemaker cells.[41][42][43] In a large genotype-phenotype study of 874 patients with hypertrophic cardiomyopathy, patients with ANK2 variants exhibited greater maximum left ventricular wall thickness.[44]
In patients with both ischemic and non-ischemic heart failure, ankyrin-B levels are altered. Further mechanistic study showed that reactive oxygen species, intracellular calcium and calpain regulate cardiac ankyrin-B levels, and ankyrin-B is required for normal cardioprotection following ischemia reperfusion injury.[45]
# Interactions
- ITPR1[12]
- HDJ1/HSP40[13]
- SPTBN1[46]
- OBSCN[22]
- DMD[47]
- DCTN4[47]
- tubulin[48] | https://www.wikidoc.org/index.php/ANK2 | |
275c6315a61d0c0f810bd1e74a145c2e1d1a3e8c | wikidoc | ANK3 | ANK3
Ankyrin-3 (ANK-3), also known as ankyrin-G, is a protein from ankyrin family that in humans is encoded by the ANK3 gene.
# Function
The protein encoded by this gene, ankyrin-3 is an immunologically distinct gene product from ankyrins ANK1 and ANK2, and was originally found at the axonal initial segment and nodes of Ranvier of neurons in the central and peripheral nervous systems. Alternatively spliced variants may be expressed in other tissues. Although multiple transcript variants encoding several different isoforms have been found for this gene, the full-length nature of only two have been characterized.
Within the nervous system, ankyrin-G is specifically localized to the neuromuscular junction, the axon initial segment and the Nodes of Ranvier. Within the nodes of Ranvier where action potentials are actively propagated, ankyrin-G has long been thought to be the intermediate binding partner to neurofascin and voltage-gated sodium channels. The genetic deletion of ankyrin-G from multiple neuron types has shown that ankyrin-G is required for the normal clustering of voltage-gated sodium channels at the axon hillock and for action potential firing.
# Disease linkage
The ANK3 protein associates with the cardiac sodium channel Nav1.5 (SCN5A). Both proteins are highly expressed at ventricular intercalated disc and T-tubule membranes in cardiomyocytes. A mutation in the Nav1.5 protein blocks interaction with ANK3 binding and therefore disrupts surface expression of Nav1.5 in cardiomyocytes resulting in Brugada syndrome, a type of cardiac arrhythmia.
Other mutations in the ANK3 gene may be involved in the bipolar disorder and intellectual disability.
# Ankyrin family
The protein encoded by the ANK3 gene is a member of the ankyrin family of proteins that link the integral membrane proteins to the underlying spectrin-actin cytoskeleton. Ankyrins play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. | ANK3
Ankyrin-3 (ANK-3), also known as ankyrin-G, is a protein from ankyrin family that in humans is encoded by the ANK3 gene.[1][2]
# Function
The protein encoded by this gene, ankyrin-3 is an immunologically distinct gene product from ankyrins ANK1 and ANK2, and was originally found at the axonal initial segment and nodes of Ranvier of neurons in the central and peripheral nervous systems. Alternatively spliced variants may be expressed in other tissues. Although multiple transcript variants encoding several different isoforms have been found for this gene, the full-length nature of only two have been characterized.[1]
Within the nervous system, ankyrin-G is specifically localized to the neuromuscular junction, the axon initial segment and the Nodes of Ranvier.[3] Within the nodes of Ranvier where action potentials are actively propagated, ankyrin-G has long been thought to be the intermediate binding partner to neurofascin and voltage-gated sodium channels.[4] The genetic deletion of ankyrin-G from multiple neuron types has shown that ankyrin-G is required for the normal clustering of voltage-gated sodium channels at the axon hillock and for action potential firing.[5][6]
# Disease linkage
The ANK3 protein associates with the cardiac sodium channel Nav1.5 (SCN5A). Both proteins are highly expressed at ventricular intercalated disc and T-tubule membranes in cardiomyocytes. A mutation in the Nav1.5 protein blocks interaction with ANK3 binding and therefore disrupts surface expression of Nav1.5 in cardiomyocytes resulting in Brugada syndrome, a type of cardiac arrhythmia.[7]
Other mutations in the ANK3 gene may be involved in the bipolar disorder and intellectual disability.[8][9][10][11]
# Ankyrin family
The protein encoded by the ANK3 gene is a member of the ankyrin family of proteins that link the integral membrane proteins to the underlying spectrin-actin cytoskeleton. Ankyrins play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation.[1] | https://www.wikidoc.org/index.php/ANK3 | |
45917e87bd23909623b4671ad0c5c532b07ae813 | wikidoc | ANLN | ANLN
Anillin is a conserved protein implicated in cytoskeletal dynamics during cellularization and cytokinesis. The ANLN gene in humans and the scraps gene in Drosophila encode Anillin. In 1989, anillin was first isolated in embryos of Drosophila melanogaster. It was identified as an F-actin binding protein. Six years later, the anillin gene was cloned from cDNA originating from a Drosophila ovary. Staining with anti-anillin (Antigen 8) antibody showed the anillin localizes to the nucleus during interphase and to the contractile ring during cytokinesis. These observations agree with further research that found anillin in high concentrations near the cleavage furrow coinciding with RhoA, a key regulator of contractile ring formation.
The name of the protein anillin originates from a Spanish word, anillo. Anillo means ring and shows that the name anillin references the observed enrichment of anillins at the contractile ring during cytokinesis. Anillins are also enriched at other actomyosin rings, most significantly, those at the leading edge of the Drosophila embryo during cellularization. These actomyosin rings invaginate to separate all nuclei for one another in the syncytial blastoderm.
# Structure
Anillin has a unique multi-domain structure. At the N-terminus, there is an actin- and myosin-binding domain. At the C-terminus, there is a PH domain. The PH domain is conserved and essential for anillin functionality. The human anillin cDNA, located on Chr7, encodes a 1,125–amino acid protein with a predicted molecular mass of 124 kD and a pI of 8.1. The mouse anillin gene is located on Chr9.
There are also numerous anillin-like protein homologues found outside of metazoans. In Schizosaccharomyces pombe (fission yeast), there are Mid1p and Mid2p. These two anillin-like proteins do not have any overlap in their functions. Mid1p has been characterized as a key regulator in cytokinesis, responsible for arranging contractile ring assembly and positioning. Mid2p acts later in cytokinesis to organize septins during septation, or the invagination of inner membranes, outer membranes, and the cell wall that occurs in order to separate daughter cells completely. Saccharomyces cerevisiae (budding yeast) also have two anillin-like proteins, Boi1p and Boi2p. Boi1p and Boi2p localize to the nucleus and contractile ring at the bud neck, respectively. They are essential for cell growth and bud formation.
# Function
Anillins are required for the faithfulness of cytokinesis and its F-actin-, myosin-, and septin-binding domains implicate anillin in actomyosin cytoskeletal organization. In agreement with this belief, anillin-mutant cells have disrupted contractile rings. Additionally, it is hypothesized that anillin couples the actomyosin cytoskeleton to microtubules by binding MgcRacGAP/CYK-4/RacGAP50C.
Anillins have also been shown to organize the actomyosin cytoskeleton into syncytial structures observed in Drosophila embryos or C. elegans gonads. ANI-1 and ANI-2 (proteins homologous to anillin) are essential for embryonic viability in both organisms. ANI-1 is required for cortical ruffling, pseudocleavage, and all contractile events that occur in embryos prior to mitosis. ANI-1 is also crucial for segregation of polar bodies during meiosis. ANI-2 functions in the maintenance of the structure of the central core of the cytoplasm, the rachis, during oogenesis. ANI-2 ensures oocytes do not disconnect prematurely from the rachis, thereby leading to the generation of embryos of varying sizes.
# Binding Partners
One of the best ways to uncover the many functions of anillin is to study the interactions of the protein with its binding partners.
## Actin
Anillin specifically binds F-actin, rather than G-actin. Binding of F-actin by anillin only occurs during cell division. Anillin is also bundles actin filaments together. Amino acids 258-340 are sufficient and necessary for F-actin binding in Drosophila, but amino acids 246-371 are necessary to bundle actin filaments. The ability of anillin to bind to and bundle actin together is conversed through many species. It is hypothesized that by regulating actin bundling, anillin increases the efficiency of actomyosin contractility during cell division. Both anillin and F-actin are found in contractile structures. They are recruited independently to the contractile ring, but F-actin increases the efficiency of anillin targeting. Anillin may also be involved in promoting the polymerization of F-actin by stabilizing formin mDia2 in an active form.
## Myosin
Anillin interacts directly with non-muscle myosin II and interacts indirectly with myosin via F-actin. Residues 142-254 (near the N-terminus) are essential for anillin binding myosin in Xenopus. The interaction of anillin and myosin is also dependent on phosphorylation of the myosin light chain. The interaction of myosin and anillin does not seem to serve in recruitment, but rather organization of myosin. In Drosophila, anillin is necessary to organize myosin into rings in the cellularization front. Depletion of anillin in Drosophila and humans leads to changes in the spatial and temporal stability of myosin during cytokinesis. In C. elegans, ANI-1 organizes myosin into foci during cytokinesis and establishment of polarity, whereas, ANI-2 is a requirement for the maintenance of myosin-rich contractile lining of oogenic gonads.
## Septins
Septin localization during cytokinesis and cellularization is dependent on its association with anillin. The direct interaction between anillin and septins was first shown by the interaction seen between Xenopus anillin and a minimal reconstituted heterooligomer of human septins 2, 6, and 7. The ability of anillin to bind to septins is dependent on the C-terminal domain, which contains a terminal PH domain and an upstream sequence known as the “Anillin Homology” (AH) domain.
## Rho
The AH domain of human anillin is essential for its interaction with RhoA. Depletion of RhoA halts contractile ring assembly and ingression, whereas, anillin depletion leads to a less severe phenotype when the contractile ring forms and ingresses partially. Depletion of anillin in Drosophila spermatocytes greatly reduces the localization of Rho and F-actin to equatorial regions.
## Ect2
Anillin interacts with Ect2, further supporting the idea that anillin stabilizes RhoA localization since Ect2 is an activator of RhoA. Independent of RhoA, the interaction between anillin and Ect2 occurs. This interaction is essential of the GEF activity of Ect2 and requires the AH domain of anillin and the PH domain of Ect2.
## Cyk-4
Drosophila anillin interacts with Cyk-4, a central spindle protein, indicating that anillin may have a role in determining the division plane during cytokinesis. In anillin-depleted larval cells, the central spindle does not extend to the cortex. Human anillin-depleted cells show improperly positioned and distorted central spindles.
## Microtubules
Anillin was first isolated from Drosophila by harnessing its interactions with both F-actin and microtubules. Furthermore, anillin-rich structures that form after Latrunculin A treatment of Drosophila cells localize to the plus-ends of microtubules. The interaction between anillin and microtubules suggest that anillin may serve as a signaling factor to relay the position of the mitotic spindle to the cortex to ensure appropriate contractile ring formation during cytokinesis.
# Regulation
Anillins in metazoans are heavily phosphorylated; however, the kinases responsible for the phosphorylation are unknown at the present time. In humans and Drosophila, anillins are recruited to the equatorial cortex in a RhoA-dependent manner. This recruitment is independent of other cytoskeletal Rho targets such as myosin, F-actin, and Rho-kinase. It has been observed that anillin proteolysis is triggered after mitotic exit by the Anaphase Promoting Complex (APC).
Most anillins can be sequestered to the nucleus during interphase, but there are exceptions – Drosophila anilins in the early embryo, C. elegans ANI-1 in early embryos, C. elegans ANI-2 in oogenic gonads, and Mid2p in fission yeast. These anillins that are not sequestered during interphase suggest that anillins may also regulate cytoskeletal dynamics outside the contractile ring during cytokinesis.
# Role in Diseases
Anillin is critical for cell division and therefore development and homeostasis in metazoans. In recent years, the expression levels of anillin have been shown to correlate to the metastatic potential of human tumours. In colorectal cancer, expression levels of anillin are higher in tumours and when anillin was over-expressed in HT29 cells, a classical colorectal cancer cell line, the cells showed faster replication kinetics due to the lengthening of G2/M phase. Increasing the expression of anillin also led to further invasiveness and migration of numerous colorectal cancer cell lines. The hypothesis from such observations is that anillin promotes EMT and cell migration through cytoskeletal remodeling, leading to enhanced proliferation, invasion, and mobility of tumour cells. | ANLN
Anillin is a conserved protein implicated in cytoskeletal dynamics during cellularization and cytokinesis. The ANLN gene in humans and the scraps gene in Drosophila encode Anillin.[1] In 1989, anillin was first isolated in embryos of Drosophila melanogaster. It was identified as an F-actin binding protein.[2] Six years later, the anillin gene was cloned from cDNA originating from a Drosophila ovary. Staining with anti-anillin (Antigen 8) antibody showed the anillin localizes to the nucleus during interphase and to the contractile ring during cytokinesis.[3] These observations agree with further research that found anillin in high concentrations near the cleavage furrow coinciding with RhoA, a key regulator of contractile ring formation.[4]
The name of the protein anillin originates from a Spanish word, anillo. Anillo means ring and shows that the name anillin references the observed enrichment of anillins at the contractile ring during cytokinesis. Anillins are also enriched at other actomyosin rings, most significantly, those at the leading edge of the Drosophila embryo during cellularization. These actomyosin rings invaginate to separate all nuclei for one another in the syncytial blastoderm.[5]
# Structure
Anillin has a unique multi-domain structure. At the N-terminus, there is an actin- and myosin-binding domain. At the C-terminus, there is a PH domain. The PH domain is conserved and essential for anillin functionality.[6] The human anillin cDNA, located on Chr7, encodes a 1,125–amino acid protein with a predicted molecular mass of 124 kD and a pI of 8.1. The mouse anillin gene is located on Chr9.[7]
There are also numerous anillin-like protein homologues found outside of metazoans. In Schizosaccharomyces pombe (fission yeast), there are Mid1p and Mid2p. These two anillin-like proteins do not have any overlap in their functions. Mid1p has been characterized as a key regulator in cytokinesis, responsible for arranging contractile ring assembly and positioning.[8] Mid2p acts later in cytokinesis to organize septins during septation, or the invagination of inner membranes, outer membranes, and the cell wall that occurs in order to separate daughter cells completely.[9] Saccharomyces cerevisiae (budding yeast) also have two anillin-like proteins, Boi1p and Boi2p. Boi1p and Boi2p localize to the nucleus and contractile ring at the bud neck, respectively. They are essential for cell growth and bud formation.[10]
# Function
Anillins are required for the faithfulness of cytokinesis and its F-actin-, myosin-, and septin-binding domains implicate anillin in actomyosin cytoskeletal organization. In agreement with this belief, anillin-mutant cells have disrupted contractile rings. Additionally, it is hypothesized that anillin couples the actomyosin cytoskeleton to microtubules by binding MgcRacGAP/CYK-4/RacGAP50C.[11]
Anillins have also been shown to organize the actomyosin cytoskeleton into syncytial structures observed in Drosophila embryos or C. elegans gonads. ANI-1 and ANI-2 (proteins homologous to anillin) are essential for embryonic viability in both organisms. ANI-1 is required for cortical ruffling, pseudocleavage, and all contractile events that occur in embryos prior to mitosis. ANI-1 is also crucial for segregation of polar bodies during meiosis. ANI-2 functions in the maintenance of the structure of the central core of the cytoplasm, the rachis, during oogenesis. ANI-2 ensures oocytes do not disconnect prematurely from the rachis, thereby leading to the generation of embryos of varying sizes.[12]
# Binding Partners
One of the best ways to uncover the many functions of anillin is to study the interactions of the protein with its binding partners.
## Actin
Anillin specifically binds F-actin, rather than G-actin. Binding of F-actin by anillin only occurs during cell division. Anillin is also bundles actin filaments together. Amino acids 258-340 are sufficient and necessary for F-actin binding in Drosophila, but amino acids 246-371 are necessary to bundle actin filaments.[13] The ability of anillin to bind to and bundle actin together is conversed through many species. It is hypothesized that by regulating actin bundling, anillin increases the efficiency of actomyosin contractility during cell division. Both anillin and F-actin are found in contractile structures. They are recruited independently to the contractile ring, but F-actin increases the efficiency of anillin targeting.[14] Anillin may also be involved in promoting the polymerization of F-actin by stabilizing formin mDia2 in an active form.[15]
## Myosin
Anillin interacts directly with non-muscle myosin II and interacts indirectly with myosin via F-actin. Residues 142-254 (near the N-terminus) are essential for anillin binding myosin in Xenopus. The interaction of anillin and myosin is also dependent on phosphorylation of the myosin light chain.[16] The interaction of myosin and anillin does not seem to serve in recruitment, but rather organization of myosin. In Drosophila, anillin is necessary to organize myosin into rings in the cellularization front.[17] Depletion of anillin in Drosophila and humans leads to changes in the spatial and temporal stability of myosin during cytokinesis.[18] In C. elegans, ANI-1 organizes myosin into foci during cytokinesis and establishment of polarity, whereas, ANI-2 is a requirement for the maintenance of myosin-rich contractile lining of oogenic gonads.[19]
## Septins
Septin localization during cytokinesis and cellularization is dependent on its association with anillin.[20] The direct interaction between anillin and septins was first shown by the interaction seen between Xenopus anillin and a minimal reconstituted heterooligomer of human septins 2, 6, and 7.[21] The ability of anillin to bind to septins is dependent on the C-terminal domain, which contains a terminal PH domain and an upstream sequence known as the “Anillin Homology” (AH) domain.[22]
## Rho
The AH domain of human anillin is essential for its interaction with RhoA. Depletion of RhoA halts contractile ring assembly and ingression, whereas, anillin depletion leads to a less severe phenotype when the contractile ring forms and ingresses partially. Depletion of anillin in Drosophila spermatocytes greatly reduces the localization of Rho and F-actin to equatorial regions.[23]
## Ect2
Anillin interacts with Ect2, further supporting the idea that anillin stabilizes RhoA localization since Ect2 is an activator of RhoA. Independent of RhoA, the interaction between anillin and Ect2 occurs. This interaction is essential of the GEF activity of Ect2 and requires the AH domain of anillin and the PH domain of Ect2.[24]
## Cyk-4
Drosophila anillin interacts with Cyk-4, a central spindle protein, indicating that anillin may have a role in determining the division plane during cytokinesis.[25] In anillin-depleted larval cells, the central spindle does not extend to the cortex.[26] Human anillin-depleted cells show improperly positioned and distorted central spindles.[27]
## Microtubules
Anillin was first isolated from Drosophila by harnessing its interactions with both F-actin and microtubules.[28] Furthermore, anillin-rich structures that form after Latrunculin A treatment of Drosophila cells localize to the plus-ends of microtubules.[29] The interaction between anillin and microtubules suggest that anillin may serve as a signaling factor to relay the position of the mitotic spindle to the cortex to ensure appropriate contractile ring formation during cytokinesis.[30]
# Regulation
Anillins in metazoans are heavily phosphorylated; however, the kinases responsible for the phosphorylation are unknown at the present time. In humans and Drosophila, anillins are recruited to the equatorial cortex in a RhoA-dependent manner. This recruitment is independent of other cytoskeletal Rho targets such as myosin, F-actin, and Rho-kinase. It has been observed that anillin proteolysis is triggered after mitotic exit by the Anaphase Promoting Complex (APC).
Most anillins can be sequestered to the nucleus during interphase, but there are exceptions – Drosophila anilins in the early embryo, C. elegans ANI-1 in early embryos, C. elegans ANI-2 in oogenic gonads, and Mid2p in fission yeast. These anillins that are not sequestered during interphase suggest that anillins may also regulate cytoskeletal dynamics outside the contractile ring during cytokinesis.[31]
# Role in Diseases
Anillin is critical for cell division and therefore development and homeostasis in metazoans. In recent years, the expression levels of anillin have been shown to correlate to the metastatic potential of human tumours. In colorectal cancer, expression levels of anillin are higher in tumours and when anillin was over-expressed in HT29 cells, a classical colorectal cancer cell line, the cells showed faster replication kinetics due to the lengthening of G2/M phase. Increasing the expression of anillin also led to further invasiveness and migration of numerous colorectal cancer cell lines. The hypothesis from such observations is that anillin promotes EMT and cell migration through cytoskeletal remodeling, leading to enhanced proliferation, invasion, and mobility of tumour cells.[32] | https://www.wikidoc.org/index.php/ANLN | |
ac39a2f995f1b55c4a5af127f3bd15cb2072ad88 | wikidoc | ANO1 | ANO1
Anoctamin-1 (ANO1) also known as Transmembrane member 16A (TMEM16A) is a protein that, in humans, is encoded by the ANO1 gene. Anoctamin-1 is a voltage-sensitive calcium-activated chloride channel that is expressed in smooth muscle and epithelial cells; it is highly expressed in human interstitial cells of Cajal (ICC) throughout the gastrointestinal tract. Changes in ANO1 channel activity directly/positively correlate with ICC activity.
# Function
ANO1 is a transmembrane protein that functions as a calcium-activated chloride channel. Ca2+, Sr2+, and Ba2+ activate the channel.
# Structure
No atomic resolution structure of this channel has yet been obtained. However, biochemical evidence suggests that the channel assembles as a dimer of two ANO1 polypeptide subunits. From hydropathy plotting, each subunit is thought to encode a molecule with eight transmembrane domains, with a reentrant loop between the fifth and sixth transmembrane domains. The reentrant loop is thought to be a P loop-like structure responsible for the ion selectivity of the protein.
# Clinical significance
ANO1 is expressed in the human gastrointestinal epithelium and is highly expressed in the gastrointestinal interstitial cells of Cajal, where it plays an important role in epithelial chloride secretion mediating intestinal motility. ANO1 blockers like niflumic acid have been shown to block slow waves, which produce motility, in the human intestine. ANO1-knockout mice fail to produce slow waves altogether. Carbachol has been shown to markedly activate the channel; in light of this, it's not surprising that secretory diarrhea is a Carbachol overdose symptom. Crofelemer, an antidiarrhoeal, inhibits this channel. Consequently, ANO1 activation is necessary for normal function of the ICC and its generated pacemaker activity in the smooth muscles of the intestine.
Its overexpression was reported in esophageal squamous cell carcinoma and breast cancer progression. | ANO1
Anoctamin-1 (ANO1) also known as Transmembrane member 16A (TMEM16A) is a protein that, in humans, is encoded by the ANO1 gene.[1][2] Anoctamin-1 is a voltage-sensitive calcium-activated chloride channel that is expressed in smooth muscle and epithelial cells;[3] it is highly expressed in human interstitial cells of Cajal (ICC) throughout the gastrointestinal tract.[4] Changes in ANO1 channel activity directly/positively correlate with ICC activity.[4]
# Function
ANO1 is a transmembrane protein that functions as a calcium-activated chloride channel.[5] Ca2+, Sr2+, and Ba2+ activate the channel.[6]
# Structure
No atomic resolution structure of this channel has yet been obtained.[7] However, biochemical evidence suggests that the channel assembles as a dimer of two ANO1 polypeptide subunits.[8][9] From hydropathy plotting, each subunit is thought to encode a molecule with eight transmembrane domains, with a reentrant loop between the fifth and sixth transmembrane domains. The reentrant loop is thought to be a P loop-like structure responsible for the ion selectivity of the protein.[10]
# Clinical significance
ANO1 is expressed in the human gastrointestinal epithelium and is highly expressed in the gastrointestinal interstitial cells of Cajal, where it plays an important role in epithelial chloride secretion mediating intestinal motility.[4][11][3] ANO1 blockers like niflumic acid have been shown to block slow waves, which produce motility, in the human intestine.[4][11] ANO1-knockout mice fail to produce slow waves altogether.[4][11] Carbachol has been shown to markedly activate the channel;[4][11] in light of this, it's not surprising that secretory diarrhea is a Carbachol overdose symptom.[12] Crofelemer, an antidiarrhoeal, inhibits this channel.[13][14] Consequently, ANO1 activation is necessary for normal function of the ICC and its generated pacemaker activity in the smooth muscles of the intestine.[4][11]
Its overexpression was reported in esophageal squamous cell carcinoma and breast cancer progression.[15][16] | https://www.wikidoc.org/index.php/ANO1 | |
a47bf8f1878c2acc147f7aa75308f0ca61e8d683 | wikidoc | AOAH | AOAH
Acyloxyacyl hydrolase, also known as AOAH, is a protein which in humans is encoded by the AOAH gene.
# Function
Acyloxyacyl hydrolase (AOAH) is a 2-subunit lipase which selectively hydrolyzes the secondary (acyloxyacyl-linked) fatty acyl chains from the lipid A region of bacterial lipopolysaccharides (LPSs, also called endotoxins). This action inactivates LPSs that are sensed by MD-2--Toll-like Receptor 4 (TLR 4) on animal cells (and probably also by the cytosolic caspase-based sensors). The enzyme's 2 disulfide-linked subunits are encoded by a single mRNA. The smaller subunit is a member of the saposin-like (SAPLIP) protein family and the larger subunit, which contains the active site serine,is a GDSL lipase.
AOAH is produced by neutrophils, macrophages (including Kupffer cells and microglia), dendritic cells, NK cells and renal proximal tubule cells. Absence of the enzyme in genetically engineered mice has been associated with distinctive phenotypes. AOAH-deficient animals are unable to inactivate even small amounts of LPS in most tissues; it remains bioactive and may pass from cell to cell in vivo for many weeks. The LPS-exposed mice develop strikingly high titers of polyclonal antibodies, prolonged hepatomegaly, and innate immune "tolerance" that gives them slow and inadequate responses to bacterial challenge. In contrast, absence of the enzyme renders mice more likely to develop severe lung injury and die if they are challenged with intratracheal LPS or Gram-negative bacteria.
AOAH has been highly conserved through evolution; the amino acid sequence of the human enzyme is almost 50% identical to that of the AOAH found in Dictyostelium discoideum, with 100% identity in the GDSL lipase consensus sequences. The enzyme has been found in many invertebrates and all vertebrates studied to date except fish. Although it seems likely that the enzyme has substrates in vivo other than LPS (it can be a phospholipase A1/B and acyl transferase in vitro), none has been identified.
A polymorphism in the gene has been associated with chronic rhinosinusitis in 2 different ethnic groups. Other studies have found that AOAH mRNA abundance is linked to HLA-DR alleles that, in turn, have been associated strongly with colitis. | AOAH
Acyloxyacyl hydrolase, also known as AOAH, is a protein which in humans is encoded by the AOAH gene.
# Function
Acyloxyacyl hydrolase (AOAH) is a 2-subunit lipase which selectively hydrolyzes the secondary (acyloxyacyl-linked) fatty acyl chains from the lipid A region of bacterial lipopolysaccharides (LPSs, also called endotoxins). This action inactivates LPSs that are sensed by MD-2--Toll-like Receptor 4 (TLR 4) on animal cells (and probably also by the cytosolic caspase-based sensors). The enzyme's 2 disulfide-linked subunits are encoded by a single mRNA. The smaller subunit is a member of the saposin-like (SAPLIP) protein family and the larger subunit, which contains the active site serine,is a GDSL lipase.
AOAH is produced by neutrophils, macrophages (including Kupffer cells and microglia), dendritic cells, NK cells and renal proximal tubule cells. Absence of the enzyme in genetically engineered mice has been associated with distinctive phenotypes. AOAH-deficient animals are unable to inactivate even small amounts of LPS in most tissues; it remains bioactive and may pass from cell to cell in vivo for many weeks. The LPS-exposed mice develop strikingly high titers of polyclonal antibodies, prolonged hepatomegaly, and innate immune "tolerance" that gives them slow and inadequate responses to bacterial challenge. In contrast, absence of the enzyme renders mice more likely to develop severe lung injury and die if they are challenged with intratracheal LPS or Gram-negative bacteria.
AOAH has been highly conserved through evolution; the amino acid sequence of the human enzyme is almost 50% identical to that of the AOAH found in Dictyostelium discoideum, with 100% identity in the GDSL lipase consensus sequences. The enzyme has been found in many invertebrates and all vertebrates studied to date except fish. Although it seems likely that the enzyme has substrates in vivo other than LPS (it can be a phospholipase A1/B and acyl transferase in vitro), none has been identified.
A polymorphism in the gene has been associated with chronic rhinosinusitis in 2 different ethnic groups. Other studies have found that AOAH mRNA abundance is linked to HLA-DR alleles that, in turn, have been associated strongly with colitis. | https://www.wikidoc.org/index.php/AOAH | |
d5da0f09b180159adc10d8fa35854b3c46ff511c | wikidoc | AOC3 | AOC3
Amine oxidase, copper containing 3, also known as vascular adhesion protein (VAP-1) and HPAO is an enzyme that in humans is encoded by the AOC3 gene on chromosome 17. This protein is a member of the semicarbazide-sensitive amine oxidase (SSAO) family and is associated with many vascular diseases.
# Structure
VAP-1 is a type 1 membrane-bound glycoprotein that has a distal adhesion domain and an enzymatically active amine oxidase site outside of the membrane. The AOC3 gene is mapped onto 17q21 and has an exon count of 6.
# Function
Amine oxidases are a family of enzymes that catalyze the oxidation of various endogenous amines, including histamine or dopamine. VAP-1 constitutes the copper dependent class of amine oxidases, such as lysyl oxidase or lysine demethylase, and is one of the four known in humans. The other class is flavin dependent such as monoamine oxidase (MAO) A and B. VAP-1, in particular, catalyzes the oxidative conversion of primary amines (methylamine and aminoacetone) to aldehydes (formaldehyde and methylglyoxal) ammonium and hydrogen peroxide in the presence of copper and quinone cofactor.
VAP-1 is primarily localized on the cell surface on the adipocyte plasma membrane. However, circulating VAP-1 has been shown to be the main source of SSAO in human serum. Serum VAP-1 originates from many tissues. VAP-1 has adhesive properties, functional monoamine oxidase activity, and possibly plays a role in glucose handling, leukocyte trafficking, and migration during inflammation. This rise in metabolic products contributes to generating advanced glycation end-products and oxidative stress along with the monoamine detoxification in the organism.
Like monoamine oxidase (MAO), VAP-1 can deaminate short-chain primary amines, but SSAO enzymes, including VAP-1, can tolerate several selective flavin-dependent MAO-A and MAO-B inhibitors like clorgiline, pargyline, and deprenyl, but are still sensitive to semicarbazide and other hydrazines, hydroxylamine and propargylamine.
VAP-1 is found in the smooth muscle of blood vessels and various other tissues, and can mostly be found in two forms: tissue-bound and soluble isoforms. The tissue-bound SSAO is primarily located in the leukocytes, adipocytes, and the endothelium of highly vascularized tissues, including the kidney, liver, and gonads. Thus, this form participates in cellular differentiation, deposition of the ECM (extracellular matrix) in smooth muscle cells, lipid trafficking in adipocytes and control of muscular tone, by mechanisms that are not completely understood. The soluble form, which is commonly known as VAP-1, is a proinflammatory protein derived from shedding of the transmembrane protein. It is highly expressed on the endothelium of the lung and trachea, and absent from leukocytes and epithelial cells. It moderates leukocyte recruitment, is both an adhesion molecule and a primary amine oxidase, and plays a role in clinical disease.
# Clinical significance
Membrane-bound VAP-1 releases an active, soluble form of the protein, which may be conducive to increased inflammation and the progression of many vascular disorders. In particular, elevation of VAP-1 activity and the increased enzymatic-mediated deamination is proposed to play a role in renal and vascular disease, oxidative stress, acute and chronic hyperglycemia, and diabetes complications.
In diabetic patients, the amine oxidase activity stimulates glucose uptake via translocation of transporters to the cell membrane in adipocytes and smooth muscle cells. This modifies hepatic glucose homeostasis and may contribute to patterns of GLUT expression in chronic disease, as insulin resistance in humans have been linked to altered expression of GLUT isoforms by granulosa cells and adipose tissues.
In particular, hydrogen peroxide, released during the deamination of SSAO, acts as a signal-transducing molecule, affecting GLUT1 and GLUT4 translocation to the plasma membrane by granulosa cells and adipose tissue. This mimics insulin and interferes with cell processes in diabetic patients. Additionally, hydrogen peroxide, along with aldehydes and glucose, is involved in generating advanced glycation end-products and oxidative stress, which leads to the development of atherosclerosis, a disease in which plaque builds up inside arteries.
Cell processes involved in insulin resistance are often associated with elevated VAP-1 expression and modified GLUT expression in patients with liver diseases. Accordingly, subjects with diabetes are often at an increased risk for the development of and mortality from various cancers, including colorectal cancer hepatocellular carcinoma. Because of hyperinsulinemia - the increased bioavailability of insulin-like growth factors-1 and hypoadiponectinemia - diabetic patients have a greater chance of developing oncogenesis and tumor progression. In one study, serum VAP-1 was shown to independently predict 10-year all-cause mortality, cardiovascular mortality, and cancer-related mortality in subjects with type 2 diabetes. This may be because VAP-1 is involved in binding TIL, lymphokine-activated killer cells, and natural killer cells to the vasculature of cancer tissue. Hence, increased serum VAP-1 activity has been repeatedly found to be associated with various vascular disorders, such as the complications of diabetes mellitus, acute and chronic hyperglycemia, congestive heart failure, atherosclerosis, and Alzheimer's disease.
The same elevation is seen in kidney disease, even when accounted for factors of age, gender, and smoking. Studies have established a strong correlation between serum VAP-1 levels and urinary albumin excretion, which supports the idea that VAP-1 may be involved in the pathogenesis of kidney damage in humans. In renal pathology, the aldehydes produced by SSAO are highly reactive and lead to the formation of protein cross-linking and oxidative stress. Additionally, VAP-1 mediates leukocyte migration and, eventually, can lead to chronic inflammatory cell accumulation and the development of kidney fibrosis.
As for stroke patients, the products from deamination induce cytotoxicity protein cross-linking and amyloid-beta (Aβ) aggregation along with oxidative stress and thus are considered a potential risk factor for stress-related angiopathy. In these patients, VAP-1 may be involved in increasing vascular damage due to increased susceptibility of endothelial cells to oxygen-glucose deprivation (OGD). In hemorrhagic stroke patients, plasmatic VAP-1 activity is increase, and in ischemic stroke patients, it can predict the appearance of parenchymal hemorrhages after tissue plasminogen activator treatment due to the transmigration of inflammatory cells into ischaemic brain. VAP-1-expression is increased in blood vessels of ischemic areas where it may be mediating neutrophil adhesion to vascular endothelium in ischemic heart. The presence of diminished expression of vascular VAP-1 in infarcted brain areas and the increased concentration of VAP-1 in serum suggests that acute cerebral ischaemia triggers early release of endothelial VAP-1 from brain vasculature.
Lastly, during pulmonary infection and airway hyper-activity,VAP-1 may also contribute to the recruitment of inflammatory cells and the transfer of neutrophils from the microvasculature. Inhibitors of VAP-1 may be effective in reducing inflammation in various vascular diseases, but more studies are needed to understand to what extent.
Whether serum VAP-1 is a good biomarker for these diseases requires further investigation. Although many studies concerning VAP-1 as a therapeutic target are becoming more frequent, it is difficult to study VAP-1 in cell or tissue systems, since the enzyme progressively loses its expression, and immortalized cell lines do not show any expression at all.
# Interactions
VAP-1 has been shown to interact with:
- MAO | AOC3
Amine oxidase, copper containing 3, also known as vascular adhesion protein (VAP-1) and HPAO is an enzyme that in humans is encoded by the AOC3 gene on chromosome 17. This protein is a member of the semicarbazide-sensitive amine oxidase (SSAO) family and is associated with many vascular diseases.[1]
# Structure
VAP-1 is a type 1 membrane-bound glycoprotein that has a distal adhesion domain and an enzymatically active amine oxidase site outside of the membrane.[2][3] The AOC3 gene is mapped onto 17q21 and has an exon count of 6.[1]
# Function
Amine oxidases are a family of enzymes that catalyze the oxidation of various endogenous amines, including histamine or dopamine. VAP-1 constitutes the copper dependent class of amine oxidases, such as lysyl oxidase or lysine demethylase, and is one of the four known in humans. The other class is flavin dependent such as monoamine oxidase (MAO) A and B.[1][4] VAP-1, in particular, catalyzes the oxidative conversion of primary amines (methylamine and aminoacetone) to aldehydes (formaldehyde and methylglyoxal) ammonium and hydrogen peroxide in the presence of copper and quinone cofactor.[4][5][6]
VAP-1 is primarily localized on the cell surface on the adipocyte plasma membrane.[1][7] However, circulating VAP-1 has been shown to be the main source of SSAO in human serum. Serum VAP-1 originates from many tissues.[7][8] VAP-1 has adhesive properties, functional monoamine oxidase activity, and possibly plays a role in glucose handling, leukocyte trafficking, and migration during inflammation.[1][5][9] This rise in metabolic products contributes to generating advanced glycation end-products and oxidative stress along with the monoamine detoxification in the organism.[7][10]
Like monoamine oxidase (MAO), VAP-1 can deaminate short-chain primary amines, but SSAO enzymes, including VAP-1, can tolerate several selective flavin-dependent MAO-A and MAO-B inhibitors like clorgiline, pargyline, and deprenyl, but are still sensitive to semicarbazide and other hydrazines, hydroxylamine and propargylamine.[1][11]
VAP-1 is found in the smooth muscle of blood vessels and various other tissues, and can mostly be found in two forms: tissue-bound and soluble isoforms.[5][11] The tissue-bound SSAO is primarily located in the leukocytes, adipocytes, and the endothelium of highly vascularized tissues, including the kidney, liver, and gonads.[5][12] Thus, this form participates in cellular differentiation, deposition of the ECM (extracellular matrix) in smooth muscle cells, lipid trafficking in adipocytes and control of muscular tone, by mechanisms that are not completely understood.[10][12] The soluble form, which is commonly known as VAP-1, is a proinflammatory protein derived from shedding of the transmembrane protein. It is highly expressed on the endothelium of the lung and trachea, and absent from leukocytes and epithelial cells. It moderates leukocyte recruitment, is both an adhesion molecule and a primary amine oxidase, and plays a role in clinical disease.[3][12][13][14]
# Clinical significance
Membrane-bound VAP-1 releases an active, soluble form of the protein, which may be conducive to increased inflammation and the progression of many vascular disorders. In particular, elevation of VAP-1 activity and the increased enzymatic-mediated deamination is proposed to play a role in renal and vascular disease, oxidative stress, acute and chronic hyperglycemia, and diabetes complications.[1][8][9][15]
In diabetic patients, the amine oxidase activity stimulates glucose uptake via translocation of transporters to the cell membrane in adipocytes and smooth muscle cells. This modifies hepatic glucose homeostasis and may contribute to patterns of GLUT expression in chronic disease, as insulin resistance in humans have been linked to altered expression of GLUT isoforms by granulosa cells and adipose tissues.[16]
In particular, hydrogen peroxide, released during the deamination of SSAO, acts as a signal-transducing molecule, affecting GLUT1 and GLUT4 translocation to the plasma membrane by granulosa cells and adipose tissue.[3] This mimics insulin and interferes with cell processes in diabetic patients. Additionally, hydrogen peroxide, along with aldehydes and glucose, is involved in generating advanced glycation end-products and oxidative stress, which leads to the development of atherosclerosis, a disease in which plaque builds up inside arteries.[12]
Cell processes involved in insulin resistance are often associated with elevated VAP-1 expression and modified GLUT expression in patients with liver diseases.[8] Accordingly, subjects with diabetes are often at an increased risk for the development of and mortality from various cancers, including colorectal cancer hepatocellular carcinoma. Because of hyperinsulinemia - the increased bioavailability of insulin-like growth factors-1 and hypoadiponectinemia - diabetic patients have a greater chance of developing oncogenesis and tumor progression. In one study, serum VAP-1 was shown to independently predict 10-year all-cause mortality, cardiovascular mortality, and cancer-related mortality in subjects with type 2 diabetes.[16] This may be because VAP-1 is involved in binding TIL, lymphokine-activated killer cells, and natural killer cells to the vasculature of cancer tissue.[17] Hence, increased serum VAP-1 activity has been repeatedly found to be associated with various vascular disorders, such as the complications of diabetes mellitus, acute and chronic hyperglycemia, congestive heart failure, atherosclerosis, and Alzheimer's disease.[6][8]
The same elevation is seen in kidney disease, even when accounted for factors of age, gender, and smoking. Studies have established a strong correlation between serum VAP-1 levels and urinary albumin excretion, which supports the idea that VAP-1 may be involved in the pathogenesis of kidney damage in humans.[8][9][15][16] In renal pathology, the aldehydes produced by SSAO are highly reactive and lead to the formation of protein cross-linking and oxidative stress. Additionally, VAP-1 mediates leukocyte migration and, eventually, can lead to chronic inflammatory cell accumulation and the development of kidney fibrosis.[12]
As for stroke patients, the products from deamination induce cytotoxicity protein cross-linking and amyloid-beta (Aβ) aggregation along with oxidative stress and thus are considered a potential risk factor for stress-related angiopathy. In these patients, VAP-1 may be involved in increasing vascular damage due to increased susceptibility of endothelial cells to oxygen-glucose deprivation (OGD).[8][13] In hemorrhagic stroke patients, plasmatic VAP-1 activity is increase, and in ischemic stroke patients, it can predict the appearance of parenchymal hemorrhages after tissue plasminogen activator treatment due to the transmigration of inflammatory cells into ischaemic brain. VAP-1-expression is increased in blood vessels of ischemic areas where it may be mediating neutrophil adhesion to vascular endothelium in ischemic heart. The presence of diminished expression of vascular VAP-1 in infarcted brain areas and the increased concentration of VAP-1 in serum suggests that acute cerebral ischaemia triggers early release of endothelial VAP-1 from brain vasculature.[18]
Lastly, during pulmonary infection and airway hyper-activity,VAP-1 may also contribute to the recruitment of inflammatory cells and the transfer of neutrophils from the microvasculature.[4] Inhibitors of VAP-1 may be effective in reducing inflammation in various vascular diseases, but more studies are needed to understand to what extent.[1]
Whether serum VAP-1 is a good biomarker for these diseases requires further investigation.[19] Although many studies concerning VAP-1 as a therapeutic target are becoming more frequent, it is difficult to study VAP-1 in cell or tissue systems, since the enzyme progressively loses its expression, and immortalized cell lines do not show any expression at all.[10]
# Interactions
VAP-1 has been shown to interact with:
- MAO [11] | https://www.wikidoc.org/index.php/AOC3 | |
c8f6a6b49afda1a04155e07617044d94fa3fdc05 | wikidoc | ARAF | ARAF
Serine/threonine-protein kinase A-Raf or simply A-Raf is an enzyme that in humans is encoded by the ARAF gene. A-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases.
Compared to the other members of this family (Raf-1 and B-Raf), very little is known about A-Raf. It seems to share many of the properties of the other isoforms, but its biological functions are not as thoroughly researched. All three Raf proteins are involved in the MAPK signaling pathway.
There are several ways A-Raf is different from the other Raf kinases. A-Raf is the only steroid hormone-regulated Raf isoform. In addition, the A-Raf protein has amino acid substitutions in a negatively charged region upstream of the kinase domain (N-region). This could be responsible for its low basal activity.
Like Raf-1 and B-Raf, A-Raf activates MEK proteins which causes the activation of ERK and ultimately leads to cell cycle progression and cell proliferation. All three Raf proteins are located in the cytosol in their inactive state when bound to 14-3-3. In the presence of active Ras, they translocate to the plasma membrane. Among the Ras kinase family, A-Raf has the lowest kinase activity towards MEK proteins in the Raf kinase family. Thus, it is possible that A-Raf has other functions outside the MAPK pathway or that it helps the other Raf kinases activate the MAPK pathway. In addition to phosphorylating MEK, A-Raf also inhibits MST2, a tumor suppressor and proapoptotic kinase not found in the MAPK pathway. By inhibiting MST2, A-Raf can prevent apoptosis from occurring. However, this inhibition is only possible when the splice factor heterogenous nuclear ribonucleoprotein H (hnRNP H) maintains the expression of a full-length A-Raf protein. Tumorous cells often overexpress hnRNP H. When hnRNP H is downregulated, the A-RAF gene is alternatively spliced. This prevents the expression of full-length A-Raf protein. Thus, overexpression of hnRNP H in tumor cells leads to full-length expression of A-Raf which then inhibits apoptosis, allowing cancerous cells that should be destroyed to stay alive.
A-Raf also binds to pyruvate kinase M2 (PKM2), again outside the MAPK pathway. PKM2 is an isozyme of pyruvate kinase that is responsible for the Warburg effect in cancer cells. A-Raf upregulates the activity of PKM2 by promoting a conformational change in PKM2. This causes PKM2 to transition from its low-activity dimeric form to a highly active tetrameric form. In cancer cells, the ratio between dimeric and tetrameric forms of PKM2 determines what happens to glucose carbons. If PKM2 is in the dimeric form, glucose is channeled into synthetic processes such as nucleic acid, amino acid, or phospholipid synthesis. If A-Raf is present, PKM2 is more likely to be in the tetrameric form. This causes more glucose carbons to be converted to pyruvate and lactate, producing energy for the cell. Thus, A-Raf can be linked to energy metabolism regulation and cell transformation, both of which are very important in tumorigenesis.
In addition, researchers have proposed a model of how A-Raf is linked to endocytosis. Upstream of A-Raf, receptor tyrosine kinases (RTKs) are activated, leading to RAS-mediated activation of Raf kinases, including A-Raf. Once activated, A-Raf binds to membranes rich in Phosphatidylinositol 4,5-bisphosphate (PtdIns (4,5)P2 and signals endosomes. This leads to activation of ARF6, a central regulator of endocytic trafficking.
# Interactions
ARAF has been shown to interact with:
- EFEMP1,
- MAP2K2,
- PRPF6,
- RRAS,
- TIMM44, and
- TH1L. | ARAF
Serine/threonine-protein kinase A-Raf or simply A-Raf is an enzyme that in humans is encoded by the ARAF gene.[1] A-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases.[2]
Compared to the other members of this family (Raf-1 and B-Raf), very little is known about A-Raf. It seems to share many of the properties of the other isoforms, but its biological functions are not as thoroughly researched. All three Raf proteins are involved in the MAPK signaling pathway.
There are several ways A-Raf is different from the other Raf kinases. A-Raf is the only steroid hormone-regulated Raf isoform.[3] In addition, the A-Raf protein has amino acid substitutions in a negatively charged region upstream of the kinase domain (N-region). This could be responsible for its low basal activity.[4]
Like Raf-1 and B-Raf, A-Raf activates MEK proteins which causes the activation of ERK and ultimately leads to cell cycle progression and cell proliferation. All three Raf proteins are located in the cytosol in their inactive state when bound to 14-3-3. In the presence of active Ras, they translocate to the plasma membrane.[5] Among the Ras kinase family, A-Raf has the lowest kinase activity towards MEK proteins in the Raf kinase family.[6] Thus, it is possible that A-Raf has other functions outside the MAPK pathway or that it helps the other Raf kinases activate the MAPK pathway. In addition to phosphorylating MEK, A-Raf also inhibits MST2, a tumor suppressor and proapoptotic kinase not found in the MAPK pathway. By inhibiting MST2, A-Raf can prevent apoptosis from occurring. However, this inhibition is only possible when the splice factor heterogenous nuclear ribonucleoprotein H (hnRNP H) maintains the expression of a full-length A-Raf protein. Tumorous cells often overexpress hnRNP H. When hnRNP H is downregulated, the A-RAF gene is alternatively spliced. This prevents the expression of full-length A-Raf protein.[7] Thus, overexpression of hnRNP H in tumor cells leads to full-length expression of A-Raf which then inhibits apoptosis, allowing cancerous cells that should be destroyed to stay alive.
A-Raf also binds to pyruvate kinase M2 (PKM2), again outside the MAPK pathway. PKM2 is an isozyme of pyruvate kinase that is responsible for the Warburg effect in cancer cells.[8] A-Raf upregulates the activity of PKM2 by promoting a conformational change in PKM2. This causes PKM2 to transition from its low-activity dimeric form to a highly active tetrameric form. In cancer cells, the ratio between dimeric and tetrameric forms of PKM2 determines what happens to glucose carbons. If PKM2 is in the dimeric form, glucose is channeled into synthetic processes such as nucleic acid, amino acid, or phospholipid synthesis. If A-Raf is present, PKM2 is more likely to be in the tetrameric form. This causes more glucose carbons to be converted to pyruvate and lactate, producing energy for the cell. Thus, A-Raf can be linked to energy metabolism regulation and cell transformation, both of which are very important in tumorigenesis.[9]
In addition, researchers have proposed a model of how A-Raf is linked to endocytosis. Upstream of A-Raf, receptor tyrosine kinases (RTKs) are activated, leading to RAS-mediated activation of Raf kinases, including A-Raf. Once activated, A-Raf binds to membranes rich in Phosphatidylinositol 4,5-bisphosphate (PtdIns (4,5)P2 and signals endosomes. This leads to activation of ARF6, a central regulator of endocytic trafficking.[10]
# Interactions
ARAF has been shown to interact with:
- EFEMP1,[11]
- MAP2K2,[12]
- PRPF6,[11][13]
- RRAS,[11][13]
- TIMM44,[11][13] and
- TH1L.[11][14] | https://www.wikidoc.org/index.php/ARAF | |
c9563c43e104908a4df2afec0572c156f4a26732 | wikidoc | ARF1 | ARF1
ADP-ribosylation factor 1 is a protein that in humans is encoded by the ARF1 gene.
# Function
ADP-ribosylation factor 1 (ARF1) is a member of the human ARF gene family. The family members encode small guanine nucleotide-binding proteins that stimulate the ADP-ribosyltransferase activity of cholera toxin and play a role in vesicular trafficking as activators of phospholipase D. The gene products, including 6 ARF proteins and 11 ARF-like proteins, constitute a family of the RAS superfamily. The ARF proteins are categorized as class I (ARF1, ARF2 and ARF3), class II (ARF4 and ARF5) and class III (ARF6), and members of each class share a common gene organization. The ARF1 protein is localized to the Golgi apparatus and has a central role in intra-Golgi transport. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene.
The major mechanism of action of Brefeldin A is through inhibition of ARF1.
# Interactions
ARF1 has been shown to interact with:
- CHRM3,
- COPB1,
- GGA3, and
- PLD2. | ARF1
ADP-ribosylation factor 1 is a protein that in humans is encoded by the ARF1 gene.[1]
# Function
ADP-ribosylation factor 1 (ARF1) is a member of the human ARF gene family. The family members encode small guanine nucleotide-binding proteins that stimulate the ADP-ribosyltransferase activity of cholera toxin and play a role in vesicular trafficking as activators of phospholipase D. The gene products, including 6 ARF proteins and 11 ARF-like proteins, constitute a family of the RAS superfamily. The ARF proteins are categorized as class I (ARF1, ARF2 and ARF3), class II (ARF4 and ARF5) and class III (ARF6), and members of each class share a common gene organization. The ARF1 protein is localized to the Golgi apparatus and has a central role in intra-Golgi transport. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene.[2]
The major mechanism of action of Brefeldin A is through inhibition of ARF1.
# Interactions
ARF1 has been shown to interact with:
- CHRM3,[3]
- COPB1,[4][5]
- GGA3,[6][7] and
- PLD2.[8][9] | https://www.wikidoc.org/index.php/ARF1 | |
135d3406c69d085d1c5aef7f4705ffc4d92f25a4 | wikidoc | ARF4 | ARF4
ADP-ribosylation factor 4 is a protein that in humans is encoded by the ARF4 gene.
# Function
ADP-ribosylation factor 4 (ARF4) is a member of the human ARF gene family. These genes encode small guanine nucleotide-binding proteins that stimulate the ADP-ribosyltransferase activity of cholera toxin and play a role in vesicular trafficking and as activators of phospholipase D. The gene products include 5 ARF proteins and 11 ARF-like proteins and constitute 1 family of the RAS superfamily. The ARF proteins are categorized as class I (ARF1 and ARF3), class II (ARF4 and ARF5) and class III (ARF6). The members of each class share a common gene organization. The ARF4 gene spans approximately 12kb and contains six exons and five introns. The ARF4 is the most divergent member of the human ARFs. Conflicting Map positions at 3p14 or 3p21 have been reported for this gene.
# Interactions
ARF4 has been shown to interact with Epidermal growth factor receptor. | ARF4
ADP-ribosylation factor 4 is a protein that in humans is encoded by the ARF4 gene.[1][2]
# Function
ADP-ribosylation factor 4 (ARF4) is a member of the human ARF gene family. These genes encode small guanine nucleotide-binding proteins that stimulate the ADP-ribosyltransferase activity of cholera toxin and play a role in vesicular trafficking and as activators of phospholipase D. The gene products include 5 ARF proteins and 11 ARF-like proteins and constitute 1 family of the RAS superfamily. The ARF proteins are categorized as class I (ARF1 and ARF3), class II (ARF4 and ARF5) and class III (ARF6). The members of each class share a common gene organization. The ARF4 gene spans approximately 12kb and contains six exons and five introns. The ARF4 is the most divergent member of the human ARFs. Conflicting Map positions at 3p14 or 3p21 have been reported for this gene.[2]
# Interactions
ARF4 has been shown to interact with Epidermal growth factor receptor.[3] | https://www.wikidoc.org/index.php/ARF4 | |
641e5c47da016aee74c12c47f459d56b04cc1a59 | wikidoc | ARL2 | ARL2
ADP-ribosylation factor-like protein 2 is a protein that in humans is encoded by the ARL2 gene.
# Function
The ADP-ribosylation factor (ARF) genes are small GTP-binding proteins of the RAS superfamily. ARL2 is a member of a functionally distinct group of ARF-like genes.
# Interactions
ARL2 has been shown to interact with Protein unc-119 homolog, TBCD and PDE6D. | ARL2
ADP-ribosylation factor-like protein 2 is a protein that in humans is encoded by the ARL2 gene.[1][2][3]
# Function
The ADP-ribosylation factor (ARF) genes are small GTP-binding proteins of the RAS superfamily. ARL2 is a member of a functionally distinct group of ARF-like genes.[3]
# Interactions
ARL2 has been shown to interact with Protein unc-119 homolog,[4] TBCD[5][6] and PDE6D.[7][8] | https://www.wikidoc.org/index.php/ARL2 | |
10b24cf7a33690b4fc9007d757583fe3997d0c3f | wikidoc | ART4 | ART4
Ecto-ADP-ribosyltransferase 4 is an enzyme that in humans is encoded by the ART4 gene. ART4 has also been designated as CD297 (cluster of differentiation 297).
# Function
This gene encodes a protein that contains a mono-ADP-ribosylation (ART) motif. It is a member of the ADP-ribosyltransferase gene family but enzymatic activity has not been demonstrated experimentally. Antigens of the Dombrock blood group system are located on the gene product, which is glycosylphosphatidylinositol-anchored to the erythrocyte membrane. Allelic variants, some of which lead to adverse transfusion reactions, are known.
# Blood group antigens
Several antigens have been recognised in this family. These are DO*A, DO*JO1, DO*A-WL, DO*DOYA, DO*B, DO*B-WL, DO*B-SH-Q149K, DO*B-(WL)-I175N, DO*HY1, DO*HY2 and DO*DOMR.
# Model organisms
Model organisms have been used in the study of ART4 function. A conditional knockout mouse line called Art4tm1a(KOMP)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 - in-depth bone and cartilage phenotyping | ART4
Ecto-ADP-ribosyltransferase 4 is an enzyme that in humans is encoded by the ART4 gene.[1][2] ART4 has also been designated as CD297 (cluster of differentiation 297).
# Function
This gene encodes a protein that contains a mono-ADP-ribosylation (ART) motif. It is a member of the ADP-ribosyltransferase gene family but enzymatic activity has not been demonstrated experimentally. Antigens of the Dombrock blood group system are located on the gene product, which is glycosylphosphatidylinositol-anchored to the erythrocyte membrane. Allelic variants, some of which lead to adverse transfusion reactions, are known.[2]
# Blood group antigens
Several antigens have been recognised in this family. These are DO*A, DO*JO1, DO*A-WL, DO*DOYA, DO*B, DO*B-WL, DO*B-SH-Q149K, DO*B-(WL)-I175N, DO*HY1, DO*HY2 and DO*DOMR.
# Model organisms
Model organisms have been used in the study of ART4 function. A conditional knockout mouse line called Art4tm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[3] Male and female animals underwent a standardized phenotypic screen[4] to determine the effects of deletion.[5][6][7][8] Additional screens performed: - In-depth immunological phenotyping[9] - in-depth bone and cartilage phenotyping[10] | https://www.wikidoc.org/index.php/ART4 | |
8e1e5da872af32343e008bb9f3bcbe3c28f028d2 | wikidoc | ASK1 | ASK1
Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5) is a member of MAP kinase kinase kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. ASK1 has been found to be involved in cancer, diabetes, cardiovascular and neurodegenerative diseases.
MAP3K5 gene coding for the protein is located on chromosome 6 at locus 6q22.33. and the transcribed protein contains 1,374 amino acids with 11 kinase subdomains. Northern blot analysis shows that MAP3K5 transcript is abundant in human heart and pancreas.
# Mechanism of activation
Under nonstress conditions ASK1 is oligomerized (a requirement for its activation) through its C-terminal coiled-coil domain (CCC), but remains in an inactive form by the suppressive effect of reduced thioredoxin (Trx) and calcium and integrin binding protein 1 (CIB1). Trx inhibits ASK1 kinase activity by direct binding to its N-terminal coiled-coil domain (NCC). Trx and CIB1 regulate ASK1 activation in a redox- or calcium- sensitive manner, respectively. Both appear to compete with TNF-α receptor-associated factor 2 (TRAF2), an ASK1 activator. TRAF2 and TRAF6 are then recruited to ASK1 to form a larger molecular mass complex. Subsequently, ASK1 forms homo-oligomeric interactions not only through the CCC, but also the NCC, which leads to full activation of ASK1 through autophosphorylation at threonine 845.
# Interactions
ASK1 has been shown to interact with:
- C-Raf,
- CDC25A,
- DAXX,
- DUSP19,
- EIF2AK2,
- GADD45B,
- HSPA1A,
- MAP2K6,
- MAP3K7 and
- MAPK8IP3,
- PDCD6,
- PPP5C,
- RB1CC1,
- TRAF2,
- TRAF5, and
- TRAF6. | ASK1
Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5) is a member of MAP kinase kinase kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. ASK1 has been found to be involved in cancer, diabetes, cardiovascular and neurodegenerative diseases.[1]
MAP3K5 gene coding for the protein is located on chromosome 6 at locus 6q22.33.[2] and the transcribed protein contains 1,374 amino acids with 11 kinase subdomains.[citation needed] Northern blot analysis shows that MAP3K5 transcript is abundant in human heart and pancreas.[3]
# Mechanism of activation
Under nonstress conditions ASK1 is oligomerized (a requirement for its activation) through its C-terminal coiled-coil domain (CCC), but remains in an inactive form by the suppressive effect of reduced thioredoxin (Trx) and calcium and integrin binding protein 1 (CIB1).[4] Trx inhibits ASK1 kinase activity by direct binding to its N-terminal coiled-coil domain (NCC). Trx and CIB1 regulate ASK1 activation in a redox- or calcium- sensitive manner, respectively. Both appear to compete with TNF-α receptor-associated factor 2 (TRAF2), an ASK1 activator. TRAF2 and TRAF6 are then recruited to ASK1 to form a larger molecular mass complex.[5] Subsequently, ASK1 forms homo-oligomeric interactions not only through the CCC, but also the NCC, which leads to full activation of ASK1 through autophosphorylation at threonine 845.[6]
# Interactions
ASK1 has been shown to interact with:
- C-Raf,[7]
- CDC25A,[8]
- DAXX,[9]
- DUSP19,[10]
- EIF2AK2,[11]
- GADD45B,[12]
- HSPA1A,[13]
- MAP2K6,[14][15]
- MAP3K7[16] and
- MAPK8IP3,[17]
- PDCD6,[18]
- PPP5C,[14]
- RB1CC1,[19]
- TRAF2,[19][20]
- TRAF5,[20][21] and
- TRAF6.[16][20][21] | https://www.wikidoc.org/index.php/ASK1 | |
4233d9bf925f20a4f494c703a0c0746d24425e7a | wikidoc | ASPH | ASPH
Aspartyl/asparaginyl beta-hydroxylase (HAAH) is an enzyme that in humans is encoded by the ASPH gene. ASPH is a alpha-ketoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins.
# Function
This gene is thought to play an important role in calcium homeostasis. Alternative splicing of this gene results in five transcript variants which vary in protein translation, the coding of catalytic domains, and tissue expression. Variation among these transcripts impacts their functions which involve roles in the calcium storage and release process in the endoplasmic and sarcoplasmic reticulum as well as hydroxylation of aspartic acid and asparagine in epidermal growth factor-like domains of various proteins.
# Clinical significance
As early as 1996, the over-expression of HAAH was recognized as an indicator of carcinoma in humans. Further research has correlated elevated HAAH levels (variously in affected tissue or blood serum) with hepatocellular (liver) carcinoma adenocarcinoma (pancreatic cancer), colorectal cancer, prostate cancer. and lung cancer. The pancreatic study showed elevated HAAH only in diseased tissue, but not in adjacent normal and inflamed tissue.
Mutations in ASPH cause Traboulsi syndrome .Patel, N; Khan, A. O.; Mansour, A; Mohamed, J. Y.; Al-Assiri, A; Haddad, R; Jia, X; Xiong, Y; Mégarbané, A; Traboulsi, E. I.; Alkuraya, F. S. (2014). "Mutations in ASPH Cause Facial Dysmorphism, Lens Dislocation, Anterior-Segment Abnormalities, and Spontaneous Filtering Blebs, or Traboulsi Syndrome". The American Journal of Human Genetics. 94 (5): 755–9. doi:10.1016/j.ajhg.2014.04.002. PMID 24768550..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} | ASPH
Aspartyl/asparaginyl beta-hydroxylase (HAAH) is an enzyme that in humans is encoded by the ASPH gene.[1][2][3] ASPH is a alpha-ketoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins.
# Function
This gene is thought to play an important role in calcium homeostasis. Alternative splicing of this gene results in five transcript variants which vary in protein translation, the coding of catalytic domains, and tissue expression. Variation among these transcripts impacts their functions which involve roles in the calcium storage and release process in the endoplasmic and sarcoplasmic reticulum as well as hydroxylation of aspartic acid and asparagine in epidermal growth factor-like domains of various proteins.[3]
# Clinical significance
As early as 1996, the over-expression of HAAH was recognized as an indicator of carcinoma in humans. Further research has correlated elevated HAAH levels (variously in affected tissue or blood serum) with hepatocellular (liver) carcinoma[4][5] adenocarcinoma (pancreatic cancer),[6] colorectal cancer,[7] prostate cancer.[5] and lung cancer.[8] The pancreatic study[6] showed elevated HAAH only in diseased tissue, but not in adjacent normal and inflamed tissue.
Mutations in ASPH cause Traboulsi syndrome .Patel, N; Khan, A. O.; Mansour, A; Mohamed, J. Y.; Al-Assiri, A; Haddad, R; Jia, X; Xiong, Y; Mégarbané, A; Traboulsi, E. I.; Alkuraya, F. S. (2014). "Mutations in ASPH Cause Facial Dysmorphism, Lens Dislocation, Anterior-Segment Abnormalities, and Spontaneous Filtering Blebs, or Traboulsi Syndrome". The American Journal of Human Genetics. 94 (5): 755–9. doi:10.1016/j.ajhg.2014.04.002. PMID 24768550..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/ASPH | |
a74d20aa98c61fedd1c722d7a182df561a185d7f | wikidoc | ATF1 | ATF1
Cyclic AMP-dependent transcription factor ATF-1 is a protein that in humans is encoded by the ATF1 gene.
This gene encodes an activating transcription factor, which belongs to the ATF subfamily and bZIP (basic-region leucine zipper) family. It influences cellular physiologic processes by regulating the expression of downstream target genes, which are related to growth, survival, and other cellular activities. This protein is phosphorylated at serine 63 in its kinase-inducible domain by serine/threonine kinases, cAMP-dependent protein kinase A, calmodulin-dependent protein kinase I/II, mitogen- and stress-activated protein kinase and cyclin-dependent kinase 3 (cdk-3). Its phosphorylation enhances its transactivation and transcriptional activities, and enhances cell transformation.
# Clinical significance
Fusion of this gene and FUS on chromosome 16 or EWSR1 on chromosome 22 induced by translocation generates chimeric proteins in angiomatoid fibrous histiocytoma and clear cell sarcoma. This gene has a pseudogene on chromosome 6. | ATF1
Cyclic AMP-dependent transcription factor ATF-1 is a protein that in humans is encoded by the ATF1 gene.
This gene encodes an activating transcription factor, which belongs to the ATF subfamily and bZIP (basic-region leucine zipper) family. It influences cellular physiologic processes by regulating the expression of downstream target genes, which are related to growth, survival, and other cellular activities. This protein is phosphorylated at serine 63 in its kinase-inducible domain by serine/threonine kinases, cAMP-dependent protein kinase A, calmodulin-dependent protein kinase I/II, mitogen- and stress-activated protein kinase and cyclin-dependent kinase 3 (cdk-3). Its phosphorylation enhances its transactivation and transcriptional activities, and enhances cell transformation.[1]
# Clinical significance
Fusion of this gene and FUS on chromosome 16 or EWSR1 on chromosome 22 induced by translocation generates chimeric proteins in angiomatoid fibrous histiocytoma and clear cell sarcoma. This gene has a pseudogene on chromosome 6.[1][2] | https://www.wikidoc.org/index.php/ATF1 | |
7c2078e47572ba7835403f02190df7a8f35bea0d | wikidoc | ATF3 | ATF3
Cyclic AMP-dependent transcription factor ATF-3 is a protein that, in humans, is encoded by the ATF3 gene.
# Function
Activating transcription factor 3 is a member of the mammalian activation transcription factor/cAMP responsive element-binding (CREB) protein family of transcription factors. Multiple transcript variants encoding two different isoforms have been found for this gene. The longer isoform represses rather than activates transcription from promoters with ATF binding elements. The shorter isoform (deltaZip2) lacks the leucine zipper protein-dimerization motif and does not bind to DNA, and it stimulates transcription, it is presumed, by sequestering inhibitory co-factors away from the promoter. It is possible that alternative splicing of the ATF3 gene may be physiologically important in the regulation of target genes.
# Clinical significance
ATF-3 is induced upon physiological stress in various tissues. It is also a marker of regeneration following injury of dorsal root ganglion neurons, as injured regenerating neurons activate this transcription factor. Functional validation studies have shown that ATF3 can promote regeneration of peripheral neurons, but is not capable of promoting regeneration of central nervous system neurons. | ATF3
Cyclic AMP-dependent transcription factor ATF-3 is a protein that, in humans, is encoded by the ATF3 gene.[1]
# Function
Activating transcription factor 3 is a member of the mammalian activation transcription factor/cAMP responsive element-binding (CREB) protein family of transcription factors. Multiple transcript variants encoding two different isoforms have been found for this gene. The longer isoform represses rather than activates transcription from promoters with ATF binding elements. The shorter isoform (deltaZip2) lacks the leucine zipper protein-dimerization motif and does not bind to DNA, and it stimulates transcription, it is presumed, by sequestering inhibitory co-factors away from the promoter. It is possible that alternative splicing of the ATF3 gene may be physiologically important in the regulation of target genes.[2]
# Clinical significance
ATF-3 is induced upon physiological stress in various tissues.[3] It is also a marker of regeneration following injury of dorsal root ganglion neurons, as injured regenerating neurons activate this transcription factor. [4] Functional validation studies have shown that ATF3 can promote regeneration of peripheral neurons, but is not capable of promoting regeneration of central nervous system neurons. [5] | https://www.wikidoc.org/index.php/ATF3 | |
b5863048eb0a191816de06e4708efeb8a4c900f6 | wikidoc | ATF4 | ATF4
Activating transcription factor 4 (tax-responsive enhancer element B67), also known as ATF4, is a protein that in humans is encoded by the ATF4 gene.
# Function
This gene encodes a transcription factor that was originally identified as a widely expressed mammalian DNA binding protein that could bind a tax-responsive enhancer element in the LTR of HTLV-1. The encoded protein was also isolated and characterized as the cAMP-response element binding protein 2 (CREB-2). The protein encoded by this gene belongs to a family of DNA-binding proteins that includes the AP-1 family of transcription factors, cAMP-response element binding proteins (CREBs) and CREB-like proteins. These transcription factors share a leucine zipper region that is involved in protein–protein interactions, located C-terminal to a stretch of basic amino acids that functions as a DNA-binding domain. Two alternative transcripts encoding the same protein have been described. Two pseudogenes are located on the X chromosome at q28 in a region containing a large inverted duplication.
ATF4 transcription factor is also known to play role in osteoblast differentiation along with RUNX2 and osterix. Terminal osteoblast differentiation, represented by matrix mineralization, is significantly inhibited by the inactivation of JNK. JNK inactivation downregulates expression of ATF-4 and, subsequently, matrix mineralization. IMPACT protein regulates ATF4 in C. elegans to promote lifespan.
# Translation
The translation of ATF4 is dependent on upstream open reading frames located in the 5'UTR. The location of the second uORF, aptly named uORF2, overlaps with the ATF4 open-reading frame. During normal conditions, the uORF1 is translated, and then translation of uORF2 occurs only after eIF2-TC has been reacquired. Translation of the uORF2 requires that the ribosomes pass by the ATF4 ORF, whose start codon is located within uORF2. This leads to its repression. However, during stress conditions, the 40S ribosome will bypass uORF2 because of a decrease in concentration of eIF2-TC, which means the ribosome does not acquire one in time to translate uORF2. Instead ATF4 is translated. | ATF4
Activating transcription factor 4 (tax-responsive enhancer element B67), also known as ATF4, is a protein that in humans is encoded by the ATF4 gene.[1][2]
# Function
This gene encodes a transcription factor that was originally identified as a widely expressed mammalian DNA binding protein that could bind a tax-responsive enhancer element in the LTR of HTLV-1. The encoded protein was also isolated and characterized as the cAMP-response element binding protein 2 (CREB-2). The protein encoded by this gene belongs to a family of DNA-binding proteins that includes the AP-1 family of transcription factors, cAMP-response element binding proteins (CREBs) and CREB-like proteins. These transcription factors share a leucine zipper region that is involved in protein–protein interactions, located C-terminal to a stretch of basic amino acids that functions as a DNA-binding domain. Two alternative transcripts encoding the same protein have been described. Two pseudogenes are located on the X chromosome at q28 in a region containing a large inverted duplication.[3]
ATF4 transcription factor is also known to play role in osteoblast differentiation along with RUNX2 and osterix.[4] Terminal osteoblast differentiation, represented by matrix mineralization, is significantly inhibited by the inactivation of JNK. JNK inactivation downregulates expression of ATF-4 and, subsequently, matrix mineralization.[5] IMPACT protein regulates ATF4 in C. elegans to promote lifespan.[6]
# Translation
The translation of ATF4 is dependent on upstream open reading frames located in the 5'UTR.[7] The location of the second uORF, aptly named uORF2, overlaps with the ATF4 open-reading frame. During normal conditions, the uORF1 is translated, and then translation of uORF2 occurs only after eIF2-TC has been reacquired. Translation of the uORF2 requires that the ribosomes pass by the ATF4 ORF, whose start codon is located within uORF2. This leads to its repression. However, during stress conditions, the 40S ribosome will bypass uORF2 because of a decrease in concentration of eIF2-TC, which means the ribosome does not acquire one in time to translate uORF2. Instead ATF4 is translated.[7] | https://www.wikidoc.org/index.php/ATF4 | |
c6b2eaa3b6e54812f4b087e56f76fec9ee2e6c07 | wikidoc | ATF5 | ATF5
Activating transcription factor 5, also known as ATF5, is a protein that, in humans, is encoded by the ATF5 gene.
# Function
First described by Nishizawa and Nagata, ATF5 has been classified as a member of the activating transcription factor (ATF)/cAMP response-element binding protein (CREB) family.
ATF5 transcripts and protein are expressed in a wide variety of tissues, in particular, high expression of transcripts in liver. It is also present in a variety of tumor cell types.
ATF5 expression is regulated at both the transcriptional and translational level.
ATF5 is expressed in VZ and SVZ during brain development.
The human ATF5 protein is made up of 282 amino acids.
ATF5 is a transcription factor that contains a bZip domain. | ATF5
Activating transcription factor 5, also known as ATF5, is a protein that, in humans, is encoded by the ATF5 gene.[1]
# Function
First described by Nishizawa and Nagata,[2] ATF5 has been classified as a member of the activating transcription factor (ATF)/cAMP response-element binding protein (CREB) family.[3][4]
ATF5 transcripts and protein are expressed in a wide variety of tissues, in particular, high expression of transcripts in liver. It is also present in a variety of tumor cell types.
ATF5 expression is regulated at both the transcriptional and translational level.
ATF5 is expressed in VZ and SVZ during brain development.
The human ATF5 protein is made up of 282 amino acids.
ATF5 is a transcription factor that contains a bZip domain. | https://www.wikidoc.org/index.php/ATF5 | |
02d7ad68f85af9b0f7670a3eacdec204866b32b1 | wikidoc | ATF7 | ATF7
Cyclic AMP-dependent transcription factor ATF-7 is a protein that in humans is encoded by the ATF7 gene.
# Homonym
In 2001, Peters et al. published a paper showing that ATF-7, a Novel bZIP Protein, interacts with PTP4A1.
This ATF-7 is actually ATF5 and not ATF7, as noted by the authors at the end of their paper ("Note Added in Proof—While this manuscript was under review, sequences for mouse and human ATF-5 were deposited in GenBankTM. It appears that ATF-7 and ATF-5 are likely to be the same protein. In addition, an unrelated sequence named ATF7 has also been deposited in GenBankTM. In order to avoid confusion, future work on the protein described in this publication will likely refer to it as either ATF-5 or ATF-5/7.") | ATF7
Cyclic AMP-dependent transcription factor ATF-7 is a protein that in humans is encoded by the ATF7 gene.[1][2][3]
# Homonym
In 2001, Peters et al. published a paper showing that ATF-7, a Novel bZIP Protein, interacts with PTP4A1.[2]
This ATF-7 is actually ATF5 and not ATF7, as noted by the authors at the end of their paper ("Note Added in Proof—While this manuscript was under review, sequences for mouse and human ATF-5 were deposited in GenBankTM. It appears that ATF-7 and ATF-5 are likely to be the same protein. In addition, an unrelated sequence named ATF7 has also been deposited in GenBankTM. In order to avoid confusion, future work on the protein described in this publication will likely refer to it as either ATF-5 or ATF-5/7.")[2] | https://www.wikidoc.org/index.php/ATF7 | |
ac9a2f9b1bc073e9e3d67d26aa9f0c087f69982a | wikidoc | ATG5 | ATG5
Autophagy related 5 (ATG5) is a protein that, in humans, is encoded by the ATG5 gene located on Chromosome 6. It is an E3 ubi autophagic cell death. ATG5 is a key protein involved in the extension of the phagophoric membrane in autophagic vesicles. It is activated by ATG7 and forms a complex with ATG12 and ATG16L1. This complex is necessary for LC3-I (microtubule-associated proteins 1A/1B light chain 3B) conjugation to PE (phosphatidylethanolamine) to form LC3-II (LC3-phosphatidylethanolamine conjugate). ATG5 can also act as a pro-apoptotic molecule targeted to the mitochondria. Under low levels of DNA damage, ATG5 can translocate to the nucleus and interact with survivin.
ATG5 is known to be regulated via various stress induced transcription factors and protein kinases.
# Structure
ATG5 comprises three domains: a ubiquitin-like N-terminal domain (UblA), a helix-rich domain (HR) and a ubiquitin-like C-terminal domain (UblB). The three domains are connected by two linker regions (L1 and L2). ATG5 also has an alpha-helix at the N terminus where on Lysine 130 conjugation with ATG12 occurs. Both UblA and UbLB are composed of a five-stranded beta-sheet and two alpha-helices, a feature conserved in most ubiquitin and ubiquitin-like proteins. HR is composed of three long and one short alpha helices, forming a helix-bundle structure.
# Regulation
ATG5 is regulated by the p73 from the p53 family of transcription factors. DNA damage induces the p300 acetylase to acetylate p73 with the assistance of c-ABL tyrosine kinase. p73 translocates to the nucleus and acts as a transcription factor for ATG5 as well as other apoptotic and autophagic genes.
Programmed Cell Death Protein 4 (PDCD4) is known to inhibit ATG5 expression via inhibition of protein translation. Two MA3 domains on PDCD4 bind to RNA-helicase EIF4A, preventing translation of ATG5 mRNA.
Many protein kinases can regulate activity of the ATG5 protein. Phosphorylation by various kinases are required in order to achieve its active conformation. Under cell stress conditions, the growth arrest and DNA damage 45 beta (Gadd45ß) protein will interact with MAPK/ERK kinase kinase 4 (MEKK4) to form the Gadd45ß-MEKK4 signaling complex. This complex then activates and selectively targets p38 MAPK to the autophagosome to phosphorylate ATG5 at threonine 75. This leads to the inactivation of ATG5 and inhibition of autophagy.
ATG5 can also be regulated post translationally by microRNA.
# Function
## Autophagy
The ATG12-ATG5:ATG16L complex is responsible for elongation of the phagophore in the autophagy pathway. ATG12 is first activated by ATG7, proceeded by the conjugation of ATG5 to the complex by ATG10 via a ubiquitination-like enzymatic process. The ATG12-ATG5 then forms a homo-oligomeric complex with ATG16L. With the help of ATG7 and ATG3, the ATG12-ATG5:ATG16L complex conjugates the C terminus of LC3-I to phosphatidylethanolamine in the phospholipid bilayer, allowing LC3 to associate with the membranes of the phagophore, becoming LC3-II. After formation of the autophagosome, the ATG12-ATG5:ATG16L complex dissociates from the autophagosome.
## Apoptosis
In instances of spontaneous apoptosis or induction of apoptosis via staurosporine, HL-60, or EOL cells, ATG5 undergoes N-terminal cleavage by Calpain-1 and Calpain-2. The cleaved ATG5 translocates from the cytosol to the mitochondria, where it interacts with Bcl-xL, triggering the release of Cytochrome c and activating caspases leading to the apoptotic pathway. This function is independent of its role in autophagy, as it does not require interaction with ATG12.
## Cell Cycle Arrest
In response to DNA damage, ATG5 expression is upregulated, increasing autophagy, preventing caspase activation and apoptosis. ATG5 is also responsible for G2/M arrest and mitotic catastrophe by leading to the phosphorylation of CDK1 and CHEK2, two important regulators of cell cycle arrest. Furthermore, ATG5 is capable of translocating to the nucleus and interacting with survivin to disturb chromosome segregation by antagonistically competing with the ligand Aurora B.
# Clinical Significance
As a key regulator of autophagy, any suppression of the ATG5 protein or loss-of-function mutations in the ATG5 gene will negatively affect autophagy. As a result, deficiencies in the ATG5 protein and variations in the gene have been associated with various inflammatory and degenerative diseases as aggregrates of ubiquitinated targets are not cleared out via autophagy. Polymorphisms within the Atg5 gene have been associated with Behçet's disease, systemic lupus erythematosus, and lupus nephritis. Mutations in the gene promoter for the Atg5 gene have been associated with sporadic Parkinson's disease and childhood asthma. Downregulation of ATG5 protein and mutations in the Atg5 gene have also been linked with prostate, gastrointestinal and colorectal cancers as ATG5 plays a role in both cell apoptosis and cell cycle arrest. Upregulation of Atg5 on the other hand has been shown to suppress melanoma tumorigenesis through induction of cell senescence. ATG5 also plays a protective role in M. tuberculosis infections by preventing PMN-mediated immunopathology.
An Atg5−/− mutation in mice is known to be embryonic lethal. When the mutation is induced only in mice neurons or hepatocytes, there is an accumulation of ubiquitin-positive inclusion bodies and a decrease in cell function. Overexpression of ATG5 on the other hand has been linked to extend mouse lifespan. In the brain, ATG5 is responsible for astrocyte differentiation through activation of the JAK2-STAT3 pathway via degradation of SOCS2. Furthermore, reduction of ATG5 levels in mice brains leads to a suppression in differentiation and increase in cell proliferation of cortical neural progenitor cells through regulation of β-Catenin. | ATG5
Autophagy related 5 (ATG5) is a protein that, in humans, is encoded by the ATG5 gene located on Chromosome 6. It is an E3 ubi autophagic cell death. ATG5 is a key protein involved in the extension of the phagophoric membrane in autophagic vesicles. It is activated by ATG7 and forms a complex with ATG12 and ATG16L1. This complex is necessary for LC3-I (microtubule-associated proteins 1A/1B light chain 3B) conjugation to PE (phosphatidylethanolamine) to form LC3-II (LC3-phosphatidylethanolamine conjugate). ATG5 can also act as a pro-apoptotic molecule targeted to the mitochondria. Under low levels of DNA damage, ATG5 can translocate to the nucleus and interact with survivin.
ATG5 is known to be regulated via various stress induced transcription factors and protein kinases.
# Structure
ATG5 comprises three domains: a ubiquitin-like N-terminal domain (UblA), a helix-rich domain (HR) and a ubiquitin-like C-terminal domain (UblB). The three domains are connected by two linker regions (L1 and L2). ATG5 also has an alpha-helix at the N terminus where on Lysine 130 conjugation with ATG12 occurs.[1] Both UblA and UbLB are composed of a five-stranded beta-sheet and two alpha-helices, a feature conserved in most ubiquitin and ubiquitin-like proteins. HR is composed of three long and one short alpha helices, forming a helix-bundle structure.[2]
# Regulation
ATG5 is regulated by the p73 from the p53 family of transcription factors. DNA damage induces the p300 acetylase to acetylate p73 with the assistance of c-ABL tyrosine kinase. p73 translocates to the nucleus and acts as a transcription factor for ATG5 as well as other apoptotic and autophagic genes.[3]
Programmed Cell Death Protein 4 (PDCD4) is known to inhibit ATG5 expression via inhibition of protein translation. Two MA3 domains on PDCD4 bind to RNA-helicase EIF4A, preventing translation of ATG5 mRNA.[4]
Many protein kinases can regulate activity of the ATG5 protein. Phosphorylation by various kinases are required in order to achieve its active conformation. Under cell stress conditions, the growth arrest and DNA damage 45 beta (Gadd45ß) protein will interact with MAPK/ERK kinase kinase 4 (MEKK4) to form the Gadd45ß-MEKK4 signaling complex. This complex then activates and selectively targets p38 MAPK to the autophagosome to phosphorylate ATG5 at threonine 75. This leads to the inactivation of ATG5 and inhibition of autophagy.[5]
ATG5 can also be regulated post translationally by microRNA.[6]
# Function
## Autophagy
The ATG12-ATG5:ATG16L complex is responsible for elongation of the phagophore in the autophagy pathway. ATG12 is first activated by ATG7, proceeded by the conjugation of ATG5 to the complex by ATG10 via a ubiquitination-like enzymatic process. The ATG12-ATG5 then forms a homo-oligomeric complex with ATG16L.[7] With the help of ATG7 and ATG3, the ATG12-ATG5:ATG16L complex conjugates the C terminus of LC3-I to phosphatidylethanolamine in the phospholipid bilayer, allowing LC3 to associate with the membranes of the phagophore, becoming LC3-II. After formation of the autophagosome, the ATG12-ATG5:ATG16L complex dissociates from the autophagosome.[8][9][1]
## Apoptosis
In instances of spontaneous apoptosis or induction of apoptosis via staurosporine, HL-60, or EOL cells, ATG5 undergoes N-terminal cleavage by Calpain-1 and Calpain-2. The cleaved ATG5 translocates from the cytosol to the mitochondria, where it interacts with Bcl-xL, triggering the release of Cytochrome c and activating caspases leading to the apoptotic pathway.[10][11] This function is independent of its role in autophagy, as it does not require interaction with ATG12.
## Cell Cycle Arrest
In response to DNA damage, ATG5 expression is upregulated, increasing autophagy, preventing caspase activation and apoptosis. ATG5 is also responsible for G2/M arrest and mitotic catastrophe by leading to the phosphorylation of CDK1 and CHEK2, two important regulators of cell cycle arrest.[12] Furthermore, ATG5 is capable of translocating to the nucleus and interacting with survivin to disturb chromosome segregation by antagonistically competing with the ligand Aurora B.[12][13][13]
# Clinical Significance
As a key regulator of autophagy, any suppression of the ATG5 protein or loss-of-function mutations in the ATG5 gene will negatively affect autophagy. As a result, deficiencies in the ATG5 protein and variations in the gene have been associated with various inflammatory and degenerative diseases as aggregrates of ubiquitinated targets are not cleared out via autophagy. Polymorphisms within the Atg5 gene have been associated with Behçet's disease,[14] systemic lupus erythematosus,[15] and lupus nephritis.[16] Mutations in the gene promoter for the Atg5 gene have been associated with sporadic Parkinson's disease[17] and childhood asthma.[18] Downregulation of ATG5 protein and mutations in the Atg5 gene have also been linked with prostate,[19] gastrointestinal[20] and colorectal[21] cancers as ATG5 plays a role in both cell apoptosis and cell cycle arrest. Upregulation of Atg5 on the other hand has been shown to suppress melanoma tumorigenesis through induction of cell senescence.[22] ATG5 also plays a protective role in M. tuberculosis infections by preventing PMN-mediated immunopathology.[23]
An Atg5−/− mutation in mice is known to be embryonic lethal.[24] When the mutation is induced only in mice neurons or hepatocytes, there is an accumulation of ubiquitin-positive inclusion bodies and a decrease in cell function.[25] Overexpression of ATG5 on the other hand has been linked to extend mouse lifespan.[26] In the brain, ATG5 is responsible for astrocyte differentiation through activation of the JAK2-STAT3 pathway via degradation of SOCS2.[27] Furthermore, reduction of ATG5 levels in mice brains leads to a suppression in differentiation and increase in cell proliferation of cortical neural progenitor cells through regulation of β-Catenin.[28] | https://www.wikidoc.org/index.php/ATG5 | |
df8a0f67b39b79f88acf64e85ae0a52898eb3bbb | wikidoc | ATG7 | ATG7
Autophagy-related protein 7 is a protein in humans encoded by ATG7 gene. Related to GSA7; APG7L; APG7-LIKE.
ATG 7, present in both plant and animal genomes, acts as an essential protein for cell degradation and its recycling. The sequence associates with the ubiquitin- proteasome system, UPS, required for the unique development of an autophagosomal membrane and fusion within cells.
ATG7 was identified based on homology to yeast cells Pichia pastoris GSA7 and Saccharomyces cerevisiae APG7. The protein appears to be required for fusion of peroxisomal and vacuolar membranes.
Autophagy is an important cellular process that helps in maintaining homeostasis. It goes through destroying and recycling the cytoplasmic organelles and macromolecules. During the initiation of autophagy, ATG7 acts like an E-1 enzyme for ubiquitin-like proteins (UBL) such as ATG12 and ATG8. ATG7 helps these UBL proteins in targeting their molecule by binding to them and activating their transfer to an E-2 enzyme. ATG7's role in both of these autophagy-specific UBL systems makes it an essential regulator of autophagosome assembly.
Homologous to the ATP-binding and catalytic sites of E1 activator proteins, ATG7 uses its cysteine residue to create a thiol-ester bond with free Ubiquitin molecules. Through UPS, Ubiquitin will continue to bind to other autophagy-related proteins, E2 conjugation proteins and E3 protein ligases, to attach Ubiquitins to a target substrate to induce autophagy.
ATG 7 is often associated with ATG12/ ATG5 sequenced ubiquitination cascade. As well in presence of p53 cell cycle pathways during stressed and nutrient poor environments. | ATG7
Autophagy-related protein 7 is a protein in humans encoded by ATG7 gene.[1][2] Related to GSA7; APG7L; APG7-LIKE.[2]
ATG 7, present in both plant and animal genomes, acts as an essential protein for cell degradation and its recycling.[3][4] The sequence associates with the ubiquitin- proteasome system, UPS, required for the unique development of an autophagosomal membrane and fusion within cells.[5]
ATG7 was identified based on homology to yeast cells Pichia pastoris GSA7 and Saccharomyces cerevisiae APG7. The protein appears to be required for fusion of peroxisomal and vacuolar membranes.[6][6]
Autophagy is an important cellular process that helps in maintaining homeostasis. It goes through destroying and recycling the cytoplasmic organelles and macromolecules. During the initiation of autophagy, ATG7 acts like an E-1 enzyme for ubiquitin-like proteins (UBL) such as ATG12 and ATG8. ATG7 helps these UBL proteins in targeting their molecule by binding to them and activating their transfer to an E-2 enzyme. ATG7's role in both of these autophagy-specific UBL systems makes it an essential regulator of autophagosome assembly.[7]
Homologous to the ATP-binding and catalytic sites of E1 activator proteins, ATG7 uses its cysteine residue to create a thiol-ester bond with free Ubiquitin molecules.[5][8] Through UPS, Ubiquitin will continue to bind to other autophagy-related proteins, E2 conjugation proteins and E3 protein ligases, to attach Ubiquitins to a target substrate to induce autophagy.[9]
ATG 7 is often associated with ATG12/ ATG5 sequenced ubiquitination cascade. As well in presence of p53 cell cycle pathways during stressed and nutrient poor environments.[10][10][11] | https://www.wikidoc.org/index.php/ATG7 | |
c077d85e220aa967d83d0deac75a06b5112a98fd | wikidoc | ATRX | ATRX
Transcriptional regulator ATRX also known as ATP-dependent helicase ATRX, X-linked helicase II, or X-linked nuclear protein (XNP) is a protein that in humans is encoded by the ATRX gene.
# Function
Transcriptional regulator ATRX contains an ATPase / helicase domain, and thus it belongs to the SWI/SNF family of chromatin remodeling proteins. ATRX is required for deposition of the histone variant H3.3 at telomeres and other genomic repeats. These interactions are important for maintaining silencing at these sites.
In addition, ATRX undergoes cell cycle-dependent phosphorylation, which regulates its nuclear matrix and chromatin association, and suggests its involvement in the gene regulation at interphase and chromosomal segregation in mitosis.
# Clinical significance
## Inherited mutations
Inherited mutations of the ATRX gene are associated with an X-linked mental retardation (XLMR) syndrome most often accompanied by alpha-thalassemia (ATR-X) syndrome. These mutations have been shown to cause diverse changes in the pattern of DNA methylation, which may provide a link between chromatin remodeling, DNA methylation, and gene expression in developmental processes. Multiple alternatively spliced transcript variants encoding distinct isoforms have been reported. Female carriers may demonstrate skewed X chromosome inactivation.
## Somatic mutations
Acquired mutations in ATRX have been reported in a number of human cancers including pancreatic neuroendocrine tumours, gliomas, astrocytomas, osteosarcomas, and malignant pheochromocytomas. There is a strong correlation between ATRX mutations and an Alternative Lengthening of Telomeres (ALT) phenotype in cancers.
# Interactions
ATRX forms a complex with DAXX which is an histone H3.3 chaperone.
ATRX has been also shown to interact with EZH2. | ATRX
Transcriptional regulator ATRX also known as ATP-dependent helicase ATRX, X-linked helicase II, or X-linked nuclear protein (XNP) is a protein that in humans is encoded by the ATRX gene.[1][2][3]
# Function
Transcriptional regulator ATRX contains an ATPase / helicase domain, and thus it belongs to the SWI/SNF family of chromatin remodeling proteins. ATRX is required for deposition of the histone variant H3.3 at telomeres and other genomic repeats.[4] These interactions are important for maintaining silencing at these sites.[5][6][7]
In addition, ATRX undergoes cell cycle-dependent phosphorylation, which regulates its nuclear matrix and chromatin association, and suggests its involvement in the gene regulation at interphase and chromosomal segregation in mitosis.[3]
# Clinical significance
## Inherited mutations
Inherited mutations of the ATRX gene are associated with an X-linked mental retardation (XLMR) syndrome most often accompanied by alpha-thalassemia (ATR-X) syndrome. These mutations have been shown to cause diverse changes in the pattern of DNA methylation, which may provide a link between chromatin remodeling, DNA methylation, and gene expression in developmental processes. Multiple alternatively spliced transcript variants encoding distinct isoforms have been reported. Female carriers may demonstrate skewed X chromosome inactivation.[3]
## Somatic mutations
Acquired mutations in ATRX have been reported in a number of human cancers including pancreatic neuroendocrine tumours,[8] gliomas,[9] astrocytomas,[10] osteosarcomas,[11] and malignant pheochromocytomas.[12] There is a strong correlation between ATRX mutations and an Alternative Lengthening of Telomeres (ALT) phenotype in cancers.[8]
# Interactions
ATRX forms a complex with DAXX which is an histone H3.3 chaperone.[13]
ATRX has been also shown to interact with EZH2.[14] | https://www.wikidoc.org/index.php/ATRX | |
55f029d982ea36229e7c8d9e1fbd6aa524cf1be6 | wikidoc | Acai | Acai
# How Acai Berry Health supplements Can Support Males Reveal Their Rock Strong Ab muscles (Greater Than Eating habits and Physical exercise!)
The Acai berry has created into quite the cultural phenomenon. It's tough to go anyplace on the Net without having seeing ads to tell you to obey one rule and burn unsightly stomach fats. Unlike numerous fads that appear and in the past although, the Acai berry is here to stay since it's 1 of the number of health supplements that is assisting individuals attain their fat loss objectives without filling their physique with dangerous laboratory created supplements. Even greater than that, gentlemen are now in a position to reap the rewards of the Acai berry craze so they can commence to display off their tight washboard ab muscles that lie underneath the floor.
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The Acai berry complement is so protected on your physique that you can continue to require it for as extended as you want. You won't have to fear about your coronary heart charge acquiring too higher or not becoming able to perform at operate due to the fact of damaging elements like ephedra. Getting able to do an action persistently, this sort of as taking an Acai berry health supplement every single day, is usually the secret to good results, specially in burning entire body excess fat.
Boosts Your Power Amounts
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When you're employing your energy and acquiring a lot more workout in your every day existence, you flip your system into a fat burning furnace that will get rid of extra fat whilst you're sleeping. | Acai
# How Acai Berry Health supplements Can Support Males Reveal Their Rock Strong Ab muscles (Greater Than Eating habits and Physical exercise!)
The Acai berry has created into quite the cultural phenomenon. It's tough to go anyplace on the Net without having seeing ads to tell you to obey one rule and burn unsightly stomach fats. Unlike numerous fads that appear and in the past although, the Acai berry is here to stay since it's 1 of the number of health supplements that is assisting individuals attain their fat loss objectives without filling their physique with dangerous laboratory created supplements. Even greater than that, gentlemen are now in a position to reap the rewards of the Acai berry craze so they can commence to display off their tight washboard ab muscles that lie underneath the floor.
But why are Acai berry supplements this kind of a good choice for gentlemen who want to reveal their six pack?
Give Your self An Edge
Right after operating a challenging working day and placing up with an bothersome boss, occasionally you don't want to do anything right after function - this incorporates heading to the gymnasium. And when you do get to go, you have to squeeze in a rushed exercise in the morning that doesn't examine to what male celebrities and fitness versions do to get their bodies in peak problem. An Acai berry dietary supplement helps make up for this predicament. If you're generating any work at all to alter the way you eat and be much more energetic, an Acai berries weightloss is heading to aid you improve the benefits you see from your work.
Who wouldn't want to see a 450% improve in outcomes just from adding an Acai berry health supplement to their diet plan? That's specifically what guys like you are locating out each working day. Now, the Men's Well being cover appear isn't for folks who make investments 1000's of dollars and hundreds of hours - it's offered to you as nicely.
Performs With your Body, Not In opposition to It
Fat burning up supplement have arrive a extended way from the harmful tablets of the 80s and 90s. Scientists are now starting to see that the solutions to difficulties like stubborn fat can't necessarily be designed in a laboratory. Instead, they are wanting to nature to discover out what functions. A health supplement like Acai berry is all organic and doesn't hurt your system or make you jittery like some other well-liked extra fat using up pills.
The Acai berry complement is so protected on your physique that you can continue to require it for as extended as you want. You won't have to fear about your coronary heart charge acquiring too higher or not becoming able to perform at operate due to the fact of damaging elements like ephedra. Getting able to do an action persistently, this sort of as taking an Acai berry health supplement every single day, is usually the secret to good results, specially in burning entire body excess fat.
Boosts Your Power Amounts
1 of the most thrilling rewards of utilizing an Acai berry health supplement is that you'll get a energy surge of vitality that will help you be a lot more lively and melt away far more fats. Believe of how several fantastic workouts you could fit in if you weren't feeling sluggish and drained at the finish of the working day. Plus, you'll sense compelled to acquire the stairs instead of the elevator or try to suit in a run in the course of your lunch break. The more energy you have, the a lot more you'll be in a position to fuel your physique with extra fat burning up workout routines that increase your metabolism.
When you're employing your energy and acquiring a lot more workout in your every day existence, you flip your system into a fat burning furnace that will get rid of extra fat whilst you're sleeping. | https://www.wikidoc.org/index.php/Acai | |
3bbd4f14fd2f9fb61983d1e766dd9664fa7abb17 | wikidoc | Acid | Acid
- Acid-base extraction
- Acid-base reaction
- Acid-base physiology
- Acid-base homeostasis
- Dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
# Overview
An acid (often represented by the generic formula HA ) is traditionally considered any chemical compound that, when dissolved in water, gives a solution with a hydrogen ion activity greater than in pure water, i.e. a pH less than 7.0. That approximates the modern definition of Johannes Nicolaus Brønsted and Martin Lowry, who independently defined an acid as a compound which donates a hydrogen ion (H+) to another compound (called a base). Common examples include acetic acid (in vinegar) and sulfuric acid (used in car batteries). Acid/base systems are different from redox reactions in that there is no change in oxidation state.
# Definitions
The word "acid" comes from the Latin acidus meaning "sour," but in chemistry the term acid has a more specific meaning. There are four common ways to define an acid:
- Arrhenius: According to this definition developed by the Swedish chemist Svante Arrhenius, an acid is a substance that increases the concentration of hydrogen ions (H+), which are carried as hydronium ions (H3O+) when dissolved in water, while bases are substances that increase the concentration of hydroxide ions (OH-). This definition limits acids and bases to substances that can dissolve in water. Around 1800, many French chemists, including Antoine Lavoisier, incorrectly believed that all acids contained oxygen. Indeed the modern German word for oxygen is Sauerstoff (lit. sour substance), as is the Afrikaans word for oxygen suurstof, with the same meaning. English chemists, including Sir Humphry Davy at the same time believed all acids contained hydrogen. Arrhenius used this belief to develop this definition of acid.
- Brønsted-Lowry: According to this definition, an acid is a proton (hydrogen nucleus) donor and a base is a proton acceptor. The acid is said to be dissociated after the proton is donated. An acid and the corresponding base are referred to as conjugate acid-base pairs. Brønsted and Lowry independently formulated this definition, which includes water-insoluble substances not in the Arrhenius definition.
- solvent-system definition: According to this definition, an acid is a substance that, when dissolved in an autodissociating solvent, increases the concentration of the solvonium cations, such as H3O+ in water, NH4+ in liquid ammonia, NO+ in liquid N2O4, SbCl2+ in SbCl3, etc. Base is defined as the substance that increases the concentration of the solvate anions, respectively OH-, NH2-, NO3-, or SbCl4-. This definition extends acid-base reactions to nonaqueous systems and even some aprotic systems, where no hydrogen nuclei are involved in the reactions. This definition is not absolute, a compound acting as acid in one solvent may act as a base in another.
- Lewis: According to this definition developed by Gilbert N. Lewis, an acid is an electron-pair acceptor and a base is an electron-pair donor. (These are frequently referred to as "Lewis acids" and "Lewis bases," and are electrophiles and nucleophiles, respectively, in organic chemistry; Lewis bases are also ligands in coordination chemistry.) Lewis acids include substances with no transferable protons (ie H+ hydrogen ions), such as iron(III) chloride, and hence the Lewis definition of an acid has wider application than the Brønsted-Lowry definition. In fact, the term Lewis acid is often used to exclude protic (Brønsted-Lowry) acids. The Lewis definition can also be explained with molecular orbital theory. In general, an acid can receive an electron pair in its lowest unoccupied orbital (LUMO) from the highest occupied orbital (HOMO) of a base. That is, the HOMO from the base and the LUMO from the acid combine to a bonding molecular orbital.
Although not the most general theory, the Brønsted-Lowry definition is the most widely used definition. The strength of an acid may be understood by this definition by the stability of hydronium and the solvated conjugate base upon dissociation. Increasing or decreasing stability of the conjugate base will increase or decrease the acidity of a compound. This concept of acidity is used frequently for organic acids such as carboxylic acid. The molecular orbital description, where the unfilled proton orbital overlaps with a lone pair, is connected to the Lewis definition.
# Properties
Bronsted-Lowry acids:
- Are generally sour in taste
- Strong or concentrated acids often produce a stinging feeling on mucous membranes
- React to indicators as follows: turn blue litmus and methyl orange red, do not change the color of phenolphthalein
- Will react with metals to produce a metal salt and hydrogen
- Will react with metal carbonates to produce water, CO2 and a salt
- Will react with a base to produce a salt and water
- Will react with a metal oxide to produce water and a salt
- Will conduct electricity, depending on the degree of dissociation
- Will produce solvonium ions, such as hydronium (H3O+) ions in water
- Will denature proteins
Strong acids and many concentrated acids are dangerous, causing severe burns for even minor contact. Acids are corrosive. Generally, acid burns are treated by rinsing the affected area abundantly with running water (15 minutes) and followed up with immediate medical attention. In the case of highly concentrated acids, the acid should first be wiped off as much as possible, otherwise the exothermic mixing of the acid and the water could cause severe thermal burns. Acids may also be dangerous for reasons not related to their acidity, see an appropriate MSDS for more detailed information.
# Nomenclature
In the classical naming system, acids are named according to their anions. That ionic suffix is dropped and replaced with a new suffix (and sometimes prefix), according to the table below. For example, HCl has chloride as its anion, so the -ide suffix makes it take the form hydrochloric acid. In the IUPAC naming system, "aqueous" is simply added to the name of the ionic compound. Thus, for hydrogen chloride, the IUPAC name would be aqueous hydrogen chloride.
Classical naming system:
# Chemical characteristics
In water the following equilibrium occurs between a weak acid (HA) and water, which acts as a base:
HA(aq) + H2O Template:Unicode H3O+(aq) + A-(aq)
The acidity constant (or acid dissociation constant) is the equilibrium constant for the reaction of HA with water:
Strong acids have large Ka values (i.e. the reaction equilibrium lies far to the right; the acid is almost completely dissociated to H3O+ and A-). Strong acids include the heavier hydrohalic acids: hydrochloric acid (HCl), hydrobromic acid (HBr), and hydroiodic acid (HI). (However, hydrofluoric acid, HF, is relatively weak.) For example, the Ka value for hydrochloric acid (HCl) is 107.
Weak acids have small Ka values (i.e. at equilibrium significant amounts of HA and A− exist together in solution; modest levels of H3O+ are present; the acid is only partially dissociated). For example, the Ka value for acetic acid is 1.8 x 10-5. Most organic acids are weak acids. Oxoacids, which tend to contain central atoms in high oxidation states surrounded by oxygen may be quite strong or weak. Nitric acid, sulfuric acid, and perchloric acid are all strong acids, whereas nitrous acid, sulfurous acid and hypochlorous acid are all weak.
Note on terms used:
- The terms "hydrogen ion" and "proton" are used interchangeably; both refer to H+.
- In aqueous solution, the water is protonated to form hydronium ion, H3O+(aq). This is often abbreviated as H+(aq) even though the symbol is not chemically correct.
- The strength of an acid is measured by its acid dissociation constant (Ka) or equivalently its pKa (pKa= - log(Ka)).
- The pH of a solution is a measurement of the concentration of hydronium. This will depend on the concentration and nature of acids and bases in solution.
## Polyprotic acids
Polyprotic acids are able to donate more than one proton per acid molecule, in contrast to monoprotic acids that only donate one proton per molecule. Specific types of polyprotic acids have more specific names, such as diprotic acid (two potential protons to donate) and triprotic acid (three potential protons to donate).
A monoprotic acid can undergo one dissociation (sometimes called ionization) as follows and simply has one acid dissociation constant as shown below:
A diprotic acid (here symbolized by H2A) can undergo one or two dissociations depending on the pH. Each dissociation has its own dissociation constant, Ka1 and Ka2.
The first dissociation constant is typically greater than the second; i.e., Ka1 > Ka2 . For example, sulfuric acid (H2SO4) can donate one proton to form the bisulfate anion (HSO4−), for which Ka1 is very large; then it can donate a second proton to form the sulfate anion (SO42−), wherein the Ka2 is intermediate strength. The large Ka1 for the first dissociation makes sulfuric a strong acid. In a similar manner, the weak unstable carbonic acid (H2CO3) can lose one proton to form bicarbonate anion (HCO3−) and lose a second to form carbonate anion (CO32−). Both Ka values are small, but Ka1 > Ka2 .
A triprotic acid (H3A) can undergo one, two, or three dissociations and has three dissociation constants, where Ka1 > Ka2 > Ka3 .
An inorganic example of a triprotic acid is orthophosphoric acid (H3PO4), usually just called phosphoric acid. All three protons can be successively lost to yield H2PO4−, then HPO42−, and finally PO43− , the orthophosphate ion, usually just called phosphate. An organic example of a triprotic acid is citric acid, which can successively lose three protons to finally form the citrate ion. Even though the positions of the protons on the original molecule may be equivalent, the successive Ka values will differ since it is energetically less favorable to lose a proton if the conjugate base is more negatively charged.
## Neutralization
Neutralization is the reaction between an acid and a base, producing a salt and water; for example, hydrochloric acid and sodium hydroxide form sodium chloride and water:
Neutralization is the basis of titration, where a pH indicator shows equivalence point when the equivalent number of moles of a base have been added to an acid. It is often wrongly assumed that neutralization should result in a solution with pH 7.0, which is only the case with similar acid and base strengths during a reaction.
Neutralization with an base weaker than the acid results in an weakly acidic salt. An example is the weakly acidic ammonium chloride, which is produced from the strong acid hydrogen chloride and the weak base ammonia. Conversely, neutralizing a weak acid with a strong base gives a weakly basic salt, e.g. sodium fluoride from hydrogen fluoride and sodium hydroxide.
## Weak acid/weak base equilibria
In order to lose a proton, it is necessary that the pH of the system rise above the pKa of the protonated acid. The decreased concentration of H+ in that basic solution shifts the equilibrium towards the conjugate base form (the deprotonated form of the acid). In lower-pH (more acidic) solutions, there is a high enough H+ concentration in the solution to cause the acid to remain in its protonated form, or to protonate its conjugate base (the deprotonated form).
Solutions of weak acids and salts of their conjugate bases form buffer solutions.
# Applications of acids
There are numerous uses for acids. Acids are often used to remove rust and other corrosion from metals in a process known as pickling. They may be used as an electrolyte in a wet cell battery, such as sulfuric acid in a car battery. In humans and many other animals, hydrochloric acid is a part of the gastric acid secreted within the stomach to help hydrolyze proteins and polysaccharides, as well as converting the inactive pro-enzyme, pepsinogen into the enzyme, pepsin. Acids are used as catalysts; for example, sulfuric acid is used in very large quantities in the alkylation process to produce gasoline.
# Common acids
- Citric Acid
## Mineral acids
- Solutions of hydrogen halides, such as hydrochloric acid (HCl) and hydrobromic acid (HBr)
- Sulfuric acid (H2SO4)
- Nitric acid (HNO3)
- Phosphoric acid (H3PO4)
- Chromic acid (H2CrO4)
## Sulfonic acids
- Methanesulfonic acid (aka mesylic acid) (MeSO3H)
- Ethanesulfonic acid (aka esylic acid) (EtSO3H)
- Benzenesulfonic acid (aka besylic acid) (PhSO3H)
- Toluenesulfonic acid (aka tosylic acid, or (C6H4(CH3)(SO3H))
## Carboxylic acids
- Formic acid
- Acetic acid | Acid
- Acid-base extraction
- Acid-base reaction
- Acid-base physiology
- Acid-base homeostasis
- Dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
An acid (often represented by the generic formula HA [H+A-]) is traditionally considered any chemical compound that, when dissolved in water, gives a solution with a hydrogen ion activity greater than in pure water, i.e. a pH less than 7.0. That approximates the modern definition of Johannes Nicolaus Brønsted and Martin Lowry, who independently defined an acid as a compound which donates a hydrogen ion (H+) to another compound (called a base). Common examples include acetic acid (in vinegar) and sulfuric acid (used in car batteries). Acid/base systems are different from redox reactions in that there is no change in oxidation state.
# Definitions
The word "acid" comes from the Latin acidus meaning "sour," but in chemistry the term acid has a more specific meaning. There are four common ways to define an acid:
- Arrhenius: According to this definition developed by the Swedish chemist Svante Arrhenius, an acid is a substance that increases the concentration of hydrogen ions (H+), which are carried as hydronium ions (H3O+) when dissolved in water, while bases are substances that increase the concentration of hydroxide ions (OH-). This definition limits acids and bases to substances that can dissolve in water. Around 1800, many French chemists, including Antoine Lavoisier, incorrectly believed that all acids contained oxygen. Indeed the modern German word for oxygen is Sauerstoff (lit. sour substance), as is the Afrikaans word for oxygen suurstof, with the same meaning. English chemists, including Sir Humphry Davy at the same time believed all acids contained hydrogen. Arrhenius used this belief to develop this definition of acid.
- Brønsted-Lowry: According to this definition, an acid is a proton (hydrogen nucleus) donor and a base is a proton acceptor. The acid is said to be dissociated after the proton is donated. An acid and the corresponding base are referred to as conjugate acid-base pairs. Brønsted and Lowry independently formulated this definition, which includes water-insoluble substances not in the Arrhenius definition.
- solvent-system definition: According to this definition, an acid is a substance that, when dissolved in an autodissociating solvent, increases the concentration of the solvonium cations, such as H3O+ in water, NH4+ in liquid ammonia, NO+ in liquid N2O4, SbCl2+ in SbCl3, etc. Base is defined as the substance that increases the concentration of the solvate anions, respectively OH-, NH2-, NO3-, or SbCl4-. This definition extends acid-base reactions to nonaqueous systems and even some aprotic systems, where no hydrogen nuclei are involved in the reactions. This definition is not absolute, a compound acting as acid in one solvent may act as a base in another.
- Lewis: According to this definition developed by Gilbert N. Lewis, an acid is an electron-pair acceptor and a base is an electron-pair donor. (These are frequently referred to as "Lewis acids" and "Lewis bases," and are electrophiles and nucleophiles, respectively, in organic chemistry; Lewis bases are also ligands in coordination chemistry.) Lewis acids include substances with no transferable protons (ie H+ hydrogen ions), such as iron(III) chloride, and hence the Lewis definition of an acid has wider application than the Brønsted-Lowry definition. In fact, the term Lewis acid is often used to exclude protic (Brønsted-Lowry) acids. The Lewis definition can also be explained with molecular orbital theory. In general, an acid can receive an electron pair in its lowest unoccupied orbital (LUMO) from the highest occupied orbital (HOMO) of a base. That is, the HOMO from the base and the LUMO from the acid combine to a bonding molecular orbital.
Although not the most general theory, the Brønsted-Lowry definition is the most widely used definition. The strength of an acid may be understood by this definition by the stability of hydronium and the solvated conjugate base upon dissociation. Increasing or decreasing stability of the conjugate base will increase or decrease the acidity of a compound. This concept of acidity is used frequently for organic acids such as carboxylic acid. The molecular orbital description, where the unfilled proton orbital overlaps with a lone pair, is connected to the Lewis definition.
# Properties
Bronsted-Lowry acids:
- Are generally sour in taste
- Strong or concentrated acids often produce a stinging feeling on mucous membranes
- React to indicators as follows: turn blue litmus and methyl orange red, do not change the color of phenolphthalein
- Will react with metals to produce a metal salt and hydrogen
- Will react with metal carbonates to produce water, CO2 and a salt
- Will react with a base to produce a salt and water
- Will react with a metal oxide to produce water and a salt
- Will conduct electricity, depending on the degree of dissociation
- Will produce solvonium ions, such as hydronium (H3O+) ions in water
- Will denature proteins
Strong acids and many concentrated acids are dangerous, causing severe burns for even minor contact. Acids are corrosive. Generally, acid burns are treated by rinsing the affected area abundantly with running water (15 minutes) and followed up with immediate medical attention. In the case of highly concentrated acids, the acid should first be wiped off as much as possible, otherwise the exothermic mixing of the acid and the water could cause severe thermal burns. Acids may also be dangerous for reasons not related to their acidity, see an appropriate MSDS for more detailed information.
# Nomenclature
In the classical naming system, acids are named according to their anions. That ionic suffix is dropped and replaced with a new suffix (and sometimes prefix), according to the table below. For example, HCl has chloride as its anion, so the -ide suffix makes it take the form hydrochloric acid. In the IUPAC naming system, "aqueous" is simply added to the name of the ionic compound. Thus, for hydrogen chloride, the IUPAC name would be aqueous hydrogen chloride.
Classical naming system:
# Chemical characteristics
In water the following equilibrium occurs between a weak acid (HA) and water, which acts as a base:
HA(aq) + H2O Template:Unicode H3O+(aq) + A-(aq)
The acidity constant (or acid dissociation constant) is the equilibrium constant for the reaction of HA with water:
Strong acids have large Ka values (i.e. the reaction equilibrium lies far to the right; the acid is almost completely dissociated to H3O+ and A-). Strong acids include the heavier hydrohalic acids: hydrochloric acid (HCl), hydrobromic acid (HBr), and hydroiodic acid (HI). (However, hydrofluoric acid, HF, is relatively weak.) For example, the Ka value for hydrochloric acid (HCl) is 107.
Weak acids have small Ka values (i.e. at equilibrium significant amounts of HA and A− exist together in solution; modest levels of H3O+ are present; the acid is only partially dissociated). For example, the Ka value for acetic acid is 1.8 x 10-5. Most organic acids are weak acids. Oxoacids, which tend to contain central atoms in high oxidation states surrounded by oxygen may be quite strong or weak. Nitric acid, sulfuric acid, and perchloric acid are all strong acids, whereas nitrous acid, sulfurous acid and hypochlorous acid are all weak.
Note on terms used:
- The terms "hydrogen ion" and "proton" are used interchangeably; both refer to H+.
- In aqueous solution, the water is protonated to form hydronium ion, H3O+(aq). This is often abbreviated as H+(aq) even though the symbol is not chemically correct.
- The strength of an acid is measured by its acid dissociation constant (Ka) or equivalently its pKa (pKa= - log(Ka)).
- The pH of a solution is a measurement of the concentration of hydronium. This will depend on the concentration and nature of acids and bases in solution.
## Polyprotic acids
Polyprotic acids are able to donate more than one proton per acid molecule, in contrast to monoprotic acids that only donate one proton per molecule. Specific types of polyprotic acids have more specific names, such as diprotic acid (two potential protons to donate) and triprotic acid (three potential protons to donate).
A monoprotic acid can undergo one dissociation (sometimes called ionization) as follows and simply has one acid dissociation constant as shown below:
A diprotic acid (here symbolized by H2A) can undergo one or two dissociations depending on the pH. Each dissociation has its own dissociation constant, Ka1 and Ka2.
The first dissociation constant is typically greater than the second; i.e., Ka1 > Ka2 . For example, sulfuric acid (H2SO4) can donate one proton to form the bisulfate anion (HSO4−), for which Ka1 is very large; then it can donate a second proton to form the sulfate anion (SO42−), wherein the Ka2 is intermediate strength. The large Ka1 for the first dissociation makes sulfuric a strong acid. In a similar manner, the weak unstable carbonic acid (H2CO3) can lose one proton to form bicarbonate anion (HCO3−) and lose a second to form carbonate anion (CO32−). Both Ka values are small, but Ka1 > Ka2 .
A triprotic acid (H3A) can undergo one, two, or three dissociations and has three dissociation constants, where Ka1 > Ka2 > Ka3 .
An inorganic example of a triprotic acid is orthophosphoric acid (H3PO4), usually just called phosphoric acid. All three protons can be successively lost to yield H2PO4−, then HPO42−, and finally PO43− , the orthophosphate ion, usually just called phosphate. An organic example of a triprotic acid is citric acid, which can successively lose three protons to finally form the citrate ion. Even though the positions of the protons on the original molecule may be equivalent, the successive Ka values will differ since it is energetically less favorable to lose a proton if the conjugate base is more negatively charged.
## Neutralization
Neutralization is the reaction between an acid and a base, producing a salt and water; for example, hydrochloric acid and sodium hydroxide form sodium chloride and water:
Neutralization is the basis of titration, where a pH indicator shows equivalence point when the equivalent number of moles of a base have been added to an acid. It is often wrongly assumed that neutralization should result in a solution with pH 7.0, which is only the case with similar acid and base strengths during a reaction.
Neutralization with an base weaker than the acid results in an weakly acidic salt. An example is the weakly acidic ammonium chloride, which is produced from the strong acid hydrogen chloride and the weak base ammonia. Conversely, neutralizing a weak acid with a strong base gives a weakly basic salt, e.g. sodium fluoride from hydrogen fluoride and sodium hydroxide.
## Weak acid/weak base equilibria
In order to lose a proton, it is necessary that the pH of the system rise above the pKa of the protonated acid. The decreased concentration of H+ in that basic solution shifts the equilibrium towards the conjugate base form (the deprotonated form of the acid). In lower-pH (more acidic) solutions, there is a high enough H+ concentration in the solution to cause the acid to remain in its protonated form, or to protonate its conjugate base (the deprotonated form).
Solutions of weak acids and salts of their conjugate bases form buffer solutions.
# Applications of acids
There are numerous uses for acids. Acids are often used to remove rust and other corrosion from metals in a process known as pickling. They may be used as an electrolyte in a wet cell battery, such as sulfuric acid in a car battery. In humans and many other animals, hydrochloric acid is a part of the gastric acid secreted within the stomach to help hydrolyze proteins and polysaccharides, as well as converting the inactive pro-enzyme, pepsinogen into the enzyme, pepsin. Acids are used as catalysts; for example, sulfuric acid is used in very large quantities in the alkylation process to produce gasoline.
# Common acids
- Citric Acid
## Mineral acids
- Solutions of hydrogen halides, such as hydrochloric acid (HCl) and hydrobromic acid (HBr)
- Sulfuric acid (H2SO4)
- Nitric acid (HNO3)
- Phosphoric acid (H3PO4)
- Chromic acid (H2CrO4)
## Sulfonic acids
- Methanesulfonic acid (aka mesylic acid) (MeSO3H)
- Ethanesulfonic acid (aka esylic acid) (EtSO3H)
- Benzenesulfonic acid (aka besylic acid) (PhSO3H)
- Toluenesulfonic acid (aka tosylic acid, or (C6H4(CH3)(SO3H))
## Carboxylic acids
- Formic acid
- Acetic acid | https://www.wikidoc.org/index.php/Acid | |
b157c7077f4230d497851c7b0d21883b55a09eb9 | wikidoc | HSN2 | HSN2
Hereditary sensory neuropathy, type II also known as HSN2 is a protein which in humans in encoded by the HSN2. It is a single-exon ORF, and a nervous system-specific exon of the WNK1 gene. HSN2 is as an alternatively spliced exon of WNK1 and this selectively occurs in nervous tissues, resulting in WNK1/HSN2 nervous system isoforms.
# Function
The WNK1/HSN2 isoforms are expressed in the sensory parts of the peripheral nervous system and central nervous system which are associated with the transmission of sensory and nociceptive signals. These parts include satellite cells, Schwann cells, and sensory neurons. The novel protein product of the isoform is more plentiful in sensory neurons than motor neurons. It is proposed that this gene product may play a role in the development and/or maintenance of peripheral sensory neurons or their supporting Schwann cells.
# Clinical significance
Mutations in the HSN2 gene are associated with congenital sensory neuropathy (HSAN Type II), an autosomal recessive disorder characterized by impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons. | HSN2
Hereditary sensory neuropathy, type II also known as HSN2 is a protein which in humans in encoded by the HSN2.[1][2] It is a single-exon ORF, and a nervous system-specific exon of the WNK1 gene. HSN2 is as an alternatively spliced exon of WNK1 and this selectively occurs in nervous tissues, resulting in WNK1/HSN2 nervous system isoforms.[3]
# Function
The WNK1/HSN2 isoforms are expressed in the sensory parts of the peripheral nervous system and central nervous system which are associated with the transmission of sensory and nociceptive signals. These parts include satellite cells, Schwann cells, and sensory neurons. The novel protein product of the isoform is more plentiful in sensory neurons than motor neurons.[3] It is proposed that this gene product may play a role in the development and/or maintenance of peripheral sensory neurons or their supporting Schwann cells.
# Clinical significance
Mutations in the HSN2 gene are associated with congenital sensory neuropathy (HSAN Type II), an autosomal recessive disorder characterized by impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons.[3] | https://www.wikidoc.org/index.php/Acroosteolysis_neurogenic | |
31681b471e31d402aa3da5e0f155d014ae56b89b | wikidoc | Acyl | Acyl
# Overview
An acyl group (IUPAC name: alkanoyl) is a functional group derived by the removal of one or more hydroxyl group from an oxoacid.. In organic chemistry, the acyl group is usually derived from a carboxylic acid of the form RC O OH. It therefore has the formula RC(=O)-, with a double bond between the carbon and oxygen atoms (i.e. a carbonyl group), and a single bond between R and the carbon. Acyl groups can also be derived from other types of acids such as sulfonic acids, phosphonic acids, and some others.
Acyl halides can be used in Friedel-Crafts acylation to introduce the acyl moiety in an aromatic compound.
In biochemistry, Acyl-CoA is a derivate of fatty acid metabolism.
# Examples
The names of acyl groups are typically derived from the corresponding acid by substituting the acid ending -ic with the ending -yl as shown in the table below. Note that methyl, ethyl, propyl, butyl etc. end in -yl are not acyl but alkyl groups, derived from alkanes.
# Acyl species
In acyloxy groups the acyl group is bonded to oxygen: R-C=O-O-R' where R-C=O is the acyl group.
Acylium ions are cations of the type R-C+=O and play an important role as intermediates in organic reactions for example the Hayashi rearrangement. | Acyl
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
An acyl group (IUPAC name: alkanoyl) is a functional group derived by the removal of one or more hydroxyl group from an oxoacid.[1]. In organic chemistry, the acyl group is usually derived from a carboxylic acid of the form RC O OH. It therefore has the formula RC(=O)-, with a double bond between the carbon and oxygen atoms (i.e. a carbonyl group), and a single bond between R and the carbon. Acyl groups can also be derived from other types of acids such as sulfonic acids, phosphonic acids, and some others.
Acyl halides can be used in Friedel-Crafts acylation to introduce the acyl moiety in an aromatic compound.
In biochemistry, Acyl-CoA is a derivate of fatty acid metabolism.
# Examples
The names of acyl groups are typically derived from the corresponding acid by substituting the acid ending -ic with the ending -yl as shown in the table below. Note that methyl, ethyl, propyl, butyl etc. end in -yl are not acyl but alkyl groups, derived from alkanes.
# Acyl species
In acyloxy groups the acyl group is bonded to oxygen: R-C=O-O-R' where R-C=O is the acyl group.
Acylium ions are cations of the type R-C+=O and play an important role as intermediates in organic reactions [1] for example the Hayashi rearrangement. | https://www.wikidoc.org/index.php/Acyl | |
b1dcc7444e16e49df6ed9b17c33a415b485d887a | wikidoc | Agar | Agar
# Overview
Agar is a gelatinous substance chiefly used as a culture medium for microbiological work. It is an unbranched polysaccharide obtained from the cell walls of some species of red algae or seaweed. It can be used as a laxative, a vegetarian gelatin substitute, a thickener for soups, in jellies, ice cream and Japanese desserts such as anmitsu, as a clarifying agent in brewing, and for paper sizing fabrics. The word agar comes from the Malay word agar-agar (meaning jelly). It is also known as kanten or agal-agal (Ceylon agar). Chemically, agar is a polymer made up of subunits of the sugar galactose. Agar polysaccharides serve as the primary structural support for the algae's cell walls.
# Uses in microbiology
Nutrient agar is used throughout the world as a medium for the growth of bacteria and fungi. Though less than 1% of all existing bacteria can be grown successfully, the basic agar formula can be used to grow most of the microbes whose needs are known. More specific nutrient agars are available, because some microbes prefer certain environmental conditions over others. For example, blood agar, which is generally combined with sheep blood, can be used to detect the presence of haemorrhagic micro-organisms such as Escherichia coli O157:H7. The bacteria digest the blood, turning the plate clear.
## Selective media
Selective media is agar specially treated to apply a selective pressure to organisms growing on it -- for example, to select for salt-tolerant, gram-positive, or gram-negative bacteria. To select for only gram negative organisms you would use MacConkey agar, which would also in turn tell you if the gram negative organism is a lactose fermenter or not indicated by red colonies instead of translucent (non- lactose fermenter).
## Differential media
Differential media includes an indicator that causes visible, easily detectable changes in the appearance of the agar gel or bacterial colonies in a specific group of bacteria. For example, EMB (Eosin Methylene Blue) agar causes E. coli colonies to have a metallic green sheen, and MSA (Mannitol Salt Agar) turns yellow in the presence of mannitol fermenting bacteria.
# Usage
## Molecular biology
Agar is a heterogeneous mixture of two classes of polysaccharide: agaropectin and agarose. Although both polysaccharide classes share the same galactose-based backbone, agaropectin is heavily modified with acidic side-groups, such as sulfate and pyruvate. The neutral charge and lower degree of chemical complexity of agarose make it less likely to interact with biomolecules, such as proteins. Gels made from purified agarose have a relatively large pore size, making them useful for size-separation of large molecules, such as proteins or protein complexes >200 kilodaltons, or DNA fragments >100 basepairs. Agarose can be used for electrophoretic separation in agarose gel electrophoresis or for column-based gel filtration chromatography.
## Culinary
Agar-Agar is the sea's natural gelatin. White and semi-translucent, it is sold in packages as washed and dried strips or in powdered form. It can be used to make jellies, puddings and custards. For making jelly, it is boiled in water until the solids dissolve. One then adds sweetener, flavouring, colouring, fruit or vegetables, and pours the liquid into molds to be served as desserts and vegetable aspics, or incorporated with other desserts, such as a jelly layer on a cake.
Agar-agar is approximately 80% fiber, so it can serve as a great intestinal regulator. Its bulk quality is behind one of the latest fad diets in Asia, the Kanten Diet. Once ingested, kanten triples in size and absorbs water. This results in the consumer feeling more full. Recently this diet has received some press coverage in the United States as well. The diet has shown promise in obesity studies.
In Indian cuisine, agar agar is known as "China Grass" and is used for making desserts.
## Plant biology
Research grade agar is used extensively in plant biology as it is supplemented with a nutrient and vitamin mixture that allows for seedling germination in petri dishes under sterile conditions (given that the seeds are sterilized as well). Nutrient and vitamin supplementation for Arabidopsis thaliana is standard across most experimental conditions. Murashige & Skoog (MS) nutrient mix and Gamborg's B5 vitamin mix are generally used. A 1.0% agar/0.44% MS+vitamin dH20 solution is suitable for growth media between normal growth temps.
The solidification of the agar within any growth media (GM) is pH-dependent, with an optimal range between 5.4-5.7. Usually, the application of KOH is needed to increase the pH to this range. A general guideline is about 600 µl 0.1M KOH per 250 ml GM. This entire mixture can be sterilised using the liquid cycle of an autoclave.
This medium nicely lends itself to the application of specific concentrations of phytohormones etc. to induce specific growth patterns in that you can easily prepare a solution containing the desired amount of hormone, add it to the known volume of GM and autoclave to both sterilize and evaporate off any solvent you may have used to dissolve the often polar hormones in. This hormone/GM solution can be spread across the surface of petri dishes sown with germinated and/or etiolated seedlings.
## Other
Agar is used as an impression material in dentistry. It is also used to make salt bridges for use in electrochemistry.
# Hysteresis
Hysteresis describes the phenomenon of the differing liquid-solid state transition temperatures that agar exhibits. Agar melts at 85 °C (358 K, 185 °F) and solidifies from 32-40 °C. (305 - 313 K, 90-104 °F) | Agar
# Overview
Agar is a gelatinous substance chiefly used as a culture medium for microbiological work. It is an unbranched polysaccharide obtained from the cell walls of some species of red algae or seaweed. It can be used as a laxative, a vegetarian gelatin substitute, a thickener for soups, in jellies, ice cream and Japanese desserts such as anmitsu, as a clarifying agent in brewing, and for paper sizing fabrics. The word agar comes from the Malay word agar-agar (meaning jelly). It is also known as kanten or agal-agal (Ceylon agar). Chemically, agar is a polymer made up of subunits of the sugar galactose. Agar polysaccharides serve as the primary structural support for the algae's cell walls.
# Uses in microbiology
Nutrient agar is used throughout the world as a medium for the growth of bacteria and fungi. Though less than 1% of all existing bacteria can be grown successfully, the basic agar formula can be used to grow most of the microbes whose needs are known. More specific nutrient agars are available, because some microbes prefer certain environmental conditions over others. For example, blood agar, which is generally combined with sheep blood, can be used to detect the presence of haemorrhagic micro-organisms such as Escherichia coli O157:H7. The bacteria digest the blood, turning the plate clear.
## Selective media
Selective media is agar specially treated to apply a selective pressure to organisms growing on it -- for example, to select for salt-tolerant, gram-positive, or gram-negative bacteria. To select for only gram negative organisms you would use MacConkey agar, which would also in turn tell you if the gram negative organism is a lactose fermenter or not indicated by red colonies instead of translucent (non- lactose fermenter).
## Differential media
Differential media includes an indicator that causes visible, easily detectable changes in the appearance of the agar gel or bacterial colonies in a specific group of bacteria. For example, EMB (Eosin Methylene Blue) agar causes E. coli colonies to have a metallic green sheen, and MSA (Mannitol Salt Agar) turns yellow in the presence of mannitol fermenting bacteria.
# Usage
## Molecular biology
Agar is a heterogeneous mixture of two classes of polysaccharide: agaropectin and agarose.[1] Although both polysaccharide classes share the same galactose-based backbone, agaropectin is heavily modified with acidic side-groups, such as sulfate and pyruvate. The neutral charge and lower degree of chemical complexity of agarose make it less likely to interact with biomolecules, such as proteins. Gels made from purified agarose have a relatively large pore size, making them useful for size-separation of large molecules, such as proteins or protein complexes >200 kilodaltons, or DNA fragments >100 basepairs. Agarose can be used for electrophoretic separation in agarose gel electrophoresis or for column-based gel filtration chromatography.
## Culinary
Agar-Agar is the sea's natural gelatin. White and semi-translucent, it is sold in packages as washed and dried strips or in powdered form. It can be used to make jellies, puddings and custards. For making jelly, it is boiled in water until the solids dissolve. One then adds sweetener, flavouring, colouring, fruit or vegetables, and pours the liquid into molds to be served as desserts and vegetable aspics, or incorporated with other desserts, such as a jelly layer on a cake.
Agar-agar is approximately 80% fiber, so it can serve as a great intestinal regulator. Its bulk quality is behind one of the latest fad diets in Asia, the Kanten Diet. Once ingested, kanten triples in size and absorbs water. This results in the consumer feeling more full. Recently this diet has received some press coverage in the United States as well. The diet has shown promise in obesity studies.
In Indian cuisine, agar agar is known as "China Grass" and is used for making desserts.
## Plant biology
Research grade agar is used extensively in plant biology as it is supplemented with a nutrient and vitamin mixture that allows for seedling germination in petri dishes under sterile conditions (given that the seeds are sterilized as well). Nutrient and vitamin supplementation for Arabidopsis thaliana is standard across most experimental conditions. Murashige & Skoog (MS) nutrient mix and Gamborg's B5 vitamin mix are generally used. A 1.0% agar/0.44% MS+vitamin dH20 solution is suitable for growth media between normal growth temps.
The solidification of the agar within any growth media (GM) is pH-dependent, with an optimal range between 5.4-5.7. Usually, the application of KOH is needed to increase the pH to this range. A general guideline is about 600 µl 0.1M KOH per 250 ml GM. This entire mixture can be sterilised using the liquid cycle of an autoclave.
This medium nicely lends itself to the application of specific concentrations of phytohormones etc. to induce specific growth patterns in that you can easily prepare a solution containing the desired amount of hormone, add it to the known volume of GM and autoclave to both sterilize and evaporate off any solvent you may have used to dissolve the often polar hormones in. This hormone/GM solution can be spread across the surface of petri dishes sown with germinated and/or etiolated seedlings.
## Other
Agar is used as an impression material in dentistry. It is also used to make salt bridges for use in electrochemistry.
# Hysteresis
Hysteresis describes the phenomenon of the differing liquid-solid state transition temperatures that agar exhibits. Agar melts at 85 °C (358 K, 185 °F) and solidifies from 32-40 °C. (305 - 313 K, 90-104 °F) | https://www.wikidoc.org/index.php/Agar | |
277013232b90129fd9939884b517363d36908d56 | wikidoc | Aloe | Aloe
Aloe, also written Aloë, is a genus containing about four hundred species of flowering succulent plants.
The genus is native to Africa and is common in South Africa's Cape Province and the mountains of tropical Africa, and neighbouring areas such as Madagascar, the Arabian peninsula and the islands off Africa.
The APG II system (2003) placed the genus in the family Asphodelaceae. In the past it has also been assigned to families Aloaceae and Liliaceae. Members of the closely allied genera Gasteria, Haworthia and Kniphofia which have a similar mode of growth, are also popularly known as aloes. Note that the plant sometimes called "American aloe" (Agave americana), belongs to Agavaceae, a different family.
Most Aloes have a rosette of large, thick, fleshy leaves. The leaves are often lance-shaped with a sharp apex and a spiny margin. Aloe flowers are tubular, frequently yellow, orange or red and are borne on densely clustered, simple or branched leafless stems.
Many species of Aloe are seemingly stemless, with the rosette growing directly at ground level; other varieties may have a branched or un-branched stem from which the fleshy leaves spring. They vary in colour from grey to bright green and are sometimes striped or mottled.
# Uses
Aloe species are frequently cultivated as ornamental plants both in gardens and in pots. Many Aloe species are highly decorative and are valued by collectors of succulents. Some species, in particular Aloe vera are purported to have medicinal properties.
Other use of Aloes include their role in alternative medicines (see Herbalism) and in home first aid. Both the translucent inner pulp as well as the resinous yellow exudate from wounding the Aloe plant is used externally to relieve skin discomforts and internally as a laxative. To date, some research has shown that Aloe vera produces positive medicinal benefits for healing damaged skin. Conversely, other research suggests Aloe vera can negatively affect healing (Vogler and Ernst, 1999).
In homeopathic medicine aloe is used for hemorrhoids.
Some Aloe species have also been used for human consumption. For example, drinks made from or containing chunks of aloe pulp are popular in Asia as commercial beverages and as a tea additive; this is notably true in Korea.
## External uses
Aloe is used externally to treat a number of skin irritations. It has antiseptic and antibiotic properties which make it highly valuable in treating cuts and abrasions. It has also been commonly used to treat first and second degree burns, as well as sunburns and poison oak, poison ivy, and poison sumac infections, and eczema. It can also be used as a hair styling gel and works especially well for curly or fuzzy hair.
## Internal uses
Aloe contains a number of medicinal substances used as a purgative. The medicinal substance is produced from various species of aloe, such as A. vera, A. vulgaris, A. socotrina, A. chinensis, and A. perryi. Several kinds of aloes are commercially available: Barbadoes, Socotrine, Hepatic, Indian, and Cape aloes. Barbadoes and Socotrine are the varieties most commonly used for curative purposes.
Aloes are the expressed juice of the leaves of the plant. When the leaves are cut, the juice that flows out is collected and evaporated. After the juice has been removed, the leaves are sometimes boiled to yield an inferior kind of aloes. The juice of the leaves of certain species, e.g. Aloe venenosa, is poisonous.
There have been very few properly conducted studies about possible benefits of aloe gel taken internally. One study found improved wound healing in mice. Another found a positive effect of lowering risk factors in patients with heart disease. Some research has shown decreasing fasting blood sugar in diabetic animals given aloe . None of these studies can be considered to be definitive, and there are many false advertising claims for aloe.
Aloe has been marketed as a remedy for coughs, wounds, ulcers, gastritis, diabetes, cancer, headaches, arthritis, immune-system deficiencies, and many other conditions when taken internally. However, these uses are unsubstantiated; the only substantiated internal use is as a laxative. Furthermore, there is evidence of potential adverse side effects (for example, acute hepatitis). Although some studies suggest that certain components of aloe such as aloe-emodin have genotoxic activity, human clinical trials and rodent carcinogenicity studies do not substantiate a genotoxic risk to humans when aloe products are consumed as directedBrusick D, Mengs U (1997). "Assessment of the genotoxic risk from laxative senna products". Environ Mol Mutagen. 29 (1): 1–9. PMID 9020301..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}.
On May 9, 2002, the U.S. Food and Drug Administration issued a final rule banning the use of aloe and cascara sagrada as laxative ingredients in over-the-counter drug products.
## Chemical properties of Aloin
According to W. A. Shenstone, two classes of Aloins are to be recognized: (1) nataloins, which yield picric and oxalic acids with nitric acid, and do not give a red coloration with nitric acid; and (2) barbaloins, which yield aloetic acid (C7H2N3O5), chrysammic acid (C7H2N2O6), picric and oxalic acids with nitric acid, being reddened by the acid. This second group may be divided into a-barbaloins, obtained from Barbadoes aloes, and reddened in the cold, and b-barbaloins, obtained from Socotrine and Zanzibar aloes, reddened by ordinary nitric acid only when warmed or by fuming acid in the cold. Nataloin (2C17H13O7·H2O) forms bright yellow scales. Barbaloin (C17H18O7) forms yellow prismatic crystals. Aloes also contain a trace of volatile oil, to which its odour is due. | Aloe
Aloe, also written Aloë, is a genus containing about four hundred species of flowering succulent plants.
The genus is native to Africa and is common in South Africa's Cape Province and the mountains of tropical Africa, and neighbouring areas such as Madagascar, the Arabian peninsula and the islands off Africa.
The APG II system (2003) placed the genus in the family Asphodelaceae. In the past it has also been assigned to families Aloaceae and Liliaceae. Members of the closely allied genera Gasteria, Haworthia and Kniphofia which have a similar mode of growth, are also popularly known as aloes. Note that the plant sometimes called "American aloe" (Agave americana), belongs to Agavaceae, a different family.
Most Aloes have a rosette of large, thick, fleshy leaves. The leaves are often lance-shaped with a sharp apex and a spiny margin. Aloe flowers are tubular, frequently yellow, orange or red and are borne on densely clustered, simple or branched leafless stems.
Many species of Aloe are seemingly stemless, with the rosette growing directly at ground level; other varieties may have a branched or un-branched stem from which the fleshy leaves spring. They vary in colour from grey to bright green and are sometimes striped or mottled.
# Uses
Aloe species are frequently cultivated as ornamental plants both in gardens and in pots. Many Aloe species are highly decorative and are valued by collectors of succulents. Some species, in particular Aloe vera are purported to have medicinal properties.
Other use of Aloes include their role in alternative medicines (see Herbalism) and in home first aid. Both the translucent inner pulp as well as the resinous yellow exudate from wounding the Aloe plant is used externally to relieve skin discomforts and internally as a laxative. To date, some research has shown that Aloe vera produces positive medicinal benefits for healing damaged skin. Conversely, other research suggests Aloe vera can negatively affect healing (Vogler and Ernst, 1999).
In homeopathic medicine aloe is used for hemorrhoids[1].
Some Aloe species have also been used for human consumption. For example, drinks made from or containing chunks of aloe pulp are popular in Asia as commercial beverages and as a tea additive; this is notably true in Korea.
## External uses
Aloe is used externally to treat a number of skin irritations. It has antiseptic and antibiotic properties which make it highly valuable in treating cuts and abrasions. It has also been commonly used to treat first and second degree burns, as well as sunburns and poison oak, poison ivy, and poison sumac infections, and eczema. It can also be used as a hair styling gel and works especially well for curly or fuzzy hair.
## Internal uses
Aloe contains a number of medicinal substances used as a purgative. The medicinal substance is produced from various species of aloe, such as A. vera, A. vulgaris, A. socotrina, A. chinensis, and A. perryi. Several kinds of aloes are commercially available: Barbadoes, Socotrine, Hepatic, Indian, and Cape aloes. Barbadoes and Socotrine are the varieties most commonly used for curative purposes[citation needed].
Aloes are the expressed juice of the leaves of the plant. When the leaves are cut, the juice that flows out is collected and evaporated. After the juice has been removed, the leaves are sometimes boiled to yield an inferior kind of aloes. The juice of the leaves of certain species, e.g. Aloe venenosa, is poisonous.
There have been very few properly conducted studies about possible benefits of aloe gel taken internally. One study found improved wound healing in mice. Another found a positive effect of lowering risk factors in patients with heart disease. Some research has shown decreasing fasting blood sugar in diabetic animals given aloe [1]. None of these studies can be considered to be definitive, and there are many false advertising claims for aloe.
Aloe has been marketed as a remedy for coughs, wounds, ulcers, gastritis, diabetes, cancer, headaches, arthritis, immune-system deficiencies, and many other conditions when taken internally. However, these uses are unsubstantiated; the only substantiated internal use is as a laxative. Furthermore, there is evidence of potential adverse side effects (for example, acute hepatitis[2]). Although some studies suggest that certain components of aloe such as aloe-emodin have genotoxic activity, human clinical trials and rodent carcinogenicity studies do not substantiate a genotoxic risk to humans when aloe products are consumed as directedBrusick D, Mengs U (1997). "Assessment of the genotoxic risk from laxative senna products". Environ Mol Mutagen. 29 (1): 1–9. PMID 9020301..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}.
On May 9, 2002, the U.S. Food and Drug Administration issued a final rule banning the use of aloe and cascara sagrada as laxative ingredients in over-the-counter drug products[2].
## Chemical properties of Aloin
According to W. A. Shenstone, two classes of Aloins are to be recognized: (1) nataloins, which yield picric and oxalic acids with nitric acid, and do not give a red coloration with nitric acid; and (2) barbaloins, which yield aloetic acid (C7H2N3O5), chrysammic acid (C7H2N2O6), picric and oxalic acids with nitric acid, being reddened by the acid. This second group may be divided into a-barbaloins, obtained from Barbadoes aloes, and reddened in the cold, and b-barbaloins, obtained from Socotrine and Zanzibar aloes, reddened by ordinary nitric acid only when warmed or by fuming acid in the cold. Nataloin (2C17H13O7·H2O) forms bright yellow scales. Barbaloin (C17H18O7) forms yellow prismatic crystals. Aloes also contain a trace of volatile oil, to which its odour is due.[citation needed] | https://www.wikidoc.org/index.php/Aloe | |
bf0b0dd88525b3b81db3928f73171fe6837f2991 | wikidoc | Alum | Alum
Alum, (Template:IPAEng) refers to a specific chemical compound and a class of chemical compounds. The specific compound is the hydrated aluminum potassium sulfate with the formula KAl(SO4)2.12H2O. The class of compounds known as alums have the related stoichiometry, AB(SO4)2.12H2O.
# Crystal chemistry of the alums
Double sulfates with the general formula A2SO4·B2(SO4)3·24H2O, are known where A is a monovalent cation such as sodium, potassium, rubidium, caesium, or thallium(I), or a compound cation such as ammonium (NH4+), methylammonium(CH3NH3+), hydroxylammonium (HONH3+) or hydrazinium (N2H5+), B is a trivalent metal ion, such as aluminium, chromium, titanium, manganese, vanadium, iron (III), cobalt(III), gallium, molybdenum, indium, ruthenium, rhodium or iridium. The specific combinations of univalent cation, trivalent cation and anion depends on the sizes of the ions. For example, unlike the other alkali metals the small lithium ion does not form alums, and there is only one sodium alum. In some case solid solutions of alums occur.
Alums crystallise in one of three different crystal structures. These classes are called α-, β- and γ-alums.
# Applications
Alums are useful for a range of industrial processes. They are soluble in water; have an astringent, acid, and sweetish taste; react acid to litmus; and crystallize in regular octahedra. When heated they liquefy; and if the heating is continued, the water of crystallization is driven off, the salt froths and swells, and at last an amorphous powder remains.
Potassium alum is the common alum of commerce, although soda alum, ferric alum, and ammonium alum are manufactured.
Aluminium sulfate is sometimes called alum in informal contexts, but this usage is not regarded as technically correct. Its properties are quite different from those of the set of alums formally described above.
# Alchemical and later discoveries and uses
The presence of sulfuric acid in potassium alum was known to the alchemists. J. H. Pott and A. S. Marggraf demonstrated that alumina was another constituent. Pott in his Lithogeognosia showed that the precipitate obtained when an alkali is poured into a solution of alum is quite different from lime and chalk, with which it had been confounded by G.E. Stahl. Marggraf showed that alumina is one of the constituents of alum, but that this earth possesses peculiar properties, and is one of the ingredients in common clay. He also showed that crystals of alum cannot be obtained by dissolving alumina in sulfuric acid and evaporating the solutions, but when a solution of potash or ammonia is dropped into this liquid, it immediately deposits perfect crystals of alum.
Torbern Bergman also observed that the addition of potash or ammonia made the solution of alumina in sulfuric acid crystallize, but that the same effect was not produced by the addition of soda or of lime, and that potassium sulfate is frequently found in alum.
After M.H. Klaproth had discovered the presence of potassium in leucite and lepidolite, it occurred to L.N. Vauquelin that it was probably an ingredient likewise in many other minerals. Knowing that alum cannot be obtained in crystals without the addition of potash, he began to suspect that this alkali constituted an essential ingredient in the salt, and in 1797 he published a dissertation demonstrating that alum is a double salt, composed of sulfuric acid, alumina, and potash. Soon after, J.A. Chaptal published the analysis of four different kinds of alum, namely, Roman alum, Levant alum, British alum and alum manufactured by himself. This analysis led to the same result as Vauquelin.
## Pliny's writings
The word "alumen," which we translate "alum," occurs in Pliny's Natural History. In the 15th chapter of his 35th book he gives a detailed description of it. By comparing this with the account of stupteria given by Dioscorides in the 123rd chapter of his 5th book, it is obvious that the two are identical. Pliny informs us that alumen was found naturally in the earth. He calls it salsugoterrae. Different substances were distinguished by the name of "alumen"; but they were all characterized by a certain degree of astringency, and were all employed in dyeing and medicine, the light-colored alumen being useful in brilliant dyes, the dark-colored only in dyeing black or very dark colors. One species was a liquid, which was apt to be adulterated; but when pure it had the property of blackening when added to pomegranate juice. This property seems to characterize a solution of iron sulfate in water; a solution of ordinary (potassium) alum would possess no such property. Pliny says that there is another kind of alum that the Greeks call schistos. It forms in white threads upon the surface of certain stones. From the name schistos, and the mode of formation, there can be little doubt that this species was the salt which forms spontaneously on certain salty minerals, as alum slate and bituminous shale, and which consists chiefly of sulfates of iron and aluminium. Possibly in certain places the iron sulfate may have been nearly wanting, and then the salt would be white, and would answer, as Pliny says it did, for dyeing bright colors. Several other species of alumen are described by Pliny, but we are unable to make out to what minerals he alludes.
The alumen of the ancients, then, was not the same as the alum of the moderns. It was most commonly an iron sulfate, sometimes probably an aluminium sulfate, and usually a mixture of the two. But the ancients were unacquainted with our alum. They were acquainted with a crystallized iron sulfate, and distinguished it by the names of misy, sory, and chalcanthum. As alum and green vitriol were applied to a variety of substances in common, and as both are distinguished by a sweetish and astringent taste, writers, even after the discovery of alum, do not seem to have discriminated the two salts accurately from each other. In the writings of the alchemists we find the words misy, sory, chalcanthum applied to alum as well as to iron sulfate; and the name atramentum sutorium, which ought to belong, one would suppose, exclusively to green vitriol, applied indifferently to both. Various minerals are employed in the manufacture of alum, the most important being alunite or alum-stone, alum schist,
bauxite and cryolite.
## Early uses in industry
Alum was imported into England mainly from the Middle East, and, from the late 15th Century onwards, the Papal States for hundreds of years. Its use there was as a dye-fixer (mordant) for wool (which was one of England's primary industries), the value of which increased significantly if dyed. These sources were unreliable, however, and there was a push to develop a source in England. With state financing, attempts were made throughout the 16th Century, but without success until early on in the 17th Century. An industry was founded in Yorkshire to process the shale which contained the key ingredient, aluminium sulfate, and made an important contribution to the Industrial Revolution.
Alum (Known as turti in local Indian languages) was also used for water treatment by Indians for hundreds of years.
# Production
## Alum from alunite
In order to obtain alum from alunite, it is calcined and then exposed to the action of air for a considerable time. During this exposure it is kept continually moistened with water, so that it ultimately falls to a very fine powder. This powder is then lixiviated with hot water, the
liquor decanted, and the alum allowed to crystallize. The alum schists employed in the manufacture of alum are mixtures of iron pyrite, aluminium silicate and various bituminous substances, and are found in upper Bavaria, Bohemia, Belgium, and Scotland. These are either roasted or exposed to the weathering action of the air. In the roasting process, sulfuric acid is formed and acts on the clay to form aluminium sulfate, a similar condition of affairs being produced during weathering. The mass is now systematically extracted with water, and a solution of aluminium sulfate of specific gravity 1.16 is prepared. This solution is allowed to stand for some time (in order that any calcium sulfate and basic ferric sulfate may separate), and is then evaporated until ferrous sulfate crystallizes on cooling; it is then drawn off and evaporated until it attains a specific gravity of 1.40. It is now allowed to stand for some time, decanted from any sediment, and finally mixed with the calculated quantity of potassium sulfa te (or if ammonium alum is required, with ammonium sulfate), well agitated, and the alum is thrown down as a finely-divided precipitate of alum meal. If much iron should be present in the shale then it is preferable to use potassium chloride in place of potassium sulfate.
## Alum from clays or bauxite
In the preparation of alum from clays or from bauxite, the material is gently calcined, then mixed with sulfuric acid and heated gradually to boiling; it is allowed to stand for some time, the clear solution drawn off and mixed with acid potassium sulfate and allowed to crystallize. When cryolite is used for the preparation of alum, it is mixed with calcium carbonate and heated. By this means, sodium aluminate is formed; it is then extracted with water and precipitated either by sodium bicarbonate or by passing a current of carbon dioxide through the solution. The precipitate is then dissolved in sulfuric acid, the requisite amount of potassium sulfate added and the solution allowed to crystallize.
# Types of alum
## Soda alum
Sodium alum, Na2SO4·Al2(SO4)3·24H2O, mainly occurs in nature as the mineral mendozite. It is very soluble in water, and is extremely difficult to purify. In the preparation of this salt, it is preferable to mix the component solutions in the cold, and to evaporate them at a temperature not exceeding 60 °C. 100 parts of water dissolve 110 parts of sodium alum at 0 °C, and 51 parts at 16 °C. Soda alum is used in the acidulent of food as well as in the manufacture of baking powder.
## Ammonium alum
Ammonia alum, NH4Al(SO4)2·12H2O, a white crystalline double sulfate of aluminium, is used in water purification, in vegetable glues, in porcelain cements, in natural deodorants (though potassium alum is more commonly used), in tanning, dyeing and in fireproofing textiles.
# Alum solubility
The solubility of the various alums in water varies greatly, sodium alum being readily soluble in water, while caesium and rubidium alums are only sparingly soluble. The various solubilities are shown in the following table.
# Selenate containing alumns
Alums are also known that contain selenium in place of sulfur. They are called selenium- or selenate-alums.
# Uses
Alum in Makeup: Alum was often used as a base in skin whiteners and treatments during the late 16th Century in the Elizabethan fashion. This is an example of a recipe:
"For the Freckles which one getteth by the heat of the Sun: Take a little Allom beaten small, temper amonst it a well brayed white of an egg, put it on a milde fire, stirring it always about that it wax not hard, and when it casteth up the scum, then it is enough, wherewith anoint the Freckles the space of three dayes: if you will defend your self that you get no Freckles on the face, then anoint your face with the whites of eggs."
Christopher Wirzung, General practise of Physicke, 1654.
- Shaving alum: is a powdered form of alum used as an astringent to prevent bleeding from small shaving cuts. The styptic pencils sold for this purpose contain aluminium sulfate or potassium aluminium sulfate. Similar products are also used on animals to prevent bleeding after nail-clipping. Alum in block form (usually potassium alum) is used as an aftershave, rubbed over the wet freshly shaved face.
- Hair Stiffener: Alum was used in rock form in the 1950's to rub on the front short hair of a "crewcut". When the hair dried, it would stay up all day.
- Crystal deodorant: Alum was used in the past as a natural underarm deodorant in Europe, Mexico, Thailand, the Far East and in the Philippines where it is called Tawas. It is now commercially sold for this purpose in many countries, often in a plastic case that protects the crystal and makes it resemble other non-liquid deodorants. Typically potassium alum is used.
- Alum powder, found amongst spices at most grocery stores, is used in pickling recipes as a preservative, to maintain crispness, and as an ingredient in some play dough recipes. It is also commonly cited as a home remedy or pain relief for canker sores.
- Fire retardant: By soaking and then drying cloth and paper materials they can be made fireproof.
- Wax: Alum is used in the Middle East as a component in wax, compounded with other ingredients to create a hair-removal substance.
- Foamite: Alum is used to make foamite which is used in many fire extinguishers for chemical and oil fires.
- Adjuvant: Alum is used regularly as an adjuvant (enhances immune response to a given immunogen when given with it) in human immunizations.
- Antibacterial agent: Alum works as a deodorant because Alum inhibits bacterial growth. This fits the definition of an antibacterial agent. Styptic pencils or Alum powder/crystals can be applied to cuts that have a mild infection.
# Related compounds
In addition to the alums, which are dodecahydrates, double sulfates and selenates of univalent and trivalent cations occur with other degrees of hydration. These materials may also be referred to as alums, including the undecahydrates such as mendozite and kalinite, hexahydrates such as guanidinium (CH6N3+) and dimethylammonium (CH3)2NH2+) "alums", tetrahydrates such as goldichite, monohydrates such as thallium plutonium sulphate and anhydrous alums (yavapaiites). These classes include differing, but overlapping, combinations of ions.
A pseudo alum is a double sulfate of the typical formula ASO4·B2(SO4)3·22H2O, where A is a divalent metal ion, such as cobalt (wupatkiite), manganese (apjohnite), magnesium (pickingerite) or iron (halotrichite or feather alum), and B is a trivalent metal ion.
A Tutton salt is a double sulfate of the typical formula A2SO4·BSO4·6H2O, where A is a univalent cation, and B a divalent metal ion.
# In popular culture
Gags in which someone ingests alum, either accidentally self-administered or surreptitiously administered by another, resulting in exaggerated effects, are a traditional staple of comedy. In live-action comedies, effects on the victim usually include extreme puckering of the mouth and lips and tightening of the throat. An example of this is in the Three Stooges short "No Census, No Feeling" when Curly is making a fruit punch and thinking it was sugar, puts alum in the fruit punch. In animated cartoons, the effects are normally expanded to include extreme shrinking of the head. | Alum
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Alum, (Template:IPAEng) refers to a specific chemical compound and a class of chemical compounds. The specific compound is the hydrated aluminum potassium sulfate with the formula KAl(SO4)2.12H2O. The class of compounds known as alums have the related stoichiometry, AB(SO4)2.12H2O.
# Crystal chemistry of the alums
Double sulfates with the general formula A2SO4·B2(SO4)3·24H2O, are known where A is a monovalent cation such as sodium, potassium, rubidium, caesium, or thallium(I), or a compound cation such as ammonium (NH4+), methylammonium(CH3NH3+), hydroxylammonium (HONH3+) or hydrazinium (N2H5+), B is a trivalent metal ion, such as aluminium, chromium, titanium, manganese, vanadium, iron (III), cobalt(III), gallium, molybdenum, indium, ruthenium, rhodium or iridium.[1] The specific combinations of univalent cation, trivalent cation and anion depends on the sizes of the ions. For example, unlike the other alkali metals the small lithium ion does not form alums, and there is only one sodium alum. In some case solid solutions of alums occur.
Alums crystallise in one of three different crystal structures. These classes are called α-, β- and γ-alums.
# Applications
Alums are useful for a range of industrial processes. They are soluble in water; have an astringent, acid, and sweetish taste; react acid to litmus; and crystallize in regular octahedra. When heated they liquefy; and if the heating is continued, the water of crystallization is driven off, the salt froths and swells, and at last an amorphous powder remains.
Potassium alum is the common alum of commerce, although soda alum, ferric alum, and ammonium alum are manufactured.
Aluminium sulfate is sometimes called alum in informal contexts, but this usage is not regarded as technically correct. Its properties are quite different from those of the set of alums formally described above.
# Alchemical and later discoveries and uses
The presence of sulfuric acid in potassium alum was known to the alchemists. J. H. Pott and A. S. Marggraf demonstrated that alumina was another constituent. Pott in his Lithogeognosia showed that the precipitate obtained when an alkali is poured into a solution of alum is quite different from lime and chalk, with which it had been confounded by G.E. Stahl. Marggraf showed that alumina is one of the constituents of alum, but that this earth possesses peculiar properties, and is one of the ingredients in common clay. He also showed that crystals of alum cannot be obtained by dissolving alumina in sulfuric acid and evaporating the solutions, but when a solution of potash or ammonia is dropped into this liquid, it immediately deposits perfect crystals of alum.
Torbern Bergman also observed that the addition of potash or ammonia made the solution of alumina in sulfuric acid crystallize, but that the same effect was not produced by the addition of soda or of lime, and that potassium sulfate is frequently found in alum.
After M.H. Klaproth had discovered the presence of potassium in leucite and lepidolite, it occurred to L.N. Vauquelin that it was probably an ingredient likewise in many other minerals. Knowing that alum cannot be obtained in crystals without the addition of potash, he began to suspect that this alkali constituted an essential ingredient in the salt, and in 1797 he published a dissertation demonstrating that alum is a double salt, composed of sulfuric acid, alumina, and potash. Soon after, J.A. Chaptal published the analysis of four different kinds of alum, namely, Roman alum, Levant alum, British alum and alum manufactured by himself. This analysis led to the same result as Vauquelin.
## Pliny's writings
The word "alumen," which we translate "alum," occurs in Pliny's Natural History. In the 15th chapter of his 35th book he gives a detailed description of it. By comparing this with the account of stupteria given by Dioscorides in the 123rd chapter of his 5th book, it is obvious that the two are identical. Pliny informs us that alumen was found naturally in the earth. He calls it salsugoterrae. Different substances were distinguished by the name of "alumen"; but they were all characterized by a certain degree of astringency, and were all employed in dyeing and medicine, the light-colored alumen being useful in brilliant dyes, the dark-colored only in dyeing black or very dark colors. One species was a liquid, which was apt to be adulterated; but when pure it had the property of blackening when added to pomegranate juice. This property seems to characterize a solution of iron sulfate in water; a solution of ordinary (potassium) alum would possess no such property. Pliny says that there is another kind of alum that the Greeks call schistos. It forms in white threads upon the surface of certain stones. From the name schistos, and the mode of formation, there can be little doubt that this species was the salt which forms spontaneously on certain salty minerals, as alum slate and bituminous shale, and which consists chiefly of sulfates of iron and aluminium. Possibly in certain places the iron sulfate may have been nearly wanting, and then the salt would be white, and would answer, as Pliny says it did, for dyeing bright colors. Several other species of alumen are described by Pliny, but we are unable to make out to what minerals he alludes.
The alumen of the ancients, then, was not the same as the alum of the moderns. It was most commonly an iron sulfate, sometimes probably an aluminium sulfate, and usually a mixture of the two. But the ancients were unacquainted with our alum. They were acquainted with a crystallized iron sulfate, and distinguished it by the names of misy, sory, and chalcanthum. As alum and green vitriol were applied to a variety of substances in common, and as both are distinguished by a sweetish and astringent taste, writers, even after the discovery of alum, do not seem to have discriminated the two salts accurately from each other. In the writings of the alchemists we find the words misy, sory, chalcanthum applied to alum as well as to iron sulfate; and the name atramentum sutorium, which ought to belong, one would suppose, exclusively to green vitriol, applied indifferently to both. Various minerals are employed in the manufacture of alum, the most important being alunite or alum-stone, alum schist,
bauxite and cryolite.
## Early uses in industry
Alum was imported into England mainly from the Middle East, and, from the late 15th Century onwards, the Papal States for hundreds of years. Its use there was as a dye-fixer (mordant) for wool (which was one of England's primary industries), the value of which increased significantly if dyed. These sources were unreliable, however, and there was a push to develop a source in England. With state financing, attempts were made throughout the 16th Century, but without success until early on in the 17th Century. An industry was founded in Yorkshire to process the shale which contained the key ingredient, aluminium sulfate, and made an important contribution to the Industrial Revolution.
Alum (Known as turti in local Indian languages) was also used for water treatment by Indians for hundreds of years.
# Production
## Alum from alunite
In order to obtain alum from alunite, it is calcined and then exposed to the action of air for a considerable time. During this exposure it is kept continually moistened with water, so that it ultimately falls to a very fine powder. This powder is then lixiviated with hot water, the
liquor decanted, and the alum allowed to crystallize. The alum schists employed in the manufacture of alum are mixtures of iron pyrite, aluminium silicate and various bituminous substances, and are found in upper Bavaria, Bohemia, Belgium, and Scotland. These are either roasted or exposed to the weathering action of the air. In the roasting process, sulfuric acid is formed and acts on the clay to form aluminium sulfate, a similar condition of affairs being produced during weathering. The mass is now systematically extracted with water, and a solution of aluminium sulfate of specific gravity 1.16 is prepared. This solution is allowed to stand for some time (in order that any calcium sulfate and basic ferric sulfate may separate), and is then evaporated until ferrous sulfate crystallizes on cooling; it is then drawn off and evaporated until it attains a specific gravity of 1.40. It is now allowed to stand for some time, decanted from any sediment, and finally mixed with the calculated quantity of potassium sulfa te (or if ammonium alum is required, with ammonium sulfate), well agitated, and the alum is thrown down as a finely-divided precipitate of alum meal. If much iron should be present in the shale then it is preferable to use potassium chloride in place of potassium sulfate.
## Alum from clays or bauxite
In the preparation of alum from clays or from bauxite, the material is gently calcined, then mixed with sulfuric acid and heated gradually to boiling; it is allowed to stand for some time, the clear solution drawn off and mixed with acid potassium sulfate and allowed to crystallize. When cryolite is used for the preparation of alum, it is mixed with calcium carbonate and heated. By this means, sodium aluminate is formed; it is then extracted with water and precipitated either by sodium bicarbonate or by passing a current of carbon dioxide through the solution. The precipitate is then dissolved in sulfuric acid, the requisite amount of potassium sulfate added and the solution allowed to crystallize.
# Types of alum
## Soda alum
Sodium alum, Na2SO4·Al2(SO4)3·24H2O, mainly occurs in nature as the mineral mendozite. It is very soluble in water, and is extremely difficult to purify. In the preparation of this salt, it is preferable to mix the component solutions in the cold, and to evaporate them at a temperature not exceeding 60 °C. 100 parts of water dissolve 110 parts of sodium alum at 0 °C, and 51 parts at 16 °C. Soda alum is used in the acidulent of food as well as in the manufacture of baking powder.
## Ammonium alum
Ammonia alum, NH4Al(SO4)2·12H2O, a white crystalline double sulfate of aluminium, is used in water purification, in vegetable glues, in porcelain cements, in natural deodorants (though potassium alum is more commonly used), in tanning, dyeing and in fireproofing textiles.
# Alum solubility
The solubility of the various alums in water varies greatly, sodium alum being readily soluble in water, while caesium and rubidium alums are only sparingly soluble. The various solubilities are shown in the following table.
# Selenate containing alumns
Alums are also known that contain selenium in place of sulfur. They are called selenium- or selenate-alums.
# Uses
Alum in Makeup: Alum was often used as a base in skin whiteners and treatments during the late 16th Century in the Elizabethan fashion. This is an example of a recipe:
"For the Freckles which one getteth by the heat of the Sun: Take a little Allom beaten small, temper amonst it a well brayed white of an egg, put it on a milde fire, stirring it always about that it wax not hard, and when it casteth up the scum, then it is enough, wherewith anoint the Freckles the space of three dayes: if you will defend your self that you get no Freckles on the face, then anoint your face with the whites of eggs."
Christopher Wirzung, General practise of Physicke, 1654.
- Shaving alum: is a powdered form of alum used as an astringent to prevent bleeding from small shaving cuts. The styptic pencils sold for this purpose contain aluminium sulfate or potassium aluminium sulfate. Similar products are also used on animals to prevent bleeding after nail-clipping. Alum in block form (usually potassium alum) is used as an aftershave, rubbed over the wet freshly shaved face.
- Hair Stiffener: Alum was used in rock form in the 1950's to rub on the front short hair of a "crewcut". When the hair dried, it would stay up all day.
- Crystal deodorant: Alum was used in the past as a natural underarm deodorant in Europe, Mexico, Thailand, the Far East and in the Philippines where it is called Tawas. It is now commercially sold for this purpose in many countries, often in a plastic case that protects the crystal and makes it resemble other non-liquid deodorants. Typically potassium alum is used.
- Alum powder, found amongst spices at most grocery stores, is used in pickling recipes as a preservative, to maintain crispness, and as an ingredient in some play dough recipes. It is also commonly cited as a home remedy or pain relief for canker sores.
- Fire retardant: By soaking and then drying cloth and paper materials they can be made fireproof.
- Wax: Alum is used in the Middle East as a component in wax, compounded with other ingredients to create a hair-removal substance.
- Foamite: Alum is used to make foamite which is used in many fire extinguishers for chemical and oil fires.
- Adjuvant: Alum is used regularly as an adjuvant (enhances immune response to a given immunogen when given with it) in human immunizations.
- Antibacterial agent: Alum works as a deodorant because Alum inhibits bacterial growth. This fits the definition of an antibacterial agent. Styptic pencils or Alum powder/crystals can be applied to cuts that have a mild infection.
# Related compounds
In addition to the alums, which are dodecahydrates, double sulfates and selenates of univalent and trivalent cations occur with other degrees of hydration. These materials may also be referred to as alums, including the undecahydrates such as mendozite and kalinite, hexahydrates such as guanidinium (CH6N3+) and dimethylammonium (CH3)2NH2+) "alums", tetrahydrates such as goldichite, monohydrates such as thallium plutonium sulphate and anhydrous alums (yavapaiites). These classes include differing, but overlapping, combinations of ions.
A pseudo alum is a double sulfate of the typical formula ASO4·B2(SO4)3·22H2O, where A is a divalent metal ion, such as cobalt (wupatkiite), manganese (apjohnite), magnesium (pickingerite) or iron (halotrichite or feather alum), and B is a trivalent metal ion.
A Tutton salt is a double sulfate of the typical formula A2SO4·BSO4·6H2O, where A is a univalent cation, and B a divalent metal ion.
# In popular culture
Gags in which someone ingests alum, either accidentally self-administered or surreptitiously administered by another, resulting in exaggerated effects, are a traditional staple of comedy. In live-action comedies, effects on the victim usually include extreme puckering of the mouth and lips and tightening of the throat. An example of this is in the Three Stooges short "No Census, No Feeling" when Curly is making a fruit punch and thinking it was sugar, puts alum in the fruit punch. In animated cartoons, the effects are normally expanded to include extreme shrinking of the head. | https://www.wikidoc.org/index.php/Alum | |
649dda07bd68c064b6dc8790d84b0a362668c3a6 | wikidoc | Anus | Anus
# Overview
In anatomy, the anus (from Latin ānus "ring (circle), anus") is the external opening of the rectum. Closure is controlled by sphincter muscles. Feces are expelled from the body through the anus during the act of defecation, which is the primary function of the anus. Most animals—from simple worms to elephants and humans—have a tubular gut, with a mouth at one end and an anus at the other.
The anus plays a role in sexuality, though attitudes towards anal sex vary and it is even illegal in some countries. The anus is also the site of potential infections and other conditions including cancer. The subject is often considered a taboo part of the body, and it is known by a large number of usually vulgar slang terms. The traditional polite synonym for anus was fundament, though this euphemism is rarely heard now that medical terms are widely acceptable.
# Role in defecation
Intra-rectal pressure builds as the rectum fills with feces, pushing the feces against the walls of the anal canal. Contractions of abdominal and pelvic floor muscles can create intra-abdominal pressure which further increases intra-rectal pressure. The internal anal sphincter (an involuntary muscle) responds to the pressure by relaxing, thus allowing the feces to enter the canal. The rectum shortens as feces are pushed into the anal canal and peristaltic waves push the feces out of the rectum. Relaxation of the internal and external anal sphincters allows the feces to exit from the anus, finally, as the levator ani muscles pull the anus up over the exiting feces.
To prevent diseases of the anus and to promote general hygiene, humans often clean the exterior of the anus after emptying the bowels. A rinse with water from a bidet or a wipe with toilet paper are often used for this purpose.
# Role in sexuality
The anus has a relatively high concentration of nerve endings and is an erogenous zone. Sigmund Freud's theory of psychosexual development, for example, described an anal stage, hypothesizing that toddlers derive pleasure from retaining and expelling feces. This is the source of the term "anal" and the derived, derogatory vulgarism "anal-retentive".
Anal intercourse can be pleasurable for both the insertive partner and the receptive partner. For the receptive partner, pleasure from anal intercourse is also thought to be related to the shared wall between the rectum and the vagina (for females) as well as the G-spot or prostate (for males). For the insertive partner, the tightness of the anus is often said to be a source of pleasure in penetrative anal sex.
Anal intercourse, sometimes referred to as sodomy or buggery, is a human sexual activity, but is considered taboo in a number of moral systems, and it has been, and in some jurisdictions continues to be, a crime carrying severe punishment.
Anal sexual activity need not include penetration. The anus also plays an important role in facesitting, coprophilia and anilingus.
Anal stretching can stimulate the nerves around the anus and can be considered pleasurable. Care must be taken to maintain elasticity.
Lubricant is widely regarded as a necessity while performing anal sex.
# Puberty
During puberty, as testosterone triggers androgenic hair growth on the body, pubic hair begins to appear around the anus. Although initially sparse, it fills out by the end of puberty, if not earlier.
# Health
Hygiene is important for good anal health and anal sex. Washing with a mild soap and water will keep the anus clean. Harsh soaps or wiping vigorously with toilet paper can irritate the skin around the anus, making it itchy or sore. Pinworms are sometimes the source of anal itching.
Care should be taken not to strip the anus of natural oils that keep the skin around the opening supple and elastic.
Penetration with a penis or sex toy can irritate or tear the inside of the anus. Lubrication is often recommended to ease penetration. The risk of injury to the anal sphincter should be a concern. Similarly if the anus is torn, this can occasionally cause a fistula formation which can not only cause fecal leaking, but also can be very difficult to treat.
Kegel exercises can improve the tone of the outer sphincter muscle.
# Cosmetics
Shaving, trimming, depilatory (hair removal), or Brazilian waxing can clear the perineum of hair.
Anal bleaching is a process in which the anus and perineum, which may darken with puberty depending on individual genetics, is lightened for a more youthful appearance. This practice has been linked to skin cancer, and other health problems.
True Anal piercing is rare because it may interfere with the function of the anus, however surface piercings of the perineum are easier to care for and much more common.
# Pathology
Diseases of the anus include anal cancer, abscess, warts, fistula, anal fissure, itching and hemorrhoid. The anus is also a frequent site of sexually transmitted infections. These benefit from medical intervention.
Birth defects of the anus include stenosis and imperforation. These benefit from surgical intervention.
Damaged anal sphincter (patulous anus in more severe cases) — caused by careless or sometimes necessarily sacrificial surgery in the perineal region or by rough/abrupt penetration in anal sex — can lead to flatus and/or fecal incontinence, chronic constipation and, ultimately, megacolon.
In psychology the Freudian term anal fixation is used.
# Additional images
- Muscles of the male perineum
- Muscles of the female perineum
- The posterior aspect of the rectum and anus exposed by removing the lower part of the sacrum and the coccyx | Anus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In anatomy, the anus (from Latin ānus "ring (circle)[1][2], anus") is the external opening of the rectum. Closure is controlled by sphincter muscles. Feces are expelled from the body through the anus during the act of defecation, which is the primary function of the anus. Most animals—from simple worms to elephants and humans—have a tubular gut, with a mouth at one end and an anus at the other.
The anus plays a role in sexuality, though attitudes towards anal sex vary and it is even illegal in some countries. The anus is also the site of potential infections and other conditions including cancer. The subject is often considered a taboo part of the body, and it is known by a large number of usually vulgar slang terms. The traditional polite synonym for anus was fundament, though this euphemism is rarely heard now that medical terms are widely acceptable.
# Role in defecation
Intra-rectal pressure builds as the rectum fills with feces, pushing the feces against the walls of the anal canal. Contractions of abdominal and pelvic floor muscles can create intra-abdominal pressure which further increases intra-rectal pressure. The internal anal sphincter (an involuntary muscle) responds to the pressure by relaxing, thus allowing the feces to enter the canal. The rectum shortens as feces are pushed into the anal canal and peristaltic waves push the feces out of the rectum. Relaxation of the internal and external anal sphincters allows the feces to exit from the anus, finally, as the levator ani muscles pull the anus up over the exiting feces.
To prevent diseases of the anus and to promote general hygiene, humans often clean the exterior of the anus after emptying the bowels. A rinse with water from a bidet or a wipe with toilet paper are often used for this purpose.
# Role in sexuality
The anus has a relatively high concentration of nerve endings and is an erogenous zone. Sigmund Freud's theory of psychosexual development, for example, described an anal stage, hypothesizing that toddlers derive pleasure from retaining and expelling feces. This is the source of the term "anal" and the derived, derogatory vulgarism "anal-retentive".
Anal intercourse can be pleasurable for both the insertive partner and the receptive partner. For the receptive partner, pleasure from anal intercourse is also thought to be related to the shared wall between the rectum and the vagina (for females) as well as the G-spot or prostate (for males). For the insertive partner, the tightness of the anus is often said to be a source of pleasure in penetrative anal sex.
Anal intercourse, sometimes referred to as sodomy or buggery, is a human sexual activity, but is considered taboo in a number of moral systems, and it has been, and in some jurisdictions continues to be, a crime carrying severe punishment.
Anal sexual activity need not include penetration. The anus also plays an important role in facesitting, coprophilia and anilingus.
Anal stretching can stimulate the nerves around the anus and can be considered pleasurable. Care must be taken to maintain elasticity.
Lubricant is widely regarded as a necessity while performing anal sex.
# Puberty
During puberty, as testosterone triggers androgenic hair growth on the body, pubic hair begins to appear around the anus. Although initially sparse, it fills out by the end of puberty, if not earlier.
# Health
Hygiene is important for good anal health and anal sex. Washing with a mild soap and water will keep the anus clean. Harsh soaps or wiping vigorously with toilet paper can irritate the skin around the anus, making it itchy or sore. Pinworms are sometimes the source of anal itching.
Care should be taken not to strip the anus of natural oils that keep the skin around the opening supple and elastic.
Penetration with a penis or sex toy can irritate or tear the inside of the anus. Lubrication is often recommended to ease penetration. The risk of injury to the anal sphincter should be a concern. Similarly if the anus is torn, this can occasionally cause a fistula formation which can not only cause fecal leaking, but also can be very difficult to treat.
Kegel exercises can improve the tone of the outer sphincter muscle.
# Cosmetics
Shaving, trimming, depilatory (hair removal), or Brazilian waxing can clear the perineum of hair.
Anal bleaching is a process in which the anus and perineum, which may darken with puberty depending on individual genetics, is lightened for a more youthful appearance. This practice has been linked to skin cancer, and other health problems.
True Anal piercing is rare because it may interfere with the function of the anus, however surface piercings of the perineum are easier to care for and much more common.
# Pathology
Diseases of the anus include anal cancer, abscess, warts, fistula, anal fissure, itching and hemorrhoid. The anus is also a frequent site of sexually transmitted infections. These benefit from medical intervention.
Birth defects of the anus include stenosis and imperforation. These benefit from surgical intervention.
Damaged anal sphincter (patulous anus in more severe cases) — caused by careless or sometimes necessarily sacrificial surgery in the perineal region or by rough/abrupt penetration in anal sex — can lead to flatus and/or fecal incontinence, chronic constipation and, ultimately, megacolon.
In psychology the Freudian term anal fixation is used.
# Additional images
- Muscles of the male perineum
- Muscles of the female perineum
- The posterior aspect of the rectum and anus exposed by removing the lower part of the sacrum and the coccyx | https://www.wikidoc.org/index.php/Anal | |
16b79687b23c710dd65fc9d620771f63b92fcb84 | wikidoc | Bite | Bite
# Overview
A bite is a wound received from the mouth (and in particular, the teeth) of an animal or person. Most animal bites are from dogs or cats, and the pathogens in the wound are composed by the normal oral flora of the biting animal and human skin flora.
Animals may bite in self-defense, in an attempt to predate food, as well as part of normal interactions. Other bite attacks may be apparently unprovoked, especially in the case of bites committed by psychologically or emotionally disturbed humans. Some disorders such as Lesch-Nyhan syndrome may cause people to bite themselves.
Bite wounds can be very complex and it is important to address the following aspects:
- Generalized tissue damage due to tearing and scratching.
- Serious hemorrhage if major blood vessels are pierced.
- Infection by bacteria or other pathogens, including rabies.
- Introduction of venom into the wound by venomous animals such as some snakes.
- Introduction of other irritants into the wound, causing inflammation and itching.
# Common Pathogens
Almost every bite will have a polimicrobial contamination and some bites have characteristic pathogens associated to the oral flora of the animal that bit.
# Treatment
- All bite wounds should be cleaned profusely with iodide soap and water.
- Bites are contaminated by a polimicrobial flora and antibiotic prophylaxis treatment is recommended to avoid subsequent infection.
- The route of administration depends on the depth and severity of the wound, as well as the time that has passed since the bite.
## Antibiotic TherapyAdapted from Guidelines for Skin and Soft-Tissue Infections CID 2005
▸ Click on the following categories to expand treatment regimens.
# Vaccination
## Tetanus Prophylaxis Adapted from CDC Vaccines and Immunizations - Tetanus
The need for active immunization, with or without passive immunization, depends on the condition of the wound and the patient’s immunization history.
The following table summarizes the indications for tetanus prophylaxis.
## Rabies Prophylaxis Adapted from CDC - ACIP Recommendations for postexposure prophylaxis (PEP) to prevent human rabies.
Animal bites inflicted by carnivores (except rodents) are considered possible cases of rabies. The animal is caught alive or dead with its head preserved, so the head can later be analyzed to detect the disease.
If the animal lives for ten days and does not develop rabies, then it is probable that no rabies infection has occurred.
If the animal is gone, prophylactic rabies treatment is recommended.
Signs of animal rabies include:
- Foaming at the mouth
- Self-mutilation
- Growling
- Jerky behavior
- Red eyes.
▸ Click on the following categories to expand prophylactic regimens.
# Post Exposure Measures
## Minor wounds
- Wash the wound thoroughly with soap and water.
- Apply an antibiotic cream.
- Cover the wound with a clean bandage.
- See a healthcare provider if the wound becomes red, painful, warm, or swollen; if you develop a fever; or if the dog that bit you was acting strangely.
## Deep wounds
- Apply pressure with a clean, dry cloth to stop the bleeding.
- If you cannot stop the bleeding or you feel faint or weak, call 911 or your local emergency medical services immediately.
- See a healthcare provider as soon as possible.
# See Also
- Snakebite
- Spider bite
- Wilderness first aid
- Insect bites and stings | Bite
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]
# Overview
A bite is a wound received from the mouth (and in particular, the teeth) of an animal or person. Most animal bites are from dogs or cats, and the pathogens in the wound are composed by the normal oral flora of the biting animal and human skin flora.
Animals may bite in self-defense, in an attempt to predate food, as well as part of normal interactions. Other bite attacks may be apparently unprovoked, especially in the case of bites committed by psychologically or emotionally disturbed humans. Some disorders such as Lesch-Nyhan syndrome may cause people to bite themselves.
Bite wounds can be very complex and it is important to address the following aspects:
- Generalized tissue damage due to tearing and scratching.
- Serious hemorrhage if major blood vessels are pierced.
- Infection by bacteria or other pathogens, including rabies.
- Introduction of venom into the wound by venomous animals such as some snakes.
- Introduction of other irritants into the wound, causing inflammation and itching.
# Common Pathogens
Almost every bite will have a polimicrobial contamination and some bites have characteristic pathogens associated to the oral flora of the animal that bit.
# Treatment
- All bite wounds should be cleaned profusely with iodide soap and water.
- Bites are contaminated by a polimicrobial flora and antibiotic prophylaxis treatment is recommended to avoid subsequent infection.
- The route of administration depends on the depth and severity of the wound, as well as the time that has passed since the bite.
## Antibiotic TherapyAdapted from Guidelines for Skin and Soft-Tissue Infections CID 2005[1]
▸ Click on the following categories to expand treatment regimens.
# Vaccination
## Tetanus Prophylaxis Adapted from CDC Vaccines and Immunizations - Tetanus [6]
The need for active immunization, with or without passive immunization, depends on the condition of the wound and the patient’s immunization history.
The following table summarizes the indications for tetanus prophylaxis.
## Rabies Prophylaxis Adapted from CDC - ACIP Recommendations for postexposure prophylaxis (PEP) to prevent human rabies.[7]
Animal bites inflicted by carnivores (except rodents) are considered possible cases of rabies. The animal is caught alive or dead with its head preserved, so the head can later be analyzed to detect the disease.
If the animal lives for ten days and does not develop rabies, then it is probable that no rabies infection has occurred.
If the animal is gone, prophylactic rabies treatment is recommended.
Signs of animal rabies include:
- Foaming at the mouth
- Self-mutilation
- Growling
- Jerky behavior
- Red eyes.
▸ Click on the following categories to expand prophylactic regimens.
# Post Exposure Measures
## Minor wounds
- Wash the wound thoroughly with soap and water.
- Apply an antibiotic cream.
- Cover the wound with a clean bandage.
- See a healthcare provider if the wound becomes red, painful, warm, or swollen; if you develop a fever; or if the dog that bit you was acting strangely.
## Deep wounds
- Apply pressure with a clean, dry cloth to stop the bleeding.
- If you cannot stop the bleeding or you feel faint or weak, call 911 or your local emergency medical services immediately.
- See a healthcare provider as soon as possible.[8]
# See Also
- Snakebite
- Spider bite
- Wilderness first aid
- Insect bites and stings | https://www.wikidoc.org/index.php/Animal_bite | |
14fb61df27cb65571850aea1f090090308f4a79f | wikidoc | H2N2 | H2N2
H2N2 is a subtype of the species Influenza A virus (sometimes called bird flu virus). H2N2 has mutated into various strains including the Asian Flu strain (now extinct in the wild), H3N2, and various strains found in birds. It is also suspected of causing a human pandemic in 1889.
# Asian flu
The "Asian Flu" was a category 2 flu pandemic outbreak of avian influenza that originated in China in early 1956 lasting until 1958. It originated from mutation in wild ducks combining with a pre-existing human strain. The virus was first identified in Guizhou. It spread to Singapore in February 1957, reached Hong Kong by April, and US by June. Death toll in the US was approximately 69,800. Estimates of worldwide infection rate varies widely depending on source, ranging from 1 million to 4 million.
Asian Flu was of the H2N2 strain (a notation that refers to the configuration of the hemagglutinin and neuraminidase proteins in the virus) of type A influenza, and a flu vaccine was developed in 1957 to contain its outbreak.
The Asian Flu strain later evolved via antigenic shift into H3N2 which caused a milder pandemic from 1968 to 1969.
Both the H2N2 and H3N2 pandemic strains contained Avian flu virus RNA segments. "While the pandemic human influenza viruses of 1957 (H2N2) and 1968 (H3N2) clearly arose through reassortment between human and avian viruses, the influenza virus causing the 'Spanish flu' in 1918 appears to be entirely derived from an avian source (Belshe 2005)."
# Test kits
From October 2004 to February 2005, some 3,700 test kits of the 1957 H2N2 virus were accidentally spread around the world from the College of American Pathologists (CAP). CAP assists laboratories in accuracy by providing unidentified samples of viruses; private contractor Meridian Bioscience in Cincinnati, U.S., chose the 1957 strand instead of one of the less deadly avian influenza virus subtypes. "CAP spokesman Dr. Jared Schwartz said Meridian knew what the virus was but believed it was safe. In selecting it, the company had determined that the virus was classified as a biosafety level 2 (BSL-2) agent, which meant it could legally be used in the kits. Before the problem came to light, the CDC had made a recommendation that the H2N2 virus be reclassified as a BSL-3 agent, Gerberding said. She promised to speed up the reclassification. The CDC determines the classifications in collaboration with the National Institutes of Health. In BSL-3 labs, agents are handled with equipment designed to prevent any airborne contamination and resulting respiratory exposure." The 1957 H2N2 virus is considered deadly and the U.S. government called for the vials containing the strain to be destroyed.
"CDC officials reported on April 21 that 99% of the samples had already been destroyed. News reports on April 25 said the last samples outside the United States had been destroyed at the American University of Beirut in Lebanon, after they were found at the Beirut airport. Earlier reports said H2N2 samples were sent to 3,747 labs under CAP auspices and to about another 2,700 labs certified by other organizations. All but about 75 labs that received the CAP samples were in the United States."
"In the United States, there is no government regulation over the 1957 flu strain. In fact, federal officials at the CDC do not even know how many U.S. laboratories keep this deadly strain in their viral libraries."
# Sources
- ↑ Sdstate.edu
- ↑ Pilva.com
- ↑ Jump up to: 3.0 3.1 Greene Jeffrey. Moline, Karen. (2006) The Bird Flu Pandemic. ISBN 0312360568.
- ↑ Goldsmith, Connie. (2007) Influenza: The Next Pandemic? 21st century publishing. ISBN 0761394575
- ↑ Starling, Arthur. (2006) Plague, SARS, and the Story of Medicine in Hong Kong. HK University Press. ISBN 9622098053
- ↑ Chapter Two : Avian Influenza by Timm C. Harder and Ortrud Werner from excellent free on-line Book called Influenza Report 2006 which is a medical textbook that provides a comprehensive overview of epidemic and pandemic influenza.
- ↑ Cidrap UMN.edu
- ↑ Flu.org
- ↑ Globalist.com
# Further reading
- Pandemic preparedness: lessons learnt from H2N2 and H9N2 candidate vaccines
- Interim CDC-NIH Recommendation for Raising the Biosafety Level for Laboratory Work Involving Noncontemporary Human Influenza Viruses
- New Scientist: Bird Flu
- Pandemic-causing 'Asian flu' accidentally released
- Persistence of Q strain of H2N2 influenza virus in avian species: antigenic, biological and genetic analysis of avian and human H2N2 viruses
de:Asiatische Grippe
it:Influenza asiatica
nl:H2N2
sv:Asiaten | H2N2
Template:Flu
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
H2N2 is a subtype of the species Influenza A virus (sometimes called bird flu virus). H2N2 has mutated into various strains including the Asian Flu strain (now extinct in the wild), H3N2, and various strains found in birds. It is also suspected of causing a human pandemic in 1889.[1][2]
# Asian flu
The "Asian Flu" was a category 2 flu pandemic outbreak of avian influenza that originated in China in early 1956 lasting until 1958. It originated from mutation in wild ducks combining with a pre-existing human strain.[3] The virus was first identified in Guizhou.[4] It spread to Singapore in February 1957, reached Hong Kong by April, and US by June. Death toll in the US was approximately 69,800.[3] Estimates of worldwide infection rate varies widely depending on source, ranging from 1 million to 4 million.
Asian Flu was of the H2N2 strain (a notation that refers to the configuration of the hemagglutinin and neuraminidase proteins in the virus) of type A influenza, and a flu vaccine was developed in 1957 to contain its outbreak.
The Asian Flu strain later evolved via antigenic shift into H3N2 which caused a milder pandemic from 1968 to 1969.[5]
Both the H2N2 and H3N2 pandemic strains contained Avian flu virus RNA segments. "While the pandemic human influenza viruses of 1957 (H2N2) and 1968 (H3N2) clearly arose through reassortment between human and avian viruses, the influenza virus causing the 'Spanish flu' in 1918 appears to be entirely derived from an avian source (Belshe 2005)." [6]
# Test kits
From October 2004 to February 2005, some 3,700 test kits of the 1957 H2N2 virus were accidentally spread around the world from the College of American Pathologists (CAP). CAP assists laboratories in accuracy by providing unidentified samples of viruses; private contractor Meridian Bioscience in Cincinnati, U.S., chose the 1957 strand instead of one of the less deadly avian influenza virus subtypes. "CAP spokesman Dr. Jared Schwartz said Meridian knew what the virus was but believed it was safe. In selecting it, the company had determined that the virus was classified as a biosafety level 2 (BSL-2) agent, which meant it could legally be used in the kits. [...] Before the problem came to light, the CDC had made a recommendation that the H2N2 virus be reclassified as a BSL-3 agent, Gerberding said. She promised to speed up the reclassification. The CDC determines the classifications in collaboration with the National Institutes of Health. In BSL-3 labs, agents are handled with equipment designed to prevent any airborne contamination and resulting respiratory exposure."[7] The 1957 H2N2 virus is considered deadly and the U.S. government called for the vials containing the strain to be destroyed.
"CDC officials reported on April 21 that 99% of the samples had already been destroyed. News reports on April 25 said the last samples outside the United States had been destroyed at the American University of Beirut in Lebanon, after they were found at the Beirut airport. Earlier reports said H2N2 samples were sent to 3,747 labs under CAP auspices and to about another 2,700 labs certified by other organizations. All but about 75 labs that received the CAP samples were in the United States."[8]
"In the United States, there is no government regulation over the 1957 flu strain. In fact, federal officials at the CDC do not even know how many U.S. laboratories keep this deadly strain in their viral libraries."[9]
# Sources
- ↑ Sdstate.edu
- ↑ Pilva.com
- ↑ Jump up to: 3.0 3.1 Greene Jeffrey. Moline, Karen. [2006] (2006) The Bird Flu Pandemic. ISBN 0312360568.
- ↑ Goldsmith, Connie. [2007] (2007) Influenza: The Next Pandemic? 21st century publishing. ISBN 0761394575
- ↑ Starling, Arthur. [2006] (2006) Plague, SARS, and the Story of Medicine in Hong Kong. HK University Press. ISBN 9622098053
- ↑ Chapter Two : Avian Influenza by Timm C. Harder and Ortrud Werner from excellent free on-line Book called Influenza Report 2006 which is a medical textbook that provides a comprehensive overview of epidemic and pandemic influenza.
- ↑ Cidrap UMN.edu
- ↑ Flu.org
- ↑ Globalist.com
# Further reading
- Pandemic preparedness: lessons learnt from H2N2 and H9N2 candidate vaccines
- Interim CDC-NIH Recommendation for Raising the Biosafety Level for Laboratory Work Involving Noncontemporary Human Influenza Viruses
- New Scientist: Bird Flu
- Pandemic-causing 'Asian flu' accidentally released
- Persistence of Q strain of H2N2 influenza virus in avian species: antigenic, biological and genetic analysis of avian and human H2N2 viruses
de:Asiatische Grippe
it:Influenza asiatica
nl:H2N2
sv:Asiaten
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Asian_Flu | |
5ce7187712aa05724fbc97fd7c429597ec1e2260 | wikidoc | Atom | Atom
Used as a slang or street name for heroin and marijuana combination.
# Overview
An atom is the smallest particle that comprises a chemical element. An atom consists of an electron cloud that surrounds a dense nucleus. This nucleus contains positively charged protons and electrically neutral neutrons, whereas the surrounding cloud is made up of negatively charged electrons. When the number of protons in the nucleus equals the number of electrons, the atom is electrically neutral; otherwise it is an ion and has a net positive or negative charge. An atom is classified according to its number of protons and neutrons: the number of protons determines the chemical element and the number of neutrons determines the isotope of that element.
The concept of the atom as an indivisible component of matter was first proposed by early Indian and Greek philosophers. In the 17th and 18th centuries, chemists provided a physical basis for this idea by showing that certain substances could not be further broken down by chemical methods. During the late 19th and the early 20th centuries, physicists discovered subatomic components and structure inside the atom, thereby demonstrating that the 'atom' was not indivisible. The principles of quantum mechanics were used to successfully model the atom.
Relative to everyday experience, atoms are minuscule objects with proportionately tiny masses that can only be observed individually using special instruments such as the scanning tunneling microscope. More than 99.9% of an atom's mass is concentrated in the nucleus, with protons and neutrons having about equal mass. In atoms with too many or too few neutrons relative to the number of protons, the nucleus is unstable and subject to radioactive decay. The electrons surrounding the nucleus occupy a set of stable energy levels, or orbitals, and they can transition between these states by the absorption or emission of photons that match the energy differences between the levels. The electrons determine the chemical properties of an element, and strongly influence an atom's magnetic properties.
# History
The concept that matter is composed of discrete units and cannot be divided into arbitrarily tiny quantities has been around for millennia, but these ideas were founded in abstract, philosophical reasoning rather than experimentation and empirical observation. The nature of atoms in philosophy varied considerably over time and between cultures and schools, and often had spiritual elements. Nevertheless, the basic idea of the atom was adopted by scientists thousands of years later because it elegantly explained new discoveries in the field of chemistry.
The earliest references to the concept of atoms date back to ancient India in the 6th century BCE. The Nyaya and Vaisheshika schools developed elaborate theories of how atoms combined into more complex objects (first in pairs, then trios of pairs). The references to atoms in the West emerged a century later from Leucippus whose student, Democritus, systemized his views. In approximately 450 BCE, Democritus coined the term átomos (Greek ἄτομος), which means "uncuttable" or "the smallest indivisible particle of matter", i.e., something that cannot be divided. Although the Indian and Greek concepts of the atom were based purely on philosophy, modern science has retained the name coined by Democritus.
Further progress in the understanding of atoms did not occur until the science of chemistry began to develop. In 1661, the natural philosopher Robert Boyle published The Sceptical Chymist in which he argued that matter was composed of various combinations of different "corpuscules" or atoms, rather than the classical elements of air, earth, fire and water. In 1789 the term element was defined by the French nobleman and scientific researcher Antoine Lavoisier to mean basic substances that could not be further broken down by the methods of chemistry.
In 1803, the Englishman John Dalton, an instructor and natural philosopher, used the concept of atoms to explain why elements always reacted in a ratio of small whole numbers—the
law of multiple proportions—and why certain gases dissolved better in water than others. He proposed that each element consists of atoms of a single, unique type, and that these atoms could join to each other, to form chemical compounds.
Additional validation of particle theory (and by extension atomic theory) occurred in 1827 when botanist Robert Brown used a microscope to look at dust grains floating in water and discovered that they moved about erratically—a phenomenon that became known as "Brownian motion". J. Desaulx suggested in 1877 that the phenomenon was caused by the thermal motion of water molecules, and in 1905 Albert Einstein produced the first mathematical analysis of the motion, thus confirming the hypothesis.
The physicist J. J. Thomson, through his work on cathode rays in 1897, discovered the electron and its subatomic nature, which destroyed the concept of atoms as being indivisible units. Thomson believed that the electrons were distributed throughout the atom, with their charge balanced by the presence of a uniform sea of positive charge (the plum pudding model).
However, in 1909, researchers under the direction of physicist Ernest Rutherford bombarded a sheet of gold foil with helium ions and discovered that a small percentage were deflected through much larger angles than was predicted using Thomson's proposal. Rutherford interpreted the gold foil experiment as suggesting that the positive charge of an atom and most of its mass was concentrated in a nucleus at the center of the atom (the Rutherford model), with the electrons orbiting it like planets around a sun. Positively charged helium ions passing close to this dense nucleus would then be deflected away at much sharper angles.
While experimenting with the products of radioactive decay, in 1913 radiochemist Frederick Soddy discovered that there appeared to be more than one type of atom at each position on the periodic table. The term isotope was coined by Margaret Todd as a suitable name for different atoms that belong to the same element. J.J. Thomson created a technique for separating atom types through his work on ionized gases, which subsequently led to the discovery of stable isotopes.
Meanwhile, in 1913, physicist Niels Bohr revised Rutherford's model by suggesting that the electrons were confined into clearly defined orbits, and could jump between these, but could not freely spiral inward or outward in intermediate states. An electron must absorb or emit specific amounts of energy to transition between these fixed orbits. When the light from a heated material is passed through a prism, it produced a multi-colored spectrum. The appearance of fixed lines in this spectrum was successfully explained by the orbital transitions.
In 1926, Erwin Schrödinger, using Louis de Broglie's 1924 proposal that particles behave to an extent like waves, developed a mathematical model of the atom that described the electrons as three-dimensional waveforms, rather than point particles. A consequence of using waveforms to describe electrons is that it is mathematically impossible to obtain precise values for both the position and momentum of a particle at the same time; this became known as the uncertainty principle. In this concept, for each measurement of a position one could only obtain a range of probable values for momentum, and vice versa. Although this model was difficult to visually conceptualize, it was able to explain observations of atomic behavior that previous models could not, such as certain structural and spectral patterns of atoms larger than hydrogen. Thus, the planetary model of the atom was discarded in favor of one that described orbital zones around the nucleus where a given electron is most likely to exist.
The development of the mass spectrometer allowed the exact mass of atoms to be measured. The device uses a magnet to bend the trajectory of a beam of ions, and the amount of deflection is determined by the ratio of an atom's mass to its charge. The chemist Francis William Aston used this instrument to demonstrate that isotopes had different masses. The mass of these isotopes varied by integer amounts, called the whole number rule. The explanation for these different atomic isotopes awaited the discovery of the neutron, a neutral-charged particle with a mass similar to the proton, by the physicist James Chadwick in 1932. Isotopes were then explained as elements with the same number of protons, but different numbers of neutrons within the nucleus.
In the 1950s, the development of improved particle accelerator and particle detectors allowed scientists to study the impacts of atoms moving at high energies. Neutrons and protons were found to be hadrons, or composites of smaller particles called quarks. Standard models of nuclear physics were developed that successfully explained the properties of the nucleus in terms of these sub-atomic particles and the forces that govern their interactions.
Around 1985, Steven Chu and co-workers at Bell Labs developed a technique for lowering the temperatures of atoms using lasers. In the same year, a team led by William D. Phillips managed to contain atoms of sodium in a magnetic trap. The combination of these two techniques and a method based on the Doppler effect, developed by Claude Cohen-Tannoudji and his group, allows small numbers of atoms to be cooled to several microkelvin. This allows the atoms to be studied with great precision, and later led to the discovery of Bose-Einstein condensation.
Historically, single atoms have been prohibitively small for scientific applications. Recently, devices have been constructed that use a single metal atom connected through organic ligands to construct a single electron transistor. Experiments have been carried out by trapping and slowing single atoms using laser cooling in a cavity to gain a better physical understanding of matter.
# Components
## Subatomic particles
Though the word atom originally denoted a particle that cannot be cut into smaller particles, in modern scientific usage the atom is composed of various subatomic particles. The constituent particles of an atom consist of the electron, the proton and, for atoms other than hydrogen-1, the neutron.
The electron is by far the least massive of these particles at 9.11Template:E g, with a negative electrical charge and a size that is too small to be measured using available techniques. Protons have a positive charge and a mass 1,836 times that of the electron, at 1.6726Template:E g, although this can be reduced by changes to the atomic binding energy. Neutrons have no electrical charge and have a free mass of 1,839 times the mass of electrons, or 1.6929Template:E g. Neutrons and protons have comparable dimensions—on the order of 2.5Template:E m—although the 'surface' of these particles is not sharply defined.
In the Standard Model of physics, both protons and neutrons are composed of elementary particles called quarks. The quark is a type of fermion, one of the two basic constituents of matter—the other being the lepton, of which the electron is an example. There are six types of quarks, and each has a fractional electric charge of either +2/3 or −1/3. Protons are composed of two up quarks and one down quark, while a neutron consists of one up quark and two down quarks. This distinction accounts for the difference in mass and charge between the two particles. The quarks are held together by the strong nuclear force, which is mediated by gluons. The gluon is a member of the family of bosons, which are elementary particles that mediate physical forces.
## Nucleus
All of the bound protons and neutrons in an atom make up a tiny atomic nucleus, and are collectively called nucleons. The radius of a nucleus is approximately equal to
\begin{smallmatrix}1.07 \cdot \sqrt{A}\end{smallmatrix} fm,
where A is the total number of nucleons. This is much smaller than the radius of the atom, which is on the order of 105 fm. The nucleons are bound together by a short-ranged attractive potential called the residual strong force. At distances smaller than 2.5 fm, this force is much more powerful than the electrostatic force that causes positively charged protons to repel each other.
Atoms of the same element have the same number of protons, called the atomic number. Within a single element, the number of neutrons may vary, determining the isotope of that element. The total number of protons and neutrons determine the nuclide. The number of neutrons relative to the protons determines the stability of the nucleus, with certain isotopes undergoing radioactive decay.
The neutron and the proton are different types of fermions. The Pauli exclusion principle is a quantum mechanical effect that prohibits identical fermions (such as multiple protons) from occupying the same quantum physical state at the same time. Thus every proton in the nucleus must occupy a different state, with its own energy level, and the same rule applies to all of the neutrons. (This prohibition does not apply to a proton and neutron occupying the same quantum state.)
A nucleus that has a different number of protons than neutrons can potentially drop to a lower energy state through a radioactive decay that causes the number of protons and neutrons to more closely match. As a result, atoms with matching numbers of protons and neutrons are more stable against decay. However, with increasing atomic number, the mutual repulsion of the protons requires an increasing proportion of neutrons to maintain the stability of the nucleus, which slightly modifies this trend of equal numbers of protons to neutrons.
The number of protons and neutrons in the atomic nucleus can be modified, although this can require very high energies because of the strong force. Nuclear fusion occurs when multiple atomic particles join to form a heavier nucleus, such as through the energetic collision of two nuclei. At the core of the Sun, protons require energies of 3–10 KeV to overcome their mutual repulsion—the coulomb barrier—and
fuse together into a single nucleus. Nuclear fission is the opposite process, causing a nucleus to split into two smaller nuclei—usually through radioactive decay. The nucleus can also be modified through bombardment by high energy subatomic particles or photons. In such processes that change the number of protons in a nucleus, the atom becomes an atom of a different chemical element.
The mass of the nucleus following a fusion reaction is less than the sum of the masses of the separate particles. The difference between these two values is emitted as energy, as described by Albert Einstein's mass–energy equivalence formula, E = mc², where m is the mass loss and c is the speed of light. This deficit is the binding energy of the nucleus.
The fusion of two nuclei that have lower atomic numbers than iron and nickel is an exothermic process that releases more energy than is required to bring them together. It is this energy-releasing process that makes nuclear fusion in stars a self-sustaining reaction. For heavier nuclei, the total binding energy begins to decrease. That means fusion processes with nuclei that have higher atomic numbers is an endothermic process. These more massive nuclei can not undergo an energy-producing fusion reaction that can sustain the hydrostatic equilibrium of a star.
## Electron cloud
The electrons in an atom are attracted to the protons in the nucleus by the electromagnetic force. This force binds the electrons inside an electrostatic potential well surrounding the smaller nucleus, which means that an external source of energy is needed in order for the electron to escape. The closer an electron is to the nucleus, the greater the attractive force. Hence electrons bound near the center of the potential well require more energy to escape than those at the exterior.
Electrons, like other particles, have properties of both a particle and a wave. The electron cloud is a region inside the potential well where each electron forms a type of three-dimensional standing wave—a wave form that does not move relative to the nucleus. This behavior is defined by an atomic orbital, a mathematical function that characterises the probability that an electron will appear to be at a particular location when its position is measured. Only a discrete (or quantized) set of these orbitals exist around the nucleus, as other possible wave patterns will rapidly decay into a more stable form. Orbitals can have one or more ring or node structures, and they differ from each other in size, shape and orientation.
Each atomic orbital corresponds to a particular energy level of the electron. The electron can change its state to a higher energy level by absorbing a photon with sufficient energy to boost it into the new quantum state. Likewise, through spontaneous emission, an electron in a higher energy state can drop to a lower energy state while radiating the excess energy as a photon. These characteristic energy values, defined by the differences in the energies of the quantum states, are responsible for atomic spectral lines.
The amount of energy needed to remove or add an electron (the electron binding energy) is far less than the binding energy of nucleons. For example, it requires only 13.6 eV to strip a ground-state electron from a hydrogen atom. Atoms are electrically neutral if they have an equal number of protons and electrons. Atoms that have either a deficit or a surplus of electrons are called ions. Electrons that are farthest from the nucleus may be transferred to other nearby atoms or shared between atoms. By this mechanism, atoms are able to bond into molecules and other types of chemical compounds like ionic and covalent network crystals.
# Properties
## Nuclear properties
By definition, any two atoms with an identical number of protons in their nuclei belong to the same chemical element. Atoms with the same number of protons but a different number of neutrons are different isotopes of the same element. Hydrogen atoms, for example, always have only a single proton, but isotopes exist with no neutrons (hydrogen-1, sometimes called protium, by far the most common form), one neutron (deuterium) and two neutrons (tritium). The known elements form a continuous range of atomic numbers from hydrogen with a single proton up to the 118-proton element ununoctium. All known isotopes of elements with atomic numbers greater than 82 are radioactive.
About 339 nuclides occur naturally on Earth, of which 269 (about 79%) are stable. Of the chemical elements, 80 have one or more stable isotopes. Elements 43, 61, and all elements numbered 83 or higher have no stable isotopes. As a rule, there is, for each atomic number (each element) only a handful of stable isotopes, the average being 3.4 stable isotopes per element which has any stable isotopes. Sixteen elements have only a single stable isotope, while the largest number of stable isotopes observed for any element is ten (for the element tin).
Stability of isotopes is affected by the ratio of protons to neutrons, and also by presence of certain "magic numbers" of neutrons or protons which represent closed and filled quantum shells. These quantum shells correspond to a set of energy levels within the shell model of the nucleus. Of the 269 known stable nuclides, only four have both an odd number of protons and odd number of neutrons: 2H, 6Li, 10B and 14N. Also, only four naturally-occurring, radioactive odd-odd nuclides have a half-life over a billion years: 40K, 50V, 138La and 180mTa. Most odd-odd nuclei are highly unstable with respect to beta decay, because the decay products are even-even, and are therefore more strongly bound, due to nuclear pairing effects.
## Mass
Because the large majority of an atom's mass comes from the protons and neutrons, the total number of these particles in an atom is called the mass number. The mass of an atom at rest is often expressed using the unified atomic mass unit (u), which is also called a Dalton (Da). This unit is defined as a twelfth of the mass of a free neutral atom of carbon-12, which is approximately 1.66×10−24 g. hydrogen-1, the lightest isotope of hydrogen and the atom with the lowest mass, has an atomic weight of 1.007825 u. An atom has a mass approximately equal to the mass number times the atomic mass unit. The heaviest stable atom is lead-208, with a mass of 207.9766521 u.
As even the most massive atoms are far too light to work with directly, chemists instead use the unit of moles. The mole is defined such that one mole of any element will always have the same number of atoms (about 6.022×1023). This number was chosen so that if an element has an atomic mass of 1 u, a mole of atoms of that element will have a mass of 1 g. Carbon, for example, has an atomic mass of 12 u, so a mole of carbon atoms weighs 12 g.
## Size
Atoms lack a well-defined outer boundary, so the dimensions are usually described in terms of the distances between two nuclei when the two atoms are joined in a chemical bond. The radius varies with the location of an atom on the atomic chart, the type of chemical bond, the number of neighboring atoms (coordination number) and a quantum mechanical property known as spin. On the periodic table of the elements, atom size tends to increase when moving down columns, but decrease when moving across rows (left to right). Consequently, the smallest atom is helium with a radius of 32 pm, while one of the largest is caesium at 225 pm. These dimensions are thousands of times smaller than the wavelengths of light (400–700 nm) so they can not be viewed using an optical microscope. However, individual atoms can be observed using a scanning tunneling microscope.
Some examples will demonstrate the minuteness of the atom. A typical human hair is about 1 million carbon atoms in width. A single drop of water contains about 2 sextillion (2Template:E) atoms of oxygen, and twice the number of hydrogen atoms. A single carat diamond with a mass of 0.2 g contains about 10 sextillion atoms of carbon. If an apple was magnified to the size of the Earth, then the atoms in the apple would be approximately the size of the original apple.
## Radioactive decay
Every element has one or more isotopes that have unstable nuclei that are subject to radioactive decay, causing the nucleus to emit particles or electromagnetic radiation. Radioactivity can occur when the radius of a nucleus is large compared with the radius of the strong force, which only acts over distances on the order of 1 fm.
There are three primary forms of radioactive decay:
- Alpha decay is caused when the nucleus emits an alpha particle, which is a helium nucleus consisting of two protons and two neutrons. The result of the emission is a new element with a lower atomic number.
- Beta decay is regulated by the weak force, and results from a transformation of a neutron into a proton, or a proton into a neutron. The first is accompanied by the emission of an electron and an antineutrino, while the second causes the emission of a positron and a neutrino. The electron or positron emissions are called beta particles. Beta decay either increases or decreases the atomic number of the nucleus by one.
- Gamma decay results from a change in the energy level of the nucleus to a lower state, resulting in the emission of electromagnetic radiation. This can occur following the emission of an alpha or a beta particle from radioactive decay.
Each radioactive isotope has a characteristic decay time period—the half-life—that is determined by the amount of time needed for half of a sample to decay. This is an exponential decay process that steadily decreases the proportion of the remaining isotope by 50% every half life. Hence after two half-lives have passed only 25% of the isotope will be present, and so forth.
## Magnetic moment
Elementary particles possess an intrinsic quantum mechanical property known as spin. This is analogous to the angular momentum of an object that is spinning around its center of mass, although strictly speaking these particles are believed to be point-like and cannot be said to be rotating. Spin is measured in units of the reduced Planck constant (\hbar), with electrons, protons and neutrons all having spin ½ \hbar, or "spin-½". In an atom, electrons in motion around the nucleus possess orbital angular momentum in addition to their spin, while the nucleus itself possesses angular momentum due to its nuclear spin.
The magnetic field produced by an atom—its magnetic moment—is determined by these various forms of angular momentum, just as a rotating charged object classically produces a magnetic field. However, the most dominant contribution comes from spin. Due to the nature of electrons to obey the Pauli exclusion principle, in which no two electrons may be found in the same quantum state, bound electrons pair up with each other, with one member of each pair in a spin up state and the other in the opposite, spin down state. Thus these spins cancel each other out, reducing the total magnetic dipole moment to zero in some atoms with even number of electrons.
In ferromagnetic elements such as iron, an odd number of electrons leads to an unpaired electron and a net overall magnetic moment. The orbitals of neighboring atoms overlap and a lower energy state is achieved when the spins of unpaired electrons are aligned with each other, a process is known as an exchange interaction. When the magnetic moments of ferromagnetic atoms are lined up, the material can produce a measurable macroscopic field. Paramagnetic materials have atoms with magnetic moments that line up in random directions when no magnetic field is present, but the magnetic moments of the individual atoms line up in the presence of a field.
The nucleus of an atom can also have a net spin. Normally these nuclei are aligned in random directions because of thermal equilibrium. However, for certain elements (such as xenon-129) it is possible to polarize a significant proportion of the nuclear spin states so that they are aligned in the same direction—a condition called hyperpolarization. This has important applications in magnetic resonance imaging.
## Energy levels
When an electron is bound to an atom, it has a potential energy that is inversely proportional to its distance from the nucleus. This is measured by the amount of energy needed to unbind the electron from the atom, and is usually given in units of electronvolts (eV). In the quantum mechanical model, a bound electron can only occupy a set of states centered on the nucleus, and each state corresponds to a specific energy level. The lowest energy state of a bound electron is called the ground state, while an electron at a higher energy level is in an excited state.
In order for an electron to transition between two different states, it must absorb or emit a photon at an energy matching the difference in the potential energy of those levels. The energy of an emitted photon is proportional to its frequency, so these specific energy levels appear as distinct bands in the electromagnetic spectrum. Each element has a characteristic spectrum that can depend on the nuclear charge, subshells filled by electrons, the electromagnetic interactions between the electrons and other factors.
When a continuous spectrum of energy is passed through a gas or plasma, some of the photons are absorbed by atoms, causing electrons to change their energy level. Those excited electrons that remain bound to their atom will spontaneously emit this energy as a photon, traveling in a random direction, and so drop back to lower energy levels. Thus the atoms behave like a filter that forms a series of dark absorption bands in the energy output. (An observer viewing the atoms from a different direction, which does not include the continuous spectrum in the background, will instead see a series of emission lines from the photons emitted by the atoms.) Spectroscopic measurements of the strength and width of spectral lines allow the composition and physical properties of a substance to be determined.
Close examination of the spectral lines reveals that some display
a fine structure splitting. This occurs because of
spin-orbit coupling, which is an interaction between the
spin and motion of the outermost electron. When an atom is in an external magnetic field, spectral lines become split into three or more components; a phenomenon called the Zeeman effect. This is caused by the interaction of the magnetic field with the magnetic moment of the atom and its electrons. Some atoms can have multiple electron configurations with the same energy level, which thus appear as a single spectral line. The interaction of the magnetic field with the atom shifts these electron configurations to slightly different energy levels, resulting in multiple spectral lines. The presence of an external electric field can cause a comparable splitting and shifting of spectral lines by modifying the electron energy levels, a phenomenon called the Stark effect.
If a bound electron is in an excited state, an interacting photon with the proper energy can cause stimulated emission of a photon with a matching energy level. For this to occur, the electron must drop to a lower energy state that has an energy difference matching the energy of the interacting photon. The emitted photon and the interacting photon will then move off in parallel and with matching phases. That is, the wave patterns of the two photons will be synchronized. This physical property is used to make lasers, which can emit a coherent beam of light energy in a narrow frequency band.
## Valence
The outermost electron shell of an atom in its uncombined
state is known as the valence shell, and the electrons in
that shell are called valence electrons. The number of
valence electrons determines the bonding
behavior with other atoms. Atoms tend to chemically react with each other in a manner that will fill (or empty) their outer valence shells.
The chemical elements are often displayed in a periodic table that is laid out to display recurring chemical properties, and elements with the same number of valence electrons form a group that is aligned in the same column of the table. (The horizontal rows correspond to the filling of a quantum shell of electrons.) The elements at the far right of the table have their outer shell completely filled with electrons, which results in chemically inert elements known as the noble gases.
## States
Quantities of atoms are found in different states of matter that depend on the physical conditions, such as temperature and pressure. By varying the conditions, materials can transition between solids, liquids, gases and plasmas. Within a state, a material can also exist in different phases. An example of this is solid carbon, which can exist as graphite or diamond.
At temperatures close to absolute zero, atoms can form a Bose–Einstein condensate, at which point quantum mechanical effects, which are normally only observed at the atomic scale, become apparent on a macroscopic scale. This super-cooled collection of atoms
then behaves as a single Super Atom, which may allow fundamental checks of quantum mechanical behavior.
# Identification
The scanning tunneling microscope is a device for viewing surfaces at the atomic level. It uses the quantum tunneling phenomenon, which allows particles to pass through a barrier that would normally be insurmountable. Electrons tunnel through the vacuum between two planar metal electrodes, on each of which is an adsorbed atom, providing a tunneling-current density that can be measured. Scanning one atom (taken as the tip) as it moves past the other (the sample) permits plotting of tip displacement versus lateral separation for a constant current. The calculation shows the extent to which scanning-tunneling-microscope images of an individual atom are visible. It confirms that for low bias, the microscope images the space-averaged dimensions of the electron orbitals across closely packed energy levels—the Fermi level local density of states.
An atom can be ionized by removing one of its electrons. The electric charge causes the trajectory of an atom to bend when it passes through a magnetic field. The radius by which the trajectory of a moving ion is turned by the magnetic field is determined by the mass of the atom. The mass spectrometer uses this principle to measure the mass-to-charge ratio of ions. If a sample contains multiple isotopes, the mass spectrometer can determine the proportion of each isotope in the sample by measuring the intensity of the different beams of ions. Techniques to vaporize atoms include inductively coupled plasma atomic emission spectroscopy and inductively coupled plasma mass spectrometry, both of which use a plasma to vaporize samples for analysis.
A more area-selective method is electron energy loss spectroscopy, which measures the energy loss of an electron beam within a transmission electron microscope when it interacts with a portion of a sample. The atom-probe tomograph has sub-nanometer resolution in 3-D and can chemically identify individual atoms using time-of-flight mass spectrometry.
Spectra of excited states can be used to analyze the atomic composition of distant stars. Specific light wavelengths contained in the observed light from stars can be separated out and related to the quantized transitions in free gas atoms. These colors can be replicated using a gas-discharge lamp containing the same element. Helium was discovered in this way in the spectrum of the Sun 23 years before it was found on Earth.
# Origin and current state
Atoms form about 4% of the total mass density of the observable universe, with an average density of about 0.25 atoms/m3. Within a galaxy such as the Milky Way, atoms have a much higher concentration, with the density of matter in the interstellar medium (ISM) ranging from 105 to 109 atoms/m3. The Sun is believed to be inside the Local Bubble, a region of highly ionized gas, so the density in the solar neighborhood is only about 103 atoms/m3. Stars form from dense clouds in the ISM, and the evolutionary processes of stars result in the steady enrichment of the ISM with elements more massive than hydrogen and helium. Up to 95% of the Milky Way's atoms are concentrated inside stars and the total mass of atoms forms about 10% of the mass of the galaxy. (The remainder of the mass is an unknown dark matter.)
## Nucleosynthesis
Stable protons and electrons appeared one second after the Big Bang. During the following three minutes, Big Bang nucleosynthesis produced most of the helium, lithium, and deuterium atoms in the universe, and perhaps some of the beryllium and boron. The first atoms (complete with bound electrons) were theoretically created 380,000 years after the Big Bang—an epoch called recombination, when the expanding universe cooled enough to allow electrons to become attached to nuclei. Since then, atomic nuclei have been combined in stars through the process of nuclear fusion to produce elements up to iron.
Isotopes such as lithium-6 are generated in space through cosmic ray spallation. This occurs when a high-energy proton strikes an atomic nucleus, causing large numbers of nucleons to be ejected. Elements heavier than iron were produced in supernovae through the r-process and in AGB stars through the s-process, both of which involve the capture of neutrons by atomic nuclei. Elements such as lead formed largely through the radioactive decay of heavier elements.
## Earth
Most of the atoms that make up the Earth and its inhabitants were present in their current form in the nebula that collapsed out of a molecular cloud to form the solar system. The rest are the result of radioactive decay, and their relative proportion can be used to determine the age of the Earth through radiometric dating. Most of the helium in the crust of the Earth (about 99% of the helium from gas wells, as shown by its lower abundance of helium-3) is a product of alpha decay.
There are a few trace atoms on Earth that were not present at the beginning (i.e., not "primordial"), nor are results of radioactive decay. Carbon-14 is continuously generated by cosmic rays in the atmosphere. Some atoms on Earth have been artificially generated either deliberately or as by-products of nuclear reactors or explosions. Of the transuranic elements—those with atomic numbers greater than 92—only plutonium and neptunium occur naturally on Earth. Transuranic elements have radioactive lifetimes shorter than the current age of the Earth and thus identifiable quantities of these elements have long since decayed, with the exception of traces of plutonium-244 possibly deposited by cosmic dust. Natural deposits of plutonium and neptunium are produced by neutron capture in uranium ore.
The Earth contains approximately 1.33Template:E atoms. In the planet's atmosphere, small numbers of independent atoms exist for the noble gases, such as argon and neon. The remaining 99% of the atmosphere is bound in the form of molecules, including carbon dioxide and diatomic oxygen and nitrogen. At the surface of the Earth, atoms combine to form various compounds, including water, salt, silicates and oxides. Atoms can also combine to create materials that do not consist of discrete molecules, including crystals and liquid or solid metals. This atomic matter forms networked arrangements that lack the particular type of small-scale interrupted order associated with molecular matter.
## Rare and theoretical forms
While isotopes with atomic numbers higher than lead (82) are known to be radioactive, an "island of stability" has been proposed for some elements with atomic numbers above 103. These superheavy elements may have a nucleus that is relatively stable against radioactive decay. The most likely candidate for a stable superheavy atom, unbihexium, has 126 protons and 184 neutrons.
Each particle of matter has a corresponding antimatter particle with the opposite electrical charge. Thus, the positron is a positively charged antielectron and the antiproton is a negatively charged equivalent of a proton. For unknown reasons, antimatter particles are rare in the universe, hence, no antimatter atoms have been discovered. Antihydrogen, the antimatter counterpart of hydrogen, was first produced at the CERN laboratory in Geneva in 1996.
Other exotic atoms have been created by replacing one of the protons, neutrons or electrons with other particles that have the same charge. For example, an electron can be replaced by a more massive muon, forming a muonic atom. These types of atoms can be used to test the fundamental predictions of physics. | Atom
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Used as a slang or street name for heroin and marijuana combination.
# Overview
An atom is the smallest particle that comprises a chemical element. An atom consists of an electron cloud that surrounds a dense nucleus. This nucleus contains positively charged protons and electrically neutral neutrons, whereas the surrounding cloud is made up of negatively charged electrons. When the number of protons in the nucleus equals the number of electrons, the atom is electrically neutral; otherwise it is an ion and has a net positive or negative charge. An atom is classified according to its number of protons and neutrons: the number of protons determines the chemical element and the number of neutrons determines the isotope of that element.
The concept of the atom as an indivisible component of matter was first proposed by early Indian and Greek philosophers. In the 17th and 18th centuries, chemists provided a physical basis for this idea by showing that certain substances could not be further broken down by chemical methods. During the late 19th and the early 20th centuries, physicists discovered subatomic components and structure inside the atom, thereby demonstrating that the 'atom' was not indivisible. The principles of quantum mechanics were used to successfully model the atom.[1][2]
Relative to everyday experience, atoms are minuscule objects with proportionately tiny masses that can only be observed individually using special instruments such as the scanning tunneling microscope. More than 99.9% of an atom's mass is concentrated in the nucleus,[3] with protons and neutrons having about equal mass. In atoms with too many or too few neutrons relative to the number of protons, the nucleus is unstable and subject to radioactive decay.[4] The electrons surrounding the nucleus occupy a set of stable energy levels, or orbitals, and they can transition between these states by the absorption or emission of photons that match the energy differences between the levels. The electrons determine the chemical properties of an element, and strongly influence an atom's magnetic properties.
# History
The concept that matter is composed of discrete units and cannot be divided into arbitrarily tiny quantities has been around for millennia, but these ideas were founded in abstract, philosophical reasoning rather than experimentation and empirical observation. The nature of atoms in philosophy varied considerably over time and between cultures and schools, and often had spiritual elements. Nevertheless, the basic idea of the atom was adopted by scientists thousands of years later because it elegantly explained new discoveries in the field of chemistry.[5]
The earliest references to the concept of atoms date back to ancient India in the 6th century BCE.[6] The Nyaya and Vaisheshika schools developed elaborate theories of how atoms combined into more complex objects (first in pairs, then trios of pairs).[7] The references to atoms in the West emerged a century later from Leucippus whose student, Democritus, systemized his views. In approximately 450 BCE, Democritus coined the term átomos (Greek ἄτομος), which means "uncuttable" or "the smallest indivisible particle of matter", i.e., something that cannot be divided. Although the Indian and Greek concepts of the atom were based purely on philosophy, modern science has retained the name coined by Democritus.[5]
Further progress in the understanding of atoms did not occur until the science of chemistry began to develop. In 1661, the natural philosopher Robert Boyle published The Sceptical Chymist in which he argued that matter was composed of various combinations of different "corpuscules" or atoms, rather than the classical elements of air, earth, fire and water.[8] In 1789 the term element was defined by the French nobleman and scientific researcher Antoine Lavoisier to mean basic substances that could not be further broken down by the methods of chemistry.[9]
In 1803, the Englishman John Dalton, an instructor and natural philosopher, used the concept of atoms to explain why elements always reacted in a ratio of small whole numbers—the
law of multiple proportions—and why certain gases dissolved better in water than others. He proposed that each element consists of atoms of a single, unique type, and that these atoms could join to each other, to form chemical compounds.[10][11]
Additional validation of particle theory (and by extension atomic theory) occurred in 1827 when botanist Robert Brown used a microscope to look at dust grains floating in water and discovered that they moved about erratically—a phenomenon that became known as "Brownian motion". J. Desaulx suggested in 1877 that the phenomenon was caused by the thermal motion of water molecules, and in 1905 Albert Einstein produced the first mathematical analysis of the motion, thus confirming the hypothesis.[12][13]
The physicist J. J. Thomson, through his work on cathode rays in 1897, discovered the electron and its subatomic nature, which destroyed the concept of atoms as being indivisible units.[14] Thomson believed that the electrons were distributed throughout the atom, with their charge balanced by the presence of a uniform sea of positive charge (the plum pudding model).
However, in 1909, researchers under the direction of physicist Ernest Rutherford bombarded a sheet of gold foil with helium ions and discovered that a small percentage were deflected through much larger angles than was predicted using Thomson's proposal. Rutherford interpreted the gold foil experiment as suggesting that the positive charge of an atom and most of its mass was concentrated in a nucleus at the center of the atom (the Rutherford model), with the electrons orbiting it like planets around a sun. Positively charged helium ions passing close to this dense nucleus would then be deflected away at much sharper angles.[15]
While experimenting with the products of radioactive decay, in 1913 radiochemist Frederick Soddy discovered that there appeared to be more than one type of atom at each position on the periodic table.[16] The term isotope was coined by Margaret Todd as a suitable name for different atoms that belong to the same element. J.J. Thomson created a technique for separating atom types through his work on ionized gases, which subsequently led to the discovery of stable isotopes.[17]
Meanwhile, in 1913, physicist Niels Bohr revised Rutherford's model by suggesting that the electrons were confined into clearly defined orbits, and could jump between these, but could not freely spiral inward or outward in intermediate states.[18] An electron must absorb or emit specific amounts of energy to transition between these fixed orbits. When the light from a heated material is passed through a prism, it produced a multi-colored spectrum. The appearance of fixed lines in this spectrum was successfully explained by the orbital transitions.[19]
In 1926, Erwin Schrödinger, using Louis de Broglie's 1924 proposal that particles behave to an extent like waves, developed a mathematical model of the atom that described the electrons as three-dimensional waveforms, rather than point particles. A consequence of using waveforms to describe electrons is that it is mathematically impossible to obtain precise values for both the position and momentum of a particle at the same time; this became known as the uncertainty principle. In this concept, for each measurement of a position one could only obtain a range of probable values for momentum, and vice versa. Although this model was difficult to visually conceptualize, it was able to explain observations of atomic behavior that previous models could not, such as certain structural and spectral patterns of atoms larger than hydrogen. Thus, the planetary model of the atom was discarded in favor of one that described orbital zones around the nucleus where a given electron is most likely to exist.[20][21]
The development of the mass spectrometer allowed the exact mass of atoms to be measured. The device uses a magnet to bend the trajectory of a beam of ions, and the amount of deflection is determined by the ratio of an atom's mass to its charge. The chemist Francis William Aston used this instrument to demonstrate that isotopes had different masses. The mass of these isotopes varied by integer amounts, called the whole number rule.[22] The explanation for these different atomic isotopes awaited the discovery of the neutron, a neutral-charged particle with a mass similar to the proton, by the physicist James Chadwick in 1932. Isotopes were then explained as elements with the same number of protons, but different numbers of neutrons within the nucleus.[23]
In the 1950s, the development of improved particle accelerator and particle detectors allowed scientists to study the impacts of atoms moving at high energies.[24] Neutrons and protons were found to be hadrons, or composites of smaller particles called quarks. Standard models of nuclear physics were developed that successfully explained the properties of the nucleus in terms of these sub-atomic particles and the forces that govern their interactions.[25]
Around 1985, Steven Chu and co-workers at Bell Labs developed a technique for lowering the temperatures of atoms using lasers. In the same year, a team led by William D. Phillips managed to contain atoms of sodium in a magnetic trap. The combination of these two techniques and a method based on the Doppler effect, developed by Claude Cohen-Tannoudji and his group, allows small numbers of atoms to be cooled to several microkelvin. This allows the atoms to be studied with great precision, and later led to the discovery of Bose-Einstein condensation.[26]
Historically, single atoms have been prohibitively small for scientific applications. Recently, devices have been constructed that use a single metal atom connected through organic ligands to construct a single electron transistor.[27] Experiments have been carried out by trapping and slowing single atoms using laser cooling in a cavity to gain a better physical understanding of matter.[28]
# Components
## Subatomic particles
Though the word atom originally denoted a particle that cannot be cut into smaller particles, in modern scientific usage the atom is composed of various subatomic particles. The constituent particles of an atom consist of the electron, the proton and, for atoms other than hydrogen-1, the neutron.
The electron is by far the least massive of these particles at 9.11Template:E g, with a negative electrical charge and a size that is too small to be measured using available techniques.[29] Protons have a positive charge and a mass 1,836 times that of the electron, at 1.6726Template:E g, although this can be reduced by changes to the atomic binding energy. Neutrons have no electrical charge and have a free mass of 1,839 times the mass of electrons,[30] or 1.6929Template:E g. Neutrons and protons have comparable dimensions—on the order of 2.5Template:E m—although the 'surface' of these particles is not sharply defined.[31]
In the Standard Model of physics, both protons and neutrons are composed of elementary particles called quarks. The quark is a type of fermion, one of the two basic constituents of matter—the other being the lepton, of which the electron is an example. There are six types of quarks, and each has a fractional electric charge of either +2/3 or −1/3. Protons are composed of two up quarks and one down quark, while a neutron consists of one up quark and two down quarks. This distinction accounts for the difference in mass and charge between the two particles. The quarks are held together by the strong nuclear force, which is mediated by gluons. The gluon is a member of the family of bosons, which are elementary particles that mediate physical forces.[32][33]
## Nucleus
All of the bound protons and neutrons in an atom make up a tiny atomic nucleus, and are collectively called nucleons. The radius of a nucleus is approximately equal to
<math>\begin{smallmatrix}1.07 \cdot \sqrt[3]{A}\end{smallmatrix}</math> fm,
where A is the total number of nucleons.[34] This is much smaller than the radius of the atom, which is on the order of 105 fm. The nucleons are bound together by a short-ranged attractive potential called the residual strong force. At distances smaller than 2.5 fm, this force is much more powerful than the electrostatic force that causes positively charged protons to repel each other.[35]
Atoms of the same element have the same number of protons, called the atomic number. Within a single element, the number of neutrons may vary, determining the isotope of that element. The total number of protons and neutrons determine the nuclide. The number of neutrons relative to the protons determines the stability of the nucleus, with certain isotopes undergoing radioactive decay.[36]
The neutron and the proton are different types of fermions. The Pauli exclusion principle is a quantum mechanical effect that prohibits identical fermions (such as multiple protons) from occupying the same quantum physical state at the same time. Thus every proton in the nucleus must occupy a different state, with its own energy level, and the same rule applies to all of the neutrons. (This prohibition does not apply to a proton and neutron occupying the same quantum state.)[37]
A nucleus that has a different number of protons than neutrons can potentially drop to a lower energy state through a radioactive decay that causes the number of protons and neutrons to more closely match. As a result, atoms with matching numbers of protons and neutrons are more stable against decay. However, with increasing atomic number, the mutual repulsion of the protons requires an increasing proportion of neutrons to maintain the stability of the nucleus, which slightly modifies this trend of equal numbers of protons to neutrons.[37]
The number of protons and neutrons in the atomic nucleus can be modified, although this can require very high energies because of the strong force. Nuclear fusion occurs when multiple atomic particles join to form a heavier nucleus, such as through the energetic collision of two nuclei. At the core of the Sun, protons require energies of 3–10 KeV to overcome their mutual repulsion—the coulomb barrier—and
fuse together into a single nucleus.[38] Nuclear fission is the opposite process, causing a nucleus to split into two smaller nuclei—usually through radioactive decay. The nucleus can also be modified through bombardment by high energy subatomic particles or photons. In such processes that change the number of protons in a nucleus, the atom becomes an atom of a different chemical element.[39][40]
The mass of the nucleus following a fusion reaction is less than the sum of the masses of the separate particles. The difference between these two values is emitted as energy, as described by Albert Einstein's mass–energy equivalence formula, E = mc², where m is the mass loss and c is the speed of light. This deficit is the binding energy of the nucleus.[41]
The fusion of two nuclei that have lower atomic numbers than iron and nickel is an exothermic process that releases more energy than is required to bring them together.[42] It is this energy-releasing process that makes nuclear fusion in stars a self-sustaining reaction. For heavier nuclei, the total binding energy begins to decrease. That means fusion processes with nuclei that have higher atomic numbers is an endothermic process. These more massive nuclei can not undergo an energy-producing fusion reaction that can sustain the hydrostatic equilibrium of a star.[37]
## Electron cloud
The electrons in an atom are attracted to the protons in the nucleus by the electromagnetic force. This force binds the electrons inside an electrostatic potential well surrounding the smaller nucleus, which means that an external source of energy is needed in order for the electron to escape. The closer an electron is to the nucleus, the greater the attractive force. Hence electrons bound near the center of the potential well require more energy to escape than those at the exterior.
Electrons, like other particles, have properties of both a particle and a wave. The electron cloud is a region inside the potential well where each electron forms a type of three-dimensional standing wave—a wave form that does not move relative to the nucleus. This behavior is defined by an atomic orbital, a mathematical function that characterises the probability that an electron will appear to be at a particular location when its position is measured. Only a discrete (or quantized) set of these orbitals exist around the nucleus, as other possible wave patterns will rapidly decay into a more stable form.[43] Orbitals can have one or more ring or node structures, and they differ from each other in size, shape and orientation.[44]
Each atomic orbital corresponds to a particular energy level of the electron. The electron can change its state to a higher energy level by absorbing a photon with sufficient energy to boost it into the new quantum state. Likewise, through spontaneous emission, an electron in a higher energy state can drop to a lower energy state while radiating the excess energy as a photon. These characteristic energy values, defined by the differences in the energies of the quantum states, are responsible for atomic spectral lines.[43]
The amount of energy needed to remove or add an electron (the electron binding energy) is far less than the binding energy of nucleons. For example, it requires only 13.6 eV to strip a ground-state electron from a hydrogen atom.[45] Atoms are electrically neutral if they have an equal number of protons and electrons. Atoms that have either a deficit or a surplus of electrons are called ions. Electrons that are farthest from the nucleus may be transferred to other nearby atoms or shared between atoms. By this mechanism, atoms are able to bond into molecules and other types of chemical compounds like ionic and covalent network crystals.[46]
# Properties
## Nuclear properties
By definition, any two atoms with an identical number of protons in their nuclei belong to the same chemical element. Atoms with the same number of protons but a different number of neutrons are different isotopes of the same element. Hydrogen atoms, for example, always have only a single proton, but isotopes exist with no neutrons (hydrogen-1, sometimes called protium, by far the most common form), one neutron (deuterium) and two neutrons (tritium).[47] The known elements form a continuous range of atomic numbers from hydrogen with a single proton up to the 118-proton element ununoctium.[48] All known isotopes of elements with atomic numbers greater than 82 are radioactive.[49][50]
About 339 nuclides occur naturally on Earth, of which 269 (about 79%) are stable.[51] Of the chemical elements, 80 have one or more stable isotopes. Elements 43, 61, and all elements numbered 83 or higher have no stable isotopes. As a rule, there is, for each atomic number (each element) only a handful of stable isotopes, the average being 3.4 stable isotopes per element which has any stable isotopes. Sixteen elements have only a single stable isotope, while the largest number of stable isotopes observed for any element is ten (for the element tin).[52]
Stability of isotopes is affected by the ratio of protons to neutrons, and also by presence of certain "magic numbers" of neutrons or protons which represent closed and filled quantum shells. These quantum shells correspond to a set of energy levels within the shell model of the nucleus. Of the 269 known stable nuclides, only four have both an odd number of protons and odd number of neutrons: 2H, 6Li, 10B and 14N. Also, only four naturally-occurring, radioactive odd-odd nuclides have a half-life over a billion years: 40K, 50V, 138La and 180mTa. Most odd-odd nuclei are highly unstable with respect to beta decay, because the decay products are even-even, and are therefore more strongly bound, due to nuclear pairing effects.[52]
## Mass
Because the large majority of an atom's mass comes from the protons and neutrons, the total number of these particles in an atom is called the mass number. The mass of an atom at rest is often expressed using the unified atomic mass unit (u), which is also called a Dalton (Da). This unit is defined as a twelfth of the mass of a free neutral atom of carbon-12, which is approximately 1.66×10−24 g.[53] hydrogen-1, the lightest isotope of hydrogen and the atom with the lowest mass, has an atomic weight of 1.007825 u.[54] An atom has a mass approximately equal to the mass number times the atomic mass unit.[55] The heaviest stable atom is lead-208,[49] with a mass of 207.9766521 u.[56]
As even the most massive atoms are far too light to work with directly, chemists instead use the unit of moles. The mole is defined such that one mole of any element will always have the same number of atoms (about 6.022×1023). This number was chosen so that if an element has an atomic mass of 1 u, a mole of atoms of that element will have a mass of 1 g. Carbon, for example, has an atomic mass of 12 u, so a mole of carbon atoms weighs 12 g.[53]
## Size
Atoms lack a well-defined outer boundary, so the dimensions are usually described in terms of the distances between two nuclei when the two atoms are joined in a chemical bond. The radius varies with the location of an atom on the atomic chart, the type of chemical bond, the number of neighboring atoms (coordination number) and a quantum mechanical property known as spin.[57] On the periodic table of the elements, atom size tends to increase when moving down columns, but decrease when moving across rows (left to right).[58] Consequently, the smallest atom is helium with a radius of 32 pm, while one of the largest is caesium at 225 pm.[59] These dimensions are thousands of times smaller than the wavelengths of light (400–700 nm) so they can not be viewed using an optical microscope. However, individual atoms can be observed using a scanning tunneling microscope.
Some examples will demonstrate the minuteness of the atom. A typical human hair is about 1 million carbon atoms in width.[60] A single drop of water contains about 2 sextillion (2Template:E) atoms of oxygen, and twice the number of hydrogen atoms.[61] A single carat diamond with a mass of 0.2 g contains about 10 sextillion atoms of carbon.[62] If an apple was magnified to the size of the Earth, then the atoms in the apple would be approximately the size of the original apple.[63]
## Radioactive decay
Every element has one or more isotopes that have unstable nuclei that are subject to radioactive decay, causing the nucleus to emit particles or electromagnetic radiation. Radioactivity can occur when the radius of a nucleus is large compared with the radius of the strong force, which only acts over distances on the order of 1 fm.[64]
There are three primary forms of radioactive decay:[65][66]
- Alpha decay is caused when the nucleus emits an alpha particle, which is a helium nucleus consisting of two protons and two neutrons. The result of the emission is a new element with a lower atomic number.
- Beta decay is regulated by the weak force, and results from a transformation of a neutron into a proton, or a proton into a neutron. The first is accompanied by the emission of an electron and an antineutrino, while the second causes the emission of a positron and a neutrino. The electron or positron emissions are called beta particles. Beta decay either increases or decreases the atomic number of the nucleus by one.
- Gamma decay results from a change in the energy level of the nucleus to a lower state, resulting in the emission of electromagnetic radiation. This can occur following the emission of an alpha or a beta particle from radioactive decay.
Each radioactive isotope has a characteristic decay time period—the half-life—that is determined by the amount of time needed for half of a sample to decay. This is an exponential decay process that steadily decreases the proportion of the remaining isotope by 50% every half life. Hence after two half-lives have passed only 25% of the isotope will be present, and so forth.[64]
## Magnetic moment
Elementary particles possess an intrinsic quantum mechanical property known as spin. This is analogous to the angular momentum of an object that is spinning around its center of mass, although strictly speaking these particles are believed to be point-like and cannot be said to be rotating. Spin is measured in units of the reduced Planck constant (<math>\hbar</math>), with electrons, protons and neutrons all having spin ½ <math>\hbar</math>, or "spin-½". In an atom, electrons in motion around the nucleus possess orbital angular momentum in addition to their spin, while the nucleus itself possesses angular momentum due to its nuclear spin.[67]
The magnetic field produced by an atom—its magnetic moment—is determined by these various forms of angular momentum, just as a rotating charged object classically produces a magnetic field. However, the most dominant contribution comes from spin. Due to the nature of electrons to obey the Pauli exclusion principle, in which no two electrons may be found in the same quantum state, bound electrons pair up with each other, with one member of each pair in a spin up state and the other in the opposite, spin down state. Thus these spins cancel each other out, reducing the total magnetic dipole moment to zero in some atoms with even number of electrons.[68]
In ferromagnetic elements such as iron, an odd number of electrons leads to an unpaired electron and a net overall magnetic moment. The orbitals of neighboring atoms overlap and a lower energy state is achieved when the spins of unpaired electrons are aligned with each other, a process is known as an exchange interaction. When the magnetic moments of ferromagnetic atoms are lined up, the material can produce a measurable macroscopic field. Paramagnetic materials have atoms with magnetic moments that line up in random directions when no magnetic field is present, but the magnetic moments of the individual atoms line up in the presence of a field.[69][68]
The nucleus of an atom can also have a net spin. Normally these nuclei are aligned in random directions because of thermal equilibrium. However, for certain elements (such as xenon-129) it is possible to polarize a significant proportion of the nuclear spin states so that they are aligned in the same direction—a condition called hyperpolarization. This has important applications in magnetic resonance imaging.[70][71]
## Energy levels
When an electron is bound to an atom, it has a potential energy that is inversely proportional to its distance from the nucleus. This is measured by the amount of energy needed to unbind the electron from the atom, and is usually given in units of electronvolts (eV). In the quantum mechanical model, a bound electron can only occupy a set of states centered on the nucleus, and each state corresponds to a specific energy level. The lowest energy state of a bound electron is called the ground state, while an electron at a higher energy level is in an excited state.[72]
In order for an electron to transition between two different states, it must absorb or emit a photon at an energy matching the difference in the potential energy of those levels. The energy of an emitted photon is proportional to its frequency, so these specific energy levels appear as distinct bands in the electromagnetic spectrum.[73] Each element has a characteristic spectrum that can depend on the nuclear charge, subshells filled by electrons, the electromagnetic interactions between the electrons and other factors.[74]
When a continuous spectrum of energy is passed through a gas or plasma, some of the photons are absorbed by atoms, causing electrons to change their energy level. Those excited electrons that remain bound to their atom will spontaneously emit this energy as a photon, traveling in a random direction, and so drop back to lower energy levels. Thus the atoms behave like a filter that forms a series of dark absorption bands in the energy output. (An observer viewing the atoms from a different direction, which does not include the continuous spectrum in the background, will instead see a series of emission lines from the photons emitted by the atoms.) Spectroscopic measurements of the strength and width of spectral lines allow the composition and physical properties of a substance to be determined.[75]
Close examination of the spectral lines reveals that some display
a fine structure splitting. This occurs because of
spin-orbit coupling, which is an interaction between the
spin and motion of the outermost electron.[76] When an atom is in an external magnetic field, spectral lines become split into three or more components; a phenomenon called the Zeeman effect. This is caused by the interaction of the magnetic field with the magnetic moment of the atom and its electrons. Some atoms can have multiple electron configurations with the same energy level, which thus appear as a single spectral line. The interaction of the magnetic field with the atom shifts these electron configurations to slightly different energy levels, resulting in multiple spectral lines.[77] The presence of an external electric field can cause a comparable splitting and shifting of spectral lines by modifying the electron energy levels, a phenomenon called the Stark effect.[78]
If a bound electron is in an excited state, an interacting photon with the proper energy can cause stimulated emission of a photon with a matching energy level. For this to occur, the electron must drop to a lower energy state that has an energy difference matching the energy of the interacting photon. The emitted photon and the interacting photon will then move off in parallel and with matching phases. That is, the wave patterns of the two photons will be synchronized. This physical property is used to make lasers, which can emit a coherent beam of light energy in a narrow frequency band.[79]
## Valence
The outermost electron shell of an atom in its uncombined
state is known as the valence shell, and the electrons in
that shell are called valence electrons. The number of
valence electrons determines the bonding
behavior with other atoms. Atoms tend to chemically react with each other in a manner that will fill (or empty) their outer valence shells.[80]
The chemical elements are often displayed in a periodic table that is laid out to display recurring chemical properties, and elements with the same number of valence electrons form a group that is aligned in the same column of the table. (The horizontal rows correspond to the filling of a quantum shell of electrons.) The elements at the far right of the table have their outer shell completely filled with electrons, which results in chemically inert elements known as the noble gases.[81][82]
## States
Quantities of atoms are found in different states of matter that depend on the physical conditions, such as temperature and pressure. By varying the conditions, materials can transition between solids, liquids, gases and plasmas.[83] Within a state, a material can also exist in different phases. An example of this is solid carbon, which can exist as graphite or diamond.[84]
At temperatures close to absolute zero, atoms can form a Bose–Einstein condensate, at which point quantum mechanical effects, which are normally only observed at the atomic scale, become apparent on a macroscopic scale.[85][86] This super-cooled collection of atoms
then behaves as a single Super Atom, which may allow fundamental checks of quantum mechanical behavior.[87]
# Identification
The scanning tunneling microscope is a device for viewing surfaces at the atomic level. It uses the quantum tunneling phenomenon, which allows particles to pass through a barrier that would normally be insurmountable. Electrons tunnel through the vacuum between two planar metal electrodes, on each of which is an adsorbed atom, providing a tunneling-current density that can be measured. Scanning one atom (taken as the tip) as it moves past the other (the sample) permits plotting of tip displacement versus lateral separation for a constant current. The calculation shows the extent to which scanning-tunneling-microscope images of an individual atom are visible. It confirms that for low bias, the microscope images the space-averaged dimensions of the electron orbitals across closely packed energy levels—the Fermi level local density of states.[88][89]
An atom can be ionized by removing one of its electrons. The electric charge causes the trajectory of an atom to bend when it passes through a magnetic field. The radius by which the trajectory of a moving ion is turned by the magnetic field is determined by the mass of the atom. The mass spectrometer uses this principle to measure the mass-to-charge ratio of ions. If a sample contains multiple isotopes, the mass spectrometer can determine the proportion of each isotope in the sample by measuring the intensity of the different beams of ions. Techniques to vaporize atoms include inductively coupled plasma atomic emission spectroscopy and inductively coupled plasma mass spectrometry, both of which use a plasma to vaporize samples for analysis.[90]
A more area-selective method is electron energy loss spectroscopy, which measures the energy loss of an electron beam within a transmission electron microscope when it interacts with a portion of a sample. The atom-probe tomograph has sub-nanometer resolution in 3-D and can chemically identify individual atoms using time-of-flight mass spectrometry.[91]
Spectra of excited states can be used to analyze the atomic composition of distant stars. Specific light wavelengths contained in the observed light from stars can be separated out and related to the quantized transitions in free gas atoms. These colors can be replicated using a gas-discharge lamp containing the same element.[92] Helium was discovered in this way in the spectrum of the Sun 23 years before it was found on Earth.[93]
# Origin and current state
Atoms form about 4% of the total mass density of the observable universe, with an average density of about 0.25 atoms/m3.[94] Within a galaxy such as the Milky Way, atoms have a much higher concentration, with the density of matter in the interstellar medium (ISM) ranging from 105 to 109 atoms/m3.[95] The Sun is believed to be inside the Local Bubble, a region of highly ionized gas, so the density in the solar neighborhood is only about 103 atoms/m3.[96] Stars form from dense clouds in the ISM, and the evolutionary processes of stars result in the steady enrichment of the ISM with elements more massive than hydrogen and helium. Up to 95% of the Milky Way's atoms are concentrated inside stars and the total mass of atoms forms about 10% of the mass of the galaxy.[97] (The remainder of the mass is an unknown dark matter.[98])
## Nucleosynthesis
Stable protons and electrons appeared one second after the Big Bang. During the following three minutes, Big Bang nucleosynthesis produced most of the helium, lithium, and deuterium atoms in the universe, and perhaps some of the beryllium and boron.[99][100][101] The first atoms (complete with bound electrons) were theoretically created 380,000 years after the Big Bang—an epoch called recombination, when the expanding universe cooled enough to allow electrons to become attached to nuclei.[102] Since then, atomic nuclei have been combined in stars through the process of nuclear fusion to produce elements up to iron.[103]
Isotopes such as lithium-6 are generated in space through cosmic ray spallation.[104] This occurs when a high-energy proton strikes an atomic nucleus, causing large numbers of nucleons to be ejected. Elements heavier than iron were produced in supernovae through the r-process and in AGB stars through the s-process, both of which involve the capture of neutrons by atomic nuclei.[105] Elements such as lead formed largely through the radioactive decay of heavier elements.[106]
## Earth
Most of the atoms that make up the Earth and its inhabitants were present in their current form in the nebula that collapsed out of a molecular cloud to form the solar system. The rest are the result of radioactive decay, and their relative proportion can be used to determine the age of the Earth through radiometric dating.[107][108] Most of the helium in the crust of the Earth (about 99% of the helium from gas wells, as shown by its lower abundance of helium-3) is a product of alpha decay.[109]
There are a few trace atoms on Earth that were not present at the beginning (i.e., not "primordial"), nor are results of radioactive decay. Carbon-14 is continuously generated by cosmic rays in the atmosphere.[110] Some atoms on Earth have been artificially generated either deliberately or as by-products of nuclear reactors or explosions.[111][112] Of the transuranic elements—those with atomic numbers greater than 92—only plutonium and neptunium occur naturally on Earth.[113][114] Transuranic elements have radioactive lifetimes shorter than the current age of the Earth[115] and thus identifiable quantities of these elements have long since decayed, with the exception of traces of plutonium-244 possibly deposited by cosmic dust.[107] Natural deposits of plutonium and neptunium are produced by neutron capture in uranium ore.[116]
The Earth contains approximately 1.33Template:E atoms.[117] In the planet's atmosphere, small numbers of independent atoms exist for the noble gases, such as argon and neon. The remaining 99% of the atmosphere is bound in the form of molecules, including carbon dioxide and diatomic oxygen and nitrogen. At the surface of the Earth, atoms combine to form various compounds, including water, salt, silicates and oxides. Atoms can also combine to create materials that do not consist of discrete molecules, including crystals and liquid or solid metals.[118][119] This atomic matter forms networked arrangements that lack the particular type of small-scale interrupted order associated with molecular matter.[120]
## Rare and theoretical forms
While isotopes with atomic numbers higher than lead (82) are known to be radioactive, an "island of stability" has been proposed for some elements with atomic numbers above 103. These superheavy elements may have a nucleus that is relatively stable against radioactive decay.[121] The most likely candidate for a stable superheavy atom, unbihexium, has 126 protons and 184 neutrons.[122]
Each particle of matter has a corresponding antimatter particle with the opposite electrical charge. Thus, the positron is a positively charged antielectron and the antiproton is a negatively charged equivalent of a proton. For unknown reasons, antimatter particles are rare in the universe, hence, no antimatter atoms have been discovered.[123][124] Antihydrogen, the antimatter counterpart of hydrogen, was first produced at the CERN laboratory in Geneva in 1996.[125][126]
Other exotic atoms have been created by replacing one of the protons, neutrons or electrons with other particles that have the same charge. For example, an electron can be replaced by a more massive muon, forming a muonic atom. These types of atoms can be used to test the fundamental predictions of physics.[127][128][129] | https://www.wikidoc.org/index.php/Atom | |
4ac4baf308dd03d946f1652d530d44748bb33ece | wikidoc | Axon | Axon
An axon or nerve fibre, is a long, slender projection
-f a nerve cell, or neuron, that conducts electrical impulses
away from the neuron's cell body or soma.
# Anatomy
Axons are in effect the primary transmission lines of the nervous system, and as bundles they help make up nerves. Individual axons are microscopic in diameter (typically about 1μm across), but may be up to multiple feet long. The longest axons in the human body, for example, are those of the sciatic nerve, which run from the base of the spine to the big toe of each foot. These single-cell fibers of the sciatic nerve may extend a meter or even longer.
In vertebrates, only the axons of many neurons are sheathed in myelin, which is formed by either of two types of glial cells: Schwann cells ensheathing peripheral neurons and oligodendrocytes insulating those of the central nervous system. Along myelinated nerve fibers, gaps in the sheath known as nodes of Ranvier occur at evenly-spaced intervals, enabling an especially rapid mode of electrical impulse propagation called saltation. The demyelination of axons is what causes the multitude of neurological symptoms found in the disease Multiple Sclerosis.
The axons of some neurons branch to form axon collaterals, that can be divided into a number of smaller branches called telodendria. Along these the bifurcated impulse travels simultaneously to signal more than one other cell.
# Physiology
The physiology can be described by the Hodgkin-Huxley Model, extended to vertebrates in Frankenhaeuser-Huxley equations.
## Types
Peripheral nerve fibers can be classified based on axonal conduction velocity, mylenation, fiber size etc. For example, there are slow-conducting unmyelinated C fibers and faster-conducting myelinated Aδ fibers. More complex mathematical modeling continues to be done today.
There are several types of sensory- as well as motorfibers. Other fibers not mentioned in table are e.g. fibers of the autonomic nervous system
### Motor
Lower motor neurons have two kind of fibers:
### Sensory
Different sensory receptors are innervated by different types of nerve fibers. Muscles and associated sensory receptors are innvervated by type I and II sensory fibers, while cutaneous receptors are innervated by Aβ, Aδ and C fibers. It is taught in most collages across the United States and across the world.½
# Growth and development
Growing axons move through their environment via the growth cone, which is at the tip of the axon. The growth cone has a broad sheet like extension called lamellipodia which contain protrusions called filopodia. The filopodia are the mechanism by which the entire process adheres to surfaces and explores the surrounding environment. Actin plays a major role in the mobility of this system.
Environments with high levels of cell adhesion molecules or CAM's create an ideal environment for axonal growth. This seems to provide a "sticky" surface for axons to grow along. Examples of CAM's specific to neural systems include N-CAM, neuroglial CAM or NgCAM, TAG-1, MAG, and DCC, all of which are part of the immunoglobulin superfamily. Another set of molecules called extracellular matrix adhesion molecules also provide a sticky substrate for axons to grow along. Examples of these molecules include laminin, fibronectin, tenascin, and perlecan. Some of these are surface bound to cells and thus act as short range attractants or repellents. Others are difusible ligands and thus can have long range effects.
Cells called guidepost cells assist in the guidance of neuronal axon growth. These cells are typically other, sometimes immature, neurons.
# History
Some of the first intracellular recordings in a nervous system were made in the late 1930's by K. Cole and H. Curtis. Alan Hodgkin and Andrew Huxley also employed the squid giant axon (1939) and by 1952 they had obtained a full quantitative description of the ionic basis of the action potential, leading the formulation of the Hodgkin-Huxley Model.
Hodgkin and Huxley were awarded jointly the Nobel Prize for this work in 1963.
The formulas detailing axonal conductance were extended to vertebrates in the Frankenhaeuser-Huxley equations. Erlanger and Gasser later developed the classification system for peripheral nerve fibers, based on axonal conduction velocity, mylenation, fiber size etc.
Even recently our understanding of the biochemical basis for action potential propagation has advanced, and now includes many details about individual ion channels.
# Concussion
Concussion is considered a mild form of diffuse axonal injury . | Axon
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Template:Neuron map
An axon or nerve fibre, is a long, slender projection
of a nerve cell, or neuron, that conducts electrical impulses
away from the neuron's cell body or soma.
# Anatomy
Axons are in effect the primary transmission lines of the nervous system, and as bundles they help make up nerves. Individual axons are microscopic in diameter (typically about 1μm across), but may be up to multiple feet long. The longest axons in the human body, for example, are those of the sciatic nerve, which run from the base of the spine to the big toe of each foot. These single-cell fibers of the sciatic nerve may extend a meter or even longer.
In vertebrates, only the axons of many neurons are sheathed in myelin, which is formed by either of two types of glial cells: Schwann cells ensheathing peripheral neurons and oligodendrocytes insulating those of the central nervous system. Along myelinated nerve fibers, gaps in the sheath known as nodes of Ranvier occur at evenly-spaced intervals, enabling an especially rapid mode of electrical impulse propagation called saltation. The demyelination of axons is what causes the multitude of neurological symptoms found in the disease Multiple Sclerosis.
The axons of some neurons branch to form axon collaterals, that can be divided into a number of smaller branches called telodendria. Along these the bifurcated impulse travels simultaneously to signal more than one other cell.
# Physiology
The physiology can be described by the Hodgkin-Huxley Model, extended to vertebrates in Frankenhaeuser-Huxley equations.
## Types
Peripheral nerve fibers can be classified based on axonal conduction velocity, mylenation, fiber size etc. For example, there are slow-conducting unmyelinated C fibers and faster-conducting myelinated Aδ fibers. More complex mathematical modeling continues to be done today.
There are several types of sensory- as well as motorfibers. Other fibers not mentioned in table are e.g. fibers of the autonomic nervous system
### Motor
Lower motor neurons have two kind of fibers:
### Sensory
Different sensory receptors are innervated by different types of nerve fibers. Muscles and associated sensory receptors are innvervated by type I and II sensory fibers, while cutaneous receptors are innervated by Aβ, Aδ and C fibers. It is taught in most collages across the United States and across the world.½
# Growth and development
Growing axons move through their environment via the growth cone, which is at the tip of the axon. The growth cone has a broad sheet like extension called lamellipodia which contain protrusions called filopodia. The filopodia are the mechanism by which the entire process adheres to surfaces and explores the surrounding environment. Actin plays a major role in the mobility of this system.
Environments with high levels of cell adhesion molecules or CAM's create an ideal environment for axonal growth. This seems to provide a "sticky" surface for axons to grow along. Examples of CAM's specific to neural systems include N-CAM, neuroglial CAM or NgCAM, TAG-1, MAG, and DCC, all of which are part of the immunoglobulin superfamily. Another set of molecules called extracellular matrix adhesion molecules also provide a sticky substrate for axons to grow along. Examples of these molecules include laminin, fibronectin, tenascin, and perlecan. Some of these are surface bound to cells and thus act as short range attractants or repellents. Others are difusible ligands and thus can have long range effects.
Cells called guidepost cells assist in the guidance of neuronal axon growth. These cells are typically other, sometimes immature, neurons.
# History
Some of the first intracellular recordings in a nervous system were made in the late 1930's by K. Cole and H. Curtis. Alan Hodgkin and Andrew Huxley also employed the squid giant axon (1939) and by 1952 they had obtained a full quantitative description of the ionic basis of the action potential, leading the formulation of the Hodgkin-Huxley Model.
Hodgkin and Huxley were awarded jointly the Nobel Prize for this work in 1963.
The formulas detailing axonal conductance were extended to vertebrates in the Frankenhaeuser-Huxley equations. Erlanger and Gasser later developed the classification system for peripheral nerve fibers, based on axonal conduction velocity, mylenation, fiber size etc.
Even recently our understanding of the biochemical basis for action potential propagation has advanced, and now includes many details about individual ion channels.
# Concussion
Concussion is considered a mild form of diffuse axonal injury [3]. | https://www.wikidoc.org/index.php/Axon | |
67b9688c482ade6577f0df69196657d3019288fe | wikidoc | Neem | Neem
(Azadirachta indica) trunk in Kolkata W IMG 6190.jpg|100px|thumb| trunk in , ]
'Neem (Azadirachta indica, Melia azadirachta L., Antelaea azadirachta (L.) Adelb.) is a ), DogonYaro (Margosa, Neeb (), Nimtree, Nimba (Vepu, Vempu, Vepa (), Bevu in language|Kannada], Veppam in (language|Tamil]),arya veppu in malayalam and Indian-lilac. In East Africa it is also known as Mwarobaini ([ which means the tree of the 40; it's said to treat 40 different diseases.
Neem is a fast-growing [ that can reach a height of 15-20 m, rarely to 35-40 m. It is [ but under severe drought it may shed most or nearly all of its leaves. The branches are wide spread. The fairly dense crown is roundish or oval and may reach the diameter of 15-20 m in old, free-standing specimens.
The trunk is relatively short, straight and may reach a diameter of 1.2 m. The bark is hard, fissured or scaly, and whitish-grey to reddish-brown. The sapwood is greyish-white and the heartwood reddish when first exposed to the air becoming reddish-brown after exposure. The root system consists of a strong taproot and well developed lateral roots.
The alternate, leaves are 20-40 cm long, with 20-31 medium to dark green leaflets about 3-8 cm long. The terminal leaflet is often missing. The s are short. Very young leaves are reddish to purplish in colour. The shape of mature leaflets is more or less asymmetric and their margins are dentate with the exception of the base of their basiscopal half, which is normally very strongly reduced and cuneate.
(Azadirachta indica) leaves & flowers in Kolkata W IMG 6199.jpg|left|thumb| leaves & flowers in , ]The [ (white and fragrant) are arranged axillary, normally more-or-less drooping [ which are up to 25 cm long. The [ which branch up to the third degree, bear 150-250 flowers. An individual flower is 5-6 mm long and 8-11 mm wide. [ bisexual flowers and male flowers exist on the same individual (polygamous).
The [ is a glabrous olive-like [ which varies in shape from elongate oval to nearly roundish, and when ripe are 1.4-2.8 x 1.0-1.5 cm. The fruit skin (exocarp) is thin and the bitter-sweet pulp (mesocarp) is yellowish-white and very fibrous. The mesocarp is 0.3-0.5 cm thick. The white, hard inner shell (endocarp) of the fruit encloses one, rarely two or three, elongated [ (kernels) having a brown seed coat.
Commercial plantations of the trees are not considered profitable. Around 50,000 neem trees have been planted near to provide shelter for the [ Ganguli (2002) [ Neem: A therapeutic for all seasons, Current Science, Vol. 82, No. 11, June. pp. 1304
The neem tree is very similar in appearance to the [ all parts of which are extremely poisonous.
# Ecology
(Azadirachta indica) tree with flowers in Kolkata W IMG 6189.jpg|100px|thumb|left|tree with flowers in , ]The neem is a tree noted for its drought resistance. Normally it thrives in areas with sub-arid to sub-humid conditions, with an annual rainfall between 400 and 1200 mm. It can grow in regions with an annual rainfall below 400 mm, but in such cases it depends largely on the ground water levels. Neem can grow in many different types of [ but it thrives best on well drained deep and sandy soils (pH 6.2-7.0). It is a typical tropical/subtropical tree and exists at annual mean temperatures between 21-32 °C. It can tolerate high to very high temperatures. It does not tolerate temperature below 4 °C (leaf shedding and death may ensue).
Neem is a life giving tree in South India, especially for the dry coastal southern districts. It is one of the very few shade giving trees that thrive in the drought prone areas. The trees are not at all delicate about the water quality and thrive on the merest trickle of water, whatever the quality be. In Tamil Nadu it is very common to see neem trees used as shade giving trees lining the streets or in most people's back yards. In very dry areas like Sivakasi, the trees are planted in large tracts of land, in whose shade fire works factories (that are banned from using electricity for lighting) function.
# Chemical compounds
The active principles of the plant were brought to the attention of products] in , while working at the Scientific and Industrial Research Laboratory at University], for the first time extracted three bitter compounds from oil], which he provisionally named as nimbin, nimbinin, and nimbidin respectively.
# Usage
products.jpg|thumb|150px]
In India, the tree is variously known as "Divine Tree", "Heal All", "Nature's Drugstore", "Village Pharmacy" and "Panacea for all diseases". Products made from neem have proven medicinal properties, being anthelmintic, antifungal, antidiabetic, antibacterial, antiviral, anti-infertility, and sedative. It is considered a major component in medicine] and is particularly prescribed for skin disease.
- Neem twigs are used for brushing teeth in India, Bangladesh and Pakistan. This practice is perhaps one of the earliest and most effective forms of dental care.
- All parts of the tree (seeds, leaves, flowers and bark) are used for preparing many different medical preparations.
- oil] is used for preparing cosmetics (soap, shampoo, balms and creams), and is useful for skin care such as acne, and keeping skin elasticity.
- Besides its use in traditional Indian medicine the neem tree is of great importance for its anti-desertification properties and possibly as a good carbon dioxide sink.
- Practictioners of traditional Indian medicine recommend that patients suffering from Chicken Pox sleep on neem leaves.
- Gum] is used as a bulking agent and for the preparation of special purpose food (those for diabetics).
## Horticultural usages
Neem is a source of environment-friendly Among the isolated , [ (such as [ are effective in insect growth-regulating activity. The unique feature of neem products is that they do not directly kill the pests, but alter the life-processing behavior in such a manner that the insect can no longer feed, breed or undergo metamorphosis.
The oil is also used in sprays against [ in [ and [
The tender shoots and flowers of the neem tree are eaten as a in India. Neem flowers are very popular for their use in which is made on Ugadi day in South India. A soup like dish called Veppampoo Rasam (translated as 'juice of neem flower') made of the flower of neem is prepared in .
Neem is also used in parts of mainland Asia], particularly in and is a rich source of protein. | Neem
(Azadirachta indica) trunk in Kolkata W IMG 6190.jpg|100px|thumb| trunk in [http://worldselectshop.com/?id=9361 [http://worldselectshop.com/?id=9361 Bengal], [1]]
'Neem (Azadirachta indica, Melia azadirachta L., Antelaea azadirachta (L.) Adelb.) is a [http://worldselectshop.com/?id=9361 in the mahogany family [http://worldselectshop.com/?id=9361 It is one of two species in the genus [http://worldselectshop.com/?id=9361 and is native to [http://worldselectshop.com/?id=9361 [http://worldselectshop.com/?id=9361 [http://worldselectshop.com/?id=9361 and [http://worldselectshop.com/?id=9361 growing in [http://worldselectshop.com/?id=9361 and semi-tropical regions. Other vernacular names include Azad Dirakht ([http://worldselectshop.com/?id=9361 language|Persian]), DogonYaro (Margosa, Neeb ([http://worldselectshop.com/?id=9361 language|Arabic]), Nimtree, Nimba (Vepu, Vempu, Vepa ([http://worldselectshop.com/?id=9361 language|Telugu]), Bevu in language|Kannada], Veppam in (language|Tamil]),arya veppu in malayalam and Indian-lilac. In East Africa it is also known as Mwarobaini ([http://worldselectshop.com/?id=9361 which means the tree of the 40; it's said to treat 40 different diseases.
Neem is a fast-growing [http://worldselectshop.com/?id=9361 that can reach a height of 15-20 m, rarely to 35-40 m. It is [http://worldselectshop.com/?id=9361 but under severe drought it may shed most or nearly all of its leaves. The branches are wide spread. The fairly dense crown is roundish or oval and may reach the diameter of 15-20 m in old, free-standing specimens.
The trunk is relatively short, straight and may reach a diameter of 1.2 m. The bark is hard, fissured or scaly, and whitish-grey to reddish-brown. The sapwood is greyish-white and the heartwood reddish when first exposed to the air becoming reddish-brown after exposure. The root system consists of a strong taproot and well developed lateral roots.
The alternate, leaves are 20-40 cm long, with 20-31 medium to dark green leaflets about 3-8 cm long. The terminal leaflet is often missing. The [http://worldselectshop.com/?id=9361 (botany)|petiole]s are short. Very young leaves are reddish to purplish in colour. The shape of mature leaflets is more or less asymmetric and their margins are dentate with the exception of the base of their basiscopal half, which is normally very strongly reduced and cuneate.
(Azadirachta indica) leaves & flowers in Kolkata W IMG 6199.jpg|left|thumb| leaves & flowers in [http://worldselectshop.com/?id=9361 [http://worldselectshop.com/?id=9361 Bengal], [2]]The [http://worldselectshop.com/?id=9361 (white and fragrant) are arranged axillary, normally more-or-less drooping [http://worldselectshop.com/?id=9361 which are up to 25 cm long. The [http://worldselectshop.com/?id=9361 which branch up to the third degree, bear 150-250 flowers. An individual flower is 5-6 mm long and 8-11 mm wide. [http://worldselectshop.com/?id=9361 bisexual flowers and male flowers exist on the same individual (polygamous).
The [http://worldselectshop.com/?id=9361 is a glabrous olive-like [http://worldselectshop.com/?id=9361 which varies in shape from elongate oval to nearly roundish, and when ripe are 1.4-2.8 x 1.0-1.5 cm. The fruit skin (exocarp) is thin and the bitter-sweet pulp (mesocarp) is yellowish-white and very fibrous. The mesocarp is 0.3-0.5 cm thick. The white, hard inner shell (endocarp) of the fruit encloses one, rarely two or three, elongated [http://worldselectshop.com/?id=9361 (kernels) having a brown seed coat.
Commercial plantations of the trees are not considered profitable. Around 50,000 neem trees have been planted near to provide shelter for the [http://worldselectshop.com/?id=9361 Ganguli (2002) [http://worldselectshop.com/?id=9361 Neem: A therapeutic for all seasons, Current Science, Vol. 82, No. 11, June. pp. 1304</ref>
The neem tree is very similar in appearance to the [http://worldselectshop.com/?id=9361 all parts of which are extremely poisonous.
# Ecology
(Azadirachta indica) tree with flowers in Kolkata W IMG 6189.jpg|100px|thumb|left|tree with flowers in [http://worldselectshop.com/?id=9361 [http://worldselectshop.com/?id=9361 Bengal], [3]]The neem is a tree noted for its drought resistance. Normally it thrives in areas with sub-arid to sub-humid conditions, with an annual rainfall between 400 and 1200 mm. It can grow in regions with an annual rainfall below 400 mm, but in such cases it depends largely on the ground water levels. Neem can grow in many different types of [http://worldselectshop.com/?id=9361 but it thrives best on well drained deep and sandy soils (pH 6.2-7.0). It is a typical tropical/subtropical tree and exists at annual mean temperatures between 21-32 °C. It can tolerate high to very high temperatures. It does not tolerate temperature below 4 °C (leaf shedding and death may ensue).
Neem is a life giving tree in South India, especially for the dry coastal southern districts. It is one of the very few shade giving trees that thrive in the drought prone areas. The trees are not at all delicate about the water quality and thrive on the merest trickle of water, whatever the quality be. In Tamil Nadu it is very common to see neem trees used as shade giving trees lining the streets or in most people's back yards. In very dry areas like Sivakasi, the trees are planted in large tracts of land, in whose shade fire works factories (that are banned from using electricity for lighting) function.
# Chemical compounds
The active principles of the plant were brought to the attention of products] in [http://worldselectshop.com/?id=9361 when [http://worldselectshop.com/?id=9361 Siddiqui], while working at the Scientific and Industrial Research Laboratory at University], for the first time extracted three bitter compounds from oil], which he provisionally named as nimbin, nimbinin, and nimbidin respectively.[1]
# Usage
products.jpg|thumb|150px]
In India, the tree is variously known as "Divine Tree", "Heal All", "Nature's Drugstore", "Village Pharmacy" and "Panacea for all diseases". Products made from neem have proven medicinal properties, being anthelmintic, antifungal, antidiabetic, antibacterial, antiviral, anti-infertility, and sedative. It is considered a major component in medicine] and is particularly prescribed for skin disease[citation needed].
- Neem twigs are used for brushing teeth in India, Bangladesh and Pakistan. This practice is perhaps one of the earliest and most effective forms of dental care.
- All parts of the tree (seeds, leaves, flowers and bark) are used for preparing many different medical preparations.
- oil] is used for preparing cosmetics (soap, shampoo, balms and creams), and is useful for skin care such as acne, and keeping skin elasticity.
- Besides its use in traditional Indian medicine the neem tree is of great importance for its anti-desertification properties and possibly as a good carbon dioxide sink.
- Practictioners of traditional Indian medicine recommend that patients suffering from Chicken Pox sleep on neem leaves.
- Gum] is used as a bulking agent and for the preparation of special purpose food (those for diabetics).
## Horticultural usages
Neem is a source of environment-friendly Among the isolated [http://worldselectshop.com/?id=9361 compounds|neem constituents], [http://worldselectshop.com/?id=9361 (such as [http://worldselectshop.com/?id=9361 are effective in insect growth-regulating activity. The unique feature of neem products is that they do not directly kill the pests, but alter the life-processing behavior in such a manner that the insect can no longer feed, breed or undergo metamorphosis.
The oil is also used in sprays against [http://worldselectshop.com/?id=9361 in [http://worldselectshop.com/?id=9361 and [http://worldselectshop.com/?id=9361
The tender shoots and flowers of the neem tree are eaten as a in India. Neem flowers are very popular for their use in [http://worldselectshop.com/?id=9361 Pachadi (soup-like pickle)[2] which is made on Ugadi day in South India. A soup like dish called Veppampoo Rasam (translated as 'juice of neem flower') made of the flower of neem is prepared in [http://worldselectshop.com/?id=9361 Nadu].
Neem is also used in parts of mainland Asia], particularly in and [http://worldselectshop.com/?id=9361 (where it is known as sadao or sdao), [http://worldselectshop.com/?id=9361 (where it is called kadao) and [http://worldselectshop.com/?id=9361 (where it is called sầu Äâu). Even lightly cooked, the flavour is quite bitter and thus the food is not enjoyed by all inhabitants of these nations, though it is believed to be good for one's health. [http://worldselectshop.com/?id=9361 Gum] is a rich source of protein. | https://www.wikidoc.org/index.php/Azadirachta_indica | |
c824fdc47e9f7d190531a099ed5844055297f7a7 | wikidoc | CD45 | CD45
In immunology, the CD45 antigen (CD stands for cluster of differentiation) is a protein which was originally called leukocyte common antigen.
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular domain, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus belongs to receptor type PTP. This gene is specifically expressed in hematopoietic cells. This PTP has been shown to be an essential regulator of T- and B-cell antigen receptor signaling. It functions through either direct interaction with components of the antigen receptor complexes, or by activating various Src family kinases required for the antigen receptor signaling. This PTP also suppresses JAK kinases, and thus functions as a regulator of cytokine receptor signaling. Four alternatively spliced transcripts variants of this gene, which encode distinct isoforms, have been reported.
It is a type I transmembrane protein which is in various forms present on all differentiated hematopoietic cells except erythrocytes and plasma cells that assists in the activation of those cells (a form of co-stimulation).
It is expressed in lymphomas, B-cell chronic lymphocytic leukemia, hairy cell leukemia, and acute nonlymphocytic leukemia.
The CD45 family consists of multiple members that are all products of a single complex gene. This gene contains 34 exons and three exons of the primary transcripts are alternatively spliced to generate up to eight different mature mRNAs and after translation eight different protein products. This three exons generate the RA, RB and RC isoforms.
Various isoforms of CD45 exist:
CD45RA, CD45RB, CD45RC, CD45RAB, CD45RAC, CD45RBC, CD45RO, CD45R (ABC).
CD45 is also highly glycosylated. CD45R is the longest protein and migrates at 200 kDa when isolated from T cells. B cells also express CD45R with heavier glycosylation, bringing the molecular weight to 220 kDa, hence the name B220; B cell isoform of 220 kDa. B220 expression is not restricted to B cells and can also be expressed on activated T cells, on a subset of dendritic cells and other antigen presenting cells.
Naive T lymphocytes express large CD45 isoforms and are usually positive for CD45RA. Activated and memory T lymphocytes express the shortest CD45 isoform, CD45RO, which lacks RA, RB and RC exons. This shortest isoform facilitates T cell activation.
The cytoplasmic domain of CD45 is one of the largest known and it has an intrinsic phosphatase activity that removes an inhibitory phosphate group on a tyrosine kinase called Lck (in T cells) or Syk (in B cells) and activates it. | CD45
In immunology, the CD45 antigen (CD stands for cluster of differentiation) is a protein which was originally called leukocyte common antigen.[1]
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular domain, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus belongs to receptor type PTP. This gene is specifically expressed in hematopoietic cells. This PTP has been shown to be an essential regulator of T- and B-cell antigen receptor signaling. It functions through either direct interaction with components of the antigen receptor complexes, or by activating various Src family kinases required for the antigen receptor signaling. This PTP also suppresses JAK kinases, and thus functions as a regulator of cytokine receptor signaling. Four alternatively spliced transcripts variants of this gene, which encode distinct isoforms, have been reported.[1]
It is a type I transmembrane protein which is in various forms present on all differentiated hematopoietic cells except erythrocytes and plasma cells that assists in the activation of those cells (a form of co-stimulation).
It is expressed in lymphomas, B-cell chronic lymphocytic leukemia, hairy cell leukemia, and acute nonlymphocytic leukemia.
The CD45 family consists of multiple members that are all products of a single complex gene. This gene contains 34 exons and three exons of the primary transcripts are alternatively spliced to generate up to eight different mature mRNAs and after translation eight different protein products. This three exons generate the RA, RB and RC isoforms.
Various isoforms of CD45 exist:
CD45RA, CD45RB, CD45RC, CD45RAB, CD45RAC, CD45RBC, CD45RO, CD45R (ABC).
CD45 is also highly glycosylated. CD45R is the longest protein and migrates at 200 kDa when isolated from T cells. B cells also express CD45R with heavier glycosylation, bringing the molecular weight to 220 kDa, hence the name B220; B cell isoform of 220 kDa. B220 expression is not restricted to B cells and can also be expressed on activated T cells, on a subset of dendritic cells and other antigen presenting cells.
Naive T lymphocytes express large CD45 isoforms and are usually positive for CD45RA. Activated and memory T lymphocytes express the shortest CD45 isoform, CD45RO, which lacks RA, RB and RC exons. This shortest isoform facilitates T cell activation.
The cytoplasmic domain of CD45 is one of the largest known and it has an intrinsic phosphatase activity that removes an inhibitory phosphate group on a tyrosine kinase called Lck (in T cells) or Syk (in B cells) and activates it. | https://www.wikidoc.org/index.php/B220 | |
67c370295735daa5b302eecf629889d5a8e49cf3 | wikidoc | BAG1 | BAG1
BAG family molecular chaperone regulator 1 is a protein that in humans is encoded by the BAG1 gene.
# Function
The oncogene BCL2 is a membrane protein that blocks a step in a pathway leading to apoptosis or programmed cell death. The protein encoded by this gene binds to BCL2 and is referred to as BCL2-associated athanogene. It enhances the anti-apoptotic effects of BCL2 and represents a link between growth factor receptors and anti-apoptotic mechanisms. At least three protein isoforms are encoded by this mRNA through the use of alternative translation initiation sites, including a non-AUG site.
# Clinical significance
BAG gene has been implicated in age related neurodegenerative diseases as Alzheimer's. It has been demonstrated that BAG1 and BAG 3 regulate the proteasomal and lysosomal protein elimination pathways, respectively.
# Interactions
BAG1 has been shown to interact with:
- Androgen receptor,
- C-Raf,
- Calcitriol receptor,
- Glucocorticoid receptor,
- HSPA8,
- HBEGF,
- PPP1R15A,
- NR1B1, and
- SIAH1. | BAG1
BAG family molecular chaperone regulator 1 is a protein that in humans is encoded by the BAG1 gene.[1]
# Function
The oncogene BCL2 is a membrane protein that blocks a step in a pathway leading to apoptosis or programmed cell death. The protein encoded by this gene binds to BCL2 and is referred to as BCL2-associated athanogene. It enhances the anti-apoptotic effects of BCL2 and represents a link between growth factor receptors and anti-apoptotic mechanisms. At least three protein isoforms are encoded by this mRNA through the use of alternative translation initiation sites, including a non-AUG site.[2]
# Clinical significance
BAG gene has been implicated in age related neurodegenerative diseases as Alzheimer's. It has been demonstrated that BAG1 and BAG 3 regulate the proteasomal and lysosomal protein elimination pathways, respectively.[3]
# Interactions
BAG1 has been shown to interact with:
- Androgen receptor,[4][5][6]
- C-Raf,[7]
- Calcitriol receptor,[8]
- Glucocorticoid receptor,[9][10]
- HSPA8,[11][12]
- HBEGF,[13]
- PPP1R15A,[14]
- NR1B1,[15] and
- SIAH1.[16] | https://www.wikidoc.org/index.php/BAG1 | |
96ff60a36db30a7350df9f8d57b062c6d9c94fc0 | wikidoc | BAG3 | BAG3
BAG family molecular chaperone regulator 3 is a protein that in humans is encoded by the BAG3 gene. BAG3 is involved in chaperone-assisted selective autophagy.
# Function
BAG proteins compete with Hip-1 for binding to the Hsc70/Hsp70 ATPase domain and promote substrate release. All the BAG proteins have an approximately 45-amino acid BAG domain near the C terminus but differ markedly in their N-terminal regions. The protein encoded by this gene contains a WW domain in the N-terminal region and a BAG domain in the C-terminal region. The BAG domains of BAG1, BAG2, and BAG3 interact specifically with the Hsc70 ATPase domain in vitro and in mammalian cells. All 3 proteins bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner.
# Clinical significance
BAG gene has been implicated in age related neurodegenerative diseases such as Alzheimer's. It has been demonstrated that BAG1 and BAG 3 regulate the proteasomal and lysosomal protein elimination pathways, respectively. It has also been shown to be a cause of familial dilated cardiomyopathy.
That BAG3 mutations are responsible for familial dilated cardiomyopathy is confirmed by another study describing 6 new molecular variants (2 missense and 4 premature Stops
). Moreover, the same publication reported that BAG3 polymorphisms are also associated with sporadic forms of the disease together with HSPB7 locus.
In muscle cells, BAG3 cooperates with the molecular chaperones Hsc70 and HspB8 to induce the degradation of mechanically damaged cytoskeleton components in lysosomes. This process is called chaperone-assisted selective autophagy and is essential for maintaining muscle activity in flies, mice and men.
BAG3 is able to stimulate the expression of cytoskeleton proteins in response to mechanical tension by activating the transcription regulators YAP1 and WWTR1. BAG3 balances protein synthesis and protein degradation under mechanical stress.
# Interactions
PLCG1 has been shown to interact with:
- FGFR1,
- CD117,
- CD31,
- Cbl gene
- CISH
- Epidermal growth factor receptor,
- Eukaryotic translation elongation factor 1 alpha 1,
- FLT1,
- GAB1,
- GIT1,
- Grb2,
- HER2/neu,
- IRS2,
- ITK,
- KHDRBS1,
- Linker of activated T cells,
- Lymphocyte cytosolic protein 2,
- PDGFRA,
- PLD2,
- RHOA,
- SOS1,
- TUB,
- TrkA,
- TrkB,
- VAV1, and
- Wiskott-Aldrich syndrome protein. | BAG3
BAG family molecular chaperone regulator 3 is a protein that in humans is encoded by the BAG3 gene. BAG3 is involved in chaperone-assisted selective autophagy.[1][2][3][4][5]
# Function
BAG proteins compete with Hip-1 for binding to the Hsc70/Hsp70 ATPase domain and promote substrate release. All the BAG proteins have an approximately 45-amino acid BAG domain near the C terminus but differ markedly in their N-terminal regions. The protein encoded by this gene contains a WW domain in the N-terminal region and a BAG domain in the C-terminal region. The BAG domains of BAG1, BAG2, and BAG3 interact specifically with the Hsc70 ATPase domain in vitro and in mammalian cells. All 3 proteins bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner.[3]
# Clinical significance
BAG gene has been implicated in age related neurodegenerative diseases such as Alzheimer's. It has been demonstrated that BAG1 and BAG 3 regulate the proteasomal and lysosomal protein elimination pathways, respectively.[6][7] It has also been shown to be a cause of familial dilated cardiomyopathy.[8]
That BAG3 mutations are responsible for familial dilated cardiomyopathy is confirmed by another study describing 6 new molecular variants (2 missense and 4 premature Stops
). Moreover, the same publication reported that BAG3 polymorphisms are also associated with sporadic forms of the disease together with HSPB7 locus.[9]
In muscle cells, BAG3 cooperates with the molecular chaperones Hsc70 and HspB8 to induce the degradation of mechanically damaged cytoskeleton components in lysosomes. This process is called chaperone-assisted selective autophagy and is essential for maintaining muscle activity in flies, mice and men.[4]
BAG3 is able to stimulate the expression of cytoskeleton proteins in response to mechanical tension by activating the transcription regulators YAP1 and WWTR1.[5] BAG3 balances protein synthesis and protein degradation under mechanical stress.
# Interactions
PLCG1 has been shown to interact with:
- FGFR1,[10]
- CD117,[11][12]
- CD31,[13]
- Cbl gene[14][15]
- CISH[16]
- Epidermal growth factor receptor,[14][17]
- Eukaryotic translation elongation factor 1 alpha 1,[18]
- FLT1,[19]
- GAB1,[20][21]
- GIT1,[22]
- Grb2,[23][24][25]
- HER2/neu,[26][27]
- IRS2,[28]
- ITK,[29][30]
- KHDRBS1,[31][32][33]
- Linker of activated T cells,[34][35][36]
- Lymphocyte cytosolic protein 2,[37]
- PDGFRA,[38]
- PLD2,[39]
- RHOA,[40]
- SOS1,[25][41]
- TUB,[42]
- TrkA,[43][44][45][46]
- TrkB,[45][47]
- VAV1,[48] and
- Wiskott-Aldrich syndrome protein.[49][50] | https://www.wikidoc.org/index.php/BAG3 | |
58dcf3a579d3a8964011df813c870afbb0f18041 | wikidoc | BAP1 | BAP1
BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) is a deubiquitinating enzyme that in humans is encoded by the BAP1 gene. BAP1 encodes an 80.4 kDa nuclear-localizing protein with a ubiquitin carboxy-terminal hydrolase (UCH) domain that gives BAP1 its deubiquitinase activity. Recent studies have shown that BAP1 and its fruit fly homolog, Calypso, are members of the polycomb-group proteins (PcG) of highly conserved transcriptional repressors required for long-term silencing of genes that regulate cell fate determination, stem cell pluripotency, and other developmental processes.
# Nomenclature
BAP1 is also known as:
- UniProt name: Ubiquitin carboxyl-terminal hydrolase BAP1
- ubiquitin carboxyl-terminal hydrolase like-2 (UCHL2)
- human cerebral protein 6 (hucep 6)
- human cerebral protein-13 (hucep-13)
# Gene
In humans, BAP1 is encoded by the BAP1 gene located on the short arm of chromosome 3 (3p21.31-p21.2).
# Structure
Human BAP1 is 729 amino acids long and has three domains:
- a ubiquitin carboxyl-terminal hydrolase (UCH) N-terminus catalytic domain, which removes ubiquitin from ubiquitylated substrates: residues 1-240, with an active site comprising the Cysteine91, Alanine95, and Glycine178 residues.
- a unique linker region, which includes a Host cell factor C1 binding domain at residues 356-385.
- a C-terminal domain: residues 598-729, which includes a UCH37-like domain (ULD) at residues 675-693 and two Nuclear localization sequences at residues 656-661 and 717-722.
# Function
In both Drosophila and humans, BAP1 functions as the catalytic subunit of the Polycomb repressive deubiquitinase (PR-DUB) complex, which controls homeobox genes by regulating the amount of ubiquitinated Histone H2A in Nucleosomes bound to their promoters. In flies and humans, the PR-DUB complex is formed through the interaction of BAP1 and ASXL1 (Asx in fruit flies) BAP1 has also been shown to associate with other factors involved in chromatin modulation and transcriptional regulation, such as Host cell factor C1, which acts as an adaptor to couple E2F transcription factors to chromatin-modifying complexes during cell cycle progression.
# Role in disease
In cancer, BAP1 can function both as a Tumor suppressor and as a Metastasis suppressor.
## Somatic mutations in cancer
- BAP1 somatic mutations were identified in a small number of breast and lung cancer cell lines, but BAP1 was first shown to act as a tumor suppressor in cultured cells, where its deubiquitinase (UCH) domain and Nuclear localization sequences were required for BAP1 to suppress cell growth.
- In 2010, J. William Harbour and colleagues published a landmark article in Science, in which they used Exome sequencing of patient tumor samples and identified inactivating mutations in BAP1 in 47% of Uveal melanomas. They were also the first to show germline BAP1 mutations, and that BAP1 mutation was strongly associated with metastasis. These mutations included multiple Nonsense mutations and splice site mutations throughout the gene. missense mutations were only found within the UCH and ULD domains, further supporting the requirement for BAP1 catalytic function. This study also identified a Germline mutation in one of the uveal melanoma patients, suggesting that, besides being a Metastasis suppressor, BAP1 could predispose certain people to more aggressive uveal melanoma tumors.
- BAP1 mutations have been identified in aggressive Mesotheliomas with similar mutations as seen in melanomas,.
- Mutations in the tumor suppressor gene BAP1 occur in approximately 15% of clear cell renal cell carcinoma (CCRCC) cases. Sequencing efforts demonstrated worse outcomes in patients with BAP1 mutated clear cell renal cell carcinoma. .
## BAP1 tumor predisposition syndrome
Two studies used Genome sequencing independently to identify Germline mutations in BAP1 in families with genetic predispositions to mesothelioma and melanocytic skin tumors The atypical melanocytic lesions resemble Spitz nevi and have been characterized as "atypical Spitz tumors" (ASTs), although they have a unique histology and exhibit both BRAF and BAP1 mutations.
Further studies have identified germline BAP1 mutations associated with other cancers. These studies suggest that germline mutation of BAP1 results in a Tumor Predisposition Syndrome linking BAP1 to many more cancers.
# Immunochemistry
Immunohistochemistry for BAP1 is a prognostic biomarker to predict poor oncologic outcomes and adverse clinicopathological features in patients with non-metastatic clear cell renal cell carcinoma (CCRCC). BAP1 assessment using immunohistochemistry on needle biopsy may benefit preoperative risk stratification and guide treatment planning.
# Interactions
BAP1 has been shown to interact with
- AHCYL2
- ANAPC7
- ANKRD17
- ASXL1
- ASXL2
- BRCA1
- CBX1
- CBX3
- EIF4EBP3
- FOXK1
- FOXK2
- HAT1
- HCFC1
- HIST2H2AC
- HSPA2
- IPO4
- IPO5
- KDM1B
- OGT
- PPM1G
- PSME3
- RBBP7
- UBE2O
# Model organisms
Model organisms have been used in the study of BAP1 function. A conditional knockout mouse line called Bap1tm1a(EUCOMM)Hmgu 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 - in-depth bone and cartilage phenotyping | BAP1
BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) is a deubiquitinating enzyme that in humans is encoded by the BAP1 gene.[1][2] BAP1 encodes an 80.4 kDa nuclear-localizing protein with a ubiquitin carboxy-terminal hydrolase (UCH) domain that gives BAP1 its deubiquitinase activity.[1] Recent studies have shown that BAP1 and its fruit fly homolog, Calypso, are members of the polycomb-group proteins (PcG) of highly conserved transcriptional repressors required for long-term silencing of genes that regulate cell fate determination, stem cell pluripotency, and other developmental processes.[3]
# Nomenclature
BAP1 is also known as:
- UniProt name: Ubiquitin carboxyl-terminal hydrolase BAP1
- ubiquitin carboxyl-terminal hydrolase like-2 (UCHL2)
- human cerebral protein 6 (hucep 6)
- human cerebral protein-13 (hucep-13)
# Gene
In humans, BAP1 is encoded by the BAP1 gene located on the short arm of chromosome 3 (3p21.31-p21.2).
# Structure
Human BAP1 is 729 amino acids long and has three domains:
- a ubiquitin carboxyl-terminal hydrolase (UCH) N-terminus catalytic domain, which removes ubiquitin from ubiquitylated substrates: residues 1-240, with an active site comprising the Cysteine91, Alanine95, and Glycine178 residues.
- a unique linker region, which includes a Host cell factor C1 binding domain at residues 356-385.
- a C-terminal domain: residues 598-729, which includes a UCH37-like domain (ULD) at residues 675-693 and two Nuclear localization sequences at residues 656-661 and 717-722.
# Function
In both Drosophila and humans, BAP1 functions as the catalytic subunit of the Polycomb repressive deubiquitinase (PR-DUB) complex, which controls homeobox genes by regulating the amount of ubiquitinated Histone H2A in Nucleosomes bound to their promoters. In flies and humans, the PR-DUB complex is formed through the interaction of BAP1 and ASXL1 (Asx in fruit flies)[4][5] BAP1 has also been shown to associate with other factors involved in chromatin modulation and transcriptional regulation, such as Host cell factor C1,[6][7][8] which acts as an adaptor to couple E2F transcription factors to chromatin-modifying complexes during cell cycle progression.
# Role in disease
In cancer, BAP1 can function both as a Tumor suppressor and as a Metastasis suppressor.
## Somatic mutations in cancer
- BAP1 somatic mutations were identified in a small number of breast and lung cancer cell lines,[1] but BAP1 was first shown to act as a tumor suppressor in cultured cells, where its deubiquitinase (UCH) domain and Nuclear localization sequences were required for BAP1 to suppress cell growth.[9]
- In 2010, J. William Harbour and colleagues published a landmark article in Science, in which they used Exome sequencing of patient tumor samples and identified inactivating mutations in BAP1 in 47% of Uveal melanomas. They were also the first to show germline BAP1 mutations, and that BAP1 mutation was strongly associated with metastasis.[10] These mutations included multiple Nonsense mutations and splice site mutations throughout the gene. missense mutations were only found within the UCH and ULD domains, further supporting the requirement for BAP1 catalytic function. This study also identified a Germline mutation in one of the uveal melanoma patients, suggesting that, besides being a Metastasis suppressor, BAP1 could predispose certain people to more aggressive uveal melanoma tumors.
- BAP1 mutations have been identified in aggressive Mesotheliomas with similar mutations as seen in melanomas,.[11]
- Mutations in the tumor suppressor gene BAP1 occur in approximately 15% of clear cell renal cell carcinoma (CCRCC) cases. Sequencing efforts demonstrated worse outcomes in patients with BAP1 mutated clear cell renal cell carcinoma. .[12]
## BAP1 tumor predisposition syndrome
Two studies used Genome sequencing independently to identify Germline mutations in BAP1 in families with genetic predispositions to mesothelioma[13] and melanocytic skin tumors[14] The atypical melanocytic lesions resemble Spitz nevi and have been characterized as "atypical Spitz tumors" (ASTs), although they have a unique histology and exhibit both BRAF and BAP1 mutations.[15]
Further studies have identified germline BAP1 mutations associated with other cancers.[16] These studies suggest that germline mutation of BAP1 results in a Tumor Predisposition Syndrome linking BAP1 to many more cancers.
# Immunochemistry
Immunohistochemistry for BAP1 is a prognostic biomarker to predict poor oncologic outcomes and adverse clinicopathological features in patients with non-metastatic clear cell renal cell carcinoma (CCRCC). BAP1 assessment using immunohistochemistry on needle biopsy may benefit preoperative risk stratification and guide treatment planning.[17]
# Interactions
BAP1 has been shown to interact with
- AHCYL2[5]
- ANAPC7[5]
- ANKRD17[5][6]
- ASXL1[4][5][6]
- ASXL2[5][6]
- BRCA1[1]
- CBX1[5]
- CBX3[5]
- EIF4EBP3[5]
- FOXK1[5][6]
- FOXK2[5][6]
- HAT1[5][6]
- HCFC1[5][6]
- HIST2H2AC[4]
- HSPA2[6]
- IPO4[5]
- IPO5[5]
- KDM1B[5][6]
- OGT[5]
- PPM1G[5]
- PSME3[5]
- RBBP7[5]
- UBE2O[5]
# Model organisms
Model organisms have been used in the study of BAP1 function. A conditional knockout mouse line called Bap1tm1a(EUCOMM)Hmgu was generated at the Wellcome Trust Sanger Institute.[18] Male and female animals underwent a standardized phenotypic screen[19] to determine the effects of deletion.[20][21][22][23] Additional screens performed: - In-depth immunological phenotyping[24] - in-depth bone and cartilage phenotyping[25] | https://www.wikidoc.org/index.php/BAP1 | |
0581882fba2a9f99df07be06c4dcdf7d7a9b7f5e | wikidoc | BBS1 | BBS1
Bardet-Biedl syndrome 1 protein is a protein that in humans is encoded by the BBS1 gene.
BBS1 is part of the BBSome complex, which required for ciliogenesis.
Mutations in this gene have been observed in patients with the major form (type 1) of Bardet-Biedl syndrome.
# History
As of 2008, research results indicated that the encoded protein may play a role in eye, limb, cardiac and reproductive system development. | BBS1
Bardet-Biedl syndrome 1 protein is a protein that in humans is encoded by the BBS1 gene.[1][2][3]
BBS1 is part of the BBSome complex, which required for ciliogenesis.
Mutations in this gene have been observed in patients with the major form (type 1) of Bardet-Biedl syndrome.
# History
As of 2008[update], research results indicated that the encoded protein may play a role in eye, limb, cardiac and reproductive system development.[3][needs update] | https://www.wikidoc.org/index.php/BBS1 | |
b379a0ca80ce05212770ec33acd5ae6794778782 | wikidoc | BCL3 | BCL3
B-cell lymphoma 3-encoded protein is a protein that in humans is encoded by the BCL3 gene.
This gene is a proto-oncogene candidate. It is identified by its translocation into the immunoglobulin alpha-locus in some cases of B-cell leukemia. The protein encoded by this gene contains seven ankyrin repeats, which are most closely related to those found in I kappa B proteins. This protein functions as a transcriptional coactivator that activates through its association with NF-kappa B homodimers. The expression of this gene can be induced by NF-kappa B, which forms a part of the autoregulatory loop that controls the nuclear residence of p50 NF-kappa B.
Like BCL2, BCL5, BCL6, BCL7A, BCL9, and BCL10, it has clinical significance in lymphoma.
# Interactions
BCL3 has been shown to interact with:
- BARD1,
- C-Fos,
- C-jun,
- C22orf25,
- COPS5,
- EP300,
- HTATIP,
- NFKB1,
- NFKB2,
- PIR, and
- NR2B1. | BCL3
B-cell lymphoma 3-encoded protein is a protein that in humans is encoded by the BCL3 gene.[1][2]
This gene is a proto-oncogene candidate. It is identified by its translocation into the immunoglobulin alpha-locus in some cases of B-cell leukemia. The protein encoded by this gene contains seven ankyrin repeats, which are most closely related to those found in I kappa B proteins. This protein functions as a transcriptional coactivator that activates through its association with NF-kappa B homodimers. The expression of this gene can be induced by NF-kappa B, which forms a part of the autoregulatory loop that controls the nuclear residence of p50 NF-kappa B.[3]
Like BCL2, BCL5, BCL6, BCL7A, BCL9, and BCL10, it has clinical significance in lymphoma.
# Interactions
BCL3 has been shown to interact with:
- BARD1,[4]
- C-Fos,[5]
- C-jun,[5]
- C22orf25,[6]
- COPS5,[4]
- EP300,[5]
- HTATIP,[4]
- NFKB1,[7][8][9]
- NFKB2,[7][10]
- PIR,[4] and
- NR2B1.[11] | https://www.wikidoc.org/index.php/BCL3 | |
2735b7b47a6c13215422888ba9c71d6fe3679b75 | wikidoc | BCL6 | BCL6
B-cell lymphoma 6 protein is a protein that in humans is encoded by the BCL6 gene. Like BCL2, BCL3, BCL5, BCL7A, BCL9 and BCL10, it has clinical significance in lymphoma.
# Function
The protein encoded by this gene is an evolutionarily conserved zinc finger transcription factor and contains an N-terminal POZ/BTB domain. This protein acts as a sequence-specific repressor of transcription and has been shown to modulate the STAT-dependent Interleukin 4 (IL-4) responses of B cells. This protein can interact with several corepressor complexes to inhibit transcription. This gene is found to be frequently translocated and hypermutated in diffuse large B cell lymphoma (DLBCL) and contributes to the pathogenesis of DLBCL. An exon 7 skipping splice variant encodes a shorter form of the protein which lacks the first two zinc fingers of the DNA binding domain.
Physiologically, BCL6 is a master transcription factor which leads the differentiation of naive helper T cells in Follicular Helper T cells (TFH cells). Its action is negatively regulated by the gene PRDM1 encoding the transcription factor Blimp-1.
# Diagnostic utility
The presence of BCL6 can be demonstrated in tissue sections using immunohistochemistry. It is exclusively present in the B-cells of both healthy and neoplastic germinal centres. It therefore demonstrates both reactive hyperplasia in lymph nodes and a range of lymphomas derived from follicular B-cells, such as Burkitt's lymphoma, follicular lymphoma and the nodular lymphocyte predominant subtype of Hodgkin's disease. It is often used together with antibodies to Bcl-2 antigen to distinguish neoplastic follicles from those found in benign hyperplasia, for which Bcl-2 is negative.
# Interactions
BCL6 has been shown to interact with
- BCOR,
- C-jun,
- HDAC1,
- HDAC4,
- HDAC7A,
- HDAC5,
- IRF4,
- NCOR2,
- SMRT,
- ZBTB7A
- T-bet,
- ZBTB16 | BCL6
B-cell lymphoma 6 protein is a protein that in humans is encoded by the BCL6 gene.[1] Like BCL2, BCL3, BCL5, BCL7A, BCL9 and BCL10, it has clinical significance in lymphoma.
# Function
The protein encoded by this gene is an evolutionarily conserved zinc finger transcription factor and contains an N-terminal POZ/BTB domain. This protein acts as a sequence-specific repressor of transcription and has been shown to modulate the STAT-dependent Interleukin 4 (IL-4) responses of B cells. This protein can interact with several corepressor complexes to inhibit transcription. This gene is found to be frequently translocated and hypermutated in diffuse large B cell lymphoma (DLBCL)[2][3][4] and contributes to the pathogenesis of DLBCL. An exon 7 skipping splice variant encodes a shorter form of the protein which lacks the first two zinc fingers of the DNA binding domain.[5]
Physiologically, BCL6 is a master transcription factor which leads the differentiation of naive helper T cells in Follicular Helper T cells (TFH cells).[6] Its action is negatively regulated by the gene PRDM1 encoding the transcription factor Blimp-1.[7]
# Diagnostic utility
The presence of BCL6 can be demonstrated in tissue sections using immunohistochemistry. It is exclusively present in the B-cells of both healthy and neoplastic germinal centres. It therefore demonstrates both reactive hyperplasia in lymph nodes and a range of lymphomas derived from follicular B-cells, such as Burkitt's lymphoma, follicular lymphoma and the nodular lymphocyte predominant subtype of Hodgkin's disease. It is often used together with antibodies to Bcl-2 antigen to distinguish neoplastic follicles from those found in benign hyperplasia, for which Bcl-2 is negative.[8]
# Interactions
BCL6 has been shown to interact with
- BCOR,[9]
- C-jun,[10]
- HDAC1,[11][12]
- HDAC4,[13]
- HDAC7A,[13]
- HDAC5,[13]
- IRF4,[14]
- NCOR2,[9][12][15]
- SMRT,[11][15]
- ZBTB7A[16]
- T-bet,[17]
- ZBTB16[18] | https://www.wikidoc.org/index.php/BCL6 | |
128e6bccde1803797140d621f6ea32beaa6efd19 | wikidoc | BCL9 | BCL9
B-cell CLL/lymphoma 9 protein is a protein that in humans is encoded by the BCL9 gene.
# Function
BCL9, together with its paralogue gene BCL9L (BCL9 like or BCL9.2), have been extensively studied for their role as transcriptional beta-catenin cofactors, fundamental for the transcription of Wnt target genes.
Recent work, using the mouse (Mus musculus) and Zebrafish (Danio rerio) as model organisms, identified an ancient role of BCL9 and BCL9L as key factors required for cardiac development . This work emphasises the tissue-specific nature of the Wnt/β-catenin mechanism of action, and implicates alterations in BCL9 and BCL9L in human congenital heart defects.
BCL9 and BCL9L have been shown to take part in other tissue-specific molecular mechanisms, showing that their role in the Wnt signaling cascade is only one aspect of their mode of action.
# Clinical significance
BCL9 is associated with B-cell acute lymphoblastic leukemia. It may be a target of translocation in B-cell malignancies with abnormalities of 1q21. The overexpression of BCL9 may be of pathogenic significance in B-cell malignancies.
BCL9 and BCL9L are potential clinical targets for human cancers; for instance, the gene expression changes that they promote is associated with a poor outcome in colorectal cancer.
Like BCL2, BCL3, BCL5, BCL6, BCL7A, and BCL10, it has clinical significance in lymphoma.
Common variations in the BCL9 gene, which is in the distal area, confer risk of schizophrenia and may also be associated with bipolar disorder and major depressive disorder.
BCL9, together with the paralogue protein BCL9l and PYGO2 also have cytoplasmic functions during tooth development and is particularly important for the formation of enamel. Mice lacking both Pygo1 and Pygo2 or both Bcl9 and Bcl9l develop teeth, a process that requires Wnt/β-catenin transcriptional regulation, but the enamel is structurally disorganized and contains less iron than teeth from control mice. Bcl9, Bcl9l, and Pygo2 are present in the cytoplasm of ameloblasts, the cells that secrete enamel proteins, and colocalize in these cells with amelogenin, the main component of enamel, encoded by the AMELX gene, which has been already implicated as a causative factor of Amelogenesis Imperfecta in humans. Bcl9 interacts with amelogenin and proteins involved in exocytosis and vesicular trafficking, suggesting that these proteins function in the trafficking or secretion of enamel proteins. Therefore, Bcl9, Bcl9l, and Pygo2 have cytoplasmic functions distinct from their roles as transcriptional cofactors downstream of Wnt signaling. This new discovery might improve our understanding for the treatment of human caries.
# Related gene problems
- 1q21.1 deletion syndrome
- 1q21.1 duplication syndrome | BCL9
B-cell CLL/lymphoma 9 protein is a protein that in humans is encoded by the BCL9 gene.[1][2]
# Function
BCL9, together with its paralogue gene BCL9L (BCL9 like or BCL9.2), have been extensively studied for their role as transcriptional beta-catenin cofactors, fundamental for the transcription of Wnt target genes.[3]
Recent work, using the mouse (Mus musculus) and Zebrafish (Danio rerio) as model organisms, identified an ancient role of BCL9 and BCL9L as key factors required for cardiac development [4]. This work emphasises the tissue-specific nature of the Wnt/β-catenin mechanism of action, and implicates alterations in BCL9 and BCL9L in human congenital heart defects.
BCL9 and BCL9L have been shown to take part in other tissue-specific molecular mechanisms, showing that their role in the Wnt signaling cascade is only one aspect of their mode of action.[5]
# Clinical significance
BCL9 is associated with B-cell acute lymphoblastic leukemia. It may be a target of translocation in B-cell malignancies with abnormalities of 1q21. The overexpression of BCL9 may be of pathogenic significance in B-cell malignancies.[2]
BCL9 and BCL9L are potential clinical targets for human cancers; for instance, the gene expression changes that they promote is associated with a poor outcome in colorectal cancer.[6]
Like BCL2, BCL3, BCL5, BCL6, BCL7A, and BCL10, it has clinical significance in lymphoma.
Common variations in the BCL9 gene, which is in the distal area, confer risk of schizophrenia and may also be associated with bipolar disorder and major depressive disorder.[7]
BCL9, together with the paralogue protein BCL9l and PYGO2 also have cytoplasmic functions during tooth development and is particularly important for the formation of enamel. Mice lacking both Pygo1 and Pygo2 or both Bcl9 and Bcl9l develop teeth, a process that requires Wnt/β-catenin transcriptional regulation, but the enamel is structurally disorganized and contains less iron than teeth from control mice. Bcl9, Bcl9l, and Pygo2 are present in the cytoplasm of ameloblasts, the cells that secrete enamel proteins, and colocalize in these cells with amelogenin, the main component of enamel, encoded by the AMELX gene, which has been already implicated as a causative factor of Amelogenesis Imperfecta in humans. Bcl9 interacts with amelogenin and proteins involved in exocytosis and vesicular trafficking, suggesting that these proteins function in the trafficking or secretion of enamel proteins. Therefore, Bcl9, Bcl9l, and Pygo2 have cytoplasmic functions distinct from their roles as transcriptional cofactors downstream of Wnt signaling.[8] This new discovery might improve our understanding for the treatment of human caries.[9]
# Related gene problems
- 1q21.1 deletion syndrome
- 1q21.1 duplication syndrome | https://www.wikidoc.org/index.php/BCL9 | |
600aee23c89b63c965f931cb470433d37c620886 | wikidoc | BIN1 | BIN1
Myc box-dependent-interacting protein 1, also known as Bridging Integrator-1 and Amphiphysin-2 is a protein that in humans is encoded by the BIN1 gene.
This gene encodes several isoforms of a nucleocytoplasmic adaptor protein, one of which was initially identified as a MYC-interacting protein with features of a tumor suppressor.
Isoforms that are expressed in the central nervous system may be involved in synaptic vesicle endocytosis and may interact with dynanim, synaptojanin, endophilin, and clathrin.
Isoforms that are expressed in muscle and ubiquitously expressed isoforms localize to the cytoplasm and nucleus and activate a caspase-independent apoptotic process.
Studies in mouse suggest that this gene plays an important role in cardiac muscle development. Alternate splicing of the gene results in ten transcript variants encoding different isoforms. Aberrant splice variants expressed in tumor cell lines have also been described.
# Clinical significance
In humans, mutations in BIN1 have been associated with skeletal myopathies including centronuclear myopathy causing muscle weakness and myotonic dystrophy causing progressive muscle wasting, myotonia, cataracts, and heart conduction defects. An association has also been found between BIN1 mutations and Alzheimer's disease. Knockdown of BIN1 in produces a cardiomyopathy phenotype in zebrafish, and in sheep BIN1 may be responsible for the loss of T-tubules seen in heart failure.
# Interactions
BIN1 has been shown to interact with Phospholipase D1, SNX4 and PLD2. | BIN1
Myc box-dependent-interacting protein 1, also known as Bridging Integrator-1 and Amphiphysin-2 is a protein that in humans is encoded by the BIN1 gene.[1][2][3]
This gene encodes several isoforms of a nucleocytoplasmic adaptor protein, one of which was initially identified as a MYC-interacting protein with features of a tumor suppressor.
Isoforms that are expressed in the central nervous system may be involved in synaptic vesicle endocytosis and may interact with dynanim, synaptojanin, endophilin, and clathrin.[4]
Isoforms that are expressed in muscle and ubiquitously expressed isoforms localize to the cytoplasm and nucleus and activate a caspase-independent apoptotic process.[4]
Studies in mouse suggest that this gene plays an important role in cardiac muscle development. Alternate splicing of the gene results in ten transcript variants encoding different isoforms. Aberrant splice variants expressed in tumor cell lines have also been described.[4]
# Clinical significance
In humans, mutations in BIN1 have been associated with skeletal myopathies including centronuclear myopathy causing muscle weakness[3] and myotonic dystrophy causing progressive muscle wasting, myotonia, cataracts, and heart conduction defects.[5] An association has also been found between BIN1 mutations and Alzheimer's disease.[5] Knockdown of BIN1 in produces a cardiomyopathy phenotype in zebrafish,[6] and in sheep BIN1 may be responsible for the loss of T-tubules seen in heart failure.[7]
# Interactions
BIN1 has been shown to interact with Phospholipase D1,[8] SNX4[9] and PLD2.[8] | https://www.wikidoc.org/index.php/BIN1 | |
1af707461473ba38d9236a34bcd4f3f3fe63c4d3 | wikidoc | BL22 | BL22
BL22, also called CAT-3888 or GCR-3888, is an immunotoxin which attaches to and, upon internalization, kills B cells. It has completed a Phase I clinical (human) trial and is currently in a Phase II clinical trial for the treatment of hairy cell leukemia at a Phase I clinical trial for pediatric acute lymphoblastic leukemia and non-Hodgkin's lymphoma at the NIH in the U.S. It may be useful against any B cell leukemia or lymphoma.
Technically, BL22 is an anti-CD22 immunotoxin fusion protein between a murine anti-CD22 disulphide-linked Fv (dsFv) antibody fragment and an edited copy of bacterial Pseudomonas exotoxin PE38. The toxin is activated intracellularly, by the low pH of the lysosome into which the entire protein was internalized via the CD22 receptor. The toxin kills the targeted cell through ribosome inactivation.
BL22 is very similar to the newer HA22, which changes one amino acid in the antibody fragment to increase the binding affinity for the target molecule. Both of these proteins are designed to bind to the CD22 receptor on the surface of B cells.
# Business History
BL22 was initially designed and produced at the U.S. National Cancer Institute, one of the agencies which make up the NIH. Early development of BL22 was funded by California biotech Genencor. The future drug was acquired by Cambridge Antibody Technology at the end of 2005; less than a year later, CAT was purchased by British pharmaceutical company AstraZeneca. | BL22
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
BL22, also called CAT-3888 or GCR-3888, is an immunotoxin which attaches to and, upon internalization, kills B cells. It has completed a Phase I clinical (human) trial and is currently in a Phase II clinical trial for the treatment of hairy cell leukemia at a Phase I clinical trial for pediatric acute lymphoblastic leukemia and non-Hodgkin's lymphoma[2] at the NIH in the U.S. It may be useful against any B cell leukemia or lymphoma.
Technically, BL22 is an anti-CD22 immunotoxin fusion protein between a murine anti-CD22 disulphide-linked Fv (dsFv) antibody fragment and an edited copy of bacterial Pseudomonas exotoxin PE38. The toxin is activated intracellularly, by the low pH of the lysosome into which the entire protein was internalized via the CD22 receptor. The toxin kills the targeted cell through ribosome inactivation.[3]
BL22 is very similar to the newer HA22, which changes one amino acid in the antibody fragment to increase the binding affinity for the target molecule. Both of these proteins are designed to bind to the CD22 receptor on the surface of B cells.
# Business History
BL22 was initially designed and produced at the U.S. National Cancer Institute, one of the agencies which make up the NIH. Early development of BL22 was funded by California biotech Genencor.[4] The future drug was acquired by Cambridge Antibody Technology at the end of 2005; less than a year later, CAT was purchased by British pharmaceutical company AstraZeneca.[5]
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/BL22 | |
3156ffb94ca87dd8c23ebbbaebdc0a80b460d5e2 | wikidoc | BMI1 | BMI1
Polycomb complex protein BMI-1 also known as polycomb group RING finger protein 4 (PCGF4) or RING finger protein 51 (RNF51) is a protein that in humans is encoded by the BMI1 gene (B cell-specific Moloney murine leukemia virus integration site 1). BMI1 is a polycomb ring finger oncogene.
# Function
BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) has been reported as an oncogene by regulating p16 and p19, which are cell cycle inhibitor genes. Bmi1 knockout in mice results in defects in hematopoiesis, skeletal patterning, neurological functions, and development of the cerebellum. Recently it has been reported BMI1 is rapidly recruited to sites of DNA damage and it sustains for over 8h. Loss of BMI1 leads to radiation sensitive and impaired repair of DNA double-strand breaks by homologous recombination.
Bmi1 is necessary for efficient self-renewing cell divisions of adult hematopoietic stem cells as well as adult peripheral and central nervous system neural stem cells. However, it is less important for the generation of differentiated progeny. Given that phenotypic changes in Bmi1 knockout mice are numerous and that Bmi1 has very broad tissue distribution, it is possible that it regulates the self-renewal of other types of somatic stem cells.
Bmi1 is also thought to inhibit ageing in neurons through the suppression of p53.
The Bmi-1 expression interacts with several signaling containing Wnt, Akt, Notch, Hedgehog and receptor tyrosine kinase (RTK) pathway. In Ewing sarcoma family of tumors (ESFT), the knockdown of BMI-1 gene would greatly influence the Notch and Wnt signaling pathway which are important for ESFT formation and development. Bmi-1 was shown to mediate the effect of Hedgehog signaling pathway on mammary stem cell proliferation. Bmi-1 also regulates multiple downstream factors or genes. It represses p19Arf and p16Ink4a. Bmi-1-/- neural stem cells and HSCs have high expression level of p19Arf and p16Ink4a which diminished the proliferation rate. Bmi-1 is also indicated as a key factor in controlling Th2 cell differentiation and development by stabilizing GATA transcription factors.
# Structure
The BMI-1 gene is 10.04 kb with 10 exon and is highly conserved sequence between species. The human BMI-1 gene localizes at chromosome 10 (10p11.23). The Bmi-1 protein is consist of 326 amino acids and has a molecular weight of 36949 Da. Bmi1 has a RING finger at the N-terminus and a central helix-turn-helix domain. The ring finger domain is a cysteine rich domain (CRD) involved in zinc binding and contributes to the ubiquitination process. The binding of bmi-1 to Ring 1B would activate the E3 ubiquitin ligase activity greatly. It is indicated that both the RING domain and the extended N-terminal tail contribute to the interaction of bmi-1 and Ring 1B.
# Clinical significance
Overexpression of Bmi1 seems to play an important role in several types of cancer, such as bladder, skin, prostate, breast, ovarian, colorectal as well as hematological malignancies. Its amplification and overexpression is especially pronounced in mantle cell lymphomas. Inhibiting BMI1 has been shown to inhibit the proliferation of glioblastoma multiforme, chemoresistant ovarian cancer, prostatic, pancreatic and skin cancers. Colorectal cancer stem cell self-renewal was reduced by BMI1 inhibition. The colon cancer stem cells in mouse xenografts could be eliminated by inhibiting BMI-1 gene, providing a novel potential method to treat colorectal cancer.
According to a study by Canadian doctors, the loss of the BMI1 gene expression in human neurons may play a direct role in the development of Alzheimer's disease.
# Interactions
BMI1 has been shown to interact with:
- PHC1,
- PHC2,
- RING1, and
- ZBTB16, | BMI1
Polycomb complex protein BMI-1 also known as polycomb group RING finger protein 4 (PCGF4) or RING finger protein 51 (RNF51) is a protein that in humans is encoded by the BMI1 gene (B cell-specific Moloney murine leukemia virus integration site 1).[1][2] BMI1 is a polycomb ring finger oncogene.
# Function
BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) has been reported as an oncogene by regulating p16 and p19, which are cell cycle inhibitor genes. Bmi1 knockout in mice results in defects in hematopoiesis, skeletal patterning, neurological functions, and development of the cerebellum. Recently it has been reported BMI1 is rapidly recruited to sites of DNA damage and it sustains for over 8h. Loss of BMI1 leads to radiation sensitive and impaired repair of DNA double-strand breaks by homologous recombination.
Bmi1 is necessary for efficient self-renewing cell divisions of adult hematopoietic stem cells as well as adult peripheral and central nervous system neural stem cells.[3][4] However, it is less important for the generation of differentiated progeny. Given that phenotypic changes in Bmi1 knockout mice are numerous and that Bmi1 has very broad tissue distribution, it is possible that it regulates the self-renewal of other types of somatic stem cells.[5]
Bmi1 is also thought to inhibit ageing in neurons through the suppression of p53.[6]
The Bmi-1 expression interacts with several signaling containing Wnt, Akt, Notch, Hedgehog and receptor tyrosine kinase (RTK) pathway. In Ewing sarcoma family of tumors (ESFT), the knockdown of BMI-1 gene would greatly influence the Notch and Wnt signaling pathway which are important for ESFT formation and development.[7] Bmi-1 was shown to mediate the effect of Hedgehog signaling pathway on mammary stem cell proliferation.[8] Bmi-1 also regulates multiple downstream factors or genes. It represses p19Arf and p16Ink4a. Bmi-1-/- neural stem cells and HSCs have high expression level of p19Arf and p16Ink4a which diminished the proliferation rate.[9][10] Bmi-1 is also indicated as a key factor in controlling Th2 cell differentiation and development by stabilizing GATA transcription factors.[11]
# Structure
The BMI-1 gene is 10.04 kb with 10 exon and is highly conserved sequence between species. The human BMI-1 gene localizes at chromosome 10 (10p11.23). The Bmi-1 protein is consist of 326 amino acids and has a molecular weight of 36949 Da. Bmi1 has a RING finger at the N-terminus and a central helix-turn-helix domain.[12] The ring finger domain is a cysteine rich domain (CRD) involved in zinc binding and contributes to the ubiquitination process. The binding of bmi-1 to Ring 1B would activate the E3 ubiquitin ligase activity greatly. It is indicated that both the RING domain and the extended N-terminal tail contribute to the interaction of bmi-1 and Ring 1B.[13]
# Clinical significance
Overexpression of Bmi1 seems to play an important role in several types of cancer, such as bladder, skin, prostate, breast, ovarian, colorectal as well as hematological malignancies. Its amplification and overexpression is especially pronounced in mantle cell lymphomas.[14] Inhibiting BMI1 has been shown to inhibit the proliferation of glioblastoma multiforme,[15] chemoresistant ovarian cancer, prostatic, pancreatic and skin cancers.[2] Colorectal cancer stem cell self-renewal was reduced by BMI1 inhibition. The colon cancer stem cells in mouse xenografts could be eliminated by inhibiting BMI-1 gene, providing a novel potential method to treat colorectal cancer.[16]
According to a study by Canadian doctors, the loss of the BMI1 gene expression in human neurons may play a direct role in the development of Alzheimer's disease. [17]
# Interactions
BMI1 has been shown to interact with:
- PHC1,[18][19]
- PHC2,[18]
- RING1,[19][20] and
- ZBTB16,[21] | https://www.wikidoc.org/index.php/BMI1 | |
7a825085f5f46d29af70cdf97b9dbb55ca87f9fe | wikidoc | BNC1 | BNC1
Zinc finger protein basonuclin-1 is a protein that in humans is encoded by the BNC1 gene.
The protein encoded by this gene is a zinc finger protein present in the basal cell layer of the epidermis and in hair follicles. It is also found in abundance in the germ cells of testis and ovary. This protein is thought to play a regulatory role in keratinocyte proliferation and it may also be a regulator for rRNA transcription. This gene seems to have multiple alternatively spliced transcript variants, but their full-length nature is not known yet. There seems to be evidence of multiple polyadenylation sites for this gene.
BNC1 or Basonuclin 1 does not interact with PICK1. This suggestion that is does is based on the article that proved that PICK1 interacts with the non-voltage gated sodium channels BNC1 (brain Na+ channel 1). Both Basonuclin 1 and brain Na+ channel 1 have the same abbreviation BNC1, but they are not similar proteins and PICK1 interacts with the second protein, not the first one. | BNC1
Zinc finger protein basonuclin-1 is a protein that in humans is encoded by the BNC1 gene.[1][2]
The protein encoded by this gene is a zinc finger protein present in the basal cell layer of the epidermis and in hair follicles. It is also found in abundance in the germ cells of testis and ovary. This protein is thought to play a regulatory role in keratinocyte proliferation and it may also be a regulator for rRNA transcription. This gene seems to have multiple alternatively spliced transcript variants, but their full-length nature is not known yet. There seems to be evidence of multiple polyadenylation sites for this gene.[2]
BNC1 or Basonuclin 1 does not interact with PICK1. This suggestion that is does is based on the article that proved that PICK1 interacts with the non-voltage gated sodium channels BNC1 (brain Na+ channel 1). Both Basonuclin 1 and brain Na+ channel 1 have the same abbreviation BNC1, but they are not similar proteins and PICK1 interacts with the second protein, not the first one. | https://www.wikidoc.org/index.php/BNC1 | |
471a338566a652777cad1e82e643ff5260849a87 | wikidoc | BOLL | BOLL
Protein boule-like is a protein that in humans is encoded by the BOLL gene.
# Function
This gene belongs to the DAZ gene family required for germ cell development. It encodes an RNA-binding protein which is more similar to Drosophila Boule than to human proteins encoded by genes DAZ (deleted in azoospermia) or DAZL (deleted in azoospermia-like). Loss of this gene function results in the absence of sperm in semen (azoospermia). Histological studies demonstrated that the primary defect is at the meiotic G2 / M transition in fruitfly but in mice the primary defect is postmeiotic at round spermatid stage. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.
The boule-like protein appears to be ubiquitously expressed in males of all animal species, except in the most primitive trichoplax. | BOLL
Protein boule-like is a protein that in humans is encoded by the BOLL gene.[1][2][3]
# Function
This gene belongs to the DAZ gene family required for germ cell development. It encodes an RNA-binding protein which is more similar to Drosophila Boule than to human proteins encoded by genes DAZ (deleted in azoospermia) or DAZL (deleted in azoospermia-like). Loss of this gene function results in the absence of sperm in semen (azoospermia). Histological studies demonstrated that the primary defect is at the meiotic G2 / M transition in fruitfly but in mice the primary defect is postmeiotic at round spermatid stage.[4] Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[3][5]
The boule-like protein appears to be ubiquitously expressed in males of all animal species, except in the most primitive trichoplax.[6] | https://www.wikidoc.org/index.php/BOLL | |
98e171bfe782bd390073ffc1f3bf5b55e8a7b2b3 | wikidoc | BOP1 | BOP1
Ribosome biogenesis protein BOP1 is a protein that in humans is encoded by the BOP1 gene.
# Function
It is a WD40 repeat-containing nucleolar protein involved in rRNA processing, thereby controlling the cell cycle. It is required for the maturation of the 25S and 5.8S ribosomal RNAs. It may serve as an essential factor in ribosome formation that coordinates processing of the spacer regions in pre-rRNA. The Pes1-Bop1 complex has several components: BOP1, GRWD1, PES1, ORC6L, and RPL3 and is involved in ribosome biogenesis and altered chromosome segregation. The overexpression of BOP1 increases the percentage of multipolar spindles in human cells. Deregulation of the BOP1 pathway may contribute to colorectal tumourigenesis in humans. Elevated levels of Bop1 induces Bop1/WDR12 and Bop1/Pes1 subcomplexes and the assembly and integrity of the PeBoW complex is highly sensitive to changes in Bop1 protein levels.
Nop7p-Erb1p-Ytm1p, found in yeast, is potentially the homologous complex of Pes1-Bop1-WDR12 as it is involved in the control of ribosome biogenesis and S phase entry. The integrity of the PeBoW complex is required for ribosome biogenesis and cell proliferation in mammalian cells. In Giardia, the species specific cytoskeleton protein, beta-giardin, interacts with Bop1.
# Structure
BOP1 contains a conserved N-terminal domain, BOP1NT. | BOP1
Ribosome biogenesis protein BOP1 is a protein that in humans is encoded by the BOP1 gene.[1][2]
# Function
It is a WD40 repeat-containing nucleolar protein involved in rRNA processing, thereby controlling the cell cycle.[3] It is required for the maturation of the 25S and 5.8S ribosomal RNAs. It may serve as an essential factor in ribosome formation that coordinates processing of the spacer regions in pre-rRNA. The Pes1-Bop1 complex has several components: BOP1, GRWD1, PES1, ORC6L, and RPL3 and is involved in ribosome biogenesis and altered chromosome segregation. The overexpression of BOP1 increases the percentage of multipolar spindles in human cells. Deregulation of the BOP1 pathway may contribute to colorectal tumourigenesis in humans.[4] Elevated levels of Bop1 induces Bop1/WDR12 and Bop1/Pes1 subcomplexes and the assembly and integrity of the PeBoW complex is highly sensitive to changes in Bop1 protein levels.[5]
Nop7p-Erb1p-Ytm1p, found in yeast, is potentially the homologous complex of Pes1-Bop1-WDR12 as it is involved in the control of ribosome biogenesis and S phase entry. The integrity of the PeBoW complex is required for ribosome biogenesis and cell proliferation in mammalian cells.[6] In Giardia, the species specific cytoskeleton protein, beta-giardin, interacts with Bop1.[3]
# Structure
BOP1 contains a conserved N-terminal domain, BOP1NT. | https://www.wikidoc.org/index.php/BOP1 | |
191e75572e8c040175e887b412d549dfb8d7f1e0 | wikidoc | BPY2 | BPY2
Testis-specific basic protein Y 2 also known as basic charge, Y-linked 2 is a protein that in humans is encoded by the BPY2 gene which resides on the Y chromosome.
# Function
This gene is located in the nonrecombining portion of the Y chromosome, and expressed specifically in testis. The encoded protein interacts with ubiquitin protein ligase
E3A and may be involved in male germ cell development and male infertility. Three nearly identical copies of this gene exist on chromosome Y; two copies are part of a palindromic region. This record represents the copy outside of the palindromic region. | BPY2
Testis-specific basic protein Y 2 also known as basic charge, Y-linked 2 is a protein that in humans is encoded by the BPY2 gene which resides on the Y chromosome.[1]
# Function
This gene is located in the nonrecombining portion of the Y chromosome, and expressed specifically in testis. The encoded protein interacts with ubiquitin protein ligase
E3A and may be involved in male germ cell development and male infertility. Three nearly identical copies of this gene exist on chromosome Y; two copies are part of a palindromic region. This record represents the copy outside of the palindromic region.[2] | https://www.wikidoc.org/index.php/BPY2 | |
cf293be8edfde7a826b7b7812607cdd85b936dac | wikidoc | BRAF | BRAF
Synonyms and keywords: BRAF1; RAFB1; B-RAF1; NS7; v-raf murine sarcoma viral oncogene homolog B
# Overview
BRAF is a human gene that codes for the protein B-Raf which is involved in signal transduction relating to cell growth. In 2002, it was shown to be faulty (mutated) in human cancers. Mutations in the BRAF gene are shown to cause birth defects.
# Biological Function
The role of Raf proteins, like B-Raf is indicated in the center.]]B-Raf is a member of the Raf kinase family of growth signal transduction protein kinases. This protein plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion.
# Protein Structure and Function
B-Raf is a 766-amino acid, regulated signal transduction serine/threonine-specific protein kinase. Broadly speaking, it is composed of three conserved domains characteristic of the Raf kinase family: conserved region 1 (CR1), a Ras-GTP-binding self-regulatory domain, conserved region 2 (CR2), a serine-rich hinge region, and conserved region 3 (CR3), a catalytic protein kinase domain that phosphorylates a consensus sequence on protein substrates. In its active conformation, B-Raf forms dimers via hydrogen-bonding and electrostatic interactions of its kinase domains.
## Conserved Region 1 (CR1)
Conserved Region 1 autoinhibits B-Raf's kinase domain (CR3) so that B-Raf signaling is regulated rather than constitutive. Residues 155-227 make up the Ras-binding domain (RBD), which binds to Ras-GTP's effector domain to release CR1 and halt kinase inhibition. Residues 234-280 comprise a phorbol ester/DAG-binding zinc finger motif that participates in B-Raf membrane docking after Ras-binding.
## Conserved Region 2 (CR2)
Conserved Region 2 (CR2) provides a flexible linker that connects CR1 and CR3 and acts as a hinge.
## Conserved Region 3 (CR3)
Conserved Region 3 (CR3), residues 457-717, makes up B-Raf's enzymatic kinase domain. This largely conserved structure is bi-lobal, connected by a short hinge region. The smaller N-lobe (residues 457-530) is primarily responsible for ATP binding while the larger C-lobe (residues 535-717) binds substrate proteins. The active site is the cleft between the two lobes, and the catalytic Asp576 residue is located on the C-lobe, facing the inside of this cleft.
### Important Subregions
P-Loop
The P-loop of B-Raf (residues 464-471) stabilizes the non-transferable phosphate groups of ATP during enzyme ATP-binding. Specifically, S467, F468, and G469 backbone amides hydrogen-bond to the β-phosphate of ATP to anchor the molecule. B-Raf functional motifs have been determined by analyzing the homology of PKA analyzed by Hanks and Hunter to the B-Raf kinase domain.
Nucleotide-Binding Pocket
V471, C532, W531, T529, L514, and A481 form a hydrophobic pocket within which the adenine of ATP is anchored through Van der Waals attractions upon ATP binding.
Catalytic Loop
Residues 574-581 compose a section of the kinase domain responsible for supporting the transfer of the γ-phosphate of ATP to B-Raf's protein substrate. In particular, D576 acts as a proton acceptor to activate the nucleophilic hydroxyl oxygen on substrate serine or threonine residues, allowing the phosphate transfer reaction to occur mediated by base-catalysis.
DFG Motif
D594, F595, and G596 compose a motif central to B-Raf's function in both its inactive and active state. In the inactive state, F595 occupies the nucleotide-binding pocket, prohibiting ATP from entering and decreasing the likelihood of enzyme catalysis. In the active state, D594 chelates the divalent magnesium cation that stabilizes the β- and γ-phosphate groups of ATP, orienting the γ-phosphate for transfer.
Activation Loop
Residues 596-600 form strong hydrophobic interactions with the P-loop in the inactive conformation of the kinase, locking the kinase in its inactive state until the activation loop is phosphorylated, destabilizing these interactions with the presence of negative charge. This triggers the shift to the active state of the kinase. Specifically, L597 and V600 of the activation loop interact with G466, F468, and V471 of the P-loop to keep the kinase domain inactive until it is phosphorylated.
# Enzymology
B-Raf is a serine/threonine-specific protein kinase. As such, it catalyzes the phosphorylation of serine and threonine residues in a consensus sequence on target proteins by ATP, yielding ADP and a phosphorylated protein as products. Since it is a highly regulated signal transduction kinase, B-Raf must first bind Ras-GTP before becoming active as an enzyme. Once B-Raf is activated, a conserved protein kinase catalytic core phosphorylates protein substrates by promoting the nucleophilic attack of the activated substrate serine or threonine hydroxyl oxygen atom on the γ-phosphate group of ATP through bimolecular nucleophilic substitution.
## Activating the Catalytic Domain
### Releasing the Autoinhibitory CR1 Domain
The kinase (CR3) domain of human Raf kinases is inhibited by two mechanisms: autoinhibition by its own regulatory Ras-GTP-binding CR1 domain and a lack of post-translational phosphorylation of key serine and tyrosine residues (S338 and Y341 for c-Raf) in the CR2 hinge region. During B-Raf activation, the protein's autoinhibitory CR1 domain first binds Ras-GTP's effector domain to the CR1 Ras-binding domain (RBD) to release the kinase CR3 domain like other members of the human Raf kinase family. The CR1-Ras interaction is later strengthened through the binding of the cysteine-rich subdomain (CRD) of CR1 to Ras and membrane phospholipids. Unlike A-Raf and C-Raf, which must be phosphorylated on hydroxyl-containing CR2 residues before fully releasing CR1 to become active, B-Raf is constituitively phosphorylated on CR2 S445. This allows the negatively charged phosphoserine to immediately repel CR1 through steric and electrostatic interactions once the regulatory domain is unbound, freeing the CR3 kinase domain to interact with substrate proteins.
### Transforming the Protein Kinase CR3 Domain into Active Conformation
After the autoinhibitory CR1 regulatory domain is released, B-Raf's CR3 kinase domain must change to its ATP-binding active conformer before it can catalyze protein phosphorylation. In the inactive conformation, F595 of the DFG motif blocks the hydrophobic adenine binding pocket while activation loop residues form hydrophobic interactions with the P-loop, stopping ATP from accessing its binding site. When the activation loop is phosphorylated, the negative charge of the phosphate is unstable in the hydrophobic environment of the P-loop. As a result, the activation loop changes conformation, stretching out across the C-lobe of the kinase domain. In this process, it forms stabilizing β-sheet interactions with the β6 strand. Meanwhile, the phosphorylated residue approaches K507, forming a stabilizing salt bridge to lock the activation loop into place. The DFG motif changes conformation with the activation loop, causing F595 to move out of the adenine nucleotide binding site and into a hydrophobic pocket bordered by the αC and αE helices. Together, DFG and activation loop movement upon phosphorylation open the ATP binding site. Since all other substrate-binding and catalytic domains are already in place, phosphorylation of the activation loop alone activates B-Raf's kinase domain through a chain reaction that essentially removes a lid from an otherwise-prepared active site.
## Enzymatic Mechanism
To effectively catalyze protein phosphorylation via the bimolecular substitution of serine and threonine residues with ADP as a leaving group, B-Raf must first bind ATP and then stabilize the transition state as the γ-phosphate of ATP is transferred.
### ATP Binding
B-Raf binds ATP by anchoring the adenine nucleotide in a nonpolar pocket (yellow, Figure 1) and orienting the molecule through hydrogen-bonding and electrostatic interactions with phosphate groups. In addition to the P-loop and DFG motif phosphate binding described above, K483 and E500 play key roles in stabilizing non-transferable phosphate groups. The positive charge on the primary amine of K483 allows it to stabilize the negative charge on ATP α- and β-phosphate groups when ATP binds. When ATP is not present, the negative charge of the E500 carboxyl group balances this charge.
### Protein Phosphorylation
Once ATP is bound to the B-Raf kinase domain, D576 of the catalytic loop activates a substrate hydroxyl group, increasing its nucleophilicity to kinetically drive the phosphorylation reaction while other catalytic loop residues stabilize the transition state.(Figure 2). N581 chelates the divalent magnesium cation associated with ATP to help orient the molecule for optimal substitution. K578 neutralizes the negative charge on the γ-phosphate group of ATP so that the activated ser/thr substrate residue won't experience as much electron-electron repulsion when attacking the phosphate. After the phosphate group is transferred, ADP and the new phosphoprotein are released.
## Inhibitors
Since constituitively active B-Raf mutants commonly cause cancer (see Clinical Significance) by excessively signaling cells to grow, inhibitors of B-Raf have been developed for both the inactive and active conformations of the kinase domain as cancer therapeutic candidates.
### BAY43-9006 (Sorafenib)
BAY43-9006 (Sorafenib, Nexavar)is a V600E mutant B-Raf and C-Raf inhibitor approved by the FDA for the treatment of primary liver and kidney cancer. Bay43-9006 disables the B-Raf kinase domain by locking the enzyme in its inactive form. The inhibitor accomplishes this by blocking the ATP binding pocket through high-affinity for the kinase domain. It then binds key activation loop and DFG motif residues to stop the movement of the activation loop and DFG motif to the active conformation. Finally, a trifluoromethyl phenyl moiety sterically blocks the DFG motif and activation loop active conformation site, making it impossible for the kinase domain to shift conformation to become active.
The distal pyridyl ring of BAY43-9006 anchors in the hydrophobic nucleotide-binding pocket of the kinase N-lobe, interacting with W531, F583, and F595. The hydrophobic interactions with catalytic loop F583 and DFG motif F595 stabilize the inactive conformation of these structures, decreasing the likelihood of enzyme activation. Further hydrophobic interaction of K483, L514, and T529 with the center phenyl ring increase the affinity of the kinase domain for the inhibitor. Hydrophobic interaction of F595 with the center ring as well decreases the energetic favorability of a DFG conformation switch further. Finally, polar interactions of BAY43-9006 with the kinase domain continue this trend of increasing enzyme affinity for the inhibitor and stabilizing DFG residues in the inactive conformation. E501 and C532 hydrogen bond the urea and pyridyl groups of the inhibitor respectively while the urea carbonyl accepts a hydrogen bond from D594's backbone amide nitrogen to lock the DFG motif in place.
The trifluoromethyl phenyl moiety cements the thermodynamic favorability of the inactive conformation when the kinase domain is bound to BAY43-9006 by sterically blocking the hydrophobic pocket between the αC and αE helices that the DFG motif and activation loop would inhabit upon shifting to their locations in the active conformation of the protein.
### PLX 4032 (Vemurafenib)
PLX4032 (Vemurafenib) is a V600 mutant B-Raf inhibitor approved by the FDA for the treatment of late-stage melanoma. Unlike BAY43-9006, which inhibits the inactive form of the kinase domain, Vemurafenib inhibits the active "DFG-in" form of the kinase, firmly anchoring itself in the ATP-binding site. By inhibiting only the active form of the kinase, Vemurafenib selectively inhibits the proliferation of cells with unregulated B-Raf, normally those that cause cancer.
Since Vemurafenib only differs from its precursor, PLX4720, in a phenyl ring added for pharmacokinetic reasons, PLX4720's mode of action is equivalent to Vemurafenib's. PLX4720 has good affinity for the ATP binding site partially because its anchor region, a 7-azaindole bicyclic, only differs from the natural adenine that occupies the site in two places where nitrogen atoms have been replaced by carbon. This enables strong intermolecular interactions like N7 hydrogen bonding to C532 and N1 hydrogen bonding to Q530 to be preserved. Excellent fit within the ATP-binding hydrophobic pocket (C532, W531, T529, L514, A481) increases binding affinity as well. Ketone linker hydrogen bonding to water and difluoro-phenyl fit in a second hydrophobic pocket (A481, V482, K483, V471, I527, T529, L514, and F583) contribute to the exceptionally high binding affinity overall. Selective binding to active Raf is accomplished by the terminal propyl group that binds to a Raf-selective pocket created by a shift of the αC helix. Selectivity for the active conformation of the kinase is further increased by a pH-sensitive deprotonated sulfonamide group that is stabilized by hydrogen bonding with the backbone peptide NH of D594 in the active state. In the inactive state, the inhibitor's sulfonamide group interacts with the backbone carbonyl of that residue instead, creating repulsion. Thus, Vemurafenib binds preferentially to the active state of B-Raf's kinase domain.
# Clinical significance
Mutations in the BRAF gene can cause disease in two ways. First, mutations can be inherited and cause birth defects. Second, mutations can appear later in life and cause cancer, as an oncogene.
Inherited mutations in this gene cause cardiofaciocutaneous syndrome, a disease characterized by heart defects, mental retardation and a distinctive facial appearance.
Acquired mutations in this gene have been found in cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, papillary thyroid carcinoma, non-small-cell lung carcinoma, and adenocarcinoma of the lung.
The V600E mutation of the BRAF gene has been associated with hairy cell leukemia in numerous studies and has been suggested for use in screening for Lynch syndrome to reduce the number of patients undergoing unnecessary MLH1 sequencing.
## BRAF mutants
More than 30 mutations of the BRAF gene associated with human cancers have been identified. The frequency of BRAF mutations varies widely in human cancers, from more than 80% in melanomas and nevi, to as little as 0-18% in other tumors, such as 1-3% in lung cancers and 5% in colorectal cancer. In 90% of the cases, thymine is substituted with adenine at nucleotide 1799. This leads to valine (V) being substituted for by glutamate (E) at codon 600 (now referred to as V600E) in the activation segment that has been found in human cancers. This mutation has been widely observed in papillary thyroid carcinoma, colorectal cancer, melanoma and non-small-cell lung cancer. In 2010 a team of scientists demonstrated presence of BRAF-V600E mutation in 57% of Langerhans cell histiocytosis patients. A team of Italian scientists used massively parallel sequencing to pinpoint mutation V600E as a likely driver mutation in 100% of cases of hairy cell leukaemia.
Other mutations which have been found are R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600K, A727V, etc. and most of these mutations are clustered to two regions: the glycine-rich P loop of the N lobe and the activation segment and flanking regions. These mutations change the activation segment from inactive state to active state, for example in the previous cited paper it has been reported that the aliphatic side chain of Val599 interacts with the phenyl ring of Phe467 in the P loop. Replacing the medium sized hydrophobic Val side chain with a larger and charged residue as found in human cancer(Glu, Asp, Lys, or Arg) would be expected to destabilize the interactions that maintain the DFG motif in an inactive conformation, so flipping the activation segment into the active position. Depending on the type of mutation the kinase activity towards MEK may also vary. In the same paper it has been reported that most of the mutants stimulate enhanced B-Raf kinase activity toward MEK. However, a few mutants act through a different mechanism because although their activity toward MEK is reduced, they adopt a conformation that activates wild-type C-RAF, which then signals to ERK.
## B-Raf inhibitors in the clinic
As mentioned above, some pharmaceutical firms are developing specific inhibitors of mutated B-raf protein for anticancer use because B-Raf is a well-understood, high yield target. Vemurafenib (RG7204 or PLX4032), licensed by the US Food and Drug Administration as Zelboraf for the treatment of metastatic melanoma in August 2011, is the current state-of-the-art example for why active B-Raf inhibitors are being pursued as drug candidates. Vemurafenib is biochemically interesting as a mechanism to target cancer due to its high efficacy and selectivity. In Phase II and Phase III clinical trials, B-Raf not only increased metastatic melanoma patient chance of survival but raised the response rate to treatment from 7-12% to 53% in the same amount of time compared to the former best chemotherapeutic treatment: dacarbazine. In spite of the drug's high efficacy, 20% of tumors still develop resistance to the treatment. In mice, 20% of tumors become resistant after 56 days. While the mechanisms of this resistance are still disputed, some hypotheses include the overexpression of B-Raf to compensate for high concentrations of Vemurafenib and upstream upregulation of growth signaling.
More general B-raf inhibitors include GDC-0879, PLX-4720, Sorafenib Tosylate. dabrafenib, LGX818
# Interactions
BRAF (gene) has been shown to interact with YWHAB, C-Raf, AKT1 and HRAS. | BRAF
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: BRAF1; RAFB1; B-RAF1; NS7; v-raf murine sarcoma viral oncogene homolog B
# Overview
BRAF is a human gene that codes for the protein B-Raf which is involved in signal transduction relating to cell growth. In 2002, it was shown to be faulty (mutated) in human cancers.[1] Mutations in the BRAF gene are shown to cause birth defects.
# Biological Function
The role of Raf proteins, like B-Raf is indicated in the center.]]B-Raf is a member of the Raf kinase family of growth signal transduction protein kinases. This protein plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion.[2]
# Protein Structure and Function
B-Raf is a 766-amino acid, regulated signal transduction serine/threonine-specific protein kinase. Broadly speaking, it is composed of three conserved domains characteristic of the Raf kinase family: conserved region 1 (CR1), a Ras-GTP-binding[3] self-regulatory domain, conserved region 2 (CR2), a serine-rich hinge region, and conserved region 3 (CR3), a catalytic protein kinase domain that phosphorylates a consensus sequence on protein substrates.[4] In its active conformation, B-Raf forms dimers via hydrogen-bonding and electrostatic interactions of its kinase domains.[5]
## Conserved Region 1 (CR1)
Conserved Region 1 autoinhibits B-Raf's kinase domain (CR3) so that B-Raf signaling is regulated rather than constitutive.[4] Residues 155-227[6] make up the Ras-binding domain (RBD), which binds to Ras-GTP's effector domain to release CR1 and halt kinase inhibition. Residues 234-280 comprise a phorbol ester/DAG-binding zinc finger motif that participates in B-Raf membrane docking after Ras-binding.[6][7]
## Conserved Region 2 (CR2)
Conserved Region 2 (CR2) provides a flexible linker that connects CR1 and CR3 and acts as a hinge.
## Conserved Region 3 (CR3)
Conserved Region 3 (CR3), residues 457-717,[6] makes up B-Raf's enzymatic kinase domain. This largely conserved structure[8] is bi-lobal, connected by a short hinge region.[9] The smaller N-lobe (residues 457-530) is primarily responsible for ATP binding while the larger C-lobe (residues 535-717) binds substrate proteins.[8] The active site is the cleft between the two lobes, and the catalytic Asp576 residue is located on the C-lobe, facing the inside of this cleft.[6][8]
### Important Subregions
P-Loop
The P-loop of B-Raf (residues 464-471) stabilizes the non-transferable phosphate groups of ATP during enzyme ATP-binding. Specifically, S467, F468, and G469 backbone amides hydrogen-bond to the β-phosphate of ATP to anchor the molecule. B-Raf functional motifs have been determined by analyzing the homology of PKA analyzed by Hanks and Hunter to the B-Raf kinase domain.[8]
Nucleotide-Binding Pocket
V471, C532, W531, T529, L514, and A481 form a hydrophobic pocket within which the adenine of ATP is anchored through Van der Waals attractions upon ATP binding.[8][10]
Catalytic Loop
Residues 574-581 compose a section of the kinase domain responsible for supporting the transfer of the γ-phosphate of ATP to B-Raf's protein substrate. In particular, D576 acts as a proton acceptor to activate the nucleophilic hydroxyl oxygen on substrate serine or threonine residues, allowing the phosphate transfer reaction to occur mediated by base-catalysis.[8]
DFG Motif
D594, F595, and G596 compose a motif central to B-Raf's function in both its inactive and active state. In the inactive state, F595 occupies the nucleotide-binding pocket, prohibiting ATP from entering and decreasing the likelihood of enzyme catalysis.[5][10][11] In the active state, D594 chelates the divalent magnesium cation that stabilizes the β- and γ-phosphate groups of ATP, orienting the γ-phosphate for transfer.[8]
Activation Loop
Residues 596-600 form strong hydrophobic interactions with the P-loop in the inactive conformation of the kinase, locking the kinase in its inactive state until the activation loop is phosphorylated, destabilizing these interactions with the presence of negative charge. This triggers the shift to the active state of the kinase. Specifically, L597 and V600 of the activation loop interact with G466, F468, and V471 of the P-loop to keep the kinase domain inactive until it is phosphorylated.[9]
# Enzymology
B-Raf is a serine/threonine-specific protein kinase. As such, it catalyzes the phosphorylation of serine and threonine residues in a consensus sequence on target proteins by ATP, yielding ADP and a phosphorylated protein as products.[8] Since it is a highly regulated signal transduction kinase, B-Raf must first bind Ras-GTP before becoming active as an enzyme.[7] Once B-Raf is activated, a conserved protein kinase catalytic core phosphorylates protein substrates by promoting the nucleophilic attack of the activated substrate serine or threonine hydroxyl oxygen atom on the γ-phosphate group of ATP through bimolecular nucleophilic substitution.[8][12][13][14]
## Activating the Catalytic Domain
### Releasing the Autoinhibitory CR1 Domain
The kinase (CR3) domain of human Raf kinases is inhibited by two mechanisms: autoinhibition by its own regulatory Ras-GTP-binding CR1 domain and a lack of post-translational phosphorylation of key serine and tyrosine residues (S338 and Y341 for c-Raf) in the CR2 hinge region. During B-Raf activation, the protein's autoinhibitory CR1 domain first binds Ras-GTP's effector domain to the CR1 Ras-binding domain (RBD) to release the kinase CR3 domain like other members of the human Raf kinase family. The CR1-Ras interaction is later strengthened through the binding of the cysteine-rich subdomain (CRD) of CR1 to Ras and membrane phospholipids.[4] Unlike A-Raf and C-Raf, which must be phosphorylated on hydroxyl-containing CR2 residues before fully releasing CR1 to become active, B-Raf is constituitively phosphorylated on CR2 S445.[15] This allows the negatively charged phosphoserine to immediately repel CR1 through steric and electrostatic interactions once the regulatory domain is unbound, freeing the CR3 kinase domain to interact with substrate proteins.
### Transforming the Protein Kinase CR3 Domain into Active Conformation
After the autoinhibitory CR1 regulatory domain is released, B-Raf's CR3 kinase domain must change to its ATP-binding active conformer before it can catalyze protein phosphorylation. In the inactive conformation, F595 of the DFG motif blocks the hydrophobic adenine binding pocket while activation loop residues form hydrophobic interactions with the P-loop, stopping ATP from accessing its binding site. When the activation loop is phosphorylated, the negative charge of the phosphate is unstable in the hydrophobic environment of the P-loop. As a result, the activation loop changes conformation, stretching out across the C-lobe of the kinase domain. In this process, it forms stabilizing β-sheet interactions with the β6 strand. Meanwhile, the phosphorylated residue approaches K507, forming a stabilizing salt bridge to lock the activation loop into place. The DFG motif changes conformation with the activation loop, causing F595 to move out of the adenine nucleotide binding site and into a hydrophobic pocket bordered by the αC and αE helices. Together, DFG and activation loop movement upon phosphorylation open the ATP binding site. Since all other substrate-binding and catalytic domains are already in place, phosphorylation of the activation loop alone activates B-Raf's kinase domain through a chain reaction that essentially removes a lid from an otherwise-prepared active site.[9]
## Enzymatic Mechanism
To effectively catalyze protein phosphorylation via the bimolecular substitution of serine and threonine residues with ADP as a leaving group, B-Raf must first bind ATP and then stabilize the transition state as the γ-phosphate of ATP is transferred.[8]
### ATP Binding
B-Raf binds ATP by anchoring the adenine nucleotide in a nonpolar pocket (yellow, Figure 1) and orienting the molecule through hydrogen-bonding and electrostatic interactions with phosphate groups. In addition to the P-loop and DFG motif phosphate binding described above, K483 and E500 play key roles in stabilizing non-transferable phosphate groups. The positive charge on the primary amine of K483 allows it to stabilize the negative charge on ATP α- and β-phosphate groups when ATP binds. When ATP is not present, the negative charge of the E500 carboxyl group balances this charge.[8][9]
### Protein Phosphorylation
Once ATP is bound to the B-Raf kinase domain, D576 of the catalytic loop activates a substrate hydroxyl group, increasing its nucleophilicity to kinetically drive the phosphorylation reaction while other catalytic loop residues stabilize the transition state.(Figure 2). N581 chelates the divalent magnesium cation associated with ATP to help orient the molecule for optimal substitution. K578 neutralizes the negative charge on the γ-phosphate group of ATP so that the activated ser/thr substrate residue won't experience as much electron-electron repulsion when attacking the phosphate. After the phosphate group is transferred, ADP and the new phosphoprotein are released.[8]
## Inhibitors
Since constituitively active B-Raf mutants commonly cause cancer (see Clinical Significance) by excessively signaling cells to grow, inhibitors of B-Raf have been developed for both the inactive and active conformations of the kinase domain as cancer therapeutic candidates.[9][10][11]
### BAY43-9006 (Sorafenib)
BAY43-9006 (Sorafenib, Nexavar)is a V600E mutant B-Raf and C-Raf inhibitor approved by the FDA for the treatment of primary liver and kidney cancer. Bay43-9006 disables the B-Raf kinase domain by locking the enzyme in its inactive form. The inhibitor accomplishes this by blocking the ATP binding pocket through high-affinity for the kinase domain. It then binds key activation loop and DFG motif residues to stop the movement of the activation loop and DFG motif to the active conformation. Finally, a trifluoromethyl phenyl moiety sterically blocks the DFG motif and activation loop active conformation site, making it impossible for the kinase domain to shift conformation to become active.[9]
The distal pyridyl ring of BAY43-9006 anchors in the hydrophobic nucleotide-binding pocket of the kinase N-lobe, interacting with W531, F583, and F595. The hydrophobic interactions with catalytic loop F583 and DFG motif F595 stabilize the inactive conformation of these structures, decreasing the likelihood of enzyme activation. Further hydrophobic interaction of K483, L514, and T529 with the center phenyl ring increase the affinity of the kinase domain for the inhibitor. Hydrophobic interaction of F595 with the center ring as well decreases the energetic favorability of a DFG conformation switch further. Finally, polar interactions of BAY43-9006 with the kinase domain continue this trend of increasing enzyme affinity for the inhibitor and stabilizing DFG residues in the inactive conformation. E501 and C532 hydrogen bond the urea and pyridyl groups of the inhibitor respectively while the urea carbonyl accepts a hydrogen bond from D594's backbone amide nitrogen to lock the DFG motif in place.[9]
The trifluoromethyl phenyl moiety cements the thermodynamic favorability of the inactive conformation when the kinase domain is bound to BAY43-9006 by sterically blocking the hydrophobic pocket between the αC and αE helices that the DFG motif and activation loop would inhabit upon shifting to their locations in the active conformation of the protein.[9]
### PLX 4032 (Vemurafenib)
PLX4032 (Vemurafenib) is a V600 mutant B-Raf inhibitor approved by the FDA for the treatment of late-stage melanoma.[5] Unlike BAY43-9006, which inhibits the inactive form of the kinase domain, Vemurafenib inhibits the active "DFG-in" form of the kinase,[10][11] firmly anchoring itself in the ATP-binding site. By inhibiting only the active form of the kinase, Vemurafenib selectively inhibits the proliferation of cells with unregulated B-Raf, normally those that cause cancer.
Since Vemurafenib only differs from its precursor, PLX4720, in a phenyl ring added for pharmacokinetic reasons,[11] PLX4720's mode of action is equivalent to Vemurafenib's. PLX4720 has good affinity for the ATP binding site partially because its anchor region, a 7-azaindole bicyclic, only differs from the natural adenine that occupies the site in two places where nitrogen atoms have been replaced by carbon. This enables strong intermolecular interactions like N7 hydrogen bonding to C532 and N1 hydrogen bonding to Q530 to be preserved. Excellent fit within the ATP-binding hydrophobic pocket (C532, W531, T529, L514, A481) increases binding affinity as well. Ketone linker hydrogen bonding to water and difluoro-phenyl fit in a second hydrophobic pocket (A481, V482, K483, V471, I527, T529, L514, and F583) contribute to the exceptionally high binding affinity overall. Selective binding to active Raf is accomplished by the terminal propyl group that binds to a Raf-selective pocket created by a shift of the αC helix. Selectivity for the active conformation of the kinase is further increased by a pH-sensitive deprotonated sulfonamide group that is stabilized by hydrogen bonding with the backbone peptide NH of D594 in the active state. In the inactive state, the inhibitor's sulfonamide group interacts with the backbone carbonyl of that residue instead, creating repulsion. Thus, Vemurafenib binds preferentially to the active state of B-Raf's kinase domain.[10][11]
# Clinical significance
Mutations in the BRAF gene can cause disease in two ways. First, mutations can be inherited and cause birth defects. Second, mutations can appear later in life and cause cancer, as an oncogene.
Inherited mutations in this gene cause cardiofaciocutaneous syndrome, a disease characterized by heart defects, mental retardation and a distinctive facial appearance.[16]
Acquired mutations in this gene have been found in cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, papillary thyroid carcinoma, non-small-cell lung carcinoma, and adenocarcinoma of the lung.[2]
The V600E mutation of the BRAF gene has been associated with hairy cell leukemia in numerous studies and has been suggested for use in screening for Lynch syndrome to reduce the number of patients undergoing unnecessary MLH1 sequencing.[17]
## BRAF mutants
More than 30 mutations of the BRAF gene associated with human cancers have been identified. The frequency of BRAF mutations varies widely in human cancers, from more than 80% in melanomas and nevi, to as little as 0-18% in other tumors, such as 1-3% in lung cancers and 5% in colorectal cancer.[18] In 90% of the cases, thymine is substituted with adenine at nucleotide 1799. This leads to valine (V) being substituted for by glutamate (E) at codon 600 (now referred to as V600E) in the activation segment that has been found in human cancers.[19] This mutation has been widely observed in papillary thyroid carcinoma, colorectal cancer, melanoma and non-small-cell lung cancer.[20][21][22][23][24][25][26] In 2010 a team of scientists demonstrated presence of BRAF-V600E mutation in 57% of Langerhans cell histiocytosis patients.[27] A team of Italian scientists used massively parallel sequencing to pinpoint mutation V600E as a likely driver mutation in 100% of cases of hairy cell leukaemia.[28]
Other mutations which have been found are R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600K, A727V, etc. and most of these mutations are clustered to two regions: the glycine-rich P loop of the N lobe and the activation segment and flanking regions.[9] These mutations change the activation segment from inactive state to active state, for example in the previous cited paper it has been reported that the aliphatic side chain of Val599 interacts with the phenyl ring of Phe467 in the P loop. Replacing the medium sized hydrophobic Val side chain with a larger and charged residue as found in human cancer(Glu, Asp, Lys, or Arg) would be expected to destabilize the interactions that maintain the DFG motif in an inactive conformation, so flipping the activation segment into the active position. Depending on the type of mutation the kinase activity towards MEK may also vary. In the same paper it has been reported that most of the mutants stimulate enhanced B-Raf kinase activity toward MEK. However, a few mutants act through a different mechanism because although their activity toward MEK is reduced, they adopt a conformation that activates wild-type C-RAF, which then signals to ERK.
## B-Raf inhibitors in the clinic
As mentioned above, some pharmaceutical firms are developing specific inhibitors of mutated B-raf protein for anticancer use because B-Raf is a well-understood, high yield target.[10][29] Vemurafenib (RG7204 or PLX4032), licensed by the US Food and Drug Administration as Zelboraf for the treatment of metastatic melanoma in August 2011, is the current state-of-the-art example for why active B-Raf inhibitors are being pursued as drug candidates. Vemurafenib is biochemically interesting as a mechanism to target cancer due to its high efficacy and selectivity.[5] In Phase II[30] and Phase III[31] clinical trials, B-Raf not only increased metastatic melanoma patient chance of survival but raised the response rate to treatment from 7-12% to 53% in the same amount of time compared to the former best chemotherapeutic treatment: dacarbazine. In spite of the drug's high efficacy, 20% of tumors still develop resistance to the treatment. In mice, 20% of tumors become resistant after 56 days.[32] While the mechanisms of this resistance are still disputed, some hypotheses include the overexpression of B-Raf to compensate for high concentrations of Vemurafenib[32] and upstream upregulation of growth signaling.[33]
More general B-raf inhibitors include GDC-0879, PLX-4720, Sorafenib Tosylate. dabrafenib, LGX818
# Interactions
BRAF (gene) has been shown to interact with YWHAB,[34][35] C-Raf,[36] AKT1[37] and HRAS.[38][39] | https://www.wikidoc.org/index.php/BRAF | |
5183489e6a7c1c54bb46eab054372011d134104a | wikidoc | BRD2 | BRD2
Bromodomain-containing protein 2 is a protein that in humans is encoded by the BRD2 gene. BRD2 is part of the Bromodomain and Extra-Terminal motif (BET) protein family that also contains BRD3, BRD4, and BRDT in mammals
Early descriptions demonstrated that BRD2 gene product is a mitogen-activated kinase which localizes to the nucleus. The gene maps to the major histocompatibility complex (MHC) class II region on chromosome 6p21.3 but sequence comparison suggests that the protein is not involved in the immune response. Homology to the Drosophila gene female sterile homeotic suggests that this human gene may be part of a signal transduction pathway involved in growth control.
# Functions
- BRD2 has been implicated in cancer.
- BRD2 loss in mice causes obesity without diabetes for unknown reasons.
- BRD2 may have functional overlap with close homolog BRD3.
- BRD2 function is blocked by BET inhibitors.
# Interactions
BRD2 has been shown to interact with E2F2, and many transcription factors including GATA1. | BRD2
Bromodomain-containing protein 2 is a protein that in humans is encoded by the BRD2 gene. BRD2 is part of the Bromodomain and Extra-Terminal motif (BET) protein family that also contains BRD3, BRD4, and BRDT in mammals [1][2][3]
Early descriptions demonstrated that BRD2 gene product is a mitogen-activated kinase which localizes to the nucleus. The gene maps to the major histocompatibility complex (MHC) class II region on chromosome 6p21.3 but sequence comparison suggests that the protein is not involved in the immune response. Homology to the Drosophila gene female sterile homeotic suggests that this human gene may be part of a signal transduction pathway involved in growth control.[3]
# Functions
- BRD2 has been implicated in cancer.[1][4]
- BRD2 loss in mice causes obesity without diabetes for unknown reasons.[1]
- BRD2 may have functional overlap with close homolog BRD3.[5]
- BRD2 function is blocked by BET inhibitors.
# Interactions
BRD2 has been shown to interact with E2F2,[6][7] and many transcription factors including GATA1.[5] | https://www.wikidoc.org/index.php/BRD2 | |
2190486fbc96db521822463219e404b72ddd6295 | wikidoc | BRD4 | BRD4
Bromodomain-containing protein 4 is a protein that in humans is encoded by the BRD4 gene.
BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which also includes BRD2, BRD3, and BRDT. BRD4, similar to other BET family members, contains two bromodomains that recognize acetylated lysine residues. BRD4 also has an extended C-terminal domain with little sequence homology to other BET family members.
# Structure
The two bromodomains in BRD4, termed BD1 and BD2, consist of 4 alpha-helices linked by 2 loops. The ET domain structure is made up of 3 alpha-helices and a loop. The C-terminal domain of BRD4 has been implicated in promoting gene transcription through interaction with the transcription elongation factor P-TEFb and RNA polymerase II.
# Function
The protein encoded by this gene is homologous to the murine protein MCAP, which associates with chromosomes during mitosis, and to the human RING3 protein, a serine/threonine kinase. Each of these proteins contains two bromodomains, a conserved sequence motif which may be involved in chromatin targeting. This gene has been implicated as the chromosome 19 target of translocation t(15;19)(q13;p13.1), which defines the NUT midline carcinoma. Two alternatively spliced transcript variants have been described.
# Role in cancer
Most cases of NUT midline carcinoma involve translocation of the BRD4 with NUT genes. BRD4 is often required for expression of Myc and other "tumor driving" oncogenes in hematologic cancers including multiple myeloma, acute myelogenous leukemia and acute lymphoblastic leukaemia.
BRD4 is a major target of BET inhibitors, a class of pharmaceutical drugs currently being evaluated in clinical trials.
# Interactions
Notably, BRD4 interacts with P-TEFb via its P-TEFb interaction domain (PID), thereby stimulating its kinase activity and stimulating its phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II. Recent review.
BRD4 has been shown to interact with GATA1, JMJD6, RFC2, RFC3, RFC1, RFC4 and RFC5.
BRD4 has also been implicated in binding with the diacetylated Twist protein, and the disruption of this interaction has been shown to suppress tumorigenesis in basal-like breast cancer.
BRD4 has also been shown to interact with a variety of inhibitors, such as MS417; inhibition of BRD4 with MS417 has been shown to down-regulate NF-κB activity seen in HIV-associated kidney disease. BRD4 also interacts with RVX-208, which is being evaluated for treatment of atherosclerosis and cardiovascular disease. | BRD4
Bromodomain-containing protein 4 is a protein that in humans is encoded by the BRD4 gene.[1][2]
BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which also includes BRD2, BRD3, and BRDT.[3] BRD4, similar to other BET family members, contains two bromodomains that recognize acetylated lysine residues.[4] BRD4 also has an extended C-terminal domain with little sequence homology to other BET family members.[3]
# Structure
The two bromodomains in BRD4, termed BD1 and BD2, consist of 4 alpha-helices linked by 2 loops.[5] The ET domain structure is made up of 3 alpha-helices and a loop.[6] The C-terminal domain of BRD4 has been implicated in promoting gene transcription through interaction with the transcription elongation factor P-TEFb and RNA polymerase II.[7][8][9]
# Function
The protein encoded by this gene is homologous to the murine protein MCAP, which associates with chromosomes during mitosis, and to the human RING3 protein, a serine/threonine kinase. Each of these proteins contains two bromodomains, a conserved sequence motif which may be involved in chromatin targeting. This gene has been implicated as the chromosome 19 target of translocation t(15;19)(q13;p13.1), which defines the NUT midline carcinoma. Two alternatively spliced transcript variants have been described.[2]
# Role in cancer
Most cases of NUT midline carcinoma involve translocation of the BRD4 with NUT genes.[10] BRD4 is often required for expression of Myc and other "tumor driving" oncogenes in hematologic cancers including multiple myeloma, acute myelogenous leukemia and acute lymphoblastic leukaemia.[11]
BRD4 is a major target of BET inhibitors,[12][11] a class of pharmaceutical drugs currently being evaluated in clinical trials.
# Interactions
Notably, BRD4 interacts with P-TEFb via its P-TEFb interaction domain (PID), thereby stimulating its kinase activity and stimulating its phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II.[13] Recent review.[14]
BRD4 has been shown to interact with GATA1,[15] JMJD6,[16] RFC2,[17] RFC3,[17] RFC1,[17] RFC4[17] and RFC5.[17]
BRD4 has also been implicated in binding with the diacetylated Twist protein, and the disruption of this interaction has been shown to suppress tumorigenesis in basal-like breast cancer.[18]
BRD4 has also been shown to interact with a variety of inhibitors, such as MS417; inhibition of BRD4 with MS417 has been shown to down-regulate NF-κB activity seen in HIV-associated kidney disease.[19] BRD4 also interacts with RVX-208,[20] which is being evaluated for treatment of atherosclerosis and cardiovascular disease. | https://www.wikidoc.org/index.php/BRD4 | |
148ab9b44d1fc1d355e76242533c5a04f83505a2 | wikidoc | BRD8 | BRD8
Bromodomain-containing protein 8 is a protein that in humans is encoded by the BRD8 gene.
The protein encoded by this gene interacts with thyroid hormone receptor in a ligand-dependent manner and enhances thyroid hormone-dependent activation from thyroid response elements. This protein contains a bromodomain and is thought to be a nuclear receptor coactivator. Three alternatively spliced transcript variants that encode distinct isoforms have been identified.
# Interactions
BRD8 has been shown to interact with Thyroid hormone receptor beta and Retinoid X receptor alpha. | BRD8
Bromodomain-containing protein 8 is a protein that in humans is encoded by the BRD8 gene.[1][2][3]
The protein encoded by this gene interacts with thyroid hormone receptor in a ligand-dependent manner and enhances thyroid hormone-dependent activation from thyroid response elements. This protein contains a bromodomain and is thought to be a nuclear receptor coactivator. Three alternatively spliced transcript variants that encode distinct isoforms have been identified.[3]
# Interactions
BRD8 has been shown to interact with Thyroid hormone receptor beta[2] and Retinoid X receptor alpha.[4] | https://www.wikidoc.org/index.php/BRD8 | |
9b35dab0c2b72dc17e64367622af7349896fda62 | wikidoc | BRDT | BRDT
Bromodomain testis-specific protein is a protein that in humans is encoded by the BRDT gene. It is a member of the Bromodomain and Extra-terminal motif (BET) protein family.
BRDT is similar to the RING3 protein family. It possesses 2 bromodomain motifs and a PEST sequence (a cluster of proline, glutamic acid, serine, and threonine residues), characteristic of proteins that undergo rapid intracellular degradation. The bromodomain is found in proteins that regulate transcription. Two transcript variants encoding the same protein have been found for this gene.
The use of three different mouse models (Brdt knock-out mice, mice expressing a non-functional Brdt and mice expressing a mutated Brdt lacking its first bromodomain) showed that Brdt drives a meiotic and post-meiotic gene expression program. It also controls the genome-wide post-meiotic genome reorganization that occurs after histone hyperacetylation in elongating spermatids.
# Model organisms
Model organisms have been used in the study of BRDT function. A conditional knockout mouse line, called Brdttm1a(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 five tests were carried out on mutant mice and two significant abnormalities were observed. Homozygous mutant males were sub-fertile and both sexes had a decreased number of lumbar and sacral vertebrae.
# Potential as target of male contraceptive medication
BET inhibitors such as JQ1 block the region of BRDT responsible for chromatin binding, and cause a reversible reduction of sperm production, sperm quality, and size of the testis in mice.
The mechanism of action of JQ1 could be explained by considering Brdt’s functions as a driver of testis-specific gene expression and post-meiotic chromatin reorganization. As BET inhibitors also inhibit other BET proteins BRD2, BRD3, and BRD4, they are likely to have effects in people beyond temporary male sterility. | BRDT
Bromodomain testis-specific protein is a protein that in humans is encoded by the BRDT gene. It is a member of the Bromodomain and Extra-terminal motif (BET) protein family.[1][2]
BRDT is similar to the RING3 protein family. It possesses 2 bromodomain motifs and a PEST sequence (a cluster of proline, glutamic acid, serine, and threonine residues), characteristic of proteins that undergo rapid intracellular degradation. The bromodomain is found in proteins that regulate transcription. Two transcript variants encoding the same protein have been found for this gene.[2]
The use of three different mouse models (Brdt knock-out mice, mice expressing a non-functional Brdt and mice expressing a mutated Brdt lacking its first bromodomain) showed that Brdt drives a meiotic and post-meiotic gene expression program. It also controls the genome-wide post-meiotic genome reorganization that occurs after histone hyperacetylation in elongating spermatids.[2][3]
# Model organisms
Model organisms have been used in the study of BRDT function. A conditional knockout mouse line, called Brdttm1a(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.[11][12][13]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[7][14] Twenty five tests were carried out on mutant mice and two significant abnormalities were observed.[7] Homozygous mutant males were sub-fertile and both sexes had a decreased number of lumbar and sacral vertebrae.[7]
# Potential as target of male contraceptive medication
BET inhibitors such as JQ1 block the region of BRDT responsible for chromatin binding, and cause a reversible reduction of sperm production, sperm quality, and size of the testis in mice.[15]
The mechanism of action of JQ1 could be explained by considering Brdt’s functions as a driver of testis-specific gene expression and post-meiotic chromatin reorganization.[2][3] As BET inhibitors also inhibit other BET proteins BRD2, BRD3, and BRD4, they are likely to have effects in people beyond temporary male sterility. | https://www.wikidoc.org/index.php/BRDT | |
f42729e2b490fdac84ede5a31331710a4bbd0cc5 | wikidoc | BTG1 | BTG1
Protein BTG1 is a protein that in humans is encoded by the BTG1 gene.
# Function
The BTG1 gene locus has been shown to be involved in a t(8;12)(q24;q22) chromosomal translocation in a case of B-cell chronic lymphocytic leukemia. It is a member of a family of antiproliferative genes. BTG1 expression is maximal in the G0/G1 phases of the cell cycle and downregulated when cells progressed through G1. It negatively regulates cell proliferation.
# Interactions
BTG1 has been shown to interact with:
- CNOT7,
- CNOT8,
- HOXB9, and
- PRMT1.
# Clinical relevance
Recurrent mutations in this gene have been associated to cases of diffuse large B-cell lymphoma.
# Maintenance of adult neural stem cells
Recent data, obtained in a new model of mouse lacking the BTG1 gene, indicate that BTG1 is essential for the proliferation and expansion of stem cells in the adult neurogenic niches, i.e. the dentate gyrus and sub ventricular zone (see for review). In particular, BTG1 keeps adult neural stem cells in quiescence, preserving the neural stem cells pool from depletion. In the absence of BTG1, the stem and progenitor cells initially hyper proliferate and then in the longer period lose the ability to proliferate and expand. Other recent data indicate that physical exercise can fully reconstitute the proliferative defect of stem cells that follows the ablation of the BTG1 gene, suggesting that the pool of neural stem cells maintains a hidden form of plasticity which is tightly controlled by BTG1; hence, BTG1 might prevent the depletion of stem cells in the presence of strong neurogenic stimuli or of neural degenerative stimuli.
Btg1 plays a role also in the expansion of cerebellar granule precursor cells. In fact the deletion of Btg1 leads in mouse to uncontrolled proliferation of the cerebellar precursor cells during the early postnatal period. Consequently, in the adult, the cerebellum lacking Btg1 is significantly larger and the motor coordination is heavily impaired.
The closest homolog of BTG1 is BTG2, which also controls the proliferation and differentiation of adult neural stem cells; the role of BTG2, however, appears to differ from that of BTG1 being probably more relevant in controlling the terminal differentiation of neural stem and progenitor cells in the adult neurogenic niches. | BTG1
Protein BTG1 is a protein that in humans is encoded by the BTG1 gene.[1][2]
# Function
The BTG1 gene locus has been shown to be involved in a t(8;12)(q24;q22) chromosomal translocation in a case of B-cell chronic lymphocytic leukemia. It is a member of a family of antiproliferative genes. BTG1 expression is maximal in the G0/G1 phases of the cell cycle and downregulated when cells progressed through G1. It negatively regulates cell proliferation.[2]
# Interactions
BTG1 has been shown to interact with:
- CNOT7,[3][4]
- CNOT8,[4][5]
- HOXB9,[6] and
- PRMT1.[7][8]
# Clinical relevance
Recurrent mutations in this gene have been associated to cases of diffuse large B-cell lymphoma.[9][10]
# Maintenance of adult neural stem cells
Recent data, obtained in a new model of mouse lacking the BTG1 gene, indicate that BTG1 is essential for the proliferation and expansion of stem cells in the adult neurogenic niches, i.e. the dentate gyrus and sub ventricular zone (see for review[11]). In particular, BTG1 keeps adult neural stem cells in quiescence, preserving the neural stem cells pool from depletion. In the absence of BTG1, the stem and progenitor cells initially hyper proliferate and then in the longer period lose the ability to proliferate and expand.[12][13] Other recent data indicate that physical exercise can fully reconstitute the proliferative defect of stem cells that follows the ablation of the BTG1 gene, suggesting that the pool of neural stem cells maintains a hidden form of plasticity which is tightly controlled by BTG1; hence, BTG1 might prevent the depletion of stem cells in the presence of strong neurogenic stimuli or of neural degenerative stimuli.[14][15]
Btg1 plays a role also in the expansion of cerebellar granule precursor cells. In fact the deletion of Btg1 leads in mouse to uncontrolled proliferation of the cerebellar precursor cells during the early postnatal period. Consequently, in the adult, the cerebellum lacking Btg1 is significantly larger and the motor coordination is heavily impaired.[16]
The closest homolog of BTG1 is BTG2, which also controls the proliferation and differentiation of adult neural stem cells; the role of BTG2, however, appears to differ from that of BTG1 being probably more relevant in controlling the terminal differentiation of neural stem and progenitor cells in the adult neurogenic niches.[13] | https://www.wikidoc.org/index.php/BTG1 | |
4e773d22898454a192d4f173aa73e47679a4e425 | wikidoc | BTG2 | BTG2
Protein BTG2 also known as BTG family member 2 or NGF-inducible anti-proliferative protein PC3 or NGF-inducible protein TIS21, is a protein that in humans is encoded by the BTG2 gene (B-cell translocation gene 2) and in other mammals by the homologous Btg2 gene. This protein controls cell cycle progression and proneural genes expression by acting as a transcription coregulator that enhances or inhibits the activity of transcription factors.
The protein BTG2 is the human homolog of the PC3 (pheochromocytoma cell 3) protein in rat and of the Tis21 (tetradecanoyl phorbol acetate-inducible sequence 21) protein in mouse. Tis21 had been originally isolated as a sequence induced by TPA in mouse fibroblasts, whereas PC3 was originally isolated as sequence induced at the beginning of neuron differentiation; BTG2 was then isolated in human cells as sequence induced by p53 and DNA damage.
The protein encoded by the gene BTG2 (which is the official name assigned to the gene PC3/Tis21/BTG2) is a member of the BTG/Tob family (that comprises six proteins BTG1, BTG2/PC3/Tis21, BTG3/ANA, BTG4/PC3B, Tob1/Tob and Tob2). This family has structurally related proteins that appear to have antiproliferative properties. In particular, the BTG2 protein has been shown to negatively control a cell cycle checkpoint at the G1 to S phase transition in fibroblasts and neuronal cells by direct inhibition of the activity of cyclin D1 promoter.
# Regulator of neuron differentiation
A number of studies in vivo have shown that BTG2 expression is associated with the neurogenic asymmetric division in neural progenitor cells. Moreover, when directly overexpressed in vivo in neural progenitor cells, BTG2 induces their differentiation. In fact, in the neuronal PC12 cell line BTG2 is not able to trigger differentiation by itself, but only to synergize with NGF, while in vivo BTG2 is fully able to induce differentiation of progenitor cells, i.e., during embryonic development in the neuroblast of the neural tube and in granule precursors of cerebellum, as well in adult progenitor cells of the dentate gyrus and of the subventricular zone. Notably, it has recently been shown that BTG2 is essential for the differentiation of new neurons, using a BTG2 knock out mouse. BTG2 is thus a pan-neural gene required for the development of the new neuron generated during adulthood, in the two neurogenic regions of adult brain, i.e., the hippocampus and the subventricular zone. Such requirement of BTG2 in neuron maturation is consistent with the fact that during brain development BTG2 is expressed in the proliferating neuroblasts of the ventricular zone of the neural tube, and to a lower extent in the differentiating neuroblasts of the mantle zone; postnatally it is expressed in cerebellar precursors mainly in the proliferating regions of the neuropithelium (i.e., in the external granular layer), and in the hippocampus in proliferating and differentiating progenitor cells. The pro-differentiative action of BTG2 appears to be consequent not only to inhibition of cell cycle progression but also to a BTG2-dependent activation of proneural genes in neural progenitor cells. In fact, BTG2 activates proneural genes by associating with the promoter of Id3, a key inhibitor of proneural gene activity, and by negatively regulating its activity.
BTG2 is a transcriptional cofactor, given that it has been shown to associate with, and regulate the promoters not only of Id3 but also of cyclin D1 and RAR-β, being part of transcriptional complexes. It has been shown that when the differentiation of new neurons of the hippocampus - a brain region important for learning and memory - is either accelerated or delayed by means of overexpression or deletion of BTG2, respectively, spatial and contextual memory is heavily altered. This suggests that the time the young neurons spend in different states of neuronal differentiation is critical for their ultimate function in learning and memory, and that BTG2 may play a role in the timing of recruitment of the new neuron into memory circuits.
In conclusion, the main action of Btg2 on neural progenitor cells of the dentate gyrus and subventricular zone during adult neurogenesis is the positive control of their terminal differentiation (see for review:). During the early postnatal development of the cerebellum, Btg2 is mainly required to control the migration and differentiation of the precursor cells of cerebellar granule neurons. In contrast, BTG1, the closest homolog to Btg2, appears to negatively regulate the proliferation of adult stem cells in the dentate gyrus and subventricular zone, maintaining in quiescence the stem cells pool and preserving it from depletion. BTG1 is also necessary to limit the proliferative expansion of cerebellar precursor cells, as without BTG1 the adult cerebellum is larger and unable to coordinate motor activity.
# Medulloblastoma suppressor
BTG2 has been shown to inhibit medulloblastoma, the very aggressive tumor of cerebellum, by inhibiting the proliferation and triggering the differentiation of the precursors of cerebellar granule neurons. This demonstration was obtained by overexpressing BTG2 in a mouse model of medulloblastoma, presenting activation of the sonic hedgehog pathway (heterozygous for the gene Patched1). More recently, it has been shown that the ablation of BTG2 greatly enhances the medulloblastoma frequency by inhibiting the migration of cerebellar granule neuron precursors. This impairment of migration of the precursors of cerebellar granule neurons forces them to remain at the surface of the cerebellum, where they continue to proliferate, becoming target of transforming insults. The impairment of migration of the precursors of cerebellar granule neurons (GCPs) depends on the inhibition of expression of the chemokine CXCL3 consequent to ablation of BTG2. In fact, the transcription of CXCL3 is directly regulated by BTG2, and CXCL3 is able to induce cell-autonomously the migration of cerebellar granule precursors. Treatment with CXCL3 prevents the growth of medulloblastoma lesions in a Shh-type mouse model of medulloblastoma. Thus, CXCL3 is a target for medulloblastoma therapy.
# Interactions
BTG2 has been shown to interact with PRMT1, HOXB9, CNOT8 and HDAC1 HDAC4 and HDAC9. | BTG2
Protein BTG2 also known as BTG family member 2 or NGF-inducible anti-proliferative protein PC3 or NGF-inducible protein TIS21, is a protein that in humans is encoded by the BTG2 gene (B-cell translocation gene 2)[1] and in other mammals by the homologous Btg2 gene.[2][3] This protein controls cell cycle progression and proneural genes expression by acting as a transcription coregulator that enhances or inhibits the activity of transcription factors.
The protein BTG2 is the human homolog of the PC3 (pheochromocytoma cell 3) protein in rat and of the Tis21 (tetradecanoyl phorbol acetate-inducible sequence 21) protein in mouse.[4][5] Tis21 had been originally isolated as a sequence induced by TPA in mouse fibroblasts,[3] whereas PC3 was originally isolated as sequence induced at the beginning of neuron differentiation;[2] BTG2 was then isolated in human cells as sequence induced by p53 and DNA damage.[1][6]
The protein encoded by the gene BTG2 (which is the official name assigned to the gene PC3/Tis21/BTG2) is a member of the BTG/Tob family (that comprises six proteins BTG1, BTG2/PC3/Tis21, BTG3/ANA, BTG4/PC3B, Tob1/Tob and Tob2).[4][5][7] This family has structurally related proteins that appear to have antiproliferative properties. In particular, the BTG2 protein has been shown to negatively control a cell cycle checkpoint at the G1 to S phase transition in fibroblasts and neuronal cells by direct inhibition of the activity of cyclin D1 promoter.[8][9][10]
# Regulator of neuron differentiation
A number of studies in vivo have shown that BTG2 expression is associated with the neurogenic asymmetric division in neural progenitor cells.[11][12][13][14][15] Moreover, when directly overexpressed in vivo in neural progenitor cells, BTG2 induces their differentiation.[16][17] In fact, in the neuronal PC12 cell line BTG2 is not able to trigger differentiation by itself, but only to synergize with NGF,[18][19] while in vivo BTG2 is fully able to induce differentiation of progenitor cells, i.e., during embryonic development in the neuroblast of the neural tube and in granule precursors of cerebellum, as well in adult progenitor cells of the dentate gyrus and of the subventricular zone.[16][17] Notably, it has recently been shown that BTG2 is essential for the differentiation of new neurons, using a BTG2 knock out mouse.[20] BTG2 is thus a pan-neural gene required for the development of the new neuron generated during adulthood, in the two neurogenic regions of adult brain, i.e., the hippocampus and the subventricular zone.[20] Such requirement of BTG2 in neuron maturation is consistent with the fact that during brain development BTG2 is expressed in the proliferating neuroblasts of the ventricular zone of the neural tube, and to a lower extent in the differentiating neuroblasts of the mantle zone; postnatally it is expressed in cerebellar precursors mainly in the proliferating regions of the neuropithelium (i.e., in the external granular layer), and in the hippocampus in proliferating and differentiating progenitor cells.[11][16][17] The pro-differentiative action of BTG2 appears to be consequent not only to inhibition of cell cycle progression but also to a BTG2-dependent activation of proneural genes in neural progenitor cells.[16][20] In fact, BTG2 activates proneural genes by associating with the promoter of Id3, a key inhibitor of proneural gene activity, and by negatively regulating its activity.[20]
BTG2 is a transcriptional cofactor, given that it has been shown to associate with, and regulate the promoters not only of Id3 but also of cyclin D1 and RAR-β, being part of transcriptional complexes.[10][21][22] It has been shown that when the differentiation of new neurons of the hippocampus - a brain region important for learning and memory - is either accelerated or delayed by means of overexpression or deletion of BTG2, respectively, spatial and contextual memory is heavily altered.[17][20] This suggests that the time the young neurons spend in different states of neuronal differentiation is critical for their ultimate function in learning and memory, and that BTG2 may play a role in the timing of recruitment of the new neuron into memory circuits.[17][20]
In conclusion, the main action of Btg2 on neural progenitor cells of the dentate gyrus and subventricular zone during adult neurogenesis is the positive control of their terminal differentiation (see for review:[23]). During the early postnatal development of the cerebellum, Btg2 is mainly required to control the migration and differentiation of the precursor cells of cerebellar granule neurons.[24] In contrast, BTG1, the closest homolog to Btg2, appears to negatively regulate the proliferation of adult stem cells in the dentate gyrus and subventricular zone, maintaining in quiescence the stem cells pool and preserving it from depletion.[25][26] BTG1 is also necessary to limit the proliferative expansion of cerebellar precursor cells, as without BTG1 the adult cerebellum is larger and unable to coordinate motor activity.[27]
# Medulloblastoma suppressor
BTG2 has been shown to inhibit medulloblastoma, the very aggressive tumor of cerebellum, by inhibiting the proliferation and triggering the differentiation of the precursors of cerebellar granule neurons. This demonstration was obtained by overexpressing BTG2 in a mouse model of medulloblastoma, presenting activation of the sonic hedgehog pathway (heterozygous for the gene Patched1).[10] More recently, it has been shown that the ablation of BTG2 greatly enhances the medulloblastoma frequency by inhibiting the migration of cerebellar granule neuron precursors. This impairment of migration of the precursors of cerebellar granule neurons forces them to remain at the surface of the cerebellum, where they continue to proliferate, becoming target of transforming insults.[28] The impairment of migration of the precursors of cerebellar granule neurons (GCPs) depends on the inhibition of expression of the chemokine CXCL3 consequent to ablation of BTG2. In fact, the transcription of CXCL3 is directly regulated by BTG2, and CXCL3 is able to induce cell-autonomously the migration of cerebellar granule precursors. Treatment with CXCL3 prevents the growth of medulloblastoma lesions in a Shh-type mouse model of medulloblastoma.[29] Thus, CXCL3 is a target for medulloblastoma therapy.[28][29]
# Interactions
BTG2 has been shown to interact with PRMT1,[22] HOXB9,[30][31] CNOT8[32] and HDAC1 HDAC4 and HDAC9.[33][10] | https://www.wikidoc.org/index.php/BTG2 | |
d820c160523135235143d608662d92b8670f41ae | wikidoc | BTLA | BTLA
B- and T-lymphocyte attenuator is a protein that in humans is encoded by the BTLA gene. BTLA has also been designated as CD272 (cluster of differentiation 272).
# Function
BTLA expression is induced during activation of T cells, and BTLA remains expressed on Th1 cells but not Th2 cells. Like PD1 and CTLA4, BTLA interacts with a B7 homolog, B7H4. However, unlike PD-1 and CTLA-4, BTLA displays T-Cell inhibition via interaction with tumor necrosis family receptors (TNF-R), not just the B7 family of cell surface receptors. BTLA is a ligand for tumour necrosis factor (receptor) superfamily, member 14 (TNFRSF14), also known as herpes virus entry mediator (HVEM). BTLA-HVEM complexes negatively regulate T-cell immune responses.
# Clinical significance
BTLA activation inhibits the function of human CD8+ cancer-specific T cells. | BTLA
B- and T-lymphocyte attenuator is a protein that in humans is encoded by the BTLA gene.[1][2] BTLA has also been designated as CD272 (cluster of differentiation 272).
# Function
BTLA expression is induced during activation of T cells, and BTLA remains expressed on Th1 cells but not Th2 cells. Like PD1 and CTLA4, BTLA interacts with a B7 homolog, B7H4.[2] However, unlike PD-1 and CTLA-4, BTLA displays T-Cell inhibition via interaction with tumor necrosis family receptors (TNF-R), not just the B7 family of cell surface receptors. BTLA is a ligand for tumour necrosis factor (receptor) superfamily, member 14 (TNFRSF14), also known as herpes virus entry mediator (HVEM). BTLA-HVEM complexes negatively regulate T-cell immune responses.
# Clinical significance
BTLA activation inhibits the function of human CD8+ cancer-specific T cells.[3] | https://www.wikidoc.org/index.php/BTLA | |
1b6eceda203640d181536d2a6bc796dce1a4ae7a | wikidoc | BUB1 | BUB1
Mitotic checkpoint serine/threonine-protein kinase BUB1 also known as BUB1 (budding uninhibited by benzimidazoles 1) is an enzyme that in humans is encoded by the BUB1 gene.
Bub1 is a serine/threonine protein kinase first identified in genetic screens of Saccharomyces cerevisiae. The protein is bound to kinetochores and plays a key role in the establishment of the mitotic spindle checkpoint and chromosome congression. The mitotic checkpoint kinase is evolutionarily conserved in organisms as diverse as Saccharomyces cerevisiae and humans. Loss-of-function mutations or absence of Bub1 has been reported to result in aneuploidy, chromosomal instability (CIN) and premature senescence.
# Structure
Bub1p comprises a conserved N-terminal region, a central non-conserved region and a C-terminal serine/threonine kinase domain. The N-terminal region mediates binding of Hs-BUB1 to the mitotic kinetochore protein blinkin (a protein also commonly referred to as AF15q14). The latter interaction is essential for kinetochore localization of Bub1 and its function in cell cycle arrest induced by spindle assembly checkpoint (SAC) activation. The crystal structure of human Bub1 revealed the presence of a N-terminal tetratricopeptide repeat (TPR) domain and a C-terminal kinase domain (residues 784–1085), adopting a canonical kinase fold with two lobes. The ATP binding and the catalytic sites are located at the interface of the two lobes. The N-terminal extension contains three β-strands and an α-helix, wrapping around the N lobe of the kinase domain.:Figure1
# Subcellular location
In humans Bub1 accumulates gradually during G1 and S phase of the cell cycle, peaks at G2/M, and drops dramatically after mitosis. During prophase it localizes as one of the first proteins to the outer kinetochore, a process generally implicated in correct mitotic timing and checkpoint response to spindle damage.
# Function
The protein kinase Bub1 possesses versatile and distinct functions during the cell cycle, mainly in the SAC and chromosome alignment during metaphase. The protein’s interaction network currently identified is similarly complex (see Figure 1).
In eukaryotic cells the SAC serves as the central surveillance mechanism to ensure chromosomes are being passed on to the next generation in a reliable manner. Several components monitor correct bipolar attachment of microtubules to the kinetochore, presumably through detection of tension. Metaphase-to-anaphase transition is halted by the SAC as long as single kinetochores lack bipolar microtubule attachment, implying the need for a highly sensitive signaling pathway. Bub1 was claimed to be the master regulator of SAC formation and signaling. At least thirteen other proteins (Mad1, MAD2, MAD3/BubR1, BUB3, Mps1 etc.) are part of the check point, among which many have been identified to interact with Bub1.
Upon activation of the SAC Bub1 directly phosphorylates APC/C’s coactivator Cdc20. This phosphorylation event is probably achieved in complex with Bub3, which itself has been subjected to prior phosphorylation by Bub1. The phosphorylation of Cdc20 ultimately leads to decreased activity of APC/C which determines the metaphase-to-anaphase transition. In turn APC/C, now in complex with Cdh1, also acts on Bub1 by priming it for degradation to exit mitosis.
In addition, kinetochore localization of Bub1 early during G2 or prophase is another aspect of SAC functioning. Bub1 is thought to serve as a platform recruiting other checkpoint and motor proteins as Mad1, Mad2, BubR1, CENP-E and PLK1 to the kinetochore. Indeed, recent data suggest that the primary role of Bub1 during SAC activity is not Cdc20 phosphorylation but rather recruitment of BubR1, Mad1 and Mad2.
Upon spindle damage Bub1 is also triggered to phosphorylate Mad1 leading to dissociation of the Mad1-Mad2 complex and thereby rendering Mad2 accessible for inhibition of Cdc20.
Bub1 generally protects sister chromatide cohesion by enhancing Shugoshin protein (Sgo1) localization to the centromeric region. Through recruitment of the phosphatase PP2A Bub1 inhibits the action of PLK1, which removes Sgo1 from the centromere.
Contrarily PLK1 localization, as mentioned, also depends on the activity of Bub1. Studies in Xenopus extracts using RNAi or antibody depletion have indicated a crucial function of Bub1 in the organization of the inner centromere. Similarly to its role in kinetochore assembly, it recruits members of the chromosomal passenger complex (CPC) like Aurora B kinase, Survivin and INCENP. Direct phosphorylation of INCENP by Bub1 has been observed.
RNAi mediated depletion of human Bub1 has indicated function in correct metaphase congression. Downstream targets identified are distinct kinetochore proteins as CENP-F, MCAK and the mentioned Sgo1.
# Implications in cancer
Disturbed mitotic checkpoints are a common feature of many human cancers. More precisely, mutations in the spindle checkpoint can lead to chromosomal instability and aneuploidy, a feature present in over 90% of all solid tumors. Loss-of-function mutations or reduced gene expression of Bub1 have been identified in several human tumors as colon, esophageal, gastric, breast cancer and melanoma. A correlation between Bub1 expression levels and the localization of tumors along with their severity was found. For instance, low Bub1 expression levels resulted in more sarcomas, lymphomas and lung tumors, whereas higher ones caused sarcomas and tumors in the liver. Moreover, Bub1 has been identified as a target of the large T antigen of the SV-40 virus, possibly contributing to its potential for oncogenic transformation.
Indications for possible Bub1 involvement in tumorigenesis also derive from animal experiments, where mice with reduced Bub1 expression showed an increase in tumor susceptibility. In vitro knockdown of Bub1 in p53 impaired cells (e.g. HeLa cells) caused aneuploidy. Whether aneuploidy alone is a sufficient driving cause during tumorigenesis or rather a mere consequence has been a matter of scientific debate.
# Link to caspase-independent mitotic death (CIMD)
Recently Bub1 has been identified as a negative regulator of CIMD. Depletion of Bub1 results in increased CIMD in order to avoid aneuploidy caused by reduced SAC functioning. The transcriptional activity of p73 is thereby inhibited via phosphorylation. Direct interaction between these two players has not been visualized so far, therefore molecules linking Bub1 and p73 are yet to be determined.
It has also been proposed that Bub1 binds p53 to prevent it from activating pro-apoptotic genes, therefore p53 is able to induce apoptosis when Bub1 is depleted. However, an interaction between p53 and Bub1 has not yet been shown while p53 binding BubR1 has been reported. | BUB1
Mitotic checkpoint serine/threonine-protein kinase BUB1 also known as BUB1 (budding uninhibited by benzimidazoles 1) is an enzyme that in humans is encoded by the BUB1 gene.[1][2]
Bub1 is a serine/threonine protein kinase first identified in genetic screens of Saccharomyces cerevisiae.[3] The protein is bound to kinetochores and plays a key role in the establishment of the mitotic spindle checkpoint and chromosome congression. The mitotic checkpoint kinase is evolutionarily conserved in organisms as diverse as Saccharomyces cerevisiae and humans. Loss-of-function mutations or absence of Bub1 has been reported to result in aneuploidy, chromosomal instability (CIN) and premature senescence.
# Structure
Bub1p comprises a conserved N-terminal region, a central non-conserved region and a C-terminal serine/threonine kinase domain.[4] The N-terminal region mediates binding of Hs-BUB1 to the mitotic kinetochore protein blinkin (a protein also commonly referred to as AF15q14). The latter interaction is essential for kinetochore localization of Bub1 and its function in cell cycle arrest induced by spindle assembly checkpoint (SAC) activation.[5] The crystal structure of human Bub1 revealed the presence of a N-terminal tetratricopeptide repeat (TPR) domain and a C-terminal kinase domain (residues 784–1085), adopting a canonical kinase fold with two lobes. The ATP binding and the catalytic sites are located at the interface of the two lobes. The N-terminal extension contains three β-strands and an α-helix, wrapping around the N lobe of the kinase domain.[6]:Figure1
# Subcellular location
In humans Bub1 accumulates gradually during G1 and S phase of the cell cycle, peaks at G2/M, and drops dramatically after mitosis. During prophase it localizes as one of the first proteins to the outer kinetochore, a process generally implicated in correct mitotic timing and checkpoint response to spindle damage.[7]
# Function
The protein kinase Bub1 possesses versatile and distinct functions during the cell cycle, mainly in the SAC and chromosome alignment during metaphase. The protein’s interaction network currently identified is similarly complex (see Figure 1).
In eukaryotic cells the SAC serves as the central surveillance mechanism to ensure chromosomes are being passed on to the next generation in a reliable manner. Several components monitor correct bipolar attachment of microtubules to the kinetochore, presumably through detection of tension. Metaphase-to-anaphase transition is halted by the SAC as long as single kinetochores lack bipolar microtubule attachment, implying the need for a highly sensitive signaling pathway. Bub1 was claimed to be the master regulator of SAC formation and signaling. At least thirteen other proteins (Mad1, MAD2, MAD3/BubR1, BUB3, Mps1 etc.) are part of the check point, among which many have been identified to interact with Bub1.
Upon activation of the SAC Bub1 directly phosphorylates APC/C’s coactivator Cdc20.[9] This phosphorylation event is probably achieved in complex with Bub3, which itself has been subjected to prior phosphorylation by Bub1. The phosphorylation of Cdc20 ultimately leads to decreased activity of APC/C which determines the metaphase-to-anaphase transition. In turn APC/C, now in complex with Cdh1, also acts on Bub1 by priming it for degradation to exit mitosis.[10]
In addition, kinetochore localization of Bub1 early during G2 or prophase is another aspect of SAC functioning. Bub1 is thought to serve as a platform recruiting other checkpoint and motor proteins as Mad1, Mad2, BubR1, CENP-E and PLK1 to the kinetochore.[11][12][13] Indeed, recent data suggest that the primary role of Bub1 during SAC activity is not Cdc20 phosphorylation but rather recruitment of BubR1, Mad1 and Mad2.[14]
Upon spindle damage Bub1 is also triggered to phosphorylate Mad1[15][16] leading to dissociation of the Mad1-Mad2 complex and thereby rendering Mad2 accessible for inhibition of Cdc20.
Bub1 generally protects sister chromatide cohesion by enhancing Shugoshin protein (Sgo1) localization to the centromeric region. Through recruitment of the phosphatase PP2A Bub1 inhibits the action of PLK1, which removes Sgo1 from the centromere.[17][18][19][20]
Contrarily PLK1 localization, as mentioned, also depends on the activity of Bub1. Studies in Xenopus extracts using RNAi or antibody depletion have indicated a crucial function of Bub1 in the organization of the inner centromere. Similarly to its role in kinetochore assembly, it recruits members of the chromosomal passenger complex (CPC) like Aurora B kinase, Survivin and INCENP. Direct phosphorylation of INCENP by Bub1 has been observed.[21]
RNAi mediated depletion of human Bub1 has indicated function in correct metaphase congression. Downstream targets identified are distinct kinetochore proteins as CENP-F, MCAK and the mentioned Sgo1.[14]
# Implications in cancer
Disturbed mitotic checkpoints are a common feature of many human cancers. More precisely, mutations in the spindle checkpoint can lead to chromosomal instability and aneuploidy, a feature present in over 90% of all solid tumors.[22] Loss-of-function mutations or reduced gene expression of Bub1 have been identified in several human tumors as colon, esophageal, gastric, breast cancer and melanoma.[14] A correlation between Bub1 expression levels and the localization of tumors along with their severity was found. For instance, low Bub1 expression levels resulted in more sarcomas, lymphomas and lung tumors, whereas higher ones caused sarcomas and tumors in the liver.[23] Moreover, Bub1 has been identified as a target of the large T antigen of the SV-40 virus, possibly contributing to its potential for oncogenic transformation.[24]
Indications for possible Bub1 involvement in tumorigenesis also derive from animal experiments, where mice with reduced Bub1 expression showed an increase in tumor susceptibility.[25][26] In vitro knockdown of Bub1 in p53 impaired cells (e.g. HeLa cells) caused aneuploidy.[27] Whether aneuploidy alone is a sufficient driving cause during tumorigenesis or rather a mere consequence has been a matter of scientific debate.
# Link to caspase-independent mitotic death (CIMD)
Recently Bub1 has been identified as a negative regulator of CIMD. Depletion of Bub1 results in increased CIMD in order to avoid aneuploidy caused by reduced SAC functioning. The transcriptional activity of p73 is thereby inhibited via phosphorylation. Direct interaction between these two players has not been visualized so far, therefore molecules linking Bub1 and p73 are yet to be determined.[28]
It has also been proposed that Bub1 binds p53 to prevent it from activating pro-apoptotic genes, therefore p53 is able to induce apoptosis when Bub1 is depleted. However, an interaction between p53 and Bub1 has not yet been shown while p53 binding BubR1 has been reported.[29] | https://www.wikidoc.org/index.php/BUB1 | |
1b3aa69b83d864faaf131220f9803c2d5ab19ff2 | wikidoc | BUB3 | BUB3
Mitotic checkpoint protein BUB3 is a protein that in humans is encoded by the BUB3 gene.
Bub3 is a protein involved with the regulation of the Spindle Assembly Checkpoint (SAC); though BUB3 is non-essential in yeast, it is essential in higher eukaryotes. As one of the checkpoint proteins, Bub3 delays the irreversible onset of anaphase through direction of kinetochore localization during prometaphase to achieve biorentation. In directing the kinetochore-microtubule interaction, this ensures the proper (and consequenctly, bioriented) attachment of the chromosomes prior to anaphase. Bub3 and its related proteins that form the Spindle Assembly Checkpoint (SAC) inhibit the action of the Anaphase Promoting Complex (APC), preventing early anaphase entry and mitotic exit; this serves as a mechanism for the fidelity of chromosomal segregation.
# Function
Bub3 is a crucial component in the formation of the mitotic spindle assembly complex, which forms a complex with other important proteins. For correct segregation of the cells it is necessary for all mitotic spindles to attach correctly to the kinetochore of each chromosome. This is controlled by the mitotic spindle checkpoint complex which operates as a feedback-response. If there is a signal of a defect in the attachment, mitosis will be stopped to ensure that all chromosomes have an amphitelic binding to spindles. After the error is corrected, the cell will proceed to anaphase. The complex of proteins which regulate the cell arrest are BUB1, BUB2, BUB3 (this protein), Mad1, Mad2, Mad3 and MPS1.
# Role in the spindle assembly checkpoint
At unattached kinetochores, a complex consisting of BubR1, Bub3, and Cdc20 interact with the Mad2-Cdc20 complex to inhibit the APC, thus inhibiting the formation of active APCCdc20. Bub3 binds constitutively to BubR1; in this arrangement, Bub3 acts as a key component of the SAC in the formation of an inhibitory complex. Securin and cyclin B are also stabilized before the anaphase transition by the unattached kinetochores. The stabilization of cyclin and securin prevent the degradation that would lead to the irreversible and fast separation of the sister chromatids.
The formation of these “inhibitory complexes” and steps feed into a ‘wait’ signal before activation of separase; at the stage prior to anaphase, securin inhibits the activity of separase and maintains the cohesion complex.
# Structure
The crystal structure of Bub3 indicates a protein of the seven-bladed beta-propeller structure with the presence of WD40 repeats, with each blade formed by four anti-parallel beta sheet strands that have been organized around a tapered channel. Mutation data suggest several important surfaces of interaction for the formation of the SAC, particularly the conserved tryptophans (in blades 1 and 3) and the conserved VAVE sequences in blade 5.
Rae1 (an mRNA export factor), another member of the WD40 protein family, shows high sequence conservation with that of Bub3. Both bind to Gle2p-binding-sequence (GLEBS) motifs; while Bub3 specifically binds Mad3 and Bub1, Rae1 has more promiscuous binding as it binds both the nuclear pore complex and Bub1. This indicates a similarity in interaction of Bub3 and Rae1 with Bub1.
# Interactions
BUB3 has been shown to interact with BUB1B, HDAC1 and Histone deacetylase 2.
Bub3 has been shown to form complexes with Mad1-Bub1 and with Cdc20 (the interaction of which does not require intact kinetochores). Additionally, it has been shown to bind Mad2 and Mad3.
Bub3 directs the localization of Bub1 at the kinetochore in order to activate the SAC. In both Saccharomyces cerevisiae and metazoans, Bub3 has been show to bind BubR1 and Bub1.
The components that are essential for the spindle assembly checkpoint in yeast have been determined to be Bub1, Bub3, Mad1, Mad2, Mad3, and the increasingly important Mps1 (a protein kinase).
# Regulation
When the SAC is activated, the production of the Bub3-Cdc20 complex is activated. After kinetochore attachment is complete, the spindle checkpoint complexes (including the BubR1-Bub3) experience a decrease in concentration.
Bub3 also acts as a regulator in that it affects binding of Mad3 to Mad2.
Structural and sequence analysis indicated the existence of three conserved regions that are referred to as WD40 repeats. Mutation of one of these motifs has indicated an impaired ability of Bub3 to interact with Mad2, Mad3, and Cdc20. The structural data suggested that Bub3 acts as a platform that mediates the interaction of SAC protein complexes.
# Clinical significance
BUB3 forms a complex with BUB1 (BUB1/BUB3 complex) to inhibit the anaphase-promoting complex or cyclosome (APC/C) as soon as the spindle-assembly checkpoint is activated. BUB3 also phosphorylates:
- CDC20 (activator) and thereby inhibits the ubiquitin ligase activity of APC/C.
- MAD1L1, which usually interacts with BUB1 and BUBR1, and in turn the BUB1/BUB3 complex interacts with MAD1L1.
Another function of BUB3 is to promote correct kinetochore-microtubule (K-MT) attachments when the spindle-assembly checkpoint is active. It plays a role in the localization of kinetochore of BUB1.
BUB3 serves in oocyte meiosis as the regulator of chromosome segregation.
Defects in BUB3 in the cell cycle can contribute to the following diseases:
- hepatocellular carcinoma
- gastric cancer
- breast cancer
- cervical cancer
- adenomatous polyposis
- osteosarcoma familial breast cancer
- glioblastoma cervicitis
- lung cancer carcinoma
- Coli polyposis | BUB3
Mitotic checkpoint protein BUB3 is a protein that in humans is encoded by the BUB3 gene.[1][2]
Bub3 is a protein involved with the regulation of the Spindle Assembly Checkpoint (SAC); though BUB3 is non-essential in yeast, it is essential in higher eukaryotes. As one of the checkpoint proteins, Bub3 delays the irreversible onset of anaphase through direction of kinetochore localization during prometaphase[1] to achieve biorentation. In directing the kinetochore-microtubule interaction, this ensures the proper (and consequenctly, bioriented) attachment of the chromosomes prior to anaphase. Bub3 and its related proteins that form the Spindle Assembly Checkpoint (SAC) inhibit the action of the Anaphase Promoting Complex (APC), preventing early anaphase entry and mitotic exit; this serves as a mechanism for the fidelity of chromosomal segregation.[3]
# Function
Bub3 is a crucial component in the formation of the mitotic spindle assembly complex, which forms a complex with other important proteins.[4] For correct segregation of the cells it is necessary for all mitotic spindles to attach correctly to the kinetochore of each chromosome. This is controlled by the mitotic spindle checkpoint complex which operates as a feedback-response.[4] If there is a signal of a defect in the attachment, mitosis will be stopped to ensure that all chromosomes have an amphitelic binding to spindles. After the error is corrected, the cell will proceed to anaphase. The complex of proteins which regulate the cell arrest are BUB1, BUB2, BUB3 (this protein), Mad1, Mad2, Mad3 and MPS1.[4]
# Role in the spindle assembly checkpoint
At unattached kinetochores, a complex consisting of BubR1, Bub3, and Cdc20 interact with the Mad2-Cdc20 complex to inhibit the APC, thus inhibiting the formation of active APCCdc20.[5][6] Bub3 binds constitutively to BubR1; in this arrangement, Bub3 acts as a key component of the SAC in the formation of an inhibitory complex.[7] Securin and cyclin B are also stabilized before the anaphase transition by the unattached kinetochores.[8] The stabilization of cyclin and securin prevent the degradation that would lead to the irreversible and fast separation of the sister chromatids.
The formation of these “inhibitory complexes” and steps feed into a ‘wait’ signal before activation of separase; at the stage prior to anaphase, securin inhibits the activity of separase and maintains the cohesion complex.[3]
# Structure
The crystal structure of Bub3 indicates a protein of the seven-bladed beta-propeller structure with the presence of WD40 repeats, with each blade formed by four anti-parallel beta sheet strands that have been organized around a tapered channel. Mutation data suggest several important surfaces of interaction for the formation of the SAC, particularly the conserved tryptophans (in blades 1 and 3) and the conserved VAVE sequences in blade 5.
Rae1 (an mRNA export factor), another member of the WD40 protein family, shows high sequence conservation with that of Bub3. Both bind to Gle2p-binding-sequence (GLEBS) motifs; while Bub3 specifically binds Mad3 and Bub1, Rae1 has more promiscuous binding as it binds both the nuclear pore complex and Bub1. This indicates a similarity in interaction of Bub3 and Rae1 with Bub1.[9]
# Interactions
BUB3 has been shown to interact with BUB1B,[1][10][11] HDAC1[12] and Histone deacetylase 2.[12]
Bub3 has been shown to form complexes with Mad1-Bub1 and with Cdc20 (the interaction of which does not require intact kinetochores). Additionally, it has been shown to bind Mad2 and Mad3.[7][13]
Bub3 directs the localization of Bub1 at the kinetochore in order to activate the SAC.[1] In both Saccharomyces cerevisiae and metazoans, Bub3 has been show to bind BubR1 and Bub1.[3]
The components that are essential for the spindle assembly checkpoint in yeast have been determined to be Bub1, Bub3, Mad1, Mad2, Mad3, and the increasingly important Mps1 (a protein kinase).
# Regulation
When the SAC is activated, the production of the Bub3-Cdc20 complex is activated. After kinetochore attachment is complete, the spindle checkpoint complexes (including the BubR1-Bub3) experience a decrease in concentration.[14][15]
Bub3 also acts as a regulator in that it affects binding of Mad3 to Mad2.[7]
Structural and sequence analysis indicated the existence of three conserved regions that are referred to as WD40 repeats. Mutation of one of these motifs has indicated an impaired ability of Bub3 to interact with Mad2, Mad3, and Cdc20. The structural data suggested that Bub3 acts as a platform that mediates the interaction of SAC protein complexes.[7][9]
# Clinical significance
BUB3 forms a complex with BUB1 (BUB1/BUB3 complex) to inhibit the anaphase-promoting complex or cyclosome (APC/C) as soon as the spindle-assembly checkpoint is activated. BUB3 also phosphorylates:
- CDC20 (activator) and thereby inhibits the ubiquitin ligase activity of APC/C.
- MAD1L1, which usually interacts with BUB1 and BUBR1, and in turn the BUB1/BUB3 complex interacts with MAD1L1.
Another function of BUB3 is to promote correct kinetochore-microtubule (K-MT) attachments when the spindle-assembly checkpoint is active. It plays a role in the localization of kinetochore of BUB1.
BUB3 serves in oocyte meiosis as the regulator of chromosome segregation.
Defects in BUB3 in the cell cycle can contribute to the following diseases:[4]
- hepatocellular carcinoma
- gastric cancer
- breast cancer
- cervical cancer
- adenomatous polyposis
- osteosarcoma familial breast cancer
- glioblastoma cervicitis
- lung cancer carcinoma
- Coli polyposis | https://www.wikidoc.org/index.php/BUB3 | |
a7cbbd8107b299403966dff111a6f6f24251272f | wikidoc | Bael | Bael
Bael (Aegle marmelos) is a fruit-bearing tree indigenous to dry forests on hills and plains of central and southern India, Myanmar, Pakistan, Bangladesh, Nepal, Vietnam, Laos and Cambodia. It is cultivated throughout India, as well as in Sri Lanka, northern Malaya, Java and in the Philippines. It is also popularly known as Bilva, Bilwa, Bel, Kuvalam, Koovalam, or Beli fruit, Bengal quince, stone apple, and wood apple. The tree, which is the only species in the genus Aegle, grows up to 18 meters tall and bears thorns and fragrant flowers. It has a woody-skinned, smooth fruit 5-15 cm in diameter. The skin of some forms of the fruit is so hard it must be cracked open with a hammer. It has numerous seeds, which are densely covered with fibrous hairs and are embedded in a thick, gluey, aromatic pulp.
The fruit is eaten fresh or dried. The juice is strained and sweetened to make a drink similar to lemonade, and is also used in making Sharbat, a refreshing drink where the pulp is mixed with tamarind. The young leaves and small shoots are eaten as salad greens. The fruit is also used in religious rituals and as a ayurvedic remedy for such ailments as diarrhea, dysentery, intestinal parasites, dryness of the eyes, and the common cold. It is a very powerful antidote for chronic constipation.
In Hinduism, the Lord Shiva is said to live under the Bael tree. In India, the tree is often found in temple gardens and its leaves are used in religious celebrations.
In the traditional culture of Nepal, the Bael tree is part of an important fertility ritual for girls known as the Bel baha.
This tree is a larval foodplant for the following two Indian Swallowtail butterflies, the Lime Butterfly Papilio demoleus and the Common Mormon Papilio polytes.
# Reference
H.K.Bakhru (1997). Foods that Heal. The Natural Way to Good Health. Orient Paperbacks. ISBN 81-222-0033-8..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} | Bael
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Bael (Aegle marmelos) is a fruit-bearing tree indigenous to dry forests on hills and plains of central and southern India, Myanmar, Pakistan, Bangladesh, Nepal, Vietnam, Laos and Cambodia. It is cultivated throughout India, as well as in Sri Lanka, northern Malaya, Java and in the Philippines. It is also popularly known as Bilva, Bilwa, Bel, Kuvalam, Koovalam, or Beli fruit, Bengal quince, stone apple, and wood apple. The tree, which is the only species in the genus Aegle, grows up to 18 meters tall and bears thorns and fragrant flowers. It has a woody-skinned, smooth fruit 5-15 cm in diameter. The skin of some forms of the fruit is so hard it must be cracked open with a hammer. It has numerous seeds, which are densely covered with fibrous hairs and are embedded in a thick, gluey, aromatic pulp.
The fruit is eaten fresh or dried. The juice is strained and sweetened to make a drink similar to lemonade, and is also used in making Sharbat, a refreshing drink where the pulp is mixed with tamarind. The young leaves and small shoots are eaten as salad greens. The fruit is also used in religious rituals and as a ayurvedic remedy for such ailments as diarrhea, dysentery, intestinal parasites, dryness of the eyes, and the common cold. It is a very powerful antidote for chronic constipation.
In Hinduism, the Lord Shiva is said to live under the Bael tree. In India, the tree is often found in temple gardens and its leaves are used in religious celebrations.
In the traditional culture of Nepal, the Bael tree is part of an important fertility ritual for girls known as the Bel baha.
This tree is a larval foodplant for the following two Indian Swallowtail butterflies, the Lime Butterfly Papilio demoleus and the Common Mormon Papilio polytes.
# Reference
H.K.Bakhru (1997). Foods that Heal. The Natural Way to Good Health. Orient Paperbacks. ISBN 81-222-0033-8..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}
# External links
- Bael Fruit entry in Fruits of Warm Climates by J. F. Morton
Template:Fruit-stub
bn:বেল (ফল)
id:Maja
ml:കൂവളം
nl:Slijmappel
th:มะตูม
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Bael | |
f48168eab53709c3d914f1b6121c18647eee1a1d | wikidoc | Basi | Basi
Basi is a fermented alcoholic beverage made of sugarcane produced in the Philippines and Guyana.
# Philippines
Basi is the local beverage of Ilocos in northern Luzon in the Philippines where it has been consumed since before the Spanish conquest. In the Philippines, commercial basi is produced by first crushing sugarcane and extracting the juice. The juice is boiled in vats and then stored in earthen jars. Once the juice has cooled, flavorings made of ground glutinous rice and duhat (java plum) bark or other fruits or barks is added. The jars are then sealed with banana leaves and allowed to ferment for several years. The resulting drink is pale red in color. If fermented longer, it turns into suka or vinegar.
The 1807 Basi Revolt in Piddig, Ilocos Norte, occurred when the Philippines' Spanish rulers effectively banning private manufacture of the beverage. A Basi festival is held annually in Naguilian, La Union.
# Guyana
Basi is produced by first cutting sugarcane into small pieces. The cane is then placed into a container with refined sugar, water, and yeast for a minimum of nine days. Finally, the beverage is strained and bottled.
# 200th anniversary
On September 28, 2007, San Ildefonso, Ilocos Sur, Philippines officials (Governor Deogracias Victor “DV” Savellano and Rep. Ronald Singson) commemorated “basi revolt.” Recently, the Sangguniang Bayan of San Ildefonso approved a resolution declaring September 16 as a non-working holiday and named the old road in Gongogong as Ambaristo street in honor Pedro Ambaristo, leader of the Basi Revolt. Mayor Christian Purisima enrolled basi as their entry into the “One Town; One Product” (OTOP) program of Savellano. | Basi
Basi is a fermented alcoholic beverage made of sugarcane produced in the Philippines and Guyana.
# Philippines
Basi is the local beverage of Ilocos in northern Luzon in the Philippines where it has been consumed since before the Spanish conquest. In the Philippines, commercial basi is produced by first crushing sugarcane and extracting the juice. The juice is boiled in vats and then stored in earthen jars. Once the juice has cooled, flavorings made of ground glutinous rice and duhat (java plum) bark or other fruits or barks is added. The jars are then sealed with banana leaves and allowed to ferment for several years. The resulting drink is pale red in color. If fermented longer, it turns into suka or vinegar.
The 1807 Basi Revolt in Piddig, Ilocos Norte, occurred when the Philippines' Spanish rulers effectively banning private manufacture of the beverage. A Basi festival is held annually in Naguilian, La Union.
# Guyana
Basi is produced by first cutting sugarcane into small pieces. The cane is then placed into a container with refined sugar, water, and yeast for a minimum of nine days. Finally, the beverage is strained and bottled.
# 200th anniversary
On September 28, 2007, San Ildefonso, Ilocos Sur, Philippines officials (Governor Deogracias Victor “DV” Savellano and Rep. Ronald Singson) commemorated “basi revolt.” Recently, the Sangguniang Bayan of San Ildefonso approved a resolution declaring September 16 as a non-working holiday and named the old road in Gongogong as Ambaristo street in honor Pedro Ambaristo, leader of the Basi Revolt. Mayor Christian Purisima enrolled basi as their entry into the “One Town; One Product” (OTOP) program of Savellano. [1] | https://www.wikidoc.org/index.php/Basi | |
f801868f9eb698a46a812f8b0cf0fe97c54466ea | wikidoc | Bile | Bile
# Overview
Bile (or gall) is a bitter, yellow or green alkaline fluid secreted by hepatocytes from the liver of most vertebrates. In many species, it is stored in the gallbladder between meals and upon eating is discharged into the duodenum where it excretes waste and aids the process of digestion of lipids.
# Components
The components of bile:
- Water
- Cholesterol
- Lecithin (a phospholipid)
- Bile pigments (bilirubin & biliverdin)
- Bile salts (sodium glycocholate & sodium taurocholate)
- Bicarbonate ions
# Production
Bile is produced by hepatocytes in the liver, draining through the many bile ducts that penetrate the liver. During this process, the epithelial cells add a watery solution that is rich in bicarbonates that dilutes and increases alkalinity of the solution. Bile then flows into the common hepatic duct, which joins with the cystic duct from the gallbladder to form the common bile duct. The common bile duct in turn joins with the pancreatic duct to empty into the duodenum. If the sphincter of Oddi is closed, bile is prevented from draining into the intestine and instead flows into the gall bladder, where it is stored and concentrated to up to five times its original potency between meals. This concentration occurs through the absorption of water and small electrolytes, while retaining all the original organic molecules. Cholesterol is also released with the bile, dissolved in the acids and fats found in the concentrated solution. When food is released by the stomach into the duodenum in the form of chyme, the gallbladder releases the concentrated bile to complete digestion.
The human liver can produce close to one litre of bile per day (depending on body size). 95% of the salts secreted in bile are reabsorbed in the terminal ileum and re-used. Blood from the ileum flows directly to the hepatic portal vein and returns to the liver where the hepatocytes resorb the salts and return them to the bile ducts to be re-used, sometimes two to three times with each meal.
# Physiological functions
Bile acts to some extent as a detergent, helping to emulsify fats (increasing surface area to help enzyme action), and thus aids in their absorption in the small intestine. The most important compounds are the salts of taurocholic acid and deoxycholic acid. Bile salts combine with phospholipids to break down fat globules in the process of emulsification by associating its hydrophobic side with lipids and the hydrophilic side with water. Emulsified droplets then are organized into many micelles which increases absorption. Since bile increases the absorption of fats, it is an important part of the absorption of the fat-soluble vitamins D, E, K and A. Besides its digestive function, bile serves as the route of excretion for the hemoglobin breakdown product (bilirubin) created by the spleen which gives bile its colour; it also neutralises any excess stomach acid before it enters the ileum, the final section of the small intestine. Bile salts are also bacteriocidal to the invading microbes that enter with food.
Bile from slaughtered animals can be mixed with soap. This mixture, applied to textiles a few hours before washing, is a traditional and rather effective method for removing various kinds of tough stains.
# Abnormal conditions associated with bile
- The cholesterol contained in bile will occasionally accrete into lumps in the gall bladder, forming gallstones.
- After excessive consumption of alcohol, a person's vomit may be green. The green component is bile.
- In the absence of bile, fats become indigestible and are instead excreted in feces. In this case, the feces lacks its characteristic brown colour and instead are white or grey, and greasy. This causes significant problems in the distal parts of the intestine as normally all fats are absorbed earlier in the gastrointestinal tract. Past the small intestine the organs and gut flora are not adapted to processing fats.
# Four humours
Yellow bile (sometimes called ichor) and black bile were two of the four vital fluids or humours of ancient and medieval medicine (the other two were phlegm and blood). The Latin names for the terms gave rise to the words "choler" (bile) and "melancholia" (black bile). Excessive bile was supposed to produce an aggressive temperament, known as "choleric". This is the origin of the word "bilious." Depressive and other mental illnesses (melancholia) were ascribed to a bodily surplus of black bile. This is the origin of the word "melancholy." | Bile
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Bile (or gall) is a bitter, yellow or green alkaline fluid secreted by hepatocytes from the liver of most vertebrates. In many species, it is stored in the gallbladder between meals and upon eating is discharged into the duodenum where it excretes waste and aids the process of digestion of lipids.
# Components
The components of bile:
- Water
- Cholesterol
- Lecithin (a phospholipid)
- Bile pigments (bilirubin & biliverdin)
- Bile salts (sodium glycocholate & sodium taurocholate)
- Bicarbonate ions
# Production
Bile is produced by hepatocytes in the liver, draining through the many bile ducts that penetrate the liver. During this process, the epithelial cells add a watery solution that is rich in bicarbonates that dilutes and increases alkalinity of the solution. Bile then flows into the common hepatic duct, which joins with the cystic duct from the gallbladder to form the common bile duct. The common bile duct in turn joins with the pancreatic duct to empty into the duodenum. If the sphincter of Oddi is closed, bile is prevented from draining into the intestine and instead flows into the gall bladder, where it is stored and concentrated to up to five times its original potency between meals. This concentration occurs through the absorption of water and small electrolytes, while retaining all the original organic molecules. Cholesterol is also released with the bile, dissolved in the acids and fats found in the concentrated solution. When food is released by the stomach into the duodenum in the form of chyme, the gallbladder releases the concentrated bile to complete digestion.
The human liver can produce close to one litre of bile per day (depending on body size). 95% of the salts secreted in bile are reabsorbed in the terminal ileum and re-used. Blood from the ileum flows directly to the hepatic portal vein and returns to the liver where the hepatocytes resorb the salts and return them to the bile ducts to be re-used, sometimes two to three times with each meal.
# Physiological functions
Bile acts to some extent as a detergent, helping to emulsify fats (increasing surface area to help enzyme action), and thus aids in their absorption in the small intestine. The most important compounds are the salts of taurocholic acid and deoxycholic acid. Bile salts combine with phospholipids to break down fat globules in the process of emulsification by associating its hydrophobic side with lipids and the hydrophilic side with water. Emulsified droplets then are organized into many micelles which increases absorption. Since bile increases the absorption of fats, it is an important part of the absorption of the fat-soluble vitamins D, E, K and A. Besides its digestive function, bile serves as the route of excretion for the hemoglobin breakdown product (bilirubin) created by the spleen which gives bile its colour; it also neutralises any excess stomach acid before it enters the ileum, the final section of the small intestine. Bile salts are also bacteriocidal to the invading microbes that enter with food.
Bile from slaughtered animals can be mixed with soap. This mixture, applied to textiles a few hours before washing, is a traditional and rather effective method for removing various kinds of tough stains.[1]
# Abnormal conditions associated with bile
- The cholesterol contained in bile will occasionally accrete into lumps in the gall bladder, forming gallstones.
- After excessive consumption of alcohol, a person's vomit may be green. The green component is bile.
- In the absence of bile, fats become indigestible and are instead excreted in feces. In this case, the feces lacks its characteristic brown colour and instead are white or grey, and greasy. This causes significant problems in the distal parts of the intestine as normally all fats are absorbed earlier in the gastrointestinal tract. Past the small intestine the organs and gut flora are not adapted to processing fats.
# Four humours
Yellow bile (sometimes called ichor) and black bile were two of the four vital fluids or humours of ancient and medieval medicine (the other two were phlegm and blood). The Latin names for the terms gave rise to the words "choler" (bile) and "melancholia" (black bile). Excessive bile was supposed to produce an aggressive temperament, known as "choleric". This is the origin of the word "bilious." Depressive and other mental illnesses (melancholia) were ascribed to a bodily surplus of black bile. This is the origin of the word "melancholy." | https://www.wikidoc.org/index.php/Bile | |
6d1cde8bd7a938937a634c73cc366c27256d9b05 | wikidoc | Bone | Bone
# Overview
Bones are rigid organs that form part of the endoskeleton of vertebrates. They function to move, support, and protect the various organs of the body, produce red and white blood cells and store minerals. Because bones come in a variety of shapes and have a complex internal and external structure, they are lightweight, yet strong and hard, in addition to fulfilling their many other functions. One of the types of tissues that makes up bone is the mineralized osseous tissue, also called bone tissue, that gives it rigidity and honeycomb-like three-dimensional internal structure. Other types of tissue found in bones include marrow, endosteum and periosteum, nerves, blood vessels and cartilage. There are 206 bones in the adult body, and about 300 bones in a infants body.
# Functions
Bones have eight main functions:
- Protection — Bones can serve to protect internal organs, such as the skull protecting the brain or the ribs protecting the heart and lungs.
- Shape — Bones provide a frame to keep the body supported.
- Blood production — The marrow, located within the medullary cavity of long bones and the interstices of cancellous bone, produces blood cells in a process called haematopoiesis.
- Mineral storage — Bones act as reserves of minerals important for the body, most notably calcium and phosphorus.
- Movement — Bones, skeletal muscles, tendons, ligaments and joints function together to generate and transfer forces so that individual body parts or the whole body can be manipulated in three-dimensional space. The interaction between bone and muscle is studied in biomechanics.
- Acid-base balance — Bone buffers the blood against excessive pH changes by absorbing or releasing alkaline salts.
- Detoxification — Bone tissues can also store heavy metals and other foreign elements, removing them from the blood and reducing their effects on other tissues. These can later be gradually released for excretion.
- Sound transduction — Bones are important in the mechanical aspect of hearing.
# Characteristics
The primary tissue of bone, osseous tissue, is a relatively hard and lightweight composite material, formed mostly of calcium phosphate in the chemical arrangement termed calcium hydroxylapatite (this is the osseous tissue that gives bones their rigidity). It has relatively high compressive strength but poor tensile strength, meaning it resists pushing forces well, but not pulling forces. While bone is essentially brittle, it does have a significant degree of elasticity contributed chiefly by collagen. All bones consist of living cells embedded in the mineralised organic matrix that makes up the osseous tissue.
# Macrostructure
Bone is not a uniformly solid material, but rather has some spaces between its hard elements.
## Compact bone
The hard outer layer of bones is composed of compact bone tissue, so-called due to its minimal gaps and spaces. This tissue gives bones their smooth, white, and solid appearance, and accounts for 80% of the total bone mass of an adult skeleton. Compact bone may also be referred to as dense bone or cortical bone.
## Trabecular bone
Filling the interior of the organ is the trabecular bone tissue (an open cell porous network also called cancellous or spongy bone) which is comprised of a network of rod- and plate-like elements that make the overall organ lighter and allowing room for blood vessels and marrow. Trabecular bone accounts for the remaining 20% of total bone mass, but has nearly ten times the surface area of compact bone.
# Cellular structure
There are several types of cells constituting the bone;
- Osteoblasts are mononucleate bone-forming cells which descend from osteoprogenitor cells. They are located on the surface of osteoid seams and make a protein mixture known as osteoid, which mineralizes to become bone. Osteoid is primarily composed of Type I collagen. Osteoblasts also manufacture hormones, such as prostaglandins, to act on the bone itself. They robustly produce alkaline phosphatase, an enzyme that has a role in the mineralisation of bone, as well as many matrix proteins. Osteoblasts are the immature bone cells.
- Bone lining cells are essentially inactive osteoblasts. They cover all of the available bone surface and function as a barrier for certain ions.
- Osteocytes originate from osteoblasts which have migrated into and become trapped and surrounded by bone matrix which they themselves produce. The spaces which they occupy are known as lacunae. Osteocytes have many processes which reach out to meet osteoblasts probably for the purposes of communication. Their functions include to varying degrees: formation of bone, matrix maintenance and calcium homeostasis. They possibly act as mechano-sensory receptors—regulating the bone's response to stress. They are mature bone cells.
- Osteoclasts are the cells responsible for bone resorption (remodeling of bone to reduce its volume). Osteoclasts are large, multinucleated cells located on bone surfaces in what are called Howship's lacunae or resorption pits. These lacunae, or resorption pits, are left behind after the breakdown of bone and often present as scalloped surfaces. Because the osteoclasts are derived from a monocyte stem-cell lineage, they are equipped with engulfment strategies similar to circulating macrophages. Osteoclasts mature and/or migrate to discrete bone surfaces. Upon arrival, active enzymes, such as tartrate resistant acid phosphatase, are secreted against the mineral substrate.
# Molecular structure
## Matrix
The matrix is the major constituent of bone, surrounding the cells. It has inorganic and organic parts.
### Inorganic
The inorganic is mainly crystalline mineral salts and calcium, which is present in the form of hydroxyapatite. The matrix is initially laid down as unmineralized osteoid (manufactured by osteoblasts). Mineralisation involves osteoblasts secreting vesicles containing alkaline phosphatase. This cleaves the phosphate groups and acts as the foci for calcium and phosphate deposition. The vesicles then rupture and act as a centre for crystals to grow on.
### Organic
The organic part of matrix is mainly Type I collagen. This is made intracellularly as tropocollagen and then exported. It then associates into fibrils. Also making up the organic part of matrix include various growth factors, the functions of which are not fully known. Other factors present include glycosaminoglycans, osteocalcin, osteonectin, bone sialo protein and Cell Attachment Factor. One of the main things that distinguishes the matrix of a bone from that of another cell is that the matrix in bone is hard.
## Woven or lamellar
Bone is first deposited as woven bone, in a disorganized structure with a high proportion of osteocytes in young and in healing injuries. Woven bone is weaker, with a small number of randomly oriented collagen fibers, but forms quickly. It is replaced by lamellar bone, which is highly organized in concentric sheets with a low proportion of osteocytes. Lamellar bone is stronger and filled with many collagen fibers parallel to other fibers in the same layer. The fibers run in opposite directions in alternating layers, much like plywood, assisting in the bone's ability to resist torsion forces. After a break, woven bone quickly forms and is gradually replaced by slow-growing lamellar bone on pre-existing calcified hyaline cartilage through a process known as "bony substitution."
# Five types of bones
There are five types of bones in the human body: long, short, flat, irregular and sesamoid.
- Long bones are longer than they are wide, consisting of a long shaft (the diaphysis) plus two articular (joint) surfaces, called epiphyses. They are comprised mostly of compact bone, but are generally thick enough to contain considerable spongy bone and marrow in the hollow centre (the medullary cavity). Most bones of the limbs (including the three bones of the fingers) are long bones, except for the kneecap (patella), and the carpal, metacarpal, tarsal and metatarsal bones of the wrist and ankle. The classification refers to shape rather than the size.
- Short bones are roughly cube-shaped, and have only a thin layer of compact bone surrounding a spongy interior. The bones of the wrist and ankle are short bones, as are the sesamoid bones.
- Flat bones are thin and generally curved, with two parallel layers of compact bones sandwiching a layer of spongy bone. Most of the bones of the skull are flat bones, as is the sternum.
- Irregular bones do not fit into the above categories. They consist of thin layers of compact bone surrounding a spongy interior. As implied by the name, their shapes are irregular and complicated. The bones of the spine and hips are irregular bones.
- Sesamoid bones are bones embedded in tendons. Since they act to hold the tendon further away from the joint, the angle of the tendon is increased and thus the force of the muscle is increased. Examples of sesamoid bones are the patella and the pisiform
# Formation
The formation of bone during the fetal stage of development occurs by two methods: intramembranous and endochondral ossification.
## Intramembranous ossification
Intramembranous ossification mainly occurs during formation of the flat bones of the skull; the bone is formed from mesenchyme tissue. The steps in intramembranous ossification are:
- Development of ossification center
- Calcification
- Formation of trabeculae
- Development of periosteum
## Endochondral ossification
Endochondral ossification, on the other hand, occurs in long bones, such as limbs; the bone is formed from cartilage. The steps in endochondral ossification are:
- Development of cartilage model
- Growth of cartilage model
- Development of the primary ossification center
- Development of medullary cavity
- Development of the secondary ossification center
- Formation of articular cartilage and epiphyseal plate
Endochondral ossification begins with points in the cartilage called "primary ossification centers." They mostly appear during fetal development, though a few short bones begin their primary ossification after birth. They are responsible for the formation of the diaphyses of long bones, short bones and certain parts of irregular bones. Secondary ossification occurs after birth, and forms the epiphyses of long bones and the extremities of irregular and flat bones. The diaphysis and both epiphyses of a long bone are separated by a growing zone of cartilage (the epiphyseal plate). When the child reaches skeletal maturity (18 to 25 years of age), all of the cartilage is replaced by bone, fusing the diaphysis and both epiphyses together (epiphyseal closure).
## Bone marrow
There are two types of bone marrow, yellow and red, most commonly seen is red
Bone marrow can be found in almost any bone that holds cancellous tissue. In newborns, all such bones are filled exclusively with red marrow (or hemopoietic marrow), but as the child ages it is mostly replaced by yellow, or fatty marrow. In adults, red marrow is mostly found in the flat bones of the skull, the ribs, the vertebrae and pelvic bones.
# Remodeling
Remodeling or bone turnover is the process of resorption followed by replacement of bone with little change in shape and occurs throughout a person's life. Osteoblasts and osteoclasts, coupled together via paracrine cell signalling, are referred to as bone remodeling units.
## Purpose
The purpose of remodeling is to regulate calcium homeostasis, repair micro-damaged bones (from everyday stress) but also to shape and sculpture the skeleton during growth.
### Calcium balance
The process of bone resorption by the osteoclasts releases stored calcium into the systemic circulation and is an important process in regulating calcium balance. As bone formation actively fixes circulating calcium in its mineral form, removing it from the bloodstream, resorption actively unfixes it thereby increasing circulating calcium levels. These processes occur in tandem at site-specific locations.
### Repair
Repeated stress, such as weight-bearing exercise or bone healing, results in the bone thickening at the points of maximum stress (Wolff's law). It has been hypothesized that this is a result of bone's piezoelectric properties, which cause bone to generate small electrical potentials under stress.
## Medical conditions related to bones
- Bone fracture
- Osteomyelitis
- Osteoporosis
- Osteosarcoma
- Osteogenesis imperfecta
- Arthritis
# Osteology
The study of bones and teeth is referred to as osteology. It is frequently used in anthropology, archeology and forensic science for a variety of tasks. This can include determining the nutritional, health, age or injury status of the individual the bones were taken from. Preparing fleshed bones for these types of studies can involve maceration - boiling fleshed bones to remove large particles, then hand-cleaning.
Typically anthropologists and archeologists study bone tools made by Homo sapiens and Homo neanderthalensis. Bones can serve a number of uses such as projectile points or artistic pigments, and can be made from endoskeletal or external bones such as antler or tusk.
# Alternatives to bony endoskeletons
There are several evolutionary alternatives to mammilary bone; though they have some similar functions, they are not completely functionally analogous to bone.
- Exoskeletons offer support, protection and levers for movement similar to endoskeletal bone. Different types of exoskeletons include shells, carapaces (consisting of calcium compounds or silica) and chitinous exoskeletons.
- A true endoskeleton (that is, protective tissue derived from mesoderm) is also present in Echinoderms. Porifera (sponges) possess simple endoskeletons that consist of calcareous or siliceous spicules and a spongin fiber network.
# Exposed bone
Bone penetrating the skin and being exposed to the outside can be both a natural process in some animals, and due to injury:
- A deer's antlers are composed of bone
- The extinct predatory fish Dunkleosteus, instead of teeth, had sharp edges of hard exposed bone along its jaws
- A compound fracture occurs when the edges of a broken bone punctures the skin
- Though not strictly speaking exposed, a bird's beak is primarily bone covered in a layer of keratin
# Terminology
Several terms are used to refer to features and components of bones throughout the body:
Several terms are used to refer to specific features of long bones: | Bone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Bones are rigid organs that form part of the endoskeleton of vertebrates. They function to move, support, and protect the various organs of the body, produce red and white blood cells and store minerals. Because bones come in a variety of shapes and have a complex internal and external structure, they are lightweight, yet strong and hard, in addition to fulfilling their many other functions. One of the types of tissues that makes up bone is the mineralized osseous tissue, also called bone tissue, that gives it rigidity and honeycomb-like three-dimensional internal structure. Other types of tissue found in bones include marrow, endosteum and periosteum, nerves, blood vessels and cartilage. There are 206 bones in the adult body, and about 300 bones in a infants body.
# Functions
Bones have eight main functions:
- Protection — Bones can serve to protect internal organs, such as the skull protecting the brain or the ribs protecting the heart and lungs.
- Shape — Bones provide a frame to keep the body supported.
- Blood production — The marrow, located within the medullary cavity of long bones and the interstices of cancellous bone, produces blood cells in a process called haematopoiesis.
- Mineral storage — Bones act as reserves of minerals important for the body, most notably calcium and phosphorus.
- Movement — Bones, skeletal muscles, tendons, ligaments and joints function together to generate and transfer forces so that individual body parts or the whole body can be manipulated in three-dimensional space. The interaction between bone and muscle is studied in biomechanics.
- Acid-base balance — Bone buffers the blood against excessive pH changes by absorbing or releasing alkaline salts.
- Detoxification — Bone tissues can also store heavy metals and other foreign elements, removing them from the blood and reducing their effects on other tissues. These can later be gradually released for excretion.
- Sound transduction — Bones are important in the mechanical aspect of hearing.
# Characteristics
The primary tissue of bone, osseous tissue, is a relatively hard and lightweight composite material, formed mostly of calcium phosphate in the chemical arrangement termed calcium hydroxylapatite (this is the osseous tissue that gives bones their rigidity). It has relatively high compressive strength but poor tensile strength, meaning it resists pushing forces well, but not pulling forces. While bone is essentially brittle, it does have a significant degree of elasticity contributed chiefly by collagen. All bones consist of living cells embedded in the mineralised organic matrix that makes up the osseous tissue.
# Macrostructure
Bone is not a uniformly solid material, but rather has some spaces between its hard elements.
## Compact bone
The hard outer layer of bones is composed of compact bone tissue, so-called due to its minimal gaps and spaces. This tissue gives bones their smooth, white, and solid appearance, and accounts for 80% of the total bone mass of an adult skeleton. Compact bone may also be referred to as dense bone or cortical bone.
## Trabecular bone
Filling the interior of the organ is the trabecular bone tissue (an open cell porous network also called cancellous or spongy bone) which is comprised of a network of rod- and plate-like elements that make the overall organ lighter and allowing room for blood vessels and marrow. Trabecular bone accounts for the remaining 20% of total bone mass, but has nearly ten times the surface area of compact bone.
# Cellular structure
There are several types of cells constituting the bone;
- Osteoblasts are mononucleate bone-forming cells which descend from osteoprogenitor cells. They are located on the surface of osteoid seams and make a protein mixture known as osteoid, which mineralizes to become bone. Osteoid is primarily composed of Type I collagen. Osteoblasts also manufacture hormones, such as prostaglandins, to act on the bone itself. They robustly produce alkaline phosphatase, an enzyme that has a role in the mineralisation of bone, as well as many matrix proteins. Osteoblasts are the immature bone cells.
- Bone lining cells are essentially inactive osteoblasts. They cover all of the available bone surface and function as a barrier for certain ions.
- Osteocytes originate from osteoblasts which have migrated into and become trapped and surrounded by bone matrix which they themselves produce. The spaces which they occupy are known as lacunae. Osteocytes have many processes which reach out to meet osteoblasts probably for the purposes of communication. Their functions include to varying degrees: formation of bone, matrix maintenance and calcium homeostasis. They possibly act as mechano-sensory receptors—regulating the bone's response to stress. They are mature bone cells.
- Osteoclasts are the cells responsible for bone resorption (remodeling of bone to reduce its volume). Osteoclasts are large, multinucleated cells located on bone surfaces in what are called Howship's lacunae or resorption pits. These lacunae, or resorption pits, are left behind after the breakdown of bone and often present as scalloped surfaces. Because the osteoclasts are derived from a monocyte stem-cell lineage, they are equipped with engulfment strategies similar to circulating macrophages. Osteoclasts mature and/or migrate to discrete bone surfaces. Upon arrival, active enzymes, such as tartrate resistant acid phosphatase, are secreted against the mineral substrate.
# Molecular structure
## Matrix
The matrix is the major constituent of bone, surrounding the cells. It has inorganic and organic parts.
### Inorganic
The inorganic is mainly crystalline mineral salts and calcium, which is present in the form of hydroxyapatite. The matrix is initially laid down as unmineralized osteoid (manufactured by osteoblasts). Mineralisation involves osteoblasts secreting vesicles containing alkaline phosphatase. This cleaves the phosphate groups and acts as the foci for calcium and phosphate deposition. The vesicles then rupture and act as a centre for crystals to grow on.
### Organic
The organic part of matrix is mainly Type I collagen. This is made intracellularly as tropocollagen and then exported. It then associates into fibrils. Also making up the organic part of matrix include various growth factors, the functions of which are not fully known. Other factors present include glycosaminoglycans, osteocalcin, osteonectin, bone sialo protein and Cell Attachment Factor. One of the main things that distinguishes the matrix of a bone from that of another cell is that the matrix in bone is hard.
## Woven or lamellar
Bone is first deposited as woven bone, in a disorganized structure with a high proportion of osteocytes in young and in healing injuries. Woven bone is weaker, with a small number of randomly oriented collagen fibers, but forms quickly. It is replaced by lamellar bone, which is highly organized in concentric sheets with a low proportion of osteocytes. Lamellar bone is stronger and filled with many collagen fibers parallel to other fibers in the same layer. The fibers run in opposite directions in alternating layers, much like plywood, assisting in the bone's ability to resist torsion forces. After a break, woven bone quickly forms and is gradually replaced by slow-growing lamellar bone on pre-existing calcified hyaline cartilage through a process known as "bony substitution."
# Five types of bones
There are five types of bones in the human body: long, short, flat, irregular and sesamoid.
- Long bones are longer than they are wide, consisting of a long shaft (the diaphysis) plus two articular (joint) surfaces, called epiphyses. They are comprised mostly of compact bone, but are generally thick enough to contain considerable spongy bone and marrow in the hollow centre (the medullary cavity). Most bones of the limbs (including the three bones of the fingers) are long bones, except for the kneecap (patella), and the carpal, metacarpal, tarsal and metatarsal bones of the wrist and ankle. The classification refers to shape rather than the size.
- Short bones are roughly cube-shaped, and have only a thin layer of compact bone surrounding a spongy interior. The bones of the wrist and ankle are short bones, as are the sesamoid bones.
- Flat bones are thin and generally curved, with two parallel layers of compact bones sandwiching a layer of spongy bone. Most of the bones of the skull are flat bones, as is the sternum.
- Irregular bones do not fit into the above categories. They consist of thin layers of compact bone surrounding a spongy interior. As implied by the name, their shapes are irregular and complicated. The bones of the spine and hips are irregular bones.
- Sesamoid bones are bones embedded in tendons. Since they act to hold the tendon further away from the joint, the angle of the tendon is increased and thus the force of the muscle is increased. Examples of sesamoid bones are the patella and the pisiform
# Formation
The formation of bone during the fetal stage of development occurs by two methods: intramembranous and endochondral ossification.
## Intramembranous ossification
Intramembranous ossification mainly occurs during formation of the flat bones of the skull; the bone is formed from mesenchyme tissue. The steps in intramembranous ossification are:
- Development of ossification center
- Calcification
- Formation of trabeculae
- Development of periosteum
## Endochondral ossification
Endochondral ossification, on the other hand, occurs in long bones, such as limbs; the bone is formed from cartilage. The steps in endochondral ossification are:
- Development of cartilage model
- Growth of cartilage model
- Development of the primary ossification center
- Development of medullary cavity
- Development of the secondary ossification center
- Formation of articular cartilage and epiphyseal plate
Endochondral ossification begins with points in the cartilage called "primary ossification centers." They mostly appear during fetal development, though a few short bones begin their primary ossification after birth. They are responsible for the formation of the diaphyses of long bones, short bones and certain parts of irregular bones. Secondary ossification occurs after birth, and forms the epiphyses of long bones and the extremities of irregular and flat bones. The diaphysis and both epiphyses of a long bone are separated by a growing zone of cartilage (the epiphyseal plate). When the child reaches skeletal maturity (18 to 25 years of age), all of the cartilage is replaced by bone, fusing the diaphysis and both epiphyses together (epiphyseal closure).
## Bone marrow
There are two types of bone marrow, yellow and red, most commonly seen is red
Bone marrow can be found in almost any bone that holds cancellous tissue. In newborns, all such bones are filled exclusively with red marrow (or hemopoietic marrow), but as the child ages it is mostly replaced by yellow, or fatty marrow. In adults, red marrow is mostly found in the flat bones of the skull, the ribs, the vertebrae and pelvic bones.
# Remodeling
Remodeling or bone turnover is the process of resorption followed by replacement of bone with little change in shape and occurs throughout a person's life. Osteoblasts and osteoclasts, coupled together via paracrine cell signalling, are referred to as bone remodeling units.
## Purpose
The purpose of remodeling is to regulate calcium homeostasis, repair micro-damaged bones (from everyday stress) but also to shape and sculpture the skeleton during growth.
### Calcium balance
The process of bone resorption by the osteoclasts releases stored calcium into the systemic circulation and is an important process in regulating calcium balance. As bone formation actively fixes circulating calcium in its mineral form, removing it from the bloodstream, resorption actively unfixes it thereby increasing circulating calcium levels. These processes occur in tandem at site-specific locations.
### Repair
Repeated stress, such as weight-bearing exercise or bone healing, results in the bone thickening at the points of maximum stress (Wolff's law). It has been hypothesized that this is a result of bone's piezoelectric properties, which cause bone to generate small electrical potentials under stress.
## Medical conditions related to bones
- Bone fracture
- Osteomyelitis
- Osteoporosis
- Osteosarcoma
- Osteogenesis imperfecta
- Arthritis
# Osteology
The study of bones and teeth is referred to as osteology. It is frequently used in anthropology, archeology and forensic science for a variety of tasks. This can include determining the nutritional, health, age or injury status of the individual the bones were taken from. Preparing fleshed bones for these types of studies can involve maceration - boiling fleshed bones to remove large particles, then hand-cleaning.
Typically anthropologists and archeologists study bone tools made by Homo sapiens and Homo neanderthalensis. Bones can serve a number of uses such as projectile points or artistic pigments, and can be made from endoskeletal or external bones such as antler or tusk.
# Alternatives to bony endoskeletons
There are several evolutionary alternatives to mammilary bone; though they have some similar functions, they are not completely functionally analogous to bone.
- Exoskeletons offer support, protection and levers for movement similar to endoskeletal bone. Different types of exoskeletons include shells, carapaces (consisting of calcium compounds or silica) and chitinous exoskeletons.
- A true endoskeleton (that is, protective tissue derived from mesoderm) is also present in Echinoderms. Porifera (sponges) possess simple endoskeletons that consist of calcareous or siliceous spicules and a spongin fiber network.
# Exposed bone
Bone penetrating the skin and being exposed to the outside can be both a natural process in some animals, and due to injury:
- A deer's antlers are composed of bone
- The extinct predatory fish Dunkleosteus, instead of teeth, had sharp edges of hard exposed bone along its jaws
- A compound fracture occurs when the edges of a broken bone punctures the skin
- Though not strictly speaking exposed, a bird's beak is primarily bone covered in a layer of keratin
# Terminology
Several terms are used to refer to features and components of bones throughout the body:
Several terms are used to refer to specific features of long bones: | https://www.wikidoc.org/index.php/Bone | |
e179a8be5e25eb7da01c95464538a3feb632609e | wikidoc | Urea | Urea
# Overview
Urea is an organic compound with the chemical formula (NH2)2CO.
Urea is also known as carbamide, especially in the recommended International Nonproprietary Names (rINN) in use in Europe. For example, the medicinal compound hydroxyurea (old British Approved Name) is now hydroxycarbamide. Other names include carbamide resin, isourea, carbonyl diamide, and carbonyldiamine.
It was the first organic compound to be artificially synthesized from inorganic starting materials, thus dispelling the concept of vitalism.
# Discovery
Urea was discovered by Hilaire Rouelle in 1773. It was the first organic compound to be artificially synthesized from inorganic starting materials, in 1828 by Friedrich Wöhler, who prepared it by the reaction of potassium cyanate with ammonium sulfate. Although Woehler was attempting to prepare ammonium cyanate, by forming urea, he inadvertently disproved vitalism, the theory that the chemicals of living organisms are fundamentally different from inanimate matter, thus starting the discipline of organic chemistry.
This discovery prompted Wohler to write triumphantly to Berzelius:
"I must tell you that I can make urea without the use of kidneys, either man or dog. Ammonium cyanate is urea."
It is found in mammalian and amphibian urine as well as in some fish. Birds and reptiles excrete uric acid, comprising a different form of nitrogen metabolism that requires less water.
# Structure
Urea is highly soluble in water and is therefore an efficient way for the human body to expel excess nitrogen. Due to extensive hydrogen bonding with water (up to six hydrogen bonds may form, two from oxygen atom and one from each hydrogen), it is very soluble and thus is also a good fertilizer.
The urea molecule is planar and retains its full molecular point symmetry. Each carbonyl oxygen atom accepts four N-H-O hydrogen bonds, a very unusual feature for such a bond type. This dense (and energetically quite favourable) hydrogen bond network is probably established at the cost of efficient molecular packing: the structure is quite open, the ribbons forming tunnels with square cross-section.
# Physiology
The individual atoms that make up a urea molecule come from carbon dioxide, water, aspartate and ammonia in a metabolic pathway known as the urea cycle, an anabolic process. This expenditure of energy is necessary because ammonia, a common metabolic waste product, is toxic and must be neutralized. Urea production occurs in the liver and is under the regulatory control of N-acetylglutamate.
The urea cycle was originally known as the Krebs-Henseleit cycle after it was partially deduced by Hans Adolf Krebs and Kurt Henseleit in 1932. Its details were clarified in the 1940s as the roles of citrulline and argininosuccinate as intermediates were understood. In this cycle, amino groups donated by ammonia and L-aspartate are converted to urea, while L-ornithine, citrulline, L-argininosuccinate, and L-arginine act as intermediates.
Most organisms have to deal with the excretion of nitrogen waste originating from protein and amino acid catabolism. In aquatic organisms the most common form of nitrogen waste is ammonia, while land-dwelling organisms convert the toxic ammonia to either urea or uric acid. Generally, birds and saurian reptiles excrete uric acid, while the remaining species, including mammals, excrete urea. Remarkably, tadpoles excrete ammonia, and shift to urea production during metamorphosis. In veterinary medicine, Dalmatian breeds of dogs are noteworthy in that they excrete urea in the form of uric acid in the urine rather than in the urea form. This is due to a defect in one of the genes controlling expression of the conversion enzymes in the urea cycle.
Despite the generalization above, the pathway has been documented not only in mammals and amphibians, but in many other organisms as well, including birds, invertebrates, insects, plants, yeast, fungi, and even microorganisms.
Urea is essentially a waste product, but is vital for forming hypertonic (concentrated) urine. In the distal portions of the kidney collecting duct, urea is reintroduced into the kidney medulla to raise osmolarity. Afterwards, water flowing through the collecting tubule flows back into the body by osmosis through aquaporins.
Urea is dissolved in blood (in humans in a concentration of 2.5 - 7.5 mmol/liter) and excreted by the kidney in the urine.
In addition, a small amount of urea is excreted (along with sodium chloride and water) in human sweat.
# Hazards
Urea can be irritating to skin and eyes. Too high concentrations in the blood can cause damage to organs of the body. Low concentrations of urea such as in urine are not dangerous.
It has been found that urea can cause algal blooms to produce toxins, and urea in runoff from fertilizers may play a role in the increase of toxic blooms.
Repeated or prolonged contact with urea in fertiliser form on the skin may cause dermatitis. The substance also irritates the eyes, the skin and the respiratory tract. The substance decomposes on heating above melting point producing toxic gases. Reacts violently with strong oxidants, nitrites, inorganic chlorides, chlorites and perchlorates causing fire and explosion hazard
# Uses
## Laboratory use
Urea is a powerful protein denaturant. This property can be exploited to increase the solubility of some proteins. For this application it is used in concentrations up to 10 M.
Urea is used to effectively disrupt the noncovalent bonds in proteins.
Urea is an ingredient in the synthesis of urea nitrate.
Urea nitrate is also a high explosive very similar to ammonium nitrate, however it may even be more powerful because of its complexity. VOD is 11,000 fps to 15,420 fps.
## Medical use
Urea is used in topical dermatological products to promote rehydration of the skin. If covered by an occlusive dressing, 40% urea preparations may also be used for nonsurgical debridement of nails.
See blood urea nitrogen ("BUN") for a commonly performed urea test, and marker of renal function.
Isotopically-labeled urea (carbon 14 - radioactive, or carbon 13 - stable isotope) is used in the Urea breath test, which is used to detect the presence of Helicobacter pylori (H. pylori, a bacterium) in the stomach and duodenum of humans. The test detects the characteristic enzyme urease, produced by H. pylori, by a reaction that produces ammonia from urea. This increases the pH (reduces acidity) of the stomach environment around the bacteria.
Similar bacteria species to H. pylori can be identified by the same test in animals (apes, dogs, cats - including big cats).
# Ureas
Ureas or carbamides are a class of chemical compounds sharing the same functional group RR'N-CO-NRR' based on a carbonyl group flanked by two organic amine residues. They can be accessed in the laboratory by reaction of phosgene with primary or secondary amines. Example of ureas are the compounds carbamide peroxide, allantoin and Hydantoin. Ureas are closely related to biurets and structurally related to amides, carbamates, diimides, carbodiimides and thiocarbamides.
# Reactions
Urea reacts with alcohols to form urethanes. Urea reacts with malonic esters to make barbituric acids. | Urea
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Template:Chembox new
Urea is an organic compound with the chemical formula (NH2)2CO.
Urea is also known as carbamide, especially in the recommended International Nonproprietary Names (rINN) in use in Europe. For example, the medicinal compound hydroxyurea (old British Approved Name) is now hydroxycarbamide. Other names include carbamide resin, isourea, carbonyl diamide, and carbonyldiamine.
It was the first organic compound to be artificially synthesized from inorganic starting materials, thus dispelling the concept of vitalism.
# Discovery
Urea was discovered by Hilaire Rouelle in 1773. It was the first organic compound to be artificially synthesized from inorganic starting materials, in 1828 by Friedrich Wöhler, who prepared it by the reaction of potassium cyanate with ammonium sulfate. Although Woehler was attempting to prepare ammonium cyanate, by forming urea, he inadvertently disproved vitalism, the theory that the chemicals of living organisms are fundamentally different from inanimate matter, thus starting the discipline of organic chemistry.
This discovery prompted Wohler to write triumphantly to Berzelius:
"I must tell you that I can make urea without the use of kidneys, either man or dog. Ammonium cyanate is urea."
It is found in mammalian and amphibian urine as well as in some fish. Birds and reptiles excrete uric acid, comprising a different form of nitrogen metabolism that requires less water.
# Structure
Urea is highly soluble in water and is therefore an efficient way for the human body to expel excess nitrogen. Due to extensive hydrogen bonding with water (up to six hydrogen bonds may form, two from oxygen atom and one from each hydrogen), it is very soluble and thus is also a good fertilizer.
The urea molecule is planar and retains its full molecular point symmetry. Each carbonyl oxygen atom accepts four N-H-O hydrogen bonds, a very unusual feature for such a bond type. This dense (and energetically quite favourable) hydrogen bond network is probably established at the cost of efficient molecular packing: the structure is quite open, the ribbons forming tunnels with square cross-section.
# Physiology
The individual atoms that make up a urea molecule come from carbon dioxide, water, aspartate and ammonia in a metabolic pathway known as the urea cycle, an anabolic process. This expenditure of energy is necessary because ammonia, a common metabolic waste product, is toxic and must be neutralized. Urea production occurs in the liver and is under the regulatory control of N-acetylglutamate.
The urea cycle was originally known as the Krebs-Henseleit cycle after it was partially deduced by Hans Adolf Krebs and Kurt Henseleit in 1932. Its details were clarified in the 1940s as the roles of citrulline and argininosuccinate as intermediates were understood. In this cycle, amino groups donated by ammonia and L-aspartate are converted to urea, while L-ornithine, citrulline, L-argininosuccinate, and L-arginine act as intermediates.
Most organisms have to deal with the excretion of nitrogen waste originating from protein and amino acid catabolism. In aquatic organisms the most common form of nitrogen waste is ammonia, while land-dwelling organisms convert the toxic ammonia to either urea or uric acid. Generally, birds and saurian reptiles excrete uric acid, while the remaining species, including mammals, excrete urea. Remarkably, tadpoles excrete ammonia, and shift to urea production during metamorphosis. In veterinary medicine, Dalmatian breeds of dogs are noteworthy in that they excrete urea in the form of uric acid in the urine rather than in the urea form. This is due to a defect in one of the genes controlling expression of the conversion enzymes in the urea cycle.
Despite the generalization above, the pathway has been documented not only in mammals and amphibians, but in many other organisms as well, including birds, invertebrates, insects, plants, yeast, fungi, and even microorganisms.
Urea is essentially a waste product, but is vital for forming hypertonic (concentrated) urine. In the distal portions of the kidney collecting duct, urea is reintroduced into the kidney medulla to raise osmolarity. Afterwards, water flowing through the collecting tubule flows back into the body by osmosis through aquaporins.
Urea is dissolved in blood (in humans in a concentration of 2.5 - 7.5 mmol/liter) and excreted by the kidney in the urine.
In addition, a small amount of urea is excreted (along with sodium chloride and water) in human sweat.
# Hazards
Urea can be irritating to skin and eyes. Too high concentrations in the blood can cause damage to organs of the body. Low concentrations of urea such as in urine are not dangerous.
It has been found that urea can cause algal blooms to produce toxins, and urea in runoff from fertilizers may play a role in the increase of toxic blooms.[2]
Repeated or prolonged contact with urea in fertiliser form on the skin may cause dermatitis. The substance also irritates the eyes, the skin and the respiratory tract. The substance decomposes on heating above melting point producing toxic gases. Reacts violently with strong oxidants, nitrites, inorganic chlorides, chlorites and perchlorates causing fire and explosion hazard
# Uses
## Laboratory use
Urea is a powerful protein denaturant. This property can be exploited to increase the solubility of some proteins. For this application it is used in concentrations up to 10 M.
Urea is used to effectively disrupt the noncovalent bonds in proteins.
Urea is an ingredient in the synthesis of urea nitrate.
Urea nitrate is also a high explosive very similar to ammonium nitrate, however it may even be more powerful because of its complexity. VOD is 11,000 fps to 15,420 fps.
## Medical use
Urea is used in topical dermatological products to promote rehydration of the skin. If covered by an occlusive dressing, 40% urea preparations may also be used for nonsurgical debridement of nails.
See blood urea nitrogen ("BUN") for a commonly performed urea test, and marker of renal function.
Isotopically-labeled urea (carbon 14 - radioactive, or carbon 13 - stable isotope) is used in the Urea breath test, which is used to detect the presence of Helicobacter pylori (H. pylori, a bacterium) in the stomach and duodenum of humans. The test detects the characteristic enzyme urease, produced by H. pylori, by a reaction that produces ammonia from urea. This increases the pH (reduces acidity) of the stomach environment around the bacteria.
Similar bacteria species to H. pylori can be identified by the same test in animals (apes, dogs, cats - including big cats).
# Ureas
Ureas or carbamides are a class of chemical compounds sharing the same functional group RR'N-CO-NRR' based on a carbonyl group flanked by two organic amine residues. They can be accessed in the laboratory by reaction of phosgene with primary or secondary amines. Example of ureas are the compounds carbamide peroxide, allantoin and Hydantoin. Ureas are closely related to biurets and structurally related to amides, carbamates, diimides, carbodiimides and thiocarbamides.
# Reactions
Urea reacts with alcohols to form urethanes. Urea reacts with malonic esters to make barbituric acids. | https://www.wikidoc.org/index.php/Bosch-Meiser_urea_process | |
28a43f482ab774dd5757a3e3474fa955ec3f2771 | wikidoc | Boza | Boza
Boza is a popular fermented beverage in Albania, Bulgaria, the Republic of Macedonia, Montenegro, Romania, Serbia, and Turkey. It is made from fermented wheat in Turkey and wheat or millet in Bulgaria and Romania. It has a thick consistency and a low alcohol content (usually around 1%), and has a slightly acidic sweet flavor.
In the Republic of Macedonia boza is much thinner and lighter, and tastes sweeter.
In Turkey it is served with cinnamon and roasted chickpeas, and is consumed mainly in the winter months. The Ottoman Empire was known to feed its army with boza as it is rich in carbohydrates and vitamins.
In Bulgaria it is part of the traditional "Banitsa with Boza" breakfast.
In Albania it is mostly produced and sold in the northern part of Albania; you can easily find it in the candy and ice-creams stores of the capital, Tirana.
In southern Serbia, boza is produced and sold in the whole country.
The variant found in Romania is called bragă, and it is sweeter than in Turkey and Bulgaria, but thicker and darker than in Republic of Macedonia.
# History
Its origin dates back from the ancient populations that lived in Anatolia and Mesopotamia. The formula was taken by the Ottomans and spread over the countries they conquered. The Greek historian Xenophon records that bozawas made in eastern Anatolia in 401 BC, and stored in clay jars that were buried beneath the ground. This local specialty remained confined to the region until the arrival of the Turks, who took this nourishing drink and spread it far and wide under the name boza, a word deriving from the Persian word buze meaning millet. Bozaenjoyed its golden age under the Ottomans, and boza making became one of the principal trades in towns and cities from the early Ottoman period.
Until the 16th century boza was drunk freely everywhere, but the custom of making the so-called Tartar boza laced with opium brought the wrath of the authorities down on the drink, and it was prohibited by Sultan Selim II (1566-1574).
In the 17th century Sultan Mehmed IV (1648-1687) prohibited alcoholic drinks, in which category he included boza, and closed down all the boza shops. The 17th century Turkish traveler Evliya Çelebi tells us that boza was widely drunk at this time, and that there were 300 boza shops employing 1005 people in Istanbul alone. He also describes a type of non-alcoholic sweet boza of a milk white color made for the most part by Albanians.
At this period boza was widely drunk by janissaries in the army. Boza contained only a low level of alcohol, so as long as it was not consumed in sufficient quantities to cause drunkenness, it was tolerated on the grounds that it was a warming and strengthening beverage for soldiers. As Evliya Çelebi explained, 'These boza makers are numerous in the army. To drink sufficient boza to cause intoxication is sinful but, unlike wine, in small quantities it is not condemned.' In the 19th century the sweet and non-alcoholic Albanian boza preferred at the Ottoman palace became increasingly popular, while the sour and alcoholic type of boza that had generally been produced by the Armenians went out of favor. In 1876 Haci Ibrahim and Haci Sadik brothers established a boza shop in the Istanbul district of Vefa, close to the then center of entertainment, Direklerarası. This boza, with its thick consistency and tart flavor, became famous throughout the city, and is the only boza shop dating from that period still in business today. The firm is now run by Haci Sadik and Haci Ibrahim's great- great-grandchildren.
"Vefa" shop, located in the Istanbul district of Vefa, is now a minor tourist attraction. Karakedi Bozacısı of Eskişehir, Akman Boza Salonu of Ankara and Soydan of Pazarcık, Bilecik are less famous but well known other vendors in Turkey.
The most famous boza shop in Macedonia is "Apche", located in Debar Maalo area, near the Universal Hall in Skopje. The shop was founded by Isman Kadri in 1934. People called him Apche (the pill), jokingly claiming that his boza is a cure for all ills. He renamed the shop in 1940. Other famous boza hotspots in Skopje are "Palma" and "Sheherezada." Besides ethnic Albanians, boza-making tradition is also present among ethnic Macedonians. One of the characters in the 1928 play Lence Kumanovce/Begalka (Lenche of Kumanovo, AKA Eloped Bride) by Vasil Iljoski is Trendo, the boza-vendor.
# Production and storage
Boza is produced in most Turkic regions, but not always using millet. The flavour varies according to the cereal which is used. In Kirghizia, for instance, boza is made with crushed wheat, in the Crimea with wheat flour, and in Turkmenistan with coarsely ground rice meal. In Albania it is made only by maize and a small part of grain flour. Vefa boza, as it is known, is made only from hulled millet, which is boiled in water and then poured into broad shallow pans. When cool the mixture is sieved, and water and sugar added.
In a scientific study of boza carried out by the Turkish Science and Technology Institute for Vefa Bozacisi, the drink was found to be extremely healthy and nourishing. One litre of boza contains a thousand calories, four types of vitamins A and B, and vitamin E. During fermentation lactic acid, which is contained by few foods, is formed, and this facilitates digestion.
As boza spoils if not kept in a cool place, boza fermenters in Turkey (traditionally) don't sell boza in summer months and sell alternative beverages such as grape juice or lemonade. However, it is now available in summer time due to demand and availability of refrigeration. In Albania and Macedonia, however, boza is produced as refreshing beverage year-round.
# Controversy
Boza allegedly has the ability to enlarge women's breasts.
It is also recommended to women during their lactation period soon after they give birth as boza stimulates the production of milk.
# Notes and references
- ↑ И по Апче ќе има добра боза (Good boza production will continue after Apche's death). Dnevnik, 24 December 2005, Retrieved 9 April 2007.
- ↑ Три урбани легенди: Апче, Карпош и Кенан (Three urban legends: Apche, Karposh, and Kenan). Forum, 2 December 2005, Retrieved 9 April 2007.
- ↑ Ви текнува ли: На уличните продавачи на боза (Do you remember: the street boza-vendors). Vest, 6 June 2005, Retrieved 9 April 2007.
- ↑ Breast beer sells like hot cakes. news.com.au, Retrieved 15 January 2007. | Boza
Boza is a popular fermented beverage in Albania, Bulgaria, the Republic of Macedonia, Montenegro, Romania, Serbia, and Turkey. It is made from fermented wheat in Turkey and wheat or millet in Bulgaria and Romania. It has a thick consistency and a low alcohol content (usually around 1%), and has a slightly acidic sweet flavor.
In the Republic of Macedonia boza is much thinner and lighter, and tastes sweeter.
In Turkey it is served with cinnamon and roasted chickpeas, and is consumed mainly in the winter months. The Ottoman Empire was known to feed its army with boza as it is rich in carbohydrates and vitamins.
In Bulgaria it is part of the traditional "Banitsa with Boza" breakfast.
In Albania it is mostly produced and sold in the northern part of Albania; you can easily find it in the candy and ice-creams stores of the capital, Tirana.
In southern Serbia, boza is produced and sold in the whole country.
The variant found in Romania is called bragă, and it is sweeter than in Turkey and Bulgaria, but thicker and darker than in Republic of Macedonia.
# History
Its origin dates back from the ancient populations that lived in Anatolia and Mesopotamia[citation needed]. The formula was taken by the Ottomans and spread over the countries they conquered[citation needed]. The Greek historian Xenophon records that bozawas made in eastern Anatolia in 401 BC, and stored in clay jars that were buried beneath the ground[citation needed]. This local specialty remained confined to the region until the arrival of the Turks, who took this nourishing drink and spread it far and wide under the name boza, a word deriving from the Persian word buze meaning millet. Bozaenjoyed its golden age under the Ottomans, and boza making became one of the principal trades in towns and cities from the early Ottoman period.
Until the 16th century boza was drunk freely everywhere, but the custom of making the so-called Tartar boza laced with opium brought the wrath of the authorities down on the drink, and it was prohibited by Sultan Selim II (1566-1574).
In the 17th century Sultan Mehmed IV (1648-1687) prohibited alcoholic drinks, in which category he included boza, and closed down all the boza shops. The 17th century Turkish traveler Evliya Çelebi tells us that boza was widely drunk at this time, and that there were 300 boza shops employing 1005 people in Istanbul alone. He also describes a type of non-alcoholic sweet boza of a milk white color made for the most part by Albanians.
At this period boza was widely drunk by janissaries in the army. Boza contained only a low level of alcohol, so as long as it was not consumed in sufficient quantities to cause drunkenness, it was tolerated on the grounds that it was a warming and strengthening beverage for soldiers. As Evliya Çelebi explained, 'These boza makers are numerous in the army. To drink sufficient boza to cause intoxication is sinful but, unlike wine, in small quantities it is not condemned.' In the 19th century the sweet and non-alcoholic Albanian boza preferred at the Ottoman palace became increasingly popular, while the sour and alcoholic type of boza that had generally been produced by the Armenians went out of favor. In 1876 Haci Ibrahim and Haci Sadik brothers established a boza shop in the Istanbul district of Vefa, close to the then center of entertainment, Direklerarası. This boza, with its thick consistency and tart flavor, became famous throughout the city, and is the only boza shop dating from that period still in business today. The firm is now run by Haci Sadik and Haci Ibrahim's great- great-grandchildren.
"Vefa" shop, located in the Istanbul district of Vefa, is now a minor tourist attraction. Karakedi Bozacısı of Eskişehir, Akman Boza Salonu of Ankara and Soydan of Pazarcık, Bilecik are less famous but well known other vendors in Turkey.
The most famous boza shop in Macedonia is "Apche", located in Debar Maalo area, near the Universal Hall in Skopje.[1] The shop was founded by Isman Kadri in 1934. People called him Apche (the pill), jokingly claiming that his boza is a cure for all ills. He renamed the shop in 1940.[2] Other famous boza hotspots in Skopje are "Palma" and "Sheherezada." Besides ethnic Albanians, boza-making tradition is also present among ethnic Macedonians. One of the characters in the 1928 play Lence Kumanovce/Begalka (Lenche of Kumanovo, AKA Eloped Bride) by Vasil Iljoski is Trendo, the boza-vendor. [3]
# Production and storage
Boza is produced in most Turkic regions, but not always using millet. The flavour varies according to the cereal which is used. In Kirghizia, for instance, boza is made with crushed wheat, in the Crimea with wheat flour, and in Turkmenistan with coarsely ground rice meal. In Albania it is made only by maize and a small part of grain flour. Vefa boza, as it is known, is made only from hulled millet, which is boiled in water and then poured into broad shallow pans. When cool the mixture is sieved, and water and sugar added.
In a scientific study of boza carried out by the Turkish Science and Technology Institute for Vefa Bozacisi, the drink was found to be extremely healthy and nourishing. One litre of boza contains a thousand calories, four types of vitamins A and B, and vitamin E. During fermentation lactic acid, which is contained by few foods, is formed, and this facilitates digestion.[citation needed]
As boza spoils if not kept in a cool place, boza fermenters in Turkey (traditionally) don't sell boza in summer months and sell alternative beverages such as grape juice or lemonade. However, it is now available in summer time due to demand and availability of refrigeration. In Albania and Macedonia, however, boza is produced as refreshing beverage year-round.
# Controversy
Boza allegedly has the ability to enlarge women's breasts.[4]
It is also recommended to women during their lactation period soon after they give birth as boza stimulates the production of milk.
# Notes and references
- ↑ И по Апче ќе има добра боза (Good boza production will continue after Apche's death). Dnevnik, 24 December 2005, Retrieved 9 April 2007.
- ↑ Три урбани легенди: Апче, Карпош и Кенан (Three urban legends: Apche, Karposh, and Kenan). Forum, 2 December 2005, Retrieved 9 April 2007.
- ↑ Ви текнува ли: На уличните продавачи на боза (Do you remember: the street boza-vendors). Vest, 6 June 2005, Retrieved 9 April 2007.
- ↑ Breast beer sells like hot cakes. news.com.au, Retrieved 15 January 2007. | https://www.wikidoc.org/index.php/Boza | |
f1f326da2919746cb7c61ec85aa215e7afbca992 | wikidoc | Bubo | Bubo
# Overview
A bubo (Greek boubôn, "groin") (plural form= buboes) is a swelling of the lymph nodes, found in an infection such as bubonic plague, gonorrhea, tuberculosis or syphilis.
According to historical records they were also characteristic of the pandemic responsible for the Black Death and perhaps other ancient pandemics. It usually appears under the armpit, in the groin or on the neck. Many doctors believed that bursting them was the answer, although in the view of modern medicine this treatment is useless or in fact harmful. There are reports of people using hen feathers in order to burst lymph nodes. When lymph nodes are burst, the puncture site can leave a patient at higher risk for dangerous infection.
Buboes rarely require any form of local care, but instead recede with systemic antibiotic therapy. In fact, for plague patients, incision and drainage poses a risk to others in contact with the patient due to aerosolization of the bubo contents.
Needle aspiration can be done for diagnostic purposes and may also provide symptomatic relief. | Bubo
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A bubo (Greek boubôn, "groin") (plural form= buboes) is a swelling of the lymph nodes, found in an infection such as bubonic plague, gonorrhea, tuberculosis or syphilis.
According to historical records they were also characteristic of the pandemic responsible for the Black Death and perhaps other ancient pandemics. It usually appears under the armpit, in the groin or on the neck. Many doctors believed that bursting them was the answer, although in the view of modern medicine this treatment is useless or in fact harmful. There are reports of people using hen feathers in order to burst lymph nodes. When lymph nodes are burst, the puncture site can leave a patient at higher risk for dangerous infection.
Buboes rarely require any form of local care, but instead recede with systemic antibiotic therapy. In fact, for plague patients, incision and drainage poses a risk to others in contact with the patient due to aerosolization of the bubo contents.
Needle aspiration can be done for diagnostic purposes and may also provide symptomatic relief. | https://www.wikidoc.org/index.php/Bubo | |
4d042f89a2ce0557bb0a562d580055fd2fdcdbcf | wikidoc | Rash | Rash
# Overview
A rash is a change in skin which affects its color, appearance, or texture. A rash may be localized to one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, dry, cracked or blistered, swell and may be painful. The causes, and therefore treatments for rashes, vary widely. Diagnosis must take into account such things as the appearance of the rash, other symptoms, what the patient may have been exposed to, occupation, and occurrence in family members.
The presence of a rash may aid associated signs and symptoms are diagnostic of certain diseases. For example, the rash in measles is an erythematous, maculopapular rash that begins a few days after the fever starts; it classically starts at the head and spreads downwards.
# Causes
## Causes by Organ System
## Causes in Alphabetical Order
# Evaluating a Rash
The causes of a rash are extremely broad, which may make the evaluation of a rash extremely difficult. An accurate evaluation by a doctor may only be made in the context of a thorough history (What medication is the patient taking? What is the patient's occupation? Where has the patient been?) and complete physical examination.
Points to note in the examination include:
- The appearance: e.g., purpuric (typical of vasculitis and meningococcal septicemia), fine and like sandpaper (typical of scarlet fever); umbilicated lesions are typical of molluscum contagiosum (and in the past, small pox); plaques with silver scales are typical of psoriasis.
- The distribution: e.g., the rash of scarlet fever becomes confluent and forms bright red lines in the skin creases of the neck, armpits and groins (Pastia's lines); the vesicles of chicken pox seem to follow the hollows of the body (they are more prominent along the depression of the spine on the back and in the hollows of both shoulder blades); very few rashes affect the palms of the hands and soles of the feet (secondary syphilis, rickettsia or spotted fevers, guttate psoriasis, hand, foot and mouth disease, keratoderma blenorrhagica);
- Symmetry: e.g., herpes zoster usually only affects one side of the body and does not cross the midline.
Typically, according to Anthony Iannazzo, it is never a good habit for one to scratch their rash; as doing so may invigorate the rash and cause it to spread. Gently rubbing the rash may provide temporary relief, but it is more than likely better to avoid contact with the affected areas altogether.
# Quick Overview of Symptoms of Skin Rashes/Diseases
# Related Chapters
- Dermatology
- Skin Disease
- Dermatitis
Seborrhoeic dermatitis
Contact dermatitis
- Seborrhoeic dermatitis
- Contact dermatitis
- Ringworm
- Plants:
Poison ivy
Poison Oak
Stinging nettle
- Poison ivy
- Poison Oak
- Stinging nettle
- Heat rash
- Flushing (physiology)
- Erythema | Rash
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shankar Kumar, M.B.B.S. [2]]
# Overview
A rash is a change in skin which affects its color, appearance, or texture. A rash may be localized to one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, dry, cracked or blistered, swell and may be painful. The causes, and therefore treatments for rashes, vary widely. Diagnosis must take into account such things as the appearance of the rash, other symptoms, what the patient may have been exposed to, occupation, and occurrence in family members.
The presence of a rash may aid associated signs and symptoms are diagnostic of certain diseases. For example, the rash in measles is an erythematous, maculopapular rash that begins a few days after the fever starts; it classically starts at the head and spreads downwards.
# Causes
## Causes by Organ System
## Causes in Alphabetical Order
# Evaluating a Rash
The causes of a rash are extremely broad, which may make the evaluation of a rash extremely difficult. An accurate evaluation by a doctor may only be made in the context of a thorough history (What medication is the patient taking? What is the patient's occupation? Where has the patient been?) and complete physical examination.
Points to note in the examination include:
- The appearance: e.g., purpuric (typical of vasculitis and meningococcal septicemia), fine and like sandpaper (typical of scarlet fever); umbilicated lesions are typical of molluscum contagiosum (and in the past, small pox); plaques with silver scales are typical of psoriasis.
- The distribution: e.g., the rash of scarlet fever becomes confluent and forms bright red lines in the skin creases of the neck, armpits and groins (Pastia's lines); the vesicles of chicken pox seem to follow the hollows of the body (they are more prominent along the depression of the spine on the back and in the hollows of both shoulder blades); very few rashes affect the palms of the hands and soles of the feet (secondary syphilis, rickettsia or spotted fevers,[1] guttate psoriasis, hand, foot and mouth disease, keratoderma blenorrhagica);
- Symmetry: e.g., herpes zoster usually only affects one side of the body and does not cross the midline.
Typically, according to Anthony Iannazzo, it is never a good habit for one to scratch their rash; as doing so may invigorate the rash and cause it to spread. Gently rubbing the rash may provide temporary relief, but it is more than likely better to avoid contact with the affected areas altogether.
# Quick Overview of Symptoms of Skin Rashes/Diseases
# Related Chapters
- Dermatology
- Skin Disease
- Dermatitis
Seborrhoeic dermatitis
Contact dermatitis
- Seborrhoeic dermatitis
- Contact dermatitis
- Ringworm
- Plants:
Poison ivy
Poison Oak
Stinging nettle
- Poison ivy
- Poison Oak
- Stinging nettle
- Heat rash
- Flushing (physiology)
- Erythema | https://www.wikidoc.org/index.php/Bullous_rashes | |
ed60cdc52b3e2d6805000d516235001c69be2ff0 | wikidoc | C1QA | C1QA
Complement C1q subcomponent subunit A is a protein that in humans is encoded by the C1QA gene.
This gene encodes a major constituent of the human complement system subcomponent C1q.
C1q associates with C1r and C1s in order to yield the first component of the serum complement system. Deficiency of C1q has been associated with lupus erythematosus and glomerulonephritis. C1q is composed of 18 polypeptide chains: six A-chains, six B-chains, and six C-chains. Each chain contains a collagen-like region located near the N terminus and a C-terminal globular region. The A-, B-, and C-chains are arranged in the order A-C-B on chromosome 1. This gene encodes the A-chain polypeptide of human complement subcomponent C1q. | C1QA
Complement C1q subcomponent subunit A is a protein that in humans is encoded by the C1QA gene.[1]
This gene encodes a major constituent of the human complement system subcomponent C1q.
C1q associates with C1r and C1s in order to yield the first component of the serum complement system. Deficiency of C1q has been associated with lupus erythematosus and glomerulonephritis. C1q is composed of 18 polypeptide chains: six A-chains, six B-chains, and six C-chains. Each chain contains a collagen-like region located near the N terminus and a C-terminal globular region. The A-, B-, and C-chains are arranged in the order A-C-B on chromosome 1. This gene encodes the A-chain polypeptide of human complement subcomponent C1q.[2] | https://www.wikidoc.org/index.php/C1QA | |
00b732a807043bd1dea216c74822b317bdf4dc0e | wikidoc | CA12 | CA12
Carbonic anhydrase 12 is an enzyme that in humans is encoded by the CA12 gene.
# Function
Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. This gene product is a type I membrane protein that is highly expressed in normal tissues, such as kidney, colon and pancreas, and has been found to be overexpressed in 10% of clear cell renal carcinomas. Two transcript variants encoding different isoforms have been identified for this gene.
# Pathology
Loss of function mutations in the CAXII gene result in defects in fluids and carbonate secretions in the following diseases:
1) Cystic fibrosis-like syndrome with normal cystic fibrosis transmembrane conductance regulator (CFTR) protein levels
2) Pancreatitis
3) Sjögren's syndrome
4) Xerostomia or dry mouth syndrome
# Molecular Basis of Cystic Fibrosis-like Syndrome
CAXII, with either the His121Gln or Glu143Lys mutation, localizes to basolateral membranes of polarized MDCK cells similar to the wild type enzyme, indicating no deleterious effect on subcellular location.
However, CAXII mutant enzymes show reduced activity. These observations made it very hard to explain the mechanism for the autosomal recessive disorder of hyponatremia, causing salt wasting in sweat due to mutant CAXII.
In a separate study, researchers observed that mutant enzyme activity is completely reduced at physiological concentrations of sodium chloride. Thus, loss of the function of CAXII in sweat glands and lungs is the molecular basis for cystic fibrosis patients with normal CFTR levels.
# High Impact Information on CAXII
Differential modulation of the active site environment of CAXII by cationic quantum dots and polylysine helps design CAXII specific activators and inhibitors of the enzyme. CAXII specific inhibition provides a tool to interfere with cell proliferation, resulting in cell apoptosis in T-cell lymphomas.
# Analytical, Diagnostic, and Therapeutic Context of CAXII
Serum CAXII levels should be applicable as a sero-diagnostic marker for lung cancer.
# Notes | CA12
Carbonic anhydrase 12 is an enzyme that in humans is encoded by the CA12 gene.[1][2]
# Function
Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. This gene product is a type I membrane protein that is highly expressed in normal tissues, such as kidney, colon and pancreas, and has been found to be overexpressed in 10% of clear cell renal carcinomas. Two transcript variants encoding different isoforms have been identified for this gene.[2]
# Pathology
Loss of function mutations in the CAXII gene result in defects in fluids and carbonate secretions in the following diseases:
1) Cystic fibrosis-like syndrome with normal cystic fibrosis transmembrane conductance regulator (CFTR) protein levels [3][4][5][6][7][8]
2) Pancreatitis[9][10]
3) Sjögren's syndrome[10][11]
4) Xerostomia or dry mouth syndrome[5][6][7]
# Molecular Basis of Cystic Fibrosis-like Syndrome
CAXII, with either the His121Gln or Glu143Lys mutation, localizes to basolateral membranes of polarized MDCK cells similar to the wild type enzyme, indicating no deleterious effect on subcellular location.[10]
However, CAXII mutant enzymes show reduced activity. These observations made it very hard to explain the mechanism for the autosomal recessive disorder of hyponatremia, causing salt wasting in sweat due to mutant CAXII.[3][4]
In a separate study, researchers observed that mutant enzyme activity is completely reduced at physiological concentrations of sodium chloride.[10] Thus, loss of the function of CAXII in sweat glands and lungs is the molecular basis for cystic fibrosis patients with normal CFTR levels.[10]
# High Impact Information on CAXII
Differential modulation of the active site environment of CAXII by cationic quantum dots and polylysine helps design CAXII specific activators and inhibitors of the enzyme.[12] CAXII specific inhibition provides a tool to interfere with cell proliferation, resulting in cell apoptosis in T-cell lymphomas.[13]
# Analytical, Diagnostic, and Therapeutic Context of CAXII
Serum CAXII levels should be applicable as a sero-diagnostic marker for lung cancer.[14]
# Notes | https://www.wikidoc.org/index.php/CA12 | |
651b54cbb51428cefad93aa5bf24fbee781d4d6d | wikidoc | CA14 | CA14
Carbonic anhydrase 14 is an enzyme that in humans is encoded by the CA14 gene.
Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. They show extensive diversity in tissue distribution and in their subcellular localization. CA XIV is predicted to be a type I membrane protein and shares highest sequence similarity with the other transmembrane CA isoform, CA XII; however, they have different patterns of tissue-specific expression and thus may play different physiologic roles.
In melanocytic cells CA14 gene expression may be regulated by MITF. | CA14
Carbonic anhydrase 14 is an enzyme that in humans is encoded by the CA14 gene.[1][2]
Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. They show extensive diversity in tissue distribution and in their subcellular localization. CA XIV is predicted to be a type I membrane protein and shares highest sequence similarity with the other transmembrane CA isoform, CA XII; however, they have different patterns of tissue-specific expression and thus may play different physiologic roles.[2]
In melanocytic cells CA14 gene expression may be regulated by MITF.[3] | https://www.wikidoc.org/index.php/CA14 | |
a72daf4dd15f94d670137e49e4d1e679d25ada0e | wikidoc | CREB | CREB
# Overview
CREB (cAMP response element-binding) proteins are transcription factors which bind to certain sequences called cAMP response elements (CRE) in DNA and thereby increase or decrease the transcription of certain genes. CREB is highly related (in structure and function) to CREM (cAMP response element modulator) and ATF-1 (activating transcription factor-1) proteins. CREB proteins are active in many animals, including humans. The typical (somewhat simplified) sequence of events is as follows: a signal arrives at the cell surface, activates the corresponding receptor, which leads to the production of a second messenger such as cAMP or Ca2+, which in turn activates a protein kinase. This protein kinase moves to the cell nucleus, where it activates a CREB protein. The activated CREB protein then binds to a CRE region, and is then bound to by a CBP (CREB binding protein) which coactivates it, allowing it to switch certain genes on or off. The DNA binding of CREB is mediated via its basic leucine zipper domain (bZIP domain) as depicted in the picture.
CREB has many functions in many different organs although most of its functions have been studied in relation to the brain. CREB proteins in neurons are thought to be involved in the formation of long-term memories; this has been shown in the marine snail Aplysia, the fruit fly Drosophila melanogaster, and in rats. They are necessary for the late stage of long term potentiation. There are activator and repressor forms of CREB. Flies genetically engineered to overexpress the inactive form of CREB lose their ability to retain long term memory. CREB is also important for the survival of neurons, as shown in genetically engineered mice, where CREB and CREM were deleted in the brain. This study supports the view that disturbance of CREB function in brain can contribute to the development and progression of Huntington's Disease in humans. If CREB is lost in the whole developing mouse embryo, the mice die immediately after birth, again highlighting the critical role of CREB in promoting survival. CREB is also thought to be involved in the growth of some types of cancer.
In humans, abnormalities of a protein which interacts with the KID domain of CREB, the CREB binding protein (CBP) is associated with Rubinstein-Taybi syndrome. | CREB
# Overview
CREB (cAMP response element-binding) proteins are transcription factors which bind to certain sequences called cAMP response elements (CRE) in DNA and thereby increase or decrease the transcription of certain genes. CREB is highly related (in structure and function) to CREM (cAMP response element modulator) and ATF-1 (activating transcription factor-1) proteins. CREB proteins are active in many animals, including humans. The typical (somewhat simplified) sequence of events is as follows: a signal arrives at the cell surface, activates the corresponding receptor, which leads to the production of a second messenger such as cAMP or Ca2+, which in turn activates a protein kinase. This protein kinase moves to the cell nucleus, where it activates a CREB protein. The activated CREB protein then binds to a CRE region, and is then bound to by a CBP (CREB binding protein) which coactivates it, allowing it to switch certain genes on or off. The DNA binding of CREB is mediated via its basic leucine zipper domain (bZIP domain) as depicted in the picture.
CREB has many functions in many different organs although most of its functions have been studied in relation to the brain. CREB proteins in neurons are thought to be involved in the formation of long-term memories; this has been shown in the marine snail Aplysia, the fruit fly Drosophila melanogaster, and in rats. They are necessary for the late stage of long term potentiation. There are activator and repressor forms of CREB. Flies genetically engineered to overexpress the inactive form of CREB lose their ability to retain long term memory. CREB is also important for the survival of neurons, as shown in genetically engineered mice, where CREB and CREM were deleted in the brain. This study supports the view that disturbance of CREB function in brain can contribute to the development and progression of Huntington's Disease in humans. If CREB is lost in the whole developing mouse embryo, the mice die immediately after birth, again highlighting the critical role of CREB in promoting survival. CREB is also thought to be involved in the growth of some types of cancer.
In humans, abnormalities of a protein which interacts with the KID domain of CREB, the CREB binding protein (CBP) is associated with Rubinstein-Taybi syndrome. | https://www.wikidoc.org/index.php/CAMP_response_element | |
205f15447c835898aaf9142199b0e0c4f44ffb4e | wikidoc | NOD2 | NOD2
Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), also known as caspase recruitment domain-containing protein 15 (CARD15) or inflammatory bowel disease protein 1 (IBD1), is a protein that in humans is encoded by the NOD2 gene located on chromosome 16. NOD2 plays an important role in the immune system. It recognizes bacterial molecules (peptidoglycans) and stimulates an immune reaction .
NOD2 is an intracellular pattern recognition receptor, which is similar in structure to resistant proteins of plants and recognizes molecules containing the specific structure called muramyl dipeptide (MDP) that is found in certain bacteria.
# Structure
The C-terminal portion of the protein contains a leucine-rich repeat domain that is known to play a role in protein–protein interactions. The middle part of the protein is characterized by a NOD domain involved in protein self-oligomerization. The N-terminal portion contains two CARD domains known to play a role in apoptosis and NF-κB activation pathways.
# Function
This gene is a member of the NOD1/Apaf-1 family (also known as NOD-like receptor family) and encodes a protein with two caspase recruitment domains (CARDs) and eleven leucine-rich repeats (LRRs). The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response by recognizing the bacterial molecules which possess the muramyl dipeptide (MDP) moiety and activating the NF-κB protein.
# Clinical significance
Mutations in this gene have been associated with Crohn's disease, Blau syndrome, severe pulmonary sarcoidosis and Graft-versus-host disease.
The NOD2 gene is linked to inflammatory diseases such as Inflammatory bowel disease/Crohn's disease and Blau syndrome.
# Interactions
NOD2 has been shown to interact with NLRC4.
NOD2 has also been shown to bind to MAVS in response to ssRNA or viral RNA treatment and activate the IFN response. This is the first report of NOD2 acting as a pattern-recognition receptor for viruses. | NOD2
Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), also known as caspase recruitment domain-containing protein 15 (CARD15) or inflammatory bowel disease protein 1 (IBD1), is a protein that in humans is encoded by the NOD2 gene located on chromosome 16.[1][2] NOD2 plays an important role in the immune system. It recognizes bacterial molecules (peptidoglycans) and stimulates an immune reaction [3].
NOD2 is an intracellular pattern recognition receptor, which is similar in structure to resistant proteins of plants and recognizes molecules containing the specific structure called muramyl dipeptide (MDP) that is found in certain bacteria.[4]
# Structure
The C-terminal portion of the protein contains a leucine-rich repeat domain that is known to play a role in protein–protein interactions. The middle part of the protein is characterized by a NOD domain involved in protein self-oligomerization. The N-terminal portion contains two CARD domains known to play a role in apoptosis and NF-κB activation pathways.[6]
# Function
This gene is a member of the NOD1/Apaf-1 family (also known as NOD-like receptor family) and encodes a protein with two caspase recruitment domains (CARDs) and eleven leucine-rich repeats (LRRs). The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response by recognizing the bacterial molecules which possess the muramyl dipeptide (MDP) moiety and activating the NF-κB protein.[7]
# Clinical significance
Mutations in this gene have been associated with Crohn's disease,[5] Blau syndrome, severe pulmonary sarcoidosis [8] and Graft-versus-host disease.[9]
The NOD2 gene is linked to inflammatory diseases such as Inflammatory bowel disease/Crohn's disease and Blau syndrome.[10][11]
# Interactions
NOD2 has been shown to interact with NLRC4.[12][13]
NOD2 has also been shown to bind to MAVS in response to ssRNA or viral RNA treatment and activate the IFN response. This is the first report of NOD2 acting as a pattern-recognition receptor for viruses.[14] | https://www.wikidoc.org/index.php/CARD15 | |
6c1eb60a387ce42c2e81a22a62b60d4c012f1f64 | wikidoc | CASK | CASK
Peripheral plasma membrane protein CASK is a protein that in humans is encoded by the CASK gene. This gene is also known by several other names: CMG 2 (CAMGUK protein 2), calcium/calmodulin-dependent serine protein kinase 3 and membrane-associated guanylate kinase 2.
# Gene
This gene is located on the short arm of the X chromosome (Xp11.4). It is 404,253 bases in length and lies on the Crick (minus) strand. The encoded protein has 926 amino acids with a predicted molecular weight of 105,123 Daltons.
# Function
This protein is a multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring and ion channel trafficking. It interacts with the transcription factor TBR1 and binds to several cell-surface proteins including amyloid precursor protein, neurexins and syndecans.
# Clinical importance
This gene has been implicated in X-linked mental retardation, including specifically mental retardation and microcephaly with pontine and cerebellar hypoplasia.
# Interactions
CASK has been shown to interact with:
- KCNJ4
- APBA1
- ATP2B4
- CINAP and TBR1
- DLG1
- DLG4
- F11 receptor
- ID1
- KCNJ12
- LIN7A
- Nephrin
- Parkin (ligase)
- RPH3A
- SDC2 | CASK
Peripheral plasma membrane protein CASK is a protein that in humans is encoded by the CASK gene.[1][2] This gene is also known by several other names: CMG 2 (CAMGUK protein 2), calcium/calmodulin-dependent serine protein kinase 3 and membrane-associated guanylate kinase 2.
# Gene
This gene is located on the short arm of the X chromosome (Xp11.4). It is 404,253 bases in length and lies on the Crick (minus) strand. The encoded protein has 926 amino acids with a predicted molecular weight of 105,123 Daltons.
# Function
This protein is a multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring and ion channel trafficking. It interacts with the transcription factor TBR1 and binds to several cell-surface proteins including amyloid precursor protein, neurexins and syndecans.
# Clinical importance
This gene has been implicated in X-linked mental retardation,[3] including specifically mental retardation and microcephaly with pontine and cerebellar hypoplasia.[4]
# Interactions
CASK has been shown to interact with:
- KCNJ4[5][6]
- APBA1[7][8]
- ATP2B4[9]
- CINAP and TBR1[10]
- DLG1[6][11][12]
- DLG4[11]
- F11 receptor[13][14]
- ID1[15]
- KCNJ12[5][6]
- LIN7A[6][7]
- Nephrin[16]
- Parkin (ligase)[17]
- RPH3A[18]
- SDC2[18][19] | https://www.wikidoc.org/index.php/CASK | |
1511281ae754d34802a2a001af4e196a3e0360d2 | wikidoc | CBFB | CBFB
Core-binding factor subunit beta is a protein that in humans is encoded by the CBFB gene.
The protein encoded by this gene is the beta subunit of a heterodimeric core-binding transcription factor belonging to the PEBP2/CBF transcription factor family which master-regulates a host of genes specific to hematopoiesis (e.g., RUNX1) and osteogenesis (e.g., RUNX2). The beta subunit is a non-DNA binding regulatory subunit; it allosterically enhances DNA binding by the alpha subunit as the complex binds to the core site of various enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers and GM-CSF promoters. Alternative splicing generates two mRNA variants, each encoding a distinct carboxyl terminus. In some cases, a pericentric inversion of chromosome 16 produces a chimeric transcript consisting of the N terminus of core-binding factor beta in a fusion with the C-terminal portion of the smooth muscle myosin heavy chain 11. This chromosomal rearrangement is associated with acute myeloid leukemia of the M4Eo subtype. Two transcript variants encoding different isoforms have been found for this gene. Mutations in CBFB are implicated in cases of breast cancer.
Core binding factor acute myeloid leukaemia is a cancer related to genetic changes in the CBF gene. It is most commonly caused by an inversion of particular region of chromosome 16; however it can also be caused by translocation between copies of chromosome 16. The rearrangements cause formation of CBF but with impaired function. This prevents proper differentiation of blood cells, leading to the formation of Myeloblast. | CBFB
Core-binding factor subunit beta is a protein that in humans is encoded by the CBFB gene.[1][2]
The protein encoded by this gene is the beta subunit of a heterodimeric core-binding transcription factor belonging to the PEBP2/CBF transcription factor family which master-regulates a host of genes specific to hematopoiesis (e.g., RUNX1) and osteogenesis (e.g., RUNX2). The beta subunit is a non-DNA binding regulatory subunit; it allosterically enhances DNA binding by the alpha subunit as the complex binds to the core site of various enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers and GM-CSF promoters. Alternative splicing generates two mRNA variants, each encoding a distinct carboxyl terminus. In some cases, a pericentric inversion of chromosome 16 [inv(16)(p13q22)] produces a chimeric transcript consisting of the N terminus of core-binding factor beta in a fusion with the C-terminal portion of the smooth muscle myosin heavy chain 11. This chromosomal rearrangement is associated with acute myeloid leukemia of the M4Eo subtype. Two transcript variants encoding different isoforms have been found for this gene.[3] Mutations in CBFB are implicated in cases of breast cancer.[4]
Core binding factor acute myeloid leukaemia is a cancer related to genetic changes in the CBF gene. It is most commonly caused by an inversion of particular region of chromosome 16; however it can also be caused by translocation between copies of chromosome 16. The rearrangements cause formation of CBF but with impaired function. This prevents proper differentiation of blood cells, leading to the formation of Myeloblast.[5] | https://www.wikidoc.org/index.php/CBFB | |
c20897e8216b03bac129edfc79343f9af392d950 | wikidoc | CBLC | CBLC
Signal transduction protein CBL-C is a protein that in humans is encoded by the CBLC gene.
CBL proteins, such as CBLC, are phosphorylated upon activation of a variety of receptors that signal via protein tyrosine kinases. Through interactions with proteins containing SRC (MIM 190090) homology-2 (SH2) and SH3 domains, CBL proteins modulate downstream cell signaling (Keane et al., 1999).
# Interactions
CBLC has been shown to interact with FYN and Epidermal growth factor receptor. | CBLC
Signal transduction protein CBL-C is a protein that in humans is encoded by the CBLC gene.[1][2][3]
CBL proteins, such as CBLC, are phosphorylated upon activation of a variety of receptors that signal via protein tyrosine kinases. Through interactions with proteins containing SRC (MIM 190090) homology-2 (SH2) and SH3 domains, CBL proteins modulate downstream cell signaling (Keane et al., 1999).[supplied by OMIM][3]
# Interactions
CBLC has been shown to interact with FYN[4] and Epidermal growth factor receptor.[2][5] | https://www.wikidoc.org/index.php/CBLC | |
b607626a54fae532e88c1527f8f61e9c34c090a9 | wikidoc | CBR1 | CBR1
Carbonyl reductase 1, also known as CBR1, is an enzyme which in humans is encoded by the CBR1 gene. The protein encoded by this gene belongs to the short-chain dehydrogenases/reductases (SDR) family, which function as NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds, such as quinones, prostaglandins, and various xenobiotics. Alternatively spliced transcript variants have been found for this gene.
# Function
Carbonyl reductase is one of several monomeric, NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds. This enzyme is widely distributed in human tissues. Another carbonyl reductase gene, CRB3, lies close to this gene on chromosome 21q. CBR1 metabolizes many toxic environmental quinones and pharmacological relevant substrates such as the anticancer doxorubicin. Several studies have shown that CBR1 plays a protective role in oxidative stress, neurodegeneration, and apoptosis. In addition, CBR1 inactivates lipid aldehydes during oxidative stress in cells. Therefore, CBR1 may play a beneficial role in protecting against cellular damage resulting from oxidative stress.
# Polymorphisms
Up-to-date two non-synonymous polymorphisms on CBR1 have been identified. The CBR1 V88I polymorphism encodes for a valine-to-isoleucin substitution at position 88 of the aminoacid chain. In vitro studies with recombinant proteins indicate that the CBR1 V88 isoform has a higher Vmax towards the substrates menadione (vitamin K3) and daunorubicin. Recent studies in human liver cytosols show that an untranslated polymorphism on the 3'UTR region of the CBR1 gene (rs9024) is associated with higher levels of the cardiotoxic metabolite doxorubicinol.
# Structure
## Gene
Human CBR1 gene maps to chromosome 21 at q22.13, and includes 8 exons.
## Protein
The enzyme consists of 277 amino acid residues and is widely distributed in human tissues such as liver, epidermis, stomach, small intestine, kidney, neuronal cells, and smooth muscle fibers. The best substrates of CBR1 are quinones, including ubiquinone-1 and tocopherolquinone (vitamin E). Ubiquinones (coenzyme Q) are constitutive parts of the respiratory chain, and tocopherolquinone protects lipids of biological membranes against lipid peroxidation, indicating that CBR1 may play an important role as an oxidation–reduction catalyst in biological processes.
# Clinical significance
CBR1 has been reported to relate to tumor progression. Suppression of CBR1 expression was associated with poor prognosis in uterine endometrial cancer and uterine cervical squamous cell carcinoma. Previous studies showed that decreased CBR1 expression is associated with lymph node metastasis and poor prognosis in ovarian cancer, and induction of CBR1 expression in ovarian tumors leads to a spontaneous decrease in tumor size.
Recent study demonstrates that CBR1 attenuates apoptosis and promotes cell survival in pancreatic β cell lines under glucotoxic and glucolipotoxic conditions via reducing ROS generation. Their data demonstrates that CBR1 expression level and enzyme activity are decreased in pancreatic islets isolated from db/db mice, an animal model of type 2 diabetes. These results suggest that CBR1 may play a role in protecting pancreatic β-cells against oxidative stress under glucotoxic or glucolipotoxic conditions, and its reduced expression or activity may contribute to β-cell dysfunction in db/db mice or human type 2 diabetes.
In addition, CBR1 may play a critical role in PGF2α synthesis in human amnion fibroblasts, and cortisol promotes the conversion of PGE2 into PGF2α via glucocorticoid receptor (GR)-mediated induction of CBR1 in human amnion fibroblasts. This stimulatory effect of cortisol on CBR1 expression may partly explain the concurrent increases of cortisol and PGF2α in human amnion tissue with labor, and these findings may account for the increased production of PGF2α in the fetal membranes prior to the onset of labor.
# Interactions
CBR1 has been shown to interact with Cortisol, C2 domain, and Flavonoid. | CBR1
Carbonyl reductase 1, also known as CBR1, is an enzyme which in humans is encoded by the CBR1 gene.[1][2][3] The protein encoded by this gene belongs to the short-chain dehydrogenases/reductases (SDR) family, which function as NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds, such as quinones, prostaglandins, and various xenobiotics. Alternatively spliced transcript variants have been found for this gene.[1]
# Function
Carbonyl reductase is one of several monomeric, NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds. This enzyme is widely distributed in human tissues. Another carbonyl reductase gene, CRB3, lies close to this gene on chromosome 21q.[1] CBR1 metabolizes many toxic environmental quinones and pharmacological relevant substrates such as the anticancer doxorubicin.[4] Several studies have shown that CBR1 plays a protective role in oxidative stress, neurodegeneration, and apoptosis.[5] In addition, CBR1 inactivates lipid aldehydes during oxidative stress in cells. Therefore, CBR1 may play a beneficial role in protecting against cellular damage resulting from oxidative stress.[6]
# Polymorphisms
Up-to-date two non-synonymous polymorphisms on CBR1 have been identified. The CBR1 V88I polymorphism encodes for a valine-to-isoleucin substitution at position 88 of the aminoacid chain. In vitro studies with recombinant proteins indicate that the CBR1 V88 isoform has a higher Vmax towards the substrates menadione (vitamin K3) and daunorubicin.[7] Recent studies in human liver cytosols show that an untranslated polymorphism on the 3'UTR region of the CBR1 gene (rs9024)[8] is associated with higher levels of the cardiotoxic metabolite doxorubicinol.[9]
# Structure
## Gene
Human CBR1 gene maps to chromosome 21 at q22.13, and includes 8 exons.[1]
## Protein
The enzyme consists of 277 amino acid residues and is widely distributed in human tissues such as liver, epidermis, stomach, small intestine, kidney, neuronal cells, and smooth muscle fibers.[10] The best substrates of CBR1 are quinones, including ubiquinone-1 and tocopherolquinone (vitamin E). Ubiquinones (coenzyme Q) are constitutive parts of the respiratory chain, and tocopherolquinone protects lipids of biological membranes against lipid peroxidation, indicating that CBR1 may play an important role as an oxidation–reduction catalyst in biological processes.[11]
# Clinical significance
CBR1 has been reported to relate to tumor progression.[12] Suppression of CBR1 expression was associated with poor prognosis in uterine endometrial cancer and uterine cervical squamous cell carcinoma.[12] Previous studies showed that decreased CBR1 expression is associated with lymph node metastasis and poor prognosis in ovarian cancer, and induction of CBR1 expression in ovarian tumors leads to a spontaneous decrease in tumor size.[13]
Recent study demonstrates that CBR1 attenuates apoptosis and promotes cell survival in pancreatic β cell lines under glucotoxic and glucolipotoxic conditions via reducing ROS generation. Their data demonstrates that CBR1 expression level and enzyme activity are decreased in pancreatic islets isolated from db/db mice, an animal model of type 2 diabetes. These results suggest that CBR1 may play a role in protecting pancreatic β-cells against oxidative stress under glucotoxic or glucolipotoxic conditions, and its reduced expression or activity may contribute to β-cell dysfunction in db/db mice or human type 2 diabetes.[10]
In addition, CBR1 may play a critical role in PGF2α synthesis in human amnion fibroblasts, and cortisol promotes the conversion of PGE2 into PGF2α via glucocorticoid receptor (GR)-mediated induction of CBR1 in human amnion fibroblasts. This stimulatory effect of cortisol on CBR1 expression may partly explain the concurrent increases of cortisol and PGF2α in human amnion tissue with labor, and these findings may account for the increased production of PGF2α in the fetal membranes prior to the onset of labor.[14]
# Interactions
CBR1 has been shown to interact with Cortisol,[14] C2 domain,[15] and Flavonoid.[16] | https://www.wikidoc.org/index.php/CBR1 | |
e7ae8caa2c5738c0ef9e647a1a24d27cf58ecf68 | wikidoc | CBX1 | CBX1
Chromobox protein homolog 1 is a protein that in humans is encoded by the CBX1 gene.
# Function
The protein is localized at heterochromatin sites, where it mediates gene silencing.
# Model organisms
Model organisms have been used in the study of CBX1 function. A conditional knockout mouse line, called Cbx1tm1a(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 two tests were carried out and two phenotypes were reported. No homozygous mutant animals survived until two weeks of age, therefore the remaining tests were carried out on heterozygous mutant mice. Male heterozygotes showed increased VO2, rate of elimination of carbon dioxide, and energy expenditure as determined by indirect calorimetry.
# Interactions
CBX1 has been shown to interact with:
- C11orf30,
- CBX3 and
- CBX5, and
- SUV39H1. | CBX1
Chromobox protein homolog 1 is a protein that in humans is encoded by the CBX1 gene.[1][2]
# Function
The protein is localized at heterochromatin sites, where it mediates gene silencing.[2]
# Model organisms
Model organisms have been used in the study of CBX1 function. A conditional knockout mouse line, called Cbx1tm1a(EUCOMM)Wtsi[6][7] 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.[8][9][10]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[4][11] Twenty two tests were carried out and two phenotypes were reported. No homozygous mutant animals survived until two weeks of age, therefore the remaining tests were carried out on heterozygous mutant mice. Male heterozygotes showed increased VO2, rate of elimination of carbon dioxide, and energy expenditure as determined by indirect calorimetry.[4]
# Interactions
CBX1 has been shown to interact with:
- C11orf30,[12]
- CBX3[13] and
- CBX5,[13] and
- SUV39H1.[14] | https://www.wikidoc.org/index.php/CBX1 | |
c88cd96b16af23e276c79d9b4d0bd9494942912a | wikidoc | CBX3 | CBX3
Chromobox protein homolog 3 is a protein that is encoded by the CBX3 gene in humans.
At the nuclear envelope, the nuclear lamina and heterochromatin are adjacent to the inner nuclear membrane. The protein encoded by this gene binds DNA and is a component of heterochromatin. This protein also can bind lamin B receptor, an integral membrane protein found in the inner nuclear membrane. The dual binding functions of the encoded protein may explain the association of heterochromatin with the inner nuclear membrane. Two transcript variants encoding the same protein but differing in the 5' UTR, have been found for this gene.
# Interactions
CBX3 has been shown to interact with PIM1, Ki-67, Lamin B receptor, CBX5 and CBX1. | CBX3
Chromobox protein homolog 3 is a protein that is encoded by the CBX3 gene in humans.[1][2]
At the nuclear envelope, the nuclear lamina and heterochromatin are adjacent to the inner nuclear membrane. The protein encoded by this gene binds DNA and is a component of heterochromatin. This protein also can bind lamin B receptor, an integral membrane protein found in the inner nuclear membrane. The dual binding functions of the encoded protein may explain the association of heterochromatin with the inner nuclear membrane. Two transcript variants encoding the same protein but differing in the 5' UTR, have been found for this gene.[2]
# Interactions
CBX3 has been shown to interact with PIM1,[3] Ki-67,[4] Lamin B receptor,[5] CBX5[6] and CBX1.[6] | https://www.wikidoc.org/index.php/CBX3 | |
01b1c51a8807844e34bbc6b0b9495adb6f280ba0 | wikidoc | CCL2 | CCL2
For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.
The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. CCL2 is a small cytokine that belongs to the CC chemokine family. CCL2 recruits monocytes, memory T cells, and dendritic cells to the sites of inflammation produced by either tissue injury or infection.
# Genomics
In the human genome, CCL2 and many other CC chemokines are located on chromosome 17 (17q11.2-q21.1). The gene span is 1,927 bases and the CCL2 gene resides on the Watson (plus) strand. The CCL2 gene has three exons and two introns. The CCL2 protein precursor contains a signal peptide of 23 amino acids. In turn, the mature CCL2 is 76 amino acids long. The CCL2 predicted weight is 11.025 kiloDaltons (kDa).
# Population genetics
In humans, the levels of CCL2 can vary considerably. In the white people of European descent, the multivariable-adjusted heritability of CCL2 concentrations is as much as 0.37 in the blood plasma and 0.44 - in the serum.
# Molecular biology
CCL2 is a monomeric polypeptide, with a molecular weight of approximately 13 kDa. CCL2 is anchored in the plasma membrane of endothelial cells by glycosaminoglycan side chains of proteoglycans. CCL2 is primarily secreted by monocytes, macrophages and dendritic cells. Platelet derived growth factor is a major inducer of CCL2 gene.
CCR2 and CCR4 are two cell surface receptors that bind CCL2.
CCL2 exhibits a chemotactic activity for monocytes and basophils. However, it does not attract neutrophils or
eosinophils. After deletion of the N-terminal residue, CCL2 loses its attractivity for basophils and becomes a chemoattractant of eosinophils. Basophils and mast cells that are treated with CCL2 release their granules to the intercellular space. This effect can be also potentiated by a pre-treatment with IL-3 or even by other cytokines. CCL2 augments monocyte anti-tumor activity and it is essential for formation of granulomas. CCL2 protein become a CCR2 antagonist when it is cleaved by metalloproteinase MMP-12.
CCL2 can be found at the sites of tooth eruption and bone degradation. In the bone, CCL2 is expressed by mature osteoclasts and osteoblasts and it is under control of nuclear factor κB (NFκB). In the human osteoclasts, CCL2 and RANTES (regulated on activation normal T cell expressed and secreted). Both MCP-1 and RANTES induce formation of TRAP-positive, multinuclear cells from M-CSF-treated monocytes in the absence of RANKL, but produced osteoclasts that lacked cathepsin K expression and resorptive capacity. It is proposed that CCL2 and RANTES act as autocrine loop in human osteoclast differentiation.
The CCL2 chemokine is also expressed by neurons, astrocytes and microglia. The expression of CCL2 in neurons is mainly found in the cerebral cortex, globus pallidus, hippocampus, paraventricular and supraoptic hypothalamic nuclei, lateral hypothalamus, substantia nigra, facial nuclei, motor and spinal trigeminal nuclei, gigantocellular reticular nucleus and in Purkinje cells in the cerebellum.
# Clinical importance
CCL2 is implicated in pathogeneses of several diseases characterized by monocytic infiltrates, such as psoriasis, rheumatoid arthritis and atherosclerosis.
Administration of anti-CCL2 antibodies in a model of glomerulonephritis reduces infiltration of macrophages and T cells, reduces crescent formation, as well as scarring and renal impairment.
CCL2 is involved in the neuroinflammatory processes that takes place in the various diseases of the central nervous system (CNS), which are characterized by neuronal degeneration. CCL2 expression in glial cells is increased in epilepsy, brain ischemia Alzheimer's disease experimental autoimmune encephalomyelitis (EAE), and traumatic brain injury.
Hypomethylation of CpG sites within the CCL2 promoter region is affected by high levels of blood glucose and TG, which increase CCL2 levels in the blood serum. The later plays an important role in the vascular complications of type 2 diabetes.
CCL2 induces amylin expression through ERK1/ERK2/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. Amylin upregulation by CCL2 contributes to the elevation of the plasma amylin and insulin resistance in obesity.
Adipocytes secrete various adipokines that may be involved in the negative cross-talk between adipose tissue and skeletal muscle. CCL2 impairs insulin signaling in skeletal muscle cells via ERK1/2 activation at doses similar to its physiological plasma concentrations (200 pg/mL), but does not involve activation of the NF-κB pathway. CCL2 significantly reduced insulin-stimulated glucose uptake in myocytes. CCL2 may represent a molecular link in the negative cross-talk between adipose tissue and skeletal muscle assigning a completely novel important role to CCL2 besides inflammation.
Incubation of HL-1 cardiomyocytes and human myocytes with oxidized-LDL induced the expression of BNP and CCL2 genes, while native LDL (N-LDL) had no effect.
Treatment with melatonin in old mice with age related liver inflammation decreased the mRNA expression of TNF-α, IL-1β, HO (HO-1 and HO-2), iNOS, CCL2, NF-κB1, NF-κB2 and NKAP in old male mice. The protein expression of TNF-α, IL-1β was also decreased and IL-10 increased with melatonin treatment. Exogenous administration of melatonin was able to reduce inflammation. | CCL2
For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.
The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. CCL2 is a small cytokine that belongs to the CC chemokine family. CCL2 recruits monocytes, memory T cells, and dendritic cells to the sites of inflammation produced by either tissue injury or infection.[1][2]
# Genomics
In the human genome, CCL2 and many other CC chemokines are located on chromosome 17 (17q11.2-q21.1).[3] The gene span is 1,927 bases and the CCL2 gene resides on the Watson (plus) strand. The CCL2 gene has three exons and two introns. The CCL2 protein precursor contains a signal peptide of 23 amino acids. In turn, the mature CCL2 is 76 amino acids long.[4][5] The CCL2 predicted weight is 11.025 kiloDaltons (kDa).
# Population genetics
In humans, the levels of CCL2 can vary considerably. In the white people of European descent, the multivariable-adjusted heritability of CCL2 concentrations is as much as 0.37 in the blood plasma and 0.44 - in the serum.[6][7]
# Molecular biology
CCL2 is a monomeric polypeptide, with a molecular weight of approximately 13 kDa. CCL2 is anchored in the plasma membrane of endothelial cells by glycosaminoglycan side chains of proteoglycans. CCL2 is primarily secreted by monocytes, macrophages and dendritic cells. Platelet derived growth factor is a major inducer of CCL2 gene.
CCR2 and CCR4 are two cell surface receptors that bind CCL2.[8]
CCL2 exhibits a chemotactic activity for monocytes and basophils. However, it does not attract neutrophils or
eosinophils. After deletion of the N-terminal residue, CCL2 loses its attractivity for basophils and becomes a chemoattractant of eosinophils. Basophils and mast cells that are treated with CCL2 release their granules to the intercellular space. This effect can be also potentiated by a pre-treatment with IL-3 or even by other cytokines.[9][10] CCL2 augments monocyte anti-tumor activity and it is essential for formation of granulomas. CCL2 protein become a CCR2 antagonist when it is cleaved by metalloproteinase MMP-12.[11]
CCL2 can be found at the sites of tooth eruption and bone degradation. In the bone, CCL2 is expressed by mature osteoclasts and osteoblasts and it is under control of nuclear factor κB (NFκB). In the human osteoclasts, CCL2 and RANTES (regulated on activation normal T cell expressed and secreted). Both MCP-1 and RANTES induce formation of TRAP-positive, multinuclear cells from M-CSF-treated monocytes in the absence of RANKL, but produced osteoclasts that lacked cathepsin K expression and resorptive capacity. It is proposed that CCL2 and RANTES act as autocrine loop in human osteoclast differentiation.[12]
The CCL2 chemokine is also expressed by neurons, astrocytes and microglia. The expression of CCL2 in neurons is mainly found in the cerebral cortex, globus pallidus, hippocampus, paraventricular and supraoptic hypothalamic nuclei, lateral hypothalamus, substantia nigra, facial nuclei, motor and spinal trigeminal nuclei, gigantocellular reticular nucleus and in Purkinje cells in the cerebellum.[13]
# Clinical importance
CCL2 is implicated in pathogeneses of several diseases characterized by monocytic infiltrates, such as psoriasis, rheumatoid arthritis and atherosclerosis.[14]
Administration of anti-CCL2 antibodies in a model of glomerulonephritis reduces infiltration of macrophages and T cells, reduces crescent formation, as well as scarring and renal impairment.[15]
CCL2 is involved in the neuroinflammatory processes that takes place in the various diseases of the central nervous system (CNS), which are characterized by neuronal degeneration.[16] CCL2 expression in glial cells is increased in epilepsy,[17][18] brain ischemia[19] Alzheimer's disease[20] experimental autoimmune encephalomyelitis (EAE),[21] and traumatic brain injury.[22]
Hypomethylation of CpG sites within the CCL2 promoter region is affected by high levels of blood glucose and TG, which increase CCL2 levels in the blood serum. The later plays an important role in the vascular complications of type 2 diabetes.[23]
CCL2 induces amylin expression through ERK1/ERK2/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. Amylin upregulation by CCL2 contributes to the elevation of the plasma amylin and insulin resistance in obesity.[24]
Adipocytes secrete various adipokines that may be involved in the negative cross-talk between adipose tissue and skeletal muscle. CCL2 impairs insulin signaling in skeletal muscle cells via ERK1/2 activation at doses similar to its physiological plasma concentrations (200 pg/mL), but does not involve activation of the NF-κB pathway. CCL2 significantly reduced insulin-stimulated glucose uptake in myocytes. CCL2 may represent a molecular link in the negative cross-talk between adipose tissue and skeletal muscle assigning a completely novel important role to CCL2 besides inflammation.[25]
Incubation of HL-1 cardiomyocytes and human myocytes with oxidized-LDL induced the expression of BNP and CCL2 genes, while native LDL (N-LDL) had no effect.[26]
Treatment with melatonin in old mice with age related liver inflammation decreased the mRNA expression of TNF-α, IL-1β, HO (HO-1 and HO-2), iNOS, CCL2, NF-κB1, NF-κB2 and NKAP in old male mice. The protein expression of TNF-α, IL-1β was also decreased and IL-10 increased with melatonin treatment. Exogenous administration of melatonin was able to reduce inflammation.[27] | https://www.wikidoc.org/index.php/CCL2 | |
c136878edabe7a1f16a6af26dbe7791e7e942b00 | wikidoc | CCL3 | CCL3
Chemokine (C-C motif) ligand 3 (CCL3) also known as macrophage inflammatory protein 1-alpha (MIP-1-alpha) is a protein that in humans is encoded by the CCL3 gene.
# Function
CCL3 is a cytokine belonging to the CC chemokine family that is involved in the acute inflammatory state in the recruitment and activation of polymorphonuclear leukocytes through binding to the receptors CCR1, CCR4 and CCR5.
Sherry et al. (1988) demonstrated 2 protein components of MIP1, called by them alpha (CCL3, this protein) and beta (CCL4).
CCL3 produces a monophasic fever of rapid onset whose magnitude is equal to or greater than that of fevers produced with either recombinant human tumor necrosis factor or recombinant human interleukin-1. However, in contrast to these two endogenous pyrogens, the fever induced by MIP-1 is not inhibited by the cyclooxygenase inhibitor ibuprofen and CCL3 may participate in the febrile response that is not mediated through prostaglandin synthesis and clinically cannot be ablated by cyclooxygenase.
# Interactions
CCL3 has been shown to interact with CCL4.
Attracts macrophages, monocytes and neutrophils. | CCL3
Chemokine (C-C motif) ligand 3 (CCL3) also known as macrophage inflammatory protein 1-alpha (MIP-1-alpha) is a protein that in humans is encoded by the CCL3 gene.[1]
# Function
CCL3 is a cytokine belonging to the CC chemokine family that is involved in the acute inflammatory state in the recruitment and activation of polymorphonuclear leukocytes[2] through binding to the receptors CCR1, CCR4 and CCR5.[1]
Sherry et al. (1988) demonstrated 2 protein components of MIP1, called by them alpha (CCL3, this protein) and beta (CCL4).[3][1]
CCL3 produces a monophasic fever of rapid onset whose magnitude is equal to or greater than that of fevers produced with either recombinant human tumor necrosis factor or recombinant human interleukin-1. However, in contrast to these two endogenous pyrogens, the fever induced by MIP-1 is not inhibited by the cyclooxygenase inhibitor ibuprofen and CCL3 may participate in the febrile response that is not mediated through prostaglandin synthesis and clinically cannot be ablated by cyclooxygenase.[4]
# Interactions
CCL3 has been shown to interact with CCL4.[5]
Attracts macrophages, monocytes and neutrophils. | https://www.wikidoc.org/index.php/CCL3 | |
9cb95717c6b7bd1799e229d3850e9e7624e1661c | wikidoc | CCL4 | CCL4
Chemokine (C-C motif) ligand 4, also known as CCL4, is a protein which in humans is encoded by the CCL4 gene.
# Function
CCL4, also known as Macrophage inflammatory protein-1β (MIP-1β) is a CC chemokine with specificity for CCR5 receptors. It is a chemoattractant for natural killer cells, monocytes and a variety of other immune cells.
CCL4 is a major HIV-suppressive factor produced by CD8+ T cells.
Perforin-low memory CD8+ T cells that normally synthesize MIP-1-beta.
CCL4 is produced by: monocytes, B cells, T cells, fibroblasts, endothelial cells, and epithelial cells.
Concentration of this chemokine has been shown to be inversely related with MicroRNA-125b. Concentration of CCL4 within the body increases with age, which may cause chronic inflammation and liver damage.
# Interactions
CCL4 has been shown to interact with CCL3.
CCL4 binds to G protein-Coupled Receptors CCR5 and CCR8. | CCL4
Chemokine (C-C motif) ligand 4, also known as CCL4, is a protein which in humans is encoded by the CCL4 gene.[1]
# Function
CCL4, also known as Macrophage inflammatory protein-1β (MIP-1β) is a CC chemokine with specificity for CCR5 receptors. It is a chemoattractant for natural killer cells, monocytes and a variety of other immune cells.[2]
CCL4 is a major HIV-suppressive factor produced by CD8+ T cells.[3]
Perforin-low memory CD8+ T cells that normally synthesize MIP-1-beta.[4]
CCL4 is produced by: monocytes, B cells, T cells, fibroblasts, endothelial cells, and epithelial cells.[5]
Concentration of this chemokine has been shown to be inversely related with MicroRNA-125b. Concentration of CCL4 within the body increases with age, which may cause chronic inflammation and liver damage.[5][6]
# Interactions
CCL4 has been shown to interact with CCL3.[7]
CCL4 binds to G protein-Coupled Receptors CCR5 and CCR8.[5] | https://www.wikidoc.org/index.php/CCL4 | |
62c8b388011148fab671bbc489e83b644ad0a8d5 | wikidoc | CCL5 | CCL5
Chemokine (C-C motif) ligand 5 (also CCL5) is a protein which in humans is encoded by the CCL5 gene. It is also known as RANTES (regulated on activation, normal T cell expressed and secreted).
# Function
CCL5 is an 8kDa protein classified as a chemotactic cytokine or chemokine. CCL5 is chemotactic for T cells, eosinophils, and basophils, and plays an active role in recruiting leukocytes into inflammatory sites. With the help of particular cytokines (i.e., IL-2 and IFN-γ) that are released by T cells, CCL5 also induces the proliferation and activation of certain natural-killer (NK) cells to form CHAK (CC-Chemokine-activated killer) cells. It is also an HIV-suppressive factor released from CD8+ T cells. This chemokine has been localized to chromosome 17 in humans.
RANTES was first identified in a search for genes expressed "late" (3–5 days) after T cell activation. It was subsequently determined to be a CC chemokine and expressed in more than 100 human diseases. RANTES expression is regulated in T lymphocytes by Kruppel like factor 13 (KLF13). RANTES, along with the related chemokines MIP-1alpha and MIP-1beta, has been identified as a natural HIV-suppressive factor secreted by activated CD8+ T cells and other immune cells. Recently, the RANTES protein has been engineered for in vivo production by Lactobacillus bacteria, and this solution is being developed into a possible HIV entry-inhibiting topical microbicide.
# Interactions
CCL5 has been shown to interact with CCR3, CCR5 and CCR1.
CCL5 also activates the G-protein coupled receptor GPR75. | CCL5
Chemokine (C-C motif) ligand 5 (also CCL5) is a protein which in humans is encoded by the CCL5 gene.[1] It is also known as RANTES (regulated on activation, normal T cell expressed and secreted).
# Function
CCL5 is an 8kDa protein classified as a chemotactic cytokine or chemokine. CCL5 is chemotactic for T cells, eosinophils, and basophils, and plays an active role in recruiting leukocytes into inflammatory sites. With the help of particular cytokines (i.e., IL-2 and IFN-γ) that are released by T cells, CCL5 also induces the proliferation and activation of certain natural-killer (NK) cells to form CHAK (CC-Chemokine-activated killer) cells.[2] It is also an HIV-suppressive factor released from CD8+ T cells[citation needed]. This chemokine has been localized to chromosome 17 in humans.[1]
RANTES was first identified in a search for genes expressed "late" (3–5 days) after T cell activation. It was subsequently determined to be a CC chemokine and expressed in more than 100 human diseases. RANTES expression is regulated in T lymphocytes by Kruppel like factor 13 (KLF13).[3][4][5][6] RANTES, along with the related chemokines MIP-1alpha and MIP-1beta, has been identified as a natural HIV-suppressive factor secreted by activated CD8+ T cells and other immune cells.[7] Recently, the RANTES protein has been engineered for in vivo production by Lactobacillus bacteria, and this solution is being developed into a possible HIV entry-inhibiting topical microbicide.[8]
# Interactions
CCL5 has been shown to interact with CCR3, [9] [10] CCR5[10][11][12] and CCR1.[10][12]
CCL5 also activates the G-protein coupled receptor GPR75. [13] | https://www.wikidoc.org/index.php/CCL5 | |
00faa9cfa42fec35294bdc1f9ecb9f9f70b3252e | wikidoc | CCL8 | CCL8
Chemokine (C-C motif) ligand 8 (CCL8), also known as monocyte chemoattractant protein 2 (MCP2), is a protein that in humans is encoded by the CCL8 gene.
CCL8 is a small cytokine belonging to the CC chemokine family. The CCL8 protein is produced as a precursor containing 109 amino acids, which is cleaved to produce mature CCL8 containing 75 amino acids. The gene for CCL8 is encoded by 3 exons and is located within a large cluster of CC chemokines on chromosome 17q11.2 in humans. MCP-2 is chemotactic for and activates many different immune cells, including mast cells, eosinophils and basophils, (that are implicated in allergic responses), and monocytes, T cells, and NK cells that are involved in the inflammatory response. CCL8 elicits its effects by binding to several different cell surface receptors called chemokine receptors. These receptors include CCR1, CCR2B, CCR3 and CCR5.
CCL8 is a CC chemokine that utilizes multiple cellular receptors to attract and activate human leukocytes. CCL8 is a potent inhibitor of HIV1 by virtue of its high-affinity binding to the receptor CCR5, one of the major co-receptors for HIV1. In addition, CCL8 attributes to the growth of metastasis in breast cancer cells. The manipulation of this chemokine activity influences the histology of tumors promoting steps of metastatic processes. CCL8 is also involved in attracting macrophages to the decidua in labor. | CCL8
Chemokine (C-C motif) ligand 8 (CCL8), also known as monocyte chemoattractant protein 2 (MCP2), is a protein that in humans is encoded by the CCL8 gene.[1][2]
CCL8 is a small cytokine belonging to the CC chemokine family. The CCL8 protein is produced as a precursor containing 109 amino acids, which is cleaved to produce mature CCL8 containing 75 amino acids. The gene for CCL8 is encoded by 3 exons and is located within a large cluster of CC chemokines on chromosome 17q11.2 in humans.[2][3] MCP-2 is chemotactic for and activates many different immune cells, including mast cells, eosinophils and basophils, (that are implicated in allergic responses), and monocytes, T cells, and NK cells that are involved in the inflammatory response.[4][5] CCL8 elicits its effects by binding to several different cell surface receptors called chemokine receptors. These receptors include CCR1, CCR2B, CCR3 and CCR5.[5][6]
CCL8 is a CC chemokine that utilizes multiple cellular receptors to attract and activate human leukocytes. CCL8 is a potent inhibitor of HIV1 by virtue of its high-affinity binding to the receptor CCR5, one of the major co-receptors for HIV1.[7] In addition, CCL8 attributes to the growth of metastasis in breast cancer cells. The manipulation of this chemokine activity influences the histology of tumors promoting steps of metastatic processes.[8] CCL8 is also involved in attracting macrophages to the decidua in labor.[9] | https://www.wikidoc.org/index.php/CCL8 | |
59b122969f390e2806af081e77065670384fc0cc | wikidoc | CCM2 | CCM2
The CCM2 gene contains 10 coding exons and an alternatively spliced exon 1B. This gene is located on chromosome 7p13 and loss of function mutations on CCM2 lead to the onset of Cerebral Cavernous Malformations (CCM) illness. Cerebral cavernous malformations (CCMs) are vascular malformations in the brain and spinal cord made of dilated capillary vessels.
# Protein
Malcavernin is a protein that in humans is encoded by the CCM2 gene. The normal function of malcavernin is to act as a scaffold for a variety of signaling complexes including p38 MAP Kinase. This protein is also involved in regulating the cellular localization of the KRIT1 protein and acts with the Rho Kinase signaling pathway to maintain normal blood vessel structure.
# Advocacy
For more information and support for Cerebral Cavernous Malformations Patients and their families, please visit the Angioma Alliance website: www.angioma.org | CCM2
The CCM2 gene contains 10 coding exons and an alternatively spliced exon 1B. This gene is located on chromosome 7p13 and loss of function mutations on CCM2 lead to the onset of Cerebral Cavernous Malformations (CCM) illness.[1] Cerebral cavernous malformations (CCMs) are vascular malformations in the brain and spinal cord made of dilated capillary vessels.
# Protein
Malcavernin is a protein that in humans is encoded by the CCM2 gene.[2][3] The normal function of malcavernin is to act as a scaffold for a variety of signaling complexes including p38 MAP Kinase.[4] This protein is also involved in regulating the cellular localization of the KRIT1 protein[5] and acts with the Rho Kinase signaling pathway to maintain normal blood vessel structure.[6][7]
# Advocacy
For more information and support for Cerebral Cavernous Malformations Patients and their families, please visit the Angioma Alliance website: www.angioma.org | https://www.wikidoc.org/index.php/CCM2 |
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