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63da35f5b0455161df6411eeaf7d1b14a5f94d66 | wikidoc | Ketone | Ketone
# Overview
A ketone (pronounced as key tone) is either the functional group characterized by a carbonyl group (O=C) linked to two other carbon atoms or a chemical compound that contains this functional group. A ketone can be generally represented by the formula:
A carbonyl carbon bonded to two carbon atoms distinguishes ketones from carboxylic acids, aldehydes, esters, amides, and other oxygen-containing compounds. The double-bond of the carbonyl group distinguishes ketones from alcohols and ethers.
The simplest ketone is acetone (systematically named 2-propanone).
The carbon atom adjacent to a carbonyl group is called the α-carbon. Hydrogens attached to this carbon are called α-hydrogens. In the presence of an acid catalyst the ketone is subjected to so-called keto-enol tautomerism. The reaction with a strong base gives the corresponding enolate. A diketone is a compound containing two ketone groups.
# Nomenclature
In general, ketones are named using IUPAC nomenclature by changing the suffix -e of the parent alkane to -one. For common ketones, some traditional names such as acetone and benzophenone predominate, and these are considered retained IUPAC names , although some introductory chemistry texts use names such as propanone.
Oxo is the formal IUPAC nomenclature for a ketone functional group. However, other prefixes are also used by various books and journals. For some common chemicals (mainly in biochemistry), keto or oxy is the term used to describe the ketone (also known as alkanone) functional group. Oxo also refers to a single oxygen atom coordinated to a transition metal (a metal oxo).
# Physical properties
A carbonyl group is polar. This makes ketones polar compounds. The carbonyl groups interact with water by hydrogen bonding, and ketones are soluble in water. It is a hydrogen-bond acceptor, but not a hydrogen-bond donator, and cannot hydrogen-bond to itself. This makes ketones more volatile than alcohols and carboxylic acids of similar molecular weight.
# Acidity
The α-hydrogen of a ketone is far more acidic (pKa ≈ 20) than the hydrogen of a regular alkane (pKa ≈ 50). This is due to resonance stabilization of the enolate ion that is formed through dissociation. The relative acidity of the α-hydrogen is important in the enolization reactions of ketones and other carbonyl compounds.
# Spectroscopic properties
Spectroscopy is an important means for identifying ketones. Ketones and aldehydes will display a significant peak in infrared spectroscopy, at around 1700 cm−1 (slightly higher or lower, depending on the chemical environment)
# Synthesis
Several methods exist for the preparation of ketones in the laboratory:
- Ketones can be created by oxidation of secondary alcohols. The process requires a strong oxidizing agent such as potassium permanganate, potassium dichromate or other agents containing Cr(VI). The alcohol is oxidized by heating under reflux in acidified solution. For example propan-2-ol is oxidised to acetone:
- Ketones are also prepared by Gem halide hydrolysis.
- Alkynes can be turned into enols through hydration in the presence of an acid and HgS04, and subsequent enol-keto tautomerization gives a ketone. This always produces a ketone, even with a terminal alkyne, and Sia2BH is needed to get an aldehyde from an alkyne
- Aromatic ketones can be prepared in the Friedel-Crafts reaction and the Fries rearrangement.
- In the Kornblum–DeLaMare rearrangement ketones are prepared from peroxides and base
- In the Ruzicka cyclization, cyclic ketones are prepared from dicarboxylic acids.
- In the Nef reaction, ketones form by hydrolysis of salts of secondary nitro compounds
# Reactions
Ketones engage in many organic reactions:
- Nucleophilic addition. The reaction of a ketone with a nucleophile gives a tetrahedral carbonyl addition compound.
the reaction with the anion of a terminal alkyne gives a hydroxyalkyne
the reaction with ammonia or a primary amine gives an imine + water
the reaction with secondary amine gives an enamine + water
the reaction with a Grignard reagent gives a magnesium alkoxide and after aqueous workup a tertiary alcohol
the reaction with an organolithium reagent also gives a tertiary alcohol
the reaction with an alcohol, an acid or base gives a hemiketal + water and further reaction with an alcohol gives the ketal + water. This is a carbonyl-protecting reaction.
reaction of RCOR' with sodium amide results in cleavage with formation of the amide RCONH2 and the alkane R'H, a reaction called the Haller-Bauer reaction (1909)
- the reaction with the anion of a terminal alkyne gives a hydroxyalkyne
- the reaction with ammonia or a primary amine gives an imine + water
- the reaction with secondary amine gives an enamine + water
- the reaction with a Grignard reagent gives a magnesium alkoxide and after aqueous workup a tertiary alcohol
- the reaction with an organolithium reagent also gives a tertiary alcohol
- the reaction with an alcohol, an acid or base gives a hemiketal + water and further reaction with an alcohol gives the ketal + water. This is a carbonyl-protecting reaction.
- reaction of RCOR' with sodium amide results in cleavage with formation of the amide RCONH2 and the alkane R'H, a reaction called the Haller-Bauer reaction (1909)
- Electrophilic addition, reaction with an electrophile gives a resonance stabilized cation.
- the reaction with phosphonium ylides in the Wittig reaction gives alkenes
- reaction with water gives geminal diols
- reaction with thiols gives a thioacetal
- reaction with hydrazine or derivatives of hydrazine gives hydrazones
- reaction with a metal hydride gives a metal alkoxide salt and then with water an alcohol
- reaction of an enol with halogens to α-haloketone
- a reaction at an α-carbon is the reaction of a ketone with heavy water to give a deuterated ketone-d.
- fragmentation in photochemical Norrish reaction
- reaction with halogens and base of methyl ketones in the Haloform reaction
- reaction of 1,4-aminodiketones to oxazoles by dehydration in the Robinson-Gabriel synthesis
- reaction of aryl alkyl ketones with sulfur and an amine to amides in the Willgerodt reaction
# Biochemistry
Acetone, acetoacetate and beta-hydroxybutyrate are ketones (or ketone bodies) generated from carbohydrates, fatty acids and amino acids in humans and most vertebrates. Ketones are elevated in blood after fasting including a night of sleep, and in both blood and urine in starvation, hypoglycemia due to causes other than hyperinsulinism, various inborn errors of metabolism, and ketoacidosis (usually due to diabetes mellitus). Although ketoacidosis is characteristic of decompensated or untreated type 1 diabetes, ketosis or even ketoacidosis can occur in type 2 diabetes in some circumstances as well. Acetoacetate and beta-hydroxybutyrate are an important fuel for many tissues, especially during fasting and starvation. The brain, in particular, relies heavily on ketone bodies as a substrate for lipid synthesis and for energy during times of reduced food intake. At the NIH, Dr. Richard Veech refers to ketones as "magic" in their ability to increase metobolic efficiency, while decreasing production of free radicals, the damaging byproducts of normal metabolism. His work has shown that ketone bodies may treat neurological diseases such as Alzheimer's and Parkinson's disease, and the heart and brain operate 25% more efficiently using ketones as a source of energy.
# Applications
Ketones are often used in perfumes and paints to stabilize the other ingredients so that they don't degrade as quickly over time. Other uses are as solvents and intermediates in chemical industry. Examples of ketones are acetone, acetophenone, and methyl ethyl ketone. | Ketone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A ketone (pronounced as key tone) is either the functional group characterized by a carbonyl group (O=C) linked to two other carbon atoms or a chemical compound that contains this functional group. A ketone can be generally represented by the formula:
A carbonyl carbon bonded to two carbon atoms distinguishes ketones from carboxylic acids, aldehydes, esters, amides, and other oxygen-containing compounds. The double-bond of the carbonyl group distinguishes ketones from alcohols and ethers.
The simplest ketone is acetone (systematically named 2-propanone[1]).
The carbon atom adjacent to a carbonyl group is called the α-carbon. Hydrogens attached to this carbon are called α-hydrogens. In the presence of an acid catalyst the ketone is subjected to so-called keto-enol tautomerism. The reaction with a strong base gives the corresponding enolate. A diketone is a compound containing two ketone groups.
# Nomenclature
In general, ketones are named using IUPAC nomenclature by changing the suffix -e of the parent alkane to -one. For common ketones, some traditional names such as acetone and benzophenone predominate, and these are considered retained IUPAC names [2], although some introductory chemistry texts use names such as propanone.
Oxo is the formal IUPAC nomenclature for a ketone functional group. However, other prefixes are also used by various books and journals. For some common chemicals (mainly in biochemistry), keto or oxy is the term used to describe the ketone (also known as alkanone) functional group. Oxo also refers to a single oxygen atom coordinated to a transition metal (a metal oxo).
# Physical properties
A carbonyl group is polar. This makes ketones polar compounds. The carbonyl groups interact with water by hydrogen bonding, and ketones are soluble in water. It is a hydrogen-bond acceptor, but not a hydrogen-bond donator, and cannot hydrogen-bond to itself. This makes ketones more volatile than alcohols and carboxylic acids of similar molecular weight.
# Acidity
The α-hydrogen of a ketone is far more acidic (pKa ≈ 20) than the hydrogen of a regular alkane (pKa ≈ 50). This is due to resonance stabilization of the enolate ion that is formed through dissociation. The relative acidity of the α-hydrogen is important in the enolization reactions of ketones and other carbonyl compounds.
# Spectroscopic properties
Spectroscopy is an important means for identifying ketones. Ketones and aldehydes will display a significant peak in infrared spectroscopy, at around 1700 cm−1 (slightly higher or lower, depending on the chemical environment)
# Synthesis
Several methods exist for the preparation of ketones in the laboratory:
- Ketones can be created by oxidation of secondary alcohols. The process requires a strong oxidizing agent such as potassium permanganate, potassium dichromate or other agents containing Cr(VI). The alcohol is oxidized by heating under reflux in acidified solution. For example propan-2-ol is oxidised to acetone:
- Ketones are also prepared by Gem halide hydrolysis.
- Alkynes can be turned into enols through hydration in the presence of an acid and HgS04, and subsequent enol-keto tautomerization gives a ketone. This always produces a ketone, even with a terminal alkyne, and Sia2BH is needed to get an aldehyde from an alkyne
- Aromatic ketones can be prepared in the Friedel-Crafts reaction and the Fries rearrangement.
- In the Kornblum–DeLaMare rearrangement ketones are prepared from peroxides and base
- In the Ruzicka cyclization, cyclic ketones are prepared from dicarboxylic acids.
- In the Nef reaction, ketones form by hydrolysis of salts of secondary nitro compounds
# Reactions
Ketones engage in many organic reactions:
- Nucleophilic addition. The reaction of a ketone with a nucleophile gives a tetrahedral carbonyl addition compound.
the reaction with the anion of a terminal alkyne gives a hydroxyalkyne
the reaction with ammonia or a primary amine gives an imine + water
the reaction with secondary amine gives an enamine + water
the reaction with a Grignard reagent gives a magnesium alkoxide and after aqueous workup a tertiary alcohol
the reaction with an organolithium reagent also gives a tertiary alcohol
the reaction with an alcohol, an acid or base gives a hemiketal + water and further reaction with an alcohol gives the ketal + water. This is a carbonyl-protecting reaction.
reaction of RCOR' with sodium amide results in cleavage with formation of the amide RCONH2 and the alkane R'H, a reaction called the Haller-Bauer reaction (1909) [3]
- the reaction with the anion of a terminal alkyne gives a hydroxyalkyne
- the reaction with ammonia or a primary amine gives an imine + water
- the reaction with secondary amine gives an enamine + water
- the reaction with a Grignard reagent gives a magnesium alkoxide and after aqueous workup a tertiary alcohol
- the reaction with an organolithium reagent also gives a tertiary alcohol
- the reaction with an alcohol, an acid or base gives a hemiketal + water and further reaction with an alcohol gives the ketal + water. This is a carbonyl-protecting reaction.
- reaction of RCOR' with sodium amide results in cleavage with formation of the amide RCONH2 and the alkane R'H, a reaction called the Haller-Bauer reaction (1909) [3]
- Electrophilic addition, reaction with an electrophile gives a resonance stabilized cation.
- the reaction with phosphonium ylides in the Wittig reaction gives alkenes
- reaction with water gives geminal diols
- reaction with thiols gives a thioacetal
- reaction with hydrazine or derivatives of hydrazine gives hydrazones
- reaction with a metal hydride gives a metal alkoxide salt and then with water an alcohol
- reaction of an enol with halogens to α-haloketone
- a reaction at an α-carbon is the reaction of a ketone with heavy water to give a deuterated ketone-d.
- fragmentation in photochemical Norrish reaction
- reaction with halogens and base of methyl ketones in the Haloform reaction
- reaction of 1,4-aminodiketones to oxazoles by dehydration in the Robinson-Gabriel synthesis
- reaction of aryl alkyl ketones with sulfur and an amine to amides in the Willgerodt reaction
# Biochemistry
Acetone, acetoacetate and beta-hydroxybutyrate are ketones (or ketone bodies) generated from carbohydrates, fatty acids and amino acids in humans and most vertebrates. Ketones are elevated in blood after fasting including a night of sleep, and in both blood and urine in starvation, hypoglycemia due to causes other than hyperinsulinism, various inborn errors of metabolism, and ketoacidosis (usually due to diabetes mellitus). Although ketoacidosis is characteristic of decompensated or untreated type 1 diabetes, ketosis or even ketoacidosis can occur in type 2 diabetes in some circumstances as well. Acetoacetate and beta-hydroxybutyrate are an important fuel for many tissues, especially during fasting and starvation. The brain, in particular, relies heavily on ketone bodies as a substrate for lipid synthesis and for energy during times of reduced food intake. At the NIH, Dr. Richard Veech refers to ketones as "magic" in their ability to increase metobolic efficiency, while decreasing production of free radicals, the damaging byproducts of normal metabolism. His work has shown that ketone bodies may treat neurological diseases such as Alzheimer's and Parkinson's disease,[4] and the heart and brain operate 25% more efficiently using ketones as a source of energy.[5]
# Applications
Ketones are often used in perfumes and paints to stabilize the other ingredients so that they don't degrade as quickly over time. Other uses are as solvents and intermediates in chemical industry. Examples of ketones are acetone, acetophenone, and methyl ethyl ketone. | https://www.wikidoc.org/index.php/Keto | |
ca1d5182ca50018d135853bca7ae429981cd5f44 | wikidoc | Kevlar | Kevlar
Kevlar is the DuPont Company's registered trademark for a very light, very strong synthetic fiber created in 1965 by Stephanie Kwolek and Herbert Blades. As a material, Kevlar was first commercially used in the early 1970s; it is spun into ropes or fabric sheets that can be used as such or as an ingredient in composite material components. Currently, kevlar has many applications, ranging from bicycles to body armor, because of its high strength-to-weight ratio, "...5 times stronger than steel on an equal weight basis...". Under water, Kevlar is less resistant to ballistic projectiles, although it is water resistant. It is a member of the Aramid family of synthetic fibres and a competitor of the material Twaron, manufactured by Teijin.
# History
In the 1970s, one of the most significant achievements in body armour development was the DuPont chemical company's invention of Kevlar ballistic fabric, a material originally meant to replace steel belting in vehicle tires. The US National Institute of Justice's development of Kevlar body armour for police use was a four-phase testing project.
The first test phase determined whether or not Kevlar fabric could stop a lead bullet. The second phase determined the number of fabric layers needed to prevent penetration by bullets of different calibres and velocities, and the development of a prototype bullet-resistant vest most protective against the more common calibre bullets (.38 Special and .22 long rifle) encountered in street policing.
In 1973 the U.S. Army researchers at the Edgewood Arsenal responsible for designing the bullet-proof vest had developed a seven-layer vest for field trials. They discovered that water, ultraviolet radiation from sunlight or other sources, dry-cleaning chemicals,chlorine bleach, and repeated washings reduced its penetration resistance. To protect against these problems, the Kevlar bullet-proof vest was water-proofed and covered with sun- and chemical-resistant fabric.
# Properties
When Kevlar is spun, the resulting fibre has great tensile strength (ca. 3 000 MPa), a relative density of 1.44, and does not rust. When used as a woven material, it is suitable for mooring lines and other underwater application objects.
There are three grades of Kevlar: (i) Kevlar, (ii) Kevlar 29, and (iii) Kevlar 49. Typically, Kevlar is used as reinforcement in tires and rubber mechanical goods. Kevlar 29's industrial applications are as cables, in asbestos replacement, brake linings, and body armour. Kevlar 49 has the greatest tensile strength of all the aramids, and is used in plastic reinforcement for boat hulls, aeroplanes, and bicycles. The ultraviolet light component of sunlight degrades and decomposes Kevlar, hence it is rarely used outdoors without protection against sunlight.
# Production
Kevlar is synthesised from the monomers 1,4-phenylene-diamine (para-phenylenediamine) and terephthaloyl chloride in condensation reaction yielding hydrochloric acid as a byproduct. The result is a liquid-crystalline behaviour and mechanical drawing orienting the polymer chains in the fibre's direction. Hexamethylphosphoramide (HMPA) was the polymerization solvent first used, but toxicology tests demonstrated it provoked tumors in the noses of rats, so DuPont replaced it by a N-methyl-pyrolidone and calcium chloride as the solvent.
Kevlar production is expensive because of the difficulties arising from using toxic concentrated sulfuric acid, needed to keep the water-insoluble polymer in solution during its synthesis and spinning.
# Chemical properties
Fibers of Kevlar consist of long molecular chains produced from poly-paraphenylene terephthalamide. There are many inter-chain bonds making the material extremely strong. Kevlar derives part of its high strength from inter-molecular hydrogen bonds formed between the carbonyl groups and protons on neighboring polymer chains and the partial pi stacking of the benzenoid aromatic stacking interactions between stacked strands. These interactions have a greater influence on Kevlar than the van der Waals interactions and chain length that typically influence the properties of other synthetic polymers and fibers such as Dyneema. The presence of salts and certain other impurities, especially calcium, could interfere with the strand interactions and caution is used to avoid inclusion in its production. Kevlar's structure consists of relatively rigid molecules which tend to form mostly planar sheet-like structures rather like silk protein.
# Thermal properties
For a polymer Kevlar has very good resistance to high temperatures, and maintains its strength and resilience down to cryogenic temperatures (-196° C); indeed, it is slightly stronger at low temperatures.
At higher temperatures the tensile strength is immediately reduced by about 10-20%, and after some hours the strength progressively reduces further. For example at 160° C about 10% reduction in strength occurs after 500 hours. At 260° C 50% reduction occurs after 70 hours.
At 450° C Kevlar sublimates. | Kevlar
Kevlar is the DuPont Company's registered trademark for a very light, very strong synthetic fiber created in 1965 by Stephanie Kwolek and Herbert Blades.[1] As a material, Kevlar was first commercially used in the early 1970s; it is spun into ropes or fabric sheets that can be used as such or as an ingredient in composite material components. Currently, kevlar has many applications, ranging from bicycles to body armor, because of its high strength-to-weight ratio, "...5 times stronger than steel on an equal weight basis...".[1] Under water, Kevlar is less resistant to ballistic projectiles, although it is water resistant. [2] It is a member of the Aramid family of synthetic fibres and a competitor of the material Twaron, manufactured by Teijin.
# History
In the 1970s, one of the most significant achievements in body armour development was the DuPont chemical company's invention of Kevlar ballistic fabric, a material originally meant to replace steel belting in vehicle tires. The US National Institute of Justice's development of Kevlar body armour for police use was a four-phase testing project.
The first test phase determined whether or not Kevlar fabric could stop a lead bullet. The second phase determined the number of fabric layers needed to prevent penetration by bullets of different calibres and velocities, and the development of a prototype bullet-resistant vest most protective against the more common calibre bullets (.38 Special and .22 long rifle) encountered in street policing.
In 1973 the U.S. Army researchers at the Edgewood Arsenal responsible for designing the bullet-proof vest had developed a seven-layer vest for field trials. They discovered that water, ultraviolet radiation from sunlight or other sources, dry-cleaning chemicals,chlorine bleach, and repeated washings reduced its penetration resistance. To protect against these problems, the Kevlar bullet-proof vest was water-proofed and covered with sun- and chemical-resistant fabric.
# Properties
When Kevlar is spun, the resulting fibre has great tensile strength (ca. 3 000 MPa), a relative density of 1.44, and does not rust. When used as a woven material, it is suitable for mooring lines and other underwater application objects.
There are three grades of Kevlar: (i) Kevlar, (ii) Kevlar 29, and (iii) Kevlar 49. Typically, Kevlar is used as reinforcement in tires and rubber mechanical goods. Kevlar 29's industrial applications are as cables, in asbestos replacement, brake linings, and body armour. Kevlar 49 has the greatest tensile strength of all the aramids, and is used in plastic reinforcement for boat hulls, aeroplanes, and bicycles. The ultraviolet light component of sunlight degrades and decomposes Kevlar, hence it is rarely used outdoors without protection against sunlight.
# Production
Kevlar is synthesised from the monomers 1,4-phenylene-diamine (para-phenylenediamine) and terephthaloyl chloride in condensation reaction yielding hydrochloric acid as a byproduct. The result is a liquid-crystalline behaviour and mechanical drawing orienting the polymer chains in the fibre's direction. Hexamethylphosphoramide (HMPA) was the polymerization solvent first used, but toxicology tests demonstrated it provoked tumors in the noses of rats, so DuPont replaced it by a N-methyl-pyrolidone and calcium chloride as the solvent.
Kevlar production is expensive because of the difficulties arising from using toxic concentrated sulfuric acid, needed to keep the water-insoluble polymer in solution during its synthesis and spinning.
# Chemical properties
Fibers of Kevlar consist of long molecular chains produced from poly-paraphenylene terephthalamide. There are many inter-chain bonds making the material extremely strong. Kevlar derives part of its high strength from inter-molecular hydrogen bonds formed between the carbonyl groups and protons on neighboring polymer chains and the partial pi stacking of the benzenoid aromatic stacking interactions between stacked strands. These interactions have a greater influence on Kevlar than the van der Waals interactions and chain length that typically influence the properties of other synthetic polymers and fibers such as Dyneema. The presence of salts and certain other impurities, especially calcium, could interfere with the strand interactions and caution is used to avoid inclusion in its production. Kevlar's structure consists of relatively rigid molecules which tend to form mostly planar sheet-like structures rather like silk protein.
# Thermal properties
For a polymer Kevlar has very good resistance to high temperatures, and maintains its strength and resilience down to cryogenic temperatures (-196° C); indeed, it is slightly stronger at low temperatures.
At higher temperatures the tensile strength is immediately reduced by about 10-20%, and after some hours the strength progressively reduces further. For example at 160° C about 10% reduction in strength occurs after 500 hours. At 260° C 50% reduction occurs after 70 hours.[3]
At 450° C Kevlar sublimates. | https://www.wikidoc.org/index.php/Kevlar | |
03af59b9e2b36692c411c0da4585ea56dc219528 | wikidoc | T cell | T cell
# Overview
T cells belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B cells and NK cells by the presence of a special receptor on their cell surface called the T cell receptor (TCR). The abbreviation T, in T cell, stands for thymus, since it is the principal organ in the T cell's development.
# T cell subsets
Several different subsets of T cells have been described, each with a distinct function.
- Helper T cells (TH cells) are the "middlemen" of the adaptive immune system. Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or "help" the immune response. Depending on the cytokine signals received, these cells differentiate into TH1, TH2, TH17, or one of other subsets, which secrete different cytokines.
- Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells, and are also implicated in transplant rejection. These cells are also known as CD8+ T cells, since they express the CD8 glycoprotein at their surface. Through interaction with helper T cells, these cells can be transformed into regulatory T cells, which prevent autoimmune diseases such as experimental autoimmune encephalomyelitis.
- Memory T cells are a subset of antigen-specific T cells that persist long-term after an infection has resolved. They quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen, thus providing the immune system with "memory" against past infections. Memory T cells comprise two subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM cells). Memory cells may be either CD4+ or CD8+.
- Regulatory T cells (Treg cells), formerly known as suppressor T cells, are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Two major classes of CD4+ regulatory T cells have been described, including the naturally occurring Treg cells and the adaptive Treg cells. Naturally occurring Treg cells (also known as CD4+CD25+FoxP3+ Treg cells) arise in the thymus, whereas the adaptive Treg cells (also known as Tr1 cells or Th3 cells) may originate during a normal immune response. Naturally occurring Treg cells can be distinguished from other T cells by the presence of an intracellular molecule called FoxP3. Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease IPEX.
- Natural Killer T cells (NKT cells) are a special kind of lymphocyte that bridges the adaptive immune system with the innate immune system. Unlike conventional T cells that recognize peptide antigen presented by major histocompatibility complex (MHC) molecules, NKT cells recognize glycolipid antigen presented by a molecule called CD1d. Once activated, these cells can perform functions ascribed to both Th and Tc cells (i.e., cytokine production and release of cytolytic/cell killing molecules).
- γδ T cells represent a small subset of T cells that possess a distinct TCR on their surface. A majority of T cells have a TCR composed of two glycoprotein chains called α- and β- TCR chains. However, in γδ T cells, the TCR is made up of one γ-chain and one δ-chain. This group of T cells is much less common (5% of total T cells) than the αβ T cells, but are found at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs). The antigenic molecules that activate γδ T cells are still widely unknown. However, γδ T cells are not MHC restricted and seem to be able to recognise whole proteins rather than requiring peptides to be presented by MHC molecules on antigen presenting cells. Some recognize MHC class IB molecules though. Human Vγ9/Vδ2 T cells, which constitute the major γδ T cell population in peripheral blood, are unique in that they specifically and rapidly respond to a small non-peptidic microbial metabolite, HMB-PP, an isopentenyl pyrophosphate precursor.
# T cell development in the thymus
See Thymocyte for in-depth review of thymic selection
All T cells originate from hematopoietic stem cells in the bone marrow. Hematopoietic progenitors derived from hematopoietic stem cells populate the thymus and expand by cell division to generate a large population of immature thymocytes. The earliest thymocytes express neither CD4 nor CD8, and are therefore classed as double-negative (CD4-CD8-) cells. As they progress through their development they become double-positive thymocytes (CD4+CD8+), and finally mature to single-positive (CD4+CD8- or CD4-CD8+) thymocytes that are then released from the thymus to peripheral tissues.
About 98% of thymocytes die during the development processes in the thymus by failing either positive selection or negative selection, whereas the other 2% survive and leave the thymus to become mature immunocompetent T cells.
## Positive selection
Double-positive thymocytes move deep into the thymic cortex where they are presented with self-antigens (i.e., antigens that are derived from molecules belonging to the host of the T cell) complexed with MHC molecules on the surface of cortical epithelial cells. Only those thymocytes that bind the MHC/antigen complex with adequate affinity will receive a vital "survival signal." Developing thymocytes that do not have adequate affinity cannot serve useful functions in the body; the cells must be able to interact with MHC and peptide complexes in order to effect immune responses. Therefore, the other thymocytes with low affinity die by apoptosis (programmed cell death), and their remains are engulfed by macrophages. This process is called positive selection.
Whether a thymocyte becomes a CD4+ cell or a CD8+ cell is also determined during positive selection. Double-positive cells that are positively selected on MHC class II molecules will become CD4+ cells, and cells positively selected on MHC class I molecules become CD8+ cells.
Note that this process does not remove from the population thymocytes that would cause autoimmunity or a reaction with one's own cells. The removal of such cells is dealt with by negative selection, which is discussed below.
## Negative selection
Thymocytes that survive positive selection migrate towards the boundary of the thymic cortex and thymic medulla. While in the medulla, they are again presented with self-antigen in complex with MHC molecules on antigen-presenting cells (APCs) such as dendritic cells and macrophages. Thymocytes that interact too strongly with the antigen receive an apoptosis signal that causes their death; the vast majority of all thymocytes initially produced end up dying during thymic selection. A small minority of the surviving cells is selected to become regulatory T cells. The remaining cells will then exit the thymus as mature naive T cells. This process is called negative selection, an important mechanism of immunological tolerance that prevents the formation of self-reactive T cells capable of generating autoimmune disease in the host.
# T cell activation
Although the specific mechanisms of activation vary slightly between different types of T cells, the "two-signal model" in CD4+ T cells holds true for most. Activation of CD4+ T cells occurs through the engagement of both the T cell receptor and CD28 on the T cell by the Major histocompatibility complex peptide and B7 family members on the APC, respectively. Both are required for production of an effective immune response; in the absence of CD28 co-stimulation, T cell receptor signalling alone results in anergy. The signalling pathways downstream from both CD28 and the T cell receptor involve many proteins.
The first signal is provided by binding of the T cell receptor to a short peptide presented by the major histocompatibility complex (MHC) on another cell. This ensures that only a T cell with a TCR specific to that peptide is activated. The partner cell is usually a professional antigen presenting cell (APC), usually a dendritic cell in the case of naïve responses, although B cells and macrophages can be important APCs. The peptides presented to CD8+ T cells by MHC class I molecules are 8-9 amino acids in length; the peptides presented to CD4+ cells by MHC class II molecules are longer, as the ends of the binding cleft of the MHC class II molecule are open.
The second signal comes from co-stimulation, in which surface receptors on the APC are induced by a relatively small number of stimuli, usually products of pathogens, but sometimes breakdown products of cells, such as necrotic-bodies or heat-shock proteins. The only co-stimulatory receptor expressed constitutively by naïve T cells is CD28, so co-stimulation for these cells comes from the CD80 and CD86 proteins on the APC. Other receptors are expressed upon activation of the T cell, such as OX40 and ICOS, but these largely depend upon CD28 for their expression. The second signal licenses the T cell to respond to an antigen. Without it, the T cell becomes anergic, and it becomes more difficult for it to activate in future. This mechanism prevents inappropriate responses to self, as self-peptides will not usually be presented with suitable co-stimulation.
The T cell receptor exists as a complex of several proteins. The actual T cell receptor is composed of two separate peptide chains, which are produced from the independent T cell receptor alpha and beta (TCRα and TCRβ) genes. The other proteins in the complex are the CD3 proteins: CD3εγ and CD3εδ heterodimers and, most important, a CD3ζ homodimer, which has a total of six ITAM motifs. The ITAM motifs on the CD3ζ can be phosphorylated by Lck and in turn recruit ZAP-70. Lck and/or ZAP-70 can also phosphorylate the tyrosines on many other molecules, not least CD28, Trim, LAT and SLP-76, which allows the aggregation of signalling complexes around these proteins.
Phosphorylated LAT recruits SLP-76 to the membrane, where it can then bring in PLCγ, VAV1, Itk and potentially PI3K. Both PLCγ and PI3K act on PI(4,5)P2 on the inner leaflet of the membrane to create the active intermediaries di-acyl glycerol (DAG), inositol-1,4,5-trisphosphate (IP3), and phosphatidlyinositol-3,4,5-trisphosphate (PIP3). DAG binds and activates some PKCs, most important, in T cells PKCθ, a process important for activating the transcription factors NF-κB and AP-1. IP3 is released from the membrane by PLCγ and diffuses rapidly to activate receptors on the ER, which induce the release of calcium. The released calcium then activates calcineurin, and calcineurin activates NFAT, which then translocates to the nucleus. NFAT is a transcription factor, which activates the transcription of a pleiotropic set of genes, most notable, IL-2, a cytokine that promotes long term proliferation of activated T cells.
# T cell Maturation
Maturation of T Cells in the Thymus
The first step is the rearrangement of the variable, joining, and constant region genes of the chain of the T cell antigen receptor in a way very similar to that of heavy chain rearrangement needed for immunoglobulin synthesis. In fact, the same enzymes are used for both.
Production of a functional TCR chain, signals expression of both CD4 and CD8 on the cell surface. This induces the genetic rearrangements needed to produce a functional TCR chain and an increase in TCR membrane expression. CD3 is then expressed, which produces a functional TCR complex (to be described later).
At this point, some of the T cells stop making CD8, so only CD4 remains on their cell membrane. The others undergo the reverse process, so they express only CD8. T cells then learn to not attack self tissues and to respond to antigen only if it is associated with a self histocompatibility antigen. This requires two steps:
- First, the immature, but CD4 or CD8 positive T cells are exposed to cells in the thymus, which have class I and class II histocompatibility antigens on them. T cells which are able to bind to one or the other of these antigens are protected, whereas the others die.
- Second, the cells that survive the above selection process are exposed to self antigens that have been taken up and associated with either class I or class II MHC antigen. Those that bind at this stage die (actually they commit suicide, called apoptosis).
The cells that survive are those that recognize non-self antigens associated with MHC antigens. After a little more maturation, they exit the thymus to perform their role in immune responses. | T cell
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
T cells belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B cells and NK cells by the presence of a special receptor on their cell surface called the T cell receptor (TCR). The abbreviation T, in T cell, stands for thymus, since it is the principal organ in the T cell's development.
# T cell subsets
Several different subsets of T cells have been described, each with a distinct function.
- Helper T cells (TH cells) are the "middlemen" of the adaptive immune system. Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or "help" the immune response. Depending on the cytokine signals received, these cells differentiate into TH1, TH2, TH17, or one of other subsets, which secrete different cytokines.
- Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells, and are also implicated in transplant rejection. These cells are also known as CD8+ T cells, since they express the CD8 glycoprotein at their surface. Through interaction with helper T cells, these cells can be transformed into regulatory T cells, which prevent autoimmune diseases such as experimental autoimmune encephalomyelitis.[1]
- Memory T cells are a subset of antigen-specific T cells that persist long-term after an infection has resolved. They quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen, thus providing the immune system with "memory" against past infections. Memory T cells comprise two subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM cells). Memory cells may be either CD4+ or CD8+.
- Regulatory T cells (Treg cells), formerly known as suppressor T cells, are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Two major classes of CD4+ regulatory T cells have been described, including the naturally occurring Treg cells and the adaptive Treg cells. Naturally occurring Treg cells (also known as CD4+CD25+FoxP3+ Treg cells) arise in the thymus, whereas the adaptive Treg cells (also known as Tr1 cells or Th3 cells) may originate during a normal immune response. Naturally occurring Treg cells can be distinguished from other T cells by the presence of an intracellular molecule called FoxP3. Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease IPEX.
- Natural Killer T cells (NKT cells) are a special kind of lymphocyte that bridges the adaptive immune system with the innate immune system. Unlike conventional T cells that recognize peptide antigen presented by major histocompatibility complex (MHC) molecules, NKT cells recognize glycolipid antigen presented by a molecule called CD1d. Once activated, these cells can perform functions ascribed to both Th and Tc cells (i.e., cytokine production and release of cytolytic/cell killing molecules).
- γδ T cells represent a small subset of T cells that possess a distinct TCR on their surface. A majority of T cells have a TCR composed of two glycoprotein chains called α- and β- TCR chains. However, in γδ T cells, the TCR is made up of one γ-chain and one δ-chain. This group of T cells is much less common (5% of total T cells) than the αβ T cells, but are found at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs). The antigenic molecules that activate γδ T cells are still widely unknown. However, γδ T cells are not MHC restricted and seem to be able to recognise whole proteins rather than requiring peptides to be presented by MHC molecules on antigen presenting cells. Some recognize MHC class IB molecules though. Human Vγ9/Vδ2 T cells, which constitute the major γδ T cell population in peripheral blood, are unique in that they specifically and rapidly respond to a small non-peptidic microbial metabolite, HMB-PP, an isopentenyl pyrophosphate precursor.
# T cell development in the thymus
See Thymocyte for in-depth review of thymic selection
All T cells originate from hematopoietic stem cells in the bone marrow. Hematopoietic progenitors derived from hematopoietic stem cells populate the thymus and expand by cell division to generate a large population of immature thymocytes.[2] The earliest thymocytes express neither CD4 nor CD8, and are therefore classed as double-negative (CD4-CD8-) cells. As they progress through their development they become double-positive thymocytes (CD4+CD8+), and finally mature to single-positive (CD4+CD8- or CD4-CD8+) thymocytes that are then released from the thymus to peripheral tissues.
About 98% of thymocytes die during the development processes in the thymus by failing either positive selection or negative selection, whereas the other 2% survive and leave the thymus to become mature immunocompetent T cells.
## Positive selection
Double-positive thymocytes move deep into the thymic cortex where they are presented with self-antigens (i.e., antigens that are derived from molecules belonging to the host of the T cell) complexed with MHC molecules on the surface of cortical epithelial cells. Only those thymocytes that bind the MHC/antigen complex with adequate affinity will receive a vital "survival signal." Developing thymocytes that do not have adequate affinity cannot serve useful functions in the body; the cells must be able to interact with MHC and peptide complexes in order to effect immune responses. Therefore, the other thymocytes with low affinity die by apoptosis (programmed cell death), and their remains are engulfed by macrophages. This process is called positive selection.
Whether a thymocyte becomes a CD4+ cell or a CD8+ cell is also determined during positive selection. Double-positive cells that are positively selected on MHC class II molecules will become CD4+ cells, and cells positively selected on MHC class I molecules become CD8+ cells.
Note that this process does not remove from the population thymocytes that would cause autoimmunity or a reaction with one's own cells. The removal of such cells is dealt with by negative selection, which is discussed below.
## Negative selection
Thymocytes that survive positive selection migrate towards the boundary of the thymic cortex and thymic medulla. While in the medulla, they are again presented with self-antigen in complex with MHC molecules on antigen-presenting cells (APCs) such as dendritic cells and macrophages. Thymocytes that interact too strongly with the antigen receive an apoptosis signal that causes their death; the vast majority of all thymocytes initially produced end up dying during thymic selection. A small minority of the surviving cells is selected to become regulatory T cells. The remaining cells will then exit the thymus as mature naive T cells. This process is called negative selection, an important mechanism of immunological tolerance that prevents the formation of self-reactive T cells capable of generating autoimmune disease in the host.
# T cell activation
Although the specific mechanisms of activation vary slightly between different types of T cells, the "two-signal model" in CD4+ T cells holds true for most. Activation of CD4+ T cells occurs through the engagement of both the T cell receptor and CD28 on the T cell by the Major histocompatibility complex peptide and B7 family members on the APC, respectively. Both are required for production of an effective immune response; in the absence of CD28 co-stimulation, T cell receptor signalling alone results in anergy. The signalling pathways downstream from both CD28 and the T cell receptor involve many proteins.
The first signal is provided by binding of the T cell receptor to a short peptide presented by the major histocompatibility complex (MHC) on another cell. This ensures that only a T cell with a TCR specific to that peptide is activated. The partner cell is usually a professional antigen presenting cell (APC), usually a dendritic cell in the case of naïve responses, although B cells and macrophages can be important APCs. The peptides presented to CD8+ T cells by MHC class I molecules are 8-9 amino acids in length; the peptides presented to CD4+ cells by MHC class II molecules are longer, as the ends of the binding cleft of the MHC class II molecule are open.
The second signal comes from co-stimulation, in which surface receptors on the APC are induced by a relatively small number of stimuli, usually products of pathogens, but sometimes breakdown products of cells, such as necrotic-bodies or heat-shock proteins. The only co-stimulatory receptor expressed constitutively by naïve T cells is CD28, so co-stimulation for these cells comes from the CD80 and CD86 proteins on the APC. Other receptors are expressed upon activation of the T cell, such as OX40 and ICOS, but these largely depend upon CD28 for their expression. The second signal licenses the T cell to respond to an antigen. Without it, the T cell becomes anergic, and it becomes more difficult for it to activate in future. This mechanism prevents inappropriate responses to self, as self-peptides will not usually be presented with suitable co-stimulation.
The T cell receptor exists as a complex of several proteins. The actual T cell receptor is composed of two separate peptide chains, which are produced from the independent T cell receptor alpha and beta (TCRα and TCRβ) genes. The other proteins in the complex are the CD3 proteins: CD3εγ and CD3εδ heterodimers and, most important, a CD3ζ homodimer, which has a total of six ITAM motifs. The ITAM motifs on the CD3ζ can be phosphorylated by Lck and in turn recruit ZAP-70. Lck and/or ZAP-70 can also phosphorylate the tyrosines on many other molecules, not least CD28, Trim, LAT and SLP-76, which allows the aggregation of signalling complexes around these proteins.
Phosphorylated LAT recruits SLP-76 to the membrane, where it can then bring in PLCγ, VAV1, Itk and potentially PI3K. Both PLCγ and PI3K act on PI(4,5)P2 on the inner leaflet of the membrane to create the active intermediaries di-acyl glycerol (DAG), inositol-1,4,5-trisphosphate (IP3), and phosphatidlyinositol-3,4,5-trisphosphate (PIP3). DAG binds and activates some PKCs, most important, in T cells PKCθ, a process important for activating the transcription factors NF-κB and AP-1. IP3 is released from the membrane by PLCγ and diffuses rapidly to activate receptors on the ER, which induce the release of calcium. The released calcium then activates calcineurin, and calcineurin activates NFAT, which then translocates to the nucleus. NFAT is a transcription factor, which activates the transcription of a pleiotropic set of genes, most notable, IL-2, a cytokine that promotes long term proliferation of activated T cells.
# T cell Maturation
Maturation of T Cells in the Thymus
The first step is the rearrangement of the variable, joining, and constant region genes of the chain of the T cell antigen receptor in a way very similar to that of heavy chain rearrangement needed for immunoglobulin synthesis. In fact, the same enzymes are used for both.
Production of a functional TCR chain, signals expression of both CD4 and CD8 on the cell surface. This induces the genetic rearrangements needed to produce a functional TCR chain and an increase in TCR membrane expression. CD3 is then expressed, which produces a functional TCR complex (to be described later).
At this point, some of the T cells stop making CD8, so only CD4 remains on their cell membrane. The others undergo the reverse process, so they express only CD8. T cells then learn to not attack self tissues and to respond to antigen only if it is associated with a self histocompatibility antigen. This requires two steps:
- First, the immature, but CD4 or CD8 positive T cells are exposed to cells in the thymus, which have class I and class II histocompatibility antigens on them. T cells which are able to bind to one or the other of these antigens are protected, whereas the others die.
- Second, the cells that survive the above selection process are exposed to self antigens that have been taken up and associated with either class I or class II MHC antigen. Those that bind at this stage die (actually they commit suicide, called apoptosis).
The cells that survive are those that recognize non-self antigens associated with MHC antigens. After a little more maturation, they exit the thymus to perform their role in immune responses. | https://www.wikidoc.org/index.php/Killer_T_cells | |
c5c3828bfa06ec95b8fe3a71478e97e9e235ce6d | wikidoc | Kilohm | Kilohm
The ohm (symbol: Ω) is the SI unit of electrical impedance or, in the direct current case, electrical resistance, named after Georg Ohm.
# Definition
The ohm is the electric resistance between two points of a conductor when a constant potential difference of 1 volt, applied to these points, produces in the conductor a current of 1 ampere, the conductor not being the seat of any electromotive force.
# Conversions
- A measurement in ohms is the reciprocal of a measurement in siemens, the SI unit of electrical conductance. Note that 'siemens' is both singular and plural. The non-SI unit, the mho (ohm written backwards), is equivalent to siemens but is mostly obsolete and rarely used.
- Ohms to watts: The power dissipated by a resistor may be calculated using resistance and voltage. The formula is a combination of Ohm's law and Joule's law:
# References and notes
- ↑ BIPM SI Brochure: Appendix 1, p. 144 | Kilohm
Template:Otheruses4
The ohm (symbol: Ω) is the SI unit of electrical impedance or, in the direct current case, electrical resistance, named after Georg Ohm.
# Definition
The ohm is the electric resistance between two points of a conductor when a constant potential difference of 1 volt, applied to these points, produces in the conductor a current of 1 ampere, the conductor not being the seat of any electromotive force.[1]
# Conversions
- A measurement in ohms is the reciprocal of a measurement in siemens, the SI unit of electrical conductance. Note that 'siemens' is both singular and plural. The non-SI unit, the mho (ohm written backwards), is equivalent to siemens but is mostly obsolete and rarely used.
- Ohms to watts: The power dissipated by a resistor may be calculated using resistance and voltage. The formula is a combination of Ohm's law and Joule's law:
# References and notes
- ↑ BIPM SI Brochure: Appendix 1, p. 144 | https://www.wikidoc.org/index.php/Kilohm | |
b54a53d4e5b61fe32bc82008a606aa7caff54b8f | wikidoc | Kir2.1 | Kir2.1
The Kir2.1 inward-rectifier potassium ion channel is encoded by the KCNJ2 gene.
# Clinical significance
A defect in this gene is associated with Andersen-Tawil syndrome.
A mutation in the KCNJ2 gene has also been shown to cause short QT syndrome.
# In research
In neurogenetics, Kir2.1 is used in Drosophila research to inhibit neurons, as overexpression of this channel will hyperpolarize cells.
In optogenetics, a trafficking sequence from Kir2.1 has been added to halorhodopsin to improve its membrane localization. The resulting protein eNpHR3.0 is used in optogenetic research to inhibit neurons with light.
Expression of Kir2.1 gene in human HEK293 cells induce a transient outward current, creating a steady membrane potential close to the reversal potential of potassium.
# Interactions
Kir2.1 has been shown to interact with:
- DLG4,
- Interleukin 16, and
- TRAK2 | Kir2.1
The Kir2.1 inward-rectifier potassium ion channel is encoded by the KCNJ2 gene.[1][2][3]
# Clinical significance
A defect in this gene is associated with Andersen-Tawil syndrome.[4]
A mutation in the KCNJ2 gene has also been shown to cause short QT syndrome.[5]
# In research
In neurogenetics, Kir2.1 is used in Drosophila research to inhibit neurons, as overexpression of this channel will hyperpolarize cells.
In optogenetics, a trafficking sequence from Kir2.1 has been added to halorhodopsin to improve its membrane localization. The resulting protein eNpHR3.0 is used in optogenetic research to inhibit neurons with light.[6]
Expression of Kir2.1 gene in human HEK293 cells induce a transient outward current, creating a steady membrane potential close to the reversal potential of potassium.[7]
# Interactions
Kir2.1 has been shown to interact with:
- DLG4,[8]
- Interleukin 16,[9] and
- TRAK2 [10] | https://www.wikidoc.org/index.php/Kir2.1 | |
58df6bdeb9f6bee1878a42aad656f111cfcb3cdd | wikidoc | Kir2.6 | Kir2.6
The Kir2.6 also known as inward rectifier potassium channel 18 is a protein that in humans is encoded by the KCNJ18 gene. Kir2.6 is an inward-rectifier potassium ion channel.
# Function
Inwardly rectifying potassium channels, such as Kir2.6, maintain resting membrane potential in excitable cells and aid in repolarization of cells following depolarization. Kir2.6 is primarily expressed in skeletal muscle and is transcriptionally regulated by thyroid hormone.
# Clinical signifiance
Mutations in this gene have been linked to thyrotoxic periodic paralysis. | Kir2.6
The Kir2.6 also known as inward rectifier potassium channel 18 is a protein that in humans is encoded by the KCNJ18 gene.[1] Kir2.6 is an inward-rectifier potassium ion channel.
# Function
Inwardly rectifying potassium channels, such as Kir2.6, maintain resting membrane potential in excitable cells and aid in repolarization of cells following depolarization. Kir2.6 is primarily expressed in skeletal muscle and is transcriptionally regulated by thyroid hormone.[1]
# Clinical signifiance
Mutations in this gene have been linked to thyrotoxic periodic paralysis.[1] | https://www.wikidoc.org/index.php/Kir2.6 | |
d59016cbf37bffb6bbe8a52699cff49d79efc25f | wikidoc | Kir6.2 | Kir6.2
Kir6.2 is a major subunit of the ATP-sensitive K+ channel, an inward-rectifier potassium ion channel. The gene encoding the channel is called KCNJ11 and mutations in this gene are associated with congenital hyperinsulinism.
# Structure
It is an integral membrane protein. The protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins and is found associated with the sulfonylurea receptor (SUR) to constitute the ATP-sensitive K+ channel.
# Pathology
Mutations in this gene are a cause of familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder characterized by unregulated insulin secretion. Defects in this gene may also contribute to autosomal dominant non-insulin-dependent diabetes mellitus type II (NIDDM). | Kir6.2
Kir6.2 is a major subunit of the ATP-sensitive K+ channel, an inward-rectifier potassium ion channel.[1] The gene encoding the channel is called KCNJ11 and mutations in this gene are associated with congenital hyperinsulinism.[2]
# Structure
It is an integral membrane protein. The protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins and is found associated with the sulfonylurea receptor (SUR) to constitute the ATP-sensitive K+ channel.
# Pathology
Mutations in this gene are a cause of familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder characterized by unregulated insulin secretion. Defects in this gene may also contribute to autosomal dominant non-insulin-dependent diabetes mellitus type II (NIDDM).[1][3] | https://www.wikidoc.org/index.php/Kir6.2 | |
e93eb4c17bc01fbcc9e59576167190a090fa580e | wikidoc | Kykeon | Kykeon
Kykeon (Gr. κυκεών, from κυκάω, "to stir, to mix") was an Ancient Greek drink made mainly of water, barley and herbs. It was used at the climax of the Eleusinian Mysteries to break a sacred fast, but it was also a favourite drink of Greek peasants.
Kykeon is mentioned in Homeric texts: the Iliad describes it as consisting of barley, water, herbs, and ground goat cheese (XV, 638–641). In the Odyssey, Circe adds some honey and pours her magic potion in it (X, 234). In the The Homeric Hymn to Demeter, the goddess refuses red wine but accepts kykeon made from water, barley and pennyroyal.
It was supposed to have digestive properties. Hermes recommends it in Aristophanes' Peace (v. 712) to the hero who ate too much dry fruit and nuts. Aristocrats shunned it as a peasant drink. Theophrastus depicts in his Characters (IV, 2–3) a peasant whose thyme breath inconveniences his neighbours at the Ecclesia.
In an attempt to solve the mystery of how so many people over the span of two millennia could have consistently experienced revelatory states during the culminating ceremony of the Eleusinian Mysteries, it has been posited that the barley used in the Eleusinian kykeon was parasitized by ergot, and that the psychoactive properties of that fungus triggered the intense experiences alluded to by the participants at Eleusis.
Various modern attempts to duplicate the kykeon using ergot have yielded inconclusive results.
For more on the possibilities of the Kykeon's psychoactive properties, see entheogenic theories of the mysteries.
# Bibliography
- French Armand Delatte, Le Cycéon, breuvage rituel des mystères d'Éleusis, Belles Lettres, Paris, 1955 | Kykeon
Kykeon (Gr. κυκεών, from κυκάω, "to stir, to mix") was an Ancient Greek drink made mainly of water, barley and herbs. It was used at the climax of the Eleusinian Mysteries to break a sacred fast, but it was also a favourite drink of Greek peasants.
Kykeon is mentioned in Homeric texts: the Iliad describes it as consisting of barley, water, herbs, and ground goat cheese (XV, 638–641). In the Odyssey, Circe adds some honey and pours her magic potion in it (X, 234). In the The Homeric Hymn to Demeter, the goddess refuses red wine but accepts kykeon made from water, barley and pennyroyal.
It was supposed to have digestive properties. Hermes recommends it in Aristophanes' Peace (v. 712) to the hero who ate too much dry fruit and nuts. Aristocrats shunned it as a peasant drink. Theophrastus depicts in his Characters (IV, 2–3) a peasant whose thyme breath inconveniences his neighbours at the Ecclesia.
In an attempt to solve the mystery of how so many people over the span of two millennia could have consistently experienced revelatory states during the culminating ceremony of the Eleusinian Mysteries, it has been posited that the barley used in the Eleusinian kykeon was parasitized by ergot, and that the psychoactive properties of that fungus triggered the intense experiences alluded to by the participants at Eleusis.
Various modern attempts to duplicate the kykeon using ergot have yielded inconclusive results.
For more on the possibilities of the Kykeon's psychoactive properties, see entheogenic theories of the mysteries.
# Bibliography
- French Armand Delatte, Le Cycéon, breuvage rituel des mystères d'Éleusis, Belles Lettres, Paris, 1955
# External links
- [1]
br:Kykeon
no:Kykeon
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Kykeon | |
cc6c0c0b10dd9f9edcc4eb4f95dafbd68c8b82a6 | wikidoc | Lysine | Lysine
Lysine (abbreviated as Lys or K) is an α-amino acid with the chemical formula HO2CCH(NH2)(CH2)4NH2. This amino acid is an essential amino acid, which means that humans cannot synthesize it. Its codons are AAA and AAG.
Lysine is a base, as are arginine and histidine. The ε-amino group often participates in hydrogen bonding and as a general base in catalysis. Common posttranslational modifications include methylation of the ε-amino group, giving methyl-, dimethyl-, and trimethyllysine. The latter occurs in calmodulin. Other posttranslational modifications include acetylation. Collagen contains hydroxylysine which is derived from lysine by lysyl hydroxylase. O-Glycosylation of lysine residues in the endoplasmic reticulum or Golgi apparatus is used to mark certain proteins for secretion from the cell.
# Biosynthesis
As an essential amino acid, lysine is not synthesized in animals, hence it must be ingested as lysine or lysine-containing proteins. In plants and microorganisms, it is synthesized from aspartic acid, which is first converted to β-aspartyl-semialdehyde. Cyclization gives dihydropicolinate, which is reduced to Δ1-piperidine-2,6-dicarboxylate. Ring-opening of this heterocycle gives a series of derivatives of pimelic acid, ultimately affording lysine. Enzymes involved in this biosynthesis include:
- Aspartokinase
- β-aspartate semialdehyde dehydrogenase
- Dihydropicolinate synthase
- Δ1-piperdine-2,6-dicarboxylate dehydrogenase
- N-succinyl-2-amino-6ketopimelate synthase
- Succinyl diaminopimelate aminotransferase
- Succinyl diaminopimelate desuccinylase
- Diaminopimelate epimerase
- Diaminopimelate decarboxylase
# Metabolism
Lysine is metabolised in mammals to give acetyl-CoA, via an initial transamination with α-ketoglutarate. The bacterial degradation of lysine yields cadaverine by decarboxylation.
# Synthesis
Synthetic, racemic lysine has long been known. A practical synthesis starts from caprolactam.
# Dietary sources
The human nutritional requirement is 1–1.5 g daily. It is the limiting amino acid (the essential amino acid found in the smallest quantity in the particular foodstuff) in all cereal grains, but is plentiful in all pulses (legumes). Plants that contain significant amounts of lysine include:
- Buffalo Gourd (10,130–33,000 ppm) in seed
- Berro, Watercress (1,340–26,800 ppm) in herb.
- Soybean (24,290–26,560 ppm) in seed.
- Carob, Locust Bean, St.John's-Bread (26,320 ppm) in seed;
- Common Bean (Black Bean, Dwarf Bean, Field Bean, Flageolet Bean, French Bean, Garden Bean, Green Bean, Haricot, Haricot Bean, Haricot Vert, Kidney Bean, Navy Bean, Pop Bean, Popping Bean, Snap Bean, String Bean, Wax Bean) (2,390–25,700 ppm) in sprout seedling;
- Ben Nut, Benzolive Tree, Jacinto (Sp.), Moringa (aka Drumstick Tree, Horseradish Tree, Ben Oil Tree), West Indian Ben (5,370–25,165 ppm) in shoot.
- Lentil (7,120–23,735 ppm) in sprout seedling.
- Asparagus Pea, Winged Bean (aka Goa Bean) (21,360–23,304 ppm) in seed.
- Fat Hen (3,540–22,550 ppm) in seed.
- Lentil (19,570–22,035 ppm) in seed.
- White Lupin (19,330–21,585 ppm) in seed.
- Black Caraway, Black Cumin, Fennel-Flower, Nutmeg-Flower, Roman Coriander (16,200–20,700 ppm) in seed.
- Spinach (1,740–20,664 ppm).
- Amaranth, Quinoa
Good sources of lysine are foods rich in protein including meat (specifically red meat, pork, and poultry), cheese (particularly parmesan), certain fish (such as cod and sardines), and eggs.
Nuts are particularly a bad source for lysine.#REDIRECT ]
# Properties
L-Lysine is a necessary building block for all protein in the body. L-Lysine plays a major role in calcium absorption; building muscle protein; recovering from surgery or sports injuries; and the body's production of hormones, enzymes, and antibodies.
# Clinical significance
It has been suggested that lysine may be beneficial for those with herpes simplex infections. However, more research is needed to fully substantiate this claim. For more information, refer to Herpes simplex - Lysine.
Lysine can help to alleviate the symptoms of coldsores. They help to speed up the healing process if taken immediately.
# Trivia
In the movie Jurassic Park the dinosaurs were genetically altered so they could not produce lysine (the "lysine contingency"). This was supposed to prevent the dinosaurs from leaving the park. | Lysine
Template:NatOrganicBox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Lysine (abbreviated as Lys or K)[1] is an α-amino acid with the chemical formula HO2CCH(NH2)(CH2)4NH2. This amino acid is an essential amino acid, which means that humans cannot synthesize it. Its codons are AAA and AAG.
Lysine is a base, as are arginine and histidine. The ε-amino group often participates in hydrogen bonding and as a general base in catalysis. Common posttranslational modifications include methylation of the ε-amino group, giving methyl-, dimethyl-, and trimethyllysine. The latter occurs in calmodulin. Other posttranslational modifications include acetylation. Collagen contains hydroxylysine which is derived from lysine by lysyl hydroxylase. O-Glycosylation of lysine residues in the endoplasmic reticulum or Golgi apparatus is used to mark certain proteins for secretion from the cell.
# Biosynthesis
As an essential amino acid, lysine is not synthesized in animals, hence it must be ingested as lysine or lysine-containing proteins. In plants and microorganisms, it is synthesized from aspartic acid, which is first converted to β-aspartyl-semialdehyde. Cyclization gives dihydropicolinate, which is reduced to Δ1-piperidine-2,6-dicarboxylate. Ring-opening of this heterocycle gives a series of derivatives of pimelic acid, ultimately affording lysine. Enzymes involved in this biosynthesis include:[2]
- Aspartokinase
- β-aspartate semialdehyde dehydrogenase
- Dihydropicolinate synthase
- Δ1-piperdine-2,6-dicarboxylate dehydrogenase
- N-succinyl-2-amino-6ketopimelate synthase
- Succinyl diaminopimelate aminotransferase
- Succinyl diaminopimelate desuccinylase
- Diaminopimelate epimerase
- Diaminopimelate decarboxylase
# Metabolism
Lysine is metabolised in mammals to give acetyl-CoA, via an initial transamination with α-ketoglutarate. The bacterial degradation of lysine yields cadaverine by decarboxylation.
# Synthesis
Synthetic, racemic lysine has long been known.[3] A practical synthesis starts from caprolactam.[4]
# Dietary sources
The human nutritional requirement is 1–1.5 g daily. It is the limiting amino acid (the essential amino acid found in the smallest quantity in the particular foodstuff) in all cereal grains, but is plentiful in all pulses (legumes). Plants that contain significant amounts of lysine include:
- Buffalo Gourd (10,130–33,000 ppm) in seed
- Berro, Watercress (1,340–26,800 ppm) in herb.
- Soybean (24,290–26,560 ppm) in seed.
- Carob, Locust Bean, St.John's-Bread (26,320 ppm) in seed;
- Common Bean (Black Bean, Dwarf Bean, Field Bean, Flageolet Bean, French Bean, Garden Bean, Green Bean, Haricot, Haricot Bean, Haricot Vert, Kidney Bean, Navy Bean, Pop Bean, Popping Bean, Snap Bean, String Bean, Wax Bean) (2,390–25,700 ppm) in sprout seedling;
- Ben Nut, Benzolive Tree, Jacinto (Sp.), Moringa (aka Drumstick Tree, Horseradish Tree, Ben Oil Tree), West Indian Ben (5,370–25,165 ppm) in shoot.
- Lentil (7,120–23,735 ppm) in sprout seedling.
- Asparagus Pea, Winged Bean (aka Goa Bean) (21,360–23,304 ppm) in seed.
- Fat Hen (3,540–22,550 ppm) in seed.
- Lentil (19,570–22,035 ppm) in seed.
- White Lupin (19,330–21,585 ppm) in seed.
- Black Caraway, Black Cumin, Fennel-Flower, Nutmeg-Flower, Roman Coriander (16,200–20,700 ppm) in seed.
- Spinach (1,740–20,664 ppm).
- Amaranth, Quinoa
Good sources of lysine are foods rich in protein including meat (specifically red meat, pork, and poultry), cheese (particularly parmesan), certain fish (such as cod and sardines), and eggs.
Nuts are particularly a bad source for lysine.#REDIRECT [[2]]
# Properties
L-Lysine is a necessary building block for all protein in the body. L-Lysine plays a major role in calcium absorption; building muscle protein; recovering from surgery or sports injuries; and the body's production of hormones, enzymes, and antibodies.
# Clinical significance
It has been suggested that lysine may be beneficial for those with herpes simplex infections.[5] However, more research is needed to fully substantiate this claim. For more information, refer to Herpes simplex - Lysine.
Lysine can help to alleviate the symptoms of coldsores. They help to speed up the healing process if taken immediately.
# Trivia
In the movie Jurassic Park the dinosaurs were genetically altered so they could not produce lysine (the "lysine contingency"). This was supposed to prevent the dinosaurs from leaving the park. | https://www.wikidoc.org/index.php/L-Lysine | |
f2b5a6ff41ec8558de322b3161e2014f5006fe58 | wikidoc | L2HGDH | L2HGDH
L-2-hydroxyglutarate dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the L2HGDH gene, also known as C14orf160, on chromosome 14.
# Function
This gene encodes L-2-hydroxyglutarate dehydrogenase, a flavin adenine dinucleotide (FAD)-dependent enzyme that oxidizes L-2-hydroxyglutarate to alpha-ketoglutarate in a variety of mammalian tissues. Mutations in this gene cause L-2-hydroxyglutaric aciduria, a rare autosomal recessive neurometabolic disorder resulting in moderate to severe mental retardation.
L2HGDH codes for a protein that is 50 kDa in size. The L2HGDH protein contains a mitochondrial-targeting transit peptide and is localized to the mitochondrial inner membrane inside mitochondria inside the cell. The L2HGDH protein catalyzes the following reaction, and requires flavin adenine dinucleotide (FAD) as a co-factor:
(S)-2-hydroxyglutarate + acceptor = 2-oxoglutarate + reduced acceptor.
L-2-hydroxyglutarate is produced by promiscuous action of malate dehydrogenase on 2-oxoglutarate; the L2HGDH protein is thus an example of a metabolite repair enzyme because it reconverts the useless damage product L-2-hydroxyglutarate back to 2-oxoglutarate.
# Clinical significance
Mutations in the L2HGDH gene cause L-2-hydroxyglutaric aciduria, a rare autosomal recessive neurometabolic disorder. Individuals with L2HGDH mutations present toxic accumulation of high concentration of L-2-hydroxyglutaric acid in the plasma and cerebrospinal fluid. At least 70 disease-causing variants in the L2HGDH gene have been discovered in patients. Patients with L-2-hydroxyglutaric aciduria are associated with moderate to severe mental retardation, psychomotor retardation, cerebellar ataxia, macrocephaly, or epilepsy.
L2HGDH has a role in mediating differentiation in T-cells via its activity on S-2HG
# Molecular interactions
KLK10 | L2HGDH
L-2-hydroxyglutarate dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the L2HGDH gene, also known as C14orf160, on chromosome 14.[1][2]
# Function
This gene encodes L-2-hydroxyglutarate dehydrogenase, a flavin adenine dinucleotide (FAD)-dependent enzyme that oxidizes L-2-hydroxyglutarate to alpha-ketoglutarate in a variety of mammalian tissues. Mutations in this gene cause L-2-hydroxyglutaric aciduria, a rare autosomal recessive neurometabolic disorder resulting in moderate to severe mental retardation.[2]
L2HGDH codes for a protein that is 50 kDa in size. The L2HGDH protein contains a mitochondrial-targeting transit peptide[3] and is localized to the mitochondrial inner membrane inside mitochondria inside the cell. The L2HGDH protein catalyzes the following reaction, and requires flavin adenine dinucleotide (FAD) as a co-factor:
(S)-2-hydroxyglutarate + acceptor = 2-oxoglutarate + reduced acceptor.[1]
L-2-hydroxyglutarate is produced by promiscuous action of malate dehydrogenase on 2-oxoglutarate; the L2HGDH protein is thus an example of a metabolite repair enzyme because it reconverts the useless damage product L-2-hydroxyglutarate back to 2-oxoglutarate.
# Clinical significance
Mutations in the L2HGDH gene cause L-2-hydroxyglutaric aciduria, a rare autosomal recessive neurometabolic disorder. Individuals with L2HGDH mutations present toxic accumulation of high concentration of L-2-hydroxyglutaric acid in the plasma and cerebrospinal fluid.[4] At least 70 disease-causing variants in the L2HGDH gene have been discovered in patients.[5] Patients with L-2-hydroxyglutaric aciduria are associated with moderate to severe mental retardation, psychomotor retardation, cerebellar ataxia, macrocephaly, or epilepsy.[5]
L2HGDH has a role in mediating differentiation in T-cells via its activity on S-2HG
[6]
# Molecular interactions
KLK10[7] | https://www.wikidoc.org/index.php/L2HGDH | |
d04f6a97411962f824d34b83c8409bbf309f3012 | wikidoc | LACTB2 | LACTB2
Lactamase, beta 2 is a protein that in humans is encoded by the LACTB2 gene.
# Structure
LACTB2 is located on the 8th chromosome, with its specific location being 8q13.3. The gene contains 7 exons.
The LACTB2 protein has a metallo β-lactamase (MBL) fold, with two zinc ions in the active site.
# Function
The metallo beta-lactamases were first identified in bacteria; they give some strains antibiotic resistance by degrading beta-lactam antibiotics (such as penicillins). However, the protein family includes many members that are ribonucleases (RNases), deoxyribonucleases (DNases) and other metabolic enzymes MBL ribonucleases are responsible for RNA processing, generating the 3' end of tRNA,(RNase Z ) eukaryotic mRNA (CPSF-73) and snRNA molecules LACTB2 is a mitochondrial endoribonuclease which may have a role in degrading mitochondrial mRNAs.
# Clinical significance
A tumor-specific LACTB2-NCOA2 fusion originating from intra-chromosomal rearrangement of chromosome 8 has been identified at both DNA and RNA levels. Unlike conventional oncogenic chimeric proteins, the fusion product lacks functional domain from respective genes, indicative of an amorphic rearrangement. This chimeric LACTB2-NCOA2 transcript was detected in 6 out of 99 (6.1%) colorectal cancer (CRC) cases, where NCOA2 was significantly downregulated. Enforced expression of wild-type NCOA2 but not the LACTB2-NCOA2 fusion protein impaired the pro-tumorigenic phenotypes of CRC cells, whereas knockdown of endogenous NCOA2 in normal colonocytes had opposite effects. Mechanistically, NCOA2 inhibited Wnt/β-catenin signaling through simultaneously upregulating inhibitors and downregulating stimulators of Wnt/β-catenin pathway. NCOA2 is a novel negative growth regulatory gene repressing the Wnt/β-catenin pathway in CRC, where recurrent fusion with LACTB2 contributes to its disruption. | LACTB2
Lactamase, beta 2 is a protein that in humans is encoded by the LACTB2 gene.[1]
# Structure
LACTB2 is located on the 8th chromosome, with its specific location being 8q13.3. The gene contains 7 exons.[1]
The LACTB2 protein has a metallo β-lactamase (MBL) fold, with two zinc ions in the active site.
# Function
The metallo beta-lactamases were first identified in bacteria; they give some strains antibiotic resistance by degrading beta-lactam antibiotics (such as penicillins). However, the protein family includes many members that are ribonucleases (RNases), deoxyribonucleases (DNases) and other metabolic enzymes [2] MBL ribonucleases are responsible for RNA processing, generating the 3' end of tRNA,(RNase Z [3]) eukaryotic mRNA (CPSF-73) and snRNA molecules [4] LACTB2 is a mitochondrial endoribonuclease which may have a role in degrading mitochondrial mRNAs.[5]
# Clinical significance
A tumor-specific LACTB2-NCOA2 fusion originating from intra-chromosomal rearrangement of chromosome 8 has been identified at both DNA and RNA levels. Unlike conventional oncogenic chimeric proteins, the fusion product lacks functional domain from respective genes, indicative of an amorphic rearrangement. This chimeric LACTB2-NCOA2 transcript was detected in 6 out of 99 (6.1%) colorectal cancer (CRC) cases, where NCOA2 was significantly downregulated. Enforced expression of wild-type NCOA2 but not the LACTB2-NCOA2 fusion protein impaired the pro-tumorigenic phenotypes of CRC cells, whereas knockdown of endogenous NCOA2 in normal colonocytes had opposite effects. Mechanistically, NCOA2 inhibited Wnt/β-catenin signaling through simultaneously upregulating inhibitors and downregulating stimulators of Wnt/β-catenin pathway. NCOA2 is a novel negative growth regulatory gene repressing the Wnt/β-catenin pathway in CRC, where recurrent fusion with LACTB2 contributes to its disruption.[6] | https://www.wikidoc.org/index.php/LACTB2 | |
7b48e15335054587c0fbd202ecb244ee0edbf5e3 | wikidoc | LANCL2 | LANCL2
LanC-like protein 2 is a protein that in humans is encoded by the LANCL2 gene. It is a protein broadly expressed in the plasma a nuclear membranes of immune, epithelial and muscle cells and a potential therapeutic target for chronic inflammatory, metabolic and immune-mediated diseases such as Crohn’s disease and diabetes.
# Function
The natural ligand of LANCL2, abscisic acid (ABA), has been identified as a new endogenous mammalian hormone implicated in glycemic control. The mammalian ABA receptor has been identified as LANCL2 on the basis of (1) modeling predictions, (2) direct and specific ABA binding to the purified recombinant protein, and (3) abrogation of the functional effects of ABA by silencing of LANCL2 expression in ABA-sensitive cells.
Selective binding between LANCL2 and ABA or other ligands such as the benzimidazole NSC61610 and piperazine BT-11, lead to elevation of intracellular cAMP, activation of PKA and suppression of inflammation in macrophages. In hepatocytes, LANCL2 regulates cell survival by phosphorylation of Akt through its interaction with the Akt kinase mTORC2. Active mTORC2 causes translocation of GLUT4 to the plasma membrane and stimulates glucose uptake. LANCL2 expression in immune cells, adipose tissue, skeletal muscle and pancreas, and the potential to manipulate LANCL2 signaling and GLUT4 translocation with ABA make this G protein-coupled receptor a novel therapeutic target for glycemic control. In humans, ABA release was detected with increasing glycemia, although this mechanism failed in people suffering from type 2 and gestational diabetes. Also, plasma ABA concentrations increase after oral glucose load (OGTT) in healthy subjects. ABA stimulates glucose-dependent insulin release from human and rodent pancreatic β-cells. At a low dose (micrograms/Kg body weight) oral ABA significantly reduces both glycemia and insulinemia in rats and in humans undergoing an OGTT indicating that ABA reduces the amount of insulin required to control hyperglycemia. This insulin-sparing effect suggests that LANCL2 can be used as a therapeutic target for the treatment of inflammatory and metabolic diseases such as metabolic syndrome, prediabetes and diabetes.
Novel LANCL2 ligands such as BT-11 significantly decrease disease activity in the Dextran Sodium Sulfate (DSS)-induced model of acute colitis and the IL-10-/- mice and CD4+ T cell transfer-induced chronic colitis models. BT-11 treatment decreased leukocytic infiltration, mucosal thickening and epithelial erosion in the colon, decreased Th1 and Th17 CD4+ T cells and TNFα while increasing regulatory T cells, LANCL2 and IL-10 expression. | LANCL2
LanC-like protein 2 is a protein that in humans is encoded by the LANCL2 gene.[1][2] It is a protein broadly expressed in the plasma a nuclear membranes of immune, epithelial and muscle cells and a potential therapeutic target for chronic inflammatory, metabolic and immune-mediated diseases such as Crohn’s disease and diabetes.[3]
# Function
The natural ligand of LANCL2, abscisic acid (ABA), has been identified as a new endogenous mammalian hormone implicated in glycemic control. The mammalian ABA receptor has been identified as LANCL2 on the basis of (1) modeling predictions,[4] (2) direct and specific ABA binding to the purified recombinant protein,[5] and (3) abrogation of the functional effects of ABA by silencing of LANCL2 expression in ABA-sensitive cells.[6]
Selective binding between LANCL2 and ABA or other ligands such as the benzimidazole NSC61610 and piperazine BT-11,[7] lead to elevation of intracellular cAMP, activation of PKA[8] and suppression of inflammation[8] in macrophages. In hepatocytes, LANCL2 regulates cell survival by phosphorylation of Akt through its interaction with the Akt kinase mTORC2.[9] Active mTORC2 causes translocation of GLUT4 to the plasma membrane and stimulates glucose uptake.[10] LANCL2 expression in immune cells, adipose tissue, skeletal muscle and pancreas, and the potential to manipulate LANCL2 signaling and GLUT4 translocation with ABA make this G protein-coupled receptor a novel therapeutic target for glycemic control.[3] In humans, ABA release was detected with increasing glycemia, although this mechanism failed in people suffering from type 2 and gestational diabetes. Also, plasma ABA concentrations increase after oral glucose load (OGTT) in healthy subjects.[11] ABA stimulates glucose-dependent insulin release from human and rodent pancreatic β-cells.[11] At a low dose (micrograms/Kg body weight) oral ABA significantly reduces both glycemia and insulinemia in rats and in humans undergoing an OGTT [12] indicating that ABA reduces the amount of insulin required to control hyperglycemia. This insulin-sparing effect suggests that LANCL2 can be used as a therapeutic target for the treatment of inflammatory and metabolic diseases such as metabolic syndrome, prediabetes and diabetes.
Novel LANCL2 ligands such as BT-11 significantly decrease disease activity in the Dextran Sodium Sulfate (DSS)-induced model of acute colitis and the IL-10-/- mice and CD4+ T cell transfer-induced chronic colitis models.[7] BT-11 treatment decreased leukocytic infiltration, mucosal thickening and epithelial erosion in the colon, decreased Th1 and Th17 CD4+ T cells and TNFα while increasing regulatory T cells, LANCL2 and IL-10 expression.[7] | https://www.wikidoc.org/index.php/LANCL2 | |
23faf42ad7d2a33e0bb9f67862b0c8ede1ba6912 | wikidoc | Leptin | Leptin
Leptin (from Greek λεπτός leptos, "thin"), "the hormone of energy expenditure", is a hormone predominantly made by adipose cells that helps to regulate energy balance by inhibiting hunger. Leptin is opposed by the actions of the hormone ghrelin, the "hunger hormone". Both hormones act on receptors in the arcuate nucleus of the hypothalamus. In obesity, a decreased sensitivity to leptin occurs (similar to insulin resistance in type 2 diabetes), resulting in an inability to detect satiety despite high energy stores and high levels of leptin.
Although regulation of fat stores is deemed to be the primary function of leptin, it also plays a role in other physiological processes, as evidenced by its many sites of synthesis other than fat cells, and the many cell types beside hypothalamic cells that have leptin receptors. Many of these additional functions are yet to be defined.
# Identification of the encoding gene
In 1949, a non-obese mouse colony being studied at the Jackson Laboratory produced a strain of obese offspring, suggesting that a mutation had occurred in a hormone regulating hunger and energy expenditure. Mice homozygous for the so-called ob mutation (ob/ob) ate voraciously and were massively obese. In the 1960s, a second mutation causing obesity and a similar phenotype was identified by Douglas Coleman, also at the Jackson Laboratory, and was named diabetes (db), as both ob/ob and db/db were obese. In 1990 Rudolph Leibel and Jeffrey M. Friedman reported mapping of the db gene.
Consistent with Coleman’s and Leibel's hypothesis, several subsequent studies from Leibel's and Friedman’s labs and other groups confirmed that the ob gene encoded a novel hormone that circulated in blood and that could suppress food intake and body weight in ob and wild type mice, but not in db mice.
In 1994, Friedman's laboratory reported the identification of the gene. In 1995, Jose F. Caro's laboratory provided evidence that the mutations in the mouse ob gene did not occur in humans. Furthermore, since ob gene expression was increased, not decreased, in human obesity, it suggested resistance to leptin to be a possibility. At the suggestion of Roger Guillemin, Friedman named this new hormone "leptin" from the Greek lepto meaning thin. Leptin was the first fat cell-derived hormone (adipokine) to be discovered.
Subsequent studies in 1995 confirmed that the db gene encodes the leptin receptor, and that it is expressed in the hypothalamus, a region of the brain known to regulate the sensation of hunger and body weight.
# Recognition of scientific advances
Coleman and Friedman have been awarded numerous prizes acknowledging their roles in discovery of leptin, including the Gairdner Foundation International Award (2005), the Shaw Prize (2009), the Lasker Award, the BBVA Foundation Frontiers of Knowledge Award and the King Faisal International Prize, Leibel has not received the same level of recognition from the discovery because he was omitted as a co-author of a scientific paper published by Friedman that reported the discovery of the gene. The various theories surrounding Friedman’s omission of Leibel and others as co-authors of this paper have been presented in a number of publications, including Ellen Ruppel Shell’s 2002 book The Hungry Gene.
The discovery of leptin also is documented in a series of books including Fat: Fighting the Obesity Epidemic by Robert Pool, The Hungry Gene by Ellen Ruppel Shell, and Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting by Gina Kolata. Fat: Fighting the Obesity Epidemic and Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting review the work in the Friedman laboratory that led to the cloning of the ob gene, while The Hungry Gene draws attention to the contributions of Leibel.
# Location of gene and structure of hormone
The Ob(Lep) gene (Ob for obese, Lep for leptin) is located on chromosome 7 in humans. Human leptin is a 16-kDa protein of 167 amino acids.
# Mutations
A human mutant leptin was first described in 1997, and subsequently six additional mutations were described. All of those affected were from Eastern countries; and all had variants of leptin not detected by the standard immunoreactive technique, so leptin levels were low or undetectable. The most recently described eighth mutation reported in January 2015, in a child with Turkish parents, is unique in that it is detected by the standard immunoreactive technique, where leptin levels are elevated; but the leptin does not turn on the leptin receptor, hence the patient has functional leptin deficiency. These eight mutations all cause extreme obesity in infancy, with hyperphagia.
## Nonsense
A nonsense mutation in the leptin gene that results in a stop codon and lack of leptin production was first observed in mice in 1950. In the mouse gene, arginine-105 is encoded by CGA and only requires one nucleotide change to create the stop codon TGA. The corresponding amino acid in humans is encoded by the sequence CGG and would require two nucleotides to be changed to produce a stop codon, which is much less likely to happen.
## Frameshift
A recessive frameshift mutation resulting in a reduction of leptin has been observed in two consanguineous children with juvenile obesity.
## Polymorphisms
A Human Genome Equivalent (HuGE) review in 2004 looked at studies of the connection between genetic mutations affecting leptin regulation and obesity. They reviewed a common polymorphism in the leptin gene (A19G; frequency 0.46), three mutations in the leptin receptor gene (Q223R, K109R and K656N) and two mutations in the PPARG gene (P12A and C161T). They found no association between any of the polymorphisms and obesity.
A 2006 study found a link between the common LEP-2548 G/A genotype and morbid obesity in Taiwanese aborigines, but a 2014 meta-analysis did not, however, this polymorphism has been associated with weight gain in patients taking antipsychotics.
The LEP-2548 G/A polymorphism has been linked with an increased risk of prostate cancer, gestational diabetes, and osteoporosis.
Other rare polymorphisms have been found but their association with obesity are not consistent.
## Transversion
A single case of a homozygous transversion mutation of the gene encoding for leptin was reported in January 2015. It leads to functional leptin deficiency with high leptin levels in circulation. The transversion of (c.298G → T) changed aspartic acid to tyrosine at position 100 (p.D100Y). The mutant leptin could neither bind to nor activate the leptin receptor in vitro, nor in leptin-deficient mice in vivo. It was found in a two-year-old boy with extreme obesity with recurrent ear and pulmonary infections. Treatment with metreleptin led to "rapid change in eating behavior, a reduction in daily energy intake, and substantial weight loss".
# Sites of synthesis
Leptin is produced primarily in the adipocytes of white adipose tissue. It also is produced by brown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach (the lower part of the fundic glands), mammary epithelial cells, bone marrow,gastric chief cells and P/D1 cells.
# Blood levels
Leptin circulates in blood in free form and bound to proteins.
## Physiologic variation
Leptin levels vary exponentially, not linearly, with fat mass. Leptin levels in blood are higher between midnight and early morning, perhaps suppressing appetite during the night. The diurnal rhythm of blood leptin levels may be modified by meal-timing.
## In specific conditions
In humans, many instances are seen where leptin dissociates from the strict role of communicating nutritional status between body and brain and no longer correlates with body fat levels:
- Leptin plays a critical role in the adaptive response to starvation.
- Leptin level is decreased after short-term fasting (24–72 hours), even when changes in fat mass are not observed.
- Serum level of leptin is reduced by sleep deprivation.
- Leptin levels are paradoxically increased in obesity.
- Leptin level is increased by emotional stress.
- Leptin level is chronically reduced by physical exercise training.
- Leptin level is decreased by increases in testosterone levels and increased by increases in estrogen levels.
- Leptin level is increased by insulin.
- Leptin release is increased by dexamethasone.
- In obese patients with obstructive sleep apnea, leptin level is increased, but decreased after the administration of continuous positive airway pressure. In non-obese individuals, however, restful sleep (i.e., 8–12 hours of unbroken sleep) can increase leptin to normal levels.
## Mutant leptins
All known leptin mutations except one are associated with low to undetectable immunoreactive leptin blood levels. The exception is a mutant leptin reported in January 2015 which is not functional, but is detected with standard immunoreactive methods. It was found in a massively obese 2-1/2-year-old boy who had high levels of circulating leptin which had no effect on leptin receptors, so he was functionally leptin-deficient.
# Effects
Predominantly, the "energy expenditure hormone" leptin is made by adipose cells, thus it is labeled fat cell-specific. In the context of its effects, it is important to recognize that the short describing words direct, central, and primary are not used interchangeably. In regard to the hormone leptin, central vs peripheral refers to the hypothalamic portion of the brain vs non-hypothalamic location of action of leptin; direct vs indirect refers to whether there is no intermediary, or there is an intermediary in the mode of action of leptin; and primary vs secondary is an arbitrary description of a particular function of leptin.
## Central nervous system
In vertebrates, the nervous system consists of two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). The primary effect of leptins is in the hypothalamus, a part of the central nervous system. Leptin receptors are expressed not only in the hypothalamus but also in other brain regions, particularly in the hippocampus. Thus some leptin receptors in the brain are classified as central (hypothalamic) and some as peripheral (non-hypothalamic).
As scientifically known so far, the general effects of leptin in the central nervous system are:
- Deficiency of leptin has been shown to alter brain proteins and neuronal functions of obese mice which can be restored by leptin injection.
- In humans, low circulating plasma leptin has been associated with cognitive changes associated with anorexia, depression, and Alzheimer’s Disease .
- Studies in transgenic mouse models of Alzheimer's disease have shown that chronic administration of leptin can ameliorate brain pathology and improve cognitive performance, by reducing b-amyloid and hyperphosphorylated Tau, two hallmarks of Alzheimer's pathology.
Generally, leptin is thought to enter the brain at the choroid plexus, where the intense expression of a form of leptin receptor molecule could act as a transport mechanism.
Increased levels of melatonin causes a downregulation of leptin, however, melatonin also appears to increase leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping. Partial sleep deprivation has also been associated with decreased leptin levels.
Mice with type 1 diabetes treated with leptin or leptin plus insulin, compared to insulin alone had better metabolic profiles: blood sugar did not fluctuate so much; cholesterol levels decreased; less body fat formed.
### Hypothalamus
Leptin acts on receptors in the lateral hypothalamus to inhibit hunger and the medial hypothalamus to stimulate satiety.
- In the lateral hypothalamus, leptin inhibits hunger by
counteracting the effects of neuropeptide Y, a potent hunger promoter secreted by cells in the gut and in the hypothalamus
counteracting the effects of anandamide, another potent hunger promoter that binds to the same receptors as THC
- counteracting the effects of neuropeptide Y, a potent hunger promoter secreted by cells in the gut and in the hypothalamus
- counteracting the effects of anandamide, another potent hunger promoter that binds to the same receptors as THC
- In the medial hypothalamus, leptin stimulates satiety by
promoting the synthesis of α-MSH, a hunger suppressant
- promoting the synthesis of α-MSH, a hunger suppressant
Thus, a lesion in the lateral hypothalamus causes anorexia (due to a lack of hunger signals) and a lesion in the medial hypothalamus causes excessive hunger (due to a lack of satiety signals).
This appetite inhibition is long-term, in contrast to the rapid inhibition of hunger by cholecystokinin (CCK) and the slower suppression of hunger between meals mediated by PYY3-36. The absence of leptin (or its receptor) leads to uncontrolled hunger and resulting obesity. Fasting or following a very-low-calorie diet lowers leptin levels.
Leptin levels change more when food intake decreases than when it increases. The dynamics of leptin due to an acute change in energy balance may be related to appetite and eventually, to food intake rather than fat stores.
- It controls food intake and energy expenditure by acting on receptors in the mediobasal hypothalamus.
Leptin binds to neuropeptide Y (NPY) neurons in the arcuate nucleus in such a way as to decrease the activity of these neurons. Leptin signals to the hypothalamus which produces a feeling of satiety. Moreover, leptin signals may make it easier for people to resist the temptation of foods high in calories.
Leptin receptor activation inhibits neuropeptide Y and agouti-related peptide (AgRP), and activates α-melanocyte-stimulating hormone (α-MSH). The NPY neurons are a key element in the regulation of hunger; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic. Conversely, α-MSH is an important mediator of satiety, and differences in the gene for the α-MSH receptor are linked to obesity in humans.
Leptin interacts with six types of receptors (Ob-Ra–Ob-Rf, or LepRa-LepRf), which in turn are encoded by a single gene, LEPR. Ob-Rb is the only receptor isoform that can signal intracellularly via the Jak-Stat and MAPK signal transduction pathways, and is present in hypothalamic nuclei.
Once leptin has bound to the Ob-Rb receptor, it activates the stat3, which is phosphorylated and travels to the nucleus to effect changes in gene expression, one of the main effects being the down-regulation of the expression of endocannabinoids, responsible for increasing hunger. In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them.
## Circulatory system
The role of leptin/leptin receptors in modulation of T cell activity in the immune system was shown in experimentation with mice. It modulates the immune response to atherosclerosis, of which obesity is a predisposing factor.
Exogenous leptin can promote angiogenesis by increasing vascular endothelial growth factor levels.
Hyperleptinemia produced by infusion or adenoviral gene transfer decreases blood pressure in rats.
Leptin microinjections into the nucleus of the solitary tract (NTS) have been shown to elicit sympathoexcitatory responses, and potentiate the cardiovascular responses to activation of the chemoreflex.
## Fetal lung
In fetal lung, leptin is induced in the alveolar interstitial fibroblasts ("lipofibroblasts") by the action of PTHrP secreted by formative alveolar epithelium (endoderm) under moderate stretch. The leptin from the mesenchyme, in turn, acts back on the epithelium at the leptin receptor carried in the alveolar type II pneumocytes and induces surfactant expression, which is one of the main functions of these type II pneumocytes.
## Reproductive system
### Ovulatory cycle
In mice, and to a lesser extent in humans, leptin is required for male and female fertility. Ovulatory cycles in females are linked to energy balance (positive or negative depending on whether a female is losing or gaining weight) and energy flux (how much energy is consumed and expended) much more than energy status (fat levels). When energy balance is highly negative (meaning the woman is starving) or energy flux is very high (meaning the woman is exercising at extreme levels, but still consuming enough calories), the ovarian cycle stops and females stop menstruating. Only if a female has an extremely low body fat percentage does energy status affect menstruation. Leptin levels outside an ideal range may have a negative effect on egg quality and outcome during in vitro fertilization. Leptin is involved in reproduction by stimulating gonadotropin-releasing hormone from the hypothalamus.
### Pregnancy
The placenta produces leptin. Leptin levels rise during pregnancy and fall after childbirth. Leptin is also expressed in fetal membranes and the uterine tissue. Uterine contractions are inhibited by leptin. Leptin plays a role in hyperemesis gravidarum (severe morning sickness of pregnancy), in polycystic ovary syndrome and hypothalamic leptin is implicated in bone growth in mice.
### Lactation
Immunoreactive leptin has been found in human breast milk; and leptin from mother's milk has been found in the blood of suckling infant animals.
### Puberty
Leptin along with kisspeptin controls the onset of puberty. High levels of leptin, as usually observed in obese females, can trigger neuroendocrine cascade resulting in early menarche. This may eventually lead to shorter stature as oestrogen secretion starts during menarche and causes early closure of epiphyses.
## Bone
Leptin's ability to regulate bone mass was first recognized in 2000. Leptin can affect bone metabolism via direct signalling from the brain. Leptin decreases cancellous bone, but increases cortical bone. This "cortical-cancellous dichotomy" may represent a mechanism for enlarging bone size, and thus bone resistance, to cope with increased body weight.
Bone metabolism can be regulated by central sympathetic outflow, since sympathetic pathways innervate bone tissue. A number of brain-signalling molecules (neuropeptides and neurotransmitters) have been found in bone, including adrenaline, noradrenaline, serotonin, calcitonin gene-related peptide, vasoactive intestinal peptide and neuropeptide Y. Leptin binds to its receptors in the hypothalamus, where it acts through the sympathetic nervous system to regulate bone metabolism. Leptin may also act directly on bone metabolism via a balance between energy intake and the IGF-I pathway. There is a potential for treatment of diseases of bone formation - such as impaired fracture healing - with leptin.
## Immune system
Factors that acutely affect leptin levels are also factors that influence other markers of inflammation, e.g., testosterone, sleep, emotional stress, caloric restriction, and body fat levels. While it is well-established that leptin is involved in the regulation of the inflammatory response, it has been further theorized that leptin's role as an inflammatory marker is to respond specifically to adipose-derived inflammatory cytokines.
In terms of both structure and function, leptin resembles IL-6 and is a member of the cytokine superfamily. Circulating leptin seems to affect the HPA axis, suggesting a role for leptin in stress response. Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women.
Similar to what is observed in chronic inflammation, chronically elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases, including hypertension, metabolic syndrome, and cardiovascular disease. While leptin is associated with body fat mass, however, the size of individual fat cells, and the act of overeating, it is interesting that it is not affected by exercise (for comparison, IL-6 is released in response to muscular contractions). Thus, it is speculated that leptin responds specifically to adipose-derived inflammation. Leptin is a pro-angiogenic, pro-inflammatory and mitogenic factor, the actions of which are reinforced through crosstalk with IL-1 family cytokines in cancer.
Taken as such, increases in leptin levels (in response to caloric intake) function as an acute pro-inflammatory response mechanism to prevent excessive cellular stress induced by overeating. When high caloric intake overtaxes the ability of fat cells to grow larger or increase in number in step with caloric intake, the ensuing stress response leads to inflammation at the cellular level and ectopic fat storage, i.e., the unhealthy storage of body fat within internal organs, arteries, and/or muscle. The insulin increase in response to the caloric load provokes a dose-dependent rise in leptin, an effect potentiated by high cortisol levels. (This insulin-leptin relationship is notably similar to insulin's effect on the increase of IL-6 gene expression and secretion from preadipocytes in a time- and dose-dependent manner.) Furthermore, plasma leptin concentrations have been observed to gradually increase when acipimox is administered to prevent lipolysis, concurrent hypocaloric dieting and weight loss notwithstanding. Such findings appear to demonstrate high caloric loads in excess of storage rate capacities of fat cells lead to stress responses that induce an increase in leptin, which then operates as an adipose-derived inflammation stopgap signaling for the cessation of food intake so as to prevent adipose-derived inflammation from reaching elevated levels. This response may then protect against the harmful process of ectopic fat storage, which perhaps explains the connection between chronically elevated leptin levels and ectopic fat storage in obese individuals.
# Role in obesity and weight loss
## Obesity
Although leptin reduces appetite as a circulating signal, obese individuals generally exhibit a higher circulating concentration of leptin than normal weight individuals due to their higher percentage body fat. These people show resistance to leptin, similar to resistance of insulin in type 2 diabetes, with the elevated levels failing to control hunger and modulate their weight. A number of explanations have been proposed to explain this. An important contributor to leptin resistance is changes to leptin receptor signalling, particularly in the arcuate nucleus, however, deficiency of, or major changes to, the leptin receptor itself are not thought to be a major cause. Other explanations suggested include changes to the way leptin crosses the blood brain barrier (BBB) or alterations occurring during development.
Studies on leptin cerebrospinal fluid (CSF) levels provide evidence for the reduction in leptin crossing the BBB and reaching obesity-relevant targets, such as the hypothalamus, in obese people. In humans it has been observed that the ratio of leptin in the CSF compared to the blood is lower in obese people than in people of a normal weight. The reason for this may be high levels of triglycerides affecting the transport of leptin across the BBB or due to the leptin transporter becoming saturated. Although deficits in the transfer of leptin from the plasma to the CSF is seen in obese people, they are still found to have 30% more leptin in their CSF than lean individuals. These higher CSF levels fail to prevent their obesity. Since the amount and quality of leptin receptors in the hypothalamus appears to be normal in the majority of obese humans (as judged from leptin-mRNA studies), it is likely that the leptin resistance in these individuals is due to a post leptin-receptor deficit, similar to the post-insulin receptor defect seen in type 2 diabetes.
When leptin binds with the leptin receptor, it activates a number of pathways. Leptin resistance may be caused by defects in one or more part of this process, particularly the JAK/STAT pathway. Mice with a mutation in the leptin receptor gene that prevents the activation of STAT3 are obese and exhibit hyperphagia. The PI3K pathway may also be involved in leptin resistance, as has been demonstrated in mice by artificial blocking of PI3K signalling. The PI3K pathway also is activated by the insulin receptor and is therefore an important area where leptin and insulin act together as part of energy homeostasis. The insulin-pI3K pathway can cause POMC neurons to become insensitive to leptin through hyperpolarization.
The consumption of a high fructose diet from birth has been associated with a reduction in leptin levels and reduced expression of leptin receptor mRNA in rats. Long-term consumption of fructose in rats has been shown to increase levels of triglycerides and trigger leptin and insulin resistance, however, another study found that leptin resistance only developed in the presence of both high fructose and high fat levels in the diet. A third study found that high fructose levels reversed leptin resistance in rats given a high fat diet. The contradictory results mean that it is uncertain whether leptin resistance is caused by high levels of carbohydrates or fats, or if an increase of both, is needed.
Leptin is known to interact with amylin, a hormone involved in gastric emptying and creating a feeling of fullness. When both leptin and amylin were given to obese, leptin-resistant rats, sustained weight loss was seen. Due to its apparent ability to reverse leptin resistance, amylin has been suggested as possible therapy for obesity.
It has been suggested that the main role of leptin is to act as a starvation signal when levels are low, to help maintain fat stores for survival during times of starvation, rather than a satiety signal to prevent overeating. Leptin levels signal when an animal has enough stored energy to spend it in pursuits besides acquiring food. This would mean that leptin resistance in obese people is a normal part of mammalian physiology and possibly, could confer a survival advantage. Leptin resistance (in combination with insulin resistance and weight gain) is seen in rats after they are given unlimited access to palatable, energy-dense foods. This effect is reversed when the animals are put back on a low-energy diet. This also may have an evolutionary advantage: allowing energy to be stored efficiently when food is plentiful would be advantageous in populations where food frequently may be scarce.
## Response to weight loss
Dieters who lose weight, particularly those with an overabundance of fat cells, experience a drop in levels of circulating leptin. This drop causes reversible decreases in thyroid activity, sympathetic tone, and energy expenditure in skeletal muscle, and increases in muscle efficiency and parasympathetic tone. Many of these changes are reversed by peripheral administration ( intravenously into the veins of the arms, hands, legs, or feet ) of recombinant leptin to restore pre-diet levels.
A decline in levels of circulating leptin also changes brain activity in areas involved in the regulatory, emotional, and cognitive control of appetite that are reversed by administration of leptin.
# Role in joint problems and obesity
## Obesity and osteoarthritis
Osteoarthritis and obesity are closely linked. Obesity is one of the most important preventable factors for the development of osteoarthritis.
Originally, the relationship between osteoarthritis and obesity was considered to be exclusively biomechanically based, according to which the excess weight caused the joint to become worn down more quickly. However, today we recognise that there is also a metabolic component which explains why obesity is a risk factor for osteoarthritis, not only for weight-bearing joints (for example, the knees), but also for joints that do not bear weight (for example, the hands). Consequently, it has been shown that decreasing body fat lessens osteoarthritis to a greater extent than weight loss per se. This metabolic component related with the release of systemic factors, of a pro-inflammatory nature, by the adipose tissues, which frequently are critically associated with the development of osteoarthritis.
Thus, the deregulated production of adipokines and inflammatory mediators, hyperlipidaemia, and the increase of systemic oxidative stress are conditions frequently associated with obesity which can favour joint degeneration. Furthermore, many regulation factors have been implicated in the development, maintenance and function, both of adipose tissues, as well as of the cartilage and other joint tissues. Alterations in these factors can be the additional link between obesity and osteoarthritis.
## Leptin and osteoarthritis
Adipocytes interact with other cells through producing and secreting a variety of signalling molecules, including the cell signalling proteins known as adipokines. Certain adipokines can be considered as hormones, as they regulate the functions of organs at a distance, and several of them have been specifically involved in the physiopathology of joint diseases. In particular, there is one, leptin, which has been the focus of attention for research in recent years.
The circulating leptin levels are positively correlated with the Body Mass Index (BMI), more specifically with fatty mass, and obese individuals have higher leptin levels in their blood circulation, compared with non-obese individuals. In obese individuals, the increased circulating leptin levels induce unwanted responses, that is, reduced food intake or losing body weight does not occur as there is a resistance to leptin (ref 9). In addition to the function of regulating energy homeostasis, leptin carries out a role in other physiological functions such as neuroendocrine communication, reproduction, angiogenesis and bone formation. More recently, leptin has been recognised as a cytokine factor as well as with pleiotropic actions also in the immune response and inflammation. For example, leptin can be found in the synovial fluid in correlation with the body mass index, and the leptin receptors are expressed in the cartilage, where leptin mediates and modulates many inflammatory responses that can damage cartilage and other joint tissues. Leptin has thus emerged as a candidate to link obesity and osteoarthritis and serves as an apparent objective as a nutritional treatment for osteoarthritis.
As in the plasma, the leptin levels in the synovial fluid are positively correlated with BMI. The leptin of the synovial fluid is synthesised at least partially in the joint and may originate in part in the circulation. Leptin has been shown to be produced by chondrocytes, as well as by other tissues in the joints, including the synovial tissue, osteophytes, the meniscus and bone. An infrapatellar fat pad located extrasynovially within the knee joint is also adjacent to the synovial membrane and cartilage, and has recently been highly appreciated as an important source of leptin, as well as other adipokines and mediators which contribute to the pathogenesis of osteoarthritis
The risk of suffering osteoarthritis can be decreased with weight loss. This reduction of risk is related in part with the decrease of the load on the joint, but also in the decrease of fatty mass, the central adipose tissue and the low-level inflammation associated with obesity and systemic factors.
This growing evidence points to leptin as a cartilage degradation factor in the pathogenesis of osteoarthritis, and as a potential biomarker in the progression of the disease, which suggests that leptin, as well as regulation and signalling mechanisms, can be a new and promising target in the treatment of osteoarthritis, especially in obese patients.
Obese individuals are predisposed to developing osteoarthritis, not only due to the excess mechanical load, but also due to the excess expression of soluble factors, that is, leptin and pro-inflammatory cytokines, which contribute to joint inflammation and cartilage destruction. As such, obese individuals are in an altered state, due to a metabolic insufficiency, which requires specific nutritional treatment capable of normalising the leptin production and reducing the systematic low-level inflammation, in order to reduce the harmful impact of these systematic mediators on the joint health.
There are nutritional supplements and pharmacological agents capable of directing these factors and improving both conditions.
# Therapeutic use
## Leptin
Leptin was approved in the United States in 2014 for use in congenital leptin deficiency and generalized lipodystrophy.
## Analog metreleptin
An analog of human leptin metreleptin (trade names Mylept, Mylepta) was first approved in Japan in 2013, and in the United States in February 2014 and in Europe in 2018. In the US it is indicated as a treatment for complications of leptin deficiency, and for the diabetes and hypertriglyceridemia associated with congenital or acquired generalized lipodystrophy. In Europe based on EMA, metreleptin should be used in addition to diet to treat lipodystrophy, where patients have loss of fatty tissue under the skin and build-up of fat elsewhere in the body such as in the liver and muscles. The medicine is used in: adults and children above the age of 2 years with generalised lipodystrophy (Berardinelli-Seip syndrome and Lawrence syndrome) and in adults and children above the age of 12 years with partial lipodystrophy (including Barraquer-Simons syndrome), when standard treatments have failed.
# History
The leptine was discovered by Jeffrey Freidman in 1994 after several decades of research conducted by others institutions since 1950 on obese mouse models | Leptin
Leptin (from Greek λεπτός leptos, "thin"), "the hormone of energy expenditure",[lower-alpha 1] is a hormone predominantly made by adipose cells that helps to regulate energy balance by inhibiting hunger. Leptin is opposed by the actions of the hormone ghrelin, the "hunger hormone". Both hormones act on receptors in the arcuate nucleus of the hypothalamus.[2] In obesity, a decreased sensitivity to leptin occurs (similar to insulin resistance in type 2 diabetes), resulting in an inability to detect satiety despite high energy stores and high levels of leptin.[3]
Although regulation of fat stores is deemed to be the primary function of leptin, it also plays a role in other physiological processes, as evidenced by its many sites of synthesis other than fat cells, and the many cell types beside hypothalamic cells that have leptin receptors. Many of these additional functions are yet to be defined.[4][5][6][7][8][9]
# Identification of the encoding gene
In 1949, a non-obese mouse colony being studied at the Jackson Laboratory produced a strain of obese offspring, suggesting that a mutation had occurred in a hormone regulating hunger and energy expenditure. Mice homozygous for the so-called ob mutation (ob/ob) ate voraciously and were massively obese.[10] In the 1960s, a second mutation causing obesity and a similar phenotype was identified by Douglas Coleman, also at the Jackson Laboratory, and was named diabetes (db), as both ob/ob and db/db were obese.[11][12][13] In 1990 Rudolph Leibel and Jeffrey M. Friedman reported mapping of the db gene.[14][15][16]
Consistent with Coleman’s and Leibel's hypothesis, several subsequent studies from Leibel's and Friedman’s labs and other groups confirmed that the ob gene encoded a novel hormone that circulated in blood and that could suppress food intake and body weight in ob and wild type mice, but not in db mice.[4][5][6][7]
In 1994, Friedman's laboratory reported the identification of the gene.[13] In 1995, Jose F. Caro's laboratory provided evidence that the mutations in the mouse ob gene did not occur in humans. Furthermore, since ob gene expression was increased, not decreased, in human obesity, it suggested resistance to leptin to be a possibility.[8] At the suggestion of Roger Guillemin, Friedman named this new hormone "leptin" from the Greek lepto meaning thin.[4][17] Leptin was the first fat cell-derived hormone (adipokine) to be discovered.[18]
Subsequent studies in 1995 confirmed that the db gene encodes the leptin receptor, and that it is expressed in the hypothalamus, a region of the brain known to regulate the sensation of hunger and body weight.[19][20][21][22]
# Recognition of scientific advances
Coleman and Friedman have been awarded numerous prizes acknowledging their roles in discovery of leptin, including the Gairdner Foundation International Award (2005),[23] the Shaw Prize (2009),[24] the Lasker Award,[25] the BBVA Foundation Frontiers of Knowledge Award[26] and the King Faisal International Prize,[27] Leibel has not received the same level of recognition from the discovery because he was omitted as a co-author of a scientific paper published by Friedman that reported the discovery of the gene. The various theories surrounding Friedman’s omission of Leibel and others as co-authors of this paper have been presented in a number of publications, including Ellen Ruppel Shell’s 2002 book The Hungry Gene.[28][29]
The discovery of leptin also is documented in a series of books including Fat: Fighting the Obesity Epidemic by Robert Pool,[30] The Hungry Gene by Ellen Ruppel Shell, and Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting by Gina Kolata.[31][32] Fat: Fighting the Obesity Epidemic and Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting review the work in the Friedman laboratory that led to the cloning of the ob gene, while The Hungry Gene draws attention to the contributions of Leibel.[citation needed]
# Location of gene and structure of hormone
The Ob(Lep) gene (Ob for obese, Lep for leptin) is located on chromosome 7 in humans.[33] Human leptin is a 16-kDa protein of 167 amino acids.
# Mutations
A human mutant leptin was first described in 1997,[34] and subsequently six additional mutations were described. All of those affected were from Eastern countries; and all had variants of leptin not detected by the standard immunoreactive technique, so leptin levels were low or undetectable. The most recently described eighth mutation reported in January 2015, in a child with Turkish parents, is unique in that it is detected by the standard immunoreactive technique, where leptin levels are elevated; but the leptin does not turn on the leptin receptor, hence the patient has functional leptin deficiency.[35] These eight mutations all cause extreme obesity in infancy, with hyperphagia.[35]
## Nonsense
A nonsense mutation in the leptin gene that results in a stop codon and lack of leptin production was first observed in mice in 1950. In the mouse gene, arginine-105 is encoded by CGA and only requires one nucleotide change to create the stop codon TGA. The corresponding amino acid in humans is encoded by the sequence CGG and would require two nucleotides to be changed to produce a stop codon, which is much less likely to happen.[8]
## Frameshift
A recessive frameshift mutation resulting in a reduction of leptin has been observed in two consanguineous children with juvenile obesity.
## Polymorphisms
A Human Genome Equivalent (HuGE) review in 2004 looked at studies of the connection between genetic mutations affecting leptin regulation and obesity. They reviewed a common polymorphism in the leptin gene (A19G; frequency 0.46), three mutations in the leptin receptor gene (Q223R, K109R and K656N) and two mutations in the PPARG gene (P12A and C161T). They found no association between any of the polymorphisms and obesity.[36]
A 2006 study found a link between the common LEP-2548 G/A genotype and morbid obesity in Taiwanese aborigines,[37][38] but a 2014 meta-analysis did not,[38] however, this polymorphism has been associated with weight gain in patients taking antipsychotics.[39][40][41]
The LEP-2548 G/A polymorphism has been linked with an increased risk of prostate cancer,[42] gestational diabetes,[43] and osteoporosis.[44]
Other rare polymorphisms have been found but their association with obesity are not consistent.[36]
## Transversion
A single case of a homozygous transversion mutation of the gene encoding for leptin was reported in January 2015.[35] It leads to functional leptin deficiency with high leptin levels in circulation. The transversion of (c.298G → T) changed aspartic acid to tyrosine at position 100 (p.D100Y). The mutant leptin could neither bind to nor activate the leptin receptor in vitro, nor in leptin-deficient mice in vivo. It was found in a two-year-old boy with extreme obesity with recurrent ear and pulmonary infections. Treatment with metreleptin led to "rapid change in eating behavior, a reduction in daily energy intake, and substantial weight loss".[35]
# Sites of synthesis
Leptin is produced primarily in the adipocytes of white adipose tissue. It also is produced by brown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach (the lower part of the fundic glands), mammary epithelial cells, bone marrow,[45]gastric chief cells and P/D1 cells.[46]
# Blood levels
Leptin circulates in blood in free form and bound to proteins.[47]
## Physiologic variation
Leptin levels vary exponentially, not linearly, with fat mass.[48][49] Leptin levels in blood are higher between midnight and early morning, perhaps suppressing appetite during the night.[50] The diurnal rhythm of blood leptin levels may be modified by meal-timing.[51]
## In specific conditions
In humans, many instances are seen where leptin dissociates from the strict role of communicating nutritional status between body and brain and no longer correlates with body fat levels:
- Leptin plays a critical role in the adaptive response to starvation.[52][53]
- Leptin level is decreased after short-term fasting (24–72 hours), even when changes in fat mass are not observed.[54][55][56]
- Serum level of leptin is reduced by sleep deprivation.[57][58]
- Leptin levels are paradoxically increased in obesity.[59]
- Leptin level is increased by emotional stress.[60]
- Leptin level is chronically reduced by physical exercise training.[61][62][63]
- Leptin level is decreased by increases in testosterone levels and increased by increases in estrogen levels.[64]
- Leptin level is increased by insulin.[65]
- Leptin release is increased by dexamethasone.[66]
- In obese patients with obstructive sleep apnea, leptin level is increased, but decreased after the administration of continuous positive airway pressure.[67][68] In non-obese individuals, however, restful sleep (i.e., 8–12 hours of unbroken sleep) can increase leptin to normal levels.
## Mutant leptins
All known leptin mutations except one are associated with low to undetectable immunoreactive leptin blood levels. The exception is a mutant leptin reported in January 2015 which is not functional, but is detected with standard immunoreactive methods. It was found in a massively obese 2-1/2-year-old boy who had high levels of circulating leptin which had no effect on leptin receptors, so he was functionally leptin-deficient.[35]
# Effects
Predominantly, the "energy expenditure hormone" leptin is made by adipose cells, thus it is labeled fat cell-specific. In the context of its effects, it is important to recognize that the short describing words direct, central, and primary are not used interchangeably. In regard to the hormone leptin, central vs peripheral refers to the hypothalamic portion of the brain vs non-hypothalamic location of action of leptin; direct vs indirect refers to whether there is no intermediary, or there is an intermediary in the mode of action of leptin; and primary vs secondary is an arbitrary description of a particular function of leptin.[69]
## Central nervous system
In vertebrates, the nervous system consists of two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). The primary effect of leptins is in the hypothalamus, a part of the central nervous system. Leptin receptors are expressed not only in the hypothalamus but also in other brain regions, particularly in the hippocampus. Thus some leptin receptors in the brain are classified as central (hypothalamic) and some as peripheral (non-hypothalamic).
As scientifically known so far, the general effects of leptin in the central nervous system are:
- Deficiency of leptin has been shown to alter brain proteins and neuronal functions of obese mice which can be restored by leptin injection.[71]
- In humans, low circulating plasma leptin has been associated with cognitive changes associated with anorexia,[72] depression, and Alzheimer’s Disease .[73]
- Studies in transgenic mouse models of Alzheimer's disease have shown that chronic administration of leptin can ameliorate brain pathology and improve cognitive performance,[74] by reducing b-amyloid and hyperphosphorylated Tau,[75][76] two hallmarks of Alzheimer's pathology.
Generally, leptin is thought to enter the brain at the choroid plexus, where the intense expression of a form of leptin receptor molecule could act as a transport mechanism.[77]
Increased levels of melatonin causes a downregulation of leptin,[78] however, melatonin also appears to increase leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping.[79] Partial sleep deprivation has also been associated with decreased leptin levels.[80]
Mice with type 1 diabetes treated with leptin or leptin plus insulin, compared to insulin alone had better metabolic profiles: blood sugar did not fluctuate so much; cholesterol levels decreased; less body fat formed.[81]
### Hypothalamus
Leptin acts on receptors in the lateral hypothalamus to inhibit hunger and the medial hypothalamus to stimulate satiety.[82]
- In the lateral hypothalamus, leptin inhibits hunger[83] by
counteracting the effects of neuropeptide Y, a potent hunger promoter secreted by cells in the gut and in the hypothalamus
counteracting the effects of anandamide, another potent hunger promoter that binds to the same receptors as THC
- counteracting the effects of neuropeptide Y, a potent hunger promoter secreted by cells in the gut and in the hypothalamus
- counteracting the effects of anandamide, another potent hunger promoter that binds to the same receptors as THC
- In the medial hypothalamus, leptin stimulates satiety[84] by
promoting the synthesis of α-MSH, a hunger suppressant
- promoting the synthesis of α-MSH, a hunger suppressant
Thus, a lesion in the lateral hypothalamus causes anorexia (due to a lack of hunger signals) and a lesion in the medial hypothalamus causes excessive hunger (due to a lack of satiety signals).[82]
This appetite inhibition is long-term, in contrast to the rapid inhibition of hunger by cholecystokinin (CCK) and the slower suppression of hunger between meals mediated by PYY3-36. The absence of leptin (or its receptor) leads to uncontrolled hunger and resulting obesity. Fasting or following a very-low-calorie diet lowers leptin levels.[85][86][87][88]
Leptin levels change more when food intake decreases than when it increases.[89] The dynamics of leptin due to an acute change in energy balance may be related to appetite and eventually, to food intake rather than fat stores.[90][91]
- It controls food intake and energy expenditure by acting on receptors in the mediobasal hypothalamus.[92]
Leptin binds to neuropeptide Y (NPY) neurons in the arcuate nucleus in such a way as to decrease the activity of these neurons. Leptin signals to the hypothalamus which produces a feeling of satiety. Moreover, leptin signals may make it easier for people to resist the temptation of foods high in calories.[93]
Leptin receptor activation inhibits neuropeptide Y and agouti-related peptide (AgRP), and activates α-melanocyte-stimulating hormone (α-MSH). The NPY neurons are a key element in the regulation of hunger; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic. Conversely, α-MSH is an important mediator of satiety, and differences in the gene for the α-MSH receptor are linked to obesity in humans.
Leptin interacts with six types of receptors (Ob-Ra–Ob-Rf, or LepRa-LepRf), which in turn are encoded by a single gene, LEPR.[94] Ob-Rb is the only receptor isoform that can signal intracellularly via the Jak-Stat and MAPK signal transduction pathways,[95] and is present in hypothalamic nuclei.[96]
Once leptin has bound to the Ob-Rb receptor, it activates the stat3, which is phosphorylated and travels to the nucleus to effect changes in gene expression, one of the main effects being the down-regulation of the expression of endocannabinoids, responsible for increasing hunger.[97] In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them.
## Circulatory system
The role of leptin/leptin receptors in modulation of T cell activity in the immune system was shown in experimentation with mice. It modulates the immune response to atherosclerosis, of which obesity is a predisposing factor.[98]
Exogenous leptin can promote angiogenesis by increasing vascular endothelial growth factor levels.
Hyperleptinemia produced by infusion or adenoviral gene transfer decreases blood pressure in rats.[99][100]
Leptin microinjections into the nucleus of the solitary tract (NTS) have been shown to elicit sympathoexcitatory responses, and potentiate the cardiovascular responses to activation of the chemoreflex.[101]
## Fetal lung
In fetal lung, leptin is induced in the alveolar interstitial fibroblasts ("lipofibroblasts") by the action of PTHrP secreted by formative alveolar epithelium (endoderm) under moderate stretch. The leptin from the mesenchyme, in turn, acts back on the epithelium at the leptin receptor carried in the alveolar type II pneumocytes and induces surfactant expression, which is one of the main functions of these type II pneumocytes.[102]
## Reproductive system
### Ovulatory cycle
In mice, and to a lesser extent in humans, leptin is required for male and female fertility. Ovulatory cycles in females are linked to energy balance (positive or negative depending on whether a female is losing or gaining weight) and energy flux (how much energy is consumed and expended) much more than energy status (fat levels). When energy balance is highly negative (meaning the woman is starving) or energy flux is very high (meaning the woman is exercising at extreme levels, but still consuming enough calories), the ovarian cycle stops and females stop menstruating. Only if a female has an extremely low body fat percentage does energy status affect menstruation. Leptin levels outside an ideal range may have a negative effect on egg quality and outcome during in vitro fertilization.[103] Leptin is involved in reproduction by stimulating gonadotropin-releasing hormone from the hypothalamus.[104]
### Pregnancy
The placenta produces leptin.[105] Leptin levels rise during pregnancy and fall after childbirth. Leptin is also expressed in fetal membranes and the uterine tissue. Uterine contractions are inhibited by leptin.[106] Leptin plays a role in hyperemesis gravidarum (severe morning sickness of pregnancy),[107] in polycystic ovary syndrome[108] and hypothalamic leptin is implicated in bone growth in mice.[109]
### Lactation
Immunoreactive leptin has been found in human breast milk; and leptin from mother's milk has been found in the blood of suckling infant animals.[110]
### Puberty
Leptin along with kisspeptin controls the onset of puberty.[111] High levels of leptin, as usually observed in obese females, can trigger neuroendocrine cascade resulting in early menarche.[112] This may eventually lead to shorter stature as oestrogen secretion starts during menarche and causes early closure of epiphyses.
## Bone
Leptin's ability to regulate bone mass was first recognized in 2000.[113] Leptin can affect bone metabolism via direct signalling from the brain. Leptin decreases cancellous bone, but increases cortical bone. This "cortical-cancellous dichotomy" may represent a mechanism for enlarging bone size, and thus bone resistance, to cope with increased body weight.[114]
Bone metabolism can be regulated by central sympathetic outflow, since sympathetic pathways innervate bone tissue.[115] A number of brain-signalling molecules (neuropeptides and neurotransmitters) have been found in bone, including adrenaline, noradrenaline, serotonin, calcitonin gene-related peptide, vasoactive intestinal peptide and neuropeptide Y.[115][116] Leptin binds to its receptors in the hypothalamus, where it acts through the sympathetic nervous system to regulate bone metabolism.[117] Leptin may also act directly on bone metabolism via a balance between energy intake and the IGF-I pathway.[114][118] There is a potential for treatment of diseases of bone formation - such as impaired fracture healing - with leptin.[119]
## Immune system
Factors that acutely affect leptin levels are also factors that influence other markers of inflammation, e.g., testosterone, sleep, emotional stress, caloric restriction, and body fat levels. While it is well-established that leptin is involved in the regulation of the inflammatory response,[120][121][122] it has been further theorized that leptin's role as an inflammatory marker is to respond specifically to adipose-derived inflammatory cytokines.
In terms of both structure and function, leptin resembles IL-6 and is a member of the cytokine superfamily.[1][121][123] Circulating leptin seems to affect the HPA axis, suggesting a role for leptin in stress response.[124] Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women.[125]
Similar to what is observed in chronic inflammation, chronically elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases, including hypertension, metabolic syndrome, and cardiovascular disease. While leptin is associated with body fat mass, however, the size of individual fat cells, and the act of overeating, it is interesting that it is not affected by exercise (for comparison, IL-6 is released in response to muscular contractions). Thus, it is speculated that leptin responds specifically to adipose-derived inflammation.[126] Leptin is a pro-angiogenic, pro-inflammatory and mitogenic factor, the actions of which are reinforced through crosstalk with IL-1 family cytokines in cancer.[127]
Taken as such, increases in leptin levels (in response to caloric intake) function as an acute pro-inflammatory response mechanism to prevent excessive cellular stress induced by overeating. When high caloric intake overtaxes the ability of fat cells to grow larger or increase in number in step with caloric intake, the ensuing stress response leads to inflammation at the cellular level and ectopic fat storage, i.e., the unhealthy storage of body fat within internal organs, arteries, and/or muscle. The insulin increase in response to the caloric load provokes a dose-dependent rise in leptin, an effect potentiated by high cortisol levels.[128] (This insulin-leptin relationship is notably similar to insulin's effect on the increase of IL-6 gene expression and secretion from preadipocytes in a time- and dose-dependent manner.)[129] Furthermore, plasma leptin concentrations have been observed to gradually increase when acipimox is administered to prevent lipolysis, concurrent hypocaloric dieting and weight loss notwithstanding.[130] Such findings appear to demonstrate high caloric loads in excess of storage rate capacities of fat cells lead to stress responses that induce an increase in leptin, which then operates as an adipose-derived inflammation stopgap signaling for the cessation of food intake so as to prevent adipose-derived inflammation from reaching elevated levels. This response may then protect against the harmful process of ectopic fat storage, which perhaps explains the connection between chronically elevated leptin levels and ectopic fat storage in obese individuals.[59]
# Role in obesity and weight loss
## Obesity
Although leptin reduces appetite as a circulating signal, obese individuals generally exhibit a higher circulating concentration of leptin than normal weight individuals due to their higher percentage body fat.[9] These people show resistance to leptin, similar to resistance of insulin in type 2 diabetes, with the elevated levels failing to control hunger and modulate their weight. A number of explanations have been proposed to explain this. An important contributor to leptin resistance is changes to leptin receptor signalling, particularly in the arcuate nucleus, however, deficiency of, or major changes to, the leptin receptor itself are not thought to be a major cause. Other explanations suggested include changes to the way leptin crosses the blood brain barrier (BBB) or alterations occurring during development.[131]
Studies on leptin cerebrospinal fluid (CSF) levels provide evidence for the reduction in leptin crossing the BBB and reaching obesity-relevant targets, such as the hypothalamus, in obese people.[132] In humans it has been observed that the ratio of leptin in the CSF compared to the blood is lower in obese people than in people of a normal weight.[133] The reason for this may be high levels of triglycerides affecting the transport of leptin across the BBB or due to the leptin transporter becoming saturated.[132] Although deficits in the transfer of leptin from the plasma to the CSF is seen in obese people, they are still found to have 30% more leptin in their CSF than lean individuals.[133] These higher CSF levels fail to prevent their obesity. Since the amount and quality of leptin receptors in the hypothalamus appears to be normal in the majority of obese humans (as judged from leptin-mRNA studies),[134] it is likely that the leptin resistance in these individuals is due to a post leptin-receptor deficit, similar to the post-insulin receptor defect seen in type 2 diabetes.[135]
When leptin binds with the leptin receptor, it activates a number of pathways. Leptin resistance may be caused by defects in one or more part of this process, particularly the JAK/STAT pathway. Mice with a mutation in the leptin receptor gene that prevents the activation of STAT3 are obese and exhibit hyperphagia. The PI3K pathway may also be involved in leptin resistance, as has been demonstrated in mice by artificial blocking of PI3K signalling. The PI3K pathway also is activated by the insulin receptor and is therefore an important area where leptin and insulin act together as part of energy homeostasis. The insulin-pI3K pathway can cause POMC neurons to become insensitive to leptin through hyperpolarization.[136]
The consumption of a high fructose diet from birth has been associated with a reduction in leptin levels and reduced expression of leptin receptor mRNA in rats. Long-term consumption of fructose in rats has been shown to increase levels of triglycerides and trigger leptin and insulin resistance,[137][138] however, another study found that leptin resistance only developed in the presence of both high fructose and high fat levels in the diet. A third study found that high fructose levels reversed leptin resistance in rats given a high fat diet. The contradictory results mean that it is uncertain whether leptin resistance is caused by high levels of carbohydrates or fats, or if an increase of both, is needed.[139]
Leptin is known to interact with amylin, a hormone involved in gastric emptying and creating a feeling of fullness. When both leptin and amylin were given to obese, leptin-resistant rats, sustained weight loss was seen. Due to its apparent ability to reverse leptin resistance, amylin has been suggested as possible therapy for obesity.[140]
It has been suggested that the main role of leptin is to act as a starvation signal when levels are low, to help maintain fat stores for survival during times of starvation, rather than a satiety signal to prevent overeating. Leptin levels signal when an animal has enough stored energy to spend it in pursuits besides acquiring food.[136][141] This would mean that leptin resistance in obese people is a normal part of mammalian physiology and possibly, could confer a survival advantage.[131] Leptin resistance (in combination with insulin resistance and weight gain) is seen in rats after they are given unlimited access to palatable, energy-dense foods.[142] This effect is reversed when the animals are put back on a low-energy diet.[143] This also may have an evolutionary advantage: allowing energy to be stored efficiently when food is plentiful would be advantageous in populations where food frequently may be scarce.[144]
## Response to weight loss
Dieters who lose weight, particularly those with an overabundance of fat cells, experience a drop in levels of circulating leptin. This drop causes reversible decreases in thyroid activity, sympathetic tone, and energy expenditure in skeletal muscle, and increases in muscle efficiency and parasympathetic tone. Many of these changes are reversed by peripheral administration ( intravenously into the veins of the arms, hands, legs, or feet ) of recombinant leptin to restore pre-diet levels.[145]
A decline in levels of circulating leptin also changes brain activity in areas involved in the regulatory, emotional, and cognitive control of appetite that are reversed by administration of leptin.[145]
# Role in joint problems and obesity
## Obesity and osteoarthritis
Osteoarthritis and obesity are closely linked. Obesity is one of the most important preventable factors for the development of osteoarthritis.
Originally, the relationship between osteoarthritis and obesity was considered to be exclusively biomechanically based, according to which the excess weight caused the joint to become worn down more quickly. However, today we recognise that there is also a metabolic component which explains why obesity is a risk factor for osteoarthritis, not only for weight-bearing joints (for example, the knees), but also for joints that do not bear weight (for example, the hands).[146] Consequently, it has been shown that decreasing body fat lessens osteoarthritis to a greater extent than weight loss per se.[147] This metabolic component related with the release of systemic factors, of a pro-inflammatory nature, by the adipose tissues, which frequently are critically associated with the development of osteoarthritis.[148][149][150][151][152]
Thus, the deregulated production of adipokines and inflammatory mediators, hyperlipidaemia, and the increase of systemic oxidative stress are conditions frequently associated with obesity which can favour joint degeneration. Furthermore, many regulation factors have been implicated in the development, maintenance and function, both of adipose tissues, as well as of the cartilage and other joint tissues. Alterations in these factors can be the additional link between obesity and osteoarthritis.
## Leptin and osteoarthritis
Adipocytes interact with other cells through producing and secreting a variety of signalling molecules, including the cell signalling proteins known as adipokines. Certain adipokines can be considered as hormones, as they regulate the functions of organs at a distance, and several of them have been specifically involved in the physiopathology of joint diseases. In particular, there is one, leptin, which has been the focus of attention for research in recent years.
The circulating leptin levels are positively correlated with the Body Mass Index (BMI), more specifically with fatty mass, and obese individuals have higher leptin levels in their blood circulation, compared with non-obese individuals.[9] In obese individuals, the increased circulating leptin levels induce unwanted responses, that is, reduced food intake or losing body weight does not occur as there is a resistance to leptin (ref 9). In addition to the function of regulating energy homeostasis, leptin carries out a role in other physiological functions such as neuroendocrine communication, reproduction, angiogenesis and bone formation. More recently, leptin has been recognised as a cytokine factor as well as with pleiotropic actions also in the immune response and inflammation.[153][154][155][156] For example, leptin can be found in the synovial fluid in correlation with the body mass index, and the leptin receptors are expressed in the cartilage, where leptin mediates and modulates many inflammatory responses that can damage cartilage and other joint tissues. Leptin has thus emerged as a candidate to link obesity and osteoarthritis and serves as an apparent objective as a nutritional treatment for osteoarthritis.
As in the plasma, the leptin levels in the synovial fluid are positively correlated with BMI.[157][158][159][160] The leptin of the synovial fluid is synthesised at least partially in the joint and may originate in part in the circulation. Leptin has been shown to be produced by chondrocytes, as well as by other tissues in the joints, including the synovial tissue, osteophytes, the meniscus and bone.[157][158][161][162][163][164] An infrapatellar fat pad located extrasynovially within the knee joint is also adjacent to the synovial membrane and cartilage, and has recently been highly appreciated as an important source of leptin, as well as other adipokines and mediators which contribute to the pathogenesis of osteoarthritis [164][165][166][167]
The risk of suffering osteoarthritis can be decreased with weight loss. This reduction of risk is related in part with the decrease of the load on the joint, but also in the decrease of fatty mass, the central adipose tissue and the low-level inflammation associated with obesity and systemic factors.
This growing evidence points to leptin as a cartilage degradation factor in the pathogenesis of osteoarthritis, and as a potential biomarker in the progression of the disease, which suggests that leptin, as well as regulation and signalling mechanisms, can be a new and promising target in the treatment of osteoarthritis, especially in obese patients.
Obese individuals are predisposed to developing osteoarthritis, not only due to the excess mechanical load, but also due to the excess expression of soluble factors, that is, leptin and pro-inflammatory cytokines, which contribute to joint inflammation and cartilage destruction. As such, obese individuals are in an altered state, due to a metabolic insufficiency, which requires specific nutritional treatment capable of normalising the leptin production and reducing the systematic low-level inflammation, in order to reduce the harmful impact of these systematic mediators on the joint health.
There are nutritional supplements and pharmacological agents capable of directing these factors and improving both conditions.
# Therapeutic use
## Leptin
Leptin was approved in the United States in 2014 for use in congenital leptin deficiency and generalized lipodystrophy.[168]
## Analog metreleptin
An analog of human leptin metreleptin (trade names Mylept, Mylepta) was first approved in Japan in 2013, and in the United States in February 2014 and in Europe in 2018. In the US it is indicated as a treatment for complications of leptin deficiency, and for the diabetes and hypertriglyceridemia associated with congenital or acquired generalized lipodystrophy.[169][170] In Europe based on EMA, metreleptin should be used in addition to diet to treat lipodystrophy, where patients have loss of fatty tissue under the skin and build-up of fat elsewhere in the body such as in the liver and muscles. The medicine is used in: adults and children above the age of 2 years with generalised lipodystrophy (Berardinelli-Seip syndrome and Lawrence syndrome) and in adults and children above the age of 12 years with partial lipodystrophy (including Barraquer-Simons syndrome), when standard treatments have failed.[171]
# History
The leptine was discovered by Jeffrey Freidman in 1994 after several decades of research conducted by others institutions since 1950 on obese mouse models [172] | https://www.wikidoc.org/index.php/LEP | |
69f19cb30aa9318f59704eeaf1a1aefb5cd3447e | wikidoc | LILRB4 | LILRB4
Leukocyte immunoglobulin-like receptor subfamily B member 4 is a protein that in humans is encoded by the LILRB4 gene.
This gene is a member of the leukocyte immunoglobulin-like receptor (LIR) family, which is found in a gene cluster at chromosomal region 19q13.4. The encoded protein belongs to the subfamily B class of LIR receptors which contain two or four extracellular immunoglobulin domains, a transmembrane domain, and two to four cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). The receptor is expressed on immune cells where it binds to MHC class I molecules on antigen-presenting cells and transduces a negative signal that inhibits stimulation of an immune response. The receptor can also function in antigen capture and presentation. It is thought to control inflammatory responses and cytotoxicity to help focus the immune response and limit autoreactivity. Multiple transcript variants encoding different isoforms have been found for this gene.
# Interactions
LILRB4 has been shown to interact with PTPN6 and INPP5D (SHIP-1). | LILRB4
Leukocyte immunoglobulin-like receptor subfamily B member 4 is a protein that in humans is encoded by the LILRB4 gene.[1][2][3]
This gene is a member of the leukocyte immunoglobulin-like receptor (LIR) family, which is found in a gene cluster at chromosomal region 19q13.4. The encoded protein belongs to the subfamily B class of LIR receptors which contain two or four extracellular immunoglobulin domains, a transmembrane domain, and two to four cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). The receptor is expressed on immune cells where it binds to MHC class I molecules on antigen-presenting cells and transduces a negative signal that inhibits stimulation of an immune response. The receptor can also function in antigen capture and presentation. It is thought to control inflammatory responses and cytotoxicity to help focus the immune response and limit autoreactivity. Multiple transcript variants encoding different isoforms have been found for this gene.[3]
# Interactions
LILRB4 has been shown to interact with PTPN6[4] and INPP5D (SHIP-1).[5] | https://www.wikidoc.org/index.php/LILRB4 | |
eda47ee858ad82dede551d8ddc0520985be81466 | wikidoc | LINGO1 | LINGO1
Leucine rich repeat and Immunoglobin-like domain-containing protein 1 also known as LINGO-1 is a protein which is encoded by the LINGO1 gene in humans. It belongs to the family of leucine-rich repeat proteins which are known for playing key roles in the biology of the central nervous system. LINGO-1 is a functional component of the Nogo (neurite outgrowth inhibitor) receptor also known as the reticulon 4 receptor.
It has been found that LINGO-1 antagonists such as BIIB033 could significantly improve and regulate survival after neural injury caused by the protein.
# Structure
The human LINGO-1 is a single-pass type 1 transmembrane protein of 614 amino acids. It contains a signal sequence of 34 residues, followed by a LRR (leucine-rich repeat) domain, an Ig (immunoglobulin-like) domain, a stalk domain, a transmembrane region and a short cytoplasmic tail. As a transmembrane protein, it can mostly be found on the cell membrane.
The LINGO-1 structure has been shown to be highly stable both in its crystal form and in solution, thanks to its leucine-rich repeat Ig-composite fold. Since the tetramer has a very large surface area into the cell membrane, it is thought that this may serve as an efficient and stable binding platform, facilitating the interaction with NgR, p75, TROY complex.
## Extracellular domain
The extracellular domain consists of the signal sequence, 11 LRR motifs comprised between an N-terminal and C-terminal capping domains, and the Immunoglobulin-like (IgC2) domain. The C-terminal LRR domain is essential for the protein's function with its screening for proteins that interact with this domain. The structure, together with biophysical analysis of LINGO-1 properties have revealed that the protein's LRR-Ig composite fold of the protein can drive it to associate with itself in a circular ring-like form, creating a closed and stable tetramer in solution and in crystal.
## Intracellular domain
The intracellular part of the protein is formed by the transmembrane region and a cytoplasmic tail of 38 residues. It contains a canonical Epidermal Growth Factor Receptor (EGFR)-like tyrosine phosphorylation site on the 591 residue that is critical for intracellular signals.
## Co-receptor
LINGO-1 is a co-receptor that interacts with the ligand-binding Nogo-66 receptor (NogoR) in the Nogo receptor signaling complex. The Nogo receptor complex is formed when Nogo-66 binds to its receptor.
LINGO-1 is an homotetramer which forms a ternary complex with RTN4R/NGFR and RTN4R/TNFRSF19.
### Post-translational modifications
LINGO-1 contains several N-glycosylation sites that could have a negative effect on its capacity to self-interact with cis or trans, with other partners, or gangliosides. It also contains high-mannose glycans.
# Tissue distribution
LINGO-1 is expressed almost exclusively in the central nervous system (CNS). It can be found in the brain and in neurons and oligodendrocytes. LINGO-1 mRNA is expressed in an almost exclusive manner in the central nervous system during both embryonic and postnatal stages. It is targeted to the plasma membrane of neurons, but it is possible that a smaller quantities of the protein may be found in other intracellular compartments. Its highest expression is in specific adult human brain regions such as the cerebral cortex, a region involved in sensory-motor function, cognition and working memory; the hippocampus, responsible for long term memory and the encoding and retrieval of multi-sensory information; the amygdala, implicated in the stress response; as well as the thalamus, with a more constant and basal level of expression across the remainder of the brain.
# Function and mode of action
Since LINGO-1 is a leucine-rich repeat protein, which are known for their important role in protein-protein interactions in a wide variety of cellular processes and their implication in important functions like neuronal differentiation and growth or the regulation of axon guidance and regeneration processes, it is logical to deduce that its functions are linked with the nervous system.
LINGO-1 is an essential negative regulator of myelination. It has been implicated in the inhibition of axon regeneration through a ternary complex formed with NgR1/Nogo-66 (ligand-binding subunit) and p75 (signal transducing subunit). NgR1 relies on its co-receptors for transmembrane signalling.The three major myelin-associated inhibitory factors are Nogo, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein which all share this trimolecular receptor complex. The inhibitory action is achieved through RhoA-GTP upregulation in response to the presence of MOG, MAG or Nogo-66 in the central nervous system. LINGO-1 also inhibits oligodendrocyte precursor differentiation and myelination, by a mechanism that also involves activation of RhoA, but which apparently does not require p75 or NgR1.
LINGO-1 is involved in the regulation of neural apoptosis by inhibiting WNK3 kinase activity. It has been shown that blocking the extracellular domain of LINGO-1 disrupts the interaction between receptor kinases and LINGO-1 which directly attenuates inhibition of neuronal survival. However among the four WNK family members, only WNK3 has been shown to regulate and increase cell survival in a caspase-3-dependant pathway.
To be able to understand how these components regulate signalling processes an experiment has been set up "model of serum deprivation" (SD) to prompt neuronal apoptosis. Research shows that treatments either with a construct containing the IgC2 or EGFR domains in the LINGO1 protein or with Nogo66 which act like a NgR1 agonist, therefore initiating a physiological response when combined with the receptor, resulting in an increased rate of apoptosis in primary cultured cortical neurons under SD.
In addition, reducing the expression levels of the serine/threonine Kinase WNK3 (using gene silencing via RNA interference (ShRNA)) or inhibiting its kinase activity had similar effects on the survival of such neurons. The adverse effects of Nogo66 have proved to enhance the co-association of LINGO1 and WNK3, causing the binding of WNK3 to the intracellular domain of LINGO1 leading to reduced WNK3 kinase activity. LINGO1 promotes neural apoptosis by inhibiting WNK3 kinase activity.
# Signaling pathways
LINGO-1 is able to interact with different co-factors and co-receptors, which can lead to the activation o signaling pathways that can have an effect on the regulation of neuronal survival, axon regeneration, oligodendrocyte differentiation, or myelination processes in the brain.
Known interactions are with proteins such as Oligodendrocyte-myelinn glycoprotein, Nogo-A (neurotic outgrowth inhibitor), and myelin associated glycoproteins. LINGO-1 also interacts with transmembrane proteins: EFGR, along with its ligand epidermal growth factor (EFG); brain derived neurotrophic factor (BNDF) and its receptor, amyloid precursor protein (APP), and tropomyosin receptor kinase A (TrkA). There are other interactions with proteins that are implicated in neurological and psychiatric disorders: WNK lysine deficient protein in kinase 1 (WNK1), mitogen activated protein kinase 2/3 (MEK 2/3), extracellular signal reduced kinase 5 (ERK5), RhoA, and others.
# Neurological and psychiatric disorders
LINGO-1 is coded by the LINGO-1 gene, which is located on the human chromosome 15, more precisely on the locus 15q24-26, which is a region that has a primordial implication in number of psychiatric, addictive and anxiety related disorders. Genomic alterations of this regions can be factors for disorders such as schizophrenia, depression, autism, panic disorder or anxiety.
Brain regions identified as highly expressing Lingo-1 transcripts have also been heavily implicated in both neurological and psychiatric disorders such as spinal cord injury, traumatic brain injury, multiple sclerosis (MS), Parkinson’s disease, essential tremor (ET), Alzheimer’s disease, epilepsy and glaucoma (central nervous system diseases); as well as stress and panic disorders, schizophrenia, amnesia, etc. The role of Lingo-1 in these neurological disorders consists on its inhibitory role in neurite outgrowth, oligodendrocyte differentiation and myelination, making it difficult for the nervous system to regenerate the injured areas, whether these injuries come from endogenous or exogenous processes.
## Spinal cord injury
Spinal cord injury results in the damage of the axonal tracts whose function is to control motor and sensory activity. This protein has been found in this axonal tracts of adolescent rat spinal cords following injury. Furthermore, a five time increase in Lingo-1 mRNA levels was detected 14 days post injury. Lingo-1-Fc, a soluble form of Lingo-1, has also been shown to antagonize Lingo-1 signaling pathways by inhibiting the binding of Lingo-1 to NgR, in consequence, vast improvements in the functional recovery of rats following lateral hemisection of the spinal cord were observed.
## Essential tremor and Parkinson
Essential tremor, one of the most common neurological diseases, is characterized by postural and action tremor. Recent research shows that around the 20% of people who suffer this disease have an increase of the protein LINGO1 in their cerebellum, therefore linking LINGO1 to essential tremor would result in the development of more effective symptomatic therapies and treatment.
It has been found that there is a marker in LINGO-1 genome, a variant (rs9652490) that is significantly associated with essential tremor, increasing the risk of having the pathology.
As for Parkinson's disease, which is also an age-related movement disorder, it was discovers that levels of LINGO-1 are more elevated in the substantia nigra of post-mortem Parkinson's disease brains compared to control groups. It is thought that dopamine neuron survival and behavioral abnormalities are due to the over expression of LINGO-1 in Parkinson's patients.
## Traumatic brain injury
Traumatic brain injury involves the necrotic and apoptotic death of brain cells in vulnerable and delicate areas such as the cerebral cortex and hippocampus, where it is known that there is an expression of Lingo-1 in both development and the adult stage of life. RhoA signaling is largely responsible for the neuronal response to neuronal inhibitory proteins and the regeneration (or lack of in case of its activation) of damaged axons. Receptor Lingo-1 stimulates RhoA, which activates ROCK (RhoA kinase) which, in turn, stimulates LIM kinase, which then stimulates cofilin, which effectively reorganizes the actin cytoskeleton of the cell. In the case of neurons, activation of this pathway results in growth cone collapse, therefore inhibits the growth and repair of neural pathways and axons. Inhibition of this pathway by its various components usually results in some level of improved re-myelination. The use of Lingo-1-Fc as an antagonist for Lingo-1 shows the inhibition of RhoA activation. Since this soluble form of Lingo-1 is able to block the interactions between Lingo-1 and NgR, it is reasonable to think that the blockade of RhoA occurs at the level of Lingo-1/NgR/p75 or TROY complex, leading to the conclusion that Lingo-1plays a very important part in the lack of re-myelination, repair of neural and axon injuries, etc.
## Schizophrenia
Schizophrenia is a chronic, severe and disabling brain disorder.
As said before, leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) is an essential negative regulator of myelination and neurite extension. Both myelination and neurite outgrowth occur during brain maturation, and it is during this late period of brain development (adolescence and early adulthood) when schizophrenia is first expressed. In fact, myelination peaks during late adolescence, coinciding with the onset of schizophrenia. Consequently, an excessive action of Lingo-1 through demyelination and blocking neurite extension may be one of the possible causes of this disorder.
The brain regions which are highly disrupted in the pathophysiology of this disease are hippocampus and dorsolateral prefrontal cortex. Therefore, clinical studies have been developed in order to study these brain regions in people who suffer schizophrenia. To investigate the hypothesis that myelin fraction is lower in schizophrenia patients than in healthy subjects, a technique called magnetic resonance spectroscopy (MRS), which allows analysis of myelin, is used. This studies reported that there was in fact, a dysfunctional profile of myelination in these two areas of the brain in schizophrenia sufferers.
Post-mortem studies were then realized in order to compare the levels of the protein Lingo-1 in these two brain regions (hippocampus and dorsolateral prefrontal cortex) between schizophrenia and healthy subjects. Effectively, it was shown that the levels of Lingo-1 where significantly higher in schizophrenia than in control groups.
Taking this into account, there is a clear relationship in between schizophrenia and demyelination, therefore, this disease is linked with Lingo-1 protein. Very possibly, an effective treatment of this disease would be the use of Lingo-1 antagonists, such as Anti-Lingo-1, which would offset the lack of myelin and hopefully avoid the disease. Thus, this treatment is still in ways of development and research.
## Multiple sclerosis
Multiple sclerosis is among the most common neurological disorders in young adults and it consists in the destructions and damage of the central nervous system (CNS) myelin due to persistent inflammation in the brain and spinal cord. This demyelination is shown to cause mitochondrial dysfunction in axons, leading to their degeneration. These damages disrupt the ability and capacity of the CNS to communicate, causing, therefore, a wide range of symptoms including physical, mental and even psychiatric ones. The best way of re-myelination is encouraging the differentiation of endogenous adult precursor cells into mature oligodendrocytes in the injured regions. These precursor cells are called oligodendrocyte precursor cells (OPCs). It is known that in early stages of MS re-myelination can be achieved successfully and efficiently whereas it cannot in late and progressive stages. Regarding Lingo-1, we know that its signaling pathway is a negative regulator of OPCs differentiation, as well as Notch's and Wnt's.
Lingo-1 antagonists are able to promote re-myelination in CNS by means of stimulating OPCs differentiation which was before blocked by this protein. This has been seen in several experiments that resulted in significant increases of oligodendrocytes differentiation by targeting Lingo-1 with its antagonists, such as the antibody Anti-LINGO-1 (BIIB033).
## Glaucoma
Glaucoma is a group neurodegenerative diseases characterized by features including morphological changes in the optic nerve head and therefore in the visual fields of the patients. There are two main types; open-angle and closed-angle glaucoma. The loss of RGCs (retinal ganglion cells) and their axons results in visual field loss.Increasing evidence also supports the existence of compartmentalized degeneration in synapses. It has been shown that the first symptoms of this disease are usually ocular hypertension. Elevated IOP (intraocular pressure) has been identified as the etiology of glaucoma which causes neural RCG degeneration in the retina.
LINGO1 was found to be expressed in the normal retina and was up regulated in RCGs after the induction of ocular hypertension in a rat chronic glaucoma model. Hence LINGO1 functions as a negative regulator of neuronal survival, axonal regeneration and oligodendrocyte differentiation. LINGO1 binds with TrkA and inhibits myelination by oligodendrocytes in vitro. Further more it binds to BDNF receptor and TrkB inhibiting the activation of TkrB by binding of BNDF after the induction of ocular hypertension.
### Neuroprotection of RCGs
Even though BDNF is an important survival factor for RGCs both during development and adult life, BDNF can only slightly increase the survival rate of RCGs, and does not significantly “rescue” injured RCGs in hypertensive eyes after episcleral vein cauterization. The negative regulatory function of LINGO1 may be involved in the limited neuroprotective effect of BDNF and it could be reversed after blocking LINGO1 function.
LINGO 1 negatively regulates TrkB activation through the signalling pathway of BDNF/TrKB, and anti-LINGO-1 exerts neuroprotective effects via activation of BDNF/TrkB.
Better than BDNF and BII003 (LINGO1 antagonist) alone, the combined treatment of both provides long term RCG neuroprotection after the induction of ocular hypertension. In conclusion BII033 may provide an attractive therapeutic strategy to promote neuroprotection in glaucoma.
# Antagonists
Blocking the activity of lingo-1 has several potential applications in the treatment of neurodegenerative diseases.
(A myelin sheath is a lipid protective coating that covers and protects nerve cells (axons). These sheaths makes possible rapid and accurate transmission of nerve signals. Multiple sclerosis destroys these myelin sheaths, leading to a deterioration in nerve signal transmission. Once this protective myelin coating is stripped away, it leads to apoptosis of the neuron; axons gradually die, causing the muscle spasms and paralysis that are characteristic of the disease.)
## Anti-lingo-1 (BIIB033)
Anti-lingo-1 (BIIB033) is a monoclonal antibody specific to the lingo-1 protein and is designed to promote remyelination (the formation of new myelin on axons) and neuroprotection. The protein lingo-1 inhibits the action of myelin-making cells, oligodendrocytes, which are surrounding the axons. Its antagonist, the antibody anti-lingo-1 would block this protein and even would be capable of myelin repair.
A number of clinical trials of the anti-lingo-1 antibody drug (BIIB033) have either been completed or are underway. Acute optic neuritis (AON) is a disease which involves damage within the nerve fibers and loss of myelin within the optic nerve (it normally involves one eye and it's characterized by inflammation). One clinical trial studying the effects on BIIB033 on acute optic neuritis. Throughout the study, optic nerve conduction latency was measured (the time for a signal to travel from the retina to the brain's visual cortex). As about half of patients with optic neuritis will later develop multiple sclerosis, BIIB033 antibody treatment is also being considered for the former disease. It is thought that Anti-Lingo-1 would produce the necessary myelin to avoid neurodegeneration. | LINGO1
Leucine rich repeat and Immunoglobin-like domain-containing protein 1[1] also known as LINGO-1 is a protein which is encoded by the LINGO1 gene in humans.[2][3] It belongs to the family of leucine-rich repeat proteins which are known for playing key roles[4] in the biology of the central nervous system. LINGO-1 is a functional component of the Nogo (neurite outgrowth inhibitor) receptor also known as the reticulon 4 receptor.
It has been found that LINGO-1 antagonists such as BIIB033[5] could significantly improve and regulate survival after neural injury caused by the protein.[6]
# Structure
The human LINGO-1 is a single-pass type 1 transmembrane protein of 614 amino acids. It contains a signal sequence of 34 residues, followed by a LRR (leucine-rich repeat) domain, an Ig (immunoglobulin-like) domain, a stalk domain, a transmembrane region and a short cytoplasmic tail. As a transmembrane protein, it can mostly be found on the cell membrane.[7]
The LINGO-1 structure has been shown to be highly stable both in its crystal form and in solution, thanks to its leucine-rich repeat Ig-composite fold. Since the tetramer has a very large surface area into the cell membrane, it is thought that this may serve as an efficient and stable binding platform, facilitating the interaction with NgR, p75, TROY complex.[citation needed]
## Extracellular domain
The extracellular domain consists of the signal sequence, 11 LRR motifs comprised between an N-terminal and C-terminal capping domains, and the Immunoglobulin-like (IgC2) domain.[3][8] The C-terminal LRR domain is essential for the protein's function with its screening for proteins that interact with this domain. The structure, together with biophysical analysis of LINGO-1 properties have revealed that the protein's LRR-Ig composite fold of the protein can drive it to associate with itself in a circular ring-like form, creating a closed and stable tetramer in solution and in crystal.
## Intracellular domain
The intracellular part of the protein is formed by the transmembrane region and a cytoplasmic tail of 38 residues. It contains a canonical Epidermal Growth Factor Receptor (EGFR)-like tyrosine phosphorylation site on the 591 residue that is critical for intracellular signals.[9]
## Co-receptor
LINGO-1 is a co-receptor that interacts with the ligand-binding Nogo-66 receptor (NogoR) in the Nogo receptor signaling complex.[8] The Nogo receptor complex is formed when Nogo-66 binds to its receptor.[10]
LINGO-1 is an homotetramer which forms a ternary complex with RTN4R/NGFR and RTN4R/TNFRSF19.
### Post-translational modifications
LINGO-1 contains several N-glycosylation sites that could have a negative effect on its capacity to self-interact with cis or trans, with other partners, or gangliosides.[11] It also contains high-mannose glycans.
# Tissue distribution
LINGO-1 is expressed almost exclusively in the central nervous system (CNS). It can be found in the brain and in neurons and oligodendrocytes. LINGO-1 mRNA is expressed in an almost exclusive manner in the central nervous system during both embryonic and postnatal stages. It is targeted to the plasma membrane of neurons, but it is possible that a smaller quantities of the protein may be found in other intracellular compartments.[12] Its highest expression is in specific adult human brain regions such as the cerebral cortex, a region involved in sensory-motor function, cognition and working memory; the hippocampus, responsible for long term memory and the encoding and retrieval of multi-sensory information; the amygdala, implicated in the stress response; as well as the thalamus, with a more constant and basal level of expression across the remainder of the brain.[13]
# Function and mode of action
Since LINGO-1 is a leucine-rich repeat protein, which are known for their important role in protein-protein interactions in a wide variety of cellular processes and their implication in important functions like neuronal differentiation and growth or the regulation of axon guidance and regeneration processes, it is logical to deduce that its functions are linked with the nervous system.[citation needed]
LINGO-1 is an essential negative regulator of myelination. It has been implicated in the inhibition of axon regeneration through a ternary complex formed with NgR1/Nogo-66 (ligand-binding subunit) and p75 (signal transducing subunit). NgR1 relies on its co-receptors for transmembrane signalling.The three major myelin-associated inhibitory factors are Nogo, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein which all share this trimolecular receptor complex. The inhibitory action is achieved through RhoA-GTP upregulation in response to the presence of MOG, MAG or Nogo-66 in the central nervous system.[8] LINGO-1 also inhibits oligodendrocyte precursor differentiation and myelination, by a mechanism that also involves activation of RhoA, but which apparently does not require p75 or NgR1.
LINGO-1 is involved in the regulation of neural apoptosis by inhibiting WNK3 kinase activity. It has been shown that blocking the extracellular domain of LINGO-1 disrupts the interaction between receptor kinases and LINGO-1 which directly attenuates inhibition of neuronal survival. However among the four WNK family members, only WNK3 has been shown to regulate and increase cell survival in a caspase-3-dependant pathway.[11][14]
To be able to understand how these components regulate signalling processes an experiment has been set up "model of serum deprivation" (SD) to prompt neuronal apoptosis.[citation needed] Research shows that treatments either with a construct containing the IgC2 or EGFR domains in the LINGO1 protein or with Nogo66 which act like a NgR1 agonist, therefore initiating a physiological response when combined with the receptor, resulting in an increased rate of apoptosis in primary cultured cortical neurons under SD.[citation needed]
In addition, reducing the expression levels of the serine/threonine Kinase WNK3 (using gene silencing via RNA interference (ShRNA)) or inhibiting its kinase activity had similar effects on the survival of such neurons. The adverse effects of Nogo66[15] have proved to enhance the co-association of LINGO1 and WNK3, causing the binding of WNK3 to the intracellular domain of LINGO1 leading to reduced WNK3 kinase activity. LINGO1 promotes neural apoptosis by inhibiting WNK3 kinase activity.[16]
# Signaling pathways
LINGO-1 is able to interact with different co-factors and co-receptors, which can lead to the activation o signaling pathways that can have an effect on the regulation of neuronal survival, axon regeneration, oligodendrocyte differentiation, or myelination processes in the brain.[17]
Known interactions are with proteins such as Oligodendrocyte-myelinn glycoprotein, Nogo-A (neurotic outgrowth inhibitor), and myelin associated glycoproteins. LINGO-1 also interacts with transmembrane proteins: EFGR, along with its ligand epidermal growth factor (EFG); brain derived neurotrophic factor (BNDF) and its receptor, amyloid precursor protein (APP), and tropomyosin receptor kinase A (TrkA). There are other interactions with proteins that are implicated in neurological and psychiatric disorders: WNK lysine deficient protein in kinase 1 (WNK1), mitogen activated protein kinase 2/3 (MEK 2/3), extracellular signal reduced kinase 5 (ERK5), RhoA, and others.[18]
# Neurological and psychiatric disorders
LINGO-1 is coded by the LINGO-1 gene, which is located on the human chromosome 15, more precisely on the locus 15q24-26, which is a region that has a primordial implication in number of psychiatric, addictive and anxiety related disorders. Genomic alterations of this regions can be factors for disorders such as schizophrenia, depression, autism, panic disorder or anxiety.[19]
Brain regions identified as highly expressing Lingo-1 transcripts have also been heavily implicated in both neurological and psychiatric disorders such as spinal cord injury, traumatic brain injury, multiple sclerosis (MS), Parkinson’s disease, essential tremor (ET), Alzheimer’s disease, epilepsy and glaucoma (central nervous system diseases); as well as stress and panic disorders, schizophrenia, amnesia, etc.[13] The role of Lingo-1 in these neurological disorders consists on its inhibitory role in neurite outgrowth, oligodendrocyte differentiation and myelination, making it difficult for the nervous system to regenerate the injured areas, whether these injuries come from endogenous or exogenous processes.
## Spinal cord injury
Spinal cord injury results in the damage of the axonal tracts whose function is to control motor and sensory activity. This protein has been found in this axonal tracts of adolescent rat spinal cords following injury. Furthermore, a five time increase in Lingo-1 mRNA levels was detected 14 days post injury. Lingo-1-Fc, a soluble form of Lingo-1, has also been shown to antagonize Lingo-1 signaling pathways by inhibiting the binding of Lingo-1 to NgR, in consequence, vast improvements in the functional recovery of rats following lateral hemisection of the spinal cord were observed.[13]
## Essential tremor and Parkinson
Essential tremor, one of the most common neurological diseases, is characterized by postural and action tremor. Recent research shows that around the 20% of people who suffer this disease have an increase of the protein LINGO1 in their cerebellum, therefore linking LINGO1 to essential tremor would result in the development of more effective symptomatic therapies and treatment.[20][21][22]
It has been found that there is a marker in LINGO-1 genome, a variant (rs9652490) that is significantly associated with essential tremor, increasing the risk of having the pathology.
As for Parkinson's disease, which is also an age-related movement disorder, it was discovers that levels of LINGO-1 are more elevated in the substantia nigra of post-mortem Parkinson's disease brains compared to control groups. It is thought that dopamine neuron survival and behavioral abnormalities are due to the over expression of LINGO-1 in Parkinson's patients.[13]
## Traumatic brain injury
Traumatic brain injury involves the necrotic and apoptotic death of brain cells in vulnerable and delicate areas such as the cerebral cortex and hippocampus, where it is known that there is an expression of Lingo-1 in both development and the adult stage of life. RhoA signaling is largely responsible for the neuronal response to neuronal inhibitory proteins and the regeneration (or lack of in case of its activation) of damaged axons. Receptor Lingo-1 stimulates RhoA, which activates ROCK (RhoA kinase) which, in turn, stimulates LIM kinase, which then stimulates cofilin, which effectively reorganizes the actin cytoskeleton of the cell. In the case of neurons, activation of this pathway results in growth cone collapse, therefore inhibits the growth and repair of neural pathways and axons. Inhibition of this pathway by its various components usually results in some level of improved re-myelination.[23] The use of Lingo-1-Fc as an antagonist for Lingo-1 shows the inhibition of RhoA activation. Since this soluble form of Lingo-1 is able to block the interactions between Lingo-1 and NgR, it is reasonable to think that the blockade of RhoA occurs at the level of Lingo-1/NgR/p75 or TROY complex, leading to the conclusion that Lingo-1plays a very important part in the lack of re-myelination, repair of neural and axon injuries, etc.[13]
## Schizophrenia
Schizophrenia is a chronic, severe and disabling brain disorder.
As said before, leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) is an essential negative regulator of myelination and neurite extension. Both myelination and neurite outgrowth occur during brain maturation, and it is during this late period of brain development (adolescence and early adulthood) when schizophrenia is first expressed. In fact, myelination peaks during late adolescence, coinciding with the onset of schizophrenia. Consequently, an excessive action of Lingo-1 through demyelination and blocking neurite extension may be one of the possible causes of this disorder.
The brain regions which are highly disrupted in the pathophysiology of this disease are hippocampus and dorsolateral prefrontal cortex. Therefore, clinical studies have been developed in order to study these brain regions in people who suffer schizophrenia. To investigate the hypothesis that myelin fraction is lower in schizophrenia patients than in healthy subjects, a technique called magnetic resonance spectroscopy (MRS), which allows analysis of myelin, is used. This studies reported that there was in fact, a dysfunctional profile of myelination in these two areas of the brain in schizophrenia sufferers.[24]
Post-mortem studies were then realized in order to compare the levels of the protein Lingo-1 in these two brain regions (hippocampus and dorsolateral prefrontal cortex) between schizophrenia and healthy subjects. Effectively, it was shown that the levels of Lingo-1 where significantly higher in schizophrenia than in control groups.[25]
Taking this into account, there is a clear relationship in between schizophrenia and demyelination, therefore, this disease is linked with Lingo-1 protein. Very possibly, an effective treatment of this disease would be the use of Lingo-1 antagonists, such as Anti-Lingo-1, which would offset the lack of myelin and hopefully avoid the disease. Thus, this treatment is still in ways of development and research.[26]
## Multiple sclerosis
Multiple sclerosis is among the most common neurological disorders in young adults and it consists in the destructions and damage of the central nervous system (CNS) myelin due to persistent inflammation in the brain and spinal cord. This demyelination is shown to cause mitochondrial dysfunction in axons, leading to their degeneration. These damages disrupt the ability and capacity of the CNS to communicate, causing, therefore, a wide range of symptoms including physical, mental and even psychiatric ones. The best way of re-myelination is encouraging the differentiation of endogenous adult precursor cells into mature oligodendrocytes in the injured regions. These precursor cells are called oligodendrocyte precursor cells (OPCs). It is known that in early stages of MS re-myelination can be achieved successfully and efficiently whereas it cannot in late and progressive stages. Regarding Lingo-1, we know that its signaling pathway is a negative regulator of OPCs differentiation, as well as Notch's and Wnt's.
Lingo-1 antagonists are able to promote re-myelination in CNS by means of stimulating OPCs differentiation which was before blocked by this protein. This has been seen in several experiments that resulted in significant increases of oligodendrocytes differentiation by targeting Lingo-1 with its antagonists, such as the antibody Anti-LINGO-1 (BIIB033).[27]
## Glaucoma
Glaucoma is a group neurodegenerative diseases characterized by features including morphological changes in the optic nerve head and therefore in the visual fields of the patients. There are two main types; open-angle and closed-angle glaucoma. The loss of RGCs (retinal ganglion cells) and their axons results in visual field loss.Increasing evidence also supports the existence of compartmentalized degeneration in synapses. It has been shown that the first symptoms of this disease are usually ocular hypertension. Elevated IOP (intraocular pressure) has been identified as the etiology of glaucoma which causes neural RCG degeneration in the retina.[28]
LINGO1 was found to be expressed in the normal retina and was up regulated in RCGs after the induction of ocular hypertension in a rat chronic glaucoma model. Hence LINGO1 functions as a negative regulator of neuronal survival, axonal regeneration and oligodendrocyte differentiation. LINGO1 binds with TrkA and inhibits myelination by oligodendrocytes in vitro. Further more it binds to BDNF receptor and TrkB inhibiting the activation of TkrB by binding of BNDF after the induction of ocular hypertension.
### Neuroprotection of RCGs
Even though BDNF is an important survival factor for RGCs both during development and adult life, BDNF can only slightly increase the survival rate of RCGs,[28] and does not significantly “rescue” injured RCGs in hypertensive eyes after episcleral vein cauterization. The negative regulatory function of LINGO1 may be involved in the limited neuroprotective effect of BDNF and it could be reversed after blocking LINGO1 function.
LINGO 1 negatively regulates TrkB activation through the signalling pathway of BDNF/TrKB, and anti-LINGO-1 exerts neuroprotective effects via activation of BDNF/TrkB.[29][30]
Better than BDNF and BII003 (LINGO1 antagonist) alone, the combined treatment of both provides long term RCG neuroprotection after the induction of ocular hypertension. In conclusion BII033 may provide an attractive therapeutic strategy to promote neuroprotection in glaucoma.[28]
# Antagonists
Blocking the activity of lingo-1 has several potential applications in the treatment of neurodegenerative diseases.[18][31]
(A myelin sheath is a lipid protective coating that covers and protects nerve cells (axons). These sheaths makes possible rapid and accurate transmission of nerve signals. Multiple sclerosis destroys these myelin sheaths, leading to a deterioration in nerve signal transmission. Once this protective myelin coating is stripped away, it leads to apoptosis of the neuron; axons gradually die, causing the muscle spasms and paralysis that are characteristic of the disease.[32])
## Anti-lingo-1 (BIIB033)
Anti-lingo-1 (BIIB033) is a monoclonal antibody specific to the lingo-1 protein and is designed to promote remyelination (the formation of new myelin on axons) and neuroprotection.[16][33] The protein lingo-1 inhibits the action of myelin-making cells, oligodendrocytes, which are surrounding the axons. Its antagonist, the antibody anti-lingo-1 would block this protein and even would be capable of myelin repair.
A number of clinical trials of the anti-lingo-1 antibody drug (BIIB033) have either been completed or are underway.[34] Acute optic neuritis (AON) is a disease which involves damage within the nerve fibers and loss of myelin within the optic nerve (it normally involves one eye and it's characterized by inflammation).[35] One clinical trial studying the effects on BIIB033 on acute optic neuritis.[36] Throughout the study, optic nerve conduction latency was measured (the time for a signal to travel from the retina to the brain's visual cortex).[37] As about half of patients with optic neuritis will later develop multiple sclerosis, BIIB033 antibody treatment is also being considered for the former disease. It is thought that Anti-Lingo-1 would produce the necessary myelin to avoid neurodegeneration.[38] | https://www.wikidoc.org/index.php/LINGO1 | |
d9f87e5c31e8b9ea04bfeb622a158e80a66389e0 | wikidoc | LRPPRC | LRPPRC
Leucine-rich PPR motif-containing protein, mitochondrial is a protein that in humans is encoded by the LRPPRC gene. Transcripts ranging in size from 4.8 to 7.0 kb which result from alternative polyadenylation have been reported for this gene.
# Function
This gene encodes a protein that is leucine-rich and is thought to play a role in regulating the interaction of the cytoskeleton with a variety of cellular processes.
# Clinical significance
An integrative genomics strategy led to the discovery that mutations in LRPPRC cause the French-Canadian variant of Leigh syndrome. Furthermore, mutation in the LRPPRC gene causes lowered expression of MT-CO1 (cytochrome c oxidase I) and MT-CO3. | LRPPRC
Leucine-rich PPR motif-containing protein, mitochondrial is a protein that in humans is encoded by the LRPPRC gene.[1][1][2][3] Transcripts ranging in size from 4.8 to 7.0 kb which result from alternative polyadenylation have been reported for this gene.[3]
# Function
This gene encodes a protein that is leucine-rich and is thought to play a role in regulating the interaction of the cytoskeleton with a variety of cellular processes.[4]
# Clinical significance
An integrative genomics strategy led to the discovery that mutations in LRPPRC cause the French-Canadian variant of Leigh syndrome.[5] Furthermore, mutation in the LRPPRC gene causes lowered expression of MT-CO1 (cytochrome c oxidase I) and MT-CO3.[6] | https://www.wikidoc.org/index.php/LRPPRC | |
4739ef05b3734e1ffe6c1328c3f66cd744b5c563 | wikidoc | LRRC23 | LRRC23
Leucine-rich repeat-containing protein 23 is a protein that in humans is encoded by the LRRC23 gene.
# Function
The function of LRRC23 is unknown. It is a member of the leucine-rich repeat family of proteins, which are known for participating in protein-protein interactions. Experimental evidence suggests that LRRC23 interacts with the CD28 protein in a pathway related to the immune system and development of regulatory T cells that control spontaneous autoimmune disease.
# Protein sequence
LRRC23 spans 343 residues containing two varieties of internally repeating sequence. Detected and aligned by RADAR, the most abundant repeat is the leucine-rich repeat, repeating 9 times in bases 89-287. The other repeated sequence occurs twice in bases 3-36. The RADAR program output, below, summarizes the composition and location of all the repeats and aligns them for comparison against each other.
File:LRRC23 RADAR Internal Repeats.png
The human genome produces three known variants of LRRC23. The largest splice variant, variant 3, contains 8 exons. Variants 1 and 2 use alternative first exons, and variant 2 excludes the seventh exon, giving it a total of seven exons making up the mRNA.
# Protein structure
Although the actual structure of LRRC23 is unknown, comparison to the crystal structures of various similar proteins such as 2OMW A (e-value 1.00e-17) reveals a structure typical of other leucine-rich repeat proteins. Alternating beta sheets and coils create a spiraled peptide chain forming an arch shape with beta-sheets occupying the concave surface.
The aligned structure of 2OMW_A with LRRC23 spans acids 72-272 of the LRRC23 protein. Conserved asparagines are highlighted in yellow, showing the regularity of spacing and repeat structure within. This model was generated using Cn3D software provided by NCBI.
File:CBlast 72-272 asparagines.png | LRRC23
Leucine-rich repeat-containing protein 23 is a protein that in humans is encoded by the LRRC23 gene.[1][2][3]
# Function
The function of LRRC23 is unknown. It is a member of the leucine-rich repeat family of proteins, which are known for participating in protein-protein interactions. Experimental evidence suggests that LRRC23 interacts with the CD28 protein in a pathway related to the immune system and development of regulatory T cells that control spontaneous autoimmune disease.[4]
# Protein sequence
LRRC23 spans 343 residues containing two varieties of internally repeating sequence. Detected and aligned by RADAR,[5] the most abundant repeat is the leucine-rich repeat, repeating 9 times in bases 89-287. The other repeated sequence occurs twice in bases 3-36. The RADAR program output, below, summarizes the composition and location of all the repeats and aligns them for comparison against each other.
File:LRRC23 RADAR Internal Repeats.png
The human genome produces three known variants of LRRC23.[3] The largest splice variant, variant 3, contains 8 exons. Variants 1 and 2 use alternative first exons, and variant 2 excludes the seventh exon, giving it a total of seven exons making up the mRNA.
# Protein structure
Although the actual structure of LRRC23 is unknown, comparison to the crystal structures of various similar proteins such as 2OMW A (e-value 1.00e-17) reveals a structure typical of other leucine-rich repeat proteins. Alternating beta sheets and coils create a spiraled peptide chain forming an arch shape with beta-sheets occupying the concave surface.[6]
The aligned structure of 2OMW_A with LRRC23 spans acids 72-272 of the LRRC23 protein. Conserved asparagines are highlighted in yellow, showing the regularity of spacing and repeat structure within. This model was generated using Cn3D software provided by NCBI.
File:CBlast 72-272 asparagines.png | https://www.wikidoc.org/index.php/LRRC23 | |
9762780a223c62d761615998962bf97e54225246 | wikidoc | LRRC24 | LRRC24
Leucine rich repeat containing 24 is a protein that, in humans, is encoded by the LRRC24 gene. The protein is represented by the official symbol LRRC24, and is alternatively known as LRRC14OS. The function of LRRC24 is currently unknown. It is a member of the leucine-rich repeat (LRR) superfamily of proteins.
# Gene
In humans, LRRC24 is located on Chromosome 8 (8q24.3). The gene spans approximately 4.66 kb on the opposite strand. LRRC24 is composed of five exons, and only a single gene isoform has been identified.
# Protein
## General features
LRRC24 is a transmembrane protein of unknown function. Human LRRC24 consists of 513 amino acids including a 23 amino acid signal peptide. The mature form of the protein has a molecular weight of 52.9 kDa. The isoelectric point of the mature human protein is 7.98 The protein is largely composed of alpha helices.
## Domains
LRRC24 is a single-pass transmembrane protein. The protein consists of six leucine-rich repeats and an immunoglobulin-like domain.
## Localization
LRRC24 is a secreted protein as is evidenced by the presence of a signal peptide. The structure of the protein suggests that it localizes to the cell membrane.
# Homology
LRRC24 is conserved in Euteleostomi with the exception of Aves. Also, based on sequence homology analysis, distant orthologs of LRRC24 are also conserved in invertebrates of phyla Mollusca and Arthropoda. No human paralogs of LRRC24 have been identified.
# Expression
Microarray and in situ hybridization experiments suggest LRRC24 is primarily expressed within the brain. Expression is observed to be especially high within the midbrain, neocortex, and tissues of the limbic system, including the hypothalamus and hippocampal formation.
# Interactions
Protein-protein interactions of LRRC24 implicate the protein with cell signaling, cell migration, and axon guidance. ROBO2 was found to interact with LRRC24. ROBO2 is a member of the Roundabout gene family, which are well known to play a significant role in nervous system development. Also, LRRC24 was found to interact with LRRTM4, a protein believed to be involved in synaptogenesis, as well as the maintenance of the nervous system in vertebrates.
LRRC24 has also been found to interact with IGFBP7, a known regulator of insulin-like growth factors (IGFs). IGFBP7 is also involved in the stimulation of cell adhesion.
# Clinical significance
To date, no study has specifically implicated LRRC24 or the LRRC24 gene with any case of clinical significance. | LRRC24
Leucine rich repeat containing 24 is a protein that, in humans, is encoded by the LRRC24 gene.[1] The protein is represented by the official symbol LRRC24, and is alternatively known as LRRC14OS.[2] The function of LRRC24 is currently unknown. It is a member of the leucine-rich repeat (LRR) superfamily of proteins.
# Gene
In humans, LRRC24 is located on Chromosome 8 (8q24.3). The gene spans approximately 4.66 kb on the opposite strand.[1] LRRC24 is composed of five exons, and only a single gene isoform has been identified.[1]
# Protein
## General features
LRRC24 is a transmembrane protein of unknown function. Human LRRC24 consists of 513 amino acids including a 23 amino acid signal peptide.[1][3] The mature form of the protein has a molecular weight of 52.9 kDa.[4] The isoelectric point of the mature human protein is 7.98[5] The protein is largely composed of alpha helices.[6]
## Domains
LRRC24 is a single-pass transmembrane protein. The protein consists of six leucine-rich repeats and an immunoglobulin-like domain.[1][7]
## Localization
LRRC24 is a secreted protein as is evidenced by the presence of a signal peptide. The structure of the protein suggests that it localizes to the cell membrane.
# Homology
LRRC24 is conserved in Euteleostomi with the exception of Aves.[1][14] Also, based on sequence homology analysis, distant orthologs of LRRC24 are also conserved in invertebrates of phyla Mollusca and Arthropoda.[1] No human paralogs of LRRC24 have been identified.
# Expression
Microarray and in situ hybridization experiments suggest LRRC24 is primarily expressed within the brain.[16][17][18] Expression is observed to be especially high within the midbrain, neocortex, and tissues of the limbic system, including the hypothalamus and hippocampal formation.[16][18][19]
# Interactions
Protein-protein interactions of LRRC24 implicate the protein with cell signaling, cell migration, and axon guidance. ROBO2 was found to interact with LRRC24.[20][21] ROBO2 is a member of the Roundabout gene family, which are well known to play a significant role in nervous system development. Also, LRRC24 was found to interact with LRRTM4, a protein believed to be involved in synaptogenesis, as well as the maintenance of the nervous system in vertebrates.[21]
LRRC24 has also been found to interact with IGFBP7, a known regulator of insulin-like growth factors (IGFs).[21] IGFBP7 is also involved in the stimulation of cell adhesion.
# Clinical significance
To date, no study has specifically implicated LRRC24 or the LRRC24 gene with any case of clinical significance.[22] | https://www.wikidoc.org/index.php/LRRC24 | |
29e4420c5ecb80b5109e64e3bfc2961b1d2e3f95 | wikidoc | LRRC40 | LRRC40
Leucine rich repeat containing 40 (LRRC40) is a protein that in humans is encoded by the LRRC40 gene.
# Species distribution
LRRC40 is conserved throughout all of its orthologs. The entire protein is highly conserved in mammals, while conservation is high within the leucine rich repeats in the rest of the orthologs. Orthologs were found all the way back to the scarlet sea anemone and homologs were found in bacteria and Archaea using BLAST. The following table gives information on the homologs of LRRC40.
# Gene
LRRC40 is located on the negative DNA strand (see Sense (molecular biology)) of chromosome 1 from 70,611,483- 70,671,223. The gene produces a 2958 base pair mRNA. There are 15 predicted exons in the human gene with four other splice patterns predicted on GeneCards by the Alternative Splice Database.
## Gene neighborhood
LRRC40 is neighbored downstream by LRRC7 (70,225,888 - 70,587,570) on the positive DNA strand and upstream by SRSF11 (70,687,320-70,716,488) on the positive DNA strand.
## Gene expression
LRRC40 is expressed between the 50th and 100th percentile in almost every tissue in the body.
# Protein
While the exact function of the LRRC40 protein is not yet understood, it is believed to participate in protein-protein interactions because it is a member of the leucine rich repeat family of proteins which are known to participate in protein-protein interactions.
## Properties
LRRC40 is a 602 amino acid protein with a molecular weight of 68.254 kDa and an isoelectric point of 6.04. LRRC40 is expected to localize to the nucleus and has no transmembrane domains to anchor it to the nuclear membrane. LRRC40 has many predicted phosphorylation sites. Of the 19 predicted phosphoserine sites, only two are conserved within the orthologs. These two sites are S38 and S391.
## Protein structure
The secondary structure of the protein has a pattern within the leucine repeat regions. Each leucine repeat has a β-sheet and α-helix. The image to the right shows the particular horseshoe-like structure of a protein with many leucine rich repeats. Depending on the area where the LRRs are located, other proteins can bind within the curve of the horseshoe or attach to the outside of the protein.
# Protein interactions
According to Genecards, LRRC40 has 756 possible protein interactions. These interactions are based on results in the Molecular Interaction database which provided two possible protein interactions. The two proteins are described in the table below. | LRRC40
Leucine rich repeat containing 40 (LRRC40) is a protein that in humans is encoded by the LRRC40 gene.[1]
# Species distribution
LRRC40 is conserved throughout all of its orthologs. The entire protein is highly conserved in mammals, while conservation is high within the leucine rich repeats in the rest of the orthologs.[2] Orthologs were found all the way back to the scarlet sea anemone and homologs were found in bacteria and Archaea using BLAST.[3] The following table gives information on the homologs of LRRC40.
# Gene
LRRC40 is located on the negative DNA strand (see Sense (molecular biology)) of chromosome 1 from 70,611,483- 70,671,223.[20] The gene produces a 2958 base pair mRNA. There are 15 predicted exons in the human gene [5] with four other splice patterns predicted on GeneCards by the Alternative Splice Database.[21]
## Gene neighborhood
LRRC40 is neighbored downstream by LRRC7 (70,225,888 - 70,587,570) on the positive DNA strand and upstream by SRSF11 (70,687,320-70,716,488) on the positive DNA strand.
## Gene expression
LRRC40 is expressed between the 50th and 100th percentile in almost every tissue in the body.[22]
# Protein
While the exact function of the LRRC40 protein is not yet understood, it is believed to participate in protein-protein interactions because it is a member of the leucine rich repeat family of proteins which are known to participate in protein-protein interactions.[23]
## Properties
LRRC40 is a 602 amino acid protein with a molecular weight of 68.254 kDa and an isoelectric point of 6.04.[24] LRRC40 is expected to localize to the nucleus [25] and has no transmembrane domains to anchor it to the nuclear membrane. LRRC40 has many predicted phosphorylation sites. Of the 19 predicted phosphoserine sites, only two are conserved within the orthologs.[26] These two sites are S38 and S391.
## Protein structure
The secondary structure of the protein has a pattern within the leucine repeat regions. Each leucine repeat has a β-sheet and α-helix. The image to the right shows the particular horseshoe-like structure of a protein with many leucine rich repeats. Depending on the area where the LRRs are located, other proteins can bind within the curve of the horseshoe or attach to the outside of the protein.
# Protein interactions
According to Genecards, LRRC40 has 756 possible protein interactions.[21] These interactions are based on results in the Molecular Interaction database which provided two possible protein interactions. The two proteins are described in the table below. | https://www.wikidoc.org/index.php/LRRC40 | |
6398e8c47387fba11ddf8344aaff170c5bb60172 | wikidoc | LRRC50 | LRRC50
Leucine-rich repeat-containing protein 50 is a protein that in humans is encoded by the LRRC50 gene.
# Function
Leucine-rich repeat-containing protein 50 is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli.
# Clinical significance
Mutations in the LRRC50 gene are associated with primary ciliary dyskinesia. | LRRC50
Leucine-rich repeat-containing protein 50 is a protein that in humans is encoded by the LRRC50 gene.[1][2]
# Function
Leucine-rich repeat-containing protein 50 is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli.[1]
# Clinical significance
Mutations in the LRRC50 gene are associated with primary ciliary dyskinesia.[2] | https://www.wikidoc.org/index.php/LRRC50 | |
d24160e9463027218755835acb4a8cb01f69bfa7 | wikidoc | LRRC57 | LRRC57
Leucine rich repeat containing 57, also known as LRRC57, is a protein that in humans is encoded by the LRRC57 gene.
# Function
The exact function of LRRC57 is not known. It is a member of the leucine-rich repeat family of proteins, which are known to be involved in protein-protein interactions.
# Protein sequence
As is customary for leucine-rich repeat proteins, the sequence is shown below with the repeats starting on their own lines. The beginning of each repeat is a β-strand, which forms a β-sheet along the concave side of the protein. The convex side of the protein is formed by the latter half of each repeat, and may consist of a variety of structures, including α-helices, 310 helices, β-turns, and even short β-strands.
Note that the 5' and 3' UTR both are rich in leucines, suggesting that they may be degenerate repeats (the overall protein is 19.7% leucine and 7.5% asparagine, both very rich).
The following layout of the LRRC57 amino acid sequence makes it easy to discern the LxxLxLxxNxxL consensus sequence of LRRs.
# Homology
LRRC57 is exceedingly well conserved, as shown by the following multiple sequence alignment, prepared using ClustalX2. The cyan and yellow highlights call out regions of high conservation and the repeats.
The following table provides a few details on orthologs of the human version of LRRC57. To save space, not all of these orthologs are included in the above multiple sequence alignment. These orthologs were gathered from BLAT. and BLAST searches
# Gene neighborhood
The LRRC57 gene has interesting relationships to its neighbors – HAUS2 upstream and SNAP23 downstream, as shown below for human.
Shown below is the neighborhood for the mouse ortholog. Note that the neighbors are the same, which is true for most vertebrates.
Note the close proximity between LRRC57 and HAUS2/CEP27 (the same gene by different names). In humans, the exons are 50bp apart, whereas in mouse, they overlap, as shown in the closeup, below. This close relationship may partially explain the high conservation of LRRC57, as it would require a mutation to be stable in both genes at the same time.
The relationship to the downstream neighbor, SNAP23 is also interesting. Quoting from the AceView entry: "373 bp of this gene are antisense to spliced gene SNAP23, raising the possibility of regulated alternate expression". Taking the reverse complement of the LRRC57 cDNA and aligning it with the SNAP23 cDNA does show high similarity, as shown in this partial alignment:
# Predicted post-translational modifications
The tools on the ExPASy Proteomics site predict the following post-translational modifications:
The predicted modifications for Homo sapiens are shown on the following conceptual translation. The cyan highlights are predicted phosphorylation sites and the yellow highlights are as labeled. The red boxes show predictions that are conserved across all four organisms.
The sites for all four organisms are highlighted on the following multiple sequence alignment.
Note that the phosphorylation at S201 and the sulfation at Y224 are the only well conserved predictions across all four organisms.
# Structure
The structure of LRRC57 is not known. However, a protein BLAST search against the protein databank returns a similar protein (PDB: 2O6Q), with an E-value of 3E−14. It is also a leucine rich repeat containing seven repeats of the same length as LRRC57, described as Eptatretus burgeri (inshore hagfish) variable lymphocyte receptors A29. | LRRC57
Leucine rich repeat containing 57, also known as LRRC57, is a protein that in humans is encoded by the LRRC57 gene.[1]
# Function
The exact function of LRRC57 is not known. It is a member of the leucine-rich repeat family of proteins, which are known to be involved in protein-protein interactions.
# Protein sequence
As is customary for leucine-rich repeat proteins,[2] the sequence[1] is shown below with the repeats starting on their own lines. The beginning of each repeat is a β-strand, which forms a β-sheet along the concave side of the protein. The convex side of the protein is formed by the latter half of each repeat, and may consist of a variety of structures, including α-helices, 310 helices, β-turns, and even short β-strands.[2]
Note that the 5' and 3' UTR both are rich in leucines, suggesting that they may be degenerate repeats (the overall protein is 19.7% leucine and 7.5% asparagine, both very rich).
The following layout of the LRRC57 amino acid sequence makes it easy to discern the LxxLxLxxNxxL consensus sequence of LRRs.[2]
# Homology
LRRC57 is exceedingly well conserved, as shown by the following multiple sequence alignment, prepared using ClustalX2.[3] The cyan and yellow highlights call out regions of high conservation and the repeats.
The following table provides a few details on orthologs of the human version of LRRC57. To save space, not all of these orthologs are included in the above multiple sequence alignment. These orthologs were gathered from BLAT.[4] and BLAST searches[5]
# Gene neighborhood
The LRRC57 gene has interesting relationships to its neighbors – HAUS2 upstream and SNAP23 downstream, as shown below for human.[6]
Shown below is the neighborhood for the mouse[7] ortholog. Note that the neighbors are the same, which is true for most vertebrates.
Note the close proximity between LRRC57 and HAUS2/CEP27 (the same gene by different names). In humans, the exons are 50bp apart, whereas in mouse, they overlap, as shown in the closeup, below. This close relationship may partially explain the high conservation of LRRC57, as it would require a mutation to be stable in both genes at the same time.
The relationship to the downstream neighbor, SNAP23 is also interesting. Quoting from the AceView[8] entry: "373 bp of this gene are antisense to spliced gene SNAP23, raising the possibility of regulated alternate expression". Taking the reverse complement of the LRRC57 cDNA and aligning it with the SNAP23 cDNA does show high similarity, as shown in this partial alignment:
# Predicted post-translational modifications
The tools on the ExPASy Proteomics site[9] predict the following post-translational modifications:
The predicted modifications for Homo sapiens are shown on the following conceptual translation. The cyan highlights are predicted phosphorylation sites and the yellow highlights are as labeled. The red boxes show predictions that are conserved across all four organisms.
The sites for all four organisms are highlighted on the following multiple sequence alignment.
Note that the phosphorylation at S201 and the sulfation at Y224 are the only well conserved predictions across all four organisms.
# Structure
The structure of LRRC57 is not known. However, a protein BLAST search against the protein databank returns a similar protein (PDB: 2O6Q), with an E-value of 3E−14. It is also a leucine rich repeat containing seven repeats of the same length as LRRC57, described as Eptatretus burgeri (inshore hagfish) variable lymphocyte receptors A29.[18] | https://www.wikidoc.org/index.php/LRRC57 | |
7d41cd88a0e0104311e92e68ce37719a8b3b7f0e | wikidoc | LRRC8A | LRRC8A
Leucine-rich repeat-containing protein 8A is a protein that in humans is encoded by the LRRC8A gene. Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8B, LRRC8C, LRRC8D, and LRRC8E, is a subunit of the heteromer protein volume-regulated anion channel (VRAC). (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane, and that is not the only function these channels have been linked to.
While LRRC8A is one of many proteins that can be part of VRAC, it is the most important subunit for the channel’s ability to function. However, while we know it is necessary for VRAC function, other studies have found that it is not sufficient for the full range of usual VRAC activity. This is where the other LRRC8 proteins come in, as the different composition of these subunits affects the range of specificity for VRACs.
In addition to its role in VRACs, the LRRC8 protein family is also associated with agammaglobulinemia-5. | LRRC8A
Leucine-rich repeat-containing protein 8A is a protein that in humans is encoded by the LRRC8A gene.[1] Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8B, LRRC8C, LRRC8D, and LRRC8E, is a subunit of the heteromer protein volume-regulated anion channel (VRAC).[2] (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane,[3] and that is not the only function these channels have been linked to.
While LRRC8A is one of many proteins that can be part of VRAC, it is the most important subunit for the channel’s ability to function.[4][5] However, while we know it is necessary for VRAC function, other studies have found that it is not sufficient for the full range of usual VRAC activity.[6] This is where the other LRRC8 proteins come in, as the different composition of these subunits affects the range of specificity for VRACs.[7][8]
In addition to its role in VRACs, the LRRC8 protein family is also associated with agammaglobulinemia-5.[9] | https://www.wikidoc.org/index.php/LRRC8A | |
ad2c1700b94820d75e837af76d0a645b18cd0a00 | wikidoc | LRRC8C | LRRC8C
Leucine-rich repeat-containing protein 8C is a protein that in humans is encoded by the LRRC8C gene. Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8A, LRRC8B, LRRC8D, and LRRC8E, is sometimes a subunit of the heteromer protein Volume-Regulated Anion Channel. Volume-Regulated Anion Channels (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane, and that is not the only function these channels have been linked to.
While LRRC8C is one of many proteins that can be part of VRAC, research has found that it is not as crucial to the activity of the channel in comparison to LRRC8A and LRRC8D. However, while we know that LRRC8A and LRRC8D are necessary for VRAC function, other studies have found that they are not sufficient for the full range of usual VRAC activity. This is where the other LRRC8 proteins come in, such as LRRC8C, as the different composition of these subunits affects the range of specificity for VRACs.
In addition to its role in VRACs, the LRRC8 protein family is also associated with agammaglobulinemia-5. | LRRC8C
Leucine-rich repeat-containing protein 8C is a protein that in humans is encoded by the LRRC8C gene.[1] Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8A, LRRC8B, LRRC8D, and LRRC8E, is sometimes a subunit of the heteromer protein Volume-Regulated Anion Channel.[2] Volume-Regulated Anion Channels (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane,[3] and that is not the only function these channels have been linked to.
While LRRC8C is one of many proteins that can be part of VRAC, research has found that it is not as crucial to the activity of the channel in comparison to LRRC8A and LRRC8D.[4][5][6] However, while we know that LRRC8A and LRRC8D are necessary for VRAC function, other studies have found that they are not sufficient for the full range of usual VRAC activity.[7] This is where the other LRRC8 proteins come in, such as LRRC8C, as the different composition of these subunits affects the range of specificity for VRACs.[8][6]
In addition to its role in VRACs, the LRRC8 protein family is also associated with agammaglobulinemia-5.[9] | https://www.wikidoc.org/index.php/LRRC8C | |
5402741079ebd2902fa77c76a6b57e3b8d0d4119 | wikidoc | LRRC8D | LRRC8D
Leucine-rich repeat-containing protein 8D is a protein that in humans is encoded by the LRRC8D gene. Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8A, LRRC8B, LRRC8C, and LRRC8E, is a subunit of the heteromer protein Volume-Regulated Anion Channel. Volume-Regulated Anion Channels (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane, and that is not the only function these channels have been linked to.
While LRRC8D is one of many proteins that can be part of VRAC, it is in fact one of the most important subunits for the channel’s ability to function; the other protein of importance is LRRC8A. However, while we know it is necessary for specific VRAC function, other studies have found that it is not sufficient for the full range of usual VRAC activity. This is where the other LRRC8 proteins come in, as the different composition of these subunits affects the range of specificity for VRACs.
In addition to its role in VRACs, the LRRC8 protein family is also associated with agammaglobulinemia-5. | LRRC8D
Leucine-rich repeat-containing protein 8D is a protein that in humans is encoded by the LRRC8D gene.[1] Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8A, LRRC8B, LRRC8C, and LRRC8E, is a subunit of the heteromer protein Volume-Regulated Anion Channel[2]. Volume-Regulated Anion Channels (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane,[3] and that is not the only function these channels have been linked to.
While LRRC8D is one of many proteins that can be part of VRAC, it is in fact one of the most important subunits for the channel’s ability to function; the other protein of importance is LRRC8A.[4][5] However, while we know it is necessary for specific VRAC function, other studies have found that it is not sufficient for the full range of usual VRAC activity.[6] This is where the other LRRC8 proteins come in, as the different composition of these subunits affects the range of specificity for VRACs.[7][8]
In addition to its role in VRACs, the LRRC8 protein family is also associated with agammaglobulinemia-5.[9] | https://www.wikidoc.org/index.php/LRRC8D | |
d4eb9b19daac5937d560b0a4f75117a74e6bde0c | wikidoc | LRRC8E | LRRC8E
Leucine-rich repeat-containing protein 8E is a protein that in humans is encoded by the LRRC8E gene. Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8A, LRRC8B, LRRC8C, and LRRC8D, is sometimes a subunit of the heteromer protein Volume-Regulated Anion Channel. Volume-Regulated Anion Channels (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane, and that is not the only function these channels have been linked to.
While LRRC8E is one of many proteins that can be part of VRAC, research has found that it is not as crucial to the activity of the channel in comparison to LRRC8A and LRRC8D. However, while we know that LRRC8A and LRRC8D are necessary for VRAC function, other studies have found that they are not sufficient for the full range of usual VRAC activity. This is where the other LRRC8 proteins come in, such as LRRC8E, as the different composition of these subunits affects the range of specificity for VRACs.
In addition to its role in VRACs, the LRRC8 protein family is also associated with agammaglobulinemia-5.
Specifically for LRRC8E, there has been a recent study that found that this gene was nominally associated with panic disorder. | LRRC8E
Leucine-rich repeat-containing protein 8E is a protein that in humans is encoded by the LRRC8E gene.[1] Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8A, LRRC8B, LRRC8C, and LRRC8D, is sometimes a subunit of the heteromer protein Volume-Regulated Anion Channel.[2] Volume-Regulated Anion Channels (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane,[3] and that is not the only function these channels have been linked to.
While LRRC8E is one of many proteins that can be part of VRAC, research has found that it is not as crucial to the activity of the channel in comparison to LRRC8A and LRRC8D.[4][5][6] However, while we know that LRRC8A and LRRC8D are necessary for VRAC function, other studies have found that they are not sufficient for the full range of usual VRAC activity.[7] This is where the other LRRC8 proteins come in, such as LRRC8E, as the different composition of these subunits affects the range of specificity for VRACs.[8][6]
In addition to its role in VRACs, the LRRC8 protein family is also associated with agammaglobulinemia-5.[9]
Specifically for LRRC8E, there has been a recent study that found that this gene was nominally associated with panic disorder.[10] | https://www.wikidoc.org/index.php/LRRC8E | |
a4872b0d6efd3619d316a8ff3b64cfcd95e76ea5 | wikidoc | LRRIQ3 | LRRIQ3
LRRIQ3 (Leucine-rich repeats and IQ motif containing 3), which is also known as LRRC44, is a protein that in humans is encoded by the LRRIQ3 gene. It is predominantly expressed in the testes, and is linked to a number of diseases.
# Gene
## Locus
LRRIQ3 is found on the minus strand of the end of the short arm of human chromosome 1 at 1p31.1.
## Overall Structure
There are a total of 7 exons in the putative sequence of LRRIQ3.
# mRNA
## Expression
LRRIQ3 is expressed as 2 primary isoforms, which produce proteins of length 624 amino acids and 464 amino acids respectively. It is expressed at low levels in human and brown rat tissues, with highest expression levels in testes tissue. There are relatively high expression levels in T cells, the epididymis, the kidney, and a number of glands.
# Protein
## General Characteristics and Compositional Features
Human protein LRRIQ3 Isoform 1 consists of 624 amino acids, and has a molecular weight of 73.7 kDa. The isoelectric point of LRRIQ3 is 9.73, which suggests that LRRIQ3 is basic at normal physiological pH (~7.4). Additionally, there is strong evidence that human LRRIQ3 localizes to the plasma membrane from antibody staining. LRRIQ3 is rich in lysine residues, with a total of 82 lysines. It is also slightly low on glycines.
## Domains and Motifs
In total, there are 4 conserved domains within LRRIQ3: 3 leucine-rich repeats and 1 IQ calmodulin-binding motif. Leucine-rich repeats are typically involved in protein-protein interactions, and form a characteristic α/β horseshoe fold. An IQ motif provides a binding site for calmodulin (CaM) or CaM-like proteins.
## Secondary and Tertiary Structure
LRRIQ3 is predicted to be mostly alpha-helical in structure, including a long alpha-helical C-terminal domain. It is also predicted to function as a monomer.
## Post-translational Modifications
LRRIQ3 is predicted to undergo many post-translational modifications. These include O-GlcNAcylation, SUMOylation, ubiquitination, and phosphorylation. LRRIQ3 is predicted to have 4 well conserved SUMOlyation sites and 1 well conserved ubiquitination site. A representation of these post-translational modifications is shown in the figure below.
## Protein Interactions
There is evidence that LRRIQ3 interacts with a number of proteins from two-hybrid assays and affinity chromatography. The proteins LRRIQ3 interact with include LYN, NCK2, GNB4, and ABL1. These proteins are associated with cell signalling, cytoskeletal reorganization, and cell differentiation, as well as others.
# Homology and evolution
## Paralogs and Orthologs
No paralogs exists for LRRIQ3 in humans. However, there are a number of orthologs, as reported by BLAST, some of which are listed below. The number of years since divergence from the human protein, listed in "million of years ago (MYA)" below, were calculated using TimeTree.
# Clinical significance
LRRIQ3 is linked to a number of cancers. RNA-seq experiments have shown that LRRIQ3 is severely down-regulated (Log2-fold changes between -3.4 and -4.2) in a number of disease states, including pancreatic cancer, colorectal cancer, and breast cancer. | LRRIQ3
LRRIQ3 (Leucine-rich repeats and IQ motif containing 3), which is also known as LRRC44, is a protein that in humans is encoded by the LRRIQ3 gene.[1] It is predominantly expressed in the testes, and is linked to a number of diseases.[2]
# Gene
## Locus
LRRIQ3 is found on the minus strand of the end of the short arm of human chromosome 1 at 1p31.1.[3]
## Overall Structure
There are a total of 7 exons in the putative sequence of LRRIQ3.[3]
# mRNA
## Expression
LRRIQ3 is expressed as 2 primary isoforms, which produce proteins of length 624 amino acids and 464 amino acids respectively.[3] It is expressed at low levels in human and brown rat tissues,[4][5] with highest expression levels in testes tissue. There are relatively high expression levels in T cells, the epididymis, the kidney, and a number of glands.[6]
# Protein
## General Characteristics and Compositional Features
Human protein LRRIQ3 Isoform 1 consists of 624 amino acids, and has a molecular weight of 73.7 kDa. The isoelectric point of LRRIQ3 is 9.73, which suggests that LRRIQ3 is basic at normal physiological pH (~7.4).[7] Additionally, there is strong evidence that human LRRIQ3 localizes to the plasma membrane from antibody staining.[8] LRRIQ3 is rich in lysine residues, with a total of 82 lysines. It is also slightly low on glycines.[9]
## Domains and Motifs
In total, there are 4 conserved domains within LRRIQ3: 3 leucine-rich repeats and 1 IQ calmodulin-binding motif.[9] Leucine-rich repeats are typically involved in protein-protein interactions, and form a characteristic α/β horseshoe fold.[10][11] An IQ motif provides a binding site for calmodulin (CaM) or CaM-like proteins.[12]
## Secondary and Tertiary Structure
LRRIQ3 is predicted to be mostly alpha-helical in structure, including a long alpha-helical C-terminal domain. It is also predicted to function as a monomer.[13][14][15][16]
## Post-translational Modifications
LRRIQ3 is predicted to undergo many post-translational modifications. These include O-GlcNAcylation, SUMOylation, ubiquitination, and phosphorylation.[18][19] LRRIQ3 is predicted to have 4 well conserved SUMOlyation sites and 1 well conserved ubiquitination site.[18] A representation of these post-translational modifications is shown in the figure below.
## Protein Interactions
There is evidence that LRRIQ3 interacts with a number of proteins from two-hybrid assays and affinity chromatography. The proteins LRRIQ3 interact with include LYN, NCK2, GNB4, and ABL1.[21][22] These proteins are associated with cell signalling, cytoskeletal reorganization, and cell differentiation, as well as others.[23][24][25][26]
# Homology and evolution
## Paralogs and Orthologs
No paralogs exists for LRRIQ3 in humans.[2] However, there are a number of orthologs, as reported by BLAST, some of which are listed below.[27] The number of years since divergence from the human protein, listed in "million of years ago (MYA)" below, were calculated using TimeTree.[28]
# Clinical significance
LRRIQ3 is linked to a number of cancers. RNA-seq experiments have shown that LRRIQ3 is severely down-regulated (Log2-fold changes between -3.4 and -4.2) in a number of disease states, including pancreatic cancer, colorectal cancer, and breast cancer.[29][30][31] | https://www.wikidoc.org/index.php/LRRIQ3 | |
5e6030f03c1c0215e8bdd505f45339871cb29a10 | wikidoc | LRRTM1 | LRRTM1
LRRTM1 is a brain-expressed imprinted gene that encodes a leucine-rich repeat transmembrane protein that interacts with neurexins and neuroligins to modulate synaptic cell adhesion in neurons. As the name implies, its protein product is a transmembrane protein that contains many leucine rich repeats. It is expressed during the development of specific forebrain structures and shows a variable pattern of maternal downregulation (genomic imprinting).
# Clinical significance
LRRTM1 is the first gene linked to increased odds of being left-handed, when inherited from the father's side. Possessing one particular variant of the LRRTM1 gene slightly raises the risk of psychotic mental illnesses such as schizophrenia, again only if inherited from the father's side. As well, LRRTM1 has been associated with measures of schizotypy in non-clinical populations, indicating that the gene may have shared effects on neurodevelopment in both healthy and unhealthy individuals and individuals with schizophrenia.
LRRTM1 is also critically involved in synapse formation within the dorsal Lateral geniculate nucleus (dLGN) of mice. LRRTM1 aids in the assembly of complex retinogenciulate synapses in mice, which are believed to help process complex visual signals. Lack of this gene shows decreased performance in complex visual tasks. | LRRTM1
LRRTM1 is a brain-expressed imprinted gene that encodes a leucine-rich repeat transmembrane protein that interacts with neurexins and neuroligins to modulate synaptic cell adhesion in neurons.[1][2] As the name implies, its protein product is a transmembrane protein that contains many leucine rich repeats. It is expressed during the development of specific forebrain structures and shows a variable pattern of maternal downregulation (genomic imprinting).[3][4]
# Clinical significance
LRRTM1 is the first gene linked to increased odds of being left-handed, when inherited from the father's side.[5] Possessing one particular variant of the LRRTM1 gene slightly raises the risk of psychotic mental illnesses such as schizophrenia, again only if inherited from the father's side.[5] As well, LRRTM1 has been associated with measures of schizotypy in non-clinical populations,[6] indicating that the gene may have shared effects on neurodevelopment in both healthy and unhealthy individuals and individuals with schizophrenia.
LRRTM1 is also critically involved in synapse formation within the dorsal Lateral geniculate nucleus (dLGN) of mice. LRRTM1 aids in the assembly of complex retinogenciulate synapses in mice, which are believed to help process complex visual signals. Lack of this gene shows decreased performance in complex visual tasks.[7] | https://www.wikidoc.org/index.php/LRRTM1 | |
162a1406fc29918f930e69cec140b073bdcf2f34 | wikidoc | LRTOMT | LRTOMT
Leucine rich transmembrane and O-methyltransferase domain containing is a protein that in humans is encoded by the LRTOMT gene.
# Clinical significance
Mutations in LRTOMT are associated to non syndromic deafness .
# Function
This gene includes two transcript forms. The short form has one open reading frame (ORF), which encodes the leucine-rich repeats (LRR)-containing protein of unknown function. This protein is called LRTOMT1 or LRRC51. The long form has two alternative ORFs; the upstream ORF has the same translation start codon as used in the short form and the resulting transcript is a candidate for nonsense-mediated decay, and the downstream ORF encodes a different protein, which is a transmembrane catechol-O-methyltransferase and is called LRTOMT2, TOMT or COMT2. The COMT2 is essential for auditory and vestibular function. Defects in the COMT2 can cause nonsyndromic deafness. Alternatively spliced transcript variants from each transcript form have been found for this gene. | LRTOMT
Leucine rich transmembrane and O-methyltransferase domain containing is a protein that in humans is encoded by the LRTOMT gene.[1]
# Clinical significance
Mutations in LRTOMT are associated to non syndromic deafness .[2]
# Function
This gene includes two transcript forms. The short form has one open reading frame (ORF), which encodes the leucine-rich repeats (LRR)-containing protein of unknown function. This protein is called LRTOMT1 or LRRC51. The long form has two alternative ORFs; the upstream ORF has the same translation start codon as used in the short form and the resulting transcript is a candidate for nonsense-mediated decay, and the downstream ORF encodes a different protein, which is a transmembrane catechol-O-methyltransferase and is called LRTOMT2, TOMT or COMT2. The COMT2 is essential for auditory and vestibular function. Defects in the COMT2 can cause nonsyndromic deafness. Alternatively spliced transcript variants from each transcript form have been found for this gene. | https://www.wikidoc.org/index.php/LRTOMT | |
74eb3e5cd89bc3a50f26731ce1981b2767cbf4f2 | wikidoc | Labium | Labium
# Overview
Labium (plural labia) is a Latin-derived term meaning "Lip". Labium and its derivatives (including labial, labrum) are used to describe any lip-like structure, but in the English language, labium often specifically refers to parts of the vulva.
# Anatomy
The labia majora are lip-like structures comprised mostly of skin and adipose tissue, which extend on either side of the vulva, and after puberty are naturally covered with pubic hair. When standing or with the legs together, they usually entirely or partially cover the other parts of the vulva.
The labia minora (obsolete: nymphae) are two soft folds of skin within the labia majora and to either side of the opening of the vagina. The clitoris is anterior to the vulva where the labia minora meet superiorly. The visible tip of the clitoris, the clitoral glans, is entirely or partially covered by a "hood" of tissue (the clitoral hood).
The coloration, size and general appearance of the labia can vary extensively from woman to woman. In some women the labia minora are almost non-existent, and in others they can be fleshy and protuberant. It is not uncommon for them to be asymmetrical. Some differences are purely personal, while others may be genetically linked; a striking example of the latter being the elongated labia minora of the Khoisan peoples, whose "khoikhoi aprons" can hang down up to four inches past their labia majora when they are standing.
During sexual arousal, the labia become engorged with blood, typically swelling slightly and darkening or reddening in color.
Labiaplasty is a controversial plastic surgery procedure that involves the creation or reshaping of the labia.
# Additional images
- Outer anatomy of clitoris.
- Organs of the female reproductive system.
- Sagittal section of the lower part of a female trunk, right segment.
- Median sagittal section of female pelvis. | Labium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Labium (plural labia) is a Latin-derived term meaning "Lip". Labium and its derivatives (including labial, labrum) are used to describe any lip-like structure, but in the English language, labium often specifically refers to parts of the vulva.
# Anatomy
The labia majora are lip-like structures comprised mostly of skin and adipose tissue, which extend on either side of the vulva, and after puberty are naturally covered with pubic hair. When standing or with the legs together, they usually entirely or partially cover the other parts of the vulva.
The labia minora (obsolete: nymphae) are two soft folds of skin within the labia majora and to either side of the opening of the vagina. The clitoris is anterior to the vulva where the labia minora meet superiorly. The visible tip of the clitoris, the clitoral glans, is entirely or partially covered by a "hood" of tissue (the clitoral hood).
The coloration, size and general appearance of the labia can vary extensively from woman to woman. [1] In some women the labia minora are almost non-existent, and in others they can be fleshy and protuberant. It is not uncommon for them to be asymmetrical. Some differences are purely personal, while others may be genetically linked; a striking example of the latter being the elongated labia minora of the Khoisan peoples, whose "khoikhoi aprons" can hang down up to four inches past their labia majora when they are standing.[2]
During sexual arousal, the labia become engorged with blood, typically swelling slightly and darkening or reddening in color.
Labiaplasty is a controversial plastic surgery procedure that involves the creation or reshaping of the labia.
# Additional images
- Outer anatomy of clitoris.
- Organs of the female reproductive system.
- Sagittal section of the lower part of a female trunk, right segment.
- Median sagittal section of female pelvis. | https://www.wikidoc.org/index.php/Labia | |
1e3c810305208da5bce2f541751f464628ed8fc9 | wikidoc | Lactam | Lactam
A lactam (the noun is a portmanteau of the words lactone + amide) is a cyclic amide. Prefixes may indicate the ring size: β-lactam (4-membered), γ-lactam (5-membered), δ-lactam (6-membered ring). That order in the nomenclature is because beta β, gamma γ and delta δ are the second, third and fourth letters in the alphabetical order of the Greek alphabet, respectively.
# Synthesis
General synthetic methods exist for the organic synthesis of lactams.
- Lactams form by the acid-catalyzed rearrangement of oximes in the Beckmann rearrangement.
- Lactams form from cyclic ketones and ammonia in the Schmidt reaction.
- lactams form from cyclisation of amino acids.
- In iodolactamization an iminium ion reacts with an halonium ion formed in situ by reaction of an alkene with iodine.
- Lactams form by copper catalyzed 1,3-dipolar cycloaddition of alkynes and nitrones in the Kinugasa reaction
# Reactions
- Lactams can polymerize to polyamides. | Lactam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A lactam (the noun is a portmanteau of the words lactone + amide) is a cyclic amide. Prefixes may indicate the ring size: β-lactam (4-membered), γ-lactam (5-membered), δ-lactam (6-membered ring). That order in the nomenclature is because beta β, gamma γ and delta δ are the second, third and fourth letters in the alphabetical order of the Greek alphabet, respectively.
# Synthesis
General synthetic methods exist for the organic synthesis of lactams.
- Lactams form by the acid-catalyzed rearrangement of oximes in the Beckmann rearrangement.
- Lactams form from cyclic ketones and ammonia in the Schmidt reaction.
- lactams form from cyclisation of amino acids.
- In iodolactamization [1] an iminium ion reacts with an halonium ion formed in situ by reaction of an alkene with iodine.
- Lactams form by copper catalyzed 1,3-dipolar cycloaddition of alkynes and nitrones in the Kinugasa reaction
# Reactions
- Lactams can polymerize to polyamides. | https://www.wikidoc.org/index.php/Lactam | |
05e85d677eca30f350f4544cdb05796a85247e22 | wikidoc | Larynx | Larynx
# Overview
The larynx (plural larynges), colloquially known as the voicebox, is an organ in the neck of mammals involved in protection of the trachea and sound production. The larynx houses the vocal folds, and is situated just below where the tract of the pharynx splits into the trachea and the esophagus.
# Function
Sound is generated in the larynx, and that is where pitch and volume are manipulated. The strength of expiration from the lungs also contributes to loudness, and is necessary for the vocal folds to produce speech.
Fine manipulation of the larynx is used in a great way to generate a source sound with a particular fundamental frequency, or pitch. This source sound is altered as it travels through the vocal tract, configured differently based on the position of the tongue, lips, mouth, and pharynx. The process of altering a source sound as it passes through the filter of the vocal tract creates the many different vowel and consonant sounds of the world's languages.
During swallowing, the backward motion of the tongue forces the epiglottis over the laryngeal opening to prevent swallowed material from entering the lungs; the larynx is also pulled upwards to assist this process. Stimulation of the larynx by ingested matter produces a strong cough reflex to protect the lungs.
The vocal folds can be held close together (by adducting the arytenoid cartilages), so that they vibrate (see phonation). The muscles attached to the arytenoid cartilages control the degree of opening. Vocal fold length and tension can be controlled by rocking the thyroid cartilage forward and backward on the cricoid cartilage, and by manipulating the tension of the muscles within the vocal folds. This causes the pitch produced during phonation to rise or fall. In most males the vocal cords are longer, producing a deeper pitch.
The vocal apparatus consists of two pairs of mucosal folds. These folds are false vocal cords(vestibular folds) and true vocal cords(folds). The false vocal cords are covered by respiratory epithelium, while the true vocal cords are covered by stratified squamous epithelium. The false vocal cords are not responsible for sound production, but rather for resonance. These false vocal cords do not contain muscle, while the true vocal cords do have skeletal muscle.
# Innervation
The larynx is innervated by branches of the vagus nerve (CN X) on each side. Sensory innervation to the glottis and supraglottis is by the internal branch of the superior laryngeal nerve. The external branch of the superior laryngeal nerve innervates the cricothyroid muscle. Motor innervation to all other muscles of the larynx and sensory innervation to the subglottis is by the recurrent laryngeal nerve.
Injury to the external laryngeal nerve causes weakened phonation because the vocal cords cannot be tightened. Injury to one of the recurrent laryngeal nerves produces hoarseness, if both are damaged the voice is completely lost and breathing becomes difficult.
# Muscles associated with the larynx
- Cricothyroid muscle lengthens and stretches the vocal cords.
- Posterior cricoarytenoid muscle abducts the vocal cords.
- Lateral cricoarytenoid muscle adducts the vocal cords.
- Thyroarytenoid muscle (also called vocalis muscle) shortens vocal cords.
- Transverse arytenoid muscle adducts the vocal folds.
Notably, the only muscle capable of separating the vocal cords for normal breathing is the posterior cricoarytenoid. If this muscle is incapacitated on both sides, the inability to pull the vocal cords apart (abduct) will cause difficulty breathing. Bilateral injury to the recurrent laryngeal nerve would cause this condition.
# Descended larynx
In most animals, including infant humans and apes, the larynx is situated very high in the throat — a position that allows it to couple more easily with the nasal passages, so that breathing and eating are not done with the same apparatus. However, some aquatic mammals, large deer, and adult humans have descended larynges. An adult human cannot raise the larynx enough to directly couple it to the nasal passage.
Some linguists have suggested that the descended larynx, by extending the length of the vocal tract and thereby increasing the variety of sounds humans could produce, was a critical element in the development of speech and language. Others cite the presence of descended larynges in non-linguistic animals, as well as the ubiquity of nonverbal communication and language among humans, as counterevidence against this claim.
# Disorders of the larynx
There are several things that can cause a larynx to not function properly. Some symptoms are hoarseness, loss of voice, pain in the throat or ears, and breathing difficulties.
- Acute laryngitis is the sudden inflammation and swelling of the larynx. It is caused by the common cold or by excessive shouting. It is not serious. Chronic laryngitis is caused by smoking, dust, frequent yelling, or prolonged exposure to polluted air. It is much more serious than acute laryngitis.
- Presbylarynx is a condition in which age-related atrophy of the soft tissues of the larynx results in weak voice and restricted vocal range and stamina. Bowing of the anterior portion of the vocal cords is found on laryngoscopy.
- Ulcers may be caused by the prolonged presence of an endotracheal tube.
- Polyps and nodules are small bumps on the vocal cords caused by prolonged exposure to cigarette smoke and vocal overuse, respectively.
- Two related types of cancer of the larynx, namely squamous cell carcinoma and verrucous carcinoma, are strongly associated with repeated exposure to cigarette smoke and alcohol.
- Vocal cord paresis is weakness of one or both vocal folds that can greatly impact daily life.
- The world's first successful larynx transplant took place in 1999 at the Cleveland Clinic.
# Cartilages
The cartilages of the larynx are the thyroid, cricoid, arytenoids, corniculates, and the cuneiforms.
# Images
- Bronchi, bronchial tree, and lungs
- Larynx
- The ligaments of the larynx. Antero-lateral view.
- Sagittal section of the larynx and upper part of the trachea.
- Coronal section of larynx and upper part of trachea.
- The entrance to the larynx, viewed from behind.
- Laryngoscopic view of interior of larynx.
- Sagittal section of nose mouth, pharynx, and larynx.
- Endoscopic image of larynx seen at the time of intubation of the esophagus during gastroscopy. | Larynx
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The larynx (plural larynges), colloquially known as the voicebox, is an organ in the neck of mammals involved in protection of the trachea and sound production. The larynx houses the vocal folds, and is situated just below where the tract of the pharynx splits into the trachea and the esophagus.
# Function
Sound is generated in the larynx, and that is where pitch and volume are manipulated. The strength of expiration from the lungs also contributes to loudness, and is necessary for the vocal folds to produce speech.
Fine manipulation of the larynx is used in a great way to generate a source sound with a particular fundamental frequency, or pitch. This source sound is altered as it travels through the vocal tract, configured differently based on the position of the tongue, lips, mouth, and pharynx. The process of altering a source sound as it passes through the filter of the vocal tract creates the many different vowel and consonant sounds of the world's languages.
During swallowing, the backward motion of the tongue forces the epiglottis over the laryngeal opening to prevent swallowed material from entering the lungs; the larynx is also pulled upwards to assist this process. Stimulation of the larynx by ingested matter produces a strong cough reflex to protect the lungs.
The vocal folds can be held close together (by adducting the arytenoid cartilages), so that they vibrate (see phonation). The muscles attached to the arytenoid cartilages control the degree of opening. Vocal fold length and tension can be controlled by rocking the thyroid cartilage forward and backward on the cricoid cartilage, and by manipulating the tension of the muscles within the vocal folds. This causes the pitch produced during phonation to rise or fall. In most males the vocal cords are longer, producing a deeper pitch.
The vocal apparatus consists of two pairs of mucosal folds. These folds are false vocal cords(vestibular folds) and true vocal cords(folds). The false vocal cords are covered by respiratory epithelium, while the true vocal cords are covered by stratified squamous epithelium. The false vocal cords are not responsible for sound production, but rather for resonance. These false vocal cords do not contain muscle, while the true vocal cords do have skeletal muscle.
# Innervation
The larynx is innervated by branches of the vagus nerve (CN X) on each side. Sensory innervation to the glottis and supraglottis is by the internal branch of the superior laryngeal nerve. The external branch of the superior laryngeal nerve innervates the cricothyroid muscle. Motor innervation to all other muscles of the larynx and sensory innervation to the subglottis is by the recurrent laryngeal nerve.
Injury to the external laryngeal nerve causes weakened phonation because the vocal cords cannot be tightened. Injury to one of the recurrent laryngeal nerves produces hoarseness, if both are damaged the voice is completely lost and breathing becomes difficult.
# Muscles associated with the larynx
- Cricothyroid muscle lengthens and stretches the vocal cords.
- Posterior cricoarytenoid muscle abducts the vocal cords.
- Lateral cricoarytenoid muscle adducts the vocal cords.
- Thyroarytenoid muscle (also called vocalis muscle) shortens vocal cords.
- Transverse arytenoid muscle adducts the vocal folds.
Notably, the only muscle capable of separating the vocal cords for normal breathing is the posterior cricoarytenoid. If this muscle is incapacitated on both sides, the inability to pull the vocal cords apart (abduct) will cause difficulty breathing. Bilateral injury to the recurrent laryngeal nerve would cause this condition.
# Descended larynx
In most animals, including infant humans and apes, the larynx is situated very high in the throat — a position that allows it to couple more easily with the nasal passages, so that breathing and eating are not done with the same apparatus. However, some aquatic mammals, large deer, and adult humans have descended larynges. An adult human cannot raise the larynx enough to directly couple it to the nasal passage.
Some linguists have suggested that the descended larynx, by extending the length of the vocal tract and thereby increasing the variety of sounds humans could produce, was a critical element in the development of speech and language. Others cite the presence of descended larynges in non-linguistic animals, as well as the ubiquity of nonverbal communication and language among humans, as counterevidence against this claim.
# Disorders of the larynx
There are several things that can cause a larynx to not function properly. Some symptoms are hoarseness, loss of voice, pain in the throat or ears, and breathing difficulties.
- Acute laryngitis is the sudden inflammation and swelling of the larynx. It is caused by the common cold or by excessive shouting. It is not serious. Chronic laryngitis is caused by smoking, dust, frequent yelling, or prolonged exposure to polluted air. It is much more serious than acute laryngitis.
- Presbylarynx is a condition in which age-related atrophy of the soft tissues of the larynx results in weak voice and restricted vocal range and stamina. Bowing of the anterior portion of the vocal cords is found on laryngoscopy.
- Ulcers may be caused by the prolonged presence of an endotracheal tube.
- Polyps and nodules are small bumps on the vocal cords caused by prolonged exposure to cigarette smoke and vocal overuse, respectively.
- Two related types of cancer of the larynx, namely squamous cell carcinoma and verrucous carcinoma, are strongly associated with repeated exposure to cigarette smoke and alcohol.
- Vocal cord paresis is weakness of one or both vocal folds that can greatly impact daily life.
- The world's first successful larynx transplant took place in 1999 at the Cleveland Clinic. [1]
# Cartilages
The cartilages of the larynx are the thyroid, cricoid, arytenoids, corniculates, and the cuneiforms.
# Images
- Bronchi, bronchial tree, and lungs
- Larynx
- The ligaments of the larynx. Antero-lateral view.
- Sagittal section of the larynx and upper part of the trachea.
- Coronal section of larynx and upper part of trachea.
- The entrance to the larynx, viewed from behind.
- Laryngoscopic view of interior of larynx.
- Sagittal section of nose mouth, pharynx, and larynx.
- Endoscopic image of larynx seen at the time of intubation of the esophagus during gastroscopy. | https://www.wikidoc.org/index.php/Laryngeal | |
62f2d5a7308d0a8a8ec154096b5960ee593b44ed | wikidoc | Lectin | Lectin
Lectins are sugar-binding proteins which are highly specific for their sugar moieties. They typically play a role in biological recognition phenomena involving cells and proteins. For example, some bacteria use lectins to attach themselves to the cells of the host organism during infection.
# Etymology
The name ‘lectin’ is derived from the Latin word legere, meaning ‘to select’.
# History
Although they were first discovered more than 100 years ago in plants, they are now known to be present throughout nature.
It is generally believed that the earliest description of such a hemagglutinin was by Peter Hermann Stillmark in his doctoral thesis presented in 1888 to the University of Dorpat, (one of the oldest universities in czarist Russia). This hemagglutinin, which was also highly toxic, was isolated by Stillmark from seeds of the castor tree (Ricinus communis) and was named ricin.
# Biological functions
Most of the lectins are basically non-enzymic in action and non-immune in origin. Lectins occur ubiquitously in nature. They may bind to a soluble carbohydrate or to a carbohydrate moiety which is a part of a glycoprotein or glycolipid. They typically agglutinate certain animal cells and/or precipitate glycoconjugates.
## Function in animals
While the function of lectins in plants is believed to be the binding of glycoproteins on the surface of parasitic cells, their role in animals also includes the binding of soluble extracellular and intercellular glycoproteins.
For example, there are lectins found on the surface of mammalian liver cells that specifically recognize galactose residues. It is believed that these cell-surface receptors are responsible for the removal of certain glycoproteins from the circulatory system.
Another example is the mannose-6-phosphate receptor that recognizes hydrolytic enzymes containing this residue and subsequently targets these proteins for delivery to the lysosomes. (one defect in this particular system is known as I-cell disease.)
Lectins serve many different biological functions from the regulation of cell adhesion to glycoprotein synthesis and the control of protein levels in the blood.
Lectins are also known to play important roles in the immune system by recognizing carbohydrates that are found exclusively on pathogens, or that are inaccessible on host cells. Examples are the lectin complement activation pathway and Mannose binding lectin.
## Function in plants
The function of lectins in plants is still uncertain. Once thought to be necessary for rhizobia binding, this proposed function was ruled out through lectin-knockout transgene studies.
The large concentration of lectins in plant seeds decreases with growth, and suggests a role in plant germination and perhaps in the seed's survival itself.
# Use in science, medicine and technology
## Use in medicine and medical research
Purified lectins are important in a clinical setting because they are used for blood typing. Some of the glycolipids and glycoproteins on an individual's red blood cells can be identified by lectins.
- A lectin from Dolichos biflorus is used to identify cells that belong to the A1 blood group.
- A lectin from Ulex europaeus is used to identify the H blood group antigen.
- A lectin from Vicia graminea is used to identify the N blood group antigen.
PHA-L, a lectin from the kidney bean, is used by neuroscientists to trace the path of efferent axons. This usage is called the anterograde labeling method.
## Use in studying carbohydrate recognition by proteins
Lectins from legume plants, such as PHA or concanavalin A, have been widely used as model systems to understand the molecular basis of how proteins recognize carbohydrates, because they are relatively easy to obtain and have a wide variety of sugar specificities. The many crystal structures of legume lectins have led to a detailed insight of the atomic interactions between carbohydrates and proteins.
## Use in biochemical warfare
One example of the powerful biological attributes of lectins is the biochemical warfare agent ricin. Ricin is isolated from seeds of the castor oil plant and is a protein that comprises two domains,
- One is a lectin that binds cell surface galactosyl residues and enables the protein to enter cells.
- The second domain is an N-glycosidase that cleaves nucleobases from ribosomal RNA resulting in inhibition of protein synthesis and cell death. | Lectin
Lectins are sugar-binding proteins which are highly specific for their sugar moieties. They typically play a role in biological recognition phenomena involving cells and proteins. For example, some bacteria use lectins to attach themselves to the cells of the host organism during infection.
# Etymology
The name ‘lectin’ is derived from the Latin word legere, meaning ‘to select’.
# History
Although they were first discovered more than 100 years ago in plants, they are now known to be present throughout nature.
It is generally believed that the earliest description of such a hemagglutinin was by Peter Hermann Stillmark in his doctoral thesis presented in 1888 to the University of Dorpat, (one of the oldest universities in czarist Russia). This hemagglutinin, which was also highly toxic, was isolated by Stillmark from seeds of the castor tree (Ricinus communis) and was named ricin.
# Biological functions
Most of the lectins are basically non-enzymic in action and non-immune in origin. Lectins occur ubiquitously in nature. They may bind to a soluble carbohydrate or to a carbohydrate moiety which is a part of a glycoprotein or glycolipid. They typically agglutinate certain animal cells and/or precipitate glycoconjugates.
## Function in animals
While the function of lectins in plants is believed to be the binding of glycoproteins on the surface of parasitic cells, their role in animals also includes the binding of soluble extracellular and intercellular glycoproteins.
For example, there are lectins found on the surface of mammalian liver cells that specifically recognize galactose residues. It is believed that these cell-surface receptors are responsible for the removal of certain glycoproteins from the circulatory system.
Another example is the mannose-6-phosphate receptor that recognizes hydrolytic enzymes containing this residue and subsequently targets these proteins for delivery to the lysosomes. (one defect in this particular system is known as I-cell disease.)
Lectins serve many different biological functions from the regulation of cell adhesion to glycoprotein synthesis and the control of protein levels in the blood.
Lectins are also known to play important roles in the immune system by recognizing carbohydrates that are found exclusively on pathogens, or that are inaccessible on host cells. Examples are the lectin complement activation pathway and Mannose binding lectin.
## Function in plants
The function of lectins in plants is still uncertain. Once thought to be necessary for rhizobia binding, this proposed function was ruled out through lectin-knockout transgene studies.
The large concentration of lectins in plant seeds decreases with growth, and suggests a role in plant germination and perhaps in the seed's survival itself.
# Use in science, medicine and technology
## Use in medicine and medical research
Purified lectins are important in a clinical setting because they are used for blood typing. Some of the glycolipids and glycoproteins on an individual's red blood cells can be identified by lectins.
- A lectin from Dolichos biflorus is used to identify cells that belong to the A1 blood group.
- A lectin from Ulex europaeus is used to identify the H blood group antigen.
- A lectin from Vicia graminea is used to identify the N blood group antigen.
PHA-L, a lectin from the kidney bean, is used by neuroscientists to trace the path of efferent axons. This usage is called the anterograde labeling method.[1]
## Use in studying carbohydrate recognition by proteins
Lectins from legume plants, such as PHA or concanavalin A, have been widely used as model systems to understand the molecular basis of how proteins recognize carbohydrates, because they are relatively easy to obtain and have a wide variety of sugar specificities. The many crystal structures of legume lectins have led to a detailed insight of the atomic interactions between carbohydrates and proteins.
## Use in biochemical warfare
One example of the powerful biological attributes of lectins is the biochemical warfare agent ricin. Ricin is isolated from seeds of the castor oil plant and is a protein that comprises two domains,
- One is a lectin that binds cell surface galactosyl residues and enables the protein to enter cells.
- The second domain is an N-glycosidase that cleaves nucleobases from ribosomal RNA resulting in inhibition of protein synthesis and cell death. | https://www.wikidoc.org/index.php/Lectin | |
793ff70751721fea96814a946daa8d0aba9a990a | wikidoc | Lepton | Lepton
In physics, a lepton is a sub-atomic particle with spin of 1/2 that does not experience the strong interaction (that is, the strong nuclear force). The leptons form a family of fermions that are distinct from the other known family of fermions, the quarks.
# Properties of leptons
There are three known flavors of lepton: the electron, the muon, and the tau lepton or tau (or sometimes tauon). Each flavor is represented by a pair of particles called a weak doublet. One is a massive charged particle that bears the same name as its flavor (like the electron). The other is a nearly massless neutral particle called a neutrino (such as the electron neutrino). All six of these particles have corresponding antiparticles (such as the positron or the electron antineutrino). All known charged leptons have a single unit of negative or positive electric charge (depending on whether they are particles or antiparticles) and all of the neutrinos and antineutrinos have zero electric charge. The charged leptons have two possible spin states, while only one helicity is observed for the neutrinos (all the neutrinos are left-handed, and all the antineutrinos are right-handed).
The masses of the leptons also obey a simple relation, known as the Koide formula, but at present this relationship cannot be explained.
When particles interact, generally the number of leptons of the same type (electrons and electron neutrinos, muons and muon neutrinos, tau leptons and tau neutrinos) remains the same. This principle is known as conservation of lepton number. Conservation of the number of leptons of different flavors (for example, electron number or muon number) may sometimes be violated (as in neutrino oscillation). A much stronger conservation law is the total number of leptons of all flavors, which is violated by a tiny amount in the Standard Model by the so-called chiral anomaly.
The couplings of the leptons to gauge bosons are flavor-independent. This property is called lepton universality and has been tested in measurements of the tau and muon lifetimes and of Z-boson partial decay widths, particularly at the Stanford Linear Collider and Large Electron-Positron Collider(LEP) experiments.
# Table of the leptons
Note that the neutrino masses are known to be non-zero because of neutrino oscillation, but their masses are sufficiently light that they have not been measured directly as of 2008. However there have been measured (indirectly based on the oscillation periods) the differences of the mass squares between the neutrinos, which have been estimated
\Delta m^2_{12} = 80{meV}^2 and \Delta m^2_{23} \approx \Delta m^2_{13} = 2400{meV}^2. This leads to the following conclusions:
- Template:SubatomicParticle and Template:SubatomicParticle are lighter than 2.2 eV (as Template:SubatomicParticle is and the mass differences between the neutrinos are of order of millielectronvolts)
- one (or more) of the neutrinos is heavier than 0.040 eV
- two (or three) of the neutrinos are heavier than 0.008 eV
The names "mu" and "tau" seem to have been selected due to their places in the Greek alphabet; μ is seven letters after ε, whereas τ is seven letters after μ.
# Etymology
According to the Oxford English Dictionary, the name "lepton" (from Greek leptos meaning 'thin') was first used by physicist Léon Rosenfeld in 1948:
The name originates from before the discovery in the 1970s of the heavy tau lepton, which is nearly twice the mass of a proton. | Lepton
In physics, a lepton is a sub-atomic particle with spin of 1/2 that does not experience the strong interaction (that is, the strong nuclear force). The leptons form a family of fermions that are distinct from the other known family of fermions, the quarks.
# Properties of leptons
There are three known flavors of lepton: the electron, the muon, and the tau lepton or tau (or sometimes tauon). Each flavor is represented by a pair of particles called a weak doublet. One is a massive charged particle that bears the same name as its flavor (like the electron). The other is a nearly massless neutral particle called a neutrino (such as the electron neutrino). All six of these particles have corresponding antiparticles (such as the positron or the electron antineutrino). All known charged leptons have a single unit of negative or positive electric charge (depending on whether they are particles or antiparticles) and all of the neutrinos and antineutrinos have zero electric charge. The charged leptons have two possible spin states, while only one helicity is observed for the neutrinos (all the neutrinos are left-handed, and all the antineutrinos are right-handed).
The masses of the leptons also obey a simple relation, known as the Koide formula, but at present this relationship cannot be explained.
When particles interact, generally the number of leptons of the same type (electrons and electron neutrinos, muons and muon neutrinos, tau leptons and tau neutrinos) remains the same. This principle is known as conservation of lepton number. Conservation of the number of leptons of different flavors (for example, electron number or muon number) may sometimes be violated (as in neutrino oscillation). A much stronger conservation law is the total number of leptons of all flavors, which is violated by a tiny amount in the Standard Model by the so-called chiral anomaly.
The couplings of the leptons to gauge bosons are flavor-independent. This property is called lepton universality and has been tested in measurements of the tau and muon lifetimes and of Z-boson partial decay widths, particularly at the Stanford Linear Collider and Large Electron-Positron Collider(LEP) experiments.
# Table of the leptons
Note that the neutrino masses are known to be non-zero because of neutrino oscillation, but their masses are sufficiently light that they have not been measured directly as of 2008. However there have been measured (indirectly based on the oscillation periods) the differences of the mass squares between the neutrinos, which have been estimated
<math>\Delta m^2_{12} = 80{meV}^2</math> and <math>\Delta m^2_{23} \approx \Delta m^2_{13} = 2400{meV}^2</math>. This leads to the following conclusions:
- Template:SubatomicParticle and Template:SubatomicParticle are lighter than 2.2 eV (as Template:SubatomicParticle is and the mass differences between the neutrinos are of order of millielectronvolts)
- one (or more) of the neutrinos is heavier than 0.040 eV
- two (or three) of the neutrinos are heavier than 0.008 eV
The names "mu" and "tau" seem to have been selected due to their places in the Greek alphabet; μ is seven letters after ε, whereas τ is seven letters after μ.
# Etymology
According to the Oxford English Dictionary, the name "lepton" (from Greek leptos meaning 'thin') was first used by physicist Léon Rosenfeld in 1948:
The name originates from before the discovery in the 1970s of the heavy tau lepton, which is nearly twice the mass of a proton. | https://www.wikidoc.org/index.php/Lepton | |
b779946d21c85d0edb140954ca4bf6cda8b5d8d1 | wikidoc | Lesion | Lesion
# Overview
Lesion is derived from the Latin word "laesio" which means "injury."
A lesion is any abnormal tissue found on or in an organism, usually damaged by disease or trauma.
# Causes of lesions
Lesions are caused by any process that damages tissues. A cancerous tumor is an example of a lesion, however the surrounding tissue damaged by a tumour is also a lesion. Trauma, including electrocution and chemical burns cause lesions. Certain diseases present lesions, for example the skin deformities caused by chicken pox. Lesions can also be caused by metabolic processes, like an ulcer or autoimmune activity, as in the case with many forms of arthritis.
Lesions are sometimes intentionally inflicted during neurosurgery, such as the carefully-placed brain lesion used to treat epilepsy and other brain disorders.
Note that lesions are not limited to animals or humans; damaged plants are said to have lesions.
# Types of lesions
Because the definition of lesion is so broad, the varieties of lesions are virtually endless. They are subsequently classified by their features. If a lesion is caused by cancer it will be classified as malignant versus benign. They may be classified by the shape they form, as is the case with many ulcers which appear like as a bullseye or 'target'. Their size may be specified as gross or histologic depending on if they are visible to the unaided eye or if they require a microscope to see.
An additional classification that is sometimes used is based on whether or not a lesion occupies space. A space occupying lesion, as the name suggests, occupies space and may impinge on nearby structures, whereas a non space occupying lesion is simply a hole in the tissue, e.g. a small area of the brain that has turned to fluid following a stroke.
Some lesions have specialized names, like the Gohn lesions in the lungs of tuberculosis victims. The characteristic skin lesions of a varicella-zoster virus infection are called chickenpox. Lesion of the teeth are usually called dental caries.
Finally, they are often classified by their location. For example, compare a 'skin lesion' versus a 'brain lesion'. | Lesion
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Lesion is derived from the Latin word "laesio" which means "injury."
A lesion is any abnormal tissue found on or in an organism, usually damaged by disease or trauma.
# Causes of lesions
Lesions are caused by any process that damages tissues. A cancerous tumor is an example of a lesion, however the surrounding tissue damaged by a tumour is also a lesion. Trauma, including electrocution and chemical burns cause lesions. Certain diseases present lesions, for example the skin deformities caused by chicken pox. Lesions can also be caused by metabolic processes, like an ulcer or autoimmune activity, as in the case with many forms of arthritis.
Lesions are sometimes intentionally inflicted during neurosurgery, such as the carefully-placed brain lesion used to treat epilepsy and other brain disorders.
Note that lesions are not limited to animals or humans; damaged plants are said to have lesions.
# Types of lesions
Because the definition of lesion is so broad, the varieties of lesions are virtually endless. They are subsequently classified by their features. If a lesion is caused by cancer it will be classified as malignant versus benign. They may be classified by the shape they form, as is the case with many ulcers which appear like as a bullseye or 'target'. Their size may be specified as gross or histologic depending on if they are visible to the unaided eye or if they require a microscope to see.
An additional classification that is sometimes used is based on whether or not a lesion occupies space. A space occupying lesion, as the name suggests, occupies space and may impinge on nearby structures, whereas a non space occupying lesion is simply a hole in the tissue, e.g. a small area of the brain that has turned to fluid following a stroke.
Some lesions have specialized names, like the Gohn lesions in the lungs of tuberculosis victims. The characteristic skin lesions of a varicella-zoster virus infection are called chickenpox. Lesion of the teeth are usually called dental caries.
Finally, they are often classified by their location. For example, compare a 'skin lesion' versus a 'brain lesion'. | https://www.wikidoc.org/index.php/Lesion | |
a2ba7d5fc38fc51237acf657fcab5f87d354557d | wikidoc | Ligase | Ligase
# Overview
In biochemistry, a ligase (from the Latin verb ligāre — "to bind" or "to glue together") is an enzyme that can catalyse the joining of two large molecules by forming a new chemical bond, usually with accompanying hydrolysis of a small chemical group pendant to one of the larger molecules. Generally ligase catalyses the following reaction:
-r sometimes
where the lower case letters signify the small, pendant groups.
# Nomenclature
The common names of ligase enzymes often include the word "ligase", such as DNA ligase, an enzyme commonly used in molecular biology laboratories to join together DNA fragments. Other common names for ligases include synthetase, because they are used to synthesize new molecules, or carboxylase when they are used to add carbon dioxide to a molecule.
Note that "synthetase" should not be confused with synthases, as synthases do not use adenosine triphosphate and belong to the lyase group, while synthetases do use adenosine triphosphate (ATP).
# Classification
Ligases are classified as EC 6 in the EC number classification of enzymes. Ligases can be further classified into six subclasses:
- EC 6.1 includes ligases used to form carbon-oxygen bonds
- EC 6.2 includes ligases used to form carbon-sulfur bonds
- EC 6.3 includes ligases used to form carbon-nitrogen bonds (including argininosuccinate synthetase)
- EC 6.4 includes ligases used to form carbon-carbon bonds
- EC 6.5 includes ligases used to form phosphoric ester bonds
- EC 6.6 includes ligases used to form nitrogen-metal bonds | Ligase
# Overview
In biochemistry, a ligase (from the Latin verb ligāre — "to bind" or "to glue together") is an enzyme that can catalyse the joining of two large molecules by forming a new chemical bond, usually with accompanying hydrolysis of a small chemical group pendant to one of the larger molecules. Generally ligase catalyses the following reaction:
or sometimes
where the lower case letters signify the small, pendant groups.
# Nomenclature
The common names of ligase enzymes often include the word "ligase", such as DNA ligase, an enzyme commonly used in molecular biology laboratories to join together DNA fragments. Other common names for ligases include synthetase, because they are used to synthesize new molecules, or carboxylase when they are used to add carbon dioxide to a molecule.
Note that "synthetase" should not be confused with synthases, as synthases do not use adenosine triphosphate and belong to the lyase group, while synthetases do use adenosine triphosphate (ATP).
# Classification
Ligases are classified as EC 6 in the EC number classification of enzymes. Ligases can be further classified into six subclasses:
- EC 6.1 includes ligases used to form carbon-oxygen bonds
- EC 6.2 includes ligases used to form carbon-sulfur bonds
- EC 6.3 includes ligases used to form carbon-nitrogen bonds (including argininosuccinate synthetase)
- EC 6.4 includes ligases used to form carbon-carbon bonds
- EC 6.5 includes ligases used to form phosphoric ester bonds
- EC 6.6 includes ligases used to form nitrogen-metal bonds | https://www.wikidoc.org/index.php/Ligase | |
779c3a9df667ffc3e0dd4b3171079ca05a3dd2f5 | wikidoc | Lignin | Lignin
Lignin (sometimes "lignen") is a complex chemical compound most commonly derived from wood and an integral part of the cell walls of plants. The term was introduced in 1819 by de Candolle and is derived from the Latin word lignum, meaning wood. It is the most abundant organic polymer on Earth after cellulose, employing 30% of non-fossil organic carbon and constituting from a quarter to a third of the dry mass of wood. The compound has several unusual properties as a biopolymer, not least its heterogeneity in lacking a defined primary structure.
# Biological function
Lignin fills the spaces in the cell wall between cellulose, hemicellulose and pectin components, especially in tracheids, sclereids and xylem. It is covalently linked to hemicellulose and thereby crosslinks different plant polysaccharides, conferring mechanical strength to the cell wall and by extension the plant as a whole. It is particularly abundant in compression wood, but curiously scarce in tension wood.
Lignin plays a crucial part in conducting water in plant stems. The polysaccharide components of plant cell walls are highly hydrophilic and thus permeable to water, whereas lignin is more hydrophobic. The crosslinking of polysaccharides by lignin is an obstacle for water absorption to the cell wall. Thus, lignin makes it possible for the plant's vascular tissue to conduct water efficiently. Lignin is present in all vascular plants, but not in bryophytes, supporting the idea that the original function of lignin was restricted to water transport.
Lignin is indigestible by mammalian and other animal enzymes, but some fungi and bacteria are able to biodegrade the polymer. The details of the reaction scheme of the biodegradation are not fully understood to date. These reactions depend on the type of wood decay - in fungi either brown rot, soft rot or white rot. The enzymes involved may employ free radicals for depolymerization reactions. Well understood lignolytic enzymes are manganese peroxidase, lignin peroxidase and cellobiose dehydrogenase. Furthermore, because of its cross-linking with the other cell wall components, it minimizes the accessibility of cellulose and hemicellulose to microbial enzymes. Hence, lignin is generally associated with reduced digestibility of the over all plant biomass, which helps defend against pathogens and pests.
Lignin peroxidase (also "ligninase", EC number 1.14.99) is a hemoprotein from the white-rot fungus Phanerochaete chrysosporium with a variety of lignin-degrading reactions, all dependent on hydrogen peroxide to incorporate molecular oxygen into reaction products. There are also several other microbial enzymes that are believed to be involved in lignin biodegradation, such as manganese peroxidase, laccase and cellobiose dehydrogenase.
# Ecological function
Lignin plays a significant role in the carbon cycle, sequestering atmospheric carbon into the living tissues of woody perennial vegetation. Lignin is one of the most slowly decomposing components of dead vegetation, contributing a major fraction of the material that becomes humus as it decomposes. The resulting soil humus generally increases the photosynthetic productivity of plant communities growing on a site as the site transitions from disturbed mineral soil through the stages of ecological succession, by providing increased cation exchange capacity in the soil and expanding the capacity of moisture retention between flood and drought conditions.
# Economic significance
Highly lignified wood is durable and therefore a good raw material for many applications. It is also an excellent fuel, since lignin yields more energy when burned than cellulose. Mechanical, or high yield pulp used to make newsprint contains most of the lignin originally present in the wood. This lignin is responsible for newsprint yellowing with age. Lignin must be removed from the pulp before high quality bleached paper can be manufactured from it.
In sulfite pulping, lignin is removed from wood pulp as sulfonates. These lignosulfonates have several uses:
- Dispersants in high performance cement applications, water treatment formulations and textile dyes
- Additives in specialty oil field applications and agricultural chemicals
- Raw materials for several chemicals, such as vanillin, DMSO, ethanol, torula yeast, xylitol sugar and humic acid
- Environmentally sustainable dust suppression agent for roads
The first investigations into commercial use of lignin were done by Marathon Corporation in Rothschild, Wisconsin (USA), starting in 1927. The first class of products which showed promise were leather tanning agents. The lignin chemical business of Marathon was operated for many years as Marathon Chemicals. It is now known as LignoTech USA, Inc., and is owned by the Norwegian company, Borregaard, itself a subsidiary of the Norwegian conglomerate Orkla AS.
Lignin removed via the kraft process (sulfate pulping) is usually burned for its fuel value, providing more than enough energy to run the mill and its associated processes.
More recently, lignin extracted from shrubby willow has been successfully used to produce expanded polyurethane foam.
# Structure
Lignin is a large, cross-linked, racemic macromolecule with molecular masses in excess of 10,000u. It is relatively hydrophobic and aromatic in nature. The degree of polymerisation in nature is difficult to measure, since it is fragmented during extraction and the molecule consists of various types of substructures which appear to repeat in a haphazard manner. Different types of lignin have been described depending on the means of isolation.
There are three monolignol monomers, methoxylated to various degrees: p-coumaryl alcohol, coniferyl alcohol, and sinapyl alcohol (Figure 3). These are incorporated into lignin in the form of the phenylpropanoids p-hydroxyphenyl (H), guaiacyl (G), and syringal (S) respectively. Gymnosperms have a lignin that consists almost entirely of G with small quantities of H. That of Dicotyledonic angiosperms is more often than not a mixture of G and S (with very little H), and monocotyledonic lignin is a mixure of all three. Many grasses have mostly G, while some palms have mainly S. All lignins contain small amounts of incomplete or modified monolignols, and other monomers are prominent in non-woody plants.
# Biosynthesis
Lignin biosynthesis (Figure 4) begins in the cytosol with the synthesis of glycosylated monolignols from the amino acid phenylalanine. These first reactions are shared with the phenylpropanoid pathway. The attached glucose renders them water soluble and less toxic. Once transported through the cell membrane to the apoplast, the glucose is removed and the polymerisation commences. Much about its anabolism is not understood even after more than a century of study.
The polymerisation step, that is a radical-radical coupling, is catalysed by oxidative enzymes. Both peroxidase and laccase enzymes are present in the plant cell walls, and it is not known whether one or both of these groups participates in the polymerisation. Low molecular weight oxidants might also be involved. The oxidative enzyme catalyses the formation of monolignol radicals. These radicals are often said to undergo uncatalyzed coupling to form the lignin polymer, but this hypothesis has been recently challenged. The alternative theory that involves an unspecified biologial control is however not accepted by most scientist in the field.
# Pyrolysis
Pyrolysis of lignin during the combustion of wood or charcoal production yields a range of products, of which the most characteristic ones are methoxy phenols. Of those, the most important are guaiacol and syringol and their derivatives; their presence can be used to trace a smoke source to a wood fire. In cooking, lignin in the form of hardwood is an important source of these two chemicals which impart the characteristic aroma and taste to smoked foods. | Lignin
Lignin (sometimes "lignen") is a complex chemical compound most commonly derived from wood and an integral part of the cell walls of plants.[1] The term was introduced in 1819 by de Candolle and is derived from the Latin word lignum,[2] meaning wood. It is the most abundant organic polymer on Earth after cellulose, employing 30% of non-fossil organic carbon[3] and constituting from a quarter to a third of the dry mass of wood. The compound has several unusual properties as a biopolymer, not least its heterogeneity in lacking a defined primary structure.
# Biological function
Lignin fills the spaces in the cell wall between cellulose, hemicellulose and pectin components, especially in tracheids, sclereids and xylem. It is covalently linked to hemicellulose and thereby crosslinks different plant polysaccharides, conferring mechanical strength to the cell wall and by extension the plant as a whole.[4] It is particularly abundant in compression wood, but curiously scarce in tension wood.
Lignin plays a crucial part in conducting water in plant stems. The polysaccharide components of plant cell walls are highly hydrophilic and thus permeable to water, whereas lignin is more hydrophobic. The crosslinking of polysaccharides by lignin is an obstacle for water absorption to the cell wall. Thus, lignin makes it possible for the plant's vascular tissue to conduct water efficiently.[5] Lignin is present in all vascular plants, but not in bryophytes, supporting the idea that the original function of lignin was restricted to water transport.
Lignin is indigestible by mammalian and other animal enzymes, but some fungi and bacteria are able to biodegrade the polymer. The details of the reaction scheme of the biodegradation are not fully understood to date. These reactions depend on the type of wood decay - in fungi either brown rot, soft rot or white rot. The enzymes involved may employ free radicals for depolymerization reactions.[6] Well understood lignolytic enzymes are manganese peroxidase, lignin peroxidase and cellobiose dehydrogenase. Furthermore, because of its cross-linking with the other cell wall components, it minimizes the accessibility of cellulose and hemicellulose to microbial enzymes. Hence, lignin is generally associated with reduced digestibility of the over all plant biomass, which helps defend against pathogens and pests.[5]
Lignin peroxidase (also "ligninase", EC number 1.14.99) is a hemoprotein from the white-rot fungus Phanerochaete chrysosporium with a variety of lignin-degrading reactions, all dependent on hydrogen peroxide to incorporate molecular oxygen into reaction products. There are also several other microbial enzymes that are believed to be involved in lignin biodegradation, such as manganese peroxidase, laccase and cellobiose dehydrogenase.
# Ecological function
Lignin plays a significant role in the carbon cycle, sequestering atmospheric carbon into the living tissues of woody perennial vegetation. Lignin is one of the most slowly decomposing components of dead vegetation, contributing a major fraction of the material that becomes humus as it decomposes. The resulting soil humus generally increases the photosynthetic productivity of plant communities growing on a site as the site transitions from disturbed mineral soil through the stages of ecological succession, by providing increased cation exchange capacity in the soil and expanding the capacity of moisture retention between flood and drought conditions.
# Economic significance
Highly lignified wood is durable and therefore a good raw material for many applications. It is also an excellent fuel, since lignin yields more energy when burned than cellulose. Mechanical, or high yield pulp used to make newsprint contains most of the lignin originally present in the wood. This lignin is responsible for newsprint yellowing with age.[2] Lignin must be removed from the pulp before high quality bleached paper can be manufactured from it.
In sulfite pulping, lignin is removed from wood pulp as sulfonates. These lignosulfonates have several uses:[7]
- Dispersants in high performance cement applications, water treatment formulations and textile dyes
- Additives in specialty oil field applications and agricultural chemicals
- Raw materials for several chemicals, such as vanillin, DMSO, ethanol, torula yeast, xylitol sugar and humic acid
- Environmentally sustainable dust suppression agent for roads
The first investigations into commercial use of lignin were done by Marathon Corporation in Rothschild, Wisconsin (USA), starting in 1927. The first class of products which showed promise were leather tanning agents. The lignin chemical business of Marathon was operated for many years as Marathon Chemicals. It is now known as LignoTech USA, Inc., and is owned by the Norwegian company, Borregaard, itself a subsidiary of the Norwegian conglomerate Orkla AS.
Lignin removed via the kraft process (sulfate pulping) is usually burned for its fuel value, providing more than enough energy to run the mill and its associated processes.
More recently, lignin extracted from shrubby willow has been successfully used to produce expanded polyurethane foam. [8]
# Structure
Lignin is a large, cross-linked, racemic macromolecule with molecular masses in excess of 10,000u. It is relatively hydrophobic and aromatic in nature. The degree of polymerisation in nature is difficult to measure, since it is fragmented during extraction and the molecule consists of various types of substructures which appear to repeat in a haphazard manner. Different types of lignin have been described depending on the means of isolation.[9]
There are three monolignol monomers, methoxylated to various degrees: p-coumaryl alcohol, coniferyl alcohol, and sinapyl alcohol[10] (Figure 3). These are incorporated into lignin in the form of the phenylpropanoids p-hydroxyphenyl (H), guaiacyl (G), and syringal (S) respectively.[3] Gymnosperms have a lignin that consists almost entirely of G with small quantities of H. That of Dicotyledonic angiosperms is more often than not a mixture of G and S (with very little H), and monocotyledonic lignin is a mixure of all three.[3] Many grasses have mostly G, while some palms have mainly S.[citation needed] All lignins contain small amounts of incomplete or modified monolignols, and other monomers are prominent in non-woody plants.[11]
# Biosynthesis
Lignin biosynthesis (Figure 4) begins in the cytosol with the synthesis of glycosylated monolignols from the amino acid phenylalanine. These first reactions are shared with the phenylpropanoid pathway. The attached glucose renders them water soluble and less toxic. Once transported through the cell membrane to the apoplast, the glucose is removed and the polymerisation commences.[citation needed] Much about its anabolism is not understood even after more than a century of study.[3]
The polymerisation step, that is a radical-radical coupling, is catalysed by oxidative enzymes. Both peroxidase and laccase enzymes are present in the plant cell walls, and it is not known whether one or both of these groups participates in the polymerisation. Low molecular weight oxidants might also be involved. The oxidative enzyme catalyses the formation of monolignol radicals. These radicals are often said to undergo uncatalyzed coupling to form the lignin polymer, but this hypothesis has been recently challenged.[12] The alternative theory that involves an unspecified biologial control is however not accepted by most scientist in the field.
# Pyrolysis
Pyrolysis of lignin during the combustion of wood or charcoal production yields a range of products, of which the most characteristic ones are methoxy phenols. Of those, the most important are guaiacol and syringol and their derivatives; their presence can be used to trace a smoke source to a wood fire. In cooking, lignin in the form of hardwood is an important source of these two chemicals which impart the characteristic aroma and taste to smoked foods. | https://www.wikidoc.org/index.php/Lignin | |
ce43aed15801e31f4f99110b85de8446ee002ca6 | wikidoc | Liquid | Liquid
# Overview
Liquid is one of the four principal states of matter. A liquid is a fluid that can freely form a distinct surface at the boundaries of its bulk material. The surface is a free surface where the liquid is not constrained by a container.
# Characteristics
A liquid's shape is confined to, not determined by, the container it fills. That is to say, liquid particles (normally molecules or clusters of molecules) are free to move within the volume, but they form a discrete surface that may not necessarily be the same as the vessel. The same cannot be said about a gas; it can also be considered a fluid, but it must conform to the shape of the container entirely. In liquid, the particles slide past each other and they move fast.
At a temperature below the boiling point, a liquid will evaporate until, if in a closed container, the concentration of the vapors belonging to the liquid reach an equilibrium partial pressure in the gas. Therefore no liquid can exist permanently in a complete vacuum. The surface of the liquid behaves as an elastic membrane in which surface tension appears, allowing the formation of drops and bubbles. Capillarity is another consequence of surface tension. Only liquids can display immiscibility. The most familiar mixture of two immiscible liquids in everyday life are the vegetable oil and water in Italian salad dressing. A familiar set of miscible liquids are water and alcohol. Only liquids display wetting properties. Liquids at their respective boiling point change to gases (except when superheating occurs), and at their freezing points, change to solids (except when supercooling occurs). Even below the boiling point liquid evaporates on the surface. Objects immersed in liquids are subject to the phenomenon of buoyancy, which is also observed in other fluids, but is especially strong in liquids due to their high density. Liquid components in a mixture can often be separated from one another via fractional distillation.
The volume of a quantity of liquid is fixed by its temperature and pressure. Unless this volume exactly matches the volume of the container, a surface is observed. Liquids in a gravitational field, like all fluids, exert pressure on the sides of a container as well as on anything within the liquid itself. This pressure is transmitted in all directions and increases with depth. In the study of fluid dynamics, liquids are often treated as incompressible, especially when studying incompressible flow.
If a liquid is at rest in a uniform gravitational field, the pressure \ p at any point is given by
where:
Note that this formula assumes that the pressure at the free surface is zero, and that surface tension effects may be neglected.
Liquids generally expand when heated, and contract when cooled. Water between 0 °C and 4 °C is a notable exception; this is why ice floats. Liquids have little compressibility : water, for example, does not change its density appreciably unless subject to pressure of the order of hundreds bar.
Examples of everyday liquids besides water are mineral oil and gasoline. There are also mixtures such as milk, blood, and a wide variety of aqueous solutions such as household bleach. Only six elements are liquid at room temperature and pressure: bromine, mercury, francium, cesium, gallium and rubidium. In terms of planetary habitability, liquid water is required for the existence of life.
# Liquid measures
Quantities of liquids are commonly measured in units of volume. These include the litre, not an SI unit, and the cubic metre (m³) which is an SI unit. | Liquid
# Overview
Liquid is one of the four principal states of matter. A liquid is a fluid that can freely form a distinct surface at the boundaries of its bulk material. The surface is a free surface where the liquid is not constrained by a container.[1]
# Characteristics
A liquid's shape is confined to, not determined by, the container it fills. That is to say, liquid particles (normally molecules or clusters of molecules) are free to move within the volume, but they form a discrete surface that may not necessarily be the same as the vessel. The same cannot be said about a gas; it can also be considered a fluid, but it must conform to the shape of the container entirely. In liquid, the particles slide past each other and they move fast.
At a temperature below the boiling point, a liquid will evaporate until, if in a closed container, the concentration of the vapors belonging to the liquid reach an equilibrium partial pressure in the gas. Therefore no liquid can exist permanently in a complete vacuum. The surface of the liquid behaves as an elastic membrane in which surface tension appears, allowing the formation of drops and bubbles. Capillarity is another consequence of surface tension. Only liquids can display immiscibility. The most familiar mixture of two immiscible liquids in everyday life are the vegetable oil and water in Italian salad dressing. A familiar set of miscible liquids are water and alcohol. Only liquids display wetting properties. Liquids at their respective boiling point change to gases (except when superheating occurs), and at their freezing points, change to solids (except when supercooling occurs). Even below the boiling point liquid evaporates on the surface. Objects immersed in liquids are subject to the phenomenon of buoyancy, which is also observed in other fluids, but is especially strong in liquids due to their high density. Liquid components in a mixture can often be separated from one another via fractional distillation.
The volume of a quantity of liquid is fixed by its temperature and pressure. Unless this volume exactly matches the volume of the container, a surface is observed. Liquids in a gravitational field, like all fluids, exert pressure on the sides of a container as well as on anything within the liquid itself. This pressure is transmitted in all directions and increases with depth. In the study of fluid dynamics, liquids are often treated as incompressible, especially when studying incompressible flow.
If a liquid is at rest in a uniform gravitational field, the pressure <math>\ p</math> at any point is given by
where:
Note that this formula assumes that the pressure at the free surface is zero, and that surface tension effects may be neglected.
Liquids generally expand when heated, and contract when cooled. Water between 0 °C and 4 °C is a notable exception; this is why ice floats. Liquids have little compressibility : water, for example, does not change its density appreciably unless subject to pressure of the order of hundreds bar.
Examples of everyday liquids besides water are mineral oil and gasoline. There are also mixtures such as milk, blood, and a wide variety of aqueous solutions such as household bleach. Only six elements are liquid at room temperature and pressure: bromine, mercury, francium, cesium, gallium and rubidium.[2] In terms of planetary habitability, liquid water is required for the existence of life.
# Liquid measures
Quantities of liquids are commonly measured in units of volume. These include the litre, not an SI unit, and the cubic metre (m³) which is an SI unit. | https://www.wikidoc.org/index.php/Liquid | |
3cc5c0f89a6540d66f2592396e042b97bd7f01c6 | wikidoc | Lochia | Lochia
# Overview
In the field of obstetrics, lochia is post-partum vaginal discharge, containing blood, mucus, and placental tissue. Lochia discharge typically continues for 4 to 6 weeks after childbirth and progresses through three stages.
# Types of Lochia
Lochia rubra is the first discharge, red in color because of the large amount of blood it contains. It typically lasts no longer than 3 to 5 days after birth.
Lochia serosa is the term for lochia which has thinned and turned brownish or pink in color. It contains serous exudate, erythrocytes, leukocytes, and cervical mucus. This stage continues until around the tenth day after delivery.
Lochia alba is the name for lochia once it has turned whitish or yellowish-white. It typically lasts from the second through the third to sixth week after delivery. It contains fewer red blood cells and is mainly made up of leukocytes, epithelial cells, cholesterol, fat, and mucus.
# Characteristics
Lochia generally has an odor similar to that of normal menstrual fluid. Any offensive odor indicates a possible infection and should be reported to a healthcare provider.
de:Wochenfluss | Lochia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In the field of obstetrics, lochia is post-partum vaginal discharge, containing blood, mucus, and placental tissue. Lochia discharge typically continues for 4 to 6 weeks after childbirth and progresses through three stages.
# Types of Lochia
Lochia rubra is the first discharge, red in color because of the large amount of blood it contains. It typically lasts no longer than 3 to 5 days after birth.
Lochia serosa is the term for lochia which has thinned and turned brownish or pink in color. It contains serous exudate, erythrocytes, leukocytes, and cervical mucus. This stage continues until around the tenth day after delivery.
Lochia alba is the name for lochia once it has turned whitish or yellowish-white. It typically lasts from the second through the third to sixth week after delivery. It contains fewer red blood cells and is mainly made up of leukocytes, epithelial cells, cholesterol, fat, and mucus.
# Characteristics
Lochia generally has an odor similar to that of normal menstrual fluid. Any offensive odor indicates a possible infection and should be reported to a healthcare provider.
Template:WH
Template:WS
de:Wochenfluss | https://www.wikidoc.org/index.php/Lochia | |
77b7cc3907fda168b4775e1e9f55ced5ef68049a | wikidoc | Lortab | Lortab
Hydrocodone/paracetamol (also known as hydrocodone/acetaminophen) is a combination of two analgesic products hydrocodone and paracetamol (acetaminophen) used to relieve moderate to severe pain. It is usually found in tablet form, produced and marketed under the trade names Vicodin, Vicodin ES, Vicodin HP, Anexsia, Anolor DH5, Bancap HC, Zydone, Dolacet, Lorcet, Lortab, and Norco, as well as generic brands. Hydrocodone also comes in a combination with ibuprofen, available under the trade name Vicoprofen.
# Medical uses
Hydrocodone/paracetamol, like other opioid analgesics, is used to manage pain. It is most commonly prescribed for relief of moderate to moderately severe pain of acute, chronic, or post-operative types.
## Formulations
Hydrocodone/paracetamol is made as a mixture of hydrocodone and paracetamol. Paracetamol acts as an analgesic/antipyretic. Hydrocodone is a semi-synthetic opioid analgesic.
## Pregnancy
This drug is classified under pregnancy category C. Although not enough research has been done to deem this drug safe for pregnant women, if taken in the time before delivery, it may give rise to respiratory depression in the baby. Mothers using any opioids regularly during pregnancy run the risk of their babies being substance-dependent and, therefore, going through withdrawal symptoms after birth. Withdrawal symptoms include excessive crying, vomiting, irritability, tremors, and fever. Nursing mothers should not use this drug, as paracetamol is transferred through breast milk; it is unknown whether hydrocodone is.
# Adverse effects
Side-effects of hydrocodone/paracetamol are most commonly upset stomach, nausea, and altered mental status (e.g., dizziness, light headedness). Other rarer side-effects include allergic reaction, seizures, clammy skin, paranoia, hallucinations, severe weakness, dizziness, hyperventilation, unconsciousness, jaundice (yellowing of eyes or skin), unusual fatigue, bleeding, bruising, stomach pain, constipation, dry mouth, decreased appetite, muscle twitches, sweating, hot flashes, itching, tinnitus, hearing loss, decreased urination and altered sex drive. Vicodin also has depressant effects on the central nervous system, which may cause irritability. However, some of the less mundane effects can be desirable effects that are sought after by some. Those effects include euphoria and drowsiness, as well as slowing of the pulse.
Unlike NSAIDs, paracetamol does not cause ulcers. However, paracetamol can cause liver damage, and, thus, dosages should never exceed 4000 mg a day; this is especially important and will be a smaller number of doses when using mixed drugs like Vicodin. It is imperative that users of this drug follow physician-prescribed dosages. Liver damage can manifest, ranging from abdominal pain to outright liver failure, and can necessitate a liver transplant to avoid death.
# Pharmacodynamics
Besides the activity of hydrocodone and acetaminophen on their own, there is observed a factor of analgesia related to the two substances in tandem that is not altogether understood, but this independent synergy has been observed to be related to the inhibition of prostaglandins. The pharmacodynamics of a mixed drug such as Vicodin depends on the kinetics of the drugs that comprise it.
Hydrocodone: Acts at μ-opioid receptors. Hydrocodone is metabolized to hydromorphone by the activity of cytochrome P450 2D6. Cytochrome 3A4 forms the substrate norhydrocodone. Note that this conversion is only somewhat responsible for the effects of hydrocodone. Hydrocodone passes through the blood–brain barrier (BBB) because of its modifications. The brain is typically where the analgesic effects are being carried out. Many of the side-effects of this drug are caused by the fact that it so readily crosses the blood–brain barrier. The half-life of hydrocodone is approximately 3.8 hrs.
Paracetamol: The major active metabolites are sulphates and glucuronide conjugates. Its main mode of action is to inhibit the activity of the enzyme cyclooxygenase (COX). COX enzymes are necessary for the production of prostaglandins. Prostaglandins are a form of hormone (although rarely classified as such) that are indicated to be mediators of pain, fever, and inflammation. The half-life of paracetamol may be measured either by salivary or by plasma counts. Both measurements give a varying half-life between 1 and 4 hours. Peak levels are reached between 40–60 minutes after ingestion. It has been proposed that paracetamol aids in the reduction of pain by increasing serotonergic neurotransmissions. Paracetamol is a peripherally acting drug, and hence does not cross the BBB as readily as hydrocodone.
# Society and culture
## Manufacture
The principal constituent of Vicodin, hydrocodone, has the same basic structure as morphine but is metabolized by different enzymes. There are three variations of Vicodin, with different amounts of hydrocodone in each. Hydrocodone, like oxycodone, is an intermediate-strength analgesic that has similar effects as morphine; hydrocodone is approximately twice as potent as morphine by mouth for acute use. The tablets are made with less hydrocodone than paracetamol. The theory of using the mix comes from the idea that these drugs alleviate pain using different mechanisms and also that the adverse side-effects of each separate drug are reduced by using reduced dosages of both drugs in order to get the same analgesic effect.
Both hydrocodone and acetaminophen are white crystalline powders, which are then manufactured into tablet form. Manufacturers of hydrocodone (generic or otherwise) include Abbott Laboratories (makers of trademark Vicodin), Amerisource Health Services Corp, Cardinal Health, Drx Pharmaceutical Consultants Inc, Eckerd Corp, Hospira Inc, Mallinckrodt Pharm. Quality Care, Pdrx Pharmaceuticals Inc, Physicians Total Care Inc, Rx Papoo
s Packaging Inc, and Watson Pharmaceuticals.
On January 13, 2011, FDA announced that it is asking manufacturers of prescription acetaminophen combination products to limit the maximum amount of acetaminophen in these products to 325 mg per tablet, capsule, or other dosage unit. FDA believes that limiting the amount of acetaminophen per tablet, capsule, or other dosage unit in prescription products will reduce the risk of severe liver injury from acetaminophen overdosing, an adverse event that can lead to liver failure, liver transplant, and death.
## Legal status
In the United States, Vicodin production is regulated in part by the Controlled Substances Act of 1970. This guarantees that all manufacturing, importing, possession, and distribution of drugs are to be overseen and regulated by the federal government.
In the U.S. Vicodin is a Schedule III drug. Pure codeine and hydrocodone are Schedule II drugs, but, when compounded with paracetamol or with an NSAID, they can become a Schedule III drug. Schedule III drugs are classified by the U.S. government as having the potential to cause moderate or low physical dependence, or a high psychological dependence if misused.
### United States
To qualify for treatment as a Schedule III medication in the United States, hydrocodone must be combined with a non-narcotic ingredient in a recognized therapeutic amount. There are four dosage forms recognized by the U.S. authorities:
- per 100 ml (i.e., a liquid), which must have no more than 300 mg of (dissolved) hydrocodone in addition to the therapeutic amount of a non-narcotic ingredient
- per dosage unit (i.e., a solid, pill or capsule), which must have no more than 15 mg of hydrocodone in addition to the therapeutic amount of a non-narcotic ingredient
## Proposed U.S. ban
On June 30, 2009, a U.S. Food and Drug Administration (FDA) advisory panel voted by a narrow margin to advise the FDA to remove Vicodin and another painkiller, Percocet, from the market because of "a high likelihood of overdose from prescription narcotics and acetaminophen products".
The panel cited concerns of liver damage from their acetaminophen component, which is also the main ingredient in commonly-used nonprescription drugs such as Tylenol.
Each year, acetaminophen overdose is linked to about 400 deaths and 42,000 hospitalizations.
The U.S. Food and Drug Administration is asking manufacturers of prescription combination products that contain acetaminophen to limit the amount of acetaminophen to no more than 325 milligrams (mg) in each tablet or capsule. Manufacturers will have three years to limit the amount of acetaminophen in their prescription drug products to 325 mg per dosage unit. The FDA also is requiring manufacturers to update labels of all prescription combination acetaminophen products to warn of the potential risk for severe liver injury.
Hydrocodone, the narcotic component of Vicodin, is still available in Canada as a single drug and marketed under the trade name Hycodan in syrup and tablet forms by Bristol-Myers-Squibb.
## Popular media
The central character on the popular American television medical drama House habitually uses (and abuses) Vicodin to manage pain stemming from an infarction in his quadriceps muscle incurred some years earlier.
Vicodin is referenced in multiple songs by rapper Eminem such as "Kill You", "Under the Influence", "Deja Vu", "Old Time's Sake", "Underground", "Going Through Changes", "Oh No", and "Cocaine". He also featured a Vicodin pill on the CD of his debut album The Slim Shady LP. The rapper has admitted to an addiction to the painkiller (along with other substances), the hiatus in rapping that it caused, and the subsequent rehabilitation required to return to his career. | Lortab
Hydrocodone/paracetamol (also known as hydrocodone/acetaminophen) is a combination of two analgesic products hydrocodone and paracetamol (acetaminophen) used to relieve moderate to severe pain.[1] It is usually found in tablet form, produced and marketed under the trade names Vicodin, Vicodin ES, Vicodin HP, Anexsia, Anolor DH5, Bancap HC, Zydone, Dolacet, Lorcet, Lortab, and Norco, as well as generic brands. Hydrocodone also comes in a combination with ibuprofen, available under the trade name Vicoprofen.
# Medical uses
Hydrocodone/paracetamol, like other opioid analgesics, is used to manage pain. It is most commonly prescribed for relief of moderate to moderately severe pain of acute, chronic, or post-operative types.
## Formulations
Hydrocodone/paracetamol is made as a mixture of hydrocodone and paracetamol. Paracetamol acts as an analgesic/antipyretic. Hydrocodone is a semi-synthetic opioid analgesic.
## Pregnancy
This drug is classified under pregnancy category C. Although not enough research has been done to deem this drug safe for pregnant women, if taken in the time before delivery, it may give rise to respiratory depression in the baby. Mothers using any opioids regularly during pregnancy run the risk of their babies being substance-dependent and, therefore, going through withdrawal symptoms after birth. Withdrawal symptoms include excessive crying, vomiting, irritability, tremors, and fever. Nursing mothers should not use this drug, as paracetamol is transferred through breast milk; it is unknown whether hydrocodone is.[2]
# Adverse effects
Side-effects of hydrocodone/paracetamol are most commonly upset stomach, nausea, and altered mental status (e.g., dizziness, light headedness). Other rarer side-effects include allergic reaction, seizures, clammy skin, paranoia, hallucinations, severe weakness, dizziness, hyperventilation, unconsciousness, jaundice (yellowing of eyes or skin), unusual fatigue, bleeding, bruising, stomach pain,[3] constipation, dry mouth, decreased appetite, muscle twitches, sweating, hot flashes, itching, tinnitus, hearing loss, decreased urination and altered sex drive. Vicodin also has depressant effects on the central nervous system, which may cause irritability. However, some of the less mundane effects can be desirable effects that are sought after by some. Those effects include euphoria and drowsiness, as well as slowing of the pulse.
Unlike NSAIDs, paracetamol does not cause ulcers. However, paracetamol can cause liver damage, and, thus, dosages should never exceed 4000 mg a day; this is especially important and will be a smaller number of doses when using mixed drugs like Vicodin. It is imperative that users of this drug follow physician-prescribed dosages. Liver damage can manifest, ranging from abdominal pain to outright liver failure, and can necessitate a liver transplant to avoid death.
# Pharmacodynamics
Besides the activity of hydrocodone and acetaminophen on their own, there is observed a factor of analgesia related to the two substances in tandem[citation needed] that is not altogether understood, but this independent synergy has been observed to be related to the inhibition of prostaglandins. The pharmacodynamics of a mixed drug such as Vicodin depends on the kinetics of the drugs that comprise it.
Hydrocodone: Acts at μ-opioid receptors.[4] Hydrocodone is metabolized to hydromorphone by the activity of cytochrome P450 2D6. Cytochrome 3A4 forms the substrate norhydrocodone. Note that this conversion is only somewhat responsible for the effects of hydrocodone.[5] Hydrocodone passes through the blood–brain barrier (BBB) because of its modifications. The brain is typically where the analgesic effects are being carried out. Many of the side-effects of this drug are caused by the fact that it so readily crosses the blood–brain barrier. The half-life of hydrocodone is approximately 3.8 hrs.
Paracetamol: The major active metabolites are sulphates and glucuronide conjugates. Its main mode of action is to inhibit the activity of the enzyme cyclooxygenase (COX). COX enzymes are necessary for the production of prostaglandins. Prostaglandins are a form of hormone (although rarely classified as such) that are indicated to be mediators of pain, fever, and inflammation. The half-life of paracetamol may be measured either by salivary or by plasma counts. Both measurements give a varying half-life between 1 and 4 hours.[6] Peak levels are reached between 40–60 minutes after ingestion. It has been proposed that paracetamol aids in the reduction of pain by increasing serotonergic neurotransmissions.[7] Paracetamol is a peripherally acting drug, and hence does not cross the BBB as readily as hydrocodone.[citation needed]
# Society and culture
## Manufacture
The principal constituent of Vicodin, hydrocodone, has the same basic structure as morphine but is metabolized by different enzymes. There are three variations of Vicodin, with different amounts of hydrocodone in each. Hydrocodone, like oxycodone, is an intermediate-strength analgesic that has similar effects as morphine; hydrocodone is approximately twice as potent as morphine by mouth for acute use. The tablets are made with less hydrocodone than paracetamol. The theory of using the mix comes from the idea that these drugs alleviate pain using different mechanisms and also that the adverse side-effects of each separate drug are reduced by using reduced dosages of both drugs in order to get the same analgesic effect.[8]
Both hydrocodone and acetaminophen are white crystalline powders, which are then manufactured into tablet form. Manufacturers of hydrocodone (generic or otherwise) include Abbott Laboratories (makers of trademark Vicodin), Amerisource Health Services Corp, Cardinal Health, Drx Pharmaceutical Consultants Inc, Eckerd Corp, Hospira Inc, Mallinckrodt Pharm. Quality Care, Pdrx Pharmaceuticals Inc, Physicians Total Care Inc, Rx Papoo
s Packaging Inc, and Watson Pharmaceuticals.
On January 13, 2011, FDA announced that it is asking manufacturers of prescription acetaminophen combination products to limit the maximum amount of acetaminophen in these products to 325 mg per tablet, capsule, or other dosage unit. FDA believes that limiting the amount of acetaminophen per tablet, capsule, or other dosage unit in prescription products will reduce the risk of severe liver injury from acetaminophen overdosing, an adverse event that can lead to liver failure, liver transplant, and death.[9]
## Legal status
In the United States, Vicodin production is regulated in part by the Controlled Substances Act of 1970. This guarantees that all manufacturing, importing, possession, and distribution of drugs are to be overseen and regulated by the federal government.
In the U.S. Vicodin is a Schedule III drug. Pure codeine and hydrocodone are Schedule II drugs, but, when compounded with paracetamol or with an NSAID, they can become a Schedule III drug. Schedule III drugs are classified by the U.S. government as having the potential to cause moderate or low physical dependence, or a high psychological dependence if misused.
### United States
To qualify for treatment as a Schedule III medication in the United States, hydrocodone must be combined with a non-narcotic ingredient in a recognized therapeutic amount. There are four dosage forms recognized by the U.S. authorities:
- per 100 ml (i.e., a liquid), which must have no more than 300 mg of (dissolved) hydrocodone in addition to the therapeutic amount of a non-narcotic ingredient
- per dosage unit (i.e., a solid, pill or capsule), which must have no more than 15 mg of hydrocodone in addition to the therapeutic amount of a non-narcotic ingredient
## Proposed U.S. ban
On June 30, 2009, a U.S. Food and Drug Administration (FDA) advisory panel voted by a narrow margin to advise the FDA to remove Vicodin and another painkiller, Percocet, from the market because of "a high likelihood of overdose from prescription narcotics and acetaminophen products".
The panel cited concerns of liver damage from their acetaminophen component, which is also the main ingredient in commonly-used nonprescription drugs such as Tylenol.[10]
Each year, acetaminophen overdose is linked to about 400 deaths and 42,000 hospitalizations.[11]
The U.S. Food and Drug Administration is asking manufacturers of prescription combination products that contain acetaminophen to limit the amount of acetaminophen to no more than 325 milligrams (mg) in each tablet or capsule.[12][13][14][15] Manufacturers will have three years to limit the amount of acetaminophen in their prescription drug products to 325 mg per dosage unit.[13][15] The FDA also is requiring manufacturers to update labels of all prescription combination acetaminophen products to warn of the potential risk for severe liver injury.[12][13][15]
Hydrocodone, the narcotic component of Vicodin, is still available in Canada as a single drug and marketed under the trade name Hycodan in syrup and tablet forms by Bristol-Myers-Squibb.[16]
## Popular media
The central character on the popular American television medical drama House habitually uses (and abuses) Vicodin to manage pain stemming from an infarction in his quadriceps muscle incurred some years earlier.
Vicodin is referenced in multiple songs by rapper Eminem such as "Kill You", "Under the Influence", "Deja Vu", "Old Time's Sake", "Underground", "Going Through Changes", "Oh No", and "Cocaine". He also featured a Vicodin pill on the CD of his debut album The Slim Shady LP. The rapper has admitted to an addiction to the painkiller (along with other substances), the hiatus in rapping that it caused, and the subsequent rehabilitation required to return to his career.[17] | https://www.wikidoc.org/index.php/Lortab | |
12e348d1679ab28e4adf7f690af797cf53903559 | wikidoc | Lovaza | Lovaza
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Lovaza is a combination of ethyl esters of omega 3 fatty acids, principally EPA and DHA that is FDA approved for the {{{indicationType}}} of hypertriglyceridemia. Common adverse reactions include eructation, dyspepsia, and taste perversion.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- LOVAZA® (omega-3-acid ethyl esters) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia (HTG).
- Dosing Information
- Assess triglyceride levels carefully before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, medications) of high triglyceride levels and manage as appropriate.
- Patients should be placed on an appropriate lipid-lowering diet before receiving LOVAZA, and should continue this diet during treatment with LOVAZA. In clinical studies, LOVAZA was administered with meals.
- The daily dose of LOVAZA is 4 grams per day. The daily dose may be taken as a single 4-gram dose (4 capsules) or as two 2-gram doses (2 capsules given twice daily).
- Patients should be advised to swallow LOVAZA capsules whole. Do not break open, crush, dissolve, or chew LOVAZA.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lovaza in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Omega-3 PUFA 2 g twice daily.
- Dosing Information
- Omega-3-acid ethyl esters (4 g/day).
- Dosing Information
- Long-term treatment with omega-3 polyunsaturated fatty acids (PUFA) 1 g daily.
- Dosing Information
- Omega-3-acid ethyl esters (P-OM3) 4 g/day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lovaza in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lovaza in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lovaza in pediatric patients.
# Contraindications
- LOVAZA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to LOVAZA or any of its components.
# Warnings
### Precautions
- Monitoring: Laboratory Tests
- In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with LOVAZA. In some patients, increases in ALT levels without a concurrent increase in AST levels were observed.
- In some patients, LOVAZA increases LDL-C levels. LDL-C levels should be monitored periodically during therapy with LOVAZA.
- Laboratory studies should be performed periodically to measure the patient’s TG levels during therapy with LOVAZA.
- Fish Allergy
- LOVAZA contains ethyl esters of omega-3 fatty acids (EPA and DHA) obtained from the oil of several fish sources. It is not known whether patients with allergies to fish and/or shellfish, are at increased risk of an allergic reaction to LOVAZA. LOVAZA should be used with caution in patients with known hypersensitivity to fish and/or shellfish.
- Recurrent Atrial Fibrillation (AF) or Flutter
- In a double-blind, placebo-controlled trial of 663 subjects with symptomatic paroxysmal AF (n = 542) or persistent AF (n = 121), recurrent AF or flutter was observed in subjects randomized to LOVAZA who received 8 grams/day for 7 days and 4 grams/day thereafter for 23 weeks at a higher rate relative to placebo. Subjects in this trial had median baseline triglycerides of 127 mg/dL, had no substantial structural heart disease, were taking no anti-arrhythmic therapy (rate control permitted), and were in normal sinus rhythm at baseline.
- At 24 weeks, in the paroxysmal AF stratum, there were 129 (47%) first recurrent symptomatic AF or flutter events on placebo and 141 (53%) on LOVAZA . In the persistent AF stratum, there were 19 (35%) events on placebo and 34 (52%) events on LOVAZA . For both strata combined, the HR was 1.25; 95% CI: 1.00, 1.40. Although the clinical significance of these results is uncertain, there is a possible association between LOVAZA and more frequent recurrences of symptomatic atrial fibrillation or flutter in patients with paroxysmal or persistent atrial fibrillation, particularly within the first 2 to 3 months of initiating therapy.
- LOVAZA is not indicated for the treatment of AF or flutter.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adverse reactions reported in at least 3% and at a greater rate than placebo for subjects treated with LOVAZA based on pooled data across 23 clinical trials are listed in Table 1.
- Additional adverse reactions from clinical trials are listed below:
Constipation, gastrointestinal disorder and vomiting.
Increased ALT and increased AST.
Pruritus and rash.
## Postmarketing Experience
- In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of LOVAZA. Because these events are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or to always establish a causal relationship to drug exposure.
- The following events have been reported: anaphylactic reaction, hemorrhagic diathesis.
# Drug Interactions
- Anticoagulants or Other Drugs Affecting Coagulation
- Some trials with omega-3-acids demonstrated prolongation of bleeding time. The prolongation of bleeding time reported in these trials has not exceeded normal limits and did not produce clinically significant bleeding episodes. Clinical trials have not been done to thoroughly examine the effect of LOVAZA and concomitant anticoagulants. Patients receiving treatment with LOVAZA and an anticoagulant or other drug affecting coagulation (e.g., anti-platelet agents) should be monitored periodically.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. It is unknown whether LOVAZA can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. LOVAZA should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.
- Omega-3-acid ethyl esters have been shown to have an embryocidal effect in pregnant rats when given in doses resulting in exposures 7 times the recommended human dose of 4 grams/day based on a body surface area comparison.
- In female rats given oral gavage doses of 100, 600, and 2,000 mg/kg/day beginning 2 weeks prior to mating and continuing through gestation and lactation, no adverse effects were observed in the high-dose group (5 times human systemic exposure following an oral dose of 4 grams/day based on body surface area comparison).
- In pregnant rats given oral gavage doses of 1,000, 3,000, and 6,000 mg/kg/day from gestation day 6 through 15, no adverse effects were observed (14 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).
- In pregnant rats given oral gavage doses of 100, 600, and 2,000 mg/kg/day from gestation day 14 through lactation day 21, no adverse effects were seen at 2,000 mg/kg/day (5 times the human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison). However, decreased live births (20% reduction) and decreased survival to postnatal day 4 (40% reduction) were observed in a dose-ranging study using higher doses of 3,000 mg/kg/day (7 times the human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).
- In pregnant rabbits given oral gavage doses of 375, 750, and 1,500 mg/kg/day from gestation day 7 through 19, no findings were observed in the fetuses in groups given 375 mg/kg/day (2 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison). However, at higher doses, evidence of maternal toxicity was observed (4 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lovaza in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lovaza during labor and delivery.
### Nursing Mothers
- Studies with omega-3-acid ethyl esters have demonstrated excretion in human milk. The effect of this excretion on the infant of a nursing mother is unknown; caution should be exercised when LOVAZA is administered to a nursing mother. An animal study in lactating rats given oral gavage 14C-ethyl EPA demonstrated that drug levels were 6 to 14 times higher in milk than in plasma.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- A limited number of subjects older than 65 years were enrolled in the clinical trials of LOVAZA. Safety and efficacy findings in subjects older than 60 years did not appear to differ from those of subjects younger than 60 years.
### Gender
There is no FDA guidance on the use of Lovaza with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lovaza with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Lovaza in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Lovaza in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lovaza in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lovaza in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Lovaza in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Lovaza in the drug label.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Lovaza in the drug label.
# Pharmacology
There is limited information regarding Lovaza Pharmacology in the drug label.
## Mechanism of Action
- The mechanism of action of LOVAZA is not completely understood. Potential mechanisms of action include inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase, increased mitochondrial and peroxisomal β-oxidation in the liver, decreased lipogenesis in the liver, and increased plasma lipoprotein lipase activity. LOVAZA may reduce the synthesis of triglycerides in the liver because EPA and DHA are poor substrates for the enzymes responsible for TG synthesis, and EPA and DHA inhibit esterification of other fatty acids.
## Structure
- LOVAZA, a lipid-regulating agent, is supplied as a liquid-filled gel capsule for oral administration. Each 1-gram capsule of LOVAZA contains at least 900 mg of the ethyl esters of omega-3 fatty acids sourced from fish oils. These are predominantly a combination of ethyl esters of eicosapentaenoic acid (EPA - approximately 465 mg) and docosahexaenoic acid (DHA - approximately 375 mg).
- The empirical formula of EPA ethyl ester is C22H34O2, and the molecular weight of EPA ethyl ester is 330.51. The structural formula of EPA ethyl ester is:
- The empirical formula of DHA ethyl ester is C24H36O2, and the molecular weight of DHA ethyl ester is 356.55. The structural formula of DHA ethyl ester is:
- LOVAZA capsules also contain the following inactive ingredients: 4 mg α-tocopherol (in a carrier of soybean oil), and gelatin, glycerol, and purified water (components of the capsule shell).
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Lovaza in the drug label.
## Pharmacokinetics
- In healthy volunteers and in subjects with hypertriglyceridemia, EPA and DHA were absorbed when administered as ethyl esters orally. Omega-3-acids administered as ethyl esters (LOVAZA) induced significant, dose-dependent increases in serum phospholipid EPA content, though increases in DHA content were less marked and not dose-dependent when administered as ethyl esters.
- Specific Populations:
- Age:
- Uptake of EPA and DHA into serum phospholipids in subjects treated with LOVAZA was independent of age (<49 years versus ≥49 years).
- Gender:
- Females tended to have more uptake of EPA into serum phospholipids than males. The clinical significance of this is unknown.
- Pediatric:
- Pharmacokinetics of LOVAZA have not been studied.
- Renal or Hepatic Impairment:
- LOVAZA has not been studied in patients with renal or hepatic impairment.
- Drug-Drug Interactions:
- Simvastatin:
- In a 14-day trial of 24 healthy adult subjects, daily coadministration of simvastatin 80 mg with LOVAZA 4 grams did not affect the extent (AUC) or rate (Cmax) of exposure to simvastatin or the major active metabolite, beta-hydroxy simvastatin at steady state.
- Atorvastatin:
- In a 14-day trial of 50 healthy adult subjects, daily coadministration of atorvastatin 80 mg with LOVAZA 4 grams did not affect AUC or Cmax of exposure to atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin at steady state.
- Rosuvastatin:
- In a 14-day trial of 48 healthy adult subjects, daily coadministration of rosuvastatin 40 mg with LOVAZA 4 grams did not affect AUC or Cmax of exposure to rosuvastatin at steady state.
- In vitro studies using human liver microsomes indicated that clinically significant cytochrome P450-mediated inhibition by EPA/DHA combinations are not expected in humans.
## Nonclinical Toxicology
- In a rat carcinogenicity study with oral gavage doses of 100, 600, and 2,000 mg/kg/day, males were treated with omega-3-acid ethyl esters for 101 weeks and females for 89 weeks without an increased incidence of tumors (up to 5 times human systemic exposures following an oral dose of 4 grams/day based on a body surface area comparison). Standard lifetime carcinogenicity bioassays were not conducted in mice.
- Omega-3-acid ethyl esters were not mutagenic or clastogenic with or without metabolic activation in the bacterial mutagenesis (Ames) test with Salmonella typhimurium and Escherichia coli or in the chromosomal aberration assay in Chinese hamster V79 lung cells or human lymphocytes. Omega-3-acid ethyl esters were negative in the in vivo mouse micronucleus assay.
- In a rat fertility study with oral gavage doses of 100, 600, and 2,000 mg/kg/day, males were treated for 10 weeks prior to mating and females were treated for 2 weeks prior to and throughout mating, gestation, and lactation. No adverse effect on fertility was observed at 2,000 mg/kg/day (5 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).
# Clinical Studies
- The effects of LOVAZA 4 grams per day were assessed in 2 randomized, placebo-controlled, double-blind, parallel-group trials of 84 adult subjects (42 on LOVAZA, 42 on placebo) with very high triglyceride levels. Subjects whose baseline triglyceride levels were between 500 and 2,000 mg/dL were enrolled in these 2 trials of 6 and 16 weeks’ duration. The median triglyceride and LDL-C levels in these subjects were 792 mg/dL and 100 mg/dL, respectively. Median HDL-C level was 23.0 mg/dL.
- The changes in the major lipoprotein lipid parameters for the groups receiving LOVAZA or placebo are shown in Table 2.
- BL = Baseline (mg/dL); % Change = Median Percent Change from Baseline; Difference = LOVAZA Median % Change – Placebo Median % Change.
- LOVAZA 4 grams per day reduced median TG, VLDL-C, and non-HDL-C levels and increased median HDL-C from baseline relative to placebo. Treatment with LOVAZA to reduce very high TG levels may result in elevations in LDL-C and non-HDL-C in some individuals. Patients should be monitored to ensure that the LDL-C level does not increase excessively.
- The effect of LOVAZA on the risk of pancreatitis has not been determined.
- The effect of LOVAZA on cardiovascular mortality and morbidity has not been determined.
# How Supplied
- LOVAZA (omega-3-acid ethyl esters) capsules are supplied as 1-gram, transparent, soft-gelatin capsules filled with light-yellow oil and bearing the designation LOVAZA.
- Bottles of 120: NDC 0173-0783-02.
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Do not freeze. Keep out of reach of children.
## Storage
There is limited information regarding Lovaza Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- LOVAZA should be used with caution in patients with known sensitivity or allergy to fish and/or shellfish.
- Advise patients that use of lipid-regulating agents does not reduce the importance of adhering to diet.
- Advise patients not to alter LOVAZA capsules in any way and to ingest intact capsules only.
- Instruct patients to take LOVAZA as prescribed. If a dose is missed, advise patients to take it as soon as they remember. However, if they miss one day of LOVAZA, they should not double the dose when they take it.
# Precautions with Alcohol
- Alcohol-Lovaza interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- LOVAZA®
# Look-Alike Drug Names
- Lovaza® — LORazepam®
- Omacor® — Amicar®
# Drug Shortage Status
# Price | Lovaza
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Lovaza is a combination of ethyl esters of omega 3 fatty acids, principally EPA and DHA that is FDA approved for the {{{indicationType}}} of hypertriglyceridemia. Common adverse reactions include eructation, dyspepsia, and taste perversion.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- LOVAZA® (omega-3-acid ethyl esters) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia (HTG).
- Dosing Information
- Assess triglyceride levels carefully before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, medications) of high triglyceride levels and manage as appropriate.
- Patients should be placed on an appropriate lipid-lowering diet before receiving LOVAZA, and should continue this diet during treatment with LOVAZA. In clinical studies, LOVAZA was administered with meals.
- The daily dose of LOVAZA is 4 grams per day. The daily dose may be taken as a single 4-gram dose (4 capsules) or as two 2-gram doses (2 capsules given twice daily).
- Patients should be advised to swallow LOVAZA capsules whole. Do not break open, crush, dissolve, or chew LOVAZA.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lovaza in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Omega-3 PUFA 2 g twice daily.
- Dosing Information
- Omega-3-acid ethyl esters (4 g/day).
- Dosing Information
- Long-term treatment with omega-3 polyunsaturated fatty acids (PUFA) 1 g daily.
- Dosing Information
- Omega-3-acid ethyl esters (P-OM3) 4 g/day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lovaza in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lovaza in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lovaza in pediatric patients.
# Contraindications
- LOVAZA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to LOVAZA or any of its components.
# Warnings
### Precautions
- Monitoring: Laboratory Tests
- In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with LOVAZA. In some patients, increases in ALT levels without a concurrent increase in AST levels were observed.
- In some patients, LOVAZA increases LDL-C levels. LDL-C levels should be monitored periodically during therapy with LOVAZA.
- Laboratory studies should be performed periodically to measure the patient’s TG levels during therapy with LOVAZA.
- Fish Allergy
- LOVAZA contains ethyl esters of omega-3 fatty acids (EPA and DHA) obtained from the oil of several fish sources. It is not known whether patients with allergies to fish and/or shellfish, are at increased risk of an allergic reaction to LOVAZA. LOVAZA should be used with caution in patients with known hypersensitivity to fish and/or shellfish.
- Recurrent Atrial Fibrillation (AF) or Flutter
- In a double-blind, placebo-controlled trial of 663 subjects with symptomatic paroxysmal AF (n = 542) or persistent AF (n = 121), recurrent AF or flutter was observed in subjects randomized to LOVAZA who received 8 grams/day for 7 days and 4 grams/day thereafter for 23 weeks at a higher rate relative to placebo. Subjects in this trial had median baseline triglycerides of 127 mg/dL, had no substantial structural heart disease, were taking no anti-arrhythmic therapy (rate control permitted), and were in normal sinus rhythm at baseline.
- At 24 weeks, in the paroxysmal AF stratum, there were 129 (47%) first recurrent symptomatic AF or flutter events on placebo and 141 (53%) on LOVAZA [primary endpoint, HR 1.19; 95% CI: 0.93, 1.35]. In the persistent AF stratum, there were 19 (35%) events on placebo and 34 (52%) events on LOVAZA [HR 1.63; 95% CI: 0.91, 2.18]. For both strata combined, the HR was 1.25; 95% CI: 1.00, 1.40. Although the clinical significance of these results is uncertain, there is a possible association between LOVAZA and more frequent recurrences of symptomatic atrial fibrillation or flutter in patients with paroxysmal or persistent atrial fibrillation, particularly within the first 2 to 3 months of initiating therapy.
- LOVAZA is not indicated for the treatment of AF or flutter.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adverse reactions reported in at least 3% and at a greater rate than placebo for subjects treated with LOVAZA based on pooled data across 23 clinical trials are listed in Table 1.
- Additional adverse reactions from clinical trials are listed below:
Constipation, gastrointestinal disorder and vomiting.
Increased ALT and increased AST.
Pruritus and rash.
## Postmarketing Experience
- In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of LOVAZA. Because these events are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or to always establish a causal relationship to drug exposure.
- The following events have been reported: anaphylactic reaction, hemorrhagic diathesis.
# Drug Interactions
- Anticoagulants or Other Drugs Affecting Coagulation
- Some trials with omega-3-acids demonstrated prolongation of bleeding time. The prolongation of bleeding time reported in these trials has not exceeded normal limits and did not produce clinically significant bleeding episodes. Clinical trials have not been done to thoroughly examine the effect of LOVAZA and concomitant anticoagulants. Patients receiving treatment with LOVAZA and an anticoagulant or other drug affecting coagulation (e.g., anti-platelet agents) should be monitored periodically.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. It is unknown whether LOVAZA can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. LOVAZA should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.
- Omega-3-acid ethyl esters have been shown to have an embryocidal effect in pregnant rats when given in doses resulting in exposures 7 times the recommended human dose of 4 grams/day based on a body surface area comparison.
- In female rats given oral gavage doses of 100, 600, and 2,000 mg/kg/day beginning 2 weeks prior to mating and continuing through gestation and lactation, no adverse effects were observed in the high-dose group (5 times human systemic exposure following an oral dose of 4 grams/day based on body surface area comparison).
- In pregnant rats given oral gavage doses of 1,000, 3,000, and 6,000 mg/kg/day from gestation day 6 through 15, no adverse effects were observed (14 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).
- In pregnant rats given oral gavage doses of 100, 600, and 2,000 mg/kg/day from gestation day 14 through lactation day 21, no adverse effects were seen at 2,000 mg/kg/day (5 times the human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison). However, decreased live births (20% reduction) and decreased survival to postnatal day 4 (40% reduction) were observed in a dose-ranging study using higher doses of 3,000 mg/kg/day (7 times the human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).
- In pregnant rabbits given oral gavage doses of 375, 750, and 1,500 mg/kg/day from gestation day 7 through 19, no findings were observed in the fetuses in groups given 375 mg/kg/day (2 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison). However, at higher doses, evidence of maternal toxicity was observed (4 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lovaza in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lovaza during labor and delivery.
### Nursing Mothers
- Studies with omega-3-acid ethyl esters have demonstrated excretion in human milk. The effect of this excretion on the infant of a nursing mother is unknown; caution should be exercised when LOVAZA is administered to a nursing mother. An animal study in lactating rats given oral gavage 14C-ethyl EPA demonstrated that drug levels were 6 to 14 times higher in milk than in plasma.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- A limited number of subjects older than 65 years were enrolled in the clinical trials of LOVAZA. Safety and efficacy findings in subjects older than 60 years did not appear to differ from those of subjects younger than 60 years.
### Gender
There is no FDA guidance on the use of Lovaza with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lovaza with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Lovaza in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Lovaza in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lovaza in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lovaza in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Lovaza in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Lovaza in the drug label.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Lovaza in the drug label.
# Pharmacology
There is limited information regarding Lovaza Pharmacology in the drug label.
## Mechanism of Action
- The mechanism of action of LOVAZA is not completely understood. Potential mechanisms of action include inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase, increased mitochondrial and peroxisomal β-oxidation in the liver, decreased lipogenesis in the liver, and increased plasma lipoprotein lipase activity. LOVAZA may reduce the synthesis of triglycerides in the liver because EPA and DHA are poor substrates for the enzymes responsible for TG synthesis, and EPA and DHA inhibit esterification of other fatty acids.
## Structure
- LOVAZA, a lipid-regulating agent, is supplied as a liquid-filled gel capsule for oral administration. Each 1-gram capsule of LOVAZA contains at least 900 mg of the ethyl esters of omega-3 fatty acids sourced from fish oils. These are predominantly a combination of ethyl esters of eicosapentaenoic acid (EPA - approximately 465 mg) and docosahexaenoic acid (DHA - approximately 375 mg).
- The empirical formula of EPA ethyl ester is C22H34O2, and the molecular weight of EPA ethyl ester is 330.51. The structural formula of EPA ethyl ester is:
- The empirical formula of DHA ethyl ester is C24H36O2, and the molecular weight of DHA ethyl ester is 356.55. The structural formula of DHA ethyl ester is:
- LOVAZA capsules also contain the following inactive ingredients: 4 mg α-tocopherol (in a carrier of soybean oil), and gelatin, glycerol, and purified water (components of the capsule shell).
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Lovaza in the drug label.
## Pharmacokinetics
- In healthy volunteers and in subjects with hypertriglyceridemia, EPA and DHA were absorbed when administered as ethyl esters orally. Omega-3-acids administered as ethyl esters (LOVAZA) induced significant, dose-dependent increases in serum phospholipid EPA content, though increases in DHA content were less marked and not dose-dependent when administered as ethyl esters.
- Specific Populations:
- Age:
- Uptake of EPA and DHA into serum phospholipids in subjects treated with LOVAZA was independent of age (<49 years versus ≥49 years).
- Gender:
- Females tended to have more uptake of EPA into serum phospholipids than males. The clinical significance of this is unknown.
- Pediatric:
- Pharmacokinetics of LOVAZA have not been studied.
- Renal or Hepatic Impairment:
- LOVAZA has not been studied in patients with renal or hepatic impairment.
- Drug-Drug Interactions:
- Simvastatin:
- In a 14-day trial of 24 healthy adult subjects, daily coadministration of simvastatin 80 mg with LOVAZA 4 grams did not affect the extent (AUC) or rate (Cmax) of exposure to simvastatin or the major active metabolite, beta-hydroxy simvastatin at steady state.
- Atorvastatin:
- In a 14-day trial of 50 healthy adult subjects, daily coadministration of atorvastatin 80 mg with LOVAZA 4 grams did not affect AUC or Cmax of exposure to atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin at steady state.
- Rosuvastatin:
- In a 14-day trial of 48 healthy adult subjects, daily coadministration of rosuvastatin 40 mg with LOVAZA 4 grams did not affect AUC or Cmax of exposure to rosuvastatin at steady state.
- In vitro studies using human liver microsomes indicated that clinically significant cytochrome P450-mediated inhibition by EPA/DHA combinations are not expected in humans.
## Nonclinical Toxicology
- In a rat carcinogenicity study with oral gavage doses of 100, 600, and 2,000 mg/kg/day, males were treated with omega-3-acid ethyl esters for 101 weeks and females for 89 weeks without an increased incidence of tumors (up to 5 times human systemic exposures following an oral dose of 4 grams/day based on a body surface area comparison). Standard lifetime carcinogenicity bioassays were not conducted in mice.
- Omega-3-acid ethyl esters were not mutagenic or clastogenic with or without metabolic activation in the bacterial mutagenesis (Ames) test with Salmonella typhimurium and Escherichia coli or in the chromosomal aberration assay in Chinese hamster V79 lung cells or human lymphocytes. Omega-3-acid ethyl esters were negative in the in vivo mouse micronucleus assay.
- In a rat fertility study with oral gavage doses of 100, 600, and 2,000 mg/kg/day, males were treated for 10 weeks prior to mating and females were treated for 2 weeks prior to and throughout mating, gestation, and lactation. No adverse effect on fertility was observed at 2,000 mg/kg/day (5 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).
# Clinical Studies
- The effects of LOVAZA 4 grams per day were assessed in 2 randomized, placebo-controlled, double-blind, parallel-group trials of 84 adult subjects (42 on LOVAZA, 42 on placebo) with very high triglyceride levels. Subjects whose baseline triglyceride levels were between 500 and 2,000 mg/dL were enrolled in these 2 trials of 6 and 16 weeks’ duration. The median triglyceride and LDL-C levels in these subjects were 792 mg/dL and 100 mg/dL, respectively. Median HDL-C level was 23.0 mg/dL.
- The changes in the major lipoprotein lipid parameters for the groups receiving LOVAZA or placebo are shown in Table 2.
- BL = Baseline (mg/dL); % Change = Median Percent Change from Baseline; Difference = LOVAZA Median % Change – Placebo Median % Change.
- LOVAZA 4 grams per day reduced median TG, VLDL-C, and non-HDL-C levels and increased median HDL-C from baseline relative to placebo. Treatment with LOVAZA to reduce very high TG levels may result in elevations in LDL-C and non-HDL-C in some individuals. Patients should be monitored to ensure that the LDL-C level does not increase excessively.
- The effect of LOVAZA on the risk of pancreatitis has not been determined.
- The effect of LOVAZA on cardiovascular mortality and morbidity has not been determined.
# How Supplied
- LOVAZA (omega-3-acid ethyl esters) capsules are supplied as 1-gram, transparent, soft-gelatin capsules filled with light-yellow oil and bearing the designation LOVAZA.
- Bottles of 120: NDC 0173-0783-02.
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Do not freeze. Keep out of reach of children.
## Storage
There is limited information regarding Lovaza Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- LOVAZA should be used with caution in patients with known sensitivity or allergy to fish and/or shellfish.
- Advise patients that use of lipid-regulating agents does not reduce the importance of adhering to diet.
- Advise patients not to alter LOVAZA capsules in any way and to ingest intact capsules only.
- Instruct patients to take LOVAZA as prescribed. If a dose is missed, advise patients to take it as soon as they remember. However, if they miss one day of LOVAZA, they should not double the dose when they take it.
# Precautions with Alcohol
- Alcohol-Lovaza interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- LOVAZA®[1]
# Look-Alike Drug Names
- Lovaza® — LORazepam®[2]
- Omacor® — Amicar®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Lovaza | |
79f23838d0c303050c2251fd5b33f465fa52b3e6 | wikidoc | Lunate | Lunate
The lunate bone (semilunar bone) is a bone in the human hand that may be distinguished by its deep concavity and crescentic outline. It is situated in the center of the proximal row of the carpus, or wrist, between the scaphoid and triangular bone.
The etymology derives from the Latin luna which means "moon."
# Surfaces
The superior surface, convex and smooth, articulates with the radius.
The inferior surface is deeply concave, and of greater extent from before backward than transversely: it articulates with the head of the capitate, and, by a long, narrow facet (separated by a ridge from the general surface), with the hamate.
The dorsal and palmar surfaces are rough, for the attachment of ligaments, the former being the broader, and of a somewhat rounded form.
The lateral surface presents a narrow, flattened, semilunar facet for articulation with the scaphoid.
The medial surface is marked by a smooth, quadrilateral facet, for articulation with the triangular bone. | Lunate
Template:Infobox Bone
The lunate bone (semilunar bone) is a bone in the human hand that may be distinguished by its deep concavity and crescentic outline. It is situated in the center of the proximal row of the carpus, or wrist, between the scaphoid and triangular bone.
The etymology derives from the Latin luna which means "moon."
# Surfaces
The superior surface, convex and smooth, articulates with the radius.
The inferior surface is deeply concave, and of greater extent from before backward than transversely: it articulates with the head of the capitate, and, by a long, narrow facet (separated by a ridge from the general surface), with the hamate.
The dorsal and palmar surfaces are rough, for the attachment of ligaments, the former being the broader, and of a somewhat rounded form.
The lateral surface presents a narrow, flattened, semilunar facet for articulation with the scaphoid.
The medial surface is marked by a smooth, quadrilateral facet, for articulation with the triangular bone. | https://www.wikidoc.org/index.php/Lunate | |
4622320f88c8a2015e78806256e543b256307eb9 | wikidoc | Lutein | Lutein
Lutein (LOO-teen) (from Latin lutea meaning "yellow") is one of over 600 known naturally occurring carotenoids. Found in green leafy vegetables such as spinach and kale, lutein is employed by organisms as an antioxidant and for blue light absorption. Lutein is covalently bound to one or more fatty acids present in some fruits and flowers, notably marigolds (Tagetes). Saponification of lutein esters yields lutein in approximately a 2:1 weight-to-weight conversion.
Lutein is a lipophilic molecule and is generally insoluble in water. The presence of the long chromophore of conjugated double bonds (polyene chain) provides the distinctive light-absorbing properties. The polyene chain is susceptible to oxidative degradation by light or heat and is chemically unstable in acids.
The principal natural stereoisomer of lutein is
(3R,3'R,6'R)-beta, epsilon-Carotene-3,3'-diol.
# As a pigment
This xanthophyll, like its sister compound zeaxanthin, has primarily been used as a natural colorant due to its orange-red color. Lutein absorbs blue light and therefore appears yellow at low concentrations and orange-red at high concentrations.
Lutein was traditionally used in chicken feed to provide the yellow color of broiler chicken skin. Polled consumers viewed yellow chicken skin more favorably than white chicken skin. Such lutein fortification also results in a darker yellow egg yolk. Today the coloring of the egg yolk has become the primary reason for feed fortification. Lutein is not used as a colorant in other foods due to its limited stability, especially in the presence of other dyes.
# Role in human eyes
Lutein was found to be present in a concentrated area of the macula, a small area of the retina responsible for central vision. The hypothesis for the natural concentration is that lutein helps protect from oxidative stress and high-energy light. Various research studies have shown that a direct relationship exists between lutein intake and pigmentation in the eye . Several studies also show that an increase in macula pigmentation decreases the risk for eye diseases such as Age-related Macular Degeneration (AMD) . The only randomized clinical trial to demonstrate a benefit for lutein in Macular Degeneration was a small study, in which the authors concluded that more study was needed.
Lutein is a natural part of human diet when fruits and vegetables are consumed. For individuals lacking sufficient lutein intake, lutein-fortified foods are available, or in the case of elderly people with a poorly absorbing digestive system, a sublingual spray is available. As early as 1996, lutein has been incorporated into dietary supplements. While no recommended daily allowance currently exists for lutein as for other nutrients, positive effects have been seen at dietary intake levels of 6 mg/day Template:Ref N. The only definitive side effect of excess lutein consumption is bronzing of the skin (carotenodermia).
The functional difference between lutein (free form) and lutein esters is not entirely known. It is suggested that the bioavailability is lower for lutein esters, but much debate continues.
As a food additive, lutein has the E number E161b.
On September 10, 2007, in a 6-year study, researchers, led by John Paul SanGiovanni of the National Eye Institute, Maryland found that Lutein and zeaxanthin (nutrients in eggs, spinach and other green vegetables) protect against blindness (macular degeneration), affecting 1.2 million Americans, mostly after age 65. Lutein and zeaxanthin reduce the risk of AMD (journal Archives of Ophthalmology). Foods considered good sources of the nutrients also include kale, turnip greens, collard greens, romaine lettuce, broccoli, zucchini, corn, garden peas and Brussels sprouts.
# Commercial value
The Lutein market is segmented into Pharmaceutical, Nutraceutical, Food, Pet Foods and Animal Feed and Fish Feed. The Pharmaceutical market is estimated to be about US $ 190 Million, Nutraceutical and Food is estimated to be about US $ 110 Million. Pet foods and other applications are estimated at US $ 175 Million annually. Apart from the customary Age related Macular Degeneration applications , newer applications are emerging in Cosmetics, Skin Care and as an Antioxidant. It is one of the fastest growing areas of the $ 2 Billion carotenoid market Template:Ref N. There are several lutein ester suppliers, but few pure lutein (Free Form) suppliers due primarily to patent protections on obtaining purified Lutein from natural products, namely marigolds. Companies like Indus Biotech Pvt. Ltd, OmniActive Health Technologies and Kemin Industries have patents. The market size of lutein is anticipated to grow at an average annual growth rate of over 22%. | Lutein
Lutein (LOO-teen) (from Latin lutea meaning "yellow") is one of over 600 known naturally occurring carotenoids. Found in green leafy vegetables such as spinach and kale, lutein is employed by organisms as an antioxidant and for blue light absorption. Lutein is covalently bound to one or more fatty acids present in some fruits and flowers, notably marigolds (Tagetes). Saponification of lutein esters yields lutein in approximately a 2:1 weight-to-weight conversion.
Lutein is a lipophilic molecule and is generally insoluble in water. The presence of the long chromophore of conjugated double bonds (polyene chain) provides the distinctive light-absorbing properties. The polyene chain is susceptible to oxidative degradation by light or heat and is chemically unstable in acids.
The principal natural stereoisomer of lutein is
(3R,3'R,6'R)-beta, epsilon-Carotene-3,3'-diol.
# As a pigment
This xanthophyll, like its sister compound zeaxanthin, has primarily been used as a natural colorant due to its orange-red color. Lutein absorbs blue light and therefore appears yellow at low concentrations and orange-red at high concentrations.
Lutein was traditionally used in chicken feed to provide the yellow color of broiler chicken skin. Polled consumers viewed yellow chicken skin more favorably than white chicken skin. Such lutein fortification also results in a darker yellow egg yolk. Today the coloring of the egg yolk has become the primary reason for feed fortification. Lutein is not used as a colorant in other foods due to its limited stability, especially in the presence of other dyes.
# Role in human eyes
Lutein was found to be present in a concentrated area of the macula, a small area of the retina responsible for central vision. The hypothesis for the natural concentration is that lutein helps protect from oxidative stress and high-energy light. Various research studies have shown that a direct relationship exists between lutein intake and pigmentation in the eye [1-7]. Several studies also show that an increase in macula pigmentation decreases the risk for eye diseases such as Age-related Macular Degeneration (AMD) [8-10]. The only randomized clinical trial to demonstrate a benefit for lutein in Macular Degeneration was a small study, in which the authors concluded that more study was needed.[9]
Lutein is a natural part of human diet when fruits and vegetables are consumed. For individuals lacking sufficient lutein intake, lutein-fortified foods are available, or in the case of elderly people with a poorly absorbing digestive system, a sublingual spray is available. As early as 1996, lutein has been incorporated into dietary supplements. While no recommended daily allowance currently exists for lutein as for other nutrients, positive effects have been seen at dietary intake levels of 6 mg/day Template:Ref N. The only definitive side effect of excess lutein consumption is bronzing of the skin (carotenodermia).
The functional difference between lutein (free form) and lutein esters is not entirely known. It is suggested that the bioavailability is lower for lutein esters, but much debate continues.
As a food additive, lutein has the E number E161b.
On September 10, 2007, in a 6-year study, researchers, led by John Paul SanGiovanni of the National Eye Institute, Maryland found that Lutein and zeaxanthin (nutrients in eggs, spinach and other green vegetables) protect against blindness (macular degeneration), affecting 1.2 million Americans, mostly after age 65. Lutein and zeaxanthin reduce the risk of AMD (journal Archives of Ophthalmology). Foods considered good sources of the nutrients also include kale, turnip greens, collard greens, romaine lettuce, broccoli, zucchini, corn, garden peas and Brussels sprouts.[1]
# Commercial value
The Lutein market is segmented into Pharmaceutical, Nutraceutical, Food, Pet Foods and Animal Feed and Fish Feed. The Pharmaceutical market is estimated to be about US $ 190 Million, Nutraceutical and Food is estimated to be about US $ 110 Million. Pet foods and other applications are estimated at US $ 175 Million annually. Apart from the customary Age related Macular Degeneration applications , newer applications are emerging in Cosmetics, Skin Care and as an Antioxidant. It is one of the fastest growing areas of the $ 2 Billion carotenoid market Template:Ref N. There are several lutein ester suppliers, but few pure lutein (Free Form) suppliers due primarily to patent protections on obtaining purified Lutein from natural products, namely marigolds. Companies like Indus Biotech Pvt. Ltd, OmniActive Health Technologies and Kemin Industries have patents. The market size of lutein is anticipated to grow at an average annual growth rate of over 22%. | https://www.wikidoc.org/index.php/Lutein | |
f124573eab69dba2c8078e64ec7e5998200400ea | wikidoc | MAD1L1 | MAD1L1
Mitotic spindle assembly checkpoint protein MAD1 is a protein that in humans is encoded by the MAD1L1 gene.
MAD1L1 is also known as Human Accelerated Region 3. It may therefore have played a key role in differentiating Humans from Apes.
# Function
MAD1L1 is a component of the mitotic spindle-assembly checkpoint that prevents the onset of anaphase until all chromosome are properly aligned at the metaphase plate. MAD1L1 functions as a homodimer and interacts with MAD2L1. MAD1L1 may play a role in cell cycle control and tumor suppression. Three transcript variants encoding the same protein have been found for this gene.
# Interactions
MAD1L1 has been shown to interact with:
- HDAC1,
- Histone deacetylase 2, and
- MAD2L1, | MAD1L1
Mitotic spindle assembly checkpoint protein MAD1 is a protein that in humans is encoded by the MAD1L1 gene.[1][2][3]
MAD1L1 is also known as Human Accelerated Region 3. It may therefore have played a key role in differentiating Humans from Apes.
# Function
MAD1L1 is a component of the mitotic spindle-assembly checkpoint that prevents the onset of anaphase until all chromosome are properly aligned at the metaphase plate. MAD1L1 functions as a homodimer and interacts with MAD2L1. MAD1L1 may play a role in cell cycle control and tumor suppression. Three transcript variants encoding the same protein have been found for this gene.[3]
# Interactions
MAD1L1 has been shown to interact with:
- HDAC1,[4]
- Histone deacetylase 2,[4] and
- MAD2L1,[5][6][7] | https://www.wikidoc.org/index.php/MAD1L1 | |
086c90bf9ad9d0d18c0bee50ef56ebf3fcd52060 | wikidoc | MAGEA3 | MAGEA3
Melanoma-associated antigen 3 (MAGE-A3) is a protein that in humans is encoded by the MAGEA3 gene.
# Genetics
This gene is a member of the melanoma-associated antigen gene family. The members of this family encode proteins with 50 to 80% sequence identity to each other. The promoters and first exons of the MAGEA genes show considerable variability, suggesting that the existence of this gene family enables the same function to be expressed under different transcriptional controls. The MAGEA genes are clustered at chromosomal location Xq28. They have been implicated in some hereditary disorders, such as dyskeratosis congenita.
# Function and Clinical relevance
The normal function of MAGE-A3 in healthy cells is unknown. The presence of the antigen on tumor cells has been associated with worse prognosis. In one study, high levels of MAGE-A3 in lung adenocarcinoma were associated with shorter survival.
MAGE-A3 is a tumor-specific protein, and has been identified on many tumors including melanoma, non-small cell lung cancer, hematologic malignancies, among others. Currently, GlaxoSmithKline is developing a cancer vaccine targeting MAGE-A3. The vaccine is a fusion protein of MAGE-A3 and Haemophilus influenzae protein D, combined with a proprietary immunoadjuvant. | MAGEA3
Melanoma-associated antigen 3 (MAGE-A3) is a protein that in humans is encoded by the MAGEA3 gene.[1][2][3]
# Genetics
This gene is a member of the melanoma-associated antigen gene family. The members of this family encode proteins with 50 to 80% sequence identity to each other. The promoters and first exons of the MAGEA genes show considerable variability, suggesting that the existence of this gene family enables the same function to be expressed under different transcriptional controls. The MAGEA genes are clustered at chromosomal location Xq28. They have been implicated in some hereditary disorders, such as dyskeratosis congenita.[3]
# Function and Clinical relevance
The normal function of MAGE-A3 in healthy cells is unknown.[4] The presence of the antigen on tumor cells has been associated with worse prognosis. In one study, high levels of MAGE-A3 in lung adenocarcinoma were associated with shorter survival.[5]
MAGE-A3 is a tumor-specific protein, and has been identified on many tumors including melanoma, non-small cell lung cancer, hematologic malignancies, among others.[6] Currently, GlaxoSmithKline is developing a cancer vaccine targeting MAGE-A3. The vaccine is a fusion protein of MAGE-A3 and Haemophilus influenzae protein D, combined with a proprietary immunoadjuvant.[7] | https://www.wikidoc.org/index.php/MAGEA3 | |
202d795644b662f8da7a79455116c232918a1dbe | wikidoc | MAGED1 | MAGED1
Melanoma-associated antigen D1 is a protein that in humans is encoded by the MAGED1 gene.
# Function
This gene is a member of the melanoma antigen gene (MAGE) family. Most of the genes of this family encode tumor specific antigens that are not expressed in normal adult tissues except testis. Although the protein encoded by this gene shares strong homology with members of the MAGE family, it is expressed in almost all normal adult tissues. This gene has been demonstrated to be involved in the p75 neurotrophin receptor mediated programmed cell death pathway. Three transcript variants encoding two different isoforms have been found for this gene.
MAGED was found to be deleted in a group of children with an intellectual disability disorder caused by a Xp11.22 deletion.
Maged1 plays a role in controlling the reward circuitry in the brain of mice that is responsible for addictive behaviors.
# Interactions
MAGED1 has been shown to interact with UNC5A, PJA1 and XIAP. | MAGED1
Melanoma-associated antigen D1 is a protein that in humans is encoded by the MAGED1 gene.[1][2]
# Function
This gene is a member of the melanoma antigen gene (MAGE) family. Most of the genes of this family encode tumor specific antigens that are not expressed in normal adult tissues except testis. Although the protein encoded by this gene shares strong homology with members of the MAGE family, it is expressed in almost all normal adult tissues. This gene has been demonstrated to be involved in the p75 neurotrophin receptor mediated programmed cell death pathway. Three transcript variants encoding two different isoforms have been found for this gene.[2]
MAGED was found to be deleted in a group of children with an intellectual disability disorder caused by a Xp11.22 deletion.[3]
Maged1 plays a role in controlling the reward circuitry in the brain of mice that is responsible for addictive behaviors.[4]
# Interactions
MAGED1 has been shown to interact with UNC5A,[5] PJA1[6] and XIAP.[7] | https://www.wikidoc.org/index.php/MAGED1 | |
84d20fc2d0e3c52136e251db7949ffac27065492 | wikidoc | MAGEH1 | MAGEH1
Melanoma-associated antigen H1 is a protein that in humans is encoded by the MAGEH1 gene.
This gene is thought to be involved in apoptosis. Multiple polyadenylation sites have been found for this gene.
# Interactions
MAGEH1 has been shown to interact with Low affinity nerve growth factor receptor. | MAGEH1
Melanoma-associated antigen H1 is a protein that in humans is encoded by the MAGEH1 gene.[1][2][3]
This gene is thought to be involved in apoptosis. Multiple polyadenylation sites have been found for this gene.[3]
# Interactions
MAGEH1 has been shown to interact with Low affinity nerve growth factor receptor.[1] | https://www.wikidoc.org/index.php/MAGEH1 | |
eda4b54c10461ac9423b458d641f4d0ab2e8752e | wikidoc | MALAT1 | MALAT1
MALAT 1 (metastasis associated lung adenocarcinoma transcript 1) also known as NEAT2 (noncoding nuclear-enriched abundant transcript 2) is a large, infrequently spliced non-coding RNA, which is highly conserved amongst mammals and highly expressed in the nucleus. MALAT1 was identified in multiple types of physiological processes, such as alternative splicing, nuclear organization, epigenetic modulating of gene expression, and a number of evidences indicate that MALAT1 also closely relate to various pathological processes, ranging from diabetes complications to cancers. It regulates the expression of metastasis-associated genes. It also positively regulates cell motility via the transcriptional and/or post-transcriptional regulation of motility-related genes. MALAT1 may play a role in temperature-dependent sex determination in the Red-eared slider turtle (Trachemys scripta).
# Expression in alcoholic brains
Transcripts of MALAT1 are significantly increased in the cerebellum of human alcoholics, as well as in similar regions of rat brains after the withdrawal of ethanol vapours. This alcohol-induced upregulation of MALAT1 may be responsible for differential expression of a number of proteins which contribute to ethanol tolerance and dependency in humans.
# Prognostic potential in cancer
The implication of MALAT1 RNA in the pathology of various cancers has been documented. Elevated MALAT1 expression is correlated with poor overall survival in various types of cancer, suggesting that this gene is a prognostic factor for different types of cancer.
# As a target for the treatment of cancer
Genetic loss or systemic knockdown of Malat1 using antisense oligonucleotides (ASO) in the mouse mammary carcinoma model results in slower tumor growth accompanied by significant differentiation into cystic tumors and a reduction in metastasis. At the molecular level, the ASO-Malat1 hybrid stimulates a naturally occurring cellular enzyme that degrades the Malat1 lncRNA. Malat1 knockdown results in alterations in gene expression and changes in splicing patterns of genes involved in differentiation and protumorigenic signaling pathways. Metastatic tumors have a dependency on Malat1—they can't thrive without it. And very importantly, only the cancer cells seem to require it. In so far as MALAT1 has been identified to be involved in tumorigenesis of various types of cancer such as lung cancer, pancreatic cancer, cervical cancer Malat1 ASOs represent a potential therapy for inhibiting such cancers progression. | MALAT1
MALAT 1 (metastasis associated lung adenocarcinoma transcript 1) also known as NEAT2 (noncoding nuclear-enriched abundant transcript 2) is a large, infrequently spliced non-coding RNA, which is highly conserved amongst mammals and highly expressed in the nucleus.[1] MALAT1 was identified in multiple types of physiological processes, such as alternative splicing, nuclear organization, epigenetic modulating of gene expression, and a number of evidences indicate that MALAT1 also closely relate to various pathological processes, ranging from diabetes complications to cancers.[2][3] It regulates the expression of metastasis-associated genes.[4] It also positively regulates cell motility via the transcriptional and/or post-transcriptional regulation of motility-related genes.[5] MALAT1 may play a role in temperature-dependent sex determination in the Red-eared slider turtle (Trachemys scripta).[6]
# Expression in alcoholic brains
Transcripts of MALAT1 are significantly increased in the cerebellum of human alcoholics, as well as in similar regions of rat brains after the withdrawal of ethanol vapours. This alcohol-induced upregulation of MALAT1 may be responsible for differential expression of a number of proteins which contribute to ethanol tolerance and dependency in humans.[7]
# Prognostic potential in cancer
The implication of MALAT1 RNA in the pathology of various cancers has been documented.[3] Elevated MALAT1 expression is correlated with poor overall survival in various types of cancer, suggesting that this gene is a prognostic factor for different types of cancer.[8][9]
# As a target for the treatment of cancer
Genetic loss or systemic knockdown of Malat1 using antisense oligonucleotides (ASO) in the mouse mammary carcinoma model results in slower tumor growth accompanied by significant differentiation into cystic tumors and a reduction in metastasis. At the molecular level, the ASO-Malat1 hybrid stimulates a naturally occurring cellular enzyme that degrades the Malat1 lncRNA. Malat1 knockdown results in alterations in gene expression and changes in splicing patterns of genes involved in differentiation and protumorigenic signaling pathways. Metastatic tumors have a dependency on Malat1—they can't thrive without it. And very importantly, only the cancer cells seem to require it. In so far as MALAT1 has been identified to be involved in tumorigenesis of various types of cancer such as lung cancer, pancreatic cancer, cervical cancer Malat1 ASOs represent a potential therapy for inhibiting such cancers progression.[10] | https://www.wikidoc.org/index.php/MALAT1 | |
f6db9d7bc081d4956bc577771a17ac9db63c8354 | wikidoc | MALSU1 | MALSU1
MALSU1 is a gene on chromosome 7 in humans that encodes the protein MALSU1. This protein localizes to mitochondria and is probably involved in mitochondrial translation or the biogenesis of the large subunit of the mitochondrial ribosome.
# Protein
MALSU1 is a member of the DUF143 family (= domain of unknown function 143, Pfam PF02410) which is highly conserved in both prokaryotes and eukaryotes but not archaea. Examples of mammalian conservation are given below using the ALIGN tool from the San Diego Supercomputer Center Biology Workbench. Percentages indicate the identity shared by the human protein and the respective mammalian protein. Accession numbers are from the NCBI database.
There are no known or predicted paralogs in Homo sapiens. That is, MALSU1 is a single-copy gene.
The domain is from position 93 to 194 on the human protein and comprises 43.2% of the sequence. This conserved domain is also present in the plant gene iojap, a pattern-striping gene in maize. However, since its function has been solved at least in bacteria, it is no longer a "domain of unknown function".
## Protein function
While the function of the protein in mitochondria is not conclusive its bacterial homolog has been shown to silence prokaryotic translation by blocking the two ribosomal subunits from joining, hence it was called RsfS (= ribosomal silencing factor in starvation or stationary phase, a synonym of RsfA).
Protein-protein interactions. RsfS has been shown via a yeast two-hybrid screen to interact with ribosomal protein L14 in four bacterial species as well as in mitochondria. MALSU1 was shown to interact with CHMP protein which is part of the ESCRT-III complex (Endosomal Sorting Complex Required for Transport). DUF143 has also been shown to interact with UFD1, tRNA synthetases class II, and Cytidylyltransferase in various architectures.
## Properties
Bioinformatics predicted the following properties for LOC_115416:
- Molecular Weight: 26.2 KDal
- Isoelectric Point: 5.155
# Gene
C7ORF30 is located on chromosome 7 in humans and runs from 23,305,465 to 23,315,705. There are four predicted exons in the human gene with conservation occurring across most mammalian species. There is no conclusive data regarding whether the gene is ubiquitously expressed in human tissues, but expressed sequence tag databases show that it is expressed in many tissues.
## Neighboring Genes
MALSU1 is neighbored by GPNMB upstream and IGF2BP3 downstream, however the latter gene is transcribed on the opposite strand running from the 3' to the 5' end. There is some slight overlap of the untranslated regions of C7ORF30 and IGF2BP3 whereas the distance between C7ORF30 and GPNMB is 24,211 base pairs. | MALSU1
MALSU1 is a gene on chromosome 7 in humans that encodes the protein MALSU1.[1] This protein localizes to mitochondria and is probably involved in mitochondrial translation or the biogenesis of the large subunit of the mitochondrial ribosome.
# Protein
MALSU1 is a member of the DUF143[2] family (= domain of unknown function 143, Pfam PF02410) which is highly conserved in both prokaryotes and eukaryotes but not archaea.[3] Examples of mammalian conservation are given below using the ALIGN tool from the San Diego Supercomputer Center Biology Workbench.[4] Percentages indicate the identity shared by the human protein and the respective mammalian protein. Accession numbers are from the NCBI database.
There are no known or predicted paralogs in Homo sapiens. That is, MALSU1 is a single-copy gene.
The domain is from position 93 to 194 on the human protein and comprises 43.2% of the sequence. This conserved domain is also present in the plant gene iojap, a pattern-striping gene in maize.[5][6] However, since its function has been solved at least in bacteria, it is no longer a "domain of unknown function".
## Protein function
While the function of the protein in mitochondria is not conclusive[7][8] its bacterial homolog has been shown to silence prokaryotic translation by blocking the two ribosomal subunits from joining, hence it was called RsfS (= ribosomal silencing factor in starvation or stationary phase, a synonym of RsfA[9]).
Protein-protein interactions. RsfS has been shown via a yeast two-hybrid screen to interact with ribosomal protein L14 in four bacterial species as well as in mitochondria.[9] MALSU1 was shown to interact with CHMP protein[10] which is part of the ESCRT-III complex (Endosomal Sorting Complex Required for Transport). DUF143 has also been shown to interact with UFD1, tRNA synthetases class II, and Cytidylyltransferase in various architectures.[11]
## Properties
Bioinformatics predicted the following properties for LOC_115416:
- Molecular Weight: 26.2 KDal
- Isoelectric Point: 5.155
# Gene
C7ORF30 is located on chromosome 7 in humans and runs from 23,305,465 to 23,315,705.[12] There are four predicted exons in the human gene with conservation occurring across most mammalian species. There is no conclusive data regarding whether the gene is ubiquitously expressed in human tissues, but expressed sequence tag databases show that it is expressed in many tissues.[13]
## Neighboring Genes
MALSU1 is neighbored by GPNMB upstream and IGF2BP3 downstream, however the latter gene is transcribed on the opposite strand running from the 3' to the 5' end. There is some slight overlap of the untranslated regions of C7ORF30 and IGF2BP3 whereas the distance between C7ORF30 and GPNMB is 24,211 base pairs. | https://www.wikidoc.org/index.php/MALSU1 | |
e403e84d099a919acf7e9b8c7de46a9bb9ffd046 | wikidoc | MAP2K1 | MAP2K1
Dual specificity mitogen-activated protein kinase kinase 1 is an enzyme that in humans is encoded by the MAP2K1 gene.
# Function
The protein encoded by this gene is a member of the dual-specificity protein kinase family that acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon activation by a wide variety of extra- and intracellular signals. As an essential component of the MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development.
# Meiosis
The genomes of diploid organisms in natural populations are highly polymorphic for insertions and deletions. During meiosis double-strand breaks (DSBs) that form within such polymorphic regions must be repaired by inter-sister chromatid exchange, rather than by inter-homolog exchange. Molecular-level studies of recombination during budding yeast meiosis have shown that recombination events initiated by DSBs in regions that lack corresponding sequences in the homolog are efficiently repaired by inter-sister chromatid recombination. This recombination occurs with the same timing as inter-homolog recombination, but with reduced (2- to 3-fold) yields of joint molecules.
MAP2K1 is also known as MEK1 (see Mitogen-activated protein kinase kinase). MEK1 is a meiotic chromosome-axis-associated kinase that is thought to slow down, but not entirely block, sister chromatid recombination. Loss of MEK1 allows inter-sister DSB repair and also inter-sister Holliday junction intermediates to increase. Despite the normal activity of MEK1 in reducing inter-sister chromatid recombination, such recombination still occurs frequently during normal budding yeast meiosis (although not as frequently as during mitosis), and up to one-third of all recombination events are between sister chromatids.
# Interactions
MAP2K1 has been shown to interact with C-Raf, Phosphatidylethanolamine binding protein 1, MAP2K1IP1, GRB10, MAPK3, MAPK8IP3, MAPK1 MP1, and MAP3K1. | MAP2K1
Dual specificity mitogen-activated protein kinase kinase 1 is an enzyme that in humans is encoded by the MAP2K1 gene.[1][2]
# Function
The protein encoded by this gene is a member of the dual-specificity protein kinase family that acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon activation by a wide variety of extra- and intracellular signals. As an essential component of the MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development.[3]
# Meiosis
The genomes of diploid organisms in natural populations are highly polymorphic for insertions and deletions. During meiosis double-strand breaks (DSBs) that form within such polymorphic regions must be repaired by inter-sister chromatid exchange, rather than by inter-homolog exchange. Molecular-level studies of recombination during budding yeast meiosis have shown that recombination events initiated by DSBs in regions that lack corresponding sequences in the homolog are efficiently repaired by inter-sister chromatid recombination.[4] This recombination occurs with the same timing as inter-homolog recombination, but with reduced (2- to 3-fold) yields of joint molecules.
MAP2K1 is also known as MEK1 (see Mitogen-activated protein kinase kinase). MEK1 is a meiotic chromosome-axis-associated kinase that is thought to slow down, but not entirely block, sister chromatid recombination. Loss of MEK1 allows inter-sister DSB repair and also inter-sister Holliday junction intermediates to increase. Despite the normal activity of MEK1 in reducing inter-sister chromatid recombination, such recombination still occurs frequently during normal budding yeast meiosis (although not as frequently as during mitosis), and up to one-third of all recombination events are between sister chromatids.[4]
# Interactions
MAP2K1 has been shown to interact with C-Raf,[5] Phosphatidylethanolamine binding protein 1,[5] MAP2K1IP1,[6][7] GRB10,[8] MAPK3,[7][9][10][11][12] MAPK8IP3,[13][14] MAPK1[5][6][15][16][17][18] MP1,[7] and MAP3K1.[19] | https://www.wikidoc.org/index.php/MAP2K1 | |
a8f06f5f5ab167664ab12582d2460186d18bb449 | wikidoc | MAP2K2 | MAP2K2
Dual specificity mitogen-activated protein kinase kinase 2 is an enzyme that in humans is encoded by the MAP2K2 gene. It is more commonly known as MEK2, but has many alternative names including CFC4, MKK2, MAPKK2 and PRKMK2.
# Function
The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is known to play a critical role in mitogen growth factor signal transduction. It phosphorylates and thus activates MAPK1/ERK2 and MAPK3/ERK1.
The activation of this kinase itself is dependent on the Ser/Thr phosphorylation by MAP kinase kinase kinases.
The inhibition or degradation of this kinase is found to be involved in the pathogenesis of Yersinia and anthrax.
# Interactions
MAP2K2 has been shown to interact with MAPK3 and ARAF. | MAP2K2
Dual specificity mitogen-activated protein kinase kinase 2 is an enzyme that in humans is encoded by the MAP2K2 gene.[1] It is more commonly known as MEK2, but has many alternative names including CFC4, MKK2, MAPKK2 and PRKMK2. [2]
# Function
The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is known to play a critical role in mitogen growth factor signal transduction. It phosphorylates and thus activates MAPK1/ERK2 and MAPK3/ERK1.
The activation of this kinase itself is dependent on the Ser/Thr phosphorylation by MAP kinase kinase kinases.
The inhibition or degradation of this kinase is found to be involved in the pathogenesis of Yersinia and anthrax.[3]
# Interactions
MAP2K2 has been shown to interact with MAPK3[4][5][6] and ARAF.[7] | https://www.wikidoc.org/index.php/MAP2K2 | |
dffca6d2ccc7aedf89b7011ae9a50cd6a3afce9a | wikidoc | MAP2K4 | MAP2K4
Dual specificity mitogen-activated protein kinase kinase 4 is an enzyme that in humans is encoded by the MAP2K4 gene.
This gene encodes a dual specificity protein kinase that belongs to the Ser/Thr protein kinase family. This kinase is a direct activator of MAP kinases in response to various environmental stresses or mitogenic stimuli. It has been shown to activate MAPK8/JNK1, MAPK9/JNK2, and MAPK14/p38, but not MAPK1/ERK2 or MAPK3/ERK1. This kinase is phosphorylated, and thus activated by MAP3K1/MEKK. The knockout studies in mice suggested the roles of this kinase in mediating survival signal in T cell development, as well as in the organogenesis of liver.
# Interactions
MAP2K4 has been shown to interact with FLNC, MAPK8, MAPK8IP3 and AKT1. | MAP2K4
Dual specificity mitogen-activated protein kinase kinase 4 is an enzyme that in humans is encoded by the MAP2K4 gene.[1]
This gene encodes a dual specificity protein kinase that belongs to the Ser/Thr protein kinase family. This kinase is a direct activator of MAP kinases in response to various environmental stresses or mitogenic stimuli. It has been shown to activate MAPK8/JNK1, MAPK9/JNK2, and MAPK14/p38, but not MAPK1/ERK2 or MAPK3/ERK1. This kinase is phosphorylated, and thus activated by MAP3K1/MEKK. The knockout studies in mice suggested the roles of this kinase in mediating survival signal in T cell development, as well as in the organogenesis of liver.[2]
# Interactions
MAP2K4 has been shown to interact with FLNC,[3] MAPK8,[4][5][6][7][8] MAPK8IP3[9][10] and AKT1.[5] | https://www.wikidoc.org/index.php/MAP2K4 | |
64c86216d27e926e466918b7ab383e7f146872d8 | wikidoc | MAP2K5 | MAP2K5
Dual specificity mitogen-activated protein kinase kinase 5 is an enzyme that in humans is encoded by the MAP2K5 gene.
# Function
The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase specifically interacts with and activates MAPK7/ERK5. This kinase itself can be phosphorylated and activated by MAP3K3/MEKK3, as well as by atypical protein kinase C isoforms (aPKCs). The signal cascade mediated by this kinase is involved in growth factor stimulated cell proliferation and muscle cell differentiation. Four alternatively spliced transcript variants of this gene encoding distinct isoforms have been described.
# Upstream
This kinase itself can be phosphorylated and activated by MAP3K3/MEKK3, as well as by atypical protein kinase C isoforms (aPKCs).
# Downstream
This kinase specifically interacts with and activates MAPK7/ERK5.
# Interactions
MAP2K5 has been shown to interact with MAPK7, MAP3K2, Protein kinase Mζ and MAP3K3. | MAP2K5
Dual specificity mitogen-activated protein kinase kinase 5 is an enzyme that in humans is encoded by the MAP2K5 gene.[1][2]
# Function
The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase specifically interacts with and activates MAPK7/ERK5. This kinase itself can be phosphorylated and activated by MAP3K3/MEKK3, as well as by atypical protein kinase C isoforms (aPKCs). The signal cascade mediated by this kinase is involved in growth factor stimulated cell proliferation and muscle cell differentiation. Four alternatively spliced transcript variants of this gene encoding distinct isoforms have been described.[2]
# Upstream
This kinase itself can be phosphorylated and activated by MAP3K3/MEKK3, as well as by atypical protein kinase C isoforms (aPKCs).
# Downstream
This kinase specifically interacts with and activates MAPK7/ERK5.
# Interactions
MAP2K5 has been shown to interact with MAPK7,[1] MAP3K2,[3] Protein kinase Mζ[4] and MAP3K3.[3][5] | https://www.wikidoc.org/index.php/MAP2K5 | |
de934c6c235bc3495adf66365a49263f40304260 | wikidoc | MAP2K6 | MAP2K6
Dual specificity mitogen-activated protein kinase kinase 6 also known as MAP kinase kinase 6 (MAPKK 6) or MAPK/ERK kinase 6 is an enzyme that in humans is encoded by the MAP2K6 gene, on chromosome 17.
# Function
MAPKK 6 is a member of the dual specificity protein kinase family, which functions as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein phosphorylates and activates p38 MAP kinase in response to inflammatory cytokines or environmental stress. As an essential component of p38 MAP kinase mediated signal transduction pathway, this gene is involved in many cellular processes such as stress-induced cell cycle arrest, transcription activation and apoptosis.
# Interactions
MAP2K6 has been shown to interact with TAOK2, ASK1, MAPK14 and MAP3K7. | MAP2K6
Dual specificity mitogen-activated protein kinase kinase 6 also known as MAP kinase kinase 6 (MAPKK 6) or MAPK/ERK kinase 6 is an enzyme that in humans is encoded by the MAP2K6 gene, on chromosome 17.[1]
# Function
MAPKK 6 is a member of the dual specificity protein kinase family, which functions as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein phosphorylates and activates p38 MAP kinase in response to inflammatory cytokines or environmental stress. As an essential component of p38 MAP kinase mediated signal transduction pathway, this gene is involved in many cellular processes such as stress-induced cell cycle arrest, transcription activation and apoptosis.[2]
# Interactions
MAP2K6 has been shown to interact with TAOK2,[3] ASK1,[4][5] MAPK14[3][6][7][8] and MAP3K7.[9][10][11][12] | https://www.wikidoc.org/index.php/MAP2K6 | |
60aaea0b53ea6df6b6001c657f0651d0bb8776d4 | wikidoc | MAP2K7 | MAP2K7
Dual specificity mitogen-activated protein kinase kinase 7, also known as MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encoded by the MAP2K7 gene. This protein is a member of the mitogen-activated protein kinase kinase family. The MKK7 protein exists as six different isoforms with three possible N-termini (α, β, and γ isoforms) and two possible C-termini (1 and 2 isoforms).
MKK7 is involved in signal transduction mediating the cell responses to proinflammatory cytokines, and environmental stresses. This kinase specifically activates MAPK8/JNK1 and MAPK9/JNK2, and this kinase itself is phosphorylated and activated by MAP kinase kinase kinases including MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK5, and MAP4K2/GCK.
MKK7 is ubiquitously expressed in all tissue. However, it displays a higher level of expression in skeletal muscle. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found.
# Nomenclature
MAP2K7 is also known as:
- MKK7
- JNK-activated kinase 2
- MAPK/ERK kinase 7 (MEK7)
- Stress-activated protein kinase kinase 4 (SAPK kinase 4, SAPKK4)
- c-Jun N-terminal kinase kinase 2 (JNK kinase 2, JNKK2)
- Stress-activated / extracellular signal-regulated protein kinase kinase 2 (SEK2)
# Isoforms
The murine MKK7 protein is encoded by 14 exons which can be alternatively spliced to yield a group of protein kinases. This results in six isoforms with three possible N-termini (α, β, and γ isoforms) and two possible C-termini (1 and 2 isoforms). The molecular mass of the isoforms spans from 38 to 52 kDa, with between 345 and 467 amino acids.
The physiological relevance of the different MKK7 isoforms is still unclear. Evidence shows that the MKK7α, which lacks an NH2-terminal extension, shows a lower basal activity in binding JNK compared to the MKKβ and γ isoforms. The increased basal activity in the β and γ isoforms can be due to the three D-motifs present in the N-terminus of these isoforms.
# Structure and function
## D-motifs
MKK7 has three conserved D-motifs (MAPK-recruiting short linear motifs) on its intinsically disordered N-terminus. D-motifs typically consist of a cluster of positively charged amino acids followed by alternating hydrophobic amino acids. D-motifs are strictly required for the recruitment of MAPKK substrates, such as JNK. The kinase domains of MAPKs contain certain surface features, such as the so-called common docking (CD) region, alongside the docking (D) groove, that specifically recognize their cognate D-motifs. The D-motifs found in MKK7 are highly specific for JNKs, but have a relatively low binding affinity. It was suggested that the motifs of MKK7 can synergize with each other to provide an efficient substrate phosphorylation It has been shown that all three D-motifs are necessary for correct JNK1:MKK7 complex formations, and for the phosphorylation and activation of JNK1 by MKK7.
## DVD region
A special extension to the C-terminal kinase domain core, the so-called "Domain for Versatile Docking" (DVD) is a region found in MKK7 as in most known MAP2Ks,. The DVD region is a stable, mostly helical fold of roughly 20 amino acids, that adds onto the back side of the catalytic core of the MAP2K kinase domains. This domain extension is both required for the specific binding to, and activation of MKK7 by respective upstream MAPKKKs. Other mitogen activated protein kinase kinases also require the DVD region (in addition to various other non-canonical elements of their kinase domains, like the "MKK1/2-loop") to be able to discriminate against the various MAPKKK upstream. These special MAPKK:MAPKKK kinase-domain/kinase-domain interactions facilitate the phosphorylation of MKK7. In addition to the activation of MKK7, binding to the DVD region may also affect the MKK7 activation loop in such a way that the Ser and Thr of the S-K-A-K-T motif become accessible for phosphorylation.
## Kinase domain
The MKK7 contains one kinase domain. The direct MKK7:MAPKKK interaction (using the DVD region), facilitates the phosphorylation of MKK7 by MAPKKKs on serine and threonine in a S-K-A-K-T motif in the catalytic domain (kinase domain).
# Signaling and regulation
MKK7 play an important part in the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In collaboration with another mitogen-activated protein kinase kinase MKK4, MKK7 work as crucial transducers upstream of JNK signaling. Through joint efforts the two MKKs phosphorylate different JNK isoforms. As a result, MKK7 has a great impact on numerous physiological processes such as proliferation and differentiation, as well as pathological processes such as apoptosis and tumorigenesis. MKK7 are activated as a result of cellular stresses. They are activated by a number of MKKKs through phosphorylation at a S-K-A-K-T motif located in the MKK7s kinase domain. The MKKKs relate to MKK7 through its DVD site at the C-terminus and phosphorylate MKK7 at serine and threonine residues. Once activated, MKK4 and MKK7 directly phosphorylate specific tyrosine and threonine residues located in the conserved T-P-Y motif of the activation loop of the JNK protein. Although MKK7 act through dual specificity it tends to phosphorylate threonine on JNK protein, leaving MKK4 to phosphorylate tyrosine. Phosphorylated and activated JNKs activate substrates like transcription factors or pro-apoptotic protein. MKK7 and MKK4 seem to be regulating the expression of each other, thereby affecting the JNK signaling. The mono-phosphorylation of JNK on a threonine residue is adequate for the increase in JNK activity, which argues that MKK7 is an important constituent for JNK activity, while the additional phosphorylation of the tyrosine residue by MKK4 provide for a more favorable activation.
## Scaffold proteins
In addition to the direct interactions between JNK, MKK7 and other upstream protein kinases, various scaffold proteins function to ensure specificity between the components of the MAPK signaling cascade. Different JNK isoforms, MAPK, and MAPKKs (e.g., MKK7 or MKK4) bind specifically to the scaffold proteins. Several mammalian scaffold proteins have been identified. These include the JNK-interacting protein (JIP) 1 and its closerly-related homolog, JIP2 or the (completely unrelated) JIP3 and JIP4 proteins. Nevertheless, JIP1/2 and JIP3/4 were shown to be capable of direct interaction with each other. Plenty of Src-homology-3 (POSH) has also been shown to be a partner of JIP1/2.
All these JNK pathway regulators assemble transport complexes, tied to kinesin-dependent vesicular transport. In this context, JIP1/2 act as cargo adaptors, binding to a motor protein and a cargo protein simultaneously. In addition to their "normal" cargoes (C-termini of transmembrane proteins), they also transport MAP2K and MAP3K enzymes, namely MKK7, DLK and MLK3. Kinases bound to the JIP1/2 scaffold are generally sequestrated and thought to be inactive. Since the cargo-linkage mechanism of this complex is believed to be phosphporylation-dependent, phosphorylation by JNK kinase can release its own upstream activators from the scaffold, thus driving a strong local positive feedback loop.
# Interactions
MAP2K7 has been shown to interact with:
- GADD45B
- MAPK8
- MAPK8IP3
- MAPK8IP1
- MAP3K12
- MAP3K2
- MAPK8IP2
- DUSP19
# Biological relevance
MKK7 is involved in the development of epithelial tissues such as skin and lungs, and also the developing teeth, during early embryogenesis in mice. Experiments also indicate that MKK7 in addition to MKK4 are required for mammalian body plan organization during embryogenesis. MKK7 has also been suggested to function as a Metastase Suppressor Gene (MSG) by promoting tumor dormancy at the metastatic site. In small mammals, stress like pressure overload can cause cardiac hypertrophy and failure if MKK7 is knocked out. | MAP2K7
Dual specificity mitogen-activated protein kinase kinase 7, also known as MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encoded by the MAP2K7 gene.[1] This protein is a member of the mitogen-activated protein kinase kinase family. The MKK7 protein exists as six different isoforms with three possible N-termini (α, β, and γ isoforms) and two possible C-termini (1 and 2 isoforms).[2]
MKK7 is involved in signal transduction mediating the cell responses to proinflammatory cytokines, and environmental stresses. This kinase specifically activates MAPK8/JNK1 and MAPK9/JNK2, and this kinase itself is phosphorylated and activated by MAP kinase kinase kinases including MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK5, and MAP4K2/GCK.
MKK7 is ubiquitously expressed in all tissue. However, it displays a higher level of expression in skeletal muscle.[3] Multiple alternatively spliced transcript variants encoding distinct isoforms have been found.[1]
# Nomenclature
MAP2K7 is also known as:
- MKK7
- JNK-activated kinase 2
- MAPK/ERK kinase 7 (MEK7)
- Stress-activated protein kinase kinase 4 (SAPK kinase 4, SAPKK4)
- c-Jun N-terminal kinase kinase 2 (JNK kinase 2, JNKK2)
- Stress-activated / extracellular signal-regulated protein kinase kinase 2 (SEK2)
# Isoforms
The murine MKK7 protein is encoded by 14 exons which can be alternatively spliced to yield a group of protein kinases. This results in six isoforms with three possible N-termini (α, β, and γ isoforms) and two possible C-termini (1 and 2 isoforms). The molecular mass of the isoforms spans from 38 to 52 kDa, with between 345 and 467 amino acids.[2]
The physiological relevance of the different MKK7 isoforms is still unclear. Evidence shows that the MKK7α, which lacks an NH2-terminal extension, shows a lower basal activity in binding JNK compared to the MKKβ and γ isoforms. The increased basal activity in the β and γ isoforms can be due to the three D-motifs present in the N-terminus of these isoforms.[4]
# Structure and function
## D-motifs
MKK7 has three conserved D-motifs (MAPK-recruiting short linear motifs) on its intinsically disordered N-terminus. D-motifs typically consist of a cluster of positively charged amino acids followed by alternating hydrophobic amino acids.[4] D-motifs are strictly required for the recruitment of MAPKK substrates, such as JNK.[6] The kinase domains of MAPKs contain certain surface features, such as the so-called common docking (CD) region, alongside the docking (D) groove, that specifically recognize their cognate D-motifs.[4] The D-motifs found in MKK7 are highly specific for JNKs, but have a relatively low binding affinity. It was suggested that the motifs of MKK7 can synergize with each other to provide an efficient substrate phosphorylation[7] It has been shown that all three D-motifs are necessary for correct JNK1:MKK7 complex formations, and for the phosphorylation and activation of JNK1 by MKK7.[8]
## DVD region
A special extension to the C-terminal kinase domain core, the so-called "Domain for Versatile Docking" (DVD) is a region found in MKK7 as in most known MAP2Ks,.[6] The DVD region is a stable, mostly helical fold of roughly 20 amino acids, that adds onto the back side of the catalytic core of the MAP2K kinase domains.[9] This domain extension is both required for the specific binding to, and activation of MKK7 by respective upstream MAPKKKs. Other mitogen activated protein kinase kinases also require the DVD region (in addition to various other non-canonical elements of their kinase domains, like the "MKK1/2-loop") to be able to discriminate against the various MAPKKK upstream.[10] These special MAPKK:MAPKKK kinase-domain/kinase-domain interactions facilitate the phosphorylation of MKK7.[4] In addition to the activation of MKK7, binding to the DVD region may also affect the MKK7 activation loop in such a way that the Ser and Thr of the S-K-A-K-T motif become accessible for phosphorylation.[4]
## Kinase domain
The MKK7 contains one kinase domain. The direct MKK7:MAPKKK interaction (using the DVD region), facilitates the phosphorylation of MKK7 by MAPKKKs on serine and threonine in a S-K-A-K-T motif in the catalytic domain (kinase domain).[5]
# Signaling and regulation
MKK7 play an important part in the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway.[11] In collaboration with another mitogen-activated protein kinase kinase MKK4, MKK7 work as crucial transducers upstream of JNK signaling.[12] Through joint efforts the two MKKs phosphorylate different JNK isoforms. As a result, MKK7 has a great impact on numerous physiological processes such as proliferation and differentiation, as well as pathological processes such as apoptosis and tumorigenesis.[5] MKK7 are activated as a result of cellular stresses.[12] They are activated by a number of MKKKs through phosphorylation at a S-K-A-K-T motif located in the MKK7s kinase domain. The MKKKs relate to MKK7 through its DVD site at the C-terminus and phosphorylate MKK7 at serine and threonine residues.[5] Once activated, MKK4 and MKK7 directly phosphorylate specific tyrosine and threonine residues located in the conserved T-P-Y motif of the activation loop of the JNK protein.[5] Although MKK7 act through dual specificity it tends to phosphorylate threonine on JNK protein, leaving MKK4 to phosphorylate tyrosine.[12] Phosphorylated and activated JNKs activate substrates like transcription factors or pro-apoptotic protein.[5] MKK7 and MKK4 seem to be regulating the expression of each other, thereby affecting the JNK signaling. The mono-phosphorylation of JNK on a threonine residue is adequate for the increase in JNK activity, which argues that MKK7 is an important constituent for JNK activity, while the additional phosphorylation of the tyrosine residue by MKK4 provide for a more favorable activation.[5]
## Scaffold proteins
In addition to the direct interactions between JNK, MKK7 and other upstream protein kinases, various scaffold proteins function to ensure specificity between the components of the MAPK signaling cascade.[4][12] Different JNK isoforms, MAPK, and MAPKKs (e.g., MKK7 or MKK4) bind specifically to the scaffold proteins. Several mammalian scaffold proteins have been identified. These include the JNK-interacting protein (JIP) 1 and its closerly-related homolog, JIP2 or the (completely unrelated) JIP3 and JIP4 proteins. Nevertheless, JIP1/2 and JIP3/4 were shown to be capable of direct interaction with each other.[14] Plenty of Src-homology-3 (POSH) has also been shown to be a partner of JIP1/2.[12]
All these JNK pathway regulators assemble transport complexes, tied to kinesin-dependent vesicular transport. In this context, JIP1/2 act as cargo adaptors, binding to a motor protein and a cargo protein simultaneously. In addition to their "normal" cargoes (C-termini of transmembrane proteins), they also transport MAP2K and MAP3K enzymes, namely MKK7, DLK and MLK3. Kinases bound to the JIP1/2 scaffold are generally sequestrated and thought to be inactive.[13] Since the cargo-linkage mechanism of this complex is believed to be phosphporylation-dependent, phosphorylation by JNK kinase can release its own upstream activators from the scaffold, thus driving a strong local positive feedback loop.[13][15]
# Interactions
MAP2K7 has been shown to interact with:
- GADD45B[16]
- MAPK8[17][18]
- MAPK8IP3[19][20]
- MAPK8IP1[21]
- MAP3K12[22]
- MAP3K2[18]
- MAPK8IP2[21][23]
- DUSP19[24][25]
# Biological relevance
MKK7 is involved in the development of epithelial tissues such as skin and lungs, and also the developing teeth, during early embryogenesis in mice.[4] Experiments also indicate that MKK7 in addition to MKK4 are required for mammalian body plan organization during embryogenesis.[12] MKK7 has also been suggested to function as a Metastase Suppressor Gene (MSG) by promoting tumor dormancy at the metastatic site.[26] In small mammals, stress like pressure overload can cause cardiac hypertrophy and failure if MKK7 is knocked out.[27] | https://www.wikidoc.org/index.php/MAP2K7 | |
c0560f2fea71687933cdfb50895f6317af404e6d | wikidoc | MAP3K1 | MAP3K1
Mitogen-activated protein kinase kinase kinase 1 is an enzyme that in humans is encoded by the MAP3K1 gene.
# Function
MAP3K, or MEK kinase or Raf, is a serine/threonine kinase that occupies a pivotal role in a network of phosphorylating enzymes integrating cellular responses to a number of mitogenic and metabolic stimuli, including insulin and many growth factors.
Mouse genetics has revealed that the kinase is important in: correct embryogenesis, keratinocyte migration, T cell cytokine production and B cell antibody production.
MAP3K1 is a regulatory target of GWAS variants associated with breast cancer risk
# Interactions
MAP3K1 has been shown to interact with:
- AXIN1,
- C-Raf,
- Grb2,
- MAP2K1,
- MAPK1,
- MAPK8,
- TRAF2, and
- UBE2I. | MAP3K1
Mitogen-activated protein kinase kinase kinase 1 is an enzyme that in humans is encoded by the MAP3K1 gene.[1][2]
# Function
MAP3K, or MEK kinase or Raf, is a serine/threonine kinase that occupies a pivotal role in a network of phosphorylating enzymes integrating cellular responses to a number of mitogenic and metabolic stimuli, including insulin and many growth factors.[2]
Mouse genetics has revealed that the kinase is important in: correct embryogenesis, keratinocyte migration, T cell cytokine production and B cell antibody production.
MAP3K1 is a regulatory target of GWAS variants associated with breast cancer risk [3]
# Interactions
MAP3K1 has been shown to interact with:
- AXIN1,[4][5]
- C-Raf,[6]
- Grb2,[7]
- MAP2K1,[6]
- MAPK1,[6]
- MAPK8,[8]
- TRAF2,[9] and
- UBE2I.[10] | https://www.wikidoc.org/index.php/MAP3K1 | |
a29c3fd1271b43f3abd8474b396f14582d308e78 | wikidoc | MAP3K3 | MAP3K3
Mitogen-activated protein kinase kinase kinase 3 is an enzyme that in humans is encoded by the MAP3K3 gene, which is located on the long arm of chromosome 17 (17q23.3).
# Function
This gene product is a 626-amino acid polypeptide that is 96.5% identical to mouse MEKK3. Its catalytic domain is closely related to those of several other kinases, including mouse MEKK2, tobacco NPK, and yeast STE11. Northern blot analysis revealed a 4.6-kb transcript that appears to be ubiquitously expressed.
MAP3Ks are involved in regulating cell fate in response to external stimuli. MAP3K3 directly regulates the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively. In cotransfection assays, it enhanced transcription from a nuclear factor kappa-B (NF-κB)-dependent reporter gene, consistent with a role in the SAPK pathway. Alternatively spliced transcript variants encoding distinct isoforms have been observed. MEKK3 regulates the p38, JNK and ERK1/2 pathways.
# Interactions
MAP3K3 has been shown to interact with ,:
- BRCA1, AKT.
- GAB1,
- MAP2K5, and
- YWHAE.
# MAP3K3 in cancer
Two SNPs in the MAP3K3 gene were found as candidates for association with colon and rectal cancers.
MEKK3 is highly expressed in 4 ovarian cancer cell lines (OVCA429, Hey, DOV13, and SKOv3). This expression level is significantly higher in those cancer cells when compared to normal cells. MEKK3 expression levels are comparable to IKK kinase activities, which also relate to activation of NFκB. High expression of MEKK3 in most of these ovarian cancer cells supposedly activate IKK kinase activity, which lead to increased levels of active NFκB. Also, MEKK3 interacts with AKT to activate NFκB. Genes related to cell survival and anti-apoptosis have increased expression in most cancer cells with high levels of MEKK3. This is probably due to constitutive activation of NFκB, which will regulate those genes. In this sense, knockdown of MEKK3 caused ovarian cancer cells to be more sensitive to drugs.
MEKK3 also interacts with BRCA1. Knocking down BRCA1 resulted in inhibited MEKK3 kinase activity. The drug paclitaxel induces MEKK3 activity and it requires functional BRCA1 to do it. It was observed that in a breast cancer cell line BRCA1-deficient (HCC1937), paclitaxel was unable to activate MEKK3. Paclitaxel may be inducing stress-response through the MEKK3/JNK/p38/MAPK pathway, but not in mutated BRCA1 cells. | MAP3K3
Mitogen-activated protein kinase kinase kinase 3 is an enzyme that in humans is encoded by the MAP3K3 gene,[1] which is located on the long arm of chromosome 17 (17q23.3).[2]
# Function
This gene product is a 626-amino acid polypeptide that is 96.5% identical to mouse MEKK3. Its catalytic domain is closely related to those of several other kinases, including mouse MEKK2, tobacco NPK, and yeast STE11. Northern blot analysis revealed a 4.6-kb transcript that appears to be ubiquitously expressed.
MAP3Ks are involved in regulating cell fate in response to external stimuli.[3] MAP3K3 directly regulates the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively. In cotransfection assays, it enhanced transcription from a nuclear factor kappa-B (NF-κB)-dependent reporter gene, consistent with a role in the SAPK pathway. Alternatively spliced transcript variants encoding distinct isoforms have been observed.[4] MEKK3 regulates the p38, JNK and ERK1/2 pathways.[3]
# Interactions
MAP3K3 has been shown to interact with [SQSTM1/p62],:
- BRCA1,[5] AKT.[6]
- GAB1,[7]
- MAP2K5,[8][9] and
- YWHAE.[10]
# MAP3K3 in cancer
Two SNPs in the MAP3K3 gene were found as candidates for association with colon and rectal cancers.[11]
MEKK3 is highly expressed in 4 ovarian cancer cell lines (OVCA429, Hey, DOV13, and SKOv3). This expression level is significantly higher in those cancer cells when compared to normal cells. MEKK3 expression levels are comparable to IKK kinase activities, which also relate to activation of NFκB. High expression of MEKK3 in most of these ovarian cancer cells supposedly activate IKK kinase activity, which lead to increased levels of active NFκB. Also, MEKK3 interacts with AKT to activate NFκB. Genes related to cell survival and anti-apoptosis have increased expression in most cancer cells with high levels of MEKK3. This is probably due to constitutive activation of NFκB, which will regulate those genes. In this sense, knockdown of MEKK3 caused ovarian cancer cells to be more sensitive to drugs.[6]
MEKK3 also interacts with BRCA1. Knocking down BRCA1 resulted in inhibited MEKK3 kinase activity. The drug paclitaxel induces MEKK3 activity and it requires functional BRCA1 to do it. It was observed that in a breast cancer cell line BRCA1-deficient (HCC1937), paclitaxel was unable to activate MEKK3. Paclitaxel may be inducing stress-response through the MEKK3/JNK/p38/MAPK pathway, but not in mutated BRCA1 cells.[5] | https://www.wikidoc.org/index.php/MAP3K3 | |
73a8c62a8da21c7fc494e922c94dbd66f05467c2 | wikidoc | MAP3K4 | MAP3K4
Mitogen-activated protein kinase kinase kinase 4 is an enzyme that in humans is encoded by the MAP3K4 gene.
The central core of each mitogen-activated protein kinase (MAPK) pathway is a conserved cascade of 3 protein kinases: an activated MAPK kinase kinase (MAPKKK) phosphorylates and activates a specific MAPK kinase (MAPKK), which then activates a specific MAPK. While the ERK MAPKs are activated by mitogenic stimulation, the CSBP2 (p38α) and JNK MAPKs are activated by environmental stresses such as osmotic shock, UV irradiation, wound stress, and inflammatory factors. This gene encodes a MAPKKK, the MEKK4 protein, also called MTK1. This protein contains a protein kinase catalytic domain at the C terminus. The N-terminal nonkinase domain may contain a regulatory domain. Expression of MEKK4 in mammalian cells activated the CSBP2 (p38α) and JNK MAPK pathways, but not the ERK pathway. In vitro kinase studies indicated that recombinant MEKK4 can specifically phosphorylate and activate PRKMK6 (MKK6) and SERK1 (MKK4), MAPKKs that activate CSBP2 (p38α) and JNK, respectively but cannot phosphorylate PRKMK1 (MKK1), an MAPKK that activates ERKs. MEKK4 is a major mediator of environmental stresses that activate the p38 MAPK pathway, and a minor mediator of the JNK pathway. Two alternatively spliced transcripts encoding distinct isoforms have been described.
# Interactions
MAP3K4 has been shown to interact with GADD45G, GADD45B and GADD45A. | MAP3K4
Mitogen-activated protein kinase kinase kinase 4 is an enzyme that in humans is encoded by the MAP3K4 gene.[1][2]
The central core of each mitogen-activated protein kinase (MAPK) pathway is a conserved cascade of 3 protein kinases: an activated MAPK kinase kinase (MAPKKK) phosphorylates and activates a specific MAPK kinase (MAPKK), which then activates a specific MAPK. While the ERK MAPKs are activated by mitogenic stimulation, the CSBP2 (p38α) and JNK MAPKs are activated by environmental stresses such as osmotic shock, UV irradiation, wound stress, and inflammatory factors. This gene encodes a MAPKKK, the MEKK4 protein, also called MTK1. This protein contains a protein kinase catalytic domain at the C terminus. The N-terminal nonkinase domain may contain a regulatory domain. Expression of MEKK4 in mammalian cells activated the CSBP2 (p38α) and JNK MAPK pathways, but not the ERK pathway. In vitro kinase studies indicated that recombinant MEKK4 can specifically phosphorylate and activate PRKMK6 (MKK6) and SERK1 (MKK4), MAPKKs that activate CSBP2 (p38α) and JNK, respectively but cannot phosphorylate PRKMK1 (MKK1), an MAPKK that activates ERKs. MEKK4 is a major mediator of environmental stresses that activate the p38 MAPK pathway, and a minor mediator of the JNK pathway. Two alternatively spliced transcripts encoding distinct isoforms have been described.[2]
# Interactions
MAP3K4 has been shown to interact with GADD45G,[3] GADD45B[3] and GADD45A.[3] | https://www.wikidoc.org/index.php/MAP3K4 | |
0ea5db45f331c3d694dd0bb3051bd81d0d5697dd | wikidoc | MAP3K8 | MAP3K8
Mitogen-activated protein kinase kinase kinase 8 is an enzyme that in humans is encoded by the MAP3K8 gene.
# Function
This gene was identified by its oncogenic transforming activity in cells. The encoded protein is a member of the serine/threonine protein kinase family. This kinase can activate both the ERK1/2 and p38 MAP kinases. This kinase was shown to activate IkappaB kinases, and thus induce the nuclear production of NF-kappaB. This kinase was also found to promote the production of TNF-alpha and IL-2 during T lymphocyte activation. Studies of a similar gene in rat suggested the direct involvement of this kinase in the proteolysis of NF-kappaB1,p105 (NFKB1). This gene may also start transcription at a downstream in-frame translation start codon, and thus produce an isoform containing a shorter N-terminus. The shorter isoform has been shown to display weaker transforming activity. In mice, this gene is known as Tpl2 and it is a tumor suppressor gene whose absence contributes to the development and progression of cancer.
# Interactions
MAP3K8 has been shown to interact with AKT1, CHUK, NFKB2, NFKB1, C22orf25 and TNIP2. | MAP3K8
Mitogen-activated protein kinase kinase kinase 8 is an enzyme that in humans is encoded by the MAP3K8 gene.[1][2][3]
# Function
This gene was identified by its oncogenic transforming activity in cells. The encoded protein is a member of the serine/threonine protein kinase family. This kinase can activate both the ERK1/2 and p38 MAP kinases.[4][5] This kinase was shown to activate IkappaB kinases, and thus induce the nuclear production of NF-kappaB. This kinase was also found to promote the production of TNF-alpha and IL-2 during T lymphocyte activation. Studies of a similar gene in rat suggested the direct involvement of this kinase in the proteolysis of NF-kappaB1,p105 (NFKB1). This gene may also start transcription at a downstream in-frame translation start codon, and thus produce an isoform containing a shorter N-terminus. The shorter isoform has been shown to display weaker transforming activity.[3] In mice, this gene is known as Tpl2 and it is a tumor suppressor gene whose absence contributes to the development and progression of cancer.[6]
# Interactions
MAP3K8 has been shown to interact with AKT1,[7] CHUK,[8] NFKB2,[9] NFKB1,[9][10] C22orf25 [11] and TNIP2.[12] | https://www.wikidoc.org/index.php/MAP3K8 | |
24960d6f168033ea6aaf877955b44731a9ce58cd | wikidoc | MAP4K4 | MAP4K4
Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) – also known as hepatocyte progenitor kinase-like/germinal center kinase-like kinase (HGK) and Nck-interacting kinase (NIK) – is an enzyme, specifically a serine/threonine (S/T) kinase encoded by the MAP4K4 gene in humans.
MAP4K4 is involved in a wide array of physiological processes including cell migration, proliferation and adhesion; its activity has been implicated in systemic inflammation, metabolic disorders, cardiovascular disease and cancer.
While MAP4K4 has been found to be upregulated in a wide array of cancers, there is currently limited information regarding its specific involvement. However, there is increasing evidence that suggests MAP4K4 has an important role in the development and progression of cancer, and may serve as a novel target for cancer therapeutics.
# Discovery and classification
MAP4K4 is categorized under the mammalian sterile 20 protein (Ste20p) kinase family due to its shared homology with the Ste20p kinase found in budding yeast and is a member of the GCK-IV subfamily. Mammalian MAP4K4 was initially identified in mice as a kinase activator for a protein called Nck followed shortly by identification and cloning of the human orthologue encoded by the MAP4K4 gene.
# Structure and expression
In humans, MAP4K4 is encoded by the MAP4K4 gene located on chromosome 2, position q11.2 and consists of 33 exons responsible for its synthesis. It contains approximately 1200 amino acids, has a molecular mass of ~140 KDa. and its orthologues across various species share molecular and structural similarities.
Structurally MAP4K4 contains the following domains:
- N-Terminal Kinase Domain
- Coiled-coil domain
- C-Terminal Hydrophobic Leucine-Rich Citron Homology Domain (CNH)
- Interdomain - Connects the kinase and CNH domains, facilitates protein-protein interactions. Although it has been identified, its structural components and functionality are currently poorly understood
Alternative splicing of the MAP4K4 gene yields five functional isoforms, all of which display fully homologous kinase and CNH domains but differences in the interdomain domain. While the biological significance of these isoforms remains to be determined, it can be speculated that such variations alter and determine MAP4K4's interactions with other proteins and factors, ultimately leading to the activation/inhibition of different biochemical and physiological cascades.
The mammalian class of Ste20 kinases require phosphorylation at specific sites for full activity. Primary phosphorylation at the activation site in their kinase domain is believed to cause a conformational change in the protein, stabilizing the structure of its activation segment to allow suitable substrate binding. Secondary sites also require phosphorylation for the enzyme to assume full activation and is achieved via autophosphorylation or by upstream kinases.
To date, MAP4K4 has been found to be expressed in all tissue types with a relatively more pronounced expression in the brain and testes. Multiple isoforms of MAP4K4 can be present at any given time in the same cell but the abundance of each isoform in the cell differs depending on the cell-type or tissue-type.
- E.g. In humans, the shorter isoform of MAP4K4 is predominantly expressed in organs including the liver, placenta, skeletal muscles while a longer isoform is expressed in the brain
# Interactions and signaling
## TNF-α
Evidence from mammalian and fly studies indicate that MAP4K4 is involved with tumour necrosis factor alpha (TNF-α) and its c-jun N-terminal kinase (JNK) signaling pathway. MAP4K4 not only mediates TNF-α signaling but also promotes its expression; moreover, TNF-α can elevate MAP4K4 expression using transcription factors
The JNK pathway is implicated in a number of physiological processes and involves JNKs – kinases responsible for the phosphorylation of a downstream protein called c-Jun. This further leads to the increase in expression and activity of specific transcription factors that respond to a variety of cellular stressors, growth factors and cytokines. The activation of the JNK signal transduction pathway by MAP4K4 has been implicated in apoptotic regulation of many different cell types, tumorigenesis and/or inflammation.
## p53
p53 is a tumour suppressor gene and is involved with cellular response to stress. When expressed, the cell cycle is halted in the G1 phase and can induce senescence or apoptosis. Mutations to the p53 gene are often found in many types of cancers.
The MAP4K4 gene contains four binding sites for p53. Upon binding, p53 up-regulates MAP4K4 expression leading to the activation of the JNK signaling pathway. siRNA knockdown experiments have also shown a reduction of p53 induced apoptosis. Current evidence therefore suggests that MAP4K4 has a modulating effect on p53 induced apoptosis in the JNK signaling pathway.
# Clinical significance
## Glucose uptake and insulin function
MAP4K4 has been identified to be involved in the negative regulation of insulin-dependent glucose transport. There is increasing evidence suggesting cytokines such as TNF-α mediate biological effects antagonistic to insulin action and induce inflammation observed in obesity. TNF-α specifically attenuates the signaling pathway initiated by insulin receptors, reducing the amount of glucose transport and uptake; and it is believed that MAP4K4 functions as an upstream signaling element in the TNF-α signaling cascade.
A recent siRNA screen identified the involvement of MAP4K4 in the regulation of the glucose transporter GLUT4. The silencing of MAP4K4 in adipocytes elevated the expression of peroxisome proliferator-activated receptor y (PPARy) – a nuclear hormone receptor responsible for the regulation of genes associated with adipocyte differentiation, including GLUT4. siRNA silencing of MAP4K4 appears to prevent insulin resistance, restoring insulin sensitivity in human skeletal muscles by down-regulating the TNF-α signaling cascade and inhibits the TNF-α-induced depletion of PPARy and GLUT4. Additionally, miRNA silencing of MAP4K4 in pancreatic beta-cells conferred protection against TNF-α repression of insulin transcription and secretion, further confirming that MAP4K4 targeting is a potential strategy for diabetes prevention and treatment.
## Atherosclerosis
Atherosclerosis is the result of an inflammatory response to lipid-mediated vascular damage. It has been identified that cytokines such as TNF-α induce the expression of pro-inflammatory genes to synthesize leukocyte adhesion molecules and chemokines. Endothelial cells highly express MAP4K4 and recent studies have reported that MAP4K4 enhances endothelial permeability. This consequently contributes to the development of atherosclerosis due to the promotion of leukocyte extravasation, transport of oxidized lipids and the formation of plaques.
Silencing of endothelial MAP4K4 ameliorated the development of atherosclerosis in mice. Additionally, treatment of a MAP4K4 protein kinase inhibitor in mice significantly reduced plaque progression and promoted plaque regression suggesting therapeutic targeting of MAP4K4 may be a beneficial strategy for cardiovascular disease.
## Cancer
The biggest causes of death for patients with cancer are tumour invasion and metastasis – processes that are highly correlated with cell migration and motility. There is limited information regarding how MAP4K4 is involved in cancer but studies have shown that MAP4K4 is overexpressed in a number of cancer types including lung, prostate, pancreatic and ovarian cancer where such up-regulation is associated with increased cell migration, adhesion and invasiveness.
Several studies have identified MAP4K4 as an upstream regulator of proteins associated with cytoskeletal dynamics or adhesion. Deletion of the MAP4K4 gene appears to affect membrane dynamics in endothelial cells, resulting in reduced cell migration and impaired angiogenesis; while an overexpression significantly elevates the rate of cell invasion and morphogenesis.
Evidence also indicates that MAP4K4 is a major contributor to the elevated growth and migratory properties of tumour cells. Poor prognosis and clinical progression of hepatocellular carcinoma, pancreatic adenocarcinoma, and colorectal cancer are all closely correlated with MAP4K4 expression levels. | MAP4K4
Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) – also known as hepatocyte progenitor kinase-like/germinal center kinase-like kinase (HGK) and Nck-interacting kinase (NIK) – is an enzyme, specifically a serine/threonine (S/T) kinase encoded by the MAP4K4 gene in humans.[1][2]
MAP4K4 is involved in a wide array of physiological processes including cell migration, proliferation and adhesion;[3] its activity has been implicated in systemic inflammation,[4] metabolic disorders,[5] cardiovascular disease[5] and cancer.[2]
While MAP4K4 has been found to be upregulated in a wide array of cancers, there is currently limited information regarding its specific involvement. However, there is increasing evidence that suggests MAP4K4 has an important role in the development and progression of cancer, and may serve as a novel target for cancer therapeutics.[2]
# Discovery and classification
MAP4K4 is categorized under the mammalian sterile 20 protein (Ste20p) kinase family due to its shared homology with the Ste20p kinase found in budding yeast[1] and is a member of the GCK-IV subfamily. Mammalian MAP4K4 was initially identified in mice as a kinase activator for a protein called Nck[6] followed shortly by identification and cloning of the human orthologue encoded by the MAP4K4 gene.[7]
# Structure and expression
In humans, MAP4K4 is encoded by the MAP4K4 gene located on chromosome 2, position q11.2 and consists of 33 exons responsible for its synthesis.[1] It contains approximately 1200 amino acids, has a molecular mass of ~140 KDa.[6][7] and its orthologues across various species share molecular and structural similarities.
Structurally MAP4K4 contains the following domains:[1]
- N-Terminal Kinase Domain
- Coiled-coil domain
- C-Terminal Hydrophobic Leucine-Rich Citron Homology Domain (CNH)
- Interdomain - Connects the kinase and CNH domains, facilitates protein-protein interactions. Although it has been identified, its structural components and functionality are currently poorly understood
Alternative splicing of the MAP4K4 gene yields five functional isoforms, all of which display fully homologous kinase and CNH domains but differences in the interdomain domain.[9] While the biological significance of these isoforms remains to be determined, it can be speculated that such variations alter and determine MAP4K4's interactions with other proteins and factors, ultimately leading to the activation/inhibition of different biochemical and physiological cascades.
The mammalian class of Ste20 kinases require phosphorylation at specific sites for full activity. Primary phosphorylation at the activation site in their kinase domain is believed to cause a conformational change in the protein, stabilizing the structure of its activation segment to allow suitable substrate binding.[1] Secondary sites also require phosphorylation for the enzyme to assume full activation and is achieved via autophosphorylation or by upstream kinases.[1]
To date, MAP4K4 has been found to be expressed in all tissue types[7] with a relatively more pronounced expression in the brain and testes.[10] Multiple isoforms of MAP4K4 can be present at any given time in the same cell but the abundance of each isoform in the cell differs depending on the cell-type or tissue-type.[10]
- E.g. In humans, the shorter isoform of MAP4K4 is predominantly expressed in organs including the liver, placenta, skeletal muscles while a longer isoform is expressed in the brain
# Interactions and signaling
## TNF-α
Evidence from mammalian and fly studies indicate that MAP4K4 is involved with tumour necrosis factor alpha (TNF-α) and its c-jun N-terminal kinase (JNK) signaling pathway.[11] MAP4K4 not only mediates TNF-α signaling but also promotes its expression;[7] moreover, TNF-α can elevate MAP4K4 expression using transcription factors[12]
The JNK pathway is implicated in a number of physiological processes and involves JNKs – kinases responsible for the phosphorylation of a downstream protein called c-Jun. This further leads to the increase in expression and activity of specific transcription factors that respond to a variety of cellular stressors, growth factors and cytokines. The activation of the JNK signal transduction pathway by MAP4K4 has been implicated in apoptotic regulation of many different cell types,[13] tumorigenesis and/or inflammation.[3]
## p53
p53 is a tumour suppressor gene and is involved with cellular response to stress. When expressed, the cell cycle is halted in the G1 phase and can induce senescence or apoptosis. Mutations to the p53 gene are often found in many types of cancers.
The MAP4K4 gene contains four binding sites for p53. Upon binding, p53 up-regulates MAP4K4 expression leading to the activation of the JNK signaling pathway. siRNA knockdown experiments have also shown a reduction of p53 induced apoptosis.[13] Current evidence therefore suggests that MAP4K4 has a modulating effect on p53 induced apoptosis in the JNK signaling pathway.
# Clinical significance
## Glucose uptake and insulin function
MAP4K4 has been identified to be involved in the negative regulation of insulin-dependent glucose transport. There is increasing evidence suggesting cytokines such as TNF-α mediate biological effects antagonistic to insulin action and induce inflammation observed in obesity.[14][15] TNF-α specifically attenuates the signaling pathway initiated by insulin receptors, reducing the amount of glucose transport and uptake;[16] and it is believed that MAP4K4 functions as an upstream signaling element in the TNF-α signaling cascade.[7]
A recent siRNA screen identified the involvement of MAP4K4 in the regulation of the glucose transporter GLUT4.[17] The silencing of MAP4K4 in adipocytes elevated the expression of peroxisome proliferator-activated receptor y (PPARy) – a nuclear hormone receptor responsible for the regulation of genes associated with adipocyte differentiation, including GLUT4.[18] siRNA silencing of MAP4K4 appears to prevent insulin resistance, restoring insulin sensitivity in human skeletal muscles by down-regulating the TNF-α signaling cascade[19] and inhibits the TNF-α-induced depletion of PPARy and GLUT4.[17] Additionally, miRNA silencing of MAP4K4 in pancreatic beta-cells conferred protection against TNF-α repression of insulin transcription and secretion,[20] further confirming that MAP4K4 targeting is a potential strategy for diabetes prevention and treatment.[20]
## Atherosclerosis
Atherosclerosis is the result of an inflammatory response to lipid-mediated vascular damage. It has been identified that cytokines such as TNF-α induce the expression of pro-inflammatory genes to synthesize leukocyte adhesion molecules and chemokines.[21] Endothelial cells highly express MAP4K4[5] and recent studies have reported that MAP4K4 enhances endothelial permeability.[22] This consequently contributes to the development of atherosclerosis due to the promotion of leukocyte extravasation, transport of oxidized lipids and the formation of plaques.[5]
Silencing of endothelial MAP4K4 ameliorated the development of atherosclerosis in mice.[23] Additionally, treatment of a MAP4K4 protein kinase inhibitor in mice significantly reduced plaque progression and promoted plaque regression[23] suggesting therapeutic targeting of MAP4K4 may be a beneficial strategy for cardiovascular disease.
## Cancer
The biggest causes of death for patients with cancer are tumour invasion and metastasis – processes that are highly correlated with cell migration and motility.[24] There is limited information regarding how MAP4K4 is involved in cancer but studies have shown that MAP4K4 is overexpressed in a number of cancer types including lung, prostate, pancreatic and ovarian cancer where such up-regulation is associated with increased cell migration, adhesion and invasiveness.[3]
Several studies have identified MAP4K4 as an upstream regulator of proteins associated with cytoskeletal dynamics or adhesion. Deletion of the MAP4K4 gene appears to affect membrane dynamics in endothelial cells, resulting in reduced cell migration and impaired angiogenesis;[25] while an overexpression significantly elevates the rate of cell invasion and morphogenesis.[10]
Evidence also indicates that MAP4K4 is a major contributor to the elevated growth and migratory properties of tumour cells.[24][26] Poor prognosis and clinical progression of hepatocellular carcinoma,[26] pancreatic adenocarcinoma,[27] and colorectal cancer[28] are all closely correlated with MAP4K4 expression levels. | https://www.wikidoc.org/index.php/MAP4K4 | |
b6f9eb80d9554ee7446b3c47a9369ea0b78adf3f | wikidoc | MAPK11 | MAPK11
Mitogen-activated protein kinase 11 is an enzyme that in humans is encoded by the MAPK11 gene.
# Function
The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation, and development. This kinase is most closely related to p38 MAP kinase, both of which can be activated by proinflammatory cytokines and environmental stress. This kinase is activated through its phosphorylation by MAP kinase kinases (MKKs), preferably by MKK6. Transcription factor ATF2/CREB2 has been shown to be a substrate of this kinase.
# Interactions
MAPK11 has been shown to interact with HDAC3 and Promyelocytic leukemia protein. | MAPK11
Mitogen-activated protein kinase 11 is an enzyme that in humans is encoded by the MAPK11 gene.[1][2]
# Function
The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation, and development. This kinase is most closely related to p38 MAP kinase, both of which can be activated by proinflammatory cytokines and environmental stress. This kinase is activated through its phosphorylation by MAP kinase kinases (MKKs), preferably by MKK6. Transcription factor ATF2/CREB2 has been shown to be a substrate of this kinase.[2]
# Interactions
MAPK11 has been shown to interact with HDAC3[3] and Promyelocytic leukemia protein.[4] | https://www.wikidoc.org/index.php/MAPK11 | |
9518bb28cfe027e86e584eb9b0c4e2ecaee3b276 | wikidoc | MAPK14 | MAPK14
Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.
MAPK14 encodes p38α mitogen-activated protein kinase (MAPK) which is the prototypic member of the p38 MAPK family. p38 MAPKs are also known as stress-activated serine/threonine-specific kinases (SAPKs). In addition to MAPK14 for p38α MAPK, the p38 MAPK family has three additional members, including MAPK11, MAPK12 and MAPK13 which encodes p38β MAPK, p38γ MAPK and p38δ MAPK isoforms, respectively. p38α MAPK was originally identified as a tyrosine phosphorylated protein detected in activated immune cell macrophages with an essential role in inflammatory cytokine induction, such as Tumor Necrotic Factor α (TNFα). However, p38α MAPK mediated kinase activity has been implicated in many tissues beyond immune systems. p38α MAPK is mainly activated through MAPK kinase kinase cascades and exerts its biological function via downstream substrate phosphorylation. p38α MAPK is implicated in diverse cellular function, from gene expression to programmed cell death through a network of signaling molecules and transcription factors. Pharmacological and genetic inhibition of p38α MAPK not only revealed its biological significance in physiological function but also the potential of targeting p38α MAPK in human diseases such as immune disorder and heart failure.
# Structure
MAPK14 is a 41 kDa protein composed of 360 amino acids.
# Function
The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various environmental stresses and proinflammatory cytokines. The activation requires its phosphorylation by MAP kinase kinases (MKKs), or its autophosphorylation triggered by the interaction of MAP3K7IP1/TAB1 protein with this kinase. The substrates of this kinase include transcription regulator ATF2, MEF2C, and MAX, cell cycle regulator CDC25B, and tumor suppressor p53, which suggest the roles of this kinase in stress-related transcription and cell cycle regulation, as well as in genotoxic stress response. Four alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.
p38α MAPK is ubiquitously expressed in many cell types, in contrast, p38β MAPK is highly expressed in brain and lung, p38γ MAPK mostly in skeletal muscle and nerve system, and p38δ MAPK in uterus and pancreas. Like all MAP kinases, p38α MAPK has 11 conserved domains (Domains I to XI) and a Thr-Gly-Tyr (TGY) dual phosphorylation motif.
Activation of p38 MAPK pathway has been implicated in a variety of stress response in addition to inflammation, including osmotic shock, heat, and oxidative stress. The canonical pathway for p38 MAPK activation involve a cascade of protein kinases, including MAP3K such as MEKK1, 2, 3 and 4, TGFβ-activated kinase (TAK1), TAO1-3, mixed-lineage kinase 2/3 (MLK2/3), and apoptosis signal-regulating kinase 1/2 (ASK1/2), as well as MAP2Ks, such as MKK3, 6 and 4. MAP2K mediated phosphorylation of the TGY motif results in conformational change of p38 MAPK which allows kinase activation and accessibility to substrates. In addition, TAK1-binding protein 1 (TAB1) and ZAP70 can induce p38 MAPK via non-canonical autophosphorylation. Furthermore, acetylation of p38 MAPK at lys-53 of the ATP-binding pocket also enhances p38 MAPK activity during cellular stress Under basal conditions, p38α MAPK is detected in both the nucleus and the cytoplasm. One of the consequences of p38 MAPK activation is translocation into the nucleus. involving both p38 MAPK phosphorylation and microtuble- and dynein-dependent process. In addition, one substrate of p38 MAPK, MAP kinase-activated protein kinase 2 (MAPAK2 or MK2) can modulate and direct p38α MAPK localization to cytosole via direct interaction.
p38α MAPK activation can be reversed by dephosphorylation of the TGY motif carried out by protein phosphatases, including ser-thr protein phosphatases (PPs), protein tyrosine phosphatases (PTP), and dual-specificity phosphatases (DUSP). For example, ser/thr phosphatases PP2Cα/β suppress activity of p38s MAPK through direct interaction as well as suppression of MKKs/TAK1 in mammalian cells. Hematopoietic PTP (HePTP) and striatal-enriched phosphatase (STEP) bind to MAPKs through a kinase-interaction motif (KIM) and inactivates them by dephosphorylating the phosphotyrosine residue in their activation loop. DUSPs, which have a docking domain to MAPKs and dual-specific phosphatase activity, can also bind to p38 MAPKs and dephosphorylate of both phosphotyrosine and phosphothreonine residues. In addition to these phosphatases, other molecular components such as Hsp90-Cdc37 chaperone complex can also modulate p38 MAPK autophosphorylation activity and prevents non-canonical activation.
p38α MAPK is implicated in cell survival/apoptosis, proliferation, differentiation, migration, mRNA stability, and inflammatory response in different cell types through variety of different target molecules MK2 is one of the well-studied downstream targets of p38α MAPK. Their downstream substrates include small heat shock protein 27 (HSP27), lymphocyte-specific protein1 (LSP1), cAMP response element-binding protein (CREB), cyclooxygenase 2 (COX2), activating transcription factor 1 (ATF1), serum response factor (SRF), and mRNA-binding protein tristetraprolin (TTP) In addition to protein kinases, many transcription factors are downstream targets of p38α MAPK, including ATF1/2/6, c-Myc, c-FOS, GATA4, MEF2A/C, SRF, STAT1, and CHOP
# Role in cardiovascular system
p38α MAPK constitutes the main p38 MAPK activity in heart. During cardiomyocyte maturation in new born mouse heart, p38α MAPK activity can regulate myocyte cytokinesis and promote cell cycle exit. while inhibition of p38 MAPK activity leads to induction of mitosis in both adult and fetal cardiomyocyte. Therefore, p38 MAPK is associated with cell-cycle arrest in mammalian cardiomyocytes and its inhibition may represent a strategy to promote cardiac regeneration in response to injury. In addition, p38α MAPK induction promotes myocyte apoptosis. via downstream targets STAT1, CHOP, FAK, SMAD, cytochrome c, NF-κB, PTEN, and p53. p38 MAPK can also target IRS-1 mediated AKT signaling and promotes myocyte death under chronic insulin stimulation. Inhibition of p38 MAPK activity confers cardioprotection against ischemia reperfusion injury in heart However, some reports demonstrated that p38 MAPK also involves in anti-apoptotic effect via phosphorylation of αβ-Crystallin or induction of Pim-3 during early response to oxidative stress or anoxic preconditioning respectively Both p38α MAPK and p38β MAPK appear to have an opposite role in apoptosis. Whereas p38α MAPK has a pro-apoptotic role via p53 activation, p38β MAPK has a pro-survival role via inhibition of ROS formation. In general, chronic activation of p38 MAPK activity is viewed as pathological and pro-apoptotic, and inhibition of p38 MAPK activity is in clinical evaluation as a potential therapy to mitigate acute injury in ischemic heart failure. p38 MAPK activity is also implicated in cardiac hypertrophy which is a significant feature of pathological remodeling in the diseased hearts and a major risk factor for heart failure and advert outcome. Most in vitro evidence supports that p38 MAPK activation promotes cardiomyocyte hypertrophy. However, in vivo evidence suggest that chronic activation of p38 MAPK activity triggers restrictive cardiomyopathy with limited hypertrophy, while genetic inactivation p38α MAPK in mouse heart results in an elevated cardiac hypertrophy in response to pressure overload or swimming exercise. Therefore, the functional role of p38 MAPK in cardiac hypertrophy remains controversial and yet to be further elucidated.
# Interactions
MAPK14 has been shown to interact with:
- AKT1,
- ATF2,
- CDC25B,
- CDC25C,
- CSNK2A1,
- DUSP10,
- DUSP16,
- DUSP1,
- FUBP1,
- HTRA2,
- KRT8
- MAP2K6,
- MAP3K7IP1,
- MAPK1,
- MEF2A,
- MAPKAPK3,
- MEF2A,
- RPS6KA4, and
- ZFP36L1.
# Notes | MAPK14
Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.[1]
MAPK14 encodes p38α mitogen-activated protein kinase (MAPK) which is the prototypic member of the p38 MAPK family. p38 MAPKs are also known as stress-activated serine/threonine-specific kinases (SAPKs). In addition to MAPK14 for p38α MAPK, the p38 MAPK family has three additional members, including MAPK11, MAPK12 and MAPK13 which encodes p38β MAPK, p38γ MAPK and p38δ MAPK isoforms, respectively. p38α MAPK was originally identified as a tyrosine phosphorylated protein detected in activated immune cell macrophages with an essential role in inflammatory cytokine induction, such as Tumor Necrotic Factor α (TNFα).[2][3] However, p38α MAPK mediated kinase activity has been implicated in many tissues beyond immune systems. p38α MAPK is mainly activated through MAPK kinase kinase cascades and exerts its biological function via downstream substrate phosphorylation. p38α MAPK is implicated in diverse cellular function, from gene expression to programmed cell death through a network of signaling molecules and transcription factors. Pharmacological and genetic inhibition of p38α MAPK not only revealed its biological significance in physiological function but also the potential of targeting p38α MAPK in human diseases such as immune disorder and heart failure.
# Structure
MAPK14 is a 41 kDa protein composed of 360 amino acids.[4][5]
# Function
The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various environmental stresses and proinflammatory cytokines. The activation requires its phosphorylation by MAP kinase kinases (MKKs), or its autophosphorylation triggered by the interaction of MAP3K7IP1/TAB1 protein with this kinase. The substrates of this kinase include transcription regulator ATF2, MEF2C, and MAX, cell cycle regulator CDC25B, and tumor suppressor p53, which suggest the roles of this kinase in stress-related transcription and cell cycle regulation, as well as in genotoxic stress response. Four alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.[6]
p38α MAPK is ubiquitously expressed in many cell types, in contrast, p38β MAPK is highly expressed in brain and lung, p38γ MAPK mostly in skeletal muscle and nerve system, and p38δ MAPK in uterus and pancreas.[7][8] Like all MAP kinases, p38α MAPK has 11 conserved domains (Domains I to XI) and a Thr-Gly-Tyr (TGY) dual phosphorylation motif.
Activation of p38 MAPK pathway has been implicated in a variety of stress response in addition to inflammation, including osmotic shock, heat, and oxidative stress.[7][9][10] The canonical pathway for p38 MAPK activation involve a cascade of protein kinases, including MAP3K such as MEKK1, 2, 3 and 4, TGFβ-activated kinase (TAK1), TAO1-3, mixed-lineage kinase 2/3 (MLK2/3), and apoptosis signal-regulating kinase 1/2 (ASK1/2), as well as MAP2Ks, such as MKK3, 6 and 4. MAP2K mediated phosphorylation of the TGY motif results in conformational change of p38 MAPK which allows kinase activation and accessibility to substrates.[11] In addition, TAK1-binding protein 1 (TAB1) and ZAP70 can induce p38 MAPK via non-canonical autophosphorylation.[12][13][14] Furthermore, acetylation of p38 MAPK at lys-53 of the ATP-binding pocket also enhances p38 MAPK activity during cellular stress[15] Under basal conditions, p38α MAPK is detected in both the nucleus and the cytoplasm. One of the consequences of p38 MAPK activation is translocation into the nucleus.[16] involving both p38 MAPK phosphorylation and microtuble- and dynein-dependent process.[17] In addition, one substrate of p38 MAPK, MAP kinase-activated protein kinase 2 (MAPAK2 or MK2) can modulate and direct p38α MAPK localization to cytosole via direct interaction.[18]
p38α MAPK activation can be reversed by dephosphorylation of the TGY motif carried out by protein phosphatases, including ser-thr protein phosphatases (PPs), protein tyrosine phosphatases (PTP), and dual-specificity phosphatases (DUSP). For example, ser/thr phosphatases PP2Cα/β suppress activity of p38s MAPK through direct interaction as well as suppression of MKKs/TAK1 in mammalian cells.[19][20] Hematopoietic PTP (HePTP) and striatal-enriched phosphatase (STEP) bind to MAPKs through a kinase-interaction motif (KIM) and inactivates them by dephosphorylating the phosphotyrosine residue in their activation loop.[21][22][23] DUSPs, which have a docking domain to MAPKs and dual-specific phosphatase activity, can also bind to p38 MAPKs and dephosphorylate of both phosphotyrosine and phosphothreonine residues.[11] In addition to these phosphatases, other molecular components such as Hsp90-Cdc37 chaperone complex can also modulate p38 MAPK autophosphorylation activity and prevents non-canonical activation.[24]
p38α MAPK is implicated in cell survival/apoptosis, proliferation, differentiation, migration, mRNA stability, and inflammatory response in different cell types through variety of different target molecules[25] MK2 is one of the well-studied downstream targets of p38α MAPK. Their downstream substrates include small heat shock protein 27 (HSP27), lymphocyte-specific protein1 (LSP1), cAMP response element-binding protein (CREB), cyclooxygenase 2 (COX2), activating transcription factor 1 (ATF1), serum response factor (SRF), and mRNA-binding protein tristetraprolin (TTP)[16][26] In addition to protein kinases, many transcription factors are downstream targets of p38α MAPK, including ATF1/2/6, c-Myc, c-FOS, GATA4, MEF2A/C, SRF, STAT1, and CHOP[27][28][29][30]
# Role in cardiovascular system
p38α MAPK constitutes the main p38 MAPK activity in heart. During cardiomyocyte maturation in new born mouse heart, p38α MAPK activity can regulate myocyte cytokinesis and promote cell cycle exit.[31] while inhibition of p38 MAPK activity leads to induction of mitosis in both adult and fetal cardiomyocyte.[32][33] Therefore, p38 MAPK is associated with cell-cycle arrest in mammalian cardiomyocytes and its inhibition may represent a strategy to promote cardiac regeneration in response to injury. In addition, p38α MAPK induction promotes myocyte apoptosis.[34][35] via downstream targets STAT1, CHOP, FAK, SMAD, cytochrome c, NF-κB, PTEN, and p53.[36][37][38][39][40][41][42] p38 MAPK can also target IRS-1 mediated AKT signaling and promotes myocyte death under chronic insulin stimulation.[43] Inhibition of p38 MAPK activity confers cardioprotection against ischemia reperfusion injury in heart[44][45] However, some reports demonstrated that p38 MAPK also involves in anti-apoptotic effect via phosphorylation of αβ-Crystallin or induction of Pim-3 during early response to oxidative stress or anoxic preconditioning respectively[46][47][48] Both p38α MAPK and p38β MAPK appear to have an opposite role in apoptosis.[49] Whereas p38α MAPK has a pro-apoptotic role via p53 activation, p38β MAPK has a pro-survival role via inhibition of ROS formation.[50][51] In general, chronic activation of p38 MAPK activity is viewed as pathological and pro-apoptotic, and inhibition of p38 MAPK activity is in clinical evaluation as a potential therapy to mitigate acute injury in ischemic heart failure.[52] p38 MAPK activity is also implicated in cardiac hypertrophy which is a significant feature of pathological remodeling in the diseased hearts and a major risk factor for heart failure and advert outcome. Most in vitro evidence supports that p38 MAPK activation promotes cardiomyocyte hypertrophy.[49][53][54][55] However, in vivo evidence suggest that chronic activation of p38 MAPK activity triggers restrictive cardiomyopathy with limited hypertrophy,[56] while genetic inactivation p38α MAPK in mouse heart results in an elevated cardiac hypertrophy in response to pressure overload [57][58] or swimming exercise.[59] Therefore, the functional role of p38 MAPK in cardiac hypertrophy remains controversial and yet to be further elucidated.
# Interactions
MAPK14 has been shown to interact with:
- AKT1,[60]
- ATF2,[61][62][63]
- CDC25B,[64]
- CDC25C,[64]
- CSNK2A1,[65]
- DUSP10,[66][67][68]
- DUSP16,[66][69]
- DUSP1,[66][70]
- FUBP1,[71]
- HTRA2,[72]
- KRT8[73]
- MAP2K6,[62][74][75][76]
- MAP3K7IP1,[13]
- MAPK1,[67][74]
- MEF2A,[60][77]
- MAPKAPK3,[67]
- MEF2A,[78][79]
- RPS6KA4,[80] and
- ZFP36L1.[81]
# Notes | https://www.wikidoc.org/index.php/MAPK14 | |
6a5531bf3f2a447032c161917ac9fd17a7caf906 | wikidoc | MAPK15 | MAPK15
Mitogen-activated protein kinase 15, also known as MAPK15, ERK7, or ERK8, is an enzyme that in humans is encoded by the MAPK15 gene.
Evolutionarily, MAPK15 is conserved in a number of species, including P. troglodytes, B. taurus, M. musculus, R. norvegicus, D. rerio, D. melanogaster, C. elegans, and X. laevis.
# Function
The protein encoded by this gene is a member of the MAP (mitogen-activated protein) kinase family. MAP kinases are also known as extracellular signal-regulated kinases (ERKs), and are involved in signaling cascades that regulate a number of cellular processes, including proliferation, differentiation, and transcriptional regulation. MAPK15 is often referred to as ERK7 or ERK8, and the latter two share 69% amino acid sequence similarity; at least one study has suggested that the two are, in fact, distinct proteins.
In vertebrate models, ERK8 is not constitutively active, and exhibits relatively low basal kinase activity. It contains two SH3 (SRC homology 3) binding motifs in its C-terminal region, and is likely activated by an SRC-dependent signaling pathway. SRC is a non-receptor tyrosine kinase (and proto-oncogene) that has been implicated in cancer growth and progression in humans when it is overexpressed. The exact function of MAPK15 is unknown, though a number of studies have implicated the enzyme in various cellular pathways.
Specifically, MAPK15 expression is significantly reduced in human lung and breast carcinomas, and MAPK15 down-regulation is correlated with increased cell motility. MAPK15 has also been found to negatively regulate protein O-glycosylation with acetyl galactosamine (GalNAc), a process in which a sugar molecule is covalently attached to an oxygen atom on an amino acid residue. Mammalian MAPK15 is a putative regulator of the cellular localization and transcriptional activity of estrogen-related receptor alpha (ERRa), as well as an inhibitor of proliferating cell nuclear antigen (PCNA) degradation. PCNA is critical for DNA replication, and is an essential factor in protecting genome stability. MAPK15 has also been shown to regulate ciliogenesis in X. laevis (African clawed frog) embryos by phosphorylating an actin regulator called CapZIP.
# Interactions
MAPK15 has been demonstrated to interact with gamma-aminobutyric acid receptor-associated protein (GABARAP) and microtubule-associated proteins 1A/1B light chain 3A (MAP1LC3A, or LC3) in a process that stimulates autophagy. A number of additional proteins also interact with MAPK15, including cyclin-dependent kinase 2 (CDK2), mitogen-activated protein kinase 12 (MAPK12), and lactotransferrin (LTF), among many others.
# Clinical significance
Due to its role in protecting genomic integrity and cell motility, MAPK15 has been identified as a potential target for cancer therapeutics. Additionally, given the putative role that MAPK15 plays in the regulation of ciliogenesis, it may be an ideal target for diseases related to human ciliary defects (often called ciliopathies). | MAPK15
Mitogen-activated protein kinase 15, also known as MAPK15, ERK7, or ERK8, is an enzyme that in humans is encoded by the MAPK15 gene.[1][2]
Evolutionarily, MAPK15 is conserved in a number of species, including P. troglodytes, B. taurus, M. musculus, R. norvegicus, D. rerio, D. melanogaster, C. elegans, and X. laevis.[2]
# Function
The protein encoded by this gene is a member of the MAP (mitogen-activated protein) kinase family. MAP kinases are also known as extracellular signal-regulated kinases (ERKs), and are involved in signaling cascades that regulate a number of cellular processes, including proliferation, differentiation, and transcriptional regulation. MAPK15 is often referred to as ERK7 or ERK8, and the latter two share 69% amino acid sequence similarity; at least one study has suggested that the two are, in fact, distinct proteins.
In vertebrate models, ERK8 is not constitutively active, and exhibits relatively low basal kinase activity.[3] It contains two SH3 (SRC homology 3) binding motifs in its C-terminal region, and is likely activated by an SRC-dependent signaling pathway.[1] SRC is a non-receptor tyrosine kinase (and proto-oncogene) that has been implicated in cancer growth and progression in humans when it is overexpressed. The exact function of MAPK15 is unknown, though a number of studies have implicated the enzyme in various cellular pathways.
Specifically, MAPK15 expression is significantly reduced in human lung and breast carcinomas, and MAPK15 down-regulation is correlated with increased cell motility.[3] MAPK15 has also been found to negatively regulate protein O-glycosylation with acetyl galactosamine (GalNAc), a process in which a sugar molecule is covalently attached to an oxygen atom on an amino acid residue.[3] Mammalian MAPK15 is a putative regulator of the cellular localization and transcriptional activity of estrogen-related receptor alpha (ERRa), as well as an inhibitor of proliferating cell nuclear antigen (PCNA) degradation.[4][5] PCNA is critical for DNA replication, and is an essential factor in protecting genome stability. MAPK15 has also been shown to regulate ciliogenesis in X. laevis (African clawed frog) embryos by phosphorylating an actin regulator called CapZIP.[6]
# Interactions
MAPK15 has been demonstrated to interact with gamma-aminobutyric acid receptor-associated protein (GABARAP) and microtubule-associated proteins 1A/1B light chain 3A (MAP1LC3A, or LC3) in a process that stimulates autophagy.[7] A number of additional proteins also interact with MAPK15, including cyclin-dependent kinase 2 (CDK2), mitogen-activated protein kinase 12 (MAPK12), and lactotransferrin (LTF), among many others.[2]
# Clinical significance
Due to its role in protecting genomic integrity and cell motility, MAPK15 has been identified as a potential target for cancer therapeutics.[8] Additionally, given the putative role that MAPK15 plays in the regulation of ciliogenesis, it may be an ideal target for diseases related to human ciliary defects (often called ciliopathies). | https://www.wikidoc.org/index.php/MAPK15 | |
6baa06c1357e21dfe90f4c511f805f6a0d8d7cb4 | wikidoc | MARCH5 | MARCH5
E3 ubiquitin-protein ligase MARCH5, also known as membrane-associated ring finger (C3HC4) 5, is an enzyme that, in humans, is encoded by the MARCH5 gene. It is localized in the mitochondrial outer membrane and has four transmembrane domains.
# Structure
## Gene
The human gene MARCH5, also known as MITOL or RNF153, has 7 Exons and locates at the chromosome band 10q23.32-q23.33.
## Protein
The human E3 ubiquitin-protein ligase MARCH5 protein, a member of the transmembrane RING‐finger protein family is 31 kDa in size and composed of 278 amino acids with a N-terminal Zinc-finger domain at amino acid sequence 6-75 and four C-terminal transmembrane spans. The theoretical PI of this protein is 9.00.
# Function
As a E3 ubiquitin ligases, enzyme MARCH 5 catalyzes the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to an identified protein substrate. MARCH5 was firstly identified as a mitofusin 2- and Drp1-binding protein. MARCH5 promotes ubiquitination of Drp1 and a knockdown of MARCH5 is by RNAi led to abnormal mitochondrial fusion. Further evidences show that MARCH 5 specifically interacts with mitofusin 1, by reducing the levels of it during certain phases of the cell cycle. Given the facts that MARCH5 regulates the protein proteostasis of Drp1, mitofusin 1, and mitofusin 2 that are pivotal regulators of mitochondrial fusion and fission, MARCH5 is critical for the regulation of standard mitochondria morphology, and deficiencies in it promote cellular senescence.
# Clinical significance
Considering that both Drp1 and MAP1B are substrates for MITOL, MITOL is thought to play a protective role against nitrosative stress-mediated disruption of mitochondrial dynamics such as morphological stability and transport of mitochondria. As significantly decreased expression of MITOL occurs in response to ageing in normal tissues, MITOL may control ageing by regulating the production of ROS in mitochondria. From a pathological perspective, in a neuronal cell model, dominant-negative MARCH5 prevents mitochondrial fragmentation during neurodegenerative stress induced by the neuron-specific reactive oxygen generator 6-hydroxydopamine, the complex I inhibitor rotenone or Alzheimer's-related amyloid beta peptide. MARCH5 is also involved in the removal of proteins associated with specific neurodegenerative disorders such as ataxin-3 in Machado–Joseph disease or mSOD1 in amyotrophic lateral sclerosis likely supporting mitochondrial function. MARCH5 has also been linked to toll-like receptors (TLRs), which recognize distinct pathogen-associated molecular patterns and play a critical role in the innate immune response.
Ubiquitin-dependent degradation pathways have clear cancer relevance due to their integral involvement in protein quality control, regulation of immune responses, signal transduction, and cell cycle regulation. | MARCH5
E3 ubiquitin-protein ligase MARCH5, also known as membrane-associated ring finger (C3HC4) 5, is an enzyme that, in humans, is encoded by the MARCH5 gene. It is localized in the mitochondrial outer membrane and has four transmembrane domains.[1][2][3]
# Structure
## Gene
The human gene MARCH5, also known as MITOL or RNF153, has 7 Exons and locates at the chromosome band 10q23.32-q23.33.[2]
## Protein
The human E3 ubiquitin-protein ligase MARCH5 protein, a member of the transmembrane RING‐finger protein family[4] is 31 kDa in size and composed of 278 amino acids with a N-terminal Zinc-finger domain at amino acid sequence 6-75 and four C-terminal transmembrane spans.[3] The theoretical PI of this protein is 9.00.[5]
# Function
As a E3 ubiquitin ligases, enzyme MARCH 5 catalyzes the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to an identified protein substrate. MARCH5 was firstly identified as a mitofusin 2- and Drp1-binding protein.[3] MARCH5 promotes ubiquitination of Drp1 and a knockdown of MARCH5 is by RNAi led to abnormal mitochondrial fusion.[6] Further evidences show that MARCH 5 specifically interacts with mitofusin 1, by reducing the levels of it during certain phases of the cell cycle.[7] Given the facts that MARCH5 regulates the protein proteostasis of Drp1, mitofusin 1, and mitofusin 2 that are pivotal regulators of mitochondrial fusion and fission, MARCH5 is critical for the regulation of standard mitochondria morphology, and deficiencies in it promote cellular senescence.[8]
# Clinical significance
Considering that both Drp1 and MAP1B are substrates for MITOL, MITOL is thought to play a protective role against nitrosative stress-mediated disruption of mitochondrial dynamics such as morphological stability and transport of mitochondria. As significantly decreased expression of MITOL occurs in response to ageing in normal tissues, MITOL may control ageing by regulating the production of ROS in mitochondria.[9] From a pathological perspective, in a neuronal cell model, dominant-negative MARCH5 prevents mitochondrial fragmentation during neurodegenerative stress induced by the neuron-specific reactive oxygen generator 6-hydroxydopamine, the complex I inhibitor rotenone or Alzheimer's-related amyloid beta peptide. MARCH5 is also involved in the removal of proteins associated with specific neurodegenerative disorders such as ataxin-3 in Machado–Joseph disease or mSOD1 in amyotrophic lateral sclerosis likely supporting mitochondrial function.[10] MARCH5 has also been linked to toll-like receptors (TLRs), which recognize distinct pathogen-associated molecular patterns and play a critical role in the innate immune response.[11]
Ubiquitin-dependent degradation pathways have clear cancer relevance due to their integral involvement in protein quality control, regulation of immune responses, signal transduction, and cell cycle regulation.[12] | https://www.wikidoc.org/index.php/MARCH5 | |
9c80a3e26579064680210dda9c529b1d90ca40b0 | wikidoc | MARCKS | MARCKS
Myristoylated alanine-rich C-kinase substrate is a protein that in humans is encoded by the MARCKS gene.
It plays important roles in cell shape, cell motility, secretion, transmembrane transport, regulation of the cell cycle, and neural development. Recently, MARCKS has been implicated in the exocytosis of a number of vesicles and granules such as mucin and chromaffin.
It is also the name of a protein family, of which MARCKS is the most studied member. They are intrinsically disordered proteins, with an acidic pH, with high proportions of alanine, glycine, proline, and glutamic acid. They are membrane-bound through a lipid anchor at the N-terminus, and a polybasic domain in the middle. They are regulated by Ca2+/calmodulin and protein kinase C. In their unphosphorylated form, they bind to actin filaments, causing them to crosslink, and sequester acidic membrane phospholipids such as PIP2.
The protein encoded by this gene is a substrate for protein kinase C. It is localized to the plasma membrane and is an actin filament crosslinking protein. Phosphorylation by protein kinase C or binding to calcium-calmodulin inhibits its association with actin and with the plasma membrane, leading to its presence in the cytoplasm. The protein is thought to be involved in cell motility, phagocytosis, membrane trafficking and mitogenesis.
# Interactions
MARCKS has been shown to interact with TOB1 and with NMT2. | MARCKS
Myristoylated alanine-rich C-kinase substrate is a protein that in humans is encoded by the MARCKS gene.[1][2][3]
It plays important roles in cell shape, cell motility, secretion, transmembrane transport, regulation of the cell cycle, and neural development.[4] Recently, MARCKS has been implicated in the exocytosis of a number of vesicles and granules such as mucin and chromaffin.
It is also the name of a protein family, of which MARCKS is the most studied member. They are intrinsically disordered proteins, with an acidic pH, with high proportions of alanine, glycine, proline, and glutamic acid. They are membrane-bound through a lipid anchor at the N-terminus, and a polybasic domain in the middle. They are regulated by Ca2+/calmodulin and protein kinase C. In their unphosphorylated form, they bind to actin filaments, causing them to crosslink, and sequester acidic membrane phospholipids such as PIP2.
The protein encoded by this gene is a substrate for protein kinase C. It is localized to the plasma membrane and is an actin filament crosslinking protein. Phosphorylation by protein kinase C or binding to calcium-calmodulin inhibits its association with actin and with the plasma membrane, leading to its presence in the cytoplasm. The protein is thought to be involved in cell motility, phagocytosis, membrane trafficking and mitogenesis.[3]
# Interactions
MARCKS has been shown to interact with TOB1[5] and with NMT2.[6] | https://www.wikidoc.org/index.php/MARCKS | |
838c0d4642a685e999412370a98a310ee0689a5e | wikidoc | MART-1 | MART-1
MART-1 / Melan-A is a protein antigen found on melanocytes. Antibodies against the antigen are used in the medical specialty of anatomic pathology in order to recognize cells of melanocytic differentiation, useful for the diagnosis of a melanoma. The same name is also used to refer to the gene which codes for the antigen.
The names MART-1 and Melan-A were coined by two groups of researchers who independently sequenced the gene for this antigen in 1994. Both names are currently in common use. Kawakami et al. at the National Cancer Institute coined the term MART-1, which stands for "Melanoma Antigen Recognized by T-cells." Coulie et al. of Belgium called the gene Melan-A, presumably an abbreviation for "melanocyte antigen."
The MART-1 / Melan-A antigen is specific for the melanocyte lineage, found in normal skin, the retina, and melanocytes, but not in other normal tissues. It is thus useful as a marker for melanocytic tumors (melanomas) with the caveat that it is normally found in benign nevi as well.
MART-1 / Melan-A is a putative 18 kDa transmembrane protein consisting of 118 amino acids. It has a single transmembrane domain. | MART-1
MART-1 / Melan-A is a protein antigen found on melanocytes. Antibodies against the antigen are used in the medical specialty of anatomic pathology in order to recognize cells of melanocytic differentiation, useful for the diagnosis of a melanoma. The same name is also used to refer to the gene which codes for the antigen.
The names MART-1 and Melan-A were coined by two groups of researchers who independently sequenced the gene for this antigen in 1994. Both names are currently in common use. Kawakami et al. at the National Cancer Institute coined the term MART-1, which stands for "Melanoma Antigen Recognized by T-cells." Coulie et al. of Belgium called the gene Melan-A, presumably an abbreviation for "melanocyte antigen."
The MART-1 / Melan-A antigen is specific for the melanocyte lineage, found in normal skin, the retina, and melanocytes, but not in other normal tissues. It is thus useful as a marker for melanocytic tumors (melanomas) with the caveat that it is normally found in benign nevi as well.
MART-1 / Melan-A is a putative 18 kDa transmembrane protein consisting of 118 amino acids. It has a single transmembrane domain. | https://www.wikidoc.org/index.php/MART-1 | |
bc53f63dc9496ffa64938794e41c01c2a9b39410 | wikidoc | MCOLN3 | MCOLN3
Mucolipin-3 also known as TRPML3 (transient receptor potential cation channel, mucolipin subfamily, member 3) is a protein that in humans is encoded by the MCOLN3 gene. It is a member of the small family of the TRPML channels, a subgroup of the large protein family of TRP ion channels.
# Gene
In human, the MCOLN3 gene resides on the short arm of chromosome 1 at 1p22.3. The gene is split in 12 exons, which entail the open reading frame of 1659 nucleotides. The encoded protein, TRPML3, has 553 amino acid with a predicted molecular weight of ≈64 kDa. Computational analyses of the secondary structure predict the presence of six transmembrane domains, an ion transport motif (PF00520) and a transient receptor potential motif (PS50272).
In the mouse, Mcoln3, is located on the distal end of chromosome 3 at cytogenetic band qH2. Human and mouse TRPML3 proteins share 91% sequence identity.
All vertebrate species, for which a genomic sequence is available, harbor the MCOLN3 gene. Homologs of MCOLN3 are also present in the genome of insects (Drosophila melanogaster), nematodes (Caenorhabditis elegans), sea urchin (Strongylocentrotus purpuratus) and lower organisms including Hydra and Dictyostelium.
# Expression
# Function
TRPML3 is an inwardly-rectifying cation channel.
# Genetics
# Phenotypes
Mutations of the MCOLN3 gene in mice result in auditory hair cell death and deafness. | MCOLN3
Mucolipin-3 also known as TRPML3 (transient receptor potential cation channel, mucolipin subfamily, member 3) is a protein that in humans is encoded by the MCOLN3 gene.[1] It is a member of the small family of the TRPML channels, a subgroup of the large protein family of TRP ion channels.[2]
# Gene
In human, the MCOLN3 gene resides on the short arm of chromosome 1 at 1p22.3. The gene is split in 12 exons, which entail the open reading frame of 1659 nucleotides. The encoded protein, TRPML3, has 553 amino acid with a predicted molecular weight of ≈64 kDa. Computational analyses of the secondary structure predict the presence of six transmembrane domains, an ion transport motif (PF00520) and a transient receptor potential motif (PS50272).
In the mouse, Mcoln3, is located on the distal end of chromosome 3 at cytogenetic band qH2. Human and mouse TRPML3 proteins share 91% sequence identity.[3]
All vertebrate species, for which a genomic sequence is available, harbor the MCOLN3 gene. Homologs of MCOLN3 are also present in the genome of insects (Drosophila melanogaster), nematodes (Caenorhabditis elegans), sea urchin (Strongylocentrotus purpuratus) and lower organisms including Hydra and Dictyostelium.
# Expression
# Function
TRPML3 is an inwardly-rectifying cation channel.[1]
# Genetics
# Phenotypes
Mutations of the MCOLN3 gene in mice result in auditory hair cell death and deafness.[4] | https://www.wikidoc.org/index.php/MCOLN3 | |
dd18e284f8607317c28c52bdafcd49a3d5fd6df1 | wikidoc | MEGF10 | MEGF10
Multiple EGF-like-domains 10 is a protein that in humans is encoded by the MEGF10 gene.
MEGF10 is a regulator of satellite cell myogenesis and interacts with Notch1 in myoblasts. It has been shown to be the cause of early-onset myopathy, areflexia, respiratory distress and dysphagia.
MEGF10 and MEGF11, have critical roles in the formation of mosaics by two retinal interneuron subtypes, starburst amacrine cells and horizontal cells in mice. These cells are less likely to be near neighbours of the same subtype than would occur by chance, resulting in 'exclusion zones' that separate them. Mosaic arrangements provide a mechanism to distribute each cell type evenly across the retina, ensuring that all parts of the visual field have access to a full set of processing elements. | MEGF10
Multiple EGF-like-domains 10 is a protein that in humans is encoded by the MEGF10 gene.[1]
MEGF10 is a regulator of satellite cell myogenesis and interacts with Notch1 in myoblasts.[2] It has been shown to be the cause of early-onset myopathy, areflexia, respiratory distress and dysphagia.[3]
MEGF10 and MEGF11, have critical roles in the formation of mosaics by two retinal interneuron subtypes, starburst amacrine cells and horizontal cells in mice. These cells are less likely to be near neighbours of the same subtype than would occur by chance, resulting in 'exclusion zones' that separate them. Mosaic arrangements provide a mechanism to distribute each cell type evenly across the retina, ensuring that all parts of the visual field have access to a full set of processing elements.[4] | https://www.wikidoc.org/index.php/MEGF10 | |
4a989004bf5a26c1490fa7c334cf94aaf6daf1f3 | wikidoc | METAP2 | METAP2
Methionine aminopeptidase 2 is an enzyme that in humans is encoded by the METAP2 gene.
Methionine aminopeptidase 2, a member of the dimetallohydrolase family, is a cytosolic metalloenzyme that catalyzes the hydrolytic removal of N-terminal methionine residues from nascent proteins.
- peptide-methionine \rightleftharpoons peptide + methionine
MetAP2 is found in all organisms and is especially important because of its critical role in tissue repair and protein degradation. Furthermore, MetAP2 is of particular interest because the enzyme plays a key role in angiogenesis, the growth of new blood vessels, which is necessary for the progression of diseases including solid tumor cancers and rheumatoid arthritis. MetAP2 is also the target of two groups of anti-angiogenic natural products, ovalicin and fumagillin, and their analogs.
# Structure
In living organisms, the start codon that initiates protein synthesis codes for either methionine (eukaryotes) or formylmethionine (prokaryotes). In E. coli (prokaryote), an enzyme called formylmethionine deformylase can cleave the formyl group, leaving just the N-terminal methionine residue. For proteins with small, uncharged penultimate N-terminal residues, a methionine aminopeptidase can cleave the methionine residue.
The number of genes encoding for a methionine aminopeptidase varies between organisms. In E. coli, there is only one known MetAP, a 29,333 Da monomeric enzyme coded for by a gene consisting of 264 codons. The knockout of this gene in E. coli leads to cell inviability. In humans, there are two genes encoding MetAP, MetAP1 and MetAP2. MetAP1 codes for a 42 kDa enzyme, while MetAP2 codes for a 67 kDa enzyme. Yeast MetAP1 is 40 percent homologous to E. coli MetAP; within S. cerevisiae, MetAP2 is 22 percent homologous with the sequence of MetAP1; MetAP2 is highly conserved between S. cerevisiae and humans. In contrast to prokaryotes, eukaryotic S. cerevisiae strains lacking the gene for either MetAP1 or MetAP2 are viable, but exhibit a slower growth rate than a control strain expressing both genes.
## Active site
The active site of MetAP2 has a structural motif characteristic of many metalloenzymes—including the dioxygen carrier protein, hemerythrin; the dinuclear non-heme iron protein, ribonucleotide reductase; leucine aminopeptidase; urease; arginase; several phosphatases and phosphoesterases—that includes two bridging carboxylate ligands and a bridging water or hydroxide ligand. Specifically in human MetAP2 (PDB: 1BOA), one of the catalytic metal ions is bound to His331, Glu364, Glu459, Asp263, and a bridging water or hydroxide, while the other metal ion is bound to Asp251 (bidentate), App262 (bidentate), Glu459, and the same bridging water or hydroxide. Here, the two bridging carboxylates are Asp262 and Glu459.
## Dimetal center
The identity of the active site metal ions under physiological conditions has not been successfully established, and remains a controversial issue. MetAP2 shows activity in the presence of Zn(II), Co(II), Mn(II), and Fe(II) ions, and various authors have argued any given metal ion is the physiological one: some in the presence of iron, others in cobalt, others in manganese, and yet others in the presence of zinc. Nonetheless, the majority of crystallographers have crystallized MetAP2 either in the presence of Zn(II) or Co(II) (see PDB database).
# Mechanism
The bridging water or hydroxide ligand acts as a nucleophile during the hydrolysis reaction, but the exact mechanism of catalysis is not yet known. The catalytic mechanisms of hydrolase enzymes depend greatly on the identity of the bridging ligand, which can be challenging to determine due to the difficulty of studying hydrogen atoms via x-ray crystallography.
The histidine residues shown in the mechanism to the right, H178 and H79, are conserved in all MetAPs (MetAP1s and MetAP2s) sequenced to date, suggesting their presence is important to catalytic activity. Based upon X-ray crystallographic data, histidine 79 (H79) has been proposed to help position the methionine residue in the active site and transfer a proton to the newly exposed N-terminal amine. Lowther and Colleagues have proposed two possible mechanisms for MetAP2 in E. coli, shown at the right.
# Function
While previous studies have indicated MetAP2 catalyzes the removal of N-terminal methionine residues in vitro, the function of this enzyme in vivo may be more complex. For example, a significant correlation exists between the inhibition of the enzymatic activity of MetAP2 and inhibition of cell growth, thus implicating the enzyme in endothelial cell proliferation. For this reason, scientists have singled out MetAP2 as a potential target for the inhibition of angiogenesis. Moreover, studies have demonstrated that MetAP2 copurifies and interacts with the α subunit of eukaryotic initiation factor 2 (eIF2), a protein that is necessary for protein synthesis in vivo. Specifically, MetAP2 protects eIF-2α from inhibitory phosphorylation from the enzyme eIF-2α kinase, inhibits RNA-dependent protein kinase (PKR)-catalyzed eIF-2 R-subunit phosphorylation, and also reverses PKR-mediated inhibition of protein synthesis in intact cells.
# Clinical significance
Numerous studies implicate MetAP2 in angiogenesis. Specifically, the covalent binding of either the ovalicin or fumagillin epoxide moiety to the active site histidine residue of MetAP2 has been shown to inactivate the enzyme, thereby inhibiting angiogenesis. The way in which MetAP2 regulates angiogenesis has yet to be established, however, such that further study is required to validate that antiangiogenic activity results directly from MetAP2 inhibition. Nevertheless, with both the growth and metastasis of solid tumors depending heavily on angiogenesis, fumagillin and its analogs—including TNP-470, caplostatin, and beloranib—as well as ovalicin represent potential anticancer agents.
Moreover, the ability of MetAP2 to decrease cell viability in prokaryotic and small eukaryotic organisms has made it a target for antibacterial agents. Thus far, both fumagillin and TNP-470 have been shown to possess antimalarial activity both in vitro and in vivo, and fumarranol, another fumagillin analog, represents a promising lead.
The METAP2 inhibitor beloranib (ZGN-433) has shown efficacy in reducing weight in severely obese subjects. MetAP2 inhibitors work by re-establishing balance to the ways the body metabolizes fat, leading to substantial loss of body weight. Development of beloranib was halted in 2016 after deaths during clinical trials.
# Interactions
METAP2 has been shown to interact with Protein kinase R. | METAP2
Methionine aminopeptidase 2 is an enzyme that in humans is encoded by the METAP2 gene.[1][2]
Methionine aminopeptidase 2, a member of the dimetallohydrolase family, is a cytosolic metalloenzyme that catalyzes the hydrolytic removal of N-terminal methionine residues from nascent proteins.[3][4][5]
- peptide-methionine <math>\rightleftharpoons</math> peptide + methionine
MetAP2 is found in all organisms and is especially important because of its critical role in tissue repair and protein degradation.[3] Furthermore, MetAP2 is of particular interest because the enzyme plays a key role in angiogenesis, the growth of new blood vessels, which is necessary for the progression of diseases including solid tumor cancers and rheumatoid arthritis.[6] MetAP2 is also the target of two groups of anti-angiogenic natural products, ovalicin and fumagillin, and their analogs.[7][8][9][10]
# Structure
In living organisms, the start codon that initiates protein synthesis codes for either methionine (eukaryotes) or formylmethionine (prokaryotes). In E. coli (prokaryote), an enzyme called formylmethionine deformylase can cleave the formyl group, leaving just the N-terminal methionine residue. For proteins with small, uncharged penultimate N-terminal residues, a methionine aminopeptidase can cleave the methionine residue.[3]
The number of genes encoding for a methionine aminopeptidase varies between organisms. In E. coli, there is only one known MetAP, a 29,333 Da monomeric enzyme coded for by a gene consisting of 264 codons.[3] The knockout of this gene in E. coli leads to cell inviability.[11] In humans, there are two genes encoding MetAP, MetAP1 and MetAP2. MetAP1 codes for a 42 kDa enzyme, while MetAP2 codes for a 67 kDa enzyme. Yeast MetAP1 is 40 percent homologous to E. coli MetAP; within S. cerevisiae, MetAP2 is 22 percent homologous with the sequence of MetAP1; MetAP2 is highly conserved between S. cerevisiae and humans.[12] In contrast to prokaryotes, eukaryotic S. cerevisiae strains lacking the gene for either MetAP1 or MetAP2 are viable, but exhibit a slower growth rate than a control strain expressing both genes.
## Active site
The active site of MetAP2 has a structural motif characteristic of many metalloenzymes—including the dioxygen carrier protein, hemerythrin; the dinuclear non-heme iron protein, ribonucleotide reductase; leucine aminopeptidase; urease; arginase; several phosphatases and phosphoesterases—that includes two bridging carboxylate ligands and a bridging water or hydroxide ligand.[3][4][13][14][15][16][17] Specifically in human MetAP2 (PDB: 1BOA), one of the catalytic metal ions is bound to His331, Glu364, Glu459, Asp263, and a bridging water or hydroxide, while the other metal ion is bound to Asp251 (bidentate), App262 (bidentate), Glu459, and the same bridging water or hydroxide. Here, the two bridging carboxylates are Asp262 and Glu459.
## Dimetal center
The identity of the active site metal ions under physiological conditions has not been successfully established, and remains a controversial issue. MetAP2 shows activity in the presence of Zn(II), Co(II), Mn(II), and Fe(II) ions, and various authors have argued any given metal ion is the physiological one: some in the presence of iron,[18] others in cobalt,[19][20] others in manganese,[21] and yet others in the presence of zinc.[22] Nonetheless, the majority of crystallographers have crystallized MetAP2 either in the presence of Zn(II) or Co(II) (see PDB database).
# Mechanism
The bridging water or hydroxide ligand acts as a nucleophile during the hydrolysis reaction, but the exact mechanism of catalysis is not yet known.[6][15][24] The catalytic mechanisms of hydrolase enzymes depend greatly on the identity of the bridging ligand,[25] which can be challenging to determine due to the difficulty of studying hydrogen atoms via x-ray crystallography.
The histidine residues shown in the mechanism to the right, H178 and H79, are conserved in all MetAPs (MetAP1s and MetAP2s) sequenced to date, suggesting their presence is important to catalytic activity.[26] Based upon X-ray crystallographic data, histidine 79 (H79) has been proposed to help position the methionine residue in the active site and transfer a proton to the newly exposed N-terminal amine.[8] Lowther and Colleagues have proposed two possible mechanisms for MetAP2 in E. coli, shown at the right.[10]
# Function
While previous studies have indicated MetAP2 catalyzes the removal of N-terminal methionine residues in vitro, the function of this enzyme in vivo may be more complex. For example, a significant correlation exists between the inhibition of the enzymatic activity of MetAP2 and inhibition of cell growth, thus implicating the enzyme in endothelial cell proliferation.[9] For this reason, scientists have singled out MetAP2 as a potential target for the inhibition of angiogenesis. Moreover, studies have demonstrated that MetAP2 copurifies and interacts with the α subunit of eukaryotic initiation factor 2 (eIF2), a protein that is necessary for protein synthesis in vivo.[27] Specifically, MetAP2 protects eIF-2α from inhibitory phosphorylation from the enzyme eIF-2α kinase, inhibits RNA-dependent protein kinase (PKR)-catalyzed eIF-2 R-subunit phosphorylation, and also reverses PKR-mediated inhibition of protein synthesis in intact cells.
# Clinical significance
Numerous studies implicate MetAP2 in angiogenesis.[9][16][28][29][30] Specifically, the covalent binding of either the ovalicin or fumagillin epoxide moiety to the active site histidine residue of MetAP2 has been shown to inactivate the enzyme, thereby inhibiting angiogenesis. The way in which MetAP2 regulates angiogenesis has yet to be established, however, such that further study is required to validate that antiangiogenic activity results directly from MetAP2 inhibition. Nevertheless, with both the growth and metastasis of solid tumors depending heavily on angiogenesis, fumagillin and its analogs—including TNP-470, caplostatin, and beloranib—as well as ovalicin represent potential anticancer agents.[29][30]
Moreover, the ability of MetAP2 to decrease cell viability in prokaryotic and small eukaryotic organisms has made it a target for antibacterial agents.[9] Thus far, both fumagillin and TNP-470 have been shown to possess antimalarial activity both in vitro and in vivo, and fumarranol, another fumagillin analog, represents a promising lead.[30]
The METAP2 inhibitor beloranib (ZGN-433) has shown efficacy in reducing weight in severely obese subjects.[31] MetAP2 inhibitors work by re-establishing balance to the ways the body metabolizes fat, leading to substantial loss of body weight. Development of beloranib was halted in 2016 after deaths during clinical trials.[32]
# Interactions
METAP2 has been shown to interact with Protein kinase R.[33] | https://www.wikidoc.org/index.php/METAP2 | |
78499e2f7ca52a743fe16c3f86ec2e6e8c4dcfa8 | wikidoc | MINDY4 | MINDY4
MINDY lysine 48 deubiquitinase 4, also known as MINDY4, is a human gene.
# Predictions
The predicted molecular weight is 84,400 Daltons and pI is 6.465. pTARGET predicts the cellular location to be in the golgi apparatus with 93.9% confidence.
# Expression
Based on the human tissue Gene Expression Omnibus profile, C7orf67 shows a marked increase in expression in the teratospermia disease state. | MINDY4
MINDY lysine 48 deubiquitinase 4, also known as MINDY4, is a human gene.[1]
# Predictions
The predicted molecular weight is 84,400 Daltons and pI is 6.465. pTARGET predicts the cellular location to be in the golgi apparatus with 93.9% confidence.[2]
# Expression
Based on the human tissue Gene Expression Omnibus profile, C7orf67 shows a marked increase in expression in the teratospermia disease state.[3] | https://www.wikidoc.org/index.php/MINDY4 | |
6845729d357ea91fa590621326abd0ce54b970dc | wikidoc | mIRN21 | mIRN21
microRNA 21 also known as hsa-mir-21 or miRNA21 is a mammalian microRNA that is encoded by the MIR21 gene.
MIRN21 was one of the first mammalian microRNAs identified. The mature miR-21 sequence is strongly conserved throughout evolution. The human microRNA-21 gene is located on plus strand of chromosome 17q23.2 (55273409–55273480) within a coding gene TMEM49 (also called vacuole membrane protein). Despite being located in intronic regions of a coding gene in the direction of transcription, it has its own promoter regions and forms a ~3433-nt long primary transcript of miR-21 (known as pri-miR-21) which is independently transcribed. The stem–loop precursor of miR-21(pre-miR-21) resides between nucleotides 2445 and 2516 of pri-miR-21.
# Structure
Gene ID: 406991: "microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA."
# Mature miR-21
Pri-miR-21 is cut by the endonuclease Drosha in the nucleus to produce pre-miR-21, which is exported into the cytosol. This pre-miR-21 is then cut into a short RNA duplex by Dicer in the cytosol. Although abundance of both strands is equal by transcription, only one strand (miR-21) is selected for processing as mature microRNA based on the thermodynamic stability of each end of the duplex, while the other strand (designated with an asterisk; miR-21*) is generally degraded. Mature microRNA is then loaded into microRNA ribonucleoprotein complex RISC (RNA-induced silencing complex) and guided to target mRNAs with near perfect complimentarily at 3’UTR.
# Targets
A number of targets for microRNA-21 have been experimentally validated and most of them are tumor suppressors, Notable targets include:
- ANP32A,
- BTG2,
- Bcl2,
- P12/CDK2AP1,
- HNRPK,
- IL-12p35,
- JAG1,
- MEF2C,
- hMSH2,
- PDCD4,
- PTEN,
- RECK,
- RhoB,
- SMARCA4,
- TGFBRII,
- SPRY1,
- SPRY2,
- TP63, and
- Tropomyosin.
# Functions
"Cystathionine gamma-lyase (CSE) is the major H2S-generating enzyme in vascular smooth muscle cells (SMCs). CSE/H2S system contributes to the maintenance of SMC phenotype, and transcript factor specificity protein-1 (SP1) is a critical regulator of CSE expression during SMC differentiation. The involvements of microRNA-21 (miR-21) in cardiovascular pathophysiology have been known expression of miR-21 was upregulated in dedifferentiated human aorta SMCs (HASMCs) and injured mouse carotid arteries. miR-21 expression was upregulated by miR-21 precursor. miR-21 overexpression significantly repressed the protein expressions of both CSE and SP1, inhibited H2S production, stimulated SMC proliferation, and reduced SMC differentiation marker gene expression, respectively. The mRNA expression of CSE but not SP1 was inhibited by miR-21 precursor. Blockage of SP1 binding by mithramycin or inhibition of CSE activity by DL-propargylglycine did not change miR-21 expression. miR-21 repressed SP1 protein expression by directly targeting at SP1 3' untranslational regions, which in turn downregulated CSE mRNA expression and stimulated SMC proliferation. miR-21 in CSE/H2S-mediated-SMC differentiation by targeting SP1."
# Transcriptions
"The miR-21 promoter contains one conserved CArG box21,22 . MRTF-A regulates miR-21 transcription. The miR-21 promoter contains one CArG box, which is a binding element for MRTF-A/SRF."
# Vascular smooth muscle cells
Nearly "all VSMC-restricted contractile protein genes and many other genes important for migration, proliferation, and extracellular matrix production, contain evolutionarily conserved CArG box DNA sequences within their promoters that are required for VSMC transcription in vivo" (Miano 2003).
# Clinical significance
## Cancer
miR-21 is one of the most frequently upregulated miRNAs in solid tumours, and its high levels were first described in B cell lymphomas. Overall, miR-21 is considered to be a typical 'onco-miR', which acts by inhibiting the expression of phosphatases, which limit the activity of signalling pathways such as AKT and MAPK.
As most of the targets of miR-21 are tumor suppressors, miR-21 is associated with a wide variety of cancers including that of breast, ovaries, cervix, colon, lung, liver, brain, esophagus, prostate, pancreas, and thyroid. A 2014 meta-analysis of 36 studies evaluated circulating miR-21 as a biomarker of various carinomas, finding it has potential as a tool for early diagnosis. miR-21 expression was associated with survival in 53 triple negative breast cancer patients. Moreover, it has been demonstrated as an independent prognostic factor in patients with pancreatic neuroendocrine neoplasms.
## Cardiac disease
miR-21 has been shown to play important role in development of heart disease. It is one of the microRNAs whose expression is increased in failing murine and human hearts. Further, inhibition of microRNAs in mice using chemically modified and cholesterol-conjugated miRNA inhibitors (antagomirs) was shown to inhibit interstitial fibrosis and improve cardiac function in a pressure- overload cardiac disease mice model. Surprisingly, miR-21 global knock-out mice did not show any overt phenotype when compared with wild type mice with respect to cardiac stress response. Similarly, short (8-nt) oligonucleotides designed to inhibit miR-21 could not inhibit cardiac hypertrophy or fibrosis. In another study with a mouse model of acute myocardial infarction, miR-21 expression was found to be significantly lower in infarcted areas and overexpression of miR-21 in those mice via adenovirus-mediated gene transfer decreased myocardial infarct size.
miR-21 has been hypothesized to be an intermediary in the effects of air pollution that lead to endothelial dysfunction and eventually to cardiac disease. Expression of miR-21 is negatively associated with exposure to PM10 air pollution and may mediate its effect on small blood vessels. | mIRN21
Associate Editor(s)-in-Chief: Henry A. Hoff
microRNA 21 also known as hsa-mir-21 or miRNA21 is a mammalian microRNA that is encoded by the MIR21 gene.[1]
MIRN21 was one of the first mammalian microRNAs identified. The mature miR-21 sequence is strongly conserved throughout evolution. The human microRNA-21 gene is located on plus strand of chromosome 17q23.2 (55273409–55273480) within a coding gene TMEM49 (also called vacuole membrane protein). Despite being located in intronic regions of a coding gene in the direction of transcription, it has its own promoter regions and forms a ~3433-nt long primary transcript of miR-21 (known as pri-miR-21) which is independently transcribed. The stem–loop precursor of miR-21(pre-miR-21) resides between nucleotides 2445 and 2516 of pri-miR-21.
# Structure
Gene ID: 406991: "microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA."[2]
# Mature miR-21
Pri-miR-21 is cut by the endonuclease Drosha in the nucleus to produce pre-miR-21, which is exported into the cytosol. This pre-miR-21 is then cut into a short RNA duplex by Dicer in the cytosol. Although abundance of both strands is equal by transcription, only one strand (miR-21) is selected for processing as mature microRNA based on the thermodynamic stability of each end of the duplex, while the other strand (designated with an asterisk; miR-21*) is generally degraded. Mature microRNA is then loaded into microRNA ribonucleoprotein complex RISC (RNA-induced silencing complex) and guided to target mRNAs with near perfect complimentarily at 3’UTR.
# Targets
A number of targets for microRNA-21 have been experimentally validated and most of them are tumor suppressors, Notable targets include:
- ANP32A,
- BTG2,[3]
- Bcl2,[4]
- P12/CDK2AP1,[5]
- HNRPK,[6]
- IL-12p35,[7]
- JAG1,[8]
- MEF2C,[9]
- hMSH2,[10]
- PDCD4,[11]
- PTEN,[12]
- RECK,[13]
- RhoB,[14]
- SMARCA4,[15]
- TGFBRII,[16]
- SPRY1,[17]
- SPRY2,[18]
- TP63,[6] and
- Tropomyosin.[6]
# Functions
"Cystathionine gamma-lyase (CSE) is the major H2S-generating enzyme in vascular smooth muscle cells (SMCs). CSE/H2S system contributes to the maintenance of SMC phenotype, and transcript factor specificity protein-1 (SP1) is a critical regulator of CSE expression during SMC differentiation. The involvements of microRNA-21 (miR-21) in cardiovascular pathophysiology have been known [The] expression of miR-21 was upregulated in dedifferentiated human aorta SMCs (HASMCs) and injured mouse carotid arteries. [...] miR-21 expression was upregulated by miR-21 precursor. [...] miR-21 overexpression significantly repressed the protein expressions of both CSE and SP1, inhibited H2S production, stimulated SMC proliferation, and reduced SMC differentiation marker gene expression, respectively. The mRNA expression of CSE but not SP1 was inhibited by miR-21 precursor. Blockage of SP1 binding by mithramycin or inhibition of CSE activity by DL-propargylglycine did not change miR-21 expression. [...] miR-21 repressed SP1 protein expression by directly targeting at SP1 3' untranslational regions, which in turn downregulated CSE mRNA expression and stimulated SMC proliferation. [...] miR-21 [may participate] in CSE/H2S-mediated-SMC differentiation by targeting SP1."[19]
# Transcriptions
"The miR-21 promoter contains one conserved CArG box21,22 [...]. [...] MRTF-A regulates miR-21 transcription. [...] The miR-21 promoter contains one CArG box, which is a binding element for MRTF-A/SRF."[20]
# Vascular smooth muscle cells
Nearly "all [Vascular smooth muscle cell] VSMC-restricted contractile protein genes and many other genes important for migration, proliferation, and extracellular matrix production, contain evolutionarily conserved CArG box DNA sequences within their promoters that are required for VSMC transcription in vivo" (Miano 2003).[21]
# Clinical significance
## Cancer
miR-21 is one of the most frequently upregulated miRNAs in solid tumours, and its high levels were first described in B cell lymphomas. Overall, miR-21 is considered to be a typical 'onco-miR', which acts by inhibiting the expression of phosphatases, which limit the activity of signalling pathways such as AKT and MAPK.
As most of the targets of miR-21 are tumor suppressors, miR-21 is associated with a wide variety of cancers including that of breast,[22] ovaries,[23] cervix,[24] colon,[11] lung,[25] liver,[12] brain,[26] esophagus,[27] prostate,[25] pancreas,[25] and thyroid.[28] A 2014 meta-analysis of 36 studies evaluated circulating miR-21 as a biomarker of various carinomas, finding it has potential as a tool for early diagnosis.[29] miR-21 expression was associated with survival in 53 triple negative breast cancer patients.[30] Moreover, it has been demonstrated as an independent prognostic factor in patients with pancreatic neuroendocrine neoplasms.[31]
## Cardiac disease
miR-21 has been shown to play important role in development of heart disease. It is one of the microRNAs whose expression is increased in failing murine and human hearts.[17][32] Further, inhibition of microRNAs in mice using chemically modified and cholesterol-conjugated miRNA inhibitors (antagomirs) was shown to inhibit interstitial fibrosis and improve cardiac function in a pressure- overload cardiac disease mice model.[17] Surprisingly, miR-21 global knock-out mice did not show any overt phenotype when compared with wild type mice with respect to cardiac stress response. Similarly, short (8-nt) oligonucleotides designed to inhibit miR-21 could not inhibit cardiac hypertrophy or fibrosis.[33] In another study with a mouse model of acute myocardial infarction, miR-21 expression was found to be significantly lower in infarcted areas and overexpression of miR-21 in those mice via adenovirus-mediated gene transfer decreased myocardial infarct size.[34]
miR-21 has been hypothesized to be an intermediary in the effects of air pollution that lead to endothelial dysfunction and eventually to cardiac disease. Expression of miR-21 is negatively associated with exposure to PM10 air pollution and may mediate its effect on small blood vessels.[35] | https://www.wikidoc.org/index.php/MIRN21 | |
545d45d82aa81d1d7dadeb341f129f38957ccd46 | wikidoc | MMACHC | MMACHC
Methylmalonic aciduria and homocystinuria type C protein (MMACHC) is a protein that in humans is encoded by the MMACHC gene.
# Function
The C-terminal region of the product of the MMACHC gene is similar to TonB, a bacterial protein involved in energy transduction for cobalamin uptake. The MMACHC gene product catalyzes the decyanation of cyanocobalamin as well as the dealkylation
-f alkylcobalamins including methylcobalamin and adenosylcobalamin. This function has also been attributed to cobalamin reductases. The MMACHC gene product and cobalamin reductases enable the interconversion of cyano- and alkylcobalamins.
# Clinical significance
Mutations are associated with methylmalonic acidemia. | MMACHC
Methylmalonic aciduria and homocystinuria type C protein (MMACHC) is a protein that in humans is encoded by the MMACHC gene.[1]
# Function
The C-terminal region of the product of the MMACHC gene is similar to TonB, a bacterial protein involved in energy transduction for cobalamin uptake.[1] The MMACHC gene product catalyzes the decyanation of cyanocobalamin as well as the dealkylation
of alkylcobalamins including methylcobalamin and adenosylcobalamin.[2] This function has also been attributed to cobalamin reductases.[3] The MMACHC gene product and cobalamin reductases enable the interconversion of cyano- and alkylcobalamins.[4][5]
# Clinical significance
Mutations are associated with methylmalonic acidemia.[1][6][7][8] | https://www.wikidoc.org/index.php/MMACHC | |
b5db4dc163481b506d54d84ce8f3feec91f3a728 | wikidoc | MMADHC | MMADHC
Methylmalonic aciduria and homocystinuria type D protein, mitochondrial also known as MMADHC is a protein that in humans is encoded by the MMADHC gene.
# Function
This gene encodes a mitochondrial protein that is involved in an early step of vitamin B12 metabolism. Vitamin B12 (cobalamin) is essential for normal development and survival in humans.
# Clinical significance
Mutations in this gene cause methylmalonic aciduria and homocystinuria type cblD (MMADHC), a disorder of cobalamin metabolism that is characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin. | MMADHC
Methylmalonic aciduria and homocystinuria type D protein, mitochondrial also known as MMADHC is a protein that in humans is encoded by the MMADHC gene.[1]
# Function
This gene encodes a mitochondrial protein that is involved in an early step of vitamin B12 metabolism. Vitamin B12 (cobalamin) is essential for normal development and survival in humans.[2]
# Clinical significance
Mutations in this gene cause methylmalonic aciduria and homocystinuria type cblD (MMADHC), a disorder of cobalamin metabolism that is characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin.[1] | https://www.wikidoc.org/index.php/MMADHC | |
e9e72e26e793132195be34c7d99436b9a48c9b88 | wikidoc | MMS22L | MMS22L
Methyl methanesulfonate-sensitivity protein 22-like also known as MMS22-like, DNA repair protein is a protein that in humans is encoded by the MMS22L gene.
# Model organisms
Model organisms have been used in the study of MMS22L function. A conditional knockout mouse line, called Mms22ltm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on mutant mice and 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. | MMS22L
Methyl methanesulfonate-sensitivity protein 22-like also known as MMS22-like, DNA repair protein is a protein that in humans is encoded by the MMS22L gene.[1]
# Model organisms
Model organisms have been used in the study of MMS22L function. A conditional knockout mouse line, called Mms22ltm1a(EUCOMM)Wtsi[6] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[7][8][9]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[4][10] Twenty six tests were carried out on mutant mice and two significant abnormalities were observed.[4] 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. [4] | https://www.wikidoc.org/index.php/MMS22L | |
87f8fdb56c6d5c194fbb8752fd7bab0a88587a37 | wikidoc | MOGAT2 | MOGAT2
2-Acylglycerol O-acyltransferase 2 also known as acyl-CoA:monoacylglycerol acyltransferase 2 (MGAT2) or Diacylglycerol O-acyltransferase candidate 5 (DC5) is an enzyme that in humans is encoded by the MOGAT2 gene.
MOGAT2 and the related MOGAT3 genes are members of the acylglycerol o-acyltransferase family (DGAT2/MOGAT) and are involved in the synthesis of diacylglycerol (DAG) and triacylglycerol (TAG) from monoacylglycerol (MAG).
MOGAT2 and also MOGAT3 are single copy genes in almost all mammals. However, in ruminants both genes have undergone tandem gene expansion, indicate of evolving functionality. MOGAT2 has more than five tandemly duplicated copies in sheep with the first copy expressed in the duodenum and the last copy expressed in the skin, with no expression of any copy detected in the liver. | MOGAT2
2-Acylglycerol O-acyltransferase 2 also known as acyl-CoA:monoacylglycerol acyltransferase 2 (MGAT2) or Diacylglycerol O-acyltransferase candidate 5 (DC5) is an enzyme that in humans is encoded by the MOGAT2 gene.
MOGAT2 and the related MOGAT3 genes are members of the acylglycerol o-acyltransferase family (DGAT2/MOGAT) and are involved in the synthesis of diacylglycerol (DAG) and triacylglycerol (TAG) from monoacylglycerol (MAG).
MOGAT2 and also MOGAT3 are single copy genes in almost all mammals. However, in ruminants both genes have undergone tandem gene expansion, indicate of evolving functionality. MOGAT2 has more than five tandemly duplicated copies in sheep with the first copy expressed in the duodenum and the last copy expressed in the skin, with no expression of any copy detected in the liver.[1][2][3] | https://www.wikidoc.org/index.php/MOGAT2 | |
33f4641058d9119af230ffe755d837b5a0b27148 | wikidoc | MRE11A | MRE11A
Double-strand break repair protein MRE11A is a protein that in humans is encoded by the MRE11A gene.
# Function
This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms.
# Orthologs
Mre11, an ortholog of human MRE11A, occurs in the prokaryote archaeon Sulfolobus acidocaldarius. In this organism the Mre11 protein interacts with the Rad50 protein and appears to have an active role in the repair of DNA damages experimentally introduced by gamma radiation. Similarly, during meiosis in the eukaryotic protist Tetrahymena Mre11 is required for repair of DNA damages, in this case double-strand breaks, by a process that likely involves homologous recombination. These observations suggest that human MRE11A is descended from prokaryotic and protist ancestral Mre11 proteins that served a role in early processes for repairing DNA damage.
# Overexpression in cancer
MRE11 has a role in microhomology-mediated end joining (MMEJ) repair of double strand breaks. It is one of 6 enzymes required for this error prone DNA repair pathway. MRE11 is over-expressed in breast cancers.
Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes). (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers. (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, MRE11 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.
# Interactions
MRE11A has been shown to interact with:
- ATM,
- BRCA1,
- Ku70,
- MDC1,
- NBN,
- Rad50, and
- TERF2. | MRE11A
Double-strand break repair protein MRE11A is a protein that in humans is encoded by the MRE11A gene.[1]
# Function
This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms.[2]
# Orthologs
Mre11, an ortholog of human MRE11A, occurs in the prokaryote archaeon Sulfolobus acidocaldarius.[3] In this organism the Mre11 protein interacts with the Rad50 protein and appears to have an active role in the repair of DNA damages experimentally introduced by gamma radiation.[3] Similarly, during meiosis in the eukaryotic protist Tetrahymena Mre11 is required for repair of DNA damages, in this case double-strand breaks,[4] by a process that likely involves homologous recombination. These observations suggest that human MRE11A is descended from prokaryotic and protist ancestral Mre11 proteins that served a role in early processes for repairing DNA damage.
# Overexpression in cancer
MRE11 has a role in microhomology-mediated end joining (MMEJ) repair of double strand breaks. It is one of 6 enzymes required for this error prone DNA repair pathway.[5] MRE11 is over-expressed in breast cancers.[6]
Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes).[7] (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers.[7] (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, MRE11 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.
# Interactions
MRE11A has been shown to interact with:
- ATM,[8][9]
- BRCA1,[9][10][11][12]
- Ku70,[13]
- MDC1,[14]
- NBN,[9][15][16][17][18]
- Rad50,[9][10][13][15][19] and
- TERF2.[20] | https://www.wikidoc.org/index.php/MRE11A | |
cab86f5da3ac423ae06f9c5881f120f564dac5ce | wikidoc | MT-CYB | MT-CYB
Cytochrome b is a protein that in humans is encoded by the MT-CYB gene. Its gene product is a subunit of the respiratory chain protein Ubiquinol Cytochrome c Reductase (UQCR, Complex III or Cytochrome bc1 complex), which consists of the products of one mitochondrially encoded gene, MT-CYB (mitochondrial cytochrome b) and ten nuclear genes: UQCRC1, UQCRC2, Cytochrome c1, UQCRFS1 (Rieske protein), UQCRB, "11kDa protein", UQCRH (cyt c1 Hinge protein), Rieske Protein presequence, "cyt. c1 associated protein", and Rieske-associated protein.
# Structure
The MT-CYB gene is located on the p arm of mitochondrial DNA in position 12 and spans 1,140 base pairs. The gene produces a 42.7 kDa protein named cytochrome b composed of 380 amino acids. Cytochrome b is an integral membrane protein with hydrophobic properties. The catalytic core of the enzyme is composed of eight transmembrane helices, the iron-sulfur protein, and cytochrome c1. Cytochrome b is a fundamental component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex) that is part of the mitochondrial respiratory chain. The b-c1 complex mediates electron transfer from ubiquinol to cytochrome c. The structure of the complex is a symmetric homodimer. It is composed of eleven structural subunits, including one mitochondrial genome encoded cytochrome b and ten other nucleus encoded subunits. These subunits include 3 respiratory subunits (MT-CYB, CYC1 and UQCRFS1), 2 core proteins (UQCRC1 and UQCRC2) and 6 low-molecular weight proteins (UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, UQCR10/QCR9, UQCR11/QCR10 and a cleavage product of UQCRFS1). The total molecular mass of the complex is about 450 kDa.
# Function
The mitochondrial cytochrome b is fundamental for the assembly and function of Complex III of the mitochondrial respiratory chain. Complex III is responsible for the catalysis of electron transfer from coenzyme Q to cytochrome c in the mitochondrial respiratory chain by translocating protons concomitantly across the inner membrane of the mitochondria. The transfer of electrons then contributes to the generation of a proton gradient across the mitochondrial membrane that is then used for ATP synthesis.
# Clinical significance
Mutations in MT-CYB can result in mitochondrial deficiencies and associated disorders. It is majorly associated with a complex III deficiency, a deficiency in an enzyme complex which catalyzes electron transfer from coenzyme Q to cytochrome c in the mitochondrial respiratory chain. A complex III deficiency can result in a highly variable phenotype depending on which tissues are affected. Most frequent clinical manifestations include progressive exercise intolerance and cardiomyopathy. Occasional multisystem disorders accompanied by exercise intolerance may arise as well, in forms of deafness, mental retardation, retinitis pigmentosa, cataract, growth retardation, and epilepsy. Other phenotypes include mitochondrial encephalomyopathy, mitochondrial myopathy, Leber hereditary optic neuropathy, muscle weakness, myoglobinuria, blood acidosis, renal tubulopathy, and more. Complex III deficiency is known to be rare among mitochondrial diseases and may follow a maternal or mendelian mode of inheritance due to its duality of genetic origin. | MT-CYB
Cytochrome b is a protein that in humans is encoded by the MT-CYB gene.[1] Its gene product is a subunit of the respiratory chain protein Ubiquinol Cytochrome c Reductase (UQCR, Complex III or Cytochrome bc1 complex), which consists of the products of one mitochondrially encoded gene, MT-CYB (mitochondrial cytochrome b) and ten nuclear genes: UQCRC1, UQCRC2, Cytochrome c1, UQCRFS1 (Rieske protein), UQCRB, "11kDa protein", UQCRH (cyt c1 Hinge protein), Rieske Protein presequence, "cyt. c1 associated protein", and Rieske-associated protein.
# Structure
The MT-CYB gene is located on the p arm of mitochondrial DNA in position 12 and spans 1,140 base pairs.[1] The gene produces a 42.7 kDa protein named cytochrome b composed of 380 amino acids.[2][3] Cytochrome b is an integral membrane protein with hydrophobic properties. The catalytic core of the enzyme is composed of eight transmembrane helices, the iron-sulfur protein, and cytochrome c1.[4] Cytochrome b is a fundamental component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex) that is part of the mitochondrial respiratory chain. The b-c1 complex mediates electron transfer from ubiquinol to cytochrome c.[5] The structure of the complex is a symmetric homodimer. It is composed of eleven structural subunits, including one mitochondrial genome encoded cytochrome b and ten other nucleus encoded subunits. These subunits include 3 respiratory subunits (MT-CYB, CYC1 and UQCRFS1), 2 core proteins (UQCRC1 and UQCRC2) and 6 low-molecular weight proteins (UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, UQCR10/QCR9, UQCR11/QCR10 and a cleavage product of UQCRFS1). The total molecular mass of the complex is about 450 kDa.[6][5]
# Function
The mitochondrial cytochrome b is fundamental for the assembly and function of Complex III of the mitochondrial respiratory chain.[7] Complex III is responsible for the catalysis of electron transfer from coenzyme Q to cytochrome c in the mitochondrial respiratory chain by translocating protons concomitantly across the inner membrane of the mitochondria.[8][5] The transfer of electrons then contributes to the generation of a proton gradient across the mitochondrial membrane that is then used for ATP synthesis.[5]
# Clinical significance
Mutations in MT-CYB can result in mitochondrial deficiencies and associated disorders. It is majorly associated with a complex III deficiency, a deficiency in an enzyme complex which catalyzes electron transfer from coenzyme Q to cytochrome c in the mitochondrial respiratory chain. A complex III deficiency can result in a highly variable phenotype depending on which tissues are affected.[5] Most frequent clinical manifestations include progressive exercise intolerance and cardiomyopathy. Occasional multisystem disorders accompanied by exercise intolerance may arise as well, in forms of deafness, mental retardation, retinitis pigmentosa, cataract, growth retardation, and epilepsy.[5] Other phenotypes include mitochondrial encephalomyopathy, mitochondrial myopathy, Leber hereditary optic neuropathy, muscle weakness, myoglobinuria, blood acidosis, renal tubulopathy, and more.[5][6] Complex III deficiency is known to be rare among mitochondrial diseases and may follow a maternal or mendelian mode of inheritance due to its duality of genetic origin.[4] | https://www.wikidoc.org/index.php/MT-CYB | |
a12255f9e58443770245f60d8d2746ae58e6dc58 | wikidoc | MT-ND1 | MT-ND1
NADH-ubiquinone oxidoreductase chain 1 is a protein that in humans is encoded by the mitochondrial gene MT-ND1. The ND1 protein is a subunit of NADH dehydrogenase, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variants of the MT-ND1 gene are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS), Leber's hereditary optic neuropathy (LHON) and increases in adult BMI.
# Structure
MT-ND1 is located in mitochondrial DNA from base pair 3,307 to 4,262. The MT-ND1 gene produces a 36 kDa protein composed of 318 amino acids. MT-ND1 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it is the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centres and the NADH binding site. MT-ND1 and the rest of the mitochondrially encoded subunits are the most hydrophobic of the subunits of Complex I and form the core of the transmembrane region.
# Function
MT-ND1 is a subunit of the respiratory chain Complex I that is believed to belong to the minimal assembly of core proteins required to catalyze NADH dehydrogenation and electron transfer to ubiquinone (coenzyme Q10). Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.
# Clinical significance
Pathogenic variants of the mitochondrial gene MT-ND1 are known to cause mtDNA-associated Leigh syndrome, as are variants of MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6 and MT-CO3. Abnormalities in mitochondrial energy generation result in neurodegenerative disorders like Leigh syndrome, which is characterized by an onset of symptoms between 12 months and three years of age. The symptoms frequently present themselves following a viral infection and include movement disorders and peripheral neuropathy, as well as hypotonia, spasticity and cerebellar ataxia. Roughly half of affected individuals die of respiratory or cardiac failure by the age of three. Leigh syndrome is a maternally inherited disorder and its diagnosis is established through genetic testing of the aforementioned mitochondrial genes, including MT-ND1. The m.4171C>A/MT-ND1 mutation also leads to a Leigh-like phenotype as well as bilateral brainstem lesions affecting the vestibular nuclei, resulting in vision loss, vomiting and vertigo. These complex I genes have been associated with a variety of neurodegenerative disorders, including Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS), overlap between LHON and MELAS, and the previously mentioned Leigh syndrome.
Mitochondrial dysfunction resulting from variants of MT-ND1, MT-ND2 and MT-ND4L have been linked to BMI in adults and implicated in metabolic disorders including obesity, diabetes and hypertension. | MT-ND1
NADH-ubiquinone oxidoreductase chain 1 is a protein that in humans is encoded by the mitochondrial gene MT-ND1.[1] The ND1 protein is a subunit of NADH dehydrogenase, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[2] Variants of the MT-ND1 gene are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS), Leber's hereditary optic neuropathy (LHON) and increases in adult BMI.[3][4][5]
# Structure
MT-ND1 is located in mitochondrial DNA from base pair 3,307 to 4,262.[1] The MT-ND1 gene produces a 36 kDa protein composed of 318 amino acids.[6][7] MT-ND1 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it is the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centres and the NADH binding site. MT-ND1 and the rest of the mitochondrially encoded subunits are the most hydrophobic of the subunits of Complex I and form the core of the transmembrane region.[2]
# Function
MT-ND1 is a subunit of the respiratory chain Complex I that is believed to belong to the minimal assembly of core proteins required to catalyze NADH dehydrogenation and electron transfer to ubiquinone (coenzyme Q10).[8] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[2]
# Clinical significance
Pathogenic variants of the mitochondrial gene MT-ND1 are known to cause mtDNA-associated Leigh syndrome, as are variants of MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6 and MT-CO3. Abnormalities in mitochondrial energy generation result in neurodegenerative disorders like Leigh syndrome, which is characterized by an onset of symptoms between 12 months and three years of age. The symptoms frequently present themselves following a viral infection and include movement disorders and peripheral neuropathy, as well as hypotonia, spasticity and cerebellar ataxia. Roughly half of affected individuals die of respiratory or cardiac failure by the age of three. Leigh syndrome is a maternally inherited disorder and its diagnosis is established through genetic testing of the aforementioned mitochondrial genes, including MT-ND1.[3] The m.4171C>A/MT-ND1 mutation also leads to a Leigh-like phenotype as well as bilateral brainstem lesions affecting the vestibular nuclei, resulting in vision loss, vomiting and vertigo.[4] These complex I genes have been associated with a variety of neurodegenerative disorders, including Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS), overlap between LHON and MELAS,[9][10] and the previously mentioned Leigh syndrome.
Mitochondrial dysfunction resulting from variants of MT-ND1, MT-ND2 and MT-ND4L have been linked to BMI in adults and implicated in metabolic disorders including obesity, diabetes and hypertension.[5] | https://www.wikidoc.org/index.php/MT-ND1 | |
c6b00245d7309a3b66c3fe5aa705c1649e222722 | wikidoc | MT-ND2 | MT-ND2
Mitochondrially encoded NADH dehydrogenase 2 is protein that in humans is encoded by the mitochondrial gene MT-ND2 gene. The ND2 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variants of MT-ND2 are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS), Leber's hereditary optic neuropathy (LHON) and increases in adult BMI.
# Structure
MT-ND2 is located in mitochondrial DNA from base pair 4,470 to 5,511. The MT-ND2 gene produces a 39 kDa protein composed of 347 amino acids. MT-ND2 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it is the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centres and the NADH binding site. MT-ND2 and the rest of the mitochondrially encoded subunits are the most hydrophobic of the subunits of Complex I and form the core of the transmembrane region.
# Function
MT-ND2 is a subunit of the respiratory chain Complex I that is believed to belong to the minimal assembly of core proteins required to catalyze NADH dehydrogenation and electron transfer to ubiquinone (coenzyme Q10). Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.
# Clinical significance
Pathogenic variants of the mitochondrial gene MT-ND2 are known to cause mtDNA-associated Leigh syndrome, as are variants of MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND3, MT-ND4, MT-ND5, MT-ND6 and MT-CO3. Abnormalities in mitochondrial energy generation result in neurodegenerative disorders like Leigh syndrome, which is characterized by an onset of symptoms between 12 months and three years of age. The symptoms frequently present themselves following a viral infection and include movement disorders and peripheral neuropathy, as well as hypotonia, spasticity and cerebellar ataxia. Roughly half of affected patients die of respiratory or cardiac failure by the age of three. Leigh syndrome is a maternally inherited disorder and its diagnosis is established through genetic testing of the aforementioned mitochondrial genes, including MT-ND2. These complex I genes have been associated with a variety of neurodegenerative disorders, including Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS) and the previously mentioned Leigh syndrome.
Mitochondrial dysfunction resulting from variants of MT-ND2, MT-ND1 and MT-ND4L have been linked to BMI in adults and implicated in metabolic disorders including obesity, diabetes and hypertension. | MT-ND2
Mitochondrially encoded NADH dehydrogenase 2 is protein that in humans is encoded by the mitochondrial gene MT-ND2 gene.[1] The ND2 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[2] Variants of MT-ND2 are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS), Leber's hereditary optic neuropathy (LHON) and increases in adult BMI.[3][4][5]
# Structure
MT-ND2 is located in mitochondrial DNA from base pair 4,470 to 5,511.[1] The MT-ND2 gene produces a 39 kDa protein composed of 347 amino acids.[6][7] MT-ND2 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it is the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centres and the NADH binding site. MT-ND2 and the rest of the mitochondrially encoded subunits are the most hydrophobic of the subunits of Complex I and form the core of the transmembrane region.[2]
# Function
MT-ND2 is a subunit of the respiratory chain Complex I that is believed to belong to the minimal assembly of core proteins required to catalyze NADH dehydrogenation and electron transfer to ubiquinone (coenzyme Q10).[8] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[2]
# Clinical significance
Pathogenic variants of the mitochondrial gene MT-ND2 are known to cause mtDNA-associated Leigh syndrome, as are variants of MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND3, MT-ND4, MT-ND5, MT-ND6 and MT-CO3. Abnormalities in mitochondrial energy generation result in neurodegenerative disorders like Leigh syndrome, which is characterized by an onset of symptoms between 12 months and three years of age. The symptoms frequently present themselves following a viral infection and include movement disorders and peripheral neuropathy, as well as hypotonia, spasticity and cerebellar ataxia. Roughly half of affected patients die of respiratory or cardiac failure by the age of three. Leigh syndrome is a maternally inherited disorder and its diagnosis is established through genetic testing of the aforementioned mitochondrial genes, including MT-ND2.[3] These complex I genes have been associated with a variety of neurodegenerative disorders, including Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS) and the previously mentioned Leigh syndrome.[4]
Mitochondrial dysfunction resulting from variants of MT-ND2, MT-ND1 and MT-ND4L have been linked to BMI in adults and implicated in metabolic disorders including obesity, diabetes and hypertension.[5] | https://www.wikidoc.org/index.php/MT-ND2 | |
5b85ab37d31881ef786f610709890c3b9ecb220f | wikidoc | MT-ND3 | MT-ND3
Mitochondrially encoded NADH dehydrogenase 3 is a protein that in humans is encoded by the mitochondrial gene MT-ND3. The ND3 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variants of MT-ND3 are associated with Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS) and Leber's hereditary optic neuropathy (LHON).
# Structure
MT-ND3 is located in human mitochondrial DNA from base pair 10,059 to 10,404. The MT-ND3 gene produces a 13 kDa protein composed of 115 amino acids. MT-ND3 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it is the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centres and the NADH binding site. MT-ND3 and the rest of the mitochondrially encoded subunits are the most hydrophobic of the subunits of Complex I and form the core of the transmembrane region.
# Function
MT-ND3 is a subunit of the respiratory chain Complex I that is believed to belong to the minimal assembly of core proteins required to catalyze NADH dehydrogenation and electron transfer to ubiquinone (coenzyme Q10). Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.
# Untranslated extra nucleotide
In the MT-ND3 gene from many species of birds and turtles there is an extra nucleotide that is not translated to protein.
Translational frameshifting or RNA editing are alternative explanations for maintenance of the functionality of the ND3 reading frame in birds possessing the one-nucleotide insertion.
This extra nucleotide feature suggests that turtles might be related to Archosauria, as evidenced by molecular phylogeny studies. The absence of the extra nucleotide in crocodilians and some birds and turtles might also indicate that the corresponding taxa have lost this feature.
# Clinical significance
Pathogenic variants of the mitochondrial gene MT-ND3 are known to cause mtDNA-associated Leigh syndrome, as are variants of MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND4, MT-ND5, MT-ND6 and MT-CO3. Abnormalities in mitochondrial energy generation result in neurodegenerative disorders like Leigh syndrome, which is characterized by an onset of symptoms between 12 months and three years of age. The symptoms frequently present themselves following a viral infection and include movement disorders and peripheral neuropathy, as well as hypotonia, spasticity and cerebellar ataxia. Roughly half of affected patients die of respiratory or cardiac failure by the age of three. Leigh syndrome is a maternally inherited disorder and its diagnosis is established through genetic testing of the aforementioned mitochondrial genes, including MT-ND3. These complex I genes have been associated with a variety of neurodegenerative disorders, including Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS) and the previously mentioned Leigh syndrome.
# Interactions
MT-ND3 has been shown to have 5 binary protein-protein interactions including 2 co-complex interactions. MT-ND3 appears to interact with APP and NDUFA9. | MT-ND3
Mitochondrially encoded NADH dehydrogenase 3 is a protein that in humans is encoded by the mitochondrial gene MT-ND3.[1] The ND3 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[2] Variants of MT-ND3 are associated with Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS) and Leber's hereditary optic neuropathy (LHON).[3][4]
# Structure
MT-ND3 is located in human mitochondrial DNA from base pair 10,059 to 10,404.[1] The MT-ND3 gene produces a 13 kDa protein composed of 115 amino acids.[5][6] MT-ND3 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it is the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centres and the NADH binding site. MT-ND3 and the rest of the mitochondrially encoded subunits are the most hydrophobic of the subunits of Complex I and form the core of the transmembrane region.[2]
# Function
MT-ND3 is a subunit of the respiratory chain Complex I that is believed to belong to the minimal assembly of core proteins required to catalyze NADH dehydrogenation and electron transfer to ubiquinone (coenzyme Q10).[7] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[2]
# Untranslated extra nucleotide
In the MT-ND3 gene from many species of birds and turtles [8] there is an extra nucleotide that is not translated to protein.[9]
Translational frameshifting or RNA editing are alternative explanations for maintenance of the functionality of the ND3 reading frame in birds possessing the one-nucleotide insertion.
This extra nucleotide feature suggests that turtles might be related to Archosauria, as evidenced by molecular phylogeny studies.[10][11] The absence of the extra nucleotide in crocodilians and some birds and turtles might also indicate that the corresponding taxa have lost this feature.
# Clinical significance
Pathogenic variants of the mitochondrial gene MT-ND3 are known to cause mtDNA-associated Leigh syndrome, as are variants of MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND4, MT-ND5, MT-ND6 and MT-CO3. Abnormalities in mitochondrial energy generation result in neurodegenerative disorders like Leigh syndrome, which is characterized by an onset of symptoms between 12 months and three years of age. The symptoms frequently present themselves following a viral infection and include movement disorders and peripheral neuropathy, as well as hypotonia, spasticity and cerebellar ataxia. Roughly half of affected patients die of respiratory or cardiac failure by the age of three. Leigh syndrome is a maternally inherited disorder and its diagnosis is established through genetic testing of the aforementioned mitochondrial genes, including MT-ND3.[3] These complex I genes have been associated with a variety of neurodegenerative disorders, including Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS) and the previously mentioned Leigh syndrome.[4]
# Interactions
MT-ND3 has been shown to have 5 binary protein-protein interactions including 2 co-complex interactions. MT-ND3 appears to interact with APP and NDUFA9.[12] | https://www.wikidoc.org/index.php/MT-ND3 | |
395451d996d8ca01b923b468a4eef4b196bb2eb2 | wikidoc | MT-ND4 | MT-ND4
NADH-ubiquinone oxidoreductase chain 4 is a protein that in humans is encoded by the mitochondrial gene MT-ND4. The ND4 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in the MT-ND4 gene are associated with age-related macular degeneration (AMD), Leber's hereditary optic neuropathy (LHON), mesial temporal lobe epilepsy (MTLE) and cystic fibrosis.
# Structure
The MT-ND4 gene is located in human mitochondrial DNA from base pair 10,760 to 12,137. An unusual feature of the human MT-ND4 gene is the 7-nucleotide gene overlap of its first three codons (5'-ATG CTA AAA-3' coding for amino acids Met-Leu-Lys) with the last three codons of the MT-ND4L gene (5'-CAA TGC TAA-3' coding for Gln, Cys and Stop). With respect to the MT-ND4L reading frame (+1), the MT-ND4 gene starts in the +3 reading frame: AA versus CA.
The MT-ND4 gene produces a 52 kDa protein composed of 459 amino acids. MT-ND4 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it is the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centres and the NADH binding site. MT-ND4 and the rest of the mitochondrially encoded subunits are the most hydrophobic of the subunits of Complex I and form the core of the transmembrane region.
# Function
MT-ND4 is a subunit of the respiratory chain Complex I that is believed to belong to the minimal assembly of core proteins required to catalyze NADH dehydrogenation and electron transfer to ubiquinone (coenzyme Q10). Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.
Studies in cystic fibrosis cases suggest that MT-ND4 expression is indirectly upregulated by the cystic fibrosis transmembrane conductance regulator (CFTR) channel chloride transport activity. Channel flow double-electrode (CFDE) cells ectopically expressing wild-type CFTR channels were used to test the effect of CFTR chloride transport inhibitors glibenclamide and CFTR(inh)172 and demonstrated a reduction in MT-ND4 expression.
# Clinical significance
MT-ND4 is one of five SNPs associated with age-related macular degeneration (AMD) in Mexican Americans.
Leber's hereditary optic neuropathy (LHON) correlates with a mutation in the MT-ND4 gene in multiple families. The mutation at codon 340 results in the elimination of an Sfa NI site by the conversion of a highly conserved arginine to a histidine. This provides a simple diagnostic test by which to identify LHON, a maternally inherited disease that results in optic nerve degeneration and cardiac dysrythmia.
Amino acid changes in MT-ND4, MT-ND5 and MT-ATP8 resulting from mutations at the 11994, 8502 and 13,231 bp of mtDNA are significantly correlated in mesial temporal lobe epilepsy (MTLE) patients with hippocampal sclerosis. The 11994 C>T mutation to the MT-ND4 gene results in a Thr to Ile shift at the 412 position. Genome analysis has never been used in MTLE cases and could provide another diagnostic method in the disease.
MT-ND4 is downregulated in cystic fibrosis, a disease that results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel.
# Interactions
MT-ND4 has been shown to have 21 binary protein-protein interactions including 15 co-complex interactions. MT-ND4 appears to interact with SP1, ZNF16, CTCF, GRB2, and ATM. | MT-ND4
NADH-ubiquinone oxidoreductase chain 4 is a protein that in humans is encoded by the mitochondrial gene MT-ND4.[1] The ND4 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[2] Variations in the MT-ND4 gene are associated with age-related macular degeneration (AMD), Leber's hereditary optic neuropathy (LHON), mesial temporal lobe epilepsy (MTLE) and cystic fibrosis.[3][4][5][6]
# Structure
The MT-ND4 gene is located in human mitochondrial DNA from base pair 10,760 to 12,137.[1][7] An unusual feature of the human MT-ND4 gene is the 7-nucleotide gene overlap of its first three codons (5'-ATG CTA AAA-3' coding for amino acids Met-Leu-Lys) with the last three codons of the MT-ND4L gene (5'-CAA TGC TAA-3' coding for Gln, Cys and Stop).[7] With respect to the MT-ND4L reading frame (+1), the MT-ND4 gene starts in the +3 reading frame: [CAA][TGC][TAA]AA versus CA[ATG][CTA][AAA].
The MT-ND4 gene produces a 52 kDa protein composed of 459 amino acids.[8][9] MT-ND4 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it is the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centres and the NADH binding site. MT-ND4 and the rest of the mitochondrially encoded subunits are the most hydrophobic of the subunits of Complex I and form the core of the transmembrane region.[2]
# Function
MT-ND4 is a subunit of the respiratory chain Complex I that is believed to belong to the minimal assembly of core proteins required to catalyze NADH dehydrogenation and electron transfer to ubiquinone (coenzyme Q10).[10] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[2]
Studies in cystic fibrosis cases suggest that MT-ND4 expression is indirectly upregulated by the cystic fibrosis transmembrane conductance regulator (CFTR) channel chloride transport activity. Channel flow double-electrode (CFDE) cells ectopically expressing wild-type CFTR channels were used to test the effect of CFTR chloride transport inhibitors glibenclamide and CFTR(inh)172 and demonstrated a reduction in MT-ND4 expression.[3]
# Clinical significance
MT-ND4 is one of five SNPs associated with age-related macular degeneration (AMD) in Mexican Americans.[6]
Leber's hereditary optic neuropathy (LHON) correlates with a mutation in the MT-ND4 gene in multiple families. The mutation at codon 340 results in the elimination of an Sfa NI site by the conversion of a highly conserved arginine to a histidine. This provides a simple diagnostic test by which to identify LHON, a maternally inherited disease that results in optic nerve degeneration and cardiac dysrythmia.[5]
Amino acid changes in MT-ND4, MT-ND5 and MT-ATP8 resulting from mutations at the 11994, 8502 and 13,231 bp of mtDNA are significantly correlated in mesial temporal lobe epilepsy (MTLE) patients with hippocampal sclerosis. The 11994 C>T mutation to the MT-ND4 gene results in a Thr to Ile shift at the 412 position. Genome analysis has never been used in MTLE cases and could provide another diagnostic method in the disease.[4]
MT-ND4 is downregulated in cystic fibrosis, a disease that results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel.[3]
# Interactions
MT-ND4 has been shown to have 21 binary protein-protein interactions including 15 co-complex interactions. MT-ND4 appears to interact with SP1, ZNF16, CTCF, GRB2, and ATM.[11] | https://www.wikidoc.org/index.php/MT-ND4 | |
1171925e9cdf281ca8aa5b74f1bb3ff2c1e97111 | wikidoc | MT-ND5 | MT-ND5
NADH-ubiquinone oxidoreductase chain 5 is a protein that in humans is encoded by the mitochondrial gene MT-ND5. The ND5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in MT-ND5 are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) as well as some symptoms of Leigh's syndrome and Leber's hereditary optic neuropathy (LHON).
# Structure
MT-ND5 is located in mitochondrial DNA from base pair 12,337 to 14,148. The MT-ND5 gene produces a 67 kDa protein composed of 603 amino acids. MT-ND5 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it is the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centres and the NADH binding site. MT-ND5 and the rest of the mitochondrially encoded subunits are the most hydrophobic of the subunits of Complex I and form the core of the transmembrane region.
# Function
MT-ND5 is a subunit of the respiratory chain Complex I that is believed to belong to the minimal assembly of core proteins required to catalyze NADH dehydrogenation and electron transfer to ubiquinone (coenzyme Q10). Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.
# Clinical Significance
A small percentage of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) are caused by a G>A mutation at base pair 13513 in the MT-ND5 gene. Mutations in the MT-ND5 gene cause impaired Complex I function of the mitochondrial electron transport system, impairing those tissues that require significant energy input, such as the brain and muscles. Cardiac and renal involvement as well as symptoms such as myopathy and lactic acidosis can also be observed. Those with MT-ND5 mutations can display the major features of MELAS and MERRF in some patients, as well as symptoms of Leigh's syndrome and/or Leber's hereditary optic neuropathy (LHON) in others.
# Interactions
MT-ND5 interacts with Glutamine synthetase (GLUL), LIG4 and YME1L1. | MT-ND5
NADH-ubiquinone oxidoreductase chain 5 is a protein that in humans is encoded by the mitochondrial gene MT-ND5.[1] The ND5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[2] Variations in MT-ND5 are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) as well as some symptoms of Leigh's syndrome and Leber's hereditary optic neuropathy (LHON).[3][4]
# Structure
MT-ND5 is located in mitochondrial DNA from base pair 12,337 to 14,148.[1] The MT-ND5 gene produces a 67 kDa protein composed of 603 amino acids.[5][6] MT-ND5 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it is the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centres and the NADH binding site. MT-ND5 and the rest of the mitochondrially encoded subunits are the most hydrophobic of the subunits of Complex I and form the core of the transmembrane region.[2]
# Function
MT-ND5 is a subunit of the respiratory chain Complex I that is believed to belong to the minimal assembly of core proteins required to catalyze NADH dehydrogenation and electron transfer to ubiquinone (coenzyme Q10).[7] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[2]
# Clinical Significance
A small percentage of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) are caused by a G>A mutation at base pair 13513 in the MT-ND5 gene. Mutations in the MT-ND5 gene cause impaired Complex I function of the mitochondrial electron transport system, impairing those tissues that require significant energy input, such as the brain and muscles. Cardiac and renal involvement as well as symptoms such as myopathy and lactic acidosis can also be observed.[8] Those with MT-ND5 mutations can display the major features of MELAS and MERRF in some patients, as well as symptoms of Leigh's syndrome and/or Leber's hereditary optic neuropathy (LHON) in others.[3][4][9][10]
# Interactions
MT-ND5 interacts with Glutamine synthetase (GLUL), LIG4 and YME1L1.[1] | https://www.wikidoc.org/index.php/MT-ND5 | |
3fe62e3ba9cc0e86a7682cc46eade31dc5567fba | wikidoc | MT-ND6 | MT-ND6
NADH-ubiquinone oxidoreductase chain 6 is a protein that in humans is encoded by the mitochondrial MT-ND6 gene. The ND6 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in the MT-ND6 gene are associated with Leigh's syndrome, Leber's hereditary optic neuropathy (LHON) and dystonia.
# Structure
The MT-ND6 gene is located in human mitochondrial DNA from base pair 14,149 to 14,673. MT-ND6 is the only protein-coding gene located on the L-strand of the human mitogenome.
The encoded protein is 18 kDa and composed of 172 amino acids. MT-ND6 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it is the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centres and the NADH binding site. MT-ND6 and the rest of the mitochondrially encoded subunits are the most hydrophobic of the subunits of Complex I and form the core of the transmembrane region.
# Function
MT-ND6 is a subunit of the respiratory chain Complex I that is believed to belong to the minimal assembly of core proteins required to catalyze NADH dehydrogenation and electron transfer to ubiquinone (coenzyme Q10). Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.
# Clinical significance
A T → C mutation at the 14484 base pair in the MT-ND6 gene has been identified in people with Leber's hereditary optic neuropathy (LHON). This common MT-ND6 mutation is responsible for about 14 percent of all cases of LHON, and it is the most common cause of this disorder among people of French Canadian descent. This mutation changes a single amino acid in the NADH dehydrogenase 6 protein at position 64, from methionine to valine. The T14484C mutation is associated with a good long-term prognosis; affected people with this genetic change have a 37 percent to 65 percent chance of some visual recovery. Researchers are investigating how mutations in the MT-ND6 gene lead to Leber's hereditary optic neuropathy. These genetic changes appear to prevent Complex I from interacting normally with ubiquinone, which may affect the generation of ATP and may also increase the production within mitochondria of potentially harmful molecules called reactive oxygen species (ROS). It remains unclear, however, why the effects of these mutations are often limited to the nerve that relays visual information from the eye to the brain (the optic nerve). Additional genetic and environmental factors probably contribute to the vision loss and other medical problems associated with Leber hereditary optic neuropathy.
A G → A mutation at the 14459 base pair in the MT-ND6 gene also has been identified in a small number of people with Leigh's syndrome, a progressive brain disorder that typically appears in infancy or early childhood. Affected children may experience vomiting, seizures, delayed development, muscle weakness, and problems with movement. Heart disease, kidney problems, and difficulty breathing can also occur in people with this disorder. This MT-ND6 G14459A mutation replaces the amino acid alanine with the amino acid valine at protein position 72 in the NADH-ubiquinone oxidoreductase chain 6 protein. This genetic change also has been found in people with LHON and a movement disorder called dystonia, which involves involuntary muscle contractions, tremors, and other uncontrolled movements. This mutation appears to disrupt the normal assembly or activity of complex I in mitochondria. It is not known, however, how this MT-ND6 gene alteration is related to the specific features of Leigh syndrome, LHON, or dystonia. It also remains unclear why a single mutation can cause such varied signs and symptoms in different people.
# Interactions
MT-ND6 interacts with the NADH dehydrogenase iron-sulfur protein 3 (NDUFS3) and the ATP-dependent metalloprotease YME1L1. | MT-ND6
NADH-ubiquinone oxidoreductase chain 6 is a protein that in humans is encoded by the mitochondrial MT-ND6 gene.[1] The ND6 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[2] Variations in the MT-ND6 gene are associated with Leigh's syndrome, Leber's hereditary optic neuropathy (LHON) and dystonia.[3]
# Structure
The MT-ND6 gene is located in human mitochondrial DNA from base pair 14,149 to 14,673.[1] MT-ND6 is the only protein-coding gene located on the L-strand of the human mitogenome.[4]
The encoded protein is 18 kDa and composed of 172 amino acids.[5][6] MT-ND6 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it is the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centres and the NADH binding site. MT-ND6 and the rest of the mitochondrially encoded subunits are the most hydrophobic of the subunits of Complex I and form the core of the transmembrane region.[2]
# Function
MT-ND6 is a subunit of the respiratory chain Complex I that is believed to belong to the minimal assembly of core proteins required to catalyze NADH dehydrogenation and electron transfer to ubiquinone (coenzyme Q10).[7] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[2]
# Clinical significance
A T → C mutation at the 14484 base pair in the MT-ND6 gene has been identified in people with Leber's hereditary optic neuropathy (LHON). This common MT-ND6 mutation is responsible for about 14 percent of all cases of LHON, and it is the most common cause of this disorder among people of French Canadian descent. This mutation changes a single amino acid in the NADH dehydrogenase 6 protein at position 64, from methionine to valine. The T14484C mutation is associated with a good long-term prognosis; affected people with this genetic change have a 37 percent to 65 percent chance of some visual recovery. Researchers are investigating how mutations in the MT-ND6 gene lead to Leber's hereditary optic neuropathy. These genetic changes appear to prevent Complex I from interacting normally with ubiquinone, which may affect the generation of ATP and may also increase the production within mitochondria of potentially harmful molecules called reactive oxygen species (ROS). It remains unclear, however, why the effects of these mutations are often limited to the nerve that relays visual information from the eye to the brain (the optic nerve). Additional genetic and environmental factors probably contribute to the vision loss and other medical problems associated with Leber hereditary optic neuropathy.[3]
A G → A mutation at the 14459 base pair in the MT-ND6 gene also has been identified in a small number of people with Leigh's syndrome, a progressive brain disorder that typically appears in infancy or early childhood. Affected children may experience vomiting, seizures, delayed development, muscle weakness, and problems with movement. Heart disease, kidney problems, and difficulty breathing can also occur in people with this disorder. This MT-ND6 G14459A mutation replaces the amino acid alanine with the amino acid valine at protein position 72 in the NADH-ubiquinone oxidoreductase chain 6 protein. This genetic change also has been found in people with LHON and a movement disorder called dystonia, which involves involuntary muscle contractions, tremors, and other uncontrolled movements. This mutation appears to disrupt the normal assembly or activity of complex I in mitochondria. It is not known, however, how this MT-ND6 gene alteration is related to the specific features of Leigh syndrome, LHON, or dystonia. It also remains unclear why a single mutation can cause such varied signs and symptoms in different people.[3]
# Interactions
MT-ND6 interacts with the NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) and the ATP-dependent metalloprotease YME1L1.[1] | https://www.wikidoc.org/index.php/MT-ND6 | |
e537c23c44d285581c95e8516ecd49f209bd2ec1 | wikidoc | MT-TL1 | MT-TL1
Mitochondrially encoded tRNA leucine 1 (UUA/G) also known as MT-TL1 is a transfer RNA which in humans is encoded by the mitochondrial MT-TL1 gene.
# Structure
The MT-TL1 gene is located on the p arm of the mitochondrial DNA at position 12 and it spans 75 base pairs. The structure of a tRNA molecule is a distinctive folded structure which contains three hairpin loops and resembles a three-leafed clover.
# Function
MT-TL1 is a small 75 nucleotide RNA (human mitochondrial map position 3230-3304) that transfers the amino acid leucine to a growing polypeptide chain at the ribosome site of protein synthesis during translation.
# Clinical significance
## Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
Mutations in MT-TL1 can result in multiple mitochondrial deficiencies and associated disorders. It is associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). MELAS is a rare mitochondrial disorder known to affect many parts of the body, especially the nervous system and the brain. Symptoms of MELAS include recurrent severe headaches, muscle weakness (myopathy), hearing loss, stroke-like episodes with a loss of consciousness, seizures, and other problems affecting the nervous system. A common mutation is A3243G. This mutation has been theorized to be associated with several other mitochondrial diseases, including diabetes mellitus and deafness. Diabetes mellitus and deafness is characterized by diabetes combined with hearing loss, particularly of high pitches. Additional symptoms includemuscle weakness (myopathy) and various problems with a patient's eyes, heart, or kidneys.
## Complex I deficiency
MT-TP mutations may result in complex I deficiency of the mitochondrial respiratory chain, which may cause a wide variety of signs and symptoms affecting many organs and systems of the body, particularly the nervous system, the heart, and the muscles used for movement (skeletal muscles). These signs and symptoms can appear at any time from birth to adulthood. Phenotypes of the condition include encephalopathy, epilepsy, dystonia, hypotonia, myalgia, exercise intolerance, and more. A 3302A>G mutation has been found in a patient with the deficiency. | MT-TL1
Mitochondrially encoded tRNA leucine 1 (UUA/G) also known as MT-TL1 is a transfer RNA which in humans is encoded by the mitochondrial MT-TL1 gene.[1]
# Structure
The MT-TL1 gene is located on the p arm of the mitochondrial DNA at position 12 and it spans 75 base pairs.[2] The structure of a tRNA molecule is a distinctive folded structure which contains three hairpin loops and resembles a three-leafed clover.[3]
# Function
MT-TL1 is a small 75 nucleotide RNA (human mitochondrial map position 3230-3304) that transfers the amino acid leucine to a growing polypeptide chain at the ribosome site of protein synthesis during translation.
# Clinical significance
## Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
Mutations in MT-TL1 can result in multiple mitochondrial deficiencies and associated disorders. It is associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).[4] MELAS is a rare mitochondrial disorder known to affect many parts of the body, especially the nervous system and the brain. Symptoms of MELAS include recurrent severe headaches, muscle weakness (myopathy), hearing loss, stroke-like episodes with a loss of consciousness, seizures, and other problems affecting the nervous system.[5] A common mutation is A3243G. This mutation has been theorized to be associated with several other mitochondrial diseases,[6] including diabetes mellitus and deafness.[7][8] Diabetes mellitus and deafness is characterized by diabetes combined with hearing loss, particularly of high pitches. Additional symptoms includemuscle weakness (myopathy) and various problems with a patient's eyes, heart, or kidneys.[9]
## Complex I deficiency
MT-TP mutations may result in complex I deficiency of the mitochondrial respiratory chain, which may cause a wide variety of signs and symptoms affecting many organs and systems of the body, particularly the nervous system, the heart, and the muscles used for movement (skeletal muscles). These signs and symptoms can appear at any time from birth to adulthood. Phenotypes of the condition include encephalopathy, epilepsy, dystonia, hypotonia, myalgia, exercise intolerance, and more. A 3302A>G mutation has been found in a patient with the deficiency.[10] | https://www.wikidoc.org/index.php/MT-TL1 | |
c558df7b071840e14d667cee10cfbed6071f731d | wikidoc | MT-TL2 | MT-TL2
Mitochondrially encoded tRNA leucine 2 (CUN) also known as MT-TL2 is a transfer RNA which in humans is encoded by the mitochondrial MT-TL2 gene.
# Function
MT-TL2 is a small 71 nucleotide RNA (human mitochondrial map position 12266-12336) that transfers the amino acid leucine to a growing polypeptide chain at the ribosome site of protein synthesis during translation.
# Structure
The MT-TL2 gene is located on the p arm of the mitochondrial DNA at position 12 and it spans 75 base pairs. The structure of a tRNA molecule is a distinctive folded structure which contains three hairpin loops and resembles a three-leafed clover.
# Clinical significance
Mutations in MT-TL2 can result in multiple mitochondrial deficiencies and associated disorders, including cardiopathy, myopathy, and encephalomyopathy. A patient with a mutation G12315A was found with encephalomyopathy with ragged-red muscle fibers. A patient with a mutation of A12320G exhibited mitochondrial myopathy, and showed signs of mitochondrial myopathy. In addition, multiple individuals with a T12297C substitution showed signs of cardiomyopathy accompanied with varying degrees.
MT-TL2 mutations have also been associated with complex IV deficiency of the mitochondrial respiratory chain, also known as the cytochrome c oxidase deficiency. Cytochrome c oxidase deficiency is a rare genetic condition that can affect multiple parts of the body, including skeletal muscles, the heart, the brain, or the liver. Common clinical manifestations include myopathy, hypotonia, and encephalomyopathy, lactic acidosis, and hypertrophic cardiomyopathy. A patient with a 12316G>A mutation in MT-TL2 was found with the deficiency. | MT-TL2
Mitochondrially encoded tRNA leucine 2 (CUN) also known as MT-TL2 is a transfer RNA which in humans is encoded by the mitochondrial MT-TL2 gene.[1]
# Function
MT-TL2 is a small 71 nucleotide RNA (human mitochondrial map position 12266-12336) that transfers the amino acid leucine to a growing polypeptide chain at the ribosome site of protein synthesis during translation.
# Structure
The MT-TL2 gene is located on the p arm of the mitochondrial DNA at position 12 and it spans 75 base pairs.[2] The structure of a tRNA molecule is a distinctive folded structure which contains three hairpin loops and resembles a three-leafed clover.[3]
# Clinical significance
Mutations in MT-TL2 can result in multiple mitochondrial deficiencies and associated disorders, including cardiopathy, myopathy, and encephalomyopathy. A patient with a mutation G12315A was found with encephalomyopathy with ragged-red muscle fibers.[4] A patient with a mutation of A12320G exhibited mitochondrial myopathy, and showed signs of mitochondrial myopathy.[5] In addition, multiple individuals with a T12297C substitution showed signs of cardiomyopathy accompanied with varying degrees.[6]
MT-TL2 mutations have also been associated with complex IV deficiency of the mitochondrial respiratory chain, also known as the cytochrome c oxidase deficiency. Cytochrome c oxidase deficiency is a rare genetic condition that can affect multiple parts of the body, including skeletal muscles, the heart, the brain, or the liver. Common clinical manifestations include myopathy, hypotonia, and encephalomyopathy, lactic acidosis, and hypertrophic cardiomyopathy.[7] A patient with a 12316G>A mutation in MT-TL2 was found with the deficiency.[8] | https://www.wikidoc.org/index.php/MT-TL2 | |
7d5ea2d58617692599dc5d62dea943af0f181673 | wikidoc | mTORC1 | mTORC1
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR. This complex embodies the classic functions of mTOR, namely as a nutrient/energy/redox sensor and controller of protein synthesis. The activity of this complex is regulated by rapamycin, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives (e.g., L-leucine and β-hydroxy β-methylbutyric acid), mechanical stimuli, and oxidative stress.
The role of mTORC1 is to activate translation of proteins. In order for cells to grow and proliferate by manufacturing more proteins, the cells must ensure that they have the resources available for protein production. Thus, for protein production, and therefore mTORC1 activation, cells must have adequate energy resources, nutrient availability, oxygen abundance, and proper growth factors in order for mRNA translation to begin.
# Activation at the lysosome
## The TSC complex
Almost all of the variables required for protein synthesis affect mTORC1 activation by interacting with the TSC1/TSC2 protein complex. TSC2 is a GTPase activating protein (GAP). Its GAP activity interacts with a G protein called Rheb by hydrolyzing the GTP of the active Rheb-GTP complex, converting it to the inactive Rheb-GDP complex. The active Rheb-GTP activates mTORC1 through unelucidated pathways. Thus, many of the pathways that influence mTORC1 activation do so through the activation or inactivation of the TSC1/TSC2 heterodimer. This control is usually performed through phosphorylation of the complex. This phosphorylation can cause the dimer to dissociate and lose its GAP activity, or the phosphorylation can cause the heterodimer to have increased GAP activity, depending on which amino acid residue becomes phosphorylated. Thus, the signals that influence mTORC1 activity do so through activation or inactivation of the TSC1/TSC2 complex, upstream of mTORC1.
## The Ragulator-Rag complex
mTORC1 interacts at the Ragulator-Rag complex on the surface of the lsyosome in response to amino acid levels in the cell. Even if a cell has the proper energy for protein synthesis, if it does not have the amino acid building blocks for proteins, no protein synthesis will occur. Studies have shown that depriving amino acid levels inhibits mTORC1 signaling to the point where both energy abundance and amino acids are necessary for mTORC1 to function. When amino acids are introduced to a deprived cell, the presence of amino acids causes Rag GTPase heterodimers to switch to their active conformation. Active Rag heterodimers interact with Raptor, localizing mTORC1 to the surface of late endosomes and lysosomes where the Rheb-GTP is located. This allows mTORC1 to physically interact with Rheb. Thus the amino acid pathway as well as the growth factor/energy pathway converge on endosomes and lysosomes. Thus the Ragulator-Rag complex recruits mTORC1 to lysosomes to interact with Rheb.
### Regulation of the Ragulator-Rag complex
Rag activity is regulated by at least two highly conserved complexes: the "GATOR1" complex containing DEPDC5, NPRL2 and NPRL3 and the ""GATOR2" complex containing Mios, WDR24, WDR59, Seh1L, Sec13. GATOR1 inhibits Rags (it is a GTPase-activating protein for Rag subunits A/B) and GATOR2 activates Rags by inhibiting DEPDC5.
# Upstream signaling
## Receptor tyrosine kinases
### Akt/PKB pathway
Insulin-like growth factors can activate mTORC1 through the receptor tyrosine kinase (RTK)-Akt/PKB signaling pathway. Ultimately, Akt phosphorylates TSC2 on serine residue 939, serine residue 981, and threonine residue 1462. These phosphorylated sites will recruit the cytosolic anchoring protein 14-3-3 to TSC2, disrupting the TSC1/TSC2 dimer. When TSC2 is not associated with TSC1, TSC2 loses its GAP activity and can no longer hydrolyze Rheb-GTP. This results in continued activation of mTORC1, allowing for protein synthesis via insulin signaling.
Akt will also phosphorylate PRAS40, causing it to fall off of the Raptor protein located on mTORC1. Since PRAS40 prevents Raptor from recruiting mTORC1's substrates 4E-BP1 and S6K1, its removal will allow the two substrates to be recruited to mTORC1 and thereby activated in this way.
Furthermore, since insulin is a factor that is secreted by pancreatic beta cells upon glucose elevation in the blood, its signaling ensures that there is energy for protein synthesis to take place. In a negative feedback loop on mTORC1 signaling, S6K1 is able to phosphorylate the insulin receptor and inhibit its sensitivity to insulin. This has great significance in diabetes mellitus, which is due to insulin resistance.
### MAPK/ERK pathway
Mitogens, such as insulin like growth factor 1 (IGF1), can activate the MAPK/ERK pathway, which can inhibit the TSC1/TSC2 complex, activating mTORC1. In this pathway, the G protein Ras is tethered to the plasma membrane via a farnesyl group and is in its inactive GDP state. Upon growth factor binding to the adjacent receptor tyrosine kinase, the adaptor protein GRB2 binds with its SH2 domains. This recruits the GEF called Sos, which activates the Ras G protein. Ras activates Raf (MAPKKK), which activates Mek (MAPKK), which activates Erk (MAPK). Erk can go on to activate RSK. Erk will phosphorylate the serine residue 644 on TSC2, while RSK will phosphorylate serine residue 1798 on TSC2. These phosphorylations will cause the heterodimer to fall apart, and prevent it from deactivating Rheb, which keeps mTORC1 active.
RSK has also been shown to phosphorylate raptor, which helps it overcome the inhibitory effects of PRAS40.
## Wnt pathway
The Wnt pathway is responsible for cellular growth and proliferation during organismal development; thus, it could be reasoned that activation of this pathway also activates mTORC1. Activation of the Wnt pathway inhibits glycogen synthase kinase 3 beta (GSK3B). When the Wnt pathway is not active, GSK3 beta is able to phosphorylate TSC2 on two serine residues of 1341 and 1337 in conjunction with AMPK phosphorylating serine residue 1345. It has been found that the AMPK is required to first phosphorylate residue 1345 before GSK3 beta can phosphorylate its target serine residues. This phosphorylation of TSC2 would activate this complex, if GSK3 beta were active. Since the Wnt pathway inhibits GSK3 signaling, the active Wnt pathway is also involved in the mTORC1 pathway. Thus, mTORC1 can activate protein synthesis for the developing organism.
## Cytokines
Cytokines like tumor necrosis factor alpha (TNF-alpha) can induce mTOR activity through IKK beta, also known as IKK2. IKK beta can phosphorylate TSC1 at serine residue 487 and TSC1 at serine residue 511. This causes the heterodimer TSC complex to fall apart, keeping Rheb in its active GTP-bound state.
## Energy and oxygen
### Energy status
In order for translation to take place, abundant sources of energy, particularly in the form of ATP, need to be present. If these levels of ATP are not present, due to its hydrolysis into other forms like AMP, and the ratio of AMP to ATP molecules gets too high, AMPK will become activated. AMPK will go on to inhibit energy consuming pathways such as protein synthesis.
AMPK can phosphorylate TSC2 on serine residue 1387, which activates the GAP activity of this complex, causing Rheb-GTP to be hydrolyzed into Rheb-GDP. This inactivates mTORC1 and blocks protein synthesis through this pathway.
AMPK can also phosphorylate Raptor on two serine residues. This phosphorylated Raptor recruits 14-3-3 to bind to it and prevents Raptor from being part of the mTORC1 complex. Since mTORC1 cannot recruit its substrates without Raptor, no protein synthesis via mTORC1 occurs.
LKB1, also known as STK11, is a known tumor suppressor that can activate AMPK. More studies on this aspect of mTORC1 may help shed light on its strong link to cancer.
### Hypoxic stress
When oxygen levels in the cell are low, it will limit its energy expenditure through the inhibition of protein synthesis. Under hypoxic conditions, hypoxia inducible factor one alpha (HIF1A) will stabilize and activate transcription of REDD1, also known as DDIT4. After translation, this REDD1 protein will bind to TSC2, which prevents 14-3-3 from inhibiting the TSC complex. Thus, TSC retains its GAP activity towards Rheb, causing Rheb to remain bound to GDP and mTORC1 to be inactive.
Due to the lack of synthesis of ATP in the mitochondria under hypoxic stress or hypoxia, AMPK will also become active and thus inhibit mTORC1 through its processes.
# Downstream signaling
mTORC1 activates transcription and translation through its interactions with p70-S6 Kinase 1 (S6K1) and 4E-BP1, the eukaryotic initiation factor 4E (eIF4E) binding protein 1. Their signaling will converge at the translation initiation complex on the 5' end of mRNA, and thus activate translation.
## 4E-BP1
Activated mTORC1 will phosphorylate translation inhibitor 4E-BP1, releasing it from eukaryotic translation initiation factor 4E (eIF4E). eIF4E is now free to join the eukaryotic translation initiation factor 4G (eIF4G) and the eukaryotic translation initiation factor 4A (eIF4A). This complex then binds to the 5' cap of mRNA and will recruit the helicase eukaryotic translation initiation factor A (eIF4A) and its cofactor eukaryotic translation initiation factor 4B (eIF4B). The helicase is required to remove hairpin loops that arise in the 5' untranslated regions of mRNA, which prevent premature translation of proteins. Once the initiation complex is assembled at the 5' cap of mRNA, it will recruit the 40S small ribosomal subunit that is now capable of scanning for the AUG start codon start site, because the hairpin loop has been eradicated by the eIF4A helicase. Once the ribosome reaches the AUG codon, translation can begin.
## S6K
Hypophosphorylated S6K is located on the eIF3 scaffold complex. Active mTORC1 gets recruited to the scaffold, and once there, will phosphorylate S6K to make it active.
mTORC1 phosphorylates S6K1 on at least two residues, with the most critical modification occurring on a threonine residue (T389). This event stimulates the subsequent phosphorylation of S6K1 by PDPK1. Active S6K1 can in turn stimulate the initiation of protein synthesis through activation of S6 Ribosomal protein (a component of the ribosome) and eIF4B, causing them to be recruited to the pre-initiation complex.
Active S6K can bind to the SKAR scaffold protein that can get recruited to exon junction complexes (EJC). Exon junction complexes span the mRNA region where two exons come together after an intron has been spliced out. Once S6K binds to this complex, increased translation on these mRNA regions occurs.
S6K1 can also participate in a positive feedback loop with mTORC1 by phosphorylating mTOR's negative regulatory domain at two sites; phosphorylation at these sites appears to stimulate mTOR activity.
S6K also can phosphorylate programmed cell death 4 (PDCD4), which marks it for degradation by ubiquitin ligase Beta-TrCP (BTRC). PDCD4 is a tumor suppressor that binds to eIF4A and prevents it from being incorporated into the initiation complex.
# Role in disease and aging
mTOR was found to be related to aging in 2001 when the ortholog of S6K, SCH9, was deleted in S. cerevisiae, doubling its lifespan. This greatly increased the interest in upstream signaling and mTORC1. Studies in inhibiting mTORC1 were thus performed on the model organisms of C. elegans, fruitflies, and mice. Inhibition of mTORC1 showed significantly increased lifespans in all model species.
Based on upstream signaling of mTORC1, a clear relationship between food consumption and mTORC1 activity has been observed. Most specifically, carbohydrate consumption activates mTORC1 through the insulin growth factor pathway. In addition, amino acid consumption will stimulate mTORC1 through the branched chain amino acid/Rag pathway. Thus dietary restriction inhibits mTORC1 signaling through both upstream pathways of mTORC that converge on the lysosome.
Dietary restriction has been shown to significantly increase lifespan in the human model of Rhesus monkeys as well as protect against their age related decline. More specifically, Rhesus monkeys on a calorie restricted diet had significantly less chance of developing cardiovascular disease, diabetes, cancer, and age related cognitive decline than those monkeys who were not placed on the calorie restricted diet.
## Autophagy
Autophagy is the major degradation pathway in eukaryotic cells and is essential for the removal of damaged organelles via macroautophagy or proteins and smaller cellular debris via microautophagy from the cytoplasm. Thus, autophagy is a way for the cell to recycle old and damaged materials by breaking them down into their smaller components, allowing for the resynthesis of newer and healthier cellular structures. Autophagy can thus remove protein aggregates and damaged organelles that can lead to cellular dysfunction.
Upon activation, mTORC1 will phosphorylate autophagy-related protein 13 (Atg 13), preventing it from entering the ULK1 kinase complex, which consists of Atg1, Atg17, and Atg101. This prevents the structure from being recruited to the preautophagosomal structure at the plasma membrane, inhibiting autophagy.
mTORC1's ability to inhibit autophagy while at the same time stimulate protein synthesis and cell growth can result in accumulations of damaged proteins and organelles, contributing to damage at the cellular level. Because autophagy appears to decline with age, activation of autophagy may help promote longevity in humans. Problems in proper autophagy processes have been linked to diabetes, cardiovascular disease, neurodegenerative diseases, and cancer.
## Lysosomal damage
mTORC1 is positioned on lysosomes and is inhibited when lysosomal membrane is damaged through a protein complex termed GALTOR. GALTOR contains galectin-8, a cytosolic lectin, which recognizes damaged lysosomal membranes by binding to the exposed glycoconjugates normally facing lysosomal lumen. Under homeostatic conditions, Galectin-8 associates with active mTOR. Following membrane damage galectin-8 no longer interacts with mTOR but instead switches to complexes containing SLC38A9, RRAGA/RRAGB, and LAMTOR1 (a component of Ragulator) thus inhibiting mTOR, mTOR inhibition in turn activates autophagy and starts a quality control program that removes damaged lysosomes, referred to as lysophagy,
## Reactive oxygen species
Reactive oxygen species can damage the DNA and proteins in cells. A majority of them arise in the mitochondria.
Deletion of the TOR1 gene in yeast increases cellular respiration in the mitochondria by enhancing the translation of mitochondrial DNA that encodes for the complexes involved in the electron transport chain. When this electron transport chain is not as efficient, the unreduced oxygen molecules in the mitochondrial cortex may accumulate and begin to produce reactive oxygen species. It is important to note that both cancer cells as well as those cells with greater levels of mTORC1 both rely more on glycolysis in the cytosol for ATP production rather than through oxidative phosphorylation in the inner membrane of the mitochondria.
Inhibition of mTORC1 has also been shown to increase transcription of the NFE2L2 (NRF2) gene, which is a transcription factor that is able to regulate the expression of electrophilic response elements as well as antioxidants in response to increased levels of reactive oxygen species.
Though AMPK induced eNOS has been shown to regulate mTORC1 in endothelium. Unlike the other cell type in endothelium eNOS induced mTORC1 and this pathway is required for mitochondrial biogenesis.
## Stem cells
Conservation of stem cells in the body has been shown to help prevent against premature aging. mTORC1 activity plays a critical role in the growth and proliferation of stem cells. Knocking out mTORC1 results in embryonic lethality due to lack of trophoblast development. Treating stem cells with rapamycin will also slow their proliferation, conserving the stem cells in their undifferentiated condition.
mTORC1 plays a role in the differentiation and proliferation of hematopoietic stem cells. Its upregulation has been shown to cause premature aging in hematopoietic stem cells. Conversely, inhibiting mTOR restores and regenerates the hematopoietic stem cell line. The mechanisms of mTORC1's inhibition on proliferation and differentiation of hematopoietic stem cells has yet to be fully elucidated.
Rapamycin is used clinically as an immunosuppressant and prevents the proliferation of T cells and B cells. Paradoxically, even though rapamycin is a federally approved immunosuppressant, its inhibition of mTORC1 results in better quantity and quality of functional memory T cells. mTORC1 inhibition with rapamycin improves the ability of naïve T cells to become precursor memory T cells during the expansion phase of T cell development . This inhibition also allows for an increase in quality of these memory T cells that become mature T cells during the contraction phase of their development. mTORC1 inhibition with rapamycin has also been linked to a dramatic increase of B cells in old mice, enhancing their immune systems. This paradox of rapamycin inhibiting the immune system response has been linked to several reasons, including its interaction with regulatory T cells.
# As a biomolecular target
## Activators
Resistance exercise, the amino acid L-leucine, and beta-hydroxy beta-methylbutyric acid (HMB) are known to induce signaling cascades in skeletal muscle cells that result in mTOR phosphorylation, the activation of mTORC1, and subsequently the initiation of myofibrillar protein synthesis (i.e., the production of proteins such as myosin, titin, and actin), thereby facilitating muscle hypertrophy.
The NMDA receptor antagonist ketamine has been found to activate the mTORC1 pathway in the medial prefrontal cortex (mPFC) of the brain as an essential downstream mechanism in the mediation of its rapid-acting antidepressant effects. NV-5138 is a ligand and modulator of sestrin2, a leucine amino acid sensor and upstream regulatory pathway of mTORC1, and is under development for the treatment of depression. The drug has been found to directly and selectively activate the mTORC1 pathway, including in the mPFC, and to produce rapid-acting antidepressant effects similar to those of ketamine.
## Inhibitors
There have been several dietary compounds that have been suggested to inhibit mTORC1 signaling including EGCG, resveratrol, curcumin, caffeine, and alcohol.
### First generation drugs
Rapamycin was the first known inhibitor of mTORC1, considering that mTORC1 was discovered as being the target of rapamycin. Rapamycin will bind to cytosolic FKBP12 and act as a scaffold molecule, allowing this protein to dock on the FRB regulatory region (FKBP12-Rapamycin Binding region/domain) on mTORC1. The binding of the FKBP12-rapamycin complex to the FRB regulatory region inhibits mTORC1 through processes not yet known. mTORC2 is also inhibited by rapamycin in some cell culture lines and tissues, particularly those that express high levels of FKBP12 and low levels of FKBP51.
Rapamycin itself is not very water soluble and is not very stable, so scientists developed rapamycin analogs, called rapalogs, to overcome these two problems with rapamycin. These drugs are considered the first generation inhibitors of mTOR. These other inhibitors include everolimus and temsirolimus.
Sirolimus, which is the drug name for rapamycin, was approved by the U.S. Food and Drug Administration (FDA) in 1999 to prevent against transplant rejection in patients undergoing kidney transplantation. In 2003, it was approved as a stent covering for people who want to widen their arteries to prevent against future heart attacks. In 2007, mTORC1 inhibitors began being approved for treatments against cancers such as renal cell carcinoma. In 2008 they were approved for treatment of mantle cell lymphoma. mTORC1 inhibitors have recently been approved for treatment of pancreatic cancer. In 2010 they were approved for treatment of tuberous sclerosis.
### Second generation drugs
The second generation of inhibitors were created to overcome problems with upstream signaling upon the introduction of first generation inhibitors to the treated cells. One problem with the first generation inhibitors of mTORC1 is that there is a negative feedback loop from phosphorylated S6K, that can inhibit the insulin RTK via phosphorylation. When this negative feedback loop is no longer there, the upstream regulators of mTORC1 become more active than they would otherwise would have been under normal mTORC1 activity. Another problem is that since mTORC2 is resistant to rapamycin, and it too acts upstream of mTORC1 by activating Akt. Thus signaling upstream of mTORC1 still remains very active upon its inhibition via rapamycin and the rapalogs.
Second generation inhibitors are able to bind to the ATP-binding motif on the kinase domain of the mTOR core protein itself and abolish activity of both mTOR complexes. In addition, since the mTOR and the PI3K proteins are both in the same phosphatidylinositol 3-kinase-related kinase (PIKK) family of kinases, some second generation inhibitors have dual inhibition towards the mTOR complexes as well as PI3K, which acts upstream of mTORC1. As of 2011, these second generation inhibitors were in phase II of clinical trials.
There have been over 1,300 clinical trials conducted with mTOR inhibitors since 1970. | mTORC1
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.[1][2]
mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR.[2][3][4] This complex embodies the classic functions of mTOR, namely as a nutrient/energy/redox sensor and controller of protein synthesis.[1][2] The activity of this complex is regulated by rapamycin, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives (e.g., L-leucine and β-hydroxy β-methylbutyric acid), mechanical stimuli, and oxidative stress.[2][5][6]
The role of mTORC1 is to activate translation of proteins. In order for cells to grow and proliferate by manufacturing more proteins, the cells must ensure that they have the resources available for protein production. Thus, for protein production, and therefore mTORC1 activation, cells must have adequate energy resources, nutrient availability, oxygen abundance, and proper growth factors in order for mRNA translation to begin.[4]
# Activation at the lysosome
## The TSC complex
Almost all of the variables required for protein synthesis affect mTORC1 activation by interacting with the TSC1/TSC2 protein complex. TSC2 is a GTPase activating protein (GAP). Its GAP activity interacts with a G protein called Rheb by hydrolyzing the GTP of the active Rheb-GTP complex, converting it to the inactive Rheb-GDP complex. The active Rheb-GTP activates mTORC1 through unelucidated pathways.[7] Thus, many of the pathways that influence mTORC1 activation do so through the activation or inactivation of the TSC1/TSC2 heterodimer. This control is usually performed through phosphorylation of the complex. This phosphorylation can cause the dimer to dissociate and lose its GAP activity, or the phosphorylation can cause the heterodimer to have increased GAP activity, depending on which amino acid residue becomes phosphorylated.[8] Thus, the signals that influence mTORC1 activity do so through activation or inactivation of the TSC1/TSC2 complex, upstream of mTORC1.
## The Ragulator-Rag complex
mTORC1 interacts at the Ragulator-Rag complex on the surface of the lsyosome in response to amino acid levels in the cell.[9][10] Even if a cell has the proper energy for protein synthesis, if it does not have the amino acid building blocks for proteins, no protein synthesis will occur. Studies have shown that depriving amino acid levels inhibits mTORC1 signaling to the point where both energy abundance and amino acids are necessary for mTORC1 to function. When amino acids are introduced to a deprived cell, the presence of amino acids causes Rag GTPase heterodimers to switch to their active conformation.[11] Active Rag heterodimers interact with Raptor, localizing mTORC1 to the surface of late endosomes and lysosomes where the Rheb-GTP is located.[12] This allows mTORC1 to physically interact with Rheb. Thus the amino acid pathway as well as the growth factor/energy pathway converge on endosomes and lysosomes. Thus the Ragulator-Rag complex recruits mTORC1 to lysosomes to interact with Rheb.[13][14]
### Regulation of the Ragulator-Rag complex
Rag activity is regulated by at least two highly conserved complexes: the "GATOR1" complex containing DEPDC5, NPRL2 and NPRL3 and the ""GATOR2" complex containing Mios, WDR24, WDR59, Seh1L, Sec13.[15] GATOR1 inhibits Rags (it is a GTPase-activating protein for Rag subunits A/B) and GATOR2 activates Rags by inhibiting DEPDC5.
# Upstream signaling
## Receptor tyrosine kinases
### Akt/PKB pathway
Insulin-like growth factors can activate mTORC1 through the receptor tyrosine kinase (RTK)-Akt/PKB signaling pathway. Ultimately, Akt phosphorylates TSC2 on serine residue 939, serine residue 981, and threonine residue 1462.[16] These phosphorylated sites will recruit the cytosolic anchoring protein 14-3-3 to TSC2, disrupting the TSC1/TSC2 dimer. When TSC2 is not associated with TSC1, TSC2 loses its GAP activity and can no longer hydrolyze Rheb-GTP. This results in continued activation of mTORC1, allowing for protein synthesis via insulin signaling.[17]
Akt will also phosphorylate PRAS40, causing it to fall off of the Raptor protein located on mTORC1. Since PRAS40 prevents Raptor from recruiting mTORC1's substrates 4E-BP1 and S6K1, its removal will allow the two substrates to be recruited to mTORC1 and thereby activated in this way.[18]
Furthermore, since insulin is a factor that is secreted by pancreatic beta cells upon glucose elevation in the blood, its signaling ensures that there is energy for protein synthesis to take place. In a negative feedback loop on mTORC1 signaling, S6K1 is able to phosphorylate the insulin receptor and inhibit its sensitivity to insulin.[16] This has great significance in diabetes mellitus, which is due to insulin resistance.[19]
### MAPK/ERK pathway
Mitogens, such as insulin like growth factor 1 (IGF1), can activate the MAPK/ERK pathway, which can inhibit the TSC1/TSC2 complex, activating mTORC1.[17] In this pathway, the G protein Ras is tethered to the plasma membrane via a farnesyl group and is in its inactive GDP state. Upon growth factor binding to the adjacent receptor tyrosine kinase, the adaptor protein GRB2 binds with its SH2 domains. This recruits the GEF called Sos, which activates the Ras G protein. Ras activates Raf (MAPKKK), which activates Mek (MAPKK), which activates Erk (MAPK).[20] Erk can go on to activate RSK. Erk will phosphorylate the serine residue 644 on TSC2, while RSK will phosphorylate serine residue 1798 on TSC2.[21] These phosphorylations will cause the heterodimer to fall apart, and prevent it from deactivating Rheb, which keeps mTORC1 active.
RSK has also been shown to phosphorylate raptor, which helps it overcome the inhibitory effects of PRAS40.[22]
## Wnt pathway
The Wnt pathway is responsible for cellular growth and proliferation during organismal development; thus, it could be reasoned that activation of this pathway also activates mTORC1. Activation of the Wnt pathway inhibits glycogen synthase kinase 3 beta (GSK3B).[23] When the Wnt pathway is not active, GSK3 beta is able to phosphorylate TSC2 on two serine residues of 1341 and 1337 in conjunction with AMPK phosphorylating serine residue 1345. It has been found that the AMPK is required to first phosphorylate residue 1345 before GSK3 beta can phosphorylate its target serine residues. This phosphorylation of TSC2 would activate this complex, if GSK3 beta were active. Since the Wnt pathway inhibits GSK3 signaling, the active Wnt pathway is also involved in the mTORC1 pathway. Thus, mTORC1 can activate protein synthesis for the developing organism.[23]
## Cytokines
Cytokines like tumor necrosis factor alpha (TNF-alpha) can induce mTOR activity through IKK beta, also known as IKK2.[24] IKK beta can phosphorylate TSC1 at serine residue 487 and TSC1 at serine residue 511. This causes the heterodimer TSC complex to fall apart, keeping Rheb in its active GTP-bound state.
## Energy and oxygen
### Energy status
In order for translation to take place, abundant sources of energy, particularly in the form of ATP, need to be present. If these levels of ATP are not present, due to its hydrolysis into other forms like AMP, and the ratio of AMP to ATP molecules gets too high, AMPK will become activated. AMPK will go on to inhibit energy consuming pathways such as protein synthesis.[25]
AMPK can phosphorylate TSC2 on serine residue 1387, which activates the GAP activity of this complex, causing Rheb-GTP to be hydrolyzed into Rheb-GDP. This inactivates mTORC1 and blocks protein synthesis through this pathway.[26]
AMPK can also phosphorylate Raptor on two serine residues. This phosphorylated Raptor recruits 14-3-3 to bind to it and prevents Raptor from being part of the mTORC1 complex. Since mTORC1 cannot recruit its substrates without Raptor, no protein synthesis via mTORC1 occurs.[27]
LKB1, also known as STK11, is a known tumor suppressor that can activate AMPK. More studies on this aspect of mTORC1 may help shed light on its strong link to cancer.[28]
### Hypoxic stress
When oxygen levels in the cell are low, it will limit its energy expenditure through the inhibition of protein synthesis. Under hypoxic conditions, hypoxia inducible factor one alpha (HIF1A) will stabilize and activate transcription of REDD1, also known as DDIT4. After translation, this REDD1 protein will bind to TSC2, which prevents 14-3-3 from inhibiting the TSC complex. Thus, TSC retains its GAP activity towards Rheb, causing Rheb to remain bound to GDP and mTORC1 to be inactive.[29][30]
Due to the lack of synthesis of ATP in the mitochondria under hypoxic stress or hypoxia, AMPK will also become active and thus inhibit mTORC1 through its processes.[31]
# Downstream signaling
mTORC1 activates transcription and translation through its interactions with p70-S6 Kinase 1 (S6K1) and 4E-BP1, the eukaryotic initiation factor 4E (eIF4E) binding protein 1.[1] Their signaling will converge at the translation initiation complex on the 5' end of mRNA, and thus activate translation.
## 4E-BP1
Activated mTORC1 will phosphorylate translation inhibitor 4E-BP1, releasing it from eukaryotic translation initiation factor 4E (eIF4E).[32] eIF4E is now free to join the eukaryotic translation initiation factor 4G (eIF4G) and the eukaryotic translation initiation factor 4A (eIF4A).[33] This complex then binds to the 5' cap of mRNA and will recruit the helicase eukaryotic translation initiation factor A (eIF4A) and its cofactor eukaryotic translation initiation factor 4B (eIF4B).[34] The helicase is required to remove hairpin loops that arise in the 5' untranslated regions of mRNA, which prevent premature translation of proteins. Once the initiation complex is assembled at the 5' cap of mRNA, it will recruit the 40S small ribosomal subunit that is now capable of scanning for the AUG start codon start site, because the hairpin loop has been eradicated by the eIF4A helicase.[35] Once the ribosome reaches the AUG codon, translation can begin.
## S6K
Hypophosphorylated S6K is located on the eIF3 scaffold complex. Active mTORC1 gets recruited to the scaffold, and once there, will phosphorylate S6K to make it active.[16]
mTORC1 phosphorylates S6K1 on at least two residues, with the most critical modification occurring on a threonine residue (T389).[36][37] This event stimulates the subsequent phosphorylation of S6K1 by PDPK1.[37][38] Active S6K1 can in turn stimulate the initiation of protein synthesis through activation of S6 Ribosomal protein (a component of the ribosome) and eIF4B, causing them to be recruited to the pre-initiation complex.[39]
Active S6K can bind to the SKAR scaffold protein that can get recruited to exon junction complexes (EJC). Exon junction complexes span the mRNA region where two exons come together after an intron has been spliced out. Once S6K binds to this complex, increased translation on these mRNA regions occurs.[40]
S6K1 can also participate in a positive feedback loop with mTORC1 by phosphorylating mTOR's negative regulatory domain at two sites; phosphorylation at these sites appears to stimulate mTOR activity.[41][42]
S6K also can phosphorylate programmed cell death 4 (PDCD4), which marks it for degradation by ubiquitin ligase Beta-TrCP (BTRC). PDCD4 is a tumor suppressor that binds to eIF4A and prevents it from being incorporated into the initiation complex.[43]
# Role in disease and aging
mTOR was found to be related to aging in 2001 when the ortholog of S6K, SCH9, was deleted in S. cerevisiae, doubling its lifespan.[44] This greatly increased the interest in upstream signaling and mTORC1. Studies in inhibiting mTORC1 were thus performed on the model organisms of C. elegans, fruitflies, and mice. Inhibition of mTORC1 showed significantly increased lifespans in all model species.[45][46]
Based on upstream signaling of mTORC1, a clear relationship between food consumption and mTORC1 activity has been observed.[47] Most specifically, carbohydrate consumption activates mTORC1 through the insulin growth factor pathway. In addition, amino acid consumption will stimulate mTORC1 through the branched chain amino acid/Rag pathway. Thus dietary restriction inhibits mTORC1 signaling through both upstream pathways of mTORC that converge on the lysosome.[48]
Dietary restriction has been shown to significantly increase lifespan in the human model of Rhesus monkeys as well as protect against their age related decline.[49] More specifically, Rhesus monkeys on a calorie restricted diet had significantly less chance of developing cardiovascular disease, diabetes, cancer, and age related cognitive decline than those monkeys who were not placed on the calorie restricted diet.[49]
## Autophagy
Autophagy is the major degradation pathway in eukaryotic cells and is essential for the removal of damaged organelles via macroautophagy or proteins and smaller cellular debris via microautophagy from the cytoplasm.[50] Thus, autophagy is a way for the cell to recycle old and damaged materials by breaking them down into their smaller components, allowing for the resynthesis of newer and healthier cellular structures.[50] Autophagy can thus remove protein aggregates and damaged organelles that can lead to cellular dysfunction.[51]
Upon activation, mTORC1 will phosphorylate autophagy-related protein 13 (Atg 13), preventing it from entering the ULK1 kinase complex, which consists of Atg1, Atg17, and Atg101.[52] This prevents the structure from being recruited to the preautophagosomal structure at the plasma membrane, inhibiting autophagy.[53]
mTORC1's ability to inhibit autophagy while at the same time stimulate protein synthesis and cell growth can result in accumulations of damaged proteins and organelles, contributing to damage at the cellular level.[54] Because autophagy appears to decline with age, activation of autophagy may help promote longevity in humans.[55] Problems in proper autophagy processes have been linked to diabetes, cardiovascular disease, neurodegenerative diseases, and cancer.[56]
## Lysosomal damage
mTORC1 is positioned on lysosomes and is inhibited when lysosomal membrane is damaged through a protein complex termed GALTOR.[57] GALTOR contains galectin-8, a cytosolic lectin, which recognizes damaged lysosomal membranes by binding to the exposed glycoconjugates normally facing lysosomal lumen. Under homeostatic conditions, Galectin-8 associates with active mTOR.[57] Following membrane damage galectin-8 no longer interacts with mTOR but instead switches to complexes containing SLC38A9, RRAGA/RRAGB, and LAMTOR1 (a component of Ragulator) thus inhibiting mTOR,[57] mTOR inhibition in turn activates autophagy and starts a quality control program that removes damaged lysosomes,[57] referred to as lysophagy,[58]
## Reactive oxygen species
Reactive oxygen species can damage the DNA and proteins in cells.[59] A majority of them arise in the mitochondria.[60]
Deletion of the TOR1 gene in yeast increases cellular respiration in the mitochondria by enhancing the translation of mitochondrial DNA that encodes for the complexes involved in the electron transport chain.[61] When this electron transport chain is not as efficient, the unreduced oxygen molecules in the mitochondrial cortex may accumulate and begin to produce reactive oxygen species.[62] It is important to note that both cancer cells as well as those cells with greater levels of mTORC1 both rely more on glycolysis in the cytosol for ATP production rather than through oxidative phosphorylation in the inner membrane of the mitochondria.[63]
Inhibition of mTORC1 has also been shown to increase transcription of the NFE2L2 (NRF2) gene, which is a transcription factor that is able to regulate the expression of electrophilic response elements as well as antioxidants in response to increased levels of reactive oxygen species.[64]
Though AMPK induced eNOS has been shown to regulate mTORC1 in endothelium. Unlike the other cell type in endothelium eNOS induced mTORC1 and this pathway is required for mitochondrial biogenesis.[65]
## Stem cells
Conservation of stem cells in the body has been shown to help prevent against premature aging.[66] mTORC1 activity plays a critical role in the growth and proliferation of stem cells.[67] Knocking out mTORC1 results in embryonic lethality due to lack of trophoblast development.[68] Treating stem cells with rapamycin will also slow their proliferation, conserving the stem cells in their undifferentiated condition.[67]
mTORC1 plays a role in the differentiation and proliferation of hematopoietic stem cells. Its upregulation has been shown to cause premature aging in hematopoietic stem cells. Conversely, inhibiting mTOR restores and regenerates the hematopoietic stem cell line.[69] The mechanisms of mTORC1's inhibition on proliferation and differentiation of hematopoietic stem cells has yet to be fully elucidated.[70]
Rapamycin is used clinically as an immunosuppressant and prevents the proliferation of T cells and B cells.[71] Paradoxically, even though rapamycin is a federally approved immunosuppressant, its inhibition of mTORC1 results in better quantity and quality of functional memory T cells. mTORC1 inhibition with rapamycin improves the ability of naïve T cells to become precursor memory T cells during the expansion phase of T cell development .[72] This inhibition also allows for an increase in quality of these memory T cells that become mature T cells during the contraction phase of their development.[73] mTORC1 inhibition with rapamycin has also been linked to a dramatic increase of B cells in old mice, enhancing their immune systems.[69] This paradox of rapamycin inhibiting the immune system response has been linked to several reasons, including its interaction with regulatory T cells.[73]
# As a biomolecular target
## Activators
Resistance exercise, the amino acid L-leucine, and beta-hydroxy beta-methylbutyric acid (HMB) are known to induce signaling cascades in skeletal muscle cells that result in mTOR phosphorylation, the activation of mTORC1, and subsequently the initiation of myofibrillar protein synthesis (i.e., the production of proteins such as myosin, titin, and actin), thereby facilitating muscle hypertrophy.
The NMDA receptor antagonist ketamine has been found to activate the mTORC1 pathway in the medial prefrontal cortex (mPFC) of the brain as an essential downstream mechanism in the mediation of its rapid-acting antidepressant effects.[74] NV-5138 is a ligand and modulator of sestrin2, a leucine amino acid sensor and upstream regulatory pathway of mTORC1, and is under development for the treatment of depression.[74] The drug has been found to directly and selectively activate the mTORC1 pathway, including in the mPFC, and to produce rapid-acting antidepressant effects similar to those of ketamine.[74]
## Inhibitors
There have been several dietary compounds that have been suggested to inhibit mTORC1 signaling including EGCG, resveratrol, curcumin, caffeine, and alcohol.[75][76]
### First generation drugs
Rapamycin was the first known inhibitor of mTORC1, considering that mTORC1 was discovered as being the target of rapamycin.[77] Rapamycin will bind to cytosolic FKBP12 and act as a scaffold molecule, allowing this protein to dock on the FRB regulatory region (FKBP12-Rapamycin Binding region/domain) on mTORC1.[78] The binding of the FKBP12-rapamycin complex to the FRB regulatory region inhibits mTORC1 through processes not yet known. mTORC2 is also inhibited by rapamycin in some cell culture lines and tissues, particularly those that express high levels of FKBP12 and low levels of FKBP51.[79][80][81]
Rapamycin itself is not very water soluble and is not very stable, so scientists developed rapamycin analogs, called rapalogs, to overcome these two problems with rapamycin.[82] These drugs are considered the first generation inhibitors of mTOR.[83] These other inhibitors include everolimus and temsirolimus.
Sirolimus, which is the drug name for rapamycin, was approved by the U.S. Food and Drug Administration (FDA) in 1999 to prevent against transplant rejection in patients undergoing kidney transplantation.[84] In 2003, it was approved as a stent covering for people who want to widen their arteries to prevent against future heart attacks.[85] In 2007, mTORC1 inhibitors began being approved for treatments against cancers such as renal cell carcinoma.[86] In 2008 they were approved for treatment of mantle cell lymphoma.[87] mTORC1 inhibitors have recently been approved for treatment of pancreatic cancer.[88] In 2010 they were approved for treatment of tuberous sclerosis.[89]
### Second generation drugs
The second generation of inhibitors were created to overcome problems with upstream signaling upon the introduction of first generation inhibitors to the treated cells.[90] One problem with the first generation inhibitors of mTORC1 is that there is a negative feedback loop from phosphorylated S6K, that can inhibit the insulin RTK via phosphorylation.[91] When this negative feedback loop is no longer there, the upstream regulators of mTORC1 become more active than they would otherwise would have been under normal mTORC1 activity. Another problem is that since mTORC2 is resistant to rapamycin, and it too acts upstream of mTORC1 by activating Akt.[82] Thus signaling upstream of mTORC1 still remains very active upon its inhibition via rapamycin and the rapalogs.
Second generation inhibitors are able to bind to the ATP-binding motif on the kinase domain of the mTOR core protein itself and abolish activity of both mTOR complexes.[90] In addition, since the mTOR and the PI3K proteins are both in the same phosphatidylinositol 3-kinase-related kinase (PIKK) family of kinases, some second generation inhibitors have dual inhibition towards the mTOR complexes as well as PI3K, which acts upstream of mTORC1.[82] As of 2011, these second generation inhibitors were in phase II of clinical trials.
There have been over 1,300 clinical trials conducted with mTOR inhibitors since 1970.[92] | https://www.wikidoc.org/index.php/MTORC1 | |
b61e72b09d47e151fa041658ad0b41b2a8b470d5 | wikidoc | mTORC2 | mTORC2
mTOR Complex 2 (mTORC2) is a protein complex that regulates cellular metabolism as well as the cytoskeleton. It is defined by the interaction of mTOR and the rapamycin-insensitive companion of mTOR (RICTOR), and also includes GβL, mammalian stress-activated protein kinase interacting protein 1 (mSIN1), as well as Protor 1/2, DEPTOR, and TTI1 and TEL2.
# Function
mTORC2 has been shown to function as an important regulator of the cytoskeleton through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42, and protein kinase C α (PKCα).
mTORC2 also regulates cellular proliferation and metabolism, in part through the regulation of IGF-IR, InsR, Akt/PKB and the serum-and glucocorticoid-induced protein kinase SGK. mTORC2 phosphorylates the serine/threonine protein kinase Akt/PKB at a serine residue S473 as well as serine residue S450. Phosphorylation of the serine stimulates Akt phosphorylation at a threonine T308 residue by PDK1 and leads to full Akt activation.. In addition, mTORC2 has tyrosine kinase activity and phosphorylates IGF-IR and insulin receptor at the tyrosine residues Y1131/1136 and Y1146/1151, respectively, leading to full activation of IGF-IR and InsR.
# Regulation
mTORC2 appears to be regulated by insulin, growth factors, serum, and nutrient levels. Originally, mTORC2 was identified as a rapamycin-insensitive entity, as acute exposure to rapamycin did not affect mTORC2 activity or Akt phosphorylation. However, subsequent studies have shown that, at least in some cell lines, chronic exposure to rapamycin, while not affecting pre-existing mTORC2s, promotes rapamycin inhibition of free mTOR molecules, thus inhibiting the formation of new mTORC2. mTORC2 can be inhibited by chronic treatment with rapamycin in vivo, both in cancer cells and normal tissues such as the liver and adipose tissue. Torin1 can also be used to inhibit mTORC2.
Localization of mTORC2 in the cell has been suggested to be at the plasma membrane; however, this may be due to its association with Akt.
mTORC2 activation has thought to be due to growth factors, given that it regulates the activity of Akt and PKC.
mTORC2 may play a role in cancer, given its regulation of the widely studied oncogenetic Akt pathway. Chronic mTORC2 activity may play a role in systemic lupus erythematosus by impairing lysosome function.
Rictor has been shown to be the scaffold protein for substrate binding to mTORC2.
Studies using mice with tissue-specific loss of Rictor, and thus inactive mTORC2, have found that mTORC2 plays a critical role in the regulation of glucose homeostasis. Liver-specific disruption of mTORC2 through hepatic deletion of the gene Rictor leads to glucose intolerance, hepatic insulin resistance, decreased hepatic lipogenesis, and decreased male lifespan. Adipose-specific disruption of mTORC2 through deletion of Rictor may protect from a high-fat diet in young mice, but results in hepatic steatosis and insulin resistance in older mice. The role of mTORC2 in skeletal muscle has taken time to uncover, but genetic loss of mTORC2/Rictor in skeletal muscle results in decreased insulin-stimulated glucose uptake, and resistance to the effects of an mTOR kinase inhibitor on insulin resistance, highlighting a critical role for mTOR in the regulation of glucose homeostasis in this tissue. Loss of mTORC2/Rictor in pancreatic beta cells results in reduced beta cell mass and insulin secretion, and hyperglycemia and glucose intolerance. | mTORC2
mTOR Complex 2 (mTORC2) is a protein complex that regulates cellular metabolism as well as the cytoskeleton. It is defined by the interaction of mTOR and the rapamycin-insensitive companion of mTOR (RICTOR), and also includes GβL, mammalian stress-activated protein kinase interacting protein 1 (mSIN1), as well as Protor 1/2, DEPTOR, and TTI1 and TEL2.[1][2][3]
# Function
mTORC2 has been shown to function as an important regulator of the cytoskeleton through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42, and protein kinase C α (PKCα).[2]
mTORC2 also regulates cellular proliferation and metabolism, in part through the regulation of IGF-IR, InsR, Akt/PKB and the serum-and glucocorticoid-induced protein kinase SGK. mTORC2 phosphorylates the serine/threonine protein kinase Akt/PKB at a serine residue S473 as well as serine residue S450. Phosphorylation of the serine stimulates Akt phosphorylation at a threonine T308 residue by PDK1 and leads to full Akt activation.[4][5] Curcumin inhibits both by preventing phosphorylation of the serine.[6] Moreover, mTORC2 activity has been implicated in the regulation of autophagy[7](macroautophagy[8] and chaperone mediated autophagy).[9] In addition, mTORC2 has tyrosine kinase activity and phosphorylates IGF-IR and insulin receptor at the tyrosine residues Y1131/1136 and Y1146/1151, respectively, leading to full activation of IGF-IR and InsR.[10]
# Regulation
mTORC2 appears to be regulated by insulin, growth factors, serum, and nutrient levels.[1] Originally, mTORC2 was identified as a rapamycin-insensitive entity, as acute exposure to rapamycin did not affect mTORC2 activity or Akt phosphorylation.[4] However, subsequent studies have shown that, at least in some cell lines, chronic exposure to rapamycin, while not affecting pre-existing mTORC2s, promotes rapamycin inhibition of free mTOR molecules, thus inhibiting the formation of new mTORC2.[11] mTORC2 can be inhibited by chronic treatment with rapamycin in vivo, both in cancer cells and normal tissues such as the liver and adipose tissue.[12][13] Torin1 can also be used to inhibit mTORC2.[8][14]
Localization of mTORC2 in the cell has been suggested to be at the plasma membrane; however, this may be due to its association with Akt.[15]
mTORC2 activation has thought to be due to growth factors, given that it regulates the activity of Akt and PKC.[4]
mTORC2 may play a role in cancer, given its regulation of the widely studied oncogenetic Akt pathway.[12] Chronic mTORC2 activity may play a role in systemic lupus erythematosus by impairing lysosome function[16].
Rictor has been shown to be the scaffold protein for substrate binding to mTORC2.[17]
Studies using mice with tissue-specific loss of Rictor, and thus inactive mTORC2, have found that mTORC2 plays a critical role in the regulation of glucose homeostasis. Liver-specific disruption of mTORC2 through hepatic deletion of the gene Rictor leads to glucose intolerance, hepatic insulin resistance, decreased hepatic lipogenesis, and decreased male lifespan.[18][19][20][21] Adipose-specific disruption of mTORC2 through deletion of Rictor may protect from a high-fat diet in young mice,[22] but results in hepatic steatosis and insulin resistance in older mice.[23] The role of mTORC2 in skeletal muscle has taken time to uncover, but genetic loss of mTORC2/Rictor in skeletal muscle results in decreased insulin-stimulated glucose uptake, and resistance to the effects of an mTOR kinase inhibitor on insulin resistance, highlighting a critical role for mTOR in the regulation of glucose homeostasis in this tissue.[24][25][26] Loss of mTORC2/Rictor in pancreatic beta cells results in reduced beta cell mass and insulin secretion, and hyperglycemia and glucose intolerance.[27] | https://www.wikidoc.org/index.php/MTORC2 | |
2b01f32cdf3d98cea83496cd4b93b9e2192441bb | wikidoc | MTRF1L | MTRF1L
Mitochondrial translational release factor 1-like is a protein that in humans is encoded by the MTRF1L gene.
Mitochondrial DNA encodes 13 proteins that play essential roles in the respiratory chain, while all proteins involved in mitochondrial translation are encoded by nuclear genes that are imported from the cytoplasm. MTRF1L is a nuclear-encoded protein that functions as a releasing factor that recognizes termination codons and releases mitochondrial ribosomes from the synthesized protein (summary by Nozaki et al., 2008 )..
# Model organisms
Model organisms have been used in the study of MTRF1L function. A conditional knockout mouse line, called Mtrf1ltm1a(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 on mutant mice and three significant abnormalities were observed. No homozygous mutant embryos were recorded during gestation and, in a separate study, no homozygous animals were observed at weaning. The remaining tests were carried out on adult heterozygous mutant animals and males displayed an increased circulating free fatty acid level. | MTRF1L
Mitochondrial translational release factor 1-like is a protein that in humans is encoded by the MTRF1L gene.[1]
Mitochondrial DNA encodes 13 proteins that play essential roles in the respiratory chain, while all proteins involved in mitochondrial translation are encoded by nuclear genes that are imported from the cytoplasm. MTRF1L is a nuclear-encoded protein that functions as a releasing factor that recognizes termination codons and releases mitochondrial ribosomes from the synthesized protein (summary by Nozaki et al., 2008 [PubMed 18429816]).[supplied by OMIM].[1]
# Model organisms
Model organisms have been used in the study of MTRF1L function. A conditional knockout mouse line, called Mtrf1ltm1a(KOMP)Wtsi[7][8] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[9][10][11] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty six tests were carried out on mutant mice and three significant abnormalities were observed. No homozygous mutant embryos were recorded during gestation and, in a separate study, no homozygous animals were observed at weaning. The remaining tests were carried out on adult heterozygous mutant animals and males displayed an increased circulating free fatty acid level.[5] | https://www.wikidoc.org/index.php/MTRF1L | |
44c8cd9a484ea7342c4cfb58ef7a64d5005a49a4 | wikidoc | MYO15A | MYO15A
Myosin-XV is a protein that in humans is encoded by the MYO15A gene.
# Gene
Read-through transcript containing an upstream gene and this gene have been identified, but they are not thought to encode a fusion protein. Several alternatively spliced transcript variants have been described, but their full length sequences have not been determined.
# Function
This gene encodes an unconventional myosin. This protein differs from other myosins in that it has a long N-terminal extension preceding the conserved motor domain. Studies in mice suggest that this protein is necessary for actin organization in the hair cells of the cochlea.
# Clinical significance
Mutations in this gene have been associated with profound, congenital, neurosensory, non syndromic deafness . This gene is located within the Smith-Magenis syndrome region on chromosome 17. | MYO15A
Myosin-XV is a protein that in humans is encoded by the MYO15A gene.[1][2]
# Gene
Read-through transcript containing an upstream gene and this gene have been identified, but they are not thought to encode a fusion protein. Several alternatively spliced transcript variants have been described, but their full length sequences have not been determined.[2]
# Function
This gene encodes an unconventional myosin. This protein differs from other myosins in that it has a long N-terminal extension preceding the conserved motor domain. Studies in mice suggest that this protein is necessary for actin organization in the hair cells of the cochlea.[2]
# Clinical significance
Mutations in this gene have been associated with profound, congenital, neurosensory, non syndromic deafness .[3] This gene is located within the Smith-Magenis syndrome region on chromosome 17.[2] | https://www.wikidoc.org/index.php/MYO15A | |
b4bd85ca9109885ec4f3064b65a6574dc23d844c | wikidoc | Maalox | Maalox
Maalox is a brand name antacid containing Aluminium hydroxide and Magnesium hydroxide to neutralize or reduce stomach acid. It helps relieve symptoms of excessive stomach acidity in patients with indigestion, heartburn, gastroesophageal reflux disease (GERD {US} or GORD {UK}), or stomach or duodenal ulcers. In large doses, it can act as a laxative.
The mixture of Aluminium hydroxide and Magnesium hydroxide is sometimes referred to as Magaldrate.
# Ingredients
Liquid Maalox® Regular Strength contains magnesium hydroxide, aluminum hydroxide and simethicone.
# Uses
Treatment of moderate symptoms of burning sensation in the stomach or chest area with accompanying bloating and/or gas pain. Usually occurs after a meal.
Maalox is also used in scientific research to simulate for silt/mud/soil in water, along with other dissolved particulates. The particulate size exceeds 11 micrometres. | Maalox
Maalox is a brand name antacid containing Aluminium hydroxide and Magnesium hydroxide to neutralize or reduce stomach acid. It helps relieve symptoms of excessive stomach acidity in patients with indigestion, heartburn, gastroesophageal reflux disease (GERD {US} or GORD {UK}), or stomach or duodenal ulcers. In large doses, it can act as a laxative.
The mixture of Aluminium hydroxide and Magnesium hydroxide is sometimes referred to as Magaldrate.
# Ingredients
Liquid Maalox® Regular Strength contains magnesium hydroxide, aluminum hydroxide and simethicone.
# Uses
Treatment of moderate symptoms of burning sensation in the stomach or chest area with accompanying bloating and/or gas pain. Usually occurs after a meal.
Maalox is also used in scientific research to simulate for silt/mud/soil in water, along with other dissolved particulates. The particulate size exceeds 11 micrometres. [1]
Template:Treatment-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Maalox | |
81096e4794e24544505f16d115b1e5e6136609bd | wikidoc | Macula | Macula
The macula or macula lutea (from Latin macula, "spot" + lutea, "yellow") is an oval yellow spot near the center of the retina of the human eye. It has a diameter of about 1.5 mm and is often histologically defined as having two or more layers of ganglion cells. Near its center is the fovea, a small pit that contains the largest concentration of cone cells in the eye and is responsible for central vision.
It is specialized for high acuity vision. Within the macula are the fovea and foveola which contain a high density of cones (photoreceptors with high acuity).
# Clinical significance
Whereas loss of peripheral vision may go unnoticed for some time, damage to the macula will result in loss of central vision, which is usually immediately obvious.
The progressive destruction of the macula is a disease known as macular degeneration and leads to the creation of a macular hole. Macular holes can rarely be caused by trauma, if a severe blow is delivered perfectly it can burst the blood vessels going to the macula, destroying it.
Visual input to the macula occupies a substantial portion of the brain's visual capacity. As a result, some forms of visual field loss can occur without involving the macula; this is termed macular sparing. (For example, visual field testing might demonstrate homonymous hemianopsia with macular sparing.) This finding can be very informative for the ophthalmologist. | Macula
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The macula or macula lutea (from Latin macula, "spot" + lutea, "yellow") is an oval yellow spot near the center of the retina of the human eye. It has a diameter of about 1.5 mm and is often histologically defined as having two or more layers of ganglion cells. Near its center is the fovea, a small pit that contains the largest concentration of cone cells in the eye and is responsible for central vision.
It is specialized for high acuity vision. Within the macula are the fovea and foveola which contain a high density of cones (photoreceptors with high acuity).
# Clinical significance
Whereas loss of peripheral vision may go unnoticed for some time, damage to the macula will result in loss of central vision, which is usually immediately obvious.
The progressive destruction of the macula is a disease known as macular degeneration and leads to the creation of a macular hole. Macular holes can rarely be caused by trauma, if a severe blow is delivered perfectly it can burst the blood vessels going to the macula, destroying it.
Visual input to the macula occupies a substantial portion of the brain's visual capacity. As a result, some forms of visual field loss can occur without involving the macula; this is termed macular sparing. (For example, visual field testing might demonstrate homonymous hemianopsia with macular sparing.) This finding can be very informative for the ophthalmologist. | https://www.wikidoc.org/index.php/Macula | |
bd3509fcd34dad87810994f40855ead80483a22c | wikidoc | Malate | Malate
# Overview
Malate (O−OC-CH2-CH(OH)-COO−) is the ionized form of malic acid. It is an important chemical compound in biochemistry. In the C4 carbon fixation process, malate is a source of CO2 in the Calvin cycle.
In the citric acid cycle, (S)-malate is an intermediate formed by the addition of an -OH group on the si face of fumarate; it can also be formed from pyruvate via anaplerotic reactions. Malate dehydrogenase catalyzes the reversible conversion of malate into oxaloacetate using NAD as a cofactor.
Malate is also produced from starch in guard cells of plant leaves. A build up of malate leads to a low water potential. Water then flows into the guard cells causing the stoma to open. However, this process does not always induce the opening of stomas. | Malate
# Overview
Malate (O−OC-CH2-CH(OH)-COO−) is the ionized form of malic acid. It is an important chemical compound in biochemistry. In the C4 carbon fixation process, malate is a source of CO2 in the Calvin cycle.
In the citric acid cycle, (S)-malate is an intermediate formed by the addition of an -OH group on the si face of fumarate; it can also be formed from pyruvate via anaplerotic reactions. Malate dehydrogenase catalyzes the reversible conversion of malate into oxaloacetate using NAD as a cofactor.
Malate is also produced from starch in guard cells of plant leaves. A build up of malate leads to a low water potential. Water then flows into the guard cells causing the stoma to open. However, this process does not always induce the opening of stomas. | https://www.wikidoc.org/index.php/Malate | |
c420c7cb7261d150d842b944862a02d0ec3f92a2 | wikidoc | Nipple | Nipple
# Overview
In its most general form, a nipple is an appurtenance from which a fluid emanates. More specifically, it is the projection on breast of a mammal by which breast milk is delivered to a mother's young.
# Anatomy
In the anatomy of mammals, a nipple or mammary papilla is a small projection of skin containing the outlets for 15-20 lactiferous ducts arranged cylindrically around the tip. The skin of the nipple is rich in a supply of special nerves that are sensitive to certain stimuli. The physiological purpose of nipples is to deliver milk to the infant, produced in the female mammary glands during lactation. In the male, nipples are often not considered functional with regard to breastfeeding, although male lactation is possible. Mammalian infants have a rooting instinct for seeking the nipple, and a sucking instinct for extracting milk.
Mammals typically have an even number of nipples arranged around bilaterally. They develop in the embryo, along the 'milk lines'. Most mammals develop multiple nipples along each milk line, with the total number approximating the maximum litter size, and half the total number (i.e. the number on one side) approximating the average litter size for that species. In the primitive mammals (monotremes such as the platypus), the mammary glands empty onto the skin without a nipple.
Most humans have two nipples after birth, located near the center of each breast and surrounded by an area of sensitive, pigmented skin known as the areola. Human fetuses develop several more nipples along the milk lines, which extend from the axilla (armpit), along the abdominal muscles, down to the pubis (groin) on both sides. Those nipples usually disappear before birth, but sometimes remain, resulting in supernumerary nipples which occasionally have lactiferous glands attached.
The pigments of the nipple and areola are brown eumelanin (a brown pigment) and to a greater extent pheomelanin (a red pigment). The nipple and areola of males and females can be erotic receptors, or considered sex organs. Stimulation or sexual arousal can cause the nipples to become erect, due to the release of the polypeptide neurotransmitter oxytocin. Breastfeeding or exposure to cold temperatures often has this effect as well.
The average projection and size of human female nipples is slightly more than 3/8 inches (10mm).. Pregnancy and nursing tend to increase nipple size, sometimes permanently. Pregnancy also increases the pigmentation. The erection of the nipple is partially due to the cylindrically arranged muscle cells found within it. In many women, there are small bulges on the areola, which are called 'Montgomery bodies'.
Sometimes, babies (male or female) are born producing milk. This is called 'witch's milk' and is caused by maternal estrogens acting on the baby and is quite normal. Witch's milk disappears after several days.
# Nipples on male mammals
Starting at conception and lasting until about 14 weeks, all mammalian fetuses within the same species look the same, regardless of sex. After 14 weeks, genetically-male fetuses begin producing male hormones such as testosterone. As "female" is the "developmental default" for mammals, by 14 weeks the nipples have already formed. In recent studies, doctors have found female nipples to be erect in the fetal stage of mammals, as well as other forms of arousal.
Most of the time, males' nipples don't change much past this point. However, some males develop a condition known as gynecomastia, in which the fatty tissue around and under the nipple develops into something similar to a female breast. For males who develop gynecomastia during puberty, it is said the effects are temporary unless they are obese. This may happen whenever the testosterone level drops because of medications. | Nipple
# Overview
In its most general form, a nipple is an appurtenance from which a fluid emanates. More specifically, it is the projection on breast of a mammal by which breast milk is delivered to a mother's young.
# Anatomy
In the anatomy of mammals, a nipple or mammary papilla is a small projection of skin containing the outlets for 15-20 lactiferous ducts arranged cylindrically around the tip. The skin of the nipple is rich in a supply of special nerves that are sensitive to certain stimuli. The physiological purpose of nipples is to deliver milk to the infant, produced in the female mammary glands during lactation. In the male, nipples are often not considered functional with regard to breastfeeding, although male lactation is possible. Mammalian infants have a rooting instinct for seeking the nipple, and a sucking instinct for extracting milk.
Mammals typically have an even number of nipples arranged around bilaterally. They develop in the embryo, along the 'milk lines'. Most mammals develop multiple nipples along each milk line, with the total number approximating the maximum litter size, and half the total number (i.e. the number on one side) approximating the average litter size for that species. In the primitive mammals (monotremes such as the platypus), the mammary glands empty onto the skin without a nipple.
Most humans have two nipples after birth, located near the center of each breast and surrounded by an area of sensitive, pigmented skin known as the areola. Human fetuses develop several more nipples along the milk lines, which extend from the axilla (armpit), along the abdominal muscles, down to the pubis (groin) on both sides. Those nipples usually disappear before birth, but sometimes remain, resulting in supernumerary nipples which occasionally have lactiferous glands attached.
The pigments of the nipple and areola are brown eumelanin (a brown pigment) and to a greater extent pheomelanin (a red pigment). The nipple and areola of males and females can be erotic receptors, or considered sex organs. Stimulation or sexual arousal can cause the nipples to become erect, due to the release of the polypeptide neurotransmitter oxytocin. Breastfeeding or exposure to cold temperatures often has this effect as well.
The average projection and size of human female nipples is slightly more than 3/8 inches (10mm).[1]. Pregnancy and nursing tend to increase nipple size, sometimes permanently. Pregnancy also increases the pigmentation. The erection of the nipple is partially due to the cylindrically arranged muscle cells found within it. In many women, there are small bulges on the areola, which are called 'Montgomery bodies'.
Sometimes, babies (male or female) are born producing milk. This is called 'witch's milk' and is caused by maternal estrogens acting on the baby and is quite normal. Witch's milk disappears after several days.
# Nipples on male mammals
Starting at conception and lasting until about 14 weeks, all mammalian fetuses within the same species look the same, regardless of sex. After 14 weeks, genetically-male fetuses begin producing male hormones such as testosterone. As "female" is the "developmental default" for mammals, by 14 weeks the nipples have already formed. In recent studies, doctors have found female nipples to be erect in the fetal stage of mammals, as well as other forms of arousal.[citation needed]
Most of the time, males' nipples don't change much past this point. However, some males develop a condition known as gynecomastia, in which the fatty tissue around and under the nipple develops into something similar to a female breast. For males who develop gynecomastia during puberty, it is said the effects are temporary unless they are obese. This may happen whenever the testosterone level drops because of medications. | https://www.wikidoc.org/index.php/Mammary_papilla | |
cd37399a390eff114a712fc9ab96259df3a838f6 | wikidoc | Manure | Manure
# Overview
Manure is organic matter used as fertilizer in agriculture. Manures contribute to the fertility of the soil by adding organic matter and nutrients, such as nitrogen that is trapped by bacteria in the soil. Higher organisms then feed on the fungi and bacteria in a chain of life that comprises the soil food web.
The term "manure" was used for inorganic fertilizers in the past, but this usage is now very rare.
# Etymology
The word manure came from Middle English "manuren" meaning "to cultivate land," and initially from French "main-oeuvre" = "hand work" alluding to the work which involved manuring land.
# Types
There are two main classes of manures in soil management: green manures and animal manures. Compost is distinguished from manure in that it is the decomposed remnants of organic materials (which may, nevertheless, include manure).
Most animal manure is feces — excrement (variously called "droppings" or "crap" etc) of plant-eating mammals (herbivores) and poultry — or plant material (often straw) which has been used as bedding for animals and thus is heavily contaminated with their feces and urine.
Green manures are crops grown for the express purpose of plowing them under. In so doing, fertility is increased through the nutrients and organic matter that are returned to the soil. Leguminous crops, such as clover, also "fix" nitrogen through rhizobia bacteria in specialized nodes in the root structure.
Other types of plant matter used as manure or fertilizer include: the contents of the rumens of slaughtered ruminants; spent hops left over from making beer.
# Uses of manure
Manure has been used for centuries as a fertilizer for farming, as it is rich in nitrogen and other nutrients which facilitate the growth of plants. Liquid manure from pig/hog operations is usually knifed (injected) directly into the soil to reduce the unpleasant odors. Manure from hogs and cattle is spread on fields using a Manure spreader. Due to the relatively lower level of proteins in grasses, which herbivores eat, cattle manure has a milder smell than the dung of carnivores — for example, elephant dung is practically odorless. However, due to the quantity of manure applied to fields, odor can be a problem in some agricultural regions. Poultry droppings are harmful to plants when fresh but after a period of composting are valuable fertilizers.
The dried manure of animals has been used as fuel throughout history. Dried manure (usually known as dung) of cow was, and still is, an important fuel source in countries such as India, while camel dung may be used in treeless regions such as deserts. On the Oregon Trail, pioneering families collected large quantities of "buffalo chips" in lieu of scarce firewood. It has been used for many purposes, in cooking fires and to combat the cold desert nights.
Another use of manure is to make paper, this has been done with dung from elephants where it is a small industry in Africa and Asia, and also horses, llamas, and kangaroos. Other than the llama, these animals are not ruminants and thus tend to pass plant fibres undigested in their dung.
# Precautions
Manure generates heat as it decomposes, and it is not unheard of for manure to ignite spontaneously should it be stored in a massive pile. Once such a large pile of manure is burning, it will foul the air over a very large area and require considerable effort to extinguish. Large feedlots must therefore take care to ensure that piles of fresh manure (faeces) do not get excessively large. There is no serious risk of spontaneous combustion in smaller operations.
There is also a risk of insects carrying feces to food and water supplies, making them unsuitable for human consumption. | Manure
# Overview
Manure is organic matter used as fertilizer in agriculture. Manures contribute to the fertility of the soil by adding organic matter and nutrients, such as nitrogen that is trapped by bacteria in the soil. Higher organisms then feed on the fungi and bacteria in a chain of life that comprises the soil food web.
The term "manure" was used for inorganic fertilizers in the past, but this usage is now very rare.[1]
# Etymology
The word manure came from Middle English "manuren" meaning "to cultivate land," and initially from French "main-oeuvre" = "hand work" alluding to the work which involved manuring land.
# Types
There are two main classes of manures in soil management: green manures and animal manures. Compost is distinguished from manure in that it is the decomposed remnants of organic materials (which may, nevertheless, include manure).
Most animal manure is feces — excrement (variously called "droppings" or "crap" etc) of plant-eating mammals (herbivores) and poultry — or plant material (often straw) which has been used as bedding for animals and thus is heavily contaminated with their feces and urine.
Green manures are crops grown for the express purpose of plowing them under. In so doing, fertility is increased through the nutrients and organic matter that are returned to the soil. Leguminous crops, such as clover, also "fix" nitrogen through rhizobia bacteria in specialized nodes in the root structure.
Other types of plant matter used as manure or fertilizer include: the contents of the rumens of slaughtered ruminants; spent hops left over from making beer.
# Uses of manure
Manure has been used for centuries as a fertilizer for farming, as it is rich in nitrogen and other nutrients which facilitate the growth of plants. Liquid manure from pig/hog operations is usually knifed (injected) directly into the soil to reduce the unpleasant odors. Manure from hogs and cattle is spread on fields using a Manure spreader. Due to the relatively lower level of proteins in grasses, which herbivores eat, cattle manure has a milder smell than the dung of carnivores — for example, elephant dung is practically odorless. However, due to the quantity of manure applied to fields, odor can be a problem in some agricultural regions. Poultry droppings are harmful to plants when fresh but after a period of composting are valuable fertilizers.
The dried manure of animals has been used as fuel throughout history. Dried manure (usually known as dung) of cow was, and still is, an important fuel source in countries such as India, while camel dung may be used in treeless regions such as deserts. On the Oregon Trail, pioneering families collected large quantities of "buffalo chips" in lieu of scarce firewood. It has been used for many purposes, in cooking fires and to combat the cold desert nights.
Another use of manure is to make paper, this has been done with dung from elephants where it is a small industry in Africa and Asia, and also horses, llamas, and kangaroos. Other than the llama, these animals are not ruminants and thus tend to pass plant fibres undigested in their dung.
# Precautions
Manure generates heat as it decomposes, and it is not unheard of for manure to ignite spontaneously should it be stored in a massive pile. Once such a large pile of manure is burning, it will foul the air over a very large area and require considerable effort to extinguish. Large feedlots must therefore take care to ensure that piles of fresh manure (faeces) do not get excessively large. There is no serious risk of spontaneous combustion in smaller operations.
There is also a risk of insects carrying feces to food and water supplies, making them unsuitable for human consumption. | https://www.wikidoc.org/index.php/Manure | |
01f67bc9155df5225ab77800030ec305da5d143a | wikidoc | Maspin | Maspin
Maspin (mammary serine protease inhibitor) is a protein that in humans is encoded by the SERPINB5 gene. This protein belongs to the serpin (serine protease inhibitor) superfamily. SERPINB5 was originally reported to function as a tumor suppressor gene in epithelial cells, suppressing the ability of cancer cells to invade and metastasize to other tissues. Furthermore, and consistent with an important biological function, Maspin knockout mice were reported to be non-viable, dying in early embryogenesis. However, a subsequent study using viral transduction as a method of gene transfer (rather than single cell cloning) was not able to reproduce the original findings and found no role for maspin in tumour biology. Furthermore, the latter study demonstrated that maspin knockout mice are viable and display no obvious phenotype. These data are consistent with the observation that maspin is not expressed in early embryogenesis. The precise molecular function of maspin is thus currently unknown.
# Tissue distribution
Maspin is expressed in the skin, prostate, testis, intestine, tongue, lung, and the thymus.
# Serpin superfamily
Maspin is a member of the serpin superfamily of serine protease inhibitors. The primary function of most members of this family is to regulate the breakdown of proteins by inhibiting the catalytic activity of proteinases. Through this mechanism of action, serpins regulate a number of cellular processes including phagocytosis, coagulation, and fibrinolysis.
Serpins have a complex structure, a key component of which is the reactive site loop, RSL. Inhibitory serpins transition between a stress and relaxed stage. The catalytic serine residue in the protease target attacks the stressed conformation of the RSL loop to form an acyl intermediate. The loop then undergoes a conformational change to the relaxed state irreversibly trapping the protease in an inactive state. Hence the serpin functions as a suicide inhibitor of the protease. This transition does not occur in serpins that lack inhibitory activity.
# Function
Given its original reported role in cancer biology, numerous studies have investigated a role for maspin in tumour metastasis. However, to date no detailed molecular mechanism for maspin function in cell proliferation or tumour biology has been comprehensively described. Further, it is suggested that original reports of maspin as a tumor suppressor may reflect clonal artefacts rather than true maspin function. Importantly, and in contrast to original reports, maspin knockout mice are viable, displaying no overt phenotype in the absence of suitable biological or environmental challenge. Accordingly, the molecular function of maspin remains unclear.
From a structural perspective, maspin is a non-inhibitory and obligate intracellular member of the serpin superfamily. Specifically, its RSL does not transition between a stressed and relaxed state following proteolytic cleavage. This region is also shorter than the RSL loop in other serpins. Accordingly, in the absence of an obvious protease-related function, other targets of maspin have been suggested. For example, rather than being a protease inhibitor, maspin is proposed to function as an inhibitor of histone deacetylase 1 (HDAC1).
# Clinical significance
A comprehensive analysis of maspin expression in breast cancer revealed no significant correlation between maspin expression and overall survival, distant metastasis-free survival or recurrence-free survival. Changes in maspin expression may, however, reflect the expression status of the known tumour suppressor PHLPP1. | Maspin
Maspin (mammary serine protease inhibitor) is a protein that in humans is encoded by the SERPINB5 gene.[1] This protein belongs to the serpin (serine protease inhibitor) superfamily.[1] SERPINB5 was originally reported to function as a tumor suppressor gene in epithelial cells, suppressing the ability of cancer cells to invade and metastasize to other tissues.[2] Furthermore, and consistent with an important biological function, Maspin knockout mice were reported to be non-viable, dying in early embryogenesis.[3] However, a subsequent study using viral transduction as a method of gene transfer (rather than single cell cloning) was not able to reproduce the original findings and found no role for maspin in tumour biology.[4] Furthermore, the latter study demonstrated that maspin knockout mice are viable and display no obvious phenotype.[4] These data are consistent with the observation that maspin is not expressed in early embryogenesis.[4] The precise molecular function of maspin is thus currently unknown.
# Tissue distribution
Maspin is expressed in the skin, prostate, testis, intestine, tongue, lung, and the thymus.[1]
# Serpin superfamily
Maspin is a member of the serpin superfamily of serine protease inhibitors.[1] The primary function of most members of this family is to regulate the breakdown of proteins by inhibiting the catalytic activity of proteinases. Through this mechanism of action, serpins regulate a number of cellular processes including phagocytosis, coagulation, and fibrinolysis.[5]
Serpins have a complex structure, a key component of which is the reactive site loop, RSL.[6] Inhibitory serpins transition between a stress and relaxed stage. The catalytic serine residue in the protease target attacks the stressed conformation of the RSL loop to form an acyl intermediate. The loop then undergoes a conformational change to the relaxed state irreversibly trapping the protease in an inactive state. Hence the serpin functions as a suicide inhibitor of the protease.[7] This transition does not occur in serpins that lack inhibitory activity.[6]
# Function
Given its original reported role in cancer biology,[2] numerous studies have investigated a role for maspin in tumour metastasis.[8] However, to date no detailed molecular mechanism for maspin function in cell proliferation or tumour biology has been comprehensively described. Further, it is suggested that original reports of maspin as a tumor suppressor may reflect clonal artefacts rather than true maspin function.[4] Importantly, and in contrast to original reports, maspin knockout mice are viable, displaying no overt phenotype in the absence of suitable biological or environmental challenge.[4] Accordingly, the molecular function of maspin remains unclear.
From a structural perspective, maspin is a non-inhibitory and obligate intracellular member of the serpin superfamily.[9] Specifically, its RSL does not transition between a stressed and relaxed state following proteolytic cleavage.[10] This region is also shorter than the RSL loop in other serpins. Accordingly, in the absence of an obvious protease-related function, other targets of maspin have been suggested. For example, rather than being a protease inhibitor, maspin is proposed to function as an inhibitor of histone deacetylase 1 (HDAC1).[6][11]
# Clinical significance
A comprehensive analysis of maspin expression in breast cancer revealed no significant correlation between maspin expression and overall survival, distant metastasis-free survival or recurrence-free survival.[4] Changes in maspin expression may, however, reflect the expression status of the known tumour suppressor PHLPP1.[4] | https://www.wikidoc.org/index.php/Maspin | |
8f9219c35a2d8a20e9728f61854896fb5e0ab00c | wikidoc | Matico | Matico
Matico (Piper aduncum, synonymous with P. angustifolium, P. celtidifolium, P. elongatum) or spiked pepper is a flowering plant in the family Piperaceae. Like many species in the family, the Matico tree has a peppery odor. The fruits are used as a condiment and for flavoring cocoa. It is sometimes used as a substitute for long pepper. In the Amazon Rainforest, many of the native tribes use matico leaves as an antiseptic. In Peru, it was used for stopping hemorrhages and treating ulcers, and in European practice in the treatment of diseases of the genitals and urinary organs, such as those for which cubeb was often prescribed.
Matico is a tropical, evergreen, shrubby tree that grows to the height of 6 to 7 meter (20 to 23 ft) with lance-shaped leaves that are 12 to 20 centimeter (5 to 8 in) long. It is native to Southern Mexico, the Caribbean, and much of tropical South America. It is grown in tropical Asia, Polynesia, and Melanesia and can even be found in Florida, Hawaii, and Puerto Rico. In some countries Matico is considered as an invasive weed. In parts of New Guinea, although Matico is notorious for drying out the soil in the areas where it is invasive, the wood of this plant is nonetheless used by local residents for a myriad of uses such as for fuel and fence posts.
According to legends, the plant was discovered by a wounded Spanish soldier named Matico. He learned, presumably from the local tribes, that applying the leaves to his wounds stopped bleeding, and it began to be called "Matico" or "soldier's herb". It was introduced into the profession of medicine in the United States and Europe by a Liverpool physician in 1839 as a styptic and astringent for wounds.
# Notes
- ↑ Barlow, Prof. Snow (2003). "Sorting Piper names". University of Melbourne. Retrieved 2007-03-29..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Jump up to: 2.0 2.1 2.2 2.3 Taylor, Dr. Leslie (2006). "Technical Data Report for Matico (Piper aduncum, angustifolium)" (PDF). Raintree Nutrition, Inc. Retrieved 2007-03-29.
- ↑ Seidemann, Johannes (2005). World Spice Plants: Economic Usage, Botany, Taxonomy. Springer. pp. p. 289. ISBN 3540222790.CS1 maint: Extra text (link)
- ↑ Remington, Joseph P. (Ed) (1918). "The Dispensatory of the United States of America". Retrieved 2007-03-29. Unknown parameter |coauthors= ignored (help)CS1 maint: Extra text: authors list (link)
- ↑ Siges, T. (2005). "The invasive shrub Piper aduncum and rural livelihoods in the Finschhafen area of Papua New Guinea" (PDF). Human Ecology. 33 (6): 875–893. Retrieved 2007-04-16. Unknown parameter |coauthors= ignored (help) | Matico
Matico (Piper aduncum, synonymous with P. angustifolium, P. celtidifolium, P. elongatum[1][2]) or spiked pepper is a flowering plant in the family Piperaceae. Like many species in the family, the Matico tree has a peppery odor. The fruits are used as a condiment and for flavoring cocoa.[3] It is sometimes used as a substitute for long pepper. In the Amazon Rainforest, many of the native tribes use matico leaves as an antiseptic. In Peru, it was used for stopping hemorrhages and treating ulcers, and in European practice in the treatment of diseases of the genitals and urinary organs, such as those for which cubeb was often prescribed.[4]
Matico is a tropical, evergreen, shrubby tree that grows to the height of 6 to 7 meter (20 to 23 ft) with lance-shaped leaves that are 12 to 20 centimeter (5 to 8 in) long. It is native to Southern Mexico, the Caribbean, and much of tropical South America. It is grown in tropical Asia, Polynesia, and Melanesia and can even be found in Florida, Hawaii, and Puerto Rico. In some countries Matico is considered as an invasive weed.[2] In parts of New Guinea, although Matico is notorious for drying out the soil in the areas where it is invasive, the wood of this plant is nonetheless used by local residents for a myriad of uses such as for fuel and fence posts.[5]
According to legends, the plant was discovered by a wounded Spanish soldier named Matico.[2] He learned, presumably from the local tribes, that applying the leaves to his wounds stopped bleeding, and it began to be called "Matico" or "soldier's herb". It was introduced into the profession of medicine in the United States and Europe by a Liverpool physician in 1839 as a styptic and astringent for wounds.[2]
# Notes
- ↑ Barlow, Prof. Snow (2003). "Sorting Piper names". University of Melbourne. Retrieved 2007-03-29..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}
- ↑ Jump up to: 2.0 2.1 2.2 2.3 Taylor, Dr. Leslie (2006). "Technical Data Report for Matico (Piper aduncum, angustifolium)" (PDF). Raintree Nutrition, Inc. Retrieved 2007-03-29.
- ↑ Seidemann, Johannes (2005). World Spice Plants: Economic Usage, Botany, Taxonomy. Springer. pp. p. 289. ISBN 3540222790.CS1 maint: Extra text (link)
- ↑ Remington, Joseph P. (Ed) (1918). "The Dispensatory of the United States of America". Retrieved 2007-03-29. Unknown parameter |coauthors= ignored (help)CS1 maint: Extra text: authors list (link)
- ↑ Siges, T. (2005). "The invasive shrub Piper aduncum and rural livelihoods in the Finschhafen area of Papua New Guinea" (PDF). Human Ecology. 33 (6): 875–893. Retrieved 2007-04-16. Unknown parameter |coauthors= ignored (help)
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Matico | |
538c946ae1f8fc11a1be64cbe4d9bd68a4a0310e | wikidoc | Matter | Matter
In chemistry and physics, matter is commonly defined as the substance of which physical objects are composed, not counting the contribution of various energy or force-fields, which are not usually considered to be matter per se (though they may contribute to the mass of objects). Matter constitutes much of the observable universe, although again, light is not ordinarily considered matter. Unfortunately, for scientific purposes, "matter" is somewhat loosely defined.
# Definition
Matter is the stuff which things are made of and consists of chemical substances. These are made of atoms, which are made of protons, neutrons and electrons. In this way, matter is contrasted with 'energy' inversely 'energy' is an expression of matter.
In physics, there is no broad consensus as to an exact definition of matter. Physicists generally do not use the word when precision is needed, preferring instead to speak of the more clearly defined concepts of mass, energy and particles.
A possible definition of matter which at least some physicists use is that it is everything that is constituted of elementary fermions. These are the leptons, including the electron, and the quarks, including the up and down quarks of which protons and neutrons are made. Since protons, neutrons and electrons combine to form atoms, atoms, molecules and the bulk substances which they make up are all matter. Matter also includes the various baryons and mesons. Things which are not matter include light (photons) and the other gauge bosons.
However, this definition is not always satisfying when examined closely. In particular, under this definition things may have mass without being matter:
- W and Z bosons have mass, but are not elementary fermions.
- Any two photons which are not moving parallel to each other, taken as a system, have an invariant mass.
- Glueballs have mass due to their binding energy, but contain no particle with mass, nor any elementary fermions.
And they may be matter without having mass:
- Most of the mass of protons and neutrons comes from the binding energy between the quarks, not the masses of the quarks themselves.
- One of the three types of neutrinos may be massless.
- The up quark may be massless.
## Usage note regarding matter and anti-matter
There is a semantic difficulty with the word "matter", since it has two meanings, one of which includes the other. "Matter" may mean either:
- The opposite of anti-matter (e.g. electrons, but not positrons)
- Both matter as defined in the previous line and anti-matter (e.g. both electrons and positrons)
The same difficulty occurs with the word particle.
# Properties of matter
## As individual particles
Quarks combine to form hadrons. Because of the principle of color confinement which occurs in the strong interaction, quarks never exist unbound from other quarks. Among the hadrons are the proton and the neutron. Usually these nuclei are surrounded by a cloud of electrons. A nucleus with as many electrons as protons is thus electrically neutral and is called an atom, otherwise it is an ion.
Leptons do not feel the strong force and so can exist unbound from other particles. On Earth, electrons are generally bound in atoms, but it is easy to free them, a fact which is exploited in the cathode ray tube. Muons may briefly form bound states known as muonic atoms. Neutrinos feel neither the strong nor the electromagnetic interactions. They are never bound to other particles.
## As bulk matter
Homogeneous matter has a definite composition and properties and any amount of it has the same composition and properties. It may be a mixture, such as brass, or elemental, like pure iron. Heterogeneous matter, such as granite, does not have a definite composition.
### Phases
In bulk, matter can exist in several different phases, according to pressure and temperature. A phase is a state of a macroscopic physical system that has relatively uniform chemical composition and physical properties (i.e. density, crystal structure, index of refraction, and so forth). These phases include the three familiar ones — solids, liquids, and gases — as well as plasmas, superfluids, supersolids, Bose-Einstein condensates, fermionic condensates, liquid crystals, strange matter and quark-gluon plasmas. There are also the paramagnetic and ferromagnetic phases of magnetic materials. As conditions change, matter may change from one phase into another. These phenomena are called phase transitions, and their energetics are studied in the field of thermodynamics.
In small quantities, matter can exhibit properties that are entirely different from those of bulk material and may not be well described by any phase.
Phases are sometimes called states of matter, but this term can lead to confusion with thermodynamic states. For example, two gases maintained at different pressures are in different thermodynamic states, but the same "state of matter".
# Antimatter
In particle physics and quantum chemistry, antimatter is matter that is composed of the antiparticles of those that constitute normal matter. If a particle and its antiparticle come into contact with each other, the two annihilate; that is, they may both be converted into other particles with equal energy in accordance with Einstein's equation E = mc2. These new particles may be high-energy photons (gamma rays) or other particle–antiparticle pairs. The resulting particles are endowed with an amount of kinetic energy equal to the difference between the rest mass of the products of the annihilation and the rest mass of the original particle-antiparticle pair, which is often quite large.
Antimatter is not found naturally on Earth, except very briefly and in vanishingly small quantities (as the result of radioactive decay or cosmic rays). This is because antimatter which came to exist on Earth outside the confines of a suitable physics laboratory would almost instantly meet the ordinary matter that Earth is made of, and be annihilated. Antiparticles and some stable antimatter (such as antihydrogen) can be made in tiny amounts, but not in enough quantity to do more than test a few of its theoretical properties.
There is considerable speculation both in science and science fiction as to why the observable universe is apparently almost entirely matter, whether other places are almost entirely antimatter instead, and what might be possible if antimatter could be harnessed, but at this time the apparent asymmetry of matter and antimatter in the visible universe is one of the great unsolved problems in physics. Possible processes by which it came about are explored in more detail under baryogenesis.
# Dark matter
In cosmology, most models of the early universe and big bang require the existence of so called dark matter. This matter would have energy and mass, but would NOT be composed of either elementary fermions (as above) OR gauge bosons. As such, it would be composed of particles unknown to present science. Its existence is inferential at this point. | Matter
Template:Otheruses1
In chemistry and physics, matter is commonly defined as the substance of which physical objects are composed, not counting the contribution of various energy or force-fields, which are not usually considered to be matter per se (though they may contribute to the mass of objects). Matter constitutes much of the observable universe, although again, light is not ordinarily considered matter. Unfortunately, for scientific purposes, "matter" is somewhat loosely defined.
# Definition
Matter is the stuff which things are made of and consists of chemical substances. These are made of atoms, which are made of protons, neutrons and electrons. In this way, matter is contrasted with 'energy' inversely 'energy' is an expression of matter.
In physics, there is no broad consensus as to an exact definition of matter. Physicists generally do not use the word when precision is needed, preferring instead to speak of the more clearly defined concepts of mass, energy and particles.
A possible definition of matter which at least some physicists use [1] is that it is everything that is constituted of elementary fermions. These are the leptons, including the electron, and the quarks, including the up and down quarks of which protons and neutrons are made. Since protons, neutrons and electrons combine to form atoms, atoms, molecules and the bulk substances which they make up are all matter. Matter also includes the various baryons and mesons. Things which are not matter include light (photons) and the other gauge bosons.
However, this definition is not always satisfying when examined closely. In particular, under this definition things may have mass without being matter:
- W and Z bosons have mass, but are not elementary fermions.
- Any two photons which are not moving parallel to each other, taken as a system, have an invariant mass.
- Glueballs have mass due to their binding energy, but contain no particle with mass, nor any elementary fermions.
And they may be matter without having mass:
- Most of the mass of protons and neutrons comes from the binding energy between the quarks, not the masses of the quarks themselves.
- One of the three types of neutrinos may be massless.
- The up quark may be massless.[2]
## Usage note regarding matter and anti-matter
There is a semantic difficulty with the word "matter", since it has two meanings, one of which includes the other. "Matter" may mean either:
- The opposite of anti-matter (e.g. electrons, but not positrons)
- Both matter as defined in the previous line and anti-matter (e.g. both electrons and positrons)
The same difficulty occurs with the word particle.
# Properties of matter
## As individual particles
Quarks combine to form hadrons. Because of the principle of color confinement which occurs in the strong interaction, quarks never exist unbound from other quarks. Among the hadrons are the proton and the neutron. Usually these nuclei are surrounded by a cloud of electrons. A nucleus with as many electrons as protons is thus electrically neutral and is called an atom, otherwise it is an ion.
Leptons do not feel the strong force and so can exist unbound from other particles. On Earth, electrons are generally bound in atoms, but it is easy to free them, a fact which is exploited in the cathode ray tube. Muons may briefly form bound states known as muonic atoms. Neutrinos feel neither the strong nor the electromagnetic interactions. They are never bound to other particles.[1]
## As bulk matter
Homogeneous matter has a definite composition and properties and any amount of it has the same composition and properties. It may be a mixture, such as brass, or elemental, like pure iron. Heterogeneous matter, such as granite, does not have a definite composition.
### Phases
In bulk, matter can exist in several different phases, according to pressure and temperature. A phase is a state of a macroscopic physical system that has relatively uniform chemical composition and physical properties (i.e. density, crystal structure, index of refraction, and so forth). These phases include the three familiar ones — solids, liquids, and gases — as well as plasmas, superfluids, supersolids, Bose-Einstein condensates, fermionic condensates, liquid crystals, strange matter and quark-gluon plasmas. There are also the paramagnetic and ferromagnetic phases of magnetic materials. As conditions change, matter may change from one phase into another. These phenomena are called phase transitions, and their energetics are studied in the field of thermodynamics.
In small quantities, matter can exhibit properties that are entirely different from those of bulk material and may not be well described by any phase.
Phases are sometimes called states of matter, but this term can lead to confusion with thermodynamic states. For example, two gases maintained at different pressures are in different thermodynamic states, but the same "state of matter".
# Antimatter
In particle physics and quantum chemistry, antimatter is matter that is composed of the antiparticles of those that constitute normal matter. If a particle and its antiparticle come into contact with each other, the two annihilate; that is, they may both be converted into other particles with equal energy in accordance with Einstein's equation E = mc2. These new particles may be high-energy photons (gamma rays) or other particle–antiparticle pairs. The resulting particles are endowed with an amount of kinetic energy equal to the difference between the rest mass of the products of the annihilation and the rest mass of the original particle-antiparticle pair, which is often quite large.
Antimatter is not found naturally on Earth, except very briefly and in vanishingly small quantities (as the result of radioactive decay or cosmic rays). This is because antimatter which came to exist on Earth outside the confines of a suitable physics laboratory would almost instantly meet the ordinary matter that Earth is made of, and be annihilated. Antiparticles and some stable antimatter (such as antihydrogen) can be made in tiny amounts, but not in enough quantity to do more than test a few of its theoretical properties.
There is considerable speculation both in science and science fiction as to why the observable universe is apparently almost entirely matter, whether other places are almost entirely antimatter instead, and what might be possible if antimatter could be harnessed, but at this time the apparent asymmetry of matter and antimatter in the visible universe is one of the great unsolved problems in physics. Possible processes by which it came about are explored in more detail under baryogenesis.
# Dark matter
In cosmology, most models of the early universe and big bang require the existence of so called dark matter. This matter would have energy and mass, but would NOT be composed of either elementary fermions (as above) OR gauge bosons. As such, it would be composed of particles unknown to present science. Its existence is inferential at this point. | https://www.wikidoc.org/index.php/Matter | |
d428a1d355f421c87484f0f6993a9f9bf41c0baa | wikidoc | Meatus | Meatus
In anatomy, a meatus is a natural body opening or canal (Latin, 4th declension pl. meatus, or meatuses - often incorrectly meati).
Examples include:
- the external acoustic meatus, the opening of the ear canal
- The internal auditory meatus, a canal in the temporal bone of the skull
- the urinary meatus, which is the opening of the urethra, situated on the glans penis in males, and in the vulva in females
- the superior meatus, middle meatus and inferior meatus of the nose | Meatus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In anatomy, a meatus is a natural body opening or canal (Latin, 4th declension pl. meatus, or meatuses - often incorrectly meati).
Examples include:
- the external acoustic meatus, the opening of the ear canal
- The internal auditory meatus, a canal in the temporal bone of the skull
- the urinary meatus, which is the opening of the urethra, situated on the glans penis in males, and in the vulva in females
- the superior meatus, middle meatus and inferior meatus of the nose | https://www.wikidoc.org/index.php/Meatus | |
9c65267f56f79fc4f7fdb43e6d80be4ee760fb74 | wikidoc | Median | Median
# Overview
In probability theory and statistics, a median is described as the number separating the higher half of a sample, a population, or a probability distribution, from the lower half. The median of a finite list of numbers can be found by arranging all the observations from lowest value to highest value and picking the middle one. If there is an even number of observations, the median is not unique, so one often takes the mean of the two middle values.
At most half the population have values less than the median and at most half have values greater than the median. If both groups contain less than half the population, then some of the population is exactly equal to the median.
# Popular explanation
The big difference between the median and mean is illustrated in a simple example.
Suppose 19 paupers and 1 billionaire are in a room. Everyone removes all money from their pockets and puts it on a table. Each pauper puts £5 on the table; the billionaire puts £1 billion (i.e.£109) there. The total is then £1,000,000,095. If that money is divided equally among the 20 people, each gets £50,000,004.75. That amount is the mean amount of money that the 20 people brought into the room. But the median amount is £5, since one may divide the group into two groups of 10 people each, and say that everyone in the first group brought in no more than £5, and each person in the second group brought in no less than £5. In a sense, the median is the amount that the typical person brought in. By contrast, the mean is not at all typical, since nobody in the room brought in an amount approximating £50,000,004.75.
# Non-uniqueness
There may be more than one median: for example if there are an even number of cases, and the two middle values are different, then there is no unique middle value. Notice, however, that at least half the numbers in the list are less than or equal to either of the two middle values, and at least half are greater than or equal to either of the two values, and the same is true of any number between the two middle values. Thus either of the two middle values and all numbers between them are medians in that case.
# Measures of statistical dispersion
When the median is used as a location parameter in descriptive statistics, there are several choices for a measure of variability: the range, the interquartile range, the mean absolute deviation, and the median absolute deviation. Since the median is the same as the second quartile, its calculation is illustrated in the article on quartiles.
Working with computers, a population of integers should have an integer median. Thus, for an integer population with an even number of elements, there are two medians known as lower median and upper median. For floating point population, the median lies somewhere between the two middle elements, depending on the distribution.So if there is not a middle number and there is two numbers left that is an example
# Medians of probability distributions
For any probability distribution on the real line with cumulative distribution function F, regardless of whether it is any kind of continuous probability distribution, in particular an absolutely continuous distribution (and therefore has a probability density function), or a discrete probability distribution, a median m satisfies the inequalities
-r
in which a Riemann-Stieltjes integral is used. For an absolutely continuous probability distribution with probability density function f, we have
Medians of particular distributions: The medians of certain types of distributions can be easily estimated from their parameters: The median of a normal distribution with mean μ and variance σ2 is μ. In fact, for a normal distribution, mean = median = mode.The median of a uniform distribution in the interval is (a + b) / 2, which is also the mean.The median of a Cauchy distribution with location parameter x0 and scale parameter y is x0, the location parameter.The median of an exponential distribution with parameter \lambda is the natural log of 2 divided by the scale parameter: \frac{\ln 2}{\lambda}The median of a Weibull distribution with shape parameter k and scale parameter \lambda is \frac{(\ln 2)^{1/k}}{\lambda}
# Medians in descriptive statistics
The median is primarily used for skewed distributions, which it represents differently than the arithmetic mean. Consider the multiset { 1, 2, 2, 2, 3, 9 }. The median is 2 in this case, as is the mode, and it might be seen as a better indication of central tendency than the arithmetic mean of 3.166….
Calculation of medians is a popular technique in summary statistics and summarizing statistical data, since it is simple to understand and easy to calculate, while also giving a measure that is more robust in the presence of outlier values than is the mean.
# Theoretical properties
## An optimality property
The median is also the central point which minimizes the average of the absolute deviations; in the example above this would be (1 + 0 + 0 + 0 + 1 + 7) / 6 = 1.5 using the median, while it would be 1.944 using the mean. In the language of probability theory, the value of c that minimizes
is the median of the probability distribution of the random variable X. Note, however, that c is not always unique, and therefore not well defined in general.
## An inequality relating means and medians
For continuous probability distributions, the difference between the median and the mean is less than or equal to one standard deviation. See an inequality on location and scale parameters.
# Efficient computation
Even though sorting n items takes in general O(n log n) operations, by using a "divide and conquer" algorithm the median of n items can be computed with only O(n) operations (in fact, you can always find the k-th element of a list of values with this method; this is called the selection problem). | Median
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In probability theory and statistics, a median is described as the number separating the higher half of a sample, a population, or a probability distribution, from the lower half. The median of a finite list of numbers can be found by arranging all the observations from lowest value to highest value and picking the middle one. If there is an even number of observations, the median is not unique, so one often takes the mean of the two middle values.
At most half the population have values less than the median and at most half have values greater than the median. If both groups contain less than half the population, then some of the population is exactly equal to the median.
# Popular explanation
The big difference between the median and mean is illustrated in a simple example.
Suppose 19 paupers and 1 billionaire are in a room. Everyone removes all money from their pockets and puts it on a table. Each pauper puts £5 on the table; the billionaire puts £1 billion (i.e.£109) there. The total is then £1,000,000,095. If that money is divided equally among the 20 people, each gets £50,000,004.75. That amount is the mean amount of money that the 20 people brought into the room. But the median amount is £5, since one may divide the group into two groups of 10 people each, and say that everyone in the first group brought in no more than £5, and each person in the second group brought in no less than £5. In a sense, the median is the amount that the typical person brought in. By contrast, the mean is not at all typical, since nobody in the room brought in an amount approximating £50,000,004.75.
# Non-uniqueness
There may be more than one median: for example if there are an even number of cases, and the two middle values are different, then there is no unique middle value. Notice, however, that at least half the numbers in the list are less than or equal to either of the two middle values, and at least half are greater than or equal to either of the two values, and the same is true of any number between the two middle values. Thus either of the two middle values and all numbers between them are medians in that case.
# Measures of statistical dispersion
When the median is used as a location parameter in descriptive statistics, there are several choices for a measure of variability: the range, the interquartile range, the mean absolute deviation, and the median absolute deviation. Since the median is the same as the second quartile, its calculation is illustrated in the article on quartiles.
Working with computers, a population of integers should have an integer median. Thus, for an integer population with an even number of elements, there are two medians known as lower median and upper median. For floating point population, the median lies somewhere between the two middle elements, depending on the distribution.So if there is not a middle number and there is two numbers left that is an example
# Medians of probability distributions
For any probability distribution on the real line with cumulative distribution function F, regardless of whether it is any kind of continuous probability distribution, in particular an absolutely continuous distribution (and therefore has a probability density function), or a discrete probability distribution, a median m satisfies the inequalities
or
in which a Riemann-Stieltjes integral is used. For an absolutely continuous probability distribution with probability density function f, we have
Medians of particular distributions: The medians of certain types of distributions can be easily estimated from their parameters: The median of a normal distribution with mean μ and variance σ2 is μ. In fact, for a normal distribution, mean = median = mode.The median of a uniform distribution in the interval [a, b] is (a + b) / 2, which is also the mean.The median of a Cauchy distribution with location parameter x0 and scale parameter y is x0, the location parameter.The median of an exponential distribution with parameter <math>\lambda</math> is the natural log of 2 divided by the scale parameter: <math>\frac{\ln 2}{\lambda}</math>The median of a Weibull distribution with shape parameter k and scale parameter <math>\lambda</math> is <math>\frac{(\ln 2)^{1/k}}{\lambda}</math>
# Medians in descriptive statistics
The median is primarily used for skewed distributions, which it represents differently than the arithmetic mean. Consider the multiset { 1, 2, 2, 2, 3, 9 }. The median is 2 in this case, as is the mode, and it might be seen as a better indication of central tendency than the arithmetic mean of 3.166….
Calculation of medians is a popular technique in summary statistics and summarizing statistical data, since it is simple to understand and easy to calculate, while also giving a measure that is more robust in the presence of outlier values than is the mean.
# Theoretical properties
## An optimality property
The median is also the central point which minimizes the average of the absolute deviations; in the example above this would be (1 + 0 + 0 + 0 + 1 + 7) / 6 = 1.5 using the median, while it would be 1.944 using the mean. In the language of probability theory, the value of c that minimizes
is the median of the probability distribution of the random variable X. Note, however, that c is not always unique, and therefore not well defined in general.
## An inequality relating means and medians
For continuous probability distributions, the difference between the median and the mean is less than or equal to one standard deviation. See an inequality on location and scale parameters.
# Efficient computation
Even though sorting n items takes in general O(n log n) operations, by using a "divide and conquer" algorithm the median of n items can be computed with only O(n) operations (in fact, you can always find the k-th element of a list of values with this method; this is called the selection problem). | https://www.wikidoc.org/index.php/Median | |
f188027f0685b6e0e021d050eb81626de52c222b | wikidoc | Memory | Memory
In psychology, memory is an organism's ability to store, retain, and subsequently retrieve information. Traditional studies of memory began in the realms of philosophy, including techniques of artificially enhancing the memory.
The late nineteenth and early twentieth century put memory within the paradigms of cognitive psychology. In recent decades, it has become one of the principal pillars of a branch of science called cognitive neuroscience, an interdisciplinary link between cognitive psychology and neuroscience.
# Processes
There are several ways to classify memories, based on duration, nature and retrieval of information. From an information processing perspective there are three main stages in the formation and retrieval of memory:
- Encoding or registration (processing and combining of received information)
- Storage (creation of a permanent record of the encoded information)
- Retrieval or recall (calling back the stored information in response to some cue for use in a process or activity)
# Classification
A basic and generally accepted classification of memory is based on the duration of memory retention, and identifies three distinct types of memory: sensory memory, short term memory and long term memory.
## Sensory
Sensory memory corresponds approximately to the initial 200 - 500 milliseconds after an item is perceived. The ability to look at an item, and remember what it looked like with just a second of observation, or memorization, is an example of sensory memory. With very short presentations, participants often report that they seem to "see" more than they can actually report. The first experiments exploring this form of sensory memory were conducted by George Sperling using the "partial report paradigm." Subjects were presented with a grid of 12 letters, arranged into three rows of 4. After a brief presentation, subjects were then played either a high, medium or low tone, cuing them which of the rows to report. Based on these partial report experiments, Sperling was able to show that the capacity of sensory memory was approximately 12 items, but that it degraded very quickly (within a few hundred milliseconds). Because this form of memory degrades so quickly, participants would see the display, but be unable to report all of the items (12 in the "whole report" procedure) before they decayed. This type of memory cannot be prolonged via rehearsal.
## Short-term
Some of the information in sensory memory is then transferred to short-term memory. Short-term memory allows one to recall something from several seconds to as long as a minute without rehearsal. Its capacity is also very limited: George A. Miller, when working at Bell Laboratories, conducted experiments showing that the store of short term memory was 7±2 items (the title of his famous paper, "The magical number 7±2"). Modern estimates of the capacity of short-term memory are lower, typically on the order of 4-5 items, and we know that memory capacity can be increased through a process called chunking. For example, if presented with the string:
people are able to remember only a few items. However, if the same information is presented in the following way:
people can remember a great deal more letters. This is because they are able to chunk the information into meaningful groups of letters. Beyond finding meaning in the abbreviations above, Herbert Simon showed that the ideal size for chunking letters and numbers, meaningful or not, was three. This may be reflected in some countries in the tendency to remember phone numbers as several chunks of three numbers with the final four-number groups generally broken down into two groups of two.
Short-term memory is believed to rely mostly on an acoustic code for storing information, and to a lesser extent a visual code. Conrad (1964) found that test subjects had more difficulty recalling collections of words that were acoustically similar (e.g. dog, hog, fog, bog, log).
## Long-term
The storage in sensory memory and short-term memory generally have a strictly limited capacity and duration, which means that information is available for a certain period of time, but is not retained indefinitely. By contrast, long-term memory can store much larger quantities of information for potentially unlimited duration (sometimes a whole life span). For example, given a random seven-digit number, we may remember it for only a few seconds before forgetting, suggesting it was stored in our short-term memory. On the other hand, we can remember telephone numbers for many years through repetition; this information is said to be stored in long-term memory.
While short-term memory encodes information acoustically, long-term memory encodes it semantically: Baddeley (1966) discovered that after 20 minutes, test subjects had the least difficulty recalling a collection of words that had similar meanings (e.g. big, large, great, huge).
Short-term memory is supported by transient patterns of neuronal communication, dependent on regions of the frontal lobe (especially dorsolateral prefrontal cortex) and the parietal lobe. Long-term memories, on the other hand, are maintained by more stable and permanent changes in neural connections widely spread throughout the brain. The hippocampus is essential to the consolidation of information from short-term to long-term memory, although it does not seem to store information itself. Rather, it may be involved in changing neural connections for a period of three months or more after the initial learning.
One of the primary functions of sleep is improving consolidation of information, as it can be shown that memory depends on getting sufficient sleep between training and test, and that the hippocampus replays activity from the current day while sleeping.
# Models
Models of memory provide abstract representations of how memory is believed to work. Below are several models proposed over the years by various psychologists. Note that there is some controversy as to whether there are several memory structures, for example, Tarnow (2005) finds that it is likely that there is only one memory structure between 6 and 600 seconds.
## Multi-store (Atkinson-Shiffrin memory model)
The multi-store model (also known as Atkinson-Shiffrin memory model) was first recognised in 1968 by Atkinson and Shiffrin.
The multi-store model has been criticized for being too simplistic. For instance, long-term memory is believed to be actually made up of multiple subcomponents, such as episodic and procedural memory. It also proposes that rehearsal is the only mechanism by which information eventually reaches long-term storage, but evidence shows us capable of remembering things without rehearsal.
(See also: Memory consolidation)
## Working memory
In 1974 Baddeley and Hitch proposed a working memory model which replaced the concept of general short term memory with specific, active components. In this model, working memory consists of three basic stores: the central executive, the phonological loop and the visuo-spatial sketchpad. In 2000 this model was expanded with the multimodal episodic buffer.
The central executive essentially acts as attention. It channels information to the three component processes: the phonological loop, the visuo-spatial sketchpad, and the episodic buffer.
The phonological loop stores auditory information by silently rehearsing sounds or words in a continuous loop; the articulatory process (the "inner voice") continuously "speaks" the words to the phonological store (the "inner ear"). The phonological loop has a very limited capacity, which is demonstrated by the fact that it is easier to remember a list of short words (e.g. dog, wish, love) than a list of long words (e.g. association, systematic, confabulate) because short words fit better in the loop. However, if the test subject is given a task that ties up the articulatory process (saying "the, the, the" over and over again), then a list of short words is no easier to remember.
The visuo-spatial sketchpad stores visual and spatial information. It is engaged when performing spatial tasks (such as judging distances) or visual ones (such as counting the windows on a house or imagining images).
The episodic buffer is dedicated to linking information across domains to form integrated units of visual, spatial, and verbal information and chronological ordering (e.g., the memory of a story or a movie scene). The episodic buffer is also assumed to have links to long-term memory and semantical meaning.
The working memory model explains many practical observations, such as why it is easier to do two different tasks (one verbal and one visual) than two similar tasks (e.g., two visual), and the aforementioned word-length effect. However, the concept of a central executive as noted here has been criticized as inadequate and vague.
## Levels of processing
Craik and Lockhart (1972) proposed that it is the method and depth of processing that affects how an experience is stored in memory, rather than rehearsal.
- Organization - Mandler (1967) gave participants a pack of word cards and asked them to sort them into any number of piles using any system of categorization they liked. When they were later asked to recall as many of the words as they could, those who used more categories remembered more words. This study suggested that the act of organizing information makes it more memorable.
- Distinctiveness - Eysenck and Eysenck (1980) asked participants to say words in a distinctive way, e.g. spell the words out loud. Such participants recalled the words better than those who simply read them off a list.
- Effort - Tyler et al. (1979) had participants solve a series of anagrams, some easy (FAHTER) and some difficult (HREFAT). The participants recalled the difficult anagrams better, presumably because they put more effort into them.
- Elaboration - Palmere et al. (1983) gave participants descriptive paragraphs of a fictitious African nation. There were some short paragraphs and some with extra sentences elaborating the main idea. Recall was higher for the ideas in the elaborated paragraphs.
# Classification by information type
Anderson (1976) divides long-term memory into declarative (explicit) and procedural (implicit) memories.
Declarative memory requires conscious recall, in that some conscious process must call back the information. It is sometimes called explicit memory, since it consists of information that is explicitly stored and retrieved.
Declarative memory can be further sub-divided into semantic memory, which concerns facts taken independent of context; and episodic memory, which concerns information specific to a particular context, such as a time and place. Semantic memory allows the encoding of abstract knowledge about the world, such as "Paris is the capital of France". Episodic memory, on the other hand, is used for more personal memories, such as the sensations, emotions, and personal associations of a particular place or time. Autobiographical memory - memory for particular events within one's own life - is generally viewed as either equivalent to, or a subset of, episodic memory. Visual memory is part of memory preserving some characteristics of our senses pertaining to visual experience. One is able to place in memory information that resembles objects, places, animals or people in sort of a mental image. Visual memory can result in priming and it is assumed some kind of perceptual representational system underlies this phenomenon.
In contrast, procedural memory (or implicit memory) is not based on the conscious recall of information, but on implicit learning. Procedural memory is primarily employed in learning motor skills and should be considered a subset of implicit memory. It is revealed when one does better in a given task due only to repetition - no new explicit memories have been formed, but one is unconsciously accessing aspects of those previous experiences. Procedural memory involved in motor learning depends on the cerebellum and basal ganglia.
So far, nobody has been able to successfully isolate the time dependence of these suggested memory structures.
# Classification by temporal direction
A further major way to distinguish different memory functions is whether the content to be remembered is in the past, retrospective memory, or whether the content is to be remembered in the future, prospective memory. Thus, retrospective memory as a category includes semantic memory and episodic/autobiographical memory. In contrast, prospective memory is memory for future intentions, or remembering to remember (Winograd, 1988). Prospective memory can be further broken down into event- and time-based prospective remembering. Time-based prospective memories are triggered by a time-cue, such as going to the doctor (action) at 4pm (cue). Event-based prospective memories are intentions triggered by cues, such as remembering to post a letter (action) after seeing a mailbox (cue). Cues do not need to be related to the action (as the mailbox example is), and lists, sticky-notes, knotted handkerchiefs, or string around the finger are all examples of cues that are produced by people as a strategy to enhance prospective memory.
# Physiology
Overall, the mechanisms of memory are not completely understood. Brain areas such as the hippocampus, the amygdala, the striatum, or the mammillary bodies are thought to be involved in specific types of memory. For example, the hippocampus is believed to be involved in spatial learning and declarative learning, while the amygdala is thought to be involved in emotional memory. Damage to certain areas in patients and animal models and subsequent memory deficits is a primary source of information. However, rather than implicating a specific area, it could be that damage to adjacent areas, or to a pathway traveling through the area is actually responsible for the observed deficit. Further, it is not sufficient to describe memory, and its counterpart, learning, as solely dependent on specific brain regions. Learning and memory are attributed to changes in neuronal synapses, thought to be mediated by long-term potentiation and long-term depression.
Hebb distinguished between short-term and long-term memory. He postulated that any memory that stayed in short-term storage for a long enough time would be consolidated into a long-term memory. Later research showed this to be false. Research has shown that direct injections of cortisol or epinephrine help the storage of recent experiences. This is also true for stimulation of the amygdala. This proves that excitement enhances memory by the stimulation of hormones that affect the amygdala. Excessive or prolonged stress (with prolonged cortisol) may hurt memory storage. Patients with amygdalar damage are no more likely to remember emotionally charged words than nonemotionally charged ones. The hippocampus is important for explicit memory. The hippocampus is also important for memory consolidation. The hippocampus receives input from different parts of the cortex and sends its output out to different parts of the brain also. The input comes from secondary and tertiary sensory areas that have processed the information a lot already. Hippocampal damage may also cause memory loss and problems with memory storage.
# Disorders
Much of the current knowledge of memory has come from studying memory disorders. Loss of memory is known as amnesia. There are many sorts of amnesia, and by studying their different forms, it has become possible to observe apparent defects in individual sub-systems of the brain's memory systems, and thus hypothesize their function in the normally working brain. Other neurological disorders such as Alzheimer's disease can also affect memory and cognition.
Hyperthymesia, or hyperthymesic syndrome, is a disorder which affects an individual's autobiographical memory, essentially meaning that they cannot forget small details that otherwise would not be stored.
While not a disorder, a common temporary failure of word retrieval from memory is the tip-of-the-tongue phenomenon. Sufferers of Nominal Aphasia (also called Anomia), however, do experience the Tip of the Tongue phenomenon on an ongoing basis due to damage to the frontal and parietal lobes of the brain.
Impaired memory can be a symptom of hypothyroidism.
# Memorization
Memorization is a method of learning that allows an individual to recall information verbatim. Rote learning is the method most often used. Methods of memorizing things have been the subject of much discussion over the years with some writers, such as Cosmos Rossellius using visual alphabets. The spacing effect shows that an individual is more likely to remember a list of items when rehearsal is spaced over an extended period of time. In contrast to this is cramming which is intensive memorization in a short period of time. Also relevant is the Zeigarnik effect which states that people remember uncompleted or interrupted tasks better than completed ones.
In March 2007 German researchers found they could use odors to re-activate new memories in the brains of people while they slept and the volunteers remembered better later.
Tony Noice, an actor, director, teacher and cognitive researcher, and his psychologist wife Helga, have studied how actors remember lines and found that their techniques can be useful to non-actors as well.
At the Center for Cognitive Science at The Ohio State University, researchers have found that memory accuracy of adults is hurt by the fact that they know more than children and tend to apply this knowledge when learning new information. The findings appeared in the August 2004 edition of the journal Psychological Science.
# Improving memory
The best way to improve memory seems to be to increase the supply of oxygen to the brain, which may be accomplished with aerobic exercises; walking for three hours each week suffices, as does swimming or bicycle riding.Ageing with Grace.David Snowden, 2001, 4th Estate, London.
Such aerobic exercises have helped elderly people switch between mental tasks, concentrate better, and improve short-term memory.(see Ageing with Grace, cited above). Exercise increases the number of connections between neurons, which is responsible for improved memory.
The International Longevity Center released in 2001 a report which includes in pages 14-16 recommendations for keeping the mind in good functionality until advanced age. Some of the recommendations are to stay intellectually active through learning, training or reading, to keep physically active so to promote blood irrigation to the brain, to socialize, to reduce stress, to keep sleep time regular, to avoid depression or emotional instability and to observe good nutrition.
# Memory tasks
- Paired associate learning - when one learns to associate one specific word with another. For example when given a word such as "safe" one must learn to say another specific word, such as green. This is stimulus and response.
- Free recall- during this task a subject would be asked to study a list of words and then sometime later they will be asked to recall or write down as many words that they can remember.
- Recognition- subjects are asked to remember a list of words or pictures, after which point they are asked to identify the previously presented words or pictures from among a list of alternatives that were not presented in the original list.
# Cultural references
- Marcel Proust's novels deal extensively with memory.
- The independent film Memento emulates the experience of anterograde amnesia (that is, of not being able to convert short-term memories into long-term memories).
- In 1993 taxi driver Tom Morton, who knew over 16,000 telephone numbers in Lancashire, beat the British Olympia Telephone Exchange computer with his recall while being interviewed by Esther Rantzan and Adrain Mills on the Popular BBC magazine Programme That's Life!.
- The short stories of Philip K. Dick and the movies based on those works deal extensively with the nature of memory and the consequences to society if memories can be artificially generated.
- Strange Days is a film about memory. New technology allows people to record all the sensory data associated with their experiences. Playing back one of these recordings is like exactly reliving moments. Lenny, the character played by Ralph Fiennes, has a storyline revolving around memories.
- Eternal Sunshine of the Spotless Mind is a film that deals with the meanings of love and memory when main character Joel gets the memories of his ex-girlfriend Clementine erased by fictitious company Lacuna.
- Funes el memorioso is a short story by Argentinian writer Jorge Luis Borges. It tells the story of Funes, who remembers, due to an accident (a blow in his head) every tiny detail of everything he observes or thinks and is unable to forget anything.
- The Animus in the video game Assassin's Creed extracts memories from the DNA of the user, passed on from descendant to descendant, allowing the user to replay those memories as if he were there himself. | Memory
Template:Neuropsychology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In psychology, memory is an organism's ability to store, retain, and subsequently retrieve information. Traditional studies of memory began in the realms of philosophy, including techniques of artificially enhancing the memory.
The late nineteenth and early twentieth century put memory within the paradigms of cognitive psychology. In recent decades, it has become one of the principal pillars of a branch of science called cognitive neuroscience, an interdisciplinary link between cognitive psychology and neuroscience.
# Processes
There are several ways to classify memories, based on duration, nature and retrieval of information. From an information processing perspective there are three main stages in the formation and retrieval of memory:
- Encoding or registration (processing and combining of received information)
- Storage (creation of a permanent record of the encoded information)
- Retrieval or recall (calling back the stored information in response to some cue for use in a process or activity)
# Classification
A basic and generally accepted classification of memory is based on the duration of memory retention, and identifies three distinct types of memory: sensory memory, short term memory and long term memory.
## Sensory
Sensory memory corresponds approximately to the initial 200 - 500 milliseconds after an item is perceived. The ability to look at an item, and remember what it looked like with just a second of observation, or memorization, is an example of sensory memory. With very short presentations, participants often report that they seem to "see" more than they can actually report. The first experiments exploring this form of sensory memory were conducted by George Sperling using the "partial report paradigm." Subjects were presented with a grid of 12 letters, arranged into three rows of 4. After a brief presentation, subjects were then played either a high, medium or low tone, cuing them which of the rows to report. Based on these partial report experiments, Sperling was able to show that the capacity of sensory memory was approximately 12 items, but that it degraded very quickly (within a few hundred milliseconds). Because this form of memory degrades so quickly, participants would see the display, but be unable to report all of the items (12 in the "whole report" procedure) before they decayed. This type of memory cannot be prolonged via rehearsal.
## Short-term
Some of the information in sensory memory is then transferred to short-term memory. Short-term memory allows one to recall something from several seconds to as long as a minute without rehearsal. Its capacity is also very limited: George A. Miller, when working at Bell Laboratories, conducted experiments showing that the store of short term memory was 7±2 items (the title of his famous paper, "The magical number 7±2"). Modern estimates of the capacity of short-term memory are lower, typically on the order of 4-5 items, and we know that memory capacity can be increased through a process called chunking. For example, if presented with the string:
people are able to remember only a few items. However, if the same information is presented in the following way:
people can remember a great deal more letters. This is because they are able to chunk the information into meaningful groups of letters. Beyond finding meaning in the abbreviations above, Herbert Simon showed that the ideal size for chunking letters and numbers, meaningful or not, was three. This may be reflected in some countries in the tendency to remember phone numbers as several chunks of three numbers with the final four-number groups generally broken down into two groups of two.
Short-term memory is believed to rely mostly on an acoustic code for storing information, and to a lesser extent a visual code. Conrad (1964)[1] found that test subjects had more difficulty recalling collections of words that were acoustically similar (e.g. dog, hog, fog, bog, log).
## Long-term
The storage in sensory memory and short-term memory generally have a strictly limited capacity and duration, which means that information is available for a certain period of time, but is not retained indefinitely. By contrast, long-term memory can store much larger quantities of information for potentially unlimited duration (sometimes a whole life span). For example, given a random seven-digit number, we may remember it for only a few seconds before forgetting, suggesting it was stored in our short-term memory. On the other hand, we can remember telephone numbers for many years through repetition; this information is said to be stored in long-term memory.
While short-term memory encodes information acoustically, long-term memory encodes it semantically: Baddeley (1966)[2] discovered that after 20 minutes, test subjects had the least difficulty recalling a collection of words that had similar meanings (e.g. big, large, great, huge).
Short-term memory is supported by transient patterns of neuronal communication, dependent on regions of the frontal lobe (especially dorsolateral prefrontal cortex) and the parietal lobe. Long-term memories, on the other hand, are maintained by more stable and permanent changes in neural connections widely spread throughout the brain. The hippocampus is essential to the consolidation of information from short-term to long-term memory, although it does not seem to store information itself. Rather, it may be involved in changing neural connections for a period of three months or more after the initial learning.
One of the primary functions of sleep is improving consolidation of information, as it can be shown that memory depends on getting sufficient sleep between training and test, and that the hippocampus replays activity from the current day while sleeping.
# Models
Models of memory provide abstract representations of how memory is believed to work. Below are several models proposed over the years by various psychologists. Note that there is some controversy as to whether there are several memory structures, for example, Tarnow (2005) finds that it is likely that there is only one memory structure between 6 and 600 seconds.
## Multi-store (Atkinson-Shiffrin memory model)
The multi-store model (also known as Atkinson-Shiffrin memory model) was first recognised in 1968 by Atkinson and Shiffrin.
The multi-store model has been criticized for being too simplistic. For instance, long-term memory is believed to be actually made up of multiple subcomponents, such as episodic and procedural memory. It also proposes that rehearsal is the only mechanism by which information eventually reaches long-term storage, but evidence shows us capable of remembering things without rehearsal.
(See also: Memory consolidation)
## Working memory
In 1974 Baddeley and Hitch proposed a working memory model which replaced the concept of general short term memory with specific, active components. In this model, working memory consists of three basic stores: the central executive, the phonological loop and the visuo-spatial sketchpad. In 2000 this model was expanded with the multimodal episodic buffer.[3]
The central executive essentially acts as attention. It channels information to the three component processes: the phonological loop, the visuo-spatial sketchpad, and the episodic buffer.
The phonological loop stores auditory information by silently rehearsing sounds or words in a continuous loop; the articulatory process (the "inner voice") continuously "speaks" the words to the phonological store (the "inner ear"). The phonological loop has a very limited capacity, which is demonstrated by the fact that it is easier to remember a list of short words (e.g. dog, wish, love) than a list of long words (e.g. association, systematic, confabulate) because short words fit better in the loop. However, if the test subject is given a task that ties up the articulatory process (saying "the, the, the" over and over again), then a list of short words is no easier to remember.
The visuo-spatial sketchpad stores visual and spatial information. It is engaged when performing spatial tasks (such as judging distances) or visual ones (such as counting the windows on a house or imagining images).
The episodic buffer is dedicated to linking information across domains to form integrated units of visual, spatial, and verbal information and chronological ordering (e.g., the memory of a story or a movie scene). The episodic buffer is also assumed to have links to long-term memory and semantical meaning.
The working memory model explains many practical observations, such as why it is easier to do two different tasks (one verbal and one visual) than two similar tasks (e.g., two visual), and the aforementioned word-length effect. However, the concept of a central executive as noted here has been criticized as inadequate and vague.
## Levels of processing
Craik and Lockhart (1972) proposed that it is the method and depth of processing that affects how an experience is stored in memory, rather than rehearsal.
- Organization - Mandler (1967) gave participants a pack of word cards and asked them to sort them into any number of piles using any system of categorization they liked. When they were later asked to recall as many of the words as they could, those who used more categories remembered more words. This study suggested that the act of organizing information makes it more memorable.
- Distinctiveness - Eysenck and Eysenck (1980) asked participants to say words in a distinctive way, e.g. spell the words out loud. Such participants recalled the words better than those who simply read them off a list.
- Effort - Tyler et al. (1979) had participants solve a series of anagrams, some easy (FAHTER) and some difficult (HREFAT). The participants recalled the difficult anagrams better, presumably because they put more effort into them.
- Elaboration - Palmere et al. (1983) gave participants descriptive paragraphs of a fictitious African nation. There were some short paragraphs and some with extra sentences elaborating the main idea. Recall was higher for the ideas in the elaborated paragraphs.
# Classification by information type
Anderson (1976)[4] divides long-term memory into declarative (explicit) and procedural (implicit) memories.
Declarative memory requires conscious recall, in that some conscious process must call back the information. It is sometimes called explicit memory, since it consists of information that is explicitly stored and retrieved.
Declarative memory can be further sub-divided into semantic memory, which concerns facts taken independent of context; and episodic memory, which concerns information specific to a particular context, such as a time and place. Semantic memory allows the encoding of abstract knowledge about the world, such as "Paris is the capital of France". Episodic memory, on the other hand, is used for more personal memories, such as the sensations, emotions, and personal associations of a particular place or time. Autobiographical memory - memory for particular events within one's own life - is generally viewed as either equivalent to, or a subset of, episodic memory. Visual memory is part of memory preserving some characteristics of our senses pertaining to visual experience. One is able to place in memory information that resembles objects, places, animals or people in sort of a mental image. Visual memory can result in priming and it is assumed some kind of perceptual representational system underlies this phenomenon. [2]
In contrast, procedural memory (or implicit memory) is not based on the conscious recall of information, but on implicit learning. Procedural memory is primarily employed in learning motor skills and should be considered a subset of implicit memory. It is revealed when one does better in a given task due only to repetition - no new explicit memories have been formed, but one is unconsciously accessing aspects of those previous experiences. Procedural memory involved in motor learning depends on the cerebellum and basal ganglia.
So far, nobody has been able to successfully isolate the time dependence of these suggested memory structures.
# Classification by temporal direction
A further major way to distinguish different memory functions is whether the content to be remembered is in the past, retrospective memory, or whether the content is to be remembered in the future, prospective memory. Thus, retrospective memory as a category includes semantic memory and episodic/autobiographical memory. In contrast, prospective memory is memory for future intentions, or remembering to remember (Winograd, 1988). Prospective memory can be further broken down into event- and time-based prospective remembering. Time-based prospective memories are triggered by a time-cue, such as going to the doctor (action) at 4pm (cue). Event-based prospective memories are intentions triggered by cues, such as remembering to post a letter (action) after seeing a mailbox (cue). Cues do not need to be related to the action (as the mailbox example is), and lists, sticky-notes, knotted handkerchiefs, or string around the finger are all examples of cues that are produced by people as a strategy to enhance prospective memory.
# Physiology
Overall, the mechanisms of memory are not completely understood. Brain areas such as the hippocampus, the amygdala, the striatum, or the mammillary bodies are thought to be involved in specific types of memory. For example, the hippocampus is believed to be involved in spatial learning and declarative learning, while the amygdala is thought to be involved in emotional memory. Damage to certain areas in patients and animal models and subsequent memory deficits is a primary source of information. However, rather than implicating a specific area, it could be that damage to adjacent areas, or to a pathway traveling through the area is actually responsible for the observed deficit. Further, it is not sufficient to describe memory, and its counterpart, learning, as solely dependent on specific brain regions. Learning and memory are attributed to changes in neuronal synapses, thought to be mediated by long-term potentiation and long-term depression.
Hebb distinguished between short-term and long-term memory. He postulated that any memory that stayed in short-term storage for a long enough time would be consolidated into a long-term memory. Later research showed this to be false. Research has shown that direct injections of cortisol or epinephrine help the storage of recent experiences. This is also true for stimulation of the amygdala. This proves that excitement enhances memory by the stimulation of hormones that affect the amygdala. Excessive or prolonged stress (with prolonged cortisol) may hurt memory storage. Patients with amygdalar damage are no more likely to remember emotionally charged words than nonemotionally charged ones. The hippocampus is important for explicit memory. The hippocampus is also important for memory consolidation. The hippocampus receives input from different parts of the cortex and sends its output out to different parts of the brain also. The input comes from secondary and tertiary sensory areas that have processed the information a lot already. Hippocampal damage may also cause memory loss and problems with memory storage[5].
# Disorders
Much of the current knowledge of memory has come from studying memory disorders. Loss of memory is known as amnesia. There are many sorts of amnesia, and by studying their different forms, it has become possible to observe apparent defects in individual sub-systems of the brain's memory systems, and thus hypothesize their function in the normally working brain. Other neurological disorders such as Alzheimer's disease can also affect memory and cognition.
Hyperthymesia, or hyperthymesic syndrome, is a disorder which affects an individual's autobiographical memory, essentially meaning that they cannot forget small details that otherwise would not be stored.[6]
While not a disorder, a common temporary failure of word retrieval from memory is the tip-of-the-tongue phenomenon. Sufferers of Nominal Aphasia (also called Anomia), however, do experience the Tip of the Tongue phenomenon on an ongoing basis due to damage to the frontal and parietal lobes of the brain.
Impaired memory can be a symptom of hypothyroidism.
# Memorization
Memorization is a method of learning that allows an individual to recall information verbatim. Rote learning is the method most often used. Methods of memorizing things have been the subject of much discussion over the years with some writers, such as Cosmos Rossellius using visual alphabets. The spacing effect shows that an individual is more likely to remember a list of items when rehearsal is spaced over an extended period of time. In contrast to this is cramming which is intensive memorization in a short period of time. Also relevant is the Zeigarnik effect which states that people remember uncompleted or interrupted tasks better than completed ones.
In March 2007 German researchers found they could use odors to re-activate new memories in the brains of people while they slept and the volunteers remembered better later.[7]
Tony Noice, an actor, director, teacher and cognitive researcher, and his psychologist wife Helga, have studied how actors remember lines and found that their techniques can be useful to non-actors as well.[8]
At the Center for Cognitive Science at The Ohio State University, researchers have found that memory accuracy of adults is hurt by the fact that they know more than children and tend to apply this knowledge when learning new information. The findings appeared in the August 2004 edition of the journal Psychological Science.
# Improving memory
The best way to improve memory seems to be to increase the supply of oxygen to the brain, which may be accomplished with aerobic exercises; walking for three hours each week suffices, as does swimming or bicycle riding.[9]Ageing with Grace.David Snowden, 2001, 4th Estate, London.
Such aerobic exercises have helped elderly people switch between mental tasks, concentrate better, and improve short-term memory.(see Ageing with Grace, cited above). Exercise increases the number of connections between neurons, which is responsible for improved memory.
The International Longevity Center [3] released in 2001 a report [4] which includes in pages 14-16 recommendations for keeping the mind in good functionality until advanced age. Some of the recommendations are to stay intellectually active through learning, training or reading, to keep physically active so to promote blood irrigation to the brain, to socialize, to reduce stress, to keep sleep time regular, to avoid depression or emotional instability and to observe good nutrition.
# Memory tasks
- Paired associate learning - when one learns to associate one specific word with another. For example when given a word such as "safe" one must learn to say another specific word, such as green. This is stimulus and response.[10]
- Free recall- during this task a subject would be asked to study a list of words and then sometime later they will be asked to recall or write down as many words that they can remember.[11]
- Recognition- subjects are asked to remember a list of words or pictures, after which point they are asked to identify the previously presented words or pictures from among a list of alternatives that were not presented in the original list.[12]
# Cultural references
- Marcel Proust's novels deal extensively with memory.
- The independent film Memento emulates the experience of anterograde amnesia (that is, of not being able to convert short-term memories into long-term memories).
- In 1993 taxi driver Tom Morton, who knew over 16,000 telephone numbers in Lancashire, beat the British Olympia Telephone Exchange computer with his recall while being interviewed by Esther Rantzan and Adrain Mills on the Popular BBC magazine Programme That's Life!. [5]
- The short stories of Philip K. Dick and the movies based on those works deal extensively with the nature of memory and the consequences to society if memories can be artificially generated.
- Strange Days is a film about memory. New technology allows people to record all the sensory data associated with their experiences. Playing back one of these recordings is like exactly reliving moments. Lenny, the character played by Ralph Fiennes, has a storyline revolving around memories.
- Eternal Sunshine of the Spotless Mind is a film that deals with the meanings of love and memory when main character Joel gets the memories of his ex-girlfriend Clementine erased by fictitious company Lacuna.
- Funes el memorioso is a short story by Argentinian writer Jorge Luis Borges. It tells the story of Funes, who remembers, due to an accident (a blow in his head) every tiny detail of everything he observes or thinks and is unable to forget anything.
- The Animus in the video game Assassin's Creed extracts memories from the DNA of the user, passed on from descendant to descendant, allowing the user to replay those memories as if he were there himself. | https://www.wikidoc.org/index.php/Memories | |
c0407ea7ef2a0f9ae11aa195d3803f76bc82d3de | wikidoc | Mentha | Mentha
Mentha (mint) is a genus of about 25 species (and many hundreds of varieties) of flowering plants in the family Lamiaceae. Species within Mentha have a subcosmopolitan distribution across Europe, Africa, Asia, Australia, and North America. Several mint hybrids commonly occur.
Mints are aromatic, almost exclusively perennial, rarely annual, herbs. They have wide-spreading underground rhizomes and erect, branched stems. The leaves are arranged in opposite pairs, from simple oblong to lanceolate, often downy, and with a serrated margin. Leaf colors range from dark green and gray-green to purple, blue and sometimes pale yellow.
# Species
This covers a selection of what are considered to be pure species of mints. As with all classifications of plants, this list can go out of date at a moment's notice. Listed here are accepted species names and common names (where available). Synonyms, along with cultivars and varieties (where available), are listed under the species.
# Selected hybrids
The mint family has a large grouping of recognized hybrids. As with all classifications of plants, this list can go out of date at a moment's notice. Synonyms, along with cultivars and varieties where available, are included within the specific species.
# Cultivation
All mints prefer, and thrive, in cool, moist spots in partial shade. In general, mints tolerate a wide range of conditions, and can also be grown in full sun.
They are fast growing, extending their reach along surfaces through a network of runners. Due to their speedy growth, one plant of each desired mint, along with a little care, will provide more than enough mint for home use. Some mint species are more invasive than others. Even with the less invasive mints, care should be taken when mixing any mint with any other plants, lest the mint take over. To control mints in an open environment, mints should be planted in deep, bottomless containers sunk in the ground, or planted above ground in tubs and barrels.
Some mints can be propagated by seed. Growth from seed can be an unreliable method for raising mint for two reasons: mint seeds are highly variable, one might not end up with what one presupposed was planted; some mint varieties are sterile. It is more effective to take and plant cuttings from the runners of healthy mints.
The most common and popular mints for cultivation are peppermint (Mentha × piperita), spearmint (Mentha spicata), and (more recently) pineapple mint (Mentha suaveolens).
Mints tend to make good companion plants, repelling pest insects and attracting beneficial ones. The common mints, like spearmint and peppermint, are considered good to grow among tomato and pepper plants, where they enhance flavor, repel aphids, attract parasitic wasps to eat caterpillars, provide "living mulch" ground cover, etc.
Chamomile is thought to make a good companion plant for mint, as well as increasing essential oil in mints, making them "stronger" in scent and flavor.
Harvesting of mint leaves can be done at anytime. Fresh mint leaves should be used immediately or stored up to a couple of days in plastic bags within a refrigerator. Optionally, mint can be frozen in ice cube trays. Dried mint leaves should be stored in an airtight container placed in a cool, dark, dry area.
(1)" culinary uses"
Image:Mint leaves.jpg|thumb|Mint Leaves
The leaf, fresh or dried, is the culinary source of mint. Fresh mint is usually preferred over dried mint when storage of the mint is not a problem. The leaves have a pleasant warm, fresh, aromatic, sweet flavor with a cool aftertaste. Mint leaves are used in teas, beverages, jellies, syrups, candies, and ice creams. In Middle Eastern cuisine mint is used on lamb dishes. In British cuisine, mint sauce is popular with lamb.
Mint is a necessary ingredient in Touareg tea, a popular tea in northern African and Arab countries.
Alcoholic drinks sometimes feature flavor of mint, namely the Mint Julep and the Mojito.
Mint essential oil and menthol are extensively used as flavorings in breath fresheners, drinks, antiseptic mouth rinses, toothpaste, chewing gum and desserts candy|candies; see mint (candy) and mint chocolate. The substances that give the mints their characteristic aromas and flavors are:
menthol: the main aroma of Spearmint, Peppermint, and Japanese Peppermint (a major commercial source).
pulegone: in Pennyroyal and Corsican Mint.
Methyl salicylate, commonly called "oil of wintergreen", is often used as a mint flavoring for foods and candies due to its mint-like flavor.
Mints are used as food plants by the larvae of some Lepidoptera species including Buff Ermine.
(2)"Medicinal and cosmetic uses"
Mint was originally used as a medicinal herb to treat stomach ache and chest pains. During the Middle Ages, powdered mint leaves were used to whiten teeth. Mint tea is a strong diuretic. Mint also aids digestion.
Menthol from mint essential oil (40-90%) is an ingredient of many cosmetics and some perfumes. Menthol and mint essential oil are also much used in medicine as a component of many drugs, and are very popular in aromatherapy.
A common use is as an antipruritic, especially in insect bite treatments (often along with camphor).
It is also used in cigarettes as an additive, because it blocks out the bitter taste of tobacco and soothes the throat.
Many people also believe the strong, sharp flavor and scent of Mint can be used as a mild decongestant for illnesses such as the common cold.
In Rome, Pliny recommended that a wreath of mint was a good thing for students to wear since it was thought to 'exhilarate their minds'. Some modern research suggests that he was right.
(3)Pragmatic"
Mint leaves are often used by many campers to repel mosquitoes. It is also said that extracts from mint leaves have a particular mosquito-killing capability.
Mint oil is also used as an environmentally-friendly insecticide for its ability to kill some common pests like wasps, hornets, ants and cockroaches.
# Diseases
# Origin and usage of the word mint
Mint descends from the Latin word mentha, which is rooted in the Greek word minthe. Minthe has linguistic connections to a woman of the same name in Greek Mythology.
Mint leaves, without a qualifier like peppermint or apple mint, generally refers to spearmint leaves.
In Central and South America, mint is known as hierbabuena (literally, "good herb"). In the Hindi and Urdu languages it is called Pudeena.
The taxonomic family Lamiaceae is known as the mint family. It includes many other aromatic herbs, including most of the more common cooking herbs, including basil, rosemary, sage, oregano and catnip.
As an English colloquial term, mint stands for any small sugar confectionery item flavored to taste like the aforementioned plant.
In common usage, several other plants with fragrant leaves may be erroneously called a mint. Vietnamese Mint, commonly used in Southeast Asian cuisine, is not a member of the mint family (taxonomic family Lamiaceae).
## Slang
In the south west of the United Kingdom, used adjectivally, the word can be used as a term of approbation or to express delight, as in "tha's mint, tha' is...". It is also used in New Zealand with the same meaning, but usually as an exclamation, as in 'mint!'. | Mentha
Mentha (mint) is a genus of about 25 species (and many hundreds of varieties[1]) of flowering plants in the family Lamiaceae. Species within Mentha have a subcosmopolitan distribution across Europe, Africa, Asia,[2] Australia, and North America. Several mint hybrids commonly occur.
Mints are aromatic, almost exclusively perennial, rarely annual, herbs. They have wide-spreading underground rhizomes and erect, branched stems. The leaves are arranged in opposite pairs, from simple oblong to lanceolate, often downy, and with a serrated margin. Leaf colors range from dark green and gray-green to purple, blue and sometimes pale yellow.
# Species
This covers a selection of what are considered to be pure species of mints. As with all classifications of plants, this list can go out of date at a moment's notice. Listed here are accepted species names and common names (where available). Synonyms, along with cultivars and varieties (where available), are listed under the species.
# Selected hybrids
The mint family has a large grouping of recognized hybrids. As with all classifications of plants, this list can go out of date at a moment's notice. Synonyms, along with cultivars and varieties where available, are included within the specific species.
# Cultivation
All mints prefer, and thrive, in cool, moist spots in partial shade[3]. In general, mints tolerate a wide range of conditions, and can also be grown in full sun.
They are fast growing, extending their reach along surfaces through a network of runners. Due to their speedy growth, one plant of each desired mint, along with a little care, will provide more than enough mint for home use. Some mint species are more invasive than others. Even with the less invasive mints, care should be taken when mixing any mint with any other plants, lest the mint take over. To control mints in an open environment, mints should be planted in deep, bottomless containers sunk in the ground, or planted above ground in tubs and barrels[3].
Some mints can be propagated by seed. Growth from seed can be an unreliable method for raising mint for two reasons: mint seeds are highly variable, one might not end up with what one presupposed was planted[3]; some mint varieties are sterile. It is more effective to take and plant cuttings from the runners of healthy mints.
The most common and popular mints for cultivation are peppermint (Mentha × piperita), spearmint (Mentha spicata), and (more recently) pineapple mint (Mentha suaveolens).
Mints tend to make good companion plants, repelling pest insects and attracting beneficial ones. The common mints, like spearmint and peppermint, are considered good to grow among tomato and pepper plants, where they enhance flavor, repel aphids, attract parasitic wasps to eat caterpillars, provide "living mulch" ground cover, etc.[citation needed]
Chamomile is thought to make a good companion plant for mint, as well as increasing essential oil in mints, making them "stronger" in scent and flavor.[citation needed]
Harvesting of mint leaves can be done at anytime. Fresh mint leaves should be used immediately or stored up to a couple of days in plastic bags within a refrigerator. Optionally, mint can be frozen in ice cube trays. Dried mint leaves should be stored in an airtight container placed in a cool, dark, dry area.[4]
(1)" culinary uses"
Image:Mint leaves.jpg|thumb|Mint Leaves
The leaf, fresh or dried, is the culinary source of mint. Fresh mint is usually preferred over dried mint when storage of the mint is not a problem. The leaves have a pleasant warm, fresh, aromatic, sweet flavor with a cool aftertaste. Mint leaves are used in teas, beverages, jellies, syrups, candies, and ice creams. In Middle Eastern cuisine mint is used on lamb dishes. In British cuisine, mint sauce is popular with lamb.
Mint is a necessary ingredient in Touareg tea, a popular tea in northern African and Arab countries.
Alcoholic drinks sometimes feature flavor of mint, namely the Mint Julep and the Mojito.
Mint essential oil and menthol are extensively used as flavorings in breath fresheners, drinks, antiseptic mouth rinses, toothpaste, chewing gum and desserts candy|candies; see mint (candy) and mint chocolate. The substances that give the mints their characteristic aromas and flavors are:
menthol: the main aroma of Spearmint, Peppermint, and Japanese Peppermint (a major commercial source).
pulegone: in Pennyroyal and Corsican Mint.
Methyl salicylate, commonly called "oil of wintergreen", is often used as a mint flavoring for foods and candies due to its mint-like flavor.
Mints are used as food plants by the larvae of some Lepidoptera species including Buff Ermine.
(2)"Medicinal and cosmetic uses"
Mint was originally used as a medicinal herb to treat stomach ache and chest pains. During the Middle Ages, powdered mint leaves were used to whiten teeth. Mint tea is a strong diuretic. Mint also aids digestion.
Menthol from mint essential oil (40-90%) is an ingredient of many cosmetics and some perfumes. Menthol and mint essential oil are also much used in medicine as a component of many drugs, and are very popular in aromatherapy.
A common use is as an antipruritic, especially in insect bite treatments (often along with camphor).
It is also used in cigarettes as an additive, because it blocks out the bitter taste of tobacco and soothes the throat.[citation needed]
Many people also believe the strong, sharp flavor and scent of Mint can be used as a mild decongestant for illnesses such as the common cold.
In Rome, Pliny recommended that a wreath of mint was a good thing for students to wear since it was thought to 'exhilarate their minds'. Some modern research suggests that he was right.
(3)Pragmatic"
Mint leaves are often used by many campers to repel mosquitoes. It is also said that extracts from mint leaves have a particular mosquito-killing capability.
Mint oil is also used as an environmentally-friendly insecticide for its ability to kill some common pests like wasps, hornets, ants and cockroaches.
# Diseases
# Origin and usage of the word mint
Mint descends from the Latin word mentha, which is rooted in the Greek word minthe. Minthe has linguistic connections to a woman of the same name in Greek Mythology. [5]
Mint leaves, without a qualifier like peppermint or apple mint, generally refers to spearmint leaves.
In Central and South America, mint is known as hierbabuena (literally, "good herb"). In the Hindi and Urdu languages it is called Pudeena.
The taxonomic family Lamiaceae is known as the mint family. It includes many other aromatic herbs, including most of the more common cooking herbs, including basil, rosemary, sage, oregano and catnip.
As an English colloquial term, mint stands for any small sugar confectionery item flavored to taste like the aforementioned plant.[1]
In common usage, several other plants with fragrant leaves may be erroneously called a mint. Vietnamese Mint, commonly used in Southeast Asian cuisine, is not a member of the mint family (taxonomic family Lamiaceae).
## Slang
In the south west of the United Kingdom, used adjectivally, the word can be used as a term of approbation or to express delight, as in "tha's mint, tha' is...". It is also used in New Zealand with the same meaning, but usually as an exclamation, as in 'mint!'. | https://www.wikidoc.org/index.php/Mentha |
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