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e7bbab1a719ab61d26206d0abaec000adc96a6c0 | wikidoc | HAVCR1 | HAVCR1
Hepatitis A virus cellular receptor 1 (HAVcr-1) also known as T-cell immunoglobulin and mucin domain 1 (TIM-1) is a protein that in humans is encoded by the HAVCR1 gene.
It is also known as KIM-1 Kidney Injury Molecule -1, which is a protein the most highly upregulated in injured kidneys by various types of insults. Its upregulation during renal injury has been found in the kidneys of the vertebrates such as Zebrafish and humans.
The hepatitis A virus cellular receptor 1 (HAVCR1/TIM-1), is a member of the TIM (T cell transmembrane, immunoglobulin, and mucin) gene family, which plays critical roles in regulating immune cell activity especially regarding the host response to viral infection. TIM-1 is also involved in allergic response, asthma, and transplant tolerance.
The TIM gene family was first cloned from the mouse model of asthma in 2001. Subsequently, it was demonstrated that members of the TIM gene family including TIM-1 participate in host immune response. The mouse TIM gene family contains eight members (TIM-1-8) while only three TIM genes (TIM-1, TIM-3, and TIM-4) have been identified in humans.
# Structure and function
TIM genes belong to type I cell-surface glycoproteins, which include an N-terminal immunoglobulin (Ig)-like domain, a mucin domain with distinct length, a single transmembrane domain, and a C-terminal short cytoplasmic tail. The localization and functions of TIM genes are divergent between each member. TIM-1 is preferentially expressed on Th2 cells and has been identified as a stimulatory molecule for T-cell activation. TIM-3 is preferentially expressed on Th1 and Tc1 cells and function as an inhibitory molecule, which mediated apoptosis of Th1 and Tc1 cells. TIM-4 is preferentially expressed on antigen-presenting cells, modulating the phagocytosis of apoptotic cells by interacting with phosphatidylserine (PS) exposed on apoptotic cell surface.
# Role in viral infection
TIM genes are also involved in host-virus interaction. As receptors for phosphatidylserine, TIM proteins bind many families of viruses that include viruses such as dengue and ebola. Entry of Lassa fever virus, influenza A virus, and SARS coronavirus were not affected by TIM-1 expression. TIM-1 and TIM-4 enhanced viral entry more than TIM-3.
## Hepatitis A
TIM-1 has been identified as the cellular receptor of hepatitis A virus (HAV). The mucin domain and IgV domain were critical for virus uncoating and infectivity. By using an expression cloning library, IgA has been demonstrated as a specific ligand of TIM-1. The association of TIM-1 and IgA was able to enhance the virus-receptor interaction.
## Ebola
Recently, TIM-1 has been shown to be a receptor or cofactor for Ebola virus entry. TIM-1 binds to Ebola virus glycoproteins (GP) and mediates Ebola virus cellular entry by increasing Ebola virus infectivity in cell lines with a low susceptibility. Moreover, reducing expression of endogenous TIM-1 in highly permissive cell lines decreased Ebola virus infectivity. Furthermore, TIM-1 IgV domain specific antibody ARD5 inhibited Ebola virus infectivity, indicating that TIM-1 was critical for Ebola virus entry. Also, TIM-1 expression on human mucosal epithelial cells from the trachea, cornea and conjunctiva demonstrated the correlation of TIM-1 expression feature and viral entry routes.
## Dengue
TIM-1 has been identified as a cellular factor for Dengue virus entry by overexpression of TIM-1 on poorly susceptible cell lines for Dengue virus infection. TIM-1 enhanced dengue virus infectivity by 500-fold, particularly increased virus internalization. TIM-1 directly interacted with Dengue virus particle by recognizing PS on the virion surface. In addition, the Dengue virus susceptibility of different cell lines was consistent with endogenous expression level of TIM-1 gene in such cell lines, suggesting that TIM-1 is crucial for Dengue virus entry. | HAVCR1
Hepatitis A virus cellular receptor 1 (HAVcr-1) also known as T-cell immunoglobulin and mucin domain 1 (TIM-1) is a protein that in humans is encoded by the HAVCR1 gene.[1][2][3]
It is also known as KIM-1 Kidney Injury Molecule -1, which is a protein the most highly upregulated in injured kidneys by various types of insults. Its upregulation during renal injury has been found in the kidneys of the vertebrates such as Zebrafish and humans.
The hepatitis A virus cellular receptor 1 (HAVCR1/TIM-1), is a member of the TIM (T cell transmembrane, immunoglobulin, and mucin) gene family, which plays critical roles in regulating immune cell activity especially regarding the host response to viral infection. TIM-1 is also involved in allergic response, asthma, and transplant tolerance.
The TIM gene family was first cloned from the mouse model of asthma in 2001.[2] Subsequently, it was demonstrated that members of the TIM gene family including TIM-1 participate in host immune response. The mouse TIM gene family contains eight members (TIM-1-8) while only three TIM genes (TIM-1, TIM-3, and TIM-4) have been identified in humans.
# Structure and function
TIM genes belong to type I cell-surface glycoproteins, which include an N-terminal immunoglobulin (Ig)-like domain, a mucin domain with distinct length, a single transmembrane domain, and a C-terminal short cytoplasmic tail. The localization and functions of TIM genes are divergent between each member. TIM-1 is preferentially expressed on Th2 cells and has been identified as a stimulatory molecule for T-cell activation.[4] TIM-3 is preferentially expressed on Th1 and Tc1 cells and function as an inhibitory molecule, which mediated apoptosis of Th1 and Tc1 cells.[5] TIM-4 is preferentially expressed on antigen-presenting cells, modulating the phagocytosis of apoptotic cells by interacting with phosphatidylserine (PS) exposed on apoptotic cell surface.[6]
# Role in viral infection
TIM genes are also involved in host-virus interaction. As receptors for phosphatidylserine, TIM proteins bind many families of viruses [filovirus, flavivirus, New World arenavirus and alphavirus] that include viruses such as dengue and ebola. Entry of Lassa fever virus, influenza A virus, and SARS coronavirus were not affected by TIM-1 expression. TIM-1 and TIM-4 enhanced viral entry more than TIM-3.[7]
## Hepatitis A
TIM-1 has been identified as the cellular receptor of hepatitis A virus (HAV). The mucin domain and IgV domain were critical for virus uncoating and infectivity. By using an expression cloning library, IgA has been demonstrated as a specific ligand of TIM-1. The association of TIM-1 and IgA was able to enhance the virus-receptor interaction.[8]
## Ebola
Recently, TIM-1 has been shown to be a receptor or cofactor for Ebola virus entry. TIM-1 binds to Ebola virus glycoproteins (GP) and mediates Ebola virus cellular entry by increasing Ebola virus infectivity in cell lines with a low susceptibility. Moreover, reducing expression of endogenous TIM-1 in highly permissive cell lines decreased Ebola virus infectivity.[9] Furthermore, TIM-1 IgV domain specific antibody ARD5 inhibited Ebola virus infectivity, indicating that TIM-1 was critical for Ebola virus entry. Also, TIM-1 expression on human mucosal epithelial cells from the trachea, cornea and conjunctiva demonstrated the correlation of TIM-1 expression feature and viral entry routes.
## Dengue
TIM-1 has been identified as a cellular factor for Dengue virus entry by overexpression of TIM-1 on poorly susceptible cell lines for Dengue virus infection. TIM-1 enhanced dengue virus infectivity by 500-fold, particularly increased virus internalization. TIM-1 directly interacted with Dengue virus particle by recognizing PS on the virion surface.[10] In addition, the Dengue virus susceptibility of different cell lines was consistent with endogenous expression level of TIM-1 gene in such cell lines, suggesting that TIM-1 is crucial for Dengue virus entry. | https://www.wikidoc.org/index.php/HAVCR1 | |
b3524b89268918eb4f2704765d3d2e840001589c | wikidoc | HAVCR2 | HAVCR2
Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells (dendritic cells, NK cells, monocytes).
# Structure
HAVCR2 belongs to TIM family cell surface receptor proteins. These proteins share a similar structure, in which the extracellular region consists of membrane distal single variable immunoglobulin domain (IgV) and a glycosylated mucin domain of variable length located closer to the membrane. Intracellular domain of HAVCR2 is called C-terminal cytoplasmic tail. It contains five conserved tyrosine residues that interact with multiple components of T-cell receptor (TCR) complex and negatively regulates its function.
# Function
HAVCR2 is an immune checkpoint and together with other inhibitory receptors including programmed cell death protein 1 (PD-1) and lymphocyte activation gene 3 protein (LAG3) mediate the CD8+ T-cell exhaustion. HAVCR2 has also been shown as a CD4+ Th1-specific cell surface protein that regulates macrophage activation and enhances the severity of experimental autoimmune encephalomyelitis in mice.
HAVCR2 is primarily activated by galectin-9. The engagement leads to stimulation of an influx of calcium to intracellular space and induction of programmed cell death, apoptosis. As a consequence, a suppression of Th1 and Th17 responses and induction of immune tolerance occurs. In addition to galectin-9, a couple other ligands have been identified, such as phospatidyl serine (PtdSer), High Mobility Group Protein 1 (HMGB1) and Carcinoembryonic Antigen Related Cell Adhesion Molecule 1 (CEACAM1). The binding of PtdSer has been shown to cause an uptake of apoptotic cells and reduced cross presentation of dying cell-associated antigens by dendritic cells. The binding of HMGB1 can interfere with nucleic acid stimulation and suppresses activation of innate immune response. The role of CEACAM1 engagement is still not clear.
# Clinical significance
HAVCR2 expression is up regulated in tumor-infiltrating lymphocytes in lung, gastric, head and neck cancer, schwannoma, melanoma and follicular B-cell non-Hodgkin lymphoma.
The HAVCR2 pathway may interact with the PD-1 pathway in the dysfunctional CD8+ T cells and Tregs in cancer. HAVCR2 is mainly expressed on activated CD8+ T cells and suppresses macrophage activation following PD-1 inhibition. Upregulation was observed in tumors progressing after anti-PD-1 therapy. This seems to be a form of adaptive resistance to immunotherapy. Multiple phase 1/2 clinical trials with anti-HAVCR2 monoclonal antibodies (LY3321367, Eli Lilly and Company; MBG453, Novartis Pharmaceuticals; TSR-022, Tesaro, Inc.) in combination with anti-PD-1 or anti-PD-L1 therapies are ongoing.
The role of HAVCR2 in the T-cell dysfunction has been investigated in chronic viral infections. | HAVCR2
Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells.[1][2] Later, the expression was detected in Th17 cells,[3] regulatory T-cells,[4] and innate immune cells (dendritic cells, NK cells, monocytes).[5]
# Structure
HAVCR2 belongs to TIM family cell surface receptor proteins. These proteins share a similar structure, in which the extracellular region consists of membrane distal single variable immunoglobulin domain (IgV) and a glycosylated mucin domain of variable length located closer to the membrane.[6] Intracellular domain of HAVCR2 is called C-terminal cytoplasmic tail. It contains five conserved tyrosine residues that interact with multiple components of T-cell receptor (TCR) complex[7][8] and negatively regulates its function.[9]
# Function
HAVCR2 is an immune checkpoint and together with other inhibitory receptors including programmed cell death protein 1 (PD-1) and lymphocyte activation gene 3 protein (LAG3) mediate the CD8+ T-cell exhaustion.[10] HAVCR2 has also been shown as a CD4+ Th1-specific cell surface protein that regulates macrophage activation and enhances the severity of experimental autoimmune encephalomyelitis in mice.[1]
HAVCR2 is primarily activated by galectin-9.[11] The engagement leads to stimulation of an influx of calcium to intracellular space and induction of programmed cell death, apoptosis.[12] As a consequence, a suppression of Th1 and Th17 responses and induction of immune tolerance occurs. In addition to galectin-9, a couple other ligands have been identified, such as phospatidyl serine (PtdSer),[13] High Mobility Group Protein 1 (HMGB1)[14] and Carcinoembryonic Antigen Related Cell Adhesion Molecule 1 (CEACAM1).[15] The binding of PtdSer has been shown to cause an uptake of apoptotic cells and reduced cross presentation of dying cell-associated antigens by dendritic cells.[16] The binding of HMGB1 can interfere with nucleic acid stimulation and suppresses activation of innate immune response.[14] The role of CEACAM1 engagement is still not clear.
# Clinical significance
HAVCR2 expression is up regulated in tumor-infiltrating lymphocytes in lung,[4] gastric,[17] head and neck cancer,[18] schwannoma,[19] melanoma[20] and follicular B-cell non-Hodgkin lymphoma.[21]
The HAVCR2 pathway may interact with the PD-1 pathway in the dysfunctional CD8+ T cells and Tregs in cancer.[22][4] HAVCR2 is mainly expressed on activated CD8+ T cells and suppresses macrophage activation following PD-1 inhibition.[23] Upregulation was observed in tumors progressing after anti-PD-1 therapy.[24] This seems to be a form of adaptive resistance to immunotherapy. Multiple phase 1/2 clinical trials with anti-HAVCR2 monoclonal antibodies (LY3321367,[25] Eli Lilly and Company; MBG453,[26] Novartis Pharmaceuticals; TSR-022,[27] Tesaro, Inc.) in combination with anti-PD-1 or anti-PD-L1 therapies are ongoing.
The role of HAVCR2 in the T-cell dysfunction has been investigated in chronic viral infections.[28] | https://www.wikidoc.org/index.php/HAVCR2 | |
05541c9cb58b33e6d4c9bef3428e03857a3b5632 | wikidoc | HDAC10 | HDAC10
Histone deacetylase 10 is an enzyme that in humans is encoded by the HDAC10 gene.
Acetylation of histone core particles modulates chromatin structure and gene expression. The opposing enzymatic activities of histone acetyltransferases and histone deacetylases, such as HDAC10, determine the acetylation status of histone tails (Kao et al., 2002).
# Interactions
HDAC10 has been shown to interact with Histone deacetylase 2 and Nuclear receptor co-repressor 2. | HDAC10
Histone deacetylase 10 is an enzyme that in humans is encoded by the HDAC10 gene.[1][2][3]
Acetylation of histone core particles modulates chromatin structure and gene expression. The opposing enzymatic activities of histone acetyltransferases and histone deacetylases, such as HDAC10, determine the acetylation status of histone tails (Kao et al., 2002).[supplied by OMIM][3]
# Interactions
HDAC10 has been shown to interact with Histone deacetylase 2[4] and Nuclear receptor co-repressor 2.[4] | https://www.wikidoc.org/index.php/HDAC10 | |
18d3ab191a58e2669724ece3eb073a56477fae7c | wikidoc | HDAC11 | HDAC11
Histone deacetylase 11 is a 39kDa histone deacetylase enzyme that in humans is encoded by the HDAC11 gene on chromosome 3 in humans and chromosome 6 in mice.
It is the only Class IV HDAC since it is not highly homologous with either Rpd3 or hda1 yeast enzymes and so does not fit into either Class I or Class II. It is the smallest HDAC isoform and it was first described in 2002.
# Function
Histone deacetylases, such as HDAC11, control DNA expression by modifying the core histone octamers that package DNA into dense chromatin structures and repress gene expression.
HDAC11 expression is normally found in brain and testis tissue, but upregulation of HDAC11 expression has also been seen in various cancer cells.
HDAC11 has been shown to be a negative regulator of IL-10 production in antigen presenting cells. It has also been shown that inhibition of HDAC11 results in increased expression of OX40L in Hodgkin lymphoma cells.
# Interactions
HDAC11 has been shown to interact with HDAC6. | HDAC11
Histone deacetylase 11 is a 39kDa histone deacetylase enzyme that in humans is encoded by the HDAC11 gene on chromosome 3 in humans and chromosome 6 in mice.[1][2]
It is the only Class IV HDAC since it is not highly homologous with either Rpd3 or hda1 yeast enzymes and so does not fit into either Class I or Class II.[3] It is the smallest HDAC isoform and it was first described in 2002.
# Function
Histone deacetylases, such as HDAC11, control DNA expression by modifying the core histone octamers that package DNA into dense chromatin structures and repress gene expression.[supplied by OMIM][2]
HDAC11 expression is normally found in brain and testis tissue, but upregulation of HDAC11 expression has also been seen in various cancer cells.
HDAC11 has been shown to be a negative regulator of IL-10 production in antigen presenting cells. It has also been shown that inhibition of HDAC11 results in increased expression of OX40L in Hodgkin lymphoma cells.
# Interactions
HDAC11 has been shown to interact with HDAC6.[1] | https://www.wikidoc.org/index.php/HDAC11 | |
b00277edc8f078701da3836b3bb1093bbe8cbf4c | wikidoc | HGSNAT | HGSNAT
Heparan-α-glucosaminide N-acetyltransferase (also called "acetyl-CoA:heparan-α-D-glucosaminide N-acetyltransferase" and "acetyl-CoA:alpha-glucosaminide N-acetyltransferase") is an enzyme that in humans is encoded by the HGSNAT gene.
In enzymology, this enzyme belongs to the family of transferases, specifically those acyltransferases transferring groups other than aminoacyl groups. It is catalysed in the chemical reaction:
This enzyme participates in glycosaminoglycan degradation and glycan structures degradation. Mutations in the gene encoding this enzyme cause mucopolysaccharidosis IIIC. | HGSNAT
Heparan-α-glucosaminide N-acetyltransferase (also called "acetyl-CoA:heparan-α-D-glucosaminide N-acetyltransferase" and "acetyl-CoA:alpha-glucosaminide N-acetyltransferase") is an enzyme that in humans is encoded by the HGSNAT gene.[1][2][3]
In enzymology, this enzyme belongs to the family of transferases, specifically those acyltransferases transferring groups other than aminoacyl groups. It is catalysed in the chemical reaction:
This enzyme participates in glycosaminoglycan degradation and glycan structures degradation. Mutations in the gene encoding this enzyme cause mucopolysaccharidosis IIIC.[2] | https://www.wikidoc.org/index.php/HGSNAT | |
5340b0591180c2a903bfd17d1b7d9f727417f2a2 | wikidoc | HHIPL1 | HHIPL1
HHIP-like protein 1 (HHIPL1), also known as HHIP2, is a protein that in humans is encoded by the HHIPL1 gene on chromosome 14. It is not significantly expressed in many tissues and cell types, though HHIPL1 mRNA has been detected in trabecular bone cells. Little is known about the precise biological function of HHIPL1, but the protein has been linked to adenomas. The HHIPL1 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
# Structure
## Gene
The HHIPL1 gene resides on chromosome 14 at the band 14q32 and contains 13 exons. This gene produces 2 isoforms through alternative splicing.
## Protein
This protein belongs to the HHIP family and is one of three members found in humans. HHIPL1 contains a SRCR domain and an N-terminal signal peptide. Processing of the signal peptide leads to this protein's secretion. As an HHIP member, it also contains a conserved HHIP-homologous (HIPH) domain composed of 18 cysteine residues.
# Function
The function of HHIPL1 is not known. The section below refers to the function of HHIP.
The function of HHIP is not well known but has been shown to be tightly associated with lung function. Knocking out HHIP in mice is neonatally lethal due to defective branching in the lung. The heterozygous knockout of HHIP has been shown to contribute to more severe emphysema induced by cigarette smoke compared to wild type mice. Furthermore, increased spontaneous emphysema and oxidative stress levels have been found in the lungs of HHIP heterozygous mice. Both the expression level and enhancer activity of HHIP is reduced in chronic obstructive pulmonary disease (COPD) lungs, suggesting a protective role of HHIP in COPD pathogenesis.
# Clinical significance
DNA methylation is one of several epigenetic modifications recognized as hallmarks of tumorigenesis. In a genome-wide survey of subtype-specific epigenomic changes in adenoma, the HHIPL1 gene was hypermethylated in 12 of 13 non-functioning (NF) adenomas, as well as in growth hormone (GH)- and prolectin-secreting adenomas. Thus, HHIPL1 has the potential to serve as a biomarker to predict or characterise tumorous growth patterns. Unlike another member of the human HHIP gene family, HHIP, which is regarded as a pharmacogenomics target in the fields of oncology and vascular medicine, HHIPL1 has yet been reported with such potential.
Additionally, in the cardiovascular field, HHIPL1 has been associated with CAD in Europeans, South Asians, and a population of Japanese. However, in another study based on a Japanese population, the association failed to be replicated, suggesting that this association is population-specific.
## Clinical marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the HHIFL1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). | HHIPL1
HHIP-like protein 1 (HHIPL1), also known as HHIP2, is a protein that in humans is encoded by the HHIPL1 gene on chromosome 14.[1] It is not significantly expressed in many tissues and cell types,[2] though HHIPL1 mRNA has been detected in trabecular bone cells.[3] Little is known about the precise biological function of HHIPL1, but the protein has been linked to adenomas.[4] The HHIPL1 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[5]
# Structure
## Gene
The HHIPL1 gene resides on chromosome 14 at the band 14q32 and contains 13 exons.[1] This gene produces 2 isoforms through alternative splicing.[6]
## Protein
This protein belongs to the HHIP family and is one of three members found in humans.[6] HHIPL1 contains a SRCR domain and an N-terminal signal peptide.[3][6] Processing of the signal peptide leads to this protein's secretion. As an HHIP member, it also contains a conserved HHIP-homologous (HIPH) domain composed of 18 cysteine residues.[3]
# Function
The function of HHIPL1 is not known. The section below refers to the function of HHIP.
The function of HHIP is not well known but has been shown to be tightly associated with lung function. Knocking out HHIP in mice is neonatally lethal due to defective branching in the lung.[7][8] The heterozygous knockout of HHIP has been shown to contribute to more severe emphysema induced by cigarette smoke compared to wild type mice.[9] Furthermore, increased spontaneous emphysema and oxidative stress levels have been found in the lungs of HHIP heterozygous mice.[10] Both the expression level and enhancer activity of HHIP is reduced in chronic obstructive pulmonary disease (COPD) lungs, suggesting a protective role of HHIP in COPD pathogenesis.[11]
# Clinical significance
DNA methylation is one of several epigenetic modifications recognized as hallmarks of tumorigenesis. In a genome-wide survey of subtype-specific epigenomic changes in adenoma, the HHIPL1 gene was hypermethylated in 12 of 13 non-functioning (NF) adenomas, as well as in growth hormone (GH)- and prolectin-secreting adenomas. Thus, HHIPL1 has the potential to serve as a biomarker to predict or characterise tumorous growth patterns.[4] Unlike another member of the human HHIP gene family, HHIP, which is regarded as a pharmacogenomics target in the fields of oncology and vascular medicine, HHIPL1 has yet been reported with such potential.[3]
Additionally, in the cardiovascular field, HHIPL1 has been associated with CAD in Europeans, South Asians, and a population of Japanese.[12][13] However, in another study based on a Japanese population, the association failed to be replicated, suggesting that this association is population-specific.[14]
## Clinical marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the HHIFL1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[5] | https://www.wikidoc.org/index.php/HHIPL1 | |
0e004d4681cb4b00af8de7f05d6c117f14d27288 | wikidoc | HIGD1A | HIGD1A
HIG1 domain family member 1A (HIGD1A), also known as hypoglycemia/hypoxia inducible mitochondrial protein1-a (HIMP1-a) and hypoxia induced gene 1 (HIG1), is a protein that in humans is encoded by the HIGD1A gene on chromosome 3. This protein promotes mitochondrial homeostasis and survival of cells under stress and is involved in inflammatory and hypoxia-related diseases, including atherosclerosis, ischemic heart disease, and Alzheimer’s disease, as well as cancer.
# Structure
The protein encoded by this gene is 10.4 kDa mitochondrial inner membrane protein with two transmembrane domains at the N- and C-terminals. These two domains are arranged such that the N- and C-terminals face outward into the intermembrane space while the rest of the protein loops inside the matrix. Though the N-terminal domain is not necessary to direct the localization of HIGD1A, it is required for the survival of the protein.
The gene HIGD1A is an isoform of HIMP1-b via alternative splicing.
# Function
HIGD1A primarily functions in mitochondrial homeostasis and, thus, cell survival when under conditions of stress, such as hypoxia and glucose deprivation. For instance, HIGD1A promotes survival of pancreatic α and β cells under stress. HIGD1A has also been found in other parts of the brain, heart, liver, and kidney, where it enhances the survival of these organs. In macrophages, HIGD1A prevents apoptosis by inhibiting cytochrome C release and caspase activity.
HIGD1A is also involved in mitochondrial fusion by regulating OPA1 activity. Its inhibition of the cleavage of OPA1 preserves mitochondrial membrane potential, protects against apoptosis, and maintains ATP levels. Its role in mitochondrial fusion also influences downstream processes such as mtDNA synthesis, cell growth, and cristae organization.
In addition, HIGD1A helps preserve mitochondrial function by regulating mitochondrial γ-secretase activity under hypoxic conditions. In the absence of HIGD1A, γ-secretase contributes to the accumulation of amyloid beta in the mitochondria, leading to increased ROS production, mitochondrial dysfunction, and eventually, cell death.
While HIGD1A predominantly contributes to cell survival, it can also promote apoptosis in neurons during the early developmental stages of the central nervous system.
# Clinical significance
Since HIGD1A promotes cell survival under hypoxia, the protein protects organs like the heart and brain from hypoxia-related diseases. In particular, HIGD1A localization to the nucleus correlates with the severity of stress in ischemic heart disease, hypoxic-ischemic encephalopathy, and cancer, and thus may serve as a biomarker for these diseases. Moreover, HIGD1A is involved in inflammatory diseases, such as atherosclerosis and rheumatoid arthritis, through its role in macrophage survival. Similarly, HIGD1A could become a key target for treating Alzheimer’s disease by inhibiting γ-secretase, and by extension, amyloid beta production. Notably, HIGD1A inhibits γ-secretase without interfering with Notch cleavage, thus minimizing detrimental side effects from targeting this protein.
# Interactions
HIGD1A is known to interact with:
- AIF,
- γ-secretase and
- OPA1. | HIGD1A
HIG1 domain family member 1A (HIGD1A), also known as hypoglycemia/hypoxia inducible mitochondrial protein1-a (HIMP1-a) and hypoxia induced gene 1 (HIG1), is a protein that in humans is encoded by the HIGD1A gene on chromosome 3.[1][2][3][4] This protein promotes mitochondrial homeostasis and survival of cells under stress and is involved in inflammatory and hypoxia-related diseases, including atherosclerosis, ischemic heart disease, and Alzheimer’s disease, as well as cancer.[4][5][6][7]
# Structure
The protein encoded by this gene is 10.4 kDa mitochondrial inner membrane protein with two transmembrane domains at the N- and C-terminals.[5][6] These two domains are arranged such that the N- and C-terminals face outward into the intermembrane space while the rest of the protein loops inside the matrix. Though the N-terminal domain is not necessary to direct the localization of HIGD1A, it is required for the survival of the protein.
The gene HIGD1A is an isoform of HIMP1-b via alternative splicing.[5]
# Function
HIGD1A primarily functions in mitochondrial homeostasis and, thus, cell survival when under conditions of stress, such as hypoxia and glucose deprivation. For instance, HIGD1A promotes survival of pancreatic α and β cells under stress.[4][5] HIGD1A has also been found in other parts of the brain, heart, liver, and kidney, where it enhances the survival of these organs.[4][7] In macrophages, HIGD1A prevents apoptosis by inhibiting cytochrome C release and caspase activity.[5][6]
HIGD1A is also involved in mitochondrial fusion by regulating OPA1 activity. Its inhibition of the cleavage of OPA1 preserves mitochondrial membrane potential, protects against apoptosis, and maintains ATP levels. Its role in mitochondrial fusion also influences downstream processes such as mtDNA synthesis, cell growth, and cristae organization.[4]
In addition, HIGD1A helps preserve mitochondrial function by regulating mitochondrial γ-secretase activity under hypoxic conditions.[4][7] In the absence of HIGD1A, γ-secretase contributes to the accumulation of amyloid beta in the mitochondria, leading to increased ROS production, mitochondrial dysfunction, and eventually, cell death.[7]
While HIGD1A predominantly contributes to cell survival, it can also promote apoptosis in neurons during the early developmental stages of the central nervous system.[6]
# Clinical significance
Since HIGD1A promotes cell survival under hypoxia, the protein protects organs like the heart and brain from hypoxia-related diseases.[5] In particular, HIGD1A localization to the nucleus correlates with the severity of stress in ischemic heart disease, hypoxic-ischemic encephalopathy, and cancer, and thus may serve as a biomarker for these diseases.[6] Moreover, HIGD1A is involved in inflammatory diseases, such as atherosclerosis and rheumatoid arthritis, through its role in macrophage survival.[5] Similarly, HIGD1A could become a key target for treating Alzheimer’s disease by inhibiting γ-secretase, and by extension, amyloid beta production. Notably, HIGD1A inhibits γ-secretase without interfering with Notch cleavage, thus minimizing detrimental side effects from targeting this protein.[7]
# Interactions
HIGD1A is known to interact with:
- AIF,[6]
- γ-secretase[7] and
- OPA1.[4] | https://www.wikidoc.org/index.php/HIGD1A | |
6ea7ad5b10ba7b654cb0495a39b8211b8821d8f8 | wikidoc | HLA-A1 | HLA-A1
HLA-A1 (A1) is an HLA-A serotype. The serotype identifies the more common HLA-A*01 gene products. A1 is more common in Europe than elsewhere, it is part of a long haplotype that appears to have been frequent in the ancient peoples
-f Northwestern Europe. Part of this haplotype is A1-Cw7-B8 (its serotype name), which has a frequency mode in Ireland where it is the highest frequency A-Cw-B type in Europe.
# Serotype
The serotyping capability of the A1 serotype is excellent. For the A1 group there are 24 alleles, 7 nulls, 14 protein variants. Two alleles, A*0101 and A*0102, comprise the overwhelming majority of alleles.
# Disease Associations
### By allele
A*0101 appears to alter risk for type 1 diabetes. Because A*0101 is linked to DR3-DQ2.5 (see below), and because this class II haplotype has a bearing on diabetes risk (2nd most potent risk factor) some of this risk could be due to linkage with DR3.
### By haplotype
A1-B58 (A1-B17 where B58 is dominant) is associated with antineutrophil cytoplasmic antibodies (ANCA)
# A-B Haplotypes
- A1-B7 Armenia, Austria, NW Europe (regional recombinant between A1-B8 and A2/A3-B7)
- A1-B13 Uralic
- A1-B35 (Albania, Belgium, Italy, Greece, France - Eastern mediterranian in origin)
- A1-B37 Yakuts, Tribal-India, Iyers-India, Mongolian, Indian, Orochon, Romanian, Yugoslavia, Korean, Albania, French, German, Manchu
- A1-B51 Yugoslavia, Germany, Iberia, Italy
- A1-B52 Bharghavas-India, Tribal-India, Italy, Iberia, France
- A1-B57 (See tables on discussion page)
- A1-B58 (See tables on discussion page)
## A1-Cw7-B8
A1-Cw7-B8 is the multi-serotype designation for the haplotype HLA-A*0101:C*0701:B*0801, the class I portion, of the "Super B8 Haplotype" ancetral "Ancestral Haplotype" (A1-B8-DR17(3)-DQ2.5). The full haplotype is (for relative distances see Human leukocyte antigens:
A*0101 : C*0701 : B*0801 : DRB1*0301 : DQA1*0501 : DQB1*0201
The frequency node for this haplotype is in Western Ireland. Where as the most allelic diversity (variations of A*01 or B*08 are within East Africa. The Cw7 locus carries several variants Europe (Cw*0701) Africa (Cw*0701 & Cw*0704)
It suprisingling maintains DR linkage, over 2 million nt distance is still shows relative linkage disequilibrium with DR3. In NW Europe linked to DRB1*0301 and in SE Europe DRB1*0301/*0302. It is also disequilibrated in its linkage to DQ2, and in NW Europe it is linked to DQA1*0501:DQB1*0201. Because of the incredible linkage disequilibrium this haplotype is believed to have been under positive selection in Europe's
prehistoric period. When DR or DQ typing is not present for a population this haplotype can substitute as a marker for DQ2.5 abundance and coeliac disease risk, as in the case for Ireland.
The rightmost column in the table on the right shows the rank of A1-B8 in A-B haplotypes, it is the most common top ranked haplotype in Western Europe, in fact it is one of the more common A-B haplotypes in the world. | HLA-A1
HLA-A1 (A1) is an HLA-A serotype. The serotype identifies the more common HLA-A*01 gene products. A1 is more common in Europe than elsewhere, it is part of a long haplotype that appears to have been frequent in the ancient peoples
of Northwestern Europe. Part of this haplotype is A1-Cw7-B8 (its serotype name), which has a frequency mode in Ireland where it is the highest frequency A-Cw-B type in Europe.
# Serotype
The serotyping capability of the A1 serotype is excellent. For the A1 group there are 24 alleles, 7 nulls, 14 protein variants. Two alleles, A*0101 and A*0102, comprise the overwhelming majority of alleles.
# Disease Associations
### By allele
A*0101 appears to alter risk for type 1 diabetes.[2] Because A*0101 is linked to DR3-DQ2.5 (see below), and because this class II haplotype has a bearing on diabetes risk (2nd most potent risk factor) some of this risk could be due to linkage with DR3.
### By haplotype
A1-B58 (A1-B17 where B58 is dominant) is associated with antineutrophil cytoplasmic antibodies (ANCA)[3]
# A-B Haplotypes
- A1-B7 Armenia, Austria, NW Europe (regional recombinant between A1-B8 and A2/A3-B7)
- A1-B13 Uralic
- A1-B35 (Albania, Belgium, Italy, Greece, France - Eastern mediterranian in origin)
- A1-B37 Yakuts, Tribal-India, Iyers-India, Mongolian, Indian, Orochon, Romanian, Yugoslavia, Korean, Albania, French, German, Manchu
- A1-B51 Yugoslavia, Germany, Iberia, Italy
- A1-B52 Bharghavas-India, Tribal-India, Italy, Iberia, France
- A1-B57 (See tables on discussion page)
- A1-B58 (See tables on discussion page)
## A1-Cw7-B8
A1-Cw7-B8 is the multi-serotype designation for the haplotype HLA-A*0101:C*0701:B*0801, the class I portion, of the "Super B8 Haplotype" ancetral "Ancestral Haplotype" (A1-B8-DR17(3)-DQ2.5). The full haplotype is (for relative distances see Human leukocyte antigens:
A*0101 : C*0701 : B*0801 : DRB1*0301 : DQA1*0501 : DQB1*0201
The frequency node for this haplotype is in Western Ireland. Where as the most allelic diversity (variations of A*01 or B*08 are within East Africa. The Cw7 locus carries several variants Europe (Cw*0701) Africa (Cw*0701 & Cw*0704)
It suprisingling maintains DR linkage, over 2 million nt distance is still shows relative linkage disequilibrium with DR3. In NW Europe linked to DRB1*0301 and in SE Europe DRB1*0301/*0302. It is also disequilibrated in its linkage to DQ2, and in NW Europe it is linked to DQA1*0501:DQB1*0201. Because of the incredible linkage disequilibrium this haplotype is believed to have been under positive selection in Europe's
prehistoric period. When DR or DQ typing is not present for a population this haplotype can substitute as a marker for DQ2.5 abundance and coeliac disease risk, as in the case for Ireland.
The rightmost column in the table on the right shows the rank of A1-B8 in A-B haplotypes, it is the most common top ranked haplotype in Western Europe, in fact it is one of the more common A-B haplotypes in the world. | https://www.wikidoc.org/index.php/HLA-A1 | |
970e51c3a9807dcdfcfaa3becce98d4d9b8b6ea1 | wikidoc | HLA-A2 | HLA-A2
# Overview
HLA-A2 (A2) is an HLA-A serotype. The serotype identifies the more common HLA-A*0201, *0202, *0203, *0206, and *0207 gene products. A*02 is globally common, but A*0201 is at high frequencies in Northern Asia and North America. A2 is the most diverse serotye, showing diversity in Eastern Africa and Southwest Asia. While the frequency of A*0201 in Northern Asia is high, its diversity is limited to A*0201 the less common asian variants A*0203, A*0206.
# Serotype
The serotyping for the most abundant A*02 alleles is good. For A*0203, A*0206, A*0207 serotyping is borderline useful. There is a separate serotyping for A203 and A210. There are over 125 alleles identified (mostly by sequence homology) as being A2, of those 8 are nulls, and a large majority have unknown serotypes.
# Disease Associations
### By serotype
A2 Associated with spontaneous abortion in A2+/A phenotypic children
### By haplotype
A*02:Cw*16 is associated with increased higher viral load in HIV
# A2-B Haplotypes
A2-B7 (Node in Netherlands)
A2-B5
- A2-B51
- A2-B52
A2-B8
A2-B13
A2-B14
- A2-B64
- A2-B65
A2-B15
- A2-B62
- A2-B63
- A2-B70,71,75,76
- A2-B46 (Node in Southern China, may be most abundant haplotype)
A2-B16
- A2-B44
- A2-B45
A2-B18
A2-B27
A2-B35
A2-B37
A2-B39 (Node in North American Amerinds)
A2-B40
- A2-B60
- A2-B61
## A2-Cw5-B44
A2-Cw5-B44 is the multi-serotype designation for the haplotype HLA-A*0201:C*0501:B*4402, the class I portion, of an ancetral haplotype (A2-B44-DR4-DQ8). The full haplotype is (for relative distances see Human leukocyte antigens:
A*0201 : C*0501 : B*4402 : DRB1*0401 : DQA1*0301 : DQB1*0302
Another haplotype that is more common in Central Europe is the (A2-B44-DR7-DQ2)
A*0201 : C*0501 : B*4402 : DRB1*0701 : DQA1*0201 : DQB1*0202
Over northwestern Europe A2-B44 shows a single common ancestor which contributed
the Cw5 allele to the haplotype. The haplotype appears to have been introduced early in european prehistoric period, frequencies of the haplotype generally correlate with A1-Cw7-B8 and A2-B7. The haplotype is considerably more equilibrated relative to A1-B8 and a possible reason is gene flow from iberia or the east with related haplotypes after initial migrations.
## A2-Cw11(1)-B46
This haplotype is rather unique in several regards, first and most importantly the B46 serotype is not from Africa, this distinquishes it from every other known B serotype. It is the result of a recombination event between B62(B*1501) and an HLA-C allele within Asia. This event happened recently as there is only one major allele and minor alleles are at trace frequencies. There has been some recombination between this haplotype, A24 and A11 bearing alleles, probably in a local (or tribal population). B46 is found whereever asian wet-rice farming peoples have traveled and is found at low frequencies in non-farming indigeonous groups. The one exception is the Ninhvet of Siberia and the Eastern Tlinglet of Alaska. This B46 contribution appears to have been recent. Because of the numbers of people represented by the sample groups, and its relative high frequency in those group A2-B46 is one of the most frequent, if not the most frequent A-B haplotype in the world, even though it is absent from the indigeonous populations of most peoples in the world.
The most common haplotype, and probably the ancestral haplotype given its distribution from the Ninhivet to Indonesia is:
A*0207 : C*0102 : B*4601 : DRB1*0901 : DQA1*0302 : DQB1*0303
A different haplotype that is more common in Korea and Japan is
A*0207 : C*0102 : B*4601 : DRB1*0803 : DQA1*0103 : DQB1*0601
B46, or a closely linked allele may have been under positive selection in rice farmers of asia. | HLA-A2
# Overview
HLA-A2 (A2) is an HLA-A serotype. The serotype identifies the more common HLA-A*0201, *0202, *0203, *0206, and *0207 gene products. A*02 is globally common, but A*0201 is at high frequencies in Northern Asia and North America. A2 is the most diverse serotye, showing diversity in Eastern Africa and Southwest Asia. While the frequency of A*0201 in Northern Asia is high, its diversity is limited to A*0201 the less common asian variants A*0203, A*0206.
# Serotype
The serotyping for the most abundant A*02 alleles is good. For A*0203, A*0206, A*0207 serotyping is borderline useful. There is a separate serotyping for A203 and A210. There are over 125 alleles identified (mostly by sequence homology) as being A2, of those 8 are nulls, and a large majority have unknown serotypes.
# Disease Associations
### By serotype
A2 Associated with spontaneous abortion in A2+/A[other] phenotypic children[2]
### By haplotype
A*02:Cw*16 is associated with increased higher viral load in HIV[3]
# A2-B Haplotypes
A2-B7 (Node in Netherlands)
A2-B5
- A2-B51
- A2-B52
A2-B8
A2-B13
A2-B14
- A2-B64
- A2-B65
A2-B15
- A2-B62
- A2-B63
- A2-B70,71,75,76
- A2-B46 (Node in Southern China, may be most abundant haplotype)
A2-B16
- A2-B44
- A2-B45
A2-B18
A2-B27
A2-B35
A2-B37
A2-B39 (Node in North American Amerinds)
A2-B40
- A2-B60
- A2-B61
## A2-Cw5-B44
A2-Cw5-B44 is the multi-serotype designation for the haplotype HLA-A*0201:C*0501:B*4402, the class I portion, of an ancetral haplotype (A2-B44-DR4-DQ8). The full haplotype is (for relative distances see Human leukocyte antigens:
A*0201 : C*0501 : B*4402 : DRB1*0401 : DQA1*0301 : DQB1*0302
Another haplotype that is more common in Central Europe is the (A2-B44-DR7-DQ2)
A*0201 : C*0501 : B*4402 : DRB1*0701 : DQA1*0201 : DQB1*0202
Over northwestern Europe A2-B44 shows a single common ancestor which contributed
the Cw5 allele to the haplotype. The haplotype appears to have been introduced early in european prehistoric period, frequencies of the haplotype generally correlate with A1-Cw7-B8 and A2-B7. The haplotype is considerably more equilibrated relative to A1-B8 and a possible reason is gene flow from iberia or the east with related haplotypes after initial migrations.
## A2-Cw11(1)-B46
This haplotype is rather unique in several regards, first and most importantly the B46 serotype is not from Africa, this distinquishes it from every other known B serotype. It is the result of a recombination event between B62(B*1501) and an HLA-C allele within Asia. This event happened recently as there is only one major allele and minor alleles are at trace frequencies. There has been some recombination between this haplotype, A24 and A11 bearing alleles, probably in a local (or tribal population). B46 is found whereever asian wet-rice farming peoples have traveled and is found at low frequencies in non-farming indigeonous groups. The one exception is the Ninhvet of Siberia and the Eastern Tlinglet of Alaska. This B46 contribution appears to have been recent. Because of the numbers of people represented by the sample groups, and its relative high frequency in those group A2-B46 is one of the most frequent, if not the most frequent A-B haplotype in the world, even though it is absent from the indigeonous populations of most peoples in the world.
The most common haplotype, and probably the ancestral haplotype given its distribution from the Ninhivet to Indonesia is:
A*0207 : C*0102 : B*4601 : DRB1*0901 : DQA1*0302 : DQB1*0303
A different haplotype that is more common in Korea and Japan is
A*0207 : C*0102 : B*4601 : DRB1*0803 : DQA1*0103 : DQB1*0601
B46, or a closely linked allele may have been under positive selection in rice farmers of asia. | https://www.wikidoc.org/index.php/HLA-A2 | |
ac26b82e15ba48eae1bb9647e3ad24b63910b417 | wikidoc | HLA-A3 | HLA-A3
HLA-A3 (A3) is an HLA-A serotype. The serotype identifies the more common HLA-A*03 gene products. A3 is more common in Northwestern and Central Europe, Central Asia, India and Arabia. It is less common on the West Pacific Rim, Africa or indigenous populations of the New World.
# Serotype
A3 is primarily composed of A*0301 and *0302 which serotype well with anti-A3 antibodies.
There are 26 non-synonymous variants of A*03, 4 nulls, and 22 protein variants.
# Disease Associations
### By serotype
A3 serotype is a secondary risk factor for myasthenia gravis, lower CD8+ levels in hemochromatosis patients
### By allele
A*0301 modulates increased risk for Multiple Sclerosis
# A3-B Haplotypes
A3-B8 (Romania, svanS)
A3-B35 (Bulgaria, Croatia, E. Black Sea)
A3-B55 (E. Black Sea)
## A3-Cw7-B7
A3-B7 is bimodal in frequency in Europe with one node in Ireland and the other in Switzerland, relatively speaking Switzerland appears to be higher. A3-Cw7-B7 is one of the most common multigene haplotypes in the western world, particularly in Central and Eastern Europe.
A*0301 : C*0702 : B*0702 : DRB1*1501 : DQA1*0102 : DQB1*0602 | HLA-A3
HLA-A3 (A3) is an HLA-A serotype. The serotype identifies the more common HLA-A*03 gene products. A3 is more common in Northwestern and Central Europe, Central Asia, India and Arabia. It is less common on the West Pacific Rim, Africa or indigenous populations of the New World.
# Serotype
A3 is primarily composed of A*0301 and *0302 which serotype well with anti-A3 antibodies.
There are 26 non-synonymous variants of A*03, 4 nulls, and 22 protein variants.
# Disease Associations
### By serotype
A3 serotype is a secondary risk factor for myasthenia gravis,[2] lower CD8+ levels in hemochromatosis patients[3][4]
### By allele
A*0301 modulates increased risk for Multiple Sclerosis[5]
# A3-B Haplotypes
A3-B8 (Romania, svanS)
A3-B35 (Bulgaria, Croatia, E. Black Sea)
A3-B55 (E. Black Sea)
## A3-Cw7-B7
A3-B7 is bimodal in frequency in Europe with one node in Ireland and the other in Switzerland, relatively speaking Switzerland appears to be higher. A3-Cw7-B7 is one of the most common multigene haplotypes in the western world, particularly in Central and Eastern Europe.
A*0301 : C*0702 : B*0702 : DRB1*1501 : DQA1*0102 : DQB1*0602 | https://www.wikidoc.org/index.php/HLA-A3 | |
9881b5a22407412639e74231345c9928f8d03b7b | wikidoc | HLA-DM | HLA-DM
HLA-DM (human leukocyte antigen DM) is an intracellular protein involved in the mechanism of antigen presentation on antigen presenting cells (APCs) of the immune system. It does this by assisting in peptide loading of major histocompatibility complex (MHC) class II membrane-bound proteins. HLA-DM is encoded by the genes HLA-DMA and HLA-DMB.
HLA-DM is a molecular chaperone that works in lysosomes and endosomes in cells of the immune system. It works APCs like macrophages, dendritic cells, and B cells by interacting with MHC class II molecules. HLA-DM protects the MHC class II molecules from breaking down, and regulates which proteins or peptides bind to them as well. This regulates how and when a peptide acts as an antigen initiating an immune response. Thus, HLA-DM is necessary for the immune system to respond effectively to a foreign invader. Impairment in HLA-DM function can result in immunodeficiency and autoimmune diseases.
# Genetics
The genes for HLA-DM are located in the MHCII region of the human chromosome 6. The genes code for the alpha and beta chains that makeup the protein.
The gene is nonpolymorphic.
# Function
## MHC class II + peptide interactions
HLA-DM is an integral protein in the mechanism regulating which antigens are presented extracellularly on APCs. It binds partially to the peptide-binding groove of MHC class II molecules. This can affect how well your immune system responds to foreign invaders.
HLA-DM is required to release CLIP from MHC class II molecules, to chaperone empty MHC molecules against denaturation, and to control proper loading and release of peptides at the peptide-binding groove. It also interacts heavily with chaperone protein HLA-DO. All of this ensures proper antigen presentation by an APC, to activate other immune cells. This is critical to rid the body of harmful infections. For example, proper antigen presentation benefits T cell activation, and memory T cell survival and generation. Without it, T cells leaving their site of production and entering the circulatory vessels of the body will not be activated against a danger. The immune system will not be able to kill dangerous or infected cells, and will not react quickly against a second infection.
### MHC class II molecule stabilization - chaperonal function
The low pH of lysosomes could cause denaturation or proteolysis of MHC class II molecules. HLA-DM binding to MHC stabilizes and protects from degradation, by covering hydrophobic surfaces. Antigen degradation could also ensue, resulting in an inability to bind to the peptide-binding groove. Thus, HLA-DM is needed to protect proteins against the lysosomal environment.
### CLIP release
In order to ensure that no false peptides bind to an MHC class II molecule, the peptide-binding groove is occupied by a protein called CLIP. Once a proper peptide is encountered, HLA-DM catalyzes the exchange of CLIP for an antigen peptide. Often, this peptide is retrieved directly from the B cell receptor which internalized it. Through expulsion of CLIP at the proper time, HLA-DM ensures that the correct antigen can bind to MHC molecules and prevent either from degrading.
### Antigen loading and release
Apart from CLIP-antigen exchange, HLA-DM also facilitates antigen-antigen exchange. It releases weakly bound peptides from the groove to load peptides with higher-affinity binding. This process occurs in endosomes once they have left the ER containing MHC and HLA-DM that have fused with antigen-containing lysosomes. Kinetic analysis studies have shown that HLA-DM loading occurs quickly and in many endosomes. Along the membrane of an endosome at the optimal acidity (pH=5.0), HLA-DM loads 3 to 12 peptides onto different MHC molecules per minute.
HLA-DM assists in catalysis of peptide exchange not only in late endosomes traveling from the ER, but also on cell membranes and in early endosomes. Much of this pathway is still being researched, but it is known that HLA-DM can load exogenous peptides onto MHC class II molecules when they are being expressed on cell surfaces. Loading can also occur in early endosomes that are quickly recycled. In both of these areas, loading occurs slower due to an altered pH environment.
Release
To release peptides from the MHC groove, HLA-DM binds to the N terminus of the groove, altering its conformation and breaking hydrogen bonds such that the peptide that was interacting with the MHC groove can no longer bind and is ejected.
Loading
Quick loading of peptides, facilitated by a stable MHC-DM complex, decreases the chances of those peptides being broken down by the proteolytic environment in the endosome. HLA-DM dissociates from the MHC once a stable enough peptide has bound. Thus, only antigens that can ‘out compete’ others by binding strongly enough to the groove end up on the surface of the antigen presenting cells in MHC class II molecules.
### Interaction with HLA-DO
HLA-DM also binds to HLA-DO, another non-classical MHC molecule. HLA-DO starts binding to DM in early endosomes, but is expressed less in late endosomes/lysosomes. The binding between HLA-DM and HLA-DO is less strong at low pH, but overall much stronger than HLA-DM binding to MHC molecules.
Before encountering an antigen, DO acts as a chaperone of DM to stabilize it against denaturation and direct it into lysosomes. It binds in the same location to HLA-DM as MHC class II molecules bind, thereby preventing HLA-DM from binding to MHC class II molecules. This inhibits peptide exchange catalysis and keeps CLIP in the MHC groove until antigen-containing lysosome fuses with DM/DO/MHC containing lysosomes, prompting the degradation of HLA-DO molecules in MIICs.
# Structure & Binding
HLA-DM contains a N-terminal class II histocompatibility antigen, alpha domain and a C-terminal Immunoglobulin C1-set domain.
Research in crystallography has resulted in advanced knowledge on HLA-DM structure, and how it binds to its substrates (HLA-DO and MHC class II molecules).
## HLA-DM Structure
The structure and sequence of HLA-DM proteins is very similar to other MHC class II molecules, all of which consist of a heterodimer composed of an alpha and beta chain. However, HLA-DM differs in that it is nonclassical (meaning it lacks a transport signal N-terminus), and does not have the capability to bind peptides. This is due to lack of a deep peptide binding groove - instead, it contains a shallow, negatively charged indent with two disulfide bonds.
On its beta chain cytoplasmic tail, a tyrosine based motif YTPL regulates trafficking to specific endosomal compartments called MHC class II compartments (MIICs) from the ER.
## Binding with MHC class II
HLA-DM catalyzes peptide exchange through binding at the beta chain of MHC class II molecules, which alters the conformation of the MHC and its peptide-binding groove. HLA-DM conformation stays constant. When a peptide is bound to the P1 locus in the peptide binding groove, it is stably bound. This also hinders HLA-DM binding to the MHC, preventing destabilization of the peptide-MHC interaction. Peptides also bind to the C-terminal site of the binding groove, but in this case the binding is a weak association, leaving the N-terminal of the groove open. HLA-DM can then bind to the N-terminal and allowing for peptide exchange.
## Binding with HLA-DO
HLA-DO binds to the same regions of HLA-DM as MHC class II molecules do, such that it blocks the ability of HLA-DM to bind with MHC. Thus, you can never have a complex containing HLA-DM, HLA-DO, and MHC class II molecules.
# Expression and Location
Intracellularly, HLA-DM is translated in the endoplasmic reticulum, then transported to endosomal MHC class II compartments (MIICs). MIICs then join with endosomes containing MHC class II molecules bound to CLIP. Here, the HLA-DM begins editing the MHC peptide binding.
HLA-DM is also expressed on the surface of B cells and dendritic cells, as well as in secreted exosomes.
During B cell development, HLA-DM is first expressed in early stages in the bone marrow. Expression then remains high throughout development and a B cell’s life, until the B cell differentiates into a plasma cell and HLA-DM expression then decreases.
Within the body, highest levels of HLA-DM expression is found in lymph nodes, the spleen, and bone marrow.
# Role in Disease and Medicine
## Immunodeficiency
In individuals lacking functional HLA-DM molecules, improper antigen presentation occurs, resulting in unwanted immune responses or lack of a response when danger is present. This has been shown experimentally through mouse knockout models. There will be an increase of CLIP, instead of peptide, presentation on APC surfaces. This can result in autoimmunity, if a T cell receptors recognize CLIP as a harmful antigen. There could also be no protein presentation at all, resulting in a lack of immune response.
## Infections and Disease
Type 1 diabetes is correlated with DM activation, which is hypothesized to be due to DM positively modulating the expression of disease-causing peptides in the MHC groove and thus presented to responding T cells. Experiments using the mouse model of type 1 diabetes which blocked DM or reduced its activity by overexpressing DO found a decrease in diabetes.
HLA-DM is implicated in viral infections like Herpes Simplex Virus Type 1. This virus causes uneven distribution of HLA-DM in endosomes, prevents peptide catalysis, and prevents presentation of MHC class II molecules on the cell surface.
HLA-DM is also implicated in celiac disease, multiple sclerosis, other autoimmune diseases, and leukemia. | HLA-DM
HLA-DM (human leukocyte antigen DM) is an intracellular protein involved in the mechanism of antigen presentation on antigen presenting cells (APCs) of the immune system.[2] It does this by assisting in peptide loading of major histocompatibility complex (MHC) class II membrane-bound proteins.[3] HLA-DM is encoded by the genes HLA-DMA and HLA-DMB.[4]
HLA-DM is a molecular chaperone[5] that works in lysosomes and endosomes in cells of the immune system. It works APCs like macrophages, dendritic cells, and B cells[6] by interacting with MHC class II molecules.[7] HLA-DM protects the MHC class II molecules from breaking down, and regulates which proteins or peptides bind to them as well.[5] This regulates how and when a peptide acts as an antigen initiating an immune response. Thus, HLA-DM is necessary for the immune system to respond effectively to a foreign invader. Impairment in HLA-DM function can result in immunodeficiency and autoimmune diseases.[8]
# Genetics
The genes for HLA-DM are located in the MHCII region of the human chromosome 6.[2] The genes code for the alpha and beta chains that makeup the protein.
The gene is nonpolymorphic.[8]
# Function
## MHC class II + peptide interactions
HLA-DM is an integral protein in the mechanism regulating which antigens are presented extracellularly on APCs. It binds partially to the peptide-binding groove of MHC class II molecules.[9] This can affect how well your immune system responds to foreign invaders.[10]
HLA-DM is required to release CLIP from MHC class II molecules, to chaperone empty MHC molecules against denaturation, and to control proper loading and release of peptides at the peptide-binding groove.[11] It also interacts heavily with chaperone protein HLA-DO.[12] All of this ensures proper antigen presentation by an APC, to activate other immune cells. This is critical to rid the body of harmful infections.[13] For example, proper antigen presentation benefits T cell activation, and memory T cell survival and generation. Without it, T cells leaving their site of production and entering the circulatory vessels of the body will not be activated against a danger.[14] The immune system will not be able to kill dangerous or infected cells, and will not react quickly against a second infection.
### MHC class II molecule stabilization - chaperonal function
The low pH of lysosomes could cause denaturation or proteolysis of MHC class II molecules. HLA-DM binding to MHC stabilizes and protects from degradation, by covering hydrophobic surfaces.[15] Antigen degradation could also ensue, resulting in an inability to bind to the peptide-binding groove. Thus, HLA-DM is needed to protect proteins against the lysosomal environment.[15]
### CLIP release
In order to ensure that no false peptides bind to an MHC class II molecule, the peptide-binding groove is occupied by a protein called CLIP. Once a proper peptide is encountered, HLA-DM catalyzes the exchange of CLIP for an antigen peptide.[16] Often, this peptide is retrieved directly from the B cell receptor which internalized it. Through expulsion of CLIP at the proper time, HLA-DM ensures that the correct antigen can bind to MHC molecules and prevent either from degrading.[13]
### Antigen loading and release
Apart from CLIP-antigen exchange, HLA-DM also facilitates antigen-antigen exchange. It releases weakly bound peptides from the groove to load peptides with higher-affinity binding. This process occurs in endosomes once they have left the ER containing MHC and HLA-DM that have fused with antigen-containing lysosomes.[16] Kinetic analysis studies have shown that HLA-DM loading occurs quickly and in many endosomes. Along the membrane of an endosome at the optimal acidity (pH=5.0), HLA-DM loads 3 to 12 peptides onto different MHC molecules per minute.[15]
HLA-DM assists in catalysis of peptide exchange not only in late endosomes traveling from the ER, but also on cell membranes and in early endosomes. Much of this pathway is still being researched, but it is known that HLA-DM can load exogenous peptides onto MHC class II molecules when they are being expressed on cell surfaces. Loading can also occur in early endosomes that are quickly recycled. In both of these areas, loading occurs slower due to an altered pH environment.[6]
Release
To release peptides from the MHC groove, HLA-DM binds to the N terminus of the groove, altering its conformation and breaking hydrogen bonds[2] such that the peptide that was interacting with the MHC groove can no longer bind and is ejected.[8]
Loading
Quick loading of peptides, facilitated by a stable MHC-DM complex, decreases the chances of those peptides being broken down by the proteolytic environment in the endosome.[11] HLA-DM dissociates from the MHC once a stable enough peptide has bound.[15] Thus, only antigens that can ‘out compete’ others by binding strongly enough to the groove end up on the surface of the antigen presenting cells in MHC class II molecules.[16]
### Interaction with HLA-DO
HLA-DM also binds to HLA-DO, another non-classical MHC molecule. HLA-DO starts binding to DM in early endosomes, but is expressed less in late endosomes/lysosomes.[12] The binding between HLA-DM and HLA-DO is less strong at low pH, but overall much stronger than HLA-DM binding to MHC molecules.[14]
Before encountering an antigen, DO acts as a chaperone of DM to stabilize it against denaturation and direct it into lysosomes. It binds in the same location to HLA-DM as MHC class II molecules bind, thereby preventing HLA-DM from binding to MHC class II molecules. This inhibits peptide exchange catalysis and keeps CLIP in the MHC groove[16] until antigen-containing lysosome fuses with DM/DO/MHC containing lysosomes, prompting the degradation of HLA-DO molecules in MIICs.[14]
# Structure & Binding
HLA-DM contains a N-terminal class II histocompatibility antigen, alpha domain and a C-terminal Immunoglobulin C1-set domain.
Research in crystallography has resulted in advanced knowledge on HLA-DM structure, and how it binds to its substrates (HLA-DO and MHC class II molecules).[9]
## HLA-DM Structure
The structure and sequence of HLA-DM proteins is very similar to other MHC class II molecules,[11] all of which consist of a heterodimer composed of an alpha and beta chain. However, HLA-DM differs in that it is nonclassical (meaning it lacks a transport signal N-terminus), and does not have the capability to bind peptides. This is due to lack of a deep peptide binding groove - instead, it contains a shallow, negatively charged indent with two disulfide bonds.[5]
On its beta chain cytoplasmic tail, a tyrosine based motif YTPL regulates trafficking to specific endosomal compartments called MHC class II compartments (MIICs) from the ER.[2]
## Binding with MHC class II
HLA-DM catalyzes peptide exchange through binding at the beta chain of MHC class II molecules,[16] which alters the conformation of the MHC and its peptide-binding groove. HLA-DM conformation stays constant.[17] When a peptide is bound to the P1 locus in the peptide binding groove, it is stably bound. This also hinders HLA-DM binding to the MHC, preventing destabilization of the peptide-MHC interaction.[12] Peptides also bind to the C-terminal site of the binding groove, but in this case the binding is a weak association, leaving the N-terminal of the groove open. HLA-DM can then bind to the N-terminal and allowing for peptide exchange.[12]
## Binding with HLA-DO
HLA-DO binds to the same regions of HLA-DM as MHC class II molecules do, such that it blocks the ability of HLA-DM to bind with MHC.[12] Thus, you can never have a complex containing HLA-DM, HLA-DO, and MHC class II molecules.
# Expression and Location
Intracellularly, HLA-DM is translated in the endoplasmic reticulum, then transported to endosomal MHC class II compartments (MIICs). MIICs then join with endosomes containing MHC class II molecules bound to CLIP. Here, the HLA-DM begins editing the MHC peptide binding.[2]
HLA-DM is also expressed on the surface of B cells and dendritic cells,[6] as well as in secreted exosomes.[18]
During B cell development, HLA-DM is first expressed in early stages in the bone marrow. Expression then remains high throughout development and a B cell’s life, until the B cell differentiates into a plasma cell and HLA-DM expression then decreases.[14]
Within the body, highest levels of HLA-DM expression is found in lymph nodes, the spleen, and bone marrow.[4]
# Role in Disease and Medicine
## Immunodeficiency
In individuals lacking functional HLA-DM molecules, improper antigen presentation occurs, resulting in unwanted immune responses or lack of a response when danger is present.[8] This has been shown experimentally through mouse knockout models.[5] There will be an increase of CLIP, instead of peptide, presentation on APC surfaces. This can result in autoimmunity, if a T cell receptors recognize CLIP as a harmful antigen. There could also be no protein presentation at all, resulting in a lack of immune response.[8]
## Infections and Disease
Type 1 diabetes is correlated with DM activation, which is hypothesized to be due to DM positively modulating the expression of disease-causing peptides in the MHC groove and thus presented to responding T cells.[12] Experiments using the mouse model of type 1 diabetes which blocked DM or reduced its activity by overexpressing DO found a decrease in diabetes.[12]
HLA-DM is implicated in viral infections like Herpes Simplex Virus Type 1. This virus causes uneven distribution of HLA-DM in endosomes, prevents peptide catalysis, and prevents presentation of MHC class II molecules on the cell surface.[2]
HLA-DM is also implicated in celiac disease, multiple sclerosis, other autoimmune diseases, and leukemia.[6][19][20] | https://www.wikidoc.org/index.php/HLA-DM | |
41060a55aed4a0fb2560a916022bf2a5f6cd4a5d | wikidoc | HLA-DO | HLA-DO
Human leukocyte histocompatibility complex DO (HLA-DO) is an intracellular, dimeric non-classical Major Histocompatibility Complex (MHC) class II protein composed of α- and β-subunits which interact with HLA-DM in order to fine tune immunodominant epitope selection. As a non-classical MHC class II molecule, HLA-DO is a non-polymorphic accessory protein that aids in antigenic peptide chaperoning and loading, as opposed to it classical counterparts, which are polymorphic and involved in antigen presentation. Though more remains to be elucidated about the function of HLA-DO, its unique distribution in the mammalian body—namely, the exclusive expression of HLA-DO in B cells, thymic medullary epithelial cells, and dendritic cells—indicate that it may be of physiological importance and has inspired further research. Moreover, HLA-DO is stable in complex with HLA-DM, and its exhibited instability in the absence of HLA-DM, as well as its evolutionary conservation, further denote its biological significance and potential to confer evolutionary benefits to its host.
# Discovery
Studies on HLA-DO transfected fibroblast cells lines and on the HLA-DO mouse homolog, H-2O, provide most of the current knowledge on the protein. In 1985, the α- and β-chains were separately discovered, and in 1990, both chains were found to be co-expressed in one protein in H-2O. In contrast to other molecules of MHC class II, interferon gamma does not induce HLA-DO expression.
# Function
The binding of HLA-DO at the MHC class II peptide-exchange catalysis site suggested that it acts as a competitive inhibitor, although biochemical studies have established its complementary function to HLA-DM in fine tuning epitope selection.
During infection, exogenous antigen is internalized by phagocytosis or receptor-mediated endocytosis, and processed in hydrolytic enzyme-containing compartments of increasing acidity. Once the degraded antigen is 13-18 residues, it is ready to bind to MHC class II molecules. To bind to the MHC-class II protein, HLA-DM catalyzes the exchange of CLIP, a protein occupying the binding groove of MHC class II, with the antigenic oligopeptide. HLA-DO is strongly associated with HLA-DM throughout the catalyzed exchange.
# Structure
Before the three-dimensional structure of complexed HLA-DO was elucidated by X-ray crystallography, its crystal structure was modeled after homology studies to classical MHC class II proteins. Following crystallization of the protein, HLA-DO was found to be conformationally similar to classical MHC class II protein, with alterations in the N-terminus. The structure of the free HLA-DO protein, however, remains to be elucidated. | HLA-DO
Human leukocyte histocompatibility complex DO (HLA-DO) is an intracellular, dimeric non-classical Major Histocompatibility Complex (MHC) class II protein composed of α- and β-subunits which interact with HLA-DM in order to fine tune immunodominant epitope selection.[1][2] As a non-classical MHC class II molecule, HLA-DO is a non-polymorphic accessory protein that aids in antigenic peptide chaperoning and loading, as opposed to it classical counterparts, which are polymorphic and involved in antigen presentation.[3][4][5] Though more remains to be elucidated about the function of HLA-DO, its unique distribution in the mammalian body—namely, the exclusive expression of HLA-DO in B cells, thymic medullary epithelial cells, and dendritic cells—indicate that it may be of physiological importance and has inspired further research.[3][6] Moreover, HLA-DO is stable in complex with HLA-DM, and its exhibited instability in the absence of HLA-DM, as well as its evolutionary conservation, further denote its biological significance and potential to confer evolutionary benefits to its host.[6][7][8]
# Discovery
Studies on HLA-DO transfected fibroblast cells lines and on the HLA-DO mouse homolog, H-2O, provide most of the current knowledge on the protein.[9] In 1985, the α- and β-chains were separately discovered, and in 1990, both chains were found to be co-expressed in one protein in H-2O.[7][8] In contrast to other molecules of MHC class II, interferon gamma does not induce HLA-DO expression.[1]
# Function
The binding of HLA-DO at the MHC class II peptide-exchange catalysis site suggested that it acts as a competitive inhibitor, although biochemical studies have established its complementary function to HLA-DM in fine tuning epitope selection.[1][5][6][7][9][3]
During infection, exogenous antigen is internalized by phagocytosis or receptor-mediated endocytosis, and processed in hydrolytic enzyme-containing compartments of increasing acidity.[1][8] Once the degraded antigen is 13-18 residues, it is ready to bind to MHC class II molecules.[1] To bind to the MHC-class II protein, HLA-DM catalyzes the exchange of CLIP, a protein occupying the binding groove of MHC class II, with the antigenic oligopeptide.[1][8] HLA-DO is strongly associated with HLA-DM throughout the catalyzed exchange.[3]
# Structure
Before the three-dimensional structure of complexed HLA-DO was elucidated by X-ray crystallography, its crystal structure was modeled after homology studies to classical MHC class II proteins.[4][8][2] Following crystallization of the protein, HLA-DO was found to be conformationally similar to classical MHC class II protein, with alterations in the N-terminus.[4][9][2] The structure of the free HLA-DO protein, however, remains to be elucidated.[9] | https://www.wikidoc.org/index.php/HLA-DO | |
5eea27479740b0a2b7cd1baed95ccaaa3286407c | wikidoc | HLA-DP | HLA-DP
HLA-DP is a protein/peptide-antigen receptor and graft-versus-host disease antigen that is composed of 2 subunits, DPα and DPβ. DPα and DPβ are encoded by two loci, HLA-DPA1 and HLA-DPB1, that are found in the MHC Class II (or HLA-D) region in the Human Leukocyte Antigen complex on human chromosome 6 (see protein boxes on right for links).
Less is known about HLA-DP relative to HLA-DQ and HLA-DR but the sequencing of DP types and determination of more frequent haplotypes has progressed greatly within the last few years.
# Structure, Functions, Genetics
## Structure
HLA-DP is an αβ-heterodimer cell-surface receptor. Each DP subunit (α-subunit, β-subunit) is composed of a α-helical N-terminal domain, an IgG-like β-sheet, a membrane spanning domain, and a cytoplasmic domain. The α-helical domain forms the sides of the peptide binding groove. The β-sheet regions form the base of the binding groove and the bulk of the molecule as well as the inter-subunit (non-covalent) binding region.
## Function
The name 'HLA-DP' originally describes a transplantation antigen of MHC class II category of the major histocompatibility complex of humans, however this antigen is an artifact of the era of organ transplantation. HLA DP functions as a cell surface receptor for foreign or self antigens. The immune system surveys antigens for foreign pathogens when presented by MHC receptors (like HLA-DP). The MHC Class II antigens are found on antigen presenting cells (APC)(macrophages, dendritic cells, and B-lymphocytes). Normally, these APC 'present' class II receptor/antigens to a great many T-cells, each with unique T-cell receptor (TCR) variants. A few TCR variants that recognize these DQ/antigen complexes are on CD4 positive T-cells. These T-cells, called T-helper (Th) cells, can promote the amplification of B-cells that recognize a different portion of the same antigen. Alternatively, macrophages and other cytotoxic lymphocytes consume or destroy cells by apoptotic signaling and present self-antigens. Self antigens, in the right context, form a suppressor T-cell population that protects self tissues from immune attack or autoimmunity.
## Genetics
The α-chain and β- of DP is encoded by the HLA-DPA1 locus and HLA-DPB1 loci, respectively. This cluster is located at the proximal (centromeric) end of the HLA superlocus in human chromosome 6p21.31. It is distal from HLA-DR and HLA-DQ encoding loci and therefore is much more equilibrated with respect to other HLA loci. In the Super B8 complex DP locus is more frequently substituted, either as a result of its distance from other loci, or because it was not as actively selected in the evolution of Super B8.
## Understanding the Heterodimeric DP Isoforms
Each combination of DPA1 allele gene product with each combination of DPB1 'gene' product can potentially recombine to produce one isoform. DP genes are highly variable in the human population. In a typical population there are many DP alpha and beta. Most isoforms are not common.
These 'cis'-isoforms will account for at least 50% of the DP isoforms. The other, trans isoforms are typically more rare, isoforms result from random 'trans' combinations of haplotypes in individuals as a result of 'trans' paternal/maternal gene product isoforms.
## Alleles
HLA-DPA1 Alleles
HLA-DPB1 Alleles
## HLA-DPB1 Allele Nomenclature Change
Before the April 2010 HLA nomenclature update, new HLA-DPB1 allele names were assigned within the existing nomenclature system. For example, the allele discovered after HLA-DPB1*9901 was assigned as DPB1*0102, the subsequent allele was named DPB1*0202, then *0302 and so on. This name assignment was decided because of the complex genetic characteristics of DPB1 alleles compared to alleles of other HLA loci. The majority of the HLA-DPB1 alleles cannot be simply grouped together by their nucleotide sequences. This name assignment has been the most confusing system within the HLA nomenclature. In the 2010 HLA nomenclature update, all DPB1 alleles, except DPB1*0202 and *0402, discovered after DPB1*9901 were reassigned with new numbers. For example, DPB1*0102 becomes DPB1*100:01
and DPB1*0203 becomes DPB1*101:01.
All renamed alleles are listed in the HLA-DPB1 Nomenclature Conversion Chart below.
To aid in migration of data to the new nomenclature the WHO Nomenclature Committee for Factors of the HLA System has provided the IMGT/HLA Nomenclature Conversion Tool. This tool allows you to enter an HLA allele name and will provide you with both the current and new versions of the allele name. New alleles that have never been assigned with a name prior to the April 2010 update are:
## Common DP Haplotypes | HLA-DP
HLA-DP is a protein/peptide-antigen receptor and graft-versus-host disease antigen that is composed of 2 subunits, DPα and DPβ. DPα and DPβ are encoded by two loci, HLA-DPA1 and HLA-DPB1, that are found in the MHC Class II (or HLA-D) region in the Human Leukocyte Antigen complex on human chromosome 6 (see protein boxes on right for links).
Less is known about HLA-DP relative to HLA-DQ and HLA-DR but the sequencing of DP types and determination of more frequent haplotypes has progressed greatly within the last few years.
# Structure, Functions, Genetics
## Structure
HLA-DP is an αβ-heterodimer cell-surface receptor. Each DP subunit (α-subunit, β-subunit) is composed of a α-helical N-terminal domain, an IgG-like β-sheet, a membrane spanning domain, and a cytoplasmic domain. The α-helical domain forms the sides of the peptide binding groove. The β-sheet regions form the base of the binding groove and the bulk of the molecule as well as the inter-subunit (non-covalent) binding region.
## Function
The name 'HLA-DP' originally describes a transplantation antigen of MHC class II category of the major histocompatibility complex of humans, however this antigen is an artifact of the era of organ transplantation. HLA DP functions as a cell surface receptor for foreign or self antigens. The immune system surveys antigens for foreign pathogens when presented by MHC receptors (like HLA-DP). The MHC Class II antigens are found on antigen presenting cells (APC)(macrophages, dendritic cells, and B-lymphocytes). Normally, these APC 'present' class II receptor/antigens to a great many T-cells, each with unique T-cell receptor (TCR) variants. A few TCR variants that recognize these DQ/antigen complexes are on CD4 positive T-cells. These T-cells, called T-helper (Th) cells, can promote the amplification of B-cells that recognize a different portion of the same antigen. Alternatively, macrophages and other cytotoxic lymphocytes consume or destroy cells by apoptotic signaling and present self-antigens. Self antigens, in the right context, form a suppressor T-cell population that protects self tissues from immune attack or autoimmunity.
## Genetics
The α-chain and β- of DP is encoded by the HLA-DPA1 locus and HLA-DPB1 loci, respectively. This cluster is located at the proximal (centromeric) end of the HLA superlocus in human chromosome 6p21.31. It is distal from HLA-DR and HLA-DQ encoding loci and therefore is much more equilibrated with respect to other HLA loci. In the Super B8 complex DP locus is more frequently substituted, either as a result of its distance from other loci, or because it was not as actively selected in the evolution of Super B8.
## Understanding the Heterodimeric DP Isoforms
Each combination of DPA1 allele gene product with each combination of DPB1 'gene' product can potentially recombine to produce one isoform. DP genes are highly variable in the human population. In a typical population there are many DP alpha and beta. Most isoforms are not common.
These 'cis'-isoforms will account for at least 50% of the DP isoforms. The other, trans isoforms are typically more rare, isoforms result from random 'trans' combinations of haplotypes in individuals as a result of 'trans' paternal/maternal gene product isoforms.
## Alleles
HLA-DPA1 Alleles
HLA-DPB1 Alleles
## HLA-DPB1 Allele Nomenclature Change
Before the April 2010 HLA nomenclature update, new HLA-DPB1 allele names were assigned within the existing nomenclature system. For example, the allele discovered after HLA-DPB1*9901 was assigned as DPB1*0102, the subsequent allele was named DPB1*0202, then *0302 and so on. This name assignment was decided because of the complex genetic characteristics of DPB1 alleles compared to alleles of other HLA loci. The majority of the HLA-DPB1 alleles cannot be simply grouped together by their nucleotide sequences. This name assignment has been the most confusing system within the HLA nomenclature. In the 2010 HLA nomenclature update,[1] all DPB1 alleles, except DPB1*0202 and *0402, discovered after DPB1*9901 were reassigned with new numbers. For example, DPB1*0102 becomes DPB1*100:01
and DPB1*0203 becomes DPB1*101:01.
All renamed alleles are listed in the HLA-DPB1 Nomenclature Conversion Chart below.[2]
To aid in migration of data to the new nomenclature the WHO Nomenclature Committee for Factors of the HLA System has provided the IMGT/HLA Nomenclature Conversion Tool. This tool allows you to enter an HLA allele name and will provide you with both the current and new versions of the allele name. New alleles that have never been assigned with a name prior to the April 2010 update are:
## Common DP Haplotypes
# External links
- Nomenclature of HLA Alleles
- The IMGT/HLA Database - HLA Dictionary.
- HLA Allele and Haplotype Frequency Database | https://www.wikidoc.org/index.php/HLA-DP | |
12c705d6de510cd2d95917c2157ab9ef6804cf3c | wikidoc | HLA-DQ | HLA-DQ
HLA-DQ (DQ) is a cell surface receptor protein found on antigen presenting cells. It is an αβ heterodimer of type MHC class II. The α and β chains are encoded by two loci, HLA-DQA1 and HLA-DQB1, that are adjacent to each other on chromosome band 6p21.3. Both α-chain and β-chain vary greatly. A person often produces two α-chain and two β-chain variants and thus 4 isoforms of DQ. The DQ loci are in close genetic linkage to HLA-DR, and less closely linked to HLA-DP, HLA-A, HLA-B and HLA-C.
Different isoforms of DQ can bind to and present different antigens to T-cells. In this process T-cells are stimulated to grow and can signal B-cells to produce antibodies. DQ functions in recognizing and presenting foreign antigens (proteins derived from potential pathogens). But DQ is also involved in recognizing common self-antigens and presenting those antigens to the immune system in order to develop tolerance from a very young age.
When tolerance to self proteins is lost, DQ may become involved in autoimmune disease. Two autoimmune diseases in which HLA-DQ is involved are coeliac disease and diabetes mellitus type 1. DQ is one of several antigens involved in rejection of organ transplants. As a variable cell surface receptor on immune cells, these D antigens, originally HL-A4 antigens, are involved in graft versus host disease when lymphoid tissues are transplanted between people. Serological studies of DQ recognized that antibodies to DQ bind primarily to the β-chain. The currently used serotypes are HLA-DQ2, -DQ3, -DQ4, -DQ5, -DQ6, -DQ7, -DQ8, -DQ9. HLA-DQ1 is a weak reaction to the α-chain and was replaced by DQ5 and DQ6 serology. Serotyping is capable of identifying most aspects of DQ isoform structure and function, however sequence specific PCR is now the preferred method of determining HLA-DQA1 and HLA-DQB1 alleles, as serotyping cannot resolve, often, the critical contribution of the DQ α-chain. This can be compensated for by examining DR serotypes as well as DQ serotypes.
# Structure, Functions, Genetics
## Function
The name 'HLA DQ' originally describes a transplantation antigen of MHC class II category of the major histocompatibility complex of humans; however, this status is an artifact of the early era of organ transplantation.
HLA DQ functions as a cell surface receptor for foreign or self antigens. The immune system surveys antigens for foreign pathogens when presented by MHC receptors (like HLA DQ). The MHC Class II antigens are found on antigen presenting cells (APC) (macrophages, dendritic cells, and B-lymphocytes). Normally, these APC 'present' class II receptor/antigens to a great many T-cells, each with unique T-cell receptor (TCR) variants. A few TCR variants that recognize these DQ/antigen complexes are on CD4 positive (CD4+) T-cells. These T-cells, called T-helper cells, can promote the amplification of B-cells which, in turn recognize a different portion of the same antigen. Alternatively, macrophages and other megalocytes consume cells by apoptotic signaling and present self-antigens. Self antigens, in the right context, form a suppressor T-cell population that protects self tissues from immune attack or autoimmunity.
## Genetics
HLA-DQ (DQ) is encoded on the HLA region of chromosome 6p21.3, in what was classically known as the "D" antigen region. This region encoded the subunits for DP,-Q and -R which are the major MHC class II antigens in humans. Each of these proteins have slightly different functions and are regulated in slightly different ways.
DQ is made up of two different subunits to form an αβ-heterodimer. Each subunit is encoded by its own "gene" (a coding locus). The
DQ α subunit is encoded by the HLA-DQA1 gene and the DQ β subunit is encoded by the HLA-DQB1 gene. Both loci are variable in the human population (see regional evolution).
### Detecting DQ isoforms
In the human population DQ is highly variable, the β subunit more so than the alpha chain. The variants are encoded by the HLA DQ genes
and are the result of single nucleotide polymorphisms (SNP). Some
SNP result in no change in amino-acid sequence. Others result in changes in regions that are removed when the proteins is processed to the cell surface, still others result in change in the non-functional regions of the protein, and some changes result in a change of function of the DQ isoform that is produced. The isoforms generally
change in the peptides they bind and present to T-cells. Much of
the isoform variation in DQ is within these 'functional' regions.
Serotyping. Antibodies raised against DQ tend to recognize these functional regions, in most cases the β-subunit. As a result, these antibodies can discriminate different classes of DQ based on the recognition similar DQβ proteins known as serotypes.
An example of a serotype is DQ2.
- Recognize HLA-DQB1*02 gene products which include gene products of the following alleles:
HLA-DQB1*02:01
HLA-DQB1*02:02
HLA-DQB1*02:03
- HLA-DQB1*02:01
- HLA-DQB1*02:02
- HLA-DQB1*02:03
Sometimes DQ2 antibodies recognize other gene products, such as DQB1*03:03, resulting in serotyping errors. Because of this mistyping serotyping is not as reliable as gene sequencing
-r SSP-PCR.
While the DQ2 isoforms are recognized by the same antibodies, and all
DQB1*02 are functionally similar, they can bind different α subunit and these αβ isoform variants can bind different sets of peptides. This difference in binding is an important feature that helps to understand autoimmune disease.
The first identified DQ were DQw1 to DQw3. DQw1 (DQ1) recognized the alpha chain of DQA1*01 alleles. This group was later split by beta chain recognition to DQ5 and DQ6. DQ3 is known as broad antigen serotypes, because they recognize a broad group of antigens. However, because of this broad antigen recognition their specificity and usefulness is somewhat less than desirable.
For most modern typing the DQ2, DQ4 - DQ9 set is used.
Genetic Typing. With the exception of DQ2 (*02:01) which
has a 98% detection capability, serotyping has drawbacks in relative accuracy. In addition, for many HLA studies genetic typing
does not offer that much greater advantage over serotyping, but in the case of DQ there is a need for precise identification
-f HLA-DQB1 and HLA-DQA1 which cannot be provided by serotyping.
Isoform functionality is dependent on αβ composition. Most studies indicate a chromosomal linkage between disease causing
DQA1 and DQB1 genes. Therefore, the DQA1, α, component is as important as DQB1. An example of this is DQ2, DQ2 mediates Coeliac disease and Type 1 diabetes but only if the α5 subunit is present. This subunit can be encoded by either DQA1*05:01 or DQA1*05:05. When the DQ2 encoding β-chain gene is on the same chromosome as the α5 subunit isoform, then individuals
who have this chromosome have a much higher risk of these two disease. When DQA1 and DQB1 alleles are linked in this way
they form a haplotype. The DQA1*05:01-DQB1*02:01 haplotype is called the DQ2.5 haplotype, and the DQ that results α5β² is the "cis-haplotype" or "cis-chromosomal" isoform of DQ2.5
To detect these potential combinations one uses a technique called SSP-PCR (Sequence specific primer polymerase chain reaction). This techniques works because, outside of a few areas of Africa, we know the overwhelming majority of all DQ alleles in the world. The primers are specific for known DQ and thus, if a product is seen it means that gene motif is present. This results in nearly 100% accurate typing of DQA1 and DQB1 alleles.
'How does one know which isoforms are functionally unique and which isoforms are functionally synonymous with other isoforms'?. The IMGT/HLA database also provides alignments for various alleles, these alignments show the variable regions and conserved regions. By examining the structure of these variable regions with different ligands bound
(such as the MMDB) one can see which residues come into close contact with peptides and those have side chains that are distal. Those changes more than 10 Angstoms away generally do not affect binding of peptides. The structure of HLA-DQ8/insulin peptide at NCBI can be view with Cn3D or Rasmol. In Cn3D one can highlight the peptide and then select for amino acids within 3 or more Angstroms of the peptide. Side chains that come close to the peptide can be identified and then examined on the sequence alignments at IMGT/HLA database. Anyone can download software and sequence. Have fun!
### Effects of heterogeneity of isoform pairing
As an MHC class II antigen-presenting receptor, DQ functions as a dimer containing two protein subunits, alpha (DQA1 gene product) and beta (DQB1 gene product), a DQ heterodimer. These receptors can be made from alpha+beta sets of two different DQ haplotypes, one set from the maternal and paternal chromosome. If one carries haplotype -A-B- from one parent and -a-b- from the other, that person makes 2 alpha isoforms (A and a) and 2 beta isoforms (B and b). This can produce 4 slightly different receptor heterodimers (or more simply, DQ isoforms). Two isoforms are in the cis-haplotype pairing (AB and ab) and 2 are in the trans-haplotype pairing (Ab and aB). Such a person is a double heterozygote for these genes, for DQ the most popular situation. If a person carries haplotypes -A-B- and -A-b- then they can only make 2 DQ (AB and Ab), but if a person carries haplotypes -A-B- and -A-B- then they can only make DQ isoform AB, called a double homozygote. In coeliac disease, certain homozygotes and are at higher risk for disease and some specific complications of coeliac disease such as Gluten-sensitive enteropathy associated T-cell lymphoma
Homozygotes and double homozygotes
Homozygotes at DQ loci can change risk for disease. In mice for instance, mice with 2 copies of the DQ-like Iab haplotype are more likely to progress toward fatal disease compared to mice that are heterozygotes only for the beta allele (MHC IAαb / IAαb, IAβb / IAβbm12). In humans, celiac disease DQ2.5/DQ2 homozygotes are several times more likely to have celiac disease versus DQ2.5/DQX individuals. DQ2/DQ2 homozygotes are at elevated risk for severe complications of disease. For an explanation of the risk association see:Talk:HLA-DQ#Effects of heterogeneity of isoform pairing-Expanded
Involvement of transhaplotypes in disease
There is some controversy in the literature whether trans-isoforms are relevant. Recent genetic studies into coeliac disease have revealed that the DQA1*05:05:X/Y:DQB1*02:02 gene products explain disease not linked to the haplotype that produces DQ8 and DQ2.5, strongly suggesting the trans-isoforms can be involved in disease. But, in this example, it is known that the transproduct is almost identical to a known cis-'isoform' produced by DQ2.5. There is other evidence that some haplotypes are linked to disease but show neutral linkage with other particular haplotypes are present. At present, the bias of relative isoform frequency toward cis pairing is unknown, it is known that some trans-isoforms occur.
see:Talk:HLA-DQ#Effects of heterogeneity of isoform pairing-Expanded
## DQ Function in Autoimmunity
HLA D (-P,-Q,-R) genes are members of the Major histocompatibility complex (MHC) gene family and have analogs in other mammalian species. In mice the MHC locus known as IA is homologous to human HLA DQ. Several autoimmune diseases that occur in humans that are mediated by DQ also can be induced in mice and are mediated through IA. Myasthenia gravis is an example of one such disease. Linking specific sites on autoantigens is more difficult in humans due to the complex variation of heterologous humans, but subtle differences in T-cell stimulation associated with DQ-types has been observed. These studies indicate that potentially a small change or increase in the presentation of a potential self-antigen can result in autoimmunity. This may explain
why there is often linkage to DR or DQ, but the linkage is often weak.
Regional Evolution
Many HLA DQ were under positive selection of 10,000s potentially 100,000s of years in some regions. As people moved they have tended to lose haplotypes and in the process lose
allelic diversity. On the other hand, on arrival at new distal locations, selection
would offer unknown selective forces that would have initially favored diversity in arrivals. By an unknown process, rapid evolution occurs, as has been seen in South Americas
indigeonous population (Parham and Ohta, 1996, Watkins 1995), and new alleles rapidly
appear. This process may be of immediate benefit of being positively selective in that new environment, but these new alleles might also be 'sloppy' in a selective perspective, having side effects if selection changed. The table to the left demonstrates how absolute diversity
at the global level translates into relative diversity at the regional level.
# Heterozygous DQ Combinations and Disease
## DQ2.5/DQ8 Heterozygotes
The distribution of this phenotype is largely the result of admixtures between peoples of eastern or central Asian origin and peoples of western or central Asian origin. The highest
frequencies, by random mating, are expected in Sweden, but pockets of high levels also occur in Mexico, and a larger range risk exists in Central Asia.
Diseases that appear to be increased in Heterozygotes are Celiac Disease and Type 1 Diabetes. New evidence is showing an increased risk for late onset Type 1 diabetes in Heterozygotes (which includes ambiguous Type I/Type II diabetes). 95% of Celiac Disease patients are positive for DQ2 or DQ8. | HLA-DQ
HLA-DQ (DQ) is a cell surface receptor protein found on antigen presenting cells. It is an αβ heterodimer of type MHC class II. The α and β chains are encoded by two loci, HLA-DQA1 and HLA-DQB1, that are adjacent to each other on chromosome band 6p21.3. Both α-chain and β-chain vary greatly. A person often produces two α-chain and two β-chain variants and thus 4 isoforms of DQ. The DQ loci are in close genetic linkage to HLA-DR, and less closely linked to HLA-DP, HLA-A, HLA-B and HLA-C.
Different isoforms of DQ can bind to and present different antigens to T-cells. In this process T-cells are stimulated to grow and can signal B-cells to produce antibodies. DQ functions in recognizing and presenting foreign antigens (proteins derived from potential pathogens). But DQ is also involved in recognizing common self-antigens and presenting those antigens to the immune system in order to develop tolerance from a very young age.
When tolerance to self proteins is lost, DQ may become involved in autoimmune disease. Two autoimmune diseases in which HLA-DQ is involved are coeliac disease and diabetes mellitus type 1. DQ is one of several antigens involved in rejection of organ transplants. As a variable cell surface receptor on immune cells, these D antigens, originally HL-A4 antigens, are involved in graft versus host disease when lymphoid tissues are transplanted between people. Serological studies of DQ recognized that antibodies to DQ bind primarily to the β-chain. The currently used serotypes are HLA-DQ2, -DQ3, -DQ4, -DQ5, -DQ6, -DQ7, -DQ8, -DQ9. HLA-DQ1 is a weak reaction to the α-chain and was replaced by DQ5 and DQ6 serology. Serotyping is capable of identifying most aspects of DQ isoform structure and function, however sequence specific PCR is now the preferred method of determining HLA-DQA1 and HLA-DQB1 alleles, as serotyping cannot resolve, often, the critical contribution of the DQ α-chain. This can be compensated for by examining DR serotypes as well as DQ serotypes.
# Structure, Functions, Genetics
## Function
The name 'HLA DQ' originally describes a transplantation antigen of MHC class II category of the major histocompatibility complex of humans; however, this status is an artifact of the early era of organ transplantation.
HLA DQ functions as a cell surface receptor for foreign or self antigens. The immune system surveys antigens for foreign pathogens when presented by MHC receptors (like HLA DQ). The MHC Class II antigens are found on antigen presenting cells (APC) (macrophages, dendritic cells, and B-lymphocytes). Normally, these APC 'present' class II receptor/antigens to a great many T-cells, each with unique T-cell receptor (TCR) variants. A few TCR variants that recognize these DQ/antigen complexes are on CD4 positive (CD4+) T-cells. These T-cells, called T-helper cells, can promote the amplification of B-cells which, in turn recognize a different portion of the same antigen. Alternatively, macrophages and other megalocytes consume cells by apoptotic signaling and present self-antigens. Self antigens, in the right context, form a suppressor T-cell population that protects self tissues from immune attack or autoimmunity.
## Genetics
HLA-DQ (DQ) is encoded on the HLA region of chromosome 6p21.3, in what was classically known as the "D" antigen region. This region encoded the subunits for DP,-Q and -R which are the major MHC class II antigens in humans. Each of these proteins have slightly different functions and are regulated in slightly different ways.
DQ is made up of two different subunits to form an αβ-heterodimer. Each subunit is encoded by its own "gene" (a coding locus). The
DQ α subunit is encoded by the HLA-DQA1 gene and the DQ β subunit is encoded by the HLA-DQB1 gene. Both loci are variable in the human population (see regional evolution).
### Detecting DQ isoforms
In the human population DQ is highly variable, the β subunit more so than the alpha chain. The variants are encoded by the HLA DQ genes
and are the result of single nucleotide polymorphisms (SNP). Some
SNP result in no change in amino-acid sequence. Others result in changes in regions that are removed when the proteins is processed to the cell surface, still others result in change in the non-functional regions of the protein, and some changes result in a change of function of the DQ isoform that is produced. The isoforms generally
change in the peptides they bind and present to T-cells. Much of
the isoform variation in DQ is within these 'functional' regions.
Serotyping. Antibodies raised against DQ tend to recognize these functional regions, in most cases the β-subunit. As a result, these antibodies can discriminate different classes of DQ based on the recognition similar DQβ proteins known as serotypes.
An example of a serotype is DQ2.
- Recognize HLA-DQB1*02 gene products which include gene products of the following alleles:
HLA-DQB1*02:01
HLA-DQB1*02:02
HLA-DQB1*02:03
- HLA-DQB1*02:01
- HLA-DQB1*02:02
- HLA-DQB1*02:03
Sometimes DQ2 antibodies recognize other gene products, such as DQB1*03:03, resulting in serotyping errors. Because of this mistyping serotyping is not as reliable as gene sequencing
or SSP-PCR.
While the DQ2 isoforms are recognized by the same antibodies, and all
DQB1*02 are functionally similar, they can bind different α subunit and these αβ isoform variants can bind different sets of peptides. This difference in binding is an important feature that helps to understand autoimmune disease.
The first identified DQ were DQw1 to DQw3. DQw1 (DQ1) recognized the alpha chain of DQA1*01 alleles. This group was later split by beta chain recognition to DQ5 and DQ6. DQ3 is known as broad antigen serotypes, because they recognize a broad group of antigens. However, because of this broad antigen recognition their specificity and usefulness is somewhat less than desirable.
For most modern typing the DQ2, DQ4 - DQ9 set is used.
Genetic Typing. With the exception of DQ2 (*02:01) which
has a 98% detection capability, serotyping has drawbacks in relative accuracy. In addition, for many HLA studies genetic typing
does not offer that much greater advantage over serotyping, but in the case of DQ there is a need for precise identification
of HLA-DQB1 and HLA-DQA1 which cannot be provided by serotyping.
Isoform functionality is dependent on αβ composition. Most studies indicate a chromosomal linkage between disease causing
DQA1 and DQB1 genes. Therefore, the DQA1, α, component is as important as DQB1. An example of this is DQ2, DQ2 mediates Coeliac disease and Type 1 diabetes but only if the α5 subunit is present. This subunit can be encoded by either DQA1*05:01 or DQA1*05:05. When the DQ2 encoding β-chain gene is on the same chromosome as the α5 subunit isoform, then individuals
who have this chromosome have a much higher risk of these two disease. When DQA1 and DQB1 alleles are linked in this way
they form a haplotype. The DQA1*05:01-DQB1*02:01 haplotype is called the DQ2.5 haplotype, and the DQ that results α5β² is the "cis-haplotype" or "cis-chromosomal" isoform of DQ2.5
To detect these potential combinations one uses a technique called SSP-PCR (Sequence specific primer polymerase chain reaction). This techniques works because, outside of a few areas of Africa, we know the overwhelming majority of all DQ alleles in the world. The primers are specific for known DQ and thus, if a product is seen it means that gene motif is present. This results in nearly 100% accurate typing of DQA1 and DQB1 alleles.
'How does one know which isoforms are functionally unique and which isoforms are functionally synonymous with other isoforms'?. The IMGT/HLA database also provides alignments for various alleles, these alignments show the variable regions and conserved regions. By examining the structure of these variable regions with different ligands bound
(such as the MMDB) one can see which residues come into close contact with peptides and those have side chains that are distal. Those changes more than 10 Angstoms away generally do not affect binding of peptides. The structure of HLA-DQ8/insulin peptide at NCBI can be view with Cn3D or Rasmol. In Cn3D one can highlight the peptide and then select for amino acids within 3 or more Angstroms of the peptide. Side chains that come close to the peptide can be identified and then examined on the sequence alignments at IMGT/HLA database. Anyone can download software and sequence. Have fun!
### Effects of heterogeneity of isoform pairing
As an MHC class II antigen-presenting receptor, DQ functions as a dimer containing two protein subunits, alpha (DQA1 gene product) and beta (DQB1 gene product), a DQ heterodimer. These receptors can be made from alpha+beta sets of two different DQ haplotypes, one set from the maternal and paternal chromosome. If one carries haplotype -A-B- from one parent and -a-b- from the other, that person makes 2 alpha isoforms (A and a) and 2 beta isoforms (B and b). This can produce 4 slightly different receptor heterodimers (or more simply, DQ isoforms). Two isoforms are in the cis-haplotype pairing (AB and ab) and 2 are in the trans-haplotype pairing (Ab and aB). Such a person is a double heterozygote for these genes, for DQ the most popular situation. If a person carries haplotypes -A-B- and -A-b- then they can only make 2 DQ (AB and Ab), but if a person carries haplotypes -A-B- and -A-B- then they can only make DQ isoform AB, called a double homozygote. In coeliac disease, certain homozygotes and are at higher risk for disease and some specific complications of coeliac disease such as Gluten-sensitive enteropathy associated T-cell lymphoma
Homozygotes and double homozygotes
Homozygotes at DQ loci can change risk for disease. In mice for instance, mice with 2 copies of the DQ-like Iab haplotype are more likely to progress toward fatal disease compared to mice that are heterozygotes only for the beta allele (MHC IAαb / IAαb, IAβb / IAβbm12). In humans, celiac disease DQ2.5/DQ2 homozygotes are several times more likely to have celiac disease versus DQ2.5/DQX individuals.[2] DQ2/DQ2 homozygotes are at elevated risk for severe complications of disease.[3] For an explanation of the risk association see:Talk:HLA-DQ#Effects of heterogeneity of isoform pairing-Expanded
Involvement of transhaplotypes in disease
There is some controversy in the literature whether trans-isoforms are relevant. Recent genetic studies into coeliac disease have revealed that the DQA1*05:05:X/Y:DQB1*02:02 gene products explain disease not linked to the haplotype that produces DQ8 and DQ2.5, strongly suggesting the trans-isoforms can be involved in disease. But, in this example, it is known that the transproduct is almost identical to a known cis-'isoform' produced by DQ2.5. There is other evidence that some haplotypes are linked to disease but show neutral linkage with other particular haplotypes are present. At present, the bias of relative isoform frequency toward cis pairing is unknown, it is known that some trans-isoforms occur.
see:Talk:HLA-DQ#Effects of heterogeneity of isoform pairing-Expanded
## DQ Function in Autoimmunity
HLA D (-P,-Q,-R) genes are members of the Major histocompatibility complex (MHC) gene family and have analogs in other mammalian species. In mice the MHC locus known as IA is homologous to human HLA DQ. Several autoimmune diseases that occur in humans that are mediated by DQ also can be induced in mice and are mediated through IA. Myasthenia gravis is an example of one such disease.[4] Linking specific sites on autoantigens is more difficult in humans due to the complex variation of heterologous humans, but subtle differences in T-cell stimulation associated with DQ-types has been observed.[5] These studies indicate that potentially a small change or increase in the presentation of a potential self-antigen can result in autoimmunity. This may explain
why there is often linkage to DR or DQ, but the linkage is often weak.
Regional Evolution
Many HLA DQ were under positive selection of 10,000s potentially 100,000s of years in some regions. As people moved they have tended to lose haplotypes and in the process lose
allelic diversity. On the other hand, on arrival at new distal locations, selection
would offer unknown selective forces that would have initially favored diversity in arrivals. By an unknown process, rapid evolution occurs, as has been seen in South Americas
indigeonous population (Parham and Ohta, 1996, Watkins 1995), and new alleles rapidly
appear. This process may be of immediate benefit of being positively selective in that new environment, but these new alleles might also be 'sloppy' in a selective perspective, having side effects if selection changed. The table to the left demonstrates how absolute diversity
at the global level translates into relative diversity at the regional level.
-
# Heterozygous DQ Combinations and Disease
## DQ2.5/DQ8 Heterozygotes
The distribution of this phenotype is largely the result of admixtures between peoples of eastern or central Asian origin and peoples of western or central Asian origin. The highest
frequencies, by random mating, are expected in Sweden, but pockets of high levels also occur in Mexico, and a larger range risk exists in Central Asia.
Diseases that appear to be increased in Heterozygotes are Celiac Disease and Type 1 Diabetes. New evidence is showing an increased risk for late onset Type 1 diabetes in Heterozygotes (which includes ambiguous Type I/Type II diabetes). 95% of Celiac Disease patients are positive for DQ2 or DQ8.[6] | https://www.wikidoc.org/index.php/HLA-DQ | |
19cc5b65eb19deaa5c734bdf191f88f440d42e6d | wikidoc | HLA-DR | HLA-DR
HLA-DR is an MHC class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31. The complex of HLA-DR (Human Leukocyte Antigen – DR isotype ) and peptide, generally between 9 and 30 amino acids in length, constitutes a ligand for the T-cell receptor (TCR). HLA (human leukocyte antigens) were originally defined as cell surface antigens that mediate graft-versus-host disease. Identification of these antigens has led to greater success and longevity in organ transplant.
Antigens most responsible for graft loss are HLA-DR (first six months), HLA-B (first two years), and HLA-A (long-term survival). Good matching of these antigens between host and donor are most critical for achieving graft survival.
HLA-DR is also involved in several autoimmune conditions, disease susceptibility and disease resistance. It is also closely linked to HLA-DQ and this linkage often makes it difficult to resolve the more causative factor in disease.
HLA-DR molecules are upregulated in response to signalling. In the instance of an infection, the peptide (such as the staphylococcal enterotoxin I peptide) is bound into a DR molecule and presented to a few of a great many T-cell receptors found on T-helper cells. These cells then bind to antigens on the surface of B-cells stimulating B-cell proliferation.
# Function
The primary function of HLA-DR is to present peptide antigens, potentially foreign in origin, to the immune system for the purpose of eliciting or suppressing T-(helper)-cell responses that eventually lead to the production of antibodies against the same peptide antigen. Antigen presenting cells (macrophages, B-cells and dendritic cells) are the cells in which DR are typically found. Increased abundance of DR 'antigen' on the cell surface is often in response to stimulation, and, therefore, DR is also a marker for immune stimulation.
# Structure
HLA-DR is an αβ heterodimer, cell surface receptor, each subunit of which contains two extracellular domains, a membrane-spanning domain and a cytoplasmic tail. Both α and β chains are anchored in the membrane. The N-terminal domain of the mature protein forms an alpha-helix that constitutes the exposed part of the binding groove, the C-terminal cytoplasmic region interact with the other chain forming a beta-sheet under the binding groove spanning to the cell membrane. The majority of the peptide contact positions are in the first 80 residues of each chain.
# Genetics
The genetics of HLA-DR is complex. HLA-DR is encoded by several loci and several 'genes' of different function at each locus. The DR α-chain is encoded by the HLA-DRA locus. Unlike the other DR loci, functional variation in mature DRA gene products is absent. (Note: see table Number of Variant Alleles HLA-DR Loci- reduces the potential functional combinations from ~1400 to ~400 ().
The DR β-chain is encoded by 4 loci, however no more
than 3 functional loci are present in a single individual, and no more than two on a single chromosome. Sometimes an individual may only possess 2 copies of the same locus,
DRB1*. The HLA-DRB1 locus is ubiquitous and encodes a very large number of functionally variable gene products (HLA-DR1 to HLA-DR17). The HLA-DRB3 locus encodes the HLA-DR52 specificity, is moderately variable and is variably associated with certain HLA-DRB1 types. The HLA-DRB4 locus encodes the HLA-DR53 specificity, has some variation, and is associated with certain HLA-DRB1 types. The HLA-DRB5 locus encodes the HLA-DR51 specificity, which is typically invariable, and is linked to the HLA-DR2 types.
- linkage (See Table)
DQA1 and DQB1
Linkage disequilibrium exists for many DR-DQ types.
Nomenclature issues. Some older studies may refer to DR15 or 16 as DR2 and DQ5 and DQ6 as DQ1 therefore a haplotype DR2-DQ1 is usually referring to DR15-DQ6 but could be referring to DR16-DQ5. DR5 is used to refer to DR11 and DR12, in which case DQ3 might be used. In these instances DQ3 almost always can be interpreted as DQ7, but DR5 is most often DR11 and less frequently DR12. Similar issues exist for DR6 versus DR13 and DR14. DR6-DQ1 can refer to either DR13-DQ6 or less frequently DR14-DQ5, but DR6-DQ3 or DR6-DQ7 generally refers to DR13-DQ7. Even older literature has more confusing designations. By looking at the change of disease association with improved testing we can see how HLA nomenclature has evolved over time.
- DQA1 and DQB1
Linkage disequilibrium exists for many DR-DQ types.
- Linkage disequilibrium exists for many DR-DQ types.
- Nomenclature issues. Some older studies may refer to DR15 or 16 as DR2 and DQ5 and DQ6 as DQ1 therefore a haplotype DR2-DQ1 is usually referring to DR15-DQ6 but could be referring to DR16-DQ5. DR5 is used to refer to DR11 and DR12, in which case DQ3 might be used. In these instances DQ3 almost always can be interpreted as DQ7, but DR5 is most often DR11 and less frequently DR12. Similar issues exist for DR6 versus DR13 and DR14. DR6-DQ1 can refer to either DR13-DQ6 or less frequently DR14-DQ5, but DR6-DQ3 or DR6-DQ7 generally refers to DR13-DQ7. Even older literature has more confusing designations. By looking at the change of disease association with improved testing we can see how HLA nomenclature has evolved over time.
## Evolution and allele frequencies
There is a high level of allelic diversity at HLA DRB1, it is second only to HLA-B locus in number of allelic variants. These two loci are highest sequence variation rate within human genome. This means HLA-DRB1 is rapidly evolving, much more rapidly than almost all other protein encoding loci. Much of the variation at HLA DRB1 occurs at peptide contact positions in the binding groove, as a result many of the alleles alter the way the DR binds peptide ligands and changes the repertoire each receptor can bind.
This means that most of the changes are functional in nature, and therefore are under selection. In the HLA region, genes are under heterozygous or balancing selection, although certain alleles appear to be under positive or negative selection, either in the past or present
HLA generally evolve through a process of gene conversion, which is a form of short distance or 'abortive' genetic recombination. Functional motifs in genes are exchanged to form new alleles, and frequently new, functionally different DR isoforms. HLA-DR represents an extreme example of this. A survey of X-linked loci reveals that most human loci have undergone fixation within the last 600,000 years, and diploid loci have undergone significant proportion of fixation in that period of time.
The level of deep branching at X-linked loci indicates loci were close to fixation or fixed at the end of the human population bottleneck 100,000 to 150,000 years ago. The HLA-DR locus represents a major exception to this observation. Based on distribution of major groupings in the human population it is possible to assert that more than a dozen major variants survived the population bottleneck. This observation is supported by the concept of a heterozygous selection coefficient operating on the HLA-DR, and at the HLA-DRB1 locus to a greater degree relative to HLA-DQB1 and HLA-DPB1. Most of the HLA alleles currently present in the human population can be explained by gene conversion between these ancient ancestral types, some that persist into the extant population.
# Serogroups
The table below provides links to subpages with information about distribution, genetic
linkage and disease association for the HLA-DR serogroups.
# Interlocus DRB linkage
DRB1 is linked with other DRB loci in four ways. | HLA-DR
HLA-DR is an MHC class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31. The complex of HLA-DR (Human Leukocyte Antigen – DR isotype ) and peptide, generally between 9 and 30 amino acids in length, constitutes a ligand for the T-cell receptor (TCR). HLA (human leukocyte antigens) were originally defined as cell surface antigens that mediate graft-versus-host disease. Identification of these antigens has led to greater success and longevity in organ transplant.
Antigens most responsible for graft loss are HLA-DR (first six months), HLA-B (first two years), and HLA-A (long-term survival).[1] Good matching of these antigens between host and donor are most critical for achieving graft survival.
HLA-DR is also involved in several autoimmune conditions, disease susceptibility and disease resistance. It is also closely linked to HLA-DQ and this linkage often makes it difficult to resolve the more causative factor in disease.
HLA-DR molecules are upregulated in response to signalling. In the instance of an infection, the peptide (such as the staphylococcal enterotoxin I peptide) is bound into a DR molecule and presented to a few of a great many T-cell receptors found on T-helper cells. These cells then bind to antigens on the surface of B-cells stimulating B-cell proliferation.
# Function
The primary function of HLA-DR is to present peptide antigens, potentially foreign in origin, to the immune system for the purpose of eliciting or suppressing T-(helper)-cell responses that eventually lead to the production of antibodies against the same peptide antigen. Antigen presenting cells (macrophages, B-cells and dendritic cells) are the cells in which DR are typically found. Increased abundance of DR 'antigen' on the cell surface is often in response to stimulation, and, therefore, DR is also a marker for immune stimulation.
# Structure
HLA-DR is an αβ heterodimer, cell surface receptor, each subunit of which contains two extracellular domains, a membrane-spanning domain and a cytoplasmic tail. Both α and β chains are anchored in the membrane. The N-terminal domain of the mature protein forms an alpha-helix that constitutes the exposed part of the binding groove, the C-terminal cytoplasmic region interact with the other chain forming a beta-sheet under the binding groove spanning to the cell membrane. The majority of the peptide contact positions are in the first 80 residues of each chain.
# Genetics
The genetics of HLA-DR is complex. HLA-DR is encoded by several loci and several 'genes' of different function at each locus. The DR α-chain is encoded by the HLA-DRA locus. Unlike the other DR loci, functional variation in mature DRA gene products is absent. (Note: see table Number of Variant Alleles HLA-DR Loci- reduces the potential functional combinations from ~1400 to ~400 ([table is not exact because new alleles are continually being added; not all new alleles are functional variants of the mature subunits]).
The DR β-chain[3] is encoded by 4 loci, however no more
than 3 functional loci are present in a single individual, and no more than two on a single chromosome. Sometimes an individual may only possess 2 copies of the same locus,
DRB1*. The HLA-DRB1 locus is ubiquitous and encodes a very large number of functionally variable gene products (HLA-DR1 to HLA-DR17). The HLA-DRB3 locus encodes the HLA-DR52 specificity, is moderately variable and is variably associated with certain HLA-DRB1 types. The HLA-DRB4 locus encodes the HLA-DR53 specificity, has some variation, and is associated with certain HLA-DRB1 types. The HLA-DRB5 locus encodes the HLA-DR51 specificity, which is typically invariable, and is linked to the HLA-DR2 types.
- linkage (See Table)
DQA1 and DQB1
Linkage disequilibrium exists for many DR-DQ types.
Nomenclature issues. Some older studies may refer to DR15 or 16 as DR2 and DQ5 and DQ6 as DQ1 therefore a haplotype DR2-DQ1 is usually referring to DR15-DQ6 but could be referring to DR16-DQ5. DR5 is used to refer to DR11 and DR12, in which case DQ3 might be used. In these instances DQ3 almost always can be interpreted as DQ7, but DR5 is most often DR11 and less frequently DR12. Similar issues exist for DR6 versus DR13 and DR14. DR6-DQ1 can refer to either DR13-DQ6 or less frequently DR14-DQ5, but DR6-DQ3 or DR6-DQ7 generally refers to DR13-DQ7. Even older literature has more confusing designations. By looking at the change of disease association with improved testing we can see how HLA nomenclature has evolved over time.
- DQA1 and DQB1
Linkage disequilibrium exists for many DR-DQ types.
- Linkage disequilibrium exists for many DR-DQ types.
- Nomenclature issues. Some older studies may refer to DR15 or 16 as DR2 and DQ5 and DQ6 as DQ1 therefore a haplotype DR2-DQ1 is usually referring to DR15-DQ6 but could be referring to DR16-DQ5. DR5 is used to refer to DR11 and DR12, in which case DQ3 might be used. In these instances DQ3 almost always can be interpreted as DQ7, but DR5 is most often DR11 and less frequently DR12. Similar issues exist for DR6 versus DR13 and DR14. DR6-DQ1 can refer to either DR13-DQ6 or less frequently DR14-DQ5, but DR6-DQ3 or DR6-DQ7 generally refers to DR13-DQ7. Even older literature has more confusing designations. By looking at the change of disease association with improved testing we can see how HLA nomenclature has evolved over time.
## Evolution and allele frequencies
There is a high level of allelic diversity at HLA DRB1, it is second only to HLA-B locus in number of allelic variants. These two loci are highest sequence variation rate within human genome. This means HLA-DRB1 is rapidly evolving, much more rapidly than almost all other protein encoding loci. Much of the variation at HLA DRB1 occurs at peptide contact positions in the binding groove, as a result many of the alleles alter the way the DR binds peptide ligands and changes the repertoire each receptor can bind.
This means that most of the changes are functional in nature, and therefore are under selection. In the HLA region, genes are under heterozygous or balancing selection, although certain alleles appear to be under positive or negative selection, either in the past or present
HLA generally evolve through a process of gene conversion, which is a form of short distance or 'abortive' genetic recombination. Functional motifs in genes are exchanged to form new alleles, and frequently new, functionally different DR isoforms. HLA-DR represents an extreme example of this. A survey of X-linked loci reveals that most human loci have undergone fixation within the last 600,000 years, and diploid loci have undergone significant proportion of fixation in that period of time.
The level of deep branching at X-linked loci indicates loci were close to fixation or fixed at the end of the human population bottleneck 100,000 to 150,000 years ago. The HLA-DR locus represents a major exception to this observation.[5] Based on distribution of major groupings in the human population it is possible to assert that more than a dozen major variants survived the population bottleneck. This observation is supported by the concept of a heterozygous selection coefficient operating on the HLA-DR, and at the HLA-DRB1 locus to a greater degree relative to HLA-DQB1 and HLA-DPB1. Most of the HLA alleles currently present in the human population can be explained by gene conversion between these ancient ancestral types,[6] some that persist into the extant population.
# Serogroups
The table below provides links to subpages with information about distribution, genetic
linkage and disease association for the HLA-DR serogroups.
# Interlocus DRB linkage
DRB1 is linked with other DRB loci in four ways. | https://www.wikidoc.org/index.php/HLA-DR | |
b12b6fb57ee8a8a62af0f3290e312a0f27f66954 | wikidoc | Statin | Statin
# Overview
The statins (or HMG-CoA reductase inhibitors) form a class of hypolipidemic agents, used as pharmaceutical agents to lower cholesterol levels in people with or at risk of cardiovascular disease. They lower cholesterol by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme in the liver stimulates LDL receptors, resulting in an increased clearance of low-density lipoprotein (LDL) from the bloodstream and a decrease in blood cholesterol levels. The first results can be seen after one week of use and the effect is maximal after four to six weeks.
# History
Akira Endo and Masao Kuroda of Tokyo, Japan commenced research into inhibitors of HMG-CoA reductase in 1971 (Endo 1992). This team reasoned that certain microorganisms may produce inhibitors of the enzyme to defend themselves against other organisms, as mevalonate is a precursor of many substances required by organisms for the maintenance of their cell wall (ergosterol) or cytoskeleton (isoprenoids).
The first agent isolated was mevastatin (ML-236B), a molecule produced by Penicillium citrinum. The pharmaceutical company Merck & Co. showed an interest in the Japanese research in 1976, and isolated lovastatin (mevinolin, MK803), the first commercially marketed statin, from the mold Aspergillus terreus. Dr Endo was awarded the 2006 Japan Prize for his work on the development of statins.
# Members
The statins are divided into two groups: fermentation-derived and synthetic.
The statins include, in alphabetical order (brand names vary in different countries):
LDL-lowering potency varies between agents. Cerivastatin is the most potent, followed by (in order of decreasing potency) rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin. The relative potency of pitavastatin has not yet been fully established.
# Mode of action
## Cholesterol lowering
Most circulating cholesterol is manufactured internally, in amounts of about 1000 mg/day, via carbohydrate metabolism through the HMG-CoA reductase pathway. Cholesterol, both from dietary intake and secreted into the duodenum as bile from the liver, is typically absorbed at a rate of 50% by the small intestines. The typical diet in the United States and many other Western countries is estimated as adding about 200-300 mg/day to intestinal intake, an amount much smaller than that secreted into the intestine in the bile. Thus internal production is an important factor.
Cholesterol is not water-soluble, and is therefore carried in the blood in the form of lipoproteins, the type being determined by the apoprotein, a protein coating that acts as an emulsifier. The relative balance between these lipoproteins is determined by various factors, including genetics, diet, and insulin resistance. Low density lipoprotein (LDL) and very low density lipoprotein (VLDL) carry cholesterol toward tissues, and elevated levels of these lipoproteins are associated with atheroma formation (fat-containing deposits in the arterial wall) and cardiovascular disease. High density lipoprotein, in contrast, carries cholesterol back to the liver and is associated with protection against cardiovascular disease.
Statins act by competitively inhibiting HMG-CoA reductase, the first committed enzyme of the HMG-CoA reductase pathway. By reducing intracellular cholesterol levels, they cause liver cells to make more LDL receptors, leading to increased clearance of low-density lipoprotein from the bloodstream.
Direct evidence of the action of statin-based cholesterol lowering on atherosclerosis was presented in the ASTEROID trial, which demonstrated regression of atheroma employing intravascular ultrasound.
## Non-cholesterol related actions
Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis. Researchers hypothesize that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):
- Improving endothelial function
- Modulate inflammatory responses
- Maintain plaque stability
- Prevent thrombus formation
# Indications and uses
Statins, the most potent cholesterol-lowering agents available, lower LDL cholesterol (so-called "bad cholesterol") by 30–50%. However, they have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol"). Professional guidelines generally require that the patient has tried a cholesterol-lowering diet before statin use is considered; statins or other pharmacologic agents may then be recommended for patients who do not meet their lipid-lowering goals through diet and lifestyle approaches.
The indications for the prescription of statins have broadened over the years. Initial studies, such as the Scandinavian Simvastatin Survival Study (4S), supported the use of statins in secondary prevention for cardiovascular disease, or as primary prevention only when the risk for cardiovascular disease was significantly raised (as indicated by the Framingham risk score). Indications were broadened considerably by studies such as the Heart Protection Study (HPS), which showed preventative effects of statin use in specific risk groups, such as diabetics. The ASTEROID trial, published in 2006, using only a statin at high dose, achieved lower than usual target calculated LDL values and showed disease regression within the coronary arteries using intravascular ultrasonography.
Based on clinical trials, the National Cholesterol Education Program guidelines, and the increasing focus on aggressively lowering LDL-cholesterol, the statins continue to play an important role in both the primary and secondary prevention of coronary heart disease, myocardial infarction, stroke and peripheral artery disease.
Research continues into other areas where statins also appear to have a favorable effect: inflammation, dementia, cancer, nuclear cataracts, and pulmonary hypertension.
## A Trial Based Approach to Statin Guidelines
Shown below is a table suggesting an approach to the use of statin according to different trials.
# Pharmacogenomics
A 2004 study showed that patients with one of two common single nucleotide polymorphisms (small genetic variations) in the HMG-CoA reductase gene were less responsive to statins.
# Safety
While some patients on statin therapy report myalgias, muscle cramps, or far less-frequent gastrointestinal or other symptoms, similar symptoms are also reported with placebo use in all the large statin safety/efficacy trials and usually resolve, either on their own or on temporarily lowering/stopping the dose.
## Hepatic Injury
While clinically important hepatotoxicity is exceedingly rare, statin hepatopathy is more common and ranges from mild liver enzyme derangements to, rarely, liver failure. The first response to liver enzyme elevation in the setting of statin use ought to be to rule out other causes..
Any drug-induced hepatopathy is defined as an elevation in the alanine aminotransferase (ALT) levels of greater than 3-times the upper limit of normal or elvation of indirect bilirubin levels of greater than 2 times the upper limit of normal. With respect to statins, the liver injury is purely hepatocellular - a 'transaminitis' - and present as a dose-dependent, class-effect in 1-3% of patients taking statins, as observed in clinical trials (though often not significantly different from transaminase elevations in the placebo groups). Generally - in more than 70% of instances - these elevations return to normal over time. Rarely, this injury becomes chronic. If patients are to experience a clinically significant liver injury from statin use, it typically manifests itself within 9-11 weeks. Liver failure is the rarest side-effect; 3 patients have required liver transplantation (though 2 were taking the long-discontinued cerivistatin).
## Myopathy
Statin induced myopathy is common while serious muscle damage is rare. Many patients complain of muscle pain without laboratory evidence of muscle damage. The chief concern, however, is frank muscle breakdown or rhabdomyolysis which can leaded to renal failure, though it is very rare. One 2004 study found that of 10,000 patients treated for one year, 0.44 will develop rhabdomyolysis. Cerivastatin, which was withdrawn by its manufacturer for this reason in 2001, had a much higher incidence (more than 10x). All commonly used statins show somewhat similar results, however the newer statins, characterized by longer pharmacological half-lives and more cellular specificity, have had a better ratio of efficacy to lower adverse effect rates. In a review of the randomized-controlled trials for statin therapy, 7 patients experienced rhabdomyolysis while receiving statins at the same time as 5 patients who were receiving placebo. Between 1990 and 2002, the Food and Drug Administration received 3339 reports of patients with rhabdomyolysis while taking a statin, 10.4% of which were life-threatening. However, 52% of these patients were taking other medications associated with rhabdomyolisis.
The pathophysiology of statin-myopathy is fairly well understood. On one hand, Co-Enzyme Q-10 (ubiquinone) levels are decreased in statin use; Ubiquinoine is a product of the steroid synthesis pathways and as such its production is reduced in statin use. It is also a key component of the electron transport chain of mitochondria. Accordingly, with less ubiquinone, the cell is less likely to meet its energy needs and may die. Coenzyme Q10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their effectiveness is currently lacking. Additionally, statins - and not their metabolites - are directly toxic to liver cells. They have been shown to increase cell-death by causing both an increase in intracellular calcium concentration and the translocation into the mitochondria of bax, a pro-apoptotic protein.
The risk of myopathy may be lowest with pravastatin and fluvastatin probably because they are less lipophillic and as a result have less muscle penetration.
N-of-1 trials have examined this:
- StatinWISE
- SAMSON (Wood)
- TaSINI
## Neuromuscular Disorders and Mitochrondrial Myopathies
There is also a small, but growing literature of statin use 'unmasking' latent neurmuscular disorders and mitochondrial myopathies such as McArdle's Disease, Kennedy's Disease, MELAS, and Myasthenia Gravis.
## Memory Loss
Memory loss have been reported by several patients taking statins, which have increased concerns about the effect of statins on the cognitive function. Statins, mainly the lipophilic types, might cause small decrease in memory and attention but there is no certainty regarding the clinical significance of this side effect nor the long term effect of statin on memory.
## Cancer Concerns
Despite initial concerns that statins might increase the risk of cancer, various studies concluded later that statins have no influence on cancer risk (including the heart protection study and a 2006 meta-analysis). Indeed, a 2005 trial showed that patients taking statins for over 5 years reduced their risk of colorectal cancer by 50%; this effect was not exhibited by fibrates. The trialists warn that the number needed to treat would approximate 5000, making statins unlikely tools for primary prevention.
## Drug interactions
Combining any statin with a fibrate, another category of lipid-lowering drugs, increases the risks for rhabdomyolysis to almost 6.0 per 10,000 person-years. Most physicians have now abandoned routine monitoring of liver enzymes and creatine kinase, although they still consider this prudent in those on high-dose statins or in those on statin/fibrate combinations, and mandatory in the case of muscle cramps or of deterioration in renal function.
Consumption of grapefruit or grapefruit juice inhibits the metabolism of statins—furanocoumarins in grapefruit juice inhibit the cytochrome P450 enzyme CYP3A4, which is involved in the metabolism of most statins (however it is a major inhibitor of only atorvastatin, lovastatin and simvastatin) and some other medications (it had been thought that flavonoids were responsible). This increases the levels of the statin, increasing the risk of dose-related adverse effects (including myopathy/rhabdomyolysis). Consequently, consumption of grapefruit juice is not recommended in patients undergoing therapy with most statins. An alternative, somewhat risky, approach is that some users take grapefruit juice to enhance the effect of lower (hence cheaper) doses of statins. This is not recommended as a result of the increased risk and potential for statin toxicity.
# Controversy
Some scientists take a skeptical view of the need for many people to require statin treatment. The International Network of Cholesterol Skeptics is a group that has questioned the "lipid hypothesis" that supports cholesterol lowering as a preventive measure for heart disease, and has argued that statins - especially at higher doses - may not be as beneficial or safe as suggested. Similarly, some authors argue that recommendations for the expanded use of statins to stave off cardiovascular disease are not supported by evidence. | Statin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-in-Chief:: Elliot B. Tapper, MD. Department of Medicine, Beth Israel Deaconess Medical Centre
# Overview
The statins (or HMG-CoA reductase inhibitors) form a class of hypolipidemic agents, used as pharmaceutical agents to lower cholesterol levels in people with or at risk of cardiovascular disease. They lower cholesterol by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme in the liver stimulates LDL receptors, resulting in an increased clearance of low-density lipoprotein (LDL) from the bloodstream and a decrease in blood cholesterol levels. The first results can be seen after one week of use and the effect is maximal after four to six weeks.
# History
Akira Endo and Masao Kuroda of Tokyo, Japan commenced research into inhibitors of HMG-CoA reductase in 1971 (Endo 1992). This team reasoned that certain microorganisms may produce inhibitors of the enzyme to defend themselves against other organisms, as mevalonate is a precursor of many substances required by organisms for the maintenance of their cell wall (ergosterol) or cytoskeleton (isoprenoids).[1]
The first agent isolated was mevastatin (ML-236B), a molecule produced by Penicillium citrinum. The pharmaceutical company Merck & Co. showed an interest in the Japanese research in 1976, and isolated lovastatin (mevinolin, MK803), the first commercially marketed statin, from the mold Aspergillus terreus. Dr Endo was awarded the 2006 Japan Prize for his work on the development of statins.
# Members
The statins are divided into two groups: fermentation-derived and synthetic.
The statins include, in alphabetical order (brand names vary in different countries):
LDL-lowering potency varies between agents. Cerivastatin is the most potent, followed by (in order of decreasing potency) rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin.[2] The relative potency of pitavastatin has not yet been fully established.
# Mode of action
## Cholesterol lowering
Most circulating cholesterol is manufactured internally, in amounts of about 1000 mg/day, via carbohydrate metabolism through the HMG-CoA reductase pathway. Cholesterol, both from dietary intake and secreted into the duodenum as bile from the liver, is typically absorbed at a rate of 50% by the small intestines. The typical diet in the United States and many other Western countries is estimated as adding about 200-300 mg/day to intestinal intake, an amount much smaller than that secreted into the intestine in the bile. Thus internal production is an important factor.
Cholesterol is not water-soluble, and is therefore carried in the blood in the form of lipoproteins, the type being determined by the apoprotein, a protein coating that acts as an emulsifier. The relative balance between these lipoproteins is determined by various factors, including genetics, diet, and insulin resistance. Low density lipoprotein (LDL) and very low density lipoprotein (VLDL) carry cholesterol toward tissues, and elevated levels of these lipoproteins are associated with atheroma formation (fat-containing deposits in the arterial wall) and cardiovascular disease. High density lipoprotein, in contrast, carries cholesterol back to the liver and is associated with protection against cardiovascular disease.
Statins act by competitively inhibiting HMG-CoA reductase, the first committed enzyme of the HMG-CoA reductase pathway. By reducing intracellular cholesterol levels, they cause liver cells to make more LDL receptors, leading to increased clearance of low-density lipoprotein from the bloodstream.[3]
Direct evidence of the action of statin-based cholesterol lowering on atherosclerosis was presented in the ASTEROID trial, which demonstrated regression of atheroma employing intravascular ultrasound.[4]
## Non-cholesterol related actions
Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis. Researchers hypothesize that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):[5]
- Improving endothelial function
- Modulate inflammatory responses
- Maintain plaque stability
- Prevent thrombus formation
# Indications and uses
Statins, the most potent cholesterol-lowering agents available, lower LDL cholesterol (so-called "bad cholesterol") by 30–50%.[6] However, they have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol"). Professional guidelines generally require that the patient has tried a cholesterol-lowering diet before statin use is considered; statins or other pharmacologic agents may then be recommended for patients who do not meet their lipid-lowering goals through diet and lifestyle approaches.
The indications for the prescription of statins have broadened over the years. Initial studies, such as the Scandinavian Simvastatin Survival Study (4S), supported the use of statins in secondary prevention for cardiovascular disease, or as primary prevention only when the risk for cardiovascular disease was significantly raised (as indicated by the Framingham risk score).[7] Indications were broadened considerably by studies such as the Heart Protection Study (HPS), which showed preventative effects of statin use in specific risk groups, such as diabetics. The ASTEROID trial, published in 2006, using only a statin at high dose, achieved lower than usual target calculated LDL values and showed disease regression within the coronary arteries using intravascular ultrasonography.[4]
Based on clinical trials, the National Cholesterol Education Program guidelines, and the increasing focus on aggressively lowering LDL-cholesterol, the statins continue to play an important role in both the primary and secondary prevention of coronary heart disease, myocardial infarction, stroke and peripheral artery disease.
Research continues into other areas where statins also appear to have a favorable effect: inflammation, dementia,[8] cancer,[9] nuclear cataracts,[10] and pulmonary hypertension.
## A Trial Based Approach to Statin Guidelines
Shown below is a table suggesting an approach to the use of statin according to different trials.[11]
# Pharmacogenomics
A 2004 study showed that patients with one of two common single nucleotide polymorphisms (small genetic variations) in the HMG-CoA reductase gene were less responsive to statins.[12]
# Safety
While some patients on statin therapy report myalgias, muscle cramps, or far less-frequent gastrointestinal or other symptoms, similar symptoms are also reported with placebo use in all the large statin safety/efficacy trials and usually resolve, either on their own or on temporarily lowering/stopping the dose.
## Hepatic Injury
While clinically important hepatotoxicity is exceedingly rare, statin hepatopathy is more common and ranges from mild liver enzyme derangements to, rarely, liver failure. The first response to liver enzyme elevation in the setting of statin use ought to be to rule out other causes.[13].
Any drug-induced hepatopathy is defined as an elevation in the alanine aminotransferase (ALT) levels of greater than 3-times the upper limit of normal or elvation of indirect bilirubin levels of greater than 2 times the upper limit of normal. With respect to statins, the liver injury is purely hepatocellular - a 'transaminitis' - and present as a dose-dependent, class-effect in 1-3% of patients taking statins, as observed in clinical trials (though often not significantly different from transaminase elevations in the placebo groups).[14][15][16] Generally - in more than 70% of instances[17] - these elevations return to normal over time. Rarely, this injury becomes chronic. If patients are to experience a clinically significant liver injury from statin use, it typically manifests itself within 9-11 weeks.[18] Liver failure is the rarest side-effect; 3 patients have required liver transplantation (though 2 were taking the long-discontinued cerivistatin).[19]
## Myopathy
Statin induced myopathy is common while serious muscle damage is rare. Many patients complain of muscle pain without laboratory evidence of muscle damage. [20] The chief concern, however, is frank muscle breakdown or rhabdomyolysis which can leaded to renal failure, though it is very rare. One 2004 study found that of 10,000 patients treated for one year, 0.44 will develop rhabdomyolysis. Cerivastatin, which was withdrawn by its manufacturer for this reason in 2001, had a much higher incidence (more than 10x).[21] All commonly used statins show somewhat similar results, however the newer statins, characterized by longer pharmacological half-lives and more cellular specificity, have had a better ratio of efficacy to lower adverse effect rates. In a review of the randomized-controlled trials for statin therapy, 7 patients experienced rhabdomyolysis while receiving statins at the same time as 5 patients who were receiving placebo.[22] Between 1990 and 2002, the Food and Drug Administration received 3339 reports of patients with rhabdomyolysis while taking a statin, 10.4% of which were life-threatening. However, 52% of these patients were taking other medications associated with rhabdomyolisis. [23]
The pathophysiology of statin-myopathy is fairly well understood. On one hand, Co-Enzyme Q-10 (ubiquinone) levels are decreased in statin use;[24] Ubiquinoine is a product of the steroid synthesis pathways and as such its production is reduced in statin use. It is also a key component of the electron transport chain of mitochondria. Accordingly, with less ubiquinone, the cell is less likely to meet its energy needs and may die. Coenzyme Q10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their effectiveness is currently lacking.[25] Additionally, statins - and not their metabolites - are directly toxic to liver cells. They have been shown to increase cell-death by causing both an increase in intracellular calcium concentration and the translocation into the mitochondria of bax, a pro-apoptotic protein.[26]
The risk of myopathy may be lowest with pravastatin and fluvastatin probably because they are less lipophillic and as a result have less muscle penetration.
N-of-1 trials have examined this:
- StatinWISE[27][28]
- SAMSON (Wood)[29][30]
- TaSINI[31]
## Neuromuscular Disorders and Mitochrondrial Myopathies
There is also a small, but growing literature of statin use 'unmasking' latent neurmuscular disorders and mitochondrial myopathies such as McArdle's Disease, Kennedy's Disease, MELAS, and Myasthenia Gravis.[32][33]
## Memory Loss
Memory loss have been reported by several patients taking statins, which have increased concerns about the effect of statins on the cognitive function. Statins, mainly the lipophilic types, might cause small decrease in memory and attention but there is no certainty regarding the clinical significance of this side effect nor the long term effect of statin on memory.[34][35]
## Cancer Concerns
Despite initial concerns that statins might increase the risk of cancer, various studies concluded later that statins have no influence on cancer risk (including the heart protection study and a 2006 meta-analysis[36]). Indeed, a 2005 trial showed that patients taking statins for over 5 years reduced their risk of colorectal cancer by 50%; this effect was not exhibited by fibrates. The trialists warn that the number needed to treat would approximate 5000, making statins unlikely tools for primary prevention.[37]
## Drug interactions
Combining any statin with a fibrate, another category of lipid-lowering drugs, increases the risks for rhabdomyolysis to almost 6.0 per 10,000 person-years.[21] Most physicians have now abandoned routine monitoring of liver enzymes and creatine kinase, although they still consider this prudent in those on high-dose statins or in those on statin/fibrate combinations, and mandatory in the case of muscle cramps or of deterioration in renal function.
Consumption of grapefruit or grapefruit juice inhibits the metabolism of statins—furanocoumarins in grapefruit juice inhibit the cytochrome P450 enzyme CYP3A4, which is involved in the metabolism of most statins (however it is a major inhibitor of only atorvastatin, lovastatin and simvastatin) and some other medications[38] (it had been thought that flavonoids were responsible). This increases the levels of the statin, increasing the risk of dose-related adverse effects (including myopathy/rhabdomyolysis). Consequently, consumption of grapefruit juice is not recommended in patients undergoing therapy with most statins. An alternative, somewhat risky, approach is that some users take grapefruit juice to enhance the effect of lower (hence cheaper) doses of statins. This is not recommended as a result of the increased risk and potential for statin toxicity.
# Controversy
Some scientists take a skeptical view of the need for many people to require statin treatment. The International Network of Cholesterol Skeptics is a group that has questioned the "lipid hypothesis" that supports cholesterol lowering as a preventive measure for heart disease, and has argued that statins - especially at higher doses - may not be as beneficial or safe as suggested.[39] Similarly, some authors argue that recommendations for the expanded use of statins to stave off cardiovascular disease are not supported by evidence.[40] | https://www.wikidoc.org/index.php/HMG-CoA_reductase_inhibitor | |
5d85051c36f376183471c7b51bdd330c69694172 | wikidoc | HNRNPC | HNRNPC
Heterogeneous nuclear ribonucleoproteins C1/C2 is a protein that in humans is encoded by the HNRNPC gene.
It is abnormally expressed in fetuses of both IVF and ICSI, which may contribute to the increase risk of birth defects in these ART.
# Function
This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing(reference: Koenig J. nature structural and Molecular Biology 2010: iCLIP) and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. Transcriptional regulation by hormonal 1,25-dihydroxyvitamin D(3) (calcitriol) involves occupancy of vitamin D response elements (VDREs) by HNRNPC or 1,25(OH)(2)D(3)-bound vitamin D receptor (VDR). This relationship is disrupted by elevated HNRNPC, causing a form of hereditary vitamin D-resistant rickets (HVDRR) in both humans and non-human primates. The protein encoded by this gene can act as a tetramer and is involved in the assembly of 40S hnRNP particles. Species-specific tetramerization of HNRNPC subunits is important to its nucleic acid binding, whereby over-expression of major human HNRNPC subunits in mouse osteoblastic cells confers vitamin D resistance. Multiple transcript variants encoding at least two different isoforms have been described for this gene.
# Interactions
HNRNPC has been shown to interact with Grb2. | HNRNPC
Heterogeneous nuclear ribonucleoproteins C1/C2 is a protein that in humans is encoded by the HNRNPC gene.[1][2]
It is abnormally expressed in fetuses of both IVF and ICSI, which may contribute to the increase risk of birth defects in these ART.[3]
# Function
This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing(reference: Koenig J. nature structural and Molecular Biology 2010: iCLIP) and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. Transcriptional regulation by hormonal 1,25-dihydroxyvitamin D(3) (calcitriol) involves occupancy of vitamin D response elements (VDREs) by HNRNPC or 1,25(OH)(2)D(3)-bound vitamin D receptor (VDR).[4][5][6] This relationship is disrupted by elevated HNRNPC, causing a form of hereditary vitamin D-resistant rickets (HVDRR) in both humans[4] and non-human primates.[7] The protein encoded by this gene can act as a tetramer and is involved in the assembly of 40S hnRNP particles. Species-specific tetramerization of HNRNPC subunits is important to its nucleic acid binding, whereby over-expression of major human HNRNPC subunits in mouse osteoblastic cells confers vitamin D resistance.[8] Multiple transcript variants encoding at least two different isoforms have been described for this gene.[2]
# Interactions
HNRNPC has been shown to interact with Grb2.[9] | https://www.wikidoc.org/index.php/HNRNPC | |
bc0e6b7a6eb148de480a419e4ed74304c11d187e | wikidoc | HNRPDL | HNRPDL
Heterogeneous nuclear ribonucleoprotein D-like, also known as HNRPDL, is a protein which in humans is encoded by the HNRPDL gene.
# Function
This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has two RRM domains that bind to RNAs. Two alternatively spliced transcript variants have been described for this gene. One of the variants is probably not translated because the transcript is a candidate for nonsense-mediated mRNA decay. The protein encoded by this gene is similar to its family member HNRPD.
# Clinical Significance
Heterozygous nonsense mutations in HNRNPDL has been identified as the cause of the autosomal disorder, Limb-girdle muscular dystrophy. | HNRPDL
Heterogeneous nuclear ribonucleoprotein D-like, also known as HNRPDL, is a protein which in humans is encoded by the HNRPDL gene.[1]
# Function
This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has two RRM domains that bind to RNAs. Two alternatively spliced transcript variants have been described for this gene. One of the variants is probably not translated because the transcript is a candidate for nonsense-mediated mRNA decay. The protein encoded by this gene is similar to its family member HNRPD.[1]
# Clinical Significance
Heterozygous nonsense mutations in HNRNPDL has been identified as the cause of the autosomal disorder, Limb-girdle muscular dystrophy. | https://www.wikidoc.org/index.php/HNRPDL | |
71e3c9db1c6a58a9b111b71ccb0b39f127bad58c | wikidoc | HOMER1 | HOMER1
Homer protein homolog 1 or Homer1 is a neuronal protein that in humans is encoded by the HOMER1 gene. Other names are Vesl and PSD-Zip45.
# Structure
Homer1 protein has an N-terminal EVH1 domain, involved in protein interaction, and a C-terminal coiled-coil domain involved in self association. It consists of two major splice variants, short-form (Homer1a) and long-form (Homer1b and c). Homer1a has only EVH1 domain and is monomeric while Homer1b and 1c have both EVH1 and coiled-coil domains and are tetrameric. The coiled-coil can be further separated into N-terminal half and C-terminal half. The N-terminal half of the coiled-coil domain is predicted to be a parallel dimer while the C-terminus half is a hybrid of dimeric and anti-parallel tetrameric coiled-coil. As a whole, long Homer is predicted to have a dumbbell-like structure where two pairs of EVH1 domains are located on two sides of long (~50 nm) coiled-coil domain. Mammals have Homer2 and Homer3, in addition to Homer1, which have similar domain structure. They also have similar alternatively spliced forms.
# Tissue distribution
Homer1 is expressed widely in the central nervous system as well as peripheral tissue including heart, kidney, ovary, testis, and skeletal muscle. Subcellularly in neurons, Homer1 is concentrated in postsynaptic structures and constitutes a major part of the postsynaptic density.
# Function
EVH1 domain interacts with PPXXF motif. This sequence motif exists in group 1 metabotrophic glutamate receptor (mGluR1 and mGluR5), IP3 receptors (IP3R), Shank, transient receptor potential canonical (TRPC) family channels, drebrin, oligophrenin, dynamin3, CENTG1, and ryanodin receptor. Through its tetrameric structure, long forms of Homer (such as Homer1b and Homer1c) are proposed to cross link different proteins. For example, group 1 mGluR is crossed linked with its signaling downstream, IP3 receptor. Also, through crosslinking another multimeric protein Shank, it is proposed to comprise a core of the postsynaptic density.
Notably, the expression of Homer1a is induced by neuronal activity while that of Homer1b and 1c are constitutive. Thus Homer1a is classified as an immediate early gene. Homer1a, acts as a natural dominant negative form that blocks interaction between long-forms and their ligand proteins by competing with the EVH1 binding site on the ligand proteins. In this way, the short form of Homer uncouples mGluR signaling and also shrinks dendritic spine structure. Therefore, the short form of Homer is considered to be a part of a mechanism of homeostatic plasticity that dampens the neuronal responsiveness when input activity is too high. The long form Homer1c plays a role in synaptic plasticity and the stabilization of synaptic changes during long-term potentiation.
The coiled-coil domain is reported to interact with syntaxin13 and activated Cdc42. The interaction with Cdc42 inhibit the activity of Cdc42 to remodel dendritic spine structure. | HOMER1
Homer protein homolog 1 or Homer1 is a neuronal protein that in humans is encoded by the HOMER1 gene.[1][2][3] Other names are Vesl and PSD-Zip45.
# Structure
Homer1 protein has an N-terminal EVH1 domain, involved in protein interaction, and a C-terminal coiled-coil domain involved in self association. It consists of two major splice variants, short-form (Homer1a) and long-form (Homer1b and c). Homer1a has only EVH1 domain and is monomeric while Homer1b and 1c have both EVH1 and coiled-coil domains and are tetrameric.[4][5] The coiled-coil can be further separated into N-terminal half and C-terminal half. The N-terminal half of the coiled-coil domain is predicted to be a parallel dimer while the C-terminus half is a hybrid of dimeric and anti-parallel tetrameric coiled-coil. As a whole, long Homer is predicted to have a dumbbell-like structure where two pairs of EVH1 domains are located on two sides of long (~50 nm) coiled-coil domain.[5] Mammals have Homer2 and Homer3, in addition to Homer1, which have similar domain structure. They also have similar alternatively spliced forms.
# Tissue distribution
Homer1 is expressed widely in the central nervous system as well as peripheral tissue including heart, kidney, ovary, testis, and skeletal muscle. Subcellularly in neurons, Homer1 is concentrated in postsynaptic structures and constitutes a major part of the postsynaptic density.
# Function
EVH1 domain interacts with PPXXF motif. This sequence motif exists in group 1 metabotrophic glutamate receptor (mGluR1 and mGluR5), IP3 receptors (IP3R), Shank, transient receptor potential canonical (TRPC) family channels, drebrin, oligophrenin, dynamin3, CENTG1, and ryanodin receptor.[1][3][6][7][8][9] Through its tetrameric structure, long forms of Homer (such as Homer1b and Homer1c) are proposed to cross link different proteins. For example, group 1 mGluR is crossed linked with its signaling downstream, IP3 receptor.[6] Also, through crosslinking another multimeric protein Shank, it is proposed to comprise a core of the postsynaptic density.[5]
Notably, the expression of Homer1a is induced by neuronal activity while that of Homer1b and 1c are constitutive. Thus Homer1a is classified as an immediate early gene. Homer1a, acts as a natural dominant negative form that blocks interaction between long-forms and their ligand proteins by competing with the EVH1 binding site on the ligand proteins. In this way, the short form of Homer uncouples mGluR signaling and also shrinks dendritic spine structure.[2][10] Therefore, the short form of Homer is considered to be a part of a mechanism of homeostatic plasticity that dampens the neuronal responsiveness when input activity is too high. The long form Homer1c plays a role in synaptic plasticity and the stabilization of synaptic changes during long-term potentiation.[11]
The coiled-coil domain is reported to interact with syntaxin13 and activated Cdc42. The interaction with Cdc42 inhibit the activity of Cdc42 to remodel dendritic spine structure. | https://www.wikidoc.org/index.php/HOMER1 | |
9f700447a40cffdbbb78c8d2779b7ff5f323d668 | wikidoc | HOT-17 | HOT-17
HOT-17, or 2,5-dimethoxy-4-(β-isobutylthio)-N-hydroxyphenethylamine, is a psychedelic phenethylamine of the 2C family. It was presumably first synthesized by Alexander Shulgin and reported in his book, PIHKAL.
# Chemistry
HOT-17's full chemical name is 2-[4-(2-isobutylthio)-2,5-dimethoxyphenyl-N-hydroxyethanamine. It has structural properties similar to 2C-T-17 and to other drugs in the HOT- series, with the most closely related compounds being HOT-2 and HOT-7.
# General Information
The dosage range of HOT-17 is typically 70-120 mg and its duration is approximately 12-18 hours according to Shulgin. HOT-17 produces time distortion and general psychedelia. It also has little to no body load.
# Categorization | HOT-17
HOT-17, or 2,5-dimethoxy-4-(β-isobutylthio)-N-hydroxyphenethylamine, is a psychedelic phenethylamine of the 2C family. It was presumably first synthesized by Alexander Shulgin and reported in his book, PIHKAL.
# Chemistry
HOT-17's full chemical name is 2-[4-(2-isobutylthio)-2,5-dimethoxyphenyl-N-hydroxyethanamine. It has structural properties similar to 2C-T-17 and to other drugs in the HOT- series, with the most closely related compounds being HOT-2 and HOT-7.
# General Information
The dosage range of HOT-17 is typically 70-120 mg and its duration is approximately 12-18 hours according to Shulgin. HOT-17 produces time distortion and general psychedelia. It also has little to no body load.
# Categorization
Template:Hallucinogenic phenethylamines
Template:PiHKAL | https://www.wikidoc.org/index.php/HOT-17 | |
13ba68948391541a75d1afa4fb5a76b1a98955df | wikidoc | HOTAIR | HOTAIR
HOTAIR (for HOX transcript antisense RNA) is a human gene located on chromosome 12. It is the first example of an RNA expressed on one chromosome that has been found to influence transcription on another chromosome.
# Gene and transcribed RNA product
The HOTAIR gene contains 6,232 bp and encodes 2.2 kb long noncoding RNA molecule, which controls gene expression. Its source DNA is located within a HOXC gene cluster. It is shuttled from chromosome 12 to chromosome 2 by the Suz-Twelve protein.
# Function
The 5' end of HOTAIR interacts with a Polycomb-group protein Polycomb Repressive Complex 2 (PRC2) and as a result regulates chromatin state. It is required for gene-silencing of the HOXD locus by PRC2. The 3' end of HOTAIR interacts with the histone demethylase LSD1.
It is an important factor in the epigenetic differentiation of skin over the surface of the body. Skin from various anatomical positions is distinct, e.g. the skin of the eyelid differs markedly from that on the sole of the foot.
# Clinical significance
HOTAIR is highly expressed in metastatic breast cancers. High levels of expression in primary breast tumours are a significant predictor of subsequent metastasis and death. This is partially due to HOTAIR-mediated overexpression of the HER2 oncogene through sequestration of miR-133-3p, which is a negative regulator of HER2 expression. In cells, especially those that over express PRC2, the prevention of HOTAIR expression leads to a reduction in invasive potential of that cell. It is also involved in esophageal squamous cell carcinoma. | HOTAIR
HOTAIR (for HOX transcript antisense RNA)[1] is a human gene located on chromosome 12. It is the first example of an RNA expressed on one chromosome that has been found to influence transcription on another chromosome.
# Gene and transcribed RNA product
The HOTAIR gene contains 6,232 bp and encodes 2.2 kb long noncoding RNA molecule, which controls gene expression. Its source DNA is located within a HOXC gene cluster. It is shuttled from chromosome 12 to chromosome 2 by the Suz-Twelve protein.[2]
# Function
The 5' end of HOTAIR interacts with a Polycomb-group protein Polycomb Repressive Complex 2 (PRC2) and as a result regulates chromatin state. It is required for gene-silencing of the HOXD locus by PRC2.[3][4] The 3' end of HOTAIR interacts with the histone demethylase LSD1.[4]
It is an important factor in the epigenetic differentiation of skin over the surface of the body. Skin from various anatomical positions is distinct, e.g. the skin of the eyelid differs markedly from that on the sole of the foot.[3][5]
# Clinical significance
HOTAIR is highly expressed in metastatic breast cancers. High levels of expression in primary breast tumours are a significant predictor of subsequent metastasis and death. This is partially due to HOTAIR-mediated overexpression of the HER2 oncogene through sequestration of miR-133-3p, which is a negative regulator of HER2 expression[6]. In cells, especially those that over express PRC2, the prevention of HOTAIR expression leads to a reduction in invasive potential of that cell. [7] It is also involved in esophageal squamous cell carcinoma.[8] | https://www.wikidoc.org/index.php/HOTAIR | |
f598c7770774a837505501d70d9ccaa849951fff | wikidoc | HOXA13 | HOXA13
Homeobox protein Hox-A13 is a protein that in humans is encoded by the HOXA13 gene.
# Function
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation.
# Clinical significance
Expansion of a polyalanine tract in the encoded protein can cause hand-foot-genital syndrome , also known as hand-foot-uterus syndrome. | HOXA13
Homeobox protein Hox-A13 is a protein that in humans is encoded by the HOXA13 gene.[1][2][3]
# Function
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation.[3]
# Clinical significance
Expansion of a polyalanine tract in the encoded protein can cause hand-foot-genital syndrome , also known as hand-foot-uterus syndrome.[4] | https://www.wikidoc.org/index.php/HOXA13 | |
9610dfa87a63746a827805bde00fc081cac0e70b | wikidoc | HOXB13 | HOXB13
Homeobox protein Hox-B13 is a protein that in humans is encoded by the HOXB13 gene.
# Function
This gene encodes a transcription factor that belongs to the homeobox gene family. Genes of this family are highly conserved among vertebrates and essential for vertebrate embryonic development. This gene has been implicated in fetal skin development and cutaneous regeneration. In mice, a similar gene was shown to exhibit temporal and spatial colinearity in the main body axis of the embryo, but was not expressed in the secondary axes, which suggests functions in body patterning along the axis. This gene and other HOXB genes form a gene cluster on chromosome 17 in the 17q21-22 region.
Men who inherit a rare (<0.1% in a selected group of patients without clinical signs of prostate cancer) genetic variant in HOXB13 (G84E or rs138213197) have a 10-20-fold increased risk of prostate cancer. | HOXB13
Homeobox protein Hox-B13 is a protein that in humans is encoded by the HOXB13 gene.[1][2][3]
# Function
This gene encodes a transcription factor that belongs to the homeobox gene family. Genes of this family are highly conserved among vertebrates and essential for vertebrate embryonic development. This gene has been implicated in fetal skin development and cutaneous regeneration. In mice, a similar gene was shown to exhibit temporal and spatial colinearity in the main body axis of the embryo, but was not expressed in the secondary axes, which suggests functions in body patterning along the axis. This gene and other HOXB genes form a gene cluster on chromosome 17 in the 17q21-22 region.[3]
Men who inherit a rare (<0.1% in a selected group of patients without clinical signs of prostate cancer) genetic variant in HOXB13 (G84E or rs138213197) have a 10-20-fold increased risk of prostate cancer.[4] | https://www.wikidoc.org/index.php/HOXB13 | |
c013268942c88e044af26d9dc410eda0e2f6373c | wikidoc | HOXC10 | HOXC10
Homeobox protein Hox-C10 is a protein that in humans is encoded by the HOXC10 gene.
# Function
This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. Mammals possess four similar homeobox gene clusters, HOXA, HOXB, HOXC and HOXD, which are located on different chromosomes and consist of 9 to 11 genes arranged in tandem. This gene is one of several homeobox HOXC genes located in a cluster on chromosome 12. The protein level is controlled during cell differentiation and proliferation, which may indicate this protein has a role in origin activation.
# Pathology
- HOXC10 is overexpressed in breast cancer and transcriptionally regulated by estrogen via involvement of histone methylases MLL3 and MLL4.
- Methylation of the estrogen-repressed gene HOXC10 in breast cancer determines resistance to aromatase inhibitors. This epigenetic reprogramming of HOXC10 is observed in endocrine-resistant breast cancer. | HOXC10
Homeobox protein Hox-C10 is a protein that in humans is encoded by the HOXC10 gene.[1][2]
# Function
This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. Mammals possess four similar homeobox gene clusters, HOXA, HOXB, HOXC and HOXD, which are located on different chromosomes and consist of 9 to 11 genes arranged in tandem. This gene is one of several homeobox HOXC genes located in a cluster on chromosome 12. The protein level is controlled during cell differentiation and proliferation, which may indicate this protein has a role in origin activation.[2]
# Pathology
- HOXC10 is overexpressed in breast cancer and transcriptionally regulated by estrogen via involvement of histone methylases MLL3 and MLL4.[3]
- Methylation of the estrogen-repressed gene HOXC10 in breast cancer determines resistance to aromatase inhibitors. This epigenetic reprogramming of HOXC10 is observed in endocrine-resistant breast cancer.[4] | https://www.wikidoc.org/index.php/HOXC10 | |
cc3492b415ecadee189c55b917d030cbe767e53c | wikidoc | HOXD10 | HOXD10
Homeobox D10, also known as HOXD10, is a protein which in humans is encoded by the HOXD10 gene.
# Function
This gene is a member of the Abd-B homeobox family and encodes a protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox D genes located on chromosome 2. The encoded nuclear protein functions as a sequence-specific transcription factor that is expressed in the developing limb buds and is involved in differentiation and limb development.
# Clinical significance
Mutations in this gene have been associated with Wilms' tumor and congenital vertical talus (also known as "rocker-bottom foot" deformity or congenital convex pes valgus) and/or a foot deformity resembling that seen in Charcot-Marie-Tooth disease.
# Regulation
The HOXD10 gene is repressed by the microRNAs miR-10a and miR-10b. | HOXD10
Homeobox D10, also known as HOXD10, is a protein which in humans is encoded by the HOXD10 gene.[1]
# Function
This gene is a member of the Abd-B homeobox family and encodes a protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox D genes located on chromosome 2. The encoded nuclear protein functions as a sequence-specific transcription factor that is expressed in the developing limb buds and is involved in differentiation and limb development.
# Clinical significance
Mutations in this gene have been associated with Wilms' tumor and congenital vertical talus (also known as "rocker-bottom foot" deformity or congenital convex pes valgus) and/or a foot deformity resembling that seen in Charcot-Marie-Tooth disease.[1][citation needed]
# Regulation
The HOXD10 gene is repressed by the microRNAs miR-10a and miR-10b.[2][3][4] | https://www.wikidoc.org/index.php/HOXD10 | |
5b064de9aa7a3a43463b5c64ae54dcb5677fe53c | wikidoc | HP1BP3 | HP1BP3
Heterochromatin protein 1, binding protein 3 is a protein that in humans is encoded by the HP1BP3 gene. It has been identified as a novel subtype of the linker histone H1, involved in the structure of heterochromatin
# Model organisms
Model organisms have been used in the study of HP1BP3 function. A conditional knockout mouse line, called Hp1bp3tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty three tests were carried out and six significant phenotypes were reported. Fewer homozygous mutant embryos were identified during gestation than predicted by Mendelian ratio. Homozygous mutant female adults had decreased body weight, heart weight and bone mineral density, and increased blood urea levels and T cell number.
HP1BP3 deficiency in mice results in severe dwarfism and impaired bone mass, caused by altered endocrine IGF-1 signaling. The gene is highly expressed in the brain and a number of behavioral phenotypes have been described for the mice. Lack of HP1BP3 led to impaired maternal behavior and reduced anxiety, leading to a dramatic reduction in litter survival. This may be related to the connection between HP1BP3 and postpartum depression in humans. Finally, HP1BP3 has been implicated in Alzheimer's disease.. | HP1BP3
Heterochromatin protein 1, binding protein 3 is a protein that in humans is encoded by the HP1BP3 gene.[1] It has been identified as a novel subtype of the linker histone H1, involved in the structure of heterochromatin [2][3][4]
# Model organisms
Model organisms have been used in the study of HP1BP3 function. A conditional knockout mouse line, called Hp1bp3tm1a(EUCOMM)Wtsi[12][13] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[14][15][16] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[10][17] Twenty three tests were carried out and six significant phenotypes were reported. Fewer homozygous mutant embryos were identified during gestation than predicted by Mendelian ratio. Homozygous mutant female adults had decreased body weight, heart weight and bone mineral density, and increased blood urea levels and T cell number.[10]
HP1BP3 deficiency in mice results in severe dwarfism and impaired bone mass, caused by altered endocrine IGF-1 signaling.[18] The gene is highly expressed in the brain and a number of behavioral phenotypes have been described for the mice. Lack of HP1BP3 led to impaired maternal behavior and reduced anxiety, leading to a dramatic reduction in litter survival.[19] This may be related to the connection between HP1BP3 and postpartum depression in humans.[20] Finally, HP1BP3 has been implicated in Alzheimer's disease.[2].[21] | https://www.wikidoc.org/index.php/HP1BP3 | |
ba95e3a15601db0c3bd23be4df4f5d56de91b186 | wikidoc | HS1BP3 | HS1BP3
HCLS1 binding protein 3 also known as HS1BP3 is a protein which in humans is encoded by the HS1BP3 gene.
# Function
The protein encoded by this gene shares similarity with mouse Hs1bp3, an Hcls1-interacting protein that may be involved in lymphocyte activation.
HS1BP3 binds members of the 14-3-3 protein family, which are highly expressed in motor neurons and Purkinje cells and regulate the Ca2+ / calmodulin-dependent protein kinase activation of tyrosine and tryptophan hydroxylase. | HS1BP3
HCLS1 binding protein 3 also known as HS1BP3 is a protein which in humans is encoded by the HS1BP3 gene.[1][2]
# Function
The protein encoded by this gene shares similarity with mouse Hs1bp3, an Hcls1-interacting protein that may be involved in lymphocyte activation.[3]
HS1BP3 binds members of the 14-3-3 protein family, which are highly expressed in motor neurons and Purkinje cells and regulate the Ca2+ / calmodulin-dependent protein kinase activation of tyrosine and tryptophan hydroxylase.[2] | https://www.wikidoc.org/index.php/HS1BP3 | |
2abb68a45b3fc08b47490be4d6c3fb1bcf98e9bc | wikidoc | HS3ST1 | HS3ST1
Heparan sulfate glucosamine 3-O-sulfotransferase 1 is an enzyme that in humans is encoded by the HS3ST1 gene.
# Function
Heparan sulfate biosynthetic enzymes are key components in generating a myriad of distinct heparan sulfate fine structures that carry out multiple biologic activities. The enzyme encoded by this gene is a member of the heparan sulfate biosynthetic enzyme family. It possesses both heparan sulfate glucosaminyl 3-O-sulfotransferase activity, anticoagulant heparan sulfate conversion activity, and is a rate limiting enzyme for synthesis of anticoagulant heparan. This enzyme is an intraluminal Golgi resident protein.
# Clinical significance
Polymorphisms in HS3ST1 appear to be a risk factor for developing Alzheimer's disease. | HS3ST1
Heparan sulfate glucosamine 3-O-sulfotransferase 1 is an enzyme that in humans is encoded by the HS3ST1 gene.[1][2]
# Function
Heparan sulfate biosynthetic enzymes are key components in generating a myriad of distinct heparan sulfate fine structures that carry out multiple biologic activities. The enzyme encoded by this gene is a member of the heparan sulfate biosynthetic enzyme family. It possesses both heparan sulfate glucosaminyl 3-O-sulfotransferase activity, anticoagulant heparan sulfate conversion activity, and is a rate limiting enzyme for synthesis of anticoagulant heparan. This enzyme is an intraluminal Golgi resident protein.[2]
# Clinical significance
Polymorphisms in HS3ST1 appear to be a risk factor for developing Alzheimer's disease.[3] | https://www.wikidoc.org/index.php/HS3ST1 | |
e17ab0d4cdf53e891d1d15b07da0436bfa171b60 | wikidoc | HSPA1A | HSPA1A
Heat shock 70 kDa protein 1, also termed Hsp72, is a protein that in humans is encoded by the HSPA1A gene. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. In addition, Hsp72 also facilitates DNA repair. Its functions contribute to biological processes including signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence and aging, and inflammatory diseases such as Diabetes mellitus type 2 and rheumatoid arthritis.
# Structure
This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 (Hsp70) family. As a Hsp70 protein, it has a C-terminal protein substrate-binding domain and an N-terminal ATP-binding domain.
The substrate-binding domain consists of two subdomains, a two-layered β-sandwich subdomain (SBDβ) and an α-helical subdomain (SBDα), which are connected by the loop Lα,β. SBDβ contains the peptide binding pocket while SBDα serves as a lid to cover the substrate binding cleft. The ATP binding domain consists of four subdomains split into two lobes by a central ATP/ADP binding pocket. The two terminal domains are linked together by a conserved region referred to as loop LL,1, which is critical for allosteric regulation. The unstructured region at the very end of the C-terminal is believed to be the docking site for co-chaperones.
# Function
This protein is a member of the Hsp70 family. In conjunction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. In order to properly fold non-native proteins, this protein interacts with the hydrophobic peptide segments of proteins in an ATP-controlled fashion. Though the exact mechanism still remains unclear, there are at least two alternative modes of action: kinetic partitioning and local unfolding. In kinetic partitioning, Hsp70s repetitively bind and release substrates in cycles that maintain low concentrations of free substrate. This effectively prevents aggregation while allowing free molecules to fold to the native state. In local unfolding, the binding and release cycles induce localized unfolding in the substrate, which helps to overcome kinetic barriers for folding to the native state. Ultimately, its role in protein folding contributes to its function in signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation.
In addition to the process of protein folding, transport and degradation, this Hsp70 member can preserve the function of mutant proteins. Nonetheless, effects of these mutations can still manifest when Hsp70 chaperones are overwhelmed during stress conditions. Hsp72 also protects against DNA damage and participates in DNA repair, including base excision repair (BER) and nucleotide excision repair (NER). Furthermore, this protein enhances antigen-specific tumor immunity by facilitating more efficient antigen presentation to cytotoxic T cells. It is also involved in the ubiquitin-proteasome pathway through interaction with the AU-rich element RNA-binding protein 1. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins. Finally, Hsp72 can protect against disrupted metabolic homeostasis by inducing production of pro-inflammatory cytokines, tumor necrosis factor-α, interleukin 1β, and interleukin-6 in immune cells, thereby reducing inflammation and improving skeletal muscle oxidation. Though at very low levels under normal conditions, HSP72 expression greatly increases under stress, effectively protecting cells from adverse effects in various pathological states.
Along with its role in DNA repair, Hsp72 is also directly involved in caspase-dependent apoptosis by binding Apaf-1, thereby inhibiting procaspase-9 activation and release of cytochrome c. Additionally, Hsp72 has been observed to inhibit apoptosis by preventing the release of SMAC/Diablo and binding XIAP to prevent its degradation. Hsp72 is also involved in caspase-independent apoptosis, as it also binds AIFM1.
# Clinical Significance
The Hsp70 member proteins are important apoptotic constituents. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
Hsp70 member proteins, including Hsp72, inhibit apoptosis by acting on the caspase-dependent pathway and against apoptosis-inducing agents such as tumor necrosis factor-α (TNFα), staurosporine, and doxorubicin. This role leads to its involvement in many pathological processes, such as oncogenesis, neurodegeneration, and senescence. In particular, overexpression of HSP72 has been linked to the development some cancers, such as hepatocellular carcinoma, gastric cancers, colon cancers, breast cancers, and lung cancers, which led to its use as a prognostic marker for these cancers. Elevated Hsp70 levels in tumor cells may increase malignancy and resistance to therapy by complexing, and hence, stabilizing, oncofetal proteins and products and transporting them into intracellular sites, thereby promoting tumor cell proliferation. As a result, tumor vaccine strategies for Hsp70s have been highly successful in animal models and progressed to clinical trials. One treatment, a Hsp72/AFP recombined vaccine, elicited robust protective immunity against AFP-expressing tumors in mice experiments. Therefore, the vaccine holds promise for treating hepatocellular carcinoma. Alternatively, overexpression of Hsp70 can mitigate damage from ischemia-reperfusion in cardiac muscle, as well damage from neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and spinocerebellar ataxias, and aging and cell senescence, as observed in centenarians subjected to heat shock challenge.
In Diabetes mellitus type 2 (T2DM), a small molecule activator of Hsp72 named BGP-15 has been shown to improve insulin sensitivity and inflammation in an insulin-resistant mouse model, increase mitochondrial volume, and improve metabolic homeostasis in a rat model of T2DM. BGP-15 has now proceeded to Phase 2b clinical trials and demonstrated no side-effects thus far. Though early speculation considered that Hsp72 expression might be affecting insulin sensitivity through a direct interaction with GLUT4, studies were unable to verify this link. Experiments did reveal that Hsp72 improved insulin sensitivity through stimulating glucose uptake during a hyperinsulemic-euglycemic clamp in T2DM patients. Additionally, Hsp72 has been associated with another inflammatory condition, rheumatoid arthritis, and could be implemented to help diagnose and monitor disease activity in patients.
# Interactions
HSPA1A has been shown to interact with:
- XIAP,
- Apaf-1,
- AIFM1,
- ASK1,
- BAG3,
- Casein kinase 2,
- FANCC,
- GPR37,
- HSF1,
- MSR1,
- PARK2,
- PARP1,
- STUB1, and
- XRCC1. | HSPA1A
Heat shock 70 kDa protein 1, also termed Hsp72, is a protein that in humans is encoded by the HSPA1A gene.[1][2] As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins.[1][2] In addition, Hsp72 also facilitates DNA repair.[3] Its functions contribute to biological processes including signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation.[2][4] It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence and aging, and inflammatory diseases such as Diabetes mellitus type 2 and rheumatoid arthritis.[5][6][4]
# Structure
This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 (Hsp70) family.[1] As a Hsp70 protein, it has a C-terminal protein substrate-binding domain and an N-terminal ATP-binding domain.[7][8][9]
The substrate-binding domain consists of two subdomains, a two-layered β-sandwich subdomain (SBDβ) and an α-helical subdomain (SBDα), which are connected by the loop Lα,β. SBDβ contains the peptide binding pocket while SBDα serves as a lid to cover the substrate binding cleft. The ATP binding domain consists of four subdomains split into two lobes by a central ATP/ADP binding pocket. The two terminal domains are linked together by a conserved region referred to as loop LL,1, which is critical for allosteric regulation. The unstructured region at the very end of the C-terminal is believed to be the docking site for co-chaperones.[9]
# Function
This protein is a member of the Hsp70 family. In conjunction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles.[1] In order to properly fold non-native proteins, this protein interacts with the hydrophobic peptide segments of proteins in an ATP-controlled fashion. Though the exact mechanism still remains unclear, there are at least two alternative modes of action: kinetic partitioning and local unfolding. In kinetic partitioning, Hsp70s repetitively bind and release substrates in cycles that maintain low concentrations of free substrate. This effectively prevents aggregation while allowing free molecules to fold to the native state. In local unfolding, the binding and release cycles induce localized unfolding in the substrate, which helps to overcome kinetic barriers for folding to the native state.[2] Ultimately, its role in protein folding contributes to its function in signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation.[2][4]
In addition to the process of protein folding, transport and degradation, this Hsp70 member can preserve the function of mutant proteins. Nonetheless, effects of these mutations can still manifest when Hsp70 chaperones are overwhelmed during stress conditions.[2] Hsp72 also protects against DNA damage and participates in DNA repair, including base excision repair (BER) and nucleotide excision repair (NER).[3] Furthermore, this protein enhances antigen-specific tumor immunity by facilitating more efficient antigen presentation to cytotoxic T cells.[4] It is also involved in the ubiquitin-proteasome pathway through interaction with the AU-rich element RNA-binding protein 1. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins.[1] Finally, Hsp72 can protect against disrupted metabolic homeostasis by inducing production of pro-inflammatory cytokines, tumor necrosis factor-α, interleukin 1β, and interleukin-6 in immune cells, thereby reducing inflammation and improving skeletal muscle oxidation.[5][10] Though at very low levels under normal conditions, HSP72 expression greatly increases under stress, effectively protecting cells from adverse effects in various pathological states.[11]
Along with its role in DNA repair, Hsp72 is also directly involved in caspase-dependent apoptosis by binding Apaf-1, thereby inhibiting procaspase-9 activation and release of cytochrome c.[7] Additionally, Hsp72 has been observed to inhibit apoptosis by preventing the release of SMAC/Diablo and binding XIAP to prevent its degradation.[8] Hsp72 is also involved in caspase-independent apoptosis, as it also binds AIFM1.[7]
# Clinical Significance
The Hsp70 member proteins are important apoptotic constituents. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[12] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
Hsp70 member proteins, including Hsp72, inhibit apoptosis by acting on the caspase-dependent pathway and against apoptosis-inducing agents such as tumor necrosis factor-α (TNFα), staurosporine, and doxorubicin. This role leads to its involvement in many pathological processes, such as oncogenesis, neurodegeneration, and senescence. In particular, overexpression of HSP72 has been linked to the development some cancers, such as hepatocellular carcinoma, gastric cancers, colon cancers, breast cancers, and lung cancers, which led to its use as a prognostic marker for these cancers.[4] Elevated Hsp70 levels in tumor cells may increase malignancy and resistance to therapy by complexing, and hence, stabilizing, oncofetal proteins and products and transporting them into intracellular sites, thereby promoting tumor cell proliferation.[2][4] As a result, tumor vaccine strategies for Hsp70s have been highly successful in animal models and progressed to clinical trials.[4] One treatment, a Hsp72/AFP recombined vaccine, elicited robust protective immunity against AFP-expressing tumors in mice experiments. Therefore, the vaccine holds promise for treating hepatocellular carcinoma.[4] Alternatively, overexpression of Hsp70 can mitigate damage from ischemia-reperfusion in cardiac muscle, as well damage from neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and spinocerebellar ataxias, and aging and cell senescence, as observed in centenarians subjected to heat shock challenge.[2][13]
In Diabetes mellitus type 2 (T2DM), a small molecule activator of Hsp72 named BGP-15 has been shown to improve insulin sensitivity and inflammation in an insulin-resistant mouse model, increase mitochondrial volume, and improve metabolic homeostasis in a rat model of T2DM. BGP-15 has now proceeded to Phase 2b clinical trials and demonstrated no side-effects thus far. Though early speculation considered that Hsp72 expression might be affecting insulin sensitivity through a direct interaction with GLUT4, studies were unable to verify this link. Experiments did reveal that Hsp72 improved insulin sensitivity through stimulating glucose uptake during a hyperinsulemic-euglycemic clamp in T2DM patients.[5] Additionally, Hsp72 has been associated with another inflammatory condition, rheumatoid arthritis, and could be implemented to help diagnose and monitor disease activity in patients.[6]
# Interactions
HSPA1A has been shown to interact with:
- XIAP,[8]
- Apaf-1,[7]
- AIFM1,[7][14]
- ASK1,[15]
- BAG3,[16][17]
- Casein kinase 2,[2]
- FANCC,[18][19]
- GPR37,[20]
- HSF1,[21][22]
- MSR1,[23]
- PARK2,[20]
- PARP1,[3]
- STUB1,[20][24] and
- XRCC1.[3] | https://www.wikidoc.org/index.php/HSPA1A | |
08d6c70fc5e3d0f617192e5a574518ca00ab560b | wikidoc | HSPA1B | HSPA1B
Heat shock 70kDa protein 1B, also known as HSPA1B, is a human gene. This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 family.
# Function
In conjunction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. It is also involved in the ubiquitin-proteasome pathway through interaction with the AU-rich element RNA-binding protein 1. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins.
# Disease linkage
Patients with chronic hepatitis B or hepatitis C virus infection who harbor a HSPA1B-1267 single nucleotide polymorphism have a higher risk for developing hepatocellular carcinoma. | HSPA1B
Heat shock 70kDa protein 1B, also known as HSPA1B, is a human gene.[1] This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 family.[2]
# Function
In conjunction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. It is also involved in the ubiquitin-proteasome pathway through interaction with the AU-rich element RNA-binding protein 1. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins.[2][3]
# Disease linkage
Patients with chronic hepatitis B or hepatitis C virus infection who harbor a HSPA1B-1267 single nucleotide polymorphism have a higher risk for developing hepatocellular carcinoma.[4] | https://www.wikidoc.org/index.php/HSPA1B | |
d89843a4180e0405f781df641be939882bf5ba1d | wikidoc | HSPA1L | HSPA1L
Heat shock 70 kDa protein 1L is a protein that in humans is encoded by the HSPA1L gene on chromosome 6. As a member of the heat shock protein 70 (Hsp70) family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. Its functions contribute to biological processes including signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence and aging, and Graft-versus-host disease.
# Structure
This gene encodes a 70kDa heat shock protein and is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which also encode isoforms of the 70kDa heat shock protein. The amino acid sequence of the encoded protein shares a 90% homology to the isoforms HSPA1A and HSPA1B. As a Hsp70 protein, it has a C-terminal protein substrate-binding domain and an N-terminal ATP-binding domain. The substrate-binding domain consists of two subdomains, a two-layered β-sandwich subdomain (SBDβ) and an α-helical subdomain (SBDα), which are connected by the loop Lα,β. SBDβ contains the peptide binding pocket while SBDα serves as a lid to cover the substrate binding cleft. The ATP binding domain consists of four subdomains split into two lobes by a central ATP/ADP binding pocket. The two terminal domains are linked together by a conserved region referred to as loop LL,1, which is critical for allosteric regulation. The unstructured region at the very end of the C-terminal is believed to be the docking site for co-chaperones.
Since a cDNA clone of this gene contains a 119 bp-region in the 5' UTR, it is likely that HSPA1L contains one or more introns in its own 5' UTR.
# Function
In general, HSPA1L is widely distributed across tissues at low abundances, but in particular, it is constitutively and abundantly expressed in the testis.
Along with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. In order to properly fold non-native proteins, this protein interacts with the hydrophobic peptide segments of proteins in an ATP-controlled fashion. Though the exact mechanism still remains unclear, there are at least two alternative modes of action: kinetic partitioning and local unfolding. In kinetic partitioning, Hsp70s repetitively bind and release substrates in cycles that maintain low concentrations of free substrate. This effectively prevents aggregation while allowing free molecules to fold to the native state. In local unfolding, the binding and release cycles induce localized unfolding in the substrate, which helps to overcome kinetic barriers for folding to the native state. Ultimately, its role in protein folding contributes to its function in signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation.
In addition to the process of protein folding, transport and degradation, this Hsp70 member can preserve the function of mutant proteins. Nonetheless, effects of these mutations can still manifest when Hsp70 chaperones are overwhelmed during stress conditions. Furthermore, this protein enhances antigen-specific tumor immunity by facilitating more efficient antigen presentation to cytotoxic T cells. Though it shares close homology to HSPA1A and HSPA1B, it is regulated differently and is not heat-inducible.
# Clinical significance
The Hsp70 member proteins are important apoptotic constituents. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
Hsp70 member proteins, including Hsp72, inhibit apoptosis by acting on the caspase-dependent pathway and against apoptosis-inducing agents such as tumor necrosis factor-α (TNFα), staurosporine, and doxorubicin. This role leads to its involvement in many pathological processes, such as oncogenesis, neurodegeneration, and senescence. In particular, overexpression of HSP72 has been linked to the development some cancers, such as hepatocellular carcinoma, gastric cancers, colon cancers, breast cancers, and lung cancers, which led to its use as a prognostic marker for these cancers. Elevated Hsp70 levels in tumor cells may increase malignancy and resistance to therapy by complexing, and hence, stabilizing, oncofetal proteins and products and transporting them into intracellular sites, thereby promoting tumor cell proliferation. As a result, tumor vaccine strategies for Hsp70s have been highly successful in animal models and progressed to clinical trials. Alternatively, overexpression of Hsp70 can mitigate the effects of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease (PD), Huntington’s disease, and spinocerebellar ataxias, and aging and cell senescence, as observed in centenarians subjected to heat shock challenge. HSPA1L may fight against PD by co-regulating the translocation of parkin to damaged mitochondria, thus facilitating their removal.
HSPA1L is also involved in Graft-versus-host disease (GVHD) and has potential to serve as a diagnostic/prognostic biomarker. Polymorphisms in the HSPA1L gene, especially those in the substrate binding domain, have been associated with disease.
# Interactions
HSPA1L has been shown to interact with PARK2. | HSPA1L
Heat shock 70 kDa protein 1L is a protein that in humans is encoded by the HSPA1L gene on chromosome 6.[1][2][3] As a member of the heat shock protein 70 (Hsp70) family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins.[3][4] Its functions contribute to biological processes including signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation.[4][5] It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence and aging, and Graft-versus-host disease.[4][5][6]
# Structure
This gene encodes a 70kDa heat shock protein and is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which also encode isoforms of the 70kDa heat shock protein.[3] The amino acid sequence of the encoded protein shares a 90% homology to the isoforms HSPA1A and HSPA1B.[7] As a Hsp70 protein, it has a C-terminal protein substrate-binding domain and an N-terminal ATP-binding domain.[8][9][10][11] The substrate-binding domain consists of two subdomains, a two-layered β-sandwich subdomain (SBDβ) and an α-helical subdomain (SBDα), which are connected by the loop Lα,β. SBDβ contains the peptide binding pocket while SBDα serves as a lid to cover the substrate binding cleft. The ATP binding domain consists of four subdomains split into two lobes by a central ATP/ADP binding pocket.[10] The two terminal domains are linked together by a conserved region referred to as loop LL,1, which is critical for allosteric regulation. The unstructured region at the very end of the C-terminal is believed to be the docking site for co-chaperones.[10][11]
Since a cDNA clone of this gene contains a 119 bp-region in the 5' UTR, it is likely that HSPA1L contains one or more introns in its own 5' UTR.[7]
# Function
In general, HSPA1L is widely distributed across tissues at low abundances, but in particular, it is constitutively and abundantly expressed in the testis.[11][12]
Along with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles.[4][5] In order to properly fold non-native proteins, this protein interacts with the hydrophobic peptide segments of proteins in an ATP-controlled fashion. Though the exact mechanism still remains unclear, there are at least two alternative modes of action: kinetic partitioning and local unfolding. In kinetic partitioning, Hsp70s repetitively bind and release substrates in cycles that maintain low concentrations of free substrate. This effectively prevents aggregation while allowing free molecules to fold to the native state. In local unfolding, the binding and release cycles induce localized unfolding in the substrate, which helps to overcome kinetic barriers for folding to the native state. Ultimately, its role in protein folding contributes to its function in signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation.[4][5]
In addition to the process of protein folding, transport and degradation, this Hsp70 member can preserve the function of mutant proteins. Nonetheless, effects of these mutations can still manifest when Hsp70 chaperones are overwhelmed during stress conditions.[4] Furthermore, this protein enhances antigen-specific tumor immunity by facilitating more efficient antigen presentation to cytotoxic T cells.[5] Though it shares close homology to HSPA1A and HSPA1B, it is regulated differently and is not heat-inducible.[7]
# Clinical significance
The Hsp70 member proteins are important apoptotic constituents. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[13] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
Hsp70 member proteins, including Hsp72, inhibit apoptosis by acting on the caspase-dependent pathway and against apoptosis-inducing agents such as tumor necrosis factor-α (TNFα), staurosporine, and doxorubicin. This role leads to its involvement in many pathological processes, such as oncogenesis, neurodegeneration, and senescence. In particular, overexpression of HSP72 has been linked to the development some cancers, such as hepatocellular carcinoma, gastric cancers, colon cancers, breast cancers, and lung cancers, which led to its use as a prognostic marker for these cancers.[5] Elevated Hsp70 levels in tumor cells may increase malignancy and resistance to therapy by complexing, and hence, stabilizing, oncofetal proteins and products and transporting them into intracellular sites, thereby promoting tumor cell proliferation.[4][5] As a result, tumor vaccine strategies for Hsp70s have been highly successful in animal models and progressed to clinical trials.[5] Alternatively, overexpression of Hsp70 can mitigate the effects of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease (PD), Huntington’s disease, and spinocerebellar ataxias, and aging and cell senescence, as observed in centenarians subjected to heat shock challenge.[4] HSPA1L may fight against PD by co-regulating the translocation of parkin to damaged mitochondria, thus facilitating their removal.[12]
HSPA1L is also involved in Graft-versus-host disease (GVHD) and has potential to serve as a diagnostic/prognostic biomarker.[6] Polymorphisms in the HSPA1L gene, especially those in the substrate binding domain, have been associated with disease.[11]
# Interactions
HSPA1L has been shown to interact with PARK2.[12] | https://www.wikidoc.org/index.php/HSPA1L | |
d106e7a2dbcdc025eb20afbcb69d4fd7c8015901 | wikidoc | HU-210 | HU-210
# Overview
HU-210 is a synthetic cannabinoid that was discovered around 1988 in the group of Dr Raphael Mechoulam at the Hebrew University. HU-210 is 100 to 800 times more potent than natural THC from cannabis and has an extended duration of action. HU-210 is the (+)-1,1-dimethylheptyl analog of 7-hydroxy-delta-6-tetrahydrocannabinol. The abbreviation HU stands for Hebrew University.
Per a 2005 article in the Journal Of Clinical Investigation, HU-210 with daily high doses over a few weeks stimulates neural growth in rats' hippocampus region, the opposite effect of drugs like alcohol, nicotine, heroin, and cocaine. It was also indicated by this increased neural growth to entail antianxiety and antidepressant effects.
HU-210, along side WIN 55,212-2 and JWH-133, is implicated in preventing the inflammation caused by Amyloid beta proteins involved in Alzheimer's Disease, in addition to preventing cognitive impairment and loss of neuronal markers. This anti-inflammatory action is induced through the agonization of cannabinoid receptors which prevents microglial activation that elicits the inflammation. Additionally, cannabinoids completely abolish neurotoxicity related to microglia activation in rat models.
HU-210 is a potent analgesic with many of the same effects as natural THC. This means that HU-210 could potentially be used in medicine as an alternative to medical marijuana, however its much stronger and longer lasting effects compared to those of THC could make appropriate titration of dosage difficult. Also because HU-210 is a CB1 full agonist as opposed to THC which is a partial agonist, the sedative effects of HU-210 are much more prominent, meaning that while fatal overdoses of THC itself are virtually impossible, they would be possible with HU-210. | HU-210
# Overview
HU-210 is a synthetic cannabinoid that was discovered around 1988 in the group of Dr Raphael Mechoulam at the Hebrew University. HU-210 is 100 to 800 times more potent than natural THC from cannabis and has an extended duration of action.[1] HU-210 is the (+)-1,1-dimethylheptyl analog of 7-hydroxy-delta-6-tetrahydrocannabinol. The abbreviation HU stands for Hebrew University.
Per a 2005 article in the Journal Of Clinical Investigation, HU-210 with daily high doses over a few weeks stimulates neural growth in rats' hippocampus region, the opposite effect of drugs like alcohol, nicotine, heroin, and cocaine. It was also indicated by this increased neural growth to entail antianxiety and antidepressant effects.
HU-210, along side WIN 55,212-2 and JWH-133, is implicated in preventing the inflammation caused by Amyloid beta proteins involved in Alzheimer's Disease, in addition to preventing cognitive impairment and loss of neuronal markers. This anti-inflammatory action is induced through the agonization of cannabinoid receptors which prevents microglial activation that elicits the inflammation. Additionally, cannabinoids completely abolish neurotoxicity related to microglia activation in rat models.
HU-210 is a potent analgesic with many of the same effects as natural THC. This means that HU-210 could potentially be used in medicine as an alternative to medical marijuana, however its much stronger and longer lasting effects compared to those of THC could make appropriate titration of dosage difficult. Also because HU-210 is a CB1 full agonist as opposed to THC which is a partial agonist, the sedative effects of HU-210 are much more prominent, meaning that while fatal overdoses of THC itself are virtually impossible[2], they would be possible with HU-210.
# External links
- Wen Jiang; et al. (2005). "Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic and antidepressant-like effects". The Journal of Clinical Investigation.CS1 maint: Explicit use of et al. (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} Scientific article about nerve cell growth.
Geoff Brumfiel (2005). "Marijuana may make your brain grow. Cannabinoid injections sprout new neurons in mice". Nature. Unknown parameter |month= ignored (help); Text " url ? http://www.nature.com/news/2005/051010/full/051010-12.html
- Geoff Brumfiel (2005). "Marijuana may make your brain grow. Cannabinoid injections sprout new neurons in mice". Nature. Unknown parameter |month= ignored (help); Text " url ? http://www.nature.com/news/2005/051010/full/051010-12.html
- Belén G. Ramírez, Cristina Blázquez, Teresa Gómez del Pulgar, Manuel Guzmán, and María L. de Ceballos (2005). "Prevention of Alzheimer's Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation". The Journal of Neuroscience.CS1 maint: Multiple names: authors list (link)
- Science News: High Times for Brain Growth: Marijuana-like drug multiplies neurons
de:Dexanabinol
it:HU-210
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/HU-210 | |
0237257983baa0d3921b2c6245fb3fe797aeb80d | wikidoc | Hadean | Hadean
The Hadean (Template:PronEng) is the geologic eon before the Archean. It started at Earth's formation about 4.6 billion years ago (4600 Ma), and ended roughly 3.8 billion years ago, though the latter date varies according to different sources. The name "Hadean" derives from Hades, Greek for "unseen" or "Hell" and suggesting the underworld or referring to the conditions on Earth at the time. The geologist Preston Cloud coined the term in 1972, originally to label the period before the earliest-known rocks. W. B. Harland later coined an almost synonymous term: the "Priscoan period". Other older texts simply refer to the eon as the Pre-Archean, while during much of the 19th and 20th centuries, the term Azoic (meaning without life) was commonly used.
# Subdivisions
Since few geological traces of this period remain on Earth there are no official subdivisions. However, several major divisions of the lunar geologic timescale occurred during the Hadean, and so these are sometimes used unofficially to refer to the same periods of time on Earth.
# Hadean rocks
In the last decades of the 20th century geologists identified a few Hadean rocks from Western Greenland, Northwestern Canada and Western Australia. The oldest known rock formations (the Isua greenstone belt) comprise sediments from Greenland dated around 3.8 billion years ago somewhat altered by a volcanic dike that penetrated the rocks after they were deposited. Individual zircon crystals redeposited in sediments in Western Canada and the Jack Hills region of Western Australia are much older. The oldest dated zircons date from about 4400 Ma - very close to the hypothesized time of the Earth's formation.
The Greenland sediments include banded iron beds. They contain possibly organic carbon and imply some possibility that photosynthetic life had already emerged at that time. The oldest known fossils (from Australia) date from a few hundred million years later.
The late heavy bombardment happened during Hadean times and affected the Earth and the Moon.
# Atmosphere and oceans
A sizeable quantity of water would have been in the material which formed the Earth. Water molecules would have escaped Earth's gravity until the planet attained a radius of about 40% of its current size; after that point, water (and other volatile substances) would have been retained. Hydrogen and helium are expected to continually leak from the atmosphere, but the lack of denser noble gases in the modern atmosphere suggests that something disastrous happened to the early atmosphere.
Part of the young planet is theorized to have been disrupted by the impact which created the Moon, which should have caused melting of one or two large areas. Present composition does not match complete melting and it is hard to completely melt and mix huge rock masses. However, a fair fraction of material should have been vaporized by this impact, creating a rock vapor atmosphere around the young planet. The rock vapor would have condensed within two thousand years, leaving behind hot volatiles which probably resulted in a heavy carbon dioxide atmosphere with hydrogen and water vapor. Liquid water oceans existed despite the surface temperature of 230°C because of the atmospheric pressure of the heavy CO2 atmosphere. As cooling continued, subduction and dissolving in ocean water removed most CO2 from the atmosphere but levels oscillated wildly as new surface and mantle cycles appeared.
Study of zircons has found that liquid water must have existed as long ago as 4400 Ma, very soon after the formation of the Earth. This requires the presence of an atmosphere. | Hadean
Template:Hadean Infobox
The Hadean (Template:PronEng) is the geologic eon before the Archean. It started at Earth's formation about 4.6 billion years ago (4600 Ma), and ended roughly 3.8 billion years ago, though the latter date varies according to different sources. The name "Hadean" derives from Hades, Greek for "unseen" or "Hell" and suggesting the underworld or referring to the conditions on Earth at the time. The geologist Preston Cloud coined the term in 1972, originally to label the period before the earliest-known rocks. W. B. Harland later coined an almost synonymous term: the "Priscoan period". Other older texts simply refer to the eon as the Pre-Archean, while during much of the 19th and 20th centuries, the term Azoic (meaning without life) was commonly used.
# Subdivisions
Since few geological traces of this period remain on Earth there are no official subdivisions. However, several major divisions of the lunar geologic timescale occurred during the Hadean, and so these are sometimes used unofficially to refer to the same periods of time on Earth.
# Hadean rocks
In the last decades of the 20th century geologists identified a few Hadean rocks from Western Greenland, Northwestern Canada and Western Australia. The oldest known rock formations (the Isua greenstone belt) comprise sediments from Greenland dated around 3.8 billion years ago somewhat altered by a volcanic dike that penetrated the rocks after they were deposited. Individual zircon crystals redeposited in sediments in Western Canada and the Jack Hills region of Western Australia are much older. The oldest dated zircons date from about 4400 Ma[1] - very close to the hypothesized time of the Earth's formation.
The Greenland sediments include banded iron beds. They contain possibly organic carbon and imply some possibility that photosynthetic life had already emerged at that time. The oldest known fossils (from Australia) date from a few hundred million years later.
The late heavy bombardment happened during Hadean times and affected the Earth and the Moon.
# Atmosphere and oceans
A sizeable quantity of water would have been in the material which formed the Earth.[2] Water molecules would have escaped Earth's gravity until the planet attained a radius of about 40% of its current size; after that point, water (and other volatile substances) would have been retained.[3] Hydrogen and helium are expected to continually leak from the atmosphere, but the lack of denser noble gases in the modern atmosphere suggests that something disastrous happened to the early atmosphere.
Part of the young planet is theorized to have been disrupted by the impact which created the Moon, which should have caused melting of one or two large areas. Present composition does not match complete melting and it is hard to completely melt and mix huge rock masses.[4] However, a fair fraction of material should have been vaporized by this impact, creating a rock vapor atmosphere around the young planet. The rock vapor would have condensed within two thousand years, leaving behind hot volatiles which probably resulted in a heavy carbon dioxide atmosphere with hydrogen and water vapor. Liquid water oceans existed despite the surface temperature of 230°C because of the atmospheric pressure of the heavy CO2 atmosphere. As cooling continued, subduction and dissolving in ocean water removed most CO2 from the atmosphere but levels oscillated wildly as new surface and mantle cycles appeared.[5]
Study of zircons has found that liquid water must have existed as long ago as 4400 Ma, very soon after the formation of the Earth.[6][7][8] This requires the presence of an atmosphere. | https://www.wikidoc.org/index.php/Hadean | |
b99c2de9a8f1e7bf7d30b48966a882c56a476f52 | wikidoc | Halide | Halide
# Overview
A halide is a binary compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative than the halogen, to make a fluoride, chloride, bromide, iodide, or astatide compound. Many salts are halides. All Group 1 metals form halides with the halogens and they are white solids.
A halide ion is a halogen atom bearing a negative charge. The halide anions are fluoride (F−), chloride (Cl−), bromide (Br−), iodide (I−) and astatide (At−). Such ions are present in all ionic halide salts.
# Halides in organic chemistry
In organic chemistry halides represent a functional group. Any organic compound that contains a halogen atom can be considered a halide. Alkyl halides are organic compounds of the type R-X, containing an alkyl group R covalently bonded to a halogen X.
Pseudohalides resemble halides in their charge and reactivity; common examples are azides NNN-, isocyanate -NCO, Isocyanide, CN-, etc.
A chemical test for the detection of halogen in chemical substances is the Carius halogen method.
# Halides in lighting
Metal halides are used in high-intensity discharge lamps called metal halide lamps, such as those used in modern street lights. These are more energy-efficient than mercury-vapor lamps, and have much better colour rendition than orange high-pressure sodium lamps. Metal halide lamps are also commonly used in greenhouses or in rainy climates to supplement natural sunlight.
HID (High-intensity discharge) lamps however, contribute highly to light pollution. Sodium-vapor are favored for this reason.
# Halide compounds
Examples of halide compounds are:
- sodium chloride (NaCl)
- potassium chloride (KCl)
- potassium iodide (KI)
- lithium chloride (LiCl)
- copper(II) chloride (CuCl2)
- chlorine fluoride (ClF)
- Bromomethane (CH3Br)
- Iodoform (CHI3)
- silver chloride (AgCl) | Halide
# Overview
A halide is a binary compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative than the halogen, to make a fluoride, chloride, bromide, iodide, or astatide compound. Many salts are halides. All Group 1 metals form halides with the halogens and they are white solids.
A halide ion is a halogen atom bearing a negative charge. The halide anions are fluoride (F−), chloride (Cl−), bromide (Br−), iodide (I−) and astatide (At−). Such ions are present in all ionic halide salts.
# Halides in organic chemistry
In organic chemistry halides represent a functional group. Any organic compound that contains a halogen atom can be considered a halide. Alkyl halides are organic compounds of the type R-X, containing an alkyl group R covalently bonded to a halogen X.
Pseudohalides resemble halides in their charge and reactivity; common examples are azides NNN-, isocyanate -NCO, Isocyanide, CN-, etc.[1]
A chemical test for the detection of halogen in chemical substances is the Carius halogen method.
# Halides in lighting
Metal halides are used in high-intensity discharge lamps called metal halide lamps, such as those used in modern street lights. These are more energy-efficient than mercury-vapor lamps, and have much better colour rendition than orange high-pressure sodium lamps. Metal halide lamps are also commonly used in greenhouses or in rainy climates to supplement natural sunlight.
HID (High-intensity discharge) lamps however, contribute highly to light pollution. Sodium-vapor are favored for this reason.
# Halide compounds
Examples of halide compounds are:
- sodium chloride (NaCl)
- potassium chloride (KCl)
- potassium iodide (KI)
- lithium chloride (LiCl)
- copper(II) chloride (CuCl2)
- chlorine fluoride (ClF)
- Bromomethane (CH3Br)
- Iodoform (CHI3)
- silver chloride (AgCl) | https://www.wikidoc.org/index.php/Halide | |
51cd0043973f5caa5a7307e9bc55e9ec02b4521b | wikidoc | Halite | Halite
Halite is the mineral form of sodium chloride, NaCl, commonly known as rock salt. Halite forms isometric crystals. The mineral is typically colourless to yellow, but may also be light blue, dark blue, and pink. It commonly occurs with other evaporite deposit minerals such as several of the sulfates, halides and borates.
# Occurrence
Halite occurs in vast beds of sedimentary evaporite minerals that result from the drying up of enclosed lakes, playas, and seas. Salt beds may be up to 405 meters thick and underlie broad areas. In the United States and Canada extensive underground beds extend from the Appalachian basin of western New York through parts of Ontario and under much of the Michigan Basin. Other deposits are in Ohio, Kansas, New Mexico, Nova Scotia and Saskatchewan.
Salt domes are vertical diapirs or pipe-like masses of salt that have been essentially "squeezed up" from underlying salt beds by mobilization due to the weight of overlying rock. Salt domes contain anhydrite, gypsum, and native sulfur, in addition to halite and sylvite. They are common along the Gulf coasts of Texas and Louisiana and are often associated with petroleum deposits. Germany, Spain, the Netherlands, Romania and Iran also have salt domes. Salt glaciers exist in arid Iran where the salt has broken through the surface at high elevation and flows downhill. In all of these cases, halite is said to be behaving in the manner of a rheid.
Unusual, purple, fibrous vein filling halite is found in France and a few other localities. Halite crystals termed hopper crystals appear to be "skeletons" of the typical cubes, with the edges present and stairstep depressions on, or rather in, each crystal face. In a rapidly crystallizing environment the edges of the cubes simply grow faster than the centers. Halite crystals form very quickly in some rapidly evaporating lakes resulting in modern artefacts with a coating or encrustation of halite crystals. Halite flowers are rare stalactites of curling fibers of halite that are found in certain arid caves of Australia's Nullarbor Plain. Halite stalactites and encrustations are also reported in the Quincy native copper mine of Hancock, Michigan.
# Uses
Halite is often used both residentially and municipally for managing ice. Because saline (a solution of water and salt) has a lower freezing point than ordinary water, putting salt on ice will cause it to melt. It is common for homeowners in cold climates to spread 'rock salt' on their walkways and sometimes driveways after a snow storm to melt the ice. It is not necessary to use so much salt that the ice is completely melted; rather, a small amount of salt will weaken the ice so that it can be easily removed with other means. Also, many cities will spread a mixture of sand and salt on roads during and after a snowstorm to improve traction.
Rock salt is also used to make ice cream. It is not actually used in the ice cream mixture; rather, it is used to melt the ice surrounding the can holding the ice cream, causing the ice to melt at a lower temperature, thus lowering the temperature of the ice bath and quickening the freezing process. | Halite
Template:Infobox mineral
Halite is the mineral form of sodium chloride, NaCl, commonly known as rock salt. Halite forms isometric crystals. The mineral is typically colourless to yellow, but may also be light blue, dark blue, and pink. It commonly occurs with other evaporite deposit minerals such as several of the sulfates, halides and borates.
# Occurrence
Halite occurs in vast beds of sedimentary evaporite minerals that result from the drying up of enclosed lakes, playas, and seas. Salt beds may be up to 405 meters thick and underlie broad areas. In the United States and Canada extensive underground beds extend from the Appalachian basin of western New York through parts of Ontario and under much of the Michigan Basin. Other deposits are in Ohio, Kansas, New Mexico, Nova Scotia and Saskatchewan.
Salt domes are vertical diapirs or pipe-like masses of salt that have been essentially "squeezed up" from underlying salt beds by mobilization due to the weight of overlying rock. Salt domes contain anhydrite, gypsum, and native sulfur, in addition to halite and sylvite. They are common along the Gulf coasts of Texas and Louisiana and are often associated with petroleum deposits. Germany, Spain, the Netherlands, Romania and Iran also have salt domes. Salt glaciers exist in arid Iran where the salt has broken through the surface at high elevation and flows downhill. In all of these cases, halite is said to be behaving in the manner of a rheid.
Unusual, purple, fibrous vein filling halite is found in France and a few other localities. Halite crystals termed hopper crystals appear to be "skeletons" of the typical cubes, with the edges present and stairstep depressions on, or rather in, each crystal face. In a rapidly crystallizing environment the edges of the cubes simply grow faster than the centers. Halite crystals form very quickly in some rapidly evaporating lakes resulting in modern artefacts with a coating or encrustation of halite crystals. Halite flowers are rare stalactites of curling fibers of halite that are found in certain arid caves of Australia's Nullarbor Plain. Halite stalactites and encrustations are also reported in the Quincy native copper mine of Hancock, Michigan.
# Uses
Halite is often used both residentially and municipally for managing ice. Because saline (a solution of water and salt) has a lower freezing point than ordinary water, putting salt on ice will cause it to melt. It is common for homeowners in cold climates to spread 'rock salt' on their walkways and sometimes driveways after a snow storm to melt the ice. It is not necessary to use so much salt that the ice is completely melted; rather, a small amount of salt will weaken the ice so that it can be easily removed with other means. Also, many cities will spread a mixture of sand and salt on roads during and after a snowstorm to improve traction.
Rock salt is also used to make ice cream. It is not actually used in the ice cream mixture; rather, it is used to melt the ice surrounding the can holding the ice cream, causing the ice to melt at a lower temperature, thus lowering the temperature of the ice bath and quickening the freezing process. | https://www.wikidoc.org/index.php/Halite | |
ef3db85154918d9641a09ee0be6f09febe75170a | wikidoc | Haptic | Haptic
# Overview
Haptic, from the Greek Template:Polytonic (Haphe), means pertaining to the sense of touch (or possibly from the Greek word Template:Polytonic haptesthai meaning “contact” or “touch”).
Haptic technology refers to technology which interfaces the user via the sense of touch by applying forces, vibrations and/or motions to the user. This mechanical stimulation may be used to assist in the creation of virtual objects (objects existing only in a computer simulation), for control of such virtual objects, and to enhance the remote control of machines and devices (teleoperators). This emerging technology promises to have wide reaching applications. In some fields, it already has. For example, haptic technology has made it possible to investigate in detail how the human sense of touch works, by allowing the creation of carefully-controlled haptic virtual objects. These objects are used to systematically probe human haptic capabilities. This is very difficult to achieve otherwise. These new research tools contribute to our understanding of how touch and its underlying brain functions work (See References below).
Although haptic devices are capable of measuring bulk or reactive forces that are applied by the user it should not to be confused with touch or tactile sensors that measure the pressure or force exerted by the user to the interface.
# History
One of the earliest forms of haptic devices is used in large modern aircraft that use servo systems to operate control systems. Such systems tend to be "one-way" in that forces applied aerodynamically to the control surfaces are not perceived at the controls, with the missing normal forces simulated with springs and weights. In earlier, lighter aircraft without servo systems, as the aircraft approached a stall the aerodynamic buffeting was felt in the pilot's controls, a useful warning to the pilot of a dangerous flight condition. This control shake is not felt when servo control systems are used. To replace this missing cue, the angle of attack is measured, and when it approaches the critical stall point a "stick shaker" (an unbalanced rotating mass) is engaged, simulating the effects of a simpler control system. This is known as haptic feedback. Alternatively the servo force may be measured and this signal directed to a servo system on the control. This method is known as force feedback. Force feedback has been implemented experimentally in some excavators. This is useful when excavating mixed materials such as large rocks embedded in silt or clay, as it allows the operator to "feel" and work around unseen obstacles, enabling significant increases in productivity.
# Teleoperators and simulators
Teleoperators are remote controlled robotic tools, and when contact forces are reproduced to the operator, it is called "haptic teleoperation".
The first electrically actuated teleoperators were built in the 1950's at the Argonne National Lab, USA, by Dr. Raymond C. Goertz, to remotely handle radioactive substances.
Since then, the use of "force feedback" has become more widespread in all kinds of teleoperators such as underwater exploration devices controlled from a remote location.
In 1988 researchers at Cybernet Systems first developed devices that generated arbitrary forces from computer models or simulations in lieu of actual physical slave devices. When such devices are simulated using a computer (as they are in operator training devices) it is useful to provide the force feedback that would be felt in actual operations. Since the objects being manipulated do not exist in a physical sense, the forces are generated using haptic (force generating) operator controls. Data representing touch sensations may be saved or played back using such haptic technologies. Cybernet licensed its force feedback patents to Immersion Corporation in 1998 and Immersion licensed Logitech, Microsoft, Sony and others to manufacture Force Feedback joysticks, wheels, and other devices worldwide.
Haptic simulators are currently used in medical simulators and flight simulators for pilot training (2004).
## Games
Some low-end haptic devices are already common in the form game controllers, in particular of joysticks and steering wheels. At first, such features and/or devices used to be optional components (like the Nintendo 64 controller's Rumble Pak). Now many of the newer generation console controllers and some joysticks feature built in devices. An example of this feature would be the simulated automobile steering wheels that are programmed to provide a "feel" of the road. As the user makes a turn or accelerates, the steering wheel responds by resisting turns or slipping out of control. Another concept of force feedback was that of the ability to change the temperature of the controlling device. This would prove especially efficient for prolonged usage of the device. However, due to the high cost of such a technology (not to mention the power drainage of such a component) the closest many manufacturers have come to realizing this concept has been to install air holes or small fans into the device to provide the user's hands with ventilation while operating the device.
## Haptics in virtual reality
Haptics is gaining widespread acceptance as a key part of virtual reality systems, adding the sense of touch to previously visual-only solutions. Most of these solutions use stylus-based haptic rendering, where the user interfaces to the virtual world via a tool or stylus, giving a form of interaction that is computationally realistic on today's hardware
## Research
Some research has been done into simulating the different kinds of tactition by means of high-speed vibrations or other stimuli. One device of this type uses a pad array of pins, where the pins vibrate to simulate a surface being touched. While this does not have a realistic feel, it does provide useful feedback, allowing discrimination between various shapes, textures, and resiliencies.
Several haptics API's have been developed for research applications, such as Chai3D, OpenHaptics and H3DAPI (Open Source).
## Medicine
Various haptic interfaces for medical simulation may prove especially useful for training of minimally invasive procedures (laparoscopy/interventional radiology) and remote surgery using teleoperators. In the future, expert surgeons may work from a central workstation, performing operations in various locations, with machine setup and patient preparation performed by local nursing staff. Rather than traveling to an operating room, the surgeon instead becomes a telepresence. A particular advantage of this type of work is that the surgeon can perform many more operations of a similar type, and with less fatigue. It is well documented that a surgeon who performs more procedures of a given kind will have statistically better outcomes for his patients.
In ophthalmology, "haptic" refers to a supporting spring, two of which hold an artificial lens within the lens capsule (after surgical removal of cataracts).
A 'Virtual Haptic Back' (VHB) is being successfully integrated in the curriculum of students at the Ohio University College of Osteopathic Medicine. Research indicates that VHB is a significant teaching aid in palpatory diagnosis (detection of medical problems via touch). The VHB simulates the contour and compliance (reciprocal of stiffness) properties of human backs, which are palpated with two haptic interfaces (SensAble Technologies, PHANToM 3.0).
## Literature
The use of haptic devices in entertainment appeared in the 1932 futurist fiction book Brave New World by Aldous Huxley. The author described a future entertainment theater where the arm rests of the seats had positions for the hands to rest that gave haptic stimulation. The programs exhibited were of an erotic nature and rather than "the movies" these theaters and shows were called "the feelies". Haptic devices, including self-propelled haptics, feature prominently in Vernor Vinge's 2006 novel Rainbows End.
## Robotics
The Shadow Dextrous Robot Hand uses the sense of touch, pressure, and position to reproduce the human grip in all its strength, delicacy, and complexity. The SDRH was first developed by Richard Greenhill and his team of engineers in Islington, London, as part of The Shadow Project, (now known as the Shadow Robot Company) an ongoing research and development program whose goal is to complete the first convincing humanoid. An early prototype can be seen in NASA's collection of humanoid robots, or robonauts. The Dextrous Hand has haptic sensors embedded in every joint and in every finger pad which relay information to a central computer for processing and analysis. Carnegie Mellon University in Pennsylvania and Bielefeld University in Germany in particular have found The Dextrous Hand is an invaluable tool in progressing our understanding of haptic awareness and are currently involved (2006) in research with wide ranging implications.
## Arts
Touching is not limited to a feeling, but it allows interactivity in real-time with virtual objects. Thus haptics are commonly used in virtual arts, such as sound synthesis or graphic design/animation. The haptic device allows the artist to have direct contact with a virtual instrument which is able to produce real-time sound or images. We can quote the physical modelling synthesis which is an efficient modelling theory to implement cross-play interaction between sound, image, and physical objects. For instance, the simulation of a violin string produces real-time vibrations of this string under the pressure and expressivity of the bow (haptic device) held by the artist.
## Design
Designers and modellers may use high-degree of freedom input devices which give touch feedback relating to the "surface" they are sculpting or creating, allowing faster and more natural workflow than with traditional methods. | Haptic
# Overview
Haptic, from the Greek Template:Polytonic (Haphe), means pertaining to the sense of touch (or possibly from the Greek word Template:Polytonic haptesthai meaning “contact” or “touch”).
Haptic technology refers to technology which interfaces the user via the sense of touch by applying forces, vibrations and/or motions to the user. This mechanical stimulation may be used to assist in the creation of virtual objects (objects existing only in a computer simulation), for control of such virtual objects, and to enhance the remote control of machines and devices (teleoperators). This emerging technology promises to have wide reaching applications. In some fields, it already has. For example, haptic technology has made it possible to investigate in detail how the human sense of touch works, by allowing the creation of carefully-controlled haptic virtual objects. These objects are used to systematically probe human haptic capabilities. This is very difficult to achieve otherwise. These new research tools contribute to our understanding of how touch and its underlying brain functions work (See References below).
Although haptic devices are capable of measuring bulk or reactive forces that are applied by the user it should not to be confused with touch or tactile sensors that measure the pressure or force exerted by the user to the interface.
# History
One of the earliest forms of haptic devices is used in large modern aircraft that use servo systems to operate control systems. Such systems tend to be "one-way" in that forces applied aerodynamically to the control surfaces are not perceived at the controls, with the missing normal forces simulated with springs and weights. In earlier, lighter aircraft without servo systems, as the aircraft approached a stall the aerodynamic buffeting was felt in the pilot's controls, a useful warning to the pilot of a dangerous flight condition. This control shake is not felt when servo control systems are used. To replace this missing cue, the angle of attack is measured, and when it approaches the critical stall point a "stick shaker" (an unbalanced rotating mass) is engaged, simulating the effects of a simpler control system. This is known as haptic feedback. Alternatively the servo force may be measured and this signal directed to a servo system on the control. This method is known as force feedback. Force feedback has been implemented experimentally in some excavators. This is useful when excavating mixed materials such as large rocks embedded in silt or clay, as it allows the operator to "feel" and work around unseen obstacles, enabling significant increases in productivity.
# Teleoperators and simulators
Teleoperators are remote controlled robotic tools, and when contact forces are reproduced to the operator, it is called "haptic teleoperation".
The first electrically actuated teleoperators were built in the 1950's at the Argonne National Lab, USA, by Dr. Raymond C. Goertz, to remotely handle radioactive substances.
Since then, the use of "force feedback" has become more widespread in all kinds of teleoperators such as underwater exploration devices controlled from a remote location.
In 1988 researchers at Cybernet Systems[1] first developed devices that generated arbitrary forces from computer models or simulations in lieu of actual physical slave devices.[2] When such devices are simulated using a computer (as they are in operator training devices) it is useful to provide the force feedback that would be felt in actual operations. Since the objects being manipulated do not exist in a physical sense, the forces are generated using haptic (force generating) operator controls. Data representing touch sensations may be saved or played back using such haptic technologies. Cybernet licensed its force feedback patents to Immersion Corporation in 1998 and Immersion licensed Logitech, Microsoft, Sony and others to manufacture Force Feedback joysticks, wheels, and other devices worldwide.
Haptic simulators are currently used in medical simulators and flight simulators for pilot training (2004).
## Games
Some low-end haptic devices are already common in the form game controllers, in particular of joysticks and steering wheels. At first, such features and/or devices used to be optional components (like the Nintendo 64 controller's Rumble Pak). Now many of the newer generation console controllers and some joysticks feature built in devices. An example of this feature would be the simulated automobile steering wheels that are programmed to provide a "feel" of the road. As the user makes a turn or accelerates, the steering wheel responds by resisting turns or slipping out of control. Another concept of force feedback was that of the ability to change the temperature of the controlling device. This would prove especially efficient for prolonged usage of the device. However, due to the high cost of such a technology (not to mention the power drainage of such a component) the closest many manufacturers have come to realizing this concept has been to install air holes or small fans into the device to provide the user's hands with ventilation while operating the device.
## Haptics in virtual reality
Haptics is gaining widespread acceptance as a key part of virtual reality systems, adding the sense of touch to previously visual-only solutions. Most of these solutions use stylus-based haptic rendering, where the user interfaces to the virtual world via a tool or stylus, giving a form of interaction that is computationally realistic on today's hardware
## Research
Some research has been done into simulating the different kinds of tactition by means of high-speed vibrations or other stimuli. One device of this type uses a pad array of pins, where the pins vibrate to simulate a surface being touched. While this does not have a realistic feel, it does provide useful feedback, allowing discrimination between various shapes, textures, and resiliencies.
Several haptics API's have been developed for research applications, such as Chai3D, OpenHaptics and H3DAPI (Open Source).
## Medicine
Various haptic interfaces for medical simulation may prove especially useful for training of minimally invasive procedures (laparoscopy/interventional radiology)[3] and remote surgery using teleoperators. In the future, expert surgeons may work from a central workstation, performing operations in various locations, with machine setup and patient preparation performed by local nursing staff. Rather than traveling to an operating room, the surgeon instead becomes a telepresence. A particular advantage of this type of work is that the surgeon can perform many more operations of a similar type, and with less fatigue. It is well documented that a surgeon who performs more procedures of a given kind will have statistically better outcomes for his patients.
In ophthalmology, "haptic" refers to a supporting spring, two of which hold an artificial lens within the lens capsule (after surgical removal of cataracts).
A 'Virtual Haptic Back' (VHB) is being successfully integrated in the curriculum of students at the Ohio University College of Osteopathic Medicine.[4] Research indicates that VHB is a significant teaching aid in palpatory diagnosis (detection of medical problems via touch). The VHB simulates the contour and compliance (reciprocal of stiffness) properties of human backs, which are palpated with two haptic interfaces (SensAble Technologies, PHANToM 3.0).
## Literature
The use of haptic devices in entertainment appeared in the 1932 futurist fiction book Brave New World by Aldous Huxley. The author described a future entertainment theater where the arm rests of the seats had positions for the hands to rest that gave haptic stimulation. The programs exhibited were of an erotic nature and rather than "the movies" these theaters and shows were called "the feelies". Haptic devices, including self-propelled haptics, feature prominently in Vernor Vinge's 2006 novel Rainbows End.
## Robotics
The Shadow Dextrous Robot Hand uses the sense of touch, pressure, and position to reproduce the human grip in all its strength, delicacy, and complexity.[5] The SDRH was first developed by Richard Greenhill and his team of engineers in Islington, London, as part of The Shadow Project, (now known as the Shadow Robot Company) an ongoing research and development program whose goal is to complete the first convincing humanoid. An early prototype can be seen in NASA's collection of humanoid robots, or robonauts.[6] The Dextrous Hand has haptic sensors embedded in every joint and in every finger pad which relay information to a central computer for processing and analysis. Carnegie Mellon University in Pennsylvania and Bielefeld University in Germany in particular have found The Dextrous Hand is an invaluable tool in progressing our understanding of haptic awareness and are currently involved (2006) in research with wide ranging implications.
## Arts
Touching is not limited to a feeling, but it allows interactivity in real-time with virtual objects. Thus haptics are commonly used in virtual arts, such as sound synthesis or graphic design/animation. The haptic device allows the artist to have direct contact with a virtual instrument which is able to produce real-time sound or images. We can quote the physical modelling synthesis which is an efficient modelling theory to implement cross-play interaction between sound, image, and physical objects. For instance, the simulation of a violin string produces real-time vibrations of this string under the pressure and expressivity of the bow (haptic device) held by the artist.
## Design
Designers and modellers may use high-degree of freedom input devices which give touch feedback relating to the "surface" they are sculpting or creating, allowing faster and more natural workflow than with traditional methods.[7] | https://www.wikidoc.org/index.php/Haptic | |
1fc8dff8622423114fc74c18f0cbae06fcba606a | wikidoc | Harmal | Harmal
Harmal (Peganum harmala) is a plant of the family Nitrariaceae, native from the eastern Mediterranean region east to India. It is also sometimes known as Syrian Rue, a confusing name as it is not related to rue (Ruta, family Rutaceae).
In the United States Peganum harmala grows as an invasive exotic in Arizona, California, Montana, New Mexico, Nevada, Oregon, Texas and Washington.
# Traditional uses
It has been used as an entheogen in the Middle East, and in modern Western culture, it is often used as an analogue of Banisteriopsis caapi to create an ad-hoc Ayahuasca, the notorious South American mixture of phyto-indoles including DMT with β-carbolines. Syrian Rue however has distinct aspects from caapi and a unique entheogenic signature.
In Turkey dried capsules from this plant are strung and hung in homes or vehicles to protect against "the evil eye".
In Iran, dried capsules (known in Persian as اسپند espænd or اسفنددانه esfænd-dāneh) - mixed with other ingredients - are burnt so as to produce a light, distinctly scented smoke or incense. It is used as an air as well as mind purifier - perhaps linked to its entheogenic properties - and mostly as a charm against "the evil eye". This Persian practice dates to pre-Islamic, Zoroastrian times.
Peganum harmala is also an abortifacient.
# Alkaloids
The active alkaloids of Harmal seeds are the MAOI (MonoAmine Oxidase Inhibitor) compounds harmine, harmaline, and tetrahydroharmine (collectively known as harmala alkaloids). Harmaline is a "reversible inhibitor of MAO-A (RIMA)." The seeds contain about 2-6% alkaloids, most of which is harmaline.
- Vasicine
- Vasicinone | Harmal
Harmal (Peganum harmala) is a plant of the family Nitrariaceae, native from the eastern Mediterranean region east to India. It is also sometimes known as Syrian Rue, a confusing name as it is not related to rue (Ruta, family Rutaceae).
In the United States Peganum harmala grows as an invasive exotic in Arizona, California, Montana, New Mexico, Nevada, Oregon, Texas and Washington.[1]
# Traditional uses
It has been used as an entheogen in the Middle East, and in modern Western culture, it is often used as an analogue of Banisteriopsis caapi to create an ad-hoc Ayahuasca, the notorious South American mixture of phyto-indoles including DMT with β-carbolines. Syrian Rue however has distinct aspects from caapi and a unique entheogenic signature.
In Turkey dried capsules from this plant are strung and hung in homes or vehicles to protect against "the evil eye".
In Iran, dried capsules (known in Persian as اسپند espænd or اسفنددانه esfænd-dāneh) - mixed with other ingredients - are burnt so as to produce a light, distinctly scented smoke or incense. It is used as an air as well as mind purifier - perhaps linked to its entheogenic properties - and mostly as a charm against "the evil eye". This Persian practice dates to pre-Islamic, Zoroastrian times.
Peganum harmala is also an abortifacient.[2]
# Alkaloids
The active alkaloids of Harmal seeds are the MAOI (MonoAmine Oxidase Inhibitor) compounds harmine, harmaline, and tetrahydroharmine (collectively known as harmala alkaloids). Harmaline is a "reversible inhibitor of MAO-A (RIMA)."[3] The seeds contain about 2-6% alkaloids, most of which is harmaline.[4]
- Vasicine[2]
- Vasicinone[2]
# External links
- Erowid Syrian Rue Vault | https://www.wikidoc.org/index.php/Harmal | |
bb92ce1be6de4af3448de2b9eeffc3c9cee0da23 | wikidoc | Hazard | Hazard
A Hazard is a situation which poses a level of threat to life, health, property or environment. Most hazards are dormant or potential, with only a theoretical risk of harm, however, once a hazard becomes 'active', it can create an emergency situation.
# Modes of a Hazard
A hazard is usually used to describe a potentially harmful situation, although not usually the event itself - once the incident has started it is classified as an emergency or incident. There are a number of modes for a hazard, which include:
- Dormant - The situation has the potential to be hazardous, but no people, property or environment is currently affected by this. For instance, a hillside may be unstable, with the potential for a landslide, but there is nothing below or on the hillside which could be affected.
- Potential - Also known as 'Armed', this is a situation where the hazard is in the position to affect persons, property or environment. This type of hazard is likely to require further risk assessment.
- Active - The hazard is certain to cause harm, as no intervention is possible before the incident occurs.
- Mitigated - A potential hazard has been identified, but actions have been taken in order to ensure it does not become an incident. This may not be an absolute guarantee of no risk, but it is likely to have been undertaken to significantly reduce the danger.
# Classifying Hazards
By its nature, a hazard involves something which could potentially be harmful to a person's life, health, property or to the environment. There are a number of methods of classifying a hazard, but most systems use some variation on the factors of Likelihood of the hazard turning into an incident and the Seriousness of the incident if it were to occur.
A common method is to score both likelihood and seriousness on a numerical scale (with the most likely and most serious scoring highest) and multiplying one by the other in order to reach a comparative score.
Risk = Likelihood of Occurrence x Seriousness if incident occurred.
This score can then be used to identify which hazards may need to be mitigated. A low score on likelihood of occurrence may mean that the hazard is dormant, whereas a high score would indicate that it may be an Active hazard.
# Causes of hazards
There are many causes , but they can broadly be termed into:
- Natural - Natural hazards include anything which is caused by a natural process, and can include obvious hazards such as volcanoes to smaller scale hazards such as loose rocks on a hillside
- Man made - Hazards created by humans, which includes a huge array of possibilities, probably too many to list, as it includes long term (and sometimes disputed) effects such as global warming to immediate hazards such as building sites
- Activity related - Some hazards are created by the undertaking of a certain activity, and the cessation of the activity will negate the risk. This includes hazards ie. flying.
de:Gefährdung
el:Κίνδυνος
fi:Hasardi | Hazard
A Hazard is a situation which poses a level of threat to life, health, property or environment. Most hazards are dormant or potential, with only a theoretical risk of harm, however, once a hazard becomes 'active', it can create an emergency situation.
# Modes of a Hazard
A hazard is usually used to describe a potentially harmful situation, although not usually the event itself - once the incident has started it is classified as an emergency or incident. There are a number of modes for a hazard, which include:
- Dormant - The situation has the potential to be hazardous, but no people, property or environment is currently affected by this. For instance, a hillside may be unstable, with the potential for a landslide, but there is nothing below or on the hillside which could be affected.
- Potential - Also known as 'Armed', this is a situation where the hazard is in the position to affect persons, property or environment. This type of hazard is likely to require further risk assessment.
- Active - The hazard is certain to cause harm, as no intervention is possible before the incident occurs.
- Mitigated - A potential hazard has been identified, but actions have been taken in order to ensure it does not become an incident. This may not be an absolute guarantee of no risk, but it is likely to have been undertaken to significantly reduce the danger.
# Classifying Hazards
By its nature, a hazard involves something which could potentially be harmful to a person's life, health, property or to the environment. There are a number of methods of classifying a hazard, but most systems use some variation on the factors of Likelihood of the hazard turning into an incident and the Seriousness of the incident if it were to occur.
A common method is to score both likelihood and seriousness on a numerical scale (with the most likely and most serious scoring highest) and multiplying one by the other in order to reach a comparative score.
Risk = Likelihood of Occurrence x Seriousness if incident occurred.
This score can then be used to identify which hazards may need to be mitigated. A low score on likelihood of occurrence may mean that the hazard is dormant, whereas a high score would indicate that it may be an Active hazard.
# Causes of hazards
There are many causes , but they can broadly be termed into:
- Natural - Natural hazards include anything which is caused by a natural process, and can include obvious hazards such as volcanoes to smaller scale hazards such as loose rocks on a hillside
- Man made - Hazards created by humans, which includes a huge array of possibilities, probably too many to list, as it includes long term (and sometimes disputed) effects such as global warming to immediate hazards such as building sites
- Activity related - Some hazards are created by the undertaking of a certain activity, and the cessation of the activity will negate the risk. This includes hazards ie. flying.
de:Gefährdung
el:Κίνδυνος
fi:Hasardi
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Hazard | |
8535f15b6805870fcbe7efd06fcea0c9d1ea0799 | wikidoc | Healia | Healia
Healia is a health vertical search engine that uses algorithms to assess quality and to categorize documents. Healia, Inc. is located in Bellevue, Washington state, USA.
# Quality Index Score
Healia use patent-pending Quality Index Score™ to judge the quality of search results.
# Management team
President & Founder: Thomas R. Eng (VMD, MPH).
Thomas (Tom) Eng received a Small Business Innovation Research (SBIR) Award from the National Institutes of Health (NIH) in 2001 to develop this website. The National Cancer Institute (part of the NIH) assisted with research and development, and Healia was incorporated in March of 2005. It became available to the public in September of 2006.
Healia was acquired by Meredith Corporation in June 2007.
Healia's CTO is Marcos Athanasoulis (MPH, DrPH) who runs the tech.
# Drawbacks
The searching results are heavily US biased with many initial search results finding information from American web sites. | Healia
Template:Expand
Healia [1] is a health vertical search engine that uses algorithms to assess quality and to categorize documents. Healia, Inc. is located in Bellevue, Washington state, USA.
# Quality Index Score
Healia use patent-pending Quality Index Score™ to judge the quality of search results.
# Management team
President & Founder: Thomas R. Eng (VMD, MPH)[1][2].
Thomas (Tom) Eng received a Small Business Innovation Research (SBIR) Award from the National Institutes of Health (NIH) in 2001 to develop this website. The National Cancer Institute (part of the NIH) assisted with research and development, and Healia was incorporated in March of 2005. It became available to the public in September of 2006. [3]
Healia was acquired by Meredith Corporation in June 2007.
Healia's CTO is Marcos Athanasoulis (MPH, DrPH) who runs the tech. [4][5]
# Drawbacks
The searching results are heavily US biased with many initial search results finding information from American web sites.
[6] | https://www.wikidoc.org/index.php/Healia | |
f034167d8bddab8050ede8dfea4fe572810a6478 | wikidoc | Heliox | Heliox
# Overview
Heliox is a breathing gas that is composed of a mixture of helium (He) and oxygen (O2).
Heliox has been used in a medical context since the 1930s, and although the medical community adopted its use initially to alleviate the symptoms of upper airway obstruction, its range of medical uses has since expanded greatly, most of which are dependent on the low density of the gas. Heliox is also used in saturation diving and sometimes during the deep phase of technical dives.
# Medical uses
In medicine, "heliox" generally describes a mixture that is 21% O2 (the same as air) and 79% He, although other mixtures are available.
Airway resistance is dictated by the diameter of the airways and by the density of the inspired gas. Therefore when nitrogen (of air) is replaced by helium, airway resistance is reduced due to the lower density of the inspired gas. This means that when one breathes Heliox, airway resistance is less, and therefore the mechanical energy required to ventilate the lungs, or the Work of Breathing (WOB) is decreased. Heliox is used mainly in the alleviation of many medical conditions that involve a decrease in airway diameter (and consequently increased airway resistance), such as upper airway obstruction, asthma, chronic obstructive pulmonary disease (COPD), bronchiolitis and croup. Patients with these conditions may suffer a range of symptoms including dyspnea (breathlessness), hypoxemia (below-normal oxygen content in the arterial blood) and eventually a weakening of the respiratory muscles due to exhaustion, which can lead to respiratory failure and require intubation and mechanical ventilation - Heliox may reduce all these effects, making it easier for the patient to breathe, and as it will reduce work of breathing, Heliox can help to prevent this respiratory failure. Heliox has also found utility in the weaning of patients off mechanical ventilation, and in the nebulization of inhalable drugs.
de:Heliox
nl:Heliox
sv:Heliox | Heliox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Heliox is a breathing gas that is composed of a mixture of helium (He) and oxygen (O2).
Heliox has been used in a medical context since the 1930s, and although the medical community adopted its use initially to alleviate the symptoms of upper airway obstruction, its range of medical uses has since expanded greatly, most of which are dependent on the low density of the gas. Heliox is also used in saturation diving and sometimes during the deep phase of technical dives.
# Medical uses
In medicine, "heliox" generally describes a mixture that is 21% O2 (the same as air) and 79% He, although other mixtures are available.
Airway resistance is dictated by the diameter of the airways and by the density of the inspired gas. Therefore when nitrogen (of air) is replaced by helium, airway resistance is reduced due to the lower density of the inspired gas. This means that when one breathes Heliox, airway resistance is less, and therefore the mechanical energy required to ventilate the lungs, or the Work of Breathing (WOB) is decreased. Heliox is used mainly in the alleviation of many medical conditions that involve a decrease in airway diameter (and consequently increased airway resistance), such as upper airway obstruction, asthma, chronic obstructive pulmonary disease (COPD), bronchiolitis and croup. Patients with these conditions may suffer a range of symptoms including dyspnea (breathlessness), hypoxemia (below-normal oxygen content in the arterial blood) and eventually a weakening of the respiratory muscles due to exhaustion, which can lead to respiratory failure and require intubation and mechanical ventilation - Heliox may reduce all these effects, making it easier for the patient to breathe, and as it will reduce work of breathing, Heliox can help to prevent this respiratory failure. Heliox has also found utility in the weaning of patients off mechanical ventilation, and in the nebulization of inhalable drugs.
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f774afeb85db93aea581a31df3ee05129dc6645b | wikidoc | Helium | Helium
Helium (He) is a colorless, odorless, tasteless, non-toxic, inert monatomic chemical element that heads the noble gas series in the periodic table and whose atomic number is 2. Its boiling and melting points are the lowest among the elements and it exists only as a gas except in extreme conditions. Extreme conditions are also needed to create the small handful of helium compounds, which are all unstable at standard temperature and pressure. It has a second, rare, stable isotope which is called helium-3. The behavior of liquid helium-4's two fluid phases, helium I and helium II, is important to researchers studying quantum mechanics (in particular the phenomenon of superfluidity) and to those looking at the effects that temperatures near absolute zero have on matter (such as superconductivity).
Helium is the second most abundant and second lightest element in the universe, and is one of the elements believed to have been created in the Big Bang. In the modern universe almost all new helium is created as a result of the nuclear fusion of hydrogen in stars. On Earth it is created by the radioactive decay of much heavier elements (alpha particles are helium nuclei). After its creation, part of it is trapped with natural gas in concentrations up to 7% by volume. It is extracted from the natural gas by a low temperature separation process called fractional distillation.
In 1868 the French astronomer Pierre Janssen first detected helium as an unknown yellow spectral line signature in light from a solar eclipse. Since then large reserves of helium have been found in the natural gas fields of the United States, which is by far the largest supplier of the gas. It is used in cryogenics, in deep-sea breathing systems, to cool superconducting magnets, in helium dating, for inflating balloons, for providing lift in airships and as a protective gas for many industrial uses (such as arc welding and growing silicon wafers).
# Notable characteristics
## Gas and plasma phases
Helium is the least reactive member of the noble gas elements, and thus also the least reactive of all elements; it is inert and monatomic in virtually all conditions. Due to helium's relatively low molar (molecular) mass, in the gas phase it has a thermal conductivity, specific heat, and sound conduction velocity that are all greater than any gas, except hydrogen. For similar reasons, and also due to the small size of its molecules, helium's diffusion rate through solids is three times that of air and around 65% that of hydrogen.
Helium is less water soluble than any other gas known, and helium's index of refraction is closer to unity than that of any other gas. Helium has a negative Joule-Thomson coefficient at normal ambient temperatures, meaning it heats up when allowed to freely expand. Only below its Joule-Thomson inversion temperature (of about 40 K at 1 atmosphere) does it cool upon free expansion. Once precooled below this temperature, helium can be liquefied through expansion cooling.
Throughout the universe, helium is found mostly in a plasma state whose properties are quite different from atomic helium. In a plasma, helium's electrons and protons are not bound together, resulting in very high electrical conductivity, even when the gas is only partially ionized. The charged particles are highly influenced by magnetic and electric fields. For example, in the solar wind together with ionized hydrogen, they interact with the Earth's magnetosphere giving rise to Birkeland currents and the aurora.
## Solid and liquid phases
Helium solidifies only under great pressure. The resulting colorless, almost invisible solid is highly compressible; applying pressure in a laboratory can decrease its volume by more than 30%. With a bulk modulus on the order of 5×107 Pa it is 50 times more compressible than water. Unlike any other element, helium will fail to solidify and remain a liquid down to absolute zero at normal pressures. This is a direct effect of quantum mechanics: specifically, the zero point energy of the system is too high to allow freezing. Solid helium requires a temperature of 1–1.5 K (about −272 °C or −457 °F) and about 25 bar (2.5 MPa) of pressure. It is often hard to distinguish solid from liquid helium since the refractive index of the two phases are nearly the same. The solid has a sharp melting point and has a crystalline structure.
Solid helium has a density of 0.214 ±0.006 g/ml (1.15 K, 66 atm) with a mean isothermal compressibility of the solid at 1.15 K between the solidus and 66 atm of 0.0031 ±0.0008/atm. Also, no difference in density was noted between 1.8 K and 1.5 K. This data projects that T=0 solid helium under 25 bar of pressure (the minimum required to freeze helium) has a density of 0.187 ±0.009 g/ml.
### Helium I state
Below its boiling point of 4.22 kelvin and above the lambda point of 2.1768 kelvin, the isotope helium-4 exists in a normal colorless liquid state, called helium I. Like other cryogenic liquids, helium I boils when it is heated. It also contracts when its temperature is lowered until it reaches the lambda point, when it stops boiling and suddenly expands. The rate of expansion decreases below the lambda point until about 1 K is reached; at which point expansion completely stops and helium I starts to contract again.
Helium I has a gas-like index of refraction of 1.026 which makes its surface so hard to see that floats of styrofoam are often used to show where the surface is. This colorless liquid has a very low viscosity and a density one-eighth that of water, which is only one-fourth the value expected from classical physics. Quantum mechanics is needed to explain this property and thus both types of liquid helium are called quantum fluids, meaning they display atomic properties on a macroscopic scale. This is probably due to its boiling point being so close to absolute zero, which prevents random molecular motion (heat) from masking the atomic properties.
### Helium II state
Liquid helium below its lambda point begins to exhibit very unusual characteristics, in a state called helium II. Boiling of helium II is not possible due to its high thermal conductivity; heat input instead causes evaporation of the liquid directly to gas. The isotope helium-3 also has a superfluid phase, but only at much lower temperatures; as a result, less is known about such properties in the isotope helium-3.
Helium II is a superfluid, a quantum-mechanical state of matter with strange properties. For example, when it flows through even capillaries of 10−7 to 10−8 m width it has no measurable viscosity. However, when measurements were done between two moving discs, a viscosity comparable to that of gaseous helium was observed. Current theory explains this using the two-fluid model for helium II. In this model, liquid helium below the lambda point is viewed as containing a proportion of helium atoms in a ground state, which are superfluid and flow with exactly zero viscosity, and a proportion of helium atoms in an excited state, which behave more like an ordinary fluid.
Helium II also exhibits a "creeping" effect. When a surface extends past the level of helium II, the helium II moves along the surface, seemingly against the force of gravity. Helium II will escape from a vessel that is not sealed by creeping along the sides until it reaches a warmer region where it evaporates. It moves in a 30 nm-thick film regardless of surface material. This film is called a Rollin film and is named after the man who first characterized this trait, Bernard V. Rollin. As a result of this creeping behavior and helium II's ability to leak rapidly through tiny openings, it is very difficult to confine liquid helium. Unless the container is carefully constructed, the helium II will creep along the surfaces and through valves until it reaches somewhere warmer, where it will evaporate. Waves propagating across a Rollin film are governed by the same equation as gravity waves in shallow water, but rather than gravity, the restoring force is the Van der Waals force. These waves are known as third sound.
In the fountain effect, a chamber is constructed which is connected to a reservoir of helium II by a sintered disc through which superfluid helium leaks easily but through which non-superfluid helium cannot pass. If the interior of the container is heated, the superfluid helium changes to non-superfluid helium. In order to maintain the equilibrium fraction of superfluid helium, superfluid helium leaks through and increases the pressure, causing liquid to fountain out of the container.
The thermal conductivity of helium II is greater than that of any other known substance, a million times that of helium I and several hundred times that of copper. This is because heat conduction occurs by an exceptional quantum-mechanical mechanism. Most materials that conduct heat well have a valence band of free electrons which serve to transfer the heat. Helium II has no such valence band but nevertheless conducts heat well. The flow of heat is governed by equations that are similar to the wave equation used to characterize sound propagation in air. So when heat is introduced, it will move at 20 meters per second at 1.8 K through helium II as waves in a phenomenon called second sound.
# Applications
Helium is used for many purposes that require some of its unique properties, such as its low boiling point, low density, low solubility, high thermal conductivity, or inertness. Helium is commercially available in either liquid or gaseous form. As a liquid, it can be supplied in small containers called dewars which hold up to 1,000 liters of helium, or in large ISO containers which have nominal capacities as large as 11,000 gallons (41,637 liters). In gaseous form, small quantities of helium are supplied in high pressure cylinders holding up to 300 standard cubic feet, while large quantities of high pressure gas are supplied in tube trailers which have capacities of up to 180,000 standard cubic feet.
- Because it is lighter than air, airships and balloons are inflated with helium for lift. In airships, helium is preferred over hydrogen because it is not flammable and has 92.64% of the buoyancy (or lifting power) of the alternative hydrogen (see calculation.)
- For its low solubility in water, the major part of human blood, air mixtures of helium with oxygen and nitrogen (Trimix), with oxygen only (Heliox), with common air (heliair), and with hydrogen and oxygen (hydreliox), are used in deep-sea breathing systems to reduce the high-pressure risk of nitrogen narcosis, decompression sickness, and oxygen toxicity.
- At extremely low temperatures, liquid helium is used to cool certain metals to produce superconductivity, such as in superconducting magnets used in magnetic resonance imaging. Helium at low temperatures is also used in cryogenics.
- For its inertness and high thermal conductivity, neutron transparency, and because it does not form radioactive isotopes under reactor conditions, helium is used as a coolant in some nuclear reactors, such as pebble-bed reactors.
- Helium is used as a shielding gas in arc welding processes on materials that are contaminated easily by air. It is especially useful in overhead welding, because it is lighter than air and thus floats, whereas other shielding gases sink.
- Because it is inert, helium is used as a protective gas in growing silicon and germanium crystals, in titanium and zirconium production, in gas chromatography, and as an atmosphere for protecting historical documents. This property also makes it useful in supersonic wind tunnels.
- In rocketry, helium is used as an ullage medium to displace fuel and oxidizers in storage tanks and to condense hydrogen and oxygen to make rocket fuel. It is also used to purge fuel and oxidizer from ground support equipment prior to launch and to pre-cool liquid hydrogen in space vehicles. For example, the Saturn V booster used in the Apollo program needed about 13 million cubic feet (370,000 m³) of helium to launch.
- The gain medium of the helium-neon laser is a mixture of helium and neon.
- Because it diffuses through solids at a rate three times that of air, helium is used as a tracer gas to detect leaks in high-vacuum equipment and high-pressure containers, as well as in other applications with less stringent requirements such as heat exchangers, valves, gas panels, etc.
- Because of its extremely low index of refraction, the use of helium reduces the distorting effects of temperature variations in the space between lenses in some telescopes.
- The age of rocks and minerals that contain uranium and thorium, radioactive elements that emit helium nuclei called alpha particles, can be discovered by measuring the level of helium with a process known as helium dating.
- The high thermal conductivity and sound velocity of helium is also desirable in thermoacoustic refrigeration. The inertness of helium adds to the environmental advantage of this technology over conventional refrigeration systems which may contribute to ozone depleting and global warming effects.
- Because helium alone is less dense than atmospheric air, it will change the timbre (not pitch) of a person's voice when inhaled. However, inhaling it from a typical commercial source, such as that used to fill balloons, can be dangerous due to the risk of asphyxiation from lack of oxygen, and the number of contaminants that may be present. These could include trace amounts of other gases, in addition to aerosolized lubricating oil.
# History
## Scientific discoveries
Evidence of helium was first detected on August 18, 1868 as a bright yellow line with a wavelength of 587.49 nanometres in the spectrum of the chromosphere of the Sun, by French astronomer Pierre Janssen during a total solar eclipse in Guntur, India. This line was initially assumed to be sodium. On October 20 of the same year, English astronomer Norman Lockyer observed a yellow line in the solar spectrum, which he named the D3 line, for it was near the known D1 and D2 lines of sodium, and concluded that it was caused by an element in the Sun unknown on Earth. He and English chemist Edward Frankland named the element with the Greek word for the Sun, ἥλιος (helios)
On 26 March 1895 British chemist William Ramsay isolated helium on Earth by treating the mineral cleveite with mineral acids. Ramsay was looking for argon but, after separating nitrogen and oxygen from the gas liberated by sulfuric acid, noticed a bright-yellow line that matched the D3 line observed in the spectrum of the Sun. These samples were identified as helium by Lockyer and British physicist William Crookes. It was independently isolated from cleveite the same year by chemists Per Teodor Cleve and Abraham Langlet in Uppsala, Sweden, who collected enough of the gas to accurately determine its atomic weight. Helium was also isolated by the American geochemist William Francis Hillebrand prior to Ramsay's discovery when he noticed unusual spectral lines while testing a sample of the mineral uraninite. Hillebrand, however, attributed the lines to nitrogen. His letter of congratulations to Ramsay offers an interesting case of discovery and near-discovery in science.
In 1907, Ernest Rutherford and Thomas Royds demonstrated that an alpha particle is a helium nucleus. In 1908, helium was first liquefied by Dutch physicist Heike Kamerlingh Onnes by cooling the gas to less than one kelvin. He tried to solidify it by further reducing the temperature but failed because helium does not have a triple point temperature where the solid, liquid, and gas phases are at equilibrium. It was first solidified in 1926 by his student Willem Hendrik Keesom by subjecting helium to 25 atmospheres of pressure.
In 1938, Russian physicist Pyotr Leonidovich Kapitsa discovered that helium-4 has almost no viscosity at temperatures near absolute zero, a phenomenon now called superfluidity. In 1972, the same phenomenon was observed in helium-3 by American physicists Douglas D. Osheroff, David M. Lee, and Robert C. Richardson.
## History of extraction and use
After an oil drilling operation in 1903 in Dexter, Kansas, U.S. produced a gas geyser that would not burn, Kansas state geologist Erasmus Haworth collected samples of the escaping gas and took them back to the University of Kansas at Lawrence where, with the help of chemists Hamilton Cady and David McFarland, he discovered that the gas contained, by volume, 72% nitrogen, 15% methane—insufficient to make the gas combustible, 1% hydrogen, and 12% of an unidentifiable gas. With further analysis, Cady and McFarland discovered that 1.84% of the gas sample was helium. Far from being a rare element, helium was present in vast quantities under the American Great Plains, available for extraction from natural gas.
This put the United States in an excellent position to become the world's leading supplier of helium. Following a suggestion by Sir Richard Threlfall, the United States Navy sponsored three small experimental helium production plants during World War I. The goal was to supply barrage balloons with the non-flammable lifting gas. A total of 200,000 cubic feet (5700 m³) of 92% helium was produced in the program even though only a few cubic feet (less than 100 liters) of the gas had previously been obtained. Some of this gas was used in the world's first helium-filled airship, the U.S. Navy's C-7, which flew its maiden voyage from Hampton Roads, Virginia to Bolling Field in Washington, D.C. on 1 December 1921.
Although the extraction process, using low-temperature gas liquefaction, was not developed in time to be significant during World War I, production continued. Helium was primarily used as a lifting gas in lighter-than-air craft. This use increased demand during World War II, as well as demands for shielded arc welding. Helium was also vital in the atomic bomb Manhattan Project.
The government of the United States set up the National Helium Reserve in 1925 at Amarillo, Texas with the goal of supplying military airships in time of war and commercial airships in peacetime. Due to a US military embargo against Germany that restricted helium supplies, the Hindenburg was forced to use hydrogen as the lift gas. Helium use following World War II was depressed but the reserve was expanded in the 1950s to ensure a supply of liquid helium as a coolant to create oxygen/hydrogen rocket fuel (among other uses) during the Space Race and Cold War. Helium use in the United States in 1965 was more than eight times the peak wartime consumption.
After the "Helium Acts Amendments of 1960" (Public Law 86–777), the U.S. Bureau of Mines arranged for five private plants to recover helium from natural gas. For this helium conservation program, the Bureau built a 425-mile (684 km) pipeline from Bushton, Kansas to connect those plants with the government's partially depleted Cliffside gas field, near Amarillo, Texas. This helium-nitrogen mixture was injected and stored in the Cliffside gas field until needed, when it then was further purified.
By 1995, a billion cubic metres of the gas had been collected and the reserve was US$1.4 billion in debt, prompting the Congress of the United States in 1996 to phase out the reserve. The resulting "Helium Privatization Act of 1996" (Public Law 104–273) directed the United States Department of the Interior to start liquidating the reserve by 2005.
Helium produced before 1945 was about 98% pure (2% nitrogen), which was adequate for airships. In 1945 a small amount of 99.9% helium was produced for welding use. By 1949 commercial quantities of Grade A 99.995% helium were available.
For many years the United States produced over 90% of commercially usable helium in the world. Extraction plants created in Canada, Poland, Russia, and other nations produced the remaining helium. In the mid 1990s, A new plant in Arzew, Algeria producing 600mmcf came on stream, with enough production to cover all of Europe's demand. Subsequently, in 2004–2006 two additional plants, one in Ras Laffen, Qatar and the other in Skikda, Algeria were built, but as of early 2007, Ras Laffen is functioning at 50%, and Skikda has yet to start up. Algeria quickly became the second leading producer of helium. Through this time, both helium consumption and the costs of producing helium increased and during 2007 the major suppliers, Air Liquide, Airgas and Praxair all raised prices from 10 to 30%.
# Occurrence and production
## Natural abundance
Helium is the second most abundant element in the known Universe after hydrogen and constitutes 23% of the elemental mass of the universe. It is concentrated in stars, where it is formed from hydrogen by the nuclear fusion of the proton-proton chain reaction and CNO cycle. According to the Big Bang model of the early development of the universe, the vast majority of helium was formed during Big Bang nucleosynthesis, from one to three minutes after the Big Bang. As such, measurements of its abundance contribute to cosmological models.
In the Earth's atmosphere, the concentration of helium by volume is only 5.2 parts per million. The concentration is low and fairly constant despite the continuous production of new helium because most helium in the Earth's atmosphere escapes into space by several processes.
In the Earth's heterosphere, a part of the upper atmosphere, helium and other lighter gases are the most abundant elements.
Nearly all helium on Earth is a result of radioactive decay. The decay product is primarily found in minerals of uranium and thorium, including cleveites, pitchblende, carnotite, monazite and beryl, because they emit alpha particles, which consist of helium nuclei (He2+) to which electrons readily combine. In this way an estimated 3.4 litres of helium per year are generated per cubic kilometer of the Earth's crust. In the Earth's crust, the concentration of helium is 8 parts per billion. In seawater, the concentration is only 4 parts per trillion. There are also small amounts in mineral springs, volcanic gas, and meteoric iron. The greatest concentrations on the planet are in natural gas, from which most commercial helium is derived.
## Modern extraction
For large-scale use, helium is extracted by fractional distillation from natural gas, which contains up to 7% helium. Since helium has a lower boiling point than any other element, low temperature and high pressure are used to liquefy nearly all the other gases (mostly nitrogen and methane). The resulting crude helium gas is purified by successive exposures to lowering temperatures, in which almost all of the remaining nitrogen and other gases are precipitated out of the gaseous mixture. Activated charcoal is used as a final purification step, usually resulting in 99.995% pure, Grade-A, helium. The principal impurity in Grade-A helium is neon. In a final production step, most of the helium that is produced is liquefied via a cryogenic process. This is necessary for applications requiring liquid helium and also allows helium suppliers to reduce the cost of long distance transportation, as the largest liquid helium containers have more than five times the capacity of the largest gaseous helium tube trailers.
In 2005, approximately one hundred and sixty million cubic meters of helium were extracted from natural gas or withdrawn from helium reserves, with approximately 83% from the United States, 11% from Algeria, and most of the remainder from Russia and Poland. In the United States, most helium is extracted from natural gas in Kansas and Texas.
Diffusion of crude natural gas through special semipermeable membranes and other barriers is another method to recover and purify helium. Helium can be synthesized by bombardment of lithium or boron with high-velocity protons, but this is not an economically viable method of production.
# Isotopes
Although there are eight known isotopes of helium, only helium-3 and helium-4 are stable. In the Earth's atmosphere, there is one He-3 atom for every million He-4 atoms. However, helium is unusual in that its isotopic abundance varies greatly depending on its origin. In the interstellar medium, the proportion of He-3 is around a hundred times higher. Rocks from the Earth's crust have isotope ratios varying by as much as a factor of ten; this is used in geology to study the origin of such rocks.
The most common isotope, helium-4, is produced on Earth by alpha decay of heavier radioactive elements; the alpha particles that emerge are fully ionized helium-4 nuclei. Helium-4 is an unusually stable nucleus because its nucleons are arranged into complete shells. It was also formed in enormous quantities during Big Bang nucleosynthesis.
Evaporative cooling of liquid helium-4, in a so-called 1-K pot, cools the liquid to about 1 kelvin. In a helium-3 refrigerator, similar cooling of helium-3, which has a lower boiling point, reaches a temperature of about 0.2 kelvin. Equal mixtures of liquid helium-3 and helium-4 below 0.8 K will separate into two immiscible phases due to their dissimilarity (they follow different quantum statistics: helium-4 atoms are bosons while helium-3 atoms are fermions). Dilution refrigerators take advantage of the immiscibility of these two isotopes to achieve temperatures of a few millikelvins.
There is only a trace amount of helium-3 on Earth, primarily present since the formation of the Earth, although some falls to Earth trapped in cosmic dust. Trace amounts are also produced by the beta decay of tritium. In stars, however, helium-3 is more abundant, a product of nuclear fusion. Extraplanetary material, such as lunar and asteroid regolith, have trace amounts of helium-3 from being bombarded by solar winds. The Moon's surface contains helium-3 at concentrations on the order of 0.01 ppm. A number of people, starting with Gerald Kulcinski in 1986, have proposed to explore the moon, mine lunar regolith and using the helium-3 for fusion.
The different formation processes of the two stable isotopes of helium produce the differing isotope abundances. These differing isotope abundances can be used to investigate the origin of rocks and the composition of the Earth's mantle.
It is possible to produce exotic helium isotopes, which rapidly decay into other substances. The shortest-lived heavy helium isotope is helium-5 with a half-life of 7.6×10−22 second. Helium-6 decays by emitting a beta particle and has a half life of 0.8 second. Helium-7 also emits a beta particle as well as a gamma ray. Helium-7 and helium-8 are hyperfragments that are created in certain nuclear reactions.
The exotics helium-6 and helium-8 are known to exhibit a nuclear halo.
Helium-2 (two protons, no neutrons) is a radioisotope of helium that decays by proton emission into protium (hydrogen) with a half-life of 3x10−27 second.
# Biological effects
The voice of a person who has inhaled helium temporarily sounds high-pitched. This is because the speed of sound in helium is nearly three times the speed of sound in air. Because the fundamental frequency of a gas-filled cavity is proportional to the speed of sound in the gas, when helium is inhaled there is a corresponding increase in the resonant frequencies of the vocal tract. (The opposite effect, lowering frequencies, can be obtained by inhaling sulfur hexafluoride)
Inhaling helium, e.g. to produce the vocal effect, can be dangerous if done to excess since helium is a simple asphyxiant, thus it displaces oxygen needed for normal respiration. Death by asphyxiation will result within minutes if pure helium is breathed continuously. In mammals (with the notable exceptions of seals and many burrowing animals) the breathing reflex is triggered by excess of carbon dioxide rather than lack of oxygen, so asphyxiation by helium progresses without the victim experiencing air hunger. Inhaling helium directly from pressurized cylinders is extremely dangerous as the high flow rate can result in barotrauma, fatally rupturing lung tissue.
Neutral helium at standard conditions is non-toxic, plays no biological role and is found in trace amounts in human blood. At high pressures, a mixture of helium and oxygen (heliox) can lead to high pressure nervous syndrome; however, increasing the proportion of nitrogen can alleviate the problem.
Containers of helium gas at 5 to 10 K should be handled as if they contain liquid helium due to the rapid and significant thermal expansion that occurs when helium gas at less than 10 K is warmed to room temperature.
# Compounds
Helium is chemically unreactive under all normal conditions due to its valence of zero. It is an electrical insulator unless ionized. As with the other noble gases, helium has metastable energy levels that allow it to remain ionized in an electrical discharge with a voltage below its ionization potential. Helium can form unstable compounds with tungsten, iodine, fluorine, sulfur and phosphorus when it is subjected to an electric glow discharge, through electron bombardment or is otherwise a plasma. HeNe, HgHe10, WHe2 and the molecular ions He2+, He22+, HeH+, and HeD+ have been created this way. This technique has also allowed the production of the neutral molecule He2, which has a large number of band systems, and HgHe, which is apparently only held together by polarization forces. Theoretically, other compounds may also be possible, such as helium fluorohydride (HHeF) which would be analogous to HArF, discovered in 2000.
Helium has been put inside the hollow carbon cage molecules (the fullerenes) by heating under high pressure of the gas. The neutral molecules formed are stable up to high temperatures. When chemical derivatives of these fullerenes are formed, the helium stays inside. If helium-3 is used, it can be readily observed by helium NMR spectroscopy. Many fullerenes containing helium-3 have been reported. These substances fit the definition of compounds in the Handbook of Chemistry and Physics. They are the first stable neutral helium compounds to be formed. | Helium
Template:Infobox helium
Helium (He) is a colorless, odorless, tasteless, non-toxic, inert monatomic chemical element that heads the noble gas series in the periodic table and whose atomic number is 2. Its boiling and melting points are the lowest among the elements and it exists only as a gas except in extreme conditions. Extreme conditions are also needed to create the small handful of helium compounds, which are all unstable at standard temperature and pressure. It has a second, rare, stable isotope which is called helium-3. The behavior of liquid helium-4's two fluid phases, helium I and helium II, is important to researchers studying quantum mechanics (in particular the phenomenon of superfluidity) and to those looking at the effects that temperatures near absolute zero have on matter (such as superconductivity).
Helium is the second most abundant and second lightest element in the universe, and is one of the elements believed to have been created in the Big Bang. In the modern universe almost all new helium is created as a result of the nuclear fusion of hydrogen in stars. On Earth it is created by the radioactive decay of much heavier elements (alpha particles are helium nuclei). After its creation, part of it is trapped with natural gas in concentrations up to 7% by volume. It is extracted from the natural gas by a low temperature separation process called fractional distillation.
In 1868 the French astronomer Pierre Janssen first detected helium as an unknown yellow spectral line signature in light from a solar eclipse. Since then large reserves of helium have been found in the natural gas fields of the United States, which is by far the largest supplier of the gas. It is used in cryogenics, in deep-sea breathing systems, to cool superconducting magnets, in helium dating, for inflating balloons, for providing lift in airships and as a protective gas for many industrial uses (such as arc welding and growing silicon wafers).
# Notable characteristics
## Gas and plasma phases
Helium is the least reactive member of the noble gas elements, and thus also the least reactive of all elements; it is inert and monatomic in virtually all conditions. Due to helium's relatively low molar (molecular) mass, in the gas phase it has a thermal conductivity, specific heat, and sound conduction velocity that are all greater than any gas, except hydrogen. For similar reasons, and also due to the small size of its molecules, helium's diffusion rate through solids is three times that of air and around 65% that of hydrogen.[1]
Helium is less water soluble than any other gas known[citation needed], and helium's index of refraction is closer to unity than that of any other gas[citation needed]. Helium has a negative Joule-Thomson coefficient at normal ambient temperatures, meaning it heats up when allowed to freely expand. Only below its Joule-Thomson inversion temperature (of about 40 K at 1 atmosphere) does it cool upon free expansion. Once precooled below this temperature, helium can be liquefied through expansion cooling.
Throughout the universe, helium is found mostly in a plasma state whose properties are quite different from atomic helium. In a plasma, helium's electrons and protons are not bound together, resulting in very high electrical conductivity, even when the gas is only partially ionized. The charged particles are highly influenced by magnetic and electric fields. For example, in the solar wind together with ionized hydrogen, they interact with the Earth's magnetosphere giving rise to Birkeland currents and the aurora.
## Solid and liquid phases
Helium solidifies only under great pressure. The resulting colorless, almost invisible solid is highly compressible; applying pressure in a laboratory can decrease its volume by more than 30%.[2] With a bulk modulus on the order of 5×107 Pa[3] it is 50 times more compressible than water. Unlike any other element, helium will fail to solidify and remain a liquid down to absolute zero at normal pressures. This is a direct effect of quantum mechanics: specifically, the zero point energy of the system is too high to allow freezing. Solid helium requires a temperature of 1–1.5 K (about −272 °C or −457 °F) and about 25 bar (2.5 MPa) of pressure.[4] It is often hard to distinguish solid from liquid helium since the refractive index of the two phases are nearly the same. The solid has a sharp melting point and has a crystalline structure.
Solid helium has a density of 0.214 ±0.006 g/ml (1.15 K, 66 atm) with a mean isothermal compressibility of the solid at 1.15 K between the solidus and 66 atm of 0.0031 ±0.0008/atm. Also, no difference in density was noted between 1.8 K and 1.5 K. This data projects that T=0 solid helium under 25 bar of pressure (the minimum required to freeze helium) has a density of 0.187 ±0.009 g/ml.[5]
### Helium I state
Below its boiling point of 4.22 kelvin and above the lambda point of 2.1768 kelvin, the isotope helium-4 exists in a normal colorless liquid state, called helium I. Like other cryogenic liquids, helium I boils when it is heated. It also contracts when its temperature is lowered until it reaches the lambda point, when it stops boiling and suddenly expands. The rate of expansion decreases below the lambda point until about 1 K is reached; at which point expansion completely stops and helium I starts to contract again.
Helium I has a gas-like index of refraction of 1.026 which makes its surface so hard to see that floats of styrofoam are often used to show where the surface is.[6] This colorless liquid has a very low viscosity and a density one-eighth that of water, which is only one-fourth the value expected from classical physics.[6] Quantum mechanics is needed to explain this property and thus both types of liquid helium are called quantum fluids, meaning they display atomic properties on a macroscopic scale. This is probably due to its boiling point being so close to absolute zero, which prevents random molecular motion (heat) from masking the atomic properties.[6]
### Helium II state
Liquid helium below its lambda point begins to exhibit very unusual characteristics, in a state called helium II. Boiling of helium II is not possible due to its high thermal conductivity; heat input instead causes evaporation of the liquid directly to gas. The isotope helium-3 also has a superfluid phase, but only at much lower temperatures; as a result, less is known about such properties in the isotope helium-3.
Helium II is a superfluid, a quantum-mechanical state of matter with strange properties. For example, when it flows through even capillaries of 10−7 to 10−8 m width it has no measurable viscosity. However, when measurements were done between two moving discs, a viscosity comparable to that of gaseous helium was observed. Current theory explains this using the two-fluid model for helium II. In this model, liquid helium below the lambda point is viewed as containing a proportion of helium atoms in a ground state, which are superfluid and flow with exactly zero viscosity, and a proportion of helium atoms in an excited state, which behave more like an ordinary fluid.[7]
Helium II also exhibits a "creeping" effect. When a surface extends past the level of helium II, the helium II moves along the surface, seemingly against the force of gravity. Helium II will escape from a vessel that is not sealed by creeping along the sides until it reaches a warmer region where it evaporates. It moves in a 30 nm-thick film regardless of surface material. This film is called a Rollin film and is named after the man who first characterized this trait, Bernard V. Rollin.[8][9] As a result of this creeping behavior and helium II's ability to leak rapidly through tiny openings, it is very difficult to confine liquid helium. Unless the container is carefully constructed, the helium II will creep along the surfaces and through valves until it reaches somewhere warmer, where it will evaporate. Waves propagating across a Rollin film are governed by the same equation as gravity waves in shallow water, but rather than gravity, the restoring force is the Van der Waals force.[10] These waves are known as third sound.
In the fountain effect, a chamber is constructed which is connected to a reservoir of helium II by a sintered disc through which superfluid helium leaks easily but through which non-superfluid helium cannot pass. If the interior of the container is heated, the superfluid helium changes to non-superfluid helium. In order to maintain the equilibrium fraction of superfluid helium, superfluid helium leaks through and increases the pressure, causing liquid to fountain out of the container.[11]
The thermal conductivity of helium II is greater than that of any other known substance, a million times that of helium I and several hundred times that of copper. This is because heat conduction occurs by an exceptional quantum-mechanical mechanism. Most materials that conduct heat well have a valence band of free electrons which serve to transfer the heat. Helium II has no such valence band but nevertheless conducts heat well. The flow of heat is governed by equations that are similar to the wave equation used to characterize sound propagation in air. So when heat is introduced, it will move at 20 meters per second at 1.8 K through helium II as waves in a phenomenon called second sound.[8]
# Applications
Helium is used for many purposes that require some of its unique properties, such as its low boiling point, low density, low solubility, high thermal conductivity, or inertness. Helium is commercially available in either liquid or gaseous form. As a liquid, it can be supplied in small containers called dewars which hold up to 1,000 liters of helium, or in large ISO containers which have nominal capacities as large as 11,000 gallons (41,637 liters). In gaseous form, small quantities of helium are supplied in high pressure cylinders holding up to 300 standard cubic feet, while large quantities of high pressure gas are supplied in tube trailers which have capacities of up to 180,000 standard cubic feet.
- Because it is lighter than air, airships and balloons are inflated with helium for lift. In airships, helium is preferred over hydrogen because it is not flammable and has 92.64% of the buoyancy (or lifting power) of the alternative hydrogen (see calculation.)
- For its low solubility in water, the major part of human blood, air mixtures of helium with oxygen and nitrogen (Trimix), with oxygen only (Heliox), with common air (heliair), and with hydrogen and oxygen (hydreliox), are used in deep-sea breathing systems to reduce the high-pressure risk of nitrogen narcosis, decompression sickness, and oxygen toxicity.
- At extremely low temperatures, liquid helium is used to cool certain metals to produce superconductivity, such as in superconducting magnets used in magnetic resonance imaging. Helium at low temperatures is also used in cryogenics.
- For its inertness and high thermal conductivity, neutron transparency, and because it does not form radioactive isotopes under reactor conditions, helium is used as a coolant in some nuclear reactors, such as pebble-bed reactors.
- Helium is used as a shielding gas in arc welding processes on materials that are contaminated easily by air. It is especially useful in overhead welding, because it is lighter than air and thus floats, whereas other shielding gases sink.
- Because it is inert, helium is used as a protective gas in growing silicon and germanium crystals, in titanium and zirconium production, in gas chromatography, and as an atmosphere for protecting historical documents. This property also makes it useful in supersonic wind tunnels.
- In rocketry, helium is used as an ullage medium to displace fuel and oxidizers in storage tanks and to condense hydrogen and oxygen to make rocket fuel. It is also used to purge fuel and oxidizer from ground support equipment prior to launch and to pre-cool liquid hydrogen in space vehicles. For example, the Saturn V booster used in the Apollo program needed about 13 million cubic feet (370,000 m³) of helium to launch.[2]
- The gain medium of the helium-neon laser is a mixture of helium and neon.
- Because it diffuses through solids at a rate three times that of air, helium is used as a tracer gas to detect leaks in high-vacuum equipment and high-pressure containers, as well as in other applications with less stringent requirements such as heat exchangers, valves, gas panels, etc.
- Because of its extremely low index of refraction, the use of helium reduces the distorting effects of temperature variations in the space between lenses in some telescopes.
- The age of rocks and minerals that contain uranium and thorium, radioactive elements that emit helium nuclei called alpha particles, can be discovered by measuring the level of helium with a process known as helium dating.
- The high thermal conductivity and sound velocity of helium is also desirable in thermoacoustic refrigeration. The inertness of helium adds to the environmental advantage of this technology over conventional refrigeration systems which may contribute to ozone depleting and global warming effects.
- Because helium alone is less dense than atmospheric air, it will change the timbre (not pitch[12]) of a person's voice when inhaled. However, inhaling it from a typical commercial source, such as that used to fill balloons, can be dangerous due to the risk of asphyxiation from lack of oxygen, and the number of contaminants that may be present. These could include trace amounts of other gases, in addition to aerosolized lubricating oil.
# History
## Scientific discoveries
Evidence of helium was first detected on August 18, 1868 as a bright yellow line with a wavelength of 587.49 nanometres in the spectrum of the chromosphere of the Sun, by French astronomer Pierre Janssen during a total solar eclipse in Guntur, India. This line was initially assumed to be sodium. On October 20 of the same year, English astronomer Norman Lockyer observed a yellow line in the solar spectrum, which he named the D3 line, for it was near the known D1 and D2 lines of sodium,[13] and concluded that it was caused by an element in the Sun unknown on Earth. He and English chemist Edward Frankland named the element with the Greek word for the Sun, ἥλιος (helios)[14]
On 26 March 1895 British chemist William Ramsay isolated helium on Earth by treating the mineral cleveite with mineral acids. Ramsay was looking for argon but, after separating nitrogen and oxygen from the gas liberated by sulfuric acid, noticed a bright-yellow line that matched the D3 line observed in the spectrum of the Sun.[15][16][17][18][15] These samples were identified as helium by Lockyer and British physicist William Crookes. It was independently isolated from cleveite the same year by chemists Per Teodor Cleve and Abraham Langlet in Uppsala, Sweden, who collected enough of the gas to accurately determine its atomic weight.[19] Helium was also isolated by the American geochemist William Francis Hillebrand prior to Ramsay's discovery when he noticed unusual spectral lines while testing a sample of the mineral uraninite. Hillebrand, however, attributed the lines to nitrogen. His letter of congratulations to Ramsay offers an interesting case of discovery and near-discovery in science.[20]
In 1907, Ernest Rutherford and Thomas Royds demonstrated that an alpha particle is a helium nucleus. In 1908, helium was first liquefied by Dutch physicist Heike Kamerlingh Onnes by cooling the gas to less than one kelvin. He tried to solidify it by further reducing the temperature but failed because helium does not have a triple point temperature where the solid, liquid, and gas phases are at equilibrium. It was first solidified in 1926 by his student Willem Hendrik Keesom by subjecting helium to 25 atmospheres of pressure.
In 1938, Russian physicist Pyotr Leonidovich Kapitsa discovered that helium-4 has almost no viscosity at temperatures near absolute zero, a phenomenon now called superfluidity. In 1972, the same phenomenon was observed in helium-3 by American physicists Douglas D. Osheroff, David M. Lee, and Robert C. Richardson.
## History of extraction and use
After an oil drilling operation in 1903 in Dexter, Kansas, U.S. produced a gas geyser that would not burn, Kansas state geologist Erasmus Haworth collected samples of the escaping gas and took them back to the University of Kansas at Lawrence where, with the help of chemists Hamilton Cady and David McFarland, he discovered that the gas contained, by volume, 72% nitrogen, 15% methane—insufficient to make the gas combustible, 1% hydrogen, and 12% of an unidentifiable gas.[21] With further analysis, Cady and McFarland discovered that 1.84% of the gas sample was helium.[22] Far from being a rare element, helium was present in vast quantities under the American Great Plains, available for extraction from natural gas.
This put the United States in an excellent position to become the world's leading supplier of helium. Following a suggestion by Sir Richard Threlfall, the United States Navy sponsored three small experimental helium production plants during World War I. The goal was to supply barrage balloons with the non-flammable lifting gas. A total of 200,000 cubic feet (5700 m³) of 92% helium was produced in the program even though only a few cubic feet (less than 100 liters) of the gas had previously been obtained.[15] Some of this gas was used in the world's first helium-filled airship, the U.S. Navy's C-7, which flew its maiden voyage from Hampton Roads, Virginia to Bolling Field in Washington, D.C. on 1 December 1921.[23]
Although the extraction process, using low-temperature gas liquefaction, was not developed in time to be significant during World War I, production continued. Helium was primarily used as a lifting gas in lighter-than-air craft. This use increased demand during World War II, as well as demands for shielded arc welding. Helium was also vital in the atomic bomb Manhattan Project.
The government of the United States set up the National Helium Reserve in 1925 at Amarillo, Texas with the goal of supplying military airships in time of war and commercial airships in peacetime. Due to a US military embargo against Germany that restricted helium supplies, the Hindenburg was forced to use hydrogen as the lift gas. Helium use following World War II was depressed but the reserve was expanded in the 1950s to ensure a supply of liquid helium as a coolant to create oxygen/hydrogen rocket fuel (among other uses) during the Space Race and Cold War. Helium use in the United States in 1965 was more than eight times the peak wartime consumption.
After the "Helium Acts Amendments of 1960" (Public Law 86–777), the U.S. Bureau of Mines arranged for five private plants to recover helium from natural gas. For this helium conservation program, the Bureau built a 425-mile (684 km) pipeline from Bushton, Kansas to connect those plants with the government's partially depleted Cliffside gas field, near Amarillo, Texas. This helium-nitrogen mixture was injected and stored in the Cliffside gas field until needed, when it then was further purified.
By 1995, a billion cubic metres of the gas had been collected and the reserve was US$1.4 billion in debt, prompting the Congress of the United States in 1996 to phase out the reserve.[21][24] The resulting "Helium Privatization Act of 1996"[25] (Public Law 104–273) directed the United States Department of the Interior to start liquidating the reserve by 2005.[26]
Helium produced before 1945 was about 98% pure (2% nitrogen), which was adequate for airships. In 1945 a small amount of 99.9% helium was produced for welding use. By 1949 commercial quantities of Grade A 99.995% helium were available.
For many years the United States produced over 90% of commercially usable helium in the world. Extraction plants created in Canada, Poland, Russia, and other nations produced the remaining helium. In the mid 1990s, A new plant in Arzew, Algeria producing 600mmcf came on stream, with enough production to cover all of Europe's demand. Subsequently, in 2004–2006 two additional plants, one in Ras Laffen, Qatar and the other in Skikda, Algeria were built, but as of early 2007, Ras Laffen is functioning at 50%, and Skikda has yet to start up. Algeria quickly became the second leading producer of helium. Through this time, both helium consumption and the costs of producing helium increased and during 2007 the major suppliers, Air Liquide, Airgas and Praxair all raised prices from 10 to 30%.
# Occurrence and production
## Natural abundance
Helium is the second most abundant element in the known Universe after hydrogen and constitutes 23% of the elemental mass of the universe. It is concentrated in stars, where it is formed from hydrogen by the nuclear fusion of the proton-proton chain reaction and CNO cycle. According to the Big Bang model of the early development of the universe, the vast majority of helium was formed during Big Bang nucleosynthesis, from one to three minutes after the Big Bang. As such, measurements of its abundance contribute to cosmological models.
In the Earth's atmosphere, the concentration of helium by volume is only 5.2 parts per million.[27] The concentration is low and fairly constant despite the continuous production of new helium because most helium in the Earth's atmosphere escapes into space by several processes.[28][29]
In the Earth's heterosphere, a part of the upper atmosphere, helium and other lighter gases are the most abundant elements.
Nearly all helium on Earth is a result of radioactive decay. The decay product is primarily found in minerals of uranium and thorium, including cleveites, pitchblende, carnotite, monazite and beryl, because they emit alpha particles, which consist of helium nuclei (He2+) to which electrons readily combine. In this way an estimated 3.4 litres of helium per year are generated per cubic kilometer of the Earth's crust. In the Earth's crust, the concentration of helium is 8 parts per billion. In seawater, the concentration is only 4 parts per trillion. There are also small amounts in mineral springs, volcanic gas, and meteoric iron. The greatest concentrations on the planet are in natural gas, from which most commercial helium is derived.
## Modern extraction
For large-scale use, helium is extracted by fractional distillation from natural gas, which contains up to 7% helium.[30] Since helium has a lower boiling point than any other element, low temperature and high pressure are used to liquefy nearly all the other gases (mostly nitrogen and methane). The resulting crude helium gas is purified by successive exposures to lowering temperatures, in which almost all of the remaining nitrogen and other gases are precipitated out of the gaseous mixture. Activated charcoal is used as a final purification step, usually resulting in 99.995% pure, Grade-A, helium.[31] The principal impurity in Grade-A helium is neon. In a final production step, most of the helium that is produced is liquefied via a cryogenic process. This is necessary for applications requiring liquid helium and also allows helium suppliers to reduce the cost of long distance transportation, as the largest liquid helium containers have more than five times the capacity of the largest gaseous helium tube trailers.
In 2005, approximately one hundred and sixty million cubic meters of helium were extracted from natural gas or withdrawn from helium reserves, with approximately 83% from the United States, 11% from Algeria, and most of the remainder from Russia and Poland. In the United States, most helium is extracted from natural gas in Kansas and Texas.
Diffusion of crude natural gas through special semipermeable membranes and other barriers is another method to recover and purify helium. Helium can be synthesized by bombardment of lithium or boron with high-velocity protons, but this is not an economically viable method of production.
# Isotopes
Although there are eight known isotopes of helium, only helium-3 and helium-4 are stable. In the Earth's atmosphere, there is one He-3 atom for every million He-4 atoms.[32] However, helium is unusual in that its isotopic abundance varies greatly depending on its origin. In the interstellar medium, the proportion of He-3 is around a hundred times higher.[33] Rocks from the Earth's crust have isotope ratios varying by as much as a factor of ten; this is used in geology to study the origin of such rocks.
The most common isotope, helium-4, is produced on Earth by alpha decay of heavier radioactive elements; the alpha particles that emerge are fully ionized helium-4 nuclei. Helium-4 is an unusually stable nucleus because its nucleons are arranged into complete shells. It was also formed in enormous quantities during Big Bang nucleosynthesis.
Evaporative cooling of liquid helium-4, in a so-called 1-K pot, cools the liquid to about 1 kelvin. In a helium-3 refrigerator, similar cooling of helium-3, which has a lower boiling point, reaches a temperature of about 0.2 kelvin. Equal mixtures of liquid helium-3 and helium-4 below 0.8 K will separate into two immiscible phases due to their dissimilarity (they follow different quantum statistics: helium-4 atoms are bosons while helium-3 atoms are fermions).[34] Dilution refrigerators take advantage of the immiscibility of these two isotopes to achieve temperatures of a few millikelvins.
There is only a trace amount of helium-3 on Earth, primarily present since the formation of the Earth, although some falls to Earth trapped in cosmic dust.[35] Trace amounts are also produced by the beta decay of tritium.[36] In stars, however, helium-3 is more abundant, a product of nuclear fusion. Extraplanetary material, such as lunar and asteroid regolith, have trace amounts of helium-3 from being bombarded by solar winds. The Moon's surface contains helium-3 at concentrations on the order of 0.01 ppm.[37][38] A number of people, starting with Gerald Kulcinski in 1986,[39] have proposed to explore the moon, mine lunar regolith and using the helium-3 for fusion.
The different formation processes of the two stable isotopes of helium produce the differing isotope abundances. These differing isotope abundances can be used to investigate the origin of rocks and the composition of the Earth's mantle.[35]
It is possible to produce exotic helium isotopes, which rapidly decay into other substances. The shortest-lived heavy helium isotope is helium-5 with a half-life of 7.6×10−22 second. Helium-6 decays by emitting a beta particle and has a half life of 0.8 second. Helium-7 also emits a beta particle as well as a gamma ray. Helium-7 and helium-8 are hyperfragments that are created in certain nuclear reactions.[40]
The exotics helium-6 and helium-8 are known to exhibit a nuclear halo.
Helium-2 (two protons, no neutrons) is a radioisotope of helium that decays by proton emission into protium (hydrogen) with a half-life of 3x10−27 second.[41]
# Biological effects
The voice of a person who has inhaled helium temporarily sounds high-pitched. This is because the speed of sound in helium is nearly three times the speed of sound in air. Because the fundamental frequency of a gas-filled cavity is proportional to the speed of sound in the gas, when helium is inhaled there is a corresponding increase in the resonant frequencies of the vocal tract.[19] (The opposite effect, lowering frequencies, can be obtained by inhaling sulfur hexafluoride)
Inhaling helium, e.g. to produce the vocal effect, can be dangerous if done to excess since helium is a simple asphyxiant, thus it displaces oxygen needed for normal respiration. Death by asphyxiation will result within minutes if pure helium is breathed continuously. In mammals (with the notable exceptions of seals and many burrowing animals) the breathing reflex is triggered by excess of carbon dioxide rather than lack of oxygen, so asphyxiation by helium progresses without the victim experiencing air hunger. Inhaling helium directly from pressurized cylinders is extremely dangerous as the high flow rate can result in barotrauma, fatally rupturing lung tissue.[42]
Neutral helium at standard conditions is non-toxic, plays no biological role and is found in trace amounts in human blood. At high pressures, a mixture of helium and oxygen (heliox) can lead to high pressure nervous syndrome; however, increasing the proportion of nitrogen can alleviate the problem.[43]
Containers of helium gas at 5 to 10 K should be handled as if they contain liquid helium due to the rapid and significant thermal expansion that occurs when helium gas at less than 10 K is warmed to room temperature.[2]
# Compounds
Helium is chemically unreactive under all normal conditions due to its valence of zero. It is an electrical insulator unless ionized. As with the other noble gases, helium has metastable energy levels that allow it to remain ionized in an electrical discharge with a voltage below its ionization potential. Helium can form unstable compounds with tungsten, iodine, fluorine, sulfur and phosphorus when it is subjected to an electric glow discharge, through electron bombardment or is otherwise a plasma. HeNe, HgHe10, WHe2 and the molecular ions He2+, He22+, HeH+, and HeD+ have been created this way. This technique has also allowed the production of the neutral molecule He2, which has a large number of band systems, and HgHe, which is apparently only held together by polarization forces.[1] Theoretically, other compounds may also be possible, such as helium fluorohydride (HHeF) which would be analogous to HArF, discovered in 2000.
Helium has been put inside the hollow carbon cage molecules (the fullerenes) by heating under high pressure of the gas. The neutral molecules formed are stable up to high temperatures. When chemical derivatives of these fullerenes are formed, the helium stays inside. If helium-3 is used, it can be readily observed by helium NMR spectroscopy. Many fullerenes containing helium-3 have been reported. These substances fit the definition of compounds in the Handbook of Chemistry and Physics. They are the first stable neutral helium compounds to be formed. | https://www.wikidoc.org/index.php/Helium | |
888acc2a281a17a2e0892ddf0df05f2c410753b2 | wikidoc | Heroic | Heroic
# Overview
In medicine, heroic refers to a treatment or course of therapy which possesses a high risk of causing further damage to a patient's health, but is undertaken as a last resort with the understanding that any lesser treatment will surely result in failure.
Heroic measures are often taken in cases of grave injury or illness, as a last-ditch attempt to save life, limb, or eyesight. Examples include emergency trauma surgery conducted outside the operating room (such as "on-scene" surgical amputation, cricothyroidotomy, or thoracotomy), or administration of medication (such as certain antibiotics and chemotherapy drugs) at dosage levels high enough to potentially cause serious or fatal side effects.
Cardiopulmonary resuscitation is a particularly well-known heroic measure; vigorous chest compressions often result in fracturing one or more of the patient's ribs, but since the alternative is certain death, the technique is accepted as necessary. | Heroic
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
In medicine, heroic refers to a treatment or course of therapy which possesses a high risk of causing further damage to a patient's health, but is undertaken as a last resort with the understanding that any lesser treatment will surely result in failure. [1]
Heroic measures are often taken in cases of grave injury or illness, as a last-ditch attempt to save life, limb, or eyesight. Examples include emergency trauma surgery conducted outside the operating room (such as "on-scene" surgical amputation, cricothyroidotomy, or thoracotomy), or administration of medication (such as certain antibiotics and chemotherapy drugs) at dosage levels high enough to potentially cause serious or fatal side effects.[2][3]
Cardiopulmonary resuscitation is a particularly well-known heroic measure; vigorous chest compressions often result in fracturing one or more of the patient's ribs, but since the alternative is certain death, the technique is accepted as necessary. | https://www.wikidoc.org/index.php/Heroic | |
bea04238883f8388c864d7bd6120f99f3514ef97 | wikidoc | Hexane | Hexane
Hexane is an alkane hydrocarbon with the chemical formula CH3(CH2)4CH3. The "hex" prefix refers to its six carbons, while the "ane" ending indicates that its carbons are connected by single bonds. Hexane isomers are largely unreactive, and are frequently used as an inert solvent in organic reactions because they are very non-polar. They are also common constituents of gasoline and glues used for shoes, leather products and roofing. Additionally, it is used in solvents to extract oils for cooking and as a cleansing agent for shoe, furniture and textile manufacturing.
# Isomers
Hexane has five isomers:
- Hexane, CH3CH2CH2CH2CH2CH3, a straight chain of six carbon atoms.
- 2-Methylpentane (Isohexane), CH3CH(CH3)CH2CH2CH3, a five-carbon chain with one methyl branch on the second.
- 3-Methylpentane, CH3CH2CH(CH3)CH2CH3, a five-carbon chain with one methyl branch on the third.
- 2,3-Dimethylbutane, CH3CH(CH3)CH(CH3)CH3, a four-carbon chain with one methyl branch on the second and third.
- 2,2-Dimethylbutane, CH3C(CH3)2CH2CH3, a four-carbon chain with two methyl branches on the second.
# Production
Hexane is produced by the refining of crude oil. The exact composition of the fraction depends largely on the source of the oil (crude or reformed) and the constraints of the refining. The industrial product (usually around 50% by weight of the straight-chain isomer) is the fraction boiling at 65–70 °C.
# Toxicity
The acute toxicity of hexane is relatively low, although it is a mild anesthetic. Inhalation of high concentrations produces first a state of mild euphoria, followed by somnolence with headaches and nausea.
Chronic intoxication from hexane has been observed in recreational solvent abusers and in workers in the shoe manufacturing, furniture restoration and automobile construction industries. The initial symptoms are tingling and cramps in the arms and legs, followed by general muscular weakness. In severe cases, atrophy of the skeletal muscles is observed, along with a loss of coordination and problems of vision.
Similar symptoms are observed in animal models. They are associated with a degeneration of the peripheral nervous system (and eventually the central nervous system), starting with the distal portions of the longer and wider nerve axons. The toxicity is not due to hexane itself but to one of its metabolites, hexane-2,5-dione. It is believed that this reacts with the amino group of the side chain of lysine residues in proteins, causing cross-linking and a loss of protein function.
The effects of hexane poisoning in humans are uncertain. In 1994, n-hexane was included in the list of chemicals on the Toxic Release Inventory (TRI). In the latter part of the 20th and early part of the 21st centuries, a number of explosions have been attributed to the combustion of hexane gas.
In 2001, the U.S. Environmental Protection Agency issued regulations on the control of emissions of hexane gas due to its potential carcinogenic properties and environmental concerns. | Hexane
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Hexane is an alkane hydrocarbon with the chemical formula CH3(CH2)4CH3. The "hex" prefix refers to its six carbons, while the "ane" ending indicates that its carbons are connected by single bonds. Hexane isomers are largely unreactive, and are frequently used as an inert solvent in organic reactions because they are very non-polar. They are also common constituents of gasoline and glues used for shoes, leather products and roofing. Additionally, it is used in solvents to extract oils for cooking and as a cleansing agent for shoe, furniture and textile manufacturing.
# Isomers
Hexane has five isomers:
- Hexane, CH3CH2CH2CH2CH2CH3, a straight chain of six carbon atoms.
- 2-Methylpentane (Isohexane), CH3CH(CH3)CH2CH2CH3, a five-carbon chain with one methyl branch on the second.
- 3-Methylpentane, CH3CH2CH(CH3)CH2CH3, a five-carbon chain with one methyl branch on the third.
- 2,3-Dimethylbutane, CH3CH(CH3)CH(CH3)CH3, a four-carbon chain with one methyl branch on the second and third.
- 2,2-Dimethylbutane, CH3C(CH3)2CH2CH3, a four-carbon chain with two methyl branches on the second.[2]
# Production
Hexane is produced by the refining of crude oil. The exact composition of the fraction depends largely on the source of the oil (crude or reformed) and the constraints of the refining. The industrial product (usually around 50% by weight of the straight-chain isomer) is the fraction boiling at 65–70 °C.
# Toxicity
The acute toxicity of hexane is relatively low, although it is a mild anesthetic. Inhalation of high concentrations produces first a state of mild euphoria, followed by somnolence with headaches and nausea.
Chronic intoxication from hexane has been observed in recreational solvent abusers and in workers in the shoe manufacturing, furniture restoration and automobile construction industries. The initial symptoms are tingling and cramps in the arms and legs, followed by general muscular weakness. In severe cases, atrophy of the skeletal muscles is observed, along with a loss of coordination and problems of vision.
Similar symptoms are observed in animal models. They are associated with a degeneration of the peripheral nervous system (and eventually the central nervous system), starting with the distal portions of the longer and wider nerve axons. The toxicity is not due to hexane itself but to one of its metabolites, hexane-2,5-dione. It is believed that this reacts with the amino group of the side chain of lysine residues in proteins, causing cross-linking and a loss of protein function.
The effects of hexane poisoning in humans are uncertain. In 1994, n-hexane was included in the list of chemicals on the Toxic Release Inventory (TRI).[1] In the latter part of the 20th and early part of the 21st centuries, a number of explosions have been attributed to the combustion of hexane gas.
In 2001, the U.S. Environmental Protection Agency issued regulations on the control of emissions of hexane gas due to its potential carcinogenic properties and environmental concerns.[2] | https://www.wikidoc.org/index.php/Hexane | |
0f9cd74756e66a627feb0a3f83404d3404b98599 | wikidoc | Hijama | Hijama
Hijama (Arabic حجامة lit. "sucking") is the name in Arab traditional medicine for wet cupping, where blood is drawn by vacuum from a small skin incision for therapeutic purposes. Hijama is generally performed by Muslims as it is a form of medicine specifically mentioned and encouraged by the prophet Muhammad. Among other hadith, it is mentioned in that recorded by Imam Bukhari (5263) and Imam Muslim (2952), saying "Hijama is among your best remedies" (خير ما تداويتم به الحجامة).
# Procedure
Hijama is normally performed on the head, but can be performed anywhere on the body, often at the site of an ache or pain in order to ease or alleviate it. A more conservative approached outlined at the Broken Earth Cupping Site site warns against over use of cupping and suggests only that six optimal points on the body are all that is required to clean the entire cardiovascular system (The back of the head, two shoulders corresponding to the acupuncture heart position, the tail or small of the back, and the two inner ankles).
The location is first shaved, if necessary, to ensure a tight seal with the cup. The mouth of a cup (metal, glass and plastic cups are generally used, although traditionally horns were used) is placed on the skin at the site chosen for cupping (alternatively leeches can be used). Then a tight seal is created. The old method was to burn a small piece of paper or cotton inside the vessel, so that the mouth of the cup clings to the skin. The new procedure is to use a machine instead. The cup is left to cling to the skin for a few minutes, then it is lifted off and a couple of very small incisions are made in the skin. The cup is then put back as it was before until it is filled with blood.
# Muhammad and hijama
According to various hadith in the Islamic tradition, Muhammad supported hijama. They include:
- Abu Kabsha al-Anmairi gave an eyewitness testimony that Muhammad cupped himself on the head and between his shoulders and then said "Whoever sheds some of this blood will experience no pain in not being treated for a certain (disease) with a certain (cure)".
- Anas's account is more anatomically precise, explaining that Muhammad cupped on two different neck veins and on the upper back.
- According to Jabir, Muhammad also cupped his hip to relieve some pain there.
- According to Abu Hurayra, Muhammad said "If there is good in one thing which cures you it is cupping".
- Also on Abu Hurarya's authority, Muhammad said that "Whoever is cupped on the seventeenth, nineteenth, or twenty-first (of the lunar month) will be healed of every disease". | Hijama
Hijama (Arabic حجامة lit. "sucking") is the name in Arab traditional medicine for wet cupping, where blood is drawn by vacuum from a small skin incision for therapeutic purposes.[1] Hijama is generally performed by Muslims as it is a form of medicine specifically mentioned and encouraged by the prophet Muhammad. Among other hadith, it is mentioned in that recorded by Imam Bukhari (5263) and Imam Muslim (2952), saying "Hijama is among your best remedies" (خير ما تداويتم به الحجامة).
# Procedure
Hijama is normally performed on the head, but can be performed anywhere on the body, often at the site of an ache or pain in order to ease or alleviate it. A more conservative approached outlined at the Broken Earth Cupping Site site warns against over use of cupping and suggests only that six optimal points on the body are all that is required to clean the entire cardiovascular system (The back of the head, two shoulders corresponding to the acupuncture heart position, the tail or small of the back, and the two inner ankles).
The location is first shaved, if necessary, to ensure a tight seal with the cup. The mouth of a cup (metal, glass and plastic cups are generally used, although traditionally horns were used) is placed on the skin at the site chosen for cupping (alternatively leeches can be used). Then a tight seal is created. The old method was to burn a small piece of paper or cotton inside the vessel, so that the mouth of the cup clings to the skin. The new procedure is to use a machine instead. The cup is left to cling to the skin for a few minutes, then it is lifted off and a couple of very small incisions are made in the skin. The cup is then put back as it was before until it is filled with blood.[citation needed]
# Muhammad and hijama
According to various hadith in the Islamic tradition, Muhammad supported hijama.[2] They include:
- Abu Kabsha al-Anmairi gave an eyewitness testimony that Muhammad cupped himself on the head and between his shoulders and then said "Whoever sheds some of this blood will experience no pain in not being treated for a certain (disease) with a certain (cure)".
- Anas's account is more anatomically precise, explaining that Muhammad cupped on two different neck veins and on the upper back.
- According to Jabir, Muhammad also cupped his hip to relieve some pain there.
- According to Abu Hurayra, Muhammad said "If there is good in one thing which cures you it is cupping".
- Also on Abu Hurarya's authority, Muhammad said that "Whoever is cupped on the seventeenth, nineteenth, or twenty-first (of the lunar month) will be healed of every disease". | https://www.wikidoc.org/index.php/Hijama | |
1a30b8c5865a221275200fc6a1bba092e39d99df | wikidoc | Holism | Holism
Holism (from Template:Polytonic holos, a Greek word meaning all, entire, total) is the idea that all the properties of a given system (biological, chemical, social, economic, mental, linguistic, etc.) cannot be determined or explained by its component parts alone. Instead, the system as a whole determines in an important way how the parts behave.
The general principle of holism was concisely summarized by Aristotle in the Metaphysics: "The whole is more than the sum of its parts."
Reductionism is sometimes seen as the opposite of holism. Reductionism in science says that a complex system can be explained by reduction to its fundamental parts. Essentially, chemistry is reducible to physics, biology is reducible to chemistry and physics, psychology and sociology are reducible to biology, etc. Some other proponents of reductionism, however, think that holism is the opposite only of greedy reductionism.
On the other hand, holism and reductionism can also be regarded as complementary viewpoints, in which case they both would be needed to get a proper account of a given system.
# History
The term holism was introduced by the South African statesman Jan Smuts in his 1926 book, Holism and Evolution. Smuts defined holism as "The tendency in nature to form wholes that are greater than the sum of the parts through creative evolution."
The idea has ancient roots. Examples of holism can be found throughout human history and in the most diverse socio-cultural contexts, as has been confirmed by many ethnological studies. The French Protestant missionary, Maurice Leenhardt coined the term cosmomorphism to indicate the state of perfect symbiosis with the surrounding environment which characterized the culture of the Melanesians of New Caledonia. For these people, an isolated individual is totally indeterminate, indistinct and featureless until he can find his position within the natural and social world in which he is inserted. The confines between the self and the world are annulled to the point that the material body itself is no guarantee of the sort of recognition of identity which is typical of our own culture.
# Holism in science
In the latter half of the 20th century, holism led to systems thinking and its derivatives, like the sciences of chaos and complexity. Systems in biology, psychology, or sociology are frequently so complex that their behavior appears "new" or "emergent": it cannot be deduced from the properties of the elements alone.
Holism has thus been used as a catchword. This contributed to the resistance encountered by the scientific interpretation of holism, which insists that there are ontological reasons that prevent reductive models in principle from providing efficient algorithms for prediction of system behavior in certain classes of systems.
Further resistance to holism has come from the long association of the concept with quackery and quantum mysticism. Scientists, who are not immune to peer pressure, were as a rule discouraged from doing any work which may perpetuate such deception. Recently, however, public understanding has grown over the realities of such concepts, and more scientists are beginning to accept serious research into the concept.
Scientific holism holds that the behavior of a system cannot be perfectly predicted, no matter how much data is available. Natural systems can produce surprisingly unexpected behavior, and it is suspected that behavior of such systems might be computationally irreducible, which means it would not be possible to even approximate the system state without a full simulation of all the events occurring in the system. Key properties of the higher level behavior of certain classes of systems may be mediated by rare "surprises" in the behavior of their elements due to the principal of interconnectivity, thus evading predictions except by brute force simulation. Stephen Wolfram has provided such examples with simple cellular automata, whose behavior is in most cases equally simple, but on rare occasions highly unpredictable.
Complexity theory (also called "science of complexity"), is a contemporary heir of systems thinking. It comprises both computational and holistic, relational approaches towards understanding complex adaptive systems and, especially in the latter, its methods can be seen as the polar opposite to reductive methods. General theories of complexity have been proposed, and numerous complexity institutes and departments have sprung up around the world. The Santa Fe Institute is arguably the most famous of them.
## Holism in anthropology
There is an ongoing dispute on the definition of anthropology as holistic and the "four-field" approach. Supporters of this definition, consider it holistic in two senses: it is concerned with all human beings across times and places, and with all dimensions of humanity (evolutionary, biophysical, sociopolitical, economic, cultural, psychological, etc.); also many academic programs following this approach take a "four-field" approach to anthropology that encompasses physical anthropology, archeology, linguistics, and cultural anthropology or social anthropology. The definition of anthropology as holistic and the "four-field" approach are disputed by leading anthropologist, that consider those as artifacts from 19th century social evolutionary thought that inappropriately impose scientific positivism upon cultural anthropology.
## Holism in ecology
The holistic approach to ecology is exemplified by the field of systems ecology, a cross-disciplinary field influenced by general systems theory.
## Holism in economics
With roots in Schumpeter, the evolutionary approach might be considered the holist theory in economics. They share certain language from the biological evolutionary approach. They take into account how the innovation system evolves over time. Knowledge and know-how, know-who, know-what and know-why are part of the whole business economics. Knowledge can also be tacit, as described by Michael Polanyi. These models are open, and consider that it is hard to predict exactly the impact of a policy measure. They are also less mathematical.
## Holism in philosophy
In philosophy, any doctrine that emphasizes the priority of a whole over its parts is holism. In the philosophy of language this becomes the claim, called semantic holism, that the meaning of an individual word or sentence can only be understood in terms of its relations to a larger body of language, even a whole theory or a whole language. In the philosophy of mind, a mental state may be identified only in terms of its relations with others. This is often referred to as content holism or holism of the mental.
Epistemological and confirmation holism are mainstream ideas in contemporary philosophy.
## Holism in sociology
Emile Durkheim developed a concept of holism which he opposed to the notion that a society was nothing more than a simple collection of individuals. In more recent times, Louis Dumont has contrasted "holism" to "individualism" as two different forms of societies. According to him, modern humans live in an individualist society, whereas ancient Greek society, for example, could be qualified as "holistic", because the individual found identity in the whole society. Thus, the individual was ready to sacrifice himself or herself for his or her community, as his or her life without the polis had no sense whatsoever.
## Holism in teleological psychology
Alfred Adler believed that the individual (an integrated whole expressed through a self-consistent unity of thinking, feeling, and action, moving toward an unconscious, fictional final goal), must be understood within the larger wholes of society, from the groups to which he belongs (starting with his face-to-face relationships), to the larger whole of mankind. The recognition of our social embeddedness and the need for developing an interest in the welfare of others, as well as a respect for nature, is at the heart of Adler's philosophy of living and principles of psychotherapy.
Edgar Morin, the French philosopher and sociobiologist, can be considered a holist based on the transdisciplinary nature of his work.
Mel Levine, M.D., author of A Mind at a Time, and Co-Founder (with Charles R. Schwab) of the not-for-profit organization All Kinds of Minds, can be considered a holist based on his view of the 'whole child' as a product of many systems and his work supporting the educational needs of children through the management of a child's educational profile as a whole rather than isolated weaknesses in that profile.
## Holism in theological anthropology
In theological anthropology, which belongs to theology and not to anthropology, holism is the belief that the nature of humans consists of an indivisible union of components such as body, soul and spirit..
## Holism in theology
Holistic concepts are strongly represented within the thoughts expressed within Logos (per Heraclitus), Panentheism and Pantheism.
# Applications of holism
## Holism in architecture and industrial design
Architecture and industrial design are often seen as enterprises, which constitute a whole, or to put it another way, design is often argued to be an holistic enterprise. In architecture and industrial design holism tends to imply an all-inclusive design perspective, which is often regarded as somewhat exclusive to the two design professions. Holism is often considered as something that sets architects and industrial designers apart from other professions that participate in design projects. This view is supported and advocated by practising designers and design scholars alike, who often argue that architecture and/or industrial design have a distinct holistic character.
## Holism in education reform
The Taxonomy of Educational Objectives identifies many levels of cognitive functioning, which can be used to create a more holistic education. In authentic assessment, rather than using computers to score multiple choice test, a standards based assessment uses trained scorers to score open-response items using holistic scoring methods. In projects such as the North Carolina Writing Project, scorers are instructed not to count errors, or count numbers of points or supporting statements. The scorer is instead, instruct to judge holistically whether "as a whole" is it more a "2" or a "3". Critics question whether such a process can be as objective as computer scoring, and the degree to which such scoring methods can result in different scores from different scorers.
## Holism in medicine
Holism appears in psychosomatic medicine. In the 1970s the holistic approach was considered one possible way to conceptualize psychosomatic phenomena. Instead of charting one-way causal links from psyche to soma, or vice-versa, it aimed at a systemic model, where multiple biological, psychological and social factors were seen as interlinked. Other, alternative approaches at that time were psychosomatic and somatopsychic approaches, which concentrated on causal links only from psyche to soma, or from soma to psyche, respectively. At present it is commonplace in psychosomatic medicine to state that psyche and soma cannot really be separated for practical or theoretical purposes. A disturbance on any level - somatic, psychic, or social - will radiate to all the other levels, too. In this sense, psychosomatic thinking is similar to the biopsychosocial model of medicine.
In alternative medicine, an holistic approach to healing recognizes that the emotional, mental, spiritual and physical elements of each person comprise a system, and attempts to treat the whole person in its context, concentrating on the cause of the illness as well as symptoms. Examples of such holistic therapies include Acupuncture, Ayurveda, Chinese medicine, Chiropractic, Osteopathic manipulation, Naturopathic medicine, Qi Gong, Reiki, and Reflexology. Some of these schools do not originate from the western medical-scientific tradition, and lack scientific evidence to verify their claims. Others, such as osteopathic medicine, make an attempt to blend allopathic medicine with other modalities.
## Holistic music
Holism in music can be seen as a gradual layering of different sounds allowing the distinction of the parts before a harmony or euphoria is reached when combined. Often disguised in genres such as IDM, downtempo or glitch; it is also used in a more minimal form for various healing therapies. A modern former of the Holistic religion is the quietly spoken DeeJay Manticore. | Holism
Holism (from Template:Polytonic holos, a Greek word meaning all, entire, total) is the idea that all the properties of a given system (biological, chemical, social, economic, mental, linguistic, etc.) cannot be determined or explained by its component parts alone. Instead, the system as a whole determines in an important way how the parts behave.
The general principle of holism was concisely summarized by Aristotle in the Metaphysics: "The whole is more than the sum of its parts."
Reductionism is sometimes seen as the opposite of holism. Reductionism in science says that a complex system can be explained by reduction to its fundamental parts. Essentially, chemistry is reducible to physics, biology is reducible to chemistry and physics, psychology and sociology are reducible to biology, etc. Some other proponents of reductionism, however, think that holism is the opposite only of greedy reductionism.
On the other hand, holism and reductionism can also be regarded as complementary viewpoints, in which case they both would be needed to get a proper account of a given system.
# History
The term holism was introduced by the South African statesman Jan Smuts in his 1926 book, Holism and Evolution.[2] Smuts defined holism as "The tendency in nature to form wholes that are greater than the sum of the parts through creative evolution."[3]
The idea has ancient roots. Examples of holism can be found throughout human history and in the most diverse socio-cultural contexts, as has been confirmed by many ethnological studies. The French Protestant missionary, Maurice Leenhardt coined the term cosmomorphism to indicate the state of perfect symbiosis with the surrounding environment which characterized the culture of the Melanesians of New Caledonia. For these people, an isolated individual is totally indeterminate, indistinct and featureless until he can find his position within the natural and social world in which he is inserted. The confines between the self and the world are annulled to the point that the material body itself is no guarantee of the sort of recognition of identity which is typical of our own culture.
# Holism in science
Template:POV-section
In the latter half of the 20th century, holism led to systems thinking and its derivatives, like the sciences of chaos and complexity. Systems in biology, psychology, or sociology are frequently so complex that their behavior appears "new" or "emergent": it cannot be deduced from the properties of the elements alone.[4]
Holism has thus been used as a catchword. This contributed to the resistance encountered by the scientific interpretation of holism, which insists that there are ontological reasons that prevent reductive models in principle from providing efficient algorithms for prediction of system behavior in certain classes of systems.
Further resistance to holism has come from the long association of the concept with quackery and quantum mysticism. Scientists, who are not immune to peer pressure, were as a rule discouraged from doing any work which may perpetuate such deception. Recently, however, public understanding has grown over the realities of such concepts, and more scientists are beginning to accept serious research into the concept.
Scientific holism holds that the behavior of a system cannot be perfectly predicted, no matter how much data is available. Natural systems can produce surprisingly unexpected behavior, and it is suspected that behavior of such systems might be computationally irreducible, which means it would not be possible to even approximate the system state without a full simulation of all the events occurring in the system. Key properties of the higher level behavior of certain classes of systems may be mediated by rare "surprises" in the behavior of their elements due to the principal of interconnectivity, thus evading predictions except by brute force simulation. Stephen Wolfram has provided such examples with simple cellular automata, whose behavior is in most cases equally simple, but on rare occasions highly unpredictable.[5]
Complexity theory (also called "science of complexity"), is a contemporary heir of systems thinking. It comprises both computational and holistic, relational approaches towards understanding complex adaptive systems and, especially in the latter, its methods can be seen as the polar opposite to reductive methods. General theories of complexity have been proposed, and numerous complexity institutes and departments have sprung up around the world. The Santa Fe Institute is arguably the most famous of them.
## Holism in anthropology
There is an ongoing dispute on the definition of anthropology as holistic and the "four-field" approach. Supporters of this definition,[6] consider it holistic in two senses: it is concerned with all human beings across times and places, and with all dimensions of humanity (evolutionary, biophysical, sociopolitical, economic, cultural, psychological, etc.); also many academic programs following this approach take a "four-field" approach to anthropology that encompasses physical anthropology, archeology, linguistics, and cultural anthropology or social anthropology. The definition of anthropology as holistic and the "four-field" approach are disputed by leading anthropologist,[7] that consider those as artifacts from 19th century social evolutionary thought that inappropriately impose scientific positivism upon cultural anthropology.[7]
## Holism in ecology
The holistic approach to ecology is exemplified by the field of systems ecology, a cross-disciplinary field influenced by general systems theory.
## Holism in economics
With roots in Schumpeter, the evolutionary approach might be considered the holist theory in economics. They share certain language from the biological evolutionary approach. They take into account how the innovation system evolves over time. Knowledge and know-how, know-who, know-what and know-why are part of the whole business economics. Knowledge can also be tacit, as described by Michael Polanyi. These models are open, and consider that it is hard to predict exactly the impact of a policy measure. They are also less mathematical.
## Holism in philosophy
In philosophy, any doctrine that emphasizes the priority of a whole over its parts is holism. In the philosophy of language this becomes the claim, called semantic holism, that the meaning of an individual word or sentence can only be understood in terms of its relations to a larger body of language, even a whole theory or a whole language. In the philosophy of mind, a mental state may be identified only in terms of its relations with others. This is often referred to as content holism or holism of the mental.
Epistemological and confirmation holism are mainstream ideas in contemporary philosophy.
## Holism in sociology
Emile Durkheim developed a concept of holism which he opposed to the notion that a society was nothing more than a simple collection of individuals. In more recent times, Louis Dumont [8] has contrasted "holism" to "individualism" as two different forms of societies. According to him, modern humans live in an individualist society, whereas ancient Greek society, for example, could be qualified as "holistic", because the individual found identity in the whole society. Thus, the individual was ready to sacrifice himself or herself for his or her community, as his or her life without the polis had no sense whatsoever.
## Holism in teleological psychology
Alfred Adler believed that the individual (an integrated whole expressed through a self-consistent unity of thinking, feeling, and action, moving toward an unconscious, fictional final goal), must be understood within the larger wholes of society, from the groups to which he belongs (starting with his face-to-face relationships), to the larger whole of mankind. The recognition of our social embeddedness and the need for developing an interest in the welfare of others, as well as a respect for nature, is at the heart of Adler's philosophy of living and principles of psychotherapy.
Edgar Morin, the French philosopher and sociobiologist, can be considered a holist based on the transdisciplinary nature of his work.
Mel Levine, M.D., author of A Mind at a Time,[9] and Co-Founder (with Charles R. Schwab) of the not-for-profit organization All Kinds of Minds, can be considered a holist based on his view of the 'whole child' as a product of many systems and his work supporting the educational needs of children through the management of a child's educational profile as a whole rather than isolated weaknesses in that profile.
## Holism in theological anthropology
In theological anthropology, which belongs to theology and not to anthropology, holism is the belief that the nature of humans consists of an indivisible union of components such as body, soul and spirit..
## Holism in theology
Holistic concepts are strongly represented within the thoughts expressed within Logos (per Heraclitus), Panentheism and Pantheism.
# Applications of holism
## Holism in architecture and industrial design
Architecture and industrial design are often seen as enterprises, which constitute a whole, or to put it another way, design is often argued to be an holistic enterprise.[10] In architecture and industrial design holism tends to imply an all-inclusive design perspective, which is often regarded as somewhat exclusive to the two design professions. Holism is often considered as something that sets architects and industrial designers apart from other professions that participate in design projects. This view is supported and advocated by practising designers and design scholars alike, who often argue that architecture and/or industrial design have a distinct holistic character.
## Holism in education reform
The Taxonomy of Educational Objectives identifies many levels of cognitive functioning, which can be used to create a more holistic education. In authentic assessment, rather than using computers to score multiple choice test, a standards based assessment uses trained scorers to score open-response items using holistic scoring methods.[11] In projects such as the North Carolina Writing Project, scorers are instructed not to count errors, or count numbers of points or supporting statements. The scorer is instead, instruct to judge holistically whether "as a whole" is it more a "2" or a "3". Critics question whether such a process can be as objective as computer scoring, and the degree to which such scoring methods can result in different scores from different scorers.
## Holism in medicine
Holism appears in psychosomatic medicine. In the 1970s the holistic approach was considered one possible way to conceptualize psychosomatic phenomena. Instead of charting one-way causal links from psyche to soma, or vice-versa, it aimed at a systemic model, where multiple biological, psychological and social factors were seen as interlinked. Other, alternative approaches at that time were psychosomatic and somatopsychic approaches, which concentrated on causal links only from psyche to soma, or from soma to psyche, respectively.[12] At present it is commonplace in psychosomatic medicine to state that psyche and soma cannot really be separated for practical or theoretical purposes. A disturbance on any level - somatic, psychic, or social - will radiate to all the other levels, too. In this sense, psychosomatic thinking is similar to the biopsychosocial model of medicine.
In alternative medicine, an holistic approach to healing recognizes that the emotional, mental, spiritual and physical elements of each person comprise a system, and attempts to treat the whole person in its context,[13] concentrating on the cause of the illness as well as symptoms. Examples of such holistic therapies include Acupuncture, Ayurveda, Chinese medicine, Chiropractic, Osteopathic manipulation, Naturopathic medicine, Qi Gong, Reiki, and Reflexology. Some of these schools do not originate from the western medical-scientific tradition, and lack scientific evidence to verify their claims. Others, such as osteopathic medicine, make an attempt to blend allopathic medicine with other modalities.
## Holistic music
Holism in music can be seen as a gradual layering of different sounds allowing the distinction of the parts before a harmony or euphoria is reached when combined. Often disguised in genres such as IDM, downtempo or glitch; it is also used in a more minimal form for various healing therapies. A modern former of the Holistic religion is the quietly spoken DeeJay Manticore[citation needed]. | https://www.wikidoc.org/index.php/Holism | |
5dc8198dfd99d338845fd799fd53c23f12effc38 | wikidoc | Humana | Humana
Humana Inc. (Template:Nyse), founded in 1961 in Louisville, Kentucky, is a Fortune 500 company that markets and administers health benefit consumer services. With a customer base of over 11.5 million in the United States, the company is the largest Fortune 500 company headquartered in the Commonwealth of Kentucky, with a market cap of over $13 billion dollars and $21.4 billion in revenue. Humana employs over 25,000 "associates" nationwide. Humana markets its health benefit consumer services in all 50 states, D.C., Puerto Rico and has international business interests in Western Europe. In its March 2007 issue, Fortune Magazine named Humana one of the Top 5 Most Admired Healthcare Companies in the United States.
# History
The company was founded by David Jones and Wendell Cherry as a nursing home company in 1961. Then known as Extendicare, the company became the largest nursing home company in the United States. Extendicare later divested the nursing home chain and moved into purchasing hospitals in 1972, becoming the world's largest hospital company in the 1980s.
To reflect the company's new direction, the corporate name was changed to Humana Inc. in 1974. Humana experienced tremendous growth in the years that followed, both organically and through the takeover of American Medicorp Inc. in 1978, which doubled the company's size. During the mid-1970s, the company used a fast-track construction process to complete and open one hospital a month. This accelerated construction schedule, which compressed time by overlapping processes, allowed Humana to develop hospital projects faster than the industry norm. During that construction boom, Humana developed the double corridor model for hospital construction. This highly efficient design minimized the distance between patients and nurses by placing nursing support services in the interior of the building with patient rooms surrounding the perimeter.
As the American health care system evolved in the 1980s, Humana developed an integrated health care delivery system by creating a family of flexible health care plans. In 1984, Humana began marketing health insurance.
Humana brought the pioneering artificial heart research of Dr. Robert Jarvik and Dr. William DeVries to Louisville, creating the Humana Heart Institute in 1985.
The 1990s marked Humana's metamorphis into a consumer health benefits company. Humana spun-off its hospital operations from the health insurance operations in 1993. The new company was called Galen Health Care Inc. Soon after, Galen merged with Columbia/HCA. United Healthcare attempted to acquire Humana in the Spring of 1998. United's effort failed when it reported an almost billion dollar quarterly loss. Humana began pioneering work in consumer driven health care in 1999; launching its first services on September 11, 2001.
In 2001, Humana partnered with Navigy, Inc., a subsidiary of Blue Cross and Blue Shield of Florida, Inc., to launch Availity to empower physicians and other health care professionals with a business solution to conduct their daily health plan transactions.
Humana began marketing health savings account services to individuals and companies in 2003 and entered into a business partnership with Richard Branson's Virgin in 2005. The Business Health Care Group of Southeast Wisconsin (BHCGSW) chose Humana as its administrative partner to drive Southeastern Wisconsin health care costs to the Midwest average in 2005, using a strategy that includes consumer education, providing cost and quality information on health care providers, structuring accountability of all stakeholders and collective purchasing. Today, the BHCGSW represents more than 200 member companies, including large and small employers representing more than 150,000 health care consumers in Southeastern Wisconsin.
Upon passage of the Medicare Prescription Drug, Improvement, and Modernization Act in the U. S. Congress, Humana aggressively launched an education campaign to market Medicare Advantage (MA) and Prescription Drug Plans (PDP) nationwide to Medicare eligible consumers in 2006. A cross country RV tour and strategic alliance with State Farm and Wal-Mart, the campaign signed up approximately 5 million consumers and catapulted Humana to #2 in industry market share for senior products. Humana also launched RightSource, a national mail-order retail pharmacy business in 2006.
## Acquisitions
This is a list represents some of the major acquisitions completed by Humana since 1990 in the U.S.:
# Locations
The Humana Building in Louisville, Kentucky is a well-known example of postmodern architecture; it was designed by Michael Graves and completed in 1985. Humana sponsored an architectural competition to determine the design of its headquarters building. Scale models of the participants (including the submissions of Helmut Jahn, IM Pei, Michael Graves and others) are contained in a vestibule located directly above the Main Street entrance of the Humana Building.
In addition to its corporate headquarters building in Louisville at 5th and Main Street, Humana owns and occupies the Waterside Building at 1st and Main, and the Riverview Square at 2nd and Main. Humana recently announced its plan to lease space in the Waterfront Plaza East Tower in the 300 block of Main Street. The company also leases space in three other downtown buildings—National City in the 400 block of Main Street, the 515 Building on Market Street, and the ISB Building on Magazine Street.
Humana recently undertook the historic preservation of a city block of several 19th Century buildings located beside its headquarters building. The company now employs more than 8,500 people in downtown Louisville.
The company is working with preservation experts to ensure that the historic integrity of the block is maintained.
# Company leadership
Michael B. McCallister, a 33 year company veteran, is president and chief executive officer of Humana. McCallister began his career in 1974 as an analyst in the company's finance department. In 2006, he was rated as one of the most successful CEOs in American business at creating shareholder value by Forbes Magazine. McCallister is a member of the Business Roundtable.
David Jones, Jr. serves as chairman of the board of directors. Jones is the son of company founder, David Jones, Sr.
In an interview published by The Courier-Journal, the day following his retirement as chairman of the board of directors, David Jones, Sr. indicated he had vehemently opposed United Healthcare's effort to takeover Humana in 1998, but was out voted by other members of the board of directors.
The year the leader joined the company is listed in brackets.
- Michael B. McCallister, President and Chief Executive Officer
- James (Jim) E. Murray, Senior Vice President and Chief Operating Officer
- James (Jim) H. Bloem, Senior Vice President, Chief Financial Officer and Treasurer
- Bruce J. Goodman, Senior Vice President and Chief Service and Information Officer
- Thomas (Tom) J. Liston, Senior Vice President, Strategy and Corporate Development
- Steve Moya, Senior Vice President and Chief Marketing Officer
- Bonita (Bonnie) C. Hathcock, Senior Vice President and Chief Human Resources Officer
- Jonathan (Jack) T. Lord, M.D., Senior Vice President and Chief Innovation Officer
- Arthur (Art) P. Hipwell, Senior Vice President and General Counsel
- Heidi Margulis, Senior Vice President of Government Relations
- Thomas (Tom) Noland, Senior Vice President of Corporate Communications
- William (Bill) Tait, Vice President, Market Operations
- Stefen Brueckner, Vice President, Senior Products
- Steven (Steve) E. McCulley, Vice President and Controller, Principal Accounting Officer
# Philanthropy
The Humana Foundation donates millions of dollars each year to non-profit organizations in the markets where the company does business.
The 2006 Humana Festival of New American Plays celebrated its 30th anniversary. Sponsored by The Humana Foundation, the Festival at Louisville’s Actors Theatre is an annual site of pilgrimage where theatre lovers from around the world converge to get the first look at the future of the American theater. Over 300 Humana Festival plays have been produced, representing the work of 206 playwrights. More than 90 million people worldwide have seen additional productions of the many plays originated in the Humana Festival, not including film audiences who have seen Humana plays adapted for the screen
The Humana Foundation donated $1 million dollars to the Gulf Coast region following Hurricane Katrina.
# Controversy
In 1987, Humana sued NBC over a story line in the television medical drama St. Elsewhere whereas the hospital was to be sold to a for-profit medical corporation and renamed "Ecumena", with subsequent changes to the hospital, both positive and negative, emanating from that change. Humana was successful at forcing NBC into showing a disclaimer at the beginning of the September 30 episode saying that the drama had no connection whatsoever with Humana.
On May 30, 1996, Linda Peeno, who was contracted to work for Humana for nine months, testified before Congress as to the downside of managed care.
On the June 21, 2007 episode of Amy Goodman's Democracy Now! radio/television program, Peeno further claimed that "just within a day or so saw a sculpture being installed in the rotunda and was told at that time that it had cost about the same as the heart transplant that we had denied...By the way, I later found out that that sculpture cost $3.8 million, so it was equivalent to eight heart transplants."
Video of Linda Peeno's testimony appeared in Michael Moore's 2007 documentary Sicko. On June 28, 2007, in a statement about the movie, Humana declared that Peeno was never a Humana associate, but rather a "part-time contractor". Humana also disputed the portions of Congressional testimony that were shown by saying that because the patient's specific healthcare plan didn't cover heart transplants, the denial of coverage was valid.
Humana was also featured in Season One of Moore's The Awful Truth, shown refusing to give a pancreatic cancer sufferer authorization for a transplant. Moore conducted a fake funeral on the front steps of Humana for the man who was sure to die without the transplant. Three days later, Humana changed their policy and authorized the man's treatment. This scene was the inspiration for Sicko.
# Trivia
- Humana Military Health Care Services is a TRICARE Regional Contractor for the Southern United States.
- David Jones and Wendell Cherry, the company founders, decided to start the business during a game of golf in Louisville. The founders each put up $1,000 as their initial investment. Over 46 years later, Humana is now the Official Health Benefits Provider of the PGA Tour and Champions Tour. PGA Tour player David Toms and LPGA player Nancy Scranton are both ambassadors for Humana.
- Humana associates serve as an internal test market for the company's next generation of consumer services.
- David Jones Sr., formerly CEO and chair of the board of directors is currently leading the City of Parks initiative in Louisville. This effort is designed to acquire land to expand parks throughout Louisville. He raised over $20 million for this effort in 2005 and 2006 through his personal fundraising efforts. In February 2005, the Trust for Public Land and Louisville Mayor Jerry Abramson announced a $20 million initiative spearheaded by the community fundraising efforts of Humana Co-founder and Chairman Emeritus David A. Jones. The funds will be used for continued land purchases that promise to make Metro Louisville a "City of Parks." The Humana Foundation contributed $1.25 million.
- The Humana Distaff Handicap is a Grade 1 race for thoroughbred fillies and mares, four-years-old and up. The race is run each spring on Kentucky Derby Day at Churchill Downs and set at a distance of 7 furlongs for a purse of $250,000.
- Michael McCallister, president and CEO, serves on the Board of Directors of National City Corp., parent company of National City Bank.
- On September 11, 2001, approximately 23 Humana leaders were in New York City to launch the company's next generation health benefit consumer services at the Digital Sandbox. The group had dined the previous evening at the Windows on the World Restaurant atop the World Trade Center Tower One. The group safely escaped New York following the collapse of the World Trade Center buildings. The leaders wrote a book: Stories from 55 Broad Street; to tell the story of their experience.
- Humana is a founding sponsor of eons.com, the online social networking site developed by Monster.com founder Jeff Taylor. The site targets the 50+ market segment.
- Humana brought the 1942 classic Casablanca back to the big screen in select movie theatres nationwide as part of a campaign to preview its 2007 Medicare Advantage consumer services. The special screening events marked the first time in more than 60 years that the classic Humphrey Bogart epic was seen nationally in movie theatres. | Humana
Template:Infobox Company
Humana Inc. (Template:Nyse), founded in 1961 in Louisville, Kentucky, is a Fortune 500 company that markets and administers health benefit consumer services. With a customer base of over 11.5 million in the United States, the company is the largest Fortune 500 company headquartered in the Commonwealth of Kentucky, with a market cap of over $13 billion dollars and $21.4 billion in revenue. Humana employs over 25,000 "associates" nationwide. Humana markets its health benefit consumer services in all 50 states, D.C., Puerto Rico and has international business interests in Western Europe. In its March 2007 issue, Fortune Magazine named Humana one of the Top 5 Most Admired Healthcare Companies in the United States.
# History
The company was founded by David Jones and Wendell Cherry as a nursing home company in 1961. Then known as Extendicare, the company became the largest nursing home company in the United States. Extendicare later divested the nursing home chain and moved into purchasing hospitals in 1972, becoming the world's largest hospital company in the 1980s.
To reflect the company's new direction, the corporate name was changed to Humana Inc. in 1974. Humana experienced tremendous growth in the years that followed, both organically and through the takeover of American Medicorp Inc. in 1978, which doubled the company's size. During the mid-1970s, the company used a fast-track construction process to complete and open one hospital a month. This accelerated construction schedule, which compressed time by overlapping processes, allowed Humana to develop hospital projects faster than the industry norm. During that construction boom, Humana developed the double corridor model for hospital construction. This highly efficient design minimized the distance between patients and nurses by placing nursing support services in the interior of the building with patient rooms surrounding the perimeter.
As the American health care system evolved in the 1980s, Humana developed an integrated health care delivery system by creating a family of flexible health care plans. In 1984, Humana began marketing health insurance.
Humana brought the pioneering artificial heart research of Dr. Robert Jarvik and Dr. William DeVries to Louisville, creating the Humana Heart Institute in 1985.
The 1990s marked Humana's metamorphis into a consumer health benefits company. Humana spun-off its hospital operations from the health insurance operations in 1993. The new company was called Galen Health Care Inc. Soon after, Galen merged with Columbia/HCA. United Healthcare attempted to acquire Humana in the Spring of 1998. United's effort failed when it reported an almost billion dollar quarterly loss. Humana began pioneering work in consumer driven health care in 1999; launching its first services on September 11, 2001.
In 2001, Humana partnered with Navigy, Inc., a subsidiary of Blue Cross and Blue Shield of Florida, Inc., to launch Availity to empower physicians and other health care professionals with a business solution to conduct their daily health plan transactions.
Humana began marketing health savings account services to individuals and companies in 2003 and entered into a business partnership with Richard Branson's Virgin in 2005. The Business Health Care Group of Southeast Wisconsin (BHCGSW) chose Humana as its administrative partner to drive Southeastern Wisconsin health care costs to the Midwest average in 2005, using a strategy that includes consumer education, providing cost and quality information on health care providers, structuring accountability of all stakeholders and collective purchasing. Today, the BHCGSW represents more than 200 member companies, including large and small employers representing more than 150,000 health care consumers in Southeastern Wisconsin.
Upon passage of the Medicare Prescription Drug, Improvement, and Modernization Act in the U. S. Congress, Humana aggressively launched an education campaign to market Medicare Advantage (MA) and Prescription Drug Plans (PDP) nationwide to Medicare eligible consumers in 2006. A cross country RV tour and strategic alliance with State Farm and Wal-Mart, the campaign signed up approximately 5 million consumers and catapulted Humana to #2 in industry market share for senior products. Humana also launched RightSource, a national mail-order retail pharmacy business in 2006.
## Acquisitions
This is a list represents some of the major acquisitions completed by Humana since 1990 in the U.S.:
# Locations
The Humana Building in Louisville, Kentucky is a well-known example of postmodern architecture; it was designed by Michael Graves and completed in 1985. Humana sponsored an architectural competition to determine the design of its headquarters building. Scale models of the participants (including the submissions of Helmut Jahn, IM Pei, Michael Graves and others) are contained in a vestibule located directly above the Main Street entrance of the Humana Building.
In addition to its corporate headquarters building in Louisville at 5th and Main Street, Humana owns and occupies the Waterside Building at 1st and Main, and the Riverview Square at 2nd and Main. Humana recently announced its plan to lease space in the Waterfront Plaza East Tower in the 300 block of Main Street. The company also leases space in three other downtown buildings—National City in the 400 block of Main Street, the 515 Building on Market Street, and the ISB Building on Magazine Street.
Humana recently undertook the historic preservation of a city block of several 19th Century buildings located beside its headquarters building. The company now employs more than 8,500 people in downtown Louisville.
The company is working with preservation experts to ensure that the historic integrity of the block is maintained.
# Company leadership
Michael B. McCallister, a 33 year company veteran, is president and chief executive officer of Humana. McCallister began his career in 1974 as an analyst in the company's finance department. In 2006, he was rated as one of the most successful CEOs in American business at creating shareholder value by Forbes Magazine. McCallister is a member of the Business Roundtable.
David Jones, Jr. serves as chairman of the board of directors. Jones is the son of company founder, David Jones, Sr.
In an interview published by The Courier-Journal, the day following his retirement as chairman of the board of directors, David Jones, Sr. indicated he had vehemently opposed United Healthcare's effort to takeover Humana in 1998, but was out voted by other members of the board of directors.
The year the leader joined the company is listed in brackets.
- Michael B. McCallister, President and Chief Executive Officer [1974]
- James (Jim) E. Murray, Senior Vice President and Chief Operating Officer [1989]
- James (Jim) H. Bloem, Senior Vice President, Chief Financial Officer and Treasurer [2001]
- Bruce J. Goodman, Senior Vice President and Chief Service and Information Officer [1999]
- Thomas (Tom) J. Liston, Senior Vice President, Strategy and Corporate Development [1997]
- Steve Moya, Senior Vice President and Chief Marketing Officer [2000]
- Bonita (Bonnie) C. Hathcock, Senior Vice President and Chief Human Resources Officer [1999]
- Jonathan (Jack) T. Lord, M.D., Senior Vice President and Chief Innovation Officer [2000]
- Arthur (Art) P. Hipwell, Senior Vice President and General Counsel [1979]
- Heidi Margulis, Senior Vice President of Government Relations [1985]
- Thomas (Tom) Noland, Senior Vice President of Corporate Communications [1985]
- William (Bill) Tait, Vice President, Market Operations [2001]
- Stefen Brueckner, Vice President, Senior Products [2001]
- Steven (Steve) E. McCulley, Vice President and Controller, Principal Accounting Officer [1990]
# Philanthropy
The Humana Foundation donates millions of dollars each year to non-profit organizations in the markets where the company does business.
The 2006 Humana Festival of New American Plays celebrated its 30th anniversary. Sponsored by The Humana Foundation, the Festival at Louisville’s Actors Theatre is an annual site of pilgrimage where theatre lovers from around the world converge to get the first look at the future of the American theater. Over 300 Humana Festival plays have been produced, representing the work of 206 playwrights. More than 90 million people worldwide have seen additional productions of the many plays originated in the Humana Festival, not including film audiences who have seen Humana plays adapted for the screen
The Humana Foundation donated $1 million dollars to the Gulf Coast region following Hurricane Katrina.
# Controversy
In 1987, Humana sued NBC over a story line in the television medical drama St. Elsewhere whereas the hospital was to be sold to a for-profit medical corporation and renamed "Ecumena", with subsequent changes to the hospital, both positive and negative, emanating from that change. Humana was successful at forcing NBC into showing a disclaimer at the beginning of the September 30 episode saying that the drama had no connection whatsoever with Humana.[1]
On May 30, 1996, Linda Peeno, who was contracted to work for Humana for nine months, testified before Congress as to the downside of managed care.[2]
On the June 21, 2007 episode of Amy Goodman's Democracy Now! radio/television program, Peeno further claimed that "just within a day or so [of the refusal of the heart transplant, I] saw a sculpture being installed in the rotunda [of Humana's headquarters] and was told at that time that it had cost about the same as the heart transplant that we had denied...By the way, I later found out that that sculpture cost $3.8 million, so it was equivalent to eight heart transplants."[3]
Video of Linda Peeno's testimony appeared in Michael Moore's 2007 documentary Sicko. On June 28, 2007, in a statement about the movie, Humana declared that Peeno was never a Humana associate, but rather a "part-time contractor". Humana also disputed the portions of Congressional testimony that were shown by saying that because the patient's specific healthcare plan didn't cover heart transplants, the denial of coverage was valid.[4]
Humana was also featured in Season One of Moore's The Awful Truth, shown refusing to give a pancreatic cancer sufferer authorization for a transplant. Moore conducted a fake funeral on the front steps of Humana for the man who was sure to die without the transplant. Three days later, Humana changed their policy and authorized the man's treatment. This scene was the inspiration for Sicko.
# Trivia
Template:Trivia
- Humana Military Health Care Services is a TRICARE Regional Contractor for the Southern United States.
- David Jones and Wendell Cherry, the company founders, decided to start the business during a game of golf in Louisville. The founders each put up $1,000 as their initial investment. Over 46 years later, Humana is now the Official Health Benefits Provider of the PGA Tour and Champions Tour. PGA Tour player David Toms and LPGA player Nancy Scranton are both ambassadors for Humana.
- Humana associates serve as an internal test market for the company's next generation of consumer services.
- David Jones Sr., formerly CEO and chair of the board of directors is currently leading the City of Parks initiative in Louisville. This effort is designed to acquire land to expand parks throughout Louisville. He raised over $20 million for this effort in 2005 and 2006 through his personal fundraising efforts. In February 2005, the Trust for Public Land and Louisville Mayor Jerry Abramson announced a $20 million initiative spearheaded by the community fundraising efforts of Humana Co-founder and Chairman Emeritus David A. Jones. The funds will be used for continued land purchases that promise to make Metro Louisville a "City of Parks." The Humana Foundation contributed $1.25 million.
- The Humana Distaff Handicap is a Grade 1 race for thoroughbred fillies and mares, four-years-old and up. The race is run each spring on Kentucky Derby Day at Churchill Downs and set at a distance of 7 furlongs for a purse of $250,000.
- Michael McCallister, president and CEO, serves on the Board of Directors of National City Corp., parent company of National City Bank.
- On September 11, 2001, approximately 23 Humana leaders were in New York City to launch the company's next generation health benefit consumer services at the Digital Sandbox. The group had dined the previous evening at the Windows on the World Restaurant atop the World Trade Center Tower One. The group safely escaped New York following the collapse of the World Trade Center buildings. The leaders wrote a book: Stories from 55 Broad Street; to tell the story of their experience.
- Humana is a founding sponsor of eons.com, the online social networking site developed by Monster.com founder Jeff Taylor. The site targets the 50+ market segment.
- Humana brought the 1942 classic Casablanca back to the big screen in select movie theatres nationwide as part of a campaign to preview its 2007 Medicare Advantage consumer services. The special screening events marked the first time in more than 60 years that the classic Humphrey Bogart epic was seen nationally in movie theatres. | https://www.wikidoc.org/index.php/Humana | |
a2cd7aed09e2c9a6a7fa4ce0f60dfaf6dffd0308 | wikidoc | Hunger | Hunger
Hunger is a feeling experienced when the glycogen level of the liver falls below a threshold, usually followed by a desire to eat. The usually unpleasant feeling originates in the hypothalamus and is released through receptors in the liver. Although an average nourished human can survive weeks without food intake, the sensation of hunger typically begins after several hours without eating.
Hunger can also be applied metaphorically to cravings of other sorts, e.g. "hungry for victory."
- Drug causes
Chlorpropamide
Pergolide
- Chlorpropamide
- Pergolide
# Hunger pains
When hunger contractions occur in the stomach, the person sometimes experiences mild pain in the pit of the stomach, called hunger pangs. Hunger pangs usually do not begin until 12 to 24 hours after the last ingestion of food, in starvation. A single hunger contraction lasts about 30 seconds, and pangs continue for around 30-45 minutes, then hunger subsides for around 30-150 minutes. Individual contractions are separated at first, but are almost continuous after a time. Emotional states (anger, joy etc.) may inhibit hunger contractions. Levels of hunger are increased by lower blood sugar levels, and are higher in diabetics. They reach their greatest intensity in 3 to 4 days and may weaken in the succeeding days, though hunger never disappears. Hunger contractions are most intense in young, healthy people who have high degrees of gastrointestinal tonus. Periods between contractions increase with old age.
# Satiety
Satiety, or the feeling of fullness, is the disappearance of hunger after a meal. It is a process mediated by the ventromedial nucleus in the hypothalamus. It is therefore the "satiety center."
Various hormones, first of all cholecystokinin, have been implicated in conveying the feeling of satiety to the brain. Leptin increases on satiety, while ghrelin increases when the stomach is empty.
Therefore, satiety refers to the psychological feeling of "fullness" or satisfaction rather than to the physical feeling of being engorged, i.e. the feeling of physical fullness after eating a very large meal.
Satiety directly influences feelings of appetite that are generated in the limbic system, and hunger that is controlled by neurohormones, especially serotonin in the lateral hypothalamus.lll
# Behavioral response
Hunger appears to increase activity and movement in many animals - for example an experiment on spiders showed increased activity and predation in starved spiders, resulting in larger weight gain. This pattern is seen in many animals, including humans while sleeping. It even occurs in rats with their cerebral cortex or stomachs completely removed. Increased activity on hamster wheels occurred when rats were deprived not only of food, but also water or B vitamins such as thiamine This response may increase the animal's chance of finding food, though it has also been speculated the reaction relieves pressure on the home population. | Hunger
Template:Two other uses
Hunger is a feeling experienced when the glycogen level of the liver falls below a threshold[citation needed], usually followed by a desire to eat. The usually unpleasant feeling originates in the hypothalamus and is released through receptors in the liver. Although an average nourished human can survive weeks without food intake,[1] the sensation of hunger typically begins after several hours without eating.
Hunger can also be applied metaphorically to cravings of other sorts, e.g. "hungry for victory."
- Drug causes
Chlorpropamide
Pergolide
- Chlorpropamide
- Pergolide
# Hunger pains
When hunger contractions occur in the stomach, the person sometimes experiences mild pain in the pit of the stomach, called hunger pangs. Hunger pangs usually do not begin until 12 to 24 hours after the last ingestion of food, in starvation. A single hunger contraction lasts about 30 seconds, and pangs continue for around 30-45 minutes, then hunger subsides for around 30-150 minutes.[2] Individual contractions are separated at first, but are almost continuous after a time.[2] Emotional states (anger, joy etc.) may inhibit hunger contractions.[2] Levels of hunger are increased by lower blood sugar levels, and are higher in diabetics.[2] They reach their greatest intensity in 3 to 4 days and may weaken in the succeeding days, though hunger never disappears.[3] Hunger contractions are most intense in young, healthy people who have high degrees of gastrointestinal tonus. Periods between contractions increase with old age.[2]
# Satiety
Satiety, or the feeling of fullness, is the disappearance of hunger after a meal. It is a process mediated by the ventromedial nucleus in the hypothalamus. It is therefore the "satiety center."
Various hormones, first of all cholecystokinin, have been implicated in conveying the feeling of satiety to the brain. Leptin increases on satiety, while ghrelin increases when the stomach is empty.
Therefore, satiety refers to the psychological feeling of "fullness" or satisfaction rather than to the physical feeling of being engorged, i.e. the feeling of physical fullness after eating a very large meal.
Satiety directly influences feelings of appetite that are generated in the limbic system, and hunger that is controlled by neurohormones, especially serotonin in the lateral hypothalamus.lll
# Behavioral response
Hunger appears to increase activity and movement in many animals - for example an experiment on spiders showed increased activity and predation in starved spiders, resulting in larger weight gain.[4] This pattern is seen in many animals, including humans while sleeping.[5] It even occurs in rats with their cerebral cortex or stomachs completely removed.[6] Increased activity on hamster wheels occurred when rats were deprived not only of food, but also water or B vitamins such as thiamine[7] This response may increase the animal's chance of finding food, though it has also been speculated the reaction relieves pressure on the home population.[5] | https://www.wikidoc.org/index.php/Hunger | |
cb99b5df4ed9b519c4ae21a4dbf71b063c03130f | wikidoc | Hybrid | Hybrid
In biology, hybrid has two meanings.
The first meaning is the result of interbreeding between two animals or plants of different taxa. Hybrids between different species within the same genus are sometimes known as interspecific hybrids or crosses. Hybrids between different sub-species within a species are known as intra-specific hybrids. Hybrids between different genera are sometimes known as intergeneric hybrids. Extremely rare interfamilial hybrids have been known to occur (such as the guineafowl hybrids).
The second type of "hybrid" are crosses between populations, breeds or cultivars within a single species. This second meaning is often used in plant and animal breeding. In plant and animal breeding, hybrids are commonly produced and selected because they have desirable characteristics not found or inconsistently present in the parent individuals or populations. This rearranging of the genetic material between populations or races is often called hybridization.
# Interspecific hybrids
An example of an intraspecific hybrid is a hybrid between a Bengal tiger and an Amur (Siberian) tiger.
Interspecific hybrids are bred by mating two species, normally from within the same genus. The offspring display traits and characteristics of both parents. The offspring of an interspecific cross very often are sterile, this hybrid sterility prevents the movement of genes from one species to the other, keeping both species distinct. Sterility is often attributed to the different number of chromosomes the two species have, for example donkeys have 62 chromosomes, while horses have 64 chromosomes, and mules and hinnies have 63 chromosomes. Mules, hinnies, and other normally sterile interspecific hybrids cannot produce viable gametes because the extra chromosome cannot make a homologous pair at meiosis, meiosis is disrupted, and viable sperm and eggs are not formed. However, fertility in female mules has been reported with a donkey as the father. Most often other mechanisms are used by plants and animals to keep gametic isolation and species distinction. Species often have different mating or courtship patterns or behavours, the breeding seasons maybe distinct and even if mating does occur antigenic reactions to the sperm of other species prevent fertilization or embryo development.
The Lonicera fly is the first known animal species that resulted from natural hybridization. Until the discovery of the Lonicera fly, this process was known to occur in nature only among plants.
While it is possible to predict the genetic composition of a backcross on average, it is not possible to accurately predict the composition of a particular backcrossed individual, due to random segregation of chromosomes. In a species with two pairs of chromosomes, a twice backcrossed individual would be predicted to contain 12.5% of one species' genome (say, species A). However, it may, in fact, still be a 50% hybrid if the chromosomes from species A were lucky in two successive segregations, and meiotic crossovers happened near the telomeres. The chance of this is fairly high, 1/2^(2×2)=1/16 (where the "two times two" comes about from two rounds of meiosis with two chromosomes); however, this probability declines markedly with chromosome number and so the actual composition of a hybrid will be increasingly closer to the predicted composition.
Hybrids are often named by the portmanteau method, combining the names of the two parent species. For example, a zeedonk is a cross between a zebra and a donkey. Since the traits of hybrid offspring often vary depending on which species was mother and which was father, it is traditional to use the father's species as the first half of the portmanteau. For example, a liger is a cross between a male lion and a female tiger, while a tigon is a cross between a male tiger and a female lion.
- Equid hybrids
Mule, a cross of female horse and a male donkey.
Hinny, a cross between a female donkey and a male horse.
- Mule, a cross of female horse and a male donkey.
- Hinny, a cross between a female donkey and a male horse.
Mule and Hinny are examples of reciprocal hybrids.
- Zebroids
Zeedonk or Zonkey, a zebra/donkey cross.
Zorse, a zebra/horse cross
Zony or Zetland, a zebra/pony cross ("zony" is a generic term; "zetland" is specifically a hybrid of the Shetland pony breed with a zebra)
- Zebroids
Zeedonk or Zonkey, a zebra/donkey cross.
Zorse, a zebra/horse cross
Zony or Zetland, a zebra/pony cross ("zony" is a generic term; "zetland" is specifically a hybrid of the Shetland pony breed with a zebra)
- Zeedonk or Zonkey, a zebra/donkey cross.
- Zorse, a zebra/horse cross
- Zony or Zetland, a zebra/pony cross ("zony" is a generic term; "zetland" is specifically a hybrid of the Shetland pony breed with a zebra)
- Bovid hybrids
Dzo, zo or yakow; a cross between a domestic cow/bull and a yak.
Beefalo, a cross of an American Bison and a domestic cow. This is a fertile breed; this along with genetic evidence has caused them to be recently reclassified into the same genus, Bos.
Zubron, a hybrid between Wisent (European Bison) and domestic cow.
- Dzo, zo or yakow; a cross between a domestic cow/bull and a yak.
- Beefalo, a cross of an American Bison and a domestic cow. This is a fertile breed; this along with genetic evidence has caused them to be recently reclassified into the same genus, Bos.
- Zubron, a hybrid between Wisent (European Bison) and domestic cow.
- Sheep-goat hybrids, such as the The Toast of Botswana.
- Ursinae hybrids, such as the Grizzly-polar bear hybrid, occur between black bears, brown bears, Kodiak and polar bears.
- Felid hybrids
Savannah cats are the hybrid cross between an African serval cat and a Domestic cat
Ligers and Tigons (crosses between a Lion and a Tiger) and other Panthera hybrids such as the Lijagulep. Various other wild cat crosses are known involving the Lynx, Bobcat, Leopard, Serval, etc.
Bengal cat, a cross between the Asian Leopard cat and the domestic cat, one of many hybrids between the domestic cat and wild cat species. The domestic cat, African wild cat and European wildcat may be considered variant populations of the same species (Felis silvestris), making such crosses non-hybrids.
- Savannah cats are the hybrid cross between an African serval cat and a Domestic cat
- Ligers and Tigons (crosses between a Lion and a Tiger) and other Panthera hybrids such as the Lijagulep. Various other wild cat crosses are known involving the Lynx, Bobcat, Leopard, Serval, etc.
- Bengal cat, a cross between the Asian Leopard cat and the domestic cat, one of many hybrids between the domestic cat and wild cat species. The domestic cat, African wild cat and European wildcat may be considered variant populations of the same species (Felis silvestris), making such crosses non-hybrids.
- Fertile Canid hybrids occur between coyotes, wolves, dingoes, jackals and domestic dogs. Dogs and wolves may be considered the same species, making wolfdogs a non-hybrid.
- Hybrids between Black Rhinos & White Rhinos have been recognized.
- Hybrids between spotted owls and barred owls
- Cama, a cross between a Camel and a Llama, also an intergeneric hybrid.
- Wolphin, a fertile but very rare cross between a False Killer Whale and a Bottlenose Dolphin.
- A fertile cross between an albino King Snake and an albino Corn Snake.
- At Chester Zoo in the United Kingdom, a cross between African elephant (male) and Asian elephant (female). The male calf was named Motty. It died of gut infection after twelve days.
- Cagebird breeders sometimes breed hybrids between species of finch, such as Goldfinch x Canary. These birds are known as Mules.
- Gamebird hybrids, hybrids between gamebirds and domestic fowl, including Chickens, Guineafowl and Peafowl, interfamilial hybrids.
- Numerous Macaw hybrids are also known.
- Red Kite x Black Kite: 5 bred unintentionally at a falconry center in England. (It is reported that the black kite (the male) refused female black kites but mated with two female red kites.)
- Hybridization between the endemic Cuban Crocodile (Crocodilus rhombifer) and the widely distributed American Crocodile (Crocodilus acutus) is causing conservation problems for the former species as a threat to is genetic integrity.
- Blood parrot cichlid, which is probably created by crossing a Gold Severum and a Midas Cichlid or Red Devil Cichlid
Some dog hybrids are becoming increasingly popular and are bred selectively.
Hybrids should not be confused with chimaeras such as the chimera between sheep and goat known as the geep.
Wider interspecific hybrids can be made via in vitro fertilization or somatic hybridization, however the resulting cells are not able to develop into a full organism. An example of interspecific hybrid cell lines is the humster (hamster x human) cells.
# Hybrid plants
Plant species hybridize more readily than animal species, and the resulting hybrids are more often fertile hybrids and may reproduce, though there still exist sterile hybrids and selective hybrid elimination where the offspring are less able to survive and are thus eliminated before they can reproduce. A number of plant species are the result of hybridization and polyploidy with many plant species easily cross pollinating and producing viable seeds, the distinction between each species is often maintained by geographical isolation or differences in the flowering period. Animals, being more mobile, have developed complex mating behaviors that maintain the species boundary and when hybrids do occur, natural selection tends to weed them out of the population since these hybrids generally can not find mates that will accept them or they are less adapted and fit for survival in their habitats. Since plants hybridize frequently without much work, they are often created by humans in order to produce improved plants. These improvements can include the production of more or improved; seeds, fruits or other plant parts for consumption, or to make a plant more winter or heat hardy or improve its growth and/or appearance for use in horticulture. Much work is now being done with hybrids to produce more disease resistant plants for both agricultural and horticultural crops. In many groups of plants hybridization has been used to produce larger and more showy flowers and new flower colors.
Many plant genera and species have their origins in polyploidy. Autopolyploidy resulting from the sudden multiplication in the number of chromosomes in typical normal populations caused by unsuccessful separation of the chromosomes during meiosis. Tetraploids or plants with four sets of chromosomes are common in a number of different groups of plants and over time these plants can differentiate into distinct species from the normal diploid line. In Oenothera lamarchiana the diploid species has 14 chromosomes, this species has spontaneously given rise to plants with 28 chromosomes that have been given the name Oenthera gigas. Tetraploids can develop into a breeding population within the diploid population and when hybrids are formed with the diploid population the resulting offspring tend to be sterile triploids, thus effectively stopping the intermixing of genes between the two groups of plants(unless the diploids, in rare cases, produce unreduced gametes) Another form of polyploidy called allopolyploidy occurs when two different species mate and produce hybrids. Usually the typical chromosome number is doubled in successful allopolyploid species, with four
sets of chromosomes the genotypes can sort out to form a complete diploid set from the parent species, thus they can produce fertile offspring that can mate and reproduce with each other but can not back-cross with the parent species. Allopolyploidy in plants often gives them a condition called hybrid vigour, which results in plants that are larger and stronger growing than either of the two parent species. Allopolyploids are often more aggressive growing and can be invaders of new habitats.
Sterility in a hybrid is often a result of chromosome number; if parents are of differing chromosome pair number, the offspring will have an odd number of chromosomes, leaving them unable to produce chromosomally balanced gametes. While this is a negative in a crop such as wheat, when growing a crop which produces no seeds would be pointless, it is an attractive attribute in some fruits. Bananas and seedless watermelon, for instance, are intentionally bred to be triploid, so that they will produce no seeds. Many hybrids are created by humans, but natural hybrids occur as well.
Plant hybrids, especially, are often stronger than either parent variety, a phenomenon which when present is known as hybrid vigour (heterosis) or heterozygote advantage. Plant breeders make use of a number of techniques to produce hybrids, including line breeding and the formation of complex hybrids.
Some plant hybrids include:
- Leyland Cypress, a hybrid between Monterey Cypress and Nootka Cypress.
- Limequat, lime and kumquat hybrid.
- Loganberry, a hybrid between raspberry and blackberry.
- London Plane, a hybrid between Oriental plane and American plane (American sycamore).
- Peppermint, a hybrid between spearmint and water mint.
- Tangelo, a hybrid of a Mandarin orange and a pomelo or a grapefruit which may have been developed in Asia about 3,500 years ago.
- Triticale, a wheat-rye hybrid.
- Wheat; most modern and ancient wheat breeds are themselves hybrids.
Some natural hybrids are:
- White Flag Iris, a sterile hybrid which spreads by rhizome division
- Evening primrose, a flower which was the subject of famous experiments by Hugo de Vries on polyploidy and diploidy.
Some horticultural hybrids:
- Dianthus ×allwoodii, is a hybrid between Dianthus caryophyllus × Dianthus plumarius. This is an "interspecific hybrid" or hybrid between two species in the same genus.
- ×Heucherella tiarelloides, or Heuchera sanguinea × Tiarella cordifolia is an "intergeneric hybrid" a hybrid between two different genera.
# Hybrids in nature
Hybridisation between two closely related species is actually a common occurrence in nature. Many hybrid zones are known where the ranges of two species meet, and hybrids are continually produced in great numbers. These hybrid zones are useful as biological model systems for studying the mechanisms of speciation (Hybrid speciation). Recently DNA analysis of a bear shot by a hunter in the North West Territories confirmed the existence of naturally occurring and fertile polar bear/grizzly bear hybrids. There have been reports of similar supposed hybrids, but this is the first to be confirmed by DNA analysis. In 1943, Clara Helgason described a male bear shot by hunters during her childhood. It was large and off-white with hair all over its paws. The presence of hair on the bottom of the feet suggests it was a natural hybrid of Kodiak and Polar bear.
In some species, hybridisation plays an important role in evolutionary biology. While most hybrids are disadvantaged as a result of genetic incompatibility, the fittest survive, regardless of species boundaries. They may have a beneficial combination of traits allowing them to exploit new habitats or to succeed in a marginal habitat where the two parent species are disadvantaged. This has been seen in experiments on sunflower species. Unlike mutation, which affects only one gene, hybridisation creates multiple variations across genes or gene combinations simultaneously. Successful hybrids could evolve into new species within 50-60 generations. This leads some scientists to speculate that life is a genetic continuum rather than a series of self-contained species.
Where there are two closely related species living in the same area, less than 1 in 1000 individuals are likely to be hybrids because animals rarely choose a mate from a different species (otherwise species boundaries would completely break down). In some closely related species there are recognized "hybrid zones".
Some species of Heliconius butterflies exhibit dramatic geographical polymorphism of their wing patterns, which act as aposematic signals advertising their unpalatability to potential predators. Where different-looking geographical races abut, inter-racial hybrids are common, healthy and fertile. Heliconius hybrids can breed with other hybrid individuals and with individuals of either parental race. These hybrid backcrosses are disadvantaged by natural selection because they lack the parental form's warning coloration, and are therefore not avoided by predators.
A similar case in mammals is hybrid White-Tail/Mule Deer. The hybrids don't inherit either parent's escape strategy. White-tail Deer dash while Mule Deer bound. The hybrids are easier prey than the parent species.
In birds, healthy Galapagos Finch hybrids are relatively common, but their beaks are intermediate in shape and less efficient feeding tools than the specialised beaks of the parental species so they lose out in the competition for food. Following a major storm in 1983, the local habitat changed so that new types of plants began to flourish, and in this changed habitat, the hybrids had an advantage over the birds with specialised beaks - demonstrating the role of hybridization in exploiting new ecological niches. If the change in environmental conditions is permanent or is radical enough that the parental species cannot survive, the hybrids become the dominant form. Otherwise, the parental species will re-establish themselves when the environmental change is reversed, and hybrids will remain in the minority.
Natural hybrids may occur when a species is introduced into a new habitat. In Britain, there is hybridisation of native European Red Deer and introduced Chinese Sika Deer. Conservationists want to protect the Red Deer, but evolution favors the Sika Deer genes. There is a similar situation with White-headed Ducks and Ruddy Ducks.
## Genetic pollution and Extinction
Purebred naturally evolved region specific wild species can be threatened with extinction in a big way through the process of Genetic Pollution i.e. uncontrolled hybridization, introgression and Genetic swamping which leads to homogenization or replacement of local genotypes as a result of either a numerical and/or fitness advantage of introduced plant or animal. Nonnative species can bring about a form of extinction of native plants and animals by hybridization and introgression either through purposeful introduction by humans or through habitat modification, bringing previously isolated species into contact. These phenomena can be especially detrimental for rare species coming into contact with more abundant ones where the abundant ones can interbreed with them swamping the entire rarer gene pool creating hybrids thus driving the entire original purebred native stock to complete extinction. Attention has to be focused on the extent of this under appreciated problem that is not always apparent from morphological (outward appearance) observations alone. Some degree of gene flow may be a normal, evolutionarily constructive process, and all constellations of genes and genotypes cannot be preserved however, hybridization with or without introgression may, nevertheless, threaten a rare species' existence.
## Effect on biodiversity and food security
In agriculture and animal husbandry, green revolution popularized the use of conventional hybridization to increase yield many folds. Often the handful of breeds of plants and animals hybridized originated in developed countries and were further hybridized with local verities, in the rest of the developing world, to create high yield strains resistant to local climate and diseases. Local governments and industry since have been pushing hybridization with such zeal that several of the wild and indigenous breeds evolved locally over thousands of years having high resistance to local extremes in climate and immunity to diseases etc. have already become extinct or are in grave danger of becoming so in the near future. Due to complete disuse because of un-profitability and uncontrolled intentional, compounded with unintentional cross-pollination and crossbreeding (genetic pollution) formerly huge gene pools of various wild and indigenous breeds have collapsed causing widespread genetic erosion and genetic pollution resulting in great loss in genetic diversity and biodiversity as a whole.
A Genetically Modified Organism (GMO) is an organism whose genetic material has been altered using the genetic engineering techniques generally known as recombinant DNA technology. Genetic Engineering today has become another serious and alarming cause of genetic pollution because artificially created and genetically engineered plants and animals in laboratories, which could never have evolved in nature even with conventional hybridization, can live and breed on their own and what is even more alarming interbreed with naturally evolved wild varieties. Genetically Modified (GM) crops today have become a common source for genetic pollution, not only of wild varieties but also of other domesticated varieties derived from relatively natural hybridization.
It is being said that genetic erosion coupled with genetic pollution is destroying that needed unique genetic base thereby creating an unforeseen hidden crisis which will result in a severe threat to our food security for the future when diverse genetic material will cease to exist to be able to further improve or hybridize weakening food crops and livestock against more resistant diseases and climatic changes.
# Limiting Factors
A number of conditions exist that limit the success of hybridization, the most obvious is great genetic diversity between most species. But in animals and plants that are more closely related hybridization barriers include morphological differences, differing times of fertility, mating behaviors and cues, physiological rejection of sperm cells or the developing embryo.
In plants, barriers to hybridization include blooming period differences, different pollinator vectors, inhibition of pollen tube growth, somatoplastic sterility, cytoplasmic-genic male sterility and structural differences of the chromosomes.
# Mythological and legendary hybrids
In ancient folktales many fictional hybrids have become part of the mythological narrative. Many mythological creatures are simple composites of known animals:
- Basilisk and Cockatrice - both a combination of a cockerel and lizard or snake.
- Bonnacon - a mixture between a horse and a bull.
- Chimera - a fire breathing mixture between a goat, a snake, and a lion.
- Griffin - beast with the body of a lion and the head and wings of an eagle.
- Manticore - the face of a man, the body of a lion and the tail of a scorpion.
- Mermaid and Merman - half fish, half human.
- Satyr - the torso of a man, the legs and feet of a goat.
Some mythological hybrids were said to be the result of two species mixing.
- Centaur - the offspring of Centaurus and the mares of Thessaly. Has the body of a horse with its neck and head replaced by the torso and head of a man.
- Harpy - the torso of a woman with the wings and feet of a bird.
- Hippogriff - the offspring of a griffin and a horse, typically a male griffin and a mare.
- Minotaur - the offspring of Pasiphaë and a white bull. Has the body of a man and the head of a bull.
- Nephilim - the offspring of a fallen angel and human woman.
# Etymology
The word has a Latin root: hybrida (or ibrida) which meant "the offspring of a tame sow and wild boar". The term entered into popular use in English in the 19th Century, though examples of its use have been found from the early 17th Century. | Hybrid
Template:This
In biology, hybrid has two meanings.[1]
The first meaning is the result of interbreeding between two animals or plants of different taxa. Hybrids between different species within the same genus are sometimes known as interspecific hybrids or crosses. Hybrids between different sub-species within a species are known as intra-specific hybrids. Hybrids between different genera are sometimes known as intergeneric hybrids. Extremely rare interfamilial hybrids have been known to occur (such as the guineafowl hybrids).
The second type of "hybrid" are crosses between populations, breeds or cultivars within a single species. This second meaning is often used in plant and animal breeding. In plant and animal breeding, hybrids are commonly produced and selected because they have desirable characteristics not found or inconsistently present in the parent individuals or populations. This rearranging of the genetic material between populations or races is often called hybridization.
# Interspecific hybrids
An example of an intraspecific hybrid is a hybrid between a Bengal tiger and an Amur (Siberian) tiger.
Interspecific hybrids are bred by mating two species, normally from within the same genus. The offspring display traits and characteristics of both parents. The offspring of an interspecific cross very often are sterile, this hybrid sterility prevents the movement of genes from one species to the other, keeping both species distinct.[2] Sterility is often attributed to the different number of chromosomes the two species have, for example donkeys have 62 chromosomes, while horses have 64 chromosomes, and mules and hinnies have 63 chromosomes. Mules, hinnies, and other normally sterile interspecific hybrids cannot produce viable gametes because the extra chromosome cannot make a homologous pair at meiosis, meiosis is disrupted, and viable sperm and eggs are not formed. However, fertility in female mules has been reported with a donkey as the father.[3] Most often other mechanisms are used by plants and animals to keep gametic isolation and species distinction. Species often have different mating or courtship patterns or behavours, the breeding seasons maybe distinct and even if mating does occur antigenic reactions to the sperm of other species prevent fertilization or embryo development.
The Lonicera fly is the first known animal species that resulted from natural hybridization. Until the discovery of the Lonicera fly, this process was known to occur in nature only among plants.
While it is possible to predict the genetic composition of a backcross on average, it is not possible to accurately predict the composition of a particular backcrossed individual, due to random segregation of chromosomes. In a species with two pairs of chromosomes, a twice backcrossed individual would be predicted to contain 12.5% of one species' genome (say, species A). However, it may, in fact, still be a 50% hybrid if the chromosomes from species A were lucky in two successive segregations, and meiotic crossovers happened near the telomeres. The chance of this is fairly high, 1/2^(2×2)=1/16 (where the "two times two" comes about from two rounds of meiosis with two chromosomes); however, this probability declines markedly with chromosome number and so the actual composition of a hybrid will be increasingly closer to the predicted composition.
Hybrids are often named by the portmanteau method, combining the names of the two parent species. For example, a zeedonk is a cross between a zebra and a donkey. Since the traits of hybrid offspring often vary depending on which species was mother and which was father, it is traditional to use the father's species as the first half of the portmanteau. For example, a liger is a cross between a male lion and a female tiger, while a tigon is a cross between a male tiger and a female lion.
- Equid hybrids
Mule, a cross of female horse and a male donkey.
Hinny, a cross between a female donkey and a male horse.
- Mule, a cross of female horse and a male donkey.
- Hinny, a cross between a female donkey and a male horse.
Mule and Hinny are examples of reciprocal hybrids.
- Zebroids
Zeedonk or Zonkey, a zebra/donkey cross.
Zorse, a zebra/horse cross
Zony or Zetland, a zebra/pony cross ("zony" is a generic term; "zetland" is specifically a hybrid of the Shetland pony breed with a zebra)
- Zebroids
Zeedonk or Zonkey, a zebra/donkey cross.
Zorse, a zebra/horse cross
Zony or Zetland, a zebra/pony cross ("zony" is a generic term; "zetland" is specifically a hybrid of the Shetland pony breed with a zebra)
- Zeedonk or Zonkey, a zebra/donkey cross.
- Zorse, a zebra/horse cross
- Zony or Zetland, a zebra/pony cross ("zony" is a generic term; "zetland" is specifically a hybrid of the Shetland pony breed with a zebra)
- Bovid hybrids
Dzo, zo or yakow; a cross between a domestic cow/bull and a yak.
Beefalo, a cross of an American Bison and a domestic cow. This is a fertile breed; this along with genetic evidence has caused them to be recently reclassified into the same genus, Bos.
Zubron, a hybrid between Wisent (European Bison) and domestic cow.
- Dzo, zo or yakow; a cross between a domestic cow/bull and a yak.
- Beefalo, a cross of an American Bison and a domestic cow. This is a fertile breed; this along with genetic evidence has caused them to be recently reclassified into the same genus, Bos.
- Zubron, a hybrid between Wisent (European Bison) and domestic cow.
- Sheep-goat hybrids, such as the The Toast of Botswana.
- Ursinae hybrids, such as the Grizzly-polar bear hybrid, occur between black bears, brown bears, Kodiak and polar bears.
- Felid hybrids
Savannah cats are the hybrid cross between an African serval cat and a Domestic cat
Ligers and Tigons (crosses between a Lion and a Tiger) and other Panthera hybrids such as the Lijagulep. Various other wild cat crosses are known involving the Lynx, Bobcat, Leopard, Serval, etc.
Bengal cat, a cross between the Asian Leopard cat and the domestic cat, one of many hybrids between the domestic cat and wild cat species. The domestic cat, African wild cat and European wildcat may be considered variant populations of the same species (Felis silvestris), making such crosses non-hybrids.
- Savannah cats are the hybrid cross between an African serval cat and a Domestic cat
- Ligers and Tigons (crosses between a Lion and a Tiger) and other Panthera hybrids such as the Lijagulep. Various other wild cat crosses are known involving the Lynx, Bobcat, Leopard, Serval, etc.
- Bengal cat, a cross between the Asian Leopard cat and the domestic cat, one of many hybrids between the domestic cat and wild cat species. The domestic cat, African wild cat and European wildcat may be considered variant populations of the same species (Felis silvestris), making such crosses non-hybrids.
- Fertile Canid hybrids occur between coyotes, wolves, dingoes, jackals and domestic dogs. Dogs and wolves may be considered the same species, making wolfdogs a non-hybrid.
- Hybrids between Black Rhinos & White Rhinos have been recognized.
- Hybrids between spotted owls and barred owls
- Cama, a cross between a Camel and a Llama, also an intergeneric hybrid.
- Wolphin, a fertile but very rare cross between a False Killer Whale and a Bottlenose Dolphin.
- A fertile cross between an albino King Snake and an albino Corn Snake.
- At Chester Zoo in the United Kingdom, a cross between African elephant (male) and Asian elephant (female). The male calf was named Motty. It died of gut infection after twelve days.
- Cagebird breeders sometimes breed hybrids between species of finch, such as Goldfinch x Canary. These birds are known as Mules.
- Gamebird hybrids, hybrids between gamebirds and domestic fowl, including Chickens, Guineafowl and Peafowl, interfamilial hybrids.
- Numerous Macaw hybrids are also known.
- Red Kite x Black Kite: 5 bred unintentionally at a falconry center in England. (It is reported that the black kite (the male) refused female black kites but mated with two female red kites.)
- Hybridization between the endemic Cuban Crocodile (Crocodilus rhombifer) and the widely distributed American Crocodile (Crocodilus acutus) is causing conservation problems for the former species as a threat to is genetic integrity. [4]
- Blood parrot cichlid, which is probably created by crossing a Gold Severum and a Midas Cichlid or Red Devil Cichlid
Some dog hybrids are becoming increasingly popular and are bred selectively.
Hybrids should not be confused with chimaeras such as the chimera between sheep and goat known as the geep.
Wider interspecific hybrids can be made via in vitro fertilization or somatic hybridization, however the resulting cells are not able to develop into a full organism. An example of interspecific hybrid cell lines is the humster (hamster x human) cells.
# Hybrid plants
Plant species hybridize more readily than animal species, and the resulting hybrids are more often fertile hybrids and may reproduce, though there still exist sterile hybrids and selective hybrid elimination where the offspring are less able to survive and are thus eliminated before they can reproduce. A number of plant species are the result of hybridization and polyploidy with many plant species easily cross pollinating and producing viable seeds, the distinction between each species is often maintained by geographical isolation or differences in the flowering period. Animals, being more mobile, have developed complex mating behaviors that maintain the species boundary and when hybrids do occur, natural selection tends to weed them out of the population since these hybrids generally can not find mates that will accept them or they are less adapted and fit for survival in their habitats. Since plants hybridize frequently without much work, they are often created by humans in order to produce improved plants. These improvements can include the production of more or improved; seeds, fruits or other plant parts for consumption, or to make a plant more winter or heat hardy or improve its growth and/or appearance for use in horticulture. Much work is now being done with hybrids to produce more disease resistant plants for both agricultural and horticultural crops. In many groups of plants hybridization has been used to produce larger and more showy flowers and new flower colors.
Many plant genera and species have their origins in polyploidy. Autopolyploidy resulting from the sudden multiplication in the number of chromosomes in typical normal populations caused by unsuccessful separation of the chromosomes during meiosis. Tetraploids or plants with four sets of chromosomes are common in a number of different groups of plants and over time these plants can differentiate into distinct species from the normal diploid line. In Oenothera lamarchiana the diploid species has 14 chromosomes, this species has spontaneously given rise to plants with 28 chromosomes that have been given the name Oenthera gigas. Tetraploids can develop into a breeding population within the diploid population and when hybrids are formed with the diploid population the resulting offspring tend to be sterile triploids, thus effectively stopping the intermixing of genes between the two groups of plants(unless the diploids, in rare cases, produce unreduced gametes) Another form of polyploidy called allopolyploidy occurs when two different species mate and produce hybrids. Usually the typical chromosome number is doubled in successful allopolyploid species, with four
sets of chromosomes the genotypes can sort out to form a complete diploid set from the parent species, thus they can produce fertile offspring that can mate and reproduce with each other but can not back-cross with the parent species. Allopolyploidy in plants often gives them a condition called hybrid vigour, which results in plants that are larger and stronger growing than either of the two parent species. Allopolyploids are often more aggressive growing and can be invaders of new habitats.
Sterility in a hybrid is often a result of chromosome number; if parents are of differing chromosome pair number, the offspring will have an odd number of chromosomes, leaving them unable to produce chromosomally balanced gametes.[4] While this is a negative in a crop such as wheat, when growing a crop which produces no seeds would be pointless, it is an attractive attribute in some fruits. Bananas and seedless watermelon, for instance, are intentionally bred to be triploid, so that they will produce no seeds. Many hybrids are created by humans, but natural hybrids occur as well.
Plant hybrids, especially, are often stronger than either parent variety, a phenomenon which when present is known as hybrid vigour (heterosis) or heterozygote advantage.[5] Plant breeders make use of a number of techniques to produce hybrids, including line breeding and the formation of complex hybrids.
Some plant hybrids include:
- Leyland Cypress, a hybrid between Monterey Cypress and Nootka Cypress.
- Limequat, lime and kumquat hybrid.
- Loganberry, a hybrid between raspberry and blackberry.
- London Plane, a hybrid between Oriental plane and American plane (American sycamore).
- Peppermint, a hybrid between spearmint and water mint.
- Tangelo, a hybrid of a Mandarin orange and a pomelo or a grapefruit which may have been developed in Asia about 3,500 years ago.
- Triticale, a wheat-rye hybrid.
- Wheat; most modern and ancient wheat breeds are themselves hybrids.
Some natural hybrids are:
- White Flag Iris, a sterile hybrid which spreads by rhizome division
- Evening primrose, a flower which was the subject of famous experiments by Hugo de Vries on polyploidy and diploidy.
Some horticultural hybrids:
- Dianthus ×allwoodii, is a hybrid between Dianthus caryophyllus × Dianthus plumarius. This is an "interspecific hybrid" or hybrid between two species in the same genus.
- ×Heucherella tiarelloides, or Heuchera sanguinea × Tiarella cordifolia is an "intergeneric hybrid" a hybrid between two different genera.
# Hybrids in nature
Hybridisation between two closely related species is actually a common occurrence in nature. Many hybrid zones are known where the ranges of two species meet, and hybrids are continually produced in great numbers. These hybrid zones are useful as biological model systems for studying the mechanisms of speciation (Hybrid speciation). Recently DNA analysis of a bear shot by a hunter in the North West Territories confirmed the existence of naturally occurring and fertile polar bear/grizzly bear hybrids.[6] There have been reports of similar supposed hybrids, but this is the first to be confirmed by DNA analysis. In 1943, Clara Helgason described a male bear shot by hunters during her childhood. It was large and off-white with hair all over its paws. The presence of hair on the bottom of the feet suggests it was a natural hybrid of Kodiak and Polar bear.
In some species, hybridisation plays an important role in evolutionary biology. While most hybrids are disadvantaged as a result of genetic incompatibility, the fittest survive, regardless of species boundaries. They may have a beneficial combination of traits allowing them to exploit new habitats or to succeed in a marginal habitat where the two parent species are disadvantaged. This has been seen in experiments on sunflower species. Unlike mutation, which affects only one gene, hybridisation creates multiple variations across genes or gene combinations simultaneously. Successful hybrids could evolve into new species within 50-60 generations. This leads some scientists to speculate that life is a genetic continuum rather than a series of self-contained species.
Where there are two closely related species living in the same area, less than 1 in 1000 individuals are likely to be hybrids because animals rarely choose a mate from a different species (otherwise species boundaries would completely break down). In some closely related species there are recognized "hybrid zones".
Some species of Heliconius butterflies exhibit dramatic geographical polymorphism of their wing patterns, which act as aposematic signals advertising their unpalatability to potential predators. Where different-looking geographical races abut, inter-racial hybrids are common, healthy and fertile. Heliconius hybrids can breed with other hybrid individuals and with individuals of either parental race. These hybrid backcrosses are disadvantaged by natural selection because they lack the parental form's warning coloration, and are therefore not avoided by predators.
A similar case in mammals is hybrid White-Tail/Mule Deer. The hybrids don't inherit either parent's escape strategy. White-tail Deer dash while Mule Deer bound. The hybrids are easier prey than the parent species.
In birds, healthy Galapagos Finch hybrids are relatively common, but their beaks are intermediate in shape and less efficient feeding tools than the specialised beaks of the parental species so they lose out in the competition for food. Following a major storm in 1983, the local habitat changed so that new types of plants began to flourish, and in this changed habitat, the hybrids had an advantage over the birds with specialised beaks - demonstrating the role of hybridization in exploiting new ecological niches. If the change in environmental conditions is permanent or is radical enough that the parental species cannot survive, the hybrids become the dominant form. Otherwise, the parental species will re-establish themselves when the environmental change is reversed, and hybrids will remain in the minority.
Natural hybrids may occur when a species is introduced into a new habitat. In Britain, there is hybridisation of native European Red Deer and introduced Chinese Sika Deer. Conservationists want to protect the Red Deer, but evolution favors the Sika Deer genes. There is a similar situation with White-headed Ducks and Ruddy Ducks.
## Genetic pollution and Extinction
Purebred naturally evolved region specific wild species can be threatened with extinction in a big way[7] through the process of Genetic Pollution i.e. uncontrolled hybridization, introgression and Genetic swamping which leads to homogenization or replacement of local genotypes as a result of either a numerical and/or fitness advantage of introduced plant or animal[8]. Nonnative species can bring about a form of extinction of native plants and animals by hybridization and introgression either through purposeful introduction by humans or through habitat modification, bringing previously isolated species into contact. These phenomena can be especially detrimental for rare species coming into contact with more abundant ones where the abundant ones can interbreed with them swamping the entire rarer gene pool creating hybrids thus driving the entire original purebred native stock to complete extinction. Attention has to be focused on the extent of this under appreciated problem that is not always apparent from morphological (outward appearance) observations alone. Some degree of gene flow may be a normal, evolutionarily constructive process, and all constellations of genes and genotypes cannot be preserved however, hybridization with or without introgression may, nevertheless, threaten a rare species' existence[9][10].
## Effect on biodiversity and food security
In agriculture and animal husbandry, green revolution popularized the use of conventional hybridization to increase yield many folds. Often the handful of breeds of plants and animals hybridized originated in developed countries and were further hybridized with local verities, in the rest of the developing world, to create high yield strains resistant to local climate and diseases. Local governments and industry since have been pushing hybridization with such zeal that several of the wild and indigenous breeds evolved locally over thousands of years having high resistance to local extremes in climate and immunity to diseases etc. have already become extinct or are in grave danger of becoming so in the near future. Due to complete disuse because of un-profitability and uncontrolled intentional, compounded with unintentional cross-pollination and crossbreeding (genetic pollution) formerly huge gene pools of various wild and indigenous breeds have collapsed causing widespread genetic erosion and genetic pollution resulting in great loss in genetic diversity and biodiversity as a whole[11].
A Genetically Modified Organism (GMO) is an organism whose genetic material has been altered using the genetic engineering techniques generally known as recombinant DNA technology. Genetic Engineering today has become another serious and alarming cause of genetic pollution because artificially created and genetically engineered plants and animals in laboratories, which could never have evolved in nature even with conventional hybridization, can live and breed on their own and what is even more alarming interbreed with naturally evolved wild varieties. Genetically Modified (GM) crops today have become a common source for genetic pollution, not only of wild varieties but also of other domesticated varieties derived from relatively natural hybridization[12][13][14][15][16].
It is being said that genetic erosion coupled with genetic pollution is destroying that needed unique genetic base thereby creating an unforeseen hidden crisis which will result in a severe threat to our food security for the future when diverse genetic material will cease to exist to be able to further improve or hybridize weakening food crops and livestock against more resistant diseases and climatic changes.
# Limiting Factors
A number of conditions exist that limit the success of hybridization, the most obvious is great genetic diversity between most species. But in animals and plants that are more closely related hybridization barriers include morphological differences, differing times of fertility, mating behaviors and cues, physiological rejection of sperm cells or the developing embryo.
In plants, barriers to hybridization include blooming period differences, different pollinator vectors, inhibition of pollen tube growth, somatoplastic sterility, cytoplasmic-genic male sterility and structural differences of the chromosomes.[17]
# Mythological and legendary hybrids
In ancient folktales many fictional hybrids have become part of the mythological narrative. Many mythological creatures are simple composites of known animals:
- Basilisk and Cockatrice - both a combination of a cockerel and lizard or snake.
- Bonnacon - a mixture between a horse and a bull.
- Chimera - a fire breathing mixture between a goat, a snake, and a lion.
- Griffin - beast with the body of a lion and the head and wings of an eagle.
- Manticore - the face of a man, the body of a lion and the tail of a scorpion.
- Mermaid and Merman - half fish, half human.
- Satyr - the torso of a man, the legs and feet of a goat.
Some mythological hybrids were said to be the result of two species mixing.
- Centaur - the offspring of Centaurus and the mares of Thessaly. Has the body of a horse with its neck and head replaced by the torso and head of a man.
- Harpy - the torso of a woman with the wings and feet of a bird.
- Hippogriff - the offspring of a griffin and a horse, typically a male griffin and a mare.
- Minotaur - the offspring of Pasiphaë and a white bull. Has the body of a man and the head of a bull.
- Nephilim - the offspring of a fallen angel and human woman.
# Etymology
The word has a Latin root: hybrida (or ibrida) which meant "the offspring of a tame sow and wild boar". The term entered into popular use in English in the 19th Century, though examples of its use have been found from the early 17th Century.[18] | https://www.wikidoc.org/index.php/Hybrid | |
52c3d4da11ce965965aedeb8f8a02b2c6713d190 | wikidoc | Hygeia | Hygeia
In Greek mythology, Hygieia was a daughter of Asclepius. She was the goddess of health, cleanliness and sanitation and afterwards, the moon. She also played an important part in her father's cult. While her father was more directly associated with healing, she was associated with the prevention of sickness and the continuation of good health.
Hygieia was the subject of a local cult since at least the 7th century BC, (it is highly probable that Greek hygiene and health development began from influences of the Celts and the world's first hospital situated in Armagh Ireland. It was built before 650 BC by Queen Macha.) "Athena Hygieia" was one of the titles given to Athene, as Plutarch recounts:
However, the cult of Hygieia as an independent goddess did not begin to spread out until the Oracle at Delphi recognized her, and after the devastating Athens plague in 429 and 427 BC and in Rome in 293 BC. Her primary temples were in Epidaurus, Corinth, Cos and Pergamon. Pausanias remarked that, at the asclepieion of Titane in Sicyon (founded by Alexanor, Asclepius' grandson), statues of Hygieia were covered by women's hair and pieces of Babylonian clothes. According to inscriptions, the same sacrifices were offered at Paros.
Ariphron, a Sicyonian artist from the 4th century BC wrote a well-known hymn celebrating her. Statues of Hygieia were created by Scopas, Bryaxis and Timotheus, among others. She was often depicted as a young woman feeding a large snake that was wrapped around her body. Sometimes the snake would be drinking from a jar that she carried. These attributes were later adopted by the Gallo-Roman healing goddess, Sirona. Hygieia was accompanied by her brother, Telesphorus. Her name is the source of the word "hygiene".
# Salus
In Roman mythology, Salus was worshipped extensively by the Romans. Under the name Salus Publica Populi Romani ("goddess of the public welfare of the Roman people"), there was a temple devoted to her on the Quirinal Hill. It was built in 302 BC. She was depicted with snakes and a bowl in many artistic representations of her. Her festival took place on March 30th. Her name is Latin for "health" and is the source of the English words salubrity, salutation etc. | Hygeia
In Greek mythology, Hygieia was a daughter of Asclepius. She was the goddess of health, cleanliness and sanitation and afterwards, the moon. She also played an important part in her father's cult. While her father was more directly associated with healing, she was associated with the prevention of sickness and the continuation of good health.
Hygieia was the subject of a local cult since at least the 7th century BC, (it is highly probable that Greek hygiene and health development began from influences of the Celts and the world's first hospital situated in Armagh Ireland. It was built before 650 BC by Queen Macha.) "Athena Hygieia" was one of the titles given to Athene, as Plutarch recounts:
However, the cult of Hygieia as an independent goddess did not begin to spread out until the Oracle at Delphi recognized her, and after the devastating Athens plague in 429 and 427 BC and in Rome in 293 BC. Her primary temples were in Epidaurus, Corinth, Cos and Pergamon. Pausanias remarked that, at the asclepieion of Titane in Sicyon (founded by Alexanor, Asclepius' grandson), statues of Hygieia were covered by women's hair and pieces of Babylonian clothes. According to inscriptions, the same sacrifices were offered at Paros.
Ariphron, a Sicyonian artist from the 4th century BC wrote a well-known hymn celebrating her. Statues of Hygieia were created by Scopas, Bryaxis and Timotheus, among others. She was often depicted as a young woman feeding a large snake that was wrapped around her body. Sometimes the snake would be drinking from a jar that she carried. These attributes were later adopted by the Gallo-Roman healing goddess, Sirona. Hygieia was accompanied by her brother, Telesphorus. Her name is the source of the word "hygiene".
# Salus
In Roman mythology, Salus was worshipped extensively by the Romans. Under the name Salus Publica Populi Romani ("goddess of the public welfare of the Roman people"), there was a temple devoted to her on the Quirinal Hill. It was built in 302 BC.[2] She was depicted with snakes and a bowl in many artistic representations of her. Her festival took place on March 30th. Her name is Latin for "health" and is the source of the English words salubrity, salutation etc. | https://www.wikidoc.org/index.php/Hygeia | |
8d43240a27f1acb6978a1d910d515f83ceaebf63 | wikidoc | Orexin | Orexin
Orexin (/ɒˈrɛksɪn/), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, in which the sufferer experiences brief losses of muscle tone (cataplexy), is caused by a lack of orexin in the brain due to destruction of the cells that produce it.
There are only 10,000–20,000 orexin-producing neurons in the human brain, located predominantly in the perifornical area and lateral hypothalamus. They project widely throughout the central nervous system, regulating wakefulness, feeding, and other behaviours. There are two types of orexin peptide and two types of orexin receptor.
Orexin was discovered in 1998 almost simultaneously by two independent groups of researchers working on the rat brain. One group named it orexin, from orexis, meaning "appetite" in Greek; the other group named it hypocretin, because it is produced in the hypothalamus and bears a weak resemblance to secretin, another peptide. The use of both terms is now a practical necessity, as hypocretin is used to refer to the genetic products and orexin is used to refer to the protein products. There is a high affinity between the orexin system in the rat brain and that in the human brain.
# Discovery
In 1998, reports of the discovery of orexin/hypocretin were published nearly simultaneously. Luis de Lecea, Thomas Kilduff, and colleagues reported the discovery of the hypocretin system at the same time as Takeshi Sakurai from Masashi Yanagisawa's lab at the University of Texas Southwestern Medical Center at Dallas reported the discovery of the orexins to reflect the orexigenic (appetite-stimulating) activity of these peptides. In their 1998 paper describing these neuropeptides, they also reported discovery of two orexin receptors, dubbed OX1R and OX2R.
The two groups also took different approaches towards their discovery. One team was interested in finding new genes that were expressed in the hypothalamus. In 1996, scientists from the Scripps Research Institute reported the discovery of several genes in the rat brain, including one they dubbed "clone 35." Their work showed that clone 35 expression was limited to the lateral hypothalamus. They extracted selective DNA found in the lateral hypothalamus. They cloned this DNA and studied it using electron microscopy. Neurotransmitters found in this area were oddly similar to the gut hormone, secretin, a member of the incretin family, so they named hypocretin to stand for a hypothalamic member of the incretin family. These cells were first thought to reside and work only within the lateral hypothalamus area, but immunocytochemistry tactics revealed the various projections this area truly had to other parts of the brain. A majority of these projections reached the limbic system and structures associated with it (including the amygdala, septum, and basal forebrain area).
On the other hand, Sakurai and colleagues were studying the orexin system as orphan receptors. To this end, they used transgenic cell lines that expressed individual orphan receptors and then exposed them to different potential ligands. They found that the orexin peptides activated the cells expressing the orexin receptors and went on to find orexin peptide expression specifically in the hypothalamus. Additionally, when either orexin peptide was administered to rats it stimulated feeding, giving rise to the name 'orexin'.
The nomenclature of the orexin/hypocretin system now recognizes the history of its discovery. "Hypocretin" refers to the gene or genetic products and "orexin" refers to the protein, reflecting the differing approaches that resulted in its discovery. The use of both terms is also a practical necessity because "HCRT" is the standard gene symbol in databases like GenBank and "OX" is used to refer to the pharmacology of the peptide system by the International Union of Basic and Clinical Pharmacology.
# Isoforms
There are two types of orexin: orexin-A and -B (hypocretin-1 and -2). They are excitatory neuropeptides with approximately 50% sequence identity, produced by cleavage of a single precursor protein. Orexin-A is 33 amino acid residues long and has two intrachain disulfide bonds; orexin-B is a linear 28 amino acid residue peptide. Although these peptides are produced by a very small population of cells in the lateral and posterior hypothalamus, they send projections throughout the brain. The orexin peptides bind to the two G-protein coupled orexin receptors, OX1 and OX2, with orexin-A binding to both OX1 and OX2 with approximately equal affinity while orexin-B binds mainly to OX2 and is 5 times less potent at OX1.
The orexins are strongly conserved peptides, found in all major classes of vertebrates.
# Function
The orexin system was initially suggested to be primarily involved in the stimulation of food intake, based on the finding that central administration of orexin-A and -B increased food intake. In addition, it stimulates wakefulness, regulates energy expenditure, and modulates visceral function.
## Brown fat activation
Obesity in orexin knockout mice is a result of inability of brown preadipocytes to differentiate into brown adipose tissue (BAT), which in turn reduces BAT thermogenesis. BAT differentiation can be restored in these knockout mice through injections of orexin. Deficiency in orexin has also been linked to narcolepsy, a sleep disorder. Furthermore, narcoleptic people are more likely to be obese. Hence obesity in narcoleptic patients may be due to orexin deficiency leading to impaired thermogenesis and energy expenditure.
## Wakefulness
Orexin seems to promote wakefulness. Recent studies indicate that a major role of the orexin system is to integrate metabolic, circadian and sleep debt influences to determine whether an animal should be asleep or awake and active. Orexin neurons strongly excite various brain nuclei with important roles in wakefulness including the dopamine, norepinephrine, histamine and acetylcholine systems and appear to play an important role in stabilizing wakefulness and sleep.
The discovery that an orexin receptor mutation causes the sleep disorder canine narcolepsy in Doberman Pinschers subsequently indicated a major role for this system in sleep regulation. Genetic knockout mice lacking the gene for orexin were also reported to exhibit narcolepsy. Transitioning frequently and rapidly between sleep and wakefulness, these mice display many of the symptoms of narcolepsy. Researchers are using this animal model of narcolepsy to study the disease. Narcolepsy results in excessive daytime sleepiness, inability to consolidate wakefulness in the day (and sleep at night), and cataplexy, which is the loss of muscle tone in response to strong, usually positive, emotions. Dogs that lack a functional receptor for orexin have narcolepsy, while animals and people lacking the orexin neuropeptide itself also have narcolepsy.
Central administration of orexin-A strongly promotes wakefulness, increases body temperature and locomotion, and elicits a strong increase in energy expenditure. Sleep deprivation also increases orexin-A transmission. The orexin system may thus be more important in the regulation of energy expenditure than food intake. In fact, orexin-deficient narcoleptic patients have increased obesity rather than decreased BMI, as would be expected if orexin were primarily an appetite stimulating peptide. Another indication that deficits of orexin cause narcolepsy is that depriving monkeys of sleep for 30–36 hours and then injecting them with the neurochemical alleviates the cognitive deficiencies normally seen with such amount of sleep loss.
In humans, narcolepsy is associated with a specific variant of the human leukocyte antigen (HLA) complex. Furthermore, genome-wide analysis shows that, in addition to the HLA variant, narcoleptic humans also exhibit a specific genetic mutation in the T-cell receptor alpha locus. In conjunction, these genetic anomalies cause the immune system to attack and kill the critical orexin neurons. Hence the absence of orexin-producing neurons in narcoleptic humans may be the result of an autoimmune disorder.
## Food intake
Orexin increases the craving for food, and correlates with the function of the substances that promote its production. Orexin is also shown to increase meal size by suppressing inhibitory postingestive feedback. However, some studies suggest that the stimulatory effects of orexin on feeding may be due to general arousal without necessarily increasing overall food intake.
Review findings suggest that hyperglycemia that occurs in mice due to a habitual high-fat diet leads to a reduction in signalling by orexin receptor-2, and that orexin receptors may be a future therapeutic target.
Leptin is a hormone produced by fat cells and acts as a long-term internal measure of energy state. Ghrelin is a short-term factor secreted by the stomach just before an expected meal, and strongly promotes food intake.
Orexin-producing cells have recently been shown to be inhibited by leptin (through the leptin receptor pathway), but are activated by ghrelin and hypoglycemia (glucose inhibits orexin production). Orexin, as of 2007, is claimed to be a very important link between metabolism and sleep regulation. Such a relationship has been long suspected, based on the observation that long-term sleep deprivation in rodents dramatically increases food intake and energy metabolism, i.e., catabolism, with lethal consequences on a long-term basis. Sleep deprivation then leads to a lack of energy. In order to make up for this lack of energy, many people use high-carbohydrate and high-fat foods that ultimately can lead to poor health and weight gain. Other dietary nutrients, amino acids, also can activate orexin neurons, and they can suppress the glucose response of orexin neurons at physiological concentration, causing the energy balance that orexin maintains to be thrown off its normal cycle.
## Addiction
Preliminary research has been conducted that shows potential for orexin blockers in the treatment of cocaine, opioid, and alcohol addiction. For example, lab rats given drugs which targeted the orexin system lost interest in alcohol despite being given free access in experiments.
Studies of orexin involvement in nicotine addiction have had mixed results. For example, blocking the orexin-1 receptor with the selective orexin antagonist SB-334,867 reduced nicotine self-administration in rats and that smokers who suffered damage to the insula, a brain region that regulates cravings and contains orexin-1 receptors, lost the desire to smoke. However, other studies in rats using the dual orexin receptor antagonist TCS 1102 have not found similar effects.
## Lipid metabolism
Orexin-A (OXA) has been recently demonstrated to have a direct effect on an aspect of lipid metabolism. OXA stimulates glucose uptake in 3T3-L1 adipocytes and that increased energy uptake is stored as lipids (triacylglycerol). OXA thus increases lipogenesis. It also inhibits lipolysis and stimulates the secretion of adiponectin. These effects are thought to be mostly conferred via the PI3K pathway because this pathway inhibitor (LY294002) completely blocks OXA effects in adipocytes. The link between OXA and the lipid metabolism is new and currently under more research.
Obesity in orexin-knockout mice is associated with impaired brown adipose tissue thermogenesis.
## Mood
High levels of orexin-A have been associated with happiness in human subjects, while low levels have been associated with sadness. The finding suggests that boosting levels of orexin-A could elevate mood in humans, being thus a possible future treatment for disorders like depression.
# Orexin neurons
## Neurotransmitters
Orexinergic neurons have been shown to be sensitive to inputs from Group III metabotropic glutamate receptors, cannabinoid receptor 1 and CB1–OX1 receptor heterodimers, adenosine A1 receptors, muscarinic M3 receptors, serotonin 5-HT1A receptors, neuropeptide Y receptors, cholecystokinin A receptors, and catecholamines, as well as to ghrelin, leptin, and glucose. Orexinergic neurons themselves regulate release of acetylcholine, serotonin, and noradrenaline.
Orexinergic neurons can be differentiated into two groups based on connectivity and functionality. Orexinergic neurons in the lateral hypothalamic group are closely associated with reward related functions, such as conditioned place preference. These neurons preferentially innervate the ventral tegmental area and the ventromedial prefrontal cortex. In contrast to the lateral hypothalamic neurons, the perifornical-dorsal group of orexinergic neurons involved in functions related to arousal and autonomic response. These neurons project inter-hypothalamically, as well as to the brainstem, where the release of orexin modulates various autonomic processes.
# Clinical uses
The orexin/hypocretin system is the target of the insomnia medication suvorexant, which works by blocking both orexin receptors. Suvorexant has undergone three phase III trials and was approved in 2014 by the US Food and Drug Administration (FDA) after being denied approval the year before. It is marketed as Belsomra.
In 2016, the University of Texas Health Science Center registered a clinical trial for the use of suvorexant for people with cocaine dependence. They plan to measure cue reactivity, anxiety and stress.
## Other potential uses
Intranasal orexin is able to increase cognition in primates, especially under sleep deprived situations, which may provide an opportunity for the treatment of excessive daytime sleepiness.
A study has reported that transplantation of orexin neurons into the pontine reticular formation in rats is feasible, indicating the development of alternative therapeutic strategies in addition to pharmacological interventions to treat narcolepsy. | Orexin
Orexin (/ɒˈrɛksɪn/), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite.[1] The most common form of narcolepsy, in which the sufferer experiences brief losses of muscle tone (cataplexy), is caused by a lack of orexin in the brain due to destruction of the cells that produce it.[2][3]
There are only 10,000–20,000 orexin-producing neurons in the human brain,[2] located predominantly in the perifornical area and lateral hypothalamus.[1][4] They project widely throughout the central nervous system, regulating wakefulness, feeding, and other behaviours.[1] There are two types of orexin peptide and two types of orexin receptor.[5][4]
Orexin was discovered in 1998 almost simultaneously by two independent groups of researchers working on the rat brain.[6][7] One group named it orexin, from orexis, meaning "appetite" in Greek; the other group named it hypocretin, because it is produced in the hypothalamus and bears a weak resemblance to secretin, another peptide.[2] The use of both terms is now a practical necessity, as hypocretin is used to refer to the genetic products and orexin is used to refer to the protein products.[8] There is a high affinity between the orexin system in the rat brain and that in the human brain.[5]
# Discovery
In 1998, reports of the discovery of orexin/hypocretin were published nearly simultaneously. Luis de Lecea, Thomas Kilduff, and colleagues reported the discovery of the hypocretin system at the same time as Takeshi Sakurai from Masashi Yanagisawa's lab at the University of Texas Southwestern Medical Center at Dallas reported the discovery of the orexins to reflect the orexigenic (appetite-stimulating) activity of these peptides. In their 1998 paper describing these neuropeptides, they also reported discovery of two orexin receptors, dubbed OX1R and OX2R.[6]
The two groups also took different approaches towards their discovery. One team was interested in finding new genes that were expressed in the hypothalamus. In 1996, scientists from the Scripps Research Institute reported the discovery of several genes in the rat brain, including one they dubbed "clone 35." Their work showed that clone 35 expression was limited to the lateral hypothalamus.[9] They extracted selective DNA found in the lateral hypothalamus. They cloned this DNA and studied it using electron microscopy. Neurotransmitters found in this area were oddly similar to the gut hormone, secretin, a member of the incretin family, so they named hypocretin to stand for a hypothalamic member of the incretin family.[10] These cells were first thought to reside and work only within the lateral hypothalamus area, but immunocytochemistry tactics revealed the various projections this area truly had to other parts of the brain. A majority of these projections reached the limbic system and structures associated with it (including the amygdala, septum, and basal forebrain area).
On the other hand, Sakurai and colleagues were studying the orexin system as orphan receptors. To this end, they used transgenic cell lines that expressed individual orphan receptors and then exposed them to different potential ligands. They found that the orexin peptides activated the cells expressing the orexin receptors and went on to find orexin peptide expression specifically in the hypothalamus. Additionally, when either orexin peptide was administered to rats it stimulated feeding, giving rise to the name 'orexin'.[6]
The nomenclature of the orexin/hypocretin system now recognizes the history of its discovery. "Hypocretin" refers to the gene or genetic products and "orexin" refers to the protein, reflecting the differing approaches that resulted in its discovery. The use of both terms is also a practical necessity because "HCRT" is the standard gene symbol in databases like GenBank and "OX" is used to refer to the pharmacology of the peptide system by the International Union of Basic and Clinical Pharmacology.[8]
# Isoforms
There are two types of orexin: orexin-A and -B (hypocretin-1 and -2). They are excitatory neuropeptides with approximately 50% sequence identity, produced by cleavage of a single precursor protein. Orexin-A is 33 amino acid residues long and has two intrachain disulfide bonds; orexin-B is a linear 28 amino acid residue peptide. Although these peptides are produced by a very small population of cells in the lateral and posterior hypothalamus, they send projections throughout the brain. The orexin peptides bind to the two G-protein coupled orexin receptors, OX1 and OX2, with orexin-A binding to both OX1 and OX2 with approximately equal affinity while orexin-B binds mainly to OX2 and is 5 times less potent at OX1.[11]
The orexins are strongly conserved peptides, found in all major classes of vertebrates.[12]
# Function
The orexin system was initially suggested to be primarily involved in the stimulation of food intake, based on the finding that central administration of orexin-A and -B increased food intake. In addition, it stimulates wakefulness, regulates energy expenditure, and modulates visceral function.
## Brown fat activation
Obesity in orexin knockout mice is a result of inability of brown preadipocytes to differentiate into brown adipose tissue (BAT), which in turn reduces BAT thermogenesis. BAT differentiation can be restored in these knockout mice through injections of orexin. Deficiency in orexin has also been linked to narcolepsy, a sleep disorder. Furthermore, narcoleptic people are more likely to be obese. Hence obesity in narcoleptic patients may be due to orexin deficiency leading to impaired thermogenesis and energy expenditure.[13]
## Wakefulness
Orexin seems to promote wakefulness. Recent studies indicate that a major role of the orexin system is to integrate metabolic, circadian and sleep debt influences to determine whether an animal should be asleep or awake and active. Orexin neurons strongly excite various brain nuclei with important roles in wakefulness including the dopamine, norepinephrine, histamine and acetylcholine systems[14][15] and appear to play an important role in stabilizing wakefulness and sleep.
The discovery that an orexin receptor mutation causes the sleep disorder canine narcolepsy[16] in Doberman Pinschers subsequently indicated a major role for this system in sleep regulation. Genetic knockout mice lacking the gene for orexin were also reported to exhibit narcolepsy.[17] Transitioning frequently and rapidly between sleep and wakefulness, these mice display many of the symptoms of narcolepsy. Researchers are using this animal model of narcolepsy to study the disease.[18] Narcolepsy results in excessive daytime sleepiness, inability to consolidate wakefulness in the day (and sleep at night), and cataplexy, which is the loss of muscle tone in response to strong, usually positive, emotions. Dogs that lack a functional receptor for orexin have narcolepsy, while animals and people lacking the orexin neuropeptide itself also have narcolepsy.
Central administration of orexin-A strongly promotes wakefulness, increases body temperature and locomotion, and elicits a strong increase in energy expenditure. Sleep deprivation also increases orexin-A transmission. The orexin system may thus be more important in the regulation of energy expenditure than food intake. In fact, orexin-deficient narcoleptic patients have increased obesity rather than decreased BMI, as would be expected if orexin were primarily an appetite stimulating peptide. Another indication that deficits of orexin cause narcolepsy is that depriving monkeys of sleep for 30–36 hours and then injecting them with the neurochemical alleviates the cognitive deficiencies normally seen with such amount of sleep loss.[19][20]
In humans, narcolepsy is associated with a specific variant of the human leukocyte antigen (HLA) complex.[21] Furthermore, genome-wide analysis shows that, in addition to the HLA variant, narcoleptic humans also exhibit a specific genetic mutation in the T-cell receptor alpha locus.[22] In conjunction, these genetic anomalies cause the immune system to attack and kill the critical orexin neurons. Hence the absence of orexin-producing neurons in narcoleptic humans may be the result of an autoimmune disorder.[23]
## Food intake
Orexin increases the craving for food, and correlates with the function of the substances that promote its production. Orexin is also shown to increase meal size by suppressing inhibitory postingestive feedback.[24] However, some studies suggest that the stimulatory effects of orexin on feeding may be due to general arousal without necessarily increasing overall food intake.[25]
Review findings suggest that hyperglycemia that occurs in mice due to a habitual high-fat diet leads to a reduction in signalling by orexin receptor-2, and that orexin receptors may be a future therapeutic target.[26]
Leptin is a hormone produced by fat cells and acts as a long-term internal measure of energy state. Ghrelin is a short-term factor secreted by the stomach just before an expected meal, and strongly promotes food intake.
Orexin-producing cells have recently been shown to be inhibited by leptin (through the leptin receptor pathway), but are activated by ghrelin and hypoglycemia (glucose inhibits orexin production). Orexin, as of 2007, is claimed to be a very important link between metabolism and sleep regulation.[27][28] Such a relationship has been long suspected, based on the observation that long-term sleep deprivation in rodents dramatically increases food intake and energy metabolism, i.e., catabolism, with lethal consequences on a long-term basis. Sleep deprivation then leads to a lack of energy. In order to make up for this lack of energy, many people use high-carbohydrate and high-fat foods that ultimately can lead to poor health and weight gain. Other dietary nutrients, amino acids, also can activate orexin neurons, and they can suppress the glucose response of orexin neurons at physiological concentration, causing the energy balance that orexin maintains to be thrown off its normal cycle.[29]
## Addiction
Preliminary research has been conducted that shows potential for orexin blockers in the treatment of cocaine, opioid, and alcohol addiction.[30][31][32] For example, lab rats given drugs which targeted the orexin system lost interest in alcohol despite being given free access in experiments.[33][34]
Studies of orexin involvement in nicotine addiction have had mixed results. For example, blocking the orexin-1 receptor with the selective orexin antagonist SB-334,867 reduced nicotine self-administration in rats and that smokers who suffered damage to the insula, a brain region that regulates cravings and contains orexin-1 receptors, lost the desire to smoke.[35] However, other studies in rats using the dual orexin receptor antagonist TCS 1102 have not found similar effects.[36]
## Lipid metabolism
Orexin-A (OXA) has been recently demonstrated to have a direct effect on an aspect of lipid metabolism. OXA stimulates glucose uptake in 3T3-L1 adipocytes and that increased energy uptake is stored as lipids (triacylglycerol). OXA thus increases lipogenesis. It also inhibits lipolysis and stimulates the secretion of adiponectin. These effects are thought to be mostly conferred via the PI3K pathway because this pathway inhibitor (LY294002) completely blocks OXA effects in adipocytes.[37] The link between OXA and the lipid metabolism is new and currently under more research.
Obesity in orexin-knockout mice is associated with impaired brown adipose tissue thermogenesis.[13]
## Mood
High levels of orexin-A have been associated with happiness in human subjects, while low levels have been associated with sadness.[38] The finding suggests that boosting levels of orexin-A could elevate mood in humans, being thus a possible future treatment for disorders like depression.
# Orexin neurons
## Neurotransmitters
Orexinergic neurons have been shown to be sensitive to inputs from Group III metabotropic glutamate receptors,[39] cannabinoid receptor 1 and CB1–OX1 receptor heterodimers,[40][41][42] adenosine A1 receptors,[43] muscarinic M3 receptors,[44] serotonin 5-HT1A receptors,[45] neuropeptide Y receptors,[46] cholecystokinin A receptors,[47] and catecholamines,[48][49] as well as to ghrelin, leptin, and glucose.[50] Orexinergic neurons themselves regulate release of acetylcholine,[51][52] serotonin, and noradrenaline.[53]
Orexinergic neurons can be differentiated into two groups based on connectivity and functionality. Orexinergic neurons in the lateral hypothalamic group are closely associated with reward related functions, such as conditioned place preference. These neurons preferentially innervate the ventral tegmental area and the ventromedial prefrontal cortex. In contrast to the lateral hypothalamic neurons, the perifornical-dorsal group of orexinergic neurons involved in functions related to arousal and autonomic response. These neurons project inter-hypothalamically, as well as to the brainstem, where the release of orexin modulates various autonomic processes.[54][55]
# Clinical uses
The orexin/hypocretin system is the target of the insomnia medication suvorexant, which works by blocking both orexin receptors. Suvorexant has undergone three phase III trials and was approved in 2014 by the US Food and Drug Administration (FDA) after being denied approval the year before.[56] It is marketed as Belsomra.[57]
In 2016, the University of Texas Health Science Center registered a clinical trial for the use of suvorexant for people with cocaine dependence. They plan to measure cue reactivity, anxiety and stress.[58]
## Other potential uses
Intranasal orexin is able to increase cognition in primates, especially under sleep deprived situations,[59] which may provide an opportunity for the treatment of excessive daytime sleepiness.[60]
A study has reported that transplantation of orexin neurons into the pontine reticular formation in rats is feasible, indicating the development of alternative therapeutic strategies in addition to pharmacological interventions to treat narcolepsy.[61] | https://www.wikidoc.org/index.php/Hypocretin | |
a9baa65632460dcb83099980c58c30d5a0c17417 | wikidoc | Hyssop | Hyssop
Hyssop (Hyssopus) is a genus of about 10-12 species of herbaceous or semi-woody plants in the family Lamiaceae, native from the Mediterranean east to central Asia. They are aromatic, with erect branched stems up to 60 cm long covered with fine hairs at the tips. The leaves are narrow oblong, 2-5 cm long. The small blue flowers are borne on the upper part of the branches during summer. By far the best-known species is the Herb Hyssop (H. officinalis), widely cultivated outside its native area in the Mediterranean.
# Cultivation and uses
The name 'hyssop' can be traced back almost unchanged through the Greek hyssopos. In the New Testament, a sponge soaked in sour wine or vinegar was stuck on a branch of hyssop and offered to Jesus of Nazareth on the cross just before he died. Both Matthew and Mark mention the occasion but refer to the plant using the general term "kalamos", which is translated as "reed" or "stick". Its purgative properties are mentioned in the Book of Psalms.
Traditionally, hyssop has been used as a strewing herb, and many of its historical healing properties that had been previously dismissed as superstition are once again being acknowledged.
The seeds are sown in spring and the seedlings planted out 40-50 cm apart. Hyssop can also be propagated from heel cuttings or root division in spring or autumn. Hyssop should be grown in full sun on well drained soil, and will benefit from occasional clipping. It is short-lived, and the plants will need to be replaced every few years. Ideal for use as a low hedge or border within the herb garden.
Hyssop is used as a food plant by the larvae of some Lepidoptera species including Cabbage Moth.
Hyssop leaves have a slightly bitter minty flavour and can be added to soups, salads
-r meats, although should be used sparingly as the flavour is very strong. Hyssop also has medicinal properties which are listed as including expectorant, carminative, relaxes peripheral blood vessels, promotes sweating, anti-inflammatory, anti-catarrhal, antispasmodic. Its active constituents are volatile oil, flavonoids, tannins and bitter substance (marrubin).
A strong tea made from the leaves and flowering tops is used in lung, nose and throat congestion and catarrhal complaints, and externally it can be applied to bruises, to reduce the swelling and discolouration. An old English country remedy for cuts and wounds suffered while working in the fields was to apply a poultice of bruised hyssop leaves and sugar in order to reduce the risk of tetanus infection. An essential oil made from hyssop is believed to increase alertness and is a gently relaxing nerve tonic suitable for treating nervous exhaustion, overwork, anxiety and depression. The Herb Society's "Complete Medicinal Herbal" cautions however that "the essential oil contains the ketone pino-camphone which in high doses can cause convulsions. Do not take more than the recommended dose."
Hyssop also has uses in the garden, it is said to be a good companion plant to cabbage, partly because it will lure away the Cabbage White butterfly, and according to Dorothy Hall (The Book Of Herbs, Pan 1972) has also "been found to improve the yield from grapevines if planted along the rows, particularly if the terrain is rocky or sandy, and the soil is not as easy to work as it might be". However hyssop is said to be antagonistic to radishes, and they should not be grown nearby. Hyssop also attracts bees, hoverflies and butterflies, thus has a place in the wild garden as well as being useful in controlling pests and encouraging pollination without the use of unnatural methods. Hyssop is also used as an ingredient in eau de Cologne, and in the liqueur Chartreuse. Also, widely used in the liquor Absinthe, along with Wormwood, Fennel, and Anise.
Hyssop leaves can be preserved by drying. They should be harvested on
a dry day at the peak of their maturity and the concentration of active ingredients is highest. They should be dried quickly, away from bright sunlight in order to preserve their aromatic ingredients and prevent oxidation of other chemicals. Good air circulation is required, such as an airing cupboard with the door left open, or a sunny room, aiming for a temperature of 20-32°C. Hyssop leaves should dry out in about six days, any longer and they will begin to discolour and lose their flavour. The dried leaves are stored in clean, dry, labelled airtight containers, and will keep for 12-18 months. | Hyssop
Hyssop (Hyssopus) is a genus of about 10-12 species of herbaceous or semi-woody plants in the family Lamiaceae, native from the Mediterranean east to central Asia. They are aromatic, with erect branched stems up to 60 cm long covered with fine hairs at the tips. The leaves are narrow oblong, 2-5 cm long. The small blue flowers are borne on the upper part of the branches during summer. By far the best-known species is the Herb Hyssop (H. officinalis), widely cultivated outside its native area in the Mediterranean.
## Cultivation and uses
The name 'hyssop' can be traced back almost unchanged through the Greek hyssopos. In the New Testament, a sponge soaked in sour wine or vinegar was stuck on a branch of hyssop and offered to Jesus of Nazareth on the cross just before he died[1]. Both Matthew and Mark mention the occasion but refer to the plant using the general term "kalamos", which is translated as "reed" or "stick". Its purgative properties are mentioned in the Book of Psalms. [2]
Traditionally, hyssop has been used as a strewing herb, and many of its historical healing properties that had been previously dismissed as superstition are once again being acknowledged.
The seeds are sown in spring and the seedlings planted out 40-50 cm apart. Hyssop can also be propagated from heel cuttings or root division in spring or autumn. Hyssop should be grown in full sun on well drained soil, and will benefit from occasional clipping. It is short-lived, and the plants will need to be replaced every few years. Ideal for use as a low hedge or border within the herb garden.
Hyssop is used as a food plant by the larvae of some Lepidoptera species including Cabbage Moth.
Hyssop leaves have a slightly bitter minty flavour and can be added to soups, salads
or meats, although should be used sparingly as the flavour is very strong. Hyssop also has medicinal properties which are listed as including expectorant, carminative, relaxes peripheral blood vessels, promotes sweating, anti-inflammatory, anti-catarrhal, antispasmodic. Its active constituents are volatile oil, flavonoids, tannins and bitter substance (marrubin).
A strong tea made from the leaves and flowering tops is used in lung, nose and throat congestion and catarrhal complaints, and externally it can be applied to bruises, to reduce the swelling and discolouration. An old English country remedy for cuts and wounds suffered while working in the fields was to apply a poultice of bruised hyssop leaves and sugar in order to reduce the risk of tetanus infection. An essential oil made from hyssop is believed to increase alertness and is a gently relaxing nerve tonic suitable for treating nervous exhaustion, overwork, anxiety and depression. The Herb Society's "Complete Medicinal Herbal" cautions however that "the essential oil contains the ketone pino-camphone which in high doses can cause convulsions. Do not take more than the recommended dose."
Hyssop also has uses in the garden, it is said to be a good companion plant to cabbage, partly because it will lure away the Cabbage White butterfly, and according to Dorothy Hall (The Book Of Herbs, Pan 1972) has also "been found to improve the yield from grapevines if planted along the rows, particularly if the terrain is rocky or sandy, and the soil is not as easy to work as it might be". However hyssop is said to be antagonistic to radishes, and they should not be grown nearby. Hyssop also attracts bees, hoverflies and butterflies, thus has a place in the wild garden as well as being useful in controlling pests and encouraging pollination without the use of unnatural methods. Hyssop is also used as an ingredient in eau de Cologne, and in the liqueur Chartreuse. Also, widely used in the liquor Absinthe, along with Wormwood, Fennel, and Anise.
Hyssop leaves can be preserved by drying. They should be harvested on
a dry day at the peak of their maturity and the concentration of active ingredients is highest. They should be dried quickly, away from bright sunlight in order to preserve their aromatic ingredients and prevent oxidation of other chemicals. Good air circulation is required, such as an airing cupboard with the door left open, or a sunny room, aiming for a temperature of 20-32°C. Hyssop leaves should dry out in about six days, any longer and they will begin to discolour and lose their flavour. The dried leaves are stored in clean, dry, labelled airtight containers, and will keep for 12-18 months. | https://www.wikidoc.org/index.php/Hyssop | |
7a4264633944f649ad2483e26aeb7e8f50354664 | wikidoc | IFITM1 | IFITM1
Interferon-induced transmembrane protein 1 is a protein that in humans is encoded by the IFITM1 gene. IFITM1 has also recently been designated CD225 (cluster of differentiation 225). This protein has several additional names: fragilis (human homolog of the mouse protein), IFI17 , 9-27 and Leu13.
IFITM1 is a member of the IFITM family (Interferon-induced transmembrane protein) which is encoded by IFITM genes. The human IFITM genes locate on chromosome 11 and have four members: IFITM1, IFITM2, IFITM3 and IFITM5. While the mouse Ifitm genes locate on chromosome 7 and 16 and have six members: Ifitm1, Ifitm2, Ifitm3, Ifitm5, Ifitm6 and Ifitm7.
# Molecular biology
The IFITM1 gene is located on the Watson (plus) strand of the short arm of chromosome 11 (11p15.5) and is 3,956 bases in length. The encoded protein has 125 amino acids (molecular weight 13.964 kDa).
It is an intrinsic membrane protein and is predicted to cross the membrane several times.
# Structure and function
IFITM proteins have a short N-terminal and C-terminal domain, two transmembrane domains (TM1 and TM2) and a short cytoplasmic domain. The first transmembrane domain (TM1) and the cytoplasmic domain are conserved among different IFITM proteins in human and mouse. In the absence of interferon stimulation, IFITM proteins can express broadly in tissues and cell lines. In human, ITITM1, IFITM2 and IFITM3 are able to express in different tissues and cells while the expression of IFITM5 is limited to osteoblasts. The type I and II interferon induce IFITM proteins expression significantly. IFITM proteins are involved in the physiological process of immune response signaling, germ cell maturation and development.
# Biochemistry
The gene is induced by interferon and the protein forms part of the signaling pathway.
# Antiviral function of IFITM proteins
By using genomic screening for cellular factors which are involved in influenza A virus life cycle such as entry, replication and release, IFITM proteins have been identified as antiviral restriction factors for influenza A virus replication. Knockout IFITM3 increased influenza virus A replication and overexpression IFITM3 inhibits influenza virus A replication. In addition to replication competent influenza A virus, IFITM proteins were able to inhibit retrovirus based psedotyped influenza A virus, indicating that IFITM protein inhibit influenza A virus at the early step of life cycle, may occur in the entry and fusion steps.
IFITM proteins also are able to inhibit several other enveloped viruses infection that belong to different virus families. These virus include flaviviruses (dengue virus and West Nile virus), filoviruses (Marburg virus and Ebola virus) coronaviruses (SARS coronavirus) and lentivirus (Human immunodeficiency virus). However, IFITM proteins did not affect alphaviruses, arenaviruses and murine leukaemia virus infection.
Potential mechanisms.IFITM proteins inhibit viral membrane and cellular endosomal or lyso¬somal vesicles membrane fusion by modify lipid components or fluidity. IFITM proteins blocked the creation of hemifusion between viral membrane and cellular membrane. Furthermore, IFITM proteins reduced membrane fluidity and affected membrane curvature to restrict viral membrane fusion with the cellular membrane. In addition, IFITM3 interacted with the cellular cholesterol regulatory proteins Vesicle-membrane-protein-associated protein A (VAPA) and oxysterol-binding protein (OSBP) to induce intracellular cholesterol accumulation, which in turn blocked viral membrane and vesicles membrane fusion. | IFITM1
Interferon-induced transmembrane protein 1 is a protein that in humans is encoded by the IFITM1 gene.[1][2] IFITM1 has also recently been designated CD225 (cluster of differentiation 225). This protein has several additional names: fragilis (human homolog of the mouse protein), IFI17 [interferon-induced protein 17], 9-27 [Interferon-inducible protein 9-27] and Leu13.
IFITM1 is a member of the IFITM family (Interferon-induced transmembrane protein) which is encoded by IFITM genes. The human IFITM genes locate on chromosome 11 and have four members: IFITM1, IFITM2, IFITM3 and IFITM5.[3] While the mouse Ifitm genes locate on chromosome 7 and 16 and have six members: Ifitm1, Ifitm2, Ifitm3, Ifitm5, Ifitm6 and Ifitm7.
# Molecular biology
The IFITM1 gene is located on the Watson (plus) strand of the short arm of chromosome 11 (11p15.5) and is 3,956 bases in length. The encoded protein has 125 amino acids (molecular weight 13.964 kDa).
It is an intrinsic membrane protein and is predicted to cross the membrane several times.
# Structure and function
IFITM proteins have a short N-terminal and C-terminal domain, two transmembrane domains (TM1 and TM2) and a short cytoplasmic domain. The first transmembrane domain (TM1) and the cytoplasmic domain are conserved among different IFITM proteins in human and mouse.[4] In the absence of interferon stimulation, IFITM proteins can express broadly in tissues and cell lines. In human, ITITM1, IFITM2 and IFITM3 are able to express in different tissues and cells while the expression of IFITM5 is limited to osteoblasts.[5] The type I and II interferon induce IFITM proteins expression significantly. IFITM proteins are involved in the physiological process of immune response signaling, germ cell maturation and development.[6]
# Biochemistry
The gene is induced by interferon and the protein forms part of the signaling pathway.
# Antiviral function of IFITM proteins
By using genomic screening for cellular factors which are involved in influenza A virus life cycle such as entry, replication and release, IFITM proteins have been identified as antiviral restriction factors for influenza A virus replication. Knockout IFITM3 increased influenza virus A replication and overexpression IFITM3 inhibits influenza virus A replication.[7] In addition to replication competent influenza A virus, IFITM proteins were able to inhibit retrovirus based psedotyped influenza A virus, indicating that IFITM protein inhibit influenza A virus at the early step of life cycle, may occur in the entry and fusion steps.
IFITM proteins also are able to inhibit several other enveloped viruses infection that belong to different virus families. These virus include flaviviruses (dengue virus and West Nile virus), filoviruses (Marburg virus and Ebola virus) coronaviruses (SARS coronavirus) and lentivirus (Human immunodeficiency virus).[8] However, IFITM proteins did not affect alphaviruses, arenaviruses and murine leukaemia virus infection.
Potential mechanisms.IFITM proteins inhibit viral membrane and cellular endosomal or lyso¬somal vesicles membrane fusion by modify lipid components or fluidity. IFITM proteins blocked the creation of hemifusion between viral membrane and cellular membrane. Furthermore, IFITM proteins reduced membrane fluidity and affected membrane curvature to restrict viral membrane fusion with the cellular membrane.[9] In addition, IFITM3 interacted with the cellular cholesterol regulatory proteins Vesicle-membrane-protein-associated protein A (VAPA) and oxysterol-binding protein (OSBP) to induce intracellular cholesterol accumulation, which in turn blocked viral membrane and vesicles membrane fusion.[10] | https://www.wikidoc.org/index.php/IFITM1 | |
edfa64e3d0927c4f87ece1b1b83de227b6c6e1f7 | wikidoc | IFITM3 | IFITM3
Interferon-induced transmembrane protein 3 (IFITM3) is a protein that in humans is encoded by the IFITM3 gene. It plays a critical role in the immune system's defense against Swine Flu, where heightened levels of IFITM3 keep viral levels low, and the removal of IFITM3 allows the virus to multiply unchecked. This observation has been further advanced by a recent study that shows that a single nucleotide polymorphism in the human IFITM3 gene purported to increase influenza susceptibility is overrepresented in people hospitalised with pandemic H1N1. The prevalence of this mutation is thought to be approximately 1/400 in European populations.
# Model organisms
Model organisms have been used in the study of IFITM3 function. A conditional knockout mouse line, called Ifitm3tm1Masu 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 four tests were carried out on mutant mice, but no significant abnormalities were observed. However, challenge with influenza A virus indicated that these mice display increased viral susceptibility. | IFITM3
Interferon-induced transmembrane protein 3 (IFITM3) is a protein that in humans is encoded by the IFITM3 gene.[1][2][3] It plays a critical role in the immune system's defense against Swine Flu, where heightened levels of IFITM3 keep viral levels low, and the removal of IFITM3 allows the virus to multiply unchecked.[4] This observation has been further advanced by a recent study that shows that a single nucleotide polymorphism in the human IFITM3 gene purported to increase influenza susceptibility is overrepresented in people hospitalised with pandemic H1N1.[5] The prevalence of this mutation is thought to be approximately 1/400 in European populations.[5][6]
# Model organisms
Model organisms have been used in the study of IFITM3 function. A conditional knockout mouse line, called Ifitm3tm1Masu[11][12] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[13][14][15]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[9][16] Twenty four tests were carried out on mutant mice, but no significant abnormalities were observed.[9] However, challenge with influenza A virus indicated that these mice display increased viral susceptibility.[5] | https://www.wikidoc.org/index.php/IFITM3 | |
675a6bfcf1ccf6d4b27c7b3d3a212068b3821bf8 | wikidoc | IFT140 | IFT140
IFT140, Intraflagellar transport 140 homolog, is a protein that in humans is encoded by the IFT140 gene.
# Clinical significance
Mutations in this gene have been associated to cases of skeletal ciliopathy.
# Model organisms
Model organisms have been used in the study of IFT140 function. A conditional knockout mouse line called Ift140tm1a(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 | IFT140
IFT140, Intraflagellar transport 140 homolog, is a protein that in humans is encoded by the IFT140 gene.
# Clinical significance
Mutations in this gene have been associated to cases of skeletal ciliopathy.[1]
# Model organisms
Model organisms have been used in the study of IFT140 function. A conditional knockout mouse line called Ift140tm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[2] Male and female animals underwent a standardized phenotypic screen[3] to determine the effects of deletion.[4][5][6][7] Additional screens performed: - In-depth immunological phenotyping[8] | https://www.wikidoc.org/index.php/IFT140 | |
934378b32a710731a21c352b09b7dfc189081f48 | wikidoc | IGFALS | IGFALS
Insulin-like growth factor binding protein, acid labile subunit, also known as IGFALS, is a protein which in humans is encoded by the IGFALS gene.
# Function
The protein encoded by this gene is a serum protein that binds insulin-like growth factors, increasing their half-life and their vascular localization. Production of the encoded protein, which contains twenty leucine-rich repeats, is stimulated by growth hormone. Three transcript variants encoding two different isoforms have been found for this gene.
# Clinical significance
Defects in this gene are a cause of acid-labile subunit deficiency, which manifests itself in a delayed and slow puberty.
# Interactions
IGFALS has been shown to interact with IGFBP3. | IGFALS
Insulin-like growth factor binding protein, acid labile subunit, also known as IGFALS, is a protein which in humans is encoded by the IGFALS gene.[1]
# Function
The protein encoded by this gene is a serum protein that binds insulin-like growth factors, increasing their half-life and their vascular localization. Production of the encoded protein, which contains twenty leucine-rich repeats, is stimulated by growth hormone. Three transcript variants encoding two different isoforms have been found for this gene.[1]
# Clinical significance
Defects in this gene are a cause of acid-labile subunit deficiency, which manifests itself in a delayed and slow puberty.[citation needed]
# Interactions
IGFALS has been shown to interact with IGFBP3.[2][3] | https://www.wikidoc.org/index.php/IGFALS | |
cd9f8e39d9c9c882d0c9f284f07193240f3eb50e | wikidoc | IGFBP3 | IGFBP3
Insulin-like growth factor-binding protein 3, also known as IGFBP-3, is a protein that in humans is encoded by the IGFBP3 gene. IGFBP-3 is one of six IGF binding proteins (IGFBP-1 to IGFBP-6) that have highly conserved structures and bind the insulin-like growth factors IGF-1 and IGF-2 with high affinity. IGFBP-7, sometimes inappropriately included in this family, shares neither the conserved structural features nor the high IGF affinity.
# Function
IGFBP-3 was first isolated, characterized, and quantitated in human plasma, in 1986. It has well-documented functions in the circulation, in the extracellular environment, and inside cells. It is the main IGF transport protein in the bloodstream, where it carries the growth factors predominantly in stable complexes that contain the binding protein, either IGF-1 or IGF-2, and a third protein called the acid-labile subunit or ALS.
For IGFs to reach the tissues from the bloodstream, the circulating complexes are believed to partly dissociate, possibly enhanced by limited proteolysis of IGFBP-3. The IGF-1/IGFBP-3 ratio has sometimes been used as an index of IGF bioavailability in the human circulation, but this ignores IGF-1 binding to other IGFBPs (so the ratio is affected by the concentrations of all six IGFBPs), and the fact that IGF-2, which is three times more abundant than IGF-1 in the bloodstream of adults, occupies the majority of binding sites on circulating IGFBP-3.
Within tissues, IGFBP-3 can bind IGF-1 and IGF-2 released by many cell types, and block their access to the IGF-1 receptor (IGF1R), which is activated by both IGFs. IGFBP-3 also interacts with cell-surface proteins, affecting cell signaling from outside the cell or after internalization, and also enters the cell nucleus where it binds to nuclear hormone receptors and other ligands. High levels of IGFBP-3 within tumors are associated with increased cancer severity (or worse outcome) for some cancers, but decreased severity or better outcome for others. No cases of IGFBP3 gene deletion in humans have been reported, but mice lacking the gene show near-normal growth.
# Gene and protein structure
The IGFBP3 gene (or IBP3), on human chromosome 7, is organized into four protein-coding exons with a 5th exon in the 3’ untranslated region. It is located adjacent to the IGFBP1 gene in tail-to-tail orientation, separated by 20 kb. The encoded protein includes a 27-residue signal peptide followed by the 264-residue mature protein. IGFBP-3 shares with the other five high-affinity IGFBPs and a 3-domain structure:
- A conserved N-terminal domain containing a cysteine rich region (12 cysteine residues) with multiple intra-domain disulfide bonds, a IGFBP motif (GCGCCXXC), the primary site of IGF binding.
- A highly variable central or linker domain (only 15% conservation between IGFBPs).
- A conserved C-terminal domain containing secondary IGF binding residues, a cysteine rich region (6 cysteine residues), an 18 residue basic motif that binds heparin, the acid labile subunit (ALS), and a nuclear localization sequence.
The linker domain is the site of most post-translational modification, which include glycosylation, phosphorylation, and limited proteolysis. By electrophoretic analysis IGFBP-3 appears as a doublet, owing to the occupancy of either two or three of its N-glycosylation sites by carbohydrate. Hypoglycosylated IGFBP-3 may be seen after extended glucose starvation.
Many proteases are known to cleave IGFBP-3 at single linker-domain sites, and in the circulation of pregnant women, IGFBP-3 is entirely proteolyzed, yet still capable of carrying normal amounts of IGF-1 and IGF-2. Binding capacity appears to be retained after proteolysis because of a cooperative interaction between the two proteolyzed fragments, that together maintain an active IGF-binding site.
# Sites and regulation of production
IGFBP-3 mRNA is expressed in all tissue examined, with kidney, stomach, placenta, uterus and liver showing highest expression in rat tissues. Rat liver IGFBP-3 mRNA is found in nonparenchymal cells including sinusoidal endothelium, but not in hepatocytes. In contrast, human hepatocytes do express IGFBP-3.
IGFBP-3 levels in human serum are, like IGF-1, dependent on growth hormone (GH); for example, serum IGFBP-3 is increased in acromegaly and low in GH-deficient children. However, IGFBP-3 gene expression in human liver is GH-independent. Because it is stabilized in human serum by forming complexes with IGF-1 and ALS, which are both GH-dependent, serum IGFBP-3 also appears regulated by GH. Its production by some non-hepatic tissues may also be directly GH-regulated. Immunoassays for serum IGFBP-3 are often used as part of the diagnosis of childhood GH-deficiency.
The most widely studied IGFBP3 polymorphism, at nucleotide-202 in the promoter region, is significantly associated with circulating IGFBP-3 levels, although the mechanism is unclear. In some studies circulating IGFBP-3 also appears to be nutritionally regulated, although this may not be seen at the mRNA level. IGFBP-3 has been identified in human lymph, nipple aspirate, milk, amniotic fluid, follicular fluid, seminal plasma, urine, peritoneal dialysate, synovial fluid, tear fluid, and cerebrospinal fluid, in addition to serum.
Many factors increase IGFBP-3 production by cells, including transforming growth factor-β (TGFβ), tumor necrosis factor-α, vitamin D, retinoic acid, IGF-1, and stimuli such as chemotherapy that activate the tumor suppressor p53. Estrogen inhibits IGFBP-3 production, and its tissue levels are lower in estrogen receptor (ER)-positive breast cancers than in ER-negative cancers.
# Interactions
The main IGFBP-3 ligands in the circulation are IGF-1 and IGF-2, and the acid-labile subunit (ALS). The serum proteins transferrin, fibronectin, and plasminogen are also known to bind IGFBP-3. In the cell and tissue environment many other interactions have been described (see Table). Two unrelated cell-surface proteins have been designated as IGFBP-3 receptors: low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor or type V TGFβ receptor and the transmembrane protein TMEM219. Both are believed to mediate antiproliferative effects. Functional interactions with the EGF receptor and the type I/type II TGFβ receptor system have also been reported, and other cell-surface proteins such as proteoglycans also bind IGFBP-3. IGFBP-3 can enter cells by both clathrin-mediated and caveolin-mediated endocytosis. possibly involving the transferrin receptor.
IGFBP-3 enters the cell nucleus by a mechanism that is incompletely understood, but involves its binding to importin-β. Within the nucleus, it can modulate nuclear hormone receptor activity by direct binding to retinoid X receptor, retinoic acid receptor, vitamin D receptor, PPARγ, and nur77, IGFBP-3 also interacts with DNA-dependent protein kinase within the nucleus to promote the repair of DNA damage.
# Cellular actions
IGFBP-3 exerts antiproliferative effects in many cell types by blocking the ability of IGF-1 and IGF-2 to activate the IGF1R (which stimulates cell proliferation). For example, in esophageal epithelial cells, responsiveness to IGF-1 stimulation is suppressed by secreted IGFBP-3 and restored when IGFBP-3 is downregulated by epidermal growth factor. IGFBP-3 can also inhibit cell function by mechanisms that are independent of effects on IGF1R signaling, even in cells that entirely lack IGF1R. IGF (or IGF1R) independent effects are commonly studied using mutant forms of IGFBP-3 with decreased IGF binding affinity. Thus, IGFBP-3-induced apoptosis in differentiating chondrocyte precursor cells is seen equally with a non-IGF binding IGFBP-3 mutant, demonstrating that the mechanism does not involve IGF binding. IGF1R-independent growth inhibition by IGFBP-3 may involve the induction of pro-apoptotic proteins such as Bax and Bad and may be mediated by ceramides (pro-apoptotic lipids), or potentiate ceramide action IGFBP-3 interaction with nuclear hormone receptors may also lead to inhibition of cell proliferation.
Contrasting with the typical growth-inhibitory effects of IGFBP-3, stimulation of cell proliferation by IGFBP-3 has also been observed. This can occur either by enhancing IGF-stimulated proliferation or in the absence of IGF-1. In endothelial cells and mammary epithelial cells, the stimulatory effect of IGFBP-3 has been shown to involve activation of the enzyme sphingosine kinase, and generation of the bioactive lipid, sphingosine-1-phosphate, which promotes growth by transactivating the EGFR receptor.
# Role in cancer
Based on cell growth experiments, animal cancer models, and epidemiological studies, it appears that IGFBP-3 functions as a low-penetrance tumor suppressor gene.
Dysregulation of IGFBP-3 has been implicated in many cancers. IGFBP-3 is sometimes referred to as a tumor suppressor, and downregulation of its tissue expression by promoter hypermethylation in some cancers, such as hepatoma. and non-small cell lung cancer may be associated with poor patient outcome. However, consistent with the dual inhibitory and stimulatory roles of IGFBP-3 seen in cell culture, there are other cancer types, such as breast cancer, pancreatic cancer, and clear cell renal cell cancer in which high tissue IGFBP-3 expression has been linked to poor prognostic features or patient outcome. The mechanisms regulating these contrasting effects of IGFBP-3 in vivo are not well understood.
Since IGFBP-3 is abundant in the bloodstream of healthy adults (typically 2–4 mg/L), and is largely stabilized by its complex formation with IGFs and ALS, it is unlikely that tumor-derived IGFBP-3 has a large influence on circulating levels. There have been many studies linking circulating IGFBP-3 levels to the presence, or risk, of various cancers, or to patient outcomes. but unequivocal conclusions have often been lacking. For example, high plasma IGFBP-3 levels were associated with a reduced prospective risk of colorectal cancer in women. but in a study including men and women, colon cancer risk was positively associated with plasma IGFBP-3, while there was no significant association for rectal cancer. A large systematic review concluded that circulating IGFBP-3 levels showed a modest association with increased risk for a number of cancers, but the results vary among sites.
IGFBP-3 protein levels decrease during the progression of prostate cancer from benign to metastatic disease although production of the protein does not cease completely. IGFBP-3 is still made (at a lower level) by prostate cancer cells and secreted into the surrounding environment. However, instead of the full length, functional protein, IGFBP-3 is found to be cleaved. This decreases the affinity of IGF binding to IGFBP-3, making the growth factors more likely to bind the IGF1R and promote cell survival.
# Table: IGFBP-3 binding partners
IGFBP3 has been shown to interact with:
- ADAM12
- ADAM28
- COL1A1
- FN1
- IGFALS
- IGF1,
- IGF2
- HSPA5
- PLG
- RXRA
- TF
- KPNB1
- PRKDC
- EGFR
- LTBP1 | IGFBP3
Insulin-like growth factor-binding protein 3, also known as IGFBP-3, is a protein that in humans is encoded by the IGFBP3 gene. IGFBP-3 is one of six IGF binding proteins (IGFBP-1 to IGFBP-6) that have highly conserved structures and bind the insulin-like growth factors IGF-1 and IGF-2 with high affinity. IGFBP-7, sometimes inappropriately included in this family, shares neither the conserved structural features nor the high IGF affinity.
# Function
IGFBP-3 was first isolated, characterized, and quantitated in human plasma, in 1986.[1][2] It has well-documented functions in the circulation, in the extracellular environment, and inside cells. It is the main IGF transport protein in the bloodstream, where it carries the growth factors predominantly in stable complexes that contain the binding protein, either IGF-1 or IGF-2, and a third protein called the acid-labile subunit or ALS.
For IGFs to reach the tissues from the bloodstream, the circulating complexes are believed to partly dissociate, possibly enhanced by limited proteolysis of IGFBP-3. The IGF-1/IGFBP-3 ratio has sometimes been used as an index of IGF bioavailability in the human circulation, but this ignores IGF-1 binding to other IGFBPs (so the ratio is affected by the concentrations of all six IGFBPs), and the fact that IGF-2, which is three times more abundant than IGF-1 in the bloodstream of adults, occupies the majority of binding sites on circulating IGFBP-3.
Within tissues, IGFBP-3 can bind IGF-1 and IGF-2 released by many cell types, and block their access to the IGF-1 receptor (IGF1R), which is activated by both IGFs. IGFBP-3 also interacts with cell-surface proteins, affecting cell signaling from outside the cell or after internalization, and also enters the cell nucleus where it binds to nuclear hormone receptors and other ligands. High levels of IGFBP-3 within tumors are associated with increased cancer severity (or worse outcome) for some cancers, but decreased severity or better outcome for others. No cases of IGFBP3 gene deletion in humans have been reported, but mice lacking the gene show near-normal growth.
# Gene and protein structure
The IGFBP3 gene (or IBP3), on human chromosome 7, is organized into four protein-coding exons with a 5th exon in the 3’ untranslated region.[3] It is located adjacent to the IGFBP1 gene in tail-to-tail orientation, separated by 20 kb.[4] The encoded protein includes a 27-residue signal peptide followed by the 264-residue mature protein. IGFBP-3 shares with the other five high-affinity IGFBPs and a 3-domain structure:[5]
- A conserved N-terminal domain containing a cysteine rich region (12 cysteine residues) with multiple intra-domain disulfide bonds, a IGFBP motif (GCGCCXXC), the primary site of IGF binding.
- A highly variable central or linker domain (only 15% conservation between IGFBPs).
- A conserved C-terminal domain containing secondary IGF binding residues, a cysteine rich region (6 cysteine residues), an 18 residue basic motif that binds heparin, the acid labile subunit (ALS), and a nuclear localization sequence.
The linker domain is the site of most post-translational modification, which include glycosylation, phosphorylation, and limited proteolysis. By electrophoretic analysis IGFBP-3 appears as a doublet, owing to the occupancy of either two or three of its N-glycosylation sites by carbohydrate. Hypoglycosylated IGFBP-3 may be seen after extended glucose starvation.
Many proteases are known to cleave IGFBP-3 at single linker-domain sites, and in the circulation of pregnant women, IGFBP-3 is entirely proteolyzed, yet still capable of carrying normal amounts of IGF-1 and IGF-2. Binding capacity appears to be retained after proteolysis because of a cooperative interaction between the two proteolyzed fragments, that together maintain an active IGF-binding site.[6]
# Sites and regulation of production
IGFBP-3 mRNA is expressed in all tissue examined, with kidney, stomach, placenta, uterus and liver showing highest expression in rat tissues.[7] Rat liver IGFBP-3 mRNA is found in nonparenchymal cells including sinusoidal endothelium, but not in hepatocytes.[8] In contrast, human hepatocytes do express IGFBP-3.[9]
IGFBP-3 levels in human serum are, like IGF-1, dependent on growth hormone (GH); for example, serum IGFBP-3 is increased in acromegaly and low in GH-deficient children. However, IGFBP-3 gene expression in human liver is GH-independent.[2][10] Because it is stabilized in human serum by forming complexes with IGF-1 and ALS, which are both GH-dependent, serum IGFBP-3 also appears regulated by GH. Its production by some non-hepatic tissues may also be directly GH-regulated. Immunoassays for serum IGFBP-3 are often used as part of the diagnosis of childhood GH-deficiency.
The most widely studied IGFBP3 polymorphism, at nucleotide-202 in the promoter region, is significantly associated with circulating IGFBP-3 levels, although the mechanism is unclear.[11] In some studies circulating IGFBP-3 also appears to be nutritionally regulated, although this may not be seen at the mRNA level. IGFBP-3 has been identified in human lymph, nipple aspirate, milk, amniotic fluid, follicular fluid, seminal plasma, urine, peritoneal dialysate, synovial fluid, tear fluid, and cerebrospinal fluid, in addition to serum.
Many factors increase IGFBP-3 production by cells, including transforming growth factor-β (TGFβ), tumor necrosis factor-α, vitamin D, retinoic acid, IGF-1, and stimuli such as chemotherapy that activate the tumor suppressor p53.[12] Estrogen inhibits IGFBP-3 production, and its tissue levels are lower in estrogen receptor (ER)-positive breast cancers than in ER-negative cancers.
# Interactions
The main IGFBP-3 ligands in the circulation are IGF-1 and IGF-2, and the acid-labile subunit (ALS).[13] The serum proteins transferrin,[14] fibronectin,[15] and plasminogen[16] are also known to bind IGFBP-3. In the cell and tissue environment many other interactions have been described (see Table). Two unrelated cell-surface proteins have been designated as IGFBP-3 receptors: low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor or type V TGFβ receptor[17] and the transmembrane protein TMEM219.[18] Both are believed to mediate antiproliferative effects. Functional interactions with the EGF receptor and the type I/type II TGFβ receptor system have also been reported, and other cell-surface proteins such as proteoglycans also bind IGFBP-3. IGFBP-3 can enter cells by both clathrin-mediated and caveolin-mediated endocytosis.[19] possibly involving the transferrin receptor.[20]
IGFBP-3 enters the cell nucleus by a mechanism that is incompletely understood, but involves its binding to importin-β.[21] Within the nucleus, it can modulate nuclear hormone receptor activity by direct binding to retinoid X receptor, retinoic acid receptor,[22] vitamin D receptor,[23] PPARγ,[24] and nur77,[25] IGFBP-3 also interacts with DNA-dependent protein kinase within the nucleus to promote the repair of DNA damage.[26]
# Cellular actions
IGFBP-3 exerts antiproliferative effects in many cell types by blocking the ability of IGF-1 and IGF-2 to activate the IGF1R (which stimulates cell proliferation). For example, in esophageal epithelial cells, responsiveness to IGF-1 stimulation is suppressed by secreted IGFBP-3 and restored when IGFBP-3 is downregulated by epidermal growth factor.[27] IGFBP-3 can also inhibit cell function by mechanisms that are independent of effects on IGF1R signaling, even in cells that entirely lack IGF1R.[28] IGF (or IGF1R) independent effects are commonly studied using mutant forms of IGFBP-3 with decreased IGF binding affinity. Thus, IGFBP-3-induced apoptosis in differentiating chondrocyte precursor cells is seen equally with a non-IGF binding IGFBP-3 mutant, demonstrating that the mechanism does not involve IGF binding.[29] IGF1R-independent growth inhibition by IGFBP-3 may involve the induction of pro-apoptotic proteins such as Bax and Bad[30] and may be mediated by ceramides (pro-apoptotic lipids),[31] or potentiate ceramide action[32] IGFBP-3 interaction with nuclear hormone receptors may also lead to inhibition of cell proliferation.
Contrasting with the typical growth-inhibitory effects of IGFBP-3, stimulation of cell proliferation by IGFBP-3 has also been observed. This can occur either by enhancing IGF-stimulated proliferation[33] or in the absence of IGF-1. In endothelial cells and mammary epithelial cells, the stimulatory effect of IGFBP-3 has been shown to involve activation of the enzyme sphingosine kinase, and generation of the bioactive lipid, sphingosine-1-phosphate, which promotes growth by transactivating the EGFR receptor.[31][34]
# Role in cancer
Based on cell growth experiments, animal cancer models, and epidemiological studies, it appears that IGFBP-3 functions as a low-penetrance tumor suppressor gene.[5]
Dysregulation of IGFBP-3 has been implicated in many cancers.[35] IGFBP-3 is sometimes referred to as a tumor suppressor, and downregulation of its tissue expression by promoter hypermethylation in some cancers, such as hepatoma.[36] and non-small cell lung cancer[37] may be associated with poor patient outcome. However, consistent with the dual inhibitory and stimulatory roles of IGFBP-3 seen in cell culture, there are other cancer types, such as breast cancer,[38][39] pancreatic cancer,[40] and clear cell renal cell cancer[41] in which high tissue IGFBP-3 expression has been linked to poor prognostic features or patient outcome. The mechanisms regulating these contrasting effects of IGFBP-3 in vivo are not well understood.
Since IGFBP-3 is abundant in the bloodstream of healthy adults (typically 2–4 mg/L), and is largely stabilized by its complex formation with IGFs and ALS, it is unlikely that tumor-derived IGFBP-3 has a large influence on circulating levels. There have been many studies linking circulating IGFBP-3 levels to the presence, or risk, of various cancers, or to patient outcomes.[35] but unequivocal conclusions have often been lacking. For example, high plasma IGFBP-3 levels were associated with a reduced prospective risk of colorectal cancer in women.[42] but in a study including men and women, colon cancer risk was positively associated with plasma IGFBP-3, while there was no significant association for rectal cancer.[43] A large systematic review concluded that circulating IGFBP-3 levels showed a modest association with increased risk for a number of cancers, but the results vary among sites.[44]
IGFBP-3 protein levels decrease during the progression of prostate cancer from benign to metastatic disease[45] although production of the protein does not cease completely. IGFBP-3 is still made (at a lower level) by prostate cancer cells and secreted into the surrounding environment. However, instead of the full length, functional protein, IGFBP-3 is found to be cleaved.[46] This decreases the affinity of IGF binding to IGFBP-3, making the growth factors more likely to bind the IGF1R and promote cell survival.
# Table: IGFBP-3 binding partners
IGFBP3 has been shown to interact with:
- ADAM12[47][48]
- ADAM28[49]
- COL1A1[50]
- FN1[15][51]
- IGFALS[13]
- IGF1,[1][52][53]
- IGF2[1][52]
- HSPA5[54]
- PLG[16]
- RXRA[22]
- TF[14][55]
- KPNB1[21]
- PRKDC[26]
- EGFR[26]
- LTBP1[56] | https://www.wikidoc.org/index.php/IGFBP3 | |
592fa8b3220b5ef43a035db7de827b0c414680de | wikidoc | IGFBP4 | IGFBP4
Insulin-like growth factor-binding protein 4 is a protein that in humans is encoded by the IGFBP4 gene.
# Function
This gene is a member of the insulin-like growth factor binding protein (IGFBP) family and encodes a protein with an IGFBP domain and a thyroglobulin type-I domain. The protein binds both insulin-like growth factors (IGFs) I and II and circulates in the plasma in both glycosylated and non-glycosylated forms. Binding of this protein prolongs the half-life of the IGFs and alters their interaction with cell surface receptors.
IGFBP-4 is a unique protein and it consistently inhibits several cancer cells in vivo and in vitro. Its inhibitory action has been shown in vivo in prostate and colon. It is secreted by all colon cancer cells.
# Clinical significance
The protein itself does not prevent the formation of cancer. However it may reduce the growth of cancer and act as an apoptotic factor.
# Interactions
IGFBP4 has been shown to interact with Insulin-like growth factor 1 and 2. | IGFBP4
Insulin-like growth factor-binding protein 4 is a protein that in humans is encoded by the IGFBP4 gene.[1][2][3]
# Function
This gene is a member of the insulin-like growth factor binding protein (IGFBP) family and encodes a protein with an IGFBP domain and a thyroglobulin type-I domain. The protein binds both insulin-like growth factors (IGFs) I and II and circulates in the plasma in both glycosylated and non-glycosylated forms. Binding of this protein prolongs the half-life of the IGFs and alters their interaction with cell surface receptors.[4]
IGFBP-4 is a unique protein and it consistently inhibits several cancer cells in vivo and in vitro. Its inhibitory action has been shown in vivo in prostate and colon. It is secreted by all colon cancer cells.
# Clinical significance
The protein itself does not prevent the formation of cancer.[5] However it may reduce the growth of cancer and act as an apoptotic factor.
# Interactions
IGFBP4 has been shown to interact with Insulin-like growth factor 1 and 2.[6][7] | https://www.wikidoc.org/index.php/IGFBP4 | |
ca1ec5ff7a894a7e24c1229597e49be39aa33ef6 | wikidoc | IGFBP7 | IGFBP7
Insulin-like growth factor-binding protein 7 is a protein that in humans is encoded by the IGFBP7 gene. The major function of the protein is the regulation of availability of insulin-like growth factors (IGFs) in tissue as well as in modulating IGF binding to its receptors. IGFBP7 binds to IGF with high affinity. It also stimulates cell adhesion. The protein is implicated in some cancers.
# Interactions
IGFBP7 has been shown to interact with Insulin-like growth factor 1 and VPS24.
# RNA Editing
The pre-mRNA of this protein is subject to RNA editing.
The two editing sites were previously recorded as single nucleotide polymorphisms in dbSNP.
## Editing type
A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine.Inosines are recognised as guanosine by the cells translational machinery.There are three members of the ADAR family ADARs 1-3 with ADAR 1 and ADAR 2 being the only enzymatically active members.ADAR3 is thought to have a regulatory role in the brain.ADAR1 and ADAR 2 are widely expressed in tissues while ADAR 3 is restricted to the brain.The double stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence.The region that base pairs with the editing region is known as an Editing Complentary Sequence (ECS). It is thought that the pre-mRNA of IGFBP7 is a substrate for ADAR1 based on the expression spectrum of the editing enzyme.
## Editing sites
The pre-mRNA of this protein is edited at two positions.These editing sites occur within the insulin growth factor domain.
### R/G site
There is an Arginine (R) to a Glycine (G) substitution at amino acid position 78 of the final protein.
### K/R site
There is a K to R substitiution at amino acid position 95.
The editing complementary sequence (ECS) is located in a region within the coding sequence about 200 base pairs upstream from the editing sites.The ECS forms 140 bp duplex structure.
The A to G discrepancies for these two editing sites were confirmed experimentally to be RNA editing by analyzing matched cDNA and genomic dna sequences from the same tissue sample. Intriguingly, those RNAs that do not need an intron sequence to pair with could, in theory, continue to undergo editing as mature mRNA. A third candidate editing site did not show evidence of RNA editing in sequence analysis, which may be an indication that either the RNA editing process is tissue specific, or editing occurs at a low frequency. One other possible explanation is that these edits are related to specific genomic polymorphisms. The editing site also overlaps with an antisense transcript which could also form a double stranded RNA structure creating a suitable substrate for ADARs.
## Editing regulation
Editing is observed in a wide range of tissues. Editing at the K/R site at amino acid position 95 is very high in the human brain.
## Consequences
### Structural
The edited sites are found within the insulin growth factor binding domain of IGFBP7 and also Heparin binding domain.This region is also a site for proteolytic cleavage.Structural analysis of the edited sites determined that the two amino acids that corresponded to the edited sites are not directly involved in binding to IGF-1 but are found in regions flanking them. At position 78 in unedited version of the transcript there is an Arginine close to residue valine-49.This Valine is important in hydrophobic interaction of Phenylalanine of IGF-1.A substitution to a Glycine at this position is thought to introduce additional flexibility leading to a change of loop conformation, thereby disrupting the hydrophobic interaction that stabilises the complex. At amino acid position 98 the unedited transcript contains a lysine .This residue makes some non specific interactions via the aliphatic part of the side chain with Glu-38 of IGF-1.In the edited version the position is an arginine.The long side chain of which is thought to be able to maintain these weak interactions
### Function
The edited region contains a proposed heparin binding site and is also part of the recognition sequence for proteolytic cleavage.Heparin binding inhibits cell binding and cell adhesion functions of the protein. Cleavage which occurs at amino acid position 97 reduces heparin binding but modulates the growth stimulatory activity of the protein. Since the editing site occurs within this proposed heparin binding region the effects of editing may have implications for heparin binding and proteolytic clevage and therefore have other affects downstream.Since the protein has been implicated in these processes it is believed editing might effect apoptosis, regulation of cell growth and angiogenesis.
### Functions in Learning and Memory
A study at the European Neuroscience Institute-Goettingen (Germany) found that fear extinction-induced IGF2/IGFBP7 signalling promotes the survival of 17- to 19-day-old newborn hippocampal neurons. This suggests that therapeutic strategies that enhance IGF2 signalling and adult neurogenesis might be suitable to treat diseases linked to excessive fear memory such as PTSD. The same group has found that IGFBP7 levels are increased in Alzheimer's disease and regulated via DNA methylation. Elevation of IGFBP7 in wild type mice causes memory impairment. Blocking IGFBP7 function in mice that develop Alzheimer's disease-like memory impairment restores memory function. These data suggest that IGFBP7 is a critical regulator of memory consolidation and might be used as biomarker for Alzheimer's disease. Targeting IGFBP7 could be a novel therapeutic avenue for the treatment of Alzheimer's disease patients. | IGFBP7
Insulin-like growth factor-binding protein 7 is a protein that in humans is encoded by the IGFBP7 gene.[1][2][3] The major function of the protein is the regulation of availability of insulin-like growth factors (IGFs) in tissue as well as in modulating IGF binding to its receptors. IGFBP7 binds to IGF with high affinity.[4] It also stimulates cell adhesion. The protein is implicated in some cancers.[5]
# Interactions
IGFBP7 has been shown to interact with Insulin-like growth factor 1[4][6] and VPS24.[7]
# RNA Editing
The pre-mRNA of this protein is subject to RNA editing.
The two editing sites were previously recorded as single nucleotide polymorphisms in dbSNP.[8]
## Editing type
A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine.Inosines are recognised as guanosine by the cells translational machinery.There are three members of the ADAR family ADARs 1-3 with ADAR 1 and ADAR 2 being the only enzymatically active members.ADAR3 is thought to have a regulatory role in the brain.ADAR1 and ADAR 2 are widely expressed in tissues while ADAR 3 is restricted to the brain.The double stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence.The region that base pairs with the editing region is known as an Editing Complentary Sequence (ECS). It is thought that the pre-mRNA of IGFBP7 is a substrate for ADAR1 based on the expression spectrum of the editing enzyme.[9]
## Editing sites
The pre-mRNA of this protein is edited at two positions.These editing sites occur within the insulin growth factor domain.
### R/G site
There is an Arginine (R) to a Glycine (G) substitution at amino acid position 78 of the final protein.
### K/R site
There is a K to R substitiution at amino acid position 95.
The editing complementary sequence (ECS) is located in a region within the coding sequence about 200 base pairs upstream from the editing sites.The ECS forms 140 bp duplex structure.[8]
The A to G discrepancies for these two editing sites were confirmed experimentally to be RNA editing by analyzing matched cDNA and genomic dna sequences from the same tissue sample.[5] Intriguingly, those RNAs that do not need an intron sequence to pair with could, in theory, continue to undergo editing as mature mRNA. A third candidate editing site did not show evidence of RNA editing in sequence analysis, which may be an indication that either the RNA editing process is tissue specific, or editing occurs at a low frequency. One other possible explanation is that these edits are related to specific genomic polymorphisms.[5] The editing site also overlaps with an antisense transcript which could also form a double stranded RNA structure creating a suitable substrate for ADARs.[8]
## Editing regulation
Editing is observed in a wide range of tissues. Editing at the K/R site at amino acid position 95 is very high in the human brain.[5]
## Consequences
### Structural
The edited sites are found within the insulin growth factor binding domain of IGFBP7 and also Heparin binding domain.This region is also a site for proteolytic cleavage.Structural analysis of the edited sites determined that the two amino acids that corresponded to the edited sites are not directly involved in binding to IGF-1 but are found in regions flanking them.[10] At position 78 in unedited version of the transcript there is an Arginine close to residue valine-49.This Valine is important in hydrophobic interaction of Phenylalanine of IGF-1.A substitution to a Glycine at this position is thought to introduce additional flexibility leading to a change of loop conformation, thereby disrupting the hydrophobic interaction that stabilises the complex. At amino acid position 98 the unedited transcript contains a lysine .This residue makes some non specific interactions via the aliphatic part of the side chain with Glu-38 of IGF-1.In the edited version the position is an arginine.The long side chain of which is thought to be able to maintain these weak interactions[8]
### Function
The edited region contains a proposed heparin binding site and is also part of the recognition sequence for proteolytic cleavage.Heparin binding inhibits cell binding and cell adhesion functions of the protein.[11] Cleavage which occurs at amino acid position 97 reduces heparin binding but modulates the growth stimulatory activity of the protein.[6] Since the editing site occurs within this proposed heparin binding region the effects of editing may have implications for heparin binding and proteolytic clevage and therefore have other affects downstream.Since the protein has been implicated in these processes it is believed editing might effect apoptosis, regulation of cell growth and angiogenesis.[5]
### Functions in Learning and Memory
A study at the European Neuroscience Institute-Goettingen (Germany) found that fear extinction-induced IGF2/IGFBP7 signalling promotes the survival of 17- to 19-day-old newborn hippocampal neurons. This suggests that therapeutic strategies that enhance IGF2 signalling and adult neurogenesis might be suitable to treat diseases linked to excessive fear memory such as PTSD.[12] The same group has found that IGFBP7 levels are increased in Alzheimer's disease and regulated via DNA methylation. Elevation of IGFBP7 in wild type mice causes memory impairment. Blocking IGFBP7 function in mice that develop Alzheimer's disease-like memory impairment restores memory function. These data suggest that IGFBP7 is a critical regulator of memory consolidation and might be used as biomarker for Alzheimer's disease. Targeting IGFBP7 could be a novel therapeutic avenue for the treatment of Alzheimer's disease patients.[13] | https://www.wikidoc.org/index.php/IGFBP7 | |
e92e95da2b587fe667d383f5f6262959246f4d56 | wikidoc | IKBKAP | IKBKAP
IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein) is a human gene encoding the IKAP protein, which is ubiquitously expressed at varying levels in all tissue types, including brain cells. The IKAP protein is thought to participate as a sub-unit in the assembly of a six-protein putative human holo-Elongator complex, which allows for transcriptional elongation by RNA polymerase II. Further evidence has implicated the IKAP protein as being critical in neuronal development, and directs that decreased expression of IKAP in certain cell types is the molecular basis for the severe, neurodevelopmental disorder familial dysautonomy. Other pathways that have been connected to IKAP protein function in a variety of organisms include tRNA modification, cell motility, and cytosolic stress signalling.
Homologs of the IKBKAP gene have been identified in multiple other Eukaryotic model organisms. Notable homologs include Elp1 in yeast, Ikbkap in mice, and D-elp1 in fruit flies. The fruit fly homolog (D-elp1) has RNA-dependent RNA polymerase activity and is involved in RNA interference.
The IKBKAP gene is located on the long (q) arm of chromosome 9 at position 31, from base pair 108,709,355 to base pair 108,775,950.
# Function and mechanism
Originally, it was proposed that the IKBKAP gene in humans was encoding a scaffolding protein (IKAP) for the IκB enzyme kinase (IKK) complex, which is involved in pro-inflammatory cytokine signal transduction in the NF-κB signalling pathway. However, this was subsequently disproven when researchers applied a gel filtration method and could not identify IKK complexes contained in fractions with IKAP, thus dissociating IKAP from having a role in the NF-κB signalling pathway.
Later, it was discovered that IKAP functions as a cytoplasmic scaffold protein in the mammalian JNK-signalling pathway which is activated in response to stress stimuli. In an in vivo experiment, researchers showed direct interaction between IKAP and JNK induced by the application of stressors such as ultraviolet light and TNF-α (a pro-inflammatory cytokine).
IKAP is now also widely acknowledged to have a role in transcriptional elongation in humans. The RNA polymerase II holoenzyme constitutes partly of a multi-subunit histone acetyltransferase element known as the RNA polymerase II elongator complex, of which IKAP is one subunit. The association of the elongator complex with RNA polymerase II holoenzyme is necessary for subsequent binding to nascent pre-mRNA of certain target genes, and thus their successful transcription. Specifically, within the cell, the depletion of functional elongater complexes due to low IKAP expression has been found to have a profound effect on transcription of genes involved in cell migration.
In yeast, experimental data shows the elongator complex functioning in a variety of processes — from exocytosis to tRNA modification. This finding demonstrates that the function of the elongator complex is not conserved among species.
# Related conditions
## Familial Dysautonomia
Familial dysautonomia (also known as “Riley-Day syndrome”) is a complex congenital neurodevelopmental disease, characterized by unusually low numbers of neurons in the sensory and autonomic nervous systems. The resulting symptoms of patients include gastrointestinal dysfunction, scoliosis, and pain insensitivity. This disease is especially prevalent in the Ashkenazi Jewish population, where 1/3600 live births present familial dysautonomia.
By 2001, the genetic cause of familial dysautonomia was localized to a dysfunctional region spanning 177kb on chromosome 9q31. With the use of blood samples from diagnosed patients, the implicated region was successfully sequenced. The IKBKAP gene, one of the five genes identified in that region, was found to have a single-base mutation in over 99.5% of cases of familial dysautonomia seen.
The single-base mutation, overwhelmingly noted as a transition from cytosine to thymine, is present in the 5’ splice donor site of intron 20 in the IKBKAP pre-mRNA. This prevents recruitment of splicing machinery, and thus exon 19 is spliced directly to exon 21 in the final mRNA product – exon 20 is removed from the pre-mRNA with the introns. The unintentional removal of an exon from the final mRNA product is termed exon skipping. Therefore, there is a decreased level of functional IKAP protein expression within affected tissue. However, this disorder is tissue-specific. Lymphoblasts, even with the mutation present, may continue to express some functional IKAP protein. In contrast, brain tissue with the single-base mutation in the IKBKAP gene predominantly express a resulting truncated, mutant IKAP protein which is nonfunctional. The exact mechanism for how the familial dysautonomia phenotype is induced due to reduced IKAP expression is unclear; still, as a protein involved in transcriptional regulation, there have been a variety of proposed mechanisms. One such theory suggests that critical genes in the development of wild-type sensory and autonomic neurons are improperly transcribed. An extension of this research suggests that genes involved in cell migration are impaired in the nervous system, creating a foundation for this disorder.
In a small number of reported familial dysautonomia cases, researchers have identified other mutations that cause a change in amino acids (the building blocks of proteins). In these cases, arginine is replaced by proline at position 696 in the IKAP protein's chain of amino acids (also written as Arg696Pro), or proline is replaced by leucine at position 914 (also written as Pro914Leu). Together, these mutations cause the resulting IKAP protein to malfunction.
As an autosomal recessive disorder, two mutated alleles of the IKBKAP gene are required for the disorder to manifest. However, despite the predominance of the same single-base mutation being the reputed cause of familial dysautonomia, the severity of the affected phenotype varies within and between families.
Kinetin (6-furfurylaminopurine) has been found to have the capacity to repair the splicing defect and increase wild-type IKBKAP mRNA expression in vivo. Further research is still required to assess the fitness of kinetin as a possible future oral treatment.
# Model organisms
Model organisms have been used in the study of IKBKAP gene function.
## Mouse
A conditional knockout mouse line, called Ikbkaptm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out and two phenotypes were reported. No homozygous mutant embryos were identified during gestation, and in a separate study, none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals.
## Saccharomyces cerevisiae
The homologous protein for IKAP in yeast is Elp1, with 29% identity and 46% similarity detected between the proteins. The yeast Elp1 protein is a subunit of a three-protein RNA polymerase II-associated elongator complex.
## Drosophila melanogaster
The IKBKAP gene homolog in fruit flies is the CG10535 gene, encoding the D-elp1 protein — the largest of three subunits making the RNA polymerase II core elongator complex. This subunit was found to have RNA-dependent RNA polymerase activity, through which it could synthesize double-stranded RNA from single-stranded RNA templates. This activity was observed in a D-elp1 protein-dependent step converting transposon RNA into double-stranded RNA for processing by Dcr-2 (a Drosophila dicer), involved in further RNA degradation and silencing. | IKBKAP
IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein) is a human gene encoding the IKAP protein, which is ubiquitously expressed at varying levels in all tissue types, including brain cells.[1] The IKAP protein is thought to participate as a sub-unit in the assembly of a six-protein putative human holo-Elongator complex,[2] which allows for transcriptional elongation by RNA polymerase II. Further evidence has implicated the IKAP protein as being critical in neuronal development, and directs that decreased expression of IKAP in certain cell types is the molecular basis for the severe, neurodevelopmental disorder familial dysautonomy.[3] Other pathways that have been connected to IKAP protein function in a variety of organisms include tRNA modification,[citation needed] cell motility,[4] and cytosolic stress signalling.[1]
Homologs of the IKBKAP gene have been identified in multiple other Eukaryotic model organisms. Notable homologs include Elp1 in yeast,[5] Ikbkap in mice,[6] and D-elp1 in fruit flies. The fruit fly homolog (D-elp1) has RNA-dependent RNA polymerase activity and is involved in RNA interference.[7]
The IKBKAP gene is located on the long (q) arm of chromosome 9 at position 31, from base pair 108,709,355 to base pair 108,775,950.
# Function and mechanism
Originally, it was proposed that the IKBKAP gene in humans was encoding a scaffolding protein (IKAP) for the IκB enzyme kinase (IKK) complex, which is involved in pro-inflammatory cytokine signal transduction in the NF-κB signalling pathway.[8] However, this was subsequently disproven when researchers applied a gel filtration method and could not identify IKK complexes contained in fractions with IKAP, thus dissociating IKAP from having a role in the NF-κB signalling pathway.[9]
Later, it was discovered that IKAP functions as a cytoplasmic scaffold protein in the mammalian JNK-signalling pathway which is activated in response to stress stimuli. In an in vivo experiment, researchers showed direct interaction between IKAP and JNK induced by the application of stressors such as ultraviolet light and TNF-α (a pro-inflammatory cytokine).[1]
IKAP is now also widely acknowledged to have a role in transcriptional elongation in humans. The RNA polymerase II holoenzyme constitutes partly of a multi-subunit histone acetyltransferase element known as the RNA polymerase II elongator complex, of which IKAP is one subunit.[10] The association of the elongator complex with RNA polymerase II holoenzyme is necessary for subsequent binding to nascent pre-mRNA of certain target genes, and thus their successful transcription.[11] Specifically, within the cell, the depletion of functional elongater complexes due to low IKAP expression has been found to have a profound effect on transcription of genes involved in cell migration.[12]
In yeast, experimental data shows the elongator complex functioning in a variety of processes — from exocytosis to tRNA modification.[13] This finding demonstrates that the function of the elongator complex is not conserved among species.
# Related conditions
## Familial Dysautonomia
Familial dysautonomia (also known as “Riley-Day syndrome”) is a complex congenital neurodevelopmental disease, characterized by unusually low numbers of neurons in the sensory and autonomic nervous systems. The resulting symptoms of patients include gastrointestinal dysfunction, scoliosis, and pain insensitivity. This disease is especially prevalent in the Ashkenazi Jewish population, where 1/3600 live births present familial dysautonomia.[3]
By 2001, the genetic cause of familial dysautonomia was localized to a dysfunctional region spanning 177kb on chromosome 9q31. With the use of blood samples from diagnosed patients, the implicated region was successfully sequenced. The IKBKAP gene, one of the five genes identified in that region, was found to have a single-base mutation in over 99.5% of cases of familial dysautonomia seen.[3]
The single-base mutation, overwhelmingly noted as a transition from cytosine to thymine, is present in the 5’ splice donor site of intron 20 in the IKBKAP pre-mRNA. This prevents recruitment of splicing machinery, and thus exon 19 is spliced directly to exon 21 in the final mRNA product – exon 20 is removed from the pre-mRNA with the introns. The unintentional removal of an exon from the final mRNA product is termed exon skipping.[3] Therefore, there is a decreased level of functional IKAP protein expression within affected tissue. However, this disorder is tissue-specific. Lymphoblasts, even with the mutation present, may continue to express some functional IKAP protein. In contrast, brain tissue with the single-base mutation in the IKBKAP gene predominantly express a resulting truncated, mutant IKAP protein which is nonfunctional.[3] The exact mechanism for how the familial dysautonomia phenotype is induced due to reduced IKAP expression is unclear; still, as a protein involved in transcriptional regulation, there have been a variety of proposed mechanisms. One such theory suggests that critical genes in the development of wild-type sensory and autonomic neurons are improperly transcribed.[3] An extension of this research suggests that genes involved in cell migration are impaired in the nervous system, creating a foundation for this disorder.[4]
In a small number of reported familial dysautonomia cases, researchers have identified other mutations that cause a change in amino acids (the building blocks of proteins). In these cases, arginine is replaced by proline at position 696 in the IKAP protein's chain of amino acids (also written as Arg696Pro), or proline is replaced by leucine at position 914 (also written as Pro914Leu). Together, these mutations cause the resulting IKAP protein to malfunction.[14]
As an autosomal recessive disorder, two mutated alleles of the IKBKAP gene are required for the disorder to manifest. However, despite the predominance of the same single-base mutation being the reputed cause of familial dysautonomia, the severity of the affected phenotype varies within and between families.[3]
Kinetin (6-furfurylaminopurine) has been found to have the capacity to repair the splicing defect and increase wild-type IKBKAP mRNA expression in vivo. Further research is still required to assess the fitness of kinetin as a possible future oral treatment.[15]
# Model organisms
Model organisms have been used in the study of IKBKAP gene function.
## Mouse
A conditional knockout mouse line, called Ikbkaptm1a(KOMP)Wtsi[19][20] 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.[21][22][23]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[17][24] Twenty five tests were carried out and two phenotypes were reported. No homozygous mutant embryos were identified during gestation, and in a separate study, none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals.[17]
## Saccharomyces cerevisiae
The homologous protein for IKAP in yeast is Elp1, with 29% identity and 46% similarity detected between the proteins. The yeast Elp1 protein is a subunit of a three-protein RNA polymerase II-associated elongator complex.[3]
## Drosophila melanogaster
The IKBKAP gene homolog in fruit flies is the CG10535 gene, encoding the D-elp1 protein — the largest of three subunits making the RNA polymerase II core elongator complex.[3] This subunit was found to have RNA-dependent RNA polymerase activity, through which it could synthesize double-stranded RNA from single-stranded RNA templates. This activity was observed in a D-elp1 protein-dependent step converting transposon RNA into double-stranded RNA for processing by Dcr-2 (a Drosophila dicer), involved in further RNA degradation and silencing.[7] | https://www.wikidoc.org/index.php/IKAP_protein | |
3858dea20cd13d1bd6063a277d7ba4c684f93d74 | wikidoc | IL1RAP | IL1RAP
Interleukin-1 receptor accessory protein is a protein that in humans is encoded by the IL1RAP gene.
Interleukin 1 induces synthesis of acute phase and proinflammatory proteins during infection, tissue damage, or stress, by forming a complex at the cell membrane with an interleukin 1 receptor and an accessory protein. This gene encodes an interleukin 1 receptor accessory protein. Alternative splicing of this gene results in two transcript variants encoding two different isoforms, one membrane-bound and one soluble.
# Interactions
IL1RAP has been shown to interact with TOLLIP and Interleukin 1 receptor, type I. | IL1RAP
Interleukin-1 receptor accessory protein is a protein that in humans is encoded by the IL1RAP gene.[1][2][3]
Interleukin 1 induces synthesis of acute phase and proinflammatory proteins during infection, tissue damage, or stress, by forming a complex at the cell membrane with an interleukin 1 receptor and an accessory protein. This gene encodes an interleukin 1 receptor accessory protein. Alternative splicing of this gene results in two transcript variants encoding two different isoforms, one membrane-bound and one soluble.[3]
# Interactions
IL1RAP has been shown to interact with TOLLIP[4] and Interleukin 1 receptor, type I.[5] | https://www.wikidoc.org/index.php/IL1RAP | |
6f75e0eb02b0b70dca715c9e1688b09ffbaf18c3 | wikidoc | IL1RL1 | IL1RL1
Interleukin 1 receptor-like 1, also known as IL1RL1 and ST2, is a protein that in humans is encoded by the IL1RL1 gene.
# Function
IL1RL1 is a member of the Toll-like receptor superfamily based on the function of its intracelluar TIR domain, but its extracellular region is composed of immunoglobulin domains. Unlike other members of the family IL1RL1 does not induce an inflammatory response through activation of NF-κB, although it does activate MAP kinases.
ST2 is a member of the interleukin 1 receptor family. The ST2 protein has two isoforms and is directly implicated in the progression of cardiac disease: a soluble form (referred to as soluble ST2 or sST2) and a membrane-bound receptor form (referred to as the ST2 receptor or ST2L). When the myocardium is stretched, the ST2 gene is upregulated, increasing the concentration of circulating soluble ST2. The ligand for ST2 is the cytokine Interleukin-33(IL-33). Binding of IL-33 to the ST2 receptor, in response to cardiac disease or injury, such as an ischemic event, elicits a cardioprotective effect resulting in preserved cardiac function. This cardioprotective IL-33 signal is counterbalanced by the level of soluble ST2, which binds IL-33 and makes it unavailable to the ST2 receptor for cardioprotective signaling. As a result, the heart is subjected to greater stress in the presence of high levels of soluble ST2.
# Molecular biology
The gene is found on the long arm of Chromosome 2 (2q12). It is 40,536 bases long and is located on the Watson (plus) strand. It encodes a protein of 556 amino acids (molecular weight 63,358 Da). Both membrane bound and soluble forms are known. The protein is known to interact with MyD88, IRAK1, IRAK4 and TRAF6. It appears to be essential for the normal function of T helper cells type 2 (Th2 cells) .
# Clinical significance
Mutations in this gene have been linked to atopic dermatitis and asthma.
The protein encoded by this gene serves as a cardiac biomarker. | IL1RL1
Interleukin 1 receptor-like 1, also known as IL1RL1 and ST2, is a protein that in humans is encoded by the IL1RL1 gene.[1][2][3]
# Function
IL1RL1 is a member of the Toll-like receptor superfamily based on the function of its intracelluar TIR domain, but its extracellular region is composed of immunoglobulin domains. Unlike other members of the family IL1RL1 does not induce an inflammatory response through activation of NF-κB, although it does activate MAP kinases.[4]
ST2 is a member of the interleukin 1 receptor family. The ST2 protein has two isoforms and is directly implicated in the progression of cardiac disease: a soluble form (referred to as soluble ST2 or sST2) and a membrane-bound receptor form (referred to as the ST2 receptor or ST2L). When the myocardium is stretched, the ST2 gene is upregulated, increasing the concentration of circulating soluble ST2.[5] The ligand for ST2 is the cytokine Interleukin-33(IL-33). Binding of IL-33 to the ST2 receptor, in response to cardiac disease or injury, such as an ischemic event, elicits a cardioprotective effect resulting in preserved cardiac function. This cardioprotective IL-33 signal is counterbalanced by the level of soluble ST2, which binds IL-33 and makes it unavailable to the ST2 receptor for cardioprotective signaling. As a result, the heart is subjected to greater stress in the presence of high levels of soluble ST2.
# Molecular biology
The gene is found on the long arm of Chromosome 2 (2q12). It is 40,536 bases long and is located on the Watson (plus) strand. It encodes a protein of 556 amino acids (molecular weight 63,358 Da). Both membrane bound and soluble forms are known. The protein is known to interact with MyD88, IRAK1, IRAK4 and TRAF6. It appears to be essential for the normal function of T helper cells type 2 (Th2 cells) .
# Clinical significance
Mutations in this gene have been linked to atopic dermatitis and asthma.
The protein encoded by this gene serves as a cardiac biomarker. | https://www.wikidoc.org/index.php/IL1RL1 | |
5df6958881f5fd317d5e27dd4de4c65693501fe6 | wikidoc | IMMP2L | IMMP2L
Inner mitochondrial membrane peptidase subunit 2 (IMMP2L) is an enzyme that in humans is encoded by the IMMP2L gene on chromosome 7. This protein catalyzes the removal of transit peptides required for the targeting of proteins from the mitochondrial matrix, across the inner membrane, into the inter-membrane space. IMMP2L processes the nuclear encoded protein DIABLO.
# Structure
## Gene
The gene IMMP2L encodes protein Inner mitochondrial membrane peptidase subunit 2 in human. The human IMMP2L gene has 18 exons and locates at chromosome band 7q31.
## Protein
The human protein Inner mitochondrial membrane peptidase subunit 2 has two isoforms due to alternative splicing. One isoform is 19.7 kDa in size and composed of 175 amino acids. The calculated theoretical pI of this protein isoform is 8.66. The other isoform is 12.3kDa in size and composed of 110 amino acids. The calculated theoretical pI of this protein isoform is 9.42.
# Function
As a peptidase, this protein catalyzes the removal of transit peptides required for the targeting of proteins from the mitochondrial matrix, across the inner membrane, into the inter-membrane space. Known to process the nuclear encoding DIABLO protein.
# Clinical significance
Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder characterized by multiple motor and phonic tics. In the clinical characterization of a patient with GTS, Petek et al discovered a breakpoint in chromosome region 7q31. Additional characterization identified that IMMP2L, a novel gene coding for the apparent human homologue of the yeast mitochondrial inner membrane peptidase subunit 2, was found to be disrupted by both the breakpoint in the duplicated fragment and the insertion site in 7q31. It is the first association of IMMP2L gene to Tourette syndrome.
Recent investigation by Bertelsen et al. further indicated that IMMP2L was one of the genes as a susceptibility factor in disease pathogenesis. Tourette syndrome is often accompanied by comorbidities such as attention-deficit hyperactivity-disorder and obsessive compulsive disorder. Tourette syndrome has a complex etiology and the underlying environmental and genetic factors responsible for this disease are still largely unknown. | IMMP2L
Inner mitochondrial membrane peptidase subunit 2 (IMMP2L) is an enzyme that in humans is encoded by the IMMP2L gene on chromosome 7.[1][2] This protein catalyzes the removal of transit peptides required for the targeting of proteins from the mitochondrial matrix, across the inner membrane, into the inter-membrane space. IMMP2L processes the nuclear encoded protein DIABLO.
# Structure
## Gene
The gene IMMP2L encodes protein Inner mitochondrial membrane peptidase subunit 2 in human. The human IMMP2L gene has 18 exons and locates at chromosome band 7q31.[2]
## Protein
The human protein Inner mitochondrial membrane peptidase subunit 2 has two isoforms due to alternative splicing. One isoform is 19.7 kDa in size and composed of 175 amino acids. The calculated theoretical pI of this protein isoform is 8.66. The other isoform is 12.3kDa in size and composed of 110 amino acids. The calculated theoretical pI of this protein isoform is 9.42.[3][4]
# Function
As a peptidase, this protein catalyzes the removal of transit peptides required for the targeting of proteins from the mitochondrial matrix, across the inner membrane, into the inter-membrane space. Known to process the nuclear encoding DIABLO protein.
# Clinical significance
Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder characterized by multiple motor and phonic tics. In the clinical characterization of a patient with GTS, Petek et al discovered a breakpoint in chromosome region 7q31. Additional characterization identified that IMMP2L, a novel gene coding for the apparent human homologue of the yeast mitochondrial inner membrane peptidase subunit 2, was found to be disrupted by both the breakpoint in the duplicated fragment and the insertion site in 7q31. It is the first association of IMMP2L gene to Tourette syndrome.[1]
Recent investigation by Bertelsen et al. further indicated that IMMP2L was one of the genes as a susceptibility factor in disease pathogenesis. Tourette syndrome is often accompanied by comorbidities such as attention-deficit hyperactivity-disorder and obsessive compulsive disorder. Tourette syndrome has a complex etiology and the underlying environmental and genetic factors responsible for this disease are still largely unknown.[5] | https://www.wikidoc.org/index.php/IMMP2L | |
21f5cc8c653ed75981a69d4705b5923bd94926c6 | wikidoc | IMPDH1 | IMPDH1
Inosine-5'-monophosphate dehydrogenase 1, also known as IMP dehydrogenase 1, is an enzyme that in humans is encoded by the IMPDH1 gene.
# Function
IMP dehydrogenase 1 acts as a homotetramer to regulate cell growth. IMPDH1 is an enzyme that catalyzes the synthesis of xanthine monophosphate (XMP) from inosine-5'-monophosphate (IMP). This is the rate-limiting step in the de novo synthesis of guanine nucleotides.
# Clinical significance
Defects in the IMPDH1 gene are a cause of retinitis pigmentosa type 10 (RP10). | IMPDH1
Inosine-5'-monophosphate dehydrogenase 1, also known as IMP dehydrogenase 1, is an enzyme that in humans is encoded by the IMPDH1 gene.[1][2]
# Function
IMP dehydrogenase 1 acts as a homotetramer to regulate cell growth. IMPDH1 is an enzyme that catalyzes the synthesis of xanthine monophosphate (XMP) from inosine-5'-monophosphate (IMP). This is the rate-limiting step in the de novo synthesis of guanine nucleotides.[1]
# Clinical significance
Defects in the IMPDH1 gene are a cause of retinitis pigmentosa type 10 (RP10).[1][3][4] | https://www.wikidoc.org/index.php/IMPDH1 | |
f612d6155ee02bf8e577100c8c75028f7bac6580 | wikidoc | IMPDH2 | IMPDH2
Inosine-5'-monophosphate dehydrogenase 2, also known as IMP dehydrogenase 2, is an enzyme that in humans is encoded by the IMPDH2 gene.
# Function
IMP dehydrogenase 2 is the rate-limiting enzyme in the de novo guanine nucleotide biosynthesis. It is thus involved in maintaining cellular guanine deoxy- and ribonucleotide pools needed for DNA and RNA synthesis. IMPDH2 catalyzes the NAD-dependent oxidation of inosine-5'-monophosphate into xanthine-5'-monophosphate, which is then converted into guanosine-5'-monophosphate. IMPDH2 has been identified as an intracellular target of the natural product sanglifehrin A
# Clinical significance
This gene is up-regulated in some neoplasms, suggesting it may play a role in malignant transformation. | IMPDH2
Inosine-5'-monophosphate dehydrogenase 2, also known as IMP dehydrogenase 2, is an enzyme that in humans is encoded by the IMPDH2 gene.[1][2][3]
# Function
IMP dehydrogenase 2 is the rate-limiting enzyme in the de novo guanine nucleotide biosynthesis. It is thus involved in maintaining cellular guanine deoxy- and ribonucleotide pools needed for DNA and RNA synthesis. IMPDH2 catalyzes the NAD-dependent oxidation of inosine-5'-monophosphate into xanthine-5'-monophosphate, which is then converted into guanosine-5'-monophosphate.[1] IMPDH2 has been identified as an intracellular target of the natural product sanglifehrin A[4]
# Clinical significance
This gene is up-regulated in some neoplasms, suggesting it may play a role in malignant transformation.[1] | https://www.wikidoc.org/index.php/IMPDH2 | |
3f47b98876289ebbd4f3d75a5b36c163765b4fcc | wikidoc | INCENP | INCENP
Inner centromere protein is a protein that in humans is encoded by the INCENP gene.
In mammalian cells, two broad groups of centromere-interacting proteins have been described: constitutively binding centromere proteins and 'passenger' (or transiently interacting) proteins. The constitutive proteins include CENPA (centromere protein A), CENPB, CENPC1, and CENPD.
The term 'passenger proteins' encompasses a broad collection of proteins that localize to the centromere during specific stages of the cell cycle. These include CENPE; MCAK; KID; cytoplasmic dynein (e.g., DYNC1H1); CliPs (e.g. CLIP1); and CENPF/mitosin (CENPF). The inner centromere proteins (INCENPs), the initial members of the passenger protein group, display a broad localization along chromosomes in the early stages of mitosis but gradually become concentrated at centromeres as the cell cycle progresses into mid-metaphase. During telophase, the proteins are located within the midbody in the intercellular bridge, where they are discarded after cytokinesis.
INCENP is a regulatory protein in the chromosome passenger complex. It is involved in regulation of the catalytic protein Aurora B. It performs this function in association with two other proteins - Survivin and Borealin. These proteins form a tight three-helical bundle. The N-terminal domain of INCENP is the domain involved in formation of this three-helical bundle.
# Interactions
INCENP has been shown to interact with H2AFZ, Survivin and CDCA8. The ARK binding region has been found to be necessary and sufficient for binding to aurora-related kinase. This interaction has been implicated in the coordination of chromosome segregation with cell division in yeast. | INCENP
Inner centromere protein is a protein that in humans is encoded by the INCENP gene.[1][2][3]
In mammalian cells, two broad groups of centromere-interacting proteins have been described: constitutively binding centromere proteins and 'passenger' (or transiently interacting) proteins.[4] The constitutive proteins include CENPA (centromere protein A), CENPB, CENPC1, and CENPD.
The term 'passenger proteins' encompasses a broad collection of proteins that localize to the centromere during specific stages of the cell cycle.[5] These include CENPE; MCAK; KID; cytoplasmic dynein (e.g., DYNC1H1); CliPs (e.g. CLIP1); and CENPF/mitosin (CENPF). The inner centromere proteins (INCENPs),[1] the initial members of the passenger protein group, display a broad localization along chromosomes in the early stages of mitosis but gradually become concentrated at centromeres as the cell cycle progresses into mid-metaphase. During telophase, the proteins are located within the midbody in the intercellular bridge, where they are discarded after cytokinesis.[3][6]
INCENP is a regulatory protein in the chromosome passenger complex. It is involved in regulation of the catalytic protein Aurora B. It performs this function in association with two other proteins - Survivin and Borealin. These proteins form a tight three-helical bundle. The N-terminal domain of INCENP is the domain involved in formation of this three-helical bundle.[7]
# Interactions
INCENP has been shown to interact with H2AFZ,[8] Survivin[9] and CDCA8.[10] The ARK binding region has been found to be necessary and sufficient for binding to aurora-related kinase. This interaction has been implicated in the coordination of chromosome segregation with cell division in yeast.[11] | https://www.wikidoc.org/index.php/INCENP | |
a92cba69d7dbba654a2927ce0a8a07ce326b97bb | wikidoc | INPP5D | INPP5D
Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 is an enzyme that in humans is encoded by the INPP5D gene.
# Function
This gene is a member of the inositol polyphosphate-5-phosphatase (INPP5) family and encodes a protein with an N-terminal SH2 domain, an inositol phosphatase domain, and two C-terminal protein interaction domains. Expression of this protein is restricted to hematopoietic cells where its movement from the cytosol to the plasma membrane is mediated by tyrosine phosphorylation. At the plasma membrane, the protein hydrolyzes the 5' phosphate from phosphatidylinositol (3,4,5)-trisphosphate and inositol-1,3,4,5-tetrakisphosphate, thereby affecting multiple signaling pathways. Overall, the protein functions as a negative regulator of myeloid cell proliferation and survival. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.
# Interactions
INPP5D has been shown to interact with DOK2, LYN, CD22, Grb2, CRKL, CD31, DOK1 and SHC1.
# Medicines
Rosiptor (AQX-1125) is an INPP5D activator that is under development as an anti-inflammatory drug. | INPP5D
Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 is an enzyme that in humans is encoded by the INPP5D gene.[1][2][3]
# Function
This gene is a member of the inositol polyphosphate-5-phosphatase (INPP5) family and encodes a protein with an N-terminal SH2 domain, an inositol phosphatase domain, and two C-terminal protein interaction domains. Expression of this protein is restricted to hematopoietic cells where its movement from the cytosol to the plasma membrane is mediated by tyrosine phosphorylation. At the plasma membrane, the protein hydrolyzes the 5' phosphate from phosphatidylinositol (3,4,5)-trisphosphate and inositol-1,3,4,5-tetrakisphosphate, thereby affecting multiple signaling pathways. Overall, the protein functions as a negative regulator of myeloid cell proliferation and survival. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[3]
# Interactions
INPP5D has been shown to interact with DOK2,[4] LYN,[5] CD22,[6] Grb2,[7] CRKL,[8] CD31,[9] DOK1[4][10] and SHC1.[1][4][11][12][13]
# Medicines
Rosiptor (AQX-1125) is an INPP5D activator that is under development as an anti-inflammatory drug.[14][15] | https://www.wikidoc.org/index.php/INPP5D | |
5557e92bd1b4de7b8f42e1ec0c4cde2fde438c6b | wikidoc | INSIG2 | INSIG2
Insulin induced gene 2, also known as INSIG2, is a protein which in humans is encoded by the INSIG2 gene.
# Regulation
Insulin activates the human INSIG2 promoter in a process mediated by phosphorylated SAP1a.
Akt mediates suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2.
MCHR2 has been observed to significantly decrease INSIG2.
Insig2 is upregulated under hypoxic conditions and is associated with the malignant potential of pancreatic cancer.
A novel 1alpha,25-dihydroxyvitamin D3 response element in the promoter region of Insig-2 gene was identified which specifically binds to the heterodimer of retinoid X receptor and vitamin D receptor (VDR) and directs VDR-mediated transcriptional activation in a 1,25-(OH)2D3-dependent manner. 1,25-(OH)2D3 transiently but strongly induces Insig-2 expression in 3T3-L1 cells. This novel regulatory circuit may also play important roles in other lipogenic cell types that express VDR.
# Function
The protein encoded by this gene is highly similar to the protein product encoded by gene INSIG1. Both INSIG1 protein and this protein are endoplasmic reticulum proteins that block the processing of sterol regulatory element binding proteins (SREBPs) by binding to SREBP cleavage-activating protein (SCAP), and thus prevent SCAP from escorting SREBPs to the Golgi.
# Clinical Significance
Insig deficiency in mice caused a marked buildup of cholesterol precursors in skin associated with a marked increase in 3-hydroxy-3-methylglutaryl coenzyme A reductase protein and hair and skin defects corrected by topical simvastatin, an inhibitor of reductase.
REV-ERBalpha participates in the circadian modulation of sterol regulatory element-binding protein (SREBP) activity, and thereby in the daily expression of SREBP target genes involved in cholesterol and lipid metabolism. This control is exerted via the cyclic transcription of Insig2, encoding a trans-membrane protein that sequesters SREBP proteins to the endoplasmic reticulum membranes and thereby interferes with the proteolytic activation of SREBPs in Golgi membranes. REV-ERBalpha also participates in the cyclic expression of cholesterol-7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in converting cholesterol to bile acids. Findings suggest that this control acts via the stimulation of LXR nuclear receptors by cyclically produced oxysterols such that rhythmic cholesterol and bile acid metabolism is not just driven by alternating feeding-fasting cycles, but also by REV-ERBalpha, a component of the circadian clockwork circuitry.
Silibinin inhibits adipocyte differentiation through a potential up-regulation of insig-1 and insig-2 at an early phase in adipocyte differentiation.
The triacylglycerol reducing effect of fibrates and thiazolidinediones, strong and selective agonists of PPARalpha and PPARgamma, is partially caused by inhibition of SREBP-1 activation via up-regulation of Insig.
Findings suggest that Insig2 is a novel colon cancer biomarker. Over-expression of Insig2 appeared to suppress chemotherapeutic drug treatment-induced Bcl2 associated X protein (Bax) expression and activation. Insig2 was also found to localize to the mitochondria/heavy membrane fraction and associate with conformationally changed Bax. Moreover, Insig2 altered the expression of several additional apoptosis genes located in mitochondria. In a study by Kumar et al., the common polymorphisms in INSIG2 gene was not found to be significant in Indian population. | INSIG2
Insulin induced gene 2, also known as INSIG2, is a protein which in humans is encoded by the INSIG2 gene.[1][2]
# Regulation
Insulin activates the human INSIG2 promoter in a process mediated by phosphorylated SAP1a.[3]
Akt mediates suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2.[4]
MCHR2 has been observed to significantly decrease INSIG2.[5]
Insig2 is upregulated under hypoxic conditions and is associated with the malignant potential of pancreatic cancer.[6]
A novel 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] response element in the promoter region of Insig-2 gene was identified which specifically binds to the heterodimer of retinoid X receptor and vitamin D receptor (VDR) and directs VDR-mediated transcriptional activation in a 1,25-(OH)2D3-dependent manner. 1,25-(OH)2D3 transiently but strongly induces Insig-2 expression in 3T3-L1 cells. This novel regulatory circuit may also play important roles in other lipogenic cell types that express VDR.[7]
# Function
The protein encoded by this gene is highly similar to the protein product encoded by gene INSIG1. Both INSIG1 protein and this protein are endoplasmic reticulum proteins that block the processing of sterol regulatory element binding proteins (SREBPs) by binding to SREBP cleavage-activating protein (SCAP), and thus prevent SCAP from escorting SREBPs to the Golgi.[2]
# Clinical Significance
Insig deficiency in mice caused a marked buildup of cholesterol precursors in skin associated with a marked increase in 3-hydroxy-3-methylglutaryl coenzyme A reductase protein and hair and skin defects corrected by topical simvastatin, an inhibitor of reductase.[8]
REV-ERBalpha participates in the circadian modulation of sterol regulatory element-binding protein (SREBP) activity, and thereby in the daily expression of SREBP target genes involved in cholesterol and lipid metabolism. This control is exerted via the cyclic transcription of Insig2, encoding a trans-membrane protein that sequesters SREBP proteins to the endoplasmic reticulum membranes and thereby interferes with the proteolytic activation of SREBPs in Golgi membranes. REV-ERBalpha also participates in the cyclic expression of cholesterol-7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in converting cholesterol to bile acids. Findings suggest that this control acts via the stimulation of LXR nuclear receptors by cyclically produced oxysterols such that rhythmic cholesterol and bile acid metabolism is not just driven by alternating feeding-fasting cycles, but also by REV-ERBalpha, a component of the circadian clockwork circuitry.[9]
Silibinin inhibits adipocyte differentiation through a potential up-regulation of insig-1 and insig-2 at an early phase in adipocyte differentiation.[10]
The triacylglycerol reducing effect of fibrates and thiazolidinediones, strong and selective agonists of PPARalpha and PPARgamma, is partially caused by inhibition of SREBP-1 activation via up-regulation of Insig.[11]
Findings suggest that Insig2 is a novel colon cancer biomarker. Over-expression of Insig2 appeared to suppress chemotherapeutic drug treatment-induced Bcl2 associated X protein (Bax) expression and activation. Insig2 was also found to localize to the mitochondria/heavy membrane fraction and associate with conformationally changed Bax. Moreover, Insig2 altered the expression of several additional apoptosis genes located in mitochondria.[12] In a study by Kumar et al., the common polymorphisms in INSIG2 gene was not found to be significant in Indian population.[13] | https://www.wikidoc.org/index.php/INSIG2 | |
316676873ed6bed2361c0e47df0a8907449b013b | wikidoc | INTS12 | INTS12
Integrator complex subunit 12 (Int12) also known as PHD finger protein 22 (PHF22) is a protein that in humans is encoded by the INTS12 gene.
INTS12 is a subunit of the Integrator complex, which associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A) and mediates 3-prime end processing of small nuclear RNAs U1 (RNU1) and U2 (RNU2)
# Model organisms
Model organisms have been used in the study of INTS12 function. A conditional knockout mouse line, called Ints12tm1a(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 seven tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals. | INTS12
Integrator complex subunit 12 (Int12) also known as PHD finger protein 22 (PHF22) is a protein that in humans is encoded by the INTS12 gene.[1]
INTS12 is a subunit of the Integrator complex, which associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A) and mediates 3-prime end processing of small nuclear RNAs U1 (RNU1) and U2 (RNU2)[1][2]
# Model organisms
Model organisms have been used in the study of INTS12 function. A conditional knockout mouse line, called Ints12tm1a(EUCOMM)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 seven tests were carried out on mutant mice and two significant abnormalities were observed.[5] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.[5] | https://www.wikidoc.org/index.php/INTS12 | |
aeb2cd748cb99386f7eaa974f2970eb1a58fa176 | wikidoc | IQGAP1 | IQGAP1
Ras GTPase-activating-like protein IQGAP1 (IQGAP1) also known as p195 is a ubiquitously expressed protein that in humans is encoded by the IQGAP1 gene. IQGAP1 is a scaffold protein involved in regulating various cellular processes ranging from organization of the actin cytoskeleton, transcription, and cellular adhesion to regulating the cell cycle.
# History
IQGAP1 was discovered in 1994.
Its name stems from the fact that its RasGAP-related domain (GRD) has sequence homology to the Sar1 GTPase. It was hypothesized that IQGAP1 would act as a GTPase activating protein (GAP) protein, promoting the switch of ras GTPases from the active GTP to GDP-bound forms. However, despite the homology of IQGAP’s GAP domain to sar1 and the fact that IQGAP1 binds Rho GTPases Rac1 and Cdc42, IQGAP does not actually have GAP function. Instead, it binds the active (GTP-bound) forms of RAC1 and CDC42 with higher affinity than GDP-bound forms, and stabilizes the active form in vivo.
IQGAP1 is now recognized as a protein scaffold that integrates signals regulating cell adhesion, actin cytoskeleton, the cell cycle, and other cellular functions. IQGAP is particularly interesting as a therapeutic target since it acts as a node for so many signaling pathways implicated in cancer progression.
# Expression
Analysis of IQGAP1 expression in human tissues has indicated that the scaffold is more or less ubiquitously expressed. It is usually found in the nucleus, plasma membrane, and cytoplasm. In other words it is found throughout the cell as well as throughout tissue types. Expression analysis has also indicated that IQGAP1 is overexpressed in many cancers, and in more aggressive colorectal and ovarian cancers, IQGAP1 is localized at the invasive front of the neoplasm, indicating a role in mobilization of the cells. Importantly, approximately 10% of genes that show increased expression in metastatic cells are IQGAP1 binding partners.
# Domains
IQGAP1 is a 190 kDa protein with 5 domains. A protein domain is a subsection of a protein that shows up multiple times in biology and can exist independently of the surrounding protein. It is very similar to subsections of other proteins, and could be cut out of the current protein, exist and function by itself, or be pasted in to a new protein strand and still function properly. Since this area of the protein is conserved in amino acid sequence and structure, it can be characterized by function or binding partner. IQGAP1 has 5 well-known domains separated by other amino acids.
Starting at the N-terminus (or front of the protein), IQGAP1 contains a calponin homology domain (CHD), which mediates actin-binding and binds calponin.
The WW, or poly-proline protein-protein domain, so named because of two functionally conserved tryptophans, W, is a protein-protein interaction domain that associates with proline-rich regions of other proteins.
The WW domain is followed by 4 IQ motifs which form an IQ domain. This domain binds calmodulin, a protein known as a calcium sensor that can bind and regulate many target proteins.
A GRD (rasGAP-related domain) follows the IQ domain. This domain is highly similar to the functional subunit of Ras GTPase-activating proteins (GAPs) and was thus thought to have GAP function. IQGAP1 does bind Rho GTPases CDC42 and RAC1, however, IQGAP1 is unusual in that it actually has no GAP function, and instead stabilizes the GTP-bound proteins in their active state.
Finally, IQGAP1 has a RasGAP_c carboxy terminal sequence important for binding Beta-catenin and E-cadherin.
# Related Proteins
Homologues of IQGAP1 are known in species as divergent as yeast, worms, and humans (as well as other mammals), though the domains are not always highly conserved.
IQGAP1 is the most well studied member of the IQGAP family of scaffold proteins. The two other members of the family include IQGAP2 and IQGAP3 which have far more restricted expression patterns in comparison with IQGAP1. IQGAP2 is found in the liver, stomach, and platelets and is 62% identical to IQGAP1, but appears to have a drastically divergent function in terms of pathology.
In the brain, IQGAP3 appears to play an important role in neuronal morphogenesis.
# Function
This gene encodes a member of the IQGAP family. The protein contains four IQ domains, one calponin homology domain, one Ras-GAP domain and one WW domain. It interacts with components of the cytoskeleton such as the formin Dia1 (mDia1), with cell adhesion molecules (CAMs), and with several signaling molecules to regulate cell morphology and motility. For example, IQGAP1 expression is necessary for neuronal process outgrowth on the cell adhesion molecule PTPmu (PTPRM). Expression of the protein is upregulated by gene amplification in two gastric cancer cell lines and its over-expression and distinct membrane localisation is also observed in a range of tumours.
# Interactions
IQGAP1 is a node intersected by many signaling pathways. As such it has many binding partners, many of which have essential roles in control of the cell cycle and actin cytoskeleton.
IQGAP1 has been shown to interact with:
- Calmodulin 1,
- CDC42,
- CDH1,
- CLIP1,
- PRKACA,
- RAC1, and
- S100B.
- Actin – cytoskeletal structure
- ARF6
- APC
- Beta-catenin–cell adhesion and WNT signaling: transcription
- B-raf – MAPK pathway
- CD44
- Erk1/2 – MAPK pathway, cell cycle control, proliferation
- Mek ½ -- MAPK pathway, cell cycle control, proliferation
- Src
- PTPmu (PTPRM)
- complete list at
# Function as a Scaffold
Protein binding does not by itself construct an interesting story. Far more important is the outcome of the binding event. Does binding change the target protein’s localization? Does it activate the target, or in some way change the target (or effector molecule’s) conformation? As a scaffolding protein, IQGAP1 binds and regulates many targets—its role is to integrate and mediate signaling from diverse pathways and insulate key pathway members from crosstalk.
Scaffolds organize signaling pathways—help regulate how various extracellular signals can be transduced by the same canonical pathway members into various cellular outputs. Generally, scaffolds regulate output, localization, and selectivity of pathways.
As a scaffold involved in different signaling pathways (actin cytoskeleton, cellular adhesion, cell cycle, transcription), IQGAP1 has a unique ability to potentially couple diverse cellular functions. For example IQGAP1 is associated with actin dynamics through direct binding of actin and indirect regulation via Cdc42/Rac1, but also modulates the MAPK pathway which is associated with cell cycle control. Thus IQGAP1 may couple MAPK signaling (decisions about cell fate) to the cytoskeleton or cellular adhesion (potentially acting out those decisions)—an important implication for cancer.
To simplify, due to its diverse range of binding partners, IQGAP1 may act as a link between logically related but molecularly distinct cellular functions. In the above example, actin cytoskeleton rearrangement is required for proliferation (cytokinesis during mitosis). IQGAP1 helps cells both listen to and act on signals, playing an integral role in connecting the dots between signals for proliferation and the actual cellular response.
# Key pathways
## ERK MAPK
The Ras→Raf→MEK→ERK MAPK signaling pathway plays an integral part in the processes of cell proliferation, differentiation, and apoptosis. This pathway is conserved across all eukaryotes.
Various extracellular signals induce the ERK MAPK pathway including EGF, IGF-1, PDGF, and NGF. The various scaffolds of this pathway, including IQGAP1, are responsible for modulating the cellular response to the activity of this pathway. For instance, in a given cell line, activation by one extracellular signal may induce differentiation but not proliferation, while activation of the same ERK MAPK pathway by a different extracellular signal will induce proliferation but not differentiation. IQGAP1 seems to be responsible for the specific output of the pathway upon activation by EGF.
IQGAP1 plays a significant role in the propagation of this MAPK signaling pathway. IQGAP directly binds b-RAF, MEK1/2 and ERK1/2, and is in fact necessary for the phosphorylation (activation) of ERK upon stimulation by EGF.
## Cytoskeletal control (actin dynamics)
Actin is a major building block of every eukaryotic cell’s cytoskeleton. Actin dynamics play a major role in cell motility (filaments are built at the leading edge of a moving cell and deconstructed at the receding edge). IQGAP1 binds actin and influences actin dynamics by localizing to the leading edge and recruiting actin polymerization machinery.
IQGAP1 binds and is a target of the Rho GTPases CDC42 and RAC1 which are well known regulators of the actin cytoskeleton. Despite its name, IQGAP1 does not have GAP function, and instead stabilizes active Cdc42. This increase in a local pool of active Cdc42 stimulates actin filament formation and thus filopodia formation.
IQGAP1 can crosslink actin, and in many organisms, IQGAP1 is involved in cytokinesis.
## Adhesion
Cadherins are a family of adhesion proteins that localize to the cell surface where they anchor a cell to its neighbors by clasping on to the extracellular portion of the neighbor’s cadherins. Actin binds a-catenin which binds beta-catenin which in turn binds E-cadherin. E-cadherin juts into the extracellular space to grasp the extracellular domains of neighboring E-cadherins. IQGAP1 localizes to cell-cell contacts and binds actin, b-catenin, and E-cadherin, weakening these junctions and thus decreasing cell-cell adhesion. IQGAP weakens cell adhesion by displacing a-catenin from the complex.
Active RAC1 binds IQGAP1 to crosslink actin filaments and prevents IQGAP1 from interacting with beta-catenin, stabilizing cell-cell contacts. When IQGAP1 does not bind Rac1, however, it binds beta-catenin, displacing a-catenin from the cadherin-catenin cellular adhesion complex.
## Transcription
IQGAP1 also affects transcription through the Wnt signaling pathway by its interaction with beta-catenin. Beta-catenin is usually sequestered in a complex and excluded from the nucleus, but upon WNT activation this complex is broken and beta-catenin translocates to the nucleus where it activates transcriptional programs. IQGAP1 binds b-catenin and increases nuclear localization and expression of beta-catenin’s transcriptional targets.
# Clinical significance
IQGAP1 is associated with cytoskeletal dynamics, transcription, cell adhesion, cell cycle, and morphology, all of which are disrupted in cancer. As a modulatory protein intersecting all of these pathways, IQGAP1 can couple many of them, and is also responsible for their proper propagation. Since cancer is a disease characterized by the perturbation of many of these cellular processes, IQGAP1 is a logical oncogene candidate and therapeutic target.
Expression analysis has implicated IQGAP1 in colorectal, squamous cell, breast, gastric, liver, lung, and ovarian cancers, and in some of these cancers, higher IQGAP1 expression levels indicate a poor prognosis.
In order for a cancer to metastasize, cells must gain migratory abilities and invade other tissues. Through Rac1/CDC42, IQGAP1 regulates cellular adhesion and actin dynamics.
In normal cells IQGAP1 localizes to areas of high actin turnover. This characteristic is echoed in invasive tissues, where IQGAP1 localizes to the leading edge of migrating cells. Over-expression of IQGAP1 was associated with increased migration and invasion in a human breast epithelial cancer cell line (MCF-7 cells). IQGAP1 may also be involved in the deregulation of proliferation and differentiation through its modulation of the ERK MAPK pathway.
IQGAP1 may be necessary for tumorigenesis. IQGAP1 knockdown in MCF-7 cancer cells reduced the malignant phenotype (serum-dependent proliferation and anchorage independent growth). 100% of mice injected with MCF-7 cells overexpressing IQGAP1 developed tumors and these tumors were highly invasive. Control MCF-7 cells formed tumors in 60% of the mice, and MCF-7 cells with stable knockdown of IQGAP1 only formed tumors 20% of the time. The mechanism for how IQGAP1 may modulate tumorigenesis/invasion through its various binding partners is of great interest.
IQGAP1 null mice appear significantly normal, with the only life history abnormality being an increase in gastric hyperplasia. Thus, IQGAP1 may be an effective therapeutic target, if its knockdown has little effect in homeostatic tissue but its expression is important in cancer. | IQGAP1
Ras GTPase-activating-like protein IQGAP1 (IQGAP1) also known as p195 is a ubiquitously expressed protein that in humans is encoded by the IQGAP1 gene.[1][2][3] IQGAP1 is a scaffold protein involved in regulating various cellular processes ranging from organization of the actin cytoskeleton, transcription, and cellular adhesion to regulating the cell cycle.
# History
IQGAP1 was discovered in 1994.[1]
Its name stems from the fact that its RasGAP-related domain (GRD) has sequence homology to the Sar1 GTPase.[4] It was hypothesized that IQGAP1 would act as a GTPase activating protein (GAP) protein, promoting the switch of ras GTPases from the active GTP to GDP-bound forms. However, despite the homology of IQGAP’s GAP domain to sar1 and the fact that IQGAP1 binds Rho GTPases Rac1 and Cdc42, IQGAP does not actually have GAP function. Instead, it binds the active (GTP-bound) forms of RAC1 and CDC42 with higher affinity than GDP-bound forms, and stabilizes the active form in vivo.[5]
IQGAP1 is now recognized as a protein scaffold that integrates signals regulating cell adhesion, actin cytoskeleton, the cell cycle,[5] and other cellular functions. IQGAP is particularly interesting as a therapeutic target since it acts as a node for so many signaling pathways implicated in cancer progression.
# Expression
Analysis of IQGAP1 expression in human tissues has indicated that the scaffold is more or less ubiquitously expressed.[6] It is usually found in the nucleus, plasma membrane, and cytoplasm. In other words it is found throughout the cell as well as throughout tissue types. Expression analysis has also indicated that IQGAP1 is overexpressed in many cancers, and in more aggressive colorectal and ovarian cancers, IQGAP1 is localized at the invasive front of the neoplasm, indicating a role in mobilization of the cells.[4] Importantly, approximately 10% of genes that show increased expression in metastatic cells are IQGAP1 binding partners.[4]
# Domains
IQGAP1 is a 190 kDa protein with 5 domains.[5] A protein domain is a subsection of a protein that shows up multiple times in biology and can exist independently of the surrounding protein. It is very similar to subsections of other proteins, and could be cut out of the current protein, exist and function by itself, or be pasted in to a new protein strand and still function properly. Since this area of the protein is conserved in amino acid sequence and structure, it can be characterized by function or binding partner. IQGAP1 has 5 well-known domains separated by other amino acids.
Starting at the N-terminus (or front of the protein), IQGAP1 contains a calponin homology domain (CHD), which mediates actin-binding[7] and binds calponin.
The WW, or poly-proline protein-protein domain, so named because of two functionally conserved tryptophans, W, is a protein-protein interaction domain that associates with proline-rich regions of other proteins.[8][9]
The WW domain is followed by 4 IQ motifs which form an IQ domain. This domain binds calmodulin,[10] a protein known as a calcium sensor that can bind and regulate many target proteins.[11]
A GRD (rasGAP-related domain) follows the IQ domain. This domain is highly similar to the functional subunit of Ras GTPase-activating proteins (GAPs) and was thus thought to have GAP function. IQGAP1 does bind Rho GTPases CDC42 and RAC1, however, IQGAP1 is unusual in that it actually has no GAP function, and instead stabilizes the GTP-bound proteins in their active state.[12]
Finally, IQGAP1 has a RasGAP_c carboxy terminal sequence important for binding Beta-catenin and E-cadherin.[5]
# Related Proteins
Homologues of IQGAP1 are known in species as divergent as yeast, worms, and humans (as well as other mammals), though the domains are not always highly conserved.[5]
IQGAP1 is the most well studied member of the IQGAP family of scaffold proteins. The two other members of the family include IQGAP2 and IQGAP3 which have far more restricted expression patterns in comparison with IQGAP1. IQGAP2 is found in the liver, stomach, and platelets and is 62% identical to IQGAP1,[5] but appears to have a drastically divergent function in terms of pathology.[13]
In the brain, IQGAP3 appears to play an important role in neuronal morphogenesis.[14]
# Function
This gene encodes a member of the IQGAP family. The protein contains four IQ domains, one calponin homology domain, one Ras-GAP domain and one WW domain. It interacts with components of the cytoskeleton[15] such as the formin Dia1 (mDia1),[16] with cell adhesion molecules (CAMs), and with several signaling molecules to regulate cell morphology and motility. For example, IQGAP1 expression is necessary for neuronal process outgrowth on the cell adhesion molecule PTPmu (PTPRM).[17] Expression of the protein is upregulated by gene amplification in two gastric cancer cell lines[3] and its over-expression and distinct membrane localisation is also observed in a range of tumours.[18]
# Interactions
IQGAP1 is a node intersected by many signaling pathways. As such it has many binding partners, many of which have essential roles in control of the cell cycle and actin cytoskeleton.
IQGAP1 has been shown to interact with:
- Calmodulin 1,[19][20]
- CDC42,[2][21][22][23][24]
- CDH1,[25]
- CLIP1,[22]
- PRKACA,[26]
- RAC1,[2][21][22][24] and
- S100B.[27]
- Actin – cytoskeletal structure
- ARF6
- APC
- Beta-catenin–cell adhesion and WNT signaling: transcription
- B-raf – MAPK pathway
- CD44
- Erk1/2 – MAPK pathway, cell cycle control, proliferation
- Mek ½ -- MAPK pathway, cell cycle control, proliferation
- Src
- PTPmu (PTPRM)[17]
- complete list at [28]
# Function as a Scaffold
Protein binding does not by itself construct an interesting story. Far more important is the outcome of the binding event. Does binding change the target protein’s localization? Does it activate the target, or in some way change the target (or effector molecule’s) conformation? As a scaffolding protein, IQGAP1 binds and regulates many targets—its role is to integrate and mediate signaling from diverse pathways and insulate key pathway members from crosstalk.
Scaffolds organize signaling pathways—help regulate how various extracellular signals can be transduced by the same canonical pathway members into various cellular outputs.[29] Generally, scaffolds regulate output, localization, and selectivity of pathways.[30]
As a scaffold involved in different signaling pathways (actin cytoskeleton, cellular adhesion, cell cycle, transcription), IQGAP1 has a unique ability to potentially couple diverse cellular functions. For example IQGAP1 is associated with actin dynamics through direct binding of actin and indirect regulation via Cdc42/Rac1, but also modulates the MAPK pathway which is associated with cell cycle control. Thus IQGAP1 may couple MAPK signaling (decisions about cell fate) to the cytoskeleton or cellular adhesion (potentially acting out those decisions)—an important implication for cancer.
To simplify, due to its diverse range of binding partners, IQGAP1 may act as a link between logically related but molecularly distinct cellular functions. In the above example, actin cytoskeleton rearrangement is required for proliferation (cytokinesis during mitosis). IQGAP1 helps cells both listen to and act on signals, playing an integral role in connecting the dots between signals for proliferation and the actual cellular response.
# Key pathways
## ERK MAPK
The Ras→Raf→MEK→ERK MAPK signaling pathway plays an integral part in the processes of cell proliferation, differentiation, and apoptosis. This pathway is conserved across all eukaryotes.
Various extracellular signals induce the ERK MAPK pathway including EGF, IGF-1, PDGF, and NGF.[29] The various scaffolds of this pathway, including IQGAP1, are responsible for modulating the cellular response to the activity of this pathway. For instance, in a given cell line, activation by one extracellular signal may induce differentiation but not proliferation, while activation of the same ERK MAPK pathway by a different extracellular signal will induce proliferation but not differentiation.[29] IQGAP1 seems to be responsible for the specific output of the pathway upon activation by EGF.
IQGAP1 plays a significant role in the propagation of this MAPK signaling pathway. IQGAP directly binds b-RAF,[31] MEK1/2 and ERK1/2, and is in fact necessary for the phosphorylation (activation) of ERK upon stimulation by EGF.[32][33]
## Cytoskeletal control (actin dynamics)
Actin is a major building block of every eukaryotic cell’s cytoskeleton. Actin dynamics play a major role in cell motility (filaments are built at the leading edge of a moving cell and deconstructed at the receding edge). IQGAP1 binds actin and influences actin dynamics by localizing to the leading edge and recruiting actin polymerization machinery.[4][5][15]
IQGAP1 binds and is a target of the Rho GTPases CDC42 and RAC1 which are well known regulators of the actin cytoskeleton.[34][35] Despite its name, IQGAP1 does not have GAP function, and instead stabilizes active Cdc42. This increase in a local pool of active Cdc42 stimulates actin filament formation and thus filopodia formation.[5]
IQGAP1 can crosslink actin,[36] and in many organisms, IQGAP1 is involved in cytokinesis.[37]
## Adhesion
Cadherins are a family of adhesion proteins that localize to the cell surface where they anchor a cell to its neighbors by clasping on to the extracellular portion of the neighbor’s cadherins. Actin binds a-catenin which binds beta-catenin which in turn binds E-cadherin. E-cadherin juts into the extracellular space to grasp the extracellular domains of neighboring E-cadherins. IQGAP1 localizes to cell-cell contacts and binds actin, b-catenin, and E-cadherin, weakening these junctions and thus decreasing cell-cell adhesion.[5][38] IQGAP weakens cell adhesion by displacing a-catenin from the complex.[39]
Active RAC1 binds IQGAP1 to crosslink actin filaments and prevents IQGAP1 from interacting with beta-catenin, stabilizing cell-cell contacts.[40] When IQGAP1 does not bind Rac1, however, it binds beta-catenin, displacing a-catenin from the cadherin-catenin cellular adhesion complex.
## Transcription
IQGAP1 also affects transcription through the Wnt signaling pathway by its interaction with beta-catenin.[4] Beta-catenin is usually sequestered in a complex and excluded from the nucleus, but upon WNT activation this complex is broken and beta-catenin translocates to the nucleus where it activates transcriptional programs. IQGAP1 binds b-catenin and increases nuclear localization and expression of beta-catenin’s transcriptional targets.
# Clinical significance
IQGAP1 is associated with cytoskeletal dynamics, transcription, cell adhesion, cell cycle, and morphology, all of which are disrupted in cancer. As a modulatory protein intersecting all of these pathways, IQGAP1 can couple many of them, and is also responsible for their proper propagation. Since cancer is a disease characterized by the perturbation of many of these cellular processes, IQGAP1 is a logical oncogene candidate and therapeutic target.
Expression analysis has implicated IQGAP1 in colorectal, squamous cell, breast, gastric, liver, lung, and ovarian cancers,[41] and in some of these cancers, higher IQGAP1 expression levels indicate a poor prognosis.[42]
In order for a cancer to metastasize, cells must gain migratory abilities and invade other tissues. Through Rac1/CDC42, IQGAP1 regulates cellular adhesion and actin dynamics.
In normal cells IQGAP1 localizes to areas of high actin turnover. This characteristic is echoed in invasive tissues, where IQGAP1 localizes to the leading edge of migrating cells.[4] Over-expression of IQGAP1 was associated with increased migration and invasion in a human breast epithelial cancer cell line (MCF-7 cells).[4][43] IQGAP1 may also be involved in the deregulation of proliferation and differentiation through its modulation of the ERK MAPK pathway.
IQGAP1 may be necessary for tumorigenesis. IQGAP1 knockdown in MCF-7 cancer cells reduced the malignant phenotype (serum-dependent proliferation and anchorage independent growth). 100% of mice injected with MCF-7 cells overexpressing IQGAP1 developed tumors and these tumors were highly invasive. Control MCF-7 cells formed tumors in 60% of the mice, and MCF-7 cells with stable knockdown of IQGAP1 only formed tumors 20% of the time.[43] The mechanism for how IQGAP1 may modulate tumorigenesis/invasion through its various binding partners is of great interest.
IQGAP1 null mice appear significantly normal, with the only life history abnormality being an increase in gastric hyperplasia.[44] Thus, IQGAP1 may be an effective therapeutic target, if its knockdown has little effect in homeostatic tissue but its expression is important in cancer. | https://www.wikidoc.org/index.php/IQGAP1 | |
03b3b7c19aa1d8fe8d0e6b7cae59659405cf3020 | wikidoc | IQSEC1 | IQSEC1
IQ motif and SEC7 domain-containing protein 1 also known as ARF-GEP100 (ADP-Ribosylation Factor - Guanine nucleotide-Exchange Protein - 100-kDa) is a protein that in humans is encoded by the IQSEC1 gene.
# Function
The ARF-GEP100 protein is involved in signal transduction. It is a guanine nucleotide exchange factor that promotes binding of GTP to ADP ribosylation factor protein ARF6 and to a lesser extent ARF1 and ARF5. This activates the ADP-ribosylation activity of the target protein and cause it to modify its substrates. ARF-GEP100, through activation of ARF6, is therefore involved in the control of processes such as endocytosis of plasma membrane proteins, E-cadherin recycling and actin cytoskeleton remodeling. ARF-GEP100 appears particularly important in regulating cell adhesion, with reductions in the level of this protein causing enhanced spreading and attachment of cells.
It is highly expressed in the prefrontal cortex, and throughout the rest of the brain, and is believed to have a role in learning and memory, having been detected as phosphorylated in a phospho screen of the PSD. | IQSEC1
IQ motif and SEC7 domain-containing protein 1 also known as ARF-GEP100 (ADP-Ribosylation Factor - Guanine nucleotide-Exchange Protein - 100-kDa) is a protein that in humans is encoded by the IQSEC1 gene.[1][2]
# Function
The ARF-GEP100 protein is involved in signal transduction. It is a guanine nucleotide exchange factor that promotes binding of GTP to ADP ribosylation factor protein ARF6 and to a lesser extent ARF1 and ARF5.[2] This activates the ADP-ribosylation activity of the target protein and cause it to modify its substrates. ARF-GEP100, through activation of ARF6, is therefore involved in the control of processes such as endocytosis of plasma membrane proteins, E-cadherin recycling and actin cytoskeleton remodeling.[3] ARF-GEP100 appears particularly important in regulating cell adhesion, with reductions in the level of this protein causing enhanced spreading and attachment of cells.[4]
It is highly expressed in the prefrontal cortex, and throughout the rest of the brain, and is believed to have a role in learning and memory, having been detected as phosphorylated in a phospho screen of the PSD.[5] | https://www.wikidoc.org/index.php/IQSEC1 | |
166678b414f1235c752d91e4b39ebf29ea7d4eb1 | wikidoc | IQSEC3 | IQSEC3
IQSEC3 is a human gene, known as IQ motif and Sec7 domain 3.
It contains an IQ domain, followed by a SEC7 and then a PH. It functions as an ARF-GEF for the ARF family of GTPases, which is to say that it causes GDP to release, and GTP to bind, thereby activating the ARF protein.
It is highly expressed in the brain, particularly in the amygdala, and is known to have a role in learning.
In a largescale phospho screening of the PSD, it was found to be phosphorylated following activation of the NMDAR complex.
IQSEC3 was originally known as 'KIAA1110', under which name it was found to act as a GEF for Arf1 but not Arf6. It is related to the other Arf-GEF protein IQSEC1. | IQSEC3
IQSEC3 is a human gene, known as IQ motif and Sec7 domain 3.[1]
It contains an IQ domain, followed by a SEC7 and then a PH. It functions as an ARF-GEF for the ARF family of GTPases, which is to say that it causes GDP to release, and GTP to bind, thereby activating the ARF protein.
It is highly expressed in the brain, particularly in the amygdala, and is known to have a role in learning.
In a largescale phospho screening of the PSD, it was found to be phosphorylated following activation of the NMDAR complex.[2]
IQSEC3 was originally known as 'KIAA1110', under which name it was found to act as a GEF for Arf1 but not Arf6.[3] It is related to the other Arf-GEF protein IQSEC1. | https://www.wikidoc.org/index.php/IQSEC3 | |
6c7869efa3a080b37be3a23b8d4042c5ab142c04 | wikidoc | ITGA11 | ITGA11
Integrin alpha-11 is a protein that, in humans, is encoded by the ITGA11 gene.
This gene encodes an alpha integrin. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. This protein contains an I domain, is expressed in muscle tissue, dimerizes with beta 1 integrin in vitro, and appears to bind collagen in this form. Therefore, the protein may be involved in attaching muscle tissue to the extracellular matrix. Alternative transcriptional splice variants have been found for this gene, but their biological validity is not determined.
According to one study, ITGA11 expression is increased in the anterior stroma of corneal buttons excised from the eyes affected by keratoconus. | ITGA11
Integrin alpha-11 is a protein that, in humans, is encoded by the ITGA11 gene.[1][2]
This gene encodes an alpha integrin. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. This protein contains an I domain, is expressed in muscle tissue, dimerizes with beta 1 integrin in vitro, and appears to bind collagen in this form. Therefore, the protein may be involved in attaching muscle tissue to the extracellular matrix. Alternative transcriptional splice variants have been found for this gene, but their biological validity is not determined.[2]
According to one study, ITGA11 expression is increased in the anterior stroma of corneal buttons excised from the eyes affected by keratoconus.[3] | https://www.wikidoc.org/index.php/ITGA11 | |
22e14176db905353ffb7899ed9419d4e54dc160c | wikidoc | IZUMO1 | IZUMO1
Izumo sperm-egg fusion 1 is a protein that in humans is encoded by the IZUMO1 gene. In mammalian fertilisation, IZUMO1 binds to its egg receptor counterpart, Juno, to facilitate recognition and fusion of the gametes.
# Function
The sperm-specific protein Izumo, named for a Japanese shrine dedicated to marriage, is essential for sperm-egg plasma membrane binding and fusion.
Studies have shown that male Izumo knockout mice are sterile because their sperm are unable to fuse to the oocyte membrane. Izumo -/- mice produced morphologically normal sperm that were able to penetrate the zona pellucida, but could not fuse with to the eggs. In fact, it is necessary to relocate the IZUMO1 to the site of oocyte fusion . In-vitro human experiments have also been conducted, suggesting that Izumo is required for human gamete fusion.
Through the use of Western Blot analyses, it has been shown that Izumo is only expressed in the testis and is found on mature spermatozoa. Izumo-1 located on mature spermatozoa that have undergone capacitation binds to its receptor Juno, which is located on the oolemma of eggs. | IZUMO1
Izumo sperm-egg fusion 1 is a protein that in humans is encoded by the IZUMO1 gene.[1] In mammalian fertilisation, IZUMO1 binds to its egg receptor counterpart, Juno, to facilitate recognition and fusion of the gametes. [2]
# Function
The sperm-specific protein Izumo, named for a Japanese shrine dedicated to marriage, is essential for sperm-egg plasma membrane binding and fusion.[3]
Studies have shown that male Izumo knockout mice are sterile because their sperm are unable to fuse to the oocyte membrane.[1] Izumo -/- mice produced morphologically normal sperm that were able to penetrate the zona pellucida, but could not fuse with to the eggs. In fact, it is necessary to relocate the IZUMO1 to the site of oocyte fusion [4]. In-vitro human experiments have also been conducted, suggesting that Izumo is required for human gamete fusion. [1]
Through the use of Western Blot analyses, it has been shown that Izumo is only expressed in the testis and is found on mature spermatozoa. [5] Izumo-1 located on mature spermatozoa that have undergone capacitation binds to its receptor Juno, which is located on the oolemma of eggs. [6] | https://www.wikidoc.org/index.php/IZUMO1 | |
5d03a4c44a8fb2053c0b884f4230c07a79d9e8d8 | wikidoc | Ice Ih | Ice Ih
Ice Ih is the hexagonal crystal form of ordinary ice, or frozen water. Virtually all ice in the biosphere is ice Ih, with the exception only of a small amount of ice Ic which is occasionally present in the upper atmosphere. Ice Ih exhibits many peculiar properties which are relevant to the existence of life and regulation of global climate.
Ice Ih is stable down to −200 °C (Expression error: Missing operand for *. ) and can exist at pressures up to 0.2 GPa. The crystal structure is characterized by hexagonal symmetry and near tetrahedral bonding angles.
# Physical properties
Ice Ih has a density less than liquid water, of 0.917 g/cm³, due
to the extremely low density of its crystal lattice. The density of ice Ih increases with decreasing temperature (density of ice at -180 °C is 0.9340 g/cm³).
The latent heat of melting is 5987 J/mol, and its latent heat of sublimation is 50911 J/mol.
The high latent heat of sublimation is principally indicative of the strength of
the hydrogen bonds in the crystal lattice. The latent heat
-f melting is much smaller partly because water near 0 °C is very strongly
H-bonded already.
The refractive index of ice Ih is 1.31.
# Crystal structure
The accepted crystal structure of ordinary ice was first proposed by Linus Pauling in 1935. The structure of ice Ih is roughly one of crinkled planes composed of tessellating hexagonal rings, with an oxygen atom on each vertex, and the edges of the rings formed by hydrogen bonds. The planes alternate in an ABAB pattern, with B planes being reflections of the A planes along the same axes as the planes themselves. The distance between oxygen atoms along each bond is about 275 pm and is the same between any two bonded oxygen atoms in the lattice. The angle between bonds in the crystal lattice is very close to the tetrahedral angle of 109.5° which is also quite close to the angle between hydrogen atoms in the water molecule (in the gas phase), which is 105°. This tetrahedral bonding angle of the water molecule essentially accounts for the unusually low density of the crystal lattice -- it is beneficial for the lattice to be arranged with tetrahedral angles even though there is an energy penalty in the increased volume of the crystal lattice. As a result, the large hexagonal rings leave almost enough room for another water molecule to exist inside. This gives naturally occurring ice its unique property of being less dense than its liquid form. The tetrahedral-angled hydrogen-bonded hexagonal rings are also the mechanism which causes liquid water to be most dense at 4 °C. Close to 0 °C, tiny hexagonal ice Ih-like lattices form in liquid water, with greater frequency closer to 0 °C. This effect decreases the density of the water, causing it to be most dense at 4 °C when the structures form infrequently.
# Proton disorder
The protons (hydrogen atoms) in the crystal lattice lie very nearly along the
hydrogen bonds, and in such a way that each water molecule is preserved. This
means that each oxygen atom in the lattice has two protons adjacent to it, and
about 101 pm along the 275 pm length of the bond. The crystal
lattice allows a substantial amount of disorder in the positions of the protons
frozen into the structure as it cools to absolute zero. As a result,
the crystal structure contains some residual entropy inherent to the
lattice and determined by the number of possible configurations of proton
positions which can be formed while still maintaining the requirement for each oxygen atom to have
-nly two protons in closest proximity, and each H-bond joining two oxygen atoms having
-nly one proton. This residual entropy S0 is equal to 3.5 J mol−1 K−1. There are various ways of approximating
this number from first principles. Assuming a given N water
molecules each has 6 possible arrangements this yields 6N possible
combinations. Given random orientations of molecules, a given bond will have
-nly a ½ chance that it has exactly one proton, or in other words, each
molecule has a ¼ chance that its protons lie on bonds containing exactly one
proton, leaving a total number of (3/2)^N possible valid combinations.
Using Boltzmann's principle, we find that S_0 = Nk
\ln(3/2), where k is Boltzmann's Constant, which yields a value of 3.37 J mol−1 K−1, a value very close to the measured value. More complex
methods can be employed to better approximate the exact number of possible
configurations, and achieve results closer to measured values.
By contrast, the structure of ice II is very proton-ordered, which helps to explain the entropy change of 3.22 J/mol when the crystal structure changes to that of ice II. Also, ice XI, an orthorhombic, proton-ordered form of ice Ih, is considered the most stable form.
# Notes
- ↑ For a description of these properties, see Ice, which deals primarily with Ice Ih. | Ice Ih
Template:Downsize
Ice Ih is the hexagonal crystal form of ordinary ice, or frozen water. Virtually all ice in the biosphere is ice Ih, with the exception only of a small amount of ice Ic which is occasionally present in the upper atmosphere. Ice Ih exhibits many peculiar properties which are relevant to the existence of life and regulation of global climate.[1]
Ice Ih is stable down to −200 °C (Expression error: Missing operand for *. ) and can exist at pressures up to 0.2 GPa. The crystal structure is characterized by hexagonal symmetry and near tetrahedral bonding angles.
# Physical properties
Ice Ih has a density less than liquid water, of 0.917 g/cm³, due
to the extremely low density of its crystal lattice. The density of ice Ih increases with decreasing temperature (density of ice at -180 °C is 0.9340 g/cm³).
The latent heat of melting is 5987 J/mol, and its latent heat of sublimation is 50911 J/mol.
The high latent heat of sublimation is principally indicative of the strength of
the hydrogen bonds in the crystal lattice. The latent heat
of melting is much smaller partly because water near 0 °C is very strongly
H-bonded already.
The refractive index of ice Ih is 1.31.
# Crystal structure
The accepted crystal structure of ordinary ice was first proposed by Linus Pauling in 1935. The structure of ice Ih is roughly one of crinkled planes composed of tessellating hexagonal rings, with an oxygen atom on each vertex, and the edges of the rings formed by hydrogen bonds. The planes alternate in an ABAB pattern, with B planes being reflections of the A planes along the same axes as the planes themselves. The distance between oxygen atoms along each bond is about 275 pm and is the same between any two bonded oxygen atoms in the lattice. The angle between bonds in the crystal lattice is very close to the tetrahedral angle of 109.5° which is also quite close to the angle between hydrogen atoms in the water molecule (in the gas phase), which is 105°. This tetrahedral bonding angle of the water molecule essentially accounts for the unusually low density of the crystal lattice -- it is beneficial for the lattice to be arranged with tetrahedral angles even though there is an energy penalty in the increased volume of the crystal lattice. As a result, the large hexagonal rings leave almost enough room for another water molecule to exist inside. This gives naturally occurring ice its unique property of being less dense than its liquid form. The tetrahedral-angled hydrogen-bonded hexagonal rings are also the mechanism which causes liquid water to be most dense at 4 °C. Close to 0 °C, tiny hexagonal ice Ih-like lattices form in liquid water, with greater frequency closer to 0 °C. This effect decreases the density of the water, causing it to be most dense at 4 °C when the structures form infrequently.
# Proton disorder
The protons (hydrogen atoms) in the crystal lattice lie very nearly along the
hydrogen bonds, and in such a way that each water molecule is preserved. This
means that each oxygen atom in the lattice has two protons adjacent to it, and
about 101 pm along the 275 pm length of the bond. The crystal
lattice allows a substantial amount of disorder in the positions of the protons
frozen into the structure as it cools to absolute zero. As a result,
the crystal structure contains some residual entropy inherent to the
lattice and determined by the number of possible configurations of proton
positions which can be formed while still maintaining the requirement for each oxygen atom to have
only two protons in closest proximity, and each H-bond joining two oxygen atoms having
only one proton. This residual entropy S0 is equal to 3.5 J mol−1 K−1. There are various ways of approximating
this number from first principles. Assuming a given N water
molecules each has 6 possible arrangements this yields 6N possible
combinations. Given random orientations of molecules, a given bond will have
only a ½ chance that it has exactly one proton, or in other words, each
molecule has a ¼ chance that its protons lie on bonds containing exactly one
proton, leaving a total number of <math>(3/2)^N</math> possible valid combinations.
Using Boltzmann's principle, we find that <math>S_0 = Nk
\ln(3/2)</math>, where <math>k</math> is Boltzmann's Constant, which yields a value of 3.37 J mol−1 K−1, a value very close to the measured value. More complex
methods can be employed to better approximate the exact number of possible
configurations, and achieve results closer to measured values.
By contrast, the structure of ice II is very proton-ordered, which helps to explain the entropy change of 3.22 J/mol when the crystal structure changes to that of ice II. Also, ice XI, an orthorhombic, proton-ordered form of ice Ih, is considered the most stable form.
# Notes
- ↑ For a description of these properties, see Ice, which deals primarily with Ice Ih. | https://www.wikidoc.org/index.php/Ice_Ih | |
89f88e5ef4e5ad4e4e71b6293e1545d8debcf6bd | wikidoc | Images | Images
# Before Inserting an Image into a Chapter, You Must First Upload the Image on the WikiDoc Server
Images can be inserted into a WikiDoc page only if they have been uploaded onto the WikiDoc server (the computer that serves up all the pages you view). If the images you want to insert are not yet on the server, you can add them (a process called "uploading" them) onto the server. To reach the upload page, you can either click Upload file or search WikiDoc for Special:Upload. This page has all of the details for adding or uploading the image to the server.
On the Upload file page you will see the following two boxes:
Where it says "Source file name:" you will click on the gray button "browse" and find the file on your computer's hard drive that you want to add to WikiDoc.
Where it says "Destination file name:" you will simply type in the name you want the image to have on WikiDoc. Please use a name that is descriptive of the image so that it will be found and cataloged by search engines. This point must be stressed, name the file similar to a search criteria that you would use to find that image using a search engine's image function.
Next, click on the button that says "Upload file".
Next, the uploaded image will appear. Hint: copy the name of the file so that you can insert it on the WikiDoc page you would like.
Once you or anyone else has added an image to the server, that image can then be inserted on an any number of pages.
You can find the file names of the images that have been uploaded to WikiDoc on the Image file list. You will need to know the file name of the image to insert the image.
You can see the images that have been uploaded to WikiDoc on the Gallery of new images
# Basic Instructions for Inserting Images onto a WikiDoc Page
Only images that have been uploaded to Wiki doc can be used. To upload images, use the upload page.
## Insert the Image Code
Images are placed on a page by typing a line of image code along with the other text. As with the typing of text, this is done in the editing window of the page being edited. Selecting the edit this page tab at the top of the page accesses the editing panel. Sign-in first so that your work will be credited to you in the record keeping.
Before placing the code, first consider the best place for the image. This usually means thinking about how the text will look when it wraps. For example, sometimes the work looks best when the image is level with the start of a section. If you want it to start there, then make an empty line immediately under the heading or immediately above it, depending on which you think looks best, and type the image code, (given later). The extra line will be ignored apart from the production of an image.
Press the Show preview button at the bottom of the editing window and wait for the system to display the reformatted page. If the image was placed on the left or the right then the text will be seen to wrap around the image from the very top of the section. If the center was selected, (or none), then the text cannot wrap, and the text will move to a point below the image. If the result is not as expected, then the text can be changed as often as necessary, until it is right. When the work is right, then press the Save page button at the bottom of the page.
Most images on the Wiki server are simply too big to display in their full sizes. In nearly every case an image reduction will be needed. The server also expects to know where to place the image, as well as what kind of frame is required. Does it need a caption? With these common requirements in mind, and to save the user much valuable time, it is proposed to go straight onto the recommended format; the one having all of the basic options in it. A selection of common examples using the recommended syntax is given in the "Examples" section below.
## Examples
See the Wikidoc's image use policy as a guideline used on Wikidoc.
All information on this page is attributed to Wikipedia and its contributors
# More Detailed Instructions for Inserting Images and its Syntax
## Type
- "thumbnail" or "thumb": Image is scaled down to a standard, user specified width, by default 180 pixels, and a box is added around the image. If a caption is written, it is shown below the image. Image defaults to placement on the 'right' unless overridden with the 'Location' attribute (see above).
- "frame": Original image size is preserved, and a box is added around the image. If a caption is written, it is shown below the image.
- (nothing specified): Original image size is preserved, no border is added around the image. If a caption is written, it is not shown.
- "border": Same as if nothing is specified, but a border is added around the image.
## Location
- "right": Image including its box is placed on the right side of the page. The article text that follows the image flows around the image.
- "left": Image including its box is placed on the left side of the page. The article text that follows the image flows around the image.
- "center": Image including its box is placed in the center of the page. The article text that follows the image is placed below the image.
- "none": Image including its box is placed on the left side of the page. The article text that follows the image is placed below the image.
## Size
- "100px": Scales the image down to make it 100 pixels wide. Replace any number for 100. If you specify "thumbnail" and a value here, this value will take precedent. If the image is already smaller than your specified value, the image stays at its size.
- "100x200px": Scales the image to be no wider than 100 pixels and no higher than 200 pixels. Image will keep its original aspect ratio
## Caption
Any element which cannot be identified as one of the above is assumed to be caption text.
# New advanced syntax for inserting images
The new syntax is backward compatible, so articles don't have to be changed.
In the syntax ] (e.g. ] shown in the left), several options can be set when including an image. Those affect the placing of the image, its size or the way the image will be presented. The options are right, left, center, none, sizepx, thumbnail (thumb), frame, and alternate (caption) text.
The options can be combined, and vertical bars ("|") are used to separate options from each other. The options can be put in any order. An unknown option is taken as the caption text, but this seems to appear only if thumbnail is specified. If there are two or more unknown options, the last one upstages the rest: ] (shown on the right).
Here is the description of the options other than the caption text:
An "enlarge"-icon is put also in the lower margin of the thumbnail. Both the image itself and the icon link to the image description page with the image in its actual size. The icon shows the link title "Enlarge" in its hoverbox, even in cases where this term does not apply, because it leads from the enlarged image to the one with the actual size. E.g. ].]] (shown on the right).
With none of the options other than sizepx and alternate (caption) text, an embedded image is rendered inline.
gives
text text text text text text
text text text text text
text text text text
The option none can be used to have thumbnails without left- or right-alignment. This is probably most useful for tables. This is an example:
# Thumbnail with caption text underneath that has one or more links
It is also possible to include links in the caption text, e.g.:
] in London]]
Just make sure the number of opening and closing square brackets are right. One extra or missing would mean the entire image syntax line would not work.
# Additional caption formatting options
Additional caption formatting options are possible.
] '''in London''']]
All of the normal text formatting options work.
# How Do I Insert a Whole Bunch of Pictures in Gallery like format?
If you use the following text below, the image below this will appear:
This code generates the following image:
# How do I get it to insert only 3 pictures across in a galler?
Displays the following
# How Do I Keep All The Text From Floating Around The Image? How Can I Get The Text To Begin Again Below the Image? Cancelling The Floating-Around-Image Mode
After having had an image floating next to text, putting further text below it and again using the full width can be done with the following markup. This blocks an image from appearing next to the material following this markup, possibly due to aesthetic reasons or a change in topics.
For legacy align="right" (etc.) floating this
isn't good enough; legacy browsers would ignore inline
CSS. To cancel floating under all conditions the
following markup (valid XHTML 1.0 transitional) works:
The same code can be issued by using template
in certain namespaces (En, meta).
# How Do I Align the Gallery to the right or left and have text float around it?
To achieve the format below:
- Normal arteriole
- Hypertensive arteriole with wall thickening and myocyte hypertrophy
- Arteriole in HCM patient with periarteriole fibrosis and thicknening
Compared to normal arterioles on the left, the arterioles from a patient with hyertension (middle) show moderate periarteriolar thickening and fibrosis. Shown on the right is a patient with HCM in which there is even more signficant periarteriolar thickening and fibrosis. This thickening of the wall of the intramyocardial arterioles leads to an increased wall/lumen ratio, subendocardial ischemia and impaired coronary flow reserve.
Use this code:
# Linking To A Page That Has A Detailed Description Of The Image
If you want to make a link to the description page for an image, use a leading colon before "image:" in an intra-wiki link, like this: ] which yields: humanbody | Images
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Before Inserting an Image into a Chapter, You Must First Upload the Image on the WikiDoc Server
Images can be inserted into a WikiDoc page only if they have been uploaded onto the WikiDoc server (the computer that serves up all the pages you view). If the images you want to insert are not yet on the server, you can add them (a process called "uploading" them) onto the server. To reach the upload page, you can either click Upload file or search WikiDoc for Special:Upload. This page has all of the details for adding or uploading the image to the server.
On the Upload file page you will see the following two boxes:
Where it says "Source file name:" you will click on the gray button "browse" and find the file on your computer's hard drive that you want to add to WikiDoc.
Where it says "Destination file name:" you will simply type in the name you want the image to have on WikiDoc. Please use a name that is descriptive of the image so that it will be found and cataloged by search engines. This point must be stressed, name the file similar to a search criteria that you would use to find that image using a search engine's image function.
Next, click on the button that says "Upload file".
Next, the uploaded image will appear. Hint: copy the name of the file so that you can insert it on the WikiDoc page you would like.
Once you or anyone else has added an image to the server, that image can then be inserted on an any number of pages.
You can find the file names of the images that have been uploaded to WikiDoc on the Image file list. You will need to know the file name of the image to insert the image.
You can see the images that have been uploaded to WikiDoc on the Gallery of new images
# Basic Instructions for Inserting Images onto a WikiDoc Page
Only images that have been uploaded to Wiki doc can be used. To upload images, use the upload page.
## Insert the Image Code
Images are placed on a page by typing a line of image code along with the other text. As with the typing of text, this is done in the editing window of the page being edited. Selecting the edit this page tab at the top of the page accesses the editing panel. Sign-in first so that your work will be credited to you in the record keeping.
Before placing the code, first consider the best place for the image. This usually means thinking about how the text will look when it wraps. For example, sometimes the work looks best when the image is level with the start of a section. If you want it to start there, then make an empty line immediately under the heading or immediately above it, depending on which you think looks best, and type the image code, (given later). The extra line will be ignored apart from the production of an image.
Press the Show preview button at the bottom of the editing window and wait for the system to display the reformatted page. If the image was placed on the left or the right then the text will be seen to wrap around the image from the very top of the section. If the center was selected, (or none), then the text cannot wrap, and the text will move to a point below the image. If the result is not as expected, then the text can be changed as often as necessary, until it is right. When the work is right, then press the Save page button at the bottom of the page.
Most images on the Wiki server are simply too big to display in their full sizes. In nearly every case an image reduction will be needed. The server also expects to know where to place the image, as well as what kind of frame is required. Does it need a caption? With these common requirements in mind, and to save the user much valuable time, it is proposed to go straight onto the recommended format; the one having all of the basic options in it. A selection of common examples using the recommended syntax is given in the "Examples" section below.
## Examples
See the Wikidoc's image use policy as a guideline used on Wikidoc.
All information on this page is attributed to Wikipedia and its contributors
# More Detailed Instructions for Inserting Images and its Syntax
## Type
- "thumbnail" or "thumb": Image is scaled down to a standard, user specified width, by default 180 pixels, and a box is added around the image. If a caption is written, it is shown below the image. Image defaults to placement on the 'right' unless overridden with the 'Location' attribute (see above).
- "frame": Original image size is preserved, and a box is added around the image. If a caption is written, it is shown below the image.
- (nothing specified): Original image size is preserved, no border is added around the image. If a caption is written, it is not shown.
- "border": Same as if nothing is specified, but a border is added around the image.
## Location
- "right": Image including its box is placed on the right side of the page. The article text that follows the image flows around the image.
- "left": Image including its box is placed on the left side of the page. The article text that follows the image flows around the image.
- "center": Image including its box is placed in the center of the page. The article text that follows the image is placed below the image.
- "none": Image including its box is placed on the left side of the page. The article text that follows the image is placed below the image.
## Size
- "100px": Scales the image down to make it 100 pixels wide. Replace any number for 100. If you specify "thumbnail" and a value here, this value will take precedent. If the image is already smaller than your specified value, the image stays at its size.
- "100x200px": Scales the image to be no wider than 100 pixels and no higher than 200 pixels. Image will keep its original aspect ratio
## Caption
Any element which cannot be identified as one of the above is assumed to be caption text.
# New advanced syntax for inserting images
The new syntax is backward compatible, so articles don't have to be changed.
In the syntax [[Image:file name|options]] (e.g. [[Image:Humanbody.jpg|thumb|100px|left|Anatomy]] shown in the left), several options can be set when including an image. Those affect the placing of the image, its size or the way the image will be presented. The options are right, left, center, none, sizepx, thumbnail (thumb), frame, and alternate (caption) text.
The options can be combined, and vertical bars ("|") are used to separate options from each other. The options can be put in any order. An unknown option is taken as the caption text, but this seems to appear only if thumbnail is specified. If there are two or more unknown options, the last one upstages the rest: [[Image:Humanbody.jpg|thumb|Anatomy|200px|right|Human Body]] (shown on the right).
Here is the description of the options other than the caption text:
An "enlarge"-icon is put also in the lower margin of the thumbnail. Both the image itself and the icon link to the image description page with the image in its actual size. The icon shows the link title "Enlarge" in its hoverbox, even in cases where this term does not apply, because it leads from the enlarged image to the one with the actual size. E.g. [[Image:tst.jpg|right|thumb|100px|This is a puzzle, and take a look at it in [[Media:tst.jpg|the actual size]].]] (shown on the right).
With none of the options other than sizepx and alternate (caption) text, an embedded image is rendered inline.
gives
text text text text text text
text text text text text
text text text text
The option none can be used to have thumbnails without left- or right-alignment. This is probably most useful for tables. This is an example:
# Thumbnail with caption text underneath that has one or more links
It is also possible to include links in the caption text, e.g.:
[[Image:Humanbody.jpg|right|thumbnail|This is the [[Palace of Westminster]] in London]]
Just make sure the number of opening and closing square brackets are right. One extra or missing would mean the entire image syntax line would not work.
# Additional caption formatting options
Additional caption formatting options are possible.
[[Image:Humanbody.jpg|right|thumbnail|<div align="center">This is <span style="color: green">the </span><br /> [[Palace of Westminster]]<br /> '''in <span style="color: red">London</span>'''</div>]]
All of the normal text formatting options work.
# How Do I Insert a Whole Bunch of Pictures in Gallery like format?
If you use the following text below, the image below this will appear:
This code generates the following image:
-
-
-
-
-
# How do I get it to insert only 3 pictures across in a galler?
Displays the following
-
-
-
-
-
# How Do I Keep All The Text From Floating Around The Image? How Can I Get The Text To Begin Again Below the Image? Cancelling The Floating-Around-Image Mode
After having had an image floating next to text, putting further text below it and again using the full width can be done with the following markup. This blocks an image from appearing next to the material following this markup, possibly due to aesthetic reasons or a change in topics.
For legacy align="right" (etc.) floating this
isn't good enough; legacy browsers would ignore inline
CSS. To cancel floating under all conditions the
following markup (valid XHTML 1.0 transitional) works:
The same code can be issued by using template
in certain namespaces (En, meta).
# How Do I Align the Gallery to the right or left and have text float around it?
To achieve the format below:
- Normal arteriole
- Hypertensive arteriole with wall thickening and myocyte hypertrophy
- Arteriole in HCM patient with periarteriole fibrosis and thicknening
Compared to normal arterioles on the left, the arterioles from a patient with hyertension (middle) show moderate periarteriolar thickening and fibrosis. Shown on the right is a patient with HCM in which there is even more signficant periarteriolar thickening and fibrosis. This thickening of the wall of the intramyocardial arterioles leads to an increased wall/lumen ratio, subendocardial ischemia and impaired coronary flow reserve.
Use this code:
# Linking To A Page That Has A Detailed Description Of The Image
If you want to make a link to the description page for an image, use a leading colon before "image:" in an intra-wiki link, like this: [[:image:humanbody.jpg|humanbody]] which yields: humanbody
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Image | |
eb510dd78d940b3e84f22e64f2d67984d9cac4ee | wikidoc | Injury | Injury
# Introduction
Injury is damage or harm caused to the structure or function of the body caused by an outside agent or force, which may be physical or chemical. Injury may also refer to injured feelings or reputation rather than injuries to the body. A severe and perhaps life-threatening injury is called a physical trauma.
# Injury
- Bruise is a hemorrhage under the skin caused by contusion.
- Wound: cuts and grazes are injuries to or through the skin, that cause bleeding (i.e., a laceration).
- Burns are injuries caused by excess heat, chemical exposure, or sometimes cold (frostbite).
- Fractures are injuries to bones.
- Joint dislocation is a displacement of a bone from its normal joint, such as a dislocated shoulder or finger.
- Concussion is mild traumatic brain injury caused by a blow, without any penetration into the skull or brain.
- Sprain is an injury which occurs to ligaments caused by a sudden over stretching; a strain injures muscles.
- Shock is a serious medical condition where the tissues cannot obtain sufficient for oxygen and nutrients.
- Amputation is the removal of a body extremity by trauma or surgery.
Serious bodily injury is any injury or injuries to the body that substantially risks death of the victim.
# Legal issues
Various legal remedies may be available for personal injury (eg. under the law negligence) or some other type of injury (eg. see damages and restitution).
In the United States, the legal definition of malicious injury is any injury committed with malice, hatred or one committed spitefully or wantonly. Such an action must be willfully committed with the knowledge that it is liable to cause injury. Injury involving element of fraud, violence, wantonness, willfulness, or criminality. An injury that is intentional, wrongful and without just cause or excuse, even in the absence of hatred, spite or ill will.
# Feigning Injury
Injuries may be feigned by a person or even non-human animal for various causes. Faking an injury may allow a person to receive compensation, injury cover, or may result in a team being awarded a penalty in a game of football. Birds such as the killdeer are known to feign injury to lead a predator away from their nest. The predator gives chase, believing them to be easy prey, but the bird then flies away, hopefully having distracted the predator sufficiently to prevent it from finding its nest. | Injury
Template:AB
# Introduction
Injury is damage or harm caused to the structure or function of the body caused by an outside agent or force, which may be physical or chemical. Injury may also refer to injured feelings or reputation rather than injuries to the body. A severe and perhaps life-threatening injury is called a physical trauma.
# Injury
- Bruise is a hemorrhage under the skin caused by contusion.
- Wound: cuts and grazes are injuries to or through the skin, that cause bleeding (i.e., a laceration).
- Burns are injuries caused by excess heat, chemical exposure, or sometimes cold (frostbite).
- Fractures are injuries to bones.
- Joint dislocation is a displacement of a bone from its normal joint, such as a dislocated shoulder or finger.
- Concussion is mild traumatic brain injury caused by a blow, without any penetration into the skull or brain.
- Sprain is an injury which occurs to ligaments caused by a sudden over stretching; a strain injures muscles.
- Shock is a serious medical condition where the tissues cannot obtain sufficient for oxygen and nutrients.
- Amputation is the removal of a body extremity by trauma or surgery.
Serious bodily injury is any injury or injuries to the body that substantially risks death of the victim.
# Legal issues
Various legal remedies may be available for personal injury (eg. under the law negligence) or some other type of injury (eg. see damages and restitution).
In the United States, the legal definition of malicious injury is any injury committed with malice, hatred or one committed spitefully or wantonly. Such an action must be willfully committed with the knowledge that it is liable to cause injury. Injury involving element of fraud, violence, wantonness, willfulness, or criminality. An injury that is intentional, wrongful and without just cause or excuse, even in the absence of hatred, spite or ill will.
# Feigning Injury
Injuries may be feigned by a person or even non-human animal for various causes. Faking an injury may allow a person to receive compensation, injury cover, or may result in a team being awarded a penalty in a game of football. Birds such as the killdeer are known to feign injury to lead a predator away from their nest. The predator gives chase, believing them to be easy prey, but the bird then flies away, hopefully having distracted the predator sufficiently to prevent it from finding its nest. | https://www.wikidoc.org/index.php/Injuries | |
2d98c89c647529d02176ac53014de600342e3ee1 | wikidoc | Pelvis | Pelvis
The pelvis (pl. pelvises or pelves) is the bony structure located at the base of the spine (properly known as the caudal end). It is part of the appendicular skeleton. Each os coxae (hipbone) consists of three bones: the illium, ischium, and the pubis. The illium is the largest and upper most part, the ischium is the posterior-inferior (back-lower) part, and the pubis is the anterior (front) part of the hipbone. The two hipbones are joined anteriorly at the symphysis pubis and posteriorly to the sacrum. The pelvis incorporates the socket portion of the hip joint for each leg (in bipeds) or hind leg (in quadrupeds). It forms the lower limb (or hind-limb) girdle of the skeleton.
# Gender differences
- Infrapubic angle is greater than 90˚ in females and less than 90˚ in males
- Pelvic inletin males is more heart-shaped, while in females it is more round or oval
- Greater sciatic notch narrower in males
- Acetabulum in males faces more laterally, while it faces more anteriorly in females
- Sacrum more triangular in females
There are four main types of pelvis
- Gynaecoid
Normal female p elvis
Round with enlarged transverse diameter
- Normal female p elvis
- Round with enlarged transverse diameter
- Android
Normal male pelvis
Heart shaped
- Normal male pelvis
- Heart shaped
- Anthropoid
Long anterior to posterior diameter
- Long anterior to posterior diameter
- Platypelloid
Long transverse diameter
- Long transverse diameter | Pelvis
Template:Infobox Bone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Template:Otheruses4
The pelvis (pl. pelvises or pelves) is the bony structure located at the base of the spine (properly known as the caudal end). It is part of the appendicular skeleton. Each os coxae (hipbone) consists of three bones: the illium, ischium, and the pubis. The illium is the largest and upper most part, the ischium is the posterior-inferior (back-lower) part, and the pubis is the anterior (front) part of the hipbone. The two hipbones are joined anteriorly at the symphysis pubis and posteriorly to the sacrum. The pelvis incorporates the socket portion of the hip joint for each leg (in bipeds) or hind leg (in quadrupeds). It forms the lower limb (or hind-limb) girdle of the skeleton.
# Gender differences
- Infrapubic angle is greater than 90˚ in females and less than 90˚ in males
- Pelvic inletin males is more heart-shaped, while in females it is more round or oval
- Greater sciatic notch narrower in males
- Acetabulum in males faces more laterally, while it faces more anteriorly in females
- Sacrum more triangular in females[1]
There are four main types of pelvis
- Gynaecoid
Normal female p elvis
Round with enlarged transverse diameter
- Normal female p elvis
- Round with enlarged transverse diameter
- Android
Normal male pelvis
Heart shaped
- Normal male pelvis
- Heart shaped
- Anthropoid
Long anterior to posterior diameter
- Long anterior to posterior diameter
- Platypelloid
Long transverse diameter
- Long transverse diameter | https://www.wikidoc.org/index.php/Innominate_bone | |
1962878a232b0862548c4b67ecd542c2304cab28 | wikidoc | Insite | Insite
Insite is the first legal supervised safe injection site in North America, located at 139 East Hastings Street, in the troubled Downtown Eastside neighbourhood of Vancouver, British Columbia. The site provides a clean, safe location for injection drug use, primarily heroin, cocaine, and morphine. Medical staff are present to provide addiction treatment, mental health assistance, and first aid in the event of an overdose or wound. Over a two year period ending March 31, 2006, the site recorded an average of 607 visits per day and 453 overdoses total, with none resulting in a fatality. Health Canada has provided $500,000 per year to operate the site, and the BC Ministry of Health contributed $1,200,000 to renovate the site and cover operating costs.
# Operation
Insite has been operated since 2003 by Vancouver Coastal Health, under a special exemption of Section 56 of the Controlled Drugs and Substances Act, granted by the Liberal government via Health Canada. The site was slated to close on September 12, 2006, as the exemption was for a three year pilot project. The new Conservative government granted a temporary extension, then added a six month extension that ends mid-2008.
# Research
Since opening, the site has been the focus of numerous scientific studies, in peer-reviewed journals such as the New England Journal of Medicine, The Lancet, the British Medical Journal, and the Canadian Medical Association Journal. Findings have shown that the site has led to a reduction of public injections, neighbourhood litter, and needle sharing. It has also led to an increase in detoxification and addiction treatment, and has not been shown to increase crime or rates of relapse in former drug users.
# Support and criticism
Partners include the City of Vancouver, the Vancouver Police Department, and the PHS Community Services Society. The site has the support of Vancouver's mayor Sam Sullivan, British Columbia's premier Gordon Campbell, and former high-profile Vancouver mayors Larry Campbell, Mike Harcourt, and Philip Owen. The International AIDS Society and the B.C. Centre for Excellence in HIV-AIDS, and the Canadian Union of Public and General Employees also support Insite. Though originally opposed to the safe injection site, Chinatown and Gastown merchants associations now support it.
International supporters include the UK-based think tank Senlis Council and the Australian Parliamentary Group for Drug Law Reform.
The site has drawn criticism from the Bush administration; the director of the White House Office of National Drug Control Policy called it "state-sponsored suicide" at the time of its opening. The Royal Canadian Mounted Police do not support Insite, despite the fact that a report commissioned by the RCMP (conducted by two criminologists) concluded in favour of the safe injection site.
# Government
While the Liberal government allowed Insite to open, since 2006 its fate has been the responsibility of the new Conservative government, which has not been as supportive of it. Conservative Prime Minister Stephen Harper has voiced opposition to the injection site in the past, saying that "We as a government will not use taxpayers' money to fund drug use." In mid-July 2006, Conservative MP David Fletcher stated that the their government would let Insite's special exemption lapse before deciding whether to continue the project. The following week a spokesman for Tony Clement, the Minister of Health, refuted that, saying that a decision had not been made yet. During the XVI International AIDS Conference, held in Toronto, two high-ranking Liberal MPs (Bill Graham and Keith Martin) put their support behind the centre, and criticized the Conservative government for delaying their decision. Insite supporters also demonstrated in Toronto during the conference, prompting the government to further delay any announcement, citing the week's 'politicized' nature.
On September 1, 2006, Health Minister Tony Clement deferred the decision of whether to extend the exemption for the site, citing a need for more research. However, on the same day the government cut all funding for future research, amounting to $1.5 million in lost research money. On August 13, 2007, the Portland Hotel Society and two drug addicts filed suit in the BC Supreme Court to keep the centre open, arguing that its closure would be a violation of the Charter right of Insite users to "security of the person."
On October 4, 2007, during the announcement of its $64-million drug strategy, the Conservative government announced that Insite will be granted another six month extension, allowing it to operate until June 30, 2008. | Insite
Insite is the first legal supervised safe injection site in North America, located at 139 East Hastings Street, in the troubled Downtown Eastside neighbourhood of Vancouver, British Columbia. The site provides a clean, safe location for injection drug use, primarily heroin, cocaine, and morphine. Medical staff are present to provide addiction treatment, mental health assistance, and first aid in the event of an overdose or wound. Over a two year period ending March 31, 2006, the site recorded an average of 607 visits per day and 453 overdoses total, with none resulting in a fatality.[1] Health Canada has provided $500,000 per year to operate the site, and the BC Ministry of Health contributed $1,200,000 to renovate the site and cover operating costs.
# Operation
Insite has been operated since 2003 by Vancouver Coastal Health, under a special exemption of Section 56 of the Controlled Drugs and Substances Act, granted by the Liberal government via Health Canada. The site was slated to close on September 12, 2006, as the exemption was for a three year pilot project. The new Conservative government granted a temporary extension, then added a six month extension that ends mid-2008.
# Research
Since opening, the site has been the focus of numerous scientific studies, in peer-reviewed journals such as the New England Journal of Medicine, The Lancet, the British Medical Journal, and the Canadian Medical Association Journal. Findings have shown that the site has led to a reduction of public injections, neighbourhood litter, and needle sharing.[2] It has also led to an increase in detoxification and addiction treatment,[3] and has not been shown to increase crime or rates of relapse in former drug users.[1]
# Support and criticism
Partners include the City of Vancouver, the Vancouver Police Department, and the PHS Community Services Society.[4] The site has the support of Vancouver's mayor Sam Sullivan,[5] British Columbia's premier Gordon Campbell,[6] and former high-profile Vancouver mayors Larry Campbell, Mike Harcourt, and Philip Owen.[7] The International AIDS Society and the B.C. Centre for Excellence in HIV-AIDS,[8] and the Canadian Union of Public and General Employees[9] also support Insite. Though originally opposed to the safe injection site, Chinatown and Gastown merchants associations now support it.[7]
International supporters include the UK-based think tank Senlis Council[10] and the Australian Parliamentary Group for Drug Law Reform.[5]
The site has drawn criticism from the Bush administration; the director of the White House Office of National Drug Control Policy called it "state-sponsored suicide" at the time of its opening.[5] The Royal Canadian Mounted Police do not support Insite, despite the fact that a report commissioned by the RCMP (conducted by two criminologists) concluded in favour of the safe injection site.[11]
# Government
While the Liberal government allowed Insite to open, since 2006 its fate has been the responsibility of the new Conservative government, which has not been as supportive of it. Conservative Prime Minister Stephen Harper has voiced opposition to the injection site in the past, saying that "We as a government will not use taxpayers' money to fund drug use."[12] In mid-July 2006, Conservative MP David Fletcher stated that the their government would let Insite's special exemption lapse before deciding whether to continue the project. The following week a spokesman for Tony Clement, the Minister of Health, refuted that, saying that a decision had not been made yet.[13] During the XVI International AIDS Conference, held in Toronto, two high-ranking Liberal MPs (Bill Graham and Keith Martin) put their support behind the centre, and criticized the Conservative government for delaying their decision. Insite supporters also demonstrated in Toronto during the conference, prompting the government to further delay any announcement, citing the week's 'politicized' nature.[12]
On September 1, 2006, Health Minister Tony Clement deferred the decision of whether to extend the exemption for the site, citing a need for more research.[11] However, on the same day the government cut all funding for future research, amounting to $1.5 million in lost research money.[14] On August 13, 2007, the Portland Hotel Society and two drug addicts filed suit in the BC Supreme Court to keep the centre open, arguing that its closure would be a violation of the Charter right of Insite users to "security of the person."[15]
On October 4, 2007, during the announcement of its $64-million drug strategy, the Conservative government announced that Insite will be granted another six month extension, allowing it to operate until June 30, 2008.[6] | https://www.wikidoc.org/index.php/Insite | |
5dd807b64688f64804026603f0c3850c4dd11510 | wikidoc | Intein | Intein
An intein is a segment of a protein that is able to excise itself and rejoin the remaining portions (the exteins) with a peptide bond. Inteins have also been called "protein introns".
Most reported inteins also contain an endonuclease domain that plays a role in intein propagation. In fact, many genes have unrelated intein-coding segments inserted at different positions. For these and other reasons, inteins (or more properly, the gene segments coding for inteins) are sometimes called selfish genetic elements but
it may be more accurate to call them parasitic. The difference is that "selfish genes" are "selfish" only insofar as to compete with other genes or alleles, but still fulfill a beneficial function for the organism as a whole, whereas "parasitic genes" are functionless.
Intein-mediated protein splicing occurs after mRNA has been translated into a protein. This precursor protein contains three segments - an N-extein followed by the intein followed by a C-extein.
After splicing has taken place, the result is also called an extein.
The first intein was discovered in 1987. Since then, inteins have been found in all three domains of life (eukaryotes, bacteria, and archaea). Knowledge regarding the evolutionary situation of inteins and related elements is reviewed in Gogarten & Hilario (2006).
The mechanism for the splicing effect is a naturally-occurring analogy to the technique for chemically generating medium-sized proteins called native chemical ligation, which was developed at the same time as inteins were discovered.
# Inteins in biotechnology
Inteins are very efficient at protein splicing and they have accordingly found an important role in biotechnology. There are more than 200 inteins identified to date, sizes range from 100-800 aa.
Inteins have been engineered for particular applications such as protein synthesis, and the selective labeling of protein segments, which is useful for NMR studies of large proteins.
Pharmaceutical inhibition of intein excision may be a useful tool for drug development, the protein that contains the intein will not carry out its normal function if the intein does not excise since its structure will be disrupted.
It has been suggested that inteins could prove useful for achieving allotopic expression of certain highly hydrophobic proteins normally encoded by the mitochondrial genome, for example in gene therapy (de Grey 2000). The hydrophobicity of these proteins is an obstacle to their import into mitochondria. Therefore, the insertion of a non-hydrophobic intein may allow this import to proceed. Excision of the intein after import would then restore the protein to wild-type.
# Intein naming conventions
The first part of an intein name is based on the scientific name of the organism in which it is found, and the second part is based on the name of the corresponding gene or extein. For example, the intein found in Thermoplasma acidophilum and associated with 'Vacuolar ATPase subunit A' (VMA) is called 'Tac VMA'.
Normally, as in this example, just three letters suffice to specify the organism, but there are variations. For example, additional letters may be added to indicate a strain.
If more than one intein is encoded in the corresponding gene, the inteins are given a numerical suffix starting from 5' to 3' or in order of their identification. For example, "Msm dnaB-1".
The segment of the gene that encodes the intein is usually given the same name as the intein, but to avoid confusion, the name of the intein proper is usually capitalized (e.g. Pfu RIR1-1), whereas the name of the corresponding gene segment is italicized.
# Full and mini inteins
Inteins can contain a homing endonuclease gene domain in addition to the splicing domains. This domain is responsible for the spread of the intein by cleaving DNA at an intein free allele on the homologous chromosome, triggering the DNA double-stranded break repair (DSBR) system, which then repairs the break, thus copying the intein into a previously intein free site. The HEG domain is not necessary for intein splicing, and so it can be lost, forming a minimal, or mini intein. Several studies have demonstrated the modular nature of inteins by adding or removing HEG domains and determining the activity of the new construct.
# Split inteins
Sometimes, the intein of the precursor protein comes from two genes. In this case, the intein is said to be a split intein. For example, in Cyanobacteria, DnaE, the catalytic subunit alpha of DNA polymerase III, is encoded by two separate genes,
dnaE-n and dnaE-c. The dnaE-n product consists of an N-extein sequence followed by a 123-aa (amino acid) intein sequence, whereas the dnaE-c product consists of a 36-aa intein
sequence followed by a C-extein sequence. | Intein
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
An intein is a segment of a protein that is able to excise itself and rejoin the remaining portions (the exteins) with a peptide bond. Inteins have also been called "protein introns".
Most reported inteins also contain an endonuclease domain that plays a role in intein propagation. In fact, many genes have unrelated intein-coding segments inserted at different positions. For these and other reasons, inteins (or more properly, the gene segments coding for inteins) are sometimes called selfish genetic elements but
it may be more accurate to call them parasitic. The difference is that "selfish genes" are "selfish" only insofar as to compete with other genes or alleles, but still fulfill a beneficial function for the organism as a whole, whereas "parasitic genes" are functionless.
Intein-mediated protein splicing occurs after mRNA has been translated into a protein. This precursor protein contains three segments - an N-extein followed by the intein followed by a C-extein.
After splicing has taken place, the result is also called an extein.
The first intein was discovered in 1987. Since then, inteins have been found in all three domains of life (eukaryotes, bacteria, and archaea). Knowledge regarding the evolutionary situation of inteins and related elements is reviewed in Gogarten & Hilario (2006).
The mechanism for the splicing effect is a naturally-occurring analogy to the technique for chemically generating medium-sized proteins called native chemical ligation, which was developed at the same time as inteins were discovered.
# Inteins in biotechnology
Inteins are very efficient at protein splicing and they have accordingly found an important role in biotechnology. There are more than 200 inteins identified to date, sizes range from 100-800 aa.
Inteins have been engineered for particular applications such as protein synthesis, and the selective labeling of protein segments, which is useful for NMR studies of large proteins.
Pharmaceutical inhibition of intein excision may be a useful tool for drug development, the protein that contains the intein will not carry out its normal function if the intein does not excise since its structure will be disrupted.
It has been suggested that inteins could prove useful for achieving allotopic expression of certain highly hydrophobic proteins normally encoded by the mitochondrial genome, for example in gene therapy (de Grey 2000). The hydrophobicity of these proteins is an obstacle to their import into mitochondria. Therefore, the insertion of a non-hydrophobic intein may allow this import to proceed. Excision of the intein after import would then restore the protein to wild-type.
# Intein naming conventions
The first part of an intein name is based on the scientific name of the organism in which it is found, and the second part is based on the name of the corresponding gene or extein. For example, the intein found in Thermoplasma acidophilum and associated with 'Vacuolar ATPase subunit A' (VMA) is called 'Tac VMA'.
Normally, as in this example, just three letters suffice to specify the organism, but there are variations. For example, additional letters may be added to indicate a strain.
If more than one intein is encoded in the corresponding gene, the inteins are given a numerical suffix starting from 5' to 3' or in order of their identification. For example, "Msm dnaB-1".
The segment of the gene that encodes the intein is usually given the same name as the intein, but to avoid confusion, the name of the intein proper is usually capitalized (e.g. Pfu RIR1-1), whereas the name of the corresponding gene segment is italicized.
# Full and mini inteins
Inteins can contain a homing endonuclease gene domain in addition to the splicing domains. This domain is responsible for the spread of the intein by cleaving DNA at an intein free allele on the homologous chromosome, triggering the DNA double-stranded break repair (DSBR) system, which then repairs the break, thus copying the intein into a previously intein free site. The HEG domain is not necessary for intein splicing, and so it can be lost, forming a minimal, or mini intein. Several studies have demonstrated the modular nature of inteins by adding or removing HEG domains and determining the activity of the new construct.
# Split inteins
Sometimes, the intein of the precursor protein comes from two genes. In this case, the intein is said to be a split intein. For example, in Cyanobacteria, DnaE, the catalytic subunit alpha of DNA polymerase III, is encoded by two separate genes,
dnaE-n and dnaE-c. The dnaE-n product consists of an N-extein sequence followed by a 123-aa (amino acid) intein sequence, whereas the dnaE-c product consists of a 36-aa intein
sequence followed by a C-extein sequence. | https://www.wikidoc.org/index.php/Intein | |
edeb108462925201d2cdb90a1c0bb9e8f71f6a8b | wikidoc | Intron | Intron
Introns, derived from the term "intragenic regions", are non-coding sections of DNA. Once a DNA sequence has been transcribed as a hnRNA strand, the introns will be spliced out. The resulting mRNA sequence will then be translated into a protein.
# Introduction
Introns are common in eukaryotic hnRNA, but in prokaryotes they are only found in tRNA and rRNA. Unlike introns, which are non-coding sections of a gene, exons are coding sections that remain in the mRNA sequence.
The number and length of introns varies widely among species, and among genes within the same species. Genes of higher organisms, such as mammals and flowering plants, have numerous introns, which can be much longer than the nearby exons. Some less advanced organisms, such as fungus Saccharomyces cerevisiae, and protists, have very few introns. In humans, the gene with the greatest number of introns is the gene for the protein Titin, with 362 introns.
Introns sometimes allow for alternative splicing of a gene, so that several different proteins which share some sequences in common can be translated from a single gene. The control of mRNA splicing is performed by a wide variety of signalling molecules.
Introns may also contain "old code", or sections of a gene that were once translated into a protein, but have since been discarded. It was generally assumed that the sequence of any given intron is junk DNA with no function. More recently, however, this is being disputed.
Introns contain several short sequences that are important for efficient splicing. The exact mechanism for these intronic splicing enhancers is not well understood, but it is thought that they serve as binding sites on the transcript for proteins which stabilize the spliceosome. It is also possible that RNA secondary structure formed by intronic sequences may have an effect on splicing.
## Discovery
The discovery of introns led to the Nobel Prize in Physiology or Medicine in 1993 for Phillip Allen Sharp and Richard J. Roberts. The term intron was introduced by American biochemist Walter Gilbert in 1978:
"The notion of the cistron must be replaced by that of a transcription unit containing regions which will be lost from the mature messenger - which I suggest we call introns (for intragenic regions) - alternating with regions which will be expressed - exons." (Gilbert 1978)
## Classification of introns
Some introns, such as Group I and Group II introns, are actually ribozymes that are capable of catalyzing their own splicing out of a primary RNA transcript. This self splicing activity was discovered by Thomas Cech, who shared the 1989 Nobel Prize in Chemistry with Sidney Altman for the discovery of the catalytic properties of RNA.
Four classes of introns are known to exist:
- Nuclear introns
- Group I intron
- Group II intron
- Group III intron
Sometimes group III introns are also identified as group II introns, because of their similarity in structure and function.
Nuclear or spliceosomal introns are spliced by the spliceosome and a series of snRNAs (small nuclear RNAs). There are certain splice signals (or consensus sequences) which abet the splicing (or identification) of these introns by the spliceosome.
Group I, II and III introns are self splicing introns and are relatively rare compared to spliceosomal introns.
Group II and III introns are similar and have a conserved secondary structure. The lariat pathway is used in their splicing. They perform functions similar to the spliceosome and may be evolutionarily related to it. Group I introns are the only class of introns whose splicing requires a free guanine nucleoside. They possess a secondary structure different from that of group II and III introns. They are found in most bacteria and protozoa.
## Intron evolution
There are two competing theories that offer alternative scenarios for the origin and early evolution of spliceosomal introns (Other classes of introns such as self-splicing and tRNA introns are not subject to much debate, but see for the former). These are popularly called as the Introns-Early (IE) or the Introns-Late (IL) views.
The IE model, championed by Walter Gilbert, proposes that introns are extremely old and numerously present in the earliest ancestors of prokaryotes and eukaryotes (the progenote). In this model introns were subsequently lost from prokaryotic organisms, allowing them to attain growth efficiency. A central prediction of this theory is that the early introns were mediators that facilitated the recombination of exons that represented the protein domains. Such a model would directly lead to the evolution of new genes.
The IL model proposes that introns were more recently inserted into original intron-less contiguous genes after the divergence of eukaryotes and prokaryotes. In this model, introns probably had their origin in parasitic transposable elements. This model is based on the observation that the spliceosomal introns are restricted to eukaryotes alone. However, there is considerable debate on the presence of introns in the early prokaryote-eukaryote ancestors and the subsequent intron loss-gain during eukaryotic evolution. It is also suggested that the evolution of introns and more generally the intron-exon structure is largely independent of the coding-sequence evolution.
# Identification
Nearly all eukaryotic nuclear introns begin with the nucleotide sequence GU, and end with AG (the GU-AG rule). These, along with a larger consensus sequence, help direct the splicing machinery to the proper intronic donor and acceptor sites. This mainly occurs in eukaryotic primary mRNA transcripts. | Intron
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Introns, derived from the term "intragenic regions", are non-coding sections of DNA. Once a DNA sequence has been transcribed as a hnRNA strand, the introns will be spliced out. The resulting mRNA sequence will then be translated into a protein.
# Introduction
Introns are common in eukaryotic hnRNA, but in prokaryotes they are only found in tRNA and rRNA. Unlike introns, which are non-coding sections of a gene, exons are coding sections that remain in the mRNA sequence.
The number and length of introns varies widely among species, and among genes within the same species. Genes of higher organisms, such as mammals and flowering plants, have numerous introns, which can be much longer than the nearby exons. Some less advanced organisms, such as fungus Saccharomyces cerevisiae, and protists, have very few introns. In humans, the gene with the greatest number of introns is the gene for the protein Titin, with 362 introns.
Introns sometimes allow for alternative splicing of a gene, so that several different proteins which share some sequences in common can be translated from a single gene. The control of mRNA splicing is performed by a wide variety of signalling molecules.
Introns may also contain "old code", or sections of a gene that were once translated into a protein, but have since been discarded. It was generally assumed that the sequence of any given intron is junk DNA with no function. More recently, however, this is being disputed.[2]
Introns contain several short sequences that are important for efficient splicing. The exact mechanism for these intronic splicing enhancers is not well understood, but it is thought that they serve as binding sites on the transcript for proteins which stabilize the spliceosome. It is also possible that RNA secondary structure formed by intronic sequences may have an effect on splicing.
## Discovery
The discovery of introns led to the Nobel Prize in Physiology or Medicine in 1993 for Phillip Allen Sharp and Richard J. Roberts. The term intron was introduced by American biochemist Walter Gilbert in 1978:
"The notion of the cistron [...] must be replaced by that of a transcription unit containing regions which will be lost from the mature messenger - which I suggest we call introns (for intragenic regions) - alternating with regions which will be expressed - exons." (Gilbert 1978)
## Classification of introns
Some introns, such as Group I and Group II introns, are actually ribozymes that are capable of catalyzing their own splicing out of a primary RNA transcript. This self splicing activity was discovered by Thomas Cech, who shared the 1989 Nobel Prize in Chemistry with Sidney Altman for the discovery of the catalytic properties of RNA.
Four classes of introns are known to exist:
- Nuclear introns
- Group I intron
- Group II intron
- Group III intron
Sometimes group III introns are also identified as group II introns, because of their similarity in structure and function.
Nuclear or spliceosomal introns are spliced by the spliceosome and a series of snRNAs (small nuclear RNAs). There are certain splice signals (or consensus sequences) which abet the splicing (or identification) of these introns by the spliceosome.
Group I, II and III introns are self splicing introns and are relatively rare compared to spliceosomal introns.
Group II and III introns are similar and have a conserved secondary structure. The lariat pathway is used in their splicing. They perform functions similar to the spliceosome and may be evolutionarily related to it. Group I introns are the only class of introns whose splicing requires a free guanine nucleoside. They possess a secondary structure different from that of group II and III introns. They are found in most bacteria and protozoa.
## Intron evolution
There are two competing theories that offer alternative scenarios for the origin and early evolution of spliceosomal introns (Other classes of introns such as self-splicing and tRNA introns are not subject to much debate, but see [1] for the former). These are popularly called as the Introns-Early (IE) or the Introns-Late (IL) views.
The IE model, championed by Walter Gilbert,[2] proposes that introns are extremely old and numerously present in the earliest ancestors of prokaryotes and eukaryotes (the progenote). In this model introns were subsequently lost from prokaryotic organisms, allowing them to attain growth efficiency. A central prediction of this theory is that the early introns were mediators that facilitated the recombination of exons that represented the protein domains. Such a model would directly lead to the evolution of new genes.
The IL model proposes that introns were more recently inserted into original intron-less contiguous genes after the divergence of eukaryotes and prokaryotes. In this model, introns probably had their origin in parasitic transposable elements. This model is based on the observation that the spliceosomal introns are restricted to eukaryotes alone. However, there is considerable debate on the presence of introns in the early prokaryote-eukaryote ancestors and the subsequent intron loss-gain during eukaryotic evolution.[3] It is also suggested that the evolution of introns and more generally the intron-exon structure is largely independent of the coding-sequence evolution.[4]
# Identification
Nearly all eukaryotic nuclear introns begin with the nucleotide sequence GU, and end with AG (the GU-AG rule). These, along with a larger consensus sequence, help direct the splicing machinery to the proper intronic donor and acceptor sites. This mainly occurs in eukaryotic primary mRNA transcripts. | https://www.wikidoc.org/index.php/Intron | |
3028c170862a5b2fa7ca6c9ee66881f6bd3d635d | wikidoc | Iodate | Iodate
An iodate is a salt of iodic acid. In the iodate anion, iodine is bonded to three oxygen atoms and the molecular formula is IO3−. The molecular geometry of iodate is trigonal pyramid.
Iodate can be obtained by reducing periodate with a thioether. The biproduct of the reaction is a sulfoxide.
Iodates are a class of chemical compounds containing this group. Examples are sodium iodate (NaIO3), silver iodate (AgIO3), and calcium iodate (Ca(IO3)2). Iodates resemble chlorates with chlorine instead of iodine.
In acid conditions, iodic acid is formed. Potassium hydrogen iodate (KH(IO3)2) is a double salt of potassium iodate and iodic acid and an acid as well. Iodates are used in the Iodine clock reaction. | Iodate
An iodate is a salt of iodic acid[1]. In the iodate anion, iodine is bonded to three oxygen atoms and the molecular formula is IO3−. The molecular geometry of iodate is trigonal pyramid.
Iodate can be obtained by reducing periodate with a thioether. The biproduct of the reaction is a sulfoxide.[2]
Iodates are a class of chemical compounds containing this group. Examples are sodium iodate (NaIO3), silver iodate (AgIO3), and calcium iodate (Ca(IO3)2). Iodates resemble chlorates with chlorine instead of iodine.
In acid conditions, iodic acid is formed. Potassium hydrogen iodate (KH(IO3)2) is a double salt of potassium iodate and iodic acid and an acid as well. Iodates are used in the Iodine clock reaction. | https://www.wikidoc.org/index.php/Iodate | |
cc446765a3ecfeabc47332d8851522f75cd734aa | wikidoc | Iodide | Iodide
An iodide ion is an iodine atom with a −1 charge. Compounds with iodine in formal oxidation state −1 are called iodides. This can include ionic compounds such as caesium iodide or covalent compounds such as carbon tetraiodide. This is the same naming scheme as is seen with chlorides and bromides The chemical test for an iodide compound is to acidify the aqueous compound by adding some drops of acid, to dispel any carbonate ions present, then adding lead nitrate, yielding a bright yellow precipitate of lead iodide. Most ionic iodides are soluble, with the exception of yellow silver iodide and yellow lead iodide. Iron(III) iodide does not exist because iron(III) ions oxidize iodide ions in aqueous solution. Aqueous solutions of iodide dissolve iodine better than pure water due to the formation of complex ions:
The colour of the triiodide ion formed is brown.
# Examples
Examples or common iodides include:
- hydrogen iodide (HI)
- sodium iodide (NaI)
- potassium iodide (KI)
- carbon tetraiodide (CI4)
- silver iodide (AgI)
- nitrogen triiodide (NI3)
# Iodide as an antioxidant
# Clinical Use
Iodide (>6mg/day) can be used to treat patients with hyperthyroidism due to its ability to block the release of thyroid hormone (TH), known as the Wolff-Chaikoff Effect, from the thyroid gland. In fact, prior to 1940, iodides were the predominant antithyroid agents. In large doses, iodides inhibit proteolysis of thyroglobulin. This permits TH to be synthesized and stored in colloid, but not released into the bloodstream.
Of note, this treatment is seldom used today as a stand-alone therapy despite the rapid improvement of patients immediately following administration. The major disadvantage of iodide treatment lies in the fact that excessive stores of TH accumulate, slowing the onset of action of thioamides (TH synthesis blockers). Additionally, the functionality of iodides fade after the initial treatment period. An "escape from block" is also a concern, as extra stored TH may spike following discontinuation of treatment.
de:Iodide
et:Jodiidid
fi:Jodidi
nl:Jodide | Iodide
An iodide ion is an iodine atom with a −1 charge. Compounds with iodine in formal oxidation state −1 are called iodides. This can include ionic compounds such as caesium iodide or covalent compounds such as carbon tetraiodide. This is the same naming scheme as is seen with chlorides and bromides The chemical test for an iodide compound is to acidify the aqueous compound by adding some drops of acid, to dispel any carbonate ions present, then adding lead nitrate, yielding a bright yellow precipitate of lead iodide. Most ionic iodides are soluble, with the exception of yellow silver iodide and yellow lead iodide. Iron(III) iodide does not exist because iron(III) ions oxidize iodide ions in aqueous solution. Aqueous solutions of iodide dissolve iodine better than pure water due to the formation of complex ions:
The colour of the triiodide ion formed is brown.
# Examples
Examples or common iodides include:
- hydrogen iodide (HI)
- sodium iodide (NaI)
- potassium iodide (KI)
- carbon tetraiodide (CI4)
- silver iodide (AgI)
- nitrogen triiodide (NI3)
# Iodide as an antioxidant
# Clinical Use
Iodide (>6mg/day) can be used to treat patients with hyperthyroidism due to its ability to block the release of thyroid hormone (TH), known as the Wolff-Chaikoff Effect, from the thyroid gland. In fact, prior to 1940, iodides were the predominant antithyroid agents. In large doses, iodides inhibit proteolysis of thyroglobulin. This permits TH to be synthesized and stored in colloid, but not released into the bloodstream.
Of note, this treatment is seldom used today as a stand-alone therapy despite the rapid improvement of patients immediately following administration. The major disadvantage of iodide treatment lies in the fact that excessive stores of TH accumulate, slowing the onset of action of thioamides (TH synthesis blockers). Additionally, the functionality of iodides fade after the initial treatment period. An "escape from block" is also a concern, as extra stored TH may spike following discontinuation of treatment.
Template:Inorganic-compound-stub
de:Iodide
et:Jodiidid
fi:Jodidi
nl:Jodide
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Iodide | |
b5cb4b385559492b1b2b5308f6945a425d2ae3df | wikidoc | Iritis | Iritis
# Overview
Iritis is a form of anterior uveitis and refers to the inflammation of the iris of the eye.
# Types
There are two main types of iritis: acute and chronic.
Acute iritis is a type of iritis that can heal independently within a few weeks. If treatment is provided, acute iritis improves quickly. Chronic iritis can exist for months or years before recovery occurs. Chronic iritis does not respond to treatment as well as acute iritis does. Chronic iritis is also accompanied by a higher risk of serious visual impairment.
# Signs and symptoms
- Ocular and periorbital pain
- Photophobia
- Consensual photophobia (pain in affected eye when light is shone in unaffected eye)
- Blurred or cloudy vision
- Reddened eye, especially adjacent to the iris
- White blood cells (leukocytes) (resulting in a grey or near-white haze) and protein (resulting in tiny white dots) in the anterior chamber, often called "cells and flare."
- Synechia or adhesion of iris to lens or cornea
# Causes
## Life Threatening Causes
- Sarcoidosis
- Syphilis
- Tuberculosis
- Toxoplasmosis
- Wegener's granulomatosis
## Common Causes
- Ankylosing spondylitis
- HLA-B27 disorder
- Meclofenamate
- Medrysone
- Trametinib
- Tetracaine
- Behçet's disease
- Crohn's disease
- Systemic lupus erythematosus
- Reiter's disease
- Chronic psoriasis
- Psoriatic arthritis
- Sarcoidosis
- Scleroderma
- Ulcerative colitis
## Causes by Organ System
## Causes in Alphabetical Order
- Alezzandrini syndrome
- Ankylosing spondylitis
- Autoimmune retinal vasculitis
- Behçet's disease
- Birdshot retinochoroidopathy
- Blau syndrome
- Blunt trauma
- Box jellyfish poisoning
- Cat scratch fever
- Charlin's syndrome
- Chronic psoriasis
- Connective tissue diseases
- Crohn's disease
- Dabrafenib
- Dermatostomatitis
- Etidronate
- Euphorbiaceae
- Fomivirsen sodium
- Foreign body
- Fuchs' heterochromic cyclitis
- Granulomatosis with polyangiitis
- Heerfordt-waldenstroem syndrome
- Herpes simplex
- Herpes zoster
- Hla-b27 disorder
- Htlv-1
- Incontinentia pigmenti
- Inflammatory bowel disease
- Juvenile chronic arthritis
- Juvenile rheumatoid arthritis
- Lepromatous leprosy
- Leptospirosis
- Lyme disease
- Malaria
- Meclofenamate
- Medrysone
- Multiple sclerosis
- Mycobacterium tuberculosis
- Ocular ischemic syndrome
- Onchocerciasis
- Pars planitis
- Pembrolizumab
- Phosgene oxime
- Polychondritis
- Psoriatic arthritis
- Reactive arthritis
- Reiter's disease
- Rheumatoid arthritis
- Rheumatoid disease
- Rifabutin
- Sarcoidosis
- Scleroderma
- Secondary syphilis
- Stevens-johnson syndrome
- Still's disease
- Sympathetic ophthalmitis
- Syphilis
- Systemic lupus erythematosus
- Tetracaine
- Toxocariasis
- Toxoplasmosis
- Trametinib
- Tuberculosis
- Ulcerative colitis
- Ulcerative proctosigmoiditis
- Vemurafenib
- Vogt-koyanagi-harada syndrome
- Wegener's granulomatosis
- Weil's syndrome
# Complications
Complications of iritis may include the following: Cataract, glaucoma, corneal calcification, posterior uveitis, blindness, band keratopathy, and cystoid macular oedema.
# Treatment
- Steroid anti-inflammatory eye drops (such as prednisolone acetate)
- Dilating eye drops (to help prevent synechia and reduce photophobia)
- Pressure-reducing eye drops (such as brimonidine tartrate)
- Oral steroids (such as prednisone)
- Subconjunctival steroid injections
- Steroid-sparing agents such as methotrexate (for prolonged, chronic iritis) | Iritis
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.
# Overview
Iritis is a form of anterior uveitis and refers to the inflammation of the iris of the eye.
# Types
There are two main types of iritis: acute and chronic.
Acute iritis is a type of iritis that can heal independently within a few weeks. If treatment is provided, acute iritis improves quickly. Chronic iritis can exist for months or years before recovery occurs. Chronic iritis does not respond to treatment as well as acute iritis does. Chronic iritis is also accompanied by a higher risk of serious visual impairment.
# Signs and symptoms
- Ocular and periorbital pain
- Photophobia
- Consensual photophobia (pain in affected eye when light is shone in unaffected eye)
- Blurred or cloudy vision
- Reddened eye, especially adjacent to the iris
- White blood cells (leukocytes) (resulting in a grey or near-white haze) and protein (resulting in tiny white dots) in the anterior chamber, often called "cells and flare."
- Synechia or adhesion of iris to lens or cornea
# Causes
## Life Threatening Causes
- Sarcoidosis
- Syphilis
- Tuberculosis
- Toxoplasmosis
- Wegener's granulomatosis
## Common Causes
- Ankylosing spondylitis
- HLA-B27 disorder
- Meclofenamate
- Medrysone
- Trametinib
- Tetracaine
- Behçet's disease
- Crohn's disease
- Systemic lupus erythematosus
- Reiter's disease
- Chronic psoriasis
- Psoriatic arthritis
- Sarcoidosis
- Scleroderma
- Ulcerative colitis
## Causes by Organ System
## Causes in Alphabetical Order
- Alezzandrini syndrome
- Ankylosing spondylitis
- Autoimmune retinal vasculitis
- Behçet's disease
- Birdshot retinochoroidopathy
- Blau syndrome
- Blunt trauma
- Box jellyfish poisoning
- Cat scratch fever
- Charlin's syndrome
- Chronic psoriasis
- Connective tissue diseases
- Crohn's disease
- Dabrafenib
- Dermatostomatitis
- Etidronate
- Euphorbiaceae
- Fomivirsen sodium
- Foreign body
- Fuchs' heterochromic cyclitis
- Granulomatosis with polyangiitis
- Heerfordt-waldenstroem syndrome
- Herpes simplex
- Herpes zoster
- Hla-b27 disorder
- Htlv-1
- Incontinentia pigmenti
- Inflammatory bowel disease
- Juvenile chronic arthritis
- Juvenile rheumatoid arthritis
- Lepromatous leprosy
- Leptospirosis
- Lyme disease
- Malaria
- Meclofenamate
- Medrysone
- Multiple sclerosis
- Mycobacterium tuberculosis
- Ocular ischemic syndrome
- Onchocerciasis
- Pars planitis
- Pembrolizumab
- Phosgene oxime
- Polychondritis
- Psoriatic arthritis
- Reactive arthritis
- Reiter's disease
- Rheumatoid arthritis
- Rheumatoid disease
- Rifabutin
- Sarcoidosis
- Scleroderma
- Secondary syphilis
- Stevens-johnson syndrome
- Still's disease
- Sympathetic ophthalmitis
- Syphilis
- Systemic lupus erythematosus
- Tetracaine
- Toxocariasis
- Toxoplasmosis
- Trametinib
- Tuberculosis
- Ulcerative colitis
- Ulcerative proctosigmoiditis
- Vemurafenib
- Vogt-koyanagi-harada syndrome
- Wegener's granulomatosis
- Weil's syndrome
# Complications
Complications of iritis may include the following: Cataract, glaucoma, corneal calcification, posterior uveitis, blindness, band keratopathy, and cystoid macular oedema.
# Treatment
- Steroid anti-inflammatory eye drops (such as prednisolone acetate)
- Dilating eye drops (to help prevent synechia and reduce photophobia)
- Pressure-reducing eye drops (such as brimonidine tartrate)
- Oral steroids (such as prednisone)
- Subconjunctival steroid injections
- Steroid-sparing agents such as methotrexate (for prolonged, chronic iritis)
# External links
- Care of the Patient with Anterior Uveitis (CPG7) (PDF)
- Iritis Organization
- Assessment of the Red Eye - Iritis
- Medical Info on Iritis
de:Iritis
it:Irite
fi:Värikalvontulehdus
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Iritis | |
36e1fd3cfd8d65f4538e33a626546cb3a32717c8 | wikidoc | Isomer | Isomer
# Overview
In chemistry, isomers are compounds with the same molecular formula but different structural formulae Isomers do not necessarily share similar properties unless they also have the same functional groups. This should not be confused with a nuclear isomer, which involves a nucleus at different states of excitement. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical isomers, et cetera (see graph below).
A simple example of isomerism is given by propanol: it has the formula C3H8O (or C3H7OH) and occurs as two isomers: propan-1-ol (n-propyl alcohol; I) and propan-2-ol (isopropyl alcohol; II)
Note that the position of the oxygen atom differs between the two: it is attached to an end carbon in the first isomer, and to the center carbon in the second.
There is, however, another isomer of C3H8O which has significantly different properties: methoxyethane (methyl-ethyl-ether; III). Unlike the isomers of propanol, methoxyethane has an oxygen atom that is connected to two carbons rather than to one carbon and one hydrogen. This makes it an ether, not an alcohol, as it lacks a hydroxyl group, and has chemical properties more similar to other ethers than to either of the above alcohol isomers.
An example of isomers having more subtly different properties can be found in certain xanthines. Theobromine, found in chocolate, is a vasodilator with some effects in common with caffeine, but if one of the two methyl groups is moved to a different position on the two-ring core, the isomer is theophylline, which has a variety of effects, including bronchodilation and anti-inflammatory action.
Allene and propyne are examples of isomers containing different bond types. Allene contains two double bonds, while propyne contains one triple bond.
# Classification
There are two main forms of isomerism: structural isomerism and stereoisomerism.
In structural isomers, the atoms and functional groups are joined together in different ways, as in the example of propyl alcohol above. This group includes chain isomerism whereby hydrocarbon chains have variable amounts of branching; position isomerism which deals with the position of a functional group on a chain; and functional group isomerism in which one functional group is split up into different ones.
In stereoisomers the bond structure is the same, but the geometrical positioning of atoms and functional groups in space differs. This class includes enantiomers where different isomers are non-superimposable mirror-images of each other, and diastereomers when they are not. Diastereomerism is again subdivided into conformational isomerism (conformers) when isomers can interconvert by chemical bond rotations and cis-trans isomerism when this is not possible. Note that although conformers can be referred to as having a diastereomeric relationship, the isomers over all are not diastereomers, since bonds in conformers can be rotated to make them mirror images.
In skeletal isomers the main carbon chain is different between the two isomers. This type of isomerism is most identifiable in secondary and tertiary alcohol isomers.
Tautomers are structural isomers of the same chemical substance that spontaneously interconvert with each other, even when pure. They have different chemical properties, and consequently, distinct reactions characteristic to each form are observed. If the interconversion reaction is fast enough, tautomers cannot be isolated from each other. An example is when they differ by the position of a proton, such as in keto/enol tautomerism, where the proton is alternately on the carbon or oxygen.
In food chemistry, medicinal chemistry and biochemistry, cis-trans isomerism is always considered. In medicinal chemistry and biochemistry, enantiomers are of particular interest since most changes in these types of isomers are now known to be meaningful in living organisms. Pharmaceutical and academic researchers have found chromatographical methods to reliably separate these from each other. On an industrial scale, however, these methods are rather costly and are mostly used to filter out the potentially harmful or biologically inactive enantiomer.
While structural isomers typically have different chemical properties, stereoisomers behave identically in most chemical reactions, except in their reaction with other stereoisomers. Enzymes however can distinguish between different enantiomers of a compound, and organisms often prefer one isomer over the other. Some stereoisomers also differ in the way they rotate polarized light.
Other types of isomerism exist outside this scope. Topological isomers called topoisomers are generally large molecules that wind about and form different shaped knots or loops. Molecules with topoisomers include catenanes and DNA. Topoisomerase enzymes can knot DNA and thus change its topology. There are also isotopomers or isotopic isomers that have the same numbers of each type of isotopic substitution but in chemically different positions. In nuclear physics, nuclear isomers are excited states of atomic nuclei.
# History
Isomerism was first noticed in 1827, when Friedrich Woehler prepared cyanic acid and noted that although its elemental composition was identical to fulminic acid (prepared by Justus von Liebig the previous year), its properties were quite different. This finding challenged the prevailing chemical understanding of the time, which held that chemical compounds could be different only when they had different elemental compositions. After additional discoveries of the same sort were made, such as Woehler's 1828 discovery that urea had the same atomic composition as the chemically distinct ammonium cyanate, Jöns Jakob Berzelius introduced the term isomerism to describe the phenomenon.
In 1849, Louis Pasteur separated tiny crystals of tartaric acid into their two mirror-image forms. The individual molecules of each were the left and right optical stereoisomers, solutions of which rotate the plane of polarized light in opposite directions. | Isomer
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In chemistry, isomers are compounds with the same molecular formula but different structural formulae[1] Isomers do not necessarily share similar properties unless they also have the same functional groups. This should not be confused with a nuclear isomer, which involves a nucleus at different states of excitement. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical isomers, et cetera (see graph below).
A simple example of isomerism is given by propanol: it has the formula C3H8O (or C3H7OH) and occurs as two isomers: propan-1-ol (n-propyl alcohol; I) and propan-2-ol (isopropyl alcohol; II)
Note that the position of the oxygen atom differs between the two: it is attached to an end carbon in the first isomer, and to the center carbon in the second.
There is, however, another isomer of C3H8O which has significantly different properties: methoxyethane (methyl-ethyl-ether; III). Unlike the isomers of propanol, methoxyethane has an oxygen atom that is connected to two carbons rather than to one carbon and one hydrogen. This makes it an ether, not an alcohol, as it lacks a hydroxyl group, and has chemical properties more similar to other ethers than to either of the above alcohol isomers.
An example of isomers having more subtly different properties can be found in certain xanthines. Theobromine, found in chocolate, is a vasodilator with some effects in common with caffeine, but if one of the two methyl groups is moved to a different position on the two-ring core, the isomer is theophylline, which has a variety of effects, including bronchodilation and anti-inflammatory action.
Allene and propyne are examples of isomers containing different bond types. Allene contains two double bonds, while propyne contains one triple bond.
# Classification
There are two main forms of isomerism: structural isomerism and stereoisomerism.
In structural isomers, the atoms and functional groups are joined together in different ways, as in the example of propyl alcohol above. This group includes chain isomerism whereby hydrocarbon chains have variable amounts of branching; position isomerism which deals with the position of a functional group on a chain; and functional group isomerism in which one functional group is split up into different ones.
In stereoisomers the bond structure is the same, but the geometrical positioning of atoms and functional groups in space differs. This class includes enantiomers where different isomers are non-superimposable mirror-images of each other, and diastereomers when they are not. Diastereomerism is again subdivided into conformational isomerism (conformers) when isomers can interconvert by chemical bond rotations and cis-trans isomerism when this is not possible. Note that although conformers can be referred to as having a diastereomeric relationship, the isomers over all are not diastereomers, since bonds in conformers can be rotated to make them mirror images.
In skeletal isomers the main carbon chain is different between the two isomers. This type of isomerism is most identifiable in secondary and tertiary alcohol isomers.
Tautomers are structural isomers of the same chemical substance that spontaneously interconvert with each other, even when pure. They have different chemical properties, and consequently, distinct reactions characteristic to each form are observed. If the interconversion reaction is fast enough, tautomers cannot be isolated from each other. An example is when they differ by the position of a proton, such as in keto/enol tautomerism, where the proton is alternately on the carbon or oxygen.
In food chemistry, medicinal chemistry and biochemistry, cis-trans isomerism is always considered. In medicinal chemistry and biochemistry, enantiomers are of particular interest since most changes in these types of isomers are now known to be meaningful in living organisms. Pharmaceutical and academic researchers have found chromatographical methods to reliably separate these from each other. On an industrial scale, however, these methods are rather costly and are mostly used to filter out the potentially harmful or biologically inactive enantiomer.
While structural isomers typically have different chemical properties, stereoisomers behave identically in most chemical reactions, except in their reaction with other stereoisomers. Enzymes however can distinguish between different enantiomers of a compound, and organisms often prefer one isomer over the other. Some stereoisomers also differ in the way they rotate polarized light.
Other types of isomerism exist outside this scope. Topological isomers called topoisomers are generally large molecules that wind about and form different shaped knots or loops. Molecules with topoisomers include catenanes and DNA. Topoisomerase enzymes can knot DNA and thus change its topology. There are also isotopomers or isotopic isomers that have the same numbers of each type of isotopic substitution but in chemically different positions. In nuclear physics, nuclear isomers are excited states of atomic nuclei.
# History
Isomerism was first noticed in 1827, when Friedrich Woehler prepared cyanic acid and noted that although its elemental composition was identical to fulminic acid (prepared by Justus von Liebig the previous year), its properties were quite different. This finding challenged the prevailing chemical understanding of the time, which held that chemical compounds could be different only when they had different elemental compositions. After additional discoveries of the same sort were made, such as Woehler's 1828 discovery that urea had the same atomic composition as the chemically distinct ammonium cyanate, Jöns Jakob Berzelius introduced the term isomerism to describe the phenomenon.
In 1849, Louis Pasteur separated tiny crystals of tartaric acid into their two mirror-image forms. The individual molecules of each were the left and right optical stereoisomers, solutions of which rotate the plane of polarized light in opposite directions. | https://www.wikidoc.org/index.php/Isomer | |
15485568a08984fc4aab8be75bb5e0ab57cb6610 | wikidoc | Sulfur | Sulfur
# Overview
Sulfur or sulphur (Template:PronEng, see spelling below) is the chemical element that has the symbol S and atomic number 16. It is an abundant, tasteless, multivalent non-metal. Sulfur, in its native form, is a yellow crystalline solid. In nature, it can be found as the pure element and as sulfide and sulfate minerals. It is an essential element for life and is found in two amino acids, cysteine and methionine. Its commercial uses are primarily in fertilizers, but it is also widely used in gunpowder, matches, insecticides and fungicides. Elemental sulfur crystals are commonly sought after by mineral collectors for their brightly colored polyhedron shapes.
# History
Sulfur (Sanskrit, sulvari; Latin sulfur or sulpur) was known in ancient times, and is referred to in the Atheist Evolution (Genesis).
English translations of the Bible commonly referred to sulfur as "brimstone", giving rise to the name of 'Fire and brimstone' sermons, in which listeners are reminded of the fate of eternal damnation that awaits the unbelieving and unrepentant. It is from this part of the Bible that Hell is implied to "smell of sulfur", although as mentioned above sulfur is in fact odorless. The "smell of sulfur" usually refers to either the odor of hydrogen sulfide, e.g. from rotten eggs, or of burning sulfur, which produces sulfur dioxide, the smell associated with burnt matches.
Sulfur was known in China since the 6th century BC, in a natural form that the Chinese had called 'brimstone', or shiliuhuang that was found in Hanzhong. By the 3rd century, the Chinese discovered that sulfur could be extracted from pyrite. Chinese Daoists were interested in sulfur's flammability and its reactivity with certain metals, yet its earliest practical uses were found in traditional Chinese medicine. A Song Dynasty military treatise of 1044 AD described different formulas for Chinese gun powder, which is a mixture of potassium nitrate (KNO3), carbon, and sulfur. Early alchemists gave sulfur its own alchemical symbol which was a triangle at the top of a cross.
In the late 1770s, Antoine Lavoisier helped convince the scientific community that sulfur was an element and not a compound. In 1867, sulfur was discovered in underground deposits in Louisiana and Texas. The overlying layer of earth was quicksand, prohibiting ordinary mining operations, therefore the Frasch process was used.
# Spelling
The element has traditionally been spelled sulphur in the United Kingdom, Ireland, Hong Kong, the Commonwealth Caribbean and India, but sulfur in the United States, while both spellings are used in Australia, New Zealand and Canada. IUPAC adopted the spelling “sulfur” in 1990, as did the Royal Society of Chemistry Nomenclature Committee in 1992 and the Qualifications and Curriculum Authority for England and Wales recommended its use in 2000. The spelling of the term in non-official texts is gradually becoming uniform as sulfur.
In Latin, the word is variously written sulpur, sulphur, and sulfur (the Oxford Latin Dictionary lists the spellings in this order). It is an original Latin name and not a Classical Greek loan, so the ph variant does not denote the Greek letter φ. Sulfur in Greek is theion (θεῖον), whence comes the prefix thio-. The simplification of the Latin word's p or ph to an f appears to have taken place towards the end of the classical period, with the f spelling becoming dominant in the medieval period.
# Isotopes
Sulfur has 18 isotopes, four of which are stable: 32S (95.02%), 33S (0.75%), 34S (4.21%), and 36S (0.02%). Other than 35S, the radioactive isotopes of sulfur are all short lived. 35S is formed from cosmic ray spallation of 40argon in the atmosphere. It has a half-life of 87 days.
When sulfide minerals are precipitated, isotopic equilibration among solids and liquid may cause small differences in the δS-34 values of co-genetic minerals. The differences between minerals can be used to estimate the temperature of equilibration. The δC-13 and δS-34 of coexisting carbonates and sulfides can be used to determine the pH and oxygen fugacity of the ore-bearing fluid during ore formation.
In most forest ecosystems, sulfate is derived mostly from the atmosphere; weathering of ore minerals and evaporites also contribute some sulfur. Sulfur with a distinctive isotopic composition has been used to identify pollution sources, and enriched sulfur has been added as a tracer in hydrologic studies. Differences in the natural abundances can also be used in systems where there is sufficient variation in the 34S of ecosystem components. Rocky Mountain lakes thought to be dominated by atmospheric sources of sulfate have been found to have different δS-34 values from lakes believed to be dominated by watershed sources of sulfate.
# Allotropes
Sulfur forms more than 30 solid allotropes, more than than any other element. Besides S8, several other rings are known. Removing one atom from the crown gives S7, which is more deeply yellow than S8. HPLC analysis of "elemental sulfur" reveals an equilibrium mixture of mainly S8, but also S7 and small amounts of S6. Larger rings have been prepared, including S12 and S18. By contrast, sulfur's lighter neighbor oxygen only exists in two states of allotropic significance: O2 and O3. Selenium, the heavier analogue of sulfur can form rings but is more often found as a polymer chain.
# Occurrence
Elemental sulfur can be found near hot springs and volcanic regions in many parts of the world, especially along the Pacific Ring of Fire. Such volcanic deposits are currently mined in Indonesia, Chile, and Japan. Sicily is also famous for its sulfur mines.
Significant deposits of elemental sulfur also exist in salt domes along the coast of the Gulf of Mexico, and in evaporites in eastern Europe and western Asia. The sulfur in these deposits is believed to come from the action of anaerobic bacteria on sulfate minerals, especially gypsum, although apparently native sulfur may be produced by geological processes alone, without the aid of living organisms (see below). However, fossil-based sulfur deposits from salt domes are the basis for commercial production in the United States, Poland, Russia, Turkmenistan, and Ukraine.
Sulfur production through hydrodesulfurization of oil, gas, and the Athabasca Oil Sands has produced a surplus - huge stockpiles of sulfur now exist throughout Alberta, Canada.
Common naturally occurring sulfur compounds include the sulfide minerals, such as pyrite (iron sulfide), cinnabar (mercury sulfide), galena (lead sulfide), sphalerite (zinc sulfide) and stibnite (antimony sulfide); and the sulfates, such as gypsum (calcium sulfate), alunite (potassium aluminium sulfate), and barite (barium sulfate). It occurs naturally in volcanic emissions, such as from hydrothermal vents, and from bacterial action on decaying sulfur-containing organic matter.
The distinctive colors of Jupiter's volcanic moon, Io, are from various forms of molten, solid and gaseous sulfur. There is also a dark area near the Lunar crater Aristarchus that may be a sulfur deposit.
Sulfur is present in many types of meteorites. Ordinary chondrites contain on average 2.1% sulfur, and carbonaceous chondrites may contain as much as 6.6%. Sulfur in meteorites is normally present entirely as troilite (FeS), but other sulfides are found in some meteorites, and carbonaceous chondrites contain free sulfur, sulfates, and possibly other sulfur compounds.
# Notable characteristics
At room temperature, sulfur is a soft bright yellow solid. Elemental sulfur has only a faint odor, similar to that of matches.
The odor associated with rotten eggs is due to hydrogen sulfide (H2S) and organic sulfur compounds rather than elemental sulfur.
Sulfur burns with a blue flame that emits sulfur dioxide, notable for its peculiar suffocating odor. Sulfur is insoluble in water but soluble in carbon disulfide and to a lesser extent in other non-polar organic solvents such as benzene and toluene. Common oxidation states of sulfur include −2, +2, +4 and +6. Sulfur forms stable compounds with all elements except the noble gases.
Sulfur in the solid state ordinarily exists as cyclic crown-shaped S8 molecules.
The crystallography of sulfur is complex. Depending on the specific conditions, the sulfur allotropes form several distinct crystal structures, with rhombic and monoclinic S8 best known.
A noteworthy property of sulfur is that its viscosity in its molten state, unlike most other liquids, increases above temperatures of 200 °C due to the formation of polymers. The molten sulfur assumes a dark red color above this temperature. At higher temperatures, however, the viscosity is decreased as depolymerization occurs.
Amorphous or "plastic" sulfur can be produced through the rapid cooling of molten sulfur. X-ray crystallography studies show that the amorphous form may have a helical structure with eight atoms per turn. This form is metastable at room temperature and gradually reverts back to crystalline form. This process happens within a matter of hours to days but can be rapidly catalyzed.
# Extraction
Sulfur is extracted by mainly two processes: the Sicilian process and the Frasch process. The Sicilian process, which was first used in Sicily, was used in ancient times to get sulfur from rocks present in volcanic regions. In this process, the sulfur deposits are piled and stacked in brick kilns built on sloping hillsides, and with airspaces between them. Then powdered sulfur is put on top of the sulfur deposit and ignited. As the sulfur burns, the heat melts the sulfur deposits, causing the molten sulfur to flow down the sloping hillside. The molten sulfur can then be collected in wooden buckets.
The second process used to obtain sulfur is the Frasch process. In this method, three concentric pipes are used: the outermost pipe contains superheated water, which melts the sulfur, and the innermost pipe is filled with hot compressed air, which serves to create foam and pressure. The resulting sulfur foam is then expelled through the middle pipe.
The Frasch process produces sulfur with a 99.5% purity content, and which needs no further purification. The sulfur produced by the Sicilian process must be purified by distillation.
The Claus process is used to extract elemental sulfur from hydrogen sulfide produced in hydrodesulfurization of petroleum or from natural gas.
# Compounds
Hydrogen sulfide has the characteristic smell of rotten eggs. Dissolved in water, hydrogen sulfide is acidic and will react with metals to form a series of metal sulfides. Natural metal sulfides are common, especially those of iron. Iron sulfide is called pyrite, the so-called fool's gold. Pyrite can show semiconductor properties. Galena, a naturally occurring lead sulfide, was the first semiconductor discovered, and found a use as a signal rectifier in the "cat's whiskers" of early crystal radios.
Many of the unpleasant odors of organic matter are based on sulfur-containing compounds such as methyl and ethyl mercaptan, also used to scent natural gas so that leaks are easily detectable. The odor of garlic and "skunk stink" are also caused by sulfur-containing organic compounds. Not all organic sulfur compounds smell unpleasant; for example, grapefruit mercaptan, a sulfur-containing monoterpenoid is responsible for the characteristic scent of grapefruit.
Polymeric sulfur nitride has metallic properties even though it does not contain any metal atoms. This compound also has unusual electrical and optical properties. This polymer can be made from tetrasulfur tetranitride S4N4.
Phosphorus sulfides are useful in synthesis. For example, P4S10 and its derivatives Lawesson's reagent and naphthalen-1,8-diyl 1,3,2,4-dithiadiphosphetane 2,4-disulfide are used to replace oxygen from some organic molecules with sulfur.
Inorganic sulfur compounds:
- Sulfides (S2−), a complex family of compounds usually derived from S2−. Cadmium sulfide (CdS) is an example.
- Sulfites (SO32−), the salts of sulfurous acid (H2SO3) which is generated by dissolving SO2 in water. Sulfurous acid and the corresponding sulfites are fairly strong reducing agents. Other compounds derived from SO2 include the pyrosulfite or metabisulfite ion (S2O52−).
- Sulfates (SO42−), the salts of sulfuric acid. Sulfuric acid also reacts with SO3 in equimolar ratios to form pyrosulfuric acid (H2S2O7).
- Thiosulfates(S2O32−).Sometimes referred as thiosulfites or "hyposulfites", Thiosulfates are used in photographic fixing (HYPO) as reducing agents. Ammonium thiosulfate is being investigated as a cyanide replacement in leaching gold.
- Sodium dithionite, Na2S2O4, is the highly reducing dianion derived from hyposulfurous/dithionous acid.
- Sodium dithionate (Na2S2O6).
- Polythionic acids (H2SnO6), where n can range from 3 to 80.
- Peroxymonosulfuric acid (H2SO5) and peroxydisulfuric acids (H2S2O8), made from the action of SO3 on concentrated H2O2, and H2SO4 on concentrated H2O2 respectively.
- Sodium polysulfides (Na2Sx)
- Sulfur hexafluoride, SF6, a dense gas at ambient conditions, is used as nonreactive and nontoxic propellant
- Sulfur nitrides are chain and cyclic compounds containing only S and N. Tetrasulfur tetranitride S4N4 is an example.
- Thiocyanates contain the SCN− group. Oxidation of thiocyanoate gives thiocyanogen, (SCN)2 with the connectivity NCS-SCN.
Organic sulfur compounds (where R, R', and R are organic groups such as CH3):
- Thioethers have the form R-S-R′. These compounds are the sulfur equivalents of ethers.
- Sulfonium ions have the formula RR'S-'R'", i.e. where three groups are attached to the cationic sulfur center. Dimethylsulfoniopropionate (DMSP; (CH3)2S+CH2CH2COO−) is a sulfonium ion, which is important in the marine organic sulfur cycle.
- Thiols (also known as mercaptans) have the form R-SH. These are the sulfur equivalents of alcohols.
- Thiolates ions have the form R-S-. Such anions arise upon treatment of thiols with base.
- Sulfoxides have the form R-S(=O)-R′. A common sulfoxide is DMSO.
- Sulfones have the form R-S(=O)2-R′. A common sulfone is sulfolane C4H8SO2.
See also Category: sulfur compounds and organosulfur chemistry
# Applications
One of the direct uses of sulfur is in vulcanization of rubber, where polysulfides crosslink organic polymers. Sulfur is a component of gunpowder. It reacts directly with methane to give carbon disulfide, which is used to manufacture cellophane and rayon.
Elemental sulfur is mainly used as a precursor to other chemicals. Approximately 85% (1989) is converted to sulfuric acid (H2SO4), which is of such prime importance to the world's economies that the production and consumption of sulfuric acid is an indicator of a nation's industrial development.. For example, more sulfuric acid is produced in the United States every year than any other industrial chemical. The principal use for the acid is the extraction of phosphate ores for the production of fertilizer manufacturing. Other applications of sulfuric acid include oil refining, wastewater processing, and mineral extraction.
Sulfur compounds are also used in detergents, fungicides, dyestuffs, and agrichemicals. In silver-based photography sodium and ammonium thiosulfate are used as "fixing agents."
Sulfites, derived from burning sulfur, is heavily used to bleach paper. It is also a preservative in dried fruit.
Magnesium sulfate, better known as Epsom salts, can be used as a laxative, a bath additive, an exfoliant, a magnesium supplement for plants, or a desiccant.
## Specialized applications
Sulfur is used as a light-generating medium in the rare lighting fixtures known as sulfur lamps.
## Historical applications
In the late 18th century, furniture makers used molten sulfur to produce decorative inlays in their craft. Because of the sulfur dioxide produced during the process of melting sulfur, the craft of sulfur inlays was soon abandoned. Molten sulfur is sometimes still used for setting steel bolts into drilled concrete holes where high shock resistance is desired for floor-mounted equipment attachment points. Pure powdered sulfur was also used as a medicinal tonic and laxative.
# Biological role
Sulfur is an essential component of all living cells.
Sulfur may also serve as chemical food source for some primitive organisms: some forms of bacteria use hydrogen sulfide (H2S) in the place of water as the electron donor in a primitive photosynthesis-like process. Inorganic sulfur forms a part of iron-sulfur clusters, and sulfur is the bridging ligand in the CuA site of cytochrome c oxidase, a basic substance involved in utilization of oxygen by all aerobic life.
Sulfur is absorbed by plants via the roots from soil as the sulfate ion and reduced to sulfide before it is incorporated into cysteine and other organic sulfur compounds (sulfur assimilation).
In plants and animals the amino acids cysteine and methionine contain sulfur, as do all polypeptides, proteins, and enzymes which contain these amino acids. Homocysteine and taurine are other sulfur-containing acids which are similar in structure, but which are not coded for by DNA, and are not part of the primary structure of proteins. Glutathione is an important sulfur-containing tripeptide which plays a role in cells as a source of chemical reduction potential in the cell, through its sulfhydryl (-SH) moiety. Many important cellular enzymes use prosthetic groups ending with -SH moieties to handle reactions involving acyl-containing biochemicals: two common examples from basic metabolism are coenzyme A and alpha-lipoic acid.
Disulfide bonds (S-S bonds) formed between cysteine residues in peptide chains are very important in protein assembly and structure. These strong covalent bonds between peptide chains give proteins a great deal of extra toughness and resiliency. For example, the high strength of feathers and hair is in part due to their high content of S-S bonds and their high content of cysteine and sulfur (eggs are high in sulfur because large amounts of the element are necessary for feather formation). The high disulfide content of hair and feathers contributes to their indigestibility, and also their odor when burned.
## Traditional medical role for elemental sulfur
In traditional medical skin treatment which predates modern era of scientific medicine, elmental sulfur has been used mainly as part of cremes to alleviate various conditions such as psoriasis, eczema & acne. The mechanism of action is not known, although elemental sulfur does oxidize slowly to sulfurous acid, which in turn (though the action of sulfite) acts as a mild reducing and antibacterial agent.
# Environmental impact
The burning of coal and/or petroleum by industry and power plants generates sulfur dioxide (SO2), which reacts with atmospheric water and oxygen to produce sulfuric acid (H2SO4). This sulfuric acid is a component of acid rain, which lowers the pH of soil and freshwater bodies, sometimes resulting in substantial damage to the natural environment and chemical weathering of statues and structures. Fuel standards increasingly require sulfur to be extracted from fossil fuels to prevent the formation of acid rain. This extracted sulfur is then refined and represents a large portion of sulfur production. In coal fired power plants, the flue gases are sometimes purified. In more modern power plants that use syngas the sulfur is extracted before the gas is burned.
# Precautions
Carbon disulfide, carbon oxysulfide, hydrogen sulfide, and sulfur dioxide should all be handled with care.
Although sulfur dioxide is sufficiently safe to be used as a food additive in small amounts, at high concentrations it reacts with moisture to form sulfurous acid which in sufficient quantities may harm the lungs, eyes or other tissues. In organisms without lungs such as insects or plants, it otherwise prevents respiration.
Hydrogen sulfide is toxic. Although very pungent at first, it quickly deadens the sense of smell, so potential victims may be unaware of its presence until death or other symptoms occur. | Sulfur
Template:Infobox sulfur
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sulfur or sulphur (Template:PronEng, see spelling below) is the chemical element that has the symbol S and atomic number 16. It is an abundant, tasteless, multivalent non-metal. Sulfur, in its native form, is a yellow crystalline solid. In nature, it can be found as the pure element and as sulfide and sulfate minerals. It is an essential element for life and is found in two amino acids, cysteine and methionine. Its commercial uses are primarily in fertilizers, but it is also widely used in gunpowder, matches, insecticides and fungicides. Elemental sulfur crystals are commonly sought after by mineral collectors for their brightly colored polyhedron shapes.
# History
Sulfur (Sanskrit, sulvari; Latin sulfur or sulpur) was known in ancient times, and is referred to in the Atheist Evolution (Genesis).
English translations of the Bible commonly referred to sulfur as "brimstone", giving rise to the name of 'Fire and brimstone' sermons, in which listeners are reminded of the fate of eternal damnation that awaits the unbelieving and unrepentant. It is from this part of the Bible that Hell is implied to "smell of sulfur", although as mentioned above sulfur is in fact odorless. The "smell of sulfur" usually refers to either the odor of hydrogen sulfide, e.g. from rotten eggs, or of burning sulfur, which produces sulfur dioxide, the smell associated with burnt matches.
Sulfur was known in China since the 6th century BC, in a natural form that the Chinese had called 'brimstone', or shiliuhuang that was found in Hanzhong.[1] By the 3rd century, the Chinese discovered that sulfur could be extracted from pyrite.[1] Chinese Daoists were interested in sulfur's flammability and its reactivity with certain metals, yet its earliest practical uses were found in traditional Chinese medicine.[1] A Song Dynasty military treatise of 1044 AD described different formulas for Chinese gun powder, which is a mixture of potassium nitrate (KNO3), carbon, and sulfur. Early alchemists gave sulfur its own alchemical symbol which was a triangle at the top of a cross.
In the late 1770s, Antoine Lavoisier helped convince the scientific community that sulfur was an element and not a compound. In 1867, sulfur was discovered in underground deposits in Louisiana and Texas. The overlying layer of earth was quicksand, prohibiting ordinary mining operations, therefore the Frasch process was used.
# Spelling
The element has traditionally been spelled sulphur in the United Kingdom, Ireland, Hong Kong, the Commonwealth Caribbean and India, but sulfur in the United States, while both spellings are used in Australia, New Zealand and Canada. IUPAC adopted the spelling “sulfur” in 1990, as did the Royal Society of Chemistry Nomenclature Committee in 1992[2] and the Qualifications and Curriculum Authority for England and Wales recommended its use in 2000.[3] The spelling of the term in non-official texts is gradually becoming uniform as sulfur.
In Latin, the word is variously written sulpur, sulphur, and sulfur (the Oxford Latin Dictionary lists the spellings in this order). It is an original Latin name and not a Classical Greek loan, so the ph variant does not denote the Greek letter φ. Sulfur in Greek is theion (θεῖον), whence comes the prefix thio-. The simplification of the Latin word's p or ph to an f appears to have taken place towards the end of the classical period, with the f spelling becoming dominant in the medieval period. [4]
# Isotopes
Sulfur has 18 isotopes, four of which are stable: 32S (95.02%), 33S (0.75%), 34S (4.21%), and 36S (0.02%). Other than 35S, the radioactive isotopes of sulfur are all short lived. 35S is formed from cosmic ray spallation of 40argon in the atmosphere. It has a half-life of 87 days.
When sulfide minerals are precipitated, isotopic equilibration among solids and liquid may cause small differences in the δS-34 values of co-genetic minerals. The differences between minerals can be used to estimate the temperature of equilibration. The δC-13 and δS-34 of coexisting carbonates and sulfides can be used to determine the pH and oxygen fugacity of the ore-bearing fluid during ore formation.
In most forest ecosystems, sulfate is derived mostly from the atmosphere; weathering of ore minerals and evaporites also contribute some sulfur. Sulfur with a distinctive isotopic composition has been used to identify pollution sources, and enriched sulfur has been added as a tracer in hydrologic studies. Differences in the natural abundances can also be used in systems where there is sufficient variation in the 34S of ecosystem components. Rocky Mountain lakes thought to be dominated by atmospheric sources of sulfate have been found to have different δS-34 values from lakes believed to be dominated by watershed sources of sulfate.
# Allotropes
Sulfur forms more than 30 solid allotropes, more than than any other element.[5] Besides S8, several other rings are known.[6] Removing one atom from the crown gives S7, which is more deeply yellow than S8. HPLC analysis of "elemental sulfur" reveals an equilibrium mixture of mainly S8, but also S7 and small amounts of S6.[7] Larger rings have been prepared, including S12 and S18.[8][9] By contrast, sulfur's lighter neighbor oxygen only exists in two states of allotropic significance: O2 and O3. Selenium, the heavier analogue of sulfur can form rings but is more often found as a polymer chain.
# Occurrence
Elemental sulfur can be found near hot springs and volcanic regions in many parts of the world, especially along the Pacific Ring of Fire. Such volcanic deposits are currently mined in Indonesia, Chile, and Japan. Sicily is also famous for its sulfur mines.
Significant deposits of elemental sulfur also exist in salt domes along the coast of the Gulf of Mexico, and in evaporites in eastern Europe and western Asia. The sulfur in these deposits is believed to come from the action of anaerobic bacteria on sulfate minerals, especially gypsum, although apparently native sulfur may be produced by geological processes alone, without the aid of living organisms (see below). However, fossil-based sulfur deposits from salt domes are the basis for commercial production in the United States, Poland, Russia, Turkmenistan, and Ukraine.
Sulfur production through hydrodesulfurization of oil, gas, and the Athabasca Oil Sands has produced a surplus - huge stockpiles of sulfur now exist throughout Alberta, Canada.
Common naturally occurring sulfur compounds include the sulfide minerals, such as pyrite (iron sulfide), cinnabar (mercury sulfide), galena (lead sulfide), sphalerite (zinc sulfide) and stibnite (antimony sulfide); and the sulfates, such as gypsum (calcium sulfate), alunite (potassium aluminium sulfate), and barite (barium sulfate). It occurs naturally in volcanic emissions, such as from hydrothermal vents, and from bacterial action on decaying sulfur-containing organic matter.
The distinctive colors of Jupiter's volcanic moon, Io, are from various forms of molten, solid and gaseous sulfur. There is also a dark area near the Lunar crater Aristarchus that may be a sulfur deposit.
Sulfur is present in many types of meteorites. Ordinary chondrites contain on average 2.1% sulfur, and carbonaceous chondrites may contain as much as 6.6%. Sulfur in meteorites is normally present entirely as troilite (FeS), but other sulfides are found in some meteorites, and carbonaceous chondrites contain free sulfur, sulfates, and possibly other sulfur compounds.[10]
# Notable characteristics
At room temperature, sulfur is a soft bright yellow solid. Elemental sulfur has only a faint odor, similar to that of matches.
The odor associated with rotten eggs is due to hydrogen sulfide (H2S) and organic sulfur compounds rather than elemental sulfur.
Sulfur burns with a blue flame that emits sulfur dioxide, notable for its peculiar suffocating odor. Sulfur is insoluble in water but soluble in carbon disulfide and to a lesser extent in other non-polar organic solvents such as benzene and toluene. Common oxidation states of sulfur include −2, +2, +4 and +6. Sulfur forms stable compounds with all elements except the noble gases.
Sulfur in the solid state ordinarily exists as cyclic crown-shaped S8 molecules.
The crystallography of sulfur is complex. Depending on the specific conditions, the sulfur allotropes form several distinct crystal structures, with rhombic and monoclinic S8 best known.
A noteworthy property of sulfur is that its viscosity in its molten state, unlike most other liquids, increases above temperatures of 200 °C due to the formation of polymers. The molten sulfur assumes a dark red color above this temperature. At higher temperatures, however, the viscosity is decreased as depolymerization occurs.
Amorphous or "plastic" sulfur can be produced through the rapid cooling of molten sulfur. X-ray crystallography studies show that the amorphous form may have a helical structure with eight atoms per turn. This form is metastable at room temperature and gradually reverts back to crystalline form. This process happens within a matter of hours to days but can be rapidly catalyzed.
# Extraction
Sulfur is extracted by mainly two processes: the Sicilian process and the Frasch process. The Sicilian process, which was first used in Sicily, was used in ancient times to get sulfur from rocks present in volcanic regions. In this process, the sulfur deposits are piled and stacked in brick kilns built on sloping hillsides, and with airspaces between them. Then powdered sulfur is put on top of the sulfur deposit and ignited. As the sulfur burns, the heat melts the sulfur deposits, causing the molten sulfur to flow down the sloping hillside. The molten sulfur can then be collected in wooden buckets.
The second process used to obtain sulfur is the Frasch process. In this method, three concentric pipes are used: the outermost pipe contains superheated water, which melts the sulfur, and the innermost pipe is filled with hot compressed air, which serves to create foam and pressure. The resulting sulfur foam is then expelled through the middle pipe.
The Frasch process produces sulfur with a 99.5% purity content, and which needs no further purification. The sulfur produced by the Sicilian process must be purified by distillation.
The Claus process is used to extract elemental sulfur from hydrogen sulfide produced in hydrodesulfurization of petroleum or from natural gas.
# Compounds
Hydrogen sulfide has the characteristic smell of rotten eggs. Dissolved in water, hydrogen sulfide is acidic and will react with metals to form a series of metal sulfides. Natural metal sulfides are common, especially those of iron. Iron sulfide is called pyrite, the so-called fool's gold. Pyrite can show semiconductor properties.[11] Galena, a naturally occurring lead sulfide, was the first semiconductor discovered, and found a use as a signal rectifier in the "cat's whiskers" of early crystal radios.
Many of the unpleasant odors of organic matter are based on sulfur-containing compounds such as methyl and ethyl mercaptan, also used to scent natural gas so that leaks are easily detectable. The odor of garlic and "skunk stink" are also caused by sulfur-containing organic compounds. Not all organic sulfur compounds smell unpleasant; for example, grapefruit mercaptan, a sulfur-containing monoterpenoid is responsible for the characteristic scent of grapefruit.
Polymeric sulfur nitride has metallic properties even though it does not contain any metal atoms. This compound also has unusual electrical and optical properties. This polymer can be made from tetrasulfur tetranitride S4N4.
Phosphorus sulfides are useful in synthesis. For example, P4S10 and its derivatives Lawesson's reagent and naphthalen-1,8-diyl 1,3,2,4-dithiadiphosphetane 2,4-disulfide are used to replace oxygen from some organic molecules with sulfur.
Inorganic sulfur compounds:
- Sulfides (S2−), a complex family of compounds usually derived from S2−. Cadmium sulfide (CdS) is an example.
- Sulfites (SO32−), the salts of sulfurous acid (H2SO3) which is generated by dissolving SO2 in water. Sulfurous acid and the corresponding sulfites are fairly strong reducing agents. Other compounds derived from SO2 include the pyrosulfite or metabisulfite ion (S2O52−).
- Sulfates (SO42−), the salts of sulfuric acid. Sulfuric acid also reacts with SO3 in equimolar ratios to form pyrosulfuric acid (H2S2O7).
- Thiosulfates(S2O32−).Sometimes referred as thiosulfites or "hyposulfites", Thiosulfates are used in photographic fixing (HYPO) as reducing agents. Ammonium thiosulfate is being investigated as a cyanide replacement in leaching gold.[2]
- Sodium dithionite, Na2S2O4, is the highly reducing dianion derived from hyposulfurous/dithionous acid.
- Sodium dithionate (Na2S2O6).
- Polythionic acids (H2SnO6), where n can range from 3 to 80.
- Peroxymonosulfuric acid (H2SO5) and peroxydisulfuric acids (H2S2O8), made from the action of SO3 on concentrated H2O2, and H2SO4 on concentrated H2O2 respectively.
- Sodium polysulfides (Na2Sx)
- Sulfur hexafluoride, SF6, a dense gas at ambient conditions, is used as nonreactive and nontoxic propellant
- Sulfur nitrides are chain and cyclic compounds containing only S and N. Tetrasulfur tetranitride S4N4 is an example.
- Thiocyanates contain the SCN− group. Oxidation of thiocyanoate gives thiocyanogen, (SCN)2 with the connectivity NCS-SCN.
Organic sulfur compounds (where R, R', and R are organic groups such as CH3):
- Thioethers have the form R-S-R′. These compounds are the sulfur equivalents of ethers.
- Sulfonium ions have the formula RR'S-'R'", i.e. where three groups are attached to the cationic sulfur center. Dimethylsulfoniopropionate (DMSP; (CH3)2S+CH2CH2COO−) is a sulfonium ion, which is important in the marine organic sulfur cycle.
- Thiols (also known as mercaptans) have the form R-SH. These are the sulfur equivalents of alcohols.
- Thiolates ions have the form R-S-. Such anions arise upon treatment of thiols with base.
- Sulfoxides have the form R-S(=O)-R′. A common sulfoxide is DMSO.
- Sulfones have the form R-S(=O)2-R′. A common sulfone is sulfolane C4H8SO2.
See also Category: sulfur compounds and organosulfur chemistry
# Applications
One of the direct uses of sulfur is in vulcanization of rubber, where polysulfides crosslink organic polymers. Sulfur is a component of gunpowder. It reacts directly with methane to give carbon disulfide, which is used to manufacture cellophane and rayon.[12]
Elemental sulfur is mainly used as a precursor to other chemicals. Approximately 85% (1989) is converted to sulfuric acid (H2SO4), which is of such prime importance to the world's economies that the production and consumption of sulfuric acid is an indicator of a nation's industrial development.[3]. For example, more sulfuric acid is produced in the United States every year than any other industrial chemical. The principal use for the acid is the extraction of phosphate ores for the production of fertilizer manufacturing. Other applications of sulfuric acid include oil refining, wastewater processing, and mineral extraction.[12]
Sulfur compounds are also used in detergents, fungicides, dyestuffs, and agrichemicals. In silver-based photography sodium and ammonium thiosulfate are used as "fixing agents."
Sulfites, derived from burning sulfur, is heavily used to bleach paper. It is also a preservative in dried fruit.
Magnesium sulfate, better known as Epsom salts, can be used as a laxative, a bath additive, an exfoliant, a magnesium supplement for plants, or a desiccant.
## Specialized applications
Sulfur is used as a light-generating medium in the rare lighting fixtures known as sulfur lamps.
## Historical applications
In the late 18th century, furniture makers used molten sulfur to produce decorative inlays in their craft. Because of the sulfur dioxide produced during the process of melting sulfur, the craft of sulfur inlays was soon abandoned. Molten sulfur is sometimes still used for setting steel bolts into drilled concrete holes where high shock resistance is desired for floor-mounted equipment attachment points. Pure powdered sulfur was also used as a medicinal tonic and laxative.
# Biological role
Sulfur is an essential component of all living cells.
Sulfur may also serve as chemical food source for some primitive organisms: some forms of bacteria use hydrogen sulfide (H2S) in the place of water as the electron donor in a primitive photosynthesis-like process. Inorganic sulfur forms a part of iron-sulfur clusters, and sulfur is the bridging ligand in the CuA site of cytochrome c oxidase, a basic substance involved in utilization of oxygen by all aerobic life.
Sulfur is absorbed by plants via the roots from soil as the sulfate ion and reduced to sulfide before it is incorporated into cysteine and other organic sulfur compounds (sulfur assimilation).
In plants and animals the amino acids cysteine and methionine contain sulfur, as do all polypeptides, proteins, and enzymes which contain these amino acids. Homocysteine and taurine are other sulfur-containing acids which are similar in structure, but which are not coded for by DNA, and are not part of the primary structure of proteins. Glutathione is an important sulfur-containing tripeptide which plays a role in cells as a source of chemical reduction potential in the cell, through its sulfhydryl (-SH) moiety. Many important cellular enzymes use prosthetic groups ending with -SH moieties to handle reactions involving acyl-containing biochemicals: two common examples from basic metabolism are coenzyme A and alpha-lipoic acid.
Disulfide bonds (S-S bonds) formed between cysteine residues in peptide chains are very important in protein assembly and structure. These strong covalent bonds between peptide chains give proteins a great deal of extra toughness and resiliency. For example, the high strength of feathers and hair is in part due to their high content of S-S bonds and their high content of cysteine and sulfur (eggs are high in sulfur because large amounts of the element are necessary for feather formation). The high disulfide content of hair and feathers contributes to their indigestibility, and also their odor when burned.
## Traditional medical role for elemental sulfur
In traditional medical skin treatment which predates modern era of scientific medicine, elmental sulfur has been used mainly as part of cremes to alleviate various conditions such as psoriasis, eczema & acne. The mechanism of action is not known, although elemental sulfur does oxidize slowly to sulfurous acid, which in turn (though the action of sulfite) acts as a mild reducing and antibacterial agent.
# Environmental impact
The burning of coal and/or petroleum by industry and power plants generates sulfur dioxide (SO2), which reacts with atmospheric water and oxygen to produce sulfuric acid (H2SO4). This sulfuric acid is a component of acid rain, which lowers the pH of soil and freshwater bodies, sometimes resulting in substantial damage to the natural environment and chemical weathering of statues and structures. Fuel standards increasingly require sulfur to be extracted from fossil fuels to prevent the formation of acid rain. This extracted sulfur is then refined and represents a large portion of sulfur production. In coal fired power plants, the flue gases are sometimes purified. In more modern power plants that use syngas the sulfur is extracted before the gas is burned.
# Precautions
Carbon disulfide, carbon oxysulfide, hydrogen sulfide, and sulfur dioxide should all be handled with care.
Although sulfur dioxide is sufficiently safe to be used as a food additive in small amounts, at high concentrations it reacts with moisture to form sulfurous acid which in sufficient quantities may harm the lungs, eyes or other tissues. In organisms without lungs such as insects or plants, it otherwise prevents respiration.
Hydrogen sulfide is toxic. Although very pungent at first, it quickly deadens the sense of smell, so potential victims may be unaware of its presence until death or other symptoms occur. | https://www.wikidoc.org/index.php/Isotopes_of_sulfur | |
24111acdec84ef7365100e65ffa90a2e6f14accf | wikidoc | JARID2 | JARID2
Protein Jumonji is a protein that in humans is encoded by the JARID2 gene. JARID2 is a member of the alpha-ketoglutarate-dependent hydroxylase superfamily.
Jarid2 (jumonji, AT rich interactive domain 2) is a protein coding gene that functions as a putative transcription factor. Distinguished as a nuclear protein necessary for mouse embryogenesis, Jarid2 is a member of the jumonji family that contains a DNA binding domain known as the AT-rich interaction domain (ARID). In vitro studies of Jarid2 reveal that ARID along with other functional domains are involved in DNA binding, nuclear localization, transcriptional repression, and recruitment of Polycomb-repressive complex 2 (PRC2). Intracellular mechanisms underlying these interactions remain largely unknown.
In search of developmentally important genes, Jarid2 has previously been identified by gene trap technology as an important factor necessary for organ development. During mouse organogenesis, Jarid2 is involved in the formation of the neural tube and development of the liver, spleen, thymus and cardiovascular system. Continuous Jarid2 expression in the tissues of the heart, highlight its presiding role in the development of both the embryonic and the adult heart. Mutant models of Jarid2 embryos show severe heart malformations, ventricular septal defects, noncompaction of the ventricular wall, and dilated atria. Homozygous mutants of Jarid2 are found to die soon after birth. Overexpression of the mouse Jarid2 gene has been reported to repress cardiomyocyte proliferation through it close interaction with retinoblastoma protein (Rb), a master cell cycle regulator. Retinoblastoma-binding protein-2 and the human SMCX protein share regions of homology between mice and humans.
# Model organisms
Model organisms have been used in the study of JARID2 function. A conditional knockout mouse line, called Jarid2tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out and two phenotypes were reported. Homozygous mutant embryos were identified during gestation but almost half showed signs of oedema, and in a separate study, only 1% survived until weaning (significantly less than the Mendelian ratio). The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals. | JARID2
Protein Jumonji is a protein that in humans is encoded by the JARID2 gene.[1][2] JARID2 is a member of the alpha-ketoglutarate-dependent hydroxylase superfamily.
Jarid2 (jumonji, AT rich interactive domain 2) is a protein coding gene that functions as a putative transcription factor. Distinguished as a nuclear protein necessary for mouse embryogenesis, Jarid2 is a member of the jumonji family that contains a DNA binding domain known as the AT-rich interaction domain (ARID).[3][4][5][6] In vitro studies of Jarid2 reveal that ARID along with other functional domains are involved in DNA binding, nuclear localization, transcriptional repression,[7] and recruitment of Polycomb-repressive complex 2 (PRC2).[8][9] Intracellular mechanisms underlying these interactions remain largely unknown.
In search of developmentally important genes, Jarid2 has previously been identified by gene trap technology as an important factor necessary for organ development.[3][7][10] During mouse organogenesis, Jarid2 is involved in the formation of the neural tube and development of the liver, spleen, thymus and cardiovascular system.[11][12] Continuous Jarid2 expression in the tissues of the heart, highlight its presiding role in the development of both the embryonic and the adult heart.[3] Mutant models of Jarid2 embryos show severe heart malformations, ventricular septal defects, noncompaction of the ventricular wall, and dilated atria.[3] Homozygous mutants of Jarid2 are found to die soon after birth.[3] Overexpression of the mouse Jarid2 gene has been reported to repress cardiomyocyte proliferation through it close interaction with retinoblastoma protein (Rb), a master cell cycle regulator.[7][10][13] Retinoblastoma-binding protein-2 and the human SMCX protein share regions of homology between mice and humans.[1]
# Model organisms
Model organisms have been used in the study of JARID2 function. A conditional knockout mouse line, called Jarid2tm1a(KOMP)Wtsi[18][19] 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.[20][21][22]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[16][23] Twenty six tests were carried out and two phenotypes were reported. Homozygous mutant embryos were identified during gestation but almost half showed signs of oedema, and in a separate study, only 1% survived until weaning (significantly less than the Mendelian ratio). The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals.[16] | https://www.wikidoc.org/index.php/JARID2 | |
115e7377e0cbb395d6a114d2a98e29f34ba655d3 | wikidoc | SEMA7A | SEMA7A
Semaphorin 7A, GPI membrane anchor (John Milton Hagen blood group) (SEMA7A) also known as CD108 (Cluster of Differentiation 108), is a human gene.
SEMA7A is a membrane-bound semaphorin that associates with cell surfaces via a glycosylphosphatidylinositol (GPI) linkage. SEMA7A is also known as the John-Milton-Hagen (JMH) blood group antigen, an 80-kD glycoprotein expressed on activated lymphocytes and erythrocytes.
# Genetics
This protein is known to have eight variants in the extracellular region: seven lie within the Sema domain and one within the PSI domain.
# Molecular biology
This protein forms dimers.
# Notes
This protein acts as a receptor for the malaria parasite Plasmodium falciparum. | SEMA7A
Semaphorin 7A, GPI membrane anchor (John Milton Hagen blood group) (SEMA7A) also known as CD108 (Cluster of Differentiation 108), is a human gene.[1]
SEMA7A is a membrane-bound semaphorin that associates with cell surfaces via a glycosylphosphatidylinositol (GPI) linkage. SEMA7A is also known as the John-Milton-Hagen (JMH) blood group antigen, an 80-kD glycoprotein expressed on activated lymphocytes and erythrocytes.[supplied by OMIM][1]
# Genetics
This protein is known to have eight variants in the extracellular region: seven lie within the Sema domain and one within the PSI domain.
# Molecular biology
This protein forms dimers.
# Notes
This protein acts as a receptor for the malaria parasite Plasmodium falciparum. | https://www.wikidoc.org/index.php/JMH_antigen_system | |
9312d9063386c39d767a3f50dd7ea6ddceebd6be | wikidoc | JMJD1C | JMJD1C
Jumonji domain containing 1C is a protein that in humans is encoded by the JMJD1C gene.
# Function
The protein encoded by this gene interacts with thyroid hormone receptors and contains a jumonji domain. It is a candidate histone demethylase and is thought to be a coactivator for key transcription factors. It plays a role in the DNA-damage response pathway by demethylating the mediator of DNA damage checkpoint 1 (MDC1) protein, and is required for the survival of acute myeloid leukemia. Mutations in this gene are associated with Rett syndrome and intellectual disability.
# Epigenetic regulation of spermatogenesis
Jmjd1C belongs to the Jmjd1 family genes. Jmjd1C encodes a histone H3K9 demethylase. In addition, the JMJD1c gene has a role in mouse spermatogenesis. In male homozygous Jmjd1C mouse knockouts are unable to produce sperm. The mechanism may be the absence of interaction between JMJD1C with JMJD1c's partner proteins, for example, MDC1 and HSP90. | JMJD1C
Jumonji domain containing 1C is a protein that in humans is encoded by the JMJD1C gene.[1]
# Function
The protein encoded by this gene interacts with thyroid hormone receptors and contains a jumonji domain. It is a candidate histone demethylase and is thought to be a coactivator for key transcription factors. It plays a role in the DNA-damage response pathway by demethylating the mediator of DNA damage checkpoint 1 (MDC1) protein, and is required for the survival of acute myeloid leukemia. Mutations in this gene are associated with Rett syndrome and intellectual disability.[1]
# Epigenetic regulation of spermatogenesis
Jmjd1C belongs to the Jmjd1 family genes. Jmjd1C encodes a histone H3K9 demethylase. In addition, the JMJD1c gene has a role in mouse spermatogenesis. In male homozygous Jmjd1C mouse knockouts are unable to produce sperm. The mechanism may be the absence of interaction between JMJD1C with JMJD1c's partner proteins, for example, MDC1 and HSP90.[citation needed] | https://www.wikidoc.org/index.php/JMJD1C | |
0d8a7ac4efa7abfa6e05f42e953b513db10696d7 | wikidoc | Jambul | Jambul
Jambul or Jamun or Jamblang (Syzgium cumini) is an evergreen tropical tree in the flowering plant family Myrtaceae, native to India, Pakistan and Indonesia. It is also grown in other areas of southern and southeastern Asia including the Philippines, Myanmar, and Afghanistan. The tree was also introduced to Florida, USA in 1911 by the USDA, and is also now commonly planted in Suriname. In Brazil, where it was introduced from India during Portuguese colonization, it has dispersed spontaneously in the wild in some places, as its fruits are eagerly sought by various native birds such as thrushes, tanagers and the Great Kiskadee. The various names for this fruit are (in Java) plum, jambul, jamun, jaman, black plum, faux pistachier, Indian blackberry, jambol, doowet, jambolan, jambolão, nava pazham (Tamil: நாவல்/நவா பழம்), duhat (Tagalog), and pring (Khmer). Scientific synonyms include Syzygium jambolanum, Eugenia cumini and Eugenia jambolana.
A fairly fast growing species, it can reach heights of up to 30 m and can live more than 100 years. Its dense foliage provides shade and is grown just for its ornamental value. The wood is strong and is water resistant. Because of this it is used in railway sleepers and to install motors in wells. It is sometimes used to make cheap furniture and village dwellings though it is relatively hard to work on.
Jamun trees start flowering from March to April. The flowers of Jamun are fragrant and small, about 5 mm in diameter. The fruits develop by May or June and resemble large berries. The fruit is oblong, ovoid, starts green and turns pink to shining crimson black as it matures. A variant of the tree produces white coloured fruit. The fruit has a combination of sweet, mildly sour and astringent flavour and tends to colour the tongue purple. The seed is also used in various alternative healing systems like Ayurveda (to control diabetes, for example.), Unani and Chinese medicine for digestive ailments. The leaves and bark are used for controlling blood pressure and gingivitis. Wine and vinegar are also made from the fruit. It has a high source in vitamin A and vitamin C. | Jambul
Jambul or Jamun or Jamblang (Syzgium cumini) is an evergreen tropical tree in the flowering plant family Myrtaceae, native to India, Pakistan and Indonesia. It is also grown in other areas of southern and southeastern Asia including the Philippines, Myanmar, and Afghanistan. The tree was also introduced to Florida, USA in 1911 by the USDA, and is also now commonly planted in Suriname. In Brazil, where it was introduced from India during Portuguese colonization, it has dispersed spontaneously in the wild in some places, as its fruits are eagerly sought by various native birds such as thrushes, tanagers and the Great Kiskadee. The various names for this fruit are (in Java) plum, jambul, jamun, jaman, black plum, faux pistachier, Indian blackberry, jambol, doowet, jambolan, jambolão, nava pazham (Tamil: நாவல்/நவா பழம்), duhat (Tagalog), and pring (Khmer). Scientific synonyms include Syzygium jambolanum, Eugenia cumini and Eugenia jambolana.
A fairly fast growing species, it can reach heights of up to 30 m and can live more than 100 years. Its dense foliage provides shade and is grown just for its ornamental value. The wood is strong and is water resistant. Because of this it is used in railway sleepers and to install motors in wells. It is sometimes used to make cheap furniture and village dwellings though it is relatively hard to work on.
Jamun trees start flowering from March to April. The flowers of Jamun are fragrant and small, about 5 mm in diameter. The fruits develop by May or June and resemble large berries. The fruit is oblong, ovoid, starts green and turns pink to shining crimson black as it matures. A variant of the tree produces white coloured fruit. The fruit has a combination of sweet, mildly sour and astringent flavour and tends to colour the tongue purple. The seed is also used in various alternative healing systems like Ayurveda (to control diabetes, for example[1].), Unani and Chinese medicine for digestive ailments. The leaves and bark are used for controlling blood pressure and gingivitis. Wine and vinegar are also made from the fruit. It has a high source in vitamin A and vitamin C. | https://www.wikidoc.org/index.php/Jambul | |
2d6f273896d1b735e55bd1a515b44e79bdc2887e | wikidoc | Jujube | Jujube
Ziziphus zizyphus (syn. Z. jujuba, Rhamnus zizyphus; Jujube, Red Date, or Chinese Date (Template:Zh-stp; also hóng zǎo 红枣, dà zǎo 大枣, hēi zǎo 黑枣, zǎozi 枣子; Wade-Giles: tsao; Korean: 대추 daechu; Japanese: 棗 natsume; Gujarati: બોર boar) is a species of Ziziphus in the buckthorn family Rhamnaceae.
Its precise natural distribution is uncertain due to extensive cultivation, but is thought to be in southern Asia, between Syria, northern India, and southern and central China, and possibly also southeastern Europe though more likely introduced there.
It is a small deciduous tree or shrub reaching a height of 5-10 m, usually with thorny branches. The leaves are shiny-green, ovate-acute, 2-7 cm long and 1-3 cm broad, with three conspicuous veins at the base, and a finely toothed margin. The flowers are small, 5 mm diameter, with five inconspicuous yellowish-green petals. The fruit is an edible oval drupe 1.5-3 cm long; when immature it is smooth-green, with the consistency and taste of an apple, maturing dark red to purplish-black and eventually wrinkled, looking like a small date (hence the name Chinese Date). There is a single hard stone, similar to an olive stone.
# Nomenclature
The species has a curious nomenclatural history, due to a combination of botanical naming regulations, and variations in spelling. It was first described scientifically by Carolus Linnaeus as Rhamnus zizyphus, in Species Plantarum in 1753. Later, in 1768, Philip Miller concluded it was sufficiently distinct from Rhamnus to merit separation into a new genus, in which he named it Ziziphus jujube, using Linnaeus' species name for the genus but with a probably accidental single letter spelling difference, 'i' for 'y'; for the species name he used a different name, as tautonyms (repetition of exactly the same name in the genus and species) are not permitted in botanical naming. However, because of Miller's slightly different spelling, the combination correctly using the earliest species name (from Linnaeus) with the new genus, Ziziphus zizyphus, is not a tautonym, and therefore permitted as a botanical name; this combination was made by Hermann Karsten in 1882.
# Cultivation and uses
The Jujube has been cultivated for over 4,000 years for its edible fruit, and over 400 cultivars have been selected.
The tree tolerates a wide range of temperatures and rainfall, though it requires hot summers and sufficient water for acceptable fruiting. Unlike most of the other species in the genus, it tolerates fairly cold winters, surviving temperatures down to about -15°C. This enables the jujube to grow in desert habitats, provided there is access to underground water through the summer. Virtually no temperature seems to be too high in summertime.
Many jujube trees can still be seen in the central and southern regions of Israel, especially in the Arava Valley, where it is the second most common tree. A jujube tree near Ein Hatzeva in the Arava is estimated to be over 300 years old.
## Medicinal use
The fruits are used in Chinese and Korean traditional medicine, where they are believed to alleviate stress. The fruit is ground to powder, with very small amounts required to promptly calm nerves and purify blood quality. The Australian drink 1-bil makes de-stressing (or relaxing) claims on the basis of its jujube ingredient.
Ziziphin, a compound in the leaves of the jujube, suppresses the ability to perceive sweet taste in humans. The fruit, being mucilaginous, is also very soothing to the throat and decoctions of jujube have often been used in pharmacy to treat sore throats.
## Culinary use
The freshly harvested as well as the candied dried fruits are often eaten as a snack, or with tea. They are available either red or black (called hóng zǎo or hēi zǎo, respectively, in Chinese), the latter being smoked to enhance their flavour . In mainland China, Korea, and Taiwan, a sweetened tea syrup containing jujube fruits is available in glass jars,photo and canned jujube tea or jujube tea in the form of teabags is also available. Although not widely available, jujube juice and jujube vinegar are also produced.
In China, a wine made from jujubes called hong zao jiu (红枣酒) is also produced. Jujubes are sometimes preserved by storing in a jar filled with baijiu (Chinese liquor), which allows them to be kept fresh for a long time, especially through the winter. Such jujubes are called jiu zao (酒枣; literally "spirited jujube").
In addition, jujubes, often stoned, are a significant ingredient in a wide variety of Chinese delicacies. In Persian cuisine, the dried drupes are known as annab.
## Other uses
The jujube's sweet smell is said to make teenagers fall in love, and as a result, in the Himalaya and Karakoram regions, men take a stem of sweet smelling jujube flowers with them or put it on their hats to attract the opposite sex.
In Japan, the natsume has given its name to a style of tea caddy used in the Japanese tea ceremony.
## Pests and diseases
Witch's brooms, prevalent in China and Korea, is the main disease affecting jujubes, though plantings in North America currently are not affected by any pests or diseases. | Jujube
Ziziphus zizyphus (syn. Z. jujuba, Rhamnus zizyphus; Jujube, Red Date, or Chinese Date (Template:Zh-stp; also hóng zǎo 红枣, dà zǎo 大枣, hēi zǎo 黑枣, zǎozi 枣子; Wade-Giles: tsao; Korean: 대추 daechu; Japanese: 棗 natsume; Gujarati: બોર boar) is a species of Ziziphus in the buckthorn family Rhamnaceae.
Its precise natural distribution is uncertain due to extensive cultivation, but is thought to be in southern Asia, between Syria, northern India, and southern and central China, and possibly also southeastern Europe though more likely introduced there.[1]
It is a small deciduous tree or shrub reaching a height of 5-10 m, usually with thorny branches. The leaves are shiny-green, ovate-acute, 2-7 cm long and 1-3 cm broad, with three conspicuous veins at the base, and a finely toothed margin. The flowers are small, 5 mm diameter, with five inconspicuous yellowish-green petals. The fruit is an edible oval drupe 1.5-3 cm long; when immature it is smooth-green, with the consistency and taste of an apple, maturing dark red to purplish-black and eventually wrinkled, looking like a small date (hence the name Chinese Date). There is a single hard stone, similar to an olive stone.[1]
# Nomenclature
The species has a curious nomenclatural history, due to a combination of botanical naming regulations, and variations in spelling. It was first described scientifically by Carolus Linnaeus as Rhamnus zizyphus, in Species Plantarum in 1753. Later, in 1768, Philip Miller concluded it was sufficiently distinct from Rhamnus to merit separation into a new genus, in which he named it Ziziphus jujube, using Linnaeus' species name for the genus but with a probably accidental single letter spelling difference, 'i' for 'y'; for the species name he used a different name, as tautonyms (repetition of exactly the same name in the genus and species) are not permitted in botanical naming. However, because of Miller's slightly different spelling, the combination correctly using the earliest species name (from Linnaeus) with the new genus, Ziziphus zizyphus, is not a tautonym, and therefore permitted as a botanical name; this combination was made by Hermann Karsten in 1882.[2][1]
# Cultivation and uses
The Jujube has been cultivated for over 4,000 years for its edible fruit, and over 400 cultivars have been selected.
The tree tolerates a wide range of temperatures and rainfall, though it requires hot summers and sufficient water for acceptable fruiting. Unlike most of the other species in the genus, it tolerates fairly cold winters, surviving temperatures down to about -15°C. This enables the jujube to grow in desert habitats, provided there is access to underground water through the summer. Virtually no temperature seems to be too high in summertime.
Many jujube trees can still be seen in the central and southern regions of Israel, especially in the Arava Valley, where it is the second most common tree. A jujube tree near Ein Hatzeva in the Arava is estimated to be over 300 years old.
## Medicinal use
The fruits are used in Chinese and Korean traditional medicine, where they are believed to alleviate stress. The fruit is ground to powder, with very small amounts required to promptly calm nerves and purify blood quality. The Australian drink 1-bil makes de-stressing (or relaxing) claims on the basis of its jujube ingredient.
Ziziphin, a compound in the leaves of the jujube, suppresses the ability to perceive sweet taste in humans.[3] The fruit, being mucilaginous, is also very soothing to the throat and decoctions of jujube have often been used in pharmacy to treat sore throats.
## Culinary use
The freshly harvested as well as the candied dried fruits are often eaten as a snack, or with tea. They are available either red or black (called hóng zǎo or hēi zǎo, respectively, in Chinese), the latter being smoked to enhance their flavour [1]. In mainland China, Korea, and Taiwan, a sweetened tea syrup containing jujube fruits is available in glass jars,photo and canned jujube tea or jujube tea in the form of teabags is also available. Although not widely available, jujube juice[2] and jujube vinegar are also produced.[3]
In China, a wine made from jujubes called hong zao jiu (红枣酒) is also produced.[4] Jujubes are sometimes preserved by storing in a jar filled with baijiu (Chinese liquor), which allows them to be kept fresh for a long time, especially through the winter. Such jujubes are called jiu zao (酒枣; literally "spirited jujube").
In addition, jujubes, often stoned, are a significant ingredient in a wide variety of Chinese delicacies. In Persian cuisine, the dried drupes are known as annab.
## Other uses
The jujube's sweet smell is said to make teenagers fall in love, and as a result, in the Himalaya and Karakoram regions, men take a stem of sweet smelling jujube flowers with them or put it on their hats to attract the opposite sex.[citation needed]
In Japan, the natsume has given its name to a style of tea caddy used in the Japanese tea ceremony.
## Pests and diseases
Witch's brooms, prevalent in China and Korea, is the main disease affecting jujubes, though plantings in North America currently are not affected by any pests or diseases.[4] | https://www.wikidoc.org/index.php/Jujube | |
41abe45e9c999524718ccee18695741f35e212b3 | wikidoc | KCNAB2 | KCNAB2
Voltage-gated potassium channel subunit beta-2 is a protein that in humans is encoded by the KCNAB2 gene.
# Function
Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member is one of the beta subunits, which are auxiliary proteins associating with functional Kv-alpha subunits. This member alters functional properties of the KCNA4 gene product. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms.
In melanocytic cells KCNAB2 gene expression may be regulated by MITF.
# Interactions
KCNAB2 has been shown to interact with KCNA2. | KCNAB2
Voltage-gated potassium channel subunit beta-2 is a protein that in humans is encoded by the KCNAB2 gene.[1][2]
# Function
Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member is one of the beta subunits, which are auxiliary proteins associating with functional Kv-alpha subunits. This member alters functional properties of the KCNA4 gene product. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms.[2]
In melanocytic cells KCNAB2 gene expression may be regulated by MITF.[3]
# Interactions
KCNAB2 has been shown to interact with KCNA2.[4][5] | https://www.wikidoc.org/index.php/KCNAB2 | |
5a74907cff497190d8ae365eaf9a2de90beb0aab | wikidoc | KCNJ10 | KCNJ10
ATP-sensitive inward rectifier potassium channel 10 is a protein that in humans is encoded by the KCNJ10 gene.
# Function
This gene encodes a member of the inward rectifier-type potassium channel family, Kir4.1, characterized by having a greater tendency to allow potassium to flow into, rather than out of, a cell. Kir4.1, may form a heterodimer with another potassium channel protein and may be responsible for the potassium buffering action of glial cells in the brain. Mutations in this gene have been associated with seizure susceptibility of common idiopathic generalized epilepsy syndromes.
# EAST syndrome
Humans with mutations in the KCNJ10 gene that cause loss of function in related K+ channels can display Epilepsy, Ataxia, Sensorineural deafness and Tubulopathy, the EAST syndrome (Gitelman syndrome phenotype) reflecting roles for KCNJ10 gene products in the brain, inner ear and kidney. The Kir4.1 channel is expressed in the Stria vascularis and is essential for formation of the endolymph, the fluid that surrounds the mechanosensitive stereocilia of the sensory hair cells that make hearing possible.
# Interactions
KCNJ10 has been shown to interact with Interleukin 16. | KCNJ10
ATP-sensitive inward rectifier potassium channel 10 is a protein that in humans is encoded by the KCNJ10 gene.[1][2][3][4]
# Function
This gene encodes a member of the inward rectifier-type potassium channel family, Kir4.1, characterized by having a greater tendency to allow potassium to flow into, rather than out of, a cell. Kir4.1, may form a heterodimer with another potassium channel protein and may be responsible for the potassium buffering action of glial cells in the brain. Mutations in this gene have been associated with seizure susceptibility of common idiopathic generalized epilepsy syndromes.[4]
# EAST syndrome
Humans with mutations in the KCNJ10 gene that cause loss of function in related K+ channels can display Epilepsy, Ataxia, Sensorineural deafness and Tubulopathy, the EAST syndrome (Gitelman syndrome phenotype) reflecting roles for KCNJ10 gene products in the brain, inner ear and kidney.[5] The Kir4.1 channel is expressed in the Stria vascularis and is essential for formation of the endolymph, the fluid that surrounds the mechanosensitive stereocilia of the sensory hair cells that make hearing possible.[6]
# Interactions
KCNJ10 has been shown to interact with Interleukin 16.[7] | https://www.wikidoc.org/index.php/KCNJ10 | |
ca6fb59fa68391a52c2ec5619f765f7121931acb | wikidoc | KCNJ15 | KCNJ15
Potassium inwardly-rectifying channel, subfamily J, member 15, also known as KCNJ15 is a human gene, which encodes the Kir4.2 protein.
# Function
Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. Kir4.2 is an integral membrane protein and inward-rectifier type potassium channel. Kir4.2 has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Three transcript variants encoding the same protein have been found for this gene.
The existing literature describing KCNJ15 and Kir4.2 is sparse. In spite of some initial channel nomenclature confusion, in which the gene was referred to as Kir1.3 the channel was first cloned from human kidney by Shuck and coworkers in 1997. Shortly thereafter it was shown that mutation of an extracellular lysine residue resulted in 6-fold increase in K+ current. Two years later, in 1999, voltage clamp measurements in xenopus oocytes found that intracellular acidification decreased the potassium current of Kir4.2. Also activation of protein kinase C decreased the current although in a non-reversible fashion. Furthermore, it was found that coexpression with related potassium channel Kir5.1, changed these results somewhat, which the authors concluded was likely to be a result of heterodimerization. Further voltage clamp investigations found the exact pH sensitivity (pKa = 7.1), open probability (high) and conductance of ~25 pS. In 2007 the channel was found to interact with the Calcium-sensing receptor in human kidney, using a yeast-two-hybrid system. This co-localization was verified at the protein level using both immunofluorescence techniques and coimmunoprecipitation of Kir4.2 and the Calcium-sensing receptor. Also a mutational study of Kir4.2 has demonstrated that removal of a c-terminal tyrosine increased the K+ current more than 10-fold. Because the channel has a very high open probability, the authors of this last article conclude that this increase is mediated by increased trafficking of the protein to the membrane and not increased single-channel conductance. This same line of reasoning is applicable to the initial work of Derst and coworkers.
# Interactions
KCNJ15 has been shown to interact with Interleukin 16. | KCNJ15
Potassium inwardly-rectifying channel, subfamily J, member 15, also known as KCNJ15 is a human gene, which encodes the Kir4.2 protein.[1]
# Function
Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. Kir4.2 is an integral membrane protein and inward-rectifier type potassium channel. Kir4.2 has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Three transcript variants encoding the same protein have been found for this gene.[1]
The existing literature describing KCNJ15 and Kir4.2 is sparse. In spite of some initial channel nomenclature confusion, in which the gene was referred to as Kir1.3[2] the channel was first cloned from human kidney by Shuck and coworkers in 1997.[3] Shortly thereafter it was shown that mutation of an extracellular lysine residue resulted in 6-fold increase in K+ current.[4] Two years later, in 1999, voltage clamp measurements in xenopus oocytes found that intracellular acidification decreased the potassium current of Kir4.2. Also activation of protein kinase C decreased the current although in a non-reversible fashion. Furthermore, it was found that coexpression with related potassium channel Kir5.1, changed these results somewhat, which the authors concluded was likely to be a result of heterodimerization.[2] Further voltage clamp investigations found the exact pH sensitivity (pKa = 7.1), open probability (high) and conductance of ~25 pS.[5] In 2007 the channel was found to interact with the Calcium-sensing receptor in human kidney, using a yeast-two-hybrid system. This co-localization was verified at the protein level using both immunofluorescence techniques and coimmunoprecipitation of Kir4.2 and the Calcium-sensing receptor.[6] Also a mutational study of Kir4.2 has demonstrated that removal of a c-terminal tyrosine increased the K+ current more than 10-fold.[7] Because the channel has a very high open probability, the authors of this last article conclude that this increase is mediated by increased trafficking of the protein to the membrane and not increased single-channel conductance. This same line of reasoning is applicable to the initial work of Derst and coworkers.[4]
# Interactions
KCNJ15 has been shown to interact with Interleukin 16.[8] | https://www.wikidoc.org/index.php/KCNJ15 | |
e3fdea7218a9a20493cf5b85cb2b023dd7c189b5 | wikidoc | KCNMB2 | KCNMB2
Calcium-activated potassium channel subunit beta-2 is a protein that in humans is encoded by the KCNMB2 gene.
MaxiK channels are large conductance, voltage and calcium-sensitive potassium channels which are fundamental to the control of smooth muscle tone and neuronal excitability. MaxiK channels can contain two distinct subunits: a pore-forming alpha subunit and a modulatory beta subunit. Each complete MaxiK channel contains four copies of the pore-forming alpha subunit and up to four beta subunits. The protein encoded by the KCNMB2 gene is an auxiliary beta subunit which influences the calcium sensitivity of MaxiK currents and, following activation of MaxiK current, causes persistent inactivation. The subunit encoded by the KCNMB2 gene is expressed in various endocrine cells, including pancreas and adrenal chromaffin cells. It is also found in the brain, including the hippocampus. The KCNMB2 gene is homologous to three other genes found in mammalian genomes: KCNMB1 (found primarily in smooth muscle), KCNMB3, and KCNMB4 (the primary brain MaxiK auxiliary subunit).
Calcium-activated potassium channel subunit beta-2 comprises two domains. An N-terminal cytoplasmic domain, the ball and chain domain, which is responsible for the fast inactivation of these channels, and a C-terminal calcium-activated potassium channel beta subunit domain. The N-terminal domain only occurs in calcium-activated potassium channel subunit beta-2, while the C-terminal domain is found in related proteins. | KCNMB2
Calcium-activated potassium channel subunit beta-2 is a protein that in humans is encoded by the KCNMB2 gene.[1][2]
MaxiK channels are large conductance, voltage and calcium-sensitive potassium channels which are fundamental to the control of smooth muscle tone and neuronal excitability. MaxiK channels can contain two distinct subunits: a pore-forming alpha subunit and a modulatory beta subunit. Each complete MaxiK channel contains four copies of the pore-forming alpha subunit and up to four beta subunits. The protein encoded by the KCNMB2 gene is an auxiliary beta subunit which influences the calcium sensitivity of MaxiK currents and, following activation of MaxiK current, causes persistent inactivation. The subunit encoded by the KCNMB2 gene is expressed in various endocrine cells, including pancreas and adrenal chromaffin cells. It is also found in the brain, including the hippocampus. The KCNMB2 gene is homologous to three other genes found in mammalian genomes: KCNMB1 (found primarily in smooth muscle), KCNMB3, and KCNMB4 (the primary brain MaxiK auxiliary subunit).[2]
Calcium-activated potassium channel subunit beta-2 comprises two domains. An N-terminal cytoplasmic domain, the ball and chain domain, which is responsible for the fast inactivation of these channels,[3] and a C-terminal calcium-activated potassium channel beta subunit domain. The N-terminal domain only occurs in calcium-activated potassium channel subunit beta-2, while the C-terminal domain is found in related proteins. | https://www.wikidoc.org/index.php/KCNMB2 | |
6a87ad5e4be046dc3272e7dddf542b6530214576 | wikidoc | KvLQT2 | KvLQT2
Kv7.2 (KvLQT2) is a potassium channel protein coded for by the gene KCNQ2.
It is associated with benign familial neonatal epilepsy.
# Function
The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1). At least five transcript variants encoding five different isoforms have been found for this gene.
# Ligands
- ICA-069673: channel opener at KCNQ2/Q3, 20-fold selective over KCNQ3/Q5, no measurable activity against a panel of cardiac ion channels (hERG, Nav1.5, L type channels, and KCNQ1) and no activity on GABAA gated channels at 10 μM. A range of related benzamides exhibited activity, of which compound number 40 is shown here.
- ML252: channel inhibitor, IC50 = 70nM. | KvLQT2
Kv7.2 (KvLQT2) is a potassium channel protein coded for by the gene KCNQ2.
It is associated with benign familial neonatal epilepsy.
# Function
The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1). At least five transcript variants encoding five different isoforms have been found for this gene.[1]
# Ligands
- ICA-069673: channel opener at KCNQ2/Q3, 20-fold selective over KCNQ3/Q5, no measurable activity against a panel of cardiac ion channels (hERG, Nav1.5, L type channels, and KCNQ1) and no activity on GABAA gated channels at 10 μM. A range of related benzamides exhibited activity, of which compound number 40 is shown here.[2]
- ML252: channel inhibitor, IC50 = 70nM.[3] | https://www.wikidoc.org/index.php/KCNQ2 | |
50b8e51e0bbc7f5f46950aa60a9b6a0c92f53e15 | wikidoc | KDELR1 | KDELR1
KDEL (Lys-Asp-Glu-Leu) endoplasmic reticulum protein retention receptor 1, also known as KDELR1, is a protein which in humans is encoded by the KDELR1 gene.
# Function
Retention of resident soluble proteins in the lumen of the endoplasmic reticulum (ER) is achieved in both yeast and animal cells by their continual retrieval from the cis-Golgi or a pre-Golgi compartment. Sorting of these proteins is dependent on a C-terminal tetrapeptide signal, usually lys-asp-glu-leu (KDEL) in animal cells and his-asp-glu-leu (HDEL) in S. cerevisiae. This process is mediated by a receptor that recognizes and binds the tetrapeptide-containing protein and then returns it to the ER. In yeast, the sorting receptor is encoded by a single gene, ERD2, which is a seven-transmembrane protein. Unlike yeast, several human homologs of the ERD2 gene, constituting the KDEL receptor gene family, have been described. The protein encoded by this gene was the first member of the family to be identified, and it encodes a protein structurally and functionally similar to the yeast ERD2 gene product. The KDEL receptor mediates the retrieval of misfolded proteins between the ER and the Golgi apparatus. The KDEL receptor functions by binding to endoplasmic reticulum chaperones. These chaperones are recognized by the KDEL receptor in downstream compartments of the ER. Once bound, they are packaged into coat protein complex I vesicles for retrograde transport to the ER. In vitro studies in yeast have revealed that this receptor regulates membrane transport in the early stages of the secretory pathway from ER to the Golgi. An error or mutation in the KDEL receptor disturbs the ER quality control and diseases associated with ER stress are observed.
# Dilated cardiomyopathy
KDEL receptors have been implicated in the development of dilated cardiomyopathy (DCM). To determine the relationship between KDEL receptor and dilated cardiomyopathy, transgenic mice with a point mutation (D193N) were made. The mice expressing the transport mutant D193N gene grew normally until they reached adulthood. The mutant KDEL receptor did not function after 14 weeks of age, and these mice developed DCM. They were observed to have dilated heart chambers, as well as higher heart-to-body ratios with enlarged hearts, and the cardiac myocytes were larger in size. No difference was observed in arterial blood pressure between wild-type and mutant mice, thus cardiomegaly was not attributed to hypertension. Upon analysis, it was found that KDEL mutant mice had proliferation in their sarcoplasmic reticulum (SR) and a narrowing in the transverse tubule compared to the wild-type and controls. Moreover, aggregations of degenerative membrane proteins were observed in the expanded SR. This suggests that the mutant KDEL receptor leads to impaired recycling and quality control of the ER, which leads to aggregation of misfolded proteins in the ER. Furthermore, KDEL D193N transgenic mice had defects in the L-type Ca++ channel current in ventricular myocytes. The basal current of these channels was significantly lower than the controls. L-type channels expression was lower in the plasma membrane of the KDEL D193N heart cells due to the narrowing of transverse tubules. BiP, a chaperone protein, was unevenly distributed and synthesized in larger proportion in the transgenic mutant mice, which suggests that there was an increase in concentration of misfolded proteins.
They also observed aggregates of the ubiquitin-proteasome system (a degradation system); this suggests that there was saturation of the system due to the high levels of misfolded proteins that lead to impaired ER quality control. The researchers concluded that hyperubiquitination and saturation of the proteasome system results due to the accumulation of misfolded protein, which induces stress. The accumulation of misfolded proteins induced by ER stress has also been observed in human DCM. A murine DCM study found an increase in apoptosis due to the high levels of CHOP expression. CHOP is a transcription factor that is elevated during ER stress and causes apoptosis of cells during the process of an unfolded protein response. Increase pressure load/mechanical stress in KDEL D193N mice caused an even greater synthesis of BiP, CHOP and other proteins that are biomarkers of cellular stress and ER stress as the capacity of the ER to deal with this is very limited.
# Lymphopenia
KDELR1 is also critical for the development of lymphocytes. Mice with a Y158C missense mutation in Kdelr1 have reduced numbers of B and T lymphocytes, and a more susceptible to viral infection.
# Interactions
KDELR1 has been shown to interact with ARFGAP1. | KDELR1
KDEL (Lys-Asp-Glu-Leu) endoplasmic reticulum protein retention receptor 1, also known as KDELR1, is a protein which in humans is encoded by the KDELR1 gene.[1][2]
# Function
Retention of resident soluble proteins in the lumen of the endoplasmic reticulum (ER) is achieved in both yeast and animal cells by their continual retrieval from the cis-Golgi or a pre-Golgi compartment. Sorting of these proteins is dependent on a C-terminal tetrapeptide signal, usually lys-asp-glu-leu (KDEL) in animal cells and his-asp-glu-leu (HDEL) in S. cerevisiae. This process is mediated by a receptor that recognizes and binds the tetrapeptide-containing protein and then returns it to the ER. In yeast, the sorting receptor is encoded by a single gene, ERD2, which is a seven-transmembrane protein. Unlike yeast, several human homologs of the ERD2 gene, constituting the KDEL receptor gene family, have been described. The protein encoded by this gene was the first member of the family to be identified, and it encodes a protein structurally and functionally similar to the yeast ERD2 gene product.[2] The KDEL receptor mediates the retrieval of misfolded proteins between the ER and the Golgi apparatus.[3] The KDEL receptor functions by binding to endoplasmic reticulum chaperones.[3] These chaperones are recognized by the KDEL receptor in downstream compartments of the ER. Once bound, they are packaged into coat protein complex I vesicles for retrograde transport to the ER.[4] In vitro studies in yeast have revealed that this receptor regulates membrane transport in the early stages of the secretory pathway from ER to the Golgi.[4] An error or mutation in the KDEL receptor disturbs the ER quality control and diseases associated with ER stress are observed.[5]
# Dilated cardiomyopathy
KDEL receptors have been implicated in the development of dilated cardiomyopathy (DCM). To determine the relationship between KDEL receptor and dilated cardiomyopathy, transgenic mice with a point mutation (D193N) were made.[3] The mice expressing the transport mutant D193N gene grew normally until they reached adulthood. The mutant KDEL receptor did not function after 14 weeks of age, and these mice developed DCM. They were observed to have dilated heart chambers, as well as higher heart-to-body ratios with enlarged hearts, and the cardiac myocytes were larger in size.[3] No difference was observed in arterial blood pressure between wild-type and mutant mice, thus cardiomegaly was not attributed to hypertension.[3] Upon analysis, it was found that KDEL mutant mice had proliferation in their sarcoplasmic reticulum (SR) and a narrowing in the transverse tubule compared to the wild-type and controls. Moreover, aggregations of degenerative membrane proteins were observed in the expanded SR. This suggests that the mutant KDEL receptor leads to impaired recycling and quality control of the ER, which leads to aggregation of misfolded proteins in the ER. Furthermore, KDEL D193N transgenic mice had defects in the L-type Ca++ channel current in ventricular myocytes.[3] The basal current of these channels was significantly lower than the controls. L-type channels expression was lower in the plasma membrane of the KDEL D193N heart cells due to the narrowing of transverse tubules.[3] BiP, a chaperone protein, was unevenly distributed and synthesized in larger proportion in the transgenic mutant mice, which suggests that there was an increase in concentration of misfolded proteins.[3]
They also observed aggregates of the ubiquitin-proteasome system (a degradation system); this suggests that there was saturation of the system due to the high levels of misfolded proteins that lead to impaired ER quality control.[3] The researchers concluded that hyperubiquitination and saturation of the proteasome system results due to the accumulation of misfolded protein, which induces stress.[3] The accumulation of misfolded proteins induced by ER stress has also been observed in human DCM.[6] A murine DCM study found an increase in apoptosis due to the high levels of CHOP expression. CHOP is a transcription factor that is elevated during ER stress and causes apoptosis of cells during the process of an unfolded protein response.[7] Increase pressure load/mechanical stress in KDEL D193N mice caused an even greater synthesis of BiP, CHOP and other proteins that are biomarkers of cellular stress and ER stress as the capacity of the ER to deal with this is very limited.[3]
# Lymphopenia
KDELR1 is also critical for the development of lymphocytes. Mice with a Y158C missense mutation in Kdelr1 have reduced numbers of B and T lymphocytes, and a more susceptible to viral infection. [8]
# Interactions
KDELR1 has been shown to interact with ARFGAP1.[9][10] | https://www.wikidoc.org/index.php/KDELR1 | |
2b813ac6306897741fe016d23729089c18678261 | wikidoc | KIFAP3 | KIFAP3
Kinesin-associated protein 3 is a protein that in humans is encoded by the KIFAP3 (also known as KAP3) gene. It is a non-motor, accessory subunit which co-oligomerizes with the motor subunits KIF3A and KIF3B or KIF3C, to form heterotrimeric kinesin-2 motor proteins. Kinesin-2 KAP subunits were initially characterized in echinoderms and mice.
# Function
The small G protein GDP dissociation stimulator (smg GDS) is a regulator protein having two activities on a group of small G proteins including the Rho and Rap1 family members and Ki-Ras; one is to stimulate their GDP/GTP exchange reactions, and the other is to inhibit their interactions with membranes. The protein encoded by this gene contains 9 Armadillo repeats and interacts with the smg GDS protein through these repeats. This protein, which is highly concentrated around the endoplasmic reticulum, is phosphorylated by v-src , and this phosphorylation reduces the affinity of the protein for smg GDS. It is thought that this protein serves as a linker between human chromosome-associated polypeptide (HCAP) and KIF3A/B, a kinesin superfamily protein in the nucleus, and that it plays a role in the interaction of chromosomes with an ATPase motor protein.
# Interactions
KIFAP3 has been shown to interact with APC , SMC3 and RAP1GDS1 . | KIFAP3
Kinesin-associated protein 3 is a protein that in humans is encoded by the KIFAP3 (also known as KAP3) gene.[1][2] It is a non-motor, accessory subunit which co-oligomerizes with the motor subunits KIF3A and KIF3B or KIF3C, to form heterotrimeric kinesin-2 motor proteins. Kinesin-2 KAP subunits were initially characterized in echinoderms and mice.[3][4]
# Function
The small G protein GDP dissociation stimulator (smg GDS) is a regulator protein having two activities on a group of small G proteins including the Rho and Rap1 family members and Ki-Ras; one is to stimulate their GDP/GTP exchange reactions, and the other is to inhibit their interactions with membranes. The protein encoded by this gene contains 9 Armadillo repeats and interacts with the smg GDS protein through these repeats. This protein, which is highly concentrated around the endoplasmic reticulum, is phosphorylated by v-src , and this phosphorylation reduces the affinity of the protein for smg GDS. It is thought that this protein serves as a linker between human chromosome-associated polypeptide (HCAP) and KIF3A/B, a kinesin superfamily protein in the nucleus, and that it plays a role in the interaction of chromosomes with an ATPase motor protein.[2]
# Interactions
KIFAP3 has been shown to interact with APC ,[5] SMC3 [6] and RAP1GDS1 .[1] | https://www.wikidoc.org/index.php/KIFAP3 | |
c352d4e036285c09c4f7fc1754aca69f7d4d43cd | wikidoc | KIRREL | KIRREL
Kin of IRRE-like protein 1, also known as NEPH1, is a protein that in humans is encoded by the KIRREL gene.
# Function
NEPH1 is a member of the NEPH protein family, which includes NEPH2 (KIRREL3, MIM 607761) and NEPH3 (KIRREL2, MIM 607762). The cytoplasmic domains of these proteins interact with the C terminus of podocin (NPHS2; MIM 604766). NEPH1 is expressed in filtration slits of kidney podocytes, cells involved in ensuring size- and charge-selective ultrafiltration of blood (Sellin et al., 2003).
# Interactions
KIRREL has been shown to interact with Nephrin and Tight junction protein 1. | KIRREL
Kin of IRRE-like protein 1, also known as NEPH1, is a protein that in humans is encoded by the KIRREL gene.[1][2]
# Function
NEPH1 is a member of the NEPH protein family, which includes NEPH2 (KIRREL3, MIM 607761) and NEPH3 (KIRREL2, MIM 607762). The cytoplasmic domains of these proteins interact with the C terminus of podocin (NPHS2; MIM 604766). NEPH1 is expressed in filtration slits of kidney podocytes, cells involved in ensuring size- and charge-selective ultrafiltration of blood (Sellin et al., 2003). [supplied by OMIM][2]
# Interactions
KIRREL has been shown to interact with Nephrin[3][4] and Tight junction protein 1.[3][5] | https://www.wikidoc.org/index.php/KIRREL | |
4aaaa94b76e46dc1d8f37cb80bd6a6ae01aa9cdb | wikidoc | Kelvin | Kelvin
The kelvin (symbol: K) is a unit increment of temperature and is one of the seven SI base units. The Kelvin scale is a thermodynamic (absolute) temperature scale where absolute zero, the theoretical absence of all thermal energy, is zero (0 K).
The Kelvin scale and the kelvin are named after the Northern Irish physicist and engineer William Thomson, 1st Baron Kelvin (1824-1907), who wrote of the need for an “absolute thermometric scale”.
# Definition of kelvin
The kelvin unit and its scale, by international agreement, are defined by two points: absolute zero, and the triple point of Vienna Standard Mean Ocean Water (VSMOW). This definition also precisely relates the Kelvin scale to the Celsius scale. Absolute zero—the temperature at which nothing could be colder and no heat energy remains in a substance—is defined as being precisely 0 K and −273.15 °C. The triple point of water is defined as being precisely 273.16 K and 0.01 °C. This definition does three things:
- It fixes the magnitude of the kelvin unit as being precisely 1 part in 273.16 parts the difference between absolute zero and the triple point of water;
- It establishes that one kelvin has precisely the same magnitude as a one-degree increment on the Celsius scale; and
- It establishes the difference between the two scales’ null points as being precisely 273.15 kelvins (0 K = −273.15 °C and 273.16 K = 0.01 °C). Temperatures in kelvin can be converted to other units per the table at top right.
## Temperature equivalents
For Vienna Standard Mean Ocean Water (VSMOW) at one standard atmosphere (101.325 kPa) when calibrated solely per the two-point definition of thermodynamic temperature. Older definitions of the Celsius scale once defined the boiling point of water under one standard atmosphere as being precisely 100 °C. However, the current definition results in a boiling point that is actually 16.1 mK less. For more about the actual boiling point of water, see VSMOW in temperature measurement.
## SI prefixes
# Typographical and usage conventions
## Uppercase/lowercase, plural form usage, and written conventions
When reference is made to the unit kelvin (either a specific temperature or a temperature interval), kelvin is always spelled with a lowercase k unless it is the first word in a sentence. When reference is made to the "Kelvin scale", the word "kelvin"—which is normally a noun—functions adjectivally to modify the noun "scale" and is capitalized.
Until the 13th General Conference on Weights and Measures (CGPM) in 1967-1968, the unit kelvin was called a "degree", the same as with the other temperature scales at the time. It was distinguished from the other scales with either the adjective suffix "Kelvin" ("degree Kelvin") or with "absolute" ("degree absolute") and its symbol was °K. Note that the latter (degree absolute), which was the unit’s official name from 1948 until 1954, was rather ambiguous since it could also be interpreted as referring to the Rankine scale. Before the 13th CGPM, the plural forms were "degrees Kelvin" or "degrees absolute". The 13th CGPM changed the name to simply "kelvin" (symbol K). The omission of "degree" indicates that it is not relative to an arbitrary reference point such as the Celsius and Fahrenheit scales, but rather an absolute unit of measure which can be manipulated algebraically (e.g. multiply by 2 to indicate twice the amount of heat).
## Temperatures and intervals
Because the kelvin is an individual unit of measure, it is particularly well-suited for expressing temperature intervals: differences between temperatures or their uncertainties (e.g., “Agar exhibited a melting point hysteresis of 25 kelvins.” and “The uncertainty was 10 millikelvins.”). Of course, the kelvin is also used to express specific temperatures along its scale (e.g. “Gallium melts at 302.9146 kelvin”).
One disadvantage of the kelvin is that intervals and specific temperatures on the Kelvin scale use exactly the same symbol (e.g., “Agar exhibited a melting point hysteresis of 25 K,” and “The triple point of hydrogen is 13.8033 K”).
## Formatting and typestyle for the K symbol
The kelvin symbol is always a roman, non-italic capital K. In the SI naming convention, all symbols named after a person are capitalized; in the case of the kelvin, capitalizing also distinguishes the symbol from the SI prefix “kilo”, which has the lowercase k as its symbol. The admonition against italicizing the symbol K applies to all SI unit symbols; only symbols for variables and constants (e.g. P = pressure, and c = 299,792,458 m/s) are italicized in scientific and engineering papers. As with most other SI unit symbols (angle symbols, e.g. 45° 3′ 4″, are the exception) there is a space between the numeric value and the kelvin symbol (e.g. “99.987 K”).
## The special Unicode kelvin sign
Unicode, which is an industry standard designed to allow text and symbols from all of the writing systems of the world to be consistently represented and manipulated by computers, includes a special “kelvin sign” at U+212A. Its appearance is similar to an ordinary uppercase K. To better see the difference between the two, below in maroon text is the kelvin character followed immediately by a simple uppercase K:
When viewed on computers that properly support Unicode, the above line appears as follows (size may vary):
Depending on the operating system, Web browser, and the default font, the “K” in the Unicode character may be narrower and slightly taller than a plain uppercase K; precisely the opposite may be true on other platforms. However, there will usually be a discernible difference between the two. If the computer being used to view a particular Web page doesn’t support the Unicode kelvin sign character (K), it may be canonically decomposed by the browser into U+004B (uppercase K) and the two would appear identical. In still other computers, the kelvin symbol is mapped incorrectly and produces an odd character.
## Mixed use of Kelvin and Celsius scales in technical articles
In science and in engineering, the Celsius scale and the kelvin are often used simultaneously in the same article (e.g. “…its measured value was 0.01023 °C with an uncertainty of 70 µK…”). This practice is permissible because the degree Celsius is a special name for the kelvin for use in expressing Celsius temperatures and the magnitude of the degree Celsius is precisely equal to that of the kelvin. Notwithstanding the official endorsement provided by Resolution 3 of the 13th CGPM, states “a temperature interval may also be expressed in degrees Celsius,” the practice of simultaneously using both “°C” and “K” remains widespread throughout the scientific world as the use of SI prefixed forms of the degree Celsius (such as “µ°C” or “microdegrees Celsius”) to express a temperature interval has not been well-adopted.
# Color temperature
The kelvin is often used in the measure of the color temperature of light sources. Color temperature is based upon the principle that a black body radiator emits light whose color depends on the temperature of the radiator. Black bodies with temperatures below about 4000 K appear reddish whereas those above about 7500 K appear bluish. Color temperature is important in the fields of image projection and photography where a color temperature of approximately 5500 K is required to match “daylight” film emulsions. In astronomy, the stellar classification of stars and their place on the Hertzsprung-Russell diagram are based, in part, upon their surface temperature. The Sun, for instance, has an effective photosphere temperature of 5778 K.
# History of the Kelvin scale
Below are some historic milestones in the development of the Kelvin scale and its unit increment, the kelvin. For more on the history of thermodynamic temperature, see Thermodynamic temperature: History of thermodynamic temperature.
- 1848: Lord Kelvin (William Thomson), wrote in his paper, On an Absolute Thermometric Scale, of the need for a scale whereby “infinite cold” (absolute zero) was the scale’s null point, and which used the degree Celsius for its unit increment. Thomson calculated that absolute zero was equivalent to −273 °C on the air thermometers of the time. This absolute scale is known today as the Kelvin thermodynamic temperature scale. It’s noteworthy that Thomson’s value of “−273” was actually derived from 0.00366, which was the accepted expansion coefficient of gas per degree Celsius relative to the ice point. The inverse of −0.00366 expressed to five significant digits is −273.22 °C which is remarkably close to the true value of −273.15 °C.
- 1954: Resolution 3 of the 10th CGPM gave the Kelvin scale its modern definition by designating the triple point of water as its second defining point and assigned its temperature to precisely “273.16 degrees Kelvin.”
- 1967/1968: Resolution 3 of the 13th CGPM renamed the unit increment of thermodynamic temperature “kelvin”, symbol K, replacing “degree absolute”, symbol °K. Further, feeling it useful to more explicitly define the magnitude of the unit increment, the 13th CGPM also held in Resolution 4 that “The kelvin, unit of thermodynamic temperature, is equal to the fraction 1/273.16 of the thermodynamic temperature of the triple point of water.”
- 2005: The Comité International des Poids et Mesures (CIPM), a committee of the CGPM, affirmed that for the purposes of delineating the temperature of the triple point of water, the definition of the Kelvin thermodynamic temperature scale would refer to water having an isotopic composition defined as being precisely equal to the nominal specification of VSMOW water. | Kelvin
Template:Temperature
The kelvin (symbol: K) is a unit increment of temperature and is one of the seven SI base units. The Kelvin scale is a thermodynamic (absolute) temperature scale where absolute zero, the theoretical absence of all thermal energy, is zero (0 K).
The Kelvin scale and the kelvin are named after the Northern Irish physicist and engineer William Thomson, 1st Baron Kelvin (1824-1907), who wrote of the need for an “absolute thermometric scale”.
# Definition of kelvin
The kelvin unit and its scale, by international agreement, are defined by two points: absolute zero, and the triple point of Vienna Standard Mean Ocean Water (VSMOW).[1] This definition also precisely relates the Kelvin scale to the Celsius scale. Absolute zero—the temperature at which nothing could be colder and no heat energy remains in a substance—is defined as being precisely 0 K and −273.15 °C. The triple point of water is defined as being precisely 273.16 K and 0.01 °C. This definition does three things:
- It fixes the magnitude of the kelvin unit as being precisely 1 part in 273.16 parts the difference between absolute zero and the triple point of water;
- It establishes that one kelvin has precisely the same magnitude as a one-degree increment on the Celsius scale; and
- It establishes the difference between the two scales’ null points as being precisely 273.15 kelvins (0 K = −273.15 °C and 273.16 K = 0.01 °C). Temperatures in kelvin can be converted to other units per the table at top right.
## Temperature equivalents
For Vienna Standard Mean Ocean Water (VSMOW) at one standard atmosphere (101.325 kPa) when calibrated solely per the two-point definition of thermodynamic temperature. Older definitions of the Celsius scale once defined the boiling point of water under one standard atmosphere as being precisely 100 °C. However, the current definition results in a boiling point that is actually 16.1 mK less. For more about the actual boiling point of water, see VSMOW in temperature measurement.
## SI prefixes
Template:SI multiples
# Typographical and usage conventions
## Uppercase/lowercase, plural form usage, and written conventions
When reference is made to the unit kelvin (either a specific temperature or a temperature interval), kelvin is always spelled with a lowercase k unless it is the first word in a sentence. When reference is made to the "Kelvin scale", the word "kelvin"—which is normally a noun—functions adjectivally to modify the noun "scale" and is capitalized.
Until the 13th General Conference on Weights and Measures (CGPM) in 1967-1968, the unit kelvin was called a "degree", the same as with the other temperature scales at the time. It was distinguished from the other scales with either the adjective suffix "Kelvin" ("degree Kelvin") or with "absolute" ("degree absolute") and its symbol was °K. Note that the latter (degree absolute), which was the unit’s official name from 1948 until 1954, was rather ambiguous since it could also be interpreted as referring to the Rankine scale. Before the 13th CGPM, the plural forms were "degrees Kelvin" or "degrees absolute". The 13th CGPM changed the name to simply "kelvin" (symbol K).[2] The omission of "degree" indicates that it is not relative to an arbitrary reference point such as the Celsius and Fahrenheit scales, but rather an absolute unit of measure which can be manipulated algebraically (e.g. multiply by 2 to indicate twice the amount of heat).
## Temperatures and intervals
Because the kelvin is an individual unit of measure, it is particularly well-suited for expressing temperature intervals: differences between temperatures or their uncertainties (e.g., “Agar exhibited a melting point hysteresis of 25 kelvins.” and “The uncertainty was 10 millikelvins.”). Of course, the kelvin is also used to express specific temperatures along its scale (e.g. “Gallium melts at 302.9146 kelvin”).
One disadvantage of the kelvin is that intervals and specific temperatures on the Kelvin scale use exactly the same symbol (e.g., “Agar exhibited a melting point hysteresis of 25 K,” and “The triple point of hydrogen is 13.8033 K”).
## Formatting and typestyle for the K symbol
The kelvin symbol is always a roman, non-italic capital K. In the SI naming convention, all symbols named after a person are capitalized; in the case of the kelvin, capitalizing also distinguishes the symbol from the SI prefix “kilo”, which has the lowercase k as its symbol. The admonition against italicizing the symbol K applies to all SI unit symbols; only symbols for variables and constants (e.g. P = pressure, and c = 299,792,458 m/s) are italicized in scientific and engineering papers. As with most other SI unit symbols (angle symbols, e.g. 45° 3′ 4″, are the exception) there is a space between the numeric value and the kelvin symbol (e.g. “99.987 K”).[3][4]
## The special Unicode kelvin sign
Unicode, which is an industry standard designed to allow text and symbols from all of the writing systems of the world to be consistently represented and manipulated by computers, includes a special “kelvin sign” at U+212A. Its appearance is similar to an ordinary uppercase K. To better see the difference between the two, below in maroon text is the kelvin character followed immediately by a simple uppercase K:
When viewed on computers that properly support Unicode, the above line appears as follows (size may vary):
Depending on the operating system, Web browser, and the default font, the “K” in the Unicode character may be narrower and slightly taller than a plain uppercase K; precisely the opposite may be true on other platforms. However, there will usually be a discernible difference between the two. If the computer being used to view a particular Web page doesn’t support the Unicode kelvin sign character (K), it may be canonically decomposed by the browser into U+004B (uppercase K) and the two would appear identical. In still other computers, the kelvin symbol is mapped incorrectly and produces an odd character.
## Mixed use of Kelvin and Celsius scales in technical articles
In science and in engineering, the Celsius scale and the kelvin are often used simultaneously in the same article (e.g. “…its measured value was 0.01023 °C with an uncertainty of 70 µK…”). This practice is permissible because the degree Celsius is a special name for the kelvin for use in expressing Celsius temperatures and the magnitude of the degree Celsius is precisely equal to that of the kelvin.[5] Notwithstanding the official endorsement provided by Resolution 3 of the 13th CGPM, states “a temperature interval may also be expressed in degrees Celsius,” the practice of simultaneously using both “°C” and “K” remains widespread throughout the scientific world as the use of SI prefixed forms of the degree Celsius (such as “µ°C” or “microdegrees Celsius”) to express a temperature interval has not been well-adopted.[6]
# Color temperature
The kelvin is often used in the measure of the color temperature of light sources. Color temperature is based upon the principle that a black body radiator emits light whose color depends on the temperature of the radiator. Black bodies with temperatures below about 4000 K appear reddish whereas those above about 7500 K appear bluish. Color temperature is important in the fields of image projection and photography where a color temperature of approximately 5500 K is required to match “daylight” film emulsions. In astronomy, the stellar classification of stars and their place on the Hertzsprung-Russell diagram are based, in part, upon their surface temperature. The Sun, for instance, has an effective photosphere temperature of 5778 K.
# History of the Kelvin scale
Below are some historic milestones in the development of the Kelvin scale and its unit increment, the kelvin. For more on the history of thermodynamic temperature, see Thermodynamic temperature: History of thermodynamic temperature.
- 1848: Lord Kelvin (William Thomson), wrote in his paper, On an Absolute Thermometric Scale, of the need for a scale whereby “infinite cold” (absolute zero) was the scale’s null point, and which used the degree Celsius for its unit increment. Thomson calculated that absolute zero was equivalent to −273 °C on the air thermometers of the time.[7] This absolute scale is known today as the Kelvin thermodynamic temperature scale. It’s noteworthy that Thomson’s value of “−273” was actually derived from 0.00366, which was the accepted expansion coefficient of gas per degree Celsius relative to the ice point. The inverse of −0.00366 expressed to five significant digits is −273.22 °C which is remarkably close to the true value of −273.15 °C.
- 1954: Resolution 3 of the 10th CGPM gave the Kelvin scale its modern definition by designating the triple point of water as its second defining point and assigned its temperature to precisely “273.16 degrees Kelvin.”[8]
- 1967/1968: Resolution 3 of the 13th CGPM renamed the unit increment of thermodynamic temperature “kelvin”, symbol K, replacing “degree absolute”, symbol °K.[6] Further, feeling it useful to more explicitly define the magnitude of the unit increment, the 13th CGPM also held in Resolution 4 that “The kelvin, unit of thermodynamic temperature, is equal to the fraction 1/273.16 of the thermodynamic temperature of the triple point of water.”[9]
- 2005: The Comité International des Poids et Mesures (CIPM), a committee of the CGPM, affirmed that for the purposes of delineating the temperature of the triple point of water, the definition of the Kelvin thermodynamic temperature scale would refer to water having an isotopic composition defined as being precisely equal to the nominal specification of VSMOW water.[1] | https://www.wikidoc.org/index.php/Kelvin | |
55df1f2527d756caa7ae4eb36c37fd997ccda173 | wikidoc | Kepone | Kepone
# Overview
Kepone, also known as chlordecone, is a carcinogenic insecticide related to mirex, used between 1966 and 1975 in the USA for ant and roach baits. It was produced by Allied Signal Company in Hopewell, Virginia and produced nationwide pollution controversy due to improper handling and dumping of the substance into the James River. Its use was banned in 1975.
Chemically, kepone is a chlorinated polycyclic ketone insecticide and fungicide with the chemical formula Template:Carbon10Template:Hydrogen2Template:Chlorine10Template:Oxygen. The dry powder is readily absorbed through the skin and respiratory tract. Some unprotected production workers exposed to Kepone powder suffered tremors, jerky eye movements, memory loss, headaches, slurred speech, unsteadiness, lack of coordination, lost of weight, rash, enlarged liver, decreased libido, sterility, chest pain, anrthralgia, and the increased risk of developing cancer. Kepone persisted in the environment, with a half-life of about 30 years.
In July 2005, a Richmond Magazine article chronicled the ill health effects on Allied Signal employees and described how Dan Rather and CBS's 60 Minutes brought nationwide attention to the problem.
Due to the pollution scare, many businesses and restaurants along the river suffered, and then-Governor Mills Godwin Jr. shut down the James River to fishing from Richmond to the Chesapeake Bay.
# Trivia
The Dead Kennedys recorded a song named Kepone Factory, deliberately referring to the Minamata disease, for their 1981 album
In God We Trust, Inc.. The song was written in 1978 and was performed live despite not appearing on any recording until 1981.
Kepone (band) was also an American indie rock band based out of Richmond, Virginia. Formed in 1991 ) the band's name is derived from the Kepone crisis that occurred in the Richmond area in the 1970's. Originally formed as a sideproject of Michael Bishop, ex-bassist of GWAR. | Kepone
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# Overview
Kepone, also known as chlordecone, is a carcinogenic[1] insecticide related to mirex, used between 1966 and 1975 in the USA for ant and roach baits. It was produced by Allied Signal Company in Hopewell, Virginia and produced nationwide pollution controversy due to improper handling and dumping of the substance into the James River.[2] Its use was banned in 1975.
Chemically, kepone is a chlorinated polycyclic ketone insecticide and fungicide with the chemical formula Template:Carbon10Template:Hydrogen2Template:Chlorine10Template:Oxygen. The dry powder is readily absorbed through the skin and respiratory tract. Some unprotected production workers exposed to Kepone powder suffered tremors, jerky eye movements, memory loss, headaches, slurred speech, unsteadiness, lack of coordination, lost of weight, rash, enlarged liver, decreased libido, sterility, chest pain, anrthralgia, and the increased risk of developing cancer. Kepone persisted in the environment, with a half-life of about 30 years.
In July 2005, a Richmond Magazine article chronicled the ill health effects on Allied Signal employees and described how Dan Rather and CBS's 60 Minutes brought nationwide attention to the problem.[3]
Due to the pollution scare, many businesses and restaurants along the river suffered, and then-Governor Mills Godwin Jr. shut down the James River to fishing from Richmond to the Chesapeake Bay.
# Trivia
The Dead Kennedys recorded a song named Kepone Factory, deliberately referring to the Minamata disease, for their 1981 album
In God We Trust, Inc.. The song was written in 1978 and was performed live despite not appearing on any recording until 1981.
Kepone (band) was also an American indie rock band based out of Richmond, Virginia. Formed in 1991 ) the band's name is derived from the Kepone crisis that occurred in the Richmond area in the 1970's. Originally formed as a sideproject of Michael Bishop, ex-bassist of GWAR. | https://www.wikidoc.org/index.php/Kepone |
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