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Soap

Soap Soap is a surfactant used in conjunction with water for washing and cleaning that is available in solid bars and in the form of a viscous liquid. Chemically, soap is a salt of a fatty acid. Traditionally, soap is made by the reaction between a fat and a strong alkali such as lye (sodium hydroxide), potash (potassium hydroxide), or soda ash (sodium carbonate). Historically, the alkali was leached from hardwood ashes. The chemical reaction that yields soap is known as saponification. In the saponification of a fat to form soap the alkali and water hydrolyze the fat thus converting it into free glycerol/glycerin and soap (fatty acid salt). Occasionally, saponification can occur naturally: an underground mass tomb in Sicily has corpses whose bodies are slowly becoming saponified. Many cleaning agents today are technically not soaps, but detergents, which are less expensive and easier to manufacture. In some countries, it’s compulsory to indicate the Total Fatty Matter (TFM) content of soap that is sold to consumers, as a percentage. Usually it averages around 70%. # How soap works Soaps are useful for cleaning because soap molecules attach readily to both nonpolar molecules (such as grease or oil) and polar molecules (such as water). Although grease will normally adhere to skin or clothing, the soap molecules can attach to it as a "handle" and make it easier to rinse away. Applied to a soiled surface, soapy water effectively holds particles in suspension so the whole of it can be rinsed off with clean water. (fatty end) :CH3-(CH2)n-CO2- +Na: (water soluble end) The hydrocarbon ("fatty") portion dissolves dirt and oils, while the ionic end makes it soluble in water. Therefore, it allows water to remove normally-insoluble matter by emulsification. # Soap making The most common soap making process today is the cold process method, where fats such as rendered lard react with lye. Some soapers also practice other processes, such as the historical hot process, and make special soaps such as clear or transparent soap, which must be made with ethanol or isopropyl alcohol. Soap makers sometimes use the melt and pour process, where a premade soap base is melted and poured in individual molds. While some people think that this is not really soap making, the Hand Crafted Soap Makers Guild does recognize this as a legitimate form of soap crafting. Handmade soap differs from industrial soap in that whole oils containing intact triglycerides are used and glycerin is a desirable byproduct. Industrial detergent manufacturers commonly use fatty acids, which are detached from the gylcerol heads found in triglycerides. Without the glycerol heads, the detached fatty acids do not yield glycerin as a byproduct. ## Lye Reacting fat with lye (sodium hydroxide) will produce a hard bar soap. Reacting fat with potassium hydroxide will produce a soap that is either soft or liquid. Historically, the alkalis used were sodium hydroxide, potassium hydroxide, and sodium carbonate leeched from hardwood ashes. ## Fat Soap is made from either vegetable or animal fats. Sodium tallowate, a fatty acid sometimes used to make soaps, is derived from tallow, which is rendered from cattle or sheep tissue. Soap can also be made of vegetable oils, such as palm oil, olive oil, or coconut oil. If soap is made from pure olive oil it may be called Castile soap or Marseille soap. Castile is also sometimes applied to soaps with a mix of oils, but a high percentage of olive oil. An array of oils and butters are used in the process such as olive oil, coconut oil, palm oil, cocoa butter, hemp oil and shea butter to provide different qualities. For example, olive oil provides mildness in soap; coconut oil provides lots of lather; while coconut and palm oils provide hardness. Most common, is a combination of coconut, palm, and olive oils. ## Process Cold process soap making is done without heating the soap batter, while hot process soap making requires that the soap batter be heated. Both processes are further described after the general soap making process description. ### General soap making process Soap making requires the use of saponification charts to determine the correct lye/fat ratio. If excess unreacted lye remains in the soap, the resultant high pH can burn or irritate skin. Conversely, a high proportion of excess fat will result in greasy sludge that will not form solid bars of soap, although some soap makers deliberately "superfat" their soap so that some oils will remain in the finished bars of soap. This can be done by either adding a small (5-10%) excess proportion of fats, or by discounting the formulated amount of lye to 90-95%. The lye is dissolved in water; as this is an exothermic process, the solution will spontaneously generate heat and may even boil. The oils are heated separately (to the point of liquefaction if they are solid at room temperature). Once fats and lye water have both cooled to 80-100°F (27-38°C), they are combined. This mixture of lye water and fats is stirred until "trace" occurs and the mixture becomes a soap batter. There are varying levels of trace: a light trace implies a thinner soap batter and a heavy trace implies a thicker soap batter. Additives, such as essential oils, fragrance oils, botanicals, clays, colorants or other fragrance materials, are combined with the soap batter at different degrees of trace, depending upon the additive. With elapsed time and continued agitation the soap batter will continue to thicken. The cold process soap batter is then poured into molds, while hot process soap batter is poured into a double boiler or crockpot to sustain a high temperature. ### Cold-process Although cold-process soapmaking takes place at room temperature, the fats are first heated to ensure the liquification of the fats used. Then, when the lye water solution is added to the fats, it should be the same temperature of the melted oils and both are typically between 80-90°F. An external heat source is not necessary but the molded soap should be incubated by being wrapped in blankets or towels for 24 hours after being poured into the mold. Milk soaps are the exception and do not require insulation, which may cause the milk to sour. The soap will continue to exothermically give off heat for many hours after being molded. During this time, it is normal for the soap to go through a "gel phase" where the opaque soap will turn semi-transparent for several hours before turning opaque again. The soap may be removed from the mold after 24 hours but the saponification process takes several weeks to complete. ### Hot-process Unlike cold processed soap, all hot processed soap experiences a "gel phase" as a result of being heated, such as in a double boiler or crockpot. Hot process soap may be used soon after being removed from the mold because the higher temperatures accelerate the saponifcation process and also drive off excess water. ## Purification and finishing The common process of purifying soap involves removal of sodium chloride, sodium hydroxide, and glycerol. These components are removed by boiling the crude soap curds in water and re-precipitating the soap with salt. Most of the water is then removed from the soap. This was traditionally done on a chill roll which produced the soap flakes commonly used in the 1940s and 1950s. This process was superseded by spray dryers and then by vacuum dryers. The dry soap (approximately 6-12% moisture) is then compacted into small pellets. These pellets are now ready for soap finishing, the process of converting raw soap pellets into a salable product, usually bars. Soap pellets are combined with fragrances and other materials and blended to homogeneity in an amalgamator (mixer). The mass is then discharged from the mixer into a refiner which, by means of an auger, forces the soap through a fine wire screen. From the refiner the soap passes over a roller mill (French milling or hard milling) in a manner similar to calendering paper or plastic or to making chocolate liquor. The soap is then passed through one or more additional refiners to further plasticize the soap mass. Immediately before extrusion it passes through a vacuum chamber to remove any entrapped air. It is then extruded into a long log or blank, cut to convenient lengths, passed through a metal detector and then stamped into shape in refrigerated tools. The pressed bars are packaged in many ways. Sand or pumice may be added to produce a scouring soap. This process is most common in creating soaps used for human hygiene. The scouring agents serve to remove dead skin cells from the surface being cleaned. This process is called exfoliation. Many newer materials are used for exfoliating soaps which are effective but do not have the sharp edges and poor size distribution of pumice. # History ## Early history The earliest recorded evidence of the production of soap-like materials dates back to around 2800 BC in Ancient Babylon. A formula for soap consisting of water, alkali and cassia oil was written on a Babylonian clay tablet around 2200 BC. The Ebers papyrus (Egypt, 1550 BC) indicates that ancient Egyptians bathed regularly and combined animal and vegetable oils with alkaline salts to create a soap-like substance. Egyptian documents mention that a soap-like substance was used in the preparation of wool for weaving. ## Roman history It had been reported that a factory producing soap-like substances was found in the ruins of Pompeii (AD 79). However, this has proven to be a misinterpretation of the survival of some soapy mineral substance, probably soapstone at the Fullonica where it was used for dressing recently cleansed textiles. Unfortunately this error has been repeated widely and can be found in otherwise reputable texts on soap history. The ancient Romans were generally ignorant of soap's detergent properties, and made use of the strigil to scrape dirt and sweat from the body. The word "soap" (Latin sapo) appears first in a European language in Pliny the Elder's Historia Naturalis, which discusses the manufacture of soap from tallow and ashes, but the only use he mentions for it is as a pomade for hair; he mentions rather disapprovingly that among the Gauls and Germans men are likelier to use it than women. A story encountered in some places claims that soap takes its name from a supposed "Mount Sapo" where ancient Romans sacrificed animals. Rain would send a mix of animal tallow and wood ash down the mountain and into the clay soil on the banks of the Tiber. Eventually, women noticed that it was easier to clean clothes with this "soap". The location of Mount Sapo is unknown, as is the source of the "ancient Roman legend" to which this tale is typically credited. In fact, the Latin word sapo simply means "soap"; it was borrowed from a Celtic or Germanic language, and is cognate with Latin sebum, "tallow" , which appears in Pliny the Elder's account. Roman animal sacrifices usually burned only the bones and inedible entrails of the sacrificed animals; edible meat and fat from the sacrifices were taken by the humans rather than the gods. Animal sacrifices in the ancient world would not have included enough fat to make much soap. The legend about Mount Sapo is probably apocryphal. ## Muslim history True soaps made from vegetable oils (such as olive oil), aromatic oils (such as thyme oil) and lye (al-Soda al-Kawia) were first produced by Muslim chemists in the medieval Islamic world. The formula for soap used since then hasn't changed (Nabulsi soap). From the beginning of the 7th century, soap was produced in Nablus (West Bank), Kufa (Iraq) and Basra (Iraq). Soaps, as we know them today, are descendants of historical Arabian Soaps. Arabian Soap was perfumed and colored, some of the soaps were liquid and others were solid. They also had special soap for shaving. It was sold for 3 Dirhams (0.3 Dinars) a piece in 981 AD. The Persian chemist Al-Razi wrote a manuscript on recipes for true soap. A recently discovered manuscript from the 13th century details more recipes for soap making; e.g. take some sesame oil, a sprinkle of potash, alkali and some lime, mix them all together and boil. When cooked, they are poured into molds and left to set, leaving hard soap. In semi-modern times soap was made by mixing animal fats with lye. Because of the caustic lye, this was a dangerous procedure (perhaps more dangerous than any present-day home activities) which could result in serious chemical burns or even blindness. Before commercially-produced lye (sodium hydroxide) was commonplace, lye (sodium hydroxide), potash (potassium hydroxide), and soda ash (sodium carbonate) were leached from the ashes of a hardwood fire for soap-making at home. ## Modern history Castile soap was later produced in Europe from the 16th century. In modern times, the use of soap has become universal in industrialized nations due to a better understanding of the role of hygiene in reducing the population size of pathogenic microorganisms. Manufactured bar soaps first became available in the late nineteenth century, and advertising campaigns in Europe and the United States helped to increase popular awareness of the relationship between cleanliness and health. Soap has also been used to punish people for cursing or occasionally, for other infractions. This is done by forcibly placing soap into a person's mouth and, sometimes, forcing them to swallow it. It is commonly known as "washing one's mouth out with soap" or any of numerous variations of that phrase, or, more recently, "mouthsoaping". ## Commercial soap production Until the Industrial Revolution, soap making was done on a small scale and the product was rough. Andrew Pears started making a high-quality, transparent soap in 1789 in London. With his grandson, Francis Pears, they opened a factory in Isleworth in 1862. William Gossage produced low-price good quality soap from the 1850s. Robert Spear Hudson began manufacturing a soap powder in 1837, initially by grinding the soap with a mortar and pestle. William Hesketh Lever and his brother, James, bought a small soap works in Warrington in 1885 and founded what is still one of the largest soap businesses, now called Unilever. These soap businesses were among the first to employ large scale advertising campaigns. In the United States, one of the first manufacturers of soap was the Armour and Company in Chicago in 1888. The soap was made from tallow, a by-product of the meat production process. In 1948, Armour soap became Dial soap, the first deodorant or antibacterial soap introduced in the USA.

Soap Soap is a surfactant used in conjunction with water for washing and cleaning that is available in solid bars and in the form of a viscous liquid. Chemically, soap is a salt of a fatty acid. Traditionally, soap is made by the reaction between a fat and a strong alkali such as lye (sodium hydroxide), potash (potassium hydroxide), or soda ash (sodium carbonate). Historically, the alkali was leached from hardwood ashes. The chemical reaction that yields soap is known as saponification. In the saponification of a fat to form soap the alkali and water hydrolyze the fat thus converting it into free glycerol/glycerin and soap (fatty acid salt).[1] Occasionally, saponification can occur naturally: an underground mass tomb in Sicily has corpses whose bodies are slowly becoming saponified.[2] Many cleaning agents today are technically not soaps, but detergents, which are less expensive and easier to manufacture. In some countries, it’s compulsory to indicate the Total Fatty Matter (TFM) content of soap that is sold to consumers, as a percentage. Usually it averages around 70%. # How soap works Soaps are useful for cleaning because soap molecules attach readily to both nonpolar molecules (such as grease or oil) and polar molecules (such as water). Although grease will normally adhere to skin or clothing, the soap molecules can attach to it as a "handle" and make it easier to rinse away. Applied to a soiled surface, soapy water effectively holds particles in suspension so the whole of it can be rinsed off with clean water. (fatty end) :CH3-(CH2)n-CO2- +Na: (water soluble end) The hydrocarbon ("fatty") portion dissolves dirt and oils, while the ionic end makes it soluble in water. Therefore, it allows water to remove normally-insoluble matter by emulsification. # Soap making The most common soap making process today is the cold process method, where fats such as rendered lard react with lye. Some soapers also practice other processes, such as the historical hot process, and make special soaps such as clear or transparent soap, which must be made with ethanol or isopropyl alcohol.[3] Soap makers sometimes use the melt and pour process, where a premade soap base is melted and poured in individual molds. While some people think that this is not really soap making, the Hand Crafted Soap Makers Guild does recognize this as a legitimate form of soap crafting. Handmade soap differs from industrial soap in that whole oils containing intact triglycerides are used and glycerin is a desirable byproduct. Industrial detergent manufacturers commonly use fatty acids, which are detached from the gylcerol heads found in triglycerides. Without the glycerol heads, the detached fatty acids do not yield glycerin as a byproduct.[4] ## Lye Reacting fat with lye (sodium hydroxide) will produce a hard bar soap. Reacting fat with potassium hydroxide will produce a soap that is either soft or liquid. Historically, the alkalis used were sodium hydroxide, potassium hydroxide, and sodium carbonate leeched from hardwood ashes.[5] ## Fat Soap is made from either vegetable or animal fats. Sodium tallowate, a fatty acid sometimes used to make soaps, is derived from tallow, which is rendered from cattle or sheep tissue. Soap can also be made of vegetable oils, such as palm oil, olive oil, or coconut oil. If soap is made from pure olive oil it may be called Castile soap or Marseille soap. Castile is also sometimes applied to soaps with a mix of oils, but a high percentage of olive oil. An array of oils and butters are used in the process such as olive oil, coconut oil, palm oil, cocoa butter, hemp oil and shea butter to provide different qualities. For example, olive oil provides mildness in soap; coconut oil provides lots of lather; while coconut and palm oils provide hardness. Most common, is a combination of coconut, palm, and olive oils. ## Process Cold process soap making is done without heating the soap batter, while hot process soap making requires that the soap batter be heated. Both processes are further described after the general soap making process description. ### General soap making process Soap making requires the use of saponification charts[6] to determine the correct lye/fat ratio. If excess unreacted lye remains in the soap[1], the resultant high pH can burn or irritate skin. Conversely, a high proportion of excess fat will result in greasy sludge that will not form solid bars of soap, although some soap makers deliberately "superfat" their soap so that some oils will remain in the finished bars of soap. This can be done by either adding a small (5-10%) excess proportion of fats, or by discounting the formulated amount of lye to 90-95%.[7] The lye is dissolved in water; as this is an exothermic process, the solution will spontaneously generate heat and may even boil. The oils are heated separately (to the point of liquefaction if they are solid at room temperature). Once fats and lye water have both cooled to 80-100°F (27-38°C), they are combined. This mixture of lye water and fats is stirred until "trace" occurs and the mixture becomes a soap batter.[7] There are varying levels of trace: a light trace implies a thinner soap batter and a heavy trace implies a thicker soap batter. Additives, such as essential oils, fragrance oils, botanicals, clays, colorants or other fragrance materials, are combined with the soap batter at different degrees of trace, depending upon the additive. With elapsed time and continued agitation the soap batter will continue to thicken. The cold process soap batter is then poured into molds, while hot process soap batter is poured into a double boiler or crockpot to sustain a high temperature. ### Cold-process Although cold-process soapmaking takes place at room temperature, the fats are first heated to ensure the liquification of the fats used. Then, when the lye water solution is added to the fats, it should be the same temperature of the melted oils and both are typically between 80-90°F. An external heat source is not necessary but the molded soap should be incubated by being wrapped in blankets or towels for 24 hours after being poured into the mold. Milk soaps are the exception and do not require insulation, which may cause the milk to sour. The soap will continue to exothermically give off heat for many hours after being molded. During this time, it is normal for the soap to go through a "gel phase" where the opaque soap will turn semi-transparent for several hours before turning opaque again. The soap may be removed from the mold after 24 hours but the saponification process takes several weeks to complete. ### Hot-process Unlike cold processed soap, all hot processed soap experiences a "gel phase" as a result of being heated, such as in a double boiler or crockpot. Hot process soap may be used soon after being removed from the mold because the higher temperatures accelerate the saponifcation process and also drive off excess water. ## Purification and finishing The common process of purifying soap involves removal of sodium chloride, sodium hydroxide, and glycerol. These components are removed by boiling the crude soap curds in water and re-precipitating the soap with salt. Most of the water is then removed from the soap. This was traditionally done on a chill roll which produced the soap flakes commonly used in the 1940s and 1950s. This process was superseded by spray dryers and then by vacuum dryers. The dry soap (approximately 6-12% moisture) is then compacted into small pellets. These pellets are now ready for soap finishing, the process of converting raw soap pellets into a salable product, usually bars. Soap pellets are combined with fragrances and other materials and blended to homogeneity in an amalgamator (mixer). The mass is then discharged from the mixer into a refiner which, by means of an auger, forces the soap through a fine wire screen. From the refiner the soap passes over a roller mill (French milling or hard milling) in a manner similar to calendering paper or plastic or to making chocolate liquor. The soap is then passed through one or more additional refiners to further plasticize the soap mass. Immediately before extrusion it passes through a vacuum chamber to remove any entrapped air. It is then extruded into a long log or blank, cut to convenient lengths, passed through a metal detector and then stamped into shape in refrigerated tools. The pressed bars are packaged in many ways. Sand or pumice may be added to produce a scouring soap. This process is most common in creating soaps used for human hygiene. The scouring agents serve to remove dead skin cells from the surface being cleaned. This process is called exfoliation. Many newer materials are used for exfoliating soaps which are effective but do not have the sharp edges and poor size distribution of pumice. # History ## Early history The earliest recorded evidence of the production of soap-like materials dates back to around 2800 BC in Ancient Babylon.[8] A formula for soap consisting of water, alkali and cassia oil was written on a Babylonian clay tablet around 2200 BC. The Ebers papyrus (Egypt, 1550 BC) indicates that ancient Egyptians bathed regularly and combined animal and vegetable oils with alkaline salts to create a soap-like substance. Egyptian documents mention that a soap-like substance was used in the preparation of wool for weaving. ## Roman history It had been reported that a factory producing soap-like substances was found in the ruins of Pompeii (AD 79). However, this has proven to be a misinterpretation of the survival of some soapy mineral substance, probably soapstone at the Fullonica where it was used for dressing recently cleansed textiles. Unfortunately this error has been repeated widely and can be found in otherwise reputable texts on soap history. The ancient Romans were generally ignorant of soap's detergent properties, and made use of the strigil to scrape dirt and sweat from the body. The word "soap" (Latin sapo) appears first in a European language in Pliny the Elder's Historia Naturalis, which discusses the manufacture of soap from tallow and ashes, but the only use he mentions for it is as a pomade for hair; he mentions rather disapprovingly that among the Gauls and Germans men are likelier to use it than women.[9] A story encountered in some places claims that soap takes its name from a supposed "Mount Sapo" where ancient Romans sacrificed animals. Rain would send a mix of animal tallow and wood ash down the mountain and into the clay soil on the banks of the Tiber. Eventually, women noticed that it was easier to clean clothes with this "soap". The location of Mount Sapo is unknown, as is the source of the "ancient Roman legend" to which this tale is typically credited.[10] In fact, the Latin word sapo simply means "soap"; it was borrowed from a Celtic or Germanic language, and is cognate with Latin sebum, "tallow" [11], which appears in Pliny the Elder's account. Roman animal sacrifices usually burned only the bones and inedible entrails of the sacrificed animals; edible meat and fat from the sacrifices were taken by the humans rather than the gods. Animal sacrifices in the ancient world would not have included enough fat to make much soap. The legend about Mount Sapo is probably apocryphal. ## Muslim history True soaps made from vegetable oils (such as olive oil), aromatic oils (such as thyme oil) and lye (al-Soda al-Kawia) were first produced by Muslim chemists in the medieval Islamic world.[12] The formula for soap used since then hasn't changed (Nabulsi soap). From the beginning of the 7th century, soap was produced in Nablus (West Bank), Kufa (Iraq) and Basra (Iraq). Soaps, as we know them today, are descendants of historical Arabian Soaps. Arabian Soap was perfumed and colored, some of the soaps were liquid and others were solid. They also had special soap for shaving. It was sold for 3 Dirhams (0.3 Dinars) a piece in 981 AD. The Persian chemist Al-Razi wrote a manuscript on recipes for true soap. A recently discovered manuscript from the 13th century details more recipes for soap making; e.g. take some sesame oil, a sprinkle of potash, alkali and some lime, mix them all together and boil. When cooked, they are poured into molds and left to set, leaving hard soap. In semi-modern times soap was made by mixing animal fats with lye. Because of the caustic lye, this was a dangerous procedure (perhaps more dangerous than any present-day home activities) which could result in serious chemical burns or even blindness. Before commercially-produced lye (sodium hydroxide) was commonplace, lye (sodium hydroxide), potash (potassium hydroxide), and soda ash (sodium carbonate) were leached from the ashes of a hardwood fire for soap-making at home. ## Modern history Castile soap was later produced in Europe from the 16th century. In modern times, the use of soap has become universal in industrialized nations due to a better understanding of the role of hygiene in reducing the population size of pathogenic microorganisms. Manufactured bar soaps first became available in the late nineteenth century, and advertising campaigns in Europe and the United States helped to increase popular awareness of the relationship between cleanliness and health. Soap has also been used to punish people for cursing or occasionally, for other infractions. This is done by forcibly placing soap into a person's mouth and, sometimes, forcing them to swallow it. It is commonly known as "washing one's mouth out with soap" or any of numerous variations of that phrase, or, more recently, "mouthsoaping". ## Commercial soap production Until the Industrial Revolution, soap making was done on a small scale and the product was rough. Andrew Pears started making a high-quality, transparent soap in 1789 in London. With his grandson, Francis Pears, they opened a factory in Isleworth in 1862. William Gossage produced low-price good quality soap from the 1850s. Robert Spear Hudson began manufacturing a soap powder in 1837, initially by grinding the soap with a mortar and pestle. William Hesketh Lever and his brother, James, bought a small soap works in Warrington in 1885 and founded what is still one of the largest soap businesses, now called Unilever. These soap businesses were among the first to employ large scale advertising campaigns. In the United States, one of the first manufacturers of soap was the Armour and Company in Chicago in 1888. The soap was made from tallow, a by-product of the meat production process. In 1948, Armour soap became Dial soap, the first deodorant or antibacterial soap introduced in the USA.

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Cube

Cube A cube is a three-dimensional solid object bounded by six square faces, facets or sides, with three meeting at each vertex. The cube can also be called a regular hexahedron and is one of the five Platonic solids. It is a special kind of square prism, of rectangular parallelepiped and of 3-sided trapezohedron. The cube is dual to the octahedron. It has cubical symmetry (also called octahedral symmetry). A cube is the three-dimensional case of the more general concept of a hypercube, which exists in any dimension. # Cartesian coordinates For a cube centered at the origin, with edges parallel to the axes and with an edge length of 2, the Cartesian coordinates of the vertices are while the interior consists of all points (x0, x1, x2) with -1 < xi < 1. # Formulae For a cube of edge length a, As the volume of a cube is the third power of its sides a×a×a, third powers are called cubes, by analogy with squares and second powers. A cube has the largest volume among cuboids (rectangular boxes) with a given surface area. Also, a cube has the largest volume among cuboids with the same total linear size (length + width + height). # Symmetry The cube has 3 classes of symmetry, which can be represented by vertex-transitive coloring the faces. The highest octahedral symmetry Oh has all the faces the same color. The dihedral symmetry D4h comes from the cube being a prism, with all four sides being the same color. The lowest symmetry D2h is also a prismatic symmetry, with sides alternating colors, so there are three colors, paired by opposite sides. Each symmetry form has a different Wythoff symbol. # Geometric relations The cube is unique among the Platonic solids for being able to tile space regularly. It is also unique among the Platonic solids in having faces with an even number of sides and, consequently, it is the only member of that group that is a zonohedron (every face has point symmetry). # Other dimensions The analogue of a cube in four-dimensional Euclidean space has a special name — a tesseract or (rarely) hypercube. The analogue of the cube in n-dimensional Euclidean space is called a hypercube or n-dimensional cube or simply n-cube. It is also called a measure polytope. There are analogues of the cube in lower dimensions too: a point in dimension 0, a segment in one dimension and a square in two dimensions. # Related polyhedra The vertices of a cube can be grouped into two groups of four, each forming a regular tetrahedron. These two together form a regular compound, the stella octangula. The intersection of the two forms a regular octahedron. The symmetries of a regular tetrahedron correspond to those of a cube which map each tetrahedron to itself; the other symmetries of the cube map the two to each other. One such regular tetrahedron has a volume of ⅓ of that of the cube. The remaining space consists of four equal irregular polyhedra with a volume of 1/6 of that of the cube, each. The rectified cube is the cuboctahedron. If smaller corners are cut off we get a polyhedron with 6 octagonal faces and 8 triangular ones. In particular we can get regular octagons (truncated cube). The rhombicuboctahedron is obtained by cutting off both corners and edges to the correct amount. A cube can be inscribed in a dodecahedron so that each vertex of the cube is a vertex of the dodecahedron and each edge is a diagonal of one of the dodecahedron's faces; taking all such cubes gives rise to the regular compound of five cubes. - The tetrahedra in the cube (stella octangula) The tetrahedra in the cube (stella octangula) - The rectified cube (cuboctahedron) The rectified cube (cuboctahedron) - Truncated cube Truncated cube - Rhombicuboctahedron Rhombicuboctahedron - Compound of three cubes Compound of three cubes - An alternately truncated cube An alternately truncated cube All but the last of the figures shown have the same symmetries as the cube (see octahedral symmetry). # Combinatorial cubes A different kind of cube is the cube graph, which is the graph of vertices and edges of the geometrical cube. It is a special case of the hypercube graph. An extension is the 3-dimensional k-ary Hamming graph, which for k = 2 is the cube graph. Graphs of this sort occur in the theory of parallel processing in computers.

Cube Template:Reg polyhedra db A cube[1] is a three-dimensional solid object bounded by six square faces, facets or sides, with three meeting at each vertex. The cube can also be called a regular hexahedron and is one of the five Platonic solids. It is a special kind of square prism, of rectangular parallelepiped and of 3-sided trapezohedron. The cube is dual to the octahedron. It has cubical symmetry (also called octahedral symmetry). A cube is the three-dimensional case of the more general concept of a hypercube, which exists in any dimension. # Cartesian coordinates For a cube centered at the origin, with edges parallel to the axes and with an edge length of 2, the Cartesian coordinates of the vertices are while the interior consists of all points (x0, x1, x2) with -1 < xi < 1. # Formulae For a cube of edge length <math>a</math>, As the volume of a cube is the third power of its sides a×a×a, third powers are called cubes, by analogy with squares and second powers. A cube has the largest volume among cuboids (rectangular boxes) with a given surface area. Also, a cube has the largest volume among cuboids with the same total linear size (length + width + height). # Symmetry The cube has 3 classes of symmetry, which can be represented by vertex-transitive coloring the faces. The highest octahedral symmetry Oh has all the faces the same color. The dihedral symmetry D4h comes from the cube being a prism, with all four sides being the same color. The lowest symmetry D2h is also a prismatic symmetry, with sides alternating colors, so there are three colors, paired by opposite sides. Each symmetry form has a different Wythoff symbol. # Geometric relations The cube is unique among the Platonic solids for being able to tile space regularly. It is also unique among the Platonic solids in having faces with an even number of sides and, consequently, it is the only member of that group that is a zonohedron (every face has point symmetry). # Other dimensions The analogue of a cube in four-dimensional Euclidean space has a special name — a tesseract or (rarely) hypercube. The analogue of the cube in n-dimensional Euclidean space is called a hypercube or n-dimensional cube or simply n-cube. It is also called a measure polytope. There are analogues of the cube in lower dimensions too: a point in dimension 0, a segment in one dimension and a square in two dimensions. # Related polyhedra The vertices of a cube can be grouped into two groups of four, each forming a regular tetrahedron. These two together form a regular compound, the stella octangula. The intersection of the two forms a regular octahedron. The symmetries of a regular tetrahedron correspond to those of a cube which map each tetrahedron to itself; the other symmetries of the cube map the two to each other. One such regular tetrahedron has a volume of ⅓ of that of the cube. The remaining space consists of four equal irregular polyhedra with a volume of 1/6 of that of the cube, each. The rectified cube is the cuboctahedron. If smaller corners are cut off we get a polyhedron with 6 octagonal faces and 8 triangular ones. In particular we can get regular octagons (truncated cube). The rhombicuboctahedron is obtained by cutting off both corners and edges to the correct amount. A cube can be inscribed in a dodecahedron so that each vertex of the cube is a vertex of the dodecahedron and each edge is a diagonal of one of the dodecahedron's faces; taking all such cubes gives rise to the regular compound of five cubes. - The tetrahedra in the cube (stella octangula) The tetrahedra in the cube (stella octangula) - The rectified cube (cuboctahedron) The rectified cube (cuboctahedron) - Truncated cube Truncated cube - Rhombicuboctahedron Rhombicuboctahedron - Compound of three cubes Compound of three cubes - An alternately truncated cube An alternately truncated cube All but the last of the figures shown have the same symmetries as the cube (see octahedral symmetry). # Combinatorial cubes A different kind of cube is the cube graph, which is the graph of vertices and edges of the geometrical cube. It is a special case of the hypercube graph. An extension is the 3-dimensional k-ary Hamming graph, which for k = 2 is the cube graph. Graphs of this sort occur in the theory of parallel processing in computers.

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Cure

Cure A cure is a substance or procedure that makes a sick or diseased person well. A cure can be a medication, a surgical operation, a change in lifestyle, or even a philosophical mindset that helps a person heal. # Difference between preventions, treatments, and cures A prevention or preventive measure is a way to avoid an injury, sickness, or disease in the first place, and generally it will not help someone who is already ill (though there are exceptions). For instance, many American babies are given a polio vaccination soon after they are born, which prevents them from contracting polio. But the vaccination does not work on patients who already have polio. A treatment or cure is applied after a medical problem has already started. A treatment treats a problem, and may lead to its cure, but treatments more often ameliorate a problem only for as long as the treatment is continued. For example, there is no cure for AIDS, but treatments are available to slow down the harm done by HIV and delay the fatality of the disease. Treatments don't always work. For example, chemotherapy is a treatment for cancer which may cure the disease sometimes - it does not have a 100% cure rate. Therefore, chemotherapy isn't considered a bona fide cure for cancer. # Examples of Cures There are a few examples of complete cures. In 1999, the CDC and the World Health Organization established a goal to cure 85% of tuberculosis patients in Russia. They reached an 80% success rate, with 75% of the diseased cured, and 5% that had successfully finished treatment.

Cure A cure is a substance or procedure that makes a sick or diseased person well. A cure can be a medication, a surgical operation, a change in lifestyle, or even a philosophical mindset that helps a person heal. # Difference between preventions, treatments, and cures A prevention or preventive measure is a way to avoid an injury, sickness, or disease in the first place, and generally it will not help someone who is already ill (though there are exceptions). For instance, many American babies are given a polio vaccination soon after they are born, which prevents them from contracting polio. But the vaccination does not work on patients who already have polio. A treatment or cure is applied after a medical problem has already started. A treatment treats a problem, and may lead to its cure, but treatments more often ameliorate a problem only for as long as the treatment is continued. For example, there is no cure for AIDS, but treatments are available to slow down the harm done by HIV and delay the fatality of the disease. Treatments don't always work. For example, chemotherapy is a treatment for cancer which may cure the disease sometimes - it does not have a 100% cure rate. Therefore, chemotherapy isn't considered a bona fide cure for cancer. # Examples of Cures There are a few examples of complete cures. In 1999, the CDC and the World Health Organization established a goal to cure 85% of tuberculosis patients in Russia. They reached an 80% success rate, with 75% of the diseased cured, and 5% that had successfully finished treatment.

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Skin

Skin In zootomy and dermatology, skin is the largest organ of the integumentary system made up of multiple layers of epithelial tissues that guard underlying muscles and organs. Skin pigmentation (see: human skin color or coloring) varies among populations, and skin type can range from dry skin to oily skin. The adjective cutaneous literally means "of the skin" (from Latin cutis, skin). As the interface with the surroundings, skin plays the most important role in protecting (the body) against pathogens. Its other main functions are insulation and temperature regulation, sensation, and synthesis of vitamin D and the protection of vitamin B folats. Severely damaged skin will try to heal by forming scar tissue, often giving rise to discoloration and depigmentation of the skin. The use of natural or synthetic cosmetics to treat the appearance of the face and condition of the skin (such as pore control and blackhead cleansing) is common among many cultures. Oily skin is caused by hormonal fluctuations in the body, which lead to a DHT sensitivity. This sensitivity means that the skin begins to lose moisture and essential fatty acids (linoleic acid in particular), causing thousands of skin cells to die, so the skin compensates for this loss of moisture by producing higher levels of oil. Oily skin can be cleaned quickly with a mild solution of laundry detergent, when pure bath soaps fail (see below: Hygiene). Afterward, body lotions could be used to recondition cleansed skin, as would be used to treat dry skin. # Skin components Skin has pigmentation, or melanin, provided by melanocytes, which absorb some of the potentially dangerous ultraviolet radiation (UV) in sunlight. It also contains DNA repair enzymes which help to reverse UV damage, and people who lack the genes for these enzymes suffer high rates of skin cancer. One form predominantly produced by UV light, malignant melanoma, is particularly invasive, causing it to spread quickly, and can often be deadly. Human skin pigmentation varies among populations in a striking manner. This has sometimes led to the classification of people(s) on the basis of skin color. Mammalian skin often contains hairs, which in sufficient density is called fur. The hair mainly serves to augment the insulation the skin provides, but can also serve as a secondary sexual characteristic or as camouflage. On some animals, the skin is very hard and thick, and can be processed to create leather. Reptiles and fish have hard protective scales on their skin for protection, and birds have hard feathers, all made of tough β-keratins. Amphibian skin is not a strong barrier to passage of chemicals and is often subject to osmosis. A frog sitting in an anesthetic solution could quickly go to sleep. The skin is often known as the largest organ of the human body. This applies to exterior surface, as it covers the body, appearing to have the largest surface area of all the organs. Moreover, it applies to weight, as it weighs more than any single internal organ, accounting for about 15 percent of body weight. For the average adult human, the skin has a surface area of between 1.5-2.0 square meters (8-10.8 sq.ft.), most of it is between 2-3 mm (0.10 inch) thick. The average square inch (6 cm²) of skin holds 650 sweat glands, 20 blood vessels, 60,000 melanocytes, and more than a thousand nerve endings. # Functions Skin performs the following functions: - Protection: an anatomical barrier between the internal and external environment in bodily defense; Langerhans cells in the skin are part of the adaptive immune system - Sensation: contains a variety of nerve endings that react to heat and cold, touch, pressure, vibration, and tissue injury; see somatosensory system and haptics. - Heat regulation: the skin contains a blood supply far greater than its requirements which allows precise control of energy loss by radiation, convection and conduction. Dilated blood vessels increase perfusion and heat loss while constricted vessels greatly reduce cutaneous blood flow and conserve heat. Erector pili muscles are significant in animals. - Control of evaporation: the skin provides a relatively dry and impermeable barrier to fluid loss. Loss of this function contributes to the massive fluid loss in burns. - Aesthetics and communication: others see our skin and can assess our mood, physical state and attractiveness. - Storage and synthesis: acts as a storage center for lipids and water, as well as a means of synthesis of vitamin D by action of UV on certain parts of the skin. - Excretion: The concentration of urea is 1/130th that of urine. Excretion by sweating is at most a secondary function to temperature regulation. - Absorption: Oxygen, nitrogen and carbon dioxide can diffuse into the epidermis in small amounts, some animals using their skin for their sole respiration organ. In addition, medicine can be administered through the skin, by ointments or by means of adhesive patch, such as the nicotine patch or iontophoresis. The skin is an important site of transport in many other organisms. # Hygiene Unclean skin favors the development of pathogenic organisms - the dead cells that continually slough off of the epidermis mix with the secretions of the sweat and sebaceous glands and the dust found on the skin to form a filthy layer on its surface. If not washed away, the slurry of sweat and sebaceous secretions mixed with dirt and dead skin is decomposed by bacterial flora, producing a foul smell. Functions of the skin are disturbed when it is excessively dirty; it becomes more easily damaged, the release of antibacterial compounds decreases, and dirty skin is more prone to develop infections. Cosmetics should be used carefully because these may cause allergic reactions. Each season requires suitable clothing in order to facilitate the evaporation of the sweat. Sunlight, water and air play an important role in keeping the skin healthy. The skin supports its own ecosystems of microorganisms, including yeasts and bacteria, which cannot be removed by any amount of cleaning. Estimates place the number of individual bacteria on the surface of one square inch (6.5 square cm) of human skin at 50 million though this figure varies greatly over the average 20 feet2 (1.9 m²) of human skin. Oily surfaces, such as the face, may contain over 500 million bacteria per square inch (6.5 cm²). Despite these vast quantities, all of the bacteria found on the skin's surface would fit into a volume the size of a pea. In general, the microorganisms keep one another in check and are part of a healthy skin. When the balance is disturbed, there may be an overgrowth and infection, such as when antibiotics kill microbes, resulting in an overgrowth of yeast. The skin is continuous with the inner epithelial lining of the body at the orifices, each of which supports its own complement of microbes. Oily skin is caused by over-active glands, that produce a substance called sebum, a naturally healthy skin lubricant. When the skin produces excessive sebum, it becomes heavy and thick in texture. Oily skin is typified by shininess, blemishes and pimples. The oily-skin type is not necessarily bad, since such skin is less prone to wrinkling, or other signs of aging, because the oil helps to keep needed moisture locked into the epidermis (outermost layer of skin). The negative aspect of the oily-skin type is that oily complexions are especially susceptible to clogged pores, blackheads, and buildup of dead skin cells on the surface of the skin. Oily skin can be sallow and rough in texture and tends to have large, clearly visible pores everywhere, except around the eyes and neck. The goal of treating oily skin is to remove excess surface sebum without complete removal of skin lipids. Severe degreasing treatment can foster an actual worsening of sebum secretion, which defeats the aim of the cleansing. A method of cleansing oily skin is to wash with a solution of a mild synthetic detergent (see: surfactant) containing no oils, waxes or other lipid agents that could aggravate the oily condition of the skin, sometimes combined with a toning lotion. Such a product removes the oily residue and debris from the skin surface. Some cleansing products have lower concentrations of hydroxy acids, which remove dead cells from the upper levels of the stratum corneum. Those products should be used on a regular basis to work adequately. A light moisturizer may be included in a product to counteract any drying effects of the cleanser. # Aging As skin ages, it becomes thinner and more easily damaged. Intensifying this effect is the decreasing ability of skin to heal itself, as a person ages and skin requires a longer time to heal in later life. Skin sagging is caused by the fall in elasticity. Ageing skin also receives less blood flow and lower gland activity. # Disease In medicine, the branch concerned with the skin is called dermatology. The skin is subject to constant attack from without, and so can be afflicted by numerous ailments, such as these: Tumors: - Benign tumors of the skin such as Squamous cell papilloma - Skin cancer Others: - Rashes - Blisters - Acne - Keratosis pilaris - Fungal infections such as athlete's foot - Microbial infections. - Calcinosis cutis - Ring worm - Sunburn - Keloid - Scabies There are several other skin diseases as well. # Variability in skin tone Individuals with ancestors from different parts of the world can have highly visible differences in skin pigmentation. Individuals with African ancestry (black people) tend towards darker skin, while those of Northern European descent (white people) have paler skin. Between these extremes are individuals of Asian, South-East Asian, Native American, Middle Eastern, Polynesian and Melanesian descent. The skin of black people has more variation in color from one part of the body to another than does the skin of other racial groups, particularly the palms of the hands and soles of the feet. Part of this is the result of the variations in the thickness of the skin or different parts of the body. The thicker the skin, the more layers of cell with melanin in them, and the darker the color. In addition, these parts of the body do not have melanin-producing cells. Darker skin hinders UV A rays from penetrating. Since vitamin B folats are degraded by UV A and vitamin D is synthesised different skin tones are more likely to produce different vitamin deficiencies. # Animal skin products Skins and hides from different animals are used for clothing, bags and other consumer products, usually in the form of leather, but also furs, rawhide, snakeskin and hagfish. Skin can also be used to make products such as gelatin and glue. See also wool. # Skin layers Skin is composed of three primary layers: the epidermis, which provides waterproofing and serves as a barrier to infection; the dermis, which serves as a location for the appendages of skin; and the hypodermis (subcutaneous adipose layer), which is called the basement membrane. ## Epidermis Epidermis, "epi" coming from the Greek meaning "over" or "upon", is the outermost layer of the skin. It forms the waterproof, protective wrap over the body's surface and is made up of stratified squamous epithelium with an underlying basal lamina. The outermost epidermis consists of stratified squamous epithelium with an underlying connective tissue section, or dermis, and a hypodermis, or basement membrane. The epidermis contains no blood vessels, and cells in the deepest layers are nourished by diffusion from blood capillaries extending to the upper layers of the dermis. The main type of cells which make up the epidermis are keratinocytes, with melanocytes and Langerhans cells also present. The epidermis can be further subdivided into the following strata (beginning with the outermost layer): corneum, lucidum (only in palms of hands and bottoms of feet), granulosum, spinosum, basale. Cells are formed through mitosis at the basale layer. The daughter cells, (see cell division) move up the strata changing shape and composition as they die due to isolation from their blood source. The cytoplasm is released and the protein keratin is inserted. They eventually reach the corneum and slough off (desquamation). This process is called keratinization and takes place within about 30 days. This keratinized layer of skin is responsible for keeping water in the body and keeping other harmful chemicals and pathogens out, making skin a natural barrier to infection. ### Components The epidermis contains no blood vessels, and is nourished by diffusion from the dermis. The main type of cells which make up the epidermis are keratinocytes, melanocytes, Langerhans cells and Merkels cells. ### Layers Epidermis is divided into several layers where cells are formed through mitosis at the innermost layers. They move up the strata changing shape and composition as they differentiate and become filled with keratin. They eventually reach the top layer called stratum corneum and become sloughed off, or desquamated. This process is called keratinization and takes place within weeks. The outermost layer of Epidermis consists of 25 to 30 layers of dead cells. ### Sublayers Epidermis is divided into the following 5 sublayers or strata: - Stratum corneum - Stratum lucidum - Stratum granulosum - Stratum spinosum - Stratum germinativum (also called "stratum basale") Mnemonics that are good for remembering the layers of the skin (using "stratum basale" instead of "stratum germinativum"): - "Cher Likes Getting Skin Botoxed" (from superficial to deep) - "Before signing, get legal counsel" (from deep to superficial) - "Before Sex Get Latex Condoms (from deep to superficial) Blood capillaries are found beneath the epidermis, and are linked to an arteriole and a venule. Arterial shunt vessels may bypass the network in ears, the nose and fingertips. ## Dermis The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many nerve endings that provide the sense of touch and heat. It contains the hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels and blood vessels. The blood vessels in the dermis provide nourishment and waste removal to its own cells as well as the Stratum basale of the epidermis. Structure The dermis is structurally divided into two areas: a superficial area adjacent to the epidermis, called the papillary region, and a deep thicker area known as the reticular region. ### Papillary region The papillary region is composed of loose areolar connective tissue. It is named for its fingerlike projections called papillae, that extend toward the epidermis. The papillae provide the dermis with a "bumpy" surface that interdigitates with the epidermis, strengthening the connection between the two layers of skin. In the palms, fingers, soles, and toes, the influence of the papillae projecting into the epidermis forms contours in the skin's surface. These are called friction ridges, because they help the hand or foot to grasp by increasing friction. Friction ridges occur in patterns (see: fingerprint) that are genetically determined and are therefore unique to the individual, making it possible to use fingerprints or footprints as a means of identification. ### Reticular region The reticular region lies deep in the papillary region and is usually much thicker. It is composed of dense irregular connective tissue, and receives its name from the dense concentration of collagenous, elastic, and reticular fibers that weave throughout it. These protein fibers give the dermis its properties of strength, extensibility, and elasticity. Also located within the reticular region are the roots of the hair, sebaceous glands, sweat glands, receptors, nails, and blood vessels. Tattoo ink is injected into the dermis. Stretch marks from pregnancy are also located in the dermis. The hypodermis is not part of the skin, and lies below the dermis. Its purpose is to attach the skin to underlying bone and muscle as well as supplying it with blood vessels and nerves. It consists of loose connective tissue and elastin. The main cell types are fibroblasts, macrophages and adipocytes (the hypodermis contains 50% of body fat). Fat serves as padding and insulation for the body. Microorganisms like Staphylococcus epidermidis colonize the skin surface. These microorganisms serve as ecoorgan. The density of skin flora depends on region of the skin. The disinfected skin surface gets recolonized from bacteria residing in the deeper areas of the hair follicle, gut and urogenital openings.

Skin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] In zootomy and dermatology, skin is the largest organ of the integumentary system made up of multiple layers of epithelial tissues that guard underlying muscles and organs. [1] Skin pigmentation (see: human skin color or coloring) varies among populations, and skin type can range from dry skin to oily skin. The adjective cutaneous literally means "of the skin" (from Latin cutis, skin). As the interface with the surroundings, skin plays the most important role in protecting (the body) against pathogens. Its other main functions are insulation and temperature regulation, sensation, and synthesis of vitamin D and the protection of vitamin B folats. Severely damaged skin will try to heal by forming scar tissue, often giving rise to discoloration and depigmentation of the skin. The use of natural or synthetic cosmetics to treat the appearance of the face and condition of the skin (such as pore control and blackhead cleansing) is common among many cultures. Oily skin is caused by hormonal fluctuations in the body, which lead to a DHT sensitivity. This sensitivity means that the skin begins to lose moisture and essential fatty acids (linoleic acid in particular), causing thousands of skin cells to die, so the skin compensates for this loss of moisture by producing higher levels of oil. [2] Oily skin can be cleaned quickly with a mild solution of laundry detergent,[1] when pure bath soaps fail (see below: Hygiene). Afterward, body lotions could be used to recondition cleansed skin,[1] as would be used to treat dry skin. # Skin components Skin has pigmentation, or melanin, provided by melanocytes, which absorb some of the potentially dangerous ultraviolet radiation (UV) in sunlight. It also contains DNA repair enzymes which help to reverse UV damage, and people who lack the genes for these enzymes suffer high rates of skin cancer. One form predominantly produced by UV light, malignant melanoma, is particularly invasive, causing it to spread quickly, and can often be deadly. Human skin pigmentation varies among populations in a striking manner. This has sometimes led to the classification of people(s) on the basis of skin color. Mammalian skin often contains hairs, which in sufficient density is called fur. The hair mainly serves to augment the insulation the skin provides, but can also serve as a secondary sexual characteristic or as camouflage. On some animals, the skin is very hard and thick, and can be processed to create leather. Reptiles and fish have hard protective scales on their skin for protection, and birds have hard feathers, all made of tough β-keratins. Amphibian skin is not a strong barrier to passage of chemicals and is often subject to osmosis. A frog sitting in an anesthetic solution could quickly go to sleep. The skin is often known as the largest organ of the human body. This applies to exterior surface, as it covers the body, appearing to have the largest surface area of all the organs. Moreover, it applies to weight, as it weighs more than any single internal organ, accounting for about 15 percent of body weight. For the average adult human, the skin has a surface area of between 1.5-2.0 square meters (8-10.8 sq.ft.), most of it is between 2-3 mm (0.10 inch) thick. The average square inch (6 cm²) of skin holds 650 sweat glands, 20 blood vessels, 60,000 melanocytes, and more than a thousand nerve endings. # Functions Skin performs the following functions: - Protection: an anatomical barrier between the internal and external environment in bodily defense; Langerhans cells in the skin are part of the adaptive immune system - Sensation: contains a variety of nerve endings that react to heat and cold, touch, pressure, vibration, and tissue injury; see somatosensory system and haptics. - Heat regulation: the skin contains a blood supply far greater than its requirements which allows precise control of energy loss by radiation, convection and conduction. Dilated blood vessels increase perfusion and heat loss while constricted vessels greatly reduce cutaneous blood flow and conserve heat. Erector pili muscles are significant in animals. - Control of evaporation: the skin provides a relatively dry and impermeable barrier to fluid loss. Loss of this function contributes to the massive fluid loss in burns. - Aesthetics and communication: others see our skin and can assess our mood, physical state and attractiveness. - Storage and synthesis: acts as a storage center for lipids and water, as well as a means of synthesis of vitamin D by action of UV on certain parts of the skin. - Excretion: The concentration of urea is 1/130th that of urine. Excretion by sweating is at most a secondary function to temperature regulation. - Absorption: Oxygen, nitrogen and carbon dioxide can diffuse into the epidermis in small amounts, some animals using their skin for their sole respiration organ. In addition, medicine can be administered through the skin, by ointments or by means of adhesive patch, such as the nicotine patch or iontophoresis. The skin is an important site of transport in many other organisms. # Hygiene Unclean skin favors the development of pathogenic organisms - the dead cells that continually slough off of the epidermis mix with the secretions of the sweat and sebaceous glands and the dust found on the skin to form a filthy layer on its surface. If not washed away, the slurry of sweat and sebaceous secretions mixed with dirt and dead skin is decomposed by bacterial flora, producing a foul smell. Functions of the skin are disturbed when it is excessively dirty; it becomes more easily damaged, the release of antibacterial compounds decreases, and dirty skin is more prone to develop infections. Cosmetics should be used carefully because these may cause allergic reactions. Each season requires suitable clothing in order to facilitate the evaporation of the sweat. Sunlight, water and air play an important role in keeping the skin healthy. The skin supports its own ecosystems of microorganisms, including yeasts and bacteria, which cannot be removed by any amount of cleaning. Estimates place the number of individual bacteria on the surface of one square inch (6.5 square cm) of human skin at 50 million though this figure varies greatly over the average 20 feet2 (1.9 m²) of human skin. Oily surfaces, such as the face, may contain over 500 million bacteria per square inch (6.5 cm²). Despite these vast quantities, all of the bacteria found on the skin's surface would fit into a volume the size of a pea.[3] In general, the microorganisms keep one another in check and are part of a healthy skin. When the balance is disturbed, there may be an overgrowth and infection, such as when antibiotics kill microbes, resulting in an overgrowth of yeast. The skin is continuous with the inner epithelial lining of the body at the orifices, each of which supports its own complement of microbes. Oily skin is caused by over-active glands, that produce a substance called sebum, a naturally healthy skin lubricant.[1] When the skin produces excessive sebum, it becomes heavy and thick in texture. Oily skin is typified by shininess, blemishes and pimples.[1] The oily-skin type is not necessarily bad, since such skin is less prone to wrinkling, or other signs of aging,[1] because the oil helps to keep needed moisture locked into the epidermis (outermost layer of skin). The negative aspect of the oily-skin type is that oily complexions are especially susceptible to clogged pores, blackheads, and buildup of dead skin cells on the surface of the skin.[1] Oily skin can be sallow and rough in texture and tends to have large, clearly visible pores everywhere, except around the eyes and neck.[1] The goal of treating oily skin is to remove excess surface sebum without complete removal of skin lipids.[1] Severe degreasing treatment can foster an actual worsening of sebum secretion, which defeats the aim of the cleansing.[1] A method of cleansing oily skin is to wash with a solution of a mild synthetic detergent[1] (see: surfactant) containing no oils, waxes or other lipid agents that could aggravate the oily condition of the skin, sometimes combined with a toning lotion. Such a product removes the oily residue and debris from the skin surface. Some cleansing products have lower concentrations of hydroxy acids, which remove dead cells from the upper levels of the stratum corneum.[1] Those products should be used on a regular basis to work adequately.[1] A light moisturizer may be included in a product to counteract any drying effects of the cleanser.[1] # Aging As skin ages, it becomes thinner and more easily damaged. Intensifying this effect is the decreasing ability of skin to heal itself, as a person ages and skin requires a longer time to heal in later life. Skin sagging is caused by the fall in elasticity. Ageing skin also receives less blood flow and lower gland activity. # Disease In medicine, the branch concerned with the skin is called dermatology. The skin is subject to constant attack from without, and so can be afflicted by numerous ailments, such as these: Tumors: - Benign tumors of the skin such as Squamous cell papilloma - Skin cancer Others: - Rashes - Blisters - Acne - Keratosis pilaris - Fungal infections such as athlete's foot - Microbial infections. - Calcinosis cutis - Ring worm - Sunburn - Keloid - Scabies There are several other skin diseases as well. # Variability in skin tone Individuals with ancestors from different parts of the world can have highly visible differences in skin pigmentation. Individuals with African ancestry (black people) tend towards darker skin, while those of Northern European descent (white people) have paler skin. Between these extremes are individuals of Asian, South-East Asian, Native American, Middle Eastern, Polynesian and Melanesian descent. The skin of black people has more variation in color from one part of the body to another than does the skin of other racial groups, particularly the palms of the hands and soles of the feet. Part of this is the result of the variations in the thickness of the skin or different parts of the body. The thicker the skin, the more layers of cell with melanin in them, and the darker the color.[4] In addition, these parts of the body do not have melanin-producing cells. Darker skin hinders UV A rays from penetrating. Since vitamin B folats are degraded by UV A and vitamin D is synthesised different skin tones are more likely to produce different vitamin deficiencies. # Animal skin products Skins and hides from different animals are used for clothing, bags and other consumer products, usually in the form of leather, but also furs, rawhide, snakeskin and hagfish. Skin can also be used to make products such as gelatin and glue. See also wool. # Skin layers Skin is composed of three primary layers: the epidermis, which provides waterproofing and serves as a barrier to infection; the dermis, which serves as a location for the appendages of skin; and the hypodermis (subcutaneous adipose layer), which is called the basement membrane. ## Epidermis Epidermis, "epi" coming from the Greek meaning "over" or "upon", is the outermost layer of the skin. It forms the waterproof, protective wrap over the body's surface and is made up of stratified squamous epithelium with an underlying basal lamina. The outermost epidermis consists of stratified squamous epithelium with an underlying connective tissue section, or dermis, and a hypodermis, or basement membrane. The epidermis contains no blood vessels, and cells in the deepest layers are nourished by diffusion from blood capillaries extending to the upper layers of the dermis. The main type of cells which make up the epidermis are keratinocytes, with melanocytes and Langerhans cells also present. The epidermis can be further subdivided into the following strata (beginning with the outermost layer): corneum, lucidum (only in palms of hands and bottoms of feet), granulosum, spinosum, basale. Cells are formed through mitosis at the basale layer. The daughter cells, (see cell division) move up the strata changing shape and composition as they die due to isolation from their blood source. The cytoplasm is released and the protein keratin is inserted. They eventually reach the corneum and slough off (desquamation). This process is called keratinization and takes place within about 30 days. This keratinized layer of skin is responsible for keeping water in the body and keeping other harmful chemicals and pathogens out, making skin a natural barrier to infection. ### Components The epidermis contains no blood vessels, and is nourished by diffusion from the dermis. The main type of cells which make up the epidermis are keratinocytes, melanocytes, Langerhans cells and Merkels cells. ### Layers Epidermis is divided into several layers where cells are formed through mitosis at the innermost layers. They move up the strata changing shape and composition as they differentiate and become filled with keratin. They eventually reach the top layer called stratum corneum and become sloughed off, or desquamated. This process is called keratinization and takes place within weeks. The outermost layer of Epidermis consists of 25 to 30 layers of dead cells. ### Sublayers Epidermis is divided into the following 5 sublayers or strata: - Stratum corneum - Stratum lucidum - Stratum granulosum - Stratum spinosum - Stratum germinativum (also called "stratum basale") Mnemonics that are good for remembering the layers of the skin (using "stratum basale" instead of "stratum germinativum"): - "Cher Likes Getting Skin Botoxed" (from superficial to deep) - "Before signing, get legal counsel" (from deep to superficial) - "Before Sex Get Latex Condoms (from deep to superficial) Blood capillaries are found beneath the epidermis, and are linked to an arteriole and a venule. Arterial shunt vessels may bypass the network in ears, the nose and fingertips. Template:Infobox Anatomy ## Dermis The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many nerve endings that provide the sense of touch and heat. It contains the hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels and blood vessels. The blood vessels in the dermis provide nourishment and waste removal to its own cells as well as the Stratum basale of the epidermis. Structure The dermis is structurally divided into two areas: a superficial area adjacent to the epidermis, called the papillary region, and a deep thicker area known as the reticular region. ### Papillary region The papillary region is composed of loose areolar connective tissue. It is named for its fingerlike projections called papillae, that extend toward the epidermis. The papillae provide the dermis with a "bumpy" surface that interdigitates with the epidermis, strengthening the connection between the two layers of skin. In the palms, fingers, soles, and toes, the influence of the papillae projecting into the epidermis forms contours in the skin's surface. These are called friction ridges, because they help the hand or foot to grasp by increasing friction. Friction ridges occur in patterns (see: fingerprint) that are genetically determined and are therefore unique to the individual, making it possible to use fingerprints or footprints as a means of identification. ### Reticular region The reticular region lies deep in the papillary region and is usually much thicker. It is composed of dense irregular connective tissue, and receives its name from the dense concentration of collagenous, elastic, and reticular fibers that weave throughout it. These protein fibers give the dermis its properties of strength, extensibility, and elasticity. Also located within the reticular region are the roots of the hair, sebaceous glands, sweat glands, receptors, nails, and blood vessels. Tattoo ink is injected into the dermis. Stretch marks from pregnancy are also located in the dermis. The hypodermis is not part of the skin, and lies below the dermis. Its purpose is to attach the skin to underlying bone and muscle as well as supplying it with blood vessels and nerves. It consists of loose connective tissue and elastin. The main cell types are fibroblasts, macrophages and adipocytes (the hypodermis contains 50% of body fat). Fat serves as padding and insulation for the body. Microorganisms like Staphylococcus epidermidis colonize the skin surface. These microorganisms serve as ecoorgan. The density of skin flora depends on region of the skin. The disinfected skin surface gets recolonized from bacteria residing in the deeper areas of the hair follicle, gut and urogenital openings.

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

39f07cb29025d81617d8155028eef14ef4520afe

wikidoc

GJA5

GJA5 Gap junction alpha-5 protein (GJA5), also known as connexin 40 (Cx40) — is a protein that in humans is encoded by the GJA5 gene. # Function This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene may be associated with atrial fibrillation. Alternatively spliced transcript variants encoding the same isoform have been described. GJA5 has been identified as the gene that is responsible for the phenotypes observed with congenital heart diseases on the 1q21.1 location. In case of a duplication of GJA5 tetralogy of Fallot is more common. In case of a deletion other congenital heart diseases than tetralogy of Fallot are more common. # Related gene problems - 1q21.1 deletion syndrome - 1q21.1 duplication syndrome

GJA5 Gap junction alpha-5 protein (GJA5), also known as connexin 40 (Cx40) — is a protein that in humans is encoded by the GJA5 gene. # Function This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene may be associated with atrial fibrillation. Alternatively spliced transcript variants encoding the same isoform have been described.[1] GJA5 has been identified as the gene that is responsible for the phenotypes observed with congenital heart diseases on the 1q21.1 location. In case of a duplication of GJA5 tetralogy of Fallot is more common. In case of a deletion other congenital heart diseases than tetralogy of Fallot are more common.[2] # Related gene problems - 1q21.1 deletion syndrome - 1q21.1 duplication syndrome

https://www.wikidoc.org/index.php/Cx40

8a5b6dffea68360caad64ed70f9971c4b17ff2e2

wikidoc

Cyst

Cyst # Overview A cyst is a closed sac having a distinct membrane and division on the nearby tissue. It may contain air, fluid, or semi-solid material. A collection of pus is called an abscess, not a cyst. Once formed, the cyst will remain in the tissue but can be removed by surgery or resolve by taking medications. A cyst may also be a sack that encloses an organism during a dormant period, such as in the case of certain parasites. This type of cyst may, for instance, protect a parasite from the churning acid of the stomach so it may pass through to the intestines unharmed where it can then break out. Cystic fibrosis is an example of a genetic disorder whereby cysts and fibrosis develop in the lungs. # Locations - Arachnoid cyst (between the surface of the brain and the cranial base or on the arachnoid membrane) - Chalazion cyst (eyelid) - Cysticercal cyst (the larval stage of Taenia sp.) - Dentigerous Cyst (associated with the crowns of non-erupted teeth) - Epididymal Cyst (found in the vessels attached to the testes) - Ganglion cyst (hand/foot joints and tendons) - Glial Cyst (in the brain) - Gartner's duct cyst (vaginal or vulvar cyst of embryological origin) - Keratocyst (in the jaws, these can appear solitary or associated with the Gorlin-Goltz or Nevoid basal cell carcinoma syndrome. The latest World Health Organization classification considers Keratocysts as tumors rather than cysts) - Meibomian cyst (eyelid) - Nabothian cyst (cervix) - Ovarian cyst (ovaries, functional and pathological) - Paratubal cyst (fallopian tube) - Pilonidal cyst (skin infection near tailbone) - Renal cyst (kidneys) - Radicular cyst (associated with the roots of non-vital teeth) - Sebaceous cyst (sac below skin) - Tarlov cyst (spine) - Vocal fold cyst - Dermoid cyst (Skull and ovaries) - Breast cyst # Related structures A pseudocyst is collection without a distinct membrane. A syrinx in the spinal cord or brainstem is sometimes inaccurately referred to as a cyst. # Resources - Template:FPnotebook - "Cyst Symptoms and Causes" by Melissa Conrad Stöppler, MD and William C. Shiel, Jr., MD, FACP, FACR. cs:Cysta (lékařství) de:Zyste io:Kisto it:Cisti (medicina) he:ציסטה hu:Ciszta nl:Cyste no:Cyste fi:Kysta sv:Cysta

Cyst Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Faizan Sheraz, M.D. [2] # Overview A cyst is a closed sac having a distinct membrane and division on the nearby tissue. It may contain air, fluid, or semi-solid material. A collection of pus is called an abscess, not a cyst. Once formed, the cyst will remain in the tissue but can be removed by surgery or resolve by taking medications. A cyst may also be a sack that encloses an organism during a dormant period, such as in the case of certain parasites. This type of cyst may, for instance, protect a parasite from the churning acid of the stomach so it may pass through to the intestines unharmed where it can then break out. Cystic fibrosis is an example of a genetic disorder whereby cysts and fibrosis develop in the lungs. # Locations - Arachnoid cyst (between the surface of the brain and the cranial base or on the arachnoid membrane) - Chalazion cyst (eyelid) - Cysticercal cyst (the larval stage of Taenia sp.) - Dentigerous Cyst (associated with the crowns of non-erupted teeth) - Epididymal Cyst (found in the vessels attached to the testes) - Ganglion cyst (hand/foot joints and tendons) - Glial Cyst (in the brain) - Gartner's duct cyst (vaginal or vulvar cyst of embryological origin) - Keratocyst (in the jaws, these can appear solitary or associated with the Gorlin-Goltz or Nevoid basal cell carcinoma syndrome. The latest World Health Organization classification considers Keratocysts as tumors rather than cysts) - Meibomian cyst (eyelid) - Nabothian cyst (cervix) - Ovarian cyst (ovaries, functional and pathological) - Paratubal cyst (fallopian tube) - Pilonidal cyst (skin infection near tailbone) - Renal cyst (kidneys) - Radicular cyst (associated with the roots of non-vital teeth) - Sebaceous cyst (sac below skin) - Tarlov cyst (spine) - Vocal fold cyst - Dermoid cyst (Skull and ovaries) - Breast cyst # Related structures A pseudocyst is collection without a distinct membrane. A syrinx in the spinal cord or brainstem is sometimes inaccurately referred to as a cyst. # Resources - Template:FPnotebook - "Cyst Symptoms and Causes" by Melissa Conrad Stöppler, MD and William C. Shiel, Jr., MD, FACP, FACR. Template:Tumors cs:Cysta (lékařství) de:Zyste io:Kisto it:Cisti (medicina) he:ציסטה hu:Ciszta nl:Cyste no:Cyste fi:Kysta sv:Cysta Template:WikiDoc Sources

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

528ec57a957602d8d9de30be1cb507341be5add1

wikidoc

DAB1

DAB1 The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway that controls cell positioning in the developing brain and during adult neurogenesis. It docks to the intracellular part of the Reelin very low density lipoprotein receptor (VLDLR) and apoE receptor type 2 (ApoER2) and becomes tyrosine-phosphorylated following binding of Reelin to cortical neurons. In mice, mutations of Dab1 and Reelin generate identical phenotypes. In humans, Reelin mutations are associated with brain malformations and mental retardation. In mice, Dab1 mutation results in the scrambler mouse phenotype. With a genomic length of 1.1 Mbp for a coding region of 5.5 kb, DAB1 provides a rare example of genomic complexity, which will impede the identification of human mutations. # Gene function Cortical neurons form in specialized proliferative regions deep in the brain and migrate past previously formed neurons to reach their proper layer. The laminar organization of multiple neuronal types in the cerebral cortex is required for normal cognitive function. The mouse 'reeler' mutation causes abnormal patterns of cortical neuronal migration as well as additional defects in cerebellar development and neuronal positioning in other brain regions. Reelin (RELN; 600514), the reeler gene product, is an extracellular protein secreted by pioneer neurons. The mouse 'scrambler' and 'yotari' recessive mutations exhibit a phenotype identical to that of reeler. Ware et al. (1997) determined that the scrambler phenotype arises from mutations in Dab1, a mouse gene related to the Drosophila gene 'disabled' (dab). Disabled-1 (Dab1) is an adaptor protein that is essential for the intracellular transduction of Reelin signaling, which regulates the migration and differentiation of postmitotic neurons during brain development in vertebrates. Dab1 function depends on its tyrosine phosphorylation by Src family kinases, especially Fyn. Dab encodes a phosphoprotein that binds nonreceptor tyrosine kinases and that has been implicated in neuronal development in flies. Sheldon et al. (1997) found that the yotari phenotype also results from a mutation in the Dab1 gene. Using in situ hybridization to embryonic day-13.5 mouse brain tissue, they demonstrated that Dab1 is expressed in neuronal populations exposed to reelin. The authors concluded that reelin and Dab1 function as signaling molecules that regulate cell positioning in the developing brain. Howell et al. (1997) showed that targeted disruption of the Dab1 gene disturbed neuronal layering in the cerebral cortex, hippocampus, and cerebellum, causing a reeler-like phenotype. Layering of neurons in the cerebral cortex and cerebellum requires RELN and DAB1. By targeted disruption experiments in mice, Trommsdorff et al. (1999) showed that 2 cell surface receptors, very low density lipoprotein receptor (VLDLR; 192977) and apolipoprotein E receptor-2 (ApoER2; 602600), are also required. Both receptors bound Dab1 on their cytoplasmic tails and were expressed in cortical and cerebellar layers adjacent to layers expressing Reln. Dab1 expression was upregulated in knockout mice lacking both the Vldlr and Apoer2 genes. Inversion of cortical layers, absence of cerebellar foliation, and the migration of Purkinje cells in these animals precisely mimicked the phenotype of mice lacking Reln or Dab1. These findings established novel signaling functions for the LDL receptor gene family and suggested that VLDLR and APOER2 participate in transmitting the extracellular RELN signal to intracellular signaling processes initiated by DAB1. In the reeler mouse, the telencephalic neurons (which are misplaced following migration) express approximately 10-fold more DAB1 than their wildtype counterpart. Such an increase in the expression of a protein that virtually functions as a receptor is expected to occur when the specific signal for the receptor is missing. # Gene variants and associated phenotypes in humans In a study by Dr. Scott Williamson of Cornell University, A newer version of the DAB1 gene had been shown to be universal among those of Chinese ancestry, but not found among other global populations. Being related to organizing the cells of the areas in the brain associated with cognitive function, it is speculated that the DAB1 mutation in the Chinese may be a parallel genetic evolutionary route to possibly accomplish an equivalent adaptation to other brain gene adaptations found in other world populations (such as the ASPM gene variant) but not in the Chinese.

DAB1 The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway that controls cell positioning in the developing brain and during adult neurogenesis. It docks to the intracellular part of the Reelin very low density lipoprotein receptor (VLDLR) and apoE receptor type 2 (ApoER2) and becomes tyrosine-phosphorylated following binding of Reelin to cortical neurons. In mice, mutations of Dab1 and Reelin generate identical phenotypes. In humans, Reelin mutations are associated with brain malformations and mental retardation. In mice, Dab1 mutation results in the scrambler mouse phenotype. With a genomic length of 1.1 Mbp for a coding region of 5.5 kb, DAB1 provides a rare example of genomic complexity, which will impede the identification of human mutations. # Gene function Cortical neurons form in specialized proliferative regions deep in the brain and migrate past previously formed neurons to reach their proper layer. The laminar organization of multiple neuronal types in the cerebral cortex is required for normal cognitive function. The mouse 'reeler' mutation causes abnormal patterns of cortical neuronal migration as well as additional defects in cerebellar development and neuronal positioning in other brain regions. Reelin (RELN; 600514), the reeler gene product, is an extracellular protein secreted by pioneer neurons. The mouse 'scrambler' and 'yotari' recessive mutations exhibit a phenotype identical to that of reeler. Ware et al. (1997) determined that the scrambler phenotype arises from mutations in Dab1, a mouse gene related to the Drosophila gene 'disabled' (dab).[1] Disabled-1 (Dab1) is an adaptor protein that is essential for the intracellular transduction of Reelin signaling, which regulates the migration and differentiation of postmitotic neurons during brain development in vertebrates. Dab1 function depends on its tyrosine phosphorylation by Src family kinases, especially Fyn.[2] Dab encodes a phosphoprotein that binds nonreceptor tyrosine kinases and that has been implicated in neuronal development in flies. Sheldon et al. (1997) found that the yotari phenotype also results from a mutation in the Dab1 gene.[3] Using in situ hybridization to embryonic day-13.5 mouse brain tissue, they demonstrated that Dab1 is expressed in neuronal populations exposed to reelin. The authors concluded that reelin and Dab1 function as signaling molecules that regulate cell positioning in the developing brain. Howell et al. (1997) showed that targeted disruption of the Dab1 gene disturbed neuronal layering in the cerebral cortex, hippocampus, and cerebellum, causing a reeler-like phenotype.[4] Layering of neurons in the cerebral cortex and cerebellum requires RELN and DAB1. By targeted disruption experiments in mice, Trommsdorff et al. (1999) showed that 2 cell surface receptors, very low density lipoprotein receptor (VLDLR; 192977) and apolipoprotein E receptor-2 (ApoER2; 602600), are also required.[5] Both receptors bound Dab1 on their cytoplasmic tails and were expressed in cortical and cerebellar layers adjacent to layers expressing Reln. Dab1 expression was upregulated in knockout mice lacking both the Vldlr and Apoer2 genes. Inversion of cortical layers, absence of cerebellar foliation, and the migration of Purkinje cells in these animals precisely mimicked the phenotype of mice lacking Reln or Dab1. These findings established novel signaling functions for the LDL receptor gene family and suggested that VLDLR and APOER2 participate in transmitting the extracellular RELN signal to intracellular signaling processes initiated by DAB1. In the reeler mouse, the telencephalic neurons (which are misplaced following migration) express approximately 10-fold more DAB1 than their wildtype counterpart. Such an increase in the expression of a protein that virtually functions as a receptor is expected to occur when the specific signal for the receptor is missing.[6] # Gene variants and associated phenotypes in humans In a study by Dr. Scott Williamson of Cornell University, A newer version of the DAB1 gene had been shown to be universal among those of Chinese ancestry, but not found among other global populations.[7][8] Being related to organizing the cells of the areas in the brain associated with cognitive function, it is speculated that the DAB1 mutation in the Chinese may be a parallel genetic evolutionary route to possibly accomplish an equivalent adaptation to other brain gene adaptations found in other world populations (such as the ASPM gene variant) but not in the Chinese.[8]

https://www.wikidoc.org/index.php/DAB1

61918b963ed2412d996515814ca0f6df5b74e4e0

wikidoc

DAP3

DAP3 28S ribosomal protein S29, mitochondrial, also known as death-associated protein 3 (DAP3), is a protein that in humans is encoded by the DAP3 gene on chromosome 1. This gene encodes a 28S subunit protein of the mitochondrial ribosome (mitoribosome) and plays key roles in translation, cellular respiration, and apoptosis. Moreover, DAP3 is associated with cancer development, but has been observed to aid some cancers while suppressing others. # Structure The DAP3 gene encodes a 46 kDa protein located in the lower area of the small mitoribosomal subunit. This protein contains a P-loop motif that binds GTP and a highly conserved 17-residue targeting sequence responsible for its localization to the mitochondria. Of interest, many of the phosphorylation sites on this protein are highly conserved and clustered around GTP-binding motifs. Several splice variants were observed in human ESTs that differ largely in the 5’ UTR region. Pseudogenes for this gene are also found in chromosomes 1 and 2. # Function DAP3 is a 28S subunit protein of mitoribosomes and localizes to the mitochondrial matrix. As part of the mitoribosome, DAP3 participates in the translation of the 13 ETC complex proteins encoded in the mitochondrial genome, and consequently, in the regulation of cellular respiration. As a member of the death-associated protein (DAP) family, DAP3 can also be found outside of the mitochondria to initiate the extrinsic apoptotic pathway through its interactions with apoptotic factors, such as tumor necrosis factor-alpha, Fas ligand, and gamma interferon. Additionally, DAP3 interacts with the factor IPS-1 to activate caspases 3, 8, and 9, resulting in a type of extracellular apoptosis called anoikis. Moreover, DAP3 may contribute to apoptosis through its mediation of mitochondrial fragmentation, as this function extends to the mediation of the oxidative stress response, reactive oxygen species (ROS) production, and ultimately, mitochondrial homeostasis. DAP3 is essential for life, and its deletion in embryos is lethal. Nonetheless, DAP3 and its apoptotic activity can be inhibited by AKT phosphorylation. # Clinical significance As aforementioned, death associated protein 3 (DAP3) has regulatory roles in cell respiration and apoptosis. Both opposites and cell respiration are important elements of cell death pathways and have underlying mechanistic roles in ischemia-reperfusion injury. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells. DAP3 has been implicated in numerous cancers. Studies demonstrated that DAP3 expression tended to be low to nonexistent in the tumor cells of B-cell lymphoma, non-small cell lung cancer, head and neck cancer, breast cancer, gastric cancer, and colon cancer, possibly due to hypermethylation of the gene’s promoter. Moreover, DAP3 expression has been positively correlated with improved cancer prognosis, indicating that the protein combats cancer progression through its proapoptotic function. As a result, DAP3 could serve as a potential biomarker to monitor the effectiveness of therapeutic treatments such as chemotherapy. However, in other cancers, such as glioblastoma multiforme (GBM) and thymoma, DAP3 expression was found to be upregulated. Thus, the specific role of DAP3 in various cancers requires further study. # Interactions DAP3 has been shown to interact with: - DELE, - IPS-1, - AKT, - PKA, - PKC, - NOA1, - FADD, - Glucocorticoid receptor, - Heat shock protein 90kDa alpha (cytosolic), member A1, and - TNFRSF10A.

DAP3 28S ribosomal protein S29, mitochondrial, also known as death-associated protein 3 (DAP3), is a protein that in humans is encoded by the DAP3 gene on chromosome 1.[1][2][3][4] This gene encodes a 28S subunit protein of the mitochondrial ribosome (mitoribosome) and plays key roles in translation, cellular respiration, and apoptosis.[3][4][5][6] Moreover, DAP3 is associated with cancer development, but has been observed to aid some cancers while suppressing others.[6][7][8] # Structure The DAP3 gene encodes a 46 kDa protein located in the lower area of the small mitoribosomal subunit.[5][8][9][10] This protein contains a P-loop motif that binds GTP and a highly conserved 17-residue targeting sequence responsible for its localization to the mitochondria.[5][7][8][9] Of interest, many of the phosphorylation sites on this protein are highly conserved and clustered around GTP-binding motifs.[5] Several splice variants were observed in human ESTs that differ largely in the 5’ UTR region.[3][10] Pseudogenes for this gene are also found in chromosomes 1 and 2.[3] # Function DAP3 is a 28S subunit protein of mitoribosomes and localizes to the mitochondrial matrix.[3][4][5] As part of the mitoribosome, DAP3 participates in the translation of the 13 ETC complex proteins encoded in the mitochondrial genome, and consequently, in the regulation of cellular respiration.[3][4][5][6] As a member of the death-associated protein (DAP) family, DAP3 can also be found outside of the mitochondria to initiate the extrinsic apoptotic pathway through its interactions with apoptotic factors, such as tumor necrosis factor-alpha, Fas ligand, and gamma interferon.[3][4][7][8][9] Additionally, DAP3 interacts with the factor IPS-1 to activate caspases 3, 8, and 9, resulting in a type of extracellular apoptosis called anoikis.[8][9] Moreover, DAP3 may contribute to apoptosis through its mediation of mitochondrial fragmentation, as this function extends to the mediation of the oxidative stress response, reactive oxygen species (ROS) production, and ultimately, mitochondrial homeostasis.[6][7][9] DAP3 is essential for life, and its deletion in embryos is lethal.[10] Nonetheless, DAP3 and its apoptotic activity can be inhibited by AKT phosphorylation.[8][9] # Clinical significance As aforementioned, death associated protein 3 (DAP3) has regulatory roles in cell respiration and apoptosis. Both opposites and cell respiration are important elements of cell death pathways and have underlying mechanistic roles in ischemia-reperfusion injury.[11][12][13] During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[14] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells. DAP3 has been implicated in numerous cancers. Studies demonstrated that DAP3 expression tended to be low to nonexistent in the tumor cells of B-cell lymphoma, non-small cell lung cancer, head and neck cancer, breast cancer, gastric cancer, and colon cancer, possibly due to hypermethylation of the gene’s promoter.[7][8] Moreover, DAP3 expression has been positively correlated with improved cancer prognosis, indicating that the protein combats cancer progression through its proapoptotic function.[7][8] As a result, DAP3 could serve as a potential biomarker to monitor the effectiveness of therapeutic treatments such as chemotherapy.[7] However, in other cancers, such as glioblastoma multiforme (GBM) and thymoma, DAP3 expression was found to be upregulated.[6][10] Thus, the specific role of DAP3 in various cancers requires further study.[13] # Interactions DAP3 has been shown to interact with: - DELE,[8] - IPS-1,[8] - AKT,[8] - PKA,[10] - PKC,[10] - NOA1,[4][10] - FADD,[15] - Glucocorticoid receptor,[16] - Heat shock protein 90kDa alpha (cytosolic), member A1,[16] and - TNFRSF10A.[15]

https://www.wikidoc.org/index.php/DAP3

7993dc0d71bcae3733328507a38a4a50f1bc300e

wikidoc

DAPI

DAPI DAPI or 4',6-diamidino-2-phenylindole is a fluorescent stain that binds strongly to DNA. It is used extensively in fluorescence microscopy. Since DAPI will pass through an intact cell membrane, it may be used to stain both live and fixed cells. For fluorescence microscopy, DAPI is excited with ultraviolet light. When bound to double-stranded DNA its absorption maximum is at 358 nm and its emission maximum is at 461 nm. (This emission is fairly broad, and appears blue/cyan.) DAPI will also bind to RNA, though it is not as strongly fluorescent. Its emission shifts to around 500 nm when bound to RNA. DAPI's blue emission is convenient for microscopists who wish to use multiple fluorescent stains in a single sample. There is fluorescence overlap between DAPI and green-fluorescent molecules like fluorescein and green fluorescent protein (GFP), or red-fluorescent stains like Texas Red, but using spectral unmixing or taking images sequentially can get around this. Apart from labelling cell nuclei, the most popular application of DAPI is in detection of mycoplasma or virus DNA in cell cultures. Because DAPI readily enters live cells and binds tightly to DNA, it is toxic and mutagenic. Care should be taken in its handling and disposal. The Hoechst stains are similar to DAPI in that they are also blue-fluorescent DNA stains which are compatible with both live- and fixed-cell applications. de:DAPI

DAPI Template:Chembox new DAPI or 4',6-diamidino-2-phenylindole is a fluorescent stain that binds strongly to DNA. It is used extensively in fluorescence microscopy. Since DAPI will pass through an intact cell membrane, it may be used to stain both live and fixed cells. For fluorescence microscopy, DAPI is excited with ultraviolet light. When bound to double-stranded DNA its absorption maximum is at 358 nm and its emission maximum is at 461 nm. (This emission is fairly broad, and appears blue/cyan.)[1] DAPI will also bind to RNA, though it is not as strongly fluorescent. Its emission shifts to around 500 nm when bound to RNA.[2] DAPI's blue emission is convenient for microscopists who wish to use multiple fluorescent stains in a single sample. There is fluorescence overlap between DAPI and green-fluorescent molecules like fluorescein and green fluorescent protein (GFP), or red-fluorescent stains like Texas Red, but using spectral unmixing or taking images sequentially can get around this. Apart from labelling cell nuclei, the most popular application of DAPI is in detection of mycoplasma or virus DNA in cell cultures. Because DAPI readily enters live cells and binds tightly to DNA, it is toxic and mutagenic. Care should be taken in its handling and disposal. The Hoechst stains are similar to DAPI in that they are also blue-fluorescent DNA stains which are compatible with both live- and fixed-cell applications. de:DAPI Template:WH Template:WikiDoc Sources

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

9f562c3448b718f5d1e9443b1d91cf7ae8a57f51

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DASB

DASB DASB is a compound that binds to the serotonin transporter. Labeled with carbon-11 — a radioactive isotope — it has been used as a radioligand in neuroimaging with positron emission tomography (PET) since around year 2000. In this context it is regarded as one of the superior radioligands for PET study of the serotonin transporter in the brain, since it has high selectivity for the serotonin transporter. The DASB image from a human PET scan shows high binding in the midbrain, thalamus and striatum, moderate binding in the medial temporal lobe and anterior cingulate, and low binding in neocortex. The cerebellum is often regarded as a region with no specific serotonin transporter binding and the brain region is used as a reference in some studies. Since the serotonin transporter is the target of SSRIs used in the treatment of major depression it has been natural to examine DASB binding in depressed patients. Several such research studies have been performed. There are a number of alternative PET radioligands for imaging the serotonin transporter: ADAM, AFM, DAPA, McN5652, and -NS 4194. A related molecule to DASB, that can be labeled with fluorine-18, has also been suggested as a PET radioligand. With single-photon emission computed tomography (SPECT) using the radioisotope iodine-123 there are further radioligands available: ODAM, IDAM, ADAM, and β-CIT. A few studies have examined the difference in binding between the radioligands in nonhuman primates, as well as in pigs. Other compounds that can be labeled to work as PET radioligands for the study of the serotonin system are, e.g., altanserin and WAY-100635. # Methodological issues The binding potential of DASB can be estimated with kinetic modeling on a series of brain scans. A test-retest reproducibility PET study indicates that DASB can be used to measure the serotonin transporter parameters with high reliability in receptor-rich brain regions. When the DASB neuroimages are analyzed the kinetic models suggested by Ichise and coworkers can be employed to estimate the binding potential. A test-retest reproducibility experiment has been performed to evaluate this approach. # Studies Besides the studies listed below a few occupancy studies have been reported.

DASB DASB is a compound that binds to the serotonin transporter. Labeled with carbon-11 — a radioactive isotope — it has been used as a radioligand in neuroimaging with positron emission tomography (PET) since around year 2000.[1] In this context it is regarded as one of the superior radioligands for PET study of the serotonin transporter in the brain,[2] since it has high selectivity for the serotonin transporter.[3] The DASB image from a human PET scan shows high binding in the midbrain, thalamus and striatum, moderate binding in the medial temporal lobe and anterior cingulate, and low binding in neocortex. The cerebellum is often regarded as a region with no specific serotonin transporter binding and the brain region is used as a reference in some studies.[4] Since the serotonin transporter is the target of SSRIs used in the treatment of major depression it has been natural to examine DASB binding in depressed patients. Several such research studies have been performed.[5] There are a number of alternative PET radioligands for imaging the serotonin transporter: [11C]ADAM, [11C]AFM, [11C]DAPA, [11C]McN5652, and [11C]-NS 4194. A related molecule to DASB, that can be labeled with fluorine-18, has also been suggested as a PET radioligand.[6] With single-photon emission computed tomography (SPECT) using the radioisotope iodine-123 there are further radioligands available: [123I]ODAM, [123I]IDAM, [123I]ADAM, and [123I]β-CIT.[2] A few studies have examined the difference in binding between the radioligands in nonhuman primates,[7][8] as well as in pigs.[9] Other compounds that can be labeled to work as PET radioligands for the study of the serotonin system are, e.g., altanserin and WAY-100635. # Methodological issues The binding potential of DASB can be estimated with kinetic modeling on a series of brain scans.[10] A test-retest reproducibility PET study indicates that [11C]DASB can be used to measure the serotonin transporter parameters with high reliability in receptor-rich brain regions.[4] When the DASB neuroimages are analyzed the kinetic models suggested by Ichise and coworkers[11] can be employed to estimate the binding potential. A test-retest reproducibility experiment has been performed to evaluate this approach.[12] # Studies Besides the studies listed below a few occupancy studies have been reported.[5]

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

aaeaa2fd7ecbffff139f54ef8164ae419d561472

wikidoc

DAX1

DAX1 DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) is a nuclear receptor protein that in humans is encoded by the NR0B1 gene (nuclear receptor subfamily 0, group B, member 1). The NR0B1 gene is located on the short (p) arm of the X chromosome between positions 21.3 and 21.2, from base pair 30,082,120 to base pair 30,087,136. # Function This gene encodes a protein that lacks the normal DNA-binding domain contained in other nuclear receptors. The encoded protein acts as a dominant-negative regulator of transcription of other nuclear receptors including steroidogenic factor 1. This protein also functions as an anti-testis gene by acting antagonistically to SRY. Mutations in this gene result in both X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism. DAX1 plays an important role in the normal development of several hormone-producing tissues. These tissues include the adrenal glands above each kidney, the pituitary gland and hypothalamus, which are located in the brain, and the reproductive structures (the testes and ovaries). DAX1 controls the activity of certain genes in the cells that form these tissues during embryonic development. Proteins that control the activity of other genes are known as transcription factors. DAX1 also plays a role in regulating hormone production in these tissues after they have been formed. # Role in disease X-linked adrenal hypoplasia congenita is caused by mutations in the NR0B1 gene. More than 90 NR0B1 mutations that cause X-linked adrenal hypoplasia congenita have been identified. Many of these mutations delete all or part of the NR0B1 gene, preventing the production of DAX1 protein. Some mutations cause the production of an abnormally short protein. Other mutations cause a change in one of the building blocks (amino acids) of DAX1. These mutations are thought to result in a misshapen, nonfunctional protein. Loss of DAX1 function leads to adrenal insufficiency and hypogonadotropic hypogonadism, which are the main characteristics of this disorder. Duplication of genetic material on the X chromosome in the region that contains the NR0B1 gene can cause a condition called dosage-sensitive sex reversal. The extra copy of the NR0B1 gene prevents the formation of male reproductive tissues. People who have this duplication usually appear to be female, but are genetically male with both an X and a Y chromosome. In some cases, genetic material is deleted from the X chromosome in a region that contains several genes, including NR0B1. This deletion results in a condition called adrenal hypoplasia congenita with complex glycerol kinase deficiency. In addition to the signs and symptoms of adrenal hypoplasia congenita, individuals with this condition may have elevated levels of lipids in their blood and urine and may have problems regulating blood sugar levels. In rare cases, the amount of genetic material deleted is even more extensive and affected individuals also have Duchenne muscular dystrophy. # Interactions DAX1 has been shown to interact with: - COPS2, - NRIP1, - Steroidogenic factor 1, and - SREBF1.

DAX1 DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) is a nuclear receptor protein that in humans is encoded by the NR0B1 gene (nuclear receptor subfamily 0, group B, member 1).[1][2][3] The NR0B1 gene is located on the short (p) arm of the X chromosome between positions 21.3 and 21.2, from base pair 30,082,120 to base pair 30,087,136. # Function This gene encodes a protein that lacks the normal DNA-binding domain contained in other nuclear receptors.[4] The encoded protein acts as a dominant-negative regulator of transcription of other nuclear receptors including steroidogenic factor 1.[5] This protein also functions as an anti-testis gene by acting antagonistically to SRY. Mutations in this gene result in both X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism.[1] DAX1 plays an important role in the normal development of several hormone-producing tissues. These tissues include the adrenal glands above each kidney, the pituitary gland and hypothalamus, which are located in the brain, and the reproductive structures (the testes and ovaries). DAX1 controls the activity of certain genes in the cells that form these tissues during embryonic development. Proteins that control the activity of other genes are known as transcription factors. DAX1 also plays a role in regulating hormone production in these tissues after they have been formed. # Role in disease X-linked adrenal hypoplasia congenita is caused by mutations in the NR0B1 gene. More than 90 NR0B1 mutations that cause X-linked adrenal hypoplasia congenita have been identified. Many of these mutations delete all or part of the NR0B1 gene, preventing the production of DAX1 protein. Some mutations cause the production of an abnormally short protein. Other mutations cause a change in one of the building blocks (amino acids) of DAX1. These mutations are thought to result in a misshapen, nonfunctional protein. Loss of DAX1 function leads to adrenal insufficiency and hypogonadotropic hypogonadism[6], which are the main characteristics of this disorder. Duplication of genetic material on the X chromosome in the region that contains the NR0B1 gene can cause a condition called dosage-sensitive sex reversal. The extra copy of the NR0B1 gene prevents the formation of male reproductive tissues. People who have this duplication usually appear to be female, but are genetically male with both an X and a Y chromosome. In some cases, genetic material is deleted from the X chromosome in a region that contains several genes, including NR0B1. This deletion results in a condition called adrenal hypoplasia congenita with complex glycerol kinase deficiency. In addition to the signs and symptoms of adrenal hypoplasia congenita, individuals with this condition may have elevated levels of lipids in their blood and urine and may have problems regulating blood sugar levels. In rare cases, the amount of genetic material deleted is even more extensive and affected individuals also have Duchenne muscular dystrophy. # Interactions DAX1 has been shown to interact with: - COPS2,[7] - NRIP1,[8] - Steroidogenic factor 1,[8][9] and - SREBF1.[9]

https://www.wikidoc.org/index.php/DAX1

2d9312545811370cd3650eba3f3606d252d5eea2

wikidoc

DAZ1

DAZ1 Deleted in azoospermia 1, also known as DAZ1, is a protein which in humans is encoded by the DAZ1 gene. # Function This gene is a member of the DAZ gene family and is a candidate for the human Y-chromosomal azoospermia factor (AZF). Its expression is restricted to pre-meiotic germ cells, particularly in spermatogonia. It encodes an RNA-binding protein that is important for spermatogenesis. Four copies of this gene are found on chromosome Y within palindromic duplications; one pair of genes is part of the P2 palindrome and the second pair is part of the P1 palindrome. Each gene contains a 2.4 kb repeat including a 72-bp exon, called the DAZ repeat; the number of DAZ repeats is variable and there are several variations in the sequence of the DAZ repeat. Each copy of the gene also contains a 10.8 kb region that may be amplified; this region includes five exons that encode an RNA recognition motif (RRM) domain. This gene contains three copies of the 10.8 kb repeat. However, no transcripts containing three copies of the RRM domain have been described; thus the RefSeq for this gene contains only two RRM domains. # Interactions DAZ1 has been shown to interact with DAZAP2, DAZL and DAZ associated protein 1.

DAZ1 Deleted in azoospermia 1, also known as DAZ1, is a protein which in humans is encoded by the DAZ1 gene.[1][2] # Function This gene is a member of the DAZ gene family and is a candidate for the human Y-chromosomal azoospermia factor (AZF). Its expression is restricted to pre-meiotic germ cells, particularly in spermatogonia. It encodes an RNA-binding protein that is important for spermatogenesis. Four copies of this gene are found on chromosome Y within palindromic duplications; one pair of genes is part of the P2 palindrome and the second pair is part of the P1 palindrome. Each gene contains a 2.4 kb repeat including a 72-bp exon, called the DAZ repeat; the number of DAZ repeats is variable and there are several variations in the sequence of the DAZ repeat. Each copy of the gene also contains a 10.8 kb region that may be amplified; this region includes five exons that encode an RNA recognition motif (RRM) domain. This gene contains three copies of the 10.8 kb repeat. However, no transcripts containing three copies of the RRM domain have been described; thus the RefSeq for this gene contains only two RRM domains.[1] # Interactions DAZ1 has been shown to interact with DAZAP2,[3] DAZL[3][4] and DAZ associated protein 1.[3]

https://www.wikidoc.org/index.php/DAZ1

5243bf84186baa8688989f1d3419dc6bdcf3642c

wikidoc

DBC1

DBC1 Deleted in bladder cancer protein 1 is a protein that in humans is encoded by the DBC1 gene. This gene is located within chromosome 9 (9q32-33), a chromosomal region that frequently shows loss of heterozygosity in transitional cell carcinoma of the bladder. It contains a 5' CpG island that may be a frequent target of hypermethylation, and it may undergo hypermethylation-based silencing in some bladder cancers. The functions of this gene are unknown, and it has not yet been placed in a protein family or functional pathway. Nonetheless, it is suspected to act as a tumor suppressor gene.

DBC1 Deleted in bladder cancer protein 1 is a protein that in humans is encoded by the DBC1 gene.[1][2][3][4][5] This gene is located within chromosome 9 (9q32-33), a chromosomal region that frequently shows loss of heterozygosity in transitional cell carcinoma of the bladder. It contains a 5' CpG island that may be a frequent target of hypermethylation, and it may undergo hypermethylation-based silencing in some bladder cancers.[3] The functions of this gene are unknown, and it has not yet been placed in a protein family or functional pathway. Nonetheless, it is suspected to act as a tumor suppressor gene.

https://www.wikidoc.org/index.php/DBC1

88a5b0baefa26ecfb7999468c11bf57fea7be803

wikidoc

DBN1

DBN1 Drebrin is a protein that in humans is encoded by the DBN1 gene. The protein encoded by this gene is a cytoplasmic actin-binding protein thought to play a role in the process of neuronal growth. It is a member of the drebrin family of proteins that are developmentally regulated in the brain. A decrease in the amount of this protein in the brain has been implicated as a possible contributing factor in the pathogenesis of memory disturbance in Alzheimer's disease. At least two alternative splice variants encoding different protein isoforms have been described for this gene. # Model organisms Model organisms have been used in the study of DBN1 function. A conditional knockout mouse line called Dbn1tm1b(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping

DBN1 Drebrin is a protein that in humans is encoded by the DBN1 gene.[1][2] The protein encoded by this gene is a cytoplasmic actin-binding protein thought to play a role in the process of neuronal growth. It is a member of the drebrin family of proteins that are developmentally regulated in the brain. A decrease in the amount of this protein in the brain has been implicated as a possible contributing factor in the pathogenesis of memory disturbance in Alzheimer's disease. At least two alternative splice variants encoding different protein isoforms have been described for this gene.[2] # Model organisms Model organisms have been used in the study of DBN1 function. A conditional knockout mouse line called Dbn1tm1b(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[3] Male and female animals underwent a standardized phenotypic screen[4] to determine the effects of deletion.[5][6][7][8] Additional screens performed: - In-depth immunological phenotyping[9]

https://www.wikidoc.org/index.php/DBN1

395fb4f5a56d57d5d1e795f0d5b3dfeaf0fb5635

wikidoc

DCC1

DCC1 Sister chromatid cohesion protein DCC1 is a protein that in humans is encoded by the DSCC1 gene. # Model organisms Model organisms have been used in the study of DSCC1 function. A conditional knockout mouse line, called Dscc1tm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice and four significant abnormalities were observed. Few homozygous mutant embryos were identified during gestation, and some displayed oedema, therefore less than expected survived until weaning. Those that did survive had increased chromosomal instability in a micronucleus test and numerous skeletal abnormalities by radiography. # Interactions DCC1 has been shown to interact with CHTF18.

DCC1 Sister chromatid cohesion protein DCC1 is a protein that in humans is encoded by the DSCC1 gene.[1][2] # Model organisms Model organisms have been used in the study of DSCC1 function. A conditional knockout mouse line, called Dscc1tm1a(KOMP)Wtsi[8][9] was generated at the Wellcome Trust Sanger Institute as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[10][11][12] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty four tests were carried out on mutant mice and four significant abnormalities were observed.[6] Few homozygous mutant embryos were identified during gestation, and some displayed oedema, therefore less than expected survived until weaning. Those that did survive had increased chromosomal instability in a micronucleus test and numerous skeletal abnormalities by radiography.[6] # Interactions DCC1 has been shown to interact with CHTF18.[14][15]

https://www.wikidoc.org/index.php/DCC1

ef040f43bf23e40ec633c9688ae05f6f39c5a9fa

wikidoc

DDB1

DDB1 DNA damage-binding protein 1 is a protein that in humans is encoded by the DDB1 gene. # Gene The gene's position is on chromosome 11q12-q13. # Protein The DDB1 gene encodes the large subunit of DNA damage-binding protein, a heterodimer composed of a large and a small (DDB2) subunit. DDB1 contains 1140 amino acids, amounting to a mass of 127 kDa. # Function As its name suggests, DDB1 was initially implicated in the process of a specific type of DNA repair known as nucleotide excision repair. Since then, researchers have found that DDB1 primarily functions as a core component of the CUL4A- and CUL4B-based E3 ubiquitin ligase complexes. DDB1 serves as a bridge or adaptor protein which interacts with dozens of proteins known as DDB1 and CUL4-associated factors (DCAFs). These DCAFs are often ubiquitin ligase substrates and regulate numerous essential processes in the cell including DNA repair (DDB2), DNA replication, chromatin remodeling (Cdt2) and more. # Interactions DDB1 has been shown to interact with Transcription initiation protein SPT3 homolog, GCN5L2, DDB2, CUL4A, CUL4B and P21.

DDB1 DNA damage-binding protein 1 is a protein that in humans is encoded by the DDB1 gene.[1][2][3] # Gene The gene's position is on chromosome 11q12-q13.[4] # Protein The DDB1 gene encodes the large subunit of DNA damage-binding protein, a heterodimer composed of a large and a small (DDB2) subunit. DDB1 contains 1140 amino acids, amounting to a mass of 127 kDa.[4] # Function As its name suggests, DDB1 was initially implicated in the process of a specific type of DNA repair known as nucleotide excision repair. Since then, researchers have found that DDB1 primarily functions as a core component of the CUL4A- and CUL4B-based E3 ubiquitin ligase complexes. DDB1 serves as a bridge or adaptor protein which interacts with dozens of proteins known as DDB1 and CUL4-associated factors (DCAFs).[5] These DCAFs are often ubiquitin ligase substrates and regulate numerous essential processes in the cell including DNA repair (DDB2), DNA replication, chromatin remodeling (Cdt2) and more. # Interactions DDB1 has been shown to interact with Transcription initiation protein SPT3 homolog,[6] GCN5L2,[7] DDB2,[8][9] CUL4A,[9] CUL4B[9] and P21.[10]

https://www.wikidoc.org/index.php/DDB1

353356575ad507565e2005a6aa85acefeb139a6f

wikidoc

DDB2

DDB2 DNA damage-binding protein 2 is a protein that in humans is encoded by the DDB2 gene. # Structure As indicated by Rapić-Otrin et al. in 2003, the DDB2 gene is located on human chromosome 11p11.2, spans a region of approximately 24 – 26 kb and includes 10 exons. The DDB2 protein contains five putative WD40 repeats (sequences of about 40 amino acids that can interact with each other) positioned downstream from the second exon. The WD40 motif identified in DDB2 is characteristic of proteins involved in the recognition of chromatin proteins. The C-terminal region of DDB2 (a 48 kDa molecular weight protein) is essential for binding to DDB1 (a larger 127 kDa protein). Together, the two proteins form a UV-damaged DNA binding protein complex (UV-DDB). # Deficiency in humans If humans have a mutation in each copy of their DDB2 gene, this causes a mild form of the human disease xeroderma pigmentosum, called XPE. Patients in the XPE group have mild dermatological manifestations and are neurologically unaffected. Mutation in the DDB2 gene causes a deficiency in nucleotide excision repair of DNA. This deficiency is also mild, showing 40 to 60% of normal repair capability and a modest sensitivity to UV light in comparison to the sensitivities of cells defective in the other XP genes XPA, XPB, XPC, XPD, XPF and XPG. # Function ## Binding to damaged DNA As shown by Wittschieben et al., when DDB2 is in a complex with DDB1, forming the heterodimer DDB, this complex binds strongly to DNA containing one type of UV light-induced photoproduct , to DNA with an abasic site, to DNA containing mismatches without a covalent lesion, and to “compound” lesions containing both mismatches and lesions. The heterodimer DDB binds with intermediate strength to DNA containing another UV light-induced photoproduct (the cyclobutane pyrimidine dimer), and binds weakly to DNA that has no DNA damage. The DDB2 component of the heterodimer contains the specificity for binding to damaged DNA, since a heterodimer DDB complex containing amino acid substitutions in the DDB2 subunit, as found in XP-E patients, is very deficient in binding to damaged DNA. DDB1 and DDB2, each acting alone, do not bind DNA. ## Chromatin remodeling The packaging of eukaryotic DNA into chromatin presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action. To allow the critical cellular process of DNA repair, the chromatin must be relaxed. DDB2, in its heterodimeric complex with DDB1, and further complexed with the ubiquitin ligase protein CUL4A and with PARP1 rapidly associates with UV-induced damage within chromatin, with half-maximum association completed in 40 seconds. The PARP1 protein, attached to both DDB1 and DDB2, then PARylates (creates a poly-ADP ribose chain) on DDB2 that attracts the DNA remodeling protein ALC1. Action of ALC1 relaxes the chromatin at the site of UV damage to DNA. This relaxation allows other proteins in the nucleotide excision repair pathway to enter the chromatin and repair the DNA damaged by the UV-induced presence of cyclobutane pyrimidine dimers. ## Other functions In 2015, Zhu et al. showed that DDB2 down-regulates the acetylation of lysine 56 in histone H3 (H3K56Ac) after UV-induced DNA damage through DDB2 interaction with histone deacetylases 1 and 2. Decreased acetylation of histones decreases transcription of associated genes in the DNA wrapped around the histones. In 2016, Zou et al. showed that DDB2 is involved in cell cycle arrest and homologous recombinational DNA repair after cells are subjected to ionizing radiation. In 2016, Christmann et al. showed that exposure of cells to the carcinogenic benzo(a)pyrene metabolite BPDE caused prompt and sustained upregulation of DDB2. This contributed to enhanced removal of BPDE adducts from DNA. In 2017, Fantini et al. showed that DDB2, in association with XRCC5 and XRCC6 (otherwise known as Ku80 and Ku70, which make up the Ku heterodimer), has transcriptional activities. The DDB2/Ku effects on transcription are separate from the actions of the Ku heterodimer in non-homologous end joining DNA repair.

DDB2 DNA damage-binding protein 2 is a protein that in humans is encoded by the DDB2 gene.[1][2] # Structure As indicated by Rapić-Otrin et al. in 2003,[3] the DDB2 gene is located on human chromosome 11p11.2, spans a region of approximately 24 – 26 kb and includes 10 exons. The DDB2 protein contains five putative WD40 repeats (sequences of about 40 amino acids that can interact with each other) positioned downstream from the second exon. The WD40 motif identified in DDB2 is characteristic of proteins involved in the recognition of chromatin proteins. The C-terminal region of DDB2 (a 48 kDa molecular weight protein) is essential for binding to DDB1 (a larger 127 kDa protein). Together, the two proteins form a UV-damaged DNA binding protein complex (UV-DDB).[4] # Deficiency in humans If humans have a mutation in each copy of their DDB2 gene, this causes a mild form of the human disease xeroderma pigmentosum, called XPE.[3] Patients in the XPE group have mild dermatological manifestations and are neurologically unaffected. Mutation in the DDB2 gene causes a deficiency in nucleotide excision repair of DNA. This deficiency is also mild, showing 40 to 60% of normal repair capability and a modest sensitivity to UV light in comparison to the sensitivities of cells defective in the other XP genes XPA, XPB, XPC, XPD, XPF and XPG.[5] # Function ## Binding to damaged DNA As shown by Wittschieben et al.,[6] when DDB2 is in a complex with DDB1, forming the heterodimer DDB, this complex binds strongly to DNA containing one type of UV light-induced photoproduct [the (6-4) photoproduct], to DNA with an abasic site, to DNA containing mismatches without a covalent lesion, and to “compound” lesions containing both mismatches and lesions. The heterodimer DDB binds with intermediate strength to DNA containing another UV light-induced photoproduct (the cyclobutane pyrimidine dimer), and binds weakly to DNA that has no DNA damage. The DDB2 component of the heterodimer contains the specificity for binding to damaged DNA, since a heterodimer DDB complex containing amino acid substitutions in the DDB2 subunit, as found in XP-E patients, is very deficient in binding to damaged DNA. DDB1 and DDB2, each acting alone, do not bind DNA. ## Chromatin remodeling The packaging of eukaryotic DNA into chromatin presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action. To allow the critical cellular process of DNA repair, the chromatin must be relaxed. DDB2, in its heterodimeric complex with DDB1, and further complexed with the ubiquitin ligase protein CUL4A[7] and with PARP1[8] rapidly associates with UV-induced damage within chromatin, with half-maximum association completed in 40 seconds.[7] The PARP1 protein, attached to both DDB1 and DDB2, then PARylates (creates a poly-ADP ribose chain) on DDB2 that attracts the DNA remodeling protein ALC1.[8] Action of ALC1 relaxes the chromatin at the site of UV damage to DNA. This relaxation allows other proteins in the nucleotide excision repair pathway to enter the chromatin and repair the DNA damaged by the UV-induced presence of cyclobutane pyrimidine dimers. ## Other functions In 2015, Zhu et al.[9] showed that DDB2 down-regulates the acetylation of lysine 56 in histone H3 (H3K56Ac) after UV-induced DNA damage through DDB2 interaction with histone deacetylases 1 and 2. Decreased acetylation of histones decreases transcription of associated genes in the DNA wrapped around the histones. In 2016, Zou et al.[10] showed that DDB2 is involved in cell cycle arrest and homologous recombinational DNA repair after cells are subjected to ionizing radiation. In 2016, Christmann et al.[11] showed that exposure of cells to the carcinogenic benzo(a)pyrene metabolite BPDE caused prompt and sustained upregulation of DDB2. This contributed to enhanced removal of BPDE adducts from DNA. In 2017, Fantini et al.[12] showed that DDB2, in association with XRCC5 and XRCC6 (otherwise known as Ku80 and Ku70, which make up the Ku heterodimer), has transcriptional activities. The DDB2/Ku effects on transcription are separate from the actions of the Ku heterodimer in non-homologous end joining DNA repair.

https://www.wikidoc.org/index.php/DDB2

47e51de3c02b3ea2cb574ba6734c76fa9584e197

wikidoc

DEET

DEET N,N-diethyl-m-toluamide, abbreviated DEET, is an insect repellent chemical. It is intended to be applied to the skin or to clothing, and is primarily used to protect against insect bites. In particular, DEET protects against tick bites (which transmit Lyme disease) and mosquito bites (which transmit dengue fever, West Nile virus, Eastern Equine Encephalitis (EEE), and malaria). DEET is believed to work by blocking insect receptors (notably those which detect carbon dioxide and lactic acid) which are used to locate hosts. DEET effectively "blinds" the insect's senses so that the biting/feeding instinct is not triggered by humans or animals which produce these chemicals. # History DEET was developed by the United States Army, following its experience of jungle warfare during World War II. It entered military use in 1946 and civilian use in 1957. Originally tested as a pesticide on farm fields,the US Government applied it for war time usage, particularly when in Vietnam and around that region of Asia. # Chemistry A slightly yellow liquid at room temperature, it can be prepared from m-methylbenzoic acid and diethylamine. This can be achieved by preparing the acid chloride and subsequently reacting that with the diethylamine. It can be distilled under vacuum: b.p. 111°C at 1 mm Hg. It is considered a mild irritant. # Concentrations DEET is often sold and used in concentrations up to 100%. Consumer Reports found a direct correlation between DEET concentration and hours of protection against insect bites. 100% DEET was found to offer up to 12 hours of protection while several lower concentration DEET formulations (20%-34%) offered 3-6 hours of protection. Other research has corroborated the effectiveness of DEET. # Effects on health DEET is the most common active ingredient in insect repellents. The American Academy of Pediatrics found no difference in safety for children, between products containing 10% and 30% DEET, when used as directed, but recommends that DEET not be used on infants less than two months old. As a precaution, manufacturers advise that DEET products should not be used under clothing or on damaged skin, and that preparations be washed off after they are no longer needed or between applications. In rare cases, it may cause skin reactions. In the DEET Reregistration Eligibility Decision (RED), the EPA reported 14 to 46 cases of potential DEET-associated seizures, including 4 deaths. The EPA states: " ..it does appear that some cases are likely related to DEET toxicity," but observed that with 30% of the US population using DEET, the likely seizure rate is only about one per 100 million users. A study which examined the risk factors for testicular cancer found evidence that use of insect repellents "mostly containing N,N-diethyl-m-toluamide (DEET)" were associated with an elevated risk of testicular cancer. The Pesticide Information Project of Cooperative Extension Offices of Cornell University states that "Everglades National Park employees having extensive Deet exposure were more likely to have insomnia, mood disturbances and impaired cognitive function than were lesser exposed co-workers". # Effects on materials DEET is an effective solvent, and may dissolve (part of) some plastics, rayon, spandex, other synthetic fabrics, leather, and painted or varnished surfaces. # Effects on the environment Although few studies have been conducted to assess possible effects on the environment, DEET is a moderate chemical pesticide and may not be suitable for use in and around water sources. Though DEET is not expected to bioaccumulate, it has been found to have a slight toxicity for coldwater fish such as the rainbow trout and the tilapia , and it has also been shown to be toxic for some species of freshwater zooplankton. DEET has been detected in significant levels in waterbodies as a result of production and use, such as in the Mississippi River and its tributaries, where a 1991 study detected levels varying from 5 to 201 ng/L. # Natural alternatives A test of various marketed insect repellents by an independent consumer organization found that synthetic repellents, including DEET, were more effective than repellents with ‘natural’ active ingredients. All the synthetics gave almost 100% repellency for the first 2 hours, whereas the natural repellent products were most effective for the first 30-60 minutes and required reapplication to be effective over several hours. Citronella oil has been used as an insect repellent for 60 years. Its mosquito repellency qualities have been verified by research, however, the repellency duration of DEET is much greater. While most essential oil based repellents are not as effective as DEET, research also shows that some EO-based formulas can be comparable to DEET, and somewhat better.

DEET Template:Chembox new N,N-diethyl-m-toluamide, abbreviated DEET, is an insect repellent chemical. It is intended to be applied to the skin or to clothing, and is primarily used to protect against insect bites. In particular, DEET protects against tick bites (which transmit Lyme disease) and mosquito bites (which transmit dengue fever, West Nile virus, Eastern Equine Encephalitis (EEE), and malaria). DEET is believed to work by blocking insect receptors (notably those which detect carbon dioxide and lactic acid) which are used to locate hosts. DEET effectively "blinds" the insect's senses so that the biting/feeding instinct is not triggered by humans or animals which produce these chemicals. # History DEET was developed by the United States Army, following its experience of jungle warfare during World War II. It entered military use in 1946 and civilian use in 1957. Originally tested as a pesticide on farm fields,the US Government applied it for war time usage, particularly when in Vietnam and around that region of Asia. # Chemistry A slightly yellow liquid at room temperature, it can be prepared from m-methylbenzoic acid and diethylamine. This can be achieved by preparing the acid chloride and subsequently reacting that with the diethylamine. It can be distilled under vacuum: b.p. 111°C at 1 mm Hg. It is considered a mild irritant. # Concentrations DEET is often sold and used in concentrations up to 100%. Consumer Reports found a direct correlation between DEET concentration and hours of protection against insect bites. 100% DEET was found to offer up to 12 hours of protection while several lower concentration DEET formulations (20%-34%) offered 3-6 hours of protection.[1] Other research has corroborated the effectiveness of DEET.[2] # Effects on health DEET is the most common active ingredient in insect repellents. The American Academy of Pediatrics found no difference in safety for children, between products containing 10% and 30% DEET, when used as directed, but recommends that DEET not be used on infants less than two months old.[3] As a precaution, manufacturers advise that DEET products should not be used under clothing or on damaged skin, and that preparations be washed off after they are no longer needed or between applications.[3] In rare cases, it may cause skin reactions.[3] In the DEET Reregistration Eligibility Decision (RED), the EPA reported 14 to 46 cases of potential DEET-associated seizures, including 4 deaths. The EPA states: " ..it does appear that some cases are likely related to DEET toxicity," but observed that with 30% of the US population using DEET, the likely seizure rate is only about one per 100 million users.[4] A study which examined the risk factors for testicular cancer found evidence that use of insect repellents "mostly containing N,N-diethyl-m-toluamide (DEET)" were associated with an elevated risk of testicular cancer.[5] The Pesticide Information Project of Cooperative Extension Offices of Cornell University states that "Everglades National Park employees having extensive Deet exposure were more likely to have insomnia, mood disturbances and impaired cognitive function than were lesser exposed co-workers". [6] # Effects on materials DEET is an effective solvent, and may dissolve (part of) some plastics, rayon, spandex, other synthetic fabrics, leather, and painted or varnished surfaces.[citation needed] # Effects on the environment Although few studies have been conducted to assess possible effects on the environment, DEET is a moderate chemical pesticide and may not be suitable for use in and around water sources. Though DEET is not expected to bioaccumulate, it has been found to have a slight toxicity for coldwater fish such as the rainbow trout[7] and the tilapia [8], and it has also been shown to be toxic for some species of freshwater zooplankton.[9] DEET has been detected in significant levels in waterbodies as a result of production and use, such as in the Mississippi River and its tributaries, where a 1991 study detected levels varying from 5 to 201 ng/L. [10] # Natural alternatives A test of various marketed insect repellents by an independent consumer organization found that synthetic repellents, including DEET, were more effective than repellents with ‘natural’ active ingredients. All the synthetics gave almost 100% repellency for the first 2 hours, whereas the natural repellent products were most effective for the first 30-60 minutes and required reapplication to be effective over several hours.[11] Citronella oil has been used as an insect repellent for 60 years.[12] Its mosquito repellency qualities have been verified by research,[13] [14][15] however, the repellency duration of DEET is much greater.[16] While most essential oil based repellents are not as effective as DEET,[16][17] research also shows that some EO-based formulas can be comparable to DEET, and somewhat better. [18]

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

a9d5308fcda4a6d16d63fbcb7c38fbe6c736982d

wikidoc

DFFA

DFFA DNA fragmentation factor subunit alpha (DFFA), also known as Inhibitor of caspase-activated DNase (ICAD), is a protein that in humans is encoded by the DFFA gene. Apoptosis is a cell death process that removes toxic and/or useless cells during mammalian development. The apoptotic process is accompanied by shrinkage and fragmentation of the cells and nuclei and degradation of the chromosomal DNA into nucleosomal units. DNA fragmentation factor (DFF) is a heterodimeric protein of 40-kD (DFFB) and 45-kD (DFFA) subunits. DFFA is the substrate for caspase-3 and triggers DNA fragmentation during apoptosis. DFF becomes activated when DFFA is cleaved by caspase-3. The cleaved fragments of DFFA dissociate from DFFB, the active component of DFF. DFFB has been found to trigger both DNA fragmentation and chromatin condensation during apoptosis. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. The C-terminal domain of DFFA (DFF-C) consists of four alpha-helices, which are folded in a helix-packing arrangement, with alpha-2 and alpha-3 packing against a long C-terminal helix (alpha-4). The main function of this domain is the inhibition of DFFB by binding to its C-terminal catalytic domain through ionic interactions, thereby inhibiting the fragmentation of DNA in the apoptotic process. In addition to blocking the DNase activity of DFFB, the C-terminal region of DFFA is also important for the DFFB-specific folding chaperone activity, as demonstrated by the ability of DFFA to refold DFFB. # Interactions DFFA has been shown to interact with DFFB.

DFFA DNA fragmentation factor subunit alpha (DFFA), also known as Inhibitor of caspase-activated DNase (ICAD), is a protein that in humans is encoded by the DFFA gene.[1][2][3] Apoptosis is a cell death process that removes toxic and/or useless cells during mammalian development. The apoptotic process is accompanied by shrinkage and fragmentation of the cells and nuclei and degradation of the chromosomal DNA into nucleosomal units. DNA fragmentation factor (DFF) is a heterodimeric protein of 40-kD (DFFB) and 45-kD (DFFA) subunits. DFFA is the substrate for caspase-3 and triggers DNA fragmentation during apoptosis. DFF becomes activated when DFFA is cleaved by caspase-3. The cleaved fragments of DFFA dissociate from DFFB, the active component of DFF. DFFB has been found to trigger both DNA fragmentation and chromatin condensation during apoptosis. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[3] The C-terminal domain of DFFA (DFF-C) consists of four alpha-helices, which are folded in a helix-packing arrangement, with alpha-2 and alpha-3 packing against a long C-terminal helix (alpha-4). The main function of this domain is the inhibition of DFFB by binding to its C-terminal catalytic domain through ionic interactions, thereby inhibiting the fragmentation of DNA in the apoptotic process. In addition to blocking the DNase activity of DFFB, the C-terminal region of DFFA is also important for the DFFB-specific folding chaperone activity, as demonstrated by the ability of DFFA to refold DFFB.[4] # Interactions DFFA has been shown to interact with DFFB.[5][6]

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

04e825303ca7fa4d92a53604027fb60183d18dba

wikidoc

DKK1

DKK1 Dickkopf-related protein 1 is a protein that in humans is encoded by the DKK1 gene. # Function This gene encodes a protein that is a member of the dickkopf family. It is a secreted protein with two cysteine rich regions and is involved in embryonic development through its inhibition of the Wnt signaling pathway. Dickkopf WNT signaling pathway inhibitor 1 (Dkk1) is a protein-coding gene that acts from the anterior visceral endoderm. The dickkopf protein encoded by DKK1 is an antagonist of the Wnt/β-catenin signalling pathway that acts by isolating the LRP6 co-receptor so that it cannot aid in activating the WNT signaling pathway. DKK1 was also demonstrated to antagonize the Wnt/β-catenin pathway via a reduction in β-catenin and an increase in OCT4 expression. This inhibition plays a key role in heart, head and forelimb development during anterior morphogenesis of the embryo. # Interactions DKK1 has been shown to interact with LRP6 and is a high affinity ligand of Kremen proteins. # Clinical significance Elevated levels of DKK1 in bone marrow, plasma and peripheral blood is associated with the presence of osteolytic bone lesions in patients with multiple myeloma. # Animal studies Scientists have created a DKK1 knockout model in mice that revealed the effects of this gene. All mice that were homozygous for the DKK1 knockout were dead at birth due to defects in the cranium and structures formed by the neural crest, such as failed development of eyes, olfactory placodes, frontonasal mass and mandibular processes, as well as incomplete development of the forebrain and midbrain and fusion of the digits of the forelimb. This evidence supports the idea that inhibition of the Wnt signaling pathway by DKK1 is crucial to proper cranial development. # In vitro studies DKK1 is one of the most upregulated genes in androgen-potentiated balding, with DKK-1 messenger RNA upregulated a few hours after DHT treatment of hair follicles at the dermal papilla in vitro. Neutralizing antibody against DKK-1 reversed DHT effects on outer root sheath keratinocytes. DKK-1 expression is attenuated by L-threonate in vitro, with the latter a metabolite of ascorbate.

DKK1 Dickkopf-related protein 1 is a protein that in humans is encoded by the DKK1 gene.[1] # Function This gene encodes a protein that is a member of the dickkopf family. It is a secreted protein with two cysteine rich regions and is involved in embryonic development through its inhibition of the Wnt signaling pathway. Dickkopf WNT signaling pathway inhibitor 1 (Dkk1) is a protein-coding gene that acts from the anterior visceral endoderm.[2][3] The dickkopf protein encoded by DKK1 is an antagonist of the Wnt/β-catenin signalling pathway that acts by isolating the LRP6 co-receptor so that it cannot aid in activating the WNT signaling pathway.[4] DKK1 was also demonstrated to antagonize the Wnt/β-catenin pathway via a reduction in β-catenin and an increase in OCT4 expression.[5] This inhibition plays a key role in heart, head and forelimb development during anterior morphogenesis of the embryo.[1][6] # Interactions DKK1 has been shown to interact with LRP6[7] and is a high affinity ligand of Kremen proteins.[8] # Clinical significance Elevated levels of DKK1 in bone marrow, plasma and peripheral blood is associated with the presence of osteolytic bone lesions in patients with multiple myeloma.[1] # Animal studies Scientists have created a DKK1 knockout model in mice that revealed the effects of this gene. All mice that were homozygous for the DKK1 knockout were dead at birth due to defects in the cranium and structures formed by the neural crest, such as failed development of eyes, olfactory placodes, frontonasal mass and mandibular processes, as well as incomplete development of the forebrain and midbrain and fusion of the digits of the forelimb.[3] This evidence supports the idea that inhibition of the Wnt signaling pathway by DKK1 is crucial to proper cranial development. # In vitro studies DKK1 is one of the most upregulated genes in androgen-potentiated balding, with DKK-1 messenger RNA upregulated a few hours after DHT treatment of hair follicles at the dermal papilla in vitro. Neutralizing antibody against DKK-1 reversed DHT effects on outer root sheath keratinocytes.[9] DKK-1 expression is attenuated by L-threonate in vitro, with the latter a metabolite of ascorbate.[10]

https://www.wikidoc.org/index.php/DKK1

0f06c83d7f261925bdd5fcc7bede7441e1eda765

wikidoc

DLC1

DLC1 Deleted in Liver Cancer 1 also known as DLC1 and StAR-related lipid transfer protein 12 (STARD12) is a protein which in humans is encoded by the DLC1 gene. This gene is deleted in the primary tumor of hepatocellular carcinoma. It maps to 8p22-p21.3, a region frequently deleted in solid tumors. It is suggested that this gene is a candidate tumor suppressor gene for human liver cancer, as well as for prostate, lung, colorectal, and breast cancers. # Gene The human DLC1 gene is located on the short arm of chromosome 8 (8p21.3-22), within a region that frequently undergoes loss of heterozygosity by either genomic deletion or epigenetic silencing mechanisms in several types of solid cancers. The gene contains 14 exons and produces an mRNA transcript that is 6.3 kb in length; the second AUG present in the open reading frame is the major translational start site, and produces a polypeptide which is 1091 amino acids long. The promoter region of the DLC1 gene contains a CpG island containing several CpG sites which can be methylated to promote gene silencing and prevent transcription. DLC1 is frequently inactivated in human hepatocellular carcinoma, as well as some nasopharyngeal, lung, breast, prostate, kidney, colon, uterine, ovarian, and gastric cancers. # Protein structure and localization The DLC1 protein contains four major functional domains: an N-terminal sterile α motif (SAM), a serine-rich (SR) region, a Rho-GAP domain, and a C-terminal steroidogenic acute regulatory protein related lipid-transfer (START) domain. DLC1 is localized to focal adhesions located at the periphery of cells. ## SAM domain The SAM domain (stretching from amino acids 11-78) is believed to be involved in protein-protein interactions. The exact function of the DLC1 SAM domain has not yet been determined. ## SR region The relatively unstructured and unconserved SR region (amino acids 86-638) contains a focal adhesion targeting (FAT) domain, including a tyrosine residue at position 442, which interacts with SH2 domains of tensin1 and cten. These interactions allow DLC1 to co-localize along with these proteins to focal adhesions at the periphery of the cell, where it is able to carry out its function as a Rho-GAP protein. ## Rho-GAP domain The highly conserved Rho-GAP domain (amino acids 639-847) functions to enhance the GTPase activity of the Rho-GTPase proteins RhoA and Cdc42, promoting the hydrolysis of their bound GTP to GDP and thus “shutting off” these proteins. DLC1 contains a conserved “arginine finger” arginine residue at position 677, which is located within the active site of the protein and is essential for catalyzation of the GTP hydrolysis. Rho-GTPases are involved in regulating cell morphology (through cytoskeletal organization) and migration (through focal adhesion formation). ## START domain The START domain (amino acids 878-1081) contains a β-sheet which forms a hydrophobic tunnel held in place by α-helices. This region interacts with phospholipase C-δ1 (PLCδ1) and activates its ability to hydrolyze the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3), which in turn activates protein kinase C (PKC) and increases intracellular calcium ion concentration, which regulates the actin cytoskeleton. In addition, hydrolysis of PIP2 releases actin regulatory proteins assembled at PIP2 molecules on the membrane and allows them to promote the disassembly of actin filaments. The C-terminus of DLC1 is also known to interact with caveolin-1, although the biological significance of this interaction has not yet been discovered. # Role in embryogenesis The mouse homologue of DLC1 was required during embryogenesis. While mice heterozygous for the dlc1 gene showed no physical abnormalities, mouse embryos which are homozygous negative for dlc-1 were not able to progress past ten and a half days gestation. Further analysis of the embryos revealed that they had defects in several organs, including the brain, heart, and placenta. In addition, cells of the DLC1-/- embryos had few long actin fibers (indicating that their cytoskeletal organization was impaired) and fewer focal adhesions than those of normal DLC1 expressing cells. # Significance in cancer As previously mentioned, the dlc1 gene is found to be deleted or down-regulated in several solid cancers, including human liver, non-small cell lung, nasopharyngeal, breast, prostate, kidney, colon, uterine, ovarian, and stomach cancers. It acts as a tumor suppressor gene to inhibit cell growth and proliferation as well as induce apoptosis when a cell is under stress. DLC1 is also involved in the formation of focal adhesions, so loss of DLC1 leads to reduced cell adhesion and increased metastatic potential of cells. ## Tumor suppressor gene activity DLC1 expression is frequently lost in tumor cells, resulting in constitutive activation of the RhoGTPases RhoA and Cdc42. This results in increased cell growth and proliferation, changes in cell morphology, and inhibition of apoptosis. A tumor suppressor gene is a gene whose protein product acts to prevent cells from proliferating at inappropriate times, or to induce apoptosis of cells which are damaged beyond repair. The loss of heterozygosity of DLC1 results when one copy of the gene is deleted or inactivated, but because of the presence of a second functional copy of the gene, no phenotypic changes are observed. However, if this second copy is then deleted or inactivated, the protein is no longer able to be expressed, and changes in cellular phenotype and tumorigenesis may result. These observations are consistent with the tumor suppression properties of DLC1. The main function of DLC1 is its Rho-GAP activity: its ability to enhance activated GTP-bound Rho-GTPases' (specifically, RhoA and Cdc42) intrinsic ability to convert their GTP into GDP, thus rendering them inactive. RhoGTPases are members of the Ras superfamily, and are involved in actin cytoskeleton organization and cell adhesion. The activity of RhoA regulates the formation of actin stress fibers and focal adhesions - complexes of many proteins located at the termini of actin stress fibers which link the actin cytoskeleton with integrin extracellular matrix receptors. Therefore, when RhoA is inactive, the actin cytoskeletal filaments are unable to form and cell morphology changes, resulting in a default round shape. In addition, focal adhesion formation is inhibited and cells are not well attached to the extracellular matrix and neighbouring cells, thus allowing them to detach and metastasize more readily. The Rho-GTPase Cdc42 is involved in regulation of the cell cycle and preventing inappropriate cell division. Constitutive activation of Cdc42 due to the absence of RhoGAP proteins such as DLC1 will contribute to the continual repetition of the cell cycle, resulting in uncontrolled cell growth and proliferation. The addition of DLC1 to tumor cells lines which are deficient in DLC1 expression reduces the RhoA-GTP levels in the cells, which in turn promotes the disassembly of actin stress fibers and cause cells to adopt a rounded morphology. Overexpression of DLC1 also results in inhibited cell growth, proliferation, tumor formation, migration, and increased apoptosis. ## Involvement in signalling pathways DLC1 is involved in the phosphoinositide and insulin signaling cascades. As mentioned, the C-terminal START domain of DLC1 is involved in phosphoinositide signaling: it is able to interact with phospholipase C-δ1 (PLC- δ1), thereby stimulating it to hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 causes calcium to be released from vesicles into the cytoplasm, which in turn regulates proteins which are sensitive to high calcium concentrations. DAG activates protein kinase C (PKC) and triggers a cascade of intracellular signals. DLC1 may have additional role in insulin signaling, as the presence of insulin results in the phosphorylation of the serine residue at position 329 (within the SR region) on DLC1 by protein kinase B (PKB) aka AKT, although the significance and function of this phosphorylation is as yet unknown. ## Apoptosis DLC1 is responsible for inducing programmed cell death by at least two mechanisms: caspase-3-mediated apoptosis and Bcl-2 activated mitochondrial-mediated apoptosis. The process of apoptosis, or programmed cell death, allows cells which are stressed or damaged to die in a controlled and contained manner. Experiments have shown that DLC1 expression initiates a signaling cascade which cleaves the precursor protein procaspase-3 into caspase-3, thereby allowing it to induce caspase-3-mediated apoptosis. Therefore, in the absence of DLC1, apoptosis of cells which are proliferating and passing through the cell cycle uncontrollably is significantly reduced. These cells are unable to destroy themselves, and therefore continue to proliferate and form tumors. DLC1 also performs a second pro-apoptotic function: it reduces cellular levels of the anti-apoptotic protein Bcl-2. Mitochondrial-mediated apoptosis occurs when the ratio of the pro-apoptotic protein Bax and Bcl-2 is high; therefore, a reduction in Bcl-2 level will lead to an increase in the Bax/Bcl-2 ratio and induce mitochondrial-mediated apoptosis. In tumor cells which are not expressing DLC1, Bcl-2 levels remain high and the ratio of Bax/Bcl-2 low, so apoptosis is inhibited. The detailed pathways by which DLC1 results in the cleavage of procaspase-3 and decrease in Bcl-2 levels require further investigation. ## Genomic instability Current research does not suggest that DLC1 plays a role in destabilizing the genome and making it more susceptible to chromosomal rearrangements or gene mutations. ## Hormonal regulation DLC1 is known to be upregulated by at least two hormones: progesterone and peroxisome proliferators. In ovarian cancers, DLC-1 expression is upregulated by the steroid hormone progesterone. Gene profiling studies have shown that the addition of progesterone to ovarian cancer cell lines results in an increase in the expression of DLC1, which in turn results in growth inhibition, decreased cell motility, and increased caspase-3-mediated apoptosis. Lung cancer cells also increase DLC1 expression in response to peroxisome proliferator-activated receptor γ (PPARγ) activators. PPARγ is a steroid hormone receptor which inhibits cellular growth of several epithelial cancers. ## Role in migration and metastasis In HCC, loss of DLC1 decreases focal adhesion turnover and allows cells to detach from primary tumors. In breast cancers, loss of DLC1 prevents cells from dividing and colonizing a new secondary tumor site. DLC1 is downregulated in hepatocellular carcinoma cell lines, which, through the inactivation of Rho-GTPases, results in anchorage-independent growth in a semi-solid medium (soft agar), indicating that these cells are not held fast to their neighbors and can detach and are able to metastasize relatively easily. Expression of DLC1 in hepatocellular carcinoma cells resulted in dephosphorylation of tyrosine residues on the molecule focal adhesion kinase (FAK), which results in the disassociation of focal adhesion complexes which are required for cell adhesion; therefore, dephosphorylation of FAK ultimately leads to an increase in focal adhesion turnover and cellular adhesion, and inhibition of cell migration. Furthermore, in breast cancer cells, DLC1 functions as a metastasis-suppressor gene by inhibiting colonization of a secondary tumor site. Expression of DLC1 inhibited colonization ability by preventing any cells which were able to detach from the primary breast tumor and migrate to a secondary site from initiating division in the microenvironment of a new organ. ## Angiogenesis As of 2010, current research indicates DLC1 negatively regulates angiogenesis in a paracrine fashion. This is by upregulation of VEGF mediated through the epidermal growth factor receptor (EGFR)-MAP/ERK Kinase (MEK)- hypoxia inducible factor 1 (HIF1) pathway. ## Epigenetic silencing DLC1 expression is downregulated by both promoter hypermethylation and histone acetylation. In hepatocellular carcinomas, the dlc1 gene is not always deleted, and can be detected in the tumor cells using PCR, indicating that gene silencing through epigenetic mechanisms must also play an important role in downregulating DLC1 expression. They also demonstrated that the CpG island in the promoter region of the dlc1 gene is hypermethylated due to the action of DNA methyltransferase enzymes in hepatocellular carcinoma tumors, thus preventing the cells’ RNA polymerase and other transcriptional machinery from binding to the promoter an initiating transcription. This result was also verified in gastric cancer cells, prostate cancer cells, and other cancer cell lines with reduced DLC1 expression. In addition, treatment of DLC1 downregulated tumor cell lines with a histone deacetylase inhibitor prevents histone deacetylase (HDAC) enzymes from removing acetyl groups from specific histones. DNA is wrapped tightly around acetylated histones, thus preventing the transcriptional machinery from accessing the dlc1 gene, which is hidden within tightly packaged chromatin, and transcribing it into mRNA. One hypothesis states that the activity of HDAC in the CpG region of the dlc1 gene promotes its silencing through interaction between the DNA and acetylated histone proteins. Following this, histone methyltransferases add methyl groups to the tail of histones (specifically, histone H3), which allows DNA methyltransferases to methylate the CpG’s of the dlc1 promoter itself, promoting the tight chromatin packaging which prevents transcription. # Drug discovery and future therapies The genomic deletion or downregulation of DLC1 expression in early tumors could serve as an indicator for future cancer progression and spread. Research into therapies for cancers with reduced levels of DLC1 expression due to epigenetic silencing could provide insight into the efficiency of epigenetic regulating molecules. For example, Zebularine, a demethylating agent, could be used to remove the methyl groups from the CpGs of the dlc1 promoter, thus increasing expression of DLC1 and helping to block tumor cell proliferation and metastasis. In addition, histone deacetylase inhibitors could potentially be used to prevent deacetylation of histones and loosen up the chromatin structure, thereby allowing RNA polymerase and other transcriptional proteins to reach the DNA and allow transcription to occur. Natural dietary flavones, found in parsley, celery, and citrus peels, reactivate DLC1 expression in breast cancer cell lines which have decreased DLC1 expression due to promoter hypermethylation, and may potentially be used as an anti-cancer agent for prevention and therapy of breast and other DLC1 downregulated cancers.

DLC1 Deleted in Liver Cancer 1 also known as DLC1 and StAR-related lipid transfer protein 12 (STARD12) is a protein which in humans is encoded by the DLC1 gene.[1][2] This gene is deleted in the primary tumor of hepatocellular carcinoma. It maps to 8p22-p21.3, a region frequently deleted in solid tumors. It is suggested that this gene is a candidate tumor suppressor gene for human liver cancer, as well as for prostate, lung, colorectal, and breast cancers.[3] # Gene The human DLC1 gene is located on the short arm of chromosome 8 (8p21.3-22), within a region that frequently undergoes loss of heterozygosity by either genomic deletion or epigenetic silencing mechanisms in several types of solid cancers.[4] The gene contains 14 exons and produces an mRNA transcript that is 6.3 kb in length; the second AUG present in the open reading frame is the major translational start site, and produces a polypeptide which is 1091 amino acids long.[5] The promoter region of the DLC1 gene contains a CpG island containing several CpG sites which can be methylated to promote gene silencing and prevent transcription.[6] DLC1 is frequently inactivated in human hepatocellular carcinoma, as well as some nasopharyngeal, lung, breast, prostate, kidney, colon, uterine, ovarian, and gastric cancers.[7] # Protein structure and localization The DLC1 protein contains four major functional domains: an N-terminal sterile α motif (SAM), a serine-rich (SR) region, a Rho-GAP domain, and a C-terminal steroidogenic acute regulatory protein related lipid-transfer (START) domain.[5] DLC1 is localized to focal adhesions located at the periphery of cells. ## SAM domain The SAM domain (stretching from amino acids 11-78) is believed to be involved in protein-protein interactions. The exact function of the DLC1 SAM domain has not yet been determined.[5] ## SR region The relatively unstructured and unconserved SR region (amino acids 86-638) contains a focal adhesion targeting (FAT) domain,[7] including a tyrosine residue at position 442, which interacts with SH2 domains of tensin1[8] and cten.[9] These interactions allow DLC1 to co-localize along with these proteins to focal adhesions at the periphery of the cell, where it is able to carry out its function as a Rho-GAP protein. ## Rho-GAP domain The highly conserved Rho-GAP domain (amino acids 639-847) functions to enhance the GTPase activity of the Rho-GTPase proteins RhoA and Cdc42, promoting the hydrolysis of their bound GTP to GDP and thus “shutting off” these proteins. DLC1 contains a conserved “arginine finger” arginine residue at position 677, which is located within the active site of the protein and is essential for catalyzation of the GTP hydrolysis.[5] Rho-GTPases are involved in regulating cell morphology (through cytoskeletal organization) and migration (through focal adhesion formation).[10] ## START domain The START domain (amino acids 878-1081) contains a β-sheet which forms a hydrophobic tunnel held in place by α-helices.[5] This region interacts with phospholipase C-δ1 (PLCδ1) and activates its ability to hydrolyze the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3), which in turn activates protein kinase C (PKC) and increases intracellular calcium ion concentration, which regulates the actin cytoskeleton.[7] In addition, hydrolysis of PIP2 releases actin regulatory proteins assembled at PIP2 molecules on the membrane and allows them to promote the disassembly of actin filaments.[5] The C-terminus of DLC1 is also known to interact with caveolin-1, although the biological significance of this interaction has not yet been discovered.[5] # Role in embryogenesis The mouse homologue of DLC1 was required during embryogenesis. While mice heterozygous for the dlc1 gene showed no physical abnormalities, mouse embryos which are homozygous negative for dlc-1 were not able to progress past ten and a half days gestation.[11] Further analysis of the embryos revealed that they had defects in several organs, including the brain, heart, and placenta. In addition, cells of the DLC1-/- embryos had few long actin fibers (indicating that their cytoskeletal organization was impaired) and fewer focal adhesions than those of normal DLC1 expressing cells.[11] # Significance in cancer As previously mentioned, the dlc1 gene is found to be deleted or down-regulated in several solid cancers, including human liver, non-small cell lung, nasopharyngeal, breast, prostate, kidney, colon, uterine, ovarian, and stomach cancers.[7] It acts as a tumor suppressor gene to inhibit cell growth and proliferation as well as induce apoptosis when a cell is under stress. DLC1 is also involved in the formation of focal adhesions, so loss of DLC1 leads to reduced cell adhesion and increased metastatic potential of cells. ## Tumor suppressor gene activity DLC1 expression is frequently lost in tumor cells, resulting in constitutive activation of the RhoGTPases RhoA and Cdc42. This results in increased cell growth and proliferation, changes in cell morphology, and inhibition of apoptosis. A tumor suppressor gene is a gene whose protein product acts to prevent cells from proliferating at inappropriate times, or to induce apoptosis of cells which are damaged beyond repair. The loss of heterozygosity of DLC1 results when one copy of the gene is deleted or inactivated, but because of the presence of a second functional copy of the gene, no phenotypic changes are observed. However, if this second copy is then deleted or inactivated, the protein is no longer able to be expressed, and changes in cellular phenotype and tumorigenesis may result. These observations are consistent with the tumor suppression properties of DLC1. The main function of DLC1 is its Rho-GAP activity: its ability to enhance activated GTP-bound Rho-GTPases' (specifically, RhoA and Cdc42) intrinsic ability to convert their GTP into GDP, thus rendering them inactive. RhoGTPases are members of the Ras superfamily, and are involved in actin cytoskeleton organization and cell adhesion.[12] The activity of RhoA regulates the formation of actin stress fibers and focal adhesions - complexes of many proteins located at the termini of actin stress fibers which link the actin cytoskeleton with integrin extracellular matrix receptors. Therefore, when RhoA is inactive, the actin cytoskeletal filaments are unable to form and cell morphology changes, resulting in a default round shape.[10] In addition, focal adhesion formation is inhibited and cells are not well attached to the extracellular matrix and neighbouring cells,[5] thus allowing them to detach and metastasize more readily. The Rho-GTPase Cdc42 is involved in regulation of the cell cycle and preventing inappropriate cell division.[13] Constitutive activation of Cdc42 due to the absence of RhoGAP proteins such as DLC1 will contribute to the continual repetition of the cell cycle, resulting in uncontrolled cell growth and proliferation. The addition of DLC1 to tumor cells lines which are deficient in DLC1 expression reduces the RhoA-GTP levels in the cells, which in turn promotes the disassembly of actin stress fibers and cause cells to adopt a rounded morphology.[10] Overexpression of DLC1 also results in inhibited cell growth, proliferation, tumor formation, migration, and increased apoptosis.[12] ## Involvement in signalling pathways DLC1 is involved in the phosphoinositide and insulin signaling cascades. As mentioned, the C-terminal START domain of DLC1 is involved in phosphoinositide signaling:[5] it is able to interact with phospholipase C-δ1 (PLC- δ1), thereby stimulating it to hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 causes calcium to be released from vesicles into the cytoplasm, which in turn regulates proteins which are sensitive to high calcium concentrations. DAG activates protein kinase C (PKC) and triggers a cascade of intracellular signals. DLC1 may have additional role in insulin signaling, as the presence of insulin results in the phosphorylation of the serine residue at position 329 (within the SR region) on DLC1 by protein kinase B (PKB) aka AKT,[14] although the significance and function of this phosphorylation is as yet unknown. ## Apoptosis DLC1 is responsible for inducing programmed cell death by at least two mechanisms: caspase-3-mediated apoptosis and Bcl-2 activated mitochondrial-mediated apoptosis. The process of apoptosis, or programmed cell death, allows cells which are stressed or damaged to die in a controlled and contained manner. Experiments have shown that DLC1 expression initiates a signaling cascade which cleaves the precursor protein procaspase-3 into caspase-3, thereby allowing it to induce caspase-3-mediated apoptosis.[12][15] Therefore, in the absence of DLC1, apoptosis of cells which are proliferating and passing through the cell cycle uncontrollably is significantly reduced.[12] These cells are unable to destroy themselves, and therefore continue to proliferate and form tumors. DLC1 also performs a second pro-apoptotic function: it reduces cellular levels of the anti-apoptotic protein Bcl-2.[12] Mitochondrial-mediated apoptosis occurs when the ratio of the pro-apoptotic protein Bax and Bcl-2 is high; therefore, a reduction in Bcl-2 level will lead to an increase in the Bax/Bcl-2 ratio and induce mitochondrial-mediated apoptosis. In tumor cells which are not expressing DLC1, Bcl-2 levels remain high and the ratio of Bax/Bcl-2 low, so apoptosis is inhibited. The detailed pathways by which DLC1 results in the cleavage of procaspase-3 and decrease in Bcl-2 levels require further investigation. ## Genomic instability Current research does not suggest that DLC1 plays a role in destabilizing the genome and making it more susceptible to chromosomal rearrangements or gene mutations. ## Hormonal regulation DLC1 is known to be upregulated by at least two hormones: progesterone and peroxisome proliferators. In ovarian cancers, DLC-1 expression is upregulated by the steroid hormone progesterone.[15] Gene profiling studies have shown that the addition of progesterone to ovarian cancer cell lines results in an increase in the expression of DLC1, which in turn results in growth inhibition, decreased cell motility, and increased caspase-3-mediated apoptosis.[15] Lung cancer cells also increase DLC1 expression in response to peroxisome proliferator-activated receptor γ (PPARγ) activators.[16] PPARγ is a steroid hormone receptor which inhibits cellular growth of several epithelial cancers. ## Role in migration and metastasis In HCC, loss of DLC1 decreases focal adhesion turnover and allows cells to detach from primary tumors. In breast cancers, loss of DLC1 prevents cells from dividing and colonizing a new secondary tumor site. DLC1 is downregulated in hepatocellular carcinoma cell lines, which, through the inactivation of Rho-GTPases, results in anchorage-independent growth in a semi-solid medium (soft agar), indicating that these cells are not held fast to their neighbors and can detach and are able to metastasize relatively easily.[10] Expression of DLC1 in hepatocellular carcinoma cells resulted in dephosphorylation of tyrosine residues on the molecule focal adhesion kinase (FAK), which results in the disassociation of focal adhesion complexes which are required for cell adhesion; therefore, dephosphorylation of FAK ultimately leads to an increase in focal adhesion turnover and cellular adhesion, and inhibition of cell migration.[10] Furthermore, in breast cancer cells, DLC1 functions as a metastasis-suppressor gene by inhibiting colonization of a secondary tumor site. Expression of DLC1 inhibited colonization ability by preventing any cells which were able to detach from the primary breast tumor and migrate to a secondary site from initiating division in the microenvironment of a new organ.[17] ## Angiogenesis As of 2010, current research indicates DLC1 negatively regulates angiogenesis in a paracrine fashion. This is by upregulation of VEGF mediated through the epidermal growth factor receptor (EGFR)-MAP/ERK Kinase (MEK)- hypoxia inducible factor 1 (HIF1) pathway.[18] ## Epigenetic silencing DLC1 expression is downregulated by both promoter hypermethylation and histone acetylation. In hepatocellular carcinomas, the dlc1 gene is not always deleted, and can be detected in the tumor cells using PCR,[19] indicating that gene silencing through epigenetic mechanisms must also play an important role in downregulating DLC1 expression. They also demonstrated that the CpG island in the promoter region of the dlc1 gene is hypermethylated due to the action of DNA methyltransferase enzymes in hepatocellular carcinoma tumors,[19] thus preventing the cells’ RNA polymerase and other transcriptional machinery from binding to the promoter an initiating transcription. This result was also verified in gastric cancer cells,[6] prostate cancer cells,[4] and other cancer cell lines with reduced DLC1 expression. In addition, treatment of DLC1 downregulated tumor cell lines with a histone deacetylase inhibitor prevents histone deacetylase (HDAC) enzymes from removing acetyl groups from specific histones.[4] DNA is wrapped tightly around acetylated histones, thus preventing the transcriptional machinery from accessing the dlc1 gene, which is hidden within tightly packaged chromatin, and transcribing it into mRNA. One hypothesis states that the activity of HDAC in the CpG region of the dlc1 gene promotes its silencing through interaction between the DNA and acetylated histone proteins. Following this, histone methyltransferases add methyl groups to the tail of histones (specifically, histone H3), which allows DNA methyltransferases to methylate the CpG’s of the dlc1 promoter itself, promoting the tight chromatin packaging which prevents transcription.[20] # Drug discovery and future therapies The genomic deletion or downregulation of DLC1 expression in early tumors could serve as an indicator for future cancer progression and spread.[5] Research into therapies for cancers with reduced levels of DLC1 expression due to epigenetic silencing could provide insight into the efficiency of epigenetic regulating molecules. For example, Zebularine, a demethylating agent, could be used to remove the methyl groups from the CpGs of the dlc1 promoter, thus increasing expression of DLC1 and helping to block tumor cell proliferation and metastasis. In addition, histone deacetylase inhibitors could potentially be used to prevent deacetylation of histones and loosen up the chromatin structure, thereby allowing RNA polymerase and other transcriptional proteins to reach the DNA and allow transcription to occur.[6] Natural dietary flavones, found in parsley, celery, and citrus peels, reactivate DLC1 expression in breast cancer cell lines which have decreased DLC1 expression due to promoter hypermethylation, and may potentially be used as an anti-cancer agent for prevention and therapy of breast and other DLC1 downregulated cancers.[21]

https://www.wikidoc.org/index.php/DLC1

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wikidoc

DLCO

DLCO # Overview DLCO stands for the Diffusing capacity of the Lung for Carbon Monoxide, the test used to determine this parameter. DLCO is the extent to which oxygen passes from the air sacs of the lungs into the blood. It was introduced in 1909. # Mechanism of test The DLCO Test This test involves measuring the partial pressure difference between inspired and expired carbon monoxide. It relies on the strong affinity and large absorption capacity of erythrocytes for carbon monoxide and thus demonstrates gas uptake by the capillaries that is less dependent on cardiac output. # Factors reducing DLCO DLCO can be reduced by the following: - Hindrance in the alveolar wall. e.g. fibrosis, alveolitis, vasculitis - Decrease of total lung area, e.g. emphysema. - Uneven spread of air in lungs, e.g. emphysema. - Cardiac insufficiency - Hemoglobin decrease in blood - Pulmonary hypertension Factors increasing dlco include polycythaemia and increased pulmonary blood volume as occurs in exercise.

DLCO Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview DLCO stands for the Diffusing capacity of the Lung for Carbon Monoxide, the test used to determine this parameter. DLCO is the extent to which oxygen passes from the air sacs of the lungs into the blood. It was introduced in 1909.[1] # Mechanism of test The DLCO Test This test involves measuring the partial pressure difference between inspired and expired carbon monoxide. It relies on the strong affinity and large absorption capacity of erythrocytes for carbon monoxide and thus demonstrates gas uptake by the capillaries that is less dependent on cardiac output[2]. # Factors reducing DLCO DLCO can be reduced by the following: - Hindrance in the alveolar wall. e.g. fibrosis, alveolitis, vasculitis - Decrease of total lung area, e.g. emphysema. - Uneven spread of air in lungs, e.g. emphysema. - Cardiac insufficiency - Hemoglobin decrease in blood - Pulmonary hypertension Factors increasing dlco include polycythaemia and increased pulmonary blood volume as occurs in exercise.

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

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wikidoc

DLG1

DLG1 Discs large homolog 1 (DLG1), also known as synapse-associated protein 97 or SAP97, is a scaffold protein that in humans is encoded by the SAP97 gene. SAP97 is a mammalian MAGUK-family member protein that is similar to the Drosophila protein Dlg1 (the protein is alternatively referred to as hDlg1, and the human gene is DLG1). SAP97 is expressed throughout the body in epithelial cells. In the brain it is involved in the trafficking of ionotropic receptors from the endoplasmic reticulum to the plasma membrane, and may be involved in the trafficking AMPAR during synaptic plasticity. # Function SAP97 is expressed throughout the body in epithelial cells, including the kidney and brain. There is some evidence that SAP97 regulates cell-to-cell adhesion during cell death, and may interact with HPV. In the brain, SAP97's function is involved in the trafficking of transmembrane receptors from the ER to the plasma membrane. SAP97's function has been investigated by reducing its expression by knockout or increasing its expression heterologously. Mice in which the SAP97 gene has been knocked out die perinatally, have a cleft palate, and deficiencies in renal function. Overexpression of SAP97 in mammalian neurons leads to increased synaptic strength. # Clinical significance Mutations in DLG1 are associated to Crohn's Disease . # Structure SAP97's protein structure consists of an alternatively-spliced n-terminal domain, three PDZ domains, an SH3 domain, hook domain, I3 domain, and finally an inactive guanylate kinase (GK) domain. Each of these domains has specific interacting partners that help define SAP97's unique function. The n-terminal of SAP97 can be alternatively spliced to contain a double-cysteine/palmitoylation site (α-isoform), or an L27 domain (β-isoform. The L27 domain is involved in SAP97 oligomerization with other SAP97 molecules, CASK, and other L27-domain-containing proteins. There is also a myosin VI binding site near n-terminal which may be involved in the internalization of AMPAR. Each of SAP97's PDZ domains have different binding partners, including the AMPAR subunit GluR1 for the first PDZ domain, and neuroligin for the last. SAP97's I3 domain is unique to SAP97 among the MAGUK family, and is known to regulate the post-synaptic localization of SAP97 and to bind the protein 4.1N. The GK domain allows SAP97 to bind to GKAP/SAPAP-family proteins.

DLG1 Discs large homolog 1 (DLG1), also known as synapse-associated protein 97 or SAP97, is a scaffold protein that in humans is encoded by the SAP97 gene. SAP97 is a mammalian MAGUK-family member protein that is similar to the Drosophila protein Dlg1 (the protein is alternatively referred to as hDlg1, and the human gene is DLG1). SAP97 is expressed throughout the body in epithelial cells. In the brain it is involved in the trafficking of ionotropic receptors from the endoplasmic reticulum to the plasma membrane, and may be involved in the trafficking AMPAR during synaptic plasticity. # Function SAP97 is expressed throughout the body in epithelial cells, including the kidney and brain.[1] There is some evidence that SAP97 regulates cell-to-cell adhesion during cell death, and may interact with HPV. In the brain, SAP97's function is involved in the trafficking of transmembrane receptors from the ER to the plasma membrane.[2] SAP97's function has been investigated by reducing its expression by knockout or increasing its expression heterologously. Mice in which the SAP97 gene has been knocked out die perinatally, have a cleft palate, and deficiencies in renal function.[3][4] Overexpression of SAP97 in mammalian neurons leads to increased synaptic strength.[5] # Clinical significance Mutations in DLG1 are associated to Crohn's Disease .[6] # Structure SAP97's protein structure consists of an alternatively-spliced n-terminal domain, three PDZ domains, an SH3 domain, hook domain, I3 domain, and finally an inactive guanylate kinase (GK) domain. Each of these domains has specific interacting partners that help define SAP97's unique function. The n-terminal of SAP97 can be alternatively spliced to contain a double-cysteine/palmitoylation site (α-isoform), or an L27 domain (β-isoform. The L27 domain is involved in SAP97 oligomerization with other SAP97 molecules, CASK, and other L27-domain-containing proteins.[7] There is also a myosin VI binding site near n-terminal which may be involved in the internalization of AMPAR.[8][9] Each of SAP97's PDZ domains have different binding partners, including the AMPAR subunit GluR1[10][11] for the first PDZ domain, and neuroligin for the last. SAP97's I3 domain is unique to SAP97 among the MAGUK family, and is known to regulate the post-synaptic localization of SAP97[5] and to bind the protein 4.1N. The GK domain allows SAP97 to bind to GKAP/SAPAP-family proteins.

https://www.wikidoc.org/index.php/DLG1

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wikidoc

DLG2

DLG2 Disks large homolog 2 (DLG2) also known as channel-associated protein of synapse-110 (chapsyn-110) or postsynaptic density protein 93 (PSD-93) is a protein that in humans is encoded by the DLG2 gene. # Function Chapsyn-110/PSD-93 a member of the membrane-associated guanylate kinase (MAGUK) family. The protein forms a heterodimer with a related family member that may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. Alternatively spliced transcript variants encoding distinct isoforms have been described but their full-length nature has yet to be completely determined. # Model organisms Model organisms have been used in the study of DLG2 function. A knockout mouse line, called Dlg2tm1Dsb was generated. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on homozygous mutant mice and five significant abnormalities were observed. Both sexes had atypical indirect calorimetry and DEXA parameters. Females also had decreased body weight, decreased circulating HDL cholesterol levels, and increased susceptibility to bacterial infection. # Interactions DLG2 has been shown to interact with GRIN2B, KCNJ12.

DLG2 Disks large homolog 2 (DLG2) also known as channel-associated protein of synapse-110 (chapsyn-110) or postsynaptic density protein 93 (PSD-93) is a protein that in humans is encoded by the DLG2 gene.[1][2] # Function Chapsyn-110/PSD-93 a member of the membrane-associated guanylate kinase (MAGUK) family. The protein forms a heterodimer with a related family member that may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. Alternatively spliced transcript variants encoding distinct isoforms have been described but their full-length nature has yet to be completely determined.[3] # Model organisms Model organisms have been used in the study of DLG2 function. A knockout mouse line, called Dlg2tm1Dsb was generated.[11][12] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[9][13] Twenty four tests were carried out on homozygous mutant mice and five significant abnormalities were observed.[9] Both sexes had atypical indirect calorimetry and DEXA parameters. Females also had decreased body weight, decreased circulating HDL cholesterol levels, and increased susceptibility to bacterial infection.[9] # Interactions DLG2 has been shown to interact with GRIN2B,[14][15] KCNJ12.[16]

https://www.wikidoc.org/index.php/DLG2

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wikidoc

DLG4

DLG4 PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the DLG4 (discs large homolog 4) gene. PSD-95 is a member of the membrane-associated guanylate kinase (MAGUK) family. With PSD-93 it is recruited into the same NMDA receptor and potassium channel clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. PSD-95 is the best studied member of the MAGUK-family of PDZ domain-containing proteins. Like all MAGUK-family proteins, its basic structure includes three PDZ domains, an SH3 domain, and a guanylate kinase-like domain (GK) connected by disordered linker regions. It is almost exclusively located in the post synaptic density of neurons, and is involved in anchoring synaptic proteins. Its direct and indirect binding partners include neuroligin, NMDA receptors, AMPA receptors, and potassium channels. It plays an important role in synaptic plasticity and the stabilization of synaptic changes during long-term potentiation. # MAGUK superfamily and constituent domains PSD-95 (encoded by DLG4) is a member of the MAGUK superfamily, and part of a subfamily which also includes PSD-93, SAP97 and SAP102. The MAGUKs are defined by their inclusion of PDZ, SH3 and GUK domains, although many of them also contain regions homologous of CaMKII, WW and L27 domains. The GUK domain that they have is structurally very similar to that of the guanylate kinases, however it is known to be catalytically inactive as the P-Loop which binds ATP is absent. It is thought that the MAGUKs have subfunctionalized the GUK domain for their own purposes, primarily based on its ability to form protein-protein interactions with cytoskeleton proteins, microtubule/actin based machinery and molecules involved in signal transduction. The PDZ domain which are contained in the MAGUKs in varying numbers, is replicated three times over in PSD-95. PDZ domains are short peptide binding sequences commonly found at the C-terminus of interacting proteins. The three copies within the gene have different binding partners, due to amino acid substitutions within the PSD-95 protein and its ligands. The SH3 domain is again a protein-protein interaction domain. Its family generally bind to PXXP sites, but in MAGUKs it is known to bind to other sites as well. One of the most well known features is that it can form an intramolecular bond with the GUK domain, creating what is known as a GUK-SH3 'closed' state. The regulatory mechanisms and function are unknown but it is hypothesized that it may involve a hook region and a calmodulin binding region located elsewhere in the gene. # Model organisms Model organisms have been used in the study of DLG4 function. A knockout mouse line, called Dlg4tm1Grnt was generated. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and seven significant abnormalities were observed. Homozygous mutant animals had decreased body weight, atypical indirect calorimetry and DEXA data and a skin phenotype. Males also had abnormal plasma chemistry while females had abnormal haematology (a decreased mean corpuscular haemoglobin count). # Interactions PSD-95 has been shown to interact with: - ADAM22 - Beta-1 adrenergic receptor - CACNG2 - CASK - DLG3 - DLGAP1 - DLGAP2 - DYNLL1 - DYNLL2 - ERBB4 - EXOC4 - FYN - FZD7 - GRIK1 - GRIK2 - GRIK5 - GRIN2A - GRIN2B - GRIN2C - HER2/neu - HGS - KCNA2 - KCNA4 - KCNA5 - KCNJ12 - Kir2.1 - LGI1 - LRP1 - LRP2 - NLGN1 - NOS1 - PTK2B - SEMA4C and - SHANK2.

DLG4 PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the DLG4 (discs large homolog 4) gene.[1][2][3] PSD-95 is a member of the membrane-associated guanylate kinase (MAGUK) family. With PSD-93 it is recruited into the same NMDA receptor and potassium channel clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins.[1] PSD-95 is the best studied member of the MAGUK-family of PDZ domain-containing proteins. Like all MAGUK-family proteins, its basic structure includes three PDZ domains, an SH3 domain, and a guanylate kinase-like domain (GK) connected by disordered linker regions. It is almost exclusively located in the post synaptic density of neurons,[4] and is involved in anchoring synaptic proteins. Its direct and indirect binding partners include neuroligin, NMDA receptors, AMPA receptors, and potassium channels.[5] It plays an important role in synaptic plasticity and the stabilization of synaptic changes during long-term potentiation.[6] # MAGUK superfamily and constituent domains PSD-95 (encoded by DLG4) is a member of the MAGUK superfamily, and part of a subfamily which also includes PSD-93, SAP97 and SAP102. The MAGUKs are defined by their inclusion of PDZ, SH3 and GUK domains, although many of them also contain regions homologous of CaMKII, WW and L27 domains.[7] The GUK domain that they have is structurally very similar to that of the guanylate kinases, however it is known to be catalytically inactive as the P-Loop which binds ATP is absent. It is thought that the MAGUKs have subfunctionalized the GUK domain for their own purposes, primarily based on its ability to form protein-protein interactions with cytoskeleton proteins, microtubule/actin based machinery and molecules involved in signal transduction. The PDZ domain which are contained in the MAGUKs in varying numbers, is replicated three times over in PSD-95. PDZ domains are short peptide binding sequences commonly found at the C-terminus of interacting proteins. The three copies within the gene have different binding partners, due to amino acid substitutions within the PSD-95 protein and its ligands. The SH3 domain is again a protein-protein interaction domain. Its family generally bind to PXXP sites, but in MAGUKs it is known to bind to other sites as well. One of the most well known features is that it can form an intramolecular bond with the GUK domain, creating what is known as a GUK-SH3 'closed' state. The regulatory mechanisms and function are unknown but it is hypothesized that it may involve a hook region and a calmodulin binding region located elsewhere in the gene. # Model organisms Model organisms have been used in the study of DLG4 function. A knockout mouse line, called Dlg4tm1Grnt[15] was generated. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[13][16] Twenty five tests were carried out on mutant mice and seven significant abnormalities were observed.[13] Homozygous mutant animals had decreased body weight, atypical indirect calorimetry and DEXA data and a skin phenotype. Males also had abnormal plasma chemistry while females had abnormal haematology (a decreased mean corpuscular haemoglobin count).[13] # Interactions PSD-95 has been shown to interact with: - ADAM22[17] - Beta-1 adrenergic receptor[18] - CACNG2[19][20] - CASK[21] - DLG3[22] - DLGAP1[23][24][25][26][27][28] - DLGAP2[24] - DYNLL1[23] - DYNLL2[23] - ERBB4[29][30] - EXOC4[31][32] - FYN[33][34] - FZD7[35] - GRIK1[36] - GRIK2[37][38] - GRIK5[37][38] - GRIN2A[26][33][39][40] - GRIN2B[31][39][41][42][43][44] - GRIN2C[41] - HER2/neu[29] - HGS[21] - KCNA2[45] - KCNA4[42][43][45][46] - KCNA5[45][47] - KCNJ12[42][48][48][49][50] - Kir2.1[50] - LGI1[17] - LRP1[51] - LRP2[51][52] - NLGN1[39] - NOS1[53][54] - PTK2B[55] - SEMA4C[56] and - SHANK2.[23][25]

https://www.wikidoc.org/index.php/DLG4

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wikidoc

DLK1

DLK1 Protein delta homolog 1 is a protein that in humans is encoded by the DLK1 gene. It is expressed as a transmembrane protein, but a soluble form cleaved off by ADAM17 is active in inhibiting adipogenesis, the differentiation of pre-adipocytes into adipocytes. It is a member of the EGF-like family of homeotic proteins.

DLK1 Protein delta homolog 1 is a protein that in humans is encoded by the DLK1 gene.[1][2][3] It is expressed as a transmembrane protein, but a soluble form cleaved off by ADAM17 is active in inhibiting adipogenesis,[4] the differentiation of pre-adipocytes into adipocytes.[5] It is a member of the EGF-like family of homeotic proteins.[6]

https://www.wikidoc.org/index.php/DLK1

b289e4da7c7bf20c5f1d6b1c372fab19d507c5ae

wikidoc

DLL3

DLL3 Delta-like 3 (Drosophila), also known as DLL3, is a protein which in humans is encoded by the DLL3 gene. Two transcript variants encoding distinct isoforms have been identified for this gene. # Function This gene encodes a member of the delta protein ligand family. This family functions as Notch ligands that are characterized by a DSL domain, EGF repeats, and a transmembrane domain. Expression of DLL3 is highest in fetal brain. It plays a key role in somitogenesis within the Paraxial mesoderm. # Clinical significance Mutations in this gene cause the autosomal recessive genetic disorder Jarcho-Levin syndrome. Expression of the gene occurs in Neuroendocrine tumors, which has been targeted as a potential pathway for treatment. An experimental drug, rovalpituzumab tesirine, targets DLL3 as a possible treatment for lung cancer.

DLL3 Delta-like 3 (Drosophila), also known as DLL3, is a protein which in humans is encoded by the DLL3 gene.[1] Two transcript variants encoding distinct isoforms have been identified for this gene. # Function This gene encodes a member of the delta protein ligand family. This family functions as Notch ligands that are characterized by a DSL domain, EGF repeats, and a transmembrane domain.[2] Expression of DLL3 is highest in fetal brain. It plays a key role in somitogenesis within the Paraxial mesoderm.[3] # Clinical significance Mutations in this gene cause the autosomal recessive genetic disorder Jarcho-Levin syndrome.[4] Expression of the gene occurs in Neuroendocrine tumors, which has been targeted as a potential pathway for treatment.[5] An experimental drug, rovalpituzumab tesirine, targets DLL3 as a possible treatment for lung cancer.[6]

https://www.wikidoc.org/index.php/DLL3

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wikidoc

DLST

DLST Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial is an enzyme that in humans is encoded by the DLST gene. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

DLST Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial is an enzyme that in humans is encoded by the DLST gene.[1][2] # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. [§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

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

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wikidoc

DLX2

DLX2 Homeobox protein DLX-2 is a protein that in humans is encoded by the DLX2 gene. Many vertebrate homeo box-containing genes have been identified on the basis of their sequence similarity with Drosophila developmental genes. Members of the Dlx gene family contain a homeobox that is related to that of Distal-less (Dll), a gene expressed in the head and limbs of the developing fruit fly. The Distal-less (Dlx) family of genes comprises at least 6 different members, DLX1-DLX6. The DLX proteins are postulated to play a role in forebrain and craniofacial development. This gene is located in a tail-to-tail configuration with another member of the gene family on the long arm of chromosome 2. # Interactions DLX2 has been shown to interact with DLX5, MSX1 and Msh homeobox 2.

DLX2 Homeobox protein DLX-2 is a protein that in humans is encoded by the DLX2 gene.[1][2] Many vertebrate homeo box-containing genes have been identified on the basis of their sequence similarity with Drosophila developmental genes. Members of the Dlx gene family contain a homeobox that is related to that of Distal-less (Dll), a gene expressed in the head and limbs of the developing fruit fly. The Distal-less (Dlx) family of genes comprises at least 6 different members, DLX1-DLX6. The DLX proteins are postulated to play a role in forebrain and craniofacial development. This gene is located in a tail-to-tail configuration with another member of the gene family on the long arm of chromosome 2.[2] # Interactions DLX2 has been shown to interact with DLX5,[3] MSX1[3] and Msh homeobox 2.[3]

https://www.wikidoc.org/index.php/DLX2

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wikidoc

DLX3

DLX3 Homeobox protein DLX-3 is a protein that in humans is encoded by the DLX3 gene. # Function Dlx3 is a crucial regulator of hair follicle differentiation and cycling. Specifically, colocalization of phosphorylated Smad1 / 5 / 8 complex and Dlx3 regulate role for BMP signaling to Dlx3 during hair morphogenesis in animal models. Many vertebrate homeo box-containing genes have been identified on the basis of their sequence similarity with Drosophila developmental genes. Members of the Dlx gene family contain a homeobox that is related to that of Distal-less (Dll), a gene expressed in the head and limbs of the developing fruit fly. The Distal-less (Dlx) family of genes comprises at least 6 different members, DLX1-DLX6. This gene is located in a tail-to-tail configuration with another member of the gene family on the long arm of chromosome 17. # Clinical significance Mutations in this gene have been associated with the autosomal dominant conditions trichodentoosseous syndrome (TDO) and amelogenesis imperfecta with taurodontism.

DLX3 Homeobox protein DLX-3 is a protein that in humans is encoded by the DLX3 gene.[1][2] # Function Dlx3 is a crucial regulator of hair follicle differentiation and cycling. Specifically, colocalization of phosphorylated Smad1 / 5 / 8 complex and Dlx3 regulate role for BMP signaling to Dlx3 during hair morphogenesis in animal models.[3][4] Many vertebrate homeo box-containing genes have been identified on the basis of their sequence similarity with Drosophila developmental genes. Members of the Dlx gene family contain a homeobox that is related to that of Distal-less (Dll), a gene expressed in the head and limbs of the developing fruit fly. The Distal-less (Dlx) family of genes comprises at least 6 different members, DLX1-DLX6. This gene is located in a tail-to-tail configuration with another member of the gene family on the long arm of chromosome 17.[2] # Clinical significance Mutations in this gene have been associated with the autosomal dominant conditions trichodentoosseous syndrome (TDO) and amelogenesis imperfecta with taurodontism.[2]

https://www.wikidoc.org/index.php/DLX3

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wikidoc

DLX5

DLX5 Homeobox protein DLX-5 is a protein that in humans is encoded by the distal-less homeobox 5 gene, or DLX5 gene. DLX5 is a member of DLX gene family. # Function This gene encodes a member of a homeobox transcription factor gene family similar to the Drosophila distal-less (Dll) gene. The encoded protein may play a role in bone development and fracture healing. Current research holds that the homeobox gene family is important in appendage development. DLX5 and DLX6 can be seen to work in conjunction and are both necessary for proper craniofacial, axial, and appendicular skeleton development. Mutation in this gene, which is located in a tail-to-tail configuration with another member of the family on the long arm of chromosome 7, may be associated with split-hand/split-foot malformation. DLX5 also acts as the early BMP-responsive transcriptional activator needed for osteoblast differentiation by stimulating the up-regulation of a variety of promoters (ALPL promoter, SP7 promoter, MYC promoter). # Clinical significance Mutations in the DLX5 gene have been shown to be involved in the hand and foot malformation syndrome. SHFM is a heterogenous limb defect in which the development of the central digital rays is hindered, leading to missing central digits and claw-like distal extremities. Other defects associated with DLX5 include sensorineural hearing loss, mental retardation, ectodermal and craniofacial findings, and orofacial clefting. In mice, the targeted disruption of DLX1, DLX2, DLX1/2, or DLX5 orthologs yields craniofacial, bone, and vestibular defects. If DLX5 is disrupted in conjunction with DLX6, bone, inner ear, and severe craniofacial defects are prevalent. Research utilizing Dlx5/6-nulls suggests that these genes have both unique and redundant functions. # Developmental Stage DLX5 begins to express DLX5 protein in the facial and branchial arch mesenchyme, otic vesicles, and frontonasal ectoderm at around day 8.5-9. By day 12.5, DLX5 protein begins to be expressed in the brain, bones, and all remaining skeletal structures. Expression in the brain and skeleton begins to decrease by day 17. # Interactions DLX5 has been shown to interact with DLX1, DLX2, DLX6, MSX1 and MSX2.

DLX5 Homeobox protein DLX-5 is a protein that in humans is encoded by the distal-less homeobox 5 gene, or DLX5 gene.[1][2] DLX5 is a member of DLX gene family. # Function This gene encodes a member of a homeobox transcription factor gene family similar to the Drosophila distal-less (Dll) gene. The encoded protein may play a role in bone development and fracture healing. Current research holds that the homeobox gene family is important in appendage development. DLX5 and DLX6 can be seen to work in conjunction and are both necessary for proper craniofacial, axial, and appendicular skeleton development. Mutation in this gene, which is located in a tail-to-tail configuration with another member of the family on the long arm of chromosome 7, may be associated with split-hand/split-foot malformation.[2] DLX5 also acts as the early BMP-responsive transcriptional activator needed for osteoblast differentiation by stimulating the up-regulation of a variety of promoters (ALPL promoter, SP7 promoter, MYC promoter).[3] # Clinical significance Mutations in the DLX5 gene have been shown to be involved in the hand and foot malformation syndrome.[4] SHFM is a heterogenous limb defect in which the development of the central digital rays is hindered, leading to missing central digits and claw-like distal extremities. Other defects associated with DLX5 include sensorineural hearing loss, mental retardation, ectodermal and craniofacial findings, and orofacial clefting. In mice, the targeted disruption of DLX1, DLX2, DLX1/2, or DLX5 orthologs yields craniofacial, bone, and vestibular defects. If DLX5 is disrupted in conjunction with DLX6, bone, inner ear, and severe craniofacial defects are prevalent. Research utilizing Dlx5/6-nulls suggests that these genes have both unique and redundant functions.[5] # Developmental Stage DLX5 begins to express DLX5 protein in the facial and branchial arch mesenchyme, otic vesicles, and frontonasal ectoderm at around day 8.5-9. By day 12.5, DLX5 protein begins to be expressed in the brain, bones, and all remaining skeletal structures. Expression in the brain and skeleton begins to decrease by day 17.[3] # Interactions DLX5 has been shown to interact with DLX1,[5] DLX2,[6] DLX6,[5] MSX1[6] and MSX2.[6]

https://www.wikidoc.org/index.php/DLX5

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wikidoc

DMT1

DMT1 The divalent metal transporter 1 (DMT1), also known as natural resistance-associated macrophage protein 2 (NRAMP 2), and divalent cation transporter 1 (DCT1), is a protein that in humans is encoded by the SLC11A2 (solute carrier family 11, member 2) gene. DMT1 represents a large family of orthologous metal ion transporter proteins that are highly conserved from bacteria to humans. As its name suggests, DMT1 binds a variety of divalent metals including cadmium (Cd2+), copper (Cu2+), and zinc (Zn2+,); however, it is best known for its role in transporting ferrous iron (Fe2+). DMT1 expression is regulated by body iron stores to maintain iron homeostasis. DMT1 is also important in the absorption and transport of manganese (Mn2+). In the digestive tract, it is located on the apical membrane of enterocytes, where it carries out H+ coupled transport of divalent metal cations from the intestinal lumen into the cell. # Function Iron is not only essential for the human body, it is required for all organisms in order for them to be able to grow. Iron also participates in many metabolic pathways. Iron deficiency can lead to iron-deficiency anemia thus iron regulation is very crucial in the human body. ## In mammals The process of iron transportation consists of iron being reduced by ferrireductases that are present on the cell surface or by dietary reductants such as ascorbate (Vitamin C). Once the Fe3+ has been reduced to Fe2+, the DMT1 transporter protein transports the Fe2+ ions into the cells that line the small intestine (enterocytes). From there, the ferroprotin/IREG1 transporter exports it across the cell membrane where is it oxidized to Fe3+ on the surface of the cell then bound by transferrin and released into the blood stream. ## Ion selectivity DMT1 is not a 100% selective transporter as it also transports Zn2+, Mn2+, and Cd2+ which can lead to toxicity problems. The reason for this is because it cannot distinguish the difference between the different metal ions due to low selectivity for iron ions. In addition, it causes the metal ions to compete for transportation and the concentration of iron ions is typically substantially lower than that of other ions. ## Yeast vs. mammal pathway The iron uptake pathway in Saccharaomyces cerevisiae, which consists of a multicopper ferroxidase (Fet3) and an iron plasma permease (FTR1) has a high affinity for iron uptake compared to the DMT1 iron uptake process present in mammals. The iron uptake process in yeasts consists of Fe3+ which is reduced to Fe2+ by ferriductases. Ferrous iron may also be present outside of the cell due to other reductants present in the extracellular medium. Ferrous iron is then oxidized to ferric iron by Fet3 on the external surface of the cell. Then Fe3+ is transferred from Fet3 to FTR1 and transferred across the cell membrane into the cell. Ferrous-oxidase mediated transport systems exist in order to transport specific ions opposed to DMT1, which does not have complete specificity. The Fet3/FTR1 iron uptake pathway is able to achieve complete specificity for iron over other ions due to the multi-step nature of the pathway. Each of the steps involved in the pathway is specific to either ferrous iron or ferric iron. The DMT1 transporter protein does not have specificity over the ions it transports because it is unable to distinguish between Fe2+ and the other divalent metal ions it transfer through the cell membrane. Although, the reason that non-specific ion transporters, such as DMT1, exist is due to their ability to function in anaerobic environments opposed to the Fet3/FTR1 pathway which requires oxygen as a co substrate. So in anaerobic environments the oxidase would not be able to function thus another means of iron uptake is necessary. # Role in neurodegenerative diseases Toxic accumulation of divalent metals, especially iron and/or manganese, are frequently discussed aetiological factors in a variety of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. DMT1 may be the major transporter of manganese across the blood brain barrier and expression of this protein in the nasal epithelium provides a route for direct absorption of metals into the brain. DMT1 expression in the brain may increase with age, increasing susceptibility to metal induced pathologies. DMT1 expression is found to be increased in the substantia nigra of Parkinson's patients and in the ventral mesencephalon of animal models intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) - a neurotoxin widely used experimentally to produce Parkinsonian symptoms. The DMT1 encoding gene SLC11A2 is located on the long arm of chromosome 12 (12q13) close to susceptibility regions for Alzheimer's disease and restless legs syndrome. The C allele of SNP rs407135 on the DMT1 encoding gene SLC11A2 is associated with shorter disease duration in cases of spinal onset amyotrophic lateral sclerosis, and is implicated in Alzheimer's disease onset in males as well. The CC haplotype for SNPs 1254T/C IVS34+44C/A is associated with Parkinson's disease susceptibility. Finally, variant alleles on several SLC11A2 SNPs are associated with iron anemia, a risk factor for manganese intoxication and restless legs syndrome.

DMT1 The divalent metal transporter 1 (DMT1), also known as natural resistance-associated macrophage protein 2 (NRAMP 2), and divalent cation transporter 1 (DCT1),[1] is a protein that in humans is encoded by the SLC11A2 (solute carrier family 11, member 2) gene.[2] DMT1 represents a large family of orthologous metal ion transporter proteins that are highly conserved from bacteria to humans.[3] As its name suggests, DMT1 binds a variety of divalent metals including cadmium (Cd2+), copper (Cu2+), and zinc (Zn2+,); however, it is best known for its role in transporting ferrous iron (Fe2+). DMT1 expression is regulated by body iron stores to maintain iron homeostasis. DMT1 is also important in the absorption and transport of manganese (Mn2+).[4] In the digestive tract, it is located on the apical membrane of enterocytes, where it carries out H+ coupled transport of divalent metal cations from the intestinal lumen into the cell. # Function Iron is not only essential for the human body, it is required for all organisms in order for them to be able to grow.[5] Iron also participates in many metabolic pathways. Iron deficiency can lead to iron-deficiency anemia thus iron regulation is very crucial in the human body. ## In mammals The process of iron transportation consists of iron being reduced by ferrireductases that are present on the cell surface or by dietary reductants such as ascorbate (Vitamin C).[6] Once the Fe3+ has been reduced to Fe2+, the DMT1 transporter protein transports the Fe2+ ions into the cells that line the small intestine (enterocytes).[6] From there, the ferroprotin/IREG1 transporter exports it across the cell membrane where is it oxidized to Fe3+ on the surface of the cell then bound by transferrin and released into the blood stream.[6] ## Ion selectivity DMT1 is not a 100% selective transporter as it also transports Zn2+, Mn2+, and Cd2+ which can lead to toxicity problems.[6] The reason for this is because it cannot distinguish the difference between the different metal ions due to low selectivity for iron ions. In addition, it causes the metal ions to compete for transportation and the concentration of iron ions is typically substantially lower than that of other ions.[6] ## Yeast vs. mammal pathway The iron uptake pathway in Saccharaomyces cerevisiae, which consists of a multicopper ferroxidase (Fet3) and an iron plasma permease (FTR1) has a high affinity for iron uptake compared to the DMT1 iron uptake process present in mammals.[7] The iron uptake process in yeasts consists of Fe3+ which is reduced to Fe2+ by ferriductases.[6] Ferrous iron may also be present outside of the cell due to other reductants present in the extracellular medium.[6] Ferrous iron is then oxidized to ferric iron by Fet3 on the external surface of the cell.[6] Then Fe3+ is transferred from Fet3 to FTR1 and transferred across the cell membrane into the cell.[6] Ferrous-oxidase mediated transport systems exist in order to transport specific ions opposed to DMT1, which does not have complete specificity.[6] The Fet3/FTR1 iron uptake pathway is able to achieve complete specificity for iron over other ions due to the multi-step nature of the pathway.[6] Each of the steps involved in the pathway is specific to either ferrous iron or ferric iron.[6] The DMT1 transporter protein does not have specificity over the ions it transports because it is unable to distinguish between Fe2+ and the other divalent metal ions it transfer through the cell membrane.[6] Although, the reason that non-specific ion transporters, such as DMT1, exist is due to their ability to function in anaerobic environments opposed to the Fet3/FTR1 pathway which requires oxygen as a co substrate.[6] So in anaerobic environments the oxidase would not be able to function thus another means of iron uptake is necessary.[6] # Role in neurodegenerative diseases Toxic accumulation of divalent metals, especially iron and/or manganese, are frequently discussed aetiological factors in a variety of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. DMT1 may be the major transporter of manganese across the blood brain barrier and expression of this protein in the nasal epithelium provides a route for direct absorption of metals into the brain.[8] DMT1 expression in the brain may increase with age,[9] increasing susceptibility to metal induced pathologies. DMT1 expression is found to be increased in the substantia nigra of Parkinson's patients and in the ventral mesencephalon of animal models intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) - a neurotoxin widely used experimentally to produce Parkinsonian symptoms. The DMT1 encoding gene SLC11A2 is located on the long arm of chromosome 12 (12q13) close to susceptibility regions for Alzheimer's disease[10] and restless legs syndrome. The C allele of SNP rs407135 on the DMT1 encoding gene SLC11A2 is associated with shorter disease duration in cases of spinal onset amyotrophic lateral sclerosis,[11] and is implicated in Alzheimer's disease onset in males as well.[10] The CC haplotype for SNPs 1254T/C IVS34+44C/A is associated with Parkinson's disease susceptibility.[12] Finally, variant alleles on several SLC11A2 SNPs are associated with iron anemia, a risk factor for manganese intoxication and restless legs syndrome.[13]

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

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wikidoc

DNM2

DNM2 Dynamin-2 is a protein that in humans is encoded by the DNM2 gene. # Function Dynamins represent one of the subfamilies of GTP-binding proteins. These proteins share considerable sequence similarity over the N-terminal portion of the molecule, which contains the GTPase domain. Dynamins are associated with microtubules. They have been implicated in cell processes such as endocytosis and cell motility, and in alterations of the membrane that accompany certain activities such as bone resorption by osteoclasts. Dynamins bind many proteins that bind actin and other cytoskeletal proteins. Dynamins can also self-assemble, a process that stimulates GTPase activity. Four alternatively spliced transcripts encoding different proteins have been described. Additional alternatively spliced transcripts may exist, but their full-length nature has not been determined. # Interactions DNM2 has been shown to interact with: - SHANK1, - SHANK2, and - SNX9. # Clinical relevance Mutations in this gene have been associated to cases of acute lymphoblastic leukaemia, -r congenital myopathy (centronuclear type).

DNM2 Dynamin-2 is a protein that in humans is encoded by the DNM2 gene.[1][2] # Function Dynamins represent one of the subfamilies of GTP-binding proteins. These proteins share considerable sequence similarity over the N-terminal portion of the molecule, which contains the GTPase domain. Dynamins are associated with microtubules. They have been implicated in cell processes such as endocytosis and cell motility, and in alterations of the membrane that accompany certain activities such as bone resorption by osteoclasts. Dynamins bind many proteins that bind actin and other cytoskeletal proteins. Dynamins can also self-assemble, a process that stimulates GTPase activity. Four alternatively spliced transcripts encoding different proteins have been described. Additional alternatively spliced transcripts may exist, but their full-length nature has not been determined.[3] # Interactions DNM2 has been shown to interact with: - SHANK1,[4] - SHANK2,[4] and - SNX9.[5] # Clinical relevance Mutations in this gene have been associated to cases of acute lymphoblastic leukaemia,[6] or congenital myopathy (centronuclear type).[7]

https://www.wikidoc.org/index.php/DNM2

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wikidoc

DOK2

DOK2 Docking protein 2 is a protein that in humans is encoded by the DOK2 gene. # Function The protein encoded by this gene is constitutively tyrosine phosphorylated in hematopoietic progenitors isolated from chronic myelogenous leukemia (CML) patients in the chronic phase. It may be a critical substrate for p210(bcr/abl), a chimeric protein whose presence is associated with CML. This encoded protein binds p120 (RasGAP) from CML cells. # Interactions DOK2 has been shown to interact with INPP5D and TEK tyrosine kinase.

DOK2 Docking protein 2 is a protein that in humans is encoded by the DOK2 gene.[1][2][3] # Function The protein encoded by this gene is constitutively tyrosine phosphorylated in hematopoietic progenitors isolated from chronic myelogenous leukemia (CML) patients in the chronic phase. It may be a critical substrate for p210(bcr/abl), a chimeric protein whose presence is associated with CML. This encoded protein binds p120 (RasGAP) from CML cells.[3] # Interactions DOK2 has been shown to interact with INPP5D[4] and TEK tyrosine kinase.[5][6]

https://www.wikidoc.org/index.php/DOK2

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wikidoc

DPM1

DPM1 Dolichol-phosphate mannosyltransferase is an enzyme that in humans is encoded by the DPM1 gene. # Function Dolichol-phosphate mannose (Dol-P-Man) serves as a donor of mannosyl residues on the lumenal side of the endoplasmic reticulum (ER). Lack of Dol-P-Man results in defective surface expression of GPI-anchored proteins. Dol-P-Man is synthesized from GDP-mannose and dolichol-phosphate on the cytosolic side of the ER by the enzyme dolichyl-phosphate mannosyltransferase. Human DPM1 lacks a carboxy-terminal transmembrane domain and signal sequence and is regulated by DPM2. # Model organisms Model organisms have been used in the study of DPM1 function. A conditional knockout mouse line called Dpm1tm1b(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping

DPM1 Dolichol-phosphate mannosyltransferase is an enzyme that in humans is encoded by the DPM1 gene.[1][2][3] # Function Dolichol-phosphate mannose (Dol-P-Man) serves as a donor of mannosyl residues on the lumenal side of the endoplasmic reticulum (ER). Lack of Dol-P-Man results in defective surface expression of GPI-anchored proteins. Dol-P-Man is synthesized from GDP-mannose and dolichol-phosphate on the cytosolic side of the ER by the enzyme dolichyl-phosphate mannosyltransferase. Human DPM1 lacks a carboxy-terminal transmembrane domain and signal sequence and is regulated by DPM2.[3] # Model organisms Model organisms have been used in the study of DPM1 function. A conditional knockout mouse line called Dpm1tm1b(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[4] Male and female animals underwent a standardized phenotypic screen[5] to determine the effects of deletion.[6][7][8][9] Additional screens performed: - In-depth immunological phenotyping[10]

https://www.wikidoc.org/index.php/DPM1

cfb1abff2f929e726b0665312a21f7d3bb1cf9d3

wikidoc

DPM2

DPM2 Dolichol phosphate-mannose biosynthesis regulatory protein is a protein that in humans is encoded by the DPM2 gene. # Function Dolichol-phosphate mannose (Dol-P-Man) serves as a donor of mannosyl residues on the lumenal side of the endoplasmic reticulum (ER). Lack of Dol-P-Man results in defective surface expression of GPI-anchored proteins, defective N-linked glycosylation and deficient O-mannosylation of α-dystroglycan. Dol-P-Man is synthesized from GDP-mannose and dolichol-phosphate on the cytosolic side of the ER by the enzyme dolichyl-phosphate mannosyltransferase. The protein encoded by this gene is a hydrophobic protein that contains 2 predicted transmembrane domains and a putative ER localization signal near the C-terminus. This protein associates with DPM1 in vivo and is required for the ER localization and stable expression of DPM1 and also enhances the binding of dolichol-phosphate to DPM1. # Clinical significance Mutations in this gene are associated with congenital disorder of glycosylation.

DPM2 Dolichol phosphate-mannose biosynthesis regulatory protein is a protein that in humans is encoded by the DPM2 gene.[1] # Function Dolichol-phosphate mannose (Dol-P-Man) serves as a donor of mannosyl residues on the lumenal side of the endoplasmic reticulum (ER). Lack of Dol-P-Man results in defective surface expression of GPI-anchored proteins, defective N-linked glycosylation and deficient O-mannosylation of α-dystroglycan. Dol-P-Man is synthesized from GDP-mannose and dolichol-phosphate on the cytosolic side of the ER by the enzyme dolichyl-phosphate mannosyltransferase. The protein encoded by this gene is a hydrophobic protein that contains 2 predicted transmembrane domains and a putative ER localization signal near the C-terminus. This protein associates with DPM1 in vivo and is required for the ER localization and stable expression of DPM1 and also enhances the binding of dolichol-phosphate to DPM1.[1] # Clinical significance Mutations in this gene are associated with congenital disorder of glycosylation.

https://www.wikidoc.org/index.php/DPM2

81d1da3e2be392d31ec7f1ce1a9b930c6aae323e

wikidoc

DPM3

DPM3 dolichyl-phosphate mannosyltransferase polypeptide 3, also known as DPM3, is a human gene. # Function Dolichol-phosphate mannose (Dol-P-Man) serves as a donor of mannosyl residues on the lumenal side of the endoplasmic reticulum (ER). Lack of Dol-P-Man results in defective surface expression of GPI-anchored proteins. Dol-P-Man is synthesized from GDP-mannose and dolichol-phosphate on the cytosolic side of the ER by the enzyme dolichyl-phosphate mannosyltransferase. The protein encoded by this gene is a subunit of dolichyl-phosphate mannosyltransferase and acts as a stabilizer subunit of the dolichyl-phosphate mannosyltransferase complex. # Clinical significance Mutations in this gene are associated with congenital disorder of glycosylation type 1O.

DPM3 dolichyl-phosphate mannosyltransferase polypeptide 3, also known as DPM3, is a human gene.[1][2] # Function Dolichol-phosphate mannose (Dol-P-Man) serves as a donor of mannosyl residues on the lumenal side of the endoplasmic reticulum (ER). Lack of Dol-P-Man results in defective surface expression of GPI-anchored proteins. Dol-P-Man is synthesized from GDP-mannose and dolichol-phosphate on the cytosolic side of the ER by the enzyme dolichyl-phosphate mannosyltransferase. The protein encoded by this gene is a subunit of dolichyl-phosphate mannosyltransferase and acts as a stabilizer subunit of the dolichyl-phosphate mannosyltransferase complex.[1] # Clinical significance Mutations in this gene are associated with congenital disorder of glycosylation type 1O.[3]

https://www.wikidoc.org/index.php/DPM3

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wikidoc

DPYD

DPYD Dihydropyrimidine dehydrogenase is an enzyme that in humans is encoded by the DPYD gene. # Function The protein encoded by this gene is a pyrimidine catabolic enzyme and the initial and rate-limiting factor in the pathway of uracil and thymidine catabolism. Genetic deficiency of this enzyme results in an error in pyrimidine metabolism associated with thymine-uraciluria and an increased risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

DPYD Dihydropyrimidine dehydrogenase [NADP+] is an enzyme that in humans is encoded by the DPYD gene.[1][2] # Function The protein encoded by this gene is a pyrimidine catabolic enzyme and the initial and rate-limiting factor in the pathway of uracil and thymidine catabolism. Genetic deficiency of this enzyme results in an error in pyrimidine metabolism associated with thymine-uraciluria and an increased risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy.[2] # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles.[§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

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

2ab856b7a0d240f4005819dba2a25860bc6f1da8

wikidoc

DPYS

DPYS Dihydropyrimidinase is an enzyme that in humans is encoded by the DPYS gene. Dihydropyrimidinase catalyzes the conversion of 5,6-dihydrouracil to 3-ureidopropionate in pyrimidine metabolism. Dihydropyrimidinase is expressed at a high level in liver and kidney as a major 2.5-kb transcript and a minor 3.8-kb transcript. Defects in the DPYS gene are linked to dihydropyrimidinuria. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

DPYS Dihydropyrimidinase is an enzyme that in humans is encoded by the DPYS gene.[1][2] Dihydropyrimidinase catalyzes the conversion of 5,6-dihydrouracil to 3-ureidopropionate in pyrimidine metabolism. Dihydropyrimidinase is expressed at a high level in liver and kidney as a major 2.5-kb transcript and a minor 3.8-kb transcript. Defects in the DPYS gene are linked to dihydropyrimidinuria.[2] # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles.[§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

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

d25aa806fb7106deebfb905ae158034bbaed90e4

wikidoc

DSC2

DSC2 Desmocollin-2 is a protein that in humans is encoded by the DSC2 gene. Desmocollin-2 is a cadherin-type protein that functions to link adjacent cells together in specialized regions known as desmosomes. Desmocollin-2 is widely expressed, and is the only desmocollin isoform expressed in cardiac muscle, where it localizes to intercalated discs. Mutations in DSC2 have been causally linked to arrhythmogenic right ventricular cardiomyopathy. # Structure Desmocollin-2 is a calcium-dependent glycoprotein that is a member of the desmocollin subfamily of the cadherin superfamily. The desmocollin family members are arranged as closely linked genes on human chromosome 18q12.1. Human DSC2 consists of greater than 32 kb of DNA and has 17 exons, with exon 16 being alternatively spliced and encoding distinct isoforms. Desmocollin-2 contains five N-terminal extracellular domains, a transmembrane-spanning domain, and a C-terminal cytoplasmic tail. Desmocollin-2 binds to desmoglein family members through a calcium-dependent interaction with its extracellular domains, and to plakoglobin through its cytoplasmic tail. Desmocollin-2 is ubiquitously expressed in desmosomal tissues, such as skin epithelia, and is the only desmocollin isoform expressed in human cardiac muscle, where it localizes to desmosomes within intercalated discs. # Function Desmosomal cadherins, including the desmocollin family members and desmogleins, are found at desmosome cell-cell junctions and are required for cell adhesion and desmosome formation via interactions with their extracellular cadherin regions. Desmosomes function to anchor intermediate filaments at sites of strong adhesion, which undergo high mechanical stress, such as in cardiac muscle. Desmocollins are integral components to desmosomes and studies have shown that in addition to tensile strength, desmocollins also function as molecular sensors and facilitators of signal transduction. Studies in zebrafish expressing a mutant desmocollin-2 have shed light on its function in the myocardium as a pivotal component for normal myocardial structure and function. Knockdown of desmcollin-2 caused malformations in desmosomal plaques and bradycardia, dilation of the ventricular chamber and reduced fractional shortening. # Clinical Significance Mutations in DSC2 are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), including mutations with a recessive inheritance. Mutations in DSC2 as well as other desmosomal genes are frequent in patients with advanced dilated cardiomyopathy that are undergoing cardiac transplantation. Hallmark features of ARVC include enlargement of the right ventricle, replacement of right ventricular cardiomyocytes with fibrofatty deposits, electrocardiographic abnormalities, and arrhythmias. Biopsies from patients with ARVC consistently show abnormalities in intercalated discs, with decreased numbers of desmosomes and widening of intercellular gaps between adjacent cardiomyocytes, suggesting that this disease is a disease of intercalated discs. Studies investigating two heterozygous DSC2 mutations have shown that certain mutations in the N-terminal region can modify the subcellular localization of desmocollin-2 from the desmosomal plaque to the cytoplasm. # Interactions Desmocollin-2 has been shown to interact with: - DSG2 - JUP

DSC2 Desmocollin-2 is a protein that in humans is encoded by the DSC2 gene.[1][2] Desmocollin-2 is a cadherin-type protein that functions to link adjacent cells together in specialized regions known as desmosomes. Desmocollin-2 is widely expressed, and is the only desmocollin isoform expressed in cardiac muscle, where it localizes to intercalated discs. Mutations in DSC2 have been causally linked to arrhythmogenic right ventricular cardiomyopathy. # Structure Desmocollin-2 is a calcium-dependent glycoprotein that is a member of the desmocollin subfamily of the cadherin superfamily. The desmocollin family members are arranged as closely linked genes on human chromosome 18q12.1. Human DSC2 consists of greater than 32 kb of DNA and has 17 exons, with exon 16 being alternatively spliced and encoding distinct isoforms.[3] Desmocollin-2 contains five N-terminal extracellular domains, a transmembrane-spanning domain, and a C-terminal cytoplasmic tail.[3] Desmocollin-2 binds to desmoglein family members through a calcium-dependent interaction with its extracellular domains,[4] and to plakoglobin through its cytoplasmic tail.[5] Desmocollin-2 is ubiquitously expressed in desmosomal tissues, such as skin epithelia, and is the only desmocollin isoform expressed in human cardiac muscle, where it localizes to desmosomes within intercalated discs.[6] # Function Desmosomal cadherins, including the desmocollin family members and desmogleins, are found at desmosome cell-cell junctions and are required for cell adhesion and desmosome formation via interactions with their extracellular cadherin regions.[7] Desmosomes function to anchor intermediate filaments at sites of strong adhesion, which undergo high mechanical stress, such as in cardiac muscle.[8] Desmocollins are integral components to desmosomes and studies have shown that in addition to tensile strength, desmocollins also function as molecular sensors and facilitators of signal transduction.[9] Studies in zebrafish expressing a mutant desmocollin-2 have shed light on its function in the myocardium as a pivotal component for normal myocardial structure and function. Knockdown of desmcollin-2 caused malformations in desmosomal plaques and bradycardia, dilation of the ventricular chamber and reduced fractional shortening.[10] # Clinical Significance Mutations in DSC2 are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC),[10][11][12][13][14][15][16][17][18] including mutations with a recessive inheritance.[18][19][20] Mutations in DSC2 as well as other desmosomal genes are frequent in patients with advanced dilated cardiomyopathy that are undergoing cardiac transplantation.[21] Hallmark features of ARVC include enlargement of the right ventricle, replacement of right ventricular cardiomyocytes with fibrofatty deposits, electrocardiographic abnormalities, and arrhythmias.[22][23][24][25] Biopsies from patients with ARVC consistently show abnormalities in intercalated discs, with decreased numbers of desmosomes and widening of intercellular gaps between adjacent cardiomyocytes, suggesting that this disease is a disease of intercalated discs.[26][27] Studies investigating two heterozygous DSC2 mutations have shown that certain mutations in the N-terminal region can modify the subcellular localization of desmocollin-2 from the desmosomal plaque to the cytoplasm.[28] # Interactions Desmocollin-2 has been shown to interact with: - DSG2 [4] - JUP [5]

https://www.wikidoc.org/index.php/DSC2

057d8c7b9d8002627bf6a2d211f6701cc3219c6b

wikidoc

DSC3

DSC3 Desmocollin-3 is a protein that in humans is encoded by the DSC3 gene. # Gene The desmosomal family members are arranged in two clusters on chromosome 18, occupying less than 650 kb combined. Alternative splicing results in two transcript variants encoding distinct isoforms. # Function Desmocollin-3 is a calcium-dependent glycoprotein that is a member of the desmocollin subfamily of the cadherin superfamily. These desmosomal family members, along with the desmogleins, are found primarily in epithelial cells where they constitute the adhesive proteins of the desmosome cell-cell junction and are required for cell adhesion and desmosome formation. The loss of these components leads to a lack of adhesion and a gain of cellular mobility. # Clinical significance ## Breast cancer Through the process of epigenetic silencing, the expression of the desmocollin 3 protein is down regulated in many breast cancers. ## Hereditary hypotrichosis A consanguineous Afghan family in which 3 sisters, 12 to 18 years of age, and their 5-year-old brother displayed features of hereditary hypotrichosis, associated with vesicles on the scalp and skin. At birth, scalp hair was present, and after ritual shaving at 1 week of age, scalp hair grew back; however, the hair was fragile and began falling out at 2 to 3 months of age, eventually leaving only sparse hair on the scalp. Vesicles that were less than 1 cm in diameter were observed on the scalp and skin of most of the body, occasionally disappearing but then reappearing; intermittently, the vesicles would burst with a release of fluid, leaving scars on the site that took 3 to 4 months to heal. There were no mucosal vesicles. Upon examination, the affected individuals were nearly devoid of eyebrows, eyelashes, axillary hair, and body hair. Teeth, nails, palms, soles, sweating, and hearing were normal, as was electrocardiography. Serum IgA, IgE, and IgD were measured in 1 individual and showed no change compared to controls. The parents were clinically unaffected. A scalp biopsy of the 18-year-old sister showed slight follicular plugging, mild perivascular and periadnexal inflammatory cell presence, and normal hair follicles. The sebaceous glands appeared morphologically normal and connected to the hair follicles. ### Mapping Genotyping and linkage analysis of the consanguineous Afghan family resulted in a maximum 2-point load score of 2.68 (theta = 0.0) at markers D18S36 and D18S547. Multipoint analysis generated a maximum load score of 3.30 at marker D18S877. Recombination events defined an 8.30-cM critical interval on chromosome 18q12.1, flanked by markers D18S66 and D18S1139, containing 30 genes. ### Molecular genetics A nonsense mutation in the DSC3 gene (600271.0001) mapping to chromosome 18q12.1 was identified in the consanguineous Afghan family with hypotrichosis and recurrent skin vesicles (613102). The unaffected parents and 3 healthy siblings were heterozygous for the mutation, which was not found in 100 unrelated ethnically matched controls. In affected members of this family with hypotrichosis were homozygous for a 2129T-G transversion in exon 14 of the DSC3 gene, resulting in a leu710-to-ter (L710X) (Ayub et al. 2009)substitution at the junction of the transmembrane and the C-terminal cytoplasmic domain, predicted to cause premature termination and nonsense mediated decay of the mRNA or instability of the truncated protein. The unaffected parents and 3 healthy siblings were heterozygous for the mutation, which was not found in 100 unrelated ethnically matched controls. # Interactions DSC3 has been shown to interact with PKP3.

DSC3 Desmocollin-3 is a protein that in humans is encoded by the DSC3 gene.[1][2][3] # Gene The desmosomal family members are arranged in two clusters on chromosome 18, occupying less than 650 kb combined. Alternative splicing results in two transcript variants encoding distinct isoforms.[3] # Function Desmocollin-3 is a calcium-dependent glycoprotein that is a member of the desmocollin subfamily of the cadherin superfamily. These desmosomal family members, along with the desmogleins, are found primarily in epithelial cells where they constitute the adhesive proteins of the desmosome cell-cell junction and are required for cell adhesion and desmosome formation.[3] The loss of these components leads to a lack of adhesion and a gain of cellular mobility.[4] # Clinical significance ## Breast cancer Through the process of epigenetic silencing, the expression of the desmocollin 3 protein is down regulated in many breast cancers.[4] ## Hereditary hypotrichosis A consanguineous Afghan family in which 3 sisters, 12 to 18 years of age, and their 5-year-old brother displayed features of hereditary hypotrichosis, associated with vesicles on the scalp and skin.[5] At birth, scalp hair was present, and after ritual shaving at 1 week of age, scalp hair grew back; however, the hair was fragile and began falling out at 2 to 3 months of age, eventually leaving only sparse hair on the scalp. Vesicles that were less than 1 cm in diameter were observed on the scalp and skin of most of the body, occasionally disappearing but then reappearing; intermittently, the vesicles would burst with a release of fluid, leaving scars on the site that took 3 to 4 months to heal. There were no mucosal vesicles. Upon examination, the affected individuals were nearly devoid of eyebrows, eyelashes, axillary hair, and body hair. Teeth, nails, palms, soles, sweating, and hearing were normal, as was electrocardiography. Serum IgA, IgE, and IgD were measured in 1 individual and showed no change compared to controls. The parents were clinically unaffected. A scalp biopsy of the 18-year-old sister showed slight follicular plugging, mild perivascular and periadnexal inflammatory cell presence, and normal hair follicles. The sebaceous glands appeared morphologically normal and connected to the hair follicles.[5] ### Mapping Genotyping and linkage analysis of the consanguineous Afghan family resulted in a maximum 2-point load score of 2.68 (theta = 0.0) at markers D18S36 and D18S547. Multipoint analysis generated a maximum load score of 3.30 at marker D18S877. Recombination events defined an 8.30-cM critical interval on chromosome 18q12.1, flanked by markers D18S66 and D18S1139, containing 30 genes.[5] ### Molecular genetics A nonsense mutation in the DSC3 gene (600271.0001) mapping to chromosome 18q12.1 was identified in the consanguineous Afghan family with hypotrichosis and recurrent skin vesicles (613102). The unaffected parents and 3 healthy siblings were heterozygous for the mutation, which was not found in 100 unrelated ethnically matched controls.[5] In affected members of this family with hypotrichosis were homozygous for a 2129T-G transversion in exon 14 of the DSC3 gene, resulting in a leu710-to-ter (L710X) (Ayub et al. 2009)substitution at the junction of the transmembrane and the C-terminal cytoplasmic domain, predicted to cause premature termination and nonsense mediated decay of the mRNA or instability of the truncated protein. The unaffected parents and 3 healthy siblings were heterozygous for the mutation, which was not found in 100 unrelated ethnically matched controls.[5] # Interactions DSC3 has been shown to interact with PKP3.[6]

https://www.wikidoc.org/index.php/DSC3

d0597fd7a0ff906de98bcd75b90da250498e4229

wikidoc

DTNA

DTNA Dystrobrevin alpha is a protein that in humans is encoded by the DTNA gene. # Function The protein encoded by this gene belongs to the dystrobrevin subfamily and the dystrophin family. This protein is a component of the dystrophin-associated protein complex (DPC). The DPC consists of dystrophin and several integral and peripheral membrane proteins, including dystroglycans, sarcoglycans, syntrophins and alpha- and beta-dystrobrevin. The DPC localizes to the sarcolemma and its disruption is associated with various forms of muscular dystrophy. This protein may be involved in the formation and stability of synapses as well as the clustering of nicotinic acetylcholine receptors. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. # Clinical significance Mutations in DTNA are associated to Meniere's disease . # Interactions DTNA has been shown to interact with dystrophin.

DTNA Dystrobrevin alpha is a protein that in humans is encoded by the DTNA gene.[1][2][3] # Function The protein encoded by this gene belongs to the dystrobrevin subfamily and the dystrophin family. This protein is a component of the dystrophin-associated protein complex (DPC). The DPC consists of dystrophin and several integral and peripheral membrane proteins, including dystroglycans, sarcoglycans, syntrophins and alpha- and beta-dystrobrevin. The DPC localizes to the sarcolemma and its disruption is associated with various forms of muscular dystrophy. This protein may be involved in the formation and stability of synapses as well as the clustering of nicotinic acetylcholine receptors. Multiple alternatively spliced transcript variants encoding different isoforms have been identified.[3] # Clinical significance Mutations in DTNA are associated to Meniere's disease .[4][5] # Interactions DTNA has been shown to interact with dystrophin.[6]

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

4e23f157ec215a7168566c7283fa5b73314061d1

wikidoc

DUID

DUID DUID is the acronym that stands for Driving Under the Influence of Drugs. It is akin to DUI or DWI for driving under the influence of alcohol or driving while intoxicated. Several American states and European countries now have "per se" DUID laws that presume a driver is impaired if they are found to have any detectable quantity of controlled substances in their body while operating an automobile and that the driver has no doctor's prescription for the substance. This is similar to the "per se" DUI/DWI laws that presume a driver is impaired when their blood alcohol content is above a certain level (currently 0.08% in the United States). There is some controversy with "per se" DUID laws in that a driver with any detectable quantity of controlled substances may not in fact be impaired and the detectable quantity may be only the remnants of drug use in days or weeks past. However testing equipment is generally calibrated to only pick up recent typically impairing usage and to not detect more historic drug use. The laws were passed in response to the problems reported by prosecutors who sometimes found it difficult to prove that a driver was impaired from using a controlled substance. Practical difficulties included the transient effects of some drugs wearing off before Police or Drs had a chance to assess many suspects for impairment. These laws make their cases much easier to win because they only have to prove the presence of a controlled substance in the blood or urine, without a prescription. The logic is that the trade off of more efficient prosecutions with wide benefit to road safety is worth the potential conviction or more often non criminal sanction of a driver who may have a slim chance of being unimpaired, because the driver was already violating the law by using a controlled substance without a prescription. # External link - Drugged Driving

DUID Template:Globalize DUID is the acronym that stands for Driving Under the Influence of Drugs. It is akin to DUI or DWI for driving under the influence of alcohol or driving while intoxicated. Several American states and European countries now have "per se" DUID laws that presume a driver is impaired if they are found to have any detectable quantity of controlled substances in their body while operating an automobile and that the driver has no doctor's prescription for the substance. This is similar to the "per se" DUI/DWI laws that presume a driver is impaired when their blood alcohol content is above a certain level (currently 0.08% in the United States). There is some controversy with "per se" DUID laws in that a driver with any detectable quantity of controlled substances may not in fact be impaired and the detectable quantity may be only the remnants of drug use in days or weeks past. However testing equipment is generally calibrated to only pick up recent typically impairing usage and to not detect more historic drug use. The laws were passed in response to the problems reported by prosecutors who sometimes found it difficult to prove that a driver was impaired from using a controlled substance. Practical difficulties included the transient effects of some drugs wearing off before Police or Drs had a chance to assess many suspects for impairment. These laws make their cases much easier to win because they only have to prove the presence of a controlled substance in the blood or urine, without a prescription. The logic is that the trade off of more efficient prosecutions with wide benefit to road safety is worth the potential conviction or more often non criminal sanction of a driver who may have a slim chance of being unimpaired, because the driver was already violating the law by using a controlled substance without a prescription. # External link - Drugged Driving Template:WikiDoc Sources

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

c4fddf43d0bb2c8ddbb9ce78b3b732fd68db8d03

wikidoc

DUX4

DUX4 Double homeobox, 4 also known as DUX4 is a protein which in humans is encoded by the DUX4 gene. # Gene This gene is located within a D4Z4 repeat array in the subtelomeric region of chromosome 4q35. The D4Z4 repeat is polymorphic in length; a similar D4Z4 repeat array has been identified on chromosome 10. Each D4Z4 repeat unit has an open reading frame (named DUX4) that contains two homeoboxes; the repeat-array and ORF is conserved in other mammals. There was no evidence for transcription from standard cDNA libraries however RTPCR and in-vitro expression experiments indicate that the ORF is transcribed. # Function The encoded protein has been reported to function as a transcriptional activator of paired-like homeodomain transcription factor 1 (PITX1). # Clinical significance Inappropriate expression of DUX4 in muscle cells is the cause of facioscapulohumeral muscular dystrophy.

DUX4 Double homeobox, 4 also known as DUX4 is a protein which in humans is encoded by the DUX4 gene.[1] # Gene This gene is located within a D4Z4 repeat array in the subtelomeric region of chromosome 4q35. The D4Z4 repeat is polymorphic in length; a similar D4Z4 repeat array has been identified on chromosome 10. Each D4Z4 repeat unit has an open reading frame (named DUX4) that contains two homeoboxes; the repeat-array and ORF is conserved in other mammals. There was no evidence for transcription from standard cDNA libraries however RTPCR and in-vitro expression experiments indicate that the ORF is transcribed.[2] # Function The encoded protein has been reported to function as a transcriptional activator of paired-like homeodomain transcription factor 1 (PITX1).[2] # Clinical significance Inappropriate expression of DUX4 in muscle cells is the cause of facioscapulohumeral muscular dystrophy.[3][4]

https://www.wikidoc.org/index.php/DUX4

ec66f498545575d5c36c919d1f1f20d77e153883

wikidoc

DVL2

DVL2 Segment polarity protein dishevelled homolog DVL-2 is a protein that in humans is encoded by the DVL2 gene. This gene encodes a member of the dishevelled (dsh) protein family. The vertebrate dsh proteins have approximately 40% amino acid sequence similarity with Drosophila dsh. This gene encodes a 90-kD protein that undergoes posttranslational phosphorylation to form a 95-kD cytoplasmic protein, which may play a role in the signal transduction pathway mediated by multiple Wnt proteins. The mechanisms of dishevelled function in Wnt signaling are likely to be conserved among metazoans. # Interactions DVL2 has been shown to interact with Zinc finger protein 165, DAB2 and Arrestin beta 1.

DVL2 Segment polarity protein dishevelled homolog DVL-2 is a protein that in humans is encoded by the DVL2 gene.[1][2] This gene encodes a member of the dishevelled (dsh) protein family. The vertebrate dsh proteins have approximately 40% amino acid sequence similarity with Drosophila dsh. This gene encodes a 90-kD protein that undergoes posttranslational phosphorylation to form a 95-kD cytoplasmic protein, which may play a role in the signal transduction pathway mediated by multiple Wnt proteins. The mechanisms of dishevelled function in Wnt signaling are likely to be conserved among metazoans.[2] # Interactions DVL2 has been shown to interact with Zinc finger protein 165,[3] DAB2[4] and Arrestin beta 1.[5]

https://www.wikidoc.org/index.php/DVL2

d7235929e3f97f40a2ccc30f7a0b518507c5e3c7

wikidoc

DVL3

DVL3 Segment polarity protein dishevelled homolog DVL-3 is a protein that in humans is encoded by the DVL3 gene. This gene is a member of a multi-gene family which shares strong similarity with the Drosophila dishevelled gene, dsh. The Drosophila dishevelled gene encodes a cytoplasmic phosphoprotein that regulates cell proliferation. # Interactions DVL3 has been shown to interact with DAB2, DVL1 and PRPF3.

DVL3 Segment polarity protein dishevelled homolog DVL-3 is a protein that in humans is encoded by the DVL3 gene.[1][2] This gene is a member of a multi-gene family which shares strong similarity with the Drosophila dishevelled gene, dsh. The Drosophila dishevelled gene encodes a cytoplasmic phosphoprotein that regulates cell proliferation.[2] # Interactions DVL3 has been shown to interact with DAB2,[3] DVL1[4] and PRPF3.[5]

https://www.wikidoc.org/index.php/DVL3

3ff57f17299536301d61d15dbf65680015761f5e

wikidoc

Data

Data Data in everyday language is a synonym for information. In the exact sciences there is a clear distinction between data and information, where data is a measurement that can be disorganized and when the data becomes organized it becomes information. Data may relate to reality, or to fiction as in a fictional movie. Data about reality consists of propositions. A large class of practically important propositions are measurements or observations of a variable. Such propositions may comprise numbers, words or images. # Etymology The word data is the plural of Latin datum, neuter past participle of dare, "to give", hence "something given". The past participle of "to give" has been used for millennia, in the sense of a statement accepted at face value; one of the works of Euclid, circa 300 BC, was the Dedomena (in Latin, Data). In discussions of problems in geometry, mathematics, engineering, and so on, the terms givens and data are used interchangeably. Such usage is the origin of data as a concept in computer science: data are numbers, words, images, etc., accepted as they stand. Pronounced dey-tuh, dat-uh, or dah-tuh. Experimental data are data generated within the context of a scientific investigation. # Usage in English In English, the word datum is still used in the general sense of "something given", and more specifically in cartography, geography, geology, NMR and drafting to mean a reference point, reference line, or reference surface. More generally speaking, any measurement or result can be called a (single) datum, but data point is more common. Both datums (see usage in datum article) and the originally Latin plural data are used as the plural of datum in English, but data is more commonly treated as a mass noun and used in the singular, especially in day-to-day usage. For example, "This is all the data from the experiment". This usage would be inconsistent with the rules of Latin grammar, which would instead suggest "These are all the data from the experiment", but these are English sentences, so Latin grammar rules do not apply. Many British and UN academic, scientific, and professional style guides (e.g., see page 43 of the World Health Organization Style Guide) request that authors treat data as a plural noun. Nevertheless, it is now usually treated as a singular mass noun in both informal and educated usage, but usage in scientific publications shows a strong UK/U.S divide. U.S. usage prefers treating data in the singular in all contexts, including serious and academic publishing. UK usage now widely accepts treating data as singular in standard English, including educated everyday usage at least in non-scientific use. UK scientific publishing usually still prefers treating it as a plural.. Some UK university style guides recommend using data for both singular and plural use and some recommend treating it only as a singular in connection with computers. # Uses of data in science and computing Raw data are numbers, characters, images or other outputs from devices to convert physical quantities into symbols, in a very broad sense. Such data are typically further processed by a human or input into a computer, stored and processed there, or transmitted (output) to another human or computer. Raw data is a relative term; data processing commonly occurs by stages, and the "processed data" from one stage may be considered the "raw data" of the next. Mechanical computing devices are classified according to the means by which they represent data. An analog computer represents a datum as a voltage, distance, position, or other physical quantity. A digital computer represents a datum as a sequence of symbols drawn from a fixed alphabet. The most common digital computers use a binary alphabet, that is, an alphabet of two characters, typically denoted "0" and "1". More familiar representations, such as numbers or letters, are then constructed from the binary alphabet. Some special forms of data are distinguished. A computer program is a collection of data, which can be interpreted as instructions. Most computer languages make a distinction between programs and the other data on which programs operate, but in some languages, notably Lisp and similar languages, programs are essentially indistinguishable from other data. It is also useful to distinguish metadata, that is, a description of other data. A similar yet earlier term for metadata is "ancillary data." The prototypical example of metadata is the library catalog, which is a description of the contents of books. # Meaning of data, information and knowledge The terms information and knowledge are frequently used for overlapping concepts. These three concepts are ill- or ambiguously defined in the subject matter literature . However, in recent interdisciplinary research a few independent specializations of these terms have been proposed.

Data Data in everyday language is a synonym for information.[1] In the exact sciences there is a clear distinction between data and information, where data is a measurement that can be disorganized and when the data becomes organized it becomes information. Data may relate to reality, or to fiction as in a fictional movie. Data about reality consists of propositions. A large class of practically important propositions are measurements or observations of a variable. Such propositions may comprise numbers, words or images. # Etymology The word data is the plural of Latin datum, neuter past participle of dare, "to give", hence "something given". The past participle of "to give" has been used for millennia, in the sense of a statement accepted at face value; one of the works of Euclid, circa 300 BC, was the Dedomena (in Latin, Data). In discussions of problems in geometry, mathematics, engineering, and so on, the terms givens and data are used interchangeably. Such usage is the origin of data as a concept in computer science: data are numbers, words, images, etc., accepted as they stand. Pronounced dey-tuh, dat-uh, or dah-tuh. Experimental data are data generated within the context of a scientific investigation. # Usage in English In English, the word datum is still used in the general sense of "something given", and more specifically in cartography, geography, geology, NMR and drafting to mean a reference point, reference line, or reference surface. More generally speaking, any measurement or result can be called a (single) datum, but data point is more common[3]. Both datums (see usage in datum article) and the originally Latin plural data are used as the plural of datum in English, but data is more commonly treated as a mass noun and used in the singular, especially in day-to-day usage. For example, "This is all the data from the experiment". This usage would be inconsistent with the rules of Latin grammar, which would instead suggest "These are all the data from the experiment", but these are English sentences, so Latin grammar rules do not apply. Many British and UN academic, scientific, and professional style guides (e.g., see page 43 of the World Health Organization Style Guide) request that authors treat data as a plural noun. Nevertheless, it is now usually treated as a singular mass noun in both informal and educated usage, but usage in scientific publications shows a strong UK/U.S divide. U.S. usage prefers treating data in the singular in all contexts, including serious and academic publishing.[2] UK usage now widely accepts treating data as singular in standard English[3], including educated everyday usage[4] at least in non-scientific use.[4] UK scientific publishing usually still prefers treating it as a plural.[5]. Some UK university style guides recommend using data for both singular and plural use[6] and some recommend treating it only as a singular in connection with computers.[7] # Uses of data in science and computing Raw data are numbers, characters, images or other outputs from devices to convert physical quantities into symbols, in a very broad sense. Such data are typically further processed by a human or input into a computer, stored and processed there, or transmitted (output) to another human or computer. Raw data is a relative term; data processing commonly occurs by stages, and the "processed data" from one stage may be considered the "raw data" of the next. Mechanical computing devices are classified according to the means by which they represent data. An analog computer represents a datum as a voltage, distance, position, or other physical quantity. A digital computer represents a datum as a sequence of symbols drawn from a fixed alphabet. The most common digital computers use a binary alphabet, that is, an alphabet of two characters, typically denoted "0" and "1". More familiar representations, such as numbers or letters, are then constructed from the binary alphabet. Some special forms of data are distinguished. A computer program is a collection of data, which can be interpreted as instructions. Most computer languages make a distinction between programs and the other data on which programs operate, but in some languages, notably Lisp and similar languages, programs are essentially indistinguishable from other data. It is also useful to distinguish metadata, that is, a description of other data. A similar yet earlier term for metadata is "ancillary data." The prototypical example of metadata is the library catalog, which is a description of the contents of books. # Meaning of data, information and knowledge The terms information and knowledge are frequently used for overlapping concepts. These three concepts are ill- or ambiguously defined in the subject matter literature . However, in recent interdisciplinary research a few independent specializations of these terms have been proposed.

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

818aae6412021e05af9364085b277eecab1383f8

wikidoc

Zinc

Zinc # Overview Zinc (Template:PronEng) is a metallic chemical element with the symbol Zn and atomic number 30. In some historical and sculptural contexts, it is (or was) known as spelter. # Notable characteristics Zinc is a moderately reactive, blue gray metal that tarnishes in moist air and burns in air with a bright bluish-green flame, giving off plumes of zinc oxide. It reacts with acids, alkalis and other non-metals. If not completely pure, zinc reacts with dilute acids to release hydrogen. The one common oxidation state of zinc is +2. From 100 °C to 210 °C (212 °F to 410 °F) zinc metal is malleable and can easily be beaten into various shapes. Above 210 °C (410 °F), the metal becomes brittle and will be pulverized by beating. Zinc is nonmagnetic. # Biological role Zinc is an essential element, necessary for sustaining all life. It is estimated that 3,000 of the hundreds of thousands of proteins in the human body contain zinc prosthetic groups, one type of which is the so-called zinc finger. In addition, there are over a dozen types of cells in the human body that secrete zinc ions, and the roles of these secreted zinc signals in medicine and health are now being actively studied. Zinc ions are now considered neurotransmitters. Cells in the salivary gland, prostate, immune system and intestine are other types that secrete zinc. Zinc is an activator of certain enzymes, such as carbonic anhydrase. Carbonic anhydrase is important in the transport of carbon dioxide in vertebrate blood. It is also required in plants for leaf formation, the synthesis of indole acetic acid (auxin) and anaerobic respiration (alcoholic fermentation). ## Food sources Zinc is found in oysters, and to a far lesser degree in most animal proteins, beans, nuts, almonds, whole grains, pumpkin seeds and sunflower seeds. A turkey's neck and beef's chuck or shank also contain good amounts of zinc. Phytates, which are found in whole grain breads, cereals, legumes and other products, have been known to decrease zinc absorption. Clinical studies have found that zinc, combined with antioxidants, may delay progression of age-related macular degeneration. Significant dietary intake of zinc has also recently been shown to impede the onset of flu. Soil conservation analyzes the vegetative uptake of naturally occurring zinc in many soil types. The (US) recommended dietary allowance of zinc from puberty on is 11mg for males and 8mg for females, with higher amounts recommended during pregnancy and lactation. ## Zinc deficiency Zinc deficiency results from inadequate intake of zinc, or inadequate absorption of zinc into the body. Signs of zinc deficiency include hair loss, skin lesions, diarrhea, and wasting of body tissues. Eyesight, taste, smell and memory are also connected with zinc. A deficiency in zinc can cause malfunctions of these organs and functions. Congenital abnormalities causing zinc deficiency may lead to a disease called Acrodermatitis enteropathica. Obtaining a sufficient zinc intake during pregnancy and in young children is a very real problem, especially among those who cannot afford a good and varied diet. Brain development is stunted by zinc insufficiency in utero and in youth. It is rarely recognised that lack of zinc can contribute to acne. Leukonychia, purple spots on the fingernails, are often seen as an indication of zinc deficiency. ### Zinc deficiency as a cause of anorexia nervosa Zinc deficiency causes a decrease in appetite -- which could degenerate in anorexia nervosa (AN). Appetite disorders, in turn, cause malnutrition and, notably, inadequate zinc intake. The use of zinc in the treatment of anorexia nervosa has been advocated since 1979 by Bakan. At least 15 trials showed that zinc improved weight gain in anorexia. A 1994 randomized, double-blind, placebo-controlled trial showed that zinc (14 mg per day) doubled the rate of body mass increase in the treatment of anorexia nervosa (AN). Deficiency of other nutrients such as tyrosine and tryptophan (precursors of the monoamine neurotransmitters norepinephrine and serotonin, respectively), as well as vitamin B1 (thiamine) could contribute to this phenomenon of malnutrition-induced malnutrition. ## Zinc toxicity Even though zinc is an essential requirement for a healthy body, too much zinc can be harmful. Excessive absorption of zinc can also suppress copper and iron absorption. The free zinc ion in solution is highly toxic to plants, invertebrates, and even vertebrate fish. The Free Ion Activity Model (FIAM) is well-established in the literature, and shows that just micromolar amounts of the free ion kills some organisms. A recent example showed 6 micromolar killing 93% of all daphnia in water. Swallowing a post 1982 American one cent piece (97.5% zinc) can also cause damage to the stomach lining due to the high solubility of the zinc ion in the acidic stomach. Zinc toxicity, mostly in the form of the ingestion of US pennies minted after 1982, is commonly fatal in dogs where it causes a severe hemolytic anemia. In pet parrots zinc is highly toxic and poisoning can often be fatal. There is evidence of induced copper deficiency at low intakes of 100–300 mg Zn/d. The USDA RDA is 15 mg Zn/d. Even lower levels, closer to the RDA, may interfere with the utilization of copper and iron or to adversely affect cholesterol.. ## Immune system Zinc salts are effective against pathogens in direct application. Gastroenteritis is strongly attenuated by ingestion of zinc, and this effect could be due to direct antimicrobial action of the zinc ions in the GI tract, or to absorption of the zinc and re-release from immune cells (all granulocytes secrete zinc), or both. In clinical trials, both zinc gluconate and zinc gluconate glycine (the formulation used in lozenges) have been shown to shorten the duration of symptoms of the common cold. The amount of glycine can vary from two to twenty moles per mole of zinc gluconate. # Compounds Zinc oxide is perhaps the best known and most widely used zinc compound, as it makes a good base for white pigments in paint. It also finds industrial use in the rubber industry, and is sold as opaque sunscreen. A variety of other zinc compounds find use industrially, such as zinc chloride (in deodorants), zinc pyrithione (anti-dandruff shampoos), zinc sulfide (in luminescent paints), and zinc methyl or zinc diethyl in the organic laboratory. Roughly one quarter of all zinc output is consumed in the form of zinc compounds. # Precautions Metallic zinc is not considered to be toxic, but free zinc ions in solution (like copper or iron ions) are highly toxic. There is also a condition called zinc shakes or zinc chills (see metal fume fever) that can be induced by the inhalation of freshly formed zinc oxide formed during the welding of galvanized materials. Excessive intake of zinc can promote deficiency in other dietary minerals.

Zinc Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Template:Infobox zinc # Overview Zinc (Template:PronEng) is a metallic chemical element with the symbol Zn and atomic number 30. In some historical and sculptural contexts, it is (or was) known as spelter. # Notable characteristics Zinc is a moderately reactive, blue gray metal that tarnishes in moist air and burns in air with a bright bluish-green flame, giving off plumes of zinc oxide. It reacts with acids, alkalis and other non-metals. If not completely pure, zinc reacts with dilute acids to release hydrogen. The one common oxidation state of zinc is +2. From 100 °C to 210 °C (212 °F to 410 °F) zinc metal is malleable and can easily be beaten into various shapes. Above 210 °C (410 °F), the metal becomes brittle and will be pulverized by beating. Zinc is nonmagnetic. # Biological role Zinc is an essential element, necessary for sustaining all life. It is estimated that 3,000 of the hundreds of thousands of proteins in the human body contain zinc prosthetic groups, one type of which is the so-called zinc finger. In addition, there are over a dozen types of cells in the human body that secrete zinc ions, and the roles of these secreted zinc signals in medicine and health are now being actively studied. Zinc ions are now considered neurotransmitters. Cells in the salivary gland, prostate, immune system and intestine are other types that secrete zinc. Zinc is an activator of certain enzymes, such as carbonic anhydrase. Carbonic anhydrase is important in the transport of carbon dioxide in vertebrate blood. It is also required in plants for leaf formation, the synthesis of indole acetic acid (auxin) and anaerobic respiration (alcoholic fermentation). ## Food sources Zinc is found in oysters, and to a far lesser degree in most animal proteins, beans, nuts, almonds, whole grains, pumpkin seeds and sunflower seeds.[1] A turkey's neck and beef's chuck or shank also contain good amounts of zinc. Phytates, which are found in whole grain breads, cereals, legumes and other products, have been known to decrease zinc absorption. Clinical studies have found that zinc, combined with antioxidants, may delay progression of age-related macular degeneration.[2] Significant dietary intake of zinc has also recently been shown to impede the onset of flu. Soil conservation analyzes the vegetative uptake of naturally occurring zinc in many soil types. The (US) recommended dietary allowance of zinc from puberty on is 11mg for males and 8mg for females, with higher amounts recommended during pregnancy and lactation. ## Zinc deficiency Zinc deficiency results from inadequate intake of zinc, or inadequate absorption of zinc into the body. Signs of zinc deficiency include hair loss, skin lesions, diarrhea, and wasting of body tissues. Eyesight, taste, smell and memory are also connected with zinc. A deficiency in zinc can cause malfunctions of these organs and functions. Congenital abnormalities causing zinc deficiency may lead to a disease called Acrodermatitis enteropathica. Obtaining a sufficient zinc intake during pregnancy and in young children is a very real problem, especially among those who cannot afford a good and varied diet. Brain development is stunted by zinc insufficiency in utero and in youth. It is rarely recognised that lack of zinc can contribute to acne. Leukonychia, purple spots on the fingernails, are often seen as an indication of zinc deficiency. ### Zinc deficiency as a cause of anorexia nervosa Zinc deficiency causes a decrease in appetite -- which could degenerate in anorexia nervosa (AN). Appetite disorders, in turn, cause malnutrition and, notably, inadequate zinc intake. The use of zinc in the treatment of anorexia nervosa has been advocated since 1979 by Bakan. At least 15 trials showed that zinc improved weight gain in anorexia. A 1994 randomized, double-blind, placebo-controlled trial showed that zinc (14 mg per day) doubled the rate of body mass increase in the treatment of anorexia nervosa (AN). Deficiency of other nutrients such as tyrosine and tryptophan (precursors of the monoamine neurotransmitters norepinephrine and serotonin, respectively), as well as vitamin B1 (thiamine) could contribute to this phenomenon of malnutrition-induced malnutrition.[3] ## Zinc toxicity Even though zinc is an essential requirement for a healthy body, too much zinc can be harmful. Excessive absorption of zinc can also suppress copper and iron absorption. The free zinc ion in solution is highly toxic to plants, invertebrates, and even vertebrate fish. The Free Ion Activity Model (FIAM) is well-established in the literature, and shows that just micromolar amounts of the free ion kills some organisms. A recent example showed 6 micromolar killing 93% of all daphnia in water.[4] Swallowing a post 1982 American one cent piece (97.5% zinc) can also cause damage to the stomach lining due to the high solubility of the zinc ion in the acidic stomach.[5] Zinc toxicity, mostly in the form of the ingestion of US pennies minted after 1982, is commonly fatal in dogs where it causes a severe hemolytic anemia.[6] In pet parrots zinc is highly toxic and poisoning can often be fatal[7]. There is evidence of induced copper deficiency at low intakes of 100–300 mg Zn/d. The USDA RDA is 15 mg Zn/d. Even lower levels, closer to the RDA, may interfere with the utilization of copper and iron or to adversely affect cholesterol.[8]. ## Immune system Zinc salts are effective against pathogens in direct application. Gastroenteritis is strongly attenuated by ingestion of zinc, and this effect could be due to direct antimicrobial action of the zinc ions in the GI tract, or to absorption of the zinc and re-release from immune cells (all granulocytes secrete zinc), or both.[9][10] In clinical trials, both zinc gluconate and zinc gluconate glycine (the formulation used in lozenges) have been shown to shorten the duration of symptoms of the common cold.[11] The amount of glycine can vary from two to twenty moles per mole of zinc gluconate. # Compounds Zinc oxide is perhaps the best known and most widely used zinc compound, as it makes a good base for white pigments in paint. It also finds industrial use in the rubber industry, and is sold as opaque sunscreen. A variety of other zinc compounds find use industrially, such as zinc chloride (in deodorants), zinc pyrithione (anti-dandruff shampoos), zinc sulfide (in luminescent paints), and zinc methyl or zinc diethyl in the organic laboratory. Roughly one quarter of all zinc output is consumed in the form of zinc compounds. # Precautions Metallic zinc is not considered to be toxic, but free zinc ions in solution (like copper or iron ions) are highly toxic. There is also a condition called zinc shakes or zinc chills (see metal fume fever) that can be induced by the inhalation of freshly formed zinc oxide formed during the welding of galvanized materials. Excessive intake of zinc can promote deficiency in other dietary minerals.

https://www.wikidoc.org/index.php/Ddx:Zinc

4434c06da850a3dc6079da82a83ec3b300bad79c

wikidoc

FOSB

FOSB FBJ murine osteosarcoma viral oncogene homolog B, also known as Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog B, FOSB or FosB, is a protein that, in humans, is encoded by the FOSB gene. The FOS gene family consists of four members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family (e.g., c-Jun, JunD), thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation. FosB and its truncated splice variants, ΔFosB and further truncated Δ2ΔFosB, are all involved in osteosclerosis, although Δ2ΔFosB lacks a known transactivation domain, in turn preventing it from affecting transcription through the AP-1 complex. The ΔFosB splice variant has been identified as playing a central, crucial (necessary and sufficient) role in the development and maintenance of pathological behavior and neuroplasticity involved in both behavioral addictions (associated with natural rewards) and drug addictions. ΔFosB overexpression (i.e., an abnormally and excessively high level of ΔFosB expression which produces a pronounced gene-related phenotype) triggers the development of addiction-related neuroplasticity throughout the reward system. ΔFosB differs from the full length FosB and further truncated Δ2ΔFosB in its capacity to produce these effects, as only accumbal ΔFosB overexpression is associated with pathological responses to drugs. # Delta FosB Delta FosB or ΔFosB is a truncated splice variant of FosB. ΔFosB has been implicated as a critical factor in the development of virtually all forms of behavioral and drug addictions. In the brain's reward system, it is linked to changes in a number of other gene products, such as CREB and sirtuins. In the body, ΔFosB regulates the commitment of mesenchymal precursor cells to the adipocyte or osteoblast lineage. In the nucleus accumbens, ΔFosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction. In other words, once "turned on" (sufficiently overexpressed) ΔFosB triggers a series of transcription events that ultimately produce an addictive state (i.e., compulsive reward-seeking involving a particular stimulus); this state is sustained for months after cessation of drug use due to the abnormal and exceptionally long half-life of ΔFosB isoforms. ΔFosB expression in D1-type nucleus accumbens medium spiny neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement while decreasing sensitivity to aversion. Based upon the accumulated evidence, a medical review from late 2014 argued that accumbal ΔFosB expression can be used as an addiction biomarker and that the degree of accumbal ΔFosB induction by a drug is a metric for how addictive it is relative to others. ## Role in addiction Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms. The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NF-κB). ΔFosB is the most significant biomolecular mechanism in addiction because the overexpression of ΔFosB in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in drug self-administration and reward sensitization) seen in drug addiction. ΔFosB overexpression has been implicated in addictions to alcohol (ethanol), cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others. ΔJunD, a transcription factor, and G9a, a histone methyltransferase, both oppose the function of ΔFosB and inhibit increases in its expression. Increases in nucleus accumbens ΔJunD expression (via viral vector-mediated gene transfer) or G9a expression (via pharmacological means) reduces, or with a large increase can even block, many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB). ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. Natural rewards, similar to drugs of abuse, induce gene expression of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression. Consequently, ΔFosB is the key mechanism involved in addictions to natural rewards (i.e., behavioral addictions) as well; in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward. Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional reward cross-sensitization effects that are mediated through ΔFosB. This phenomenon is notable since, in humans, a dopamine dysregulation syndrome, characterized by drug-induced compulsive engagement in natural rewards (specifically, sexual activity, shopping, and gambling), has also been observed in some individuals taking dopaminergic medications. ΔFosB inhibitors (drugs or treatments that oppose its action or reduce its expression) may be an effective treatment for addiction and addictive disorders. Current medical reviews of research involving lab animals have identified a drug class – class I histone deacetylase inhibitors – that indirectly inhibits the function and further increases in the expression of accumbal ΔFosB by inducing G9a expression in the nucleus accumbens after prolonged use. These reviews and subsequent preliminary evidence which used oral administration or intraperitoneal administration of the sodium salt of butyric acid or other class I HDAC inhibitors for an extended period indicate that these drugs have efficacy in reducing addictive behavior in lab animals that have developed addictions to ethanol, psychostimulants (i.e., amphetamine and cocaine), nicotine, and opiates; however, as of August 2015 no clinical trials involving human addicts and any HDAC class I inhibitors have been conducted to test for treatment efficacy in humans or identify an optimal dosing regimen. ### Plasticity in cocaine addiction ΔFosB levels have been found to increase upon the use of cocaine. Each subsequent dose of cocaine continues to increase ΔFosB levels with no ceiling of tolerance. Elevated levels of ΔFosB leads to increases in brain-derived neurotrophic factor (BDNF) levels, which in turn increases the number of dendritic branches and spines present on neurons involved with the nucleus accumbens and prefrontal cortex areas of the brain. This change can be identified rather quickly, and may be sustained weeks after the last dose of the drug. Transgenic mice exhibiting inducible expression of ΔFosB primarily in the nucleus accumbens and dorsal striatum exhibit sensitized behavioural responses to cocaine. They self-administer cocaine at lower doses than control, but have a greater likelihood of relapse when the drug is withheld. ΔFosB increases the expression of AMPA receptor subunit GluR2 and also decreases expression of dynorphin, thereby enhancing sensitivity to reward. ## Summary of addiction-related plasticity ## Other functions in the brain Viral overexpression of ΔFosB in the output neurons of the nigrostriatal dopamine pathway (i.e., the medium spiny neurons in the dorsal striatum) induces levodopa-induced dyskinesias in animal models of Parkinson's disease. Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias; postmortem studies of individuals with Parkinson's disease that were treated with levodopa have also observed similar dorsal striatal ΔFosB overexpression. Levetiracetam, an antiepileptic drug which has been demonstrated to reduce the severity of levodopa-induced dyskinesias, has been shown to dose-dependently decrease the induction of dorsal striatal ΔFosB expression in rats when co-administered with levodopa; the signal transduction involved in this effect is unknown. ΔFosB expression in the nucleus accumbens shell increases resilience to stress and is induced in this region by acute exposure to social defeat stress. Antipsychotic drugs have been shown to increase ΔFosB as well, more specifically in the prefrontal cortex. This increase has been found to be part of pathways for the negative side effects that such drugs produce.

FOSB FBJ murine osteosarcoma viral oncogene homolog B, also known as Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog B, FOSB or FosB, is a protein that, in humans, is encoded by the FOSB gene.[1][2][3] The FOS gene family consists of four members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family (e.g., c-Jun, JunD), thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation.[1] FosB and its truncated splice variants, ΔFosB and further truncated Δ2ΔFosB, are all involved in osteosclerosis, although Δ2ΔFosB lacks a known transactivation domain, in turn preventing it from affecting transcription through the AP-1 complex.[4] The ΔFosB splice variant has been identified as playing a central, crucial (necessary and sufficient)[5][6] role in the development and maintenance of pathological behavior and neuroplasticity involved in both behavioral addictions (associated with natural rewards) and drug addictions.[5][7][8] ΔFosB overexpression (i.e., an abnormally and excessively high level of ΔFosB expression which produces a pronounced gene-related phenotype) triggers the development of addiction-related neuroplasticity throughout the reward system.[9] ΔFosB differs from the full length FosB and further truncated Δ2ΔFosB in its capacity to produce these effects, as only accumbal ΔFosB overexpression is associated with pathological responses to drugs.[10] # Delta FosB Delta FosB or ΔFosB is a truncated splice variant of FosB.[11] ΔFosB has been implicated as a critical factor in the development of virtually all forms of behavioral and drug addictions.[6][7][12] In the brain's reward system, it is linked to changes in a number of other gene products, such as CREB and sirtuins.[13][14][15] In the body, ΔFosB regulates the commitment of mesenchymal precursor cells to the adipocyte or osteoblast lineage.[16] In the nucleus accumbens, ΔFosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction.[5][17][18] In other words, once "turned on" (sufficiently overexpressed) ΔFosB triggers a series of transcription events that ultimately produce an addictive state (i.e., compulsive reward-seeking involving a particular stimulus); this state is sustained for months after cessation of drug use due to the abnormal and exceptionally long half-life of ΔFosB isoforms.[5][17][18] ΔFosB expression in D1-type nucleus accumbens medium spiny neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement while decreasing sensitivity to aversion.[5][8] Based upon the accumulated evidence, a medical review from late 2014 argued that accumbal ΔFosB expression can be used as an addiction biomarker and that the degree of accumbal ΔFosB induction by a drug is a metric for how addictive it is relative to others.[5] ## Role in addiction Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.[6][28][29] The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NF-κB).[6] ΔFosB is the most significant biomolecular mechanism in addiction because the overexpression of ΔFosB in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in drug self-administration and reward sensitization) seen in drug addiction.[5][6][8] ΔFosB overexpression has been implicated in addictions to alcohol (ethanol), cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[5][6][28][30][31] ΔJunD, a transcription factor, and G9a, a histone methyltransferase, both oppose the function of ΔFosB and inhibit increases in its expression.[6][8][32] Increases in nucleus accumbens ΔJunD expression (via viral vector-mediated gene transfer) or G9a expression (via pharmacological means) reduces, or with a large increase can even block, many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[9][6] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[6][12] Natural rewards, similar to drugs of abuse, induce gene expression of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression.[6][7][12] Consequently, ΔFosB is the key mechanism involved in addictions to natural rewards (i.e., behavioral addictions) as well;[6][7][12] in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.[12] Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional reward cross-sensitization effects[note 1] that are mediated through ΔFosB.[7][33] This phenomenon is notable since, in humans, a dopamine dysregulation syndrome, characterized by drug-induced compulsive engagement in natural rewards (specifically, sexual activity, shopping, and gambling), has also been observed in some individuals taking dopaminergic medications.[7] ΔFosB inhibitors (drugs or treatments that oppose its action or reduce its expression) may be an effective treatment for addiction and addictive disorders.[34] Current medical reviews of research involving lab animals have identified a drug class – class I histone deacetylase inhibitors[note 2] – that indirectly inhibits the function and further increases in the expression of accumbal ΔFosB by inducing G9a expression in the nucleus accumbens after prolonged use.[9][32][35][36] These reviews and subsequent preliminary evidence which used oral administration or intraperitoneal administration of the sodium salt of butyric acid or other class I HDAC inhibitors for an extended period indicate that these drugs have efficacy in reducing addictive behavior in lab animals[note 3] that have developed addictions to ethanol, psychostimulants (i.e., amphetamine and cocaine), nicotine, and opiates;[32][36][37][38] however, as of August 2015[update] no clinical trials involving human addicts and any HDAC class I inhibitors have been conducted to test for treatment efficacy in humans or identify an optimal dosing regimen. ### Plasticity in cocaine addiction ΔFosB levels have been found to increase upon the use of cocaine.[39] Each subsequent dose of cocaine continues to increase ΔFosB levels with no ceiling of tolerance. Elevated levels of ΔFosB leads to increases in brain-derived neurotrophic factor (BDNF) levels, which in turn increases the number of dendritic branches and spines present on neurons involved with the nucleus accumbens and prefrontal cortex areas of the brain. This change can be identified rather quickly, and may be sustained weeks after the last dose of the drug. Transgenic mice exhibiting inducible expression of ΔFosB primarily in the nucleus accumbens and dorsal striatum exhibit sensitized behavioural responses to cocaine.[40] They self-administer cocaine at lower doses than control,[41] but have a greater likelihood of relapse when the drug is withheld.[18][41] ΔFosB increases the expression of AMPA receptor subunit GluR2[40] and also decreases expression of dynorphin, thereby enhancing sensitivity to reward.[18] ## Summary of addiction-related plasticity ## Other functions in the brain Viral overexpression of ΔFosB in the output neurons of the nigrostriatal dopamine pathway (i.e., the medium spiny neurons in the dorsal striatum) induces levodopa-induced dyskinesias in animal models of Parkinson's disease.[42][43] Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias;[43] postmortem studies of individuals with Parkinson's disease that were treated with levodopa have also observed similar dorsal striatal ΔFosB overexpression.[43] Levetiracetam, an antiepileptic drug which has been demonstrated to reduce the severity of levodopa-induced dyskinesias, has been shown to dose-dependently decrease the induction of dorsal striatal ΔFosB expression in rats when co-administered with levodopa;[43] the signal transduction involved in this effect is unknown.[43] ΔFosB expression in the nucleus accumbens shell increases resilience to stress and is induced in this region by acute exposure to social defeat stress.[44][45][46] Antipsychotic drugs have been shown to increase ΔFosB as well, more specifically in the prefrontal cortex. This increase has been found to be part of pathways for the negative side effects that such drugs produce.[47]

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

31ab9eb2fe7e63641453c874021e0a803e829d41

wikidoc

Diff

Diff A diff is the difference otherwise known as a diff between two versions of a page. It can be viewed from the page history: for every version there are potentially two radio buttons: the left column is for selecting the older version, the right column for selecting the newer one. Pressing "Compare selected versions" gives the difference between the two versions. For special cases (the diff for a single edit or between an old and the current version) other possibilities are clicking cur or last in the page history or on the Recent Changes page. The diff is also shown during an edit conflict so you can see exactly what you need to reintegrate. From MediaWiki 1.5 diff works also in preview, showing the difference between the currently stored version and the current version in the edit box # How it looks The two versions are shown side-by-side. In the old version paragraphs which differ are yellow and in the new version they are green. In left-to-right languages, the old version is on the left. This is reversed in right-to-left scripts. Text removed within a paragraph is shown in red on the old version. New text within a paragraph is shown in red on the new version. If a whole paragraph was removed or added, the text is not red but just black, while the other side is blank (white). Unchanged text is black on grey, only parts before and after changed text is shown. The diff shows differences per line. Some editors find that adding manual line breaks improves the diff function. As well as showing the difference between versions, the diff page has links to the user page and talk page of the users who edited both the last and current versions. Links to the users' contribution lists are also shown. For sysops, a rollback button is shown allowing them to revert from the new version to the old one. Note however that this is even shown when viewing the diff between the recent version of a page and a version older than the last version by an author other than the one of the most current version, in which case the rollback would not undo the change that is displayed. Thus if user A vandalized a page, and user B partially reverted that vandalism, the diff of the two together shows the remaining vandalism, but rollback reverts the partial repair by user B! Edit summaries are also shown on the diff page. These appear in the row beneath the user names. If the user has used links in their edit summary, these act as links on the diff page as well. In 1.4 there are also links to both versions, and the previous and next diff. This example shows the top of the diff page, with the links described above. When moving or copying a piece of text within a page or from another page, and also making other edits, it is useful to separate these edits. This way the diff function can be usefully applied for checking these other edits. # Width After the table of differences, the latest of the two compared versions is shown fully. In the case of the Classic skin with quickbar, the diff page does not have the quickbar, to provide more space. Therefore the diff page is also useful for viewing the page on full screen width, without changing the preferences. With the Monobook skin the panels on the left are also on the diff page. Page widening is more likely on a diff page, because there are two columns, but also because URLs (especially long ones) are not hidden. # URL To do a comparison with the older page rendered below the table of differences, provide the URL as follows. Open the revision of one page that you wish to compare to another, for example :Diff&oldid=78722, and the revision of the other page that you wish to compare, for example . Copy the oldid number of one page (&oldid=78722 in the first example) and replace the text oldid with diff: &diff=78722. Paste this string into the URL of the other page between that page's title and its oldid (&oldid=98420 in the second example), so you have something like this: You may remove the page title (title=Main_Page in the example above) from the URL if you wish, but this is not necessary. The resulting diff will compare the given versions of the two pages . To compare the current version of the page and a given oldid, you can put "current" after "diff=" instead of an oldid. For example, :Diff&diff=current&oldid=124558 would compare the current version of this page with the version that has oldid 124558.

Diff A diff is the difference otherwise known as a diff between two versions of a page. It can be viewed from the page history: for every version there are potentially two radio buttons: the left column is for selecting the older version, the right column for selecting the newer one. Pressing "Compare selected versions" gives the difference between the two versions. For special cases (the diff for a single edit or between an old and the current version) other possibilities are clicking cur or last in the page history or on the Recent Changes page. The diff is also shown during an edit conflict so you can see exactly what you need to reintegrate. From MediaWiki 1.5 diff works also in preview, showing the difference between the currently stored version and the current version in the edit box # How it looks The two versions are shown side-by-side. In the old version paragraphs which differ are yellow and in the new version they are green. In left-to-right languages, the old version is on the left. This is reversed in right-to-left scripts. Text removed within a paragraph is shown in red on the old version. New text within a paragraph is shown in red on the new version. If a whole paragraph was removed or added, the text is not red but just black, while the other side is blank (white). Unchanged text is black on grey, only parts before and after changed text is shown. The diff shows differences per line. Some editors find that adding manual line breaks improves the diff function. As well as showing the difference between versions, the diff page has links to the user page and talk page of the users who edited both the last and current versions. Links to the users' contribution lists are also shown. For sysops, a rollback button is shown allowing them to revert from the new version to the old one. Note however that this is even shown when viewing the diff between the recent version of a page and a version older than the last version by an author other than the one of the most current version, in which case the rollback would not undo the change that is displayed. Thus if user A vandalized a page, and user B partially reverted that vandalism, the diff of the two together shows the remaining vandalism, but rollback reverts the partial repair by user B! Edit summaries are also shown on the diff page. These appear in the row beneath the user names. If the user has used links in their edit summary, these act as links on the diff page as well. In 1.4 there are also links to both versions, and the previous and next diff. This example shows the top of the diff page, with the links described above. When moving or copying a piece of text within a page or from another page, and also making other edits, it is useful to separate these edits. This way the diff function can be usefully applied for checking these other edits. # Width After the table of differences, the latest of the two compared versions is shown fully. In the case of the Classic skin with quickbar, the diff page does not have the quickbar, to provide more space. Therefore the diff page is also useful for viewing the page on full screen width, without changing the preferences. With the Monobook skin the panels on the left are also on the diff page. Page widening is more likely on a diff page, because there are two columns, but also because URLs (especially long ones) are not hidden. # URL To do a comparison with the older page rendered below the table of differences, provide the URL as follows. Open the revision of one page that you wish to compare to another, for example http://meta.wikimedia.org/w/index.php?title=Help:Diff&oldid=78722, and the revision of the other page that you wish to compare, for example http://meta.wikimedia.org/w/index.php?title=Main_Page&oldid=98420. Copy the oldid number of one page (&oldid=78722 in the first example) and replace the text oldid with diff: &diff=78722. Paste this string into the URL of the other page between that page's title and its oldid (&oldid=98420 in the second example), so you have something like this: You may remove the page title (title=Main_Page in the example above) from the URL if you wish, but this is not necessary. The resulting diff will compare the given versions of the two pages [1]. To compare the current version of the page and a given oldid, you can put "current" after "diff=" instead of an oldid. For example, http://meta.wikimedia.org/w/index.php?title=Help:Diff&diff=current&oldid=124558 would compare the current version of this page with the version that has oldid 124558.

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

3f6db5ea11773809deab2affef1cd56402d3bd97

wikidoc

Dill

Dill Dill (Anethum graveolens) is a short-lived annual herb, native to southwest and central Asia. It is the sole species of the genus Anethum, though classified by some botanists in the related genus Peucedanum as Peucedanum graveolens (L.) C.B.Clarke. It grows to 40-60 cm tall, with slender stems and alternate, finely divided, softly delicate leaves 10-20 cm long. The ultimate leaf divisions are 1-2 mm broad, slightly broader than the similar leaves of fennel, which are threadlike, less than 1 mm broad, but harder in texture. The flowers are white to yellow, in small umbels 2-9 cm diameter. The seeds are 4-5 mm long and 1 mm thick, and straight to slightly curved with a longitudinally ridged surface. Its seeds, dill seed are used as a spice, and its fresh leaves, dill, and its dried leaves, dill weed, are used as herbs. # Origins and history Dill originated in central Asia. Zohary and Hopf remark that "wild and weedy types of dill are widespread in the Mediterranean basin and in West Asia." Although several twigs of dill were found in the tomb of Amenhotep II, they report that the earliest archeological evidence for its cultivation comes from late Neolithic lake shore settlements in Switzerland. Traces have been found in Roman ruins in Great Britain. In Semitic languages it is known by the name of Shubit. The Talmud requires that tithes shall be paid on the seeds, leaves, and stem of dill. The Bible states that the Pharisees were in the habit of paying dill as tithe (Matthew 23:23) ; Jesus Christ is said to have rebuked them for tithing dill but omitting mercy. # Name The name dill is thought to have originated from a Norse or Anglo-Saxon word 'dylle' meaning to soothe or lull, the plant having the carminative property of relieving gas. In some English speaking countries, it is sometimes called Dillby. In some Asian local languages it is called as "Shepu" or "Sowa". # Uses Fresh and dried dill leaves (sometimes called "dill weed" to distinguish it from dill seed) are used as herbs. Like caraway, its fernlike leaves are aromatic, and are used to flavor many foods, such as gravlax (cured salmon), borscht and other soups, and pickles. Dill is said to be best when used fresh, as it lose its flavor rapidly if dried; however, freeze-dried dill leaves preserve their flavor relatively well for a few months. In the Middle Ages, dill was thought to protect against witchcraft. Dill seed is used as a spice, with a flavor similar to caraway. Dill oil can be extracted from the leaves, stems and seeds of the plant. Medicinal value - Dill is an herb effective for the treatment of colic, gas, and indigestion. # Cultivation Successful cultivation requires warm to hot summers with high sunshine levels; even partial shade will reduce the yield substantially. It also prefers rich, well drained soil. The seeds are viable for 3-10 years. Plants intended for seed for further planting should not be grown near fennel, as the two species can hybridise. The seed is harvested by cutting the flower heads off the stalks when the seed is beginning to ripen. The seed heads are placed upside down in a paper bag and left in a warm dry place for a week. The seeds then separate from the stems easily for storage in an airtight container.

Dill Dill (Anethum graveolens) is a short-lived annual herb, native to southwest and central Asia. It is the sole species of the genus Anethum, though classified by some botanists in the related genus Peucedanum as Peucedanum graveolens (L.) C.B.Clarke. It grows to 40-60 cm tall, with slender stems and alternate, finely divided, softly delicate leaves 10-20 cm long. The ultimate leaf divisions are 1-2 mm broad, slightly broader than the similar leaves of fennel, which are threadlike, less than 1 mm broad, but harder in texture. The flowers are white to yellow, in small umbels 2-9 cm diameter. The seeds are 4-5 mm long and 1 mm thick, and straight to slightly curved with a longitudinally ridged surface. Its seeds, dill seed are used as a spice, and its fresh leaves, dill, and its dried leaves, dill weed, are used as herbs. # Origins and history Dill originated in central Asia. Zohary and Hopf remark that "wild and weedy types of dill are widespread in the Mediterranean basin and in West Asia." Although several twigs of dill were found in the tomb of Amenhotep II, they report that the earliest archeological evidence for its cultivation comes from late Neolithic lake shore settlements in Switzerland.[1] Traces have been found in Roman ruins in Great Britain. In Semitic languages it is known by the name of Shubit. The Talmud requires that tithes shall be paid on the seeds, leaves, and stem of dill. The Bible states that the Pharisees were in the habit of paying dill as tithe (Matthew 23:23) ; Jesus Christ is said to have rebuked them for tithing dill but omitting mercy. # Name The name dill is thought to have originated from a Norse or Anglo-Saxon word 'dylle' meaning to soothe or lull, the plant having the carminative property of relieving gas. In some English speaking countries, it is sometimes called Dillby. In some Asian local languages it is called as "Shepu" or "Sowa". # Uses Fresh and dried dill leaves (sometimes called "dill weed" to distinguish it from dill seed) are used as herbs. Like caraway, its fernlike leaves are aromatic, and are used to flavor many foods, such as gravlax (cured salmon), borscht and other soups, and pickles. Dill is said to be best when used fresh, as it lose its flavor rapidly if dried; however, freeze-dried dill leaves preserve their flavor relatively well for a few months. In the Middle Ages, dill was thought to protect against witchcraft.[citation needed] Dill seed is used as a spice, with a flavor similar to caraway. Dill oil can be extracted from the leaves, stems and seeds of the plant. Medicinal value - Dill is an herb effective for the treatment of colic, gas, and indigestion. # Cultivation Successful cultivation requires warm to hot summers with high sunshine levels; even partial shade will reduce the yield substantially. It also prefers rich, well drained soil. The seeds are viable for 3-10 years. Plants intended for seed for further planting should not be grown near fennel, as the two species can hybridise. The seed is harvested by cutting the flower heads off the stalks when the seed is beginning to ripen. The seed heads are placed upside down in a paper bag and left in a warm dry place for a week. The seeds then separate from the stems easily for storage in an airtight container. # External links - Plants for a Future: Anethum graveolens - 'A Modern Herbal' (Grieves, 1931)

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

9666a0cc6929e657f78d5bc789c366f6371ef035

wikidoc

Diol

Diol # Overview A diol or glycol is a chemical compound containing two hydroxyl groups (-OH groups). Vicinal diols have hydroxyl groups attached to adjacent atoms. Examples of vicinal diol compounds are ethylene glycol and propylene glycol. Geminal diols have hydroxyl groups bonded to the same atom. In general, organic geminal diols readily dehydrate to form a carbonyl group. For example, carbonic acid ((HO)2C=O) is unstable and has a tendency to convert to carbon dioxide (CO2) and water (H2O). Nevertheless, in rare situations the chemical equilibrium is in favor of the geminal diol. For example, when formaldehyde (H2C=O) is dissolved in water the geminal diol (H2C(OH)2) is favored. Examples of diols in which the hydroxyl functional groups are more widely separated include 1,4-butanediol and bisphenol A. # Synthesis of diols Because diols are a common functional group arrangement, numerous methods of preparation have been developed. - Vicinal diols can be produced from the oxidation of alkenes, usually with dilute acidic potassium permanganate, also known as potassium manganate(VII). Using alkaline potassium manganate(VII) produces a colour change from clear deep purple to clear green; acidic potassium manganate(VII) turns clear colourless. - Osmium tetroxide can similarly be used to oxidize alkenes to vicinal diols. - A chemical reaction called Sharpless bishydroxylation can be used to produce chiral diols from alkenes using an osmate reagent and a chiral catalyst. - Another method is the Woodward cis-hydroxylation. - In the Prins reaction 1,3-diols can be formed in a reaction between an alkene and formaldehyde. # Reactions - A diol reacts like an alcohol, such as esterification and ether formation. - Diols such as ethylene glycol are used as co-monomers in polymerization reactions forming polymers including some polyesters and polyurethanes. A different monomer with two identical functional groups, such as a dioyl dichloride or dioic acid is required to continue the process of polymerization through repeated esterification processes. - In glycol cleavage the C-C bond in a vicinal diol is cleaved with formation of two aldehyde groups.

Diol # Overview A diol or glycol is a chemical compound containing two hydroxyl groups (-OH groups). Vicinal diols have hydroxyl groups attached to adjacent atoms. Examples of vicinal diol compounds are ethylene glycol and propylene glycol. Geminal diols have hydroxyl groups bonded to the same atom. In general, organic geminal diols readily dehydrate to form a carbonyl group. For example, carbonic acid ((HO)2C=O) is unstable and has a tendency to convert to carbon dioxide (CO2) and water (H2O). Nevertheless, in rare situations the chemical equilibrium is in favor of the geminal diol. For example, when formaldehyde (H2C=O) is dissolved in water the geminal diol (H2C(OH)2) is favored. Examples of diols in which the hydroxyl functional groups are more widely separated include 1,4-butanediol and bisphenol A. # Synthesis of diols Because diols are a common functional group arrangement, numerous methods of preparation have been developed. - Vicinal diols can be produced from the oxidation of alkenes, usually with dilute acidic potassium permanganate, also known as potassium manganate(VII). Using alkaline potassium manganate(VII) produces a colour change from clear deep purple to clear green; acidic potassium manganate(VII) turns clear colourless. - Osmium tetroxide can similarly be used to oxidize alkenes to vicinal diols. - A chemical reaction called Sharpless bishydroxylation can be used to produce chiral diols from alkenes using an osmate reagent and a chiral catalyst. - Another method is the Woodward cis-hydroxylation. - In the Prins reaction 1,3-diols can be formed in a reaction between an alkene and formaldehyde. # Reactions - A diol reacts like an alcohol, such as esterification and ether formation. - Diols such as ethylene glycol are used as co-monomers in polymerization reactions forming polymers including some polyesters and polyurethanes. A different monomer with two identical functional groups, such as a dioyl dichloride or dioic acid is required to continue the process of polymerization through repeated esterification processes. - In glycol cleavage the C-C bond in a vicinal diol is cleaved with formation of two aldehyde groups.

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

c2d10392837c3889fa586630474d91ca6288833e

wikidoc

Twin

Twin Twins are a form of multiple birth in which the mother gives birth to two offspring from the same pregnancy, either of the same or opposite sex. The general term for more than one offspring from the same pregnancy is multiples, for example triplets refers to cases of three offspring from the same pregnancy. A fetus alone in the womb is called a singleton. Human twins are two individuals who have shared the uterus during a single pregnancy and are usually, but not necessarily, born in close succession. Due to the limited size of the mother's womb, multiple pregnancies are much less likely to carry to full term than singleton births, with twin pregnancies lasting only 37 weeks on average, 3 weeks less than full term. Since premature births can have health consequences for the babies, twin births are often handled with special precautions. There are estimated to be approximately 125 million human twins and triplets in the world (roughly 1.9% of the world population), and just 10 million identical twins (roughly 0.2% of the world population and 8% of all twins). Twins can either be monozygotic or dizygotic. # Types of twins There are five variations of twinning that commonly occur. The three most common variations are all fraternal: (1) male-female twins are the most common result, at about 40% of all twins born; (2) female fraternal twins (sometimes called sororal twins); (3) male fraternal twins. The last two are identical: (4) female identical twins and (5) (least common) male identical twins. Male singletons are slightly, about 5%, more common than female singletons. However, males are also more susceptible than females to death in utero, and since the death rate in utero is higher for twins, it leads to female twins being more common than male twins. Another variety of twins, "polar body twins," (one egg fertilized by two different sperm) is a phenomenon that was hypothesized to occur and may recently have been proven to exist. Polar body twinning would result in "half-identical" twins. ## Fraternal twins Fraternal twins (commonly known as "non-identical twins") usually occur when two fertilized eggs are implanted in the uterine wall at the same time. The two eggs form two zygotes, and these twins are therefore also known as dizygotic as well as "biovular" twins. When two eggs are independently fertilized by two different sperm cells, fraternal twins result. Dizygotic twins, like any other siblings, have an extremely small chance of having the exact same chromosome profile. Like any other siblings, fraternal twins may look very similar, particularly given that they are the same age. However, fraternal twins may also look very different from each other. They may be different sexes or the same sex. The same holds true for brothers and sisters from the same parents, meaning that fraternal twins are simply brothers and/or sisters who happen to have the same age. Studies show that there is a genetic basis for fraternal twinning. However, it is only the female partner that has any influence on the chances of having fraternal twins as the male cannot make her release more than one ovum. Fraternal twinning ranges from 6 per thousand births in Japan (similar to the rate of identical twins) to 14 and more per thousand in some African states. Fraternals are also more common for older mothers, with twinning rates doubling in mothers over the age of 35. With the advent of technologies and techniques to assist women in getting pregnant, the rate of fraternals has increased markedly. For example, in New York City's Upper East Side there were 3,707 twin births in 1995; there were 4,153 in 2003; and there were 4,655 in 2004. Triplet births have also risen, from 60 in 1995 to 299 in 2004. ## Identical twins Identical twins occur when a single egg is fertilized to form one zygote (monozygotic) which then divides into two separate embryos. Although their traits and physical appearances are not exactly the same due to environmental conditions both in and outside the womb, they do have identical DNA. This is not considered to be a hereditary trait, but rather an anomaly that occurs in birthing at a rate of about 3 in every 1000 deliveries worldwide, regardless of ethnic background. The two embryos develop into fetuses sharing the same womb. When one egg is fertilized by one sperm cell, and then divides and separates, two identical cells will result. If the zygote splits very early (in the first 2 days after fertilization) they may develop separate placentas (chorion) and separate sacs (amnion). These are called dichorionic, diamniotic (or "di/di") twins, which occurs 20-30% of the time. Most of the time in identical twins the zygote will split after 2 days, resulting in a shared placenta, but two separate sacs. These are called monochorionic, diamniotic ("mono/di") twins. In about 1% of identical twins the splitting occurs late enough to result in both a shared placenta and a shared sac called; monochorionic, monoamniotic ("mono/mono") twins. Finally, the zygote may split extremely late, resulting in conjoined twins. Mortality is highest for conjoined twins due to the many complications resulting from shared organs. Mono/mono twins have an overall in-utero mortality of about 60%, principally due to cord entanglement prior to 32 weeks gestation. Many times, monoamniotic twins are delivered at 32 weeks electively for the safety of the babies. In higher order multiples, there can sometimes be a combination of fraternal/identical twins. Mono/di twins have about a 25% mortality due to twin-twin transfusion. Di/di twins have the lowest mortality risk at about 9%, although that is still significantly higher than that of singletons. Monozygotic twins are genetically identical (unless there has been a mutation in development) and they are usually the same sex. (On rare occasions, Monozygotic twins may express different phenotypes (normally due to an environmental factor or the deactivation of different X chromosomes in monozygotic female twins), and in some extremely rare cases, due to aneuploidy, twins may express different sexual phenotypes, normally due to an XXY Klinefelter's syndrome zygote splitting unevenly ). Monozygotic twins generally look alike. Although they do not have the same fingerprints (which are environmental as well as genetic). As they mature, identical twins often become less alike because of lifestyle choices or external influences. Genetically speaking, the children of identical twins are half-siblings rather than cousins. If each member of one set of identical twins marries one member of another set of identical twins then the resulting children would be genetic full siblings. It is estimated that there are around 10 million identical twins and triplets in the world. The likelihood of a single fertilisation resulting in identical twins appears to be a random event, not a hereditary trait, and is uniformly distributed in all populations around the world. This is in marked contrast to fraternal twinning which ranges from about 6 per thousand births in Japan (almost similar to the rate of identical twins, which is around 4-5) to 15 and more per thousand in some parts of India (and up to 24 in the US, which might mainly be due to IVF, in vitro fertilisation). The exact cause for the splitting of a zygote or embryo is unknown. Studies have shown that identical twins reared in different environments share similar personality traits, mannerisms, job choices, attitudes, and interests. These findings add to the belief that many behaviors are derived from genes. Identical twins have identical DNA but differing environmental influences throughout their lives affect which genes are switched on or off. This is called epigenetic modification. A study of 80 pairs of human twins ranging in age from 3 to 74 showed that the youngest twins have relatively few epigenetic differences. The number of epigenetic differences between identical twins increases with age. 50-year-old twins had over three times the epigenetic difference of 3-year-old twins. Twins who had spent their lives apart (such as those adopted by two different sets of parents at birth) had the greatest difference. However, certain characteristics become more alike as twins age, such as IQ and personality. This phenomenon illustrates the influence of genetics in many aspects of human characteristics and behaviour. A new theory (July 3, 2007) found that identical twins are formed after an embryo essentially collapses, splitting the progenitor cells (those that contain the body's fundamental genetic material) in half. That leaves the same genetic material divided in two on opposite sides of the embryo. Eventually, two separate fetuses develop. The research was presented at a meeting of the European Society for Human Reproduction and Embryology in Lyon, France. Utilizing computer software to take photos every 2 minutes of 33 embryos growing in a laboratory, Dr. Dianna Payne, a visiting research fellow at the Mio Fertility Clinic in Japan, documented for the first time the early days of twin development. Payne also discovered explanation for why in-vitro fertilization techniques are more likely to create twins. Only about 3 pairs of twins per 1,000 deliveries occur as a result of natural conception. But for IVF deliveries, there are nearly 21 pairs of twins for every 1,000.Also, the latest twin study found that ability to listen to 2 things at once is largely inherited. Thus, listening to someone talking, speech entering the right ear travels in large part to the left side of the brain, where language is processed. Speech entering the left ear travels first to the right side of the brain before crossing to the brain's language center on the left side by way of the corpus callosum, a pathway connecting the brain's right and left hemispheres. NIDCD researchers based this finding from studies of identical and fraternal twins (national twins festival in Twinsburg, OH, during the years 2002 through 2005). 194 same-sex pairs of twins participated in the study (138 identical pairs and 56 fraternal pairs), representing ages 12 through 50. Researchers found a significantly higher correlation among identical twins than fraternal twins, indicating that differences in performance for those activities had a strong genetic component. It was found that if a trait is purely genetic, identical twins, who share the same DNA, will be alike nearly 100 percent of the time, while fraternal twins, who share roughly half of their DNA, will be less similar. Conversely, if a trait is primarily due to a person's environment, both identical and fraternal twins should have roughly the same degree of similarity, since most twins grow up in the same household. ### Semi-identical Monozygotic twins can develop differently, due to different genes being activated.. More unusual are "Semi-identical twins". These "half-identical twins" are hypothesized to occur when an unfertilized egg cleaves into two identical attached ova and which are viable for fertilization. Both cloned ova are then fertilized by different sperm and the coalesced eggs undergo further cell duplications developing as a chimeric zygote. If this chimeric blastomere then undergoes a twinning event, two embryos will be formed, each of which is chimeric for the paternal genes (and identical for maternal genes). This results in a set of twins with identical genes from the mother's side, but different genes from the father's side. Cells in each fetus carry genes from either sperm, resulting in chimeras. This form had been speculated until only recently being recorded in western medicine # Demographics A recent study found that vegan mothers are five times less likely to have twins than those who eat animal products. From 1980–97, the number of twin births in the United States rose 52%. This rise can at least partly be attributed to the increasing popularity of fertility drugs like Clomid and procedures like in vitro fertilization, which result in multiple births more frequently than unassisted fertilizations do. It may also be linked to the increase of growth hormones in food. ## Ethnicity About 1 in 90 human births (1.1%) results from a twin pregnancy. The rate of fraternal twinning varies greatly among ethnic groups, ranging as high as about 6% for the Yoruba or 10% for Linha Sao Pedro, a tiny Brazilian village. The widespread use of fertility drugs causing hyperovulation (stimulated release of multiple eggs by the mother) has caused what some call an "epidemic of multiple births". In 2001, for the first time ever in the US, the twinning rate exceeded 3% of all births. Thus, approximately 5.8% of children born in the US in 2001 were twins. Among Hausa of Nigeria and Niger the incidence of multiple births was studied using the maternity records of 5750 Hausa women living in the savannah zone of Nigeria. There were 40 twins and 2 triplets/1000 births. Twenty six per cent of twins were monozygous. The incidence of multiple births, which was about five times higher than that observed in any western population, was significantly lower than that of other ethnic groups, who live in the hot and humid climate of the southern part of country. The incidence of multiple births was related to maternal age but did not bear any association to the climate or prevalence of malaria. Nevertheless, the rate of identical twins remains at about 1 in 333 across the globe, further suggesting that pregnancies resulting in identical twins occur randomly. ## Predisposing factors The cause of monozygotic twinning is unknown. Dizygotic twin pregnancies are slightly more likely when the following factors are present in the woman: - She is of West African descent (especially Yoruba or Hausa) - She is between the age of 30 and 40 years - She is greater than average height and weight - She has had several previous pregnancies. - She has a family history of dizygotic twinning, especially a mother who is a twin. Women undergoing certain fertility treatments may have a greater chance of dizygotic multiple births. This can vary depending on what types of fertility treatments are used. With in vitro fertilisation (IVF), this is primarily due to the insertion of multiple embryos into the uterus. Some other treatments such as the drug Clomid can stimulate a woman to release multiple eggs, allowing the possibility of multiples. Many fertility treatments have no effect on the likelihood of multiple births. There is also speculation that the West African predisposition to twinning is due to the large amount of yams in their diet because yams contain phytoestrogens, which may stimulate the ovaries. Most likely this is nothing but a myth, as phytoestrogens would tend to suppress twinning by reducing gonadotropin levels. # Complications of twin pregnancy ## Vanishing twins Researchers suspect that as many as 1 in 8 pregnancies start out as multiples, but only a single fetus is brought to full term, because the other has died very early in the pregnancy and not been detected or recorded. Early obstetric ultrasonography exams sometimes reveal an "extra" fetus, which fails to develop and instead disintegrates and vanishes. This is known as vanishing twin syndrome. ## Conjoined twins Conjoined twins (or "Siamese twins") are monozygotic twins whose bodies are joined together at birth. This occurs where the single zygote of identical twins fails to separate completely, and the zygote starts to split after day 13 following fertilization. This condition occurs in about 1 in 50,000 human pregnancies. Most conjoined twins are now evaluated for surgery to attempt to separate them into separate functional bodies. The degree of difficulty rises if a vital organ or structure is shared between twins, such as brain, heart or liver. ## Chimerism A chimera is an ordinary person or animal except that some of his or her parts actually came from his or her twin or from the mother. A chimera may arise either from identical twin fetuses (where it would be impossible to detect), or from dizygotic fetuses, which can be identified by chromosomal comparisons from various parts of the body. The number of cells derived from each fetus can vary from one part of the body to another, and often leads to characteristic mosaicism skin colouration in human chimeras. A chimera may be a hermaphrodite, composed of cells from a male twin and a female twin. ## Parasitic twins Sometimes one twin fetus will fail to develop completely and continue to cause problems for its surviving twin. One fetus acts as a parasite towards the other. Sometimes the parasitic twin becomes an almost indistinguishable part of the other. ## Partial molar twins A very rare type of parasitic twinning is where a single viable twin is endangered when the other zygote becomes cancerous, or molar. This means that the molar zygote's cellular division continues unchecked, resulting in a cancerous growth that overtakes the viable fetus. Typically, this results when one twin has either triploidy or complete paternal uniparental disomy, resulting in little or no fetus and a cancerous, overgrown placenta, resembling a bunch of grapes. ## Miscarried twin Occasionally, a woman will suffer a miscarriage early in pregnancy, yet the pregnancy will continue; one twin was miscarried but the other was able to be carried to term. This occurrence is similar to the vanishing twin syndrome. ## Low birth weight Twins typically suffer from the lower birth weights and greater likelihood of prematurity that is more commonly associated with the higher multiple pregnancies. Throughout their lives twins tend to be smaller than singletons on average. ### Twin-to-twin transfusion syndrome Identical twins who share a placenta can develop twin-to-twin transfusion syndrome. This condition means that blood from one twin is being diverted into the other twin. One twin, the 'donor' twin, is small and anemic, the other, the 'recipient' twin, is large and polycythemic. The lives of both twins are endangered by this condition. # Human twin studies Twin studies are studies that assess identical (monozygotic) twins for medical, genetic, or psychological characteristics to try to isolate genetic influence from environmental influence. Twins that have been separated early in life and raised in separate households are especially sought-after for these studies, which have been invaluable in the exploration of human nature. # Unusual twinnings There are some patterns of twinning that are exceedingly rare: while they have been reported to happen, they are so unusual that most obstetricians or midwives may go their entire careers without encountering a single case. Among fraternal twins, in rare cases, the eggs are fertilized at different times with two or more acts of sexual intercourse, either within one menstrual cycle (superfecundation) or, even more rarely, later on in the pregnancy (superfetation). This can lead to the possibility of a woman carrying fraternal twins with different fathers (that is, half-siblings). This phenomenon is known as heteropaternal superfecundation. One 1992 study estimates that the frequency of heteropaternal superfecundation among dizygotic twins whose parents were involved in paternity suits was approximately 2.4%; see the references section, below, for more details. Fraternal twins from biracial couples can sometimes be mixed twins - which exhibit differing ethnic and racial features. Among monozygotic twins, in extremely rare cases, twins have been born with opposite sexes (one male, one female). The probability of this is so vanishingly small (only 3 documented cases) that multiples having different sexes is universally accepted as a sound basis for a clinical determination that in utero multiples are not monozygotic. When monozygotic twins are born with different sexes it is because of chromosomal birth defects. In this case, although the twins did come from the same egg, it is incorrect to refer to them as genetically identical, since they have different karyotypes. The Largest Annual Gathering of Twins takes place in Twinsburg, Ohio every year on the first full weekend of August. Over three thousand sets of twins typically attend the weekend-long event. # Animal twins Twins are common in many animal species, such as cats, sheep, ferrets and deer. The incidence of twinning among cattle is about 1-4%, and research is underway to improve the odds of twinning, which can be more profitable for the breeder if complications can be sidestepped or managed. A species of armadillo (Dasypus novemcinctus) has identical twins (usually four babies) as its regular reproduction and not as exceptional cases.

Twin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3] Twins are a form of multiple birth in which the mother gives birth to two offspring from the same pregnancy, either of the same or opposite sex. The general term for more than one offspring from the same pregnancy is multiples, for example triplets refers to cases of three offspring from the same pregnancy. A fetus alone in the womb is called a singleton. Human twins are two individuals who have shared the uterus during a single pregnancy and are usually, but not necessarily, born in close succession. Due to the limited size of the mother's womb, multiple pregnancies are much less likely to carry to full term than singleton births, with twin pregnancies lasting only 37 weeks on average, 3 weeks less than full term.[citation needed] Since premature births can have health consequences for the babies, twin births are often handled with special precautions. There are estimated to be approximately 125 million human twins and triplets in the world (roughly 1.9% of the world population), and just 10 million identical twins (roughly 0.2% of the world population and 8% of all twins).[citation needed] Twins can either be monozygotic or dizygotic. # Types of twins There are five variations of twinning that commonly occur. The three most common variations are all fraternal: (1) male-female twins are the most common result, at about 40% of all twins born; (2) female fraternal twins (sometimes called sororal twins); (3) male fraternal twins. The last two are identical: (4) female identical twins and (5) (least common) male identical twins. Male singletons are slightly, about 5%, more common than female singletons. However, males are also more susceptible than females to death in utero, and since the death rate in utero is higher for twins, it leads to female twins being more common than male twins. Another variety of twins, "polar body twins," (one egg fertilized by two different sperm) is a phenomenon that was hypothesized to occur and may recently have been proven to exist. Polar body twinning would result in "half-identical" twins.[1] ## Fraternal twins Fraternal twins (commonly known as "non-identical twins") usually occur when two fertilized eggs are implanted in the uterine wall at the same time. The two eggs form two zygotes, and these twins are therefore also known as dizygotic as well as "biovular" twins. When two eggs are independently fertilized by two different sperm cells, fraternal twins result. Dizygotic twins, like any other siblings, have an extremely small chance of having the exact same chromosome profile. Like any other siblings, fraternal twins may look very similar, particularly given that they are the same age. However, fraternal twins may also look very different from each other. They may be different sexes or the same sex. The same holds true for brothers and sisters from the same parents, meaning that fraternal twins are simply brothers and/or sisters who happen to have the same age. Studies show that there is a genetic basis for fraternal twinning. However, it is only the female partner that has any influence on the chances of having fraternal twins as the male cannot make her release more than one ovum. Fraternal twinning ranges from 6 per thousand births in Japan (similar to the rate of identical twins) to 14 and more per thousand in some African states.[citation needed] Fraternals are also more common for older mothers, with twinning rates doubling in mothers over the age of 35.[citation needed] With the advent of technologies and techniques to assist women in getting pregnant, the rate of fraternals has increased markedly. For example, in New York City's Upper East Side there were 3,707 twin births in 1995; there were 4,153 in 2003; and there were 4,655 in 2004. Triplet births have also risen, from 60 in 1995 to 299 in 2004. ## Identical twins Identical twins occur when a single egg is fertilized to form one zygote (monozygotic) which then divides into two separate embryos. Although their traits and physical appearances are not exactly the same due to environmental conditions both in and outside the womb, they do have identical DNA. This is not considered to be a hereditary trait, but rather an anomaly that occurs in birthing at a rate of about 3 in every 1000 deliveries worldwide,[2] regardless of ethnic background. The two embryos develop into fetuses sharing the same womb. When one egg is fertilized by one sperm cell, and then divides and separates, two identical cells will result. If the zygote splits very early (in the first 2 days after fertilization) they may develop separate placentas (chorion) and separate sacs (amnion). These are called dichorionic, diamniotic (or "di/di") twins, which occurs 20-30% of the time. Most of the time in identical twins the zygote will split after 2 days, resulting in a shared placenta, but two separate sacs. These are called monochorionic, diamniotic ("mono/di") twins. In about 1% of identical twins the splitting occurs late enough to result in both a shared placenta and a shared sac called; monochorionic, monoamniotic ("mono/mono") twins. Finally, the zygote may split extremely late, resulting in conjoined twins. Mortality is highest for conjoined twins due to the many complications resulting from shared organs. Mono/mono twins have an overall in-utero mortality of about 60%, principally due to cord entanglement prior to 32 weeks gestation. Many times, monoamniotic twins are delivered at 32 weeks electively for the safety of the babies. In higher order multiples, there can sometimes be a combination of fraternal/identical twins. Mono/di twins have about a 25% mortality due to twin-twin transfusion. Di/di twins have the lowest mortality risk at about 9%, although that is still significantly higher than that of singletons.[3] Monozygotic twins are genetically identical (unless there has been a mutation in development) and they are usually the same sex. (On rare occasions, Monozygotic twins may express different phenotypes (normally due to an environmental factor or the deactivation of different X chromosomes in monozygotic female twins), and in some extremely rare cases, due to aneuploidy, twins may express different sexual phenotypes, normally due to an XXY Klinefelter's syndrome zygote splitting unevenly [4] [5]). Monozygotic twins generally look alike. Although they do not have the same fingerprints (which are environmental as well as genetic). As they mature, identical twins often become less alike because of lifestyle choices or external influences. Genetically speaking, the children of identical twins are half-siblings rather than cousins. If each member of one set of identical twins marries one member of another set of identical twins then the resulting children would be genetic full siblings. It is estimated that there are around 10 million identical twins and triplets in the world. The likelihood of a single fertilisation resulting in identical twins appears to be a random event, not a hereditary trait, and is uniformly distributed in all populations around the world.[citation needed] This is in marked contrast to fraternal twinning which ranges from about 6 per thousand births in Japan (almost similar to the rate of identical twins, which is around 4-5) to 15 and more per thousand in some parts of India[6] (and up to 24 in the US, which might mainly be due to IVF, in vitro fertilisation). The exact cause for the splitting of a zygote or embryo is unknown. Studies have shown that identical twins reared in different environments share similar personality traits, mannerisms, job choices, attitudes, and interests. These findings add to the belief that many behaviors are derived from genes.[citation needed] Identical twins have identical DNA but differing environmental influences throughout their lives affect which genes are switched on or off. This is called epigenetic modification. A study of 80 pairs of human twins ranging in age from 3 to 74 showed that the youngest twins have relatively few epigenetic differences. The number of epigenetic differences between identical twins increases with age. 50-year-old twins had over three times the epigenetic difference of 3-year-old twins. Twins who had spent their lives apart (such as those adopted by two different sets of parents at birth) had the greatest difference.[7] However, certain characteristics become more alike as twins age, such as IQ and personality.[8][9] This phenomenon illustrates the influence of genetics in many aspects of human characteristics and behaviour. A new theory (July 3, 2007) found that identical twins are formed after an embryo essentially collapses, splitting the progenitor cells (those that contain the body's fundamental genetic material) in half. That leaves the same genetic material divided in two on opposite sides of the embryo. Eventually, two separate fetuses develop. The research was presented at a meeting of the European Society for Human Reproduction and Embryology in Lyon, France. Utilizing computer software to take photos every 2 minutes of 33 embryos growing in a laboratory, Dr. Dianna Payne, a visiting research fellow at the Mio Fertility Clinic in Japan, documented for the first time the early days of twin development. Payne also discovered explanation for why in-vitro fertilization techniques are more likely to create twins. Only about 3 pairs of twins per 1,000 deliveries occur as a result of natural conception. But for IVF deliveries, there are nearly 21 pairs of twins for every 1,000.[10]Also, the latest twin study found that ability to listen to 2 things at once is largely inherited. Thus, listening to someone talking, speech entering the right ear travels in large part to the left side of the brain, where language is processed. Speech entering the left ear travels first to the right side of the brain before crossing to the brain's language center on the left side by way of the corpus callosum, a pathway connecting the brain's right and left hemispheres. NIDCD researchers based this finding from studies of identical and fraternal twins (national twins festival in Twinsburg, OH, during the years 2002 through 2005). 194 same-sex pairs of twins participated in the study (138 identical pairs and 56 fraternal pairs), representing ages 12 through 50. Researchers found a significantly higher correlation among identical twins than fraternal twins, indicating that differences in performance for those activities had a strong genetic component. It was found that if a trait is purely genetic, identical twins, who share the same DNA, will be alike nearly 100 percent of the time, while fraternal twins, who share roughly half of their DNA, will be less similar. Conversely, if a trait is primarily due to a person's environment, both identical and fraternal twins should have roughly the same degree of similarity, since most twins grow up in the same household.[11] ### Semi-identical Monozygotic twins can develop differently, due to different genes being activated.[12]. More unusual are "Semi-identical twins". These "half-identical twins" are hypothesized to occur when an unfertilized egg cleaves into two identical attached ova and which are viable for fertilization. Both cloned ova are then fertilized by different sperm and the coalesced eggs undergo further cell duplications developing as a chimeric zygote. If this chimeric blastomere then undergoes a twinning event, two embryos will be formed, each of which is chimeric for the paternal genes (and identical for maternal genes). This results in a set of twins with identical genes from the mother's side, but different genes from the father's side. Cells in each fetus carry genes from either sperm, resulting in chimeras. This form had been speculated until only recently being recorded in western medicine[13] [14] [15]. # Demographics A recent study found that vegan mothers are five times less likely to have twins than those who eat animal products.[16] From 1980–97, the number of twin births in the United States rose 52%.[17] This rise can at least partly be attributed to the increasing popularity of fertility drugs like Clomid and procedures like in vitro fertilization, which result in multiple births more frequently than unassisted fertilizations do. It may also be linked to the increase of growth hormones in food.[16] ## Ethnicity About 1 in 90 human births (1.1%) results from a twin pregnancy.[18] The rate of fraternal twinning varies greatly among ethnic groups, ranging as high as about 6% for the Yoruba or 10% for Linha Sao Pedro, a tiny Brazilian village.[19] The widespread use of fertility drugs causing hyperovulation (stimulated release of multiple eggs by the mother) has caused what some call an "epidemic of multiple births". In 2001, for the first time ever in the US, the twinning rate exceeded 3% of all births. Thus, approximately 5.8% of children born in the US in 2001 were twins. Among Hausa of Nigeria and Niger the incidence of multiple births was studied using the maternity records of 5750 Hausa women living in the savannah zone of Nigeria. There were 40 twins and 2 triplets/1000 births. Twenty six per cent of twins were monozygous. The incidence of multiple births, which was about five times higher than that observed in any western population, was significantly lower than that of other ethnic groups, who live in the hot and humid climate of the southern part of country. The incidence of multiple births was related to maternal age but did not bear any association to the climate or prevalence of malaria.[20] Nevertheless, the rate of identical twins remains at about 1 in 333 across the globe, further suggesting that pregnancies resulting in identical twins occur randomly. ## Predisposing factors The cause of monozygotic twinning is unknown. Dizygotic twin pregnancies are slightly more likely when the following factors are present in the woman: - She is of West African descent (especially Yoruba or Hausa)[citation needed] - She is between the age of 30 and 40 years - She is greater than average height and weight - She has had several previous pregnancies. - She has a family history of dizygotic twinning, especially a mother who is a twin. Women undergoing certain fertility treatments may have a greater chance of dizygotic multiple births. This can vary depending on what types of fertility treatments are used. With in vitro fertilisation (IVF), this is primarily due to the insertion of multiple embryos into the uterus. Some other treatments such as the drug Clomid can stimulate a woman to release multiple eggs, allowing the possibility of multiples. Many fertility treatments have no effect on the likelihood of multiple births. There is also speculation that the West African predisposition to twinning is due to the large amount of yams in their diet because yams contain phytoestrogens, which may stimulate the ovaries. Most likely this is nothing but a myth, as phytoestrogens would tend to suppress twinning by reducing gonadotropin levels. # Complications of twin pregnancy ## Vanishing twins Researchers suspect that as many as 1 in 8 pregnancies start out as multiples, but only a single fetus is brought to full term, because the other has died very early in the pregnancy and not been detected or recorded. Early obstetric ultrasonography exams sometimes reveal an "extra" fetus, which fails to develop and instead disintegrates and vanishes. This is known as vanishing twin syndrome. ## Conjoined twins Conjoined twins (or "Siamese twins") are monozygotic twins whose bodies are joined together at birth. This occurs where the single zygote of identical twins fails to separate completely, and the zygote starts to split after day 13 following fertilization. This condition occurs in about 1 in 50,000 human pregnancies. Most conjoined twins are now evaluated for surgery to attempt to separate them into separate functional bodies. The degree of difficulty rises if a vital organ or structure is shared between twins, such as brain, heart or liver. ## Chimerism A chimera is an ordinary person or animal except that some of his or her parts actually came from his or her twin or from the mother. A chimera may arise either from identical twin fetuses (where it would be impossible to detect), or from dizygotic fetuses, which can be identified by chromosomal comparisons from various parts of the body. The number of cells derived from each fetus can vary from one part of the body to another, and often leads to characteristic mosaicism skin colouration in human chimeras. A chimera may be a hermaphrodite, composed of cells from a male twin and a female twin. ## Parasitic twins Sometimes one twin fetus will fail to develop completely and continue to cause problems for its surviving twin. One fetus acts as a parasite towards the other. Sometimes the parasitic twin becomes an almost indistinguishable part of the other. ## Partial molar twins A very rare type of parasitic twinning is where a single viable twin is endangered when the other zygote becomes cancerous, or molar. This means that the molar zygote's cellular division continues unchecked, resulting in a cancerous growth that overtakes the viable fetus. Typically, this results when one twin has either triploidy or complete paternal uniparental disomy, resulting in little or no fetus and a cancerous, overgrown placenta, resembling a bunch of grapes. ## Miscarried twin Occasionally, a woman will suffer a miscarriage early in pregnancy, yet the pregnancy will continue; one twin was miscarried but the other was able to be carried to term. This occurrence is similar to the vanishing twin syndrome. ## Low birth weight Twins typically suffer from the lower birth weights and greater likelihood of prematurity that is more commonly associated with the higher multiple pregnancies. Throughout their lives twins tend to be smaller than singletons on average. ### Twin-to-twin transfusion syndrome Identical twins who share a placenta can develop twin-to-twin transfusion syndrome. This condition means that blood from one twin is being diverted into the other twin. One twin, the 'donor' twin, is small and anemic, the other, the 'recipient' twin, is large and polycythemic. The lives of both twins are endangered by this condition. # Human twin studies Twin studies are studies that assess identical (monozygotic) twins for medical, genetic, or psychological characteristics to try to isolate genetic influence from environmental influence. Twins that have been separated early in life and raised in separate households are especially sought-after for these studies, which have been invaluable in the exploration of human nature. # Unusual twinnings There are some patterns of twinning that are exceedingly rare: while they have been reported to happen, they are so unusual that most obstetricians or midwives may go their entire careers without encountering a single case. Among fraternal twins, in rare cases, the eggs are fertilized at different times with two or more acts of sexual intercourse, either within one menstrual cycle (superfecundation) or, even more rarely, later on in the pregnancy (superfetation). This can lead to the possibility of a woman carrying fraternal twins with different fathers (that is, half-siblings). This phenomenon is known as heteropaternal superfecundation. One 1992 study estimates that the frequency of heteropaternal superfecundation among dizygotic twins whose parents were involved in paternity suits was approximately 2.4%; see the references section, below, for more details. Fraternal twins from biracial couples can sometimes be mixed twins - which exhibit differing ethnic and racial features. Among monozygotic twins, in extremely rare cases, twins have been born with opposite sexes (one male, one female). The probability of this is so vanishingly small (only 3 documented cases[21]) that multiples having different sexes is universally accepted as a sound basis for a clinical determination that in utero multiples are not monozygotic. When monozygotic twins are born with different sexes it is because of chromosomal birth defects. In this case, although the twins did come from the same egg, it is incorrect to refer to them as genetically identical, since they have different karyotypes. The Largest Annual Gathering of Twins takes place in Twinsburg, Ohio every year on the first full weekend of August. Over three thousand sets of twins typically attend the weekend-long event.[22] # Animal twins Twins are common in many animal species, such as cats, sheep, ferrets and deer. The incidence of twinning among cattle is about 1-4%, and research is underway to improve the odds of twinning, which can be more profitable for the breeder if complications can be sidestepped or managed. A species of armadillo (Dasypus novemcinctus) has identical twins (usually four babies) as its regular reproduction and not as exceptional cases.[citation needed]

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

d6d0e50f7ec79b7ca791a8eac976ea6137bc57a5

wikidoc

Dust

Dust Dust is a general name for minute solid particles with diameters less than 500 micrometers. On Earth, dust occurs in the atmosphere from various sources; soil dust lifted up by wind, volcanic eruptions, and pollution are some examples. Airborne dust is considered an aerosol and can have a strong local radiative forcing on the atmosphere and significant effects on climate. In addition, if enough of the minute particles are dispersed within the air in a given area (such as flour or coal dust), under certain circumstances this can be an explosion hazard. Coal dust is responsible for the lung disease known as Pneumoconiosis, including black lung disease, which occurs among coal miners. This danger has resulted in a number of laws regulating environmental standards for working conditions. # Dust in outer space Cosmic dust is widely present in space, where gas and dust clouds are primary precursors for planetary systems. The zodiacal light, seen in the sky on a dark night, is produced by sunlight reflected from particles of dust in orbit around the Sun. The tails of comets are produced by emissions of dust and ionized gas from the body of the comet. Dust also covers solid planetary bodies, and vast dust storms can occur on Mars that can cover almost the entire planet. Interstellar dust is found between the stars, and high concentrations can produce diffuse nebulae and reflection nebulae. Dust samples returned from outer space could provide information about conditions in the early solar system. Several spacecraft have been launched in an attempt to gather samples of dust and other materials. Among these was Stardust, which flew past Comet Wild 2 in 2004 and returned a capsule of the comet's remains to Earth in January 2006. The Japanese Hayabusa spacecraft is currently on a mission to collect samples of dust from the surface of an asteroid. # Domestic dust Dust in homes, offices, and other human environments consists of human skin cells, plant pollen, human and animal hairs, textile fibers, paper fibers, minerals from outdoor soil and dust, and many other materials which may be found in the local environment. The precise composition of domestic dust can vary widely: The quantity and composition of house dust varies greatly with seasonal and environmental factors such as the surroundings, exchange of outside air, age of the house, building materials and their condition, and the quantity of furniture and carpets, as well as their state of preservation. It varies further with ventilation and heating systems, cleaning habits, activities of the occupants or users of a room, etc. House dust consists of inorganic and organic matter, yet the relative proportions of these components may vary considerably. "House dust" from kindergartens often consists almost completely of inorganic materials such as sand, loam, and clay from sand pits. On the other hand, house dust from residences of animal owners with worn out carpets may consist nearly completely of organic material. The proportion of organic matter in 318 house dust samples was found to vary between 95% (Butte and Walker, 1994). Fergusson et al. (1986) reported the organic content of house dust from 11 homes in Christchurch, New Zealand, to be within the range from 25.7% to 41.5%. Floor dust from seven Danish offices had a mean organic fraction of 33% (Mølhave et al., 2000). According to the German Environmental Survey, approximately 6 mg/m²/day of house dust is formed in private households, depending primarily on the amount of time spent at home. Nearly 1000 dust particles per square centimeter settle on domestic surfaces every hour. Some dust consists of human skin; it is estimated that the entire outer layer of skin is shed every day or two at a rate of 7 million skin flakes per minute, which corresponds to a mass emission rate of about 20 mg/minute. Insects and other small fauna found in houses have their own subtle interactions with dust that may have adverse impact on the health of its regular occupants. Thus, in many climates it is wise to keep a modicum of airflow going through a house, by keeping doors and windows open or at least slightly ajar. In colder climates, it is essential to manage dust and airflow, since the climate encourages occupants to seal even the smallest air gaps, and thus eliminate any possibility of fresh air entering. House dust mites are on all surfaces and even suspended in air. Dust mites feed on minute particles of organic matter, the main constituent of house dust. They excrete enzymes to digest dust particles; these enzymes and their feces, in turn, become part of house dust and can provoke allergic reactions in humans. Dust mites flourish in the fibers of bedding, furniture, and carpets. The particles that make up house dust can easily become airborne, so care must be exercised when removing dust, as the activity intended to sanitize or remove dust may make it airborne. One way to repel dust is with some kind of electrical charge, but house dust can be removed by many methods, including wiping, swiping, or sweeping by hand, or with a dust cloth, sponge, feather duster, or broom, or by suction by a vacuum cleaner or air filter. The device being used traps the dust; however, some may become airborne and come to settle in the cleaner's lungs, thus making the activity somewhat hazardous. "Dust bunnies" are little clumps of fluff that form when sufficient dust accumulates. Dust is known to worsen hay fever. # Dust control Dust control is the suppression of solid particles with diameters less than 500 micrometers. Because dust in the air is a serious health threat to children, older people, and those with respiratory illnesses, the U. S. Environment Protection Agency (EPA) mandates facilities that generate dust must work to minimize it in their operations. The most frequent dust control violations occurred at new residential housing developments in urban areas. Federal law requires permits for earth moving at construction sites, include plans to control dust emissions. Control measures include such simple practices as watering down construction and demolition sites, as well as preventing dust from being tracked out onto adjacent roads. In addition, federal laws require dust controls on sources such as vacant lots, unpaved parking lots, and unpaved roads. Control measures for these sources include paving, gravel, or stabilizing the surface with water or other dust suppressants. # Dust in fiction - In JM Barrie's children's novel Peter Pan (1911), "pixie dust" is a substance used to help make people fly who can't already. - In Clark Ashton Smith's short horror story "The Treader In The Dust" (1935) , a scholar unwittingly calls forth a demon that personifies dustiness. - In Arthur C. Clarke's A Fall of Moondust (1961), 21st century tourists "cruise" across the Moon's "Seas" that have filled over eons with very fine dust, which is so fine that it almost behaves like water. - In Hal Clement's short science fiction story "Dust Rag" (1965), two astronauts struggle with dust that stuck to their helmets, blinding them. - In the science fiction series Babylon 5, Dust was a psychoactive illegal drug that enhanced latent telepathic abilities in non-humanoids, that often led to fatalities in both the user and "victim". - In the novel by Phillip Pullman, His Dark Materials trilogy referrs to a shadow particle that created angels and is a concious particle. It created the first angel, the Authority, not God, and in the trilogy a young girl named Lyra and a boy name Will try to find out what Dust is in order to save it and destroy the Authority thus building a Republic of Heaven that lets the dead rise again. (1995-2000) - In the T.V. series Buffy the Vampire Slayer by Joss Whedon, vampires are reduced to dust when staked- or "dusted"- a reference to earlier mythology in which vampires consist of earth or dust. # Dust in religion In ancient Sumerian mythology: - The afterlife consists of the dreary "House of Dust and Darkness". In the Bible: - In Genesis 3:19, God — following The Fall, Adam and Eve's transgression — states to the couple: This latter clause is used in the Ash Wednesday service in some churches for the administering of ashes, and is adapted in funeral services to the common prayer "Dust to Dust". - In Genesis 13:16, God states to Abram (later Abraham): Note however that in both of these Biblical passages, the Hebrew word is עפר (`âfâr), which can also mean earth or dirt. - Micah 7:17, "They shall lick dust like a serpent..." - John 8:1-11 features Jesus "writing on the ground." Many translators substitute "dust" for "ground". This scripture provides the only witness of any writing by Jesus. The choice of dust as a medium for writing has created speculation as to what Jesus wrote.

Dust Template:Wiktionarypar Dust is a general name for minute solid particles with diameters less than 500 micrometers. On Earth, dust occurs in the atmosphere from various sources; soil dust lifted up by wind, volcanic eruptions, and pollution are some examples. Airborne dust is considered an aerosol and can have a strong local radiative forcing on the atmosphere and significant effects on climate. In addition, if enough of the minute particles are dispersed within the air in a given area (such as flour or coal dust), under certain circumstances this can be an explosion hazard. Coal dust is responsible for the lung disease known as Pneumoconiosis, including black lung disease, which occurs among coal miners. This danger has resulted in a number of laws regulating environmental standards for working conditions. # Dust in outer space Cosmic dust is widely present in space, where gas and dust clouds are primary precursors for planetary systems. The zodiacal light, seen in the sky on a dark night, is produced by sunlight reflected from particles of dust in orbit around the Sun. The tails of comets are produced by emissions of dust and ionized gas from the body of the comet. Dust also covers solid planetary bodies, and vast dust storms can occur on Mars that can cover almost the entire planet. Interstellar dust is found between the stars, and high concentrations can produce diffuse nebulae and reflection nebulae. Dust samples returned from outer space could provide information about conditions in the early solar system. Several spacecraft have been launched in an attempt to gather samples of dust and other materials. Among these was Stardust, which flew past Comet Wild 2 in 2004 and returned a capsule of the comet's remains to Earth in January 2006. The Japanese Hayabusa spacecraft is currently on a mission to collect samples of dust from the surface of an asteroid. # Domestic dust Dust in homes, offices, and other human environments consists of human skin cells, plant pollen, human and animal hairs, textile fibers, paper fibers, minerals from outdoor soil and dust, and many other materials which may be found in the local environment.[1] The precise composition of domestic dust can vary widely: The quantity and composition of house dust varies greatly with seasonal and environmental factors such as the surroundings, exchange of outside air, age of the house, building materials and their condition, and the quantity of furniture and carpets, as well as their state of preservation. It varies further with ventilation and heating systems, cleaning habits, activities of the occupants or users of a room, etc. House dust consists of inorganic and organic matter, yet the relative proportions of these components may vary considerably. "House dust" from kindergartens often consists almost completely of inorganic materials such as sand, loam, and clay from sand pits. On the other hand, house dust from residences of animal owners with worn out carpets may consist nearly completely of organic material. The proportion of organic matter in 318 house dust samples was found to vary between <5% and >95% (Butte and Walker, 1994). Fergusson et al. (1986) reported the organic content of house dust from 11 homes in Christchurch, New Zealand, to be within the range from 25.7% to 41.5%. Floor dust from seven Danish offices had a mean organic fraction of 33% (Mølhave et al., 2000).[2] According to the German Environmental Survey, approximately 6 mg/m²/day of house dust is formed in private households,[3] depending primarily on the amount of time spent at home. Nearly 1000 dust particles per square centimeter settle on domestic surfaces every hour.[1] Some dust consists of human skin; it is estimated that the entire outer layer of skin is shed every day or two at a rate of 7 million skin flakes per minute, which corresponds to a mass emission rate of about 20 mg/minute.[4] Insects and other small fauna found in houses have their own subtle interactions with dust that may have adverse impact on the health of its regular occupants. Thus, in many climates it is wise to keep a modicum of airflow going through a house, by keeping doors and windows open or at least slightly ajar. In colder climates, it is essential to manage dust and airflow, since the climate encourages occupants to seal even the smallest air gaps, and thus eliminate any possibility of fresh air entering. House dust mites are on all surfaces and even suspended in air. Dust mites feed on minute particles of organic matter, the main constituent of house dust. They excrete enzymes to digest dust particles; these enzymes and their feces, in turn, become part of house dust and can provoke allergic reactions in humans. Dust mites flourish in the fibers of bedding, furniture, and carpets. The particles that make up house dust can easily become airborne, so care must be exercised when removing dust, as the activity intended to sanitize or remove dust may make it airborne. One way to repel dust is with some kind of electrical charge, but house dust can be removed by many methods, including wiping, swiping, or sweeping by hand, or with a dust cloth, sponge, feather duster, or broom, or by suction by a vacuum cleaner or air filter. The device being used traps the dust; however, some may become airborne and come to settle in the cleaner's lungs, thus making the activity somewhat hazardous. "Dust bunnies" are little clumps of fluff that form when sufficient dust accumulates. Dust is known to worsen hay fever. # Dust control Dust control is the suppression of solid particles with diameters less than 500 micrometers. Because dust in the air is a serious health threat to children, older people, and those with respiratory illnesses, the U. S. Environment Protection Agency (EPA) mandates facilities that generate dust must work to minimize it in their operations. The most frequent dust control violations occurred at new residential housing developments in urban areas. Federal law requires permits for earth moving at construction sites, include plans to control dust emissions. Control measures include such simple practices as watering down construction and demolition sites, as well as preventing dust from being tracked out onto adjacent roads. In addition, federal laws require dust controls on sources such as vacant lots, unpaved parking lots, and unpaved roads. Control measures for these sources include paving, gravel, or stabilizing the surface with water or other dust suppressants. # Dust in fiction Template:Trivia - In JM Barrie's children's novel Peter Pan (1911), "pixie dust" is a substance used to help make people fly who can't already. - In Clark Ashton Smith's short horror story "The Treader In The Dust" (1935) [1], a scholar unwittingly calls forth a demon that personifies dustiness. - In Arthur C. Clarke's A Fall of Moondust (1961), 21st century tourists "cruise" across the Moon's "Seas" that have filled over eons with very fine dust, which is so fine that it almost behaves like water. - In Hal Clement's short science fiction story "Dust Rag" (1965), two astronauts struggle with dust that stuck to their helmets, blinding them. - In the science fiction series Babylon 5, Dust was a psychoactive illegal drug that enhanced latent telepathic abilities in non-humanoids, that often led to fatalities in both the user and "victim". - In the novel by Phillip Pullman, His Dark Materials trilogy referrs to a shadow particle that created angels and is a concious particle. It created the first angel, the Authority, not God, and in the trilogy a young girl named Lyra and a boy name Will try to find out what Dust is in order to save it and destroy the Authority thus building a Republic of Heaven that lets the dead rise again. (1995-2000) - In the T.V. series Buffy the Vampire Slayer by Joss Whedon, vampires are reduced to dust when staked- or "dusted"- a reference to earlier mythology in which vampires consist of earth or dust. # Dust in religion In ancient Sumerian mythology: - The afterlife consists of the dreary "House of Dust and Darkness". In the Bible: - In Genesis 3:19, God — following The Fall, Adam and Eve's transgression — states to the couple: This latter clause is used in the Ash Wednesday service in some churches for the administering of ashes, and is adapted in funeral services to the common prayer "Dust to Dust". - In Genesis 13:16, God states to Abram (later Abraham): Note however that in both of these Biblical passages, the Hebrew word is עפר (`âfâr), which can also mean earth or dirt. - Micah 7:17, "They shall lick dust like a serpent..." - John 8:1-11 features Jesus "writing on the ground." Many translators substitute "dust" for "ground". This scripture provides the only witness of any writing by Jesus. The choice of dust as a medium for writing has created speculation as to what Jesus wrote.

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

97f2c800d1f70331a9855082fff4b50a88d2482f

wikidoc

E2F1

E2F1 Transcription factor E2F1 is a protein that in humans is encoded by the E2F1 gene. # Function The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses. The E2F proteins contain several evolutionarily conserved domains found in most members of the family. These domains include a DNA binding domain, a dimerization domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids, and a tumor suppressor protein association domain which is embedded within the transactivation domain. This protein and another 2 members, E2F2 and E2F3, have an additional cyclin binding domain. This protein binds preferentially to retinoblastoma protein pRB in a cell-cycle dependent manner. It can mediate both cell proliferation and p53-dependent/independent apoptosis. # Transcription E2F1 promoter => E2F1 .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}PMID 21602887 # Interactions E2F1 has been shown to interact with: - ARID3A, - CUL1, - Cyclin A1, - Cyclin A2, - GTF2H1, - MDM4, - NCOA6, - NDN, - NPDC1, - PURA, - PHB, - RB1, - RBL1, - SKP2, - SP1, - SP2, - SP3, - SP4, - TFDP1 - TOPBP1, - TP53BP1, and - UBC.

E2F1 Transcription factor E2F1 is a protein that in humans is encoded by the E2F1 gene.[1] # Function The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses. The E2F proteins contain several evolutionarily conserved domains found in most members of the family. These domains include a DNA binding domain, a dimerization domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids, and a tumor suppressor protein association domain which is embedded within the transactivation domain. This protein and another 2 members, E2F2 and E2F3, have an additional cyclin binding domain. This protein binds preferentially to retinoblastoma protein pRB in a cell-cycle dependent manner. It can mediate both cell proliferation and p53-dependent/independent apoptosis.[2] # Transcription E2F1 promoter[PAX8] => E2F1 .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}PMID 21602887 # Interactions E2F1 has been shown to interact with: - ARID3A,[3] - CUL1,[4] - Cyclin A1,[5] - Cyclin A2,[6] - GTF2H1,[7] - MDM4,[8] - NCOA6,[9] - NDN,[10][11] - NPDC1,[12] - PURA,[13] - PHB,[14][15][16][17] - RB1,[10][18][19][20][21][22][23] - RBL1,[18] - SKP2,[4] - SP1,[24][25][26] - SP2,[24] - SP3,[24] - SP4,[24] - TFDP1[3][23][27][28] - TOPBP1,[29][30] - TP53BP1,[21] and - UBC.[31]

https://www.wikidoc.org/index.php/E2F1

480b6a906aac8222fb44e9e3a52f57ca5b256b83

wikidoc

E2F4

E2F4 Transcription factor E2F4 is a protein that in humans is encoded by the E2F4 gene. # Function Gene ID: 1874 E2F transcription factor 4, "The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses. The E2F proteins contain several evolutionally conserved domains found in most members of the family. These domains include a DNA binding domain, a dimerization domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids, and a tumor suppressor protein association domain which is embedded within the transactivation domain. This protein binds to all three of the tumor suppressor proteins pRB, p107 and p130, but with higher affinity to the last two. It plays an important role in the suppression of proliferation-associated genes, and its gene mutation and increased expression may be associated with human cancer." # Structure The E2F proteins contain several evolutionally conserved domains found in most members of the family. These domains include a DNA binding domain, a dimerization domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids (Asp + Glu), and a tumor suppressor protein association domain which is embedded within the transactivation domain. # Interactions E2F4 has been shown to interact with Smad3. # Clinical significance ## Colorectal cancers "The AGC triplet repeat in the coding region of the E2F-4 gene, a member of the family, has been reported to be mutated in colorectal cancers with a microsatellite instability (MSI) phenotype. We found a wider range variation of the repeat number in DNAs from tumors, the corresponding normal mucosa, and healthy individuals. A total of 5 repeat variants, ranging from 8 to 17 AGC repeats, was detected in 6 (9.7%) of the 62 healthy individuals and 8 (8.9%) of the 90 normal DNAs of the patients. The wild-type 13 repeat was present in all of these individuals. The variation of the AGC repeat number may be a polymorphism. Further, loss of heterozygosity (LOH) at the E2F-4 locus in the tumor tissues of 2 (25%) of the 8 informative cases was detected."

E2F4 Associate Editor(s)-in-Chief: Henry A. Hoff Transcription factor E2F4 is a protein that in humans is encoded by the E2F4 gene.[1][2] # Function Gene ID: 1874 E2F transcription factor 4, "The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses. The E2F proteins contain several evolutionally conserved domains found in most members of the family. These domains include a DNA binding domain, a dimerization domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids, and a tumor suppressor protein association domain which is embedded within the transactivation domain. This protein binds to all three of the tumor suppressor proteins pRB, p107 and p130, but with higher affinity to the last two. It plays an important role in the suppression of proliferation-associated genes, and its gene mutation and increased expression may be associated with human cancer."[3] # Structure The E2F proteins contain several evolutionally conserved domains found in most members of the family. These domains include a DNA binding domain, a dimerization domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids (Asp + Glu), and a tumor suppressor protein association domain which is embedded within the transactivation domain. # Interactions E2F4 has been shown to interact with Smad3.[4] # Clinical significance ## Colorectal cancers "The AGC triplet repeat in the coding region of the E2F-4 gene, a member of the family, has been reported to be mutated in colorectal cancers with a microsatellite instability (MSI) phenotype. We found a wider range variation of the repeat number in DNAs from tumors, the corresponding normal mucosa, and healthy individuals. A total of 5 repeat variants, ranging from 8 to 17 AGC repeats, was detected in 6 (9.7%) of the 62 healthy individuals and 8 (8.9%) of the 90 normal DNAs of the patients. The wild-type 13 repeat was present in all of these individuals. The variation of the AGC repeat number may be a polymorphism. Further, loss of heterozygosity (LOH) at the E2F-4 locus in the tumor tissues of 2 (25%) of the 8 informative cases was detected."[5]

https://www.wikidoc.org/index.php/E2F4

3776ed5aa269ee9619c34f8ce75b811be9489989

wikidoc

EBF1

EBF1 Transcription factor COE1 is a protein that in humans is encoded by the EBF1 gene. EBF1 stands for Early B-Cell Factor 1. EBF1 controls the expression of key proteins required for B cell differentiation, signal transduction and function. The crucial role of this factor is shown in the regulation of expression of SLAM family co-receptors in B-cells. # Interactions EBF1 has been shown to interact with ZNF423 and CREB binding protein.

EBF1 Transcription factor COE1 is a protein that in humans is encoded by the EBF1 gene. EBF1 stands for Early B-Cell Factor 1.[1][2][3] EBF1 controls the expression of key proteins required for B cell differentiation, signal transduction and function.[4][5] The crucial role of this factor is shown in the regulation of expression of SLAM family co-receptors in B-cells.[6] # Interactions EBF1 has been shown to interact with ZNF423[7] and CREB binding protein.[8]

https://www.wikidoc.org/index.php/EBF1

90561ccb72ad4005cb20ccdee5ca63685495d82a

wikidoc

EBI3

EBI3 Epstein-Barr virus induced gene 3, also known as interleukin-27 subunit beta or IL-27B, is a protein which in humans is encoded by the EBI3 gene. # Function This gene was identified by the induction of its expression in B lymphocytes by Epstein-Barr virus infection. The protein encoded by this gene is a secreted glycoprotein, which is a member of the hematopoietin receptor family related to the p40 subunit of interleukin 12 (IL-12). It plays a role in regulating cell-mediated immune responses. EBI3 is a subunit in 2 distinct heterodimeric cytokines: interleukin-27 (IL27) and IL35. IL27 is composed of p28 (IL27) and EBI3. IL27 can trigger signaling in T cells, B cells, and myeloid cells. IL35, an inhibitory cytokine involved in regulatory T-cell function, is composed of EBI3 and the p35 subunit of IL12.

EBI3 Epstein-Barr virus induced gene 3, also known as interleukin-27 subunit beta or IL-27B, is a protein which in humans is encoded by the EBI3 gene.[1][2] # Function This gene was identified by the induction of its expression in B lymphocytes by Epstein-Barr virus infection. The protein encoded by this gene is a secreted glycoprotein, which is a member of the hematopoietin receptor family related to the p40 subunit of interleukin 12 (IL-12). It plays a role in regulating cell-mediated immune responses.[3] EBI3 is a subunit in 2 distinct heterodimeric cytokines: interleukin-27 (IL27) and IL35. IL27 is composed of p28 (IL27) and EBI3. IL27 can trigger signaling in T cells, B cells, and myeloid cells.[4] IL35, an inhibitory cytokine involved in regulatory T-cell function, is composed of EBI3 and the p35 subunit of IL12.[3][5]

https://www.wikidoc.org/index.php/EBI3

1ffa47c4654cd1b1449d49ab09fe96f7291bb879

wikidoc

EEA1

EEA1 The gene EEA1 encodes for the 1400 amino acid protein, Early Endosome Antigen 1. EEA1 localizes exclusively to early endosomes and has an important role in endosomal trafficking. EEA1 binds directly to the phospholipid phosphatidylinositol 3-phosphate through its C-terminal FYVE domain and forms a homodimer through a coiled coil. EEA1 acts as a tethering molecule that couples vesicle docking with SNAREs such as N-ethylmaleimide sensitive fusion protein, bringing the endosomes physically closer and ultimately resulting in the fusion and delivery of endosomal cargo. # Function EEA1 is a RAB5A effector protein which binds via an N-terminal zinc finger domain and is required for fusion of early and late endosomes and for sorting at the early endosome level. # Involvement in pathogenesis Due to the proteins importance in vesicular trafficking, a number of intracellular bacteria prevent EEA1 recruitment to the vacuole. Mycobacterium tuberculosis is known to inhibit the recruitment of EEA1 to the phagosomal membrane through CamKII. Legionella pneumophila also prevents EEA1 recruitment through a currently unknown mechanism. The related pathogen Legionella longbeachae recruits EEA1 and appears to replicate within a modified early endosome.

EEA1 The gene EEA1 encodes for the 1400 amino acid protein, Early Endosome Antigen 1. EEA1 localizes exclusively to early endosomes and has an important role in endosomal trafficking. EEA1 binds directly to the phospholipid phosphatidylinositol 3-phosphate through its C-terminal FYVE domain and forms a homodimer through a coiled coil. EEA1 acts as a tethering molecule that couples vesicle docking with SNAREs such as N-ethylmaleimide sensitive fusion protein, bringing the endosomes physically closer and ultimately resulting in the fusion and delivery of endosomal cargo. # Function EEA1 is a RAB5A effector protein which binds via an N-terminal zinc finger domain and is required for fusion of early and late endosomes and for sorting at the early endosome level.[1][2] # Involvement in pathogenesis Due to the proteins importance in vesicular trafficking, a number of intracellular bacteria prevent EEA1 recruitment to the vacuole. Mycobacterium tuberculosis is known to inhibit the recruitment of EEA1 to the phagosomal membrane through CamKII.[3] Legionella pneumophila also prevents EEA1 recruitment through a currently unknown mechanism.[4] The related pathogen Legionella longbeachae recruits EEA1 and appears to replicate within a modified early endosome.[5]

https://www.wikidoc.org/index.php/EEA1

d479584d908353f7e7bebce22faf6a38f0ef0a25

wikidoc

EEF2

EEF2 Eukaryotic elongation factor 2 is a protein that in humans is encoded by the EEF2 gene. This gene encodes a member of the GTP-binding translation elongation factor family. This protein is an essential factor for protein synthesis. It promotes the GTP-dependent translocation of the ribosome. This protein is completely inactivated by EF-2 kinase phosphorylation. EEF2 contains a post transcriptionally modified histadine diphthamide. It is the target of diphtheria toxin (from Corynebacterium diphtheriae), and exotoxin A (from Pseudomonas aeruginosa). The inactivation of EF-2 by toxins inhibits protein production in the host, causing symptoms due to loss of function in affected cells.

EEF2 Eukaryotic elongation factor 2 is a protein that in humans is encoded by the EEF2 gene.[1][2][3] This gene encodes a member of the GTP-binding translation elongation factor family. This protein is an essential factor for protein synthesis. It promotes the GTP-dependent translocation of the ribosome. This protein is completely inactivated by EF-2 kinase phosphorylation.[3] EEF2 contains a post transcriptionally modified histadine diphthamide. It is the target of diphtheria toxin (from Corynebacterium diphtheriae), and exotoxin A (from Pseudomonas aeruginosa).[4] The inactivation of EF-2 by toxins inhibits protein production in the host, causing symptoms due to loss of function in affected cells.

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EGR1

EGR1 EGR-1 (Early growth response protein 1) also known as Zif268 (zinc finger protein 225) or NGFI-A (nerve growth factor-induced protein A) is a protein that in humans is encoded by the EGR1 gene. EGR-1 is a mammalian transcription factor. It was also named Krox-24, TIS8, and ZENK. It was originally discovered in mice. # Function The protein encoded by this gene belongs to the EGR family of Cys2His2-type zinc finger proteins. It is a nuclear protein and functions as a transcriptional regulator. The products of target genes it activates are required for differentiation and mitogenesis. Studies suggest this is a tumor suppressor gene. It has a distinct pattern of expression in the brain, and its induction has been shown to be associated with neuronal activity. Several studies suggest it has a role in neuronal plasticity. EGR-1 has also been found to regulate the expression of VAMP2 (a protein important for synaptic exocytosis). # Structure The DNA-binding domain of EGR-1 consists of three zinc finger domains of the Cys2His2 type. The amino acid structure of the EGR-1 zinc finger domain is given in this table, using the single letter amino acid code. The fingers 1 to 3 are indicated by f1 - f3. The numbers are in reference to the residues (amino acids) of alpha helix (there is no zero). The residues marked 'x' are not part of the zinc fingers, but rather serve to connect them all together. Amino acid key: Alanine (Ala, A), Arginine (Arg, R), Asparagine (Asn, N), Aspartic acid (Asp, D), Cysteine (Cys, C), Glutamic acid (Glu, E), Glutamine (Gln, Q), Glycine (Gly, G), Histidine (His, H), Isoleucine (Ile, I), Leucine (Leu, L), Lysine (Lys, K), Methionine (Met, M), Phenylalanine (Phe, F), Proline (Pro, P), Serine (Ser, S), Threonine (Thr, T), Tryptophan (Trp, W), Tyrosine (Tyr, Y), Valine (Val, V) The crystal structure of DNA bound by the zinc finger domain of EGR-1 was solved in 1991, which greatly aided early research in zinc finger DNA-binding domains. The human EGR-1 protein contains (in its unprocessed form) 543 amino acids with a molecular weight of 57.5 kDa, and the gene is located on the chromosome 5. # DNA binding specificity EGR-1 binds the DNA sequence 5'-GCG TGG GCG-3' (and similar ones like 5'-GCG GGG GCG-3'). The f1 position 6 binds the 5' G (the first base count from the left); the f1 position 3 to the second base (C); f1 position -1 binds to the third position (G); f2 position 6 to the fourth base (T); and so on. # Interactions EGR-1 has been shown to interact with: - CEBPB, - CREB-binding protein, - EP300, - NAB1, - P53, and - PSMA3

EGR1 EGR-1 (Early growth response protein 1) also known as Zif268 (zinc finger protein 225) or NGFI-A (nerve growth factor-induced protein A) is a protein that in humans is encoded by the EGR1 gene. EGR-1 is a mammalian transcription factor. It was also named Krox-24, TIS8, and ZENK. It was originally discovered in mice. # Function The protein encoded by this gene belongs to the EGR family of Cys2His2-type zinc finger proteins. It is a nuclear protein and functions as a transcriptional regulator. The products of target genes it activates are required for differentiation and mitogenesis. Studies suggest this is a tumor suppressor gene.[1] It has a distinct pattern of expression in the brain, and its induction has been shown to be associated with neuronal activity. Several studies suggest it has a role in neuronal plasticity.[2] EGR-1 has also been found to regulate the expression of VAMP2 (a protein important for synaptic exocytosis).[3] # Structure The DNA-binding domain of EGR-1 consists of three zinc finger domains of the Cys2His2 type. The amino acid structure of the EGR-1 zinc finger domain is given in this table, using the single letter amino acid code. The fingers 1 to 3 are indicated by f1 - f3. The numbers are in reference to the residues (amino acids) of alpha helix (there is no zero). The residues marked 'x' are not part of the zinc fingers, but rather serve to connect them all together. Amino acid key: Alanine (Ala, A), Arginine (Arg, R), Asparagine (Asn, N), Aspartic acid (Asp, D), Cysteine (Cys, C), Glutamic acid (Glu, E), Glutamine (Gln, Q), Glycine (Gly, G), Histidine (His, H), Isoleucine (Ile, I), Leucine (Leu, L), Lysine (Lys, K), Methionine (Met, M), Phenylalanine (Phe, F), Proline (Pro, P), Serine (Ser, S), Threonine (Thr, T), Tryptophan (Trp, W), Tyrosine (Tyr, Y), Valine (Val, V) The crystal structure of DNA bound by the zinc finger domain of EGR-1 was solved in 1991, which greatly aided early research in zinc finger DNA-binding domains.[4] The human EGR-1 protein contains (in its unprocessed form) 543 amino acids with a molecular weight of 57.5 kDa, and the gene is located on the chromosome 5. # DNA binding specificity EGR-1 binds the DNA sequence 5'-GCG TGG GCG-3' (and similar ones like 5'-GCG GGG GCG-3').[5][6] The f1 position 6 binds the 5' G (the first base count from the left); the f1 position 3 to the second base (C); f1 position -1 binds to the third position (G); f2 position 6 to the fourth base (T); and so on. # Interactions EGR-1 has been shown to interact with: - CEBPB,[7] - CREB-binding protein,[8] - EP300,[8] - NAB1,[9] - P53,[10] and - PSMA3[11]

https://www.wikidoc.org/index.php/EGR1

f95a21e434118596ed50b2b90d445838a6b57cc7

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EGR2

EGR2 Early growth response protein 2 is a protein that in humans is encoded by the EGR2 gene. EGR2 (also termed Krox20) is a transcription regulatory factor, containing two zinc finger DNA-binding sites, and is highly expressed in a population of migrating neural crest cells. It is later expressed in the neural crest derived cells of the cranial ganglion. The protein encoded by Krox20 contains two cys2his2-type zinc fingers. Krox20 gene expression is restricted to the early hindbrain development. It is evolutionarily conserved in vertebrates, humans, mice, chicks, and zebra fish. In addition, the amino acid sequence and most aspects of the embryonic gene pattern is conserved among vertebrates, further implicating its role in hindbrain development. When the Krox20 is deleted in mice, the protein coding ability of the Krox20 gene (including the DNA-binding domain of the zinc finger) is diminished. These mice are unable to survive after birth and exhibit major hindbrain defects. These defects include but are not limited to defects in formation of cranial sensory ganglia, partial fusion of the trigeminal nerve (V) with the facial (VII) and auditory (VII) nerves, the proximal nerve roots coming off of these ganglia were disorganized and intertwined among one another as they entered the brainstem, and there was fusion of the glossopharyngeal (IX) nerve complex. # Function The early growth response protein 2 is a transcription factor with three tandem C2H2-type zinc fingers. Mutations in this gene are associated with the autosomal dominant Charcot-Marie-Tooth disease, type 1D, Dejerine–Sottas disease, and Congenital Hypomyelinating Neuropathy. Two studies have linked EGR2 expression to proliferation of osteoprogenitors and cell lines derived from Ewing sarcoma, which is a highly aggressive bone-associated cancer. New research suggests that Krox20 - or the lack of it - is the reason for male baldness.

EGR2 Early growth response protein 2 is a protein that in humans is encoded by the EGR2 gene. EGR2 (also termed Krox20) is a transcription regulatory factor, containing two zinc finger DNA-binding sites, and is highly expressed in a population of migrating neural crest cells.[1][2][3] It is later expressed in the neural crest derived cells of the cranial ganglion. The protein encoded by Krox20 contains two cys2his2-type zinc fingers. Krox20 gene expression is restricted to the early hindbrain development.[2][4] It is evolutionarily conserved in vertebrates, humans, mice, chicks, and zebra fish.[5] In addition, the amino acid sequence and most aspects of the embryonic gene pattern is conserved among vertebrates, further implicating its role in hindbrain development.[3][6][7][8] When the Krox20 is deleted in mice, the protein coding ability of the Krox20 gene (including the DNA-binding domain of the zinc finger) is diminished. These mice are unable to survive after birth and exhibit major hindbrain defects.[2][4] These defects include but are not limited to defects in formation of cranial sensory ganglia, partial fusion of the trigeminal nerve (V) with the facial (VII) and auditory (VII) nerves, the proximal nerve roots coming off of these ganglia were disorganized and intertwined among one another as they entered the brainstem, and there was fusion of the glossopharyngeal (IX) nerve complex.[9][10][11] # Function The early growth response protein 2 is a transcription factor with three tandem C2H2-type zinc fingers. Mutations in this gene are associated with the autosomal dominant Charcot-Marie-Tooth disease, type 1D,[12] Dejerine–Sottas disease,[13] and Congenital Hypomyelinating Neuropathy.[14] Two studies have linked EGR2 expression to proliferation of osteoprogenitors [15] and cell lines derived from Ewing sarcoma, which is a highly aggressive bone-associated cancer.[16] New research suggests that Krox20 - or the lack of it - is the reason for male baldness.[17]

https://www.wikidoc.org/index.php/EGR2

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EHD1

EHD1 EH domain-containing protein 1, also known as testilin or PAST homolog 1 (PAST1), is a protein that in humans is encoded by the EHD1 gene belonging to the EHD protein family. # Function This gene belongs to a highly conserved gene family encoding EPS15 homology (EH) domain-containing proteins. The protein-binding EH domain was first noted in EPS15, a substrate for the epidermal growth factor receptor. The EH domain has been shown to be an important motif in proteins involved in protein-protein interactions and in intracellular sorting. The protein encoded by this gene is thought to play a role in the endocytosis of IGF1 receptors. # Interactions EHD1 has been shown to interact with Insulin-like growth factor 1 receptor and SNAP29.

EHD1 EH domain-containing protein 1, also known as testilin or PAST homolog 1 (PAST1), is a protein that in humans is encoded by the EHD1 gene[1] belonging to the EHD protein family. # Function This gene belongs to a highly conserved gene family encoding EPS15 homology (EH) domain-containing proteins. The protein-binding EH domain was first noted in EPS15, a substrate for the epidermal growth factor receptor. The EH domain has been shown to be an important motif in proteins involved in protein-protein interactions and in intracellular sorting. The protein encoded by this gene is thought to play a role in the endocytosis of IGF1 receptors.[1] # Interactions EHD1 has been shown to interact with Insulin-like growth factor 1 receptor[2] and SNAP29.[2]

https://www.wikidoc.org/index.php/EHD1

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EID2

EID2 EP300 interacting inhibitor of differentiation 2, also known as EID2 is a human gene. # Function The protein encoded by this gene may function as an endogenous suppressor of TGF-beta signaling and inhibits differentiation by blocking the histone acetyltransferase activity of p300, class I histone deacetylase, HDACs. The N-terminal portion of EID-2 was required for the binding to HDACs. This region was also involved in the transcriptional repression and nuclear localization, suggesting the importance of the involvement of HDACs in the EID-2 function. EID-2 inhibits TGF-beta/Smad transcriptional responses. EID-2 interacts constitutively with Smad proteins, and most strongly with Smad3. Stable expression of EID-2 in the TGF-beta1-responsive cell line inhibits endogenous Smad3-Smad4 complex formation and TGF-beta1-induced expression of p21 and p15. EID-2 displays developmentally regulated expression with high levels in adult heart and brain. Overexpression of EID-2 inhibits muscle-specific gene expression through inhibition of MyoD-dependent transcription. This inhibitory effect on gene expression can be explained by EID-2's ability to associate with and inhibit the acetyltransferase activity of p300.

EID2 EP300 interacting inhibitor of differentiation 2, also known as EID2 is a human gene.[1] # Function The protein encoded by this gene may function as an endogenous suppressor of TGF-beta signaling and inhibits differentiation by blocking the histone acetyltransferase activity of p300, class I histone deacetylase, HDACs. The N-terminal portion of EID-2 was required for the binding to HDACs. This region was also involved in the transcriptional repression and nuclear localization, suggesting the importance of the involvement of HDACs in the EID-2 function. EID-2 inhibits TGF-beta/Smad transcriptional responses. EID-2 interacts constitutively with Smad proteins, and most strongly with Smad3. Stable expression of EID-2 in the TGF-beta1-responsive cell line inhibits endogenous Smad3-Smad4 complex formation and TGF-beta1-induced expression of p21 and p15. EID-2 displays developmentally regulated expression with high levels in adult heart and brain. Overexpression of EID-2 inhibits muscle-specific gene expression through inhibition of MyoD-dependent transcription. This inhibitory effect on gene expression can be explained by EID-2's ability to associate with and inhibit the acetyltransferase activity of p300.

https://www.wikidoc.org/index.php/EID2

22df9e097aabfe416194b927ee721b65775f86d6

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EIF1

EIF1 Eukaryotic translation initiation factor 1 (eIF1) is a protein that in humans is encoded by the EIF1 gene. eIF1 interacts with the eukaryotic small (40S) ribosomal subunit and eIF3, and is a component of the 43S preinitiation complex (PIC). eIF1 and eIF1A bind cooperatively to the 40S to stabilize an "open" conformation of the preinitiation complex (PIC) during eukaryotic translation initiation. eIF1 binds to a region near the ribosomal A-site in the 40S subunit and functions in a manner similar to the structurally related bacterial counterpart IF1. # Structure eIF1 is a conserved translation protein in all eukaryotic cells that is responsible for the investigation of codon-anticodon mismatches during the initiation of translation. In order to determine the structure of human eIF1, an experiment with N-terminal His tag and eIF1 are conducted via using NMR spectroscopy. Scientists have discovered a binding site by generating yeast mutation and study the neighbor conserved residues located in the same region. GST pull-down experiments has shown that eIF1 binds precisely to the p110 subunit of eIF3 as a result explaining eIF1 recruiting. # Function The function of eIf1 has some hidden aspects. However, in all eukaryotic cells initiation of mRNA translation starts with scanning via ribosomal 43S preinitiation complexes starting from the 5’ end of the mRNA. Next, induction via eIF1 and eIF1A are needed to disclose the conformation of the 40S subunit in order to induce DEAD-box RNA helicase eIF4A, its cofactor eIF4B, and eIF4G activity.

EIF1 Eukaryotic translation initiation factor 1 (eIF1) is a protein that in humans is encoded by the EIF1 gene.[1][2][3] eIF1 interacts with the eukaryotic small (40S) ribosomal subunit and eIF3, and is a component of the 43S preinitiation complex (PIC).[4] eIF1 and eIF1A bind cooperatively to the 40S to stabilize an "open" conformation of the preinitiation complex (PIC) during eukaryotic translation initiation.[4] eIF1 binds to a region near the ribosomal A-site in the 40S subunit and functions in a manner similar to the structurally related bacterial counterpart IF1.[5] # Structure eIF1 is a conserved translation protein in all eukaryotic cells that is responsible for the investigation of codon-anticodon mismatches during the initiation of translation. In order to determine the structure of human eIF1, an experiment with N-terminal His tag and eIF1 are conducted via using NMR spectroscopy. Scientists have discovered a binding site by generating yeast mutation and study the neighbor conserved residues located in the same region. GST pull-down experiments has shown that eIF1 binds precisely to the p110 subunit of eIF3 as a result explaining eIF1 recruiting. [6] # Function The function of eIf1 has some hidden aspects. However, in all eukaryotic cells initiation of mRNA translation starts with scanning via ribosomal 43S preinitiation complexes starting from the 5’ end of the mRNA. Next, induction via eIF1 and eIF1A are needed to disclose the conformation of the 40S subunit in order to induce DEAD-box RNA helicase eIF4A, its cofactor eIF4B, and eIF4G activity.[7]

https://www.wikidoc.org/index.php/EIF1

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EIF6

EIF6 Eukaryotic translation initiation factor 6 (EIF6), also known as Integrin beta 4 binding protein (ITGB4BP), is a human gene. Hemidesmosomes are structures which link the basal lamina to the intermediate filament cytoskeleton. An important functional component of hemidesmosomes is the integrin beta-4 subunit (ITGB4), a protein containing two fibronectin type III domains. The protein encoded by this gene binds to the fibronectin type III domains of ITGB4 and may help link ITGB4 to the intermediate filament cytoskeleton. The encoded protein, which is insoluble and found both in the nucleus and in the cytoplasm, can function as a translation initiation factor and catalyzes the association of the 40S and 60S ribosomal subunits along with eIF5 bound to GTP. Multiple transcript variants encoding several different isoforms have been found for this gene. # Overview EIF6 plays important roles in 80S ribosome formation, cell growth and gene expression. eukaryotic ribosome is 80S ribosome, which can separate to 40S and 60S subunits. EIF6 helps to product mature 60s subunit and then EIF6 should disassociate with 60s subunit so that it can binds to 40s subunit to form ribosome. Keeping in balance of EIF6 is essential for the body: few EIF6 helps synthesis of normal ribosome, while large amount of EIF6 inhibited 60s subunits bind to 40s subunits. # Function EIF6 exists both in nucleolus and cytoplasm. In the eukaryotic nucleolus, a 90S pre-ribosomal complex separate to a 60S pre-ribosomal complex and a 40S pre-ribosomal complex, which are involved in synthesis of mature ribosome. EIF6 is indispensable in 60S subunit biogenesis and deletion of EIF6 has lethal effect. The partial deletion of eIF6 results in decreasing of free 60S ribosomal subunit, which means it knocks the 40S/60S subunit ratio off balance,and limiting the speed of protein synthesis. 60S pre-ribosomal complex associated with eIF6 shuttle from nucleolus to cytoplasm and then eIF6 disassociated with pre-60S so that 60S subunit can binds to 40S subunit and continues to subsequent prograss. EIF6 can act as a rate-limiting translational initiation factor, and its expression levels influence the translational rate. Few of eIF6 will small accelerate protein translation, while large of eIF6 will block translational process by inhibiting production of ribosome. The activity of eIF6 also cause glycolysis and fatty acid synthesis by mRNAs' translational controlling. # Expression EIF6 has different level of expression in different tissue and cell. EIF6 has high level of expression in stem cells and cycling cells, while it doesn't in postmitotic cells; high level in brain and epithelia, while low level in muscle. # Interactions EIF6 has been shown to interact with FHL2, ITGB4 and GNB2L1. EIF6 plays important roles in 80S ribosome formation, cell growth and gene expression.

EIF6 Eukaryotic translation initiation factor 6 (EIF6), also known as Integrin beta 4 binding protein (ITGB4BP), is a human gene.[1] Hemidesmosomes are structures which link the basal lamina to the intermediate filament cytoskeleton. An important functional component of hemidesmosomes is the integrin beta-4 subunit (ITGB4), a protein containing two fibronectin type III domains. The protein encoded by this gene binds to the fibronectin type III domains of ITGB4 and may help link ITGB4 to the intermediate filament cytoskeleton. The encoded protein, which is insoluble and found both in the nucleus and in the cytoplasm, can function as a translation initiation factor and catalyzes the association of the 40S and 60S ribosomal subunits along with eIF5 bound to GTP. Multiple transcript variants encoding several different isoforms have been found for this gene.[1] # Overview EIF6 plays important roles in 80S ribosome formation, cell growth and gene expression. eukaryotic ribosome is 80S ribosome, which can separate to 40S and 60S subunits. EIF6 helps to product mature 60s subunit and then EIF6 should disassociate with 60s subunit so that it can binds to 40s subunit to form ribosome. Keeping in balance of EIF6 is essential for the body: few EIF6 helps synthesis of normal ribosome, while large amount of EIF6 inhibited 60s subunits bind to 40s subunits.[2] # Function EIF6 exists both in nucleolus and cytoplasm. In the eukaryotic nucleolus, a 90S pre-ribosomal complex separate to a 60S pre-ribosomal complex and a 40S pre-ribosomal complex, which are involved in synthesis of mature ribosome. EIF6 is indispensable in 60S subunit biogenesis and deletion of EIF6 has lethal effect. The partial deletion of eIF6 results in decreasing of free 60S ribosomal subunit, which means it knocks the 40S/60S subunit ratio off balance,and limiting the speed of protein synthesis. 60S pre-ribosomal complex associated with eIF6 shuttle from nucleolus to cytoplasm and then eIF6 disassociated with pre-60S so that 60S subunit can binds to 40S subunit and continues to subsequent prograss. EIF6 can act as a rate-limiting translational initiation factor, and its expression levels influence the translational rate. Few of eIF6 will small accelerate protein translation, while large of eIF6 will block translational process by inhibiting production of ribosome.[3] The activity of eIF6 also cause glycolysis and fatty acid synthesis by mRNAs' translational controlling.[4] # Expression EIF6 has different level of expression in different tissue and cell. EIF6 has high level of expression in stem cells and cycling cells, while it doesn't in postmitotic cells; high level in brain and epithelia, while low level in muscle.[5] # Interactions EIF6 has been shown to interact with FHL2,[6] ITGB4[7] and GNB2L1.[8] EIF6 plays important roles in 80S ribosome formation, cell growth and gene expression.[9]

https://www.wikidoc.org/index.php/EIF6

8adbcdf9dbe7b2b3fdab9115b04fe67db5de9073

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ELK1

ELK1 ETS domain-containing protein Elk-1 is a protein that in humans is encoded by the ELK1 gene. Elk-1 functions as a transcription activator. It is classified as a ternary complex factor (TCF), a subclass of the ETS family, which is characterized by a common protein domain that regulates DNA binding to target sequences. Elk1 plays important roles in various contexts, including long-term memory formation, drug addiction, Alzheimer's disease, Down syndrome, breast cancer, and depression. # Structure As depicted in Figure 1, the Elk1 protein is composed of several domains. Localized in the N-terminal region, the A domain is required for the binding of Elk1 to DNA. This region also contains a nuclear localization signal (NLS) and a nuclear export signal (NES), which are responsible for nuclear import and export, respectively. The B domain allows Elk1 to bind to a dimer of its cofactor, serum response factor (SRF). Located adjacent to the B domain, the R domain is involved in suppressing Elk1 transcriptional activity. This domain harbors the lysine residues that are likely to undergo SUMOylation, a post-translational event that strengthens the inhibition function of the R domain. The D domain plays the key role of binding to active Mitogen-activated protein kinases (MAPKs). Located in the C-terminal region of Elk1, the C domain includes the amino acids that actually become phosphorylated by MAPKs. In this region, Serine 383 and 389 are key sites that need to be phosphorylated for Elk1-mediated transcription to occur. Finally, the DEF domain is specific for the interaction of activated extracellular signal-regulated kinase (Erk), a type of MAPK, with Elk1. # Expression Given its role as a transcription factor, Elk1 is expressed in the nuclei of non-neuronal cells. The protein is present in the cytoplasm as well as in the nucleus of mature neurons. In post-mitotic neurons, a variant of Elk1, sElk1, is expressed solely in the nucleus because it lacks the NES site present in the full-length protein. Moreover, while Elk1 is broadly expressed, actual levels vary among tissues. The rat brain, for example, is extremely rich in Elk1, but the protein is exclusively expressed in neurons. # Splice variants Aside from the full-length protein, the Elk1 gene can yield two shortened versions of Elk1: ∆Elk1 and sElk1. Alternative splicing produces ∆Elk1. This variant lacks part of the DNA-binding domain that allows interaction with SRF. On the other hand, sElk1 has an intact region that binds to SRF, but it lacks the first 54 amino acids that contain the NES. Found only in neurons, sElk1 is created by employing an internal translation start site. Both ∆Elk1 and sElk1, truncated versions of full-length protein, are capable of binding to DNA and inducing various cellular signaling. In fact, sElk1 counteracts Elk1 in neuronal differentiation and the regulation of nerve growth factor/ERK signaling. # Signaling The downstream target of Elk1 is the serum response element (SRE) of the c-fos proto-oncogene. To produce c-fos, a protein encoded by the Fos gene, Elk1 needs to be phosphorylated by MAPKs at its C-terminus. MAPKs are the final effectors of signal transduction pathways that begin at the plasma membrane. Phosphorylation by MAPKs results in a conformational change of Elk1. As seen in Figure 2, Raf kinase acts upstream of MAPKs to activate them by phosphorylating and, thereby activating, MEKs, or MAPK or ERK kinases. Raf itself is activated by Ras, which is linked to growth factor receptors with tyrosine kinase activity via Grb2 and Sos. Grb2 and Sos can stimulate Ras only after the binding of growth factors to their corresponding receptors. However, Raf activation does not exclusively depend on Ras. Protein kinase C, which is activated by phorbol esters, can fulfill the same function as Ras. MEK kinase (MEKK) can also activate MEKs, which then activate MAPKs, making Raf unnecessary at times. Various signal transduction pathways, therefore, funnel through MEKs and MAPKs and lead to the activation of Elk1. After stimulation of Elk1, SRF, which allows Elk1 to bind to the c-fos promoter, must be recruited. The binding of Elk1 to SRF happens due to protein-protein interaction between the B domain of Elk1 and SRF and the protein-DNA interaction via the A domain. The aforementioned proteins are like recipes for a certain signaling output. If one of these ingredients, such as SRF, is missing, then a different output occurs. In this case, lack of SRF leads to Elk1's activation of another gene. Elk1 can, thus, independently interact with an ETS binding site, as in the case of the lck proto-oncogene in Figure 2. Moreover, the spacing and relative orientation of the Elk1 binding site to the SRE is rather flexible, suggesting that the SRE-regulated early genes other than c-fos could be targets of Elk1. egr-1 is an example of an Elk1 target that depends on SRE interaction. Ultimately, phosphorylation of Elk1 can result in the production of many proteins, depending on the other factors involved and their specific interactions with each other. When studying signaling pathways, mutations can further highlight the importance of each component used to activate the downstream target. For instance, disruption of the C-terminal domain of Elk1 that MAPK phosphorylates triggers inhibition of c-fos activation. Similarly, dysfunctional SRF, which normally tethers Elk1 to the SRE, leads to Fos not being transcribed. At the same time, without Elk1, SRF cannot induce c-fos transcription after MAPK stimulation. For these reasons, Elk1 represents an essential link between signal transduction pathways and the initiation of gene transcription. # Clinical significance ## Long-term memory Formation of long-term memory may be dependent on Elk1. MEK inhibitors block Elk1 phosphorylation and, thus, impair acquired conditioned taste aversion. Moreover, avoidance learning, which involves the subject learning that a particular response leads to prevention of an aversive stimulus, is correlated with a definite increase in activation of Erk, Elk1, and c-fos in the hippocampus. This area of the brain is involved in short-term and long-term information storage. When Elk1 or SRF binding to DNA is blocked in the rat hippocampus, only sequestration of SRF interferes with long-term spatial memory. While the interaction of Elk1 with DNA may not be essential for memory formation, its specific role still needs to be explored. This is because activation of Elk1 can trigger other molecular events that do not require Elk1 to bind DNA. For example, Elk1 is involved in the phosphorylation of histones, increased interaction with SRF, and recruitment of the basal transcriptional machinery, all of which do not require direct binding of Elk1 to DNA. ## Drug addiction Elk1 activation plays a central role in drug addiction. After mice are given cocaine, a strong and momentary hyperphosphorylation of Erk and Elk1 is observed in the striatum. When these mice are then given MEK inhibitors, Elk1 phosphorylation is absent. Without active Elk1, c-fos production and cocaine-induced conditioned place preference are shown to be blocked. Moreover, acute ethanol ingestion leads to excessive phosphorylation of Elk1 in the amygdala. Silencing of Elk1 activity has also been found to decrease cellular responses to withdrawal signals and lingering treatment of opioids, one of the world's oldest known drugs. Altogether, these results highlight that Elk1 is an important component of drug addiction. ## Pathophysiology Buildup of beta amyloid (Aβ) peptides is shown to cause and/or trigger Alzheimer's disease. Aβ interferes with BDNF-induced phosphorylation of Elk1. With Elk1 activation being hindered in this pathway, the SRE-driven gene regulation leads to increased vulnerability of neurons. Elk1 also inhibits transcription of presenilin 1 (PS1), which encodes a protein that is necessary for the last step of the sequential proteolytic processing of amyloid precursor protein (APP). APP makes variants of Aβ (Aβ42/43 polypeptide). Moroever, PS1 is genetically associated with most early-onset cases of familial Alzheimer's disease. These data emphasize the intriguing link between Aβ, Elk1, and PS1. Another condition associated with Elk1 is Down syndrome. Fetal and aged mice with this pathophysiological condition have shown a decrease in the activity of calcineurin, the major phosphatase for Elk1. These mice also have age-dependent changes in ERK activation. Moreover, expression of SUMO3, which represses Elk1 activity, increases in the adult Down syndrome patient. Therefore, Down syndrome is correlated with changes in ERK, calcineurin, and SUMO pathways, all of which act antagonistically on Elk1 activity. Elk1 also interacts with BRCA1 splice variants, namely BRCA1a and BRCA1b. This interaction enhances BRCA1-mediated growth suppression in breast cancer cells. Elk1 may be a downstream target of BRCA1 in its growth control pathway. Recent literature reveals that c-fos promoter activity is inhibited, while overexpression of BRCA1a/1b reduces MEK-induced activation of the SRE. These results show that one mechanism of growth and tumor suppression by BRCA1a/1b proteins acts through repression of the expression of Elk1 downstream target genes like Fos. Depression has been linked with Elk1. Decreased Erk-mediated Elk1 phosphorylation is observed in the hippocampus and prefrontal cortex of post-mortem brains of depressed suicide individuals. Imbalanced Erk signaling is correlated with depression and suicidal behavior. Future research will reveal the exact role of Elk1 in the pathophysiology of depression.

ELK1 ETS domain-containing protein Elk-1 is a protein that in humans is encoded by the ELK1 gene. Elk-1 functions as a transcription activator. It is classified as a ternary complex factor (TCF), a subclass of the ETS family, which is characterized by a common protein domain that regulates DNA binding to target sequences. Elk1 plays important roles in various contexts, including long-term memory formation, drug addiction, Alzheimer's disease, Down syndrome, breast cancer, and depression. # Structure As depicted in Figure 1, the Elk1 protein is composed of several domains. Localized in the N-terminal region, the A domain is required for the binding of Elk1 to DNA. This region also contains a nuclear localization signal (NLS) and a nuclear export signal (NES), which are responsible for nuclear import and export, respectively. The B domain allows Elk1 to bind to a dimer of its cofactor, serum response factor (SRF). Located adjacent to the B domain, the R domain is involved in suppressing Elk1 transcriptional activity. This domain harbors the lysine residues that are likely to undergo SUMOylation, a post-translational event that strengthens the inhibition function of the R domain. The D domain plays the key role of binding to active Mitogen-activated protein kinases (MAPKs). Located in the C-terminal region of Elk1, the C domain includes the amino acids that actually become phosphorylated by MAPKs. In this region, Serine 383 and 389 are key sites that need to be phosphorylated for Elk1-mediated transcription to occur. Finally, the DEF domain is specific for the interaction of activated extracellular signal-regulated kinase (Erk), a type of MAPK, with Elk1.[1] # Expression Given its role as a transcription factor, Elk1 is expressed in the nuclei of non-neuronal cells. The protein is present in the cytoplasm as well as in the nucleus of mature neurons.[1] In post-mitotic neurons, a variant of Elk1, sElk1, is expressed solely in the nucleus because it lacks the NES site present in the full-length protein.[2] Moreover, while Elk1 is broadly expressed, actual levels vary among tissues. The rat brain, for example, is extremely rich in Elk1, but the protein is exclusively expressed in neurons.[3] # Splice variants Aside from the full-length protein, the Elk1 gene can yield two shortened versions of Elk1: ∆Elk1 and sElk1. Alternative splicing produces ∆Elk1. This variant lacks part of the DNA-binding domain that allows interaction with SRF.[4] On the other hand, sElk1 has an intact region that binds to SRF, but it lacks the first 54 amino acids that contain the NES. Found only in neurons, sElk1 is created by employing an internal translation start site.[5] Both ∆Elk1 and sElk1, truncated versions of full-length protein, are capable of binding to DNA and inducing various cellular signaling. In fact, sElk1 counteracts Elk1 in neuronal differentiation and the regulation of nerve growth factor/ERK signaling.[3] # Signaling The downstream target of Elk1 is the serum response element (SRE) of the c-fos proto-oncogene.[6][7] To produce c-fos, a protein encoded by the Fos gene, Elk1 needs to be phosphorylated by MAPKs at its C-terminus.[8][9] MAPKs are the final effectors of signal transduction pathways that begin at the plasma membrane.[10] Phosphorylation by MAPKs results in a conformational change of Elk1.[11] As seen in Figure 2, Raf kinase acts upstream of MAPKs to activate them by phosphorylating and, thereby activating, MEKs, or MAPK or ERK kinases.[12][13][14][15] Raf itself is activated by Ras, which is linked to growth factor receptors with tyrosine kinase activity via Grb2 and Sos.[16] Grb2 and Sos can stimulate Ras only after the binding of growth factors to their corresponding receptors. However, Raf activation does not exclusively depend on Ras. Protein kinase C, which is activated by phorbol esters, can fulfill the same function as Ras.[17] MEK kinase (MEKK) can also activate MEKs, which then activate MAPKs, making Raf unnecessary at times.[18] Various signal transduction pathways, therefore, funnel through MEKs and MAPKs and lead to the activation of Elk1. After stimulation of Elk1, SRF, which allows Elk1 to bind to the c-fos promoter, must be recruited. The binding of Elk1 to SRF happens due to protein-protein interaction between the B domain of Elk1 and SRF and the protein-DNA interaction via the A domain.[1] The aforementioned proteins are like recipes for a certain signaling output. If one of these ingredients, such as SRF, is missing, then a different output occurs. In this case, lack of SRF leads to Elk1's activation of another gene.[11] Elk1 can, thus, independently interact with an ETS binding site, as in the case of the lck proto-oncogene in Figure 2.[11] Moreover, the spacing and relative orientation of the Elk1 binding site to the SRE is rather flexible,[19] suggesting that the SRE-regulated early genes other than c-fos could be targets of Elk1. egr-1 is an example of an Elk1 target that depends on SRE interaction.[11] Ultimately, phosphorylation of Elk1 can result in the production of many proteins, depending on the other factors involved and their specific interactions with each other. When studying signaling pathways, mutations can further highlight the importance of each component used to activate the downstream target. For instance, disruption of the C-terminal domain of Elk1 that MAPK phosphorylates triggers inhibition of c-fos activation.[11] Similarly, dysfunctional SRF, which normally tethers Elk1 to the SRE, leads to Fos not being transcribed.[16] At the same time, without Elk1, SRF cannot induce c-fos transcription after MAPK stimulation.[11] For these reasons, Elk1 represents an essential link between signal transduction pathways and the initiation of gene transcription. # Clinical significance ## Long-term memory Formation of long-term memory may be dependent on Elk1. MEK inhibitors block Elk1 phosphorylation and, thus, impair acquired conditioned taste aversion. Moreover, avoidance learning, which involves the subject learning that a particular response leads to prevention of an aversive stimulus, is correlated with a definite increase in activation of Erk, Elk1, and c-fos in the hippocampus. This area of the brain is involved in short-term and long-term information storage. When Elk1 or SRF binding to DNA is blocked in the rat hippocampus, only sequestration of SRF interferes with long-term spatial memory. While the interaction of Elk1 with DNA may not be essential for memory formation, its specific role still needs to be explored. This is because activation of Elk1 can trigger other molecular events that do not require Elk1 to bind DNA. For example, Elk1 is involved in the phosphorylation of histones, increased interaction with SRF, and recruitment of the basal transcriptional machinery, all of which do not require direct binding of Elk1 to DNA.[1] ## Drug addiction Elk1 activation plays a central role in drug addiction. After mice are given cocaine, a strong and momentary hyperphosphorylation of Erk and Elk1 is observed in the striatum. When these mice are then given MEK inhibitors, Elk1 phosphorylation is absent. Without active Elk1, c-fos production and cocaine-induced conditioned place preference are shown to be blocked. Moreover, acute ethanol ingestion leads to excessive phosphorylation of Elk1 in the amygdala. Silencing of Elk1 activity has also been found to decrease cellular responses to withdrawal signals and lingering treatment of opioids, one of the world's oldest known drugs. Altogether, these results highlight that Elk1 is an important component of drug addiction.[1] ## Pathophysiology Buildup of beta amyloid (Aβ) peptides is shown to cause and/or trigger Alzheimer's disease. Aβ interferes with BDNF-induced phosphorylation of Elk1. With Elk1 activation being hindered in this pathway, the SRE-driven gene regulation leads to increased vulnerability of neurons. Elk1 also inhibits transcription of presenilin 1 (PS1), which encodes a protein that is necessary for the last step of the sequential proteolytic processing of amyloid precursor protein (APP). APP makes variants of Aβ (Aβ42/43 polypeptide). Moroever, PS1 is genetically associated with most early-onset cases of familial Alzheimer's disease. These data emphasize the intriguing link between Aβ, Elk1, and PS1.[1] Another condition associated with Elk1 is Down syndrome. Fetal and aged mice with this pathophysiological condition have shown a decrease in the activity of calcineurin, the major phosphatase for Elk1. These mice also have age-dependent changes in ERK activation. Moreover, expression of SUMO3, which represses Elk1 activity, increases in the adult Down syndrome patient. Therefore, Down syndrome is correlated with changes in ERK, calcineurin, and SUMO pathways, all of which act antagonistically on Elk1 activity.[1] Elk1 also interacts with BRCA1 splice variants, namely BRCA1a and BRCA1b. This interaction enhances BRCA1-mediated growth suppression in breast cancer cells. Elk1 may be a downstream target of BRCA1 in its growth control pathway. Recent literature reveals that c-fos promoter activity is inhibited, while overexpression of BRCA1a/1b reduces MEK-induced activation of the SRE. These results show that one mechanism of growth and tumor suppression by BRCA1a/1b proteins acts through repression of the expression of Elk1 downstream target genes like Fos.[20] Depression has been linked with Elk1. Decreased Erk-mediated Elk1 phosphorylation is observed in the hippocampus and prefrontal cortex of post-mortem brains of depressed suicide individuals. Imbalanced Erk signaling is correlated with depression and suicidal behavior. Future research will reveal the exact role of Elk1 in the pathophysiology of depression.[1]

https://www.wikidoc.org/index.php/ELK1

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wikidoc

ELP4

ELP4 Elongation protein 4 homolog (S. cerevisiae), also known as ELP4, is a protein which in humans is encoded by the ELP4 gene. # Function This gene encodes a component of the six subunit elongator complex, a histone acetyltransferase complex that associates directly with RNA polymerase II during transcriptional elongation. The human gene can partially complement sensitivity phenotypes of yeast ELP4 deletion mutants. Alternatively spliced variants that encode different protein isoforms have been described but the full-length nature of only one has been determined. # Clinical significance In a study published in February 2009, researcher linked this gene to the most common form of human epilepsy, namely Rolandic epilepsy. This is the first gene to be linked with rolandic epilepsy. # Background It has been found that children with Rolandic epilepsy have a mutation of gene coding for the Elongator Protein Complex 4, which is involved in transcription and tRNA modification. Furthermore, Elp4 is needed for histone acetyltransferase (HAT) activity which makes DNA more accessible for transcription. The lack of the Elp4/5/6 led to no HAT activity. The importance of HAT activity is the initiation of transcription as well as its assistance of RNA polymerase II in transcription elongation through chromatin and acetyl-CoA dependent pathways. Although Rolandic epilepsy (RE), which has been observed as autosomal dominant with high penetrance, develops around age 3 and disappears by age 12 there are serious problems that need to be addressed that occur while a child has RE. One of the major problems that can arise from RE is cognitive impairment. Though the cognitive impairment seen in Rolandic Epilepsy is of unclear etiology, one contributing factor may be increased glucose uptake in cortical areas, most notably in the associative cortex. These changes in glucose uptake may somehow disrupt the learning process and prevents the child from making the associations necessary to learn new things, which is how most human learning is achieved. Other factors which may contribute to cognitive impairment include seizure frequency, abnormal electrical activity in between seizures, and medication side effects, to only name a few. The Elongator Protein Complex (ELP) is what regulates the growth of cortical projection neurons. This means that it helps cortical neurons to exhibit dendrite branching and radial migration of neurons to form the close knit neural network of the cerebral cortex. If ELP is not working properly or is not being expressed at the correct levels (too low) then the neurons in that region in particular would not be properly situated in relation to each other for proper brain activity. The expression of ELP and the fourth sub-unit (ELP4) in particular is the cause of Rolandic epilepsy and possibly other cognitive impairment later in life if the condition is severe enough or if it is not treated effectively.

ELP4 Elongation protein 4 homolog (S. cerevisiae), also known as ELP4, is a protein which in humans is encoded by the ELP4 gene.[1][2][3] # Function This gene encodes a component of the six subunit elongator complex, a histone acetyltransferase complex that associates directly with RNA polymerase II during transcriptional elongation. The human gene can partially complement sensitivity phenotypes of yeast ELP4 deletion mutants. Alternatively spliced variants that encode different protein isoforms have been described but the full-length nature of only one has been determined.[1] # Clinical significance In a study published in February 2009, researcher linked this gene to the most common form of human epilepsy, namely Rolandic epilepsy.[4] This is the first gene to be linked with rolandic epilepsy. # Background It has been found that children with Rolandic epilepsy have a mutation of gene coding for the Elongator Protein Complex 4, which is involved in transcription and tRNA modification. Furthermore, Elp4 is needed for histone acetyltransferase (HAT) activity which makes DNA more accessible for transcription. The lack of the Elp4/5/6 led to no HAT activity. The importance of HAT activity is the initiation of transcription as well as its assistance of RNA polymerase II in transcription elongation through chromatin and acetyl-CoA dependent pathways.[5] Although Rolandic epilepsy (RE), which has been observed as autosomal dominant with high penetrance,[6] develops around age 3 and disappears by age 12 there are serious problems that need to be addressed that occur while a child has RE. One of the major problems that can arise from RE is cognitive impairment. Though the cognitive impairment seen in Rolandic Epilepsy is of unclear etiology, one contributing factor may be increased glucose uptake in cortical areas, most notably in the associative cortex.[7] These changes in glucose uptake may somehow disrupt the learning process and prevents the child from making the associations necessary to learn new things, which is how most human learning is achieved. Other factors which may contribute to cognitive impairment include seizure frequency, abnormal electrical activity in between seizures, and medication side effects, to only name a few. The Elongator Protein Complex (ELP) is what regulates the growth of cortical projection neurons. This means that it helps cortical neurons to exhibit dendrite branching and radial migration of neurons to form the close knit neural network of the cerebral cortex.[8] If ELP is not working properly or is not being expressed at the correct levels (too low) then the neurons in that region in particular would not be properly situated in relation to each other for proper brain activity. The expression of ELP and the fourth sub-unit (ELP4) in particular is the cause of Rolandic epilepsy and possibly other cognitive impairment later in life if the condition is severe enough or if it is not treated effectively.

https://www.wikidoc.org/index.php/ELP4

611e5b09f1b5b028f453cb1cbc67dd1e9a05d0fb

wikidoc

ELSI

ELSI # Overview ELSI stands for Ethical, Legal and Social Issues. It's a term associated with the Human genome project. This project didn't only have the goal to identify all the approximately 24.000 genes in the human DNA, but also to address the ELSI that might arise from the project. 5% of the US annual Human genome project (HGP) funds is allocated to address associated ELSI of the work. # The failure of ELSI to help the impacted groups As Debra Harry, Executive Director of the Indigenous Peoples Council on Biocolonialism (IPCB), would explain; despite a decade of ELSI funding, the burden of genetics education has fallen on the tribes themselves to understand the motives of Human genome project and its potential impacts on their lives. Meanwhile, the government has been busily funding projects studying indigenous groups, without any meaningful consultation with the group. (See Biopiracy) The main criticism of ELSI is the failure to address the conditions raised by population-based research, especially with regard to unique processes for group decision-making and cultural worldviews. Genetic variation research such as HGP is group population research, but most ethical guidelines, as Harry mentions, are not euipped to address group rights. She is making such claim because those research represents a clash of culture: indigenous people's life revolves around collectivity and group decision making whereas the Western culture promotes individuality. Harry suggests that one of the challenges of ethical research is to include respect for collective review and decision making, while also upholding the traditional model of individual rights.

ELSI # Overview ELSI stands for Ethical, Legal and Social Issues. It's a term associated with the Human genome project. This project didn't only have the goal to identify all the approximately 24.000 genes in the human DNA, but also to address the ELSI that might arise from the project. 5% of the US annual Human genome project (HGP) funds is allocated to address associated ELSI of the work. # The failure of ELSI to help the impacted groups As Debra Harry, Executive Director of the Indigenous Peoples Council on Biocolonialism (IPCB), would explain; despite a decade of ELSI funding, the burden of genetics education has fallen on the tribes themselves to understand the motives of Human genome project and its potential impacts on their lives. Meanwhile, the government has been busily funding projects studying indigenous groups, without any meaningful consultation with the group. (See Biopiracy) The main criticism of ELSI is the failure to address the conditions raised by population-based research, especially with regard to unique processes for group decision-making and cultural worldviews. Genetic variation research such as HGP is group population research, but most ethical guidelines, as Harry mentions, are not euipped to address group rights. She is making such claim because those research represents a clash of culture: indigenous people's life revolves around collectivity and group decision making whereas the Western culture promotes individuality. Harry suggests that one of the challenges of ethical research is to include respect for collective review and decision making, while also upholding the traditional model of individual rights.

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

9a9d7ff193fd9cb123c6f82d861511f655869ae3

wikidoc

EMP3

EMP3 Epithelial membrane protein 3 (EMP3) is a trans-membrane signaling molecule that is encoded by the myelin-related gene EMP3. EMP3 is a member of the peripheral myelin protein gene family 22-kDa (PMP22), which is mainly responsible for the formation of the sheath of compact myelin. Although the detailed functions and mechanisms of EMP3 still remain unclear, it is suggested that EMP3 is possibly epigenetically linked to certain carcinomas. # Structure EMP3 is a protein composed of a 163-amino acid sequence, which is expressed from its gene located on the band of the 19q13.3 in the Homo sapiens chromosome. EMP3 has the highest expression in the peripheral blood leukocytes compared to the expression in other body tissues. The protein is characterized by 4 transmembrane domains and two N-linked glycosylation sites in the first extracellular loop. # Function EMP3 is a transmembrane protein which participates in cell to cell interaction and cell proliferation. Overexpression and silencing of EMP3 both interrupt the normal expression of the EMP3 gene, which induces the progression(and formation) of cancers. Based on these properties of EMP3 and the prognostic analyses on several types of tumors and cancers, EMP3 has a tumor-suppressor-like role in regulating differentiation, apoptosis and development of cancer cells. However, the detailed mechanism still needs to be investigated. ## Tumorgenesis and carcinogenesis ### Primary breast carcinomas The detailed functions as well as the mechanism of EMP3 in the development of various carcinomas have remained unclear. However, it was found that the levels of expression of EMP3 mRNA have a positive correlation in primary breast carcinomas. According to the study, EMP3 mRNA has a higher level of expression in the carcinoma compared to normal breast tissues. The overexpression of EMP3 has a significant correlation with histological grade III, lymph node metastasis, and strong Her-2 expression. Additionally, the hypermethylation on the promoter region of EMP3 has appeared in about 35% of the studies breast carcinoma cases. However, higher EMP3 expression levels occur in patients with both types of breast carcinomas, regardless of the promoter regions of EMP3 being hypermethylated or unmethylated. ### Hepatocellular carcinoma (HCC) Hepatocellular carcinoma (HCC), which is mainly caused by the chronic infections of hepatitis B virus and hepatitis C virus, become one of the major causes of cancer mortality worldwide in the recent years. EMP3 expression in HCC tumor cells has a higher expression level than that it does in normal tissues at similar regions of the liver. It was also found that the HCC patients who have a relatively lower historlogical grade inversely possess a higher level of expression in EMP3. Then, the researchers found that knockdown (gene silencing) of EMP3 resulted in reduction of cell proliferation and arrest of cell cycle, which suggests a potential role of EMP3 in tumor-suppressing. ### Brain cancer EMP3 is found to play a large role in the progression of neuroblastomas and glioblastomas, which are two of the most common types of brain cancers. Both have fast carinogenesis result in a high rate of mortality. EMP3 is proposed as an oncogene whose overexpression in the progression correlated with glioblastoma (GBM). Reduction in EMP3 expression in CD44-high GBM cell lines promotes apoptosis of the cancer cell lines and disables potential tumorigenesis. One of the signaling activation pathway involving EMP3 in the progression of glioblastoma was identified in 2016. The pathway was identified as TGF-β/Smad2/3 signaling, in which the unregulated TGF-β signaling promotes tumorigenesis in various human cells, especially CD44-high glioma cells. The interaction between EMP3 and the receptor of TGF-β regulate the TGF-β/Smad2/3 signaling activation, which eventually suppresses cell proliferation and weakens tumorigenesis in glioblastoma. # Clinical significance Due to the controversial effects of EMP3 on tumor suppression, the applicable treatments for certain carcinomas related to EMP3 are still unvalidated in humans. However, some animal experiments have showed a positive result on suppressing the tumorous tissues by modifying the EMP3 gene.

EMP3 Epithelial membrane protein 3 (EMP3) is a trans-membrane signaling molecule that is encoded by the myelin-related gene EMP3. EMP3 is a member of the peripheral myelin protein gene family 22-kDa (PMP22), which is mainly responsible for the formation of the sheath of compact myelin.[1][2] Although the detailed functions and mechanisms of EMP3 still remain unclear, it is suggested that EMP3 is possibly epigenetically linked to certain carcinomas. # Structure EMP3 is a protein composed of a 163-amino acid sequence, which is expressed from its gene located on the band of the 19q13.3 in the Homo sapiens chromosome.[3] EMP3 has the highest expression in the peripheral blood leukocytes compared to the expression in other body tissues.[4] The protein is characterized by 4 transmembrane domains and two N-linked glycosylation sites in the first extracellular loop.[1] # Function EMP3 is a transmembrane protein which participates in cell to cell interaction and cell proliferation.[5] Overexpression and silencing of EMP3 both interrupt the normal expression of the EMP3 gene, which induces the progression(and formation) of cancers. Based on these properties of EMP3 and the prognostic analyses on several types of tumors and cancers, EMP3 has a tumor-suppressor-like role in regulating differentiation, apoptosis and development of cancer cells. However, the detailed mechanism still needs to be investigated.[1][2][6] ## Tumorgenesis and carcinogenesis ### Primary breast carcinomas The detailed functions as well as the mechanism of EMP3 in the development of various carcinomas have remained unclear.[1][2] However, it was found that the levels of expression of EMP3 mRNA have a positive correlation in primary breast carcinomas. According to the study, EMP3 mRNA has a higher level of expression in the carcinoma compared to normal breast tissues. The overexpression of EMP3 has a significant correlation with histological grade III, lymph node metastasis, and strong Her-2 expression. Additionally, the hypermethylation on the promoter region of EMP3 has appeared in about 35% of the studies breast carcinoma cases. However, higher EMP3 expression levels occur in patients with both types of breast carcinomas, regardless of the promoter regions of EMP3 being hypermethylated or unmethylated.[6] ### Hepatocellular carcinoma (HCC) Hepatocellular carcinoma (HCC), which is mainly caused by the chronic infections of hepatitis B virus and hepatitis C virus, become one of the major causes of cancer mortality worldwide in the recent years.[7][8] EMP3 expression in HCC tumor cells has a higher expression level than that it does in normal tissues at similar regions of the liver. It was also found that the HCC patients who have a relatively lower historlogical grade inversely possess a higher level of expression in EMP3. Then, the researchers found that knockdown (gene silencing) of EMP3 resulted in reduction of cell proliferation and arrest of cell cycle, which suggests a potential role of EMP3 in tumor-suppressing.[9] ### Brain cancer EMP3 is found to play a large role in the progression of neuroblastomas and glioblastomas, which are two of the most common types of brain cancers. Both have fast carinogenesis result in a high rate of mortality.[1][5] EMP3 is proposed as an oncogene whose overexpression in the progression correlated with glioblastoma (GBM).[5] Reduction in EMP3 expression in CD44-high GBM cell lines promotes apoptosis of the cancer cell lines and disables potential tumorigenesis.[5] One of the signaling activation pathway involving EMP3 in the progression of glioblastoma was identified in 2016. The pathway was identified as TGF-β/Smad2/3 signaling, in which the unregulated TGF-β signaling promotes tumorigenesis in various human cells, especially CD44-high glioma cells.[5] The interaction between EMP3 and the receptor of TGF-β regulate the TGF-β/Smad2/3 signaling activation, which eventually suppresses cell proliferation and weakens tumorigenesis in glioblastoma.[5] # Clinical significance Due to the controversial effects of EMP3 on tumor suppression, the applicable treatments for certain carcinomas related to EMP3 are still unvalidated in humans.[9][10] However, some animal experiments have showed a positive result on suppressing the tumorous tissues by modifying the EMP3 gene.[9]

https://www.wikidoc.org/index.php/EMP3

56cf4d2549a7eb30077795596b14198bc0243874

wikidoc

EMR1

EMR1 EGF-like module-containing mucin-like hormone receptor-like 1 also known as F4/80 is a protein encoded by the ADGRE1 gene. EMR1 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain. EMR1 expression in human is restricted to eosinophils and is a specific marker for these cells. The murine homolog of EMR1, F4/80, is a well-known and widely used marker of murine macrophage populations. The N-terminal fragment (NTF) of EMR1 contains 4-6 Epidermal Growth Factor-like (EGF-like) domains in human and 4-7 EGF-like domains in the mouse. # Function Utilizing F4/80 knockout mice, Lin et al. showed that F4/80 is not necessary for the development of tissue macrophages but is required for the induction of efferent CD8+ regulatory T cells needed for peripheral tolerance. # Clinical significance Legrand et al. demonstrated that EMR1 can serve as a therapeutic target for depletion of these cells in eosinophilic disorders by using afucosylated antibodies.

EMR1 EGF-like module-containing mucin-like hormone receptor-like 1 also known as F4/80 is a protein encoded by the ADGRE1 gene.[1][2][3][4][5] EMR1 is a member of the adhesion GPCR family.[6][7] Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.[8] EMR1 expression in human is restricted to eosinophils and is a specific marker for these cells.[9] The murine homolog of EMR1, F4/80, is a well-known and widely used marker of murine macrophage populations.[10] The N-terminal fragment (NTF) of EMR1 contains 4-6 Epidermal Growth Factor-like (EGF-like) domains in human and 4-7 EGF-like domains in the mouse.[11] # Function Utilizing F4/80 knockout mice, Lin et al. showed that F4/80 is not necessary for the development of tissue macrophages but is required for the induction of efferent CD8+ regulatory T cells needed for peripheral tolerance.[12] # Clinical significance Legrand et al. demonstrated that EMR1 can serve as a therapeutic target for depletion of these cells in eosinophilic disorders by using afucosylated antibodies.[13]

https://www.wikidoc.org/index.php/EMR1

87415f0ac1145cf07cf36dd06b4646e678ac3987

wikidoc

EMR2

EMR2 EGF-like module-containing mucin-like hormone receptor-like 2 also known as CD312 (cluster of differentiation 312) is a protein encoded by the ADGRE2 gene. EMR2 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain. EMR2 is expressed by monocytes/macrophages, dendritic cells and all types of granulocytes. In the case of EMR2 the N-terminal domains consist of alternatively spliced epidermal growth factor-like (EGF-like) domains. EMR2 is closely related to CD97 with 97% amino-acid identity in the EGF-like domains. The N-terminal fragment (NTF) of EMR2 presents 2-5 EGF-like domains in human. Mice lack the Emr2 gene. This gene is closely linked to the gene encoding EGF-like molecule containing mucin-like hormone receptor 3 EMR3 on chromosome 19. # Ligand Like the related CD97 protein, the fourth EGF-like domain of EMR2 binds chondroitin sulfate B to mediate cell attachment. However, unlike CD97 EMR2 does not interact with the complement regulatory protein, decay accelerating factor CD55, and indicating that these very closely related proteins likely have nonredundant functions. # Signaling Inositol phosphate (IP3) accumulation assays in overexpressing HEK293 cells have demonstrated coupling of EMR2 to Gα15. EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2) is an adhesion GPCR that undergoes GPS autoproteolysis before being trafficked to the plasma membrane. Further, distribution, translocation, co-localization of the N-terminal fragment (NTF) and N-terminal fragment (CTF) of EMR2 within lipid rafts may affect cell signaling. Mutations in the GPS have shown that EMR2 does not need to undergo autoproteolysis to be trafficked, but loses function. EMR2 has been shown to be necessary for in vitro cell migration. Upon cleavage the N-terminus has been shown to associate with the 7TM, but to also dissociate, giving two possible functions. When the N-terminus dissociates it can be found in lipid rafts. Additionally, the cleaved EMR2 protein 7TM has been found to associate with EMR4 N-terminus. # Function The expression of EMR2 and CD97 on activated lymphocytes and myeloid cells promotes binding with their ligand chondroitin sulfate B on peripheral B cells, indicating a role in leukocyte interaction. The interaction between EMR2 and chondroitin sulfate B in inflamed rheumatoid synovial tissue suggests a role of the receptors in the recruitment and retention of leukocytes in synovium of arthritis patients. Upon neutrophil activation, EMR2 rapidly moves to membrane ruffles and the leading edge of the cell. Additionally, ligation of EMR2 by antibody promotes neutrophil and macrophage effector functions suggesting a role in potentiating inflammatory responses. # Clinical significance EMR2 is rarely expressed by tumor cell lines and tumors, but has been found on breast and colorectal adenocarcinoma. In breast cancer, robust expression and different distribution of EMR2 is inversely correlated with survival. Gain of function mutations within the GAIN domain of EMR2 of certain patient cohorts were shown to result in excessive degranulation by mast cells resulting in vibratory urticaria

EMR2 EGF-like module-containing mucin-like hormone receptor-like 2 also known as CD312 (cluster of differentiation 312) is a protein encoded by the ADGRE2 gene.[1] EMR2 is a member of the adhesion GPCR family.[2][3] Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.[4] EMR2 is expressed by monocytes/macrophages, dendritic cells and all types of granulocytes.[5] In the case of EMR2 the N-terminal domains consist of alternatively spliced epidermal growth factor-like (EGF-like) domains. EMR2 is closely related to CD97 with 97% amino-acid identity in the EGF-like domains. The N-terminal fragment (NTF) of EMR2 presents 2-5 EGF-like domains in human.[6] Mice lack the Emr2 gene.[7] This gene is closely linked to the gene encoding EGF-like molecule containing mucin-like hormone receptor 3 EMR3 on chromosome 19. # Ligand Like the related CD97 protein, the fourth EGF-like domain of EMR2 binds chondroitin sulfate B to mediate cell attachment.[8] However, unlike CD97 EMR2 does not interact with the complement regulatory protein, decay accelerating factor CD55, and indicating that these very closely related proteins likely have nonredundant functions.[9] # Signaling Inositol phosphate (IP3) accumulation assays in overexpressing HEK293 cells have demonstrated coupling of EMR2 to Gα15.[10] EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2) is an adhesion GPCR that undergoes GPS autoproteolysis before being trafficked to the plasma membrane.[11] Further, distribution, translocation, co-localization of the N-terminal fragment (NTF) and N-terminal fragment (CTF) of EMR2 within lipid rafts may affect cell signaling.[12] Mutations in the GPS have shown that EMR2 does not need to undergo autoproteolysis to be trafficked, but loses function. EMR2 has been shown to be necessary for in vitro cell migration. Upon cleavage the N-terminus has been shown to associate with the 7TM, but to also dissociate, giving two possible functions. When the N-terminus dissociates it can be found in lipid rafts. Additionally, the cleaved EMR2 protein 7TM has been found to associate with EMR4 N-terminus. # Function The expression of EMR2 and CD97 on activated lymphocytes and myeloid cells promotes binding with their ligand chondroitin sulfate B on peripheral B cells, indicating a role in leukocyte interaction.[13] The interaction between EMR2 and chondroitin sulfate B in inflamed rheumatoid synovial tissue suggests a role of the receptors in the recruitment and retention of leukocytes in synovium of arthritis patients.[14] Upon neutrophil activation, EMR2 rapidly moves to membrane ruffles and the leading edge of the cell. Additionally, ligation of EMR2 by antibody promotes neutrophil and macrophage effector functions suggesting a role in potentiating inflammatory responses.[12][15] # Clinical significance EMR2 is rarely expressed by tumor cell lines and tumors, but has been found on breast and colorectal adenocarcinoma.[16][17] In breast cancer, robust expression and different distribution of EMR2 is inversely correlated with survival.[18] Gain of function mutations within the GAIN domain of EMR2 of certain patient cohorts were shown to result in excessive degranulation by mast cells resulting in vibratory urticaria[19]

https://www.wikidoc.org/index.php/EMR2

e6bd74b74ab435d388a553bdab6508311e1fd468

wikidoc

EMR3

EMR3 EGF-like module-containing mucin-like hormone receptor-like 3 is a protein encoded by the ADGRE3 gene. EMR3 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain. EMR3 expression is restricted to monocytes/macrophages, myeloid dendritic cells, and mature granulocytes in human. Transcription of the EMR3 gene results in two alternative spliced forms: a surface protein with extracellular, 7TM, and intracellular domains as well as a truncated soluble form of only the extracellular domain. Mice, next to Emr2, lack the Emr3 gene. # Function The protein may play a role in myeloid-myeloid interactions during immune and inflammatory responses. # Ligands A potential ligand of EMR3 likely is expressed on human macrophage and activated neutrophils.

EMR3 EGF-like module-containing mucin-like hormone receptor-like 3 is a protein encoded by the ADGRE3 gene.[1][2] EMR3 is a member of the adhesion GPCR family.[3][4] Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.[5] EMR3 expression is restricted to monocytes/macrophages, myeloid dendritic cells, and mature granulocytes in human.[6] Transcription of the EMR3 gene results in two alternative spliced forms: a surface protein with extracellular, 7TM, and intracellular domains as well as a truncated soluble form of only the extracellular domain.[7] Mice, next to Emr2, lack the Emr3 gene.[8] # Function The protein may play a role in myeloid-myeloid interactions during immune and inflammatory responses.[9] # Ligands A potential ligand of EMR3 likely is expressed on human macrophage and activated neutrophils.[7]

https://www.wikidoc.org/index.php/EMR3

cd8487cebf151b83488da876fc2997272dc32a91

wikidoc

EMSY

EMSY EMSY is a protein that in humans is encoded by the EMSY gene. # Clinical significance EMSY has been shown to associate with atopy and susceptibility to poly-sensitisation. # Interactions EMSY has been shown to interact with ZMYND11, BRCA2 and CBX1.

EMSY EMSY is a protein that in humans is encoded by the EMSY gene.[1] # Clinical significance EMSY has been shown to associate with atopy and susceptibility to poly-sensitisation.[2] # Interactions EMSY has been shown to interact with ZMYND11,[3] BRCA2[3] and CBX1.[3]

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

3fe9ee4a21dd818d19afc56bd03c19d6b34104ca

wikidoc

EMX1

EMX1 Homeobox protein EMX1 is a protein that in humans is encoded by the EMX1 gene. The transcribed EMX1 gene is a member of the EMX family of transcription factors. The EMX1 gene, along with its family members, are expressed in the developing cerebrum (also known as the telencephalon). Emx1 plays a role in specification of positional identity, the proliferation of neural stem cells, differentiation of layer-specific neuronal phenotypes and commitment to a neuronal or glial cell fate. # Function The precise function of the Emx1 transcription factor is not known, however its ubiquitous nature throughout corticogenesis suggests it may confer cellular identity to cortical neurons. Emx -/- (mice that have had Emx1 gene knocked out) are still viable and display only slight defects. These defects are restricted to the forebrain. Histologically and molecularly, the structures of the cerebral cortex appear to be normal. The hippocampus in Emx1 -/- mice, however, is typically smaller. The major deficit in Emx1-/- mice is that they completely lack the corpus callosum. # Tissue distribution Most of Emx1 transcript is detected in cell nuclei of the developing telencephalon, including the prospective cerebral cortex, olfactory bulbs and hippocampus. Emx1 is present in practically all cortical neurons during proliferation, migration, differentiation and maturation. However, the amount of Emx 1 varies. Emx1 first appears at E9.5 in its respective mRNA, until E11.5. After this, the Emx1 signal becomes particularly potent in the ventricular zone (VZ) until E17.5. At birth and shortly thereafter, Emx1 levels in layers V and VI as well as in the SP increase. # Telencephalic development Emx1 and Emx2 each play a critical role in regulating dorsal telencephalic development and are amongst the earliest expressed pallial-specific genes. During embryonic development, the telencephalon is the birthplace of a diverse collection of neuronal and glial cells. These cells undergo varying patterns of cell migration in order to reach their final positions in what will become the mature cerebral cortex and basal ganglia. The embryonic telencephalon is subdivided into dorsal pallium and ventral subpallium. These two pallia become the mammalian cerebral cortex and basal ganglia, respectively. The dorsal telencephalon is then further divided into: Each of the aforementioned pallial domains will give rise to a distinct neuroanatomical region of the developed human brain. The ventral telencephalon can also be subdivided into two distinguishable progenitor domains: The dorsal and ventral telencephalic domains can be distinguished embryonically through distinct gene expression patterns. These genes are regionally restricted and take part in identity specification of the area of the telencephalon in which they are expressed. ## Role in the mouse embryo Emx1 expression has been shown to start from E9.5 (see gestational age). In the developing mouse embryo, the Emx genes are expressed principally in extended regions of the developing rostral brain, including the cerebral cortex, olfactory bulbs and olfactory epithelium. Emx1 gene expression is constricted to the dorsal telencephalon. From E9.5 until post-natal stages, Emx1 expression is associated with cortical neurogenesis, differentiation and migration, and synaptic connection generation. This suggests that Emx1 plays a crucial role in determining the identity of the developing cortex. Emx1 is not only limited to the telencephalon, rather it is also expressed in branchial patterns and in the apical ectodermal ridge of the developing limbs. ## Developing forebrain At E9.5, Emx1 expression can be witnessed within the dorsal telencephalon slightly anterior to the boundary between the diencephalon and telencephalon Emx1 is expressed in most cortical neurons within the developing telencephalon. Expression can be seen irrespective of whether the neurons are proliferating, migrating or differentiating. This means that in the developed cerebral cortex, the transcript for Emx1 is widely distributed. While distribution of the transcript may be seen throughout the developed cortex, the transcript intensity varies greatly according to developmental time. For example, the transcript for Emx1 is shown to be stronger in the ventricular zone (VZ) between E10.5 and E17.5. However, around birth and immediately thereafter, the Emx1 transcript is absent from the marginal zone (MZ), only becoming stronger in cortical layers V and VI as well as subset subplate (SP) neurons. In cortical layers V and VI as well as the SP neurons, Emx1 might take part in development of early functional circuitry, as well as in defining specific cellular identities. The distribution of Emx1 is so ubiquitous in the developing brain that in mid- and late-gestation embryos, as well as postnatal mice, it is found in cerebral cortex, olfactory bulbs, dentate gyrus and hippocampus. # Regulation by Gli3 The Gli3 zinc finger transcription factor has been shown to play a role as a regulator of Emx1. In Gli3 Extra-toes mutants, the transcription factor Gli3 is mutated and as a result, Emx1 and Emx2 gene expression is lost.

EMX1 Homeobox protein EMX1 is a protein that in humans is encoded by the EMX1 gene.[1][2] The transcribed EMX1 gene is a member of the EMX family of transcription factors. The EMX1 gene, along with its family members, are expressed in the developing cerebrum (also known as the telencephalon).[3] Emx1 plays a role in specification of positional identity, the proliferation of neural stem cells, differentiation of layer-specific neuronal phenotypes and commitment to a neuronal or glial cell fate.[4] # Function The precise function of the Emx1 transcription factor is not known, however its ubiquitous nature throughout corticogenesis suggests it may confer cellular identity to cortical neurons. Emx -/- (mice that have had Emx1 gene knocked out) are still viable and display only slight defects. These defects are restricted to the forebrain. Histologically and molecularly, the structures of the cerebral cortex appear to be normal. The hippocampus in Emx1 -/- mice, however, is typically smaller. The major deficit in Emx1-/- mice is that they completely lack the corpus callosum. # Tissue distribution Most of Emx1 transcript is detected in cell nuclei of the developing telencephalon, including the prospective cerebral cortex, olfactory bulbs and hippocampus. Emx1 is present in practically all cortical neurons during proliferation, migration, differentiation and maturation. However, the amount of Emx 1 varies. Emx1 first appears at E9.5 in its respective mRNA, until E11.5. After this, the Emx1 signal becomes particularly potent in the ventricular zone (VZ) until E17.5. At birth and shortly thereafter, Emx1 levels in layers V and VI as well as in the SP increase. # Telencephalic development Emx1 and Emx2 each play a critical role in regulating dorsal telencephalic development and are amongst the earliest expressed pallial-specific genes.[4] During embryonic development, the telencephalon is the birthplace of a diverse collection of neuronal and glial cells. These cells undergo varying patterns of cell migration in order to reach their final positions in what will become the mature cerebral cortex and basal ganglia. The embryonic telencephalon is subdivided into dorsal pallium and ventral subpallium. These two pallia become the mammalian cerebral cortex and basal ganglia, respectively. The dorsal telencephalon is then further divided into: Each of the aforementioned pallial domains will give rise to a distinct neuroanatomical region of the developed human brain. The ventral telencephalon can also be subdivided into two distinguishable progenitor domains: The dorsal and ventral telencephalic domains can be distinguished embryonically through distinct gene expression patterns. These genes are regionally restricted and take part in identity specification of the area of the telencephalon in which they are expressed. ## Role in the mouse embryo Emx1 expression has been shown to start from E9.5 (see gestational age).[5] In the developing mouse embryo, the Emx genes are expressed principally in extended regions of the developing rostral brain, including the cerebral cortex, olfactory bulbs and olfactory epithelium. Emx1 gene expression is constricted to the dorsal telencephalon. From E9.5 until post-natal stages, Emx1 expression is associated with cortical neurogenesis, differentiation and migration, and synaptic connection generation. This suggests that Emx1 plays a crucial role in determining the identity of the developing cortex. Emx1 is not only limited to the telencephalon, rather it is also expressed in branchial patterns and in the apical ectodermal ridge of the developing limbs. ## Developing forebrain At E9.5, Emx1 expression can be witnessed within the dorsal telencephalon slightly anterior to the boundary between the diencephalon and telencephalon Emx1 is expressed in most cortical neurons within the developing telencephalon.[3] Expression can be seen irrespective of whether the neurons are proliferating, migrating or differentiating. This means that in the developed cerebral cortex, the transcript for Emx1 is widely distributed. While distribution of the transcript may be seen throughout the developed cortex, the transcript intensity varies greatly according to developmental time. For example, the transcript for Emx1 is shown to be stronger in the ventricular zone (VZ) between E10.5 and E17.5. However, around birth and immediately thereafter, the Emx1 transcript is absent from the marginal zone (MZ), only becoming stronger in cortical layers V and VI as well as subset subplate (SP) neurons. In cortical layers V and VI as well as the SP neurons, Emx1 might take part in development of early functional circuitry, as well as in defining specific cellular identities. The distribution of Emx1 is so ubiquitous in the developing brain that in mid- and late-gestation embryos, as well as postnatal mice, it is found in cerebral cortex, olfactory bulbs, dentate gyrus and hippocampus.[3] # Regulation by Gli3 The Gli3 zinc finger transcription factor has been shown to play a role as a regulator of Emx1. In Gli3 Extra-toes mutants, the transcription factor Gli3 is mutated and as a result, Emx1 and Emx2 gene expression is lost.[4][6]

https://www.wikidoc.org/index.php/EMX1

86ec48d620da35e7b045aac5511f1f6491f6fdfa

wikidoc

EMX2

EMX2 Homeobox protein Emx2 is a protein that in humans is encoded by the EMX2 gene. # Function The homeodomain transcription factor EMX2 is critical for central nervous system and urogenital development. EMX1 (MIM 600034) and EMX2 are related to the 'empty spiracles' gene expressed in the developing Drosophila head.. The EMX2 gene encodes for a transcription factor that is a homolog to Drosophila melanogaster “empty spiracles” gene. The “empty spiracles gene” is needed for the proper head development/formation as well as the development of posterior spiracles in Drosophila melanogaster. In humans, EMX2 shows high expression in the dorsal telencephalon, olfactory neuroepithelium, as well as the urogenetial system. In the developing uroepithelium, EMX2 is negatively regulated by HOXA10. EMX2 has been associated with Schizencephaly, a disease where there are large parts of the brain hemispheres absent and that are replaced with cerebrospinal fluid, clinical observations can include seizures, blindness, and inability to walk/speak. EMX2 has also been shown to have an important role in tumorigenesis. One study found that the expression of EMX2 is significantly decreased in tissues and cells with colorectal cancer. It is suspected that EMX2 could be used as a treatment of colorectal cancer.

EMX2 Homeobox protein Emx2 is a protein that in humans is encoded by the EMX2 gene.[1][2] # Function The homeodomain transcription factor EMX2 is critical for central nervous system and urogenital development. EMX1 (MIM 600034) and EMX2 are related to the 'empty spiracles' gene expressed in the developing Drosophila head.[supplied by OMIM].[2] The EMX2 gene encodes for a transcription factor that is a homolog to Drosophila melanogaster “empty spiracles” gene.[2] The “empty spiracles gene” is needed for the proper head development/formation as well as the development of posterior spiracles in Drosophila melanogaster.[3] In humans, EMX2 shows high expression in the dorsal telencephalon, olfactory neuroepithelium, as well as the urogenetial system.[2] In the developing uroepithelium, EMX2 is negatively regulated by HOXA10.[2] EMX2 has been associated with Schizencephaly,[2] a disease where there are large parts of the brain hemispheres absent and that are replaced with cerebrospinal fluid, clinical observations can include seizures, blindness, and inability to walk/speak.[4] EMX2 has also been shown to have an important role in tumorigenesis. One study found that the expression of EMX2 is significantly decreased in tissues and cells with colorectal cancer. It is suspected that EMX2 could be used as a treatment of colorectal cancer.[5]

https://www.wikidoc.org/index.php/EMX2

5688383330ea8aecb2f57a4b86ac9a28306bc2a3

wikidoc

ENAM

ENAM Enamelin is a protein that in humans is encoded by the ENAM gene. Dental enamel is a highly mineralized tissue with 85% of its volume occupied by unusually large, highly organized, hydroxyapatite crystals. This highly organized and unusual structure is thought to be rigorously controlled in ameloblasts through the interaction of a number of organic matrix molecules that include enamelin, amelogenin (AMELX; MIM 300391), ameloblastin (AMBN; MIM 601259), tuftelin (TUFT1; MIM 600087), dentine sialophosphoprotein (DSPP; MIM 125485), and a variety of enzymes. Enamelin is the largest protein in the enamel matrix of developing teeth and comprises approximately 5% of total enamel matrix protein. Mutations in the ENAM gene can give rise to autosomal dominant Amelogenesis imperfecta, indicating a role in Amelogenesis.

ENAM Enamelin is a protein that in humans is encoded by the ENAM gene.[1][2] Dental enamel is a highly mineralized tissue with 85% of its volume occupied by unusually large, highly organized, hydroxyapatite crystals. This highly organized and unusual structure is thought to be rigorously controlled in ameloblasts through the interaction of a number of organic matrix molecules that include enamelin, amelogenin (AMELX; MIM 300391), ameloblastin (AMBN; MIM 601259), tuftelin (TUFT1; MIM 600087), dentine sialophosphoprotein (DSPP; MIM 125485), and a variety of enzymes. Enamelin is the largest protein in the enamel matrix of developing teeth and comprises approximately 5% of total enamel matrix protein.[supplied by OMIM][2] Mutations in the ENAM gene can give rise to autosomal dominant Amelogenesis imperfecta,[1][3] indicating a role in Amelogenesis.

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

d8a9b8a187cc6cd6d206f9c059a5b54e1ab6f35a

wikidoc

ENC1

ENC1 Ectoderm-neural cortex protein 1 is a protein that in humans is encoded by the ENC1 gene. # Function DNA damage and/or hyperproliferative signals activate wildtype p53 tumor suppressor protein (TP53; MIM 191170), inducing cell cycle arrest or apoptosis. Mutations that inactivate p53 occur in 50% of all tumors. Polyak et al. (1997) used serial analysis of gene expression (SAGE) to evaluate cellular mRNA levels in a colorectal cancer cell line transfected with p53. Of 7,202 transcripts identified, only 14 were expressed at levels more than 10-fold higher in p53-expressing cells than in control cells. Polyak et al. (1997) termed these genes 'p53-induced genes,' or PIGs, several of which were predicted to encode redox-controlling proteins. They noted that reactive oxygen species (ROS) are potent inducers of apoptosis. Flow cytometric analysis showed that p53 expression induces ROS production, which increases as apoptosis progresses under some conditions. The authors stated that the PIG10 gene, also called ENC1, encodes an actin-binding protein. # Interactions ENC1 has been shown to interact with Retinoblastoma protein. # Model organisms Model organisms have been used in the study of ENC1 function. A conditional knockout mouse line called Enc1tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping

ENC1 Ectoderm-neural cortex protein 1 is a protein that in humans is encoded by the ENC1 gene.[1][2][3] # Function DNA damage and/or hyperproliferative signals activate wildtype p53 tumor suppressor protein (TP53; MIM 191170), inducing cell cycle arrest or apoptosis. Mutations that inactivate p53 occur in 50% of all tumors. Polyak et al. (1997) used serial analysis of gene expression (SAGE) to evaluate cellular mRNA levels in a colorectal cancer cell line transfected with p53. Of 7,202 transcripts identified, only 14 were expressed at levels more than 10-fold higher in p53-expressing cells than in control cells. Polyak et al. (1997) termed these genes 'p53-induced genes,' or PIGs, several of which were predicted to encode redox-controlling proteins. They noted that reactive oxygen species (ROS) are potent inducers of apoptosis. Flow cytometric analysis showed that p53 expression induces ROS production, which increases as apoptosis progresses under some conditions. The authors stated that the PIG10 gene, also called ENC1, encodes an actin-binding protein.[supplied by OMIM][3] # Interactions ENC1 has been shown to interact with Retinoblastoma protein.[2] # Model organisms Model organisms have been used in the study of ENC1 function. A conditional knockout mouse line called Enc1tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[4] Male and female animals underwent a standardized phenotypic screen[5] to determine the effects of deletion.[6][7][8][9] Additional screens performed: - In-depth immunological phenotyping[10]

https://www.wikidoc.org/index.php/ENC1

b380b5de0ce5f843c758dbe82e3454615ad99c08

wikidoc

ENO3

ENO3 Enolase 3 (ENO3), more commonly known as beta-enolase (ENO-β), is an enzyme that in humans is encoded by the ENO3 gene. This gene encodes one of the three enolase isoenzymes found in mammals. This isoenzyme is found in skeletal muscle cells in the adult where it may play a role in muscle development and regeneration. A switch from alpha enolase to beta enolase occurs in muscle tissue during development in rodents. Mutations in this gene have been associated with glycogen storage disease. Alternatively spliced transcript variants encoding different isoforms have been described. # Structure ENO3 is one of three enolase isoforms, the other two being ENO1 (ENO-α) and ENO2 (ENO-γ). Each isoform is a protein subunit that can form hetero- or homodimers of the following combinations: αα, αβ, αγ, ββ, and γγ. ## Gene The ENO3 gene spans 6 kb and contains 12 exons, though the first exon is an untranslated region and, thus, non-coding. This first intron, along with the 5'-flanking region, contains a consensus sequence for muscle-specific regulatory factors that includes a CC(A + T-rich)6GG box, a M-CAT-box CAATCCT, and two myocyte-specific enhancer-binding factor 1 boxes. Upstream of the first exon lies a TATA-like box and CpG-rich region, which contains recognition motifs for binding transcriptional regulatory factors such as Sp1, activator protein 1 and 2, CCAAT box transcription factor/nuclear factor I, and cyclic AMP. Unlike the other enolase genes, which possess multiple transcription initiation sites, ENO3 possesses a single initiation site located 26 bp downstream of the TATA-like box. ## Protein This gene encodes a 433-residue dimeric protein. Due to its comparatively small length and highly conserved intron/exon organization among the three enolase isoforms, ENO3 is suggested to have been the last to diverge from a common ancestral gene. # Function As an enolase, ENO3 is a glycolytic enzyme that catalyzes the reversible conversion of 2-phosphoglycerate to phosphoenolpyruvate. This particular isoform is predominantly expressed in adult striated muscle, including skeletal and cardiac muscle. During fetal muscle development, there is a transcriptional switch from expressing ENO1 to ENO3 influenced by muscle innervation and Myo D1. ENO3 is expressed at higher levels in fast-twitch fibers than in slow-twitch fibers. # Clinical significance ENO3 has been associated with energy metabolism in cancer cells. TFG-TEC, an oncoprotein, activates ENO3 expression by altering the chromatin structure of the ENO3 promoter and increasing the acetylation of histone H3. Muscle β-enolase deficiency (glycogen storage disease type XIII) is a rare inherited metabolic myopathy caused by a defect in the enzyme's active site, thus disrupting its glycolytic activity. Though this deficiency is characterized as an autosomal recessive condition, both heterozygous and homozygous mutations were identified in the ENO3 gene. The heterozygous mutations were linked to milder symptoms while the homozygous mutations tended to produce more severe symptoms, including rhabdomyolysis. Advances in genetic testing, such as exome sequencing and specific gene panels, can provide greater access to diagnoses for muscle β-enolase deficiency and other rare disorders. # Interactions TFG-TEC binds to the proximal promoter region of the ENO3 gene. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

ENO3 Enolase 3 (ENO3), more commonly known as beta-enolase (ENO-β), is an enzyme that in humans is encoded by the ENO3 gene. This gene encodes one of the three enolase isoenzymes found in mammals. This isoenzyme is found in skeletal muscle cells in the adult where it may play a role in muscle development and regeneration. A switch from alpha enolase to beta enolase occurs in muscle tissue during development in rodents. Mutations in this gene have been associated with glycogen storage disease. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Jul 2010][1] # Structure ENO3 is one of three enolase isoforms, the other two being ENO1 (ENO-α) and ENO2 (ENO-γ).[2][3] Each isoform is a protein subunit that can form hetero- or homodimers of the following combinations: αα, αβ, αγ, ββ, and γγ.[4][5][6] ## Gene The ENO3 gene spans 6 kb and contains 12 exons, though the first exon is an untranslated region and, thus, non-coding. This first intron, along with the 5'-flanking region, contains a consensus sequence for muscle-specific regulatory factors that includes a CC(A + T-rich)6GG box, a M-CAT-box CAATCCT, and two myocyte-specific enhancer-binding factor 1 boxes.[3][6] Upstream of the first exon lies a TATA-like box and CpG-rich region, which contains recognition motifs for binding transcriptional regulatory factors such as Sp1, activator protein 1 and 2, CCAAT box transcription factor/nuclear factor I, and cyclic AMP.[3] Unlike the other enolase genes, which possess multiple transcription initiation sites, ENO3 possesses a single initiation site located 26 bp downstream of the TATA-like box.[6] ## Protein This gene encodes a 433-residue dimeric protein.[3] Due to its comparatively small length and highly conserved intron/exon organization among the three enolase isoforms, ENO3 is suggested to have been the last to diverge from a common ancestral gene.[6] # Function As an enolase, ENO3 is a glycolytic enzyme that catalyzes the reversible conversion of 2-phosphoglycerate to phosphoenolpyruvate.[3][4] This particular isoform is predominantly expressed in adult striated muscle, including skeletal and cardiac muscle.[2][3][6] During fetal muscle development, there is a transcriptional switch from expressing ENO1 to ENO3 influenced by muscle innervation and Myo D1.[3][6] ENO3 is expressed at higher levels in fast-twitch fibers than in slow-twitch fibers.[6] # Clinical significance ENO3 has been associated with energy metabolism in cancer cells. TFG-TEC, an oncoprotein, activates ENO3 expression by altering the chromatin structure of the ENO3 promoter and increasing the acetylation of histone H3.[4] Muscle β-enolase deficiency (glycogen storage disease type XIII) is a rare inherited metabolic myopathy caused by a defect in the enzyme's active site, thus disrupting its glycolytic activity. Though this deficiency is characterized as an autosomal recessive condition, both heterozygous and homozygous mutations were identified in the ENO3 gene. The heterozygous mutations were linked to milder symptoms while the homozygous mutations tended to produce more severe symptoms, including rhabdomyolysis. Advances in genetic testing, such as exome sequencing and specific gene panels, can provide greater access to diagnoses for muscle β-enolase deficiency and other rare disorders.[5] # Interactions TFG-TEC binds to the proximal promoter region of the ENO3 gene.[4] # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. [§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

https://www.wikidoc.org/index.php/ENO3

9549c4fb60ef0e2465d6eb3d2ea52c26dde80d71

wikidoc

ENTJ

ENTJ ENTJ (Extroverted iNtuitive Thinking Judging) is one of the sixteen personality types from personality type systems based on C.G. Jung, of which the best-known is the Myers-Briggs Type Indicator (MBTI). Under 2 percent of the population rank as ENTJ. Referring to Keirsey, ENTJs belong to the temperament of the Rationals and are called Fieldmarshals. ENTJ is sometimes considered to be the ideal type in business - for example MBA students who take the MBTI are expected to test as ENTJ. One could argue however that ESTJ are more apt at the routine of working one's way up in a large business organization than the visionary and original ENTJ. # MBTI cognitive functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality types Achille's heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity. - Dominant Extroverted Thinking (Te) - Auxiliary Introverted Intuition (Ni) - Tertiary Extroverted Sensing (Se) - inferior Introverted Feeling (Fi) # Famous People U.S. Presidents: Franklin D. Roosevelt Richard M. Nixon - Benny Goodman, "Big Band" leader - General Norman Schwarzkopf - Harrison Ford - Steve Martin - Whoopi Goldberg - Sigourney Weaver - Margaret Thatcher - Al Gore (U.S. Vice President, 1993-2001) - Lamar Alexander (former governor, U.S. Secretary of Education) - Les Aspen, former U.S. Secretary of Defense - Candace Bergen (Murphy Brown) - Dave Letterman - Newt Gingrich - Patrick Stewart (STNG: Jean Luc Picard) - Robert James Waller (author: The Bridges of Madison County) - Jim Carrey (Ace Ventura: Pet Detective, The Mask) - Steve Jobs - Hitler - Penn Jillette - Bill Gates - Quentin Tarantino - Jack London

ENTJ ENTJ (Extroverted iNtuitive Thinking Judging) is one of the sixteen personality types from personality type systems based on C.G. Jung, of which the best-known is the Myers-Briggs Type Indicator (MBTI). Under 2 percent of the population rank as ENTJ. Referring to Keirsey, ENTJs belong to the temperament of the Rationals and are called Fieldmarshals. ENTJ is sometimes considered to be the ideal type in business - for example MBA students who take the MBTI are expected to test as ENTJ. One could argue however that ESTJ are more apt at the routine of working one's way up in a large business organization than the visionary and original ENTJ. # MBTI cognitive functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality types Achille's heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity.[1] - Dominant Extroverted Thinking (Te) - Auxiliary Introverted Intuition (Ni) - Tertiary Extroverted Sensing (Se) - inferior Introverted Feeling (Fi) # Famous People U.S. Presidents: Franklin D. Roosevelt Richard M. Nixon - Benny Goodman, "Big Band" leader - General Norman Schwarzkopf - Harrison Ford - Steve Martin - Whoopi Goldberg - Sigourney Weaver - Margaret Thatcher - Al Gore (U.S. Vice President, 1993-2001) - Lamar Alexander (former governor, U.S. Secretary of Education) - Les Aspen, former U.S. Secretary of Defense - Candace Bergen (Murphy Brown) - Dave Letterman - Newt Gingrich - Patrick Stewart (STNG: Jean Luc Picard) - Robert James Waller (author: The Bridges of Madison County) - Jim Carrey (Ace Ventura: Pet Detective, The Mask) - Steve Jobs - Hitler - Penn Jillette - Bill Gates - Quentin Tarantino - Jack London

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

7b49dad6001cb7732f85341201d877ffa1d8c863

wikidoc

EPN1

EPN1 Epsin-1 is a protein that in humans is encoded by the EPN1 gene. EPN1 is an endocytic accessory protein that interacts with EPS15 (MIM 600051), the alpha subunit of the clathrin adaptor AP2 (AP2A1; MIM 601026), and clathrin (see MIM 118960), as well as with other accessory proteins for the endocytosis of clathrin-coated vesicles. # Interactions EPN1 has been shown to interact with REPS2, AP2A2 and EPS15.

EPN1 Epsin-1 is a protein that in humans is encoded by the EPN1 gene.[1][2][3] EPN1 is an endocytic accessory protein that interacts with EPS15 (MIM 600051), the alpha subunit of the clathrin adaptor AP2 (AP2A1; MIM 601026), and clathrin (see MIM 118960), as well as with other accessory proteins for the endocytosis of clathrin-coated vesicles.[supplied by OMIM][3] # Interactions EPN1 has been shown to interact with REPS2,[2] AP2A2[1] and EPS15.[1]

https://www.wikidoc.org/index.php/EPN1

c096a91096b47e8d89734cfabfe88117255af309

wikidoc

EPRS

EPRS Bifunctional aminoacyl-tRNA synthetase is an enzyme that in humans is encoded by the EPRS gene. # Gene Alternative splicing has been observed for this gene, but the full-length nature and biological validity of the variant have not been determined. # Function Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is a multifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species. Phosphorylation of EPRS is reported to be essential for the formation of GAIT (Gamma-interferon Activated Inhibitor of Translation) complex that regulates the translation of multiple genes in monocytes and macrophages. # Interactions EPRS has been shown to interact with POU2F1, Heat shock protein 90kDa alpha (cytosolic), member A1 and IARS.

EPRS Bifunctional aminoacyl-tRNA synthetase is an enzyme that in humans is encoded by the EPRS gene.[1][2] # Gene Alternative splicing has been observed for this gene, but the full-length nature and biological validity of the variant have not been determined.[2] # Function Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is a multifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species.[2] Phosphorylation of EPRS is reported to be essential for the formation of GAIT (Gamma-interferon Activated Inhibitor of Translation) complex that regulates the translation of multiple genes in monocytes and macrophages.[3] # Interactions EPRS has been shown to interact with POU2F1,[4] Heat shock protein 90kDa alpha (cytosolic), member A1[5] and IARS.[6]

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

207a26ec5f01673c15411c6725dc64258060d887

wikidoc

EPS8

EPS8 Epidermal growth factor receptor kinase substrate 8 is an enzyme that in humans is encoded by the EPS8 gene. # Function This gene encodes a member of the EPS8 family. This protein contains one PH domain and one SH3 domain. It functions as part of the EGFR pathway, though its exact role has not been determined. Highly similar proteins in other organisms are involved in the transduction of signals from Ras to Rac and growth factor-mediated actin remodeling. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. # Clinical significance Mutations in EPS8 cause congenital deafness .Behlouli A, Bonnet C, Abdi S, Bouaita A, Lelli A, Hardelin JP, Schietroma C, Rous Y, Louha M, Cheknane A, Lebdi H, Boudjelida K, Makrelouf M, Zenati A, Petit C (2014). "EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness". Orphanet Journal of Rare Diseases. 9 (1): 55. doi:10.1186/1750-1172-9-55. PMC 4022326. PMID 24741995..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} # Interactions EPS8 has been shown to interact with: - ABI1, - BAIAP2, - DVL1, - SHB, - SHC1 - SOS1, and - Src.

EPS8 Epidermal growth factor receptor kinase substrate 8 is an enzyme that in humans is encoded by the EPS8 gene.[1][2] # Function This gene encodes a member of the EPS8 family. This protein contains one PH domain and one SH3 domain. It functions as part of the EGFR pathway, though its exact role has not been determined. Highly similar proteins in other organisms are involved in the transduction of signals from Ras to Rac and growth factor-mediated actin remodeling. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.[2] # Clinical significance Mutations in EPS8 cause congenital deafness .Behlouli A, Bonnet C, Abdi S, Bouaita A, Lelli A, Hardelin JP, Schietroma C, Rous Y, Louha M, Cheknane A, Lebdi H, Boudjelida K, Makrelouf M, Zenati A, Petit C (2014). "EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness". Orphanet Journal of Rare Diseases. 9 (1): 55. doi:10.1186/1750-1172-9-55. PMC 4022326. PMID 24741995..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} # Interactions EPS8 has been shown to interact with: - ABI1,[3][4][5] - BAIAP2,[6][7] - DVL1,[8] - SHB,[9] - SHC1[10] - SOS1,[3][11] and - Src.[12]

https://www.wikidoc.org/index.php/EPS8

ff4350ced8ac4d1b8ab1b2431ea7b10a3482f49e

wikidoc

ERN1

ERN1 The serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 α (IRE1α) is an enzyme that in humans is encoded by the ERN1 gene. # Function The protein encoded by this gene is the ER to nucleus signalling 1 protein, a human homologue of the yeast Ire1 gene product. This protein possesses intrinsic kinase activity and an endoribonuclease activity and it is important in altering gene expression as a response to endoplasmic reticulum-based stress signals (mainly the unfolded protein response). Two alternatively spliced transcript variants encoding different isoforms have been found for this gene. # Signaling IRE1α possesses two functional enzymatic domains, an endonuclease and a trans-autophosphorylation kinase domain. Upon activation, IRE1α oligomerizes and carries out an unconventional RNA splicing activity, removing an intron from the X-box binding protein 1 (XBP1) mRNA, and allowing it to become translated into a functional transcription factor, XBP1s. XBP1s upregulates ER chaperones and endoplasmic reticulum associated degradation (ERAD) genes that facilitate recovery from ER stress. # Interactions ERN1 has been shown to interact with Heat shock protein 90kDa alpha (cytosolic), member A1. # Inhibitors Two types of inhibitors exist targeting either the catalytic core of the RNase domain or the ATP-binding pocket of the kinase domain. ## RNase domain inhibitors Salicylaldehydes (3-methoxy-6-bromosalicylaldehyde, 4μ8C, MKC-3946, STF-083010, toyocamycin. ## ATP-binding pocket Sunitinib and APY29 inhibit the ATP-binding pocket but allosterically activate the IRE1α RNase domain. Compound 3 prevents kinase activity, oligomerization and RNase activity.

ERN1 The serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 α (IRE1α) is an enzyme that in humans is encoded by the ERN1 gene.[1][2] # Function The protein encoded by this gene is the ER to nucleus signalling 1 protein, a human homologue of the yeast Ire1 gene product. This protein possesses intrinsic kinase activity and an endoribonuclease activity and it is important in altering gene expression as a response to endoplasmic reticulum-based stress signals (mainly the unfolded protein response). Two alternatively spliced transcript variants encoding different isoforms have been found for this gene.[2] # Signaling IRE1α possesses two functional enzymatic domains, an endonuclease and a trans-autophosphorylation kinase domain. Upon activation, IRE1α oligomerizes and carries out an unconventional RNA splicing activity, removing an intron from the X-box binding protein 1 (XBP1) mRNA, and allowing it to become translated into a functional transcription factor, XBP1s.[3] XBP1s upregulates ER chaperones and endoplasmic reticulum associated degradation (ERAD) genes that facilitate recovery from ER stress. # Interactions ERN1 has been shown to interact with Heat shock protein 90kDa alpha (cytosolic), member A1.[4] # Inhibitors Two types of inhibitors exist targeting either the catalytic core of the RNase domain or the ATP-binding pocket of the kinase domain. ## RNase domain inhibitors Salicylaldehydes (3-methoxy-6-bromosalicylaldehyde,[5] 4μ8C,[6] MKC-3946,[7] STF-083010,[8] toyocamycin.[9] ## ATP-binding pocket Sunitinib and APY29 inhibit the ATP-binding pocket but allosterically activate the IRE1α RNase domain. Compound 3 prevents kinase activity, oligomerization and RNase activity.[10]

https://www.wikidoc.org/index.php/ERN1

27c5477c313d9c7671ef727e268f1b7bce2b33d2

wikidoc

ESFJ

ESFJ ESFJ (Extroverted Sensing Feeling Judging) is one of the sixteen personality types from the Myers-Briggs Type Indicator (MBTI), and the Keirsey Temperament Sorter. Referring to Keirsey, ESFJs belong to the temperament of the Guardians and are called Providers. ESFJ are the best hosts/hostesses, they love to organize social events and they will be very attentive to the well being of the guests. ESFJ are very sympathetic to the feelings of others. They also are very good at remembering names after only one introduction to the person. When an ESFJ admires something, they are apt to put it in a high place and when they dislike something, they put it down hard. ESFJ do not accept criticism, even when it is constructive. The reason is that they take it emotionally (like most things) and equate criticism with rejection. Likewise, they will rarely express a disagreement with someone, preferring to avoid sensitive subjects or pretend to agree. ESFJ are usually very popular. They can do well in commercial professions. # MBTI cognitive functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality types Achille's heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity. - Dominant Extroverted Feeling (Fe) - Auxiliary Introverted Sensing (Si) - Tertiary Extroverted Intuition (Ni) - inferior Introverted Thinking (Ti)

ESFJ ESFJ (Extroverted Sensing Feeling Judging) is one of the sixteen personality types from the Myers-Briggs Type Indicator (MBTI), and the Keirsey Temperament Sorter. Referring to Keirsey, ESFJs belong to the temperament of the Guardians and are called Providers. ESFJ are the best hosts/hostesses, they love to organize social events and they will be very attentive to the well being of the guests. ESFJ are very sympathetic to the feelings of others. They also are very good at remembering names after only one introduction to the person. When an ESFJ admires something, they are apt to put it in a high place and when they dislike something, they put it down hard. ESFJ do not accept criticism, even when it is constructive. The reason is that they take it emotionally (like most things) and equate criticism with rejection. Likewise, they will rarely express a disagreement with someone, preferring to avoid sensitive subjects or pretend to agree. ESFJ are usually very popular. They can do well in commercial professions. # MBTI cognitive functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality types Achille's heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity.[1] - Dominant Extroverted Feeling (Fe) - Auxiliary Introverted Sensing (Si) - Tertiary Extroverted Intuition (Ni) - inferior Introverted Thinking (Ti)[1]

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

146ad8a827cdee0931a8848b50173bc74421fd87

wikidoc

ESFP

ESFP ESFP (Extroverted Sensing Feeling Perceiving) is one of the sixteen personality types which is used in the Myers-Briggs Type Indicator (MBTI) and is based on the well-known research of Carl Jung. Carl Jung first developed the theory that every person has their own psychological type. Myers and Briggs further developed Jung’s Theory. The MBTI preferences indicate the differences in people based on the following: - How they focus their attention or get their energy (Extraversion or Introversion) - How they perceive or take in information (Sensing or Intuition) - How they prefer to make decisions (Thinking or Feeling) - How they orient themselves to the external world (Judging or Perceiving) As a person uses their preference in each of these areas, they develop what Jung and Myers defined as psychological type, which is an underlying personality pattern resulting from the dynamic interaction of their four preferences, environmental influences, and their own personal tendencies. People are likely to develop behaviors, skills, and attitudes based on their particular type. Each personality type has its own potential strengths as well as areas which need improvement. # MBTI Cognitive Functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality types Achilles' heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity. - Dominant Extroverted Sensing (Se) - Auxiliary Introverted Feeling (Fi) - Tertiary Extroverted Thinking (Ti) - Inferior Introverted Intuition (Ni) # ESFP (Extraverted Sensing with Introverted Feeling) According to the Myers-Briggs Type Indicator, people with ESFP preferences live life to the fullest. They live in the moment and find great enjoyment in people and material comforts. They rarely let conventions interfere with their lives and find creative ways to meet human needs. ESFPs are excellent team players, focused on completing the task at hand with a maximum amount of fun and a minimum amount of discord. # Characteristics of ESFPs ESFPs are interested in people and take pleasure in new experiences. Because they learn more by doing rather from studying or reading, they tend to rush into things, learning as they go. ESFPs are most likely to be - Observant - Practical, realistic, and specific - Active, involved in immediate experiences. ESFPs make decisions by using their own personal standards. They use their Feeling judgment internally to make decisions by identifying and empathizing with others. They are good at interpersonal interactions and often play the role of peacemaker. Thus, ESFPs are likely to be - Generous, optimistic, and persuasive - Warm, sympathetic, and tactful ESFPs are keen observers of human behavior. Being attentive and observant by nature, they quickly sense what is happening with other people and immediately respond to their individual needs. They are especially good at mobilizing people to deal with crises. # How Others May Perceive Them ESFPs get a lot of satisfaction out of life and are fun to be around. Their exuberance and enthusiasm draw others to them. They are flexible, adaptable, congenial, and easygoing. They seldom plan ahead, trusting their ability to respond in the moment and deal effectively with whatever presents itself. They dislike structure and routine and will generally find ways to bend the rules. ESFPs tend to learn by doing and take the hands on approach in most things. They also learn by interacting with their environment. They usually dislike theory and written explanations. Traditional schools can be difficult for ESFPs, though they do extremely well when they see the relevance and are allowed to interact with people or the subject area being studied is of interest to them. Others usually see ESFPs as - Resourceful and supportive - Gregarious, fun-loving, playful, and spontaneous # Potential Areas for Growth Sometimes life circumstances do not support ESFPs in the development and expression of the Feeling and Sensing preferences. - If they have not developed their Feeling preference, ESFPs may get caught up in the interactions of the moment, with no mechanism for weighing, evaluating, or anchoring themselves. - If they have not developed their Sensing preference, they may focus on the sensory data available in the moment. Their decisions may then be limited to gratification of the sensual desires, particularly those involving interactions with other people. If ESFPs do not find a place where they can use their gifts and be appreciated for their contributions, they usually feel frustrated and may - Become distracted and overly impulsive - Have trouble accepting and meeting deadlines - Can be hypersensitive and internalize others’ actions and decisions It is natural for ESFPs to give less attention to their non-preferred Intuitive and Thinking parts. If they neglect these too much, they may - Fail to look at long-term consequences, acting on immediate needs of themselves and others - Avoid complex or ambiguous situations and people - Put enjoyment ahead of obligations Under great stress, ESFPs may feel overwhelmed internally by negative possibilities. They then put energy into developing simplistic global explanations for their negativity. # Things to Remember about Personality Type Each person is unique and there is not a right or wrong type. The purpose of learning about your type is to help you understand yourself better and to enhance your relationships with others. Your results on the MBTI suggest your probable type based on the choices you made when you answered the questions; however, only you know your true preference. Lastly, type does not explain everything. Human personality is much more complex. References: 1. Myers, Isabel Briggs (1998). Introduction to Type: A Guide to Understanding your Results on the Myers-Briggs Type Indicator. Mountain View, CA: CPP, Inc.

ESFP ESFP (Extroverted Sensing Feeling Perceiving) is one of the sixteen personality types which is used in the Myers-Briggs Type Indicator (MBTI) and is based on the well-known research of Carl Jung. Carl Jung first developed the theory that every person has their own psychological type. Myers and Briggs further developed Jung’s Theory. The MBTI preferences indicate the differences in people based on the following: • How they focus their attention or get their energy (Extraversion or Introversion) • How they perceive or take in information (Sensing or Intuition) • How they prefer to make decisions (Thinking or Feeling) • How they orient themselves to the external world (Judging or Perceiving) As a person uses their preference in each of these areas, they develop what Jung and Myers defined as psychological type, which is an underlying personality pattern resulting from the dynamic interaction of their four preferences, environmental influences, and their own personal tendencies. People are likely to develop behaviors, skills, and attitudes based on their particular type. Each personality type has its own potential strengths as well as areas which need improvement. # MBTI Cognitive Functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality types Achilles' heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity.[1] - Dominant Extroverted Sensing (Se) - Auxiliary Introverted Feeling (Fi) - Tertiary Extroverted Thinking (Ti) - Inferior Introverted Intuition (Ni) # ESFP (Extraverted Sensing with Introverted Feeling) According to the Myers-Briggs Type Indicator, people with ESFP preferences live life to the fullest. They live in the moment and find great enjoyment in people and material comforts. They rarely let conventions interfere with their lives and find creative ways to meet human needs. ESFPs are excellent team players, focused on completing the task at hand with a maximum amount of fun and a minimum amount of discord. # Characteristics of ESFPs ESFPs are interested in people and take pleasure in new experiences. Because they learn more by doing rather from studying or reading, they tend to rush into things, learning as they go. ESFPs are most likely to be • Observant • Practical, realistic, and specific • Active, involved in immediate experiences. ESFPs make decisions by using their own personal standards. They use their Feeling judgment internally to make decisions by identifying and empathizing with others. They are good at interpersonal interactions and often play the role of peacemaker. Thus, ESFPs are likely to be • Generous, optimistic, and persuasive • Warm, sympathetic, and tactful ESFPs are keen observers of human behavior. Being attentive and observant by nature, they quickly sense what is happening with other people and immediately respond to their individual needs. They are especially good at mobilizing people to deal with crises. # How Others May Perceive Them ESFPs get a lot of satisfaction out of life and are fun to be around. Their exuberance and enthusiasm draw others to them. They are flexible, adaptable, congenial, and easygoing. They seldom plan ahead, trusting their ability to respond in the moment and deal effectively with whatever presents itself. They dislike structure and routine and will generally find ways to bend the rules. ESFPs tend to learn by doing and take the hands on approach in most things. They also learn by interacting with their environment. They usually dislike theory and written explanations. Traditional schools can be difficult for ESFPs, though they do extremely well when they see the relevance and are allowed to interact with people or the subject area being studied is of interest to them. Others usually see ESFPs as • Resourceful and supportive • Gregarious, fun-loving, playful, and spontaneous # Potential Areas for Growth Sometimes life circumstances do not support ESFPs in the development and expression of the Feeling and Sensing preferences. • If they have not developed their Feeling preference, ESFPs may get caught up in the interactions of the moment, with no mechanism for weighing, evaluating, or anchoring themselves. • If they have not developed their Sensing preference, they may focus on the sensory data available in the moment. Their decisions may then be limited to gratification of the sensual desires, particularly those involving interactions with other people. If ESFPs do not find a place where they can use their gifts and be appreciated for their contributions, they usually feel frustrated and may • Become distracted and overly impulsive • Have trouble accepting and meeting deadlines • Can be hypersensitive and internalize others’ actions and decisions It is natural for ESFPs to give less attention to their non-preferred Intuitive and Thinking parts. If they neglect these too much, they may • Fail to look at long-term consequences, acting on immediate needs of themselves and others • Avoid complex or ambiguous situations and people • Put enjoyment ahead of obligations Under great stress, ESFPs may feel overwhelmed internally by negative possibilities. They then put energy into developing simplistic global explanations for their negativity. # Things to Remember about Personality Type Each person is unique and there is not a right or wrong type. The purpose of learning about your type is to help you understand yourself better and to enhance your relationships with others. Your results on the MBTI suggest your probable type based on the choices you made when you answered the questions; however, only you know your true preference. Lastly, type does not explain everything. Human personality is much more complex. References: 1. Myers, Isabel Briggs (1998). Introduction to Type: A Guide to Understanding your Results on the Myers-Briggs Type Indicator. Mountain View, CA: CPP, Inc.

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

7724f68028dc7f6361b1cc0938c026910712130a

wikidoc

ESM1

ESM1 Endothelial cell-specific molecule 1 is a protein that in humans is encoded by the ESM1 gene. This gene encodes a secreted protein which is mainly expressed in the endothelial cells in human lung and kidney tissues. The expression of this gene is regulated by cytokines, suggesting that it may play a role in endothelium-dependent pathological disorders. The transcript contains multiple polyadenylation and mRNA instability signals. The ESM-1 gene product is also called endocan since 2001, when it was characterized as a dermatan sulfate proteoglycan by Bechard et al. Recently, endocan / ESM-1 has been described as a specific biomarker of tip cells during neoangiogenesis by independent teams. Endocan expression has been shown to be increase in presence of pro-angiogenic growth factors such as vascular endothelial growth factor (VEGF) or fibroblast growth factor 2 (FGF-2). In hypervascularized cancers, overexpression of endocan has been detected by immunohistochemistry using monoclonal antibodies against endocan / ESM-1.

ESM1 Endothelial cell-specific molecule 1 is a protein that in humans is encoded by the ESM1 gene.[1][2] This gene encodes a secreted protein which is mainly expressed in the endothelial cells in human lung and kidney tissues. The expression of this gene is regulated by cytokines, suggesting that it may play a role in endothelium-dependent pathological disorders. The transcript contains multiple polyadenylation and mRNA instability signals.[2] The ESM-1 gene product is also called endocan since 2001, when it was characterized as a dermatan sulfate proteoglycan by Bechard et al. Recently, endocan / ESM-1 has been described as a specific biomarker of tip cells during neoangiogenesis by independent teams. Endocan expression has been shown to be increase in presence of pro-angiogenic growth factors such as vascular endothelial growth factor (VEGF) or fibroblast growth factor 2 (FGF-2). In hypervascularized cancers, overexpression of endocan has been detected by immunohistochemistry using monoclonal antibodies against endocan / ESM-1.

https://www.wikidoc.org/index.php/ESM1

d3ef9a83d859c66de7a0baff38c79df8e435777f

wikidoc

ESTJ

ESTJ ESTJ (Extroverted Sensing Thinking Judging) is one of the sixteen personality types from the Myers-Briggs Type Indicator (MBTI), and the Keirsey Temperament Sorter. Referring to Keirsey, ESTJs belong to the temperament of the guardians and are called "Supervisors". # Myers-Briggs Characteristics ESTJs are practical, realistic, and matter-of-fact, with a natural head for business or mechanics. Though they are not interested in subjects they see no use for, they can apply themselves when necessary. They like to organize and run activities. ESTJs make good administrators, especially if they remember to consider others' feelings and points of view, which they often miss. # Keirsey Characteristics According to Keirsey, ESTJs, or "Supervisor Guardians", are civic-minded individuals who dedicate themselves to maintaining the institutions behind a smooth-running society. They are defenders of the status quo and strong believers in rules and procedures. Outgoing, they don't hesitate to communicate their opinions and expectations to others. # MBTI cognitive functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality types Achille's heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity. - Dominant Extroverted Thinking - Auxiliary Introverted Sensing - Tertiary Extroverted iNtuition - inferior Introverted Feeling

ESTJ ESTJ (Extroverted Sensing Thinking Judging) is one of the sixteen personality types from the Myers-Briggs Type Indicator (MBTI), and the Keirsey Temperament Sorter. Referring to Keirsey, ESTJs belong to the temperament of the guardians and are called "Supervisors". # Myers-Briggs Characteristics ESTJs are practical, realistic, and matter-of-fact, with a natural head for business or mechanics. Though they are not interested in subjects they see no use for, they can apply themselves when necessary. They like to organize and run activities. ESTJs make good administrators, especially if they remember to consider others' feelings and points of view, which they often miss. # Keirsey Characteristics According to Keirsey, ESTJs, or "Supervisor Guardians", are civic-minded individuals who dedicate themselves to maintaining the institutions behind a smooth-running society. They are defenders of the status quo and strong believers in rules and procedures. Outgoing, they don't hesitate to communicate their opinions and expectations to others. # MBTI cognitive functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality types Achille's heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity.[1] - Dominant Extroverted Thinking - Auxiliary Introverted Sensing - Tertiary Extroverted iNtuition - inferior Introverted Feeling[1]

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

2baa517781432361beb36192f60ef561d7dd2a18

wikidoc

ESTP

ESTP ESTP (Extroverted Sensing Thinking Perceiving) is one of the sixteen personality types from the Myers-Briggs Type Indicator (MBTI), and the Keirsey Temperament Sorter. Referring to Keirsey, ESTPs belong to the Artisan temperament and are called "Promoters". # Myers-Briggs Characteristics According to Myers-Briggs, ESTPs are hands-on learners who live in the moment, seeking the best in life, wanting to share it with their friends. The ESTP is open to situations, able to improvise to bring about desired results. They are active people who want to solve their problems rather than simply discuss them. # Keirsey Characteristics According to Keirsey, ESTPs, or "Promoter Artisans", are the most adept among the types at manipulating other people. The ESTP knows everyone who matters and everything there is to do. They like to indulge themselves in the finer things in life and to bring other people with them. Their goal in life is to sell themselves and their ideas to others. Dramatic and debonair, they are gifted at earning others' confidence. # MBTI cognitive functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality types Achille's heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity. - Dominant Extroverted Sensing - Auxiliary Introverted Thinking - Tertiary Extroverted Feeling - inferior Introverted iNtuition

ESTP ESTP (Extroverted Sensing Thinking Perceiving) is one of the sixteen personality types from the Myers-Briggs Type Indicator (MBTI), and the Keirsey Temperament Sorter. Referring to Keirsey, ESTPs belong to the Artisan temperament and are called "Promoters". # Myers-Briggs Characteristics According to Myers-Briggs, ESTPs are hands-on learners who live in the moment, seeking the best in life, wanting to share it with their friends. The ESTP is open to situations, able to improvise to bring about desired results. They are active people who want to solve their problems rather than simply discuss them. # Keirsey Characteristics According to Keirsey, ESTPs, or "Promoter Artisans", are the most adept among the types at manipulating other people. The ESTP knows everyone who matters and everything there is to do. They like to indulge themselves in the finer things in life and to bring other people with them. Their goal in life is to sell themselves and their ideas to others. Dramatic and debonair, they are gifted at earning others' confidence. # MBTI cognitive functions The attributes of each personality form a hierarchy. This represents the person's "default" pattern of behavior in their day to day life. The Dominant is the personality type's preferred role, the task they feel most comfortable with. The auxiliary function is the role they feel the next most comfortable with. It serves to support and expand on the dominant function. One of these first two will always be an information gathering function (sensing or intuition) and the other will be a decision making function(thinking or feeling) in some order. The tertiary function is less developed than the Dominant and Auxiliary functions, but develops as the person matures and provides roundness of ability. The inferior function is the personality types Achille's heel. This is the function they are least comfortable with. Like the tertiary function, this function strengthens with maturity.[1] - Dominant Extroverted Sensing - Auxiliary Introverted Thinking - Tertiary Extroverted Feeling - inferior Introverted iNtuition[1]

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

07248161e86ebb9bd9a70971b04146d962e7d93f

wikidoc

ETS1

ETS1 Protein C-ets-1 is a protein that in humans is encoded by the ETS1 gene. The protein encoded by this gene belongs to the ETS family of transcription factors. # Function There are 28 ETS genes in humans and 27 in mice. They bind the DNA via their winged-helix-turn-helix DNA binding motif known as the Ets domain that specifically recognizes DNA sequences that contain a GGAA/T core element. However, Ets proteins differ significantly in their preference for the sequence flanking the GGAA/T core motif. For instance, the consensus sequence for Ets1 is PuCC/a-GGAA/T-GCPy. On the other hand, many natural Ets1-responsive GGAA/T elements differ from this consensus sequence. The later suggests that several other transcription factors may facilitate Ets1 binding to unfavorable DNA sequences. Ets1 binds to DNA as a monomer. Phosphorylation of serine residues of the C-terminal domain (in the nucleotide sequence they belong to exon VII) known as autoinhibition makes Ets1 inactive. There are several ways to activate Ets1. First, Ets1 can be dephosphorylated. Second, two Ets1 can be activated If two Ets molecules homodimerize. The homodimerization occurs if DNA binding sites are present in the correct orientation and spacing. Thus, the exact layout of binding sites within an enhancer or promoter segment to either relieve or allow autoinhibition of Ets1 to occur may strongly influence whether or not Ets1 actually binds to particular site. Third, Ets1 can be activated by Erk2 and Ras at Thr38. The truncated isoform cannot be phosphorylated by the Erk2. It is localized in the cytoplasm and acts as a dominant negative isoform. Contrary, another isoform that misses exon VII is constitutively active. Many Ras responsive genes harbor combinatorial Ets/AP1 recognition motifs through which Ets1 and AP1 synergistically activate transcription when stimulated by Ras. In adult humans, Ets1 is expressed at high levels mainly in immune tissues such as thymus, spleen, and lymph node (B cells, T cells, NK cells, and NK T cells and non-lymphoid immune cells). An enforced expression of Ets1 blocks differentiation of B- and T-cells. Contrary, knocking Ets1 down is causing multiple defects in the immune system. # Knockout mice Ets1 knockout mice have aberrant thymic differentiation, reduced peripheral T cell numbers, reduced IL-2 production, a skewing towards a memory/effector phenotype and impairments in the production of Th1 and Th2 cytokines. Although Ets1 knockout mice have an impaired development of Th1, Th2, and Treg cells, they have higher numbers of Th17 cells. There are also partial defects in bone marrow B cell development with reduced cellularity and inefficient transition from pro-B to pre-B cell stages. # Clinical significance Meta-analyses of multiple genome-wide association studies has suggested an association of SNPs in the ETS1locus with psoriasis in European populations. This is not surprising because Ets1 is a negative regulator of Th17 cells. Ets1 overexpression in stratified squamous epithelial cells causes pro-oncogenic changes, such as suspension of terminal differentiation, high secretion of matrix metalloproteases (Mmps), epidermal growth factor ligands, and inflammatory mediators. # Interactions Ets1 directly interacts with various transcription factors. Their interaction results in formation of multiprotein complexes. When Ets1 interacts with other transcription factors (Runx1, Pax5, TFE3, and USF1) its final effect on transcription depends on whether C-terminal domain is phosphorylated. Acetyltransferases CBP and p300 bind to the transactivation domain. AP1, STAT5 and VDR bind to C-terminal domain. Also, ETS1 has been shown to interact with TTRAP, UBE2I and Death associated protein 6. # Interaction with DNA repair promoters and proteins ## DNA repair promoters The messenger RNA and protein levels of DNA repair protein PARP1 are controlled, in part, by the expression level of the ETS1 transcription factor which interacts with multiple ETS1 binding sites in the promoter region of PARP1. The degree to which the ETS1 transcription factor can bind to its binding sites on the PARP1 promoter depends on the methylation status of the CpG islands in the ETS1 binding sites in the PARP1 promoter. If these CpG islands in ETS1 binding sites of the PARP1 promoter are epigenetically hypomethylated, PARP1 is expressed at an elevated level. The high constitutive levels of PARP1 in centenarians, providing more effective DNA repair, is thought to contribute to their unusual longevity. These levels of PARP1 expression are considered to be due to altered epigenetic control of transactivation of PARP1 expression. As shown by Wilson et al., increased ETS1 expression causes about 50 target genes to increase expression, including DNA repair genes MUTYH, BARD1, ERCC1 and XPA. Increased ETS1 expression causes resistance to cell killing by cisplatin, the resistance thought to be partly due to increased expression of DNA repair genes. ## DNA repair protein interactions ETS1 functions are regulated by protein – protein interactions. In particular, ETS1 protein interacts with several DNA repair proteins. ETS1 binds with DNA-dependent protein kinase (DNA-PK) . ETS1 interaction with DNA-PK phosphorylates ETS1. Such phosphorylation of ETS1 alters its target gene repertoire. The Ku80 portion of DNA-PK, acting alone, interacts with ETS1 to down-regulate at least one of its transcriptional activities. As shown by Legrand et al., ETS1 protein interacts with PARP1 protein. ETS1 activates PARP1, causing poly ADP-ribosylation of PARP1 itself and of other proteins, even in the absence of nicked DNA. PARP1 (without self- poly ADP-ribosylation), in turn, is needed for activation of the transactivating activity of ETS1 on a tested promoter. Active PARP1 subsequently causes poly ADP-ribosylation of ETS1, and this appears to promote ETS1 ubiquitination and proteasomal degradation, preventing excessive activity of ETS1.

ETS1 Protein C-ets-1 is a protein that in humans is encoded by the ETS1 gene.[1] The protein encoded by this gene belongs to the ETS family of transcription factors.[2] # Function There are 28 ETS genes in humans and 27 in mice. They bind the DNA via their winged-helix-turn-helix DNA binding motif known as the Ets domain that specifically recognizes DNA sequences that contain a GGAA/T core element. However, Ets proteins differ significantly in their preference for the sequence flanking the GGAA/T core motif. For instance, the consensus sequence for Ets1 is PuCC/a-GGAA/T-GCPy. On the other hand, many natural Ets1-responsive GGAA/T elements differ from this consensus sequence. The later suggests that several other transcription factors may facilitate Ets1 binding to unfavorable DNA sequences. Ets1 binds to DNA as a monomer. Phosphorylation of serine residues of the C-terminal domain (in the nucleotide sequence they belong to exon VII) known as autoinhibition makes Ets1 inactive. There are several ways to activate Ets1. First, Ets1 can be dephosphorylated. Second, two Ets1 can be activated If two Ets molecules homodimerize. The homodimerization occurs if DNA binding sites are present in the correct orientation and spacing. Thus, the exact layout of binding sites within an enhancer or promoter segment to either relieve or allow autoinhibition of Ets1 to occur may strongly influence whether or not Ets1 actually binds to particular site. Third, Ets1 can be activated by Erk2 and Ras at Thr38. The truncated isoform cannot be phosphorylated by the Erk2. It is localized in the cytoplasm and acts as a dominant negative isoform. Contrary, another isoform that misses exon VII is constitutively active. Many Ras responsive genes harbor combinatorial Ets/AP1 recognition motifs through which Ets1 and AP1 synergistically activate transcription when stimulated by Ras.[3] In adult humans, Ets1 is expressed at high levels mainly in immune tissues such as thymus, spleen, and lymph node (B cells, T cells, NK cells, and NK T cells and non-lymphoid immune cells). An enforced expression of Ets1 blocks differentiation of B- and T-cells. Contrary, knocking Ets1 down is causing multiple defects in the immune system. # Knockout mice Ets1 knockout mice have aberrant thymic differentiation, reduced peripheral T cell numbers, reduced IL-2 production, a skewing towards a memory/effector phenotype and impairments in the production of Th1 and Th2 cytokines. Although Ets1 knockout mice have an impaired development of Th1, Th2, and Treg cells, they have higher numbers of Th17 cells. There are also partial defects in bone marrow B cell development with reduced cellularity and inefficient transition from pro-B to pre-B cell stages. # Clinical significance Meta-analyses of multiple genome-wide association studies has suggested an association of SNPs in the ETS1locus with psoriasis in European populations. This is not surprising because Ets1 is a negative regulator of Th17 cells. Ets1 overexpression in stratified squamous epithelial cells causes pro-oncogenic changes, such as suspension of terminal differentiation, high secretion of matrix metalloproteases (Mmps), epidermal growth factor ligands, and inflammatory mediators. # Interactions Ets1 directly interacts with various transcription factors. Their interaction results in formation of multiprotein complexes. When Ets1 interacts with other transcription factors (Runx1, Pax5, TFE3, and USF1) its final effect on transcription depends on whether C-terminal domain is phosphorylated. Acetyltransferases CBP and p300 bind to the transactivation domain. AP1, STAT5 and VDR bind to C-terminal domain. Also, ETS1 has been shown to interact with TTRAP,[4] UBE2I[5] and Death associated protein 6.[6] # Interaction with DNA repair promoters and proteins ## DNA repair promoters The messenger RNA and protein levels of DNA repair protein PARP1 are controlled, in part, by the expression level of the ETS1 transcription factor which interacts with multiple ETS1 binding sites in the promoter region of PARP1.[7] The degree to which the ETS1 transcription factor can bind to its binding sites on the PARP1 promoter depends on the methylation status of the CpG islands in the ETS1 binding sites in the PARP1 promoter.[8] If these CpG islands in ETS1 binding sites of the PARP1 promoter are epigenetically hypomethylated, PARP1 is expressed at an elevated level.[8][9] The high constitutive levels of PARP1 in centenarians, providing more effective DNA repair, is thought to contribute to their unusual longevity. These levels of PARP1 expression are considered to be due to altered epigenetic control of transactivation of PARP1 expression.[10] As shown by Wilson et al.,[11] increased ETS1 expression causes about 50 target genes to increase expression, including DNA repair genes MUTYH, BARD1, ERCC1 and XPA. Increased ETS1 expression causes resistance to cell killing by cisplatin, the resistance thought to be partly due to increased expression of DNA repair genes. ## DNA repair protein interactions ETS1 functions are regulated by protein – protein interactions.[12][13] In particular, ETS1 protein interacts with several DNA repair proteins. ETS1 binds with DNA-dependent protein kinase (DNA-PK) [where the DNA-PK complex is made up of DNA-PKcs and DNA repair Ku (protein), and where Ku itself is a heterodimer of two polypeptides, Ku70 (XRCC6) and Ku80 (XRCC5)].[13] ETS1 interaction with DNA-PK phosphorylates ETS1.[13] Such phosphorylation of ETS1 alters its target gene repertoire.[14] The Ku80 portion of DNA-PK, acting alone, interacts with ETS1 to down-regulate at least one of its transcriptional activities.[13] As shown by Legrand et al.,[15] ETS1 protein interacts with PARP1 protein. ETS1 activates PARP1, causing poly ADP-ribosylation of PARP1 itself and of other proteins, even in the absence of nicked DNA. PARP1 (without self- poly ADP-ribosylation), in turn, is needed for activation of the transactivating activity of ETS1 on a tested promoter. Active PARP1 subsequently causes poly ADP-ribosylation of ETS1, and this appears to promote ETS1 ubiquitination and proteasomal degradation, preventing excessive activity of ETS1.

https://www.wikidoc.org/index.php/ETS1

dfe86b2709b1abe163b707c828ca8027cb3d2ffc

wikidoc

ETV6

ETV6 ETV6 (i.e. translocation-Ets-leukemia virus) protein is a transcription factor that in humans is encoded by the ETV6 (previously known as TEL) gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However, ETV6 is also an anti-oncogene or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers. # Gene The human ETV6 gene is located at position "13.2" on the short (i.e. "p") arm of chromosome 12, i.e. its notated position is 12p13.2. The gene has 8 exons and two start codons, one located at exon 1 at the start of the gene and an alternative located upstream of exon 3. ETV6 codes for a full length protein consisting of 452 amino acids; the gene is expressed in virtually all cell types and tissues. Mice depleted of the ETV6 gene by Gene knockout die between day 10.5 and 11.5 of embryonic life with defective yolk sac angiogenesis and extensive losses in mesenchymal and neural cells due to apoptosis. Other genetic manipulation studies in mice indicate that the gene is required for the development and maintenance of bone marrow-based blood cell formation and the vascular network. # Protein The human ETV6 protein is a member of the ETS transcription factor family; however, it more often acts to inhibit than stimulate transcription of its target genes. ETV6 protein contains 3 domains: a) the pointed N-terminal (i.e. PNT) domain which forms oligomer partners with itself as well as other transcription factors (e.g. FLI1) and is required for ETV6's transcriptional repressing activity; b) the central regulatory domain; and c) the C-terminal DNA-binding domain, ETS, which binds to the consensus DNA sequence, 5-GGAA/T-3 within a 9-to-10 bp sequence, in the target genes it regulates. ETV6 interacts with other proteins that regulate the differentiation and growth of cells. It binds to and thereby inhibits FLI1, another member of the ETS transcription factor family, which is active in promoting the maturation of blood platelet-forming megakaryocytes and blocking the Cellular differentiation of erythroblasts into red blood cells; this results in the excessive proliferation and abnormal morphology of erythroblasts. ETV6 likewise binds to HTATIP, a histone acetyl transferase that regulates the expression of various genes involved in gene transcription, DNA repair, and cellular apoptosis; this binding promotes the transcription-repressing activity of ETV6. # Medical significance ## Inherited mutations Rare missense and other loss of function mutations in ETV6 cause thrombocytopenia 5, an autosomal dominant familial disease characterized by variable thrombocytopenia (blood platelet counts from 5% to 90% of normal), mild to modest bleeding tendencies, and bone marrow biopsy findings of abnormal appearing megakaryocytes (i.e. nuclei with fewer than the normal number of lobulations) and red cell macrocytosis. Thrombocytopenia 5 is associated with an increased incidence of developing hematological (e.g. chronic myelomonocytic leukemia, acute myelocytic leukemia, B cell acute lymphoblastic leukemia, mixed phenotype acute leukemia, Myelodysplastic syndrome, and multiple myeloma) and non-hematological (e.g. skin and colon) cancers as well as non-malignant diseases such as refractory anemia myopathies, and gastroesophageal reflux disease. Two unrelated kindreds were found to have autosomal dominant inherited mutations in the ETV6 gene, one family with a germline DNA substitution termed L349P that lead to replacing leucine with proline at amino acid 349 in the DNA binding domain of the ETV6, the second, termed N385fs, in germline DNA caused the lose of five base pairs ETV6 and a truncated ETV6 protein. Both mutant proteins failed to enter cell nuclei normally and had a reduced capacity to target genes regulated by the normal ETV6 protein. Afflicted members of these families had low platelet counts (i.e. thrombocytopenia) and acute lymphoblastic leukemia. Fifteen members of the two kindreds had thrombocytopenia, five of whom also had acute lymphoblastic leukemia. The L249P kindred also had one family member with renal cell carcinoma and another family member with Duodenal cancer. The relationship of these two cancers to the L249P mutation has not been investigated. In all events these two familial thrombocytopenia syndromes appear distinctly different than the thrombocytopenia 5 syndrome. ### Treatment Family members with thrombocytopenia 5 need to be regularly monitored with complete blood count and blood smear screenings to detect the early changes brought on by the malignant transformations of this disease into hematological neoplasms. Patients who developed these transformations have generally been treated similarly to patients who have the same hematological neoplasms but on a non-familial basis. Patients developing non-malignant hematological or non-hematological solid tumor manifestations of thrombocytopenia 5 are also treated like to patients with the same but no-familial disease. The acute lymphoblastic leukemia associated with L349P or N385fs mutations in ETV6 appeared far less sensitive to standard chemotherapy for acute lymphoblastic leukemia with 2 among 3 family members moving rather quickly from chemotherapy to bone marrow transplantation and the third family member expiring. This suggest that these mutation-related forms of acute lymphoblastic leukemia require aggressive therapy. ## Acquired mutations The ETV6 gene is prone to develop a wide range of acquired mutations in hematological precursor cells that lead to various types of leukemia and/or lymphoma. It may also suffer a smaller number of mutations in non-hematological tissues that leads to solid tumors. These mutations involve chromosome translocations which fuse the ETV6 on chromosome 12's the short (i.e. "p") arm ("q" stands for long arm) at position p13.2 (site notation: 12p12.2) near to a second gene on another chromosome or, more rarely, its own chromosome. This creates a fusion gene of the oncogene category which encodes a chimeric protein that promotes the malignant growth of its parent cells. It may be unclear which portion of the newly formed oncoprotein contributes to the ensuing malignancy but fusions between ETV6 and proteins with tyrosine kinase activity generally are converted from a protein with tightly regulated tyrosine kinase activity to an uncontrolled and continuously active tyrosine kinase that thereby promotes the malignant transformation of its parent cells. ### Hematological malignancies The following table lists the more frequently occurring genes to which ETV6 fuses, the function of these genes, these genes' chromosomal locations, the notation designating the most common sites of the translocations of these fused genes, and the malignancies resulting from these translocations. These translocation mutations commonly occur in pluripotent hematopoietic stem cells that differentiate into various types of mature hematological cells. Consequently, a given mutation may lead to various types of hematological malignancies. The table includes abbreviations for tyrosine kinase receptor (TK receptor), non-receptor tyrosine kinase (non-receptor TK), homeobox protein type of transcription factor (homeobox protein), acute lymphocytic leukemia (ALL), Philadelphia chromosome negative chronic myelogenous leukemia (Ph(-)CML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), and acute myeloid leukemia (AML). (The presence of ETV6 gene mutations in myelodysplastic syndromes is associated with shortened survival.) transcription factors In addition to the fusion gene-producing translocations given in the table, ETV6 has been reported to fuse with other genes in very rare cases (i.e. 1-10 published reports). These translocations lead to one or more of the same types of hematological malignancies listed in the table. Thus, the ETV6 gene reportedly forms translocation-induced fusion genes with: a) tyrosine kinase receptor gene FGFR3; b) non-receptor tyrosine kinase genes ABL2, NTRK3, JAK2, SYK, FRK, and LYN; c) transcription factor genes MN1 and PER1; d) homeobox protein transcription factor CDX2; e) Protein tyrosine phosphatase receptor-type R gene PTPRR; f) transcriptional coactivator for nuclear hormone receptors gene NCOA2; f) Immunoglobulin heavy chain gene IGH; g) enzyme genes TTL (adds and removes tyrosine residues on α-tubulin), GOT1 (an Aspartate transaminase), and ACSL6 (a Long-chain-fatty-acid—CoA ligase); h) transporter gene ARNT (binds to ligand-bound aryl hydrocarbon receptor to aid in its movement to the nucleus where it promotes the expression of genes involved in xenobiotic metabolism); i) unknown function genes CHIC2, MDS2, FCHO2 and BAZ2A.; and j) non-annotated gene STL (which has no long open reading frame). At least 9 frameshift mutations in the'ETV6 gene have been associated with ~12% of adult T cell Acute lymphoblastic leukemia cases. These mutations involve insertions or deletions in the gene that lead to its encoding a truncated and therefore inactive ETV6 protein. These mutations commonly occur alongside mutations in another oncogene, NOTCH1, which is associated with T cell acute lymphoblastic lymphoma quite independently of ETV6. It is suggested that suppressor mutations in the ETV6 gene may be a contributing factor in the development ant/or progression of this leukemia type. Patients developing hematological malignancies secondary to the ETV6 gene fusion to receptor tyrosine kinases and non-receptor tyrosine kinases may be sensitive to therapy with tyrosine kinase inhibitors. For example, patients with clonal eosinophilias due to PDGFRA or PDGFRB fusion genes experience long-term, complete remission when treated with are highly sensitive tyrosine kinase inhibitor, gleevec. Larotrectinib, entrectinib, merestinib, and server other broadly acting tyrosine kinase inhibitors target the NTRK3 gene. Many of these drugs are in phase 1 or phase 2 clinical trials for the treatment of ETV6-NTRK3-related solid tumors and may ultimately prove useful for treating hematologic malignancies associated with this fusion gene. Clinical trials have found that the first generation tyrosine kinase inhibitors sorafenib, sunitinib, midostaurin, lestaurtinib have shown some promise in treating acute myelogenous leukemia associated with the FLT3-TKI fusion gene; the second generation tyrosine kinase inhibitors quizartinib and crenolanib which are highly selective in inhibiting the FLT3 protein, have shown significant promise in treating relapsed and refractory acute myelogenous leukemia related to the FLT3-TKI fusion gene. One patient with ETV6-FLT3-related myeloid/lymphoid neoplasm obtained a short term remission on sunitinib and following relapse, on sorafenib suggesting that the cited FLT3 protein tyrosine kinase inhibitors may prove useful for treating ETV6-FLT-related hematologic malignancies. Two patients suffering hematologic malignancies related to PCM1-JAK2 or BCR-JAK2 fusion genes experienced complete and cytogenetic remissions in response to the tyrosine kinase inhibitor ruxolitinib; while both remissions were short-term (12 months), these results suggest that tyrosine kinase inhibitors that target JAK2 may be of some use for treating hematologic malignancies associated with ETV6-JAK2 fusion stems. An inhibitor of SYK tyrosine kinase, TAK-659 is currently undergoing Phase I clinical trials for advanced lymphoma malignancies and may prove to be useful in treating this disease when associated with the ETV6-SYK fusion gene. It is possible that hematological malignancies associated with ETV6 gene fusions to either the SYK or FRK tyrosine kinase genes may someday be shown susceptible to tyrosine kinase inhibitor therapy. However, children with ETV6-RUNX1-associated acute lymphoblastic leukemia are in an especially good-risk subgroup and therefore have been almost uniformly treated with standard-risk chemotherapy protocols. Hematological malignancies associated with ETY6 gene fusions to other transcription factor genes appear to reflect a loss or gain in function of ETV6 and/or the other genes in regulating expression of their target genes; this results in the formation or lack of formation of products which influence cell growth, proliferation, and/or survival. In vitro studies of ETV6-RUNX, ETV6-MN1, ETV6-PER1, and ETV6-MECOM fusion genes support this notion. Thus, the ETV6-MECOM fusion gene is overexpressed because it is driven by the promoter derived from ETV6 whereas the ETV6-RUNX, ETV6-MN1, and ETV6-PER1 fusion genes produce chimeric proteins which lack ETV6 protein's gene-suppressing activity. The chimeric protein products of ETV6 gene fusions with ARNT, TTL, BA22A, FCHO2, MDS2, and CHIC2 likewise lack ETV6 protein's transcription factor activity. Gene fusions between ETV6 and the homeobox gens (i.e. CDX2, PAX5, and MNX1) produce chimeric proteins with lack either ETV6s and/or CDX2s, PAX5s or MNX1s transcription factor activity. In all events, hematological malignancies associated with these fusion genes have been treated with standard chemotherapy protocols selected on the basis of the malignancies phenotype. ## Solid Tumors Mutations in the ETV6 gene are also associated with solid tumors. In particular, the ETV6-NTRK3 fusion gene occurs in and is thought or proposed to drive certain types of cancers. These cancers include secretory breast cancer (also termed juvenile breast cancer), mammary analogue secretory carcinoma of the parotid and other salivary glands, congenital fibrosarcoma, congenital mesoblastic nephroma, inflammatory myofibroblastic tumor, and radiation-induced papillary thyroid carcinoma. ### Treatment The treatment of ETV6 gene-associated solid tumors has not advanced as far as that for ETV6 gene-associated hematological malignancies. It is proposed that tyrosine kinase inhibitors with specificity for NTRK3's tyrosine kinase activity in ETV6-NTRK3 gene-associated solid tumors may be of therapeutic usefulness. Entrectinib, a pan-NTRK as well as an ALK and ROS1 tyrosine kinase inhibitor has been found useful in treating a single patient with ETV6-NRTK3 fusion gene-associated mammary analogue secretory carcinoma and lends support to the clinical development of NTRK3-directed tyrosine kinase inhibitors to treat ETV6-NTRK3 fusion protein associated malignancies. Three clinical trials are in the recruitment phase for determining the efficacy of treating a wide range of solid tumors associated with mutated, overactive tyrosine kinase proteins, including the ETV6-TRK3 protein, with larotrectinib, a non-selective inhibitor of NTRK1, NTRK2, and NTRK3 tyrosine kinases.

ETV6 ETV6 (i.e. translocation-Ets-leukemia virus) protein is a transcription factor that in humans is encoded by the ETV6 (previously known as TEL) gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However, ETV6 is also an anti-oncogene or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers. # Gene The human ETV6 gene is located at position "13.2" on the short (i.e. "p") arm of chromosome 12, i.e. its notated position is 12p13.2. The gene has 8 exons and two start codons, one located at exon 1 at the start of the gene and an alternative located upstream of exon 3. ETV6 codes for a full length protein consisting of 452 amino acids; the gene is expressed in virtually all cell types and tissues.[1][2] Mice depleted of the ETV6 gene by Gene knockout die between day 10.5 and 11.5 of embryonic life with defective yolk sac angiogenesis and extensive losses in mesenchymal and neural cells due to apoptosis. Other genetic manipulation studies in mice indicate that the gene is required for the development and maintenance of bone marrow-based blood cell formation and the vascular network.[1][3] # Protein The human ETV6 protein is a member of the ETS transcription factor family; however, it more often acts to inhibit than stimulate transcription of its target genes. ETV6 protein contains 3 domains: a) the pointed N-terminal (i.e. PNT) domain which forms oligomer partners with itself as well as other transcription factors (e.g. FLI1) and is required for ETV6's transcriptional repressing activity; b) the central regulatory domain; and c) the C-terminal DNA-binding domain, ETS, which binds to the consensus DNA sequence, 5-GGAA/T-3 within a 9-to-10 bp sequence, in the target genes it regulates.[1][4] ETV6 interacts with other proteins that regulate the differentiation and growth of cells. It binds to and thereby inhibits FLI1, another member of the ETS transcription factor family, which is active in promoting the maturation of blood platelet-forming megakaryocytes and blocking the Cellular differentiation of erythroblasts into red blood cells; this results in the excessive proliferation and abnormal morphology of erythroblasts.[5][3] ETV6 likewise binds to HTATIP, a histone acetyl transferase that regulates the expression of various genes involved in gene transcription, DNA repair, and cellular apoptosis; this binding promotes the transcription-repressing activity of ETV6.[6] # Medical significance ## Inherited mutations Rare missense and other loss of function mutations in ETV6 cause thrombocytopenia 5, an autosomal dominant familial disease characterized by variable thrombocytopenia (blood platelet counts from 5% to 90% of normal), mild to modest bleeding tendencies, and bone marrow biopsy findings of abnormal appearing megakaryocytes (i.e. nuclei with fewer than the normal number of lobulations) and red cell macrocytosis.[3][7] Thrombocytopenia 5 is associated with an increased incidence of developing hematological (e.g. chronic myelomonocytic leukemia, acute myelocytic leukemia, B cell acute lymphoblastic leukemia, mixed phenotype acute leukemia, Myelodysplastic syndrome, and multiple myeloma) and non-hematological (e.g. skin and colon) cancers as well as non-malignant diseases such as refractory anemia myopathies, and gastroesophageal reflux disease.[7][8] Two unrelated kindreds were found to have autosomal dominant inherited mutations in the ETV6 gene, one family with a germline DNA substitution termed L349P that lead to replacing leucine with proline at amino acid 349 in the DNA binding domain of the ETV6, the second, termed N385fs, in germline DNA caused the lose of five base pairs ETV6 and a truncated ETV6 protein. Both mutant proteins failed to enter cell nuclei normally and had a reduced capacity to target genes regulated by the normal ETV6 protein. Afflicted members of these families had low platelet counts (i.e. thrombocytopenia) and acute lymphoblastic leukemia. Fifteen members of the two kindreds had thrombocytopenia, five of whom also had acute lymphoblastic leukemia. The L249P kindred also had one family member with renal cell carcinoma and another family member with Duodenal cancer. The relationship of these two cancers to the L249P mutation has not been investigated. In all events these two familial thrombocytopenia syndromes appear distinctly different than the thrombocytopenia 5 syndrome.[9] ### Treatment Family members with thrombocytopenia 5 need to be regularly monitored with complete blood count and blood smear screenings to detect the early changes brought on by the malignant transformations of this disease into hematological neoplasms. Patients who developed these transformations have generally been treated similarly to patients who have the same hematological neoplasms but on a non-familial basis. Patients developing non-malignant hematological or non-hematological solid tumor manifestations of thrombocytopenia 5 are also treated like to patients with the same but no-familial disease.[7][8] The acute lymphoblastic leukemia associated with L349P or N385fs mutations in ETV6 appeared far less sensitive to standard chemotherapy for acute lymphoblastic leukemia with 2 among 3 family members moving rather quickly from chemotherapy to bone marrow transplantation and the third family member expiring. This suggest that these mutation-related forms of acute lymphoblastic leukemia require aggressive therapy.[9] ## Acquired mutations The ETV6 gene is prone to develop a wide range of acquired mutations in hematological precursor cells that lead to various types of leukemia and/or lymphoma. It may also suffer a smaller number of mutations in non-hematological tissues that leads to solid tumors. These mutations involve chromosome translocations which fuse the ETV6 on chromosome 12's the short (i.e. "p") arm ("q" stands for long arm) at position p13.2 (site notation: 12p12.2) near to a second gene on another chromosome or, more rarely, its own chromosome. This creates a fusion gene of the oncogene category which encodes a chimeric protein that promotes the malignant growth of its parent cells. It may be unclear which portion of the newly formed oncoprotein contributes to the ensuing malignancy but fusions between ETV6 and proteins with tyrosine kinase activity generally are converted from a protein with tightly regulated tyrosine kinase activity to an uncontrolled and continuously active tyrosine kinase that thereby promotes the malignant transformation of its parent cells.[10] ### Hematological malignancies The following table lists the more frequently occurring genes to which ETV6 fuses, the function of these genes, these genes' chromosomal locations, the notation designating the most common sites of the translocations of these fused genes, and the malignancies resulting from these translocations. These translocation mutations commonly occur in pluripotent hematopoietic stem cells that differentiate into various types of mature hematological cells. Consequently, a given mutation may lead to various types of hematological malignancies.[1][10] The table includes abbreviations for tyrosine kinase receptor (TK receptor), non-receptor tyrosine kinase (non-receptor TK), homeobox protein type of transcription factor (homeobox protein), acute lymphocytic leukemia (ALL), Philadelphia chromosome negative chronic myelogenous leukemia (Ph(-)CML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), and acute myeloid leukemia (AML). (The presence of ETV6 gene mutations in myelodysplastic syndromes is associated with shortened survival.[11]) transcription factors In addition to the fusion gene-producing translocations given in the table, ETV6 has been reported to fuse with other genes in very rare cases (i.e. 1-10 published reports). These translocations lead to one or more of the same types of hematological malignancies listed in the table. Thus, the ETV6 gene reportedly forms translocation-induced fusion genes with:[1] a) tyrosine kinase receptor gene FGFR3; b) non-receptor tyrosine kinase genes ABL2, NTRK3, JAK2, SYK, FRK, and LYN; c) transcription factor genes MN1 and PER1; d) homeobox protein transcription factor CDX2; e) Protein tyrosine phosphatase receptor-type R gene PTPRR;[12] f) transcriptional coactivator for nuclear hormone receptors gene NCOA2; f) Immunoglobulin heavy chain gene IGH;[13] g) enzyme genes TTL (adds and removes tyrosine residues on α-tubulin),[14] GOT1 (an Aspartate transaminase), and ACSL6 (a Long-chain-fatty-acid—CoA ligase); h) transporter gene ARNT (binds to ligand-bound aryl hydrocarbon receptor to aid in its movement to the nucleus where it promotes the expression of genes involved in xenobiotic metabolism); i) unknown function genes CHIC2,[15] MDS2,[16] FCHO2[17] and BAZ2A.;[18] and j) non-annotated gene STL (which has no long open reading frame[19]). At least 9 frameshift mutations in the'ETV6 gene have been associated with ~12% of adult T cell Acute lymphoblastic leukemia cases. These mutations involve insertions or deletions in the gene that lead to its encoding a truncated and therefore inactive ETV6 protein. These mutations commonly occur alongside mutations in another oncogene, NOTCH1, which is associated with T cell acute lymphoblastic lymphoma quite independently of ETV6. It is suggested that suppressor mutations in the ETV6 gene may be a contributing factor in the development ant/or progression of this leukemia type.[4][20][21] Patients developing hematological malignancies secondary to the ETV6 gene fusion to receptor tyrosine kinases and non-receptor tyrosine kinases may be sensitive to therapy with tyrosine kinase inhibitors.[22] For example, patients with clonal eosinophilias due to PDGFRA or PDGFRB fusion genes experience long-term, complete remission when treated with are highly sensitive tyrosine kinase inhibitor, gleevec.[10] Larotrectinib, entrectinib, merestinib, and server other broadly acting tyrosine kinase inhibitors target the NTRK3 gene. Many of these drugs are in phase 1 or phase 2 clinical trials for the treatment of ETV6-NTRK3-related solid tumors and may ultimately prove useful for treating hematologic malignancies associated with this fusion gene.[23] Clinical trials have found that the first generation tyrosine kinase inhibitors sorafenib, sunitinib, midostaurin, lestaurtinib have shown some promise in treating acute myelogenous leukemia associated with the FLT3-TKI fusion gene; the second generation tyrosine kinase inhibitors quizartinib and crenolanib which are highly selective in inhibiting the FLT3 protein, have shown significant promise in treating relapsed and refractory acute myelogenous leukemia related to the FLT3-TKI fusion gene.[24] One patient with ETV6-FLT3-related myeloid/lymphoid neoplasm obtained a short term remission on sunitinib and following relapse, on sorafenib suggesting that the cited FLT3 protein tyrosine kinase inhibitors may prove useful for treating ETV6-FLT-related hematologic malignancies.[25] Two patients suffering hematologic malignancies related to PCM1-JAK2 or BCR-JAK2 fusion genes experienced complete and cytogenetic remissions in response to the tyrosine kinase inhibitor ruxolitinib; while both remissions were short-term (12 months), these results suggest that tyrosine kinase inhibitors that target JAK2 may be of some use for treating hematologic malignancies associated with ETV6-JAK2 fusion stems.[10] An inhibitor of SYK tyrosine kinase, TAK-659 is currently undergoing Phase I clinical trials for advanced lymphoma malignancies and may prove to be useful in treating this disease when associated with the ETV6-SYK fusion gene.[26] It is possible that hematological malignancies associated with ETV6 gene fusions to either the SYK or FRK tyrosine kinase genes may someday be shown susceptible to tyrosine kinase inhibitor therapy. However, children with ETV6-RUNX1-associated acute lymphoblastic leukemia are in an especially good-risk subgroup and therefore have been almost uniformly treated with standard-risk chemotherapy protocols.[27] Hematological malignancies associated with ETY6 gene fusions to other transcription factor genes appear to reflect a loss or gain in function of ETV6 and/or the other genes in regulating expression of their target genes; this results in the formation or lack of formation of products which influence cell growth, proliferation, and/or survival. In vitro studies of ETV6-RUNX, ETV6-MN1, ETV6-PER1, and ETV6-MECOM fusion genes support this notion. Thus, the ETV6-MECOM fusion gene is overexpressed because it is driven by the promoter derived from ETV6[1] whereas the ETV6-RUNX, ETV6-MN1, and ETV6-PER1 fusion genes produce chimeric proteins which lack ETV6 protein's gene-suppressing activity.[28] The chimeric protein products of ETV6 gene fusions with ARNT, TTL, BA22A, FCHO2, MDS2, and CHIC2 likewise lack ETV6 protein's transcription factor activity.[28] Gene fusions between ETV6 and the homeobox gens (i.e. CDX2, PAX5, and MNX1) produce chimeric proteins with lack either ETV6s and/or CDX2s, PAX5s or MNX1s transcription factor activity.[1] In all events, hematological malignancies associated with these fusion genes have been treated with standard chemotherapy protocols selected on the basis of the malignancies phenotype. ## Solid Tumors Mutations in the ETV6 gene are also associated with solid tumors. In particular, the ETV6-NTRK3 fusion gene occurs in and is thought or proposed to drive certain types of cancers. These cancers include secretory breast cancer (also termed juvenile breast cancer), mammary analogue secretory carcinoma of the parotid and other salivary glands, congenital fibrosarcoma, congenital mesoblastic nephroma, inflammatory myofibroblastic tumor, and radiation-induced papillary thyroid carcinoma.[4][29][30][31][23][32][28][33] ### Treatment The treatment of ETV6 gene-associated solid tumors has not advanced as far as that for ETV6 gene-associated hematological malignancies. It is proposed that tyrosine kinase inhibitors with specificity for NTRK3's tyrosine kinase activity in ETV6-NTRK3 gene-associated solid tumors may be of therapeutic usefulness. Entrectinib, a pan-NTRK as well as an ALK and ROS1 tyrosine kinase inhibitor has been found useful in treating a single patient with ETV6-NRTK3 fusion gene-associated mammary analogue secretory carcinoma and lends support to the clinical development of NTRK3-directed tyrosine kinase inhibitors to treat ETV6-NTRK3 fusion protein associated malignancies.[23] Three clinical trials are in the recruitment phase for determining the efficacy of treating a wide range of solid tumors associated with mutated, overactive tyrosine kinase proteins, including the ETV6-TRK3 protein, with larotrectinib, a non-selective inhibitor of NTRK1, NTRK2, and NTRK3 tyrosine kinases.[34]

https://www.wikidoc.org/index.php/ETV6

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EVAR

EVAR # Overview Endovascular aneurysm repair (or endovascular aortic repair) (EVAR) is a type of endovascular surgery used to treat an abdominal aortic aneurysm (AAA) or thoracic aortic aneurysm, the procedure then specifically termed TEVAR (thoracic endovascular aortic/aneurysm repair). In certain occasions, a specially designed custom-made graft device, which has holes (fenestrations) on the graft body to maintain the patency of certain important blood vessels, is used for the procedure, which is called FEVAR (fenestrated endovascular aortic/aneurysm repair). # Historical Perspective The world's first EVAR was performed in 1987 by Nicholas Volodos in Kharkov, Soviet Union and introduced in an article written in 1988. In Argentina it was first introduced in 1991 by Juan Parodi and the very same year in the USA by Michael Dake. # Indications and Screening Before patients are deemed to be a suitable candidate for this treatment, they have to go through a rigorous set of tests. These include a CT scan of the complete thorax/abdomen/pelvis, and blood tests. The CT scan gives precise measurements of the aneurysm and the surrounding anatomy. In particular the calibre/tortuosity of the iliac arteries and the relationship of the neck of the aneurysm to the renal arteries are important determinants of whether the aneurysm is amenable to endoluminal repair. In certain occasions that the renal arteries are too close to the aneurysm, the custom-made fenestrated graft stent is now an accepted alternative to doing open surgery. # The Procedure The procedure is carried out in a sterile environment, usually a theatre, under x-ray fluoroscopic guidance. It is usually carried out by an interventional radiologist or vascular surgeon. The patient is either given a full GA (general anaestheic) or regional anaesthesia. Vascular 'sheaths' are introduced into the patient's femoral arteries, through which the guidewires, catheters and eventually, the Stent Graft is passed. Diagnostic angiography images or 'runs' are captured of the aorta to determine the location on the patient's renal arteries, so the stent graft can be deployed without blocking these. Failure to achieve this will cause renal failure, thus the precision and control of the graft stent deployment is extremely important. The main 'body' of the stent graft is placed first, follow by the 'limbs' which join on to the main body and sit on the Aortic Bifurcation for better support, and extend to the Iliac arteries. For certain occasions that the aneurysm extends down to the Common Iliac Arteries, a specially designed graft stent, named as Iliac Branch Device (IBD), can be used, instead of blocking the Internal Iliac Arteries, but to preserve them. The preservation of the Internal Iliac Arteries is important to prevent Buttock Claudication, and to preserve the full genital function. The idea is that the stent graft (covered stent), once in place acts as an artificial lumen for blood to flow down, and not into the surrounding aneurysm sac. This therefore immediately takes the pressure off the aneurysm wall, which itself will thrombose in time. A newer adaption of EVAR is the Hybrid Procedure. A hybrid procedure occurs in the angiography room and aims to combine endovascular procedures with limited open surgery. In this procedure the stent graft deployment is planned to combine with an open operation to revascularise selected arteries that will be "covered" by the stent graft i.e. deprived of arterial inflow. In this method more extensive EVAR devices can be deployed to treat the primary lesion while preserving arterial flow to critical arteries. Thoraco-abdominal aneurysms (TAA) typically involve such vessels and deployment of the EVAR device will cover important arteries e.g. visceral or renal arteries, resulting in end organ ischaemia which may not be survivable. The open operation component aims to bring a bypass graft from an artery outside the stent graft coverage to vital arteries within the coverage region. This component adds to the EVAR procedure in time and risk but is usually judged to be lesser that the risk of the major totally open operation. Staging such procedures is common. A common example is revascularisation of the left common carotid artery and/or the left subclavian artery from the innominate artery or the right common carotid artery to allow treatment of a thoracic aortic aneurysm that encroachs proximally into the aortic arch to be treated without thoracotomy. Continued design improvement in stent graft including branched endografts will reduce but not eliminate this category of surgery. 'Chimney stents into the innominate artery with TEVAR into the proximal aortic arch have recently been described. Other surgeons favor limited thoracotomy with carotid-carotid bypass i.e. hybrid procedures. All such procedures aim to reduce the morbidity and mortality of treating arterial disease in a patient polpulation that is increasingly older and less fit than when major open repairs were developed and popularised. Even in those days, significant risks were accepted in the understanding than the large open operation was the only option. That is not the case in most patients today. Durability and problems such as 'endoleaks' may require careful surveillance and adjuvant procedures to ensure success of the EVAR or EVAR/hybrid procedure. CT Angiography (CTA) imaging has in particular made a key contribution to planning, success, durabity in this complex area of vascular surgery. # Complications ## Systemic Myocardial infarction, congestive heart failure, arrhythmias, respiratory failure, renal failure ## Procedure related Dissection, malpositioning, renal failure, thromboembolizaton, ischemic colitis, groin hematoma, wound infection ## Device related Migration, detachment, rupture, stenosis, kinking ## Endoleaks An endoleak is a leak into the aneurysm sac after endovascular repair. Five types of endoleaks exist: - Type I - Perigraft leakage at proximal or distal graft attachment sites (near the renal and iliac arteries) - Type II - Retrograde flow from collateral branches such as the lumbar, testicular and inferior mesenteric arteries - Type III - Leakage between different parts of the stent (at the anastomosis between components) - Type IV - Leakage through the graft wall due to the quality of the graft material - Type V - Leakage from unknown origin # Use in aortic dissection In uncomplicated type B aortic dissection, TEVAR does not seem either improve or compromise 2-year survival and adverse event rates. Its use in complicated aortic dissection is under investigation.

EVAR Template:Interventions infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Endovascular aneurysm repair (or endovascular aortic repair) (EVAR) is a type of endovascular surgery used to treat an abdominal aortic aneurysm (AAA) or thoracic aortic aneurysm, the procedure then specifically termed TEVAR (thoracic endovascular aortic/aneurysm repair). In certain occasions, a specially designed custom-made graft device, which has holes (fenestrations) on the graft body to maintain the patency of certain important blood vessels, is used for the procedure, which is called FEVAR (fenestrated endovascular aortic/aneurysm repair). # Historical Perspective The world's first EVAR was performed in 1987 by Nicholas Volodos in Kharkov, Soviet Union and introduced in an article written in 1988.[1] In Argentina it was first introduced in 1991 by Juan Parodi[2] and the very same year in the USA by Michael Dake.[3] # Indications and Screening Before patients are deemed to be a suitable candidate for this treatment, they have to go through a rigorous set of tests. These include a CT scan of the complete thorax/abdomen/pelvis, and blood tests. The CT scan gives precise measurements of the aneurysm and the surrounding anatomy. In particular the calibre/tortuosity of the iliac arteries and the relationship of the neck of the aneurysm to the renal arteries are important determinants of whether the aneurysm is amenable to endoluminal repair. In certain occasions that the renal arteries are too close to the aneurysm, the custom-made fenestrated graft stent is now an accepted alternative to doing open surgery. # The Procedure The procedure is carried out in a sterile environment, usually a theatre, under x-ray fluoroscopic guidance. It is usually carried out by an interventional radiologist or vascular surgeon. The patient is either given a full GA (general anaestheic) or regional anaesthesia. Vascular 'sheaths' are introduced into the patient's femoral arteries, through which the guidewires, catheters and eventually, the Stent Graft is passed. Diagnostic angiography images or 'runs' are captured of the aorta to determine the location on the patient's renal arteries, so the stent graft can be deployed without blocking these. Failure to achieve this will cause renal failure, thus the precision and control of the graft stent deployment is extremely important. The main 'body' of the stent graft is placed first, follow by the 'limbs' which join on to the main body and sit on the Aortic Bifurcation for better support, and extend to the Iliac arteries. For certain occasions that the aneurysm extends down to the Common Iliac Arteries, a specially designed graft stent, named as Iliac Branch Device (IBD), can be used, instead of blocking the Internal Iliac Arteries, but to preserve them. The preservation of the Internal Iliac Arteries is important to prevent Buttock Claudication, and to preserve the full genital function. The idea is that the stent graft (covered stent), once in place acts as an artificial lumen for blood to flow down, and not into the surrounding aneurysm sac. This therefore immediately takes the pressure off the aneurysm wall, which itself will thrombose in time.[4] A newer adaption of EVAR is the Hybrid Procedure. A hybrid procedure occurs in the angiography room and aims to combine endovascular procedures with limited open surgery. In this procedure the stent graft deployment is planned to combine with an open operation to revascularise selected arteries that will be "covered" by the stent graft i.e. deprived of arterial inflow. In this method more extensive EVAR devices can be deployed to treat the primary lesion while preserving arterial flow to critical arteries. Thoraco-abdominal aneurysms (TAA) typically involve such vessels and deployment of the EVAR device will cover important arteries e.g. visceral or renal arteries, resulting in end organ ischaemia which may not be survivable. The open operation component aims to bring a bypass graft from an artery outside the stent graft coverage to vital arteries within the coverage region. This component adds to the EVAR procedure in time and risk but is usually judged to be lesser that the risk of the major totally open operation. Staging such procedures is common. A common example is revascularisation of the left common carotid artery and/or the left subclavian artery from the innominate artery or the right common carotid artery to allow treatment of a thoracic aortic aneurysm that encroachs proximally into the aortic arch to be treated without thoracotomy. Continued design improvement in stent graft including branched endografts will reduce but not eliminate this category of surgery. 'Chimney stents into the innominate artery with TEVAR into the proximal aortic arch have recently been described. Other surgeons favor limited thoracotomy with carotid-carotid bypass i.e. hybrid procedures. All such procedures aim to reduce the morbidity and mortality of treating arterial disease in a patient polpulation that is increasingly older and less fit than when major open repairs were developed and popularised. Even in those days, significant risks were accepted in the understanding than the large open operation was the only option. That is not the case in most patients today. Durability and problems such as 'endoleaks' may require careful surveillance and adjuvant procedures to ensure success of the EVAR or EVAR/hybrid procedure. CT Angiography (CTA) imaging has in particular made a key contribution to planning, success, durabity in this complex area of vascular surgery. # Complications ## Systemic Myocardial infarction, congestive heart failure, arrhythmias, respiratory failure, renal failure ## Procedure related Dissection, malpositioning, renal failure, thromboembolizaton, ischemic colitis, groin hematoma, wound infection ## Device related Migration, detachment, rupture, stenosis, kinking ## Endoleaks An endoleak is a leak into the aneurysm sac after endovascular repair. Five types of endoleaks exist:[4] - Type I - Perigraft leakage at proximal or distal graft attachment sites (near the renal and iliac arteries) - Type II - Retrograde flow from collateral branches such as the lumbar, testicular and inferior mesenteric arteries - Type III - Leakage between different parts of the stent (at the anastomosis between components) - Type IV - Leakage through the graft wall due to the quality of the graft material - Type V - Leakage from unknown origin # Use in aortic dissection In uncomplicated type B aortic dissection, TEVAR does not seem either improve or compromise 2-year survival and adverse event rates.[5] Its use in complicated aortic dissection is under investigation.

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

82ce711a98a952166340bdfe71dcdc5405c06f16

wikidoc

EVI1

EVI1 Ecotropic viral integration site 1 is a human protein encoded by the EVI1 gene. EVI1 was first identified as a common retroviral integration site in AKXD murine myeloid tumors. It has since been identified in a plethora of other organisms, and seems to play a relatively conserved developmental role in embryogenesis. EVI1 is a nuclear transcription factor involved in many signaling pathways for both corepression and coactivation of cell cycle genes. # Gene structure The EVI1 gene is located in the human genome on chromosome 3 (3q26.2). The gene spans 60 kilobases and encodes 16 exons, 10 of which are protein coding. The first in-frame ATG start codon is in exon 3. ## mRNA A large number of transcript variations exist, encoding different isoforms or chimeric proteins. Some of the most common ones are: ## Protein # Biological role EVI1 is a proto-oncogene conserved across humans, mice and rats, sharing 91% homology in nucleotide sequence and 94% homology in amino acid sequence between humans and mice . It is a transcription factor localized to the nucleus and binds DNA through specific conserved sequences of GACAAGATA with the potential to interact with both corepressors and coactivators. Embryogenesis: The role of EVI1 in embryogenesis and development is not completely understood, but it has been shown that EVI1 deficiency in mice is an embryonic lethal mutation, characterized primarily by widespread hypocellularity and poor/disrupted development of the cardiovascular and neural system . EVI1 is highly expressed in the murine embryo, found in the urinary system, lungs, and heart, but is is only minutely detectable in most adult tissues , indicating a likely role in tissue development. EVI1 and the fusion transcript MDS1-EVI1 are both expressed in the adult human kidney, lung, pancreas, brain and ovaries . Cell cycle and differentiation: In vitro experiments using both human and mouse cell lines have shown that EVI1 prevents the terminal differentiation of bone marrow progenitor cells to granulocytes and erythroid cells, however it favors the differentiation of hematopoietic cell to megakaryocytes . The chimeric gene of AML1-MDS1-EVI1 (AME) formed by the chromosomal translocation (3;21)(q26;q22) has also been shown in vitro to upregulate the cell cycle and block granulocytic differentiation of murine hematopoietic cells, as well as to delay the myeloid differentiation of bone marrow progenitors . # Association with cancer EVI1 has been described as a proto-oncogene since its first discovery in 1988 . Overexpression and aberrant expression of EVI1 has been associated with human acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS) and chronic myelogenous leukemia (CML), and more recently has been shown as a poor prognostic indicator. All of these involve erratic cellular development and differentiation in the bone marrow leading to dramatic alterations in the normal population of blood cells. EVI1 has also been found to play a role in solid ovarian and colon tumors , although it is not yet well characterized in this context. It has been hypothesized that it acts as a survival factor in tumor cell lines, preventing therapeutic-induced apoptosis and rendering the tumor cells more resistant to current treatments . ## Role in tumor suppressor signaling and prevention of apoptosis - TGF-β AND CELL CYCLE PROGRESSION EVI1 has been shown to be involved in the downstream signaling pathway of transforming growth factor beta (TGF-β). TGF-β, along with other TGF-β family ligands such as bone morphogenic protein (BMP) and activin are involved in regulating important cellular functions such as proliferation, differentiation, apoptosis, and matrix production . These biological roles are not only important for cellular development, but also in understanding oncogenesis. TGF-β signaling induces transcription of the cyclin-dependent kinase (CDK) inhibitors p15Ink4B or p21Cip1, which consequently act to halt the cell cycle and stop proliferation. This inhibition can lead to cellular differentiation or apoptosis, and therefore any resistance to TGF-β is thought to contribute in some way to human leukemogenesis . As shown in the figure below, the downstream effectors of TGF-β are the Smad receptors (also known as receptor-activated Smads). Smad2 and Smad3 are phosphorylated in response to TGF-β ligand binding, and translocate into the nucleus of the cell where they can then bind to DNA and other transcription factors . Stable binding to promoters occurs through a conserved MH1 domain and transcription activation occurs through an MH2 domain, and involves accompanying coactivators such as CBP/p300 and Sp1 . The majority of literature discusses the interaction between EVI1 and Smad3, however there have been some experiments done showing that EVI1 interacts with all of the Smad proteins at varying levels, indicating a potential involvement in all of the pathways that include Smads as downstream effectors . The translocation of phosphorylated Smad3 into the nucleus allows for direct interaction with EVI1, mediated by the first zinc finger domain on EVI1 and the MH2 domain on Smad3 . As the Smad3 MH2 domain is required for transcription activation, EVI1 binding effectively prevents transcription of the TGF-β induced anti-growth genes through structural blocking, and also leads to recruitment of other transcriptional repressors (see Epigenetics). By inhibiting an important checkpoint pathway for tumor suppression and growth control, overexpression or aberrant expression of EVI1 has characteristic oncogenic activity. As an additional confirmation of the role of EVI1 expression on cell cycle progression, it has been shown that high EVI1 expression is correlated with the well-known tumor suppressor and cell cycle mediator Retinoblastoma remaining in a hyperphosphorylated state, even in the presence of TGF-β . - JNK AND INHIBITION OF APOPTOSIS c-Jun N-terminal kinase (JNK) is a MAP kinase activated by extracellular stress signals such as gamma-radiation, ultraviolet light, Fas ligand, tumor necrosis factor α (TNF-α), and interleukin-1 . Phosphorylation on two separate residues, Thr183 and Tyr185, cause JNK to become activated and translocate to the nucleus to phosphorylate and activate key transcription factors for the apoptotic response . Experiments co-expressing EVI1 and JNK have shown that levels of JNK-phosphorylated transcription factors (such as c-Jun) are drastically decreased in the presence of EVI1. Binding of EVI1 and JNK has been shown to occur through the the first zinc finger motif on EVI1, and that this interaction does not block JNK phosphorylation and activation, but blocks JNK binding to substrate in the nucleus. Subsequent in vitro assays showed that stress-induced cell death from a variety of stimuli is significantly inhibited by EVI1 and JNK binding . Interestingly, EVI1 does not bind other MAP kinases such as p38 or ERK . ## Oncogenesis and induced proliferation of HSCs Among the many other observed defects, EVI1-/- mouse embryos have been shown to have defects in both the development and proliferation of hematopoietic stem cells (HSCs). This is likely due to direct interaction with the trancription factor GATA-2, which is crucial for HSC development . It has subsequently been shown many times in vitro that EVI1 upregulation can induce proliferation and differentiation of HSCs and some other cell types such as rat fibroblasts . It should be noted, however, that existing data is inconclusive regarding the absolute role of EVI1 in cell cycle progression. It appears to depend on the specific cell type, cell line and growth conditions being used whether EVI1 expression induces growth arrest, cell differentiation/proliferation, or has no effect at all . The data showing direct interaction of EVI1 with the promoters for a diverse array of genes supports the theory that this is a complex transcription factor associated with many different signalling pathways involved in development and growth. ### Angiogenesis Although the literature is limited on the subject, the well-documented effects on HSCs imply that there is a potential indirect effect of aberrant EVI1 expression on tumoral angiogenesis. HSCs secrete angiopoietin, and its receptor molecule Tie2 has been implicated in angiogenesis of tumors in both humans and mice . Upregulation of Tie2 has been shown to occur under hypoxic conditions, and to increase angiogenesis when coinjected with tumor cells in mice . Observations that EVI1-/- mutants have substantially downregulated Tie2 and Ang-I expression therefore hints at an interesting role of high EVI1 expression in tumor progression. This is likely, at least in part, a reason for the widespread hemorrhaging and minimal vascular development in EVI1 deleted embryos , and potentially indicates yet another reason for poor prognosis of EVI1 positive cancers. ## Epigenetics EVI1 has also been shown to directly interact with C-terminal binding protein (CtBP, a known transcriptional repressor) through in vitro techniques such as yeast 2-hybrid screens and immunoprecipitation . This interaction has been specifically shown to rely on amino acids 544-607 on the EVI1 protein, a stretch which contains two CtBP binding consensus motifs . This binding leads to recruitment of histone deacetylases (HDACs) as well as many other corepressor molecules leading to transcription repression via chromatin remodelling . Interestingly enough, EVI1 interaction with Smad3 followed by recruitment of corepressors can inhibit transcription and de-sensitize a cell to TGF-β signaling without ever displacing Smad3 from a gene's promoter . The epigenetic modification is clearly enough to make the DNA inaccessible to the transcription machinery. It should be noted that although EVI1 has mainly been implicated as a transcription repressor, there is some data that has shown a possible dual role for this protein. Studies show that EVI1 also binds to known coactivators cAMP responsive element binding protein (CBP) and p300/CBP-associated factor (P/CAF). These both lead have histone acetyltransferase activity, and lead to subsequent transcription activation. Additionally, structural changes have been visualized within the nucleus of a cell depending on the presence of corepressors or coactivators, leading researchers to believe that EVI1 has a unique response to each kind of molecule. In approximately 90% of cells, EVI1 is diffuse within the nucleus, however when CBP and P/CAF are added extensive nuclear speckle formation occurs . The complete physiological repercussions of this complex role of EVI1 have yet to be elucidated, however could provide insight into the wide variety of results that have been reported regarding the effect of EVI1 on in vitro cell proliferation . Interaction with corepressors and coactivators appears to occur in distinct domains and there are theories that EVI1 exists in a periodical, reversible acetylated state within the cell. Contrasting theories indicate that the interplay between different EVI1 binding proteins acts to stabilize interactions with different transcription factors and DNA leading to a response of EVI1 to a diverse set of stimuli. ## Chromosome instability Since it was first identified in murine myeloid leukemia as a common site of retroviral integration into the chromosome, EVI1 and its surrounding DNA have been a site of many identified chromosomal translocations and abnormalities . This can lead to aberrant expression of EVI1, and as shown in the figure below, commonly involved chromosomal breakpoints have been mapped extensively. One major cause of EVI1 activation and consequent overexpression is a clinical condition called 3q21q26 syndrome from inv(3)(q21q26) or t(3;3)(q21;q26) . The result is the placement of a strong enhancing region for the housekeeping gene Ribophorin I next to the EVI1 coding sequence, resulting in a dramatic increase of EVI1 levels in the cell . A summary of common chromosomal abnormalities involving EVI1 and its fusion genes can be found in a review by Nucifora et al . Most commonly, chromosomal translocations in human AML or MDS leads to constitutive expression of EVI1 and eventually to cancer . These abnormalities in the 3q26 region are not only associated with very poor patient prognosis, they are also commonly accompanied by additional karyotypic changes such as chromosome 7 monosomy, deletion of the short arm of chromosome 7, or partial deletions of chromosome 5 . In addition, it has been shown that development of acute myelogenous leukemia is likely due to several sequential genetic changes, and that expression of EVI1 or its chimeric counterparts ME and AME alone is not enough to completely block myeloid differentiation . BCR-Abl, a fusion gene caused by t(9;22)(q34;q11)is thought to have a cooperative effect with EVI1 during the progression of AML and CML . Together, these two systems disrupt tyrosine kinase signaling and hematopoietic gene transcription. Despite the extensively studied chromosomal abnormalities at the EVI1 locus, it should be noted that in anywhere from 10-50% of identified cases, EVI1 overexpression is detectable without any chromosomal abnormalities; indicating that there are other not yet understood systems, likely epigenetic, leading to EVI1 promoter activation . In many of these cases, it is noted that a variety of 5' transcript variants are detectable at relatively high levels. Clinical studies have shown that these variants (EVI1_1a, EVI1_1b, EVI1_1d, EVI1_3L) as well as the MDS1-EVI1 fusion transcript are all associated with poor prognosis and increased likelihood of rapid remission in cases of de novo AML . ## Pharmacogenomics and cancer treatment Very little research has been done in an attempt to therapeutically target EVI1 or any of its chimeric counterparts. However, since it has become an established fact that overexpression of EVI1 derivatives is a bad prognostic indicator, it is likely that the literature will begin to examine specific targeting within the next few years. One very promising therapeutic agent for myelogenous leukemia and potentially other forms of cancer is arsenic trioxide (ATO). One study has been done showing that ATO treatment leads to specific degradation of the AML1/MDS1/EVI1 oncoprotein and induces both apoptosis and differentiation . As an atypical use of traditional pharmacogenomics, this knowledge may lead to an increased ability to treat EVI1 positive leukemias that would normally have poor prognoses. If it is established that a clinical cancer case is EVI1 positive, altering the chemotherapeutic cocktail to include a specific EVI1 antagonist may aid to increase life span and prevent potential remission. Arsenic is a fairly ancient human therapeutic , however it has only recently returned to the forefront of cancer treatment. It has been observed that it not only induces apoptosis, but can also inhibit the cell cycle, and has marked anti-angiogenesis effects . As of 2006, Phase I and II clinical trials were being conducted to test this compound on a wide variety of cancer types, and currently (2008) a number of publications are showing positive outcomes in individual case studies, both pediatric and adult. ## Hormones The important and essential role of EVI1 in embryogenesis clearly indicates a close association with hormonal fluctuations in developing cells. However, to date, the presence of EVI1 in cancer has not been linked to aberrant production of any hormones or hormone receptors. It is likely that EVI1 is far enough downstream of hormonal signaling that once overproduced, it can function independently. # Future and current research More in-depth investigations into the biological role of EVI1 in development are required, as well as further characterizing the mode(s) of activation of this gene in cancer cells. Once the knowledge base is more developed, it is likely that screening for specific EVI1 antagonists or inhibitors will become more feasible, and improve the current treatment regime for patients. Areas where retroviral integration into the human genome is favored such as EVI1 have very important implications for the development of gene therapy. It was initially thought that delivery of genetic material through a non-replicating virus vector would pose no significant risk, as the likelihood of a random incorporation near a proto-oncogene was minimal. However, it has now been shown that sites such as EVI1 are "highly over-represented" when it comes to vector insertions . With gene therapy gradually becoming a more popular idea, large studies must be conducted to understand the dynamic of why vector integration occurs where it does, and what factors influence the 'non-randomness' of the process.

EVI1 Ecotropic viral integration site 1 is a human protein encoded by the EVI1 gene. EVI1 was first identified as a common retroviral integration site in AKXD murine myeloid tumors. It has since been identified in a plethora of other organisms, and seems to play a relatively conserved developmental role in embryogenesis. EVI1 is a nuclear transcription factor involved in many signaling pathways for both corepression and coactivation of cell cycle genes. # Gene structure The EVI1 gene is located in the human genome on chromosome 3 (3q26.2). The gene spans 60 kilobases and encodes 16 exons, 10 of which are protein coding. The first in-frame ATG start codon is in exon 3.[1] ## mRNA A large number of transcript variations exist, encoding different isoforms or chimeric proteins. Some of the most common ones are: ## Protein # Biological role EVI1 is a proto-oncogene conserved across humans, mice and rats, sharing 91% homology in nucleotide sequence and 94% homology in amino acid sequence between humans and mice [3]. It is a transcription factor localized to the nucleus and binds DNA through specific conserved sequences of GACAAGATA [4] with the potential to interact with both corepressors and coactivators. Embryogenesis: The role of EVI1 in embryogenesis and development is not completely understood, but it has been shown that EVI1 deficiency in mice is an embryonic lethal mutation, characterized primarily by widespread hypocellularity and poor/disrupted development of the cardiovascular and neural system [3]. EVI1 is highly expressed in the murine embryo, found in the urinary system, lungs, and heart, but is is only minutely detectable in most adult tissues [3], indicating a likely role in tissue development. EVI1 and the fusion transcript MDS1-EVI1 are both expressed in the adult human kidney, lung, pancreas, brain and ovaries [3]. Cell cycle and differentiation: In vitro experiments using both human and mouse cell lines have shown that EVI1 prevents the terminal differentiation of bone marrow progenitor cells to granulocytes and erythroid cells, however it favors the differentiation of hematopoietic cell to megakaryocytes [3]. The chimeric gene of AML1-MDS1-EVI1 (AME) formed by the chromosomal translocation (3;21)(q26;q22) has also been shown in vitro to upregulate the cell cycle and block granulocytic differentiation of murine hematopoietic cells, as well as to delay the myeloid differentiation of bone marrow progenitors [3]. # Association with cancer EVI1 has been described as a proto-oncogene since its first discovery in 1988 [5]. Overexpression and aberrant expression of EVI1 has been associated with human acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS) and chronic myelogenous leukemia (CML), and more recently has been shown as a poor prognostic indicator. All of these involve erratic cellular development and differentiation in the bone marrow leading to dramatic alterations in the normal population of blood cells. EVI1 has also been found to play a role in solid ovarian and colon tumors [6], although it is not yet well characterized in this context. It has been hypothesized that it acts as a survival factor in tumor cell lines, preventing therapeutic-induced apoptosis and rendering the tumor cells more resistant to current treatments [7]. ## Role in tumor suppressor signaling and prevention of apoptosis - TGF-β AND CELL CYCLE PROGRESSION EVI1 has been shown to be involved in the downstream signaling pathway of transforming growth factor beta (TGF-β). TGF-β, along with other TGF-β family ligands such as bone morphogenic protein (BMP) and activin are involved in regulating important cellular functions such as proliferation, differentiation, apoptosis, and matrix production [8]. These biological roles are not only important for cellular development, but also in understanding oncogenesis. TGF-β signaling induces transcription of the cyclin-dependent kinase (CDK) inhibitors p15Ink4B or p21Cip1, which consequently act to halt the cell cycle and stop proliferation. This inhibition can lead to cellular differentiation or apoptosis, and therefore any resistance to TGF-β is thought to contribute in some way to human leukemogenesis [9]. As shown in the figure below, the downstream effectors of TGF-β are the Smad receptors (also known as receptor-activated Smads). Smad2 and Smad3 are phosphorylated in response to TGF-β ligand binding, and translocate into the nucleus of the cell where they can then bind to DNA and other transcription factors [8]. Stable binding to promoters occurs through a conserved MH1 domain and transcription activation occurs through an MH2 domain, and involves accompanying coactivators such as CBP/p300 and Sp1 [8]. The majority of literature discusses the interaction between EVI1 and Smad3, however there have been some experiments done showing that EVI1 interacts with all of the Smad proteins at varying levels, indicating a potential involvement in all of the pathways that include Smads as downstream effectors [8]. The translocation of phosphorylated Smad3 into the nucleus allows for direct interaction with EVI1, mediated by the first zinc finger domain on EVI1 and the MH2 domain on Smad3 [8][9]. As the Smad3 MH2 domain is required for transcription activation, EVI1 binding effectively prevents transcription of the TGF-β induced anti-growth genes through structural blocking, and also leads to recruitment of other transcriptional repressors (see Epigenetics). By inhibiting an important checkpoint pathway for tumor suppression and growth control, overexpression or aberrant expression of EVI1 has characteristic oncogenic activity. As an additional confirmation of the role of EVI1 expression on cell cycle progression, it has been shown that high EVI1 expression is correlated with the well-known tumor suppressor and cell cycle mediator Retinoblastoma remaining in a hyperphosphorylated state, even in the presence of TGF-β [10]. - JNK AND INHIBITION OF APOPTOSIS c-Jun N-terminal kinase (JNK) is a MAP kinase activated by extracellular stress signals such as gamma-radiation, ultraviolet light, Fas ligand, tumor necrosis factor α (TNF-α), and interleukin-1 [11]. Phosphorylation on two separate residues, Thr183 and Tyr185, cause JNK to become activated and translocate to the nucleus to phosphorylate and activate key transcription factors for the apoptotic response [11]. Experiments co-expressing EVI1 and JNK have shown that levels of JNK-phosphorylated transcription factors (such as c-Jun) are drastically decreased in the presence of EVI1. Binding of EVI1 and JNK has been shown to occur through the the first zinc finger motif on EVI1, and that this interaction does not block JNK phosphorylation and activation, but blocks JNK binding to substrate in the nucleus[11]. Subsequent in vitro assays showed that stress-induced cell death from a variety of stimuli is significantly inhibited by EVI1 and JNK binding [11]. Interestingly, EVI1 does not bind other MAP kinases such as p38 or ERK [11]. ## Oncogenesis and induced proliferation of HSCs Among the many other observed defects, EVI1-/- mouse embryos have been shown to have defects in both the development and proliferation of hematopoietic stem cells (HSCs). This is likely due to direct interaction with the trancription factor GATA-2, which is crucial for HSC development [12]. It has subsequently been shown many times in vitro that EVI1 upregulation can induce proliferation and differentiation of HSCs and some other cell types such as rat fibroblasts [2]. It should be noted, however, that existing data is inconclusive regarding the absolute role of EVI1 in cell cycle progression. It appears to depend on the specific cell type, cell line and growth conditions being used whether EVI1 expression induces growth arrest, cell differentiation/proliferation, or has no effect at all [2]. The data showing direct interaction of EVI1 with the promoters for a diverse array of genes supports the theory that this is a complex transcription factor associated with many different signalling pathways involved in development and growth. ### Angiogenesis Although the literature is limited on the subject, the well-documented effects on HSCs imply that there is a potential indirect effect of aberrant EVI1 expression on tumoral angiogenesis. HSCs secrete angiopoietin, and its receptor molecule Tie2 has been implicated in angiogenesis of tumors in both humans and mice [13]. Upregulation of Tie2 has been shown to occur under hypoxic conditions, and to increase angiogenesis when coinjected with tumor cells in mice [13]. Observations that EVI1-/- mutants have substantially downregulated Tie2 and Ang-I expression therefore hints at an interesting role of high EVI1 expression in tumor progression. This is likely, at least in part, a reason for the widespread hemorrhaging and minimal vascular development in EVI1 deleted embryos [12], and potentially indicates yet another reason for poor prognosis of EVI1 positive cancers. ## Epigenetics EVI1 has also been shown to directly interact with C-terminal binding protein (CtBP, a known transcriptional repressor) through in vitro techniques such as yeast 2-hybrid screens and immunoprecipitation [9]. This interaction has been specifically shown to rely on amino acids 544-607 on the EVI1 protein, a stretch which contains two CtBP binding consensus motifs [10]. This binding leads to recruitment of histone deacetylases (HDACs) as well as many other corepressor molecules leading to transcription repression via chromatin remodelling [9]. Interestingly enough, EVI1 interaction with Smad3 followed by recruitment of corepressors can inhibit transcription and de-sensitize a cell to TGF-β signaling without ever displacing Smad3 from a gene's promoter [8]. The epigenetic modification is clearly enough to make the DNA inaccessible to the transcription machinery. It should be noted that although EVI1 has mainly been implicated as a transcription repressor, there is some data that has shown a possible dual role for this protein. Studies show that EVI1 also binds to known coactivators cAMP responsive element binding protein (CBP) and p300/CBP-associated factor (P/CAF)[8]. These both lead have histone acetyltransferase activity, and lead to subsequent transcription activation. Additionally, structural changes have been visualized within the nucleus of a cell depending on the presence of corepressors or coactivators, leading researchers to believe that EVI1 has a unique response to each kind of molecule. In approximately 90% of cells, EVI1 is diffuse within the nucleus, however when CBP and P/CAF are added extensive nuclear speckle formation occurs [14]. The complete physiological repercussions of this complex role of EVI1 have yet to be elucidated, however could provide insight into the wide variety of results that have been reported regarding the effect of EVI1 on in vitro cell proliferation [2]. Interaction with corepressors and coactivators appears to occur in distinct domains [14] and there are theories that EVI1 exists in a periodical, reversible acetylated state [3] within the cell. Contrasting theories indicate that the interplay between different EVI1 binding proteins acts to stabilize interactions with different transcription factors and DNA leading to a response of EVI1 to a diverse set of stimuli[8]. ## Chromosome instability Since it was first identified in murine myeloid leukemia as a common site of retroviral integration into the chromosome, EVI1 and its surrounding DNA have been a site of many identified chromosomal translocations and abnormalities [15]. This can lead to aberrant expression of EVI1, and as shown in the figure below, commonly involved chromosomal breakpoints have been mapped extensively. One major cause of EVI1 activation and consequent overexpression is a clinical condition called 3q21q26 syndrome from inv(3)(q21q26) or t(3;3)(q21;q26) [3]. The result is the placement of a strong enhancing region for the housekeeping gene Ribophorin I next to the EVI1 coding sequence, resulting in a dramatic increase of EVI1 levels in the cell [3]. A summary of common chromosomal abnormalities involving EVI1 and its fusion genes can be found in a review by Nucifora et al [16]. Most commonly, chromosomal translocations in human AML or MDS leads to constitutive expression of EVI1 and eventually to cancer [16]. These abnormalities in the 3q26 region are not only associated with very poor patient prognosis, they are also commonly accompanied by additional karyotypic changes such as chromosome 7 monosomy, deletion of the short arm of chromosome 7, or partial deletions of chromosome 5 [17]. In addition, it has been shown that development of acute myelogenous leukemia is likely due to several sequential genetic changes, and that expression of EVI1 or its chimeric counterparts ME and AME alone is not enough to completely block myeloid differentiation [18]. BCR-Abl, a fusion gene caused by t(9;22)(q34;q11)is thought to have a cooperative effect with EVI1 during the progression of AML and CML [18]. Together, these two systems disrupt tyrosine kinase signaling and hematopoietic gene transcription. Despite the extensively studied chromosomal abnormalities at the EVI1 locus, it should be noted that in anywhere from 10-50% of identified cases, EVI1 overexpression is detectable without any chromosomal abnormalities; indicating that there are other not yet understood systems, likely epigenetic, leading to EVI1 promoter activation [2]. In many of these cases, it is noted that a variety of 5' transcript variants are detectable at relatively high levels. Clinical studies have shown that these variants (EVI1_1a, EVI1_1b, EVI1_1d, EVI1_3L) as well as the MDS1-EVI1 fusion transcript are all associated with poor prognosis and increased likelihood of rapid remission in cases of de novo AML [19]. ## Pharmacogenomics and cancer treatment Very little research has been done in an attempt to therapeutically target EVI1 or any of its chimeric counterparts. However, since it has become an established fact that overexpression of EVI1 derivatives is a bad prognostic indicator, it is likely that the literature will begin to examine specific targeting within the next few years. One very promising therapeutic agent for myelogenous leukemia and potentially other forms of cancer is arsenic trioxide (ATO). One study has been done showing that ATO treatment leads to specific degradation of the AML1/MDS1/EVI1 oncoprotein and induces both apoptosis and differentiation [6]. As an atypical use of traditional pharmacogenomics, this knowledge may lead to an increased ability to treat EVI1 positive leukemias that would normally have poor prognoses. If it is established that a clinical cancer case is EVI1 positive, altering the chemotherapeutic cocktail to include a specific EVI1 antagonist may aid to increase life span and prevent potential remission. Arsenic is a fairly ancient human therapeutic [6], however it has only recently returned to the forefront of cancer treatment. It has been observed that it not only induces apoptosis, but can also inhibit the cell cycle, and has marked anti-angiogenesis effects [20]. As of 2006, Phase I and II clinical trials were being conducted to test this compound on a wide variety of cancer types, and currently (2008) a number of publications are showing positive outcomes in individual case studies, both pediatric and adult. ## Hormones The important and essential role of EVI1 in embryogenesis clearly indicates a close association with hormonal fluctuations in developing cells. However, to date, the presence of EVI1 in cancer has not been linked to aberrant production of any hormones or hormone receptors. It is likely that EVI1 is far enough downstream of hormonal signaling that once overproduced, it can function independently. # Future and current research More in-depth investigations into the biological role of EVI1 in development are required, as well as further characterizing the mode(s) of activation of this gene in cancer cells. Once the knowledge base is more developed, it is likely that screening for specific EVI1 antagonists or inhibitors will become more feasible, and improve the current treatment regime for patients. Areas where retroviral integration into the human genome is favored such as EVI1 have very important implications for the development of gene therapy. It was initially thought that delivery of genetic material through a non-replicating virus vector would pose no significant risk, as the likelihood of a random incorporation near a proto-oncogene was minimal. However, it has now been shown that sites such as EVI1 are "highly over-represented" when it comes to vector insertions [1]. With gene therapy gradually becoming a more popular idea, large studies must be conducted to understand the dynamic of why vector integration occurs where it does, and what factors influence the 'non-randomness' of the process.

https://www.wikidoc.org/index.php/EVI1

4cadd0620868d53bfbadc88674205d7a79d8f898

wikidoc

EZH2

EZH2 Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme (EC 2.1.1.43) encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis. EZH2 is the functional enzymatic component of the Polycomb Repressive Complex 2 (PRC2), which is responsible for healthy embryonic development through the epigenetic maintenance of genes responsible for regulating development and differentiation. EZH2 is responsible for the methylation activity of PRC2, and the complex also contains proteins required for optimal function (EED, SUZ12, JARID2, AEBP2, RbAp46/48, and PCL). Mutation or over-expression of EZH2 has been linked to many forms of cancer. EZH2 inhibits genes responsible for suppressing tumor development, and blocking EZH2 activity may slow tumor growth. EZH2 has been targeted for inhibition because it is upregulated in multiple cancers including, but not limited to, breast, prostate, melanoma, and bladder cancer. Mutations in the EZH2 gene are also associated with Weaver syndrome, a rare congenital disorder, and EZH2 is involved in causing neurodegenerative symptoms in the nervous system disorder, ataxia telangiectasia. # Function EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). EZH2's catalytic activity relies on its formation of a complex with at least two other PRC2 components, SUZ12 and EED. As a histone methyltransferase (HMTase), EZH2's primary function is to methylate Lys-27 on histone 3 (H3K27me) by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM). EZH2 is capable of mono-, di-, and tri-methylation of H3K27 and has been associated with a variety of biological functions, including transcriptional regulation in hematopoiesis, development, and cell differentiation. Recent studies have indicated that EZH2 is also capable of methylating non-histone proteins. ## Transcription repression EZH2, as a part of PRC2, catalyzes trimethylation of H3K27 (H3K27me3), which is a histone modification that has been characterized as part of the histone code. The histone code is the theory that chemical modifications, such as methylation, acetylation, and ubiquitination, of histone proteins play distinctive roles in epigenetic regulation of gene transcription. EZH2-mediated catalysis of H3K27me3 is associated with long term transcription repression. EZH2, as well as other Polycomb group proteins, are involved in establishing and maintaining gene repression through cell division. This transcriptionally repressive state is thought to be due to PRC2/EZH2-EED-mediated H3K27 methylation and subsequent recruitment of PRC1 which facilitates condensation of chromatin and formation of heterochromatin. Heterochromatin is tightly packed chromatin which limits the accessibility of transcription machinery to the underlying DNA, thereby suppressing transcription. During cell division, heterochromatin formation is required for proper chromosome segregation. PRC2/EED-EZH2 complex may also be involved in the recruitment of DNA methyltransferases (DNMTs), which results in increased DNA methylation, another epigenetic layer of transcription repression. Specific genes that have been identified as targets of EZH2-mediated transcriptional repression include HOXA9, HOXC8, MYT1, CDKN2A and retinoic acid target genes. ## Transcription activation In cancer, EZH2 may play a role in activation of transcription, independently of PRC2. In breast cancer cells, EZH2 has been demonstrated to activate NF-κB target genes, which are involved in responses to stimuli. The functional role of this activity and its mechanism are still unknown. ## Development and cell differentiation EZH2 plays an essential role in development. In particular, it helps control transcriptional repression of genes that regulate cell differentiation. In embryonic stem cells, EZH2-mediated trimethylation of H3K27me3 in regions containing developmental genes appears to be important for maintenance of normal cell differentiation. H3K27me3 is also important in driving X-inactivation, the silencing of one X-chromosome in females during development. During X-inactivation, it is thought that EZH2 is involved in initiating heterochromatin formation by trimethylating H3K27 and that other histone methyltransferases and histone marks may be involved in maintaining the silenced state. Further, EZH2 has been identified as an essential protein involved in development and differentiation of B-cells and T-cells. H3K27me3 is involved in suppressing genes that promote differentiation, thus maintaining an undifferentiated state of B- and T-cells and playing an important role in regulating hematopoiesis. ## Regulation of EZH2 activity The activity of EZH2 is regulated by the post-translational phosphorylation of threonine and serine residues on EZH2. Specifically, phosphorylation of T350 has been linked to an increase in EZH2 activity while phosphorylation of T492 and S21 have been linked to a decrease in EZH2 activity. Phosphorylation of T492 has been suggested to disrupt contacts between human EZH2 and its binding partners in the PRC2 complex, thus hindering its catalytic activity. In addition to phosphorylation, it has also been shown that PRC2/EZH2-EED activity is antagonized by transcription-activating histone marks, such as acetylation of H3K27 (H3K27ac) and methylation of H3K36 (H3K36me). # Enzymatic activity EZH2 function is highly dependent upon its recruitment by the PRC2 complex. In particular, WD40-repeat protein embryonic ectoderm development (EED) and zinc finger protein suppressor of zeste 12 (SUZ12) are needed to stabilize the interaction of EZH2 with its histone substrate Recently, two isoforms of EZH2 generated from alternative splicing have been identified in humans: EZH2α and EZH2β. Both isoforms contain elements that have been identified as important for EZH2 function including the nuclear localization signal, the EED and SUZ12 binding sites as well as the conserved SET domain. Most studies have thus far focused on the longer isoform EZH2α, but EZH2β, which lacks exons 4 and 8, has been shown to be active. Furthermore, PRC2/EZH2β complexes act on distinct genes from that of its PRC2/EZH2α counterpart suggesting that each isoform may act to regulate a specific subset of genes. Additional evidence suggests that EZH2 may also be capable of lysine methylation independent of association with PRC2, when EZH2 is highly upregulated. ## Lysine methylation Methylation is the addition of a -CH3, or methyl group, to another molecule. In biology, methylation is typically catalyzed by enzymes, and methyl groups are commonly added to either proteins or nucleic acids. In EZH2-catalyzed methylation, the amino acid lysine in the histone h3 is methylated. This amino acid residue can be methylated up to three times on its terminal ammonium group. These methylated lysines are important in the control of mammalian gene expression and have a functional role in heterochromatin formation, X-chromosome inactivation and transcriptional regulation. In mammalian chromosomes, histone lysine methylation can either activate or repress genes depending the site of methylation. Recent work has shown that at least part of the silencing function of the EZH2 complex is the methylation of histone H3 on lysine 27. Methylation, and other modifications, take place on the histones. Methyl modifications can affect the binding of proteins to these histones and either activate or inhibit transcription. ## Mechanism of catalysis EZH2 is a member of the SET domain family of lysine methyltransferases which function to add methyl groups to lysine side chains of substrate proteins. SET methyltransferases depend on a S-Adenosyl methionine (SAM) cofactor to act as a methyl donor for their catalytic activity. SET domain proteins differ from other SAM-dependent methyltransferases in that they bind their substrate and SAM cofactor on opposite sides of the active site of the enzyme. This orientation of substrate and cofactor allows SAM to dissociate without disrupting substrate binding and can lead to multiple rounds of lysine methylation without substrate dissociation. Although neither a substrate-bound or SAM-bound crystal structure for EZH2 has been determined, STAMP structure alignment with the human SET7/9 methyltransferase shows conserved tyrosine residues in almost identical positions within the putative active site of EZH2. It had been previously suggested that tyrosine 726 in the EZH2 active site was acting as a general base to de-protonate the substrate lysine but kinetic isotope effects have indicated that active site residues are not directly involved in the chemistry of the methyltransferase reaction. Instead these experiments support a mechanism in which the residues lower the pKa of the substrate lysine residue while simultaneously providing a channel for water to access the lysine side chain within the interior of the active site. Bulk solvent water can then easily deprotonate the lysine side chain, activating it for nucleophilic attack of the SAM cofactor in an SN2-like reaction resulting in transfer of the methyl group from SAM to the lysine side chain. EZH2 primarily catalyzes mono- and di-methylation of H3K27 but a clinically relevant mutation of residue tyrosine 641 to phenylalanine (Y641F) results in higher H3K27 tri-methylation activity. It is proposed that the removal of the hydroxyl group on Y641 abrogates steric hindrance and allows for accommodation of a third methyl group on the substrate lysine. This EZH2 Y641F mutant is associated with many cancer phenotypes and implies that Y641 may be involved in regulating the number of methyl groups added to a single lysine residue. # Clinical significance ## Cancer EZH2 is an attractive target for anti-cancer therapy because it helps cancerous cells divide and proliferate. It is found in larger amounts than in healthy cells in a wide range of cancers including breast, prostate, bladder, uterine, and renal cancers, as well as melanoma and lymphoma. EZH2 is a gene suppressor, so when it becomes overexpressed, many tumor suppressor genes that are normally turned on, are turned off. Inhibition of EZH2 function shrinks malignant tumors in some reported cases because those tumor suppressor genes are not silenced by EZH2. EZH2 typically is not expressed in healthy adults; it is only found in actively dividing cells, like those active during fetal development. Because of this characteristic, overexpression of EZH2 can be used as a diagnostic marker of cancer and some neurodegenerative disorders. However, there are cases where it is difficult to tell whether overexpression of EZH2 is the cause of a disease, or simply a consequence. If it is only a consequence, targeting EZH2 for inhibition may not cure the disease. One example of a cancer pathway in which EZH2 plays a role is the pRB-E2F pathway. It is downstream from the pRB-E2F pathway, and signals from this pathway lead to EZH2 overexpression. Another important characteristic of EZH2 is that when EZH2 is overexpressed, it can activate genes without forming PRC2. This is an issue because it means the methylation activity of the enzyme is not mediated by complex formation. In breast cancer cells, EZH2 activates genes that promote cell proliferation and survival. It can also activate regulatory genes like c-myc and cyclin D1 by interacting with Wnt signaling factors. Importantly, the mutation of tyrosine 641 to phenylalanine in the active SET domain of EZH2 results in preference for H3K27 tri-methylation and has been linked to lymphoma. ## Inhibitors Developing an inhibitor of EZH2 and preventing unwanted histone methylation of tumor suppressor genes is a viable area of cancer research. EZH2 inhibitor development has focused on targeting the SET domain active site of the protein. Several inhibitors of EZH2 have been developed as of 2015, including 3-deazaneplanocin A (DZNep), EPZ005687, EI1, GSK126, and UNC1999. DZNep has potential antiviral and anti-cancer properties because it lowers EZH2 levels and induces apoptosis in breast and colon cancer cells. DZNep inhibits the hydrolysis of S-adenosyl-L-homocysteine (SAH), which is a product-based inhibitor of all protein methyltransferases, leading to increased cellular concentrations of SAH which in turn inhibits EZH2. However, DZNep is not specific to EZH2 and also inhibits other DNA methyltransferases. In 2012, a company called Epizyme revealed EPZ005687, an S-adenosylmethionine (SAM) competitive inhibitor that is more selective than DZNep; it has a 50-fold increase in selectivity for EZH2 compared to EZH1. The drug blocks EZH2 activity by binding to the SET domain active site of the enzyme. EPZ005687 can also inhibit the Y641 and A677 mutants of EZH2, which may be applicable for treating non-Hodgkin's lymphoma. In 2013, Epizyme began Phase I clinical trials with another EZH2 inhibitor, tazemetostat (EPZ-6438), for patients with B-cell lymphoma. Sinefungin is another SAM-competitive inhibitor, however, like DZNep, it is not specific to EZH2. It works by binding in the cofactor binding pocket of DNA methyltransferases to block methyl transfer. EI1 is another inhibitor, developed by Novartis, that showed EZH2 inhibitory activity in lymphoma tumor cells, including cells with the Y641 mutation. The mechanism of this inhibitor also involves competing with the SAM cofactor for binding to EZH2. GSK126 is a potent, SAM-competitive EZH2 inhibitor developed by GlaxoSmithKline, that has 150-fold selectivity over EZH1 and a Ki of 0.5-3 nM. UNC1999 was developed as an analogue of GSK126, and was the first orally bioavailable EZH2 inhibitor to show activity. However, it is less selective than its counterpart GSK126, and it binds to EZH1 as well, increasing the potential for off-target effects. Combination therapies are being studied as possible treatments when primary treatments begin to fail. Etoposide, a topoisomerase inhibitor, when combined with an EZH2 inhibitor, becomes more effective for non-small cell lung cancers with BRG1 and EGFR mutations. However, EZH2 and lysine methylation can have tumor suppressing activity, for example in myelodysplastic syndrome, indicating that EZH2 inhibition may not be beneficial in all cases. ## Weaver Syndrome Mutations in the EZH2 gene have been linked with Weaver syndrome, a rare disorder characterized by advanced bone age, macrocephaly, and hypertelorism. The histidine residue in the active site of the wild-type EZH2 was mutated to tyrosine in patients diagnosed with Weaver syndrome. The mutation likely interferes with cofactor binding and causes disruption of the natural function of the protein. # Taxonomic distribution Enhancer of zeste (E(z)) was originally identified in Drosophila melanogaster, and its mammalian homologs were subsequently identified and named EZH1 (enhancer of zeste homolog 1) and EZH2 (enhancer of zeste homolog 2). EZH2 is highly conserved through evolution. It and its homologs play essential roles in development, cell differentiation, and cell division in plants, insects, fish, and mammals. The following taxonomic tree is a depiction of EZH2's distribution throughout a wide variety of species.

EZH2 Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme (EC 2.1.1.43) encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression.[1] EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27,[2] by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function.[1] Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis. EZH2 is the functional enzymatic component of the Polycomb Repressive Complex 2 (PRC2), which is responsible for healthy embryonic development through the epigenetic maintenance of genes responsible for regulating development and differentiation.[3] EZH2 is responsible for the methylation activity of PRC2, and the complex also contains proteins required for optimal function (EED, SUZ12, JARID2, AEBP2, RbAp46/48, and PCL).[4] Mutation or over-expression of EZH2 has been linked to many forms of cancer.[5] EZH2 inhibits genes responsible for suppressing tumor development, and blocking EZH2 activity may slow tumor growth. EZH2 has been targeted for inhibition because it is upregulated in multiple cancers including, but not limited to, breast,[6] prostate,[7] melanoma,[8] and bladder cancer.[9] Mutations in the EZH2 gene are also associated with Weaver syndrome, a rare congenital disorder,[10] and EZH2 is involved in causing neurodegenerative symptoms in the nervous system disorder, ataxia telangiectasia.[11] # Function EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2).[12] EZH2's catalytic activity relies on its formation of a complex with at least two other PRC2 components, SUZ12 and EED.[13] As a histone methyltransferase (HMTase), EZH2's primary function is to methylate Lys-27 on histone 3 (H3K27me) by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM). EZH2 is capable of mono-, di-, and tri-methylation of H3K27 and has been associated with a variety of biological functions, including transcriptional regulation in hematopoiesis, development, and cell differentiation.[13][14][15][16] Recent studies have indicated that EZH2 is also capable of methylating non-histone proteins.[13][14] ## Transcription repression EZH2, as a part of PRC2, catalyzes trimethylation of H3K27 (H3K27me3), which is a histone modification that has been characterized as part of the histone code.[12][16][17][18] The histone code is the theory that chemical modifications, such as methylation, acetylation, and ubiquitination, of histone proteins play distinctive roles in epigenetic regulation of gene transcription. EZH2-mediated catalysis of H3K27me3 is associated with long term transcription repression.[12][16][17] EZH2, as well as other Polycomb group proteins, are involved in establishing and maintaining gene repression through cell division.[13][16] This transcriptionally repressive state is thought to be due to PRC2/EZH2-EED-mediated H3K27 methylation and subsequent recruitment of PRC1 which facilitates condensation of chromatin and formation of heterochromatin.[16] Heterochromatin is tightly packed chromatin which limits the accessibility of transcription machinery to the underlying DNA, thereby suppressing transcription.[19] During cell division, heterochromatin formation is required for proper chromosome segregation.[20] PRC2/EED-EZH2 complex may also be involved in the recruitment of DNA methyltransferases (DNMTs), which results in increased DNA methylation, another epigenetic layer of transcription repression.[12][13] Specific genes that have been identified as targets of EZH2-mediated transcriptional repression include HOXA9, HOXC8, MYT1, CDKN2A and retinoic acid target genes.[12] ## Transcription activation In cancer, EZH2 may play a role in activation of transcription, independently of PRC2.[13] In breast cancer cells, EZH2 has been demonstrated to activate NF-κB target genes, which are involved in responses to stimuli.[13] The functional role of this activity and its mechanism are still unknown. ## Development and cell differentiation EZH2 plays an essential role in development. In particular, it helps control transcriptional repression of genes that regulate cell differentiation.[13][14][16][17] In embryonic stem cells, EZH2-mediated trimethylation of H3K27me3 in regions containing developmental genes appears to be important for maintenance of normal cell differentiation.[16] H3K27me3 is also important in driving X-inactivation, the silencing of one X-chromosome in females during development.[18] During X-inactivation, it is thought that EZH2 is involved in initiating heterochromatin formation by trimethylating H3K27 and that other histone methyltransferases and histone marks may be involved in maintaining the silenced state.[21] Further, EZH2 has been identified as an essential protein involved in development and differentiation of B-cells and T-cells.[14] H3K27me3 is involved in suppressing genes that promote differentiation, thus maintaining an undifferentiated state of B- and T-cells and playing an important role in regulating hematopoiesis.[14] ## Regulation of EZH2 activity The activity of EZH2 is regulated by the post-translational phosphorylation of threonine and serine residues on EZH2.[22] Specifically, phosphorylation of T350 has been linked to an increase in EZH2 activity while phosphorylation of T492 and S21 have been linked to a decrease in EZH2 activity.[17][22] Phosphorylation of T492 has been suggested to disrupt contacts between human EZH2 and its binding partners in the PRC2 complex, thus hindering its catalytic activity.[17] In addition to phosphorylation, it has also been shown that PRC2/EZH2-EED activity is antagonized by transcription-activating histone marks, such as acetylation of H3K27 (H3K27ac) and methylation of H3K36 (H3K36me).[17][23] # Enzymatic activity EZH2 function is highly dependent upon its recruitment by the PRC2 complex. In particular, WD40-repeat protein embryonic ectoderm development (EED) and zinc finger protein suppressor of zeste 12 (SUZ12) are needed to stabilize the interaction of EZH2 with its histone substrate[24][25] Recently, two isoforms of EZH2 generated from alternative splicing have been identified in humans: EZH2α and EZH2β.[26] Both isoforms contain elements that have been identified as important for EZH2 function including the nuclear localization signal, the EED and SUZ12 binding sites as well as the conserved SET domain.[26] Most studies have thus far focused on the longer isoform EZH2α, but EZH2β, which lacks exons 4 and 8, has been shown to be active.[26] Furthermore, PRC2/EZH2β complexes act on distinct genes from that of its PRC2/EZH2α counterpart suggesting that each isoform may act to regulate a specific subset of genes.[26] Additional evidence suggests that EZH2 may also be capable of lysine methylation independent of association with PRC2, when EZH2 is highly upregulated.[13] ## Lysine methylation Methylation is the addition of a -CH3, or methyl group, to another molecule. In biology, methylation is typically catalyzed by enzymes, and methyl groups are commonly added to either proteins or nucleic acids. In EZH2-catalyzed methylation, the amino acid lysine in the histone h3 is methylated. This amino acid residue can be methylated up to three times on its terminal ammonium group. These methylated lysines are important in the control of mammalian gene expression and have a functional role in heterochromatin formation, X-chromosome inactivation and transcriptional regulation.[27] In mammalian chromosomes, histone lysine methylation can either activate or repress genes depending the site of methylation. Recent work has shown that at least part of the silencing function of the EZH2 complex is the methylation of histone H3 on lysine 27.[28] Methylation, and other modifications, take place on the histones. Methyl modifications can affect the binding of proteins to these histones and either activate or inhibit transcription.[20] ## Mechanism of catalysis EZH2 is a member of the SET domain family of lysine methyltransferases which function to add methyl groups to lysine side chains of substrate proteins.[29] SET methyltransferases depend on a S-Adenosyl methionine (SAM) cofactor to act as a methyl donor for their catalytic activity. SET domain proteins differ from other SAM-dependent methyltransferases in that they bind their substrate and SAM cofactor on opposite sides of the active site of the enzyme. This orientation of substrate and cofactor allows SAM to dissociate without disrupting substrate binding and can lead to multiple rounds of lysine methylation without substrate dissociation.[29] Although neither a substrate-bound or SAM-bound crystal structure for EZH2 has been determined, STAMP structure alignment with the human SET7/9 methyltransferase shows conserved tyrosine residues in almost identical positions within the putative active site of EZH2. It had been previously suggested that tyrosine 726 in the EZH2 active site was acting as a general base to de-protonate the substrate lysine but kinetic isotope effects have indicated that active site residues are not directly involved in the chemistry of the methyltransferase reaction.[30] Instead these experiments support a mechanism in which the residues lower the pKa of the substrate lysine residue while simultaneously providing a channel for water to access the lysine side chain within the interior of the active site. Bulk solvent water can then easily deprotonate the lysine side chain, activating it for nucleophilic attack of the SAM cofactor in an SN2-like reaction resulting in transfer of the methyl group from SAM to the lysine side chain.[30] EZH2 primarily catalyzes mono- and di-methylation of H3K27 but a clinically relevant mutation of residue tyrosine 641 to phenylalanine (Y641F) results in higher H3K27 tri-methylation activity.[30] It is proposed that the removal of the hydroxyl group on Y641 abrogates steric hindrance and allows for accommodation of a third methyl group on the substrate lysine. This EZH2 Y641F mutant is associated with many cancer phenotypes and implies that Y641 may be involved in regulating the number of methyl groups added to a single lysine residue.[30] # Clinical significance ## Cancer EZH2 is an attractive target for anti-cancer therapy because it helps cancerous cells divide and proliferate. It is found in larger amounts than in healthy cells in a wide range of cancers including breast, prostate, bladder, uterine, and renal cancers, as well as melanoma and lymphoma. EZH2 is a gene suppressor, so when it becomes overexpressed, many tumor suppressor genes that are normally turned on, are turned off. Inhibition of EZH2 function shrinks malignant tumors in some reported cases because those tumor suppressor genes are not silenced by EZH2.[31] EZH2 typically is not expressed in healthy adults; it is only found in actively dividing cells, like those active during fetal development.[32] Because of this characteristic, overexpression of EZH2 can be used as a diagnostic marker of cancer and some neurodegenerative disorders.[11] However, there are cases where it is difficult to tell whether overexpression of EZH2 is the cause of a disease, or simply a consequence. If it is only a consequence, targeting EZH2 for inhibition may not cure the disease. One example of a cancer pathway in which EZH2 plays a role is the pRB-E2F pathway. It is downstream from the pRB-E2F pathway, and signals from this pathway lead to EZH2 overexpression.[33] Another important characteristic of EZH2 is that when EZH2 is overexpressed, it can activate genes without forming PRC2. This is an issue because it means the methylation activity of the enzyme is not mediated by complex formation. In breast cancer cells, EZH2 activates genes that promote cell proliferation and survival.[13] It can also activate regulatory genes like c-myc and cyclin D1 by interacting with Wnt signaling factors.[34] Importantly, the mutation of tyrosine 641 to phenylalanine in the active SET domain of EZH2 results in preference for H3K27 tri-methylation and has been linked to lymphoma.[35] ## Inhibitors Developing an inhibitor of EZH2 and preventing unwanted histone methylation of tumor suppressor genes is a viable area of cancer research. EZH2 inhibitor development has focused on targeting the SET domain active site of the protein. Several inhibitors of EZH2 have been developed as of 2015, including 3-deazaneplanocin A (DZNep), EPZ005687, EI1, GSK126, and UNC1999. DZNep has potential antiviral and anti-cancer properties because it lowers EZH2 levels and induces apoptosis in breast and colon cancer cells.[36] DZNep inhibits the hydrolysis of S-adenosyl-L-homocysteine (SAH), which is a product-based inhibitor of all protein methyltransferases, leading to increased cellular concentrations of SAH which in turn inhibits EZH2. However, DZNep is not specific to EZH2 and also inhibits other DNA methyltransferases. In 2012, a company called Epizyme revealed EPZ005687, an S-adenosylmethionine (SAM) competitive inhibitor that is more selective than DZNep; it has a 50-fold increase in selectivity for EZH2 compared to EZH1. The drug blocks EZH2 activity by binding to the SET domain active site of the enzyme. EPZ005687 can also inhibit the Y641 and A677 mutants of EZH2, which may be applicable for treating non-Hodgkin's lymphoma.[37] In 2013, Epizyme began Phase I clinical trials with another EZH2 inhibitor, tazemetostat (EPZ-6438), for patients with B-cell lymphoma.[41] Sinefungin is another SAM-competitive inhibitor, however, like DZNep, it is not specific to EZH2.[40] It works by binding in the cofactor binding pocket of DNA methyltransferases to block methyl transfer. EI1 is another inhibitor, developed by Novartis, that showed EZH2 inhibitory activity in lymphoma tumor cells, including cells with the Y641 mutation.[38] The mechanism of this inhibitor also involves competing with the SAM cofactor for binding to EZH2.[38] GSK126 is a potent, SAM-competitive EZH2 inhibitor developed by GlaxoSmithKline, that has 150-fold selectivity over EZH1 and a Ki of 0.5-3 nM.[39] UNC1999 was developed as an analogue of GSK126, and was the first orally bioavailable EZH2 inhibitor to show activity. However, it is less selective than its counterpart GSK126, and it binds to EZH1 as well, increasing the potential for off-target effects. Combination therapies are being studied as possible treatments when primary treatments begin to fail. Etoposide, a topoisomerase inhibitor, when combined with an EZH2 inhibitor, becomes more effective for non-small cell lung cancers with BRG1 and EGFR mutations.[31] However, EZH2 and lysine methylation can have tumor suppressing activity, for example in myelodysplastic syndrome,[42] indicating that EZH2 inhibition may not be beneficial in all cases. ## Weaver Syndrome Mutations in the EZH2 gene have been linked with Weaver syndrome, a rare disorder characterized by advanced bone age, macrocephaly, and hypertelorism.[10] The histidine residue in the active site of the wild-type EZH2 was mutated to tyrosine in patients diagnosed with Weaver syndrome.[10] The mutation likely interferes with cofactor binding and causes disruption of the natural function of the protein.[10] # Taxonomic distribution Enhancer of zeste (E(z)) was originally identified in Drosophila melanogaster, and its mammalian homologs were subsequently identified and named EZH1 (enhancer of zeste homolog 1) and EZH2 (enhancer of zeste homolog 2).[44] EZH2 is highly conserved through evolution. It and its homologs play essential roles in development, cell differentiation, and cell division in plants, insects, fish, and mammals.[13][17][45][46] The following taxonomic tree is a depiction of EZH2's distribution throughout a wide variety of species.[47][48]

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Salt

Salt Salt from ancient Greek "άλς" (sea) is a mineral essential for animal life, composed primarily of sodium chloride. Salt for human consumption is produced in different forms: unrefined salt (such as sea salt), refined salt (table salt), and iodized salt. It is a crystalline solid, white, pale pink or light grey in color, normally obtained from sea water or rock deposits. Edible rock salts may be slightly greyish in color due to this mineral content. Sodium and chlorine, the two components of salt, are necessary for the survival of all living creatures, including humans, but they need not be consumed as salt, where they are found together in very concentrated form. Some isolated cultures, such as the Yanomami in South America, have been found to consume little salt. Salt is involved in regulating the water content (fluid balance) of the body. Salt flavor is one of the basic tastes. Salt cravings may be caused by trace mineral deficiencies as well as by a deficiency of sodium chloride itself. Overconsumption of salt can increase the risk of health problems, including high blood pressure. In food preparation, salt is used as a preservative and as a seasoning. # History At the dawn of civilization, salt's preservative ability eliminated dependency on the seasonal availability of food, allowed travel over long distances, and was a vital food additive. However, because salt (NaCl) was difficult to obtain, it became a highly valued trade item throughout history. Until the 1900s, salt was one of the prime movers of national economies and wars. Salt was often taxed; research has discovered this practice to have existed as early as the 20th century BC in China. By the Middle Ages, caravans consisting of as many as forty thousand camels traversed four hundred miles of the Sahara bearing salt, sometimes trading it for slaves. The first registers of salt use were produced around 4000 B.C. in Egypt, and later in Greece and Rome. Salt was very valuable and used to preserve and flavor foods. In Ancient Rome, salt was used as a currency. The Latin word salarium; meaning a payment made in salt, is the root of the word "salary." Unfortunately for those paid with salt, it was easily ruined by rain and other weather conditions. Payments to Roman workers and soldiers were made in salt. Salt was also given to the parents of the groom in marriage until the 8th century. Template:Who From the Phoenicians dates the evidence of harvesting solid salt from the sea. They also exported it to other civilizations. As a result of the increased salt supply from the sea, the value of salt depreciated. The harvest method used was flooding plains of land with seawater, then leaving the plains to dry. After the water dried, the salt which was left was collected and sold. In the Mali Empire, merchants in 12th century Timbuktu—the gateway to the Sahara Desert and the seat of scholars—valued salt (NaCl) enough to buy it for its weight in gold; this trade led to the legends of the incredibly wealthy city of Timbuktu, and fueled inflation in Europe, which was importing the salt. During his protests in India, Mohandas Gandhi performed the famous salt march to challenge the British-imposed monopoly on salt. # In religion Among the ancients, as with ourselves, "sol" (sun) and "sal" (salt) were considered essential to the maintenance of life. There are thirty-five references (verses) to salt in the Bible (King James Version), the most familiar probably being the story of Lot's wife, who was turned into a pillar of salt when she disobeyed the angels and looked back at the wicked city of Sodom (Genesis 19:26). In the Sermon on the Mount, Jesus also referred to his followers as the "salt of the earth". The apostle Paul also encouraged Christians to "let your conversation be always full of grace, seasoned with salt" (Colossians 4:6) so that when others enquire about their beliefs, the Christian's answer generates a 'thirst' to know more about Christ. Salt is mandatory in the rite of the Tridentine Mass. Salt is used in the third item (which includes an Exorcism) of the Celtic Consecration (refer Gallican rite) that is employed in the Consecration of a Church. Salt may be added to the water "where it is customary" in the Roman Catholic rite of Holy water. The earliest Biblical mention of salt appears to be in reference to the destruction of Sodom and Gomorrah (Genesis 19:24-26)When King Abimelech destroyed the city of Shechem, held to have occurred in the thirteenth century BCE., he is said to have "sowed salt on it," this phrase expressing the completeness of its ruin. (Judges 9:45.) In the native Japanese religion Shinto, salt is used for ritual purification of locations and people, such as in Sumo Wrestling. In Aztec mythology, Huixtocihuatl was a fertility goddess who presided over salt and salt water. # Forms of salt ## Unrefined salt Different natural salts have different mineralities, giving each one a unique flavor. Fleur de sel, natural sea salt harvested by hand, has a unique flavor varying from region to region. Some assert that unrefined sea salt is more healthy than refined salts. However, completely raw sea salt is bitter due to magnesium and calcium compounds, and thus is rarely eaten. Other people think that raw sea and rock salts do not contain sufficient iodine salts to prevent iodine deficiency diseases like hypothyroidism. ## Refined salt Refined salt, which is most widely used presently, is mainly sodium chloride. Food grade salt accounts for only a small part of salt production in industrialised countries (3% in Europe) although world-wide, food uses account for 17.5% of salt production. The majority is sold for industrial use. Salt has great commercial value, because it is a necessary ingredient in the manufacturing of many things. A few common examples include: the production of pulp and paper, setting dyes in textiles and fabrics, and the making of soaps and detergents. The manufacture and use of salt is one of the oldest chemical industries. Salt is also obtained by evaporation of sea water, usually in shallow basins warmed by sunlight; salt so obtained was formerly called bay salt, and is now often called sea salt or solar salt. Today, most refined salt is prepared from rock salt: mineral deposits high in salt. These rock salt deposits were formed by the evaporation of ancient salt lakes. These deposits may be mined conventionally or through the injection of water. Injected water dissolves the salt, and the brine solution can be pumped to the surface where the salt is collected. After the raw salt is obtained, it is refined to purify it and improve its storage and handling characteristics. Purification usually involves recrystallization. In recrystallization, a brine solution is treated with chemicals that precipitate most impurities (largely magnesium and calcium salts). Multiple stages of evaporation are then used to collect pure sodium chloride crystals, which are kiln-dried. Since the 1950's it has been common to add a trace of sodium hexacyanoferrate II to the brine, this acts as an anticaking agent by promoting irregular crystals. Other anticaking agents (and potassium iodide, for iodised salt) are generally added after crystallization. These agents are hygroscopic chemicals which absorb humidity, keeping the salt crystals from sticking together. Some anticaking agents used are tricalcium phosphate, calcium or magnesium carbonates, fatty acid salts (acid salts), magnesium oxide, silicon dioxide, calcium silicate, sodium alumino-silicate, and alumino-calcium silicate. Concerns have been raised regarding the possible toxic effects of aluminium in the latter two compounds, however both the European Union and the United States Food and Drug Administration (FDA) permit their use. The refined salt is then ready for packing and distribution. ## Table salt Table salt is refined salt, 99% sodium chloride. It usually contains substances that make it free flowing (anticaking agents) such as sodium silicoaluminate or magnesium carbonate. It is common practice to put a few grains of uncooked rice in salt shakers to absorb extra moisture when anticaking agents are not enough. ### Iodized salt Iodized salt (BrE: iodised salt), table salt mixed with a minute amount of sodium iodide, iodate, or sometimes potassium iodide, is used to help reduce the chance of iodine deficiency in humans. Iodine deficiency commonly leads to thyroid gland problems, specifically endemic goiter. Endemic goiter is a disease characterized by a swelling of the thyroid gland, usually resulting in a bulbous protrusion on the neck. While only tiny quantities of iodine are required in a diet to prevent goiter, the United States Food and Drug Administration recommends (21 CFR 101.9 (c)(8)(iv)) 150 microgrammes of iodine per day for both men and women, and there are many places around the world where natural levels of iodine in the soil are low and the iodine is not taken up by vegetables. Today, iodized salt is more common in the United States, Australia and New Zealand than in Britain. Table salt is also often iodized—a small amount of potassium iodide (in the US) or potassium iodate (in the EU) is added as an important dietary supplement. Table salt is mainly employed in cooking and as a table condiment. Iodized table salt has significantly reduced disorders of iodine deficiency in countries where it is used. Iodine is important to prevent the insufficient production of thyroid hormones (hypothyroidism), which can cause goitre, cretinism in children, and myxedema in adults. ### Fluorinated salt In some European countries where fluoridation of drinking water is not practiced, fluorinated table salt is available. In France, 35% of sold table salt contains sodium or potassium fluoride. Another additive, especially important for pregnant women is Folic acid (B vitamin) giving the table salt a yellow color. ## Salty condiments In many Asian cultures, table salt is not traditionally used as a condiment.However, condiments such as soy sauce, fish sauce and oyster sauce tend to have a high salt content and fill much the same role as a salt-providing table condiment that table salt serves in western cultures. # Health effects Sodium is one of the primary electrolytes in the body. All three electrolytes (sodium, potassium, and calcium) are available in unrefined salt, as are other vital minerals needed for optimal bodily function. Too much or too little salt in the diet can lead to muscle cramps, dizziness, or even an electrolyte disturbance, which can cause severe, even fatal, neurological problems. Drinking too much water, with insufficient salt intake, puts a person at risk of water intoxication. Salt is even sometimes used as a health aid, such as in treatment of dysautonomia. People's risk for disease due to insufficient or excessive salt intake varies due to biochemical individuality. Some have asserted that while the risks of consuming too much salt are real, the risks have been exaggerated for most people, or that the studies done on the consumption of salt can be interpreted in many different ways. Excess salt consumption has been linked to: - exercise-induced asthma. On the other hand, another source counters, "…we still don't know whether salt contributes to asthma. If there is a link then it's very weak…". - heartburn. - osteoporosis: One report shows that a high salt diet does reduce bone density in girls.. Yet "While high salt intakes have been associated with detrimental effects on bone health, there are insufficient data to draw firm conclusions." (, p3) - Gastric cancer (Stomach cancer) is associated with high levels of sodium, "but the evidence does not generally relate to foods typically consumed in the UK." (, p18) However, in Japan, salt consumption is higher. - hypertension (high blood pressure): "Since 1994, the evidence of an association between dietary salt intakes and blood pressure has increased. The data have been consistent in various study populations and across the age range in adults." ( p3). "The CMO of England, in his Annual Report (DH, 2001), highlighted that people with high blood pressure are three times more likely to develop heart disease and stroke, and twice as likely to die from these diseases than those with normal levels."(, p14). Professor Dr. Diederick Grobbee claims that there is no evidence of a causal link between salt intake and mortality or cardiovascular events.. One study found that low urinary sodium is associated with greater risk of myocardial infarction among treated hypertensive men . - left ventricular hypertrophy (cardiac enlargement): "Evidence suggests that high salt intake causes left ventricular hypertrophy, a strong risk factor for cardiovascular disease, independently of blood pressure effects." ( p3) "…there is accumulating evidence that high salt intake predicts left ventricular hypertrophy." (, p12) Excessive salt (sodium) intake, combined with an inadequate intake of water, can cause hypernatremia. It can exacerbate renal disease. - edema (BE: oedema): A decrease in salt intake has been suggested to treat edema (fluid retention). - duodenal ulcers and gastric ulcers A large scale study by Nancy Cook et al shows that people with high-normal blood pressure who significantly reduced the amount of salt in their diet decreased their chances of developing cardiovascular disease by 25% over the following 10 to 15 years. Their risk of dying from cardiovascular disease decreased by 20%. # Recommended intake This section summarizes the salt intake recommended by the health agencies of various countries. Recommendations tend to be similar. Note that targets for the population as a whole tend to be pragmatic (what is achievable) while advice for an individual is ideal (what is best for health). For example, in the UK target for the population is "eat no more than 6 g a day" but for a person is 4 g. Intakes can be expressed variously as salt or sodium and in various units. - 1 g sodium = 1,000 mg sodium = 42 mmol sodium = 2.5 g salt United Kingdom: In 2003, the UK's Scientific Advisory Committee on Nutrition (SACN) recommended that, for a typical adult, the Reference Nutrient Intake is 4 g salt per day (1.6 g or 70 mmol sodium). However, average adult intake is two and a half times the Reference Nutrient Intake for sodium. "Although accurate data are not available for children, conservative estimates indicate that, on a body weight basis, the average salt intake of children is higher than that of adults." SACN aimed for an achievable target reduction in average intake of salt to 6 g per day (2.4 g or 100 mmol sodium) — this is roughly equivalent to a teaspoonful of salt. The SACN recommendations for children are: - 0–6 months old: less than 1 g/day - 7–12 months: 1 g/day - 1–3 years: 2 g/day - 4–6 years: 3 g/day - 7–10 years: 5 g/day - 11–14 years: 6 g/day SACN states, "The target salt intakes set for adults and children do not represent ideal or optimum consumption levels, but achievable population goals." Republic of Ireland: The Food Safety Authority of Ireland endorses the UK targets "emphasising that the RDA of 1.6 g sodium (4 g salt) per day should form the basis of advice targeted at individuals as distinct from the population health target of a mean salt intake of 6 g per day."(, p16) Canada: Health Canada recommends an Adequate Intake (AI) and an Upper Limit (UL) in terms of sodium. - 0–6 months old: 0.12 g/day (AI) - 7–12 months: 0.37 g/day (AI) - 1–3 years: 1 g/day (AI) 1.5 g/day (UL) - 4–8 years: 1.2/day (AI) 1.9 g/day (UL) - 9–13 years: 1.5 g/day (AI) 2.2 g/day (UL) - 14–50 years: 1.5 g/day (AI) 2.3 g/day (UL) - 51–70 years: 1.3 g/day (AI) 2.3 g/day (UL) - 70 years and older: 1.2 g/day (AI) 2.3 g/day (UL) New Zealand - Adequate Intake (AI) 0.46 – 0.92 g sodium = 1.2 – 2.3g salt - Upper Limit (UL)) 2.3 g sodium = 5.8 g salt Australia: The recommended dietary intake (RDI) is 0.92 g–2.3 g sodium per day (= 2.3 g–5.8 g salt) USA: The Food and Drug Administration itself does not make a recommendation but refers readers to Dietary Guidelines for Americans 2005. These suggest that US citizens should consume less than 2,300 mg of sodium (= 2.3 g sodium = 5.8 g salt) per day. # Labeling UK: The Food Standards Agency defines the level of salt in foods as follows: "High is more than 1.5g salt per 100g (or 0.6g sodium). Low is 0.3g salt or less per 100g (or 0.1g sodium). If the amount of salt per 100g is in between these figures, then that is a medium level of salt." In the UK, foods produced by some supermarkets and manufacturers have ‘traffic light’ colors on the front of the pack: Red (High), Amber (Medium), or Green (Low). USA: The FDA Food Labeling Guide stipulates whether a food can be labelled as "free", "low", or "reduced/less" in respect of sodium. When other health claims are made about a food (e.g. low in fat, calories, etc.), a disclosure statement is required if the food exceeds 480mg of sodium per 'serving.' # Campaigns In 2004, Britain's Food Standards Agency started a public health campaign called "Salt - Watch it", which recommends no more than 6g of salt per day; it features a character called Sid the Slug and was criticised by the Salt Manufacturers Association (SMA). The Advertising Standards Authority did not uphold the SMA complaint in its adjudication.. In March 2007, the FSA launched the third phase of their campaign with the slogan "Salt. Is your food full of it?" fronted by comedienne Jenny Eclair. The Menzies Research Institute in Tasmania, Australia, maintains a website dedicated to educating people about the potential problems of a salt-laden diet. # Salt substitutes Salt intake can be reduced by simply reducing the quantity of salty foods in a diet, without recourse to salt substitutes. Salt substitutes have a taste similar to table salt and contain mostly potassium chloride, which will increase potassium intake. Excess potassium intake can cause hyperkalemia. Various diseases and medications may decrease the body's excretion of potassium, thereby increasing the risk of hyperkalemia. If you have kidney failure, heart failure or diabetes, seek medical advice before using a salt substitute. A manufacturer, LoSalt, has issued an advisory statement that people taking the following prescription drugs should not use a salt substitute: Amiloride, Triamterene, Dytac, Spironolactone (Brand name Aldactone), Eplerenone and Inspra. # Production trends Salt is produced by evaporation of seawater or brine from other sources, such as brine wells and salt lakes, and by mining rock salt, called halite. In 2002, total world production was estimated at 210 million metric tonnes, the top five producers being the United States (40.3 million tonnes), China (32.9), Germany (17.7), India (14.5), and Canada (12.3). Note that these figures are not just for table salt but for sodium chloride in general.

Salt Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Salt from ancient Greek "άλς" (sea) is a mineral essential for animal life, composed primarily of sodium chloride. Salt for human consumption is produced in different forms: unrefined salt (such as sea salt), refined salt (table salt), and iodized salt. It is a crystalline solid, white, pale pink or light grey in color, normally obtained from sea water or rock deposits. Edible rock salts may be slightly greyish in color due to this mineral content. Sodium and chlorine, the two components of salt, are necessary for the survival of all living creatures, including humans, but they need not be consumed as salt, where they are found together in very concentrated form. Some isolated cultures, such as the Yanomami in South America, have been found to consume little salt.[1] Salt is involved in regulating the water content (fluid balance) of the body. Salt flavor is one of the basic tastes. Salt cravings may be caused by trace mineral deficiencies as well as by a deficiency of sodium chloride itself. Overconsumption of salt can increase the risk of health problems, including high blood pressure. In food preparation, salt is used as a preservative and as a seasoning. # History At the dawn of civilization, salt's preservative ability eliminated dependency on the seasonal availability of food, allowed travel over long distances, and was a vital food additive. However, because salt (NaCl) was difficult to obtain, it became a highly valued trade item throughout history. Until the 1900s, salt was one of the prime movers of national economies and wars. Salt was often taxed; research has discovered this practice to have existed as early as the 20th century BC in China. By the Middle Ages, caravans consisting of as many as forty thousand camels traversed four hundred miles of the Sahara bearing salt, sometimes trading it for slaves.[citation needed] The first registers of salt use were produced around 4000 B.C. in Egypt, and later in Greece and Rome. Salt was very valuable and used to preserve and flavor foods. In Ancient Rome, salt was used as a currency. The Latin word salarium; meaning a payment made in salt, is the root of the word "salary." Unfortunately for those paid with salt, it was easily ruined by rain and other weather conditions. Payments to Roman workers and soldiers were made in salt.[2] Salt was also given to the parents of the groom in marriage until the 8th century. Template:Who From the Phoenicians dates the evidence of harvesting solid salt from the sea. They also exported it to other civilizations. As a result of the increased salt supply from the sea, the value of salt depreciated. The harvest method used was flooding plains of land with seawater, then leaving the plains to dry. After the water dried, the salt which was left was collected and sold. In the Mali Empire, merchants in 12th century Timbuktu—the gateway to the Sahara Desert and the seat of scholars—valued salt (NaCl) enough to buy it for its weight in gold; this trade led to the legends of the incredibly wealthy city of Timbuktu, and fueled inflation in Europe, which was importing the salt.[3] During his protests in India, Mohandas Gandhi performed the famous salt march to challenge the British-imposed monopoly on salt. # In religion Among the ancients, as with ourselves, "sol" (sun) and "sal" (salt) were considered essential to the maintenance of life. There are thirty-five references (verses) to salt in the Bible (King James Version), the most familiar probably being the story of Lot's wife, who was turned into a pillar of salt when she disobeyed the angels and looked back at the wicked city of Sodom (Genesis 19:26). In the Sermon on the Mount, Jesus also referred to his followers as the "salt of the earth". The apostle Paul also encouraged Christians to "let your conversation be always full of grace, seasoned with salt" (Colossians 4:6) so that when others enquire about their beliefs, the Christian's answer generates a 'thirst' to know more about Christ. Salt is mandatory in the rite of the Tridentine Mass. Salt is used in the third item (which includes an Exorcism) of the Celtic Consecration (refer Gallican rite) that is employed in the Consecration of a Church. Salt may be added to the water "where it is customary" in the Roman Catholic rite of Holy water. The earliest Biblical mention of salt appears to be in reference to the destruction of Sodom and Gomorrah (Genesis 19:24-26)When King Abimelech destroyed the city of Shechem, held to have occurred in the thirteenth century BCE., he is said to have "sowed salt on it," this phrase expressing the completeness of its ruin. (Judges 9:45.) In the native Japanese religion Shinto, salt is used for ritual purification of locations and people, such as in Sumo Wrestling. In Aztec mythology, Huixtocihuatl was a fertility goddess who presided over salt and salt water. # Forms of salt ## Unrefined salt Different natural salts have different mineralities, giving each one a unique flavor. Fleur de sel, natural sea salt harvested by hand, has a unique flavor varying from region to region. Some assert that unrefined sea salt is more healthy than refined salts.[4] However, completely raw sea salt is bitter due to magnesium and calcium compounds, and thus is rarely eaten. Other people think that raw sea and rock salts do not contain sufficient iodine salts to prevent iodine deficiency diseases like hypothyroidism.[5] ## Refined salt Refined salt, which is most widely used presently, is mainly sodium chloride. Food grade salt accounts for only a small part of salt production in industrialised countries (3% in Europe[6]) although world-wide, food uses account for 17.5% of salt production[7]. The majority is sold for industrial use. Salt has great commercial value, because it is a necessary ingredient in the manufacturing of many things. A few common examples include: the production of pulp and paper, setting dyes in textiles and fabrics, and the making of soaps and detergents. The manufacture and use of salt is one of the oldest chemical industries.[8] Salt is also obtained by evaporation of sea water, usually in shallow basins warmed by sunlight;[9] salt so obtained was formerly called bay salt, and is now often called sea salt or solar salt. Today, most refined salt is prepared from rock salt: mineral deposits high in salt.[citation needed] These rock salt deposits were formed by the evaporation of ancient salt lakes.[10] These deposits may be mined conventionally or through the injection of water. Injected water dissolves the salt, and the brine solution can be pumped to the surface where the salt is collected. After the raw salt is obtained, it is refined to purify it and improve its storage and handling characteristics. Purification usually involves recrystallization. In recrystallization, a brine solution is treated with chemicals that precipitate most impurities (largely magnesium and calcium salts).[11] Multiple stages of evaporation are then used to collect pure sodium chloride crystals, which are kiln-dried. Since the 1950's it has been common to add a trace of sodium hexacyanoferrate II to the brine, this acts as an anticaking agent by promoting irregular crystals.[12] Other anticaking agents (and potassium iodide, for iodised salt) are generally added after crystallization.[citation needed] These agents are hygroscopic chemicals which absorb humidity, keeping the salt crystals from sticking together. Some anticaking agents used are tricalcium phosphate, calcium or magnesium carbonates, fatty acid salts (acid salts), magnesium oxide, silicon dioxide, calcium silicate, sodium alumino-silicate, and alumino-calcium silicate. Concerns have been raised regarding the possible toxic effects of aluminium in the latter two compounds,[citation needed] however both the European Union and the United States Food and Drug Administration (FDA) permit their use.[13] The refined salt is then ready for packing and distribution. ## Table salt Table salt is refined salt, 99% sodium chloride.[14][15] It usually contains substances that make it free flowing (anticaking agents) such as sodium silicoaluminate or magnesium carbonate. It is common practice to put a few grains of uncooked rice in salt shakers to absorb extra moisture when anticaking agents are not enough. ### Iodized salt Iodized salt (BrE: iodised salt), table salt mixed with a minute amount of sodium iodide, iodate, or sometimes potassium iodide, is used to help reduce the chance of iodine deficiency in humans. Iodine deficiency commonly leads to thyroid gland problems, specifically endemic goiter. Endemic goiter is a disease characterized by a swelling of the thyroid gland, usually resulting in a bulbous protrusion on the neck. While only tiny quantities of iodine are required in a diet to prevent goiter, the United States Food and Drug Administration recommends (21 CFR 101.9 (c)(8)(iv)) 150 microgrammes of iodine per day for both men and women, and there are many places around the world where natural levels of iodine in the soil are low and the iodine is not taken up by vegetables. Today, iodized salt is more common in the United States, Australia and New Zealand than in Britain. Table salt is also often iodized—a small amount of potassium iodide (in the US) or potassium iodate (in the EU) is added as an important dietary supplement. Table salt is mainly employed in cooking and as a table condiment. Iodized table salt has significantly reduced disorders of iodine deficiency in countries where it is used.[16] Iodine is important to prevent the insufficient production of thyroid hormones (hypothyroidism), which can cause goitre, cretinism in children, and myxedema in adults. ### Fluorinated salt In some European countries where fluoridation of drinking water is not practiced, fluorinated table salt is available. In France, 35% of sold table salt contains sodium or potassium fluoride.[17] Another additive, especially important for pregnant women is Folic acid (B vitamin) giving the table salt a yellow color. ## Salty condiments In many Asian cultures, table salt is not traditionally used as a condiment.[18]However, condiments such as soy sauce, fish sauce and oyster sauce tend to have a high salt content and fill much the same role as a salt-providing table condiment that table salt serves in western cultures. # Health effects Sodium is one of the primary electrolytes in the body. All three electrolytes (sodium, potassium, and calcium) are available in unrefined salt, as are other vital minerals needed for optimal bodily function. Too much or too little salt in the diet can lead to muscle cramps, dizziness, or even an electrolyte disturbance, which can cause severe, even fatal, neurological problems.[19] Drinking too much water, with insufficient salt intake, puts a person at risk of water intoxication. Salt is even sometimes used as a health aid, such as in treatment of dysautonomia.[20] People's risk for disease due to insufficient or excessive salt intake varies due to biochemical individuality. Some have asserted that while the risks of consuming too much salt are real, the risks have been exaggerated for most people, or that the studies done on the consumption of salt can be interpreted in many different ways.[21] [22] Excess salt consumption has been linked to: - exercise-induced asthma.[23] On the other hand, another source counters, "…we still don't know whether salt contributes to asthma. If there is a link then it's very weak…".[24] - heartburn[25]. - osteoporosis: One report shows that a high salt diet does reduce bone density in girls.[26]. Yet "While high salt intakes have been associated with detrimental effects on bone health, there are insufficient data to draw firm conclusions." ([27], p3) - Gastric cancer (Stomach cancer) is associated with high levels of sodium, "but the evidence does not generally relate to foods typically consumed in the UK." ([27], p18) However, in Japan, salt consumption is higher.[28] - hypertension (high blood pressure): "Since 1994, the evidence of an association between dietary salt intakes and blood pressure has increased. The data have been consistent in various study populations and across the age range in adults." ([27] p3). "The CMO [Chief Medical Officer] of England, in his Annual Report (DH, 2001), highlighted that people with high blood pressure are three times more likely to develop heart disease and stroke, and twice as likely to die from these diseases than those with normal levels."([27], p14). Professor Dr. Diederick Grobbee claims that there is no evidence of a causal link between salt intake and mortality or cardiovascular events.[29]. One study found that low urinary sodium is associated with greater risk of myocardial infarction among treated hypertensive men [30]. - left ventricular hypertrophy (cardiac enlargement): "Evidence suggests that high salt intake causes left ventricular hypertrophy, a strong risk factor for cardiovascular disease, independently of blood pressure effects." ([27] p3) "…there is accumulating evidence that high salt intake predicts left ventricular hypertrophy." ([31], p12) Excessive salt (sodium) intake, combined with an inadequate intake of water, can cause hypernatremia. It can exacerbate renal disease.[19] - edema (BE: oedema): A decrease in salt intake has been suggested to treat edema (fluid retention).[32][19] - duodenal ulcers and gastric ulcers[33] A large scale study by Nancy Cook et al shows that people with high-normal[2] blood pressure who significantly reduced the amount of salt in their diet decreased their chances of developing cardiovascular disease by 25% over the following 10 to 15 years. Their risk of dying from cardiovascular disease decreased by 20%.[34][35] # Recommended intake This section summarizes the salt intake recommended by the health agencies of various countries. Recommendations tend to be similar. Note that targets for the population as a whole tend to be pragmatic (what is achievable) while advice for an individual is ideal (what is best for health). For example, in the UK target for the population is "eat no more than 6 g a day" but for a person is 4 g. Intakes can be expressed variously as salt or sodium and in various units. - 1 g sodium = 1,000 mg sodium = 42 mmol sodium = 2.5 g salt United Kingdom: In 2003, the UK's Scientific Advisory Committee on Nutrition (SACN) recommended that, for a typical adult, the Reference Nutrient Intake is 4 g salt per day (1.6 g or 70 mmol sodium). However, average adult intake is two and a half times the Reference Nutrient Intake for sodium. "Although accurate data are not available for children, conservative estimates indicate that, on a body weight basis, the average salt intake of children is higher than that of adults." SACN aimed for an achievable target reduction in average intake of salt to 6 g per day (2.4 g or 100 mmol sodium) — this is roughly equivalent to a teaspoonful of salt. The SACN recommendations for children are: - 0–6 months old: less than 1 g/day - 7–12 months: 1 g/day - 1–3 years: 2 g/day - 4–6 years: 3 g/day - 7–10 years: 5 g/day - 11–14 years: 6 g/day SACN states, "The target salt intakes set for adults and children do not represent ideal or optimum consumption levels, but achievable population goals."[27] Republic of Ireland: The Food Safety Authority of Ireland endorses the UK targets "emphasising that the RDA of 1.6 g sodium (4 g salt) per day should form the basis of advice targeted at individuals as distinct from the population health target of a mean salt intake of 6 g per day."([31], p16) Canada: Health Canada recommends an Adequate Intake (AI) and an Upper Limit (UL) in terms of sodium. - 0–6 months old: 0.12 g/day (AI) - 7–12 months: 0.37 g/day (AI) - 1–3 years: 1 g/day (AI) 1.5 g/day (UL) - 4–8 years: 1.2/day (AI) 1.9 g/day (UL) - 9–13 years: 1.5 g/day (AI) 2.2 g/day (UL) - 14–50 years: 1.5 g/day (AI) 2.3 g/day (UL) - 51–70 years: 1.3 g/day (AI) 2.3 g/day (UL) - 70 years and older: 1.2 g/day (AI) 2.3 g/day (UL)[36] New Zealand - Adequate Intake (AI) 0.46 – 0.92 g sodium = 1.2 – 2.3g salt - Upper Limit (UL)) 2.3 g sodium = 5.8 g salt[37] Australia: The recommended dietary intake (RDI) is 0.92 g–2.3 g sodium per day (= 2.3 g–5.8 g salt)[38] USA: The Food and Drug Administration itself does not make a recommendation[39] but refers readers to Dietary Guidelines for Americans 2005. These suggest that US citizens should consume less than 2,300 mg of sodium (= 2.3 g sodium = 5.8 g salt) per day. [40] # Labeling UK: The Food Standards Agency defines the level of salt in foods as follows: "High is more than 1.5g salt per 100g (or 0.6g sodium). Low is 0.3g salt or less per 100g (or 0.1g sodium). If the amount of salt per 100g is in between these figures, then that is a medium level of salt." In the UK, foods produced by some supermarkets and manufacturers have ‘traffic light’ colors on the front of the pack: Red (High), Amber (Medium), or Green (Low).[41] USA: The FDA Food Labeling Guide stipulates whether a food can be labelled as "free", "low", or "reduced/less" in respect of sodium. When other health claims are made about a food (e.g. low in fat, calories, etc.), a disclosure statement is required if the food exceeds 480mg of sodium per 'serving.'[42] # Campaigns In 2004, Britain's Food Standards Agency started a public health campaign called "Salt - Watch it", which recommends no more than 6g of salt per day; it features a character called Sid the Slug and was criticised by the Salt Manufacturers Association (SMA).[43] The Advertising Standards Authority did not uphold the SMA complaint in its adjudication.[44]. In March 2007, the FSA launched the third phase of their campaign with the slogan "Salt. Is your food full of it?" fronted by comedienne Jenny Eclair.[45] The Menzies Research Institute in Tasmania, Australia, maintains a website [46] dedicated to educating people about the potential problems of a salt-laden diet. # Salt substitutes Salt intake can be reduced by simply reducing the quantity of salty foods in a diet, without recourse to salt substitutes. Salt substitutes have a taste similar to table salt and contain mostly potassium chloride, which will increase potassium intake. Excess potassium intake can cause hyperkalemia. Various diseases and medications may decrease the body's excretion of potassium, thereby increasing the risk of hyperkalemia. If you have kidney failure, heart failure or diabetes, seek medical advice before using a salt substitute. A manufacturer, LoSalt, has issued an advisory statement[47] that people taking the following prescription drugs should not use a salt substitute: Amiloride, Triamterene, Dytac, Spironolactone (Brand name Aldactone), Eplerenone and Inspra. # Production trends Salt is produced by evaporation of seawater or brine from other sources, such as brine wells and salt lakes, and by mining rock salt, called halite. In 2002, total world production was estimated at 210 million metric tonnes, the top five producers being the United States (40.3 million tonnes), China (32.9), Germany (17.7), India (14.5), and Canada (12.3).[48] Note that these figures are not just for table salt but for sodium chloride in general.

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Ovum

Ovum # Overview An ovum (plural ova) is a haploid female reproductive cell or gamete. The word is derived from Latin, meaning egg or egg cell. Both animals and embryophytes have ova. The term ovule is used for the young ovum of an animal, as well as the plant structure that carries the female gametophyte and egg cell and develops into a seed after fertilization. In some plants, such as algae, it is also called oosphere. # Material contribution to offspring The egg is the sole provider of such endosymbiotic organelles, including mitochondria within the cytoplasm. These cannot be produced with nuclear DNA alone and must be manufactured from DNA within existing organelles of their type (such as mitochondrial DNA) — this is important in Human mitochondrial genetics and can be used to trace maternal and paternal ancestry, especially as plants contain chloroplasts as well. Sperm are often too small to contribute anything physical except DNA and its own mitochondria gets destroyed by the egg. # Ova production In higher animals, ova are produced by female gonads (sexual glands) called ovaries and all of them are present at birth in mammals, and mature via oogenesis. ## Human and mammal ova In the viviparous animals (which include humans and all other placental mammals), the ovum is fertilized inside the female body, and the embryo then develops inside the uterus, receiving nutrition directly from the mother. The ovum is the largest cell in the human body, typically visible to the naked eye without the aid of a microscope or other magnification device. The human ovum measures on average, 145 µm in diameter. ## Protist and plant ova In protists, fungi and many plants, such as bryophytes, ferns, and gymnosperms, ova are produced inside archegonia. Since the archegonium is a haploid structure, egg cells are produced via mitosis. The typical bryophyte archegonium consists of a long neck with a wider base containing the egg cell. Upon maturation, the neck opens to allow sperm cells to swim into the archegonium and fertilize the egg. The resulting zygote then gives rise to an embryo, which will grow out of the archegonium as a sporeling (young sporophyte). In the flowering plants, the female gametophyte, which usually gives rise to the archegonium, has been reduced to just eight cells referred to as the embryo sac inside the ovule. The gametophyte cell closest to the micropyle opening of the embryo sac develops into the egg cell. Upon pollination, a pollen tube delivers sperm into the embryo sac and one sperm nucleus fuses with the egg nucleus. The resulting zygote develops into an embryo inside the ovule. The ovule in turn develops into a seed and in many cases the plant ovary develops into a fruit to facilitate the dispersal of the seeds. Upon germination, the embryo grows into a seedling. # Ova development in oviparous animals In the oviparous animals (all birds, most fishes, amphibians and reptiles) the ova develop protective layers and pass through the oviduct to the outside of the body. They are fertilized by male sperm either inside the female body (as in birds), or outside (as in many fishes). After fertilization, an embryo develops, nourished by nutrients contained in the egg. It then hatches from the egg, outside the mother's body. See egg (biology) for a discussion of eggs of oviparous animals. The egg cell's cytoplasm and mitochondria (and chloroplasts in plants) are the sole means of the egg being able to reproduce by mitosis and eventually form a blastocyst after fertilization. # Ovoviviparity There is an intermediate form, the ovoviviparous animals: the embryo develops within and is nourished by an egg as in the oviparous case, but then it hatches inside the mother's body shortly before birth, or just after the egg leaves the mother's body. Some fish, reptiles and many invertebrates use this technique.

Ovum # Overview An ovum (plural ova) is a haploid female reproductive cell or gamete. The word is derived from Latin, meaning egg or egg cell. Both animals and embryophytes have ova. The term ovule is used for the young ovum of an animal, as well as the plant structure that carries the female gametophyte and egg cell and develops into a seed after fertilization. In some plants, such as algae, it is also called oosphere. # Material contribution to offspring The egg is the sole provider of such endosymbiotic organelles, including mitochondria within the cytoplasm. These cannot be produced with nuclear DNA alone and must be manufactured from DNA within existing organelles of their type (such as mitochondrial DNA) — this is important in Human mitochondrial genetics and can be used to trace maternal and paternal ancestry, especially as plants contain chloroplasts as well. Sperm are often too small to contribute anything physical except DNA and its own mitochondria gets destroyed by the egg. # Ova production In higher animals, ova are produced by female gonads (sexual glands) called ovaries and all of them are present at birth in mammals, and mature via oogenesis. ## Human and mammal ova In the viviparous animals (which include humans and all other placental mammals), the ovum is fertilized inside the female body, and the embryo then develops inside the uterus, receiving nutrition directly from the mother. The ovum is the largest cell in the human body, typically visible to the naked eye without the aid of a microscope or other magnification device. The human ovum measures on average, 145 µm in diameter. ## Protist and plant ova In protists, fungi and many plants, such as bryophytes, ferns, and gymnosperms, ova are produced inside archegonia. Since the archegonium is a haploid structure, egg cells are produced via mitosis. The typical bryophyte archegonium consists of a long neck with a wider base containing the egg cell. Upon maturation, the neck opens to allow sperm cells to swim into the archegonium and fertilize the egg. The resulting zygote then gives rise to an embryo, which will grow out of the archegonium as a sporeling (young sporophyte). In the flowering plants, the female gametophyte, which usually gives rise to the archegonium, has been reduced to just eight cells referred to as the embryo sac inside the ovule. The gametophyte cell closest to the micropyle opening of the embryo sac develops into the egg cell. Upon pollination, a pollen tube delivers sperm into the embryo sac and one sperm nucleus fuses with the egg nucleus. The resulting zygote develops into an embryo inside the ovule. The ovule in turn develops into a seed and in many cases the plant ovary develops into a fruit to facilitate the dispersal of the seeds. Upon germination, the embryo grows into a seedling. # Ova development in oviparous animals In the oviparous animals (all birds, most fishes, amphibians and reptiles) the ova develop protective layers and pass through the oviduct to the outside of the body. They are fertilized by male sperm either inside the female body (as in birds), or outside (as in many fishes). After fertilization, an embryo develops, nourished by nutrients contained in the egg. It then hatches from the egg, outside the mother's body. See egg (biology) for a discussion of eggs of oviparous animals. The egg cell's cytoplasm and mitochondria (and chloroplasts in plants) are the sole means of the egg being able to reproduce by mitosis and eventually form a blastocyst after fertilization. # Ovoviviparity There is an intermediate form, the ovoviviparous animals: the embryo develops within and is nourished by an egg as in the oviparous case, but then it hatches inside the mother's body shortly before birth, or just after the egg leaves the mother's body. Some fish, reptiles and many invertebrates use this technique.

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

5bd7dd496b6aab19fae7d12a8841ec7c54cc2f25

wikidoc

Enol

Enol Enols (also known as alkenols) are alkenes with a hydroxyl group affixed to one of the carbon atoms composing the double bond. Enols and carbonyl compounds (such as ketones and aldehydes) are in fact isomers; this is called keto-enol tautomerism: The enol form is shown on the left. It is usually unstable, does not survive long, and changes into the keto (ketone) form shown on the right. This is because oxygen is more electronegative than carbon and thus forms stronger multiple bonds. Hence, a carbon-oxygen (carbonyl) double bond is more than twice as strong as a carbon-oxygen single bond, but a carbon-carbon double bond is weaker than two carbon-carbon single bonds. Only in 1,3-dicarbonyl and 1,3,5-tricarbonyl compounds does the (mono)enol form predominate. This is because the resonance and intermolecular hydrogen bonding that occurs in the enol form is not possible in the keto form. Thus, at equilibrium, over 99% of propanedial (OHCCH2CHO) molecules exist as the monoenol. The percentage is lower for 1,3-aldehyde ketones and diketones. Enols (and enolates) are important intermediates in many organic reactions. The words enol and alkenol are portmanteaux of the words alkene (or just -ene, the suffix given to alkenes) and alcohol (which represents the enol's hydroxyl group). # Enolate ion When the hydroxyl group (−OH) in an enol loses a hydrogen ion (H+), a negative enolate ion is formed as shown here: Enolates can exist in quantitative amounts in strictly Brønsted acid free conditions, since they are generally very basic. 1,3-dicarbonyl and 1,3,5-tricarbonyl compounds are quite acidic because of the strong resonance stabilization created when one of the hydrogens is removed (from either the keto or enol forms). The resonance of the enol is exactly analogous to that used to explain the acidity of phenols and consists of the delocalisation of the enolate ion's negative charge to the alpha carbon. These enolate ions are very valuable in synthesis of complicated alcohols and carbonyl compounds (aldol additions). The synthetic value is due to the nucleophilicity of α-carbon of enolate group. In ketones (a type of carbonyl) with acidic α-hydrogens on either side of the carbonyl carbon, selectivity of deprotonation may be achieved to generate the enolate directly from the ketone. At low temperatures (-78°C, i.e. dry ice bath), in aprotic solvents, and with bulky non-equilibrating bases (e.g. LDA) the "kinetic" proton may be removed. The "kinetic" proton is the one which is sterically most accessible. Under thermodynamic conditions (warmer temperatures, weak base, and protic solvent) equilibrium is established between the ketone and the two possible enolates, the enolate favoured is termed the "thermodynamic" enolate and is favoured because of its lower energy level than the other possible enolate. Thus, by choosing the "correct" conditions to generate an enolate, one can increase the yield of the desired product while minimizing formation of undesired products. # Natural occurrences Vitamin C is a sugar acid containg an enol bond. It can lose a proton as pictured, which makes it an acid: de:Enole he:אנול hu:Enol mk:Енол fi:Enoli sv:Enol

Enol Enols (also known as alkenols) are alkenes with a hydroxyl group affixed to one of the carbon atoms composing the double bond. Enols and carbonyl compounds (such as ketones and aldehydes) are in fact isomers; this is called keto-enol tautomerism: The enol form is shown on the left. It is usually unstable, does not survive long, and changes into the keto (ketone) form shown on the right. This is because oxygen is more electronegative than carbon and thus forms stronger multiple bonds. Hence, a carbon-oxygen (carbonyl) double bond is more than twice as strong as a carbon-oxygen single bond, but a carbon-carbon double bond is weaker than two carbon-carbon single bonds. Only in 1,3-dicarbonyl and 1,3,5-tricarbonyl compounds does the (mono)enol form predominate. This is because the resonance and intermolecular hydrogen bonding that occurs in the enol form is not possible in the keto form. Thus, at equilibrium, over 99% of propanedial (OHCCH2CHO) molecules exist as the monoenol. The percentage is lower for 1,3-aldehyde ketones and diketones. Enols (and enolates) are important intermediates in many organic reactions. The words enol and alkenol are portmanteaux of the words alkene (or just -ene, the suffix given to alkenes) and alcohol (which represents the enol's hydroxyl group). # Enolate ion When the hydroxyl group (−OH) in an enol loses a hydrogen ion (H+), a negative enolate ion is formed as shown here: Enolates can exist in quantitative amounts in strictly Brønsted acid free conditions, since they are generally very basic. 1,3-dicarbonyl and 1,3,5-tricarbonyl compounds are quite acidic because of the strong resonance stabilization created when one of the hydrogens is removed (from either the keto or enol forms). The resonance of the enol is exactly analogous to that used to explain the acidity of phenols and consists of the delocalisation of the enolate ion's negative charge to the alpha carbon. These enolate ions are very valuable in synthesis of complicated alcohols and carbonyl compounds (aldol additions). The synthetic value is due to the nucleophilicity of α-carbon of enolate group. In ketones (a type of carbonyl) with acidic α-hydrogens on either side of the carbonyl carbon, selectivity of deprotonation may be achieved to generate the enolate directly from the ketone. At low temperatures (-78°C, i.e. dry ice bath), in aprotic solvents, and with bulky non-equilibrating bases (e.g. LDA) the "kinetic" proton may be removed. The "kinetic" proton is the one which is sterically most accessible. Under thermodynamic conditions (warmer temperatures, weak base, and protic solvent) equilibrium is established between the ketone and the two possible enolates, the enolate favoured is termed the "thermodynamic" enolate and is favoured because of its lower energy level than the other possible enolate. Thus, by choosing the "correct" conditions to generate an enolate, one can increase the yield of the desired product while minimizing formation of undesired products. # Natural occurrences Vitamin C is a sugar acid containg an enol bond. It can lose a proton as pictured, which makes it an acid: de:Enole he:אנול hu:Enol mk:Енол fi:Enoli sv:Enol Template:WikiDoc Sources

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

afdfe3d2ee11ab943a6994effffa721a39ba0e79

wikidoc

Envy

Envy Envy may be defined as an emotion that "occurs when a person lacks another’s superior quality, achievement, or possession and either desires it or wishes that the other lacked it." It can also derive from a sense of low self-esteem that results from an upward social comparison threatening a person's self image: another person has something that the envier considers to be important to have. If the other person is perceived to be similar to the envier, the aroused envy will be particularly intense, because it signals to the envier that it just as well could have been him or her who had the desired object. Bertrand Russell said envy was one of the most potent causes of unhappiness. It is a universal and most unfortunate aspect of human nature because not only does the envious person wish to inflict misfortune on others, but is also rendered unhappy by his envy. Although envy is generally seen as something negative, Russell(1930, p. 90-91)also believed that envy was a driving force behind the movement towards democracy and must be endured in order to achieve a more just social system. The tendency to feel envy seems to be present in all cultures . # Envy and jealousy Envy and jealousy are distinct emotions. In its correct usage, jealousy is the fear of losing something that one possesses to another person (a loved one in the prototypical form), while envy is the pain or frustration caused by another person having something that one does not have oneself. Envy typically involves two people, and jealousy typically involves three people. Envy and jealousy result from different situations and are distinct emotional experiences. # Envy in philosophy Aristotle (in Rhetoric) defined envy "as the pain caused by the good fortune of others", while Kant defined it as "a reluctance to see our own well-being overshadowed by another's because the standard we use to see how well off we are is not the intrinsic worth of our own well-being but how it compares with that of others" (in Metaphysics of Morals). # Envy in the arts In some cultures, envy is often associated with the color green, as in "green with envy". The phrase "green-eyed monster" refers to an individual whose current actions appear motivated by envy. This is based on a line from Shakespeare's Othello. Shakespeare mentions it also in The Merchant of Venice when Portia states: "How all the other passions fleet to air, as doubtful thoughts and rash embraced despair and shuddering fear and green-eyed jealousy!" Envy is known as one of the most powerful human emotions for its ability to control one as if envy was an entity in itself. Countless men and women have fallen prey to brief periods of intense envy followed by anger which then translates into aggression. One of the most common examples is a pair of lovers in which a secret love is discovered and can lead to sorrow, then intense envy, and eventually anger and aggression. # Envy in religion Envy was one of the Seven deadly sins of the Christian Church. The book of Exodus (20:17) states: "Thou shalt not covet thy neighbour’s house; neither shalt thou desire his wife, nor his servant, nor his handmaid, nor his ox, nor his ass, nor any thing that is his." Perhaps today the donkey (ass) corresponds to a car, but it could represent anything desirable owned by another. The donkey cannot be readily stolen as it would be obvious. However being envious of the donkey as a possession is to be avoided, as it could lead to ungodly thoughts or deeds toward the neighbour or the donkey. It's important to make the distinction between desiring something someone else has, and envying them because of something they have. Envy relates to negative feelings toward a person because of something they own.

Envy Template:Emotion Envy may be defined as an emotion that "occurs when a person lacks another’s superior quality, achievement, or possession and either desires it or wishes that the other lacked it."[1] It can also derive from a sense of low self-esteem that results from an upward social comparison threatening a person's self image: another person has something that the envier considers to be important to have. If the other person is perceived to be similar to the envier, the aroused envy will be particularly intense, because it signals to the envier that it just as well could have been him or her who had the desired object.[2][3] Bertrand Russell said envy was one of the most potent causes of unhappiness.[4] It is a universal and most unfortunate aspect of human nature because not only does the envious person wish to inflict misfortune on others, but is also rendered unhappy by his envy. Although envy is generally seen as something negative, Russell(1930, p. 90-91)also believed that envy was a driving force behind the movement towards democracy and must be endured in order to achieve a more just social system. The tendency to feel envy seems to be present in all cultures [5][6]. # Envy and jealousy Envy and jealousy are distinct emotions. In its correct usage, jealousy is the fear of losing something that one possesses to another person (a loved one in the prototypical form), while envy is the pain or frustration caused by another person having something that one does not have oneself. Envy typically involves two people, and jealousy typically involves three people. Envy and jealousy result from different situations and are distinct emotional experiences. [7] # Envy in philosophy Aristotle (in Rhetoric) defined envy "as the pain caused by the good fortune of others", while Kant defined it as "a reluctance to see our own well-being overshadowed by another's because the standard we use to see how well off we are is not the intrinsic worth of our own well-being but how it compares with that of others" (in Metaphysics of Morals). # Envy in the arts In some cultures, envy is often associated with the color green, as in "green with envy". The phrase "green-eyed monster" refers to an individual whose current actions appear motivated by envy. This is based on a line from Shakespeare's Othello. Shakespeare mentions it also in The Merchant of Venice when Portia states: "How all the other passions fleet to air, as doubtful thoughts and rash embraced despair and shuddering fear and green-eyed jealousy!" Envy is known as one of the most powerful human emotions for its ability to control one as if envy was an entity in itself. Countless men and women have fallen prey to brief periods of intense envy followed by anger which then translates into aggression. One of the most common examples is a pair of lovers in which a secret love is discovered and can lead to sorrow, then intense envy, and eventually anger and aggression. # Envy in religion Envy was one of the Seven deadly sins of the Christian Church. The book of Exodus (20:17) states: "Thou shalt not covet thy neighbour’s house; neither shalt thou desire his wife, nor his servant, nor his handmaid, nor his ox, nor his ass, nor any thing that is his." Perhaps today the donkey (ass) corresponds to a car, but it could represent anything desirable owned by another. The donkey cannot be readily stolen as it would be obvious. However being envious of the donkey as a possession is to be avoided, as it could lead to ungodly thoughts or deeds toward the neighbour or the donkey. It's important to make the distinction between desiring something someone else has, and envying them because of something they have. Envy relates to negative feelings toward a person because of something they own.

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

c46e1fce9ac8414ea7c9a2110129301dc27a66c2

wikidoc

ErbB

ErbB # Overview The ErbB protein family or epidermal growth factor receptor (EGFR) family is a family of four structurally related receptor tyrosine kinases. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's Disease. In mice loss of signaling by any member of the ErbB family results in embryonic lethality with defects in organs including the lungs, skin, heart and brain. Excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor. ErbB-1 and ErbB-2 are found in many human cancers and their excessive signaling may be critical factors in the development and malignancy of these tumors. # Family members The ErbB protein family consists of 4 members - ErbB-1, also named epidermal growth factor receptor (EGFR) - ErbB-2, also named HER2 in humans and neu in rodents - ErbB-3, also named HER3 and - ErbB-4, also named HER4 # Structure ErbB receptors are made up of an extracellular region which contains approximately 620 amino acids, a single transmembrane spanning region and a cytoplasmic tyrosine kinase domain. The extracellular region of each family member is made up of four subdomains, L1, CR1, L2 and CR2, were "L" signifies a leucine-rich repeat domain and "CR" a cysteine-rich region. These subdomains are shown in blue (L1), green (CR1), yellow (L2) and red (CR2) in the figure below. These subdomains are also referred to as domains I-IV respectively. The figure below was created using the pdb files 1NQL (ErbB-1), 1S78 (ErbB-2), 1M6B (ErbB-3) and 2AHX (ErbB-4). # Kinase activation The four members of the ErbB protein family are capable of forming homodimers, heterodimers, and possibly higher order oligomers upon activation by a subset of potential growth factor ligands. There are 11 growth factors that activate ErbB receptors. The ability of each growth factor to activate each of the ErbB receptors is shown in the table below, + and - signifying ability and inability to activate each of the ErbB receptors respectively. # Role in cancer ErbB-1 is overexpressed in many cancers. Drugs such as cetuximab, gefitinib, erlotinib are used to inhibit it. It has recently been shown that acquired resistance to the two first can be linked to hyperactivity of ErbB-3. This is linked to an acquired overexpression of c-MET which phosphorylates ErbB-3, which in turn activates the Akt pathway.

ErbB # Overview The ErbB protein family or epidermal growth factor receptor (EGFR) family is a family of four structurally related receptor tyrosine kinases. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's Disease.[1] In mice loss of signaling by any member of the ErbB family results in embryonic lethality with defects in organs including the lungs, skin, heart and brain. Excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor. ErbB-1 and ErbB-2 are found in many human cancers and their excessive signaling may be critical factors in the development and malignancy of these tumors.[2] # Family members The ErbB protein family consists of 4 members - ErbB-1, also named epidermal growth factor receptor (EGFR) - ErbB-2, also named HER2 in humans and neu in rodents - ErbB-3, also named HER3 and - ErbB-4, also named HER4 # Structure ErbB receptors are made up of an extracellular region which contains approximately 620 amino acids, a single transmembrane spanning region and a cytoplasmic tyrosine kinase domain. The extracellular region of each family member is made up of four subdomains, L1, CR1, L2 and CR2, were "L" signifies a leucine-rich repeat domain and "CR" a cysteine-rich region. These subdomains are shown in blue (L1), green (CR1), yellow (L2) and red (CR2) in the figure below. These subdomains are also referred to as domains I-IV respectively.[3][4] The figure below was created using the pdb files 1NQL (ErbB-1), 1S78 (ErbB-2), 1M6B (ErbB-3) and 2AHX (ErbB-4).[5][6][2][7] # Kinase activation The four members of the ErbB protein family are capable of forming homodimers, heterodimers, and possibly higher order oligomers upon activation by a subset of potential growth factor ligands.[3] There are 11 growth factors that activate ErbB receptors. The ability of each growth factor to activate each of the ErbB receptors is shown in the table below, + and - signifying ability and inability to activate each of the ErbB receptors respectively.[8] . # Role in cancer ErbB-1 is overexpressed in many cancers. Drugs such as cetuximab, gefitinib, erlotinib are used to inhibit it. It has recently been shown that acquired resistance to the two first can be linked to hyperactivity of ErbB-3.[9] This is linked to an acquired overexpression of c-MET which phosphorylates ErbB-3, which in turn activates the Akt pathway.[10]

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

d177ac518c87a3dc21d02bc073de4d7feb0e8688

wikidoc

F13B

F13B Coagulation factor XIII B chain is a protein that in humans is encoded by the F13B gene. This gene encodes coagulation factor XIII B subunit. Coagulation factor XIII is the last zymogen to become activated in the blood coagulation cascade. Plasma factor XIII is a heterotetramer composed of 2 A subunits and 2 B subunits. The A subunits have catalytic function, and the B subunits do not have enzymatic activity and may serve as a plasma carrier molecules. Platelet factor XIII is composed of just 2 A subunits, which are identical to those of plasma origin. Upon activation by the cleavage of the activation peptide by thrombin and in the presence of calcium ion, the plasma factor XIII dissociates its B subunits and yields the same active enzyme, factor XIIIa, as platelet factor XIII. This enzyme acts as a transglutaminase to catalyze the formation of gamma-glutamyl-epsilon-lysine crosslinking between fibrin molecules, thus stabilizing the fibrin clot. Factor XIII deficiency is classified into two categories: type I deficiency, characterized by the lack of both the A and B subunits; and type II deficiency, characterized by the lack of the A subunit alone. These defects can result in a lifelong bleeding tendency, defective wound healing, and habitual abortion. # Interactions F13B has been shown to interact with Coagulation factor XIII, A1 polypeptide.

F13B Coagulation factor XIII B chain is a protein that in humans is encoded by the F13B gene.[1][2] This gene encodes coagulation factor XIII B subunit. Coagulation factor XIII is the last zymogen to become activated in the blood coagulation cascade. Plasma factor XIII is a heterotetramer composed of 2 A subunits and 2 B subunits. The A subunits have catalytic function, and the B subunits do not have enzymatic activity and may serve as a plasma carrier molecules. Platelet factor XIII is composed of just 2 A subunits, which are identical to those of plasma origin. Upon activation by the cleavage of the activation peptide by thrombin and in the presence of calcium ion, the plasma factor XIII dissociates its B subunits and yields the same active enzyme, factor XIIIa, as platelet factor XIII. This enzyme acts as a transglutaminase to catalyze the formation of gamma-glutamyl-epsilon-lysine crosslinking between fibrin molecules, thus stabilizing the fibrin clot. Factor XIII deficiency is classified into two categories: type I deficiency, characterized by the lack of both the A and B subunits; and type II deficiency, characterized by the lack of the A subunit alone. These defects can result in a lifelong bleeding tendency, defective wound healing, and habitual abortion.[3] # Interactions F13B has been shown to interact with Coagulation factor XIII, A1 polypeptide.[4][5]

https://www.wikidoc.org/index.php/F13B