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Mean

Mean In statistics, mean has two related meanings: - the arithmetic mean (and is distinguished from the geometric mean or harmonic mean). - the expected value of a random variable, which is also called the population mean. It is sometimes stated that the 'mean' means average. This is incorrect as there are different types of averages: the mean, median, and mode. For instance, average house prices almost always use the median value for the average. For a real-valued random variable X, the mean is the expectation of X. Note that not every probability distribution has a defined mean (or variance); see the Cauchy distribution for an example. For a data set, the mean is the sum of the observations divided by the number of observations. The mean is often quoted along with the standard deviation: the mean describes the central location of the data, and the standard deviation describes the spread. An alternative measure of dispersion is the mean deviation, equivalent to the average absolute deviation from the mean. It is less sensitive to outliers, but less mathematically tractable. As well as statistics, means are often used in geometry and analysis; a wide range of means have been developed for these purposes, which are not much used in statistics. These are listed below. # Examples of means ## Arithmetic mean The arithmetic mean is the "standard" average, often simply called the "mean". The mean may often be confused with the median or mode. The mean is the arithmetic average of a set of values, or distribution; however, for skewed distributions, the mean is not necessarily the same as the middle value (median), or the most likely (mode). For example, mean income is skewed upwards by a small number of people with very large incomes, so that the majority have an income lower than the mean. By contrast, the median income is the level at which half the population is below and half is above. The mode income is the most likely income, and favors the larger number of people with lower incomes. The median or mode are often more intuitive measures of such data. That said, many skewed distributions are best described by their mean - such as the Exponential and Poisson distributions. For example, the arithmetic mean of 34, 27, 45, 55, 22, 34 (six values) is (34+27+45+55+22+34)/6 = 217/6 ≈ 36.167. ## Geometric mean The geometric mean is an average that is useful for sets of numbers that are interpreted according to their product and not their sum (as is the case with the arithmetic mean). For example rates of growth. For example, the geometric mean of 34, 27, 45, 55, 22, 34 (six values) is (34×27×45×55×22×34)1/6 = 1,699,493,4001/6 ≈ 34.545. ## Harmonic mean The harmonic mean is an average which is useful for sets of numbers which are defined in relation to some unit, for example speed (distance per unit of time). For example, the harmonic mean of the numbers 34, 27, 45, 55, 22, and 34 is ## Generalized means ### Power mean The generalized mean, also known as the power mean or Hölder mean, is an abstraction of the quadratic, arithmetic, geometric and harmonic means. It is defined by By choosing the appropriate value for the parameter m we get - m\rightarrow\infty - maximum, - m=2 - quadratic mean, - m=1 - arithmetic mean, - m\rightarrow0 - geometric mean, - m=-1 - harmonic mean, - m\rightarrow-\infty - minimum. ### f-mean This can be generalized further as the generalized f-mean and again a suitable choice of an invertible f will give - f(x) = x - arithmetic mean, - f(x) = \frac{1}{x} - harmonic mean, - f(x) = x^m - power mean, - f(x) = \ln x - geometric mean. ## Weighted arithmetic mean The weighted arithmetic mean is used, if one wants to combine average values from samples of the same population with different sample sizes: The weights w_i represent the bounds of the partial sample. In other applications they represent a measure for the reliability of the influence upon the mean by respective values. ## Truncated mean Sometimes a set of numbers (the data) might be contaminated by inaccurate outliers, i.e. values which are much too low or much too high. In this case one can use a truncated mean. It involves discarding given parts of the data at the top or the bottom end, typically an equal amount at each end, and then taking the arithmetic mean of the remaining data. The number of values removed is indicated as a percentage of total number of values. ## Interquartile mean The interquartile mean is a specific example of a truncated mean. It is simply the arithmetic mean after removing the lowest and the highest quarter of values. assuming the values have been ordered. ## Mean of a function In calculus, and especially multivariable calculus, the mean of a function is loosely defined as the average value of the function over its domain. In one variable, the mean of a function f(x) over the interval (a,b) is defined by (See also mean value theorem.) In several variables, the mean over a relatively compact domain U in a Euclidean space is defined by This generalizes the arithmetic mean. On the other hand, it is also possible to generalize the geometric mean to functions by defining the geometric mean of f to be More generally, in measure theory and probability theory either sort of mean plays an important role. In this context, Jensen's inequality places sharp estimates on the relationship between these two different notions of the mean of a function. ## Mean of angles Most of the usual means fail on circular quantities, like angles, daytimes, fractional parts of real numbers. For those quantities you need a mean of circular quantities. ## Other means - Arithmetic-geometric mean - Arithmetic-harmonic mean - Cesàro mean - Chisini mean - Contraharmonic mean - Elementary symmetric mean - Geometric-harmonic mean - Heinz mean - Heronian mean - Identric mean - Least squares mean - Lehmer mean - Logarithmic mean - Median - Root mean square - Stolarsky mean - Weighted geometric mean - Weighted harmonic mean - Rényi's entropy (a generalized f-mean) # Properties Except some examples there seems to be no consensus, what a mean actually is. However many means share some properties, that we collect here as a trial of defining the term mean. ## Weighted mean A weighted mean M is a function which maps tuples of positive numbers to a positive number (\mathbb{R}_{>0}^n\to\mathbb{R}_{>0}). - "Fixed point": M(1,1,\dots,1) = 1 - Homogenity: \forall\lambda\ \forall x\ M(\lambda\cdot x_1, \dots, \lambda\cdot x_n) = \lambda \cdot M(x_1, \dots, x_n) - Monotony: \forall x\ \forall y\ (\forall i\ x_i \le y_i) \Rightarrow M x \le M y It follows - Boundedness: \forall x\ M x \in - Continuity: \lim_{x\to y} M x = M y - There are means, which are not differentiable. For instance, the maximum number of a tuple is considered a mean (as an extreme case of the power mean, or as a special case of a median), but is not differentiable. - All means listed above, with the exception of most of the Generalized f-means, satisfy the presented properties. If f is bijective, then the generalized f-mean satisfies the fixed point property. If f is strictly monotonic, then the generalized f-mean satisfy also the monotony property. In general a generalized f-mean will miss homogenity. - If f is bijective, then the generalized f-mean satisfies the fixed point property. - If f is strictly monotonic, then the generalized f-mean satisfy also the monotony property. - In general a generalized f-mean will miss homogenity. The above properties imply techniques to construct more complex means: If C, M_1, \dots, M_m are weighted means, p is a positive real number, then A, B with are also a weighted mean. ## Unweighted mean Intuitively spoken, an unweighted mean is a weighted mean with equal weights. Since our definition of weighted mean above does not expose particular weights, equal weights must be asserted by a different way. A different view on homogeneous weighting is, that the inputs can be swapped without altering the result. Thus we define M being an unweighted mean if it is a weighted mean and for each permutation \pi of inputs, the result is the same. Let P be the set of permutations of n-tuples. Analogously to the weighted means, if C is a weighted mean and M_1, \dots, M_m are unweighted means, p is a positive real number, then A, B with are also unweighted means. ## Convert unweighted mean to weighted mean An unweighted mean can be turned into a weighted mean by repeating elements. This connection can also be used to state that a mean is the weighted version of an unweighted mean. Say you have the unweighted mean M and weight the numbers by natural numbers a_1,\dots,a_n. (If the numbers are rational, then multiply them with the least common denominator.) Then the corresponding weighted mean A is obtained by ## Means of tuples of different sizes If a mean M is defined for tuples of several sizes, then one also expects that the mean of a tuple is bounded by the means of partitions. More precisely - Given an arbitrary tuple x, which is partitioned into y_1, \dots, y_k, then it holds M x \in \mathrm{convexhull}(M y_1, \dots, M y_k). (See Convex hull) # Population and sample means The mean of a normally distributed population has an expected value of μ, known as the population mean. The sample mean makes a good estimator of the population mean, as its expected value is the same as the population mean. The sample mean of a population is a random variable, not a constant, and consequently it will have its own distribution. For a random sample of n observations from a normally distributed population, the sample mean distribution is Often, since the population variance is an unknown parameter, it is estimated by the mean sum of squares, which changes the distribution of the sample mean from a normal distribution to a Student's t distribution with n − 1 degrees of freedom. # Mathematics education In many state and government curriculum standards, students are traditionally expected to learn either the meaning or formula for computing the mean by the fourth grade. However, in many standards-based mathematics curricula, students are encouraged to invent their own methods, and may not be taught the traditional method. Reform based texts such as TERC in fact discourage teaching the traditional "add the numbers and divide by the number of items" method in favor of spending more time on the concept of median, which does not require division. However, mean can be computed with a simple four-function calculator, while median requires a computer. The same teacher guide devotes several pages on how to find the median of a set, which is judged to be simpler than finding the mean.

Mean Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] In statistics, mean has two related meanings: - the arithmetic mean (and is distinguished from the geometric mean or harmonic mean). - the expected value of a random variable, which is also called the population mean. It is sometimes stated that the 'mean' means average. This is incorrect as there are different types of averages: the mean, median, and mode. For instance, average house prices almost always use the median value for the average. For a real-valued random variable X, the mean is the expectation of X. Note that not every probability distribution has a defined mean (or variance); see the Cauchy distribution for an example. For a data set, the mean is the sum of the observations divided by the number of observations. The mean is often quoted along with the standard deviation: the mean describes the central location of the data, and the standard deviation describes the spread. An alternative measure of dispersion is the mean deviation, equivalent to the average absolute deviation from the mean. It is less sensitive to outliers, but less mathematically tractable. As well as statistics, means are often used in geometry and analysis; a wide range of means have been developed for these purposes, which are not much used in statistics. These are listed below. # Examples of means ## Arithmetic mean The arithmetic mean is the "standard" average, often simply called the "mean". The mean may often be confused with the median or mode. The mean is the arithmetic average of a set of values, or distribution; however, for skewed distributions, the mean is not necessarily the same as the middle value (median), or the most likely (mode). For example, mean income is skewed upwards by a small number of people with very large incomes, so that the majority have an income lower than the mean. By contrast, the median income is the level at which half the population is below and half is above. The mode income is the most likely income, and favors the larger number of people with lower incomes. The median or mode are often more intuitive measures of such data. That said, many skewed distributions are best described by their mean - such as the Exponential and Poisson distributions. For example, the arithmetic mean of 34, 27, 45, 55, 22, 34 (six values) is (34+27+45+55+22+34)/6 = 217/6 ≈ 36.167. ## Geometric mean The geometric mean is an average that is useful for sets of numbers that are interpreted according to their product and not their sum (as is the case with the arithmetic mean). For example rates of growth. For example, the geometric mean of 34, 27, 45, 55, 22, 34 (six values) is (34×27×45×55×22×34)1/6 = 1,699,493,4001/6 ≈ 34.545. ## Harmonic mean The harmonic mean is an average which is useful for sets of numbers which are defined in relation to some unit, for example speed (distance per unit of time). For example, the harmonic mean of the numbers 34, 27, 45, 55, 22, and 34 is ## Generalized means ### Power mean The generalized mean, also known as the power mean or Hölder mean, is an abstraction of the quadratic, arithmetic, geometric and harmonic means. It is defined by By choosing the appropriate value for the parameter m we get - <math>m\rightarrow\infty</math> - maximum, - <math>m=2</math> - quadratic mean, - <math>m=1</math> - arithmetic mean, - <math>m\rightarrow0</math> - geometric mean, - <math>m=-1</math> - harmonic mean, - <math>m\rightarrow-\infty</math> - minimum. ### f-mean This can be generalized further as the generalized f-mean and again a suitable choice of an invertible <math>f</math> will give - <math>f(x) = x</math> - arithmetic mean, - <math>f(x) = \frac{1}{x}</math> - harmonic mean, - <math>f(x) = x^m</math> - power mean, - <math>f(x) = \ln x</math> - geometric mean. ## Weighted arithmetic mean The weighted arithmetic mean is used, if one wants to combine average values from samples of the same population with different sample sizes: The weights <math>w_i</math> represent the bounds of the partial sample. In other applications they represent a measure for the reliability of the influence upon the mean by respective values. ## Truncated mean Sometimes a set of numbers (the data) might be contaminated by inaccurate outliers, i.e. values which are much too low or much too high. In this case one can use a truncated mean. It involves discarding given parts of the data at the top or the bottom end, typically an equal amount at each end, and then taking the arithmetic mean of the remaining data. The number of values removed is indicated as a percentage of total number of values. ## Interquartile mean The interquartile mean is a specific example of a truncated mean. It is simply the arithmetic mean after removing the lowest and the highest quarter of values. assuming the values have been ordered. ## Mean of a function In calculus, and especially multivariable calculus, the mean of a function is loosely defined as the average value of the function over its domain. In one variable, the mean of a function f(x) over the interval (a,b) is defined by (See also mean value theorem.) In several variables, the mean over a relatively compact domain U in a Euclidean space is defined by This generalizes the arithmetic mean. On the other hand, it is also possible to generalize the geometric mean to functions by defining the geometric mean of f to be More generally, in measure theory and probability theory either sort of mean plays an important role. In this context, Jensen's inequality places sharp estimates on the relationship between these two different notions of the mean of a function. ## Mean of angles Most of the usual means fail on circular quantities, like angles, daytimes, fractional parts of real numbers. For those quantities you need a mean of circular quantities. ## Other means - Arithmetic-geometric mean - Arithmetic-harmonic mean - Cesàro mean - Chisini mean - Contraharmonic mean - Elementary symmetric mean - Geometric-harmonic mean - Heinz mean - Heronian mean - Identric mean - Least squares mean - Lehmer mean - Logarithmic mean - Median - Root mean square - Stolarsky mean - Weighted geometric mean - Weighted harmonic mean - Rényi's entropy (a generalized f-mean) # Properties Except some examples there seems to be no consensus, what a mean actually is. However many means share some properties, that we collect here as a trial of defining the term mean. ## Weighted mean A weighted mean <math>M</math> is a function which maps tuples of positive numbers to a positive number (<math>\mathbb{R}_{>0}^n\to\mathbb{R}_{>0}</math>). - "Fixed point": <math> M(1,1,\dots,1) = 1 </math> - Homogenity: <math> \forall\lambda\ \forall x\ M(\lambda\cdot x_1, \dots, \lambda\cdot x_n) = \lambda \cdot M(x_1, \dots, x_n) </math> - Monotony: <math> \forall x\ \forall y\ (\forall i\ x_i \le y_i) \Rightarrow M x \le M y </math> It follows - Boundedness: <math> \forall x\ M x \in [\min x, \max x] </math> - Continuity: <math> \lim_{x\to y} M x = M y </math> - There are means, which are not differentiable. For instance, the maximum number of a tuple is considered a mean (as an extreme case of the power mean, or as a special case of a median), but is not differentiable. - All means listed above, with the exception of most of the Generalized f-means, satisfy the presented properties. If <math>f</math> is bijective, then the generalized f-mean satisfies the fixed point property. If <math>f</math> is strictly monotonic, then the generalized f-mean satisfy also the monotony property. In general a generalized f-mean will miss homogenity. - If <math>f</math> is bijective, then the generalized f-mean satisfies the fixed point property. - If <math>f</math> is strictly monotonic, then the generalized f-mean satisfy also the monotony property. - In general a generalized f-mean will miss homogenity. The above properties imply techniques to construct more complex means: If <math>C, M_1, \dots, M_m</math> are weighted means, <math>p</math> is a positive real number, then <math>A, B</math> with are also a weighted mean. ## Unweighted mean Intuitively spoken, an unweighted mean is a weighted mean with equal weights. Since our definition of weighted mean above does not expose particular weights, equal weights must be asserted by a different way. A different view on homogeneous weighting is, that the inputs can be swapped without altering the result. Thus we define <math>M</math> being an unweighted mean if it is a weighted mean and for each permutation <math>\pi</math> of inputs, the result is the same. Let <math>P</math> be the set of permutations of <math>n</math>-tuples. Analogously to the weighted means, if <math>C</math> is a weighted mean and <math>M_1, \dots, M_m</math> are unweighted means, <math>p</math> is a positive real number, then <math>A, B</math> with are also unweighted means. ## Convert unweighted mean to weighted mean An unweighted mean can be turned into a weighted mean by repeating elements. This connection can also be used to state that a mean is the weighted version of an unweighted mean. Say you have the unweighted mean <math>M</math> and weight the numbers by natural numbers <math>a_1,\dots,a_n</math>. (If the numbers are rational, then multiply them with the least common denominator.) Then the corresponding weighted mean <math>A</math> is obtained by ## Means of tuples of different sizes If a mean <math>M</math> is defined for tuples of several sizes, then one also expects that the mean of a tuple is bounded by the means of partitions. More precisely - Given an arbitrary tuple <math>x</math>, which is partitioned into <math>y_1, \dots, y_k</math>, then it holds <math>M x \in \mathrm{convexhull}(M y_1, \dots, M y_k)</math>. (See Convex hull) # Population and sample means The mean of a normally distributed population has an expected value of μ, known as the population mean. The sample mean makes a good estimator of the population mean, as its expected value is the same as the population mean. The sample mean of a population is a random variable, not a constant, and consequently it will have its own distribution. For a random sample of n observations from a normally distributed population, the sample mean distribution is Often, since the population variance is an unknown parameter, it is estimated by the mean sum of squares, which changes the distribution of the sample mean from a normal distribution to a Student's t distribution with n − 1 degrees of freedom. # Mathematics education In many state and government curriculum standards, students are traditionally expected to learn either the meaning or formula for computing the mean by the fourth grade. However, in many standards-based mathematics curricula, students are encouraged to invent their own methods, and may not be taught the traditional method. Reform based texts such as TERC in fact discourage teaching the traditional "add the numbers and divide by the number of items" method in favor of spending more time on the concept of median, which does not require division. However, mean can be computed with a simple four-function calculator, while median requires a computer. The same teacher guide devotes several pages on how to find the median of a set, which is judged to be simpler than finding the mean.

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Mesh

Mesh Mesh products are similar to fabric or a web in that it has many connected or woven strands. In clothing, a mesh is often defined as a loosely woven fabric that has a large number of closely-spaced holes, frequently used for modern sports jerseys and other clothing. # Types of mesh - A plastic mesh is extruded, oriented, expanded or tubular Plastic mesh can be made from polypropylene, polyethylene, nylon, PVC or PTFE. - A metal mesh can be woven, welded, expanded, photo-chemically etched or electroformed (screen filter) from steel or other metals. # Uses of meshes - Meshes are often used to screen out unwanted things, such as insects. Wire screens on windows and mosquito netting can be considered as types of meshes. - Wire screens can be used to shield against radio frequency radiation, e.g. in microwave ovens and Faraday cages. - On a larger scale, in terms of the spaces in between, chicken wire and chain-link fences can also be considered a type of mesh. - Metal and nylon wire mesh filters are used in water filtration. - Wire Mesh is used in guarding for secure areas and as protection in the form of Vandal Screens. - Wire Mesh can be fabricated to produce Park Benches, Waste Baskets and other baskets for Material Handling. - Wire Mesh is the separation media in Vibratory Screening Units.

Mesh Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Mesh products are similar to fabric or a web in that it has many connected or woven strands. In clothing, a mesh is often defined as a loosely woven fabric that has a large number of closely-spaced holes, frequently used for modern sports jerseys and other clothing. # Types of mesh - A plastic mesh is extruded, oriented, expanded or tubular Plastic mesh can be made from polypropylene, polyethylene, nylon, PVC or PTFE. - A metal mesh can be woven, welded, expanded, photo-chemically etched or electroformed (screen filter) from steel or other metals. # Uses of meshes - Meshes are often used to screen out unwanted things, such as insects. Wire screens on windows and mosquito netting can be considered as types of meshes. - Wire screens can be used to shield against radio frequency radiation, e.g. in microwave ovens and Faraday cages. - On a larger scale, in terms of the spaces in between, chicken wire and chain-link fences can also be considered a type of mesh. - Metal and nylon wire mesh filters are used in water filtration. - Wire Mesh is used in guarding for secure areas and as protection in the form of Vandal Screens. - Wire Mesh can be fabricated to produce Park Benches, Waste Baskets and other baskets for Material Handling. - Wire Mesh is the separation media in Vibratory Screening Units.

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Mile

Mile A mile is a unit of length, usually used to measure distance, in a number of different systems, including Imperial units, United States customary units and Norwegian/Swedish mil. Its size can vary from system to system, but in each is between one and ten kilometers. In contemporary English contexts, mile most commonly refers to the international mile of 5,280 feet, 1,760 yards, or exactly 1,609.344 meters. However it can also refer to either of the following for specific uses: - the U.S. survey mile (also known as U.S. statute mile) of 5,280 survey feet which is slightly longer at approximately 1,609.347 219 meters (1 international mile is exactly 0.999 998 survey mile). - the international nautical mile of exactly 1,852 meters (about 6,076 feet). There have been several abbreviations for mile (with and without trailing period): mi, ml, m, M. In the United States, the National Institute of Standards and Technology now uses and recommends mi but in everyday usage (at least in the United States and in the United Kingdom) usages such as miles per hour and miles per gallon are almost always abbreviated as mph or mpg (rather than mi/h or mi/gal). The formula "multiply by 8 and divide by 5" to convert international miles to kilometers gives a conversion of 1.6, accurate to 0.6%, which is a useful approximation. # Historical definitions The unit of distance mille passus (literally "a thousand paces" in Latin, with one pace being equal to two steps) was first used by the Romans and denoted a distance of 1,000 paces or 5,000 Roman feet, and corresponded to about 1,480 meters, or 1,618 modern yards. This unit is now known as the Roman mile. The current definition of a mile as 5,280 feet (as opposed to 5,000) dates to the 13th century, and was confirmed by statute in the reign of Queen Elizabeth I; However, various English-speaking countries maintained independent length standards for the yard, which differed by small but measurable amounts, and thus led to miles of slightly different lengths. This was resolved in 1959 with the definition of the current international mile by Australia, Canada, New Zealand, South Africa, the United Kingdom, and the United States. # Types of mile In modern usage, various distances are referred to as miles. ## International and statute miles The international mile (and before 1959, the statute mile) is the distance typically meant when the word mile is used without other qualifying words (e.g. nautical mile, see below). The international and statute miles are both equal to 5,280 feet, but the international mile is defined in terms of the international foot (0.3048 m), while the statute miles of the various English-speaking countries were based on the national foot of each country. The (mostly obsolete) U.S. statute mile is based on the U.S. survey foot (which is exactly 1200/3937 m) and differs from the international mile by about 3 mm. The name statute mile originates from a Statute of the Parliament of England in 1592 during the reign of Elizabeth I. This defined the statute mile as 5,280 ft or 1,760 yards; or 63,360 inches. Both statute and international miles are divided into eight furlongs (the length generally that a furrow was ploughed before the horses were turned, furlong = furrow-long). In turn a furlong is ten chains (a surveyor's chain, used as such until laser range finders took over); a chain is 22 yards and a yard is three feet, making up 5,280 ft. ## Other miles in the British Isles Before the statute of the English parliament, there was confusion on the length of the "mile". The Irish mile was 6,721 feet and the Scottish mile was 5,951 feet. Perhaps the earliest tables of English linear measures, Arnold's Customs of London (c. 1500) indicates a mile consisted of 8 furlongs, each of 625 feet, for a total of 5,000 feet. For other "miles" see the list below. ## Nautical miles The nautical mile was originally defined as one minute of arc along a meridian (or in some instances any great circle) of the Earth. Although this distance varies depending on the latitude of the meridian (or great circle) where it is used, on average it is about 6,076 feet (about 1852 meters or 1.15 statute miles). The nautical mile per hour is known as the knot. Navigators use dividers to step off the distance between two points on the nautical chart, then place the open dividers against the minutes-of-latitude scale at the edge of the nautical chart, and read off the distance in nautical miles. Since it is now known that the Earth is an ellipsoid (oblate spheroid), not a sphere, the distance of nautical miles derived from this method varies from the equator to the poles. For instance, using the WGS84 Ellipsoid, the commonly accepted Earth model for many purposes today, one minute of latitude at the WGS84 equator is 6,087 feet and at the poles is 6,067 feet. In the United States of America, the nautical mile was defined in the nineteenth century as 6,080.2 feet (1,853.249 m), whereas in the United Kingdom the Admiralty nautical mile was defined as 6,080 feet (1,853.184 m) and was approximately one minute of latitude in the latitudes of the south of the UK. Other nations had different definitions of the nautical mile, but it is now internationally defined to be exactly 1,852 meters. The nautical mile is almost universally used for navigation in aviation, maritime, and nautical roles because of its relationship with degrees and minutes of latitude and the ability to use the latitude scale of a map for distance measuring. # Other miles - The Danish mil (traditional) was 24,000 Danish feet or 7.5325 kilometers. Sometimes it was interpreted as exactly 7.5 kilometers. It is the same as the north German meile (below). - The data mile is used in radar-related subjects and is equal to 6,000 feet (1.8288 kilometers). - The Meile was a traditional unit in German speaking countries, much longer than a western European mile. It was 24,000 German feet; the SI equivalent was 7586 meters in Austria or 7532.5 meters in northern Germany. There was a version known as the geographische Meile which was 4 Admiralty nautical miles, 7,412.7 meters, or 1/15 degree. - The term metric mile is used in sports such as athletics (track and field) and speed skating to denote a distance of 1.5 kilometers. In United States high school competition the term is sometimes used for a race of 1.6 kilometers. - In Norway and Sweden a mil is measurement unit much more used than kilometers in every day language. However in more formal situations, like on road signs and when there is risk of confusion with English miles, kilometers are used instead. The traditional Swedish mil spanned the range from 6000-14,485 meters, depending on province. It was however standardized in 1649 to 36,000 Swedish feet, or 10.687 kilometers. The Norwegian mil was 11.298 kilometers. When the metric system was introduced in the Norwegian-Swedish union in 1889, one standardized the mil to exactly 10 kilometers - The radar mile is a unit of time, equal to the time required for a radar pulse to travel a distance of two miles (one mile each way). Thus, the radar statute mile is 10.8 μs and the radar nautical mile is 12.4 μs. - The Russian milya (русская миля) was a traditional Russian unit of distance, equal to 7 verst, or 7.468 km - The hrvatska milja (Croatian mile) is 11130 metres = 11,13 kilometres = 1/10 of equator's degree., first time used by Jesuit Stjepan Glavač on map from 1673. - The banska milja" (also called "hrvatska milja") (mile of Croatian Ban, Croatian mile) was 7586 metres=7,586 kilometres, or 24000 feet.. # Idioms Even in countries that have moved from the Imperial to the Metric system (for example, Australia and New Zealand), the mile is still used in a variety of idioms. These include: - A country mile is used colloquially to denote a very long distance. - "A miss is as good as a mile" (Failure by a narrow margin is no better than any other failure) - "Give him an inch and he'll take a mile" (The person in question will become greedy if shown generosity) - "Missed by a mile" (Missed by a wide margin) - "Talk a mile a minute" (Speak at a rapid rate) - "To go the extra mile" (To put in extra effort) - "Miles away" (Lost in thought, or daydreaming)

Mile Template:Unit of length A mile is a unit of length, usually used to measure distance, in a number of different systems, including Imperial units, United States customary units and Norwegian/Swedish mil. Its size can vary from system to system, but in each is between one and ten kilometers. In contemporary English contexts, mile most commonly refers to the international mile of 5,280 feet, 1,760 yards, or exactly 1,609.344 meters. However it can also refer to either of the following for specific uses: - the U.S. survey mile (also known as U.S. statute mile) of 5,280 survey feet which is slightly longer at approximately 1,609.347 219 meters (1 international mile is exactly 0.999 998 survey mile).[1][2] - the international nautical mile of exactly 1,852 meters (about 6,076 feet). There have been several abbreviations for mile (with and without trailing period): mi, ml, m, M. In the United States, the National Institute of Standards and Technology now uses and recommends mi[3] but in everyday usage (at least in the United States and in the United Kingdom) usages such as miles per hour and miles per gallon are almost always abbreviated as mph or mpg (rather than mi/h or mi/gal). The formula "multiply by 8 and divide by 5" to convert international miles to kilometers gives a conversion of 1.6, accurate to 0.6%, which is a useful approximation. # Historical definitions The unit of distance mille passus (literally "a thousand paces" in Latin, with one pace being equal to two steps) was first used by the Romans and denoted a distance of 1,000 paces or 5,000 Roman feet, and corresponded to about 1,480 meters, or 1,618 modern yards. This unit is now known as the Roman mile.[4] The current definition of a mile as 5,280 feet (as opposed to 5,000) dates to the 13th century, and was confirmed by statute in the reign of Queen Elizabeth I;[5] However, various English-speaking countries maintained independent length standards for the yard, which differed by small but measurable amounts, and thus led to miles of slightly different lengths. This was resolved in 1959 with the definition of the current international mile by Australia, Canada, New Zealand, South Africa, the United Kingdom, and the United States.[6] # Types of mile In modern usage, various distances are referred to as miles. ## International and statute miles The international mile (and before 1959, the statute mile) is the distance typically meant when the word mile is used without other qualifying words (e.g. nautical mile, see below). The international and statute miles are both equal to 5,280 feet, but the international mile is defined in terms of the international foot (0.3048 m), while the statute miles of the various English-speaking countries were based on the national foot of each country. The (mostly obsolete) U.S. statute mile is based on the U.S. survey foot (which is exactly 1200/3937 m) and differs from the international mile by about 3 mm. [7] The name statute mile originates from a Statute of the Parliament of England in 1592 during the reign of Elizabeth I. This defined the statute mile as 5,280 ft or 1,760 yards; or 63,360 inches. Both statute and international miles are divided into eight furlongs (the length generally that a furrow was ploughed before the horses were turned, furlong = furrow-long). In turn a furlong is ten chains (a surveyor's chain, used as such until laser range finders took over); a chain is 22 yards and a yard is three feet, making up 5,280 ft. ## Other miles in the British Isles Before the statute of the English parliament, there was confusion on the length of the "mile". The Irish mile was 6,721 feet and the Scottish mile was 5,951 feet.[8] Perhaps the earliest tables of English linear measures, Arnold's Customs of London (c. 1500) indicates a mile consisted of 8 furlongs, each of 625 feet, for a total of 5,000 feet.[9] For other "miles" see the list below. ## Nautical miles The nautical mile was originally defined as one minute of arc along a meridian (or in some instances any great circle) of the Earth.[10] Although this distance varies depending on the latitude of the meridian (or great circle) where it is used, on average it is about 6,076 feet (about 1852 meters or 1.15 statute miles). The nautical mile per hour is known as the knot. Navigators use dividers to step off the distance between two points on the nautical chart, then place the open dividers against the minutes-of-latitude scale at the edge of the nautical chart, and read off the distance in nautical miles.[11] Since it is now known that the Earth is an ellipsoid (oblate spheroid), not a sphere, the distance of nautical miles derived from this method varies from the equator to the poles. For instance, using the WGS84 Ellipsoid, the commonly accepted Earth model for many purposes today, one minute of latitude at the WGS84 equator is 6,087 feet and at the poles is 6,067 feet. In the United States of America, the nautical mile was defined in the nineteenth century as 6,080.2 feet (1,853.249 m), whereas in the United Kingdom the Admiralty nautical mile was defined as 6,080 feet (1,853.184 m) and was approximately one minute of latitude in the latitudes of the south of the UK. Other nations had different definitions of the nautical mile, but it is now internationally defined to be exactly 1,852 meters. The nautical mile is almost universally used for navigation in aviation, maritime, and nautical roles because of its relationship with degrees and minutes of latitude and the ability to use the latitude scale of a map for distance measuring. # Other miles - The Danish mil (traditional) was 24,000 Danish feet or 7.5325 kilometers. Sometimes it was interpreted as exactly 7.5 kilometers. It is the same as the north German meile (below).[12] - The data mile is used in radar-related subjects and is equal to 6,000 feet (1.8288 kilometers).[13] - The Meile was a traditional unit in German speaking countries, much longer than a western European mile. It was 24,000 German feet; the SI equivalent was 7586 meters in Austria or 7532.5 meters in northern Germany. There was a version known as the geographische Meile which was 4 Admiralty nautical miles, 7,412.7 meters, or 1/15 degree.[14] - The term metric mile is used in sports such as athletics (track and field) and speed skating to denote a distance of 1.5 kilometers. In United States high school competition the term is sometimes used for a race of 1.6 kilometers.[15] - In Norway and Sweden a mil is measurement unit much more used than kilometers in every day language.[citation needed] However in more formal situations, like on road signs and when there is risk of confusion with English miles, kilometers are used instead. The traditional Swedish mil spanned the range from 6000-14,485 meters, depending on province. It was however standardized in 1649 to 36,000 Swedish feet, or 10.687 kilometers[16]. The Norwegian mil was 11.298 kilometers. When the metric system was introduced in the Norwegian-Swedish union in 1889, one standardized the mil to exactly 10 kilometers [17] - The radar mile is a unit of time, equal to the time required for a radar pulse to travel a distance of two miles (one mile each way). Thus, the radar statute mile is 10.8 μs and the radar nautical mile is 12.4 μs.[18] - The Russian milya (русская миля) was a traditional Russian unit of distance, equal to 7 verst, or 7.468 km - The hrvatska milja (Croatian mile) is 11130 metres = 11,13 kilometres = 1/10 of equator's degree.[19], first time used by Jesuit Stjepan Glavač on map from 1673. - The banska milja" (also called "hrvatska milja") (mile of Croatian Ban, Croatian mile) was 7586 metres=7,586 kilometres, or 24000 feet.[20]. # Idioms Even in countries that have moved from the Imperial to the Metric system (for example, Australia and New Zealand), the mile is still used in a variety of idioms. These include: - A country mile is used colloquially to denote a very long distance. - "A miss is as good as a mile" (Failure by a narrow margin is no better than any other failure) - "Give him an inch and he'll take a mile" (The person in question will become greedy if shown generosity) - "Missed by a mile" (Missed by a wide margin) - "Talk a mile a minute" (Speak at a rapid rate) - "To go the extra mile" (To put in extra effort) - "Miles away" (Lost in thought, or daydreaming)

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Milk

Milk # Overview Milk is an opaque white liquid produced by the mammary glands of female mammals (including monotremes). Mammary glands are highly specialized sweat glands. The female ability to produce milk is one of the defining characteristics of mammals. It provides the primary source of nutrition for newborns before they are able to digest other types of food. The early lactation milk is known as colostrum, and carries the mother's antibodies to the baby. It can reduce the risk of many diseases in the baby. Males of all mammal species retain the breasts that are part of the fundamental mammalian animal structure, hence their nipples. Lactation occurs in males in certain rare circumstances, both naturally and artificially, however, some pharmaceuticals precipitate lactation in males readily. The exact components of raw milk varies by species, but it contains significant amounts of saturated fat, protein and calcium as well as vitamin C. # Physical and chemical structure Milk is an emulsion of butterfat globules within a water-based fluid. Each fat globule is surrounded by a membrane consisting of phospholipids and proteins; these emulsifiers keep the individual globules from joining together into noticeable grains of butterfat and also protect the globules from the fat-digesting activity of enzymes found in the fluid portion of the milk. In unhomogenized cow's milk, the fat globules average about four micrometers across. The fat-soluble vitamins A, D, E, and K are found within the milkfat portion of the milk (McGee 18). The largest structures in the fluid portion of the milk are casein protein micelles: aggregates of several thousand protein molecules, bonded with the help of nanometer-scale particles of calcium phosphate. Each micelle is roughly spherical and about a tenth of a micrometer across. There are four different types of casein proteins, and collectively they make up around 80 percent of the protein in milk, by weight. Most of the casein proteins are bound into the micelles. There are several competing theories regarding the precise structure of the micelles, but they share one important feature: the outermost layer consists of strands of one type of protein, kappa-casein, reaching out from the body of the micelle into the surrounding fluid. These Kappa-casein molecules all have a negative electrical charge and therefore repel each other, keeping the micelles separated under normal conditions and in a stable colloidal suspension in the water-based surrounding fluid (McGee 19–20). Both the fat globules and the smaller casein micelles, which are just large enough to deflect light, contribute to the opaque white color of milk. The fat globules contain some yellow-orange carotene, enough in some breeds — Guernsey and Jersey cows, for instance — to impart a golden or "creamy" hue to a glass of milk. The riboflavin in the whey portion of milk has a greenish color, which can sometimes be discerned in skim milk or whey products (McGee 17). Fat-free skim milk has only the casein micelles to scatter light, and they tend to scatter shorter-wavelength blue light more than they do red, giving skim milk a bluish tint. Milk contains dozens of other types of proteins besides the caseins. They are more water-soluble than the caseins and do not form larger structures. Because these proteins remain suspended in the whey left behind when the caseins coagulate into curds, they are collectively known as whey proteins. Whey proteins make up around twenty percent of the protein in milk, by weight. Lactoglobulin is the most common whey protein by a large margin (McGee 20–21). The carbohydrate lactose gives milk its sweet taste and contributes about 40% of whole cow milk's calories. Lactose is a composite of two simple sugars, glucose and galactose. In nature, lactose is found only in milk and a small number of plants (McGee 17). Other components found in raw cow milk are living white blood cells. Mammary-gland cells, various bacteria, and a large number of active enzymes are some other components in milk (McGee 16). # Nutrition and health The composition of milk differs widely between species. Factors such as the type of protein; the proportion of protein, fat, and sugar; the levels of various vitamins and minerals; and the size of the butterfat globules and the strength of the curd are among those than can vary. For example: - Human milk contains, on average, 1.1% protein, 4.2% fat, 7.0% lactose (a sugar), and supplies 72 kcal of energy per 100 grams. - Cow's milk contains, on average, 3.4% protein, 3.6% fat, and 4.6% lactose, and supplies 66 kcal of energy per 100 grams. See also Nutritional benefits further on. Aquatic mammals, such as seals and whales, produce milk that is very rich in fats and other solid nutrients when compared with land mammals' milk. ## Nutritional benefits Processed milk began containing differing amounts of fat during the 1950s. A serving (1 cup or 250 ml) of 2%-fat milk contains 285 mg of calcium, which represents 22% to 29% of the daily recommended intake (DRI) of calcium for an adult. Depending on the age, 8 grams of protein, and a number of other nutrients (either naturally or through fortification): - Vitamins D and K are essential for bone health. - Iodine is a mineral essential for thyroid function. - Vitamin B12 and riboflavin are necessary for cardiovascular health and energy production, and B12 is difficult to get outside of animal products or else as supplemental pills. - Biotin and pantothenic acid are B vitamins important for energy production. - Vitamin A is critical for immune function. - Potassium and magnesium are for cardiovascular health. - Selenium is a cancer-preventive trace mineral. - Thiamine is a B-vitamin important for cognitive function, especially memory - Conjugated linoleic acid is a beneficial fatty acid that inhibits several types of cancer in mice, it has been shown to kill human skin cancer, colorectal cancer and breast cancer cells in vitro studies, and may help lower cholesterol and prevent atherosclerosis; only available in milk from grass-fed cows. Studies show possible links between low-fat milk consumption and reduced risk of arterial hypertension, coronary heart disease, colorectal cancer and obesity. Overweight individuals who drink milk may benefit from decreased risk of insulin resistance and type 2 diabetes. Interestingly, a study has shown that for women desiring to have a child, those who consume full fat dairy products may actually slightly increase their fertility, while those consuming low fat dairy products may slightly reduce their fertility due to interference with ovulation. However, studies in this area are still inconsistent. ## Nutritional and physiological detriments - Milk contains casein, a substance that breaks down in the human stomach to produce casomorphin, an opioid peptide. In the early 1990s it was hypothesized that casomorphin can cause or aggravate autism, and casein-free diets are widely promoted. Studies supporting these claims have had significant flaws, and the data are inadequate to guide autism treatment recommendations. - Lactose intolerance, discussed below. - Cow milk allergy (CMA) is as an immunologically mediated adverse reaction to one or more cow's milk proteins. Rarely is it severe enough to cause death. - There are some groups debating the amount of calcium from milk that is actually absorbed by the human body. However, it is argued by detractors that calcium from dairy products has greater bio-availability than calcium from vegetable products. - One study demonstrated that men, and to some degree women, who drink a large amount of milk and consume dairy products were at a slightly increased risk of developing Parkinson's disease. The reason behind this is not fully understood, and it also remains unclear why there is less of a risk for women. - Several sources suggest a correlation between high calcium intake (2000 mg per day, or twice the US recommended daily allowance, equivalent to six or more glasses of milk per day) and prostate cancer. A large study specifically implicates dairy. A review published by the World Cancer Research Fund and the American Institute for Cancer Research states that at least eleven human population studies have linked excessive dairy product consumption and prostate cancer, however randomized clinical trial data with appropriate controls only exists for calcium, not dairy produce, where there was no correlation. ### Controversy A number of groups e.g. PETA and the Vegetarian & Vegan Foundation (VVF) have provided strong scientific evidence linking cows' milk and dairy products to a wide range of illnesses and diseases White Lies. Common claims cited by anti-milk advocates: - White blood cells -- Milk contains varying levels of white blood cells depending upon the health of the source animals, according to guidelines set up by the Food and Drug Administration and statistics reported by the dairy industry. - Bovine Growth Hormone(rbst) -- Since November 1993, with FDA approval, Monsanto has been selling recombinant bovine somatotropin (rbST)--or rBGH--to dairy farmers. Additional bovine growth hormone is administered to cattle in order to increase their milk production, though the hormone also naturally fosters liver production of insulin-like growth factor 1 (IGF1). The deposit thereof in the milk of rBGH-affected cattle has been the source of concern; however, all milk contains IGF1 since all milking cows produce bovine growth hormone naturally. The IGF1 in milk from rBGH-affected cattle does not vary from the range normally found in a non-supplemented cow. Elevated levels of IGF1 in human blood has been linked to increased rates of breast, colon, and prostate cancer by stimulating their growth, though this has not been linked to milk consumption. The EU has recommended against Monsanto milk. In addition, the cows receiving rBGH supplements may more frequently contract an udder infection known as mastitis, partly responsible for the aforementioned prevalence of blood cells in dairy products. Milk from rBGH-affected cattle is banned in Canada, Australia, New Zealand, and Japan due to the mastitis problems. On June 9, 2006 the largest milk processor in the world and the two largest supermarkets in the United States--Dean Foods, Wal-Mart, and Kroger--announced that they are "on a nationwide search for rBGH-free milk ." No study has indicated that consumption of rBST-produced milk increases IGF1 levels, nor has any study demonstrated an increased risk of any disease between those consuming rBST and non-rBST produced milk. In 1994, the FDA has concluded that no significant difference has been shown between milk derived from rBST-treated and non-rBST-treated cows, nor does any test exist which can differentiate between milk from rBST-treated and non-rBST treated cows. ### Lactose intolerance Lactose, the disaccharide sugar component of all milk must be cleaved in the small intestine by the enzyme lactase in order for its constituents (galactose and glucose) to be absorbed. The production of this enzyme declines significantly after weaning in all mammals including humans (except for most northern westerners and a few other ethnic groups, lactase decline occurs after weaning, sometime between the ages of two and five). Once lactase levels have decreased sufficiently, consumption of small amounts of lactose can cause diarrhea, intestinal gas, cramps and bloating, as the undigested lactose travels through the gastrointestinal tract and serves as nourishment for intestinal microflora who excrete gas. ## Nutrition - comparison by animal source Milk Composition Analysis, per 100 grams Source: McCane, Widdowson, Scherz, Kloos. These compositions vary by breed, animal, and point in the lactation period. Jersey cows produce milk of about 5.2% fat, Zebu cows produce milk of about 4.7% fat, Brown Swiss cows produce milk of about 4.0% fat, and Holstein-Friesian cows produce milk of about 3.6% fat. The protein range for these four breeds is 3.3% to 3.9%, while the lactose range is 4.7% to 4.9%. Milk fat percentages in all dairy breeds vary according to digestible fibre, starch and oil intakes, and can therefore be manipulated by dairy farmers' diet formulation strategies. Mastitis infection can cause fat levels to decline. ## Spoilage and Fermented Milk Products When raw milk is left standing for a while, it turns "sour". This is the result of fermentation, where lactic acid bacteria ferment the lactose inside the milk into lactic acid. Prolonged fermentation may render the milk unpleasant to consume. This fermentation process is exploited by the introduction of bacterial cultures (e.g. Lactobacilli sp., Streptococcus sp., Leuconostoc sp., etc) to produce a variety of fermented milk products. The reduced pH from lactic acid accumulation denatures proteins and caused the milk to undergo a variety of different transformations in appearance and texture, ranging from an aggregate to smooth consistency. Some of these products include sour cream, yogurt, cheese, buttermilk, viili, kefir and kumis. See Dairy product for more information. Pasteurization of cow's milk initially destroys any potential pathogens and increases the shelf-life , but eventually results in spoilage that makes it unsuitable for consumption. This causes it to assume an unpleasant odor, and the milk is deemed non-consumable due to unpleasant taste and an increased risk of food poisoning. In raw milk, the presence of lactic acid-producing bacteria, under suitable conditions, ferments the lactose present to lactic acid. The increasing acidity in turn prevents the growth of other organisms, or slows their growth significantly. During pasteurization however, these lactic acid bacteria are mostly destroyed. In order to prevent spoilage, milk can be kept refrigerated and stored between 1 and 4 degrees Celsius in bulk tanks. Most milk is pasteurized by heating briefly and then refrigerated to allow transport from factory farms to local markets. The spoilage of milk can be forestalled by using ultra-high temperature (UHT) treatment; milk so treated can be stored unrefrigerated for several months until opened. Sterilized milk, which is heated for a much longer period of time, will last even longer, but also loses more nutrients and assume a different taste. Condensed milk, made by removing most of the water, can be stored in cans for many years, unrefrigerated, as can evaporated milk. The most durable form of milk is milk powder, which is produced from milk by removing almost all water. The moisture content is usually less than 5% in both drum and spray dried milk powder. # Notes - ↑ Dairy Chemistry and Physics, webpage of University of Guelph - ↑ Dairy Chemistry and Physics, webpage of University of Guelph - ↑ Introduction to Dairy Science and Technology, webpage of University of Guelph - ↑ Dairy's Role in Managing Blood Pressure, web page of the US National Dairy Council - ↑ Reichelt KL, Knivsberg A-M, Lind G, Nødland M (1991). "Probable etiology and possible treatment of childhood autism". Brain Dysfunct. 4: 308–19.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")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} - ↑ Christison GW, Ivany K (2006). "Elimination diets in autism spectrum disorders: any wheat amidst the chaff?". J Dev Behav Pediatr. 27 (2 Suppl 2): S162–71. PMID 16685183. - ↑ Christison GW, Ivany K (2006). "Elimination diets in autism spectrum disorders: any wheat amidst the chaff?". J Dev Behav Pediatr. 27 (2 Suppl 2): S162–71. PMID 16685183. - ↑ Calcium Rich Foods: Get All The Calcium You Need Without Milk - ↑ Feskanich D, Willett WC, Stampfer MJ, Colditz GA. Milk, dietary calcium, and bone fractures in women: a 12-year prospective study. Am J Public Health 1997; 87:992-7. - ↑ Brody T. Calcium and phosphate. In: Nutritional biochemistry. 2nd ed. Boston: Academic Press, 1999:761–94 - ↑ H. Chen et al., Consumption of Dairy Products and Risk of Parkinson's Disease, American Journal of Epidemiology. 2007 May;165(9):998-1006 - ↑ H. Chen et al., Consumption of Dairy Products and Risk of Parkinson's Disease, American Journal of Epidemiology. 2007 May;165(9):998-1006 - ↑ "Milk linked to Parkinson's risk". BBC News. - ↑ Giovannucci, E. et al., Calcium and fructose intake in relation to risk of prostate cancer., Cancer Res. 1998 Feb 1;58(3):442-7. - ↑ Chan, J.M., Dairy products, calcium, and prostate cancer risk in the Physicians' Health Study. Am J Clin Nutr. 2001 Oct;74(4):549-54. (disputed publication) - ↑ The World Cancer Research Fund and American Institute for Cancer Research (1997). "Food, nutrition and the prevention of cancer: a global perspective". Food, nutrition and the prevention of cancer: a global perspective. - ↑ Chan JM et al., (2005) Role of diet in prostate cancer development and progression. J Clin Oncol 23:8152-60. - ↑ Greger, Michael. Paratuberculosis and Crohn's Disease: Got Milk? Pro-vegan online publication, January 2001 - ↑ Kahan, Z et al., Elevated levels of circulating insulin-like growth factor-I, IGF-binding globulin-3 and testosterone predict hormone-dependent breast cancer in postmenopausal women: a case-control study. Int J Oncol. 2006 Jul;29(1):193-200. - ↑ Pacher, M. et al., Impact of constitutive IGF1/IGF2 stimulation on the transcriptional program of human breast cancer cells. Carcinogenesis. 2006 Jun 14 - ↑ International Scientific Committee Warns of Serious Risks of Breast and Prostate Cancer from Monsanto's Hormonal Milk. Press release of the Cancer Prevention Coalition. - ↑ Milk: Epstein, S., America's Health Problem. Web page of the Cancer Prevention Coalition. - ↑ McGee, Harold (2004). On Food and Cooking: The Science and Lore of the Kitchen, Completely Revised and Updated. New York, NY: Scribner. p. 13. ISBN 9780684800011. - ↑ +and+milk+fat+levels&source=web&ots=PrguNhnHdm&sig=W_MS2A7FWTBksmBYvZZk38dRh4A

Milk # Overview Milk is an opaque white liquid produced by the mammary glands of female mammals (including monotremes). Mammary glands are highly specialized sweat glands. The female ability to produce milk is one of the defining characteristics of mammals. It provides the primary source of nutrition for newborns before they are able to digest other types of food. The early lactation milk is known as colostrum, and carries the mother's antibodies to the baby. It can reduce the risk of many diseases in the baby. Males of all mammal species retain the breasts that are part of the fundamental mammalian animal structure, hence their nipples. Lactation occurs in males in certain rare circumstances, both naturally and artificially, however, some pharmaceuticals precipitate lactation in males readily. The exact components of raw milk varies by species, but it contains significant amounts of saturated fat, protein and calcium as well as vitamin C. # Physical and chemical structure Milk is an emulsion of butterfat globules within a water-based fluid. Each fat globule is surrounded by a membrane consisting of phospholipids and proteins; these emulsifiers keep the individual globules from joining together into noticeable grains of butterfat and also protect the globules from the fat-digesting activity of enzymes found in the fluid portion of the milk. In unhomogenized cow's milk, the fat globules average about four micrometers across. The fat-soluble vitamins A, D, E, and K are found within the milkfat portion of the milk (McGee 18). The largest structures in the fluid portion of the milk are casein protein micelles: aggregates of several thousand protein molecules, bonded with the help of nanometer-scale particles of calcium phosphate. Each micelle is roughly spherical and about a tenth of a micrometer across. There are four different types of casein proteins, and collectively they make up around 80 percent of the protein in milk, by weight. Most of the casein proteins are bound into the micelles. There are several competing theories regarding the precise structure of the micelles, but they share one important feature: the outermost layer consists of strands of one type of protein, kappa-casein, reaching out from the body of the micelle into the surrounding fluid. These Kappa-casein molecules all have a negative electrical charge and therefore repel each other, keeping the micelles separated under normal conditions and in a stable colloidal suspension in the water-based surrounding fluid[1] (McGee 19–20). Both the fat globules and the smaller casein micelles, which are just large enough to deflect light, contribute to the opaque white color of milk. The fat globules contain some yellow-orange carotene, enough in some breeds — Guernsey and Jersey cows, for instance — to impart a golden or "creamy" hue to a glass of milk. The riboflavin in the whey portion of milk has a greenish color, which can sometimes be discerned in skim milk or whey products (McGee 17). Fat-free skim milk has only the casein micelles to scatter light, and they tend to scatter shorter-wavelength blue light more than they do red, giving skim milk a bluish tint.[2] Milk contains dozens of other types of proteins besides the caseins. They are more water-soluble than the caseins and do not form larger structures. Because these proteins remain suspended in the whey left behind when the caseins coagulate into curds, they are collectively known as whey proteins. Whey proteins make up around twenty percent of the protein in milk, by weight. Lactoglobulin is the most common whey protein by a large margin (McGee 20–21). The carbohydrate lactose gives milk its sweet taste and contributes about 40% of whole cow milk's calories. Lactose is a composite of two simple sugars, glucose and galactose. In nature, lactose is found only in milk and a small number of plants (McGee 17). Other components found in raw cow milk are living white blood cells. Mammary-gland cells, various bacteria, and a large number of active enzymes are some other components in milk (McGee 16). # Nutrition and health The composition of milk differs widely between species. Factors such as the type of protein; the proportion of protein, fat, and sugar; the levels of various vitamins and minerals; and the size of the butterfat globules and the strength of the curd are among those than can vary.[3] For example: - Human milk contains, on average, 1.1% protein, 4.2% fat, 7.0% lactose (a sugar), and supplies 72 kcal of energy per 100 grams. - Cow's milk contains, on average, 3.4% protein, 3.6% fat, and 4.6% lactose, and supplies 66 kcal of energy per 100 grams. See also Nutritional benefits further on. Aquatic mammals, such as seals and whales, produce milk that is very rich in fats and other solid nutrients when compared with land mammals' milk. ## Nutritional benefits Template:Nutritionalvalue Processed milk began containing differing amounts of fat during the 1950s. A serving (1 cup or 250 ml) of 2%-fat milk contains 285 mg of calcium, which represents 22% to 29% of the daily recommended intake (DRI) of calcium for an adult. Depending on the age, 8 grams of protein, and a number of other nutrients (either naturally or through fortification): - Vitamins D and K are essential for bone health. - Iodine is a mineral essential for thyroid function. - Vitamin B12 and riboflavin are necessary for cardiovascular health and energy production, and B12 is difficult to get outside of animal products or else as supplemental pills. - Biotin and pantothenic acid are B vitamins important for energy production. - Vitamin A is critical for immune function. - Potassium and magnesium are for cardiovascular health. - Selenium is a cancer-preventive trace mineral. - Thiamine is a B-vitamin important for cognitive function, especially memory - Conjugated linoleic acid is a beneficial fatty acid that inhibits several types of cancer in mice, it has been shown to kill human skin cancer, colorectal cancer and breast cancer cells in vitro studies, and may help lower cholesterol and prevent atherosclerosis; only available in milk from grass-fed cows. Studies show possible links between low-fat milk consumption and reduced risk of arterial hypertension, coronary heart disease, colorectal cancer and obesity. Overweight individuals who drink milk may benefit from decreased risk of insulin resistance and type 2 diabetes.[4] Interestingly, a study has shown that for women desiring to have a child, those who consume full fat dairy products may actually slightly increase their fertility, while those consuming low fat dairy products may slightly reduce their fertility due to interference with ovulation. However, studies in this area are still inconsistent.[5] ## Nutritional and physiological detriments - Milk contains casein, a substance that breaks down in the human stomach to produce casomorphin, an opioid peptide. In the early 1990s it was hypothesized that casomorphin can cause or aggravate autism,[6] [7] and casein-free diets are widely promoted. Studies supporting these claims have had significant flaws, and the data are inadequate to guide autism treatment recommendations.[8] - Lactose intolerance, discussed below. - Cow milk allergy (CMA) is as an immunologically mediated adverse reaction to one or more cow's milk proteins. Rarely is it severe enough to cause death.[4] - There are some groups [9] [10]debating the amount of calcium from milk that is actually absorbed by the human body. However, it is argued by detractors that calcium from dairy products has greater bio-availability than calcium from vegetable products. [11] - One study [12] demonstrated that men, and to some degree women, who drink a large amount of milk and consume dairy products were at a slightly increased risk of developing Parkinson's disease. The reason behind this is not fully understood, and it also remains unclear why there is less of a risk for women.[13][14] - Several sources suggest a correlation between high calcium intake (2000 mg per day, or twice the US recommended daily allowance, equivalent to six or more glasses of milk per day) and prostate cancer.[15] A large study specifically implicates dairy.[16] A review published by the World Cancer Research Fund and the American Institute for Cancer Research states that at least eleven human population studies have linked excessive dairy product consumption and prostate cancer,[17] however randomized clinical trial data with appropriate controls only exists for calcium, not dairy produce, where there was no correlation.[18] ### Controversy A number of groups e.g. PETA and the Vegetarian & Vegan Foundation (VVF) have provided strong scientific evidence linking cows' milk and dairy products to a wide range of illnesses and diseases [19] White Lies. Common claims cited by anti-milk advocates: - White blood cells -- Milk contains varying levels of white blood cells depending upon the health of the source animals, according to guidelines set up by the Food and Drug Administration and statistics reported by the dairy industry.[20] - Bovine Growth Hormone(rbst) -- Since November 1993, with FDA approval, Monsanto has been selling recombinant bovine somatotropin (rbST)--or rBGH--to dairy farmers. Additional bovine growth hormone is administered to cattle in order to increase their milk production, though the hormone also naturally fosters liver production of insulin-like growth factor 1 (IGF1). The deposit thereof in the milk of rBGH-affected cattle has been the source of concern; however, all milk contains IGF1 since all milking cows produce bovine growth hormone naturally. The IGF1 in milk from rBGH-affected cattle does not vary from the range normally found in a non-supplemented cow.[21] Elevated levels of IGF1 in human blood has been linked to increased rates of breast, colon, and prostate cancer by stimulating their growth,[22][23] though this has not been linked to milk consumption. The EU has recommended against Monsanto milk.[24] In addition, the cows receiving rBGH supplements may more frequently contract an udder infection known as mastitis, partly responsible for the aforementioned prevalence of blood cells in dairy products.[25] Milk from rBGH-affected cattle is banned in Canada, Australia, New Zealand, and Japan due to the mastitis problems. On June 9, 2006 the largest milk processor in the world and the two largest supermarkets in the United States--Dean Foods, Wal-Mart, and Kroger--announced that they are "on a nationwide search for rBGH-free milk [5]." No study has indicated that consumption of rBST-produced milk increases IGF1 levels, nor has any study demonstrated an increased risk of any disease between those consuming rBST and non-rBST produced milk. In 1994, the FDA has concluded that no significant difference has been shown between milk derived from rBST-treated and non-rBST-treated cows, nor does any test exist which can differentiate between milk from rBST-treated and non-rBST treated cows. [26] ### Lactose intolerance Lactose, the disaccharide sugar component of all milk must be cleaved in the small intestine by the enzyme lactase in order for its constituents (galactose and glucose) to be absorbed. The production of this enzyme declines significantly after weaning in all mammals including humans (except for most northern westerners and a few other ethnic groups, lactase decline occurs after weaning, sometime between the ages of two and five). Once lactase levels have decreased sufficiently, consumption of small amounts of lactose can cause diarrhea, intestinal gas, cramps and bloating, as the undigested lactose travels through the gastrointestinal tract and serves as nourishment for intestinal microflora who excrete gas. [27] ## Nutrition - comparison by animal source Milk Composition Analysis, per 100 grams Source: McCane, Widdowson, Scherz, Kloos.[6] These compositions vary by breed, animal, and point in the lactation period. Jersey cows produce milk of about 5.2% fat, Zebu cows produce milk of about 4.7% fat, Brown Swiss cows produce milk of about 4.0% fat, and Holstein-Friesian cows produce milk of about 3.6% fat. The protein range for these four breeds is 3.3% to 3.9%, while the lactose range is 4.7% to 4.9%. [28] Milk fat percentages in all dairy breeds vary according to digestible fibre, starch and oil intakes[29], and can therefore be manipulated by dairy farmers' diet formulation strategies. Mastitis infection can cause fat levels to decline.[30] ## Spoilage and Fermented Milk Products When raw milk is left standing for a while, it turns "sour". This is the result of fermentation, where lactic acid bacteria ferment the lactose inside the milk into lactic acid. Prolonged fermentation may render the milk unpleasant to consume. This fermentation process is exploited by the introduction of bacterial cultures (e.g. Lactobacilli sp., Streptococcus sp., Leuconostoc sp., etc) to produce a variety of fermented milk products. The reduced pH from lactic acid accumulation denatures proteins and caused the milk to undergo a variety of different transformations in appearance and texture, ranging from an aggregate to smooth consistency. Some of these products include sour cream, yogurt, cheese, buttermilk, viili, kefir and kumis. See Dairy product for more information. Pasteurization of cow's milk initially destroys any potential pathogens and increases the shelf-life [31][32], but eventually results in spoilage that makes it unsuitable for consumption. This causes it to assume an unpleasant odor, and the milk is deemed non-consumable due to unpleasant taste and an increased risk of food poisoning. In raw milk, the presence of lactic acid-producing bacteria, under suitable conditions, ferments the lactose present to lactic acid. The increasing acidity in turn prevents the growth of other organisms, or slows their growth significantly. During pasteurization however, these lactic acid bacteria are mostly destroyed. In order to prevent spoilage, milk can be kept refrigerated and stored between 1 and 4 degrees Celsius in bulk tanks. Most milk is pasteurized by heating briefly and then refrigerated to allow transport from factory farms to local markets. The spoilage of milk can be forestalled by using ultra-high temperature (UHT) treatment; milk so treated can be stored unrefrigerated for several months until opened. Sterilized milk, which is heated for a much longer period of time, will last even longer, but also loses more nutrients and assume a different taste. Condensed milk, made by removing most of the water, can be stored in cans for many years, unrefrigerated, as can evaporated milk. The most durable form of milk is milk powder, which is produced from milk by removing almost all water. The moisture content is usually less than 5% in both drum and spray dried milk powder. # Notes - ↑ Dairy Chemistry and Physics, webpage of University of Guelph - ↑ Dairy Chemistry and Physics, webpage of University of Guelph - ↑ Introduction to Dairy Science and Technology, webpage of University of Guelph - ↑ Dairy's Role in Managing Blood Pressure, web page of the US National Dairy Council - ↑ [1] - ↑ Reichelt KL, Knivsberg A-M, Lind G, Nødland M (1991). "Probable etiology and possible treatment of childhood autism". Brain Dysfunct. 4: 308–19.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Christison GW, Ivany K (2006). "Elimination diets in autism spectrum disorders: any wheat amidst the chaff?". J Dev Behav Pediatr. 27 (2 Suppl 2): S162–71. PMID 16685183. - ↑ Christison GW, Ivany K (2006). "Elimination diets in autism spectrum disorders: any wheat amidst the chaff?". J Dev Behav Pediatr. 27 (2 Suppl 2): S162–71. PMID 16685183. - ↑ Calcium Rich Foods: Get All The Calcium You Need Without Milk - ↑ Feskanich D, Willett WC, Stampfer MJ, Colditz GA. Milk, dietary calcium, and bone fractures in women: a 12-year prospective study. Am J Public Health 1997; 87:992-7. - ↑ Brody T. Calcium and phosphate. In: Nutritional biochemistry. 2nd ed. Boston: Academic Press, 1999:761–94 - ↑ H. Chen et al., Consumption of Dairy Products and Risk of Parkinson's Disease, American Journal of Epidemiology. 2007 May;165(9):998-1006 - ↑ H. Chen et al., Consumption of Dairy Products and Risk of Parkinson's Disease, American Journal of Epidemiology. 2007 May;165(9):998-1006 - ↑ "Milk linked to Parkinson's risk". BBC News. - ↑ Giovannucci, E. et al., Calcium and fructose intake in relation to risk of prostate cancer., Cancer Res. 1998 Feb 1;58(3):442-7. - ↑ Chan, J.M., Dairy products, calcium, and prostate cancer risk in the Physicians' Health Study. Am J Clin Nutr. 2001 Oct;74(4):549-54. (disputed publication) - ↑ The World Cancer Research Fund and American Institute for Cancer Research (1997). "Food, nutrition and the prevention of cancer: a global perspective". Food, nutrition and the prevention of cancer: a global perspective. - ↑ Chan JM et al., (2005) Role of diet in prostate cancer development and progression. J Clin Oncol 23:8152-60. - ↑ [2] - ↑ Greger, Michael. Paratuberculosis and Crohn's Disease: Got Milk? Pro-vegan online publication, January 2001 - ↑ http://www.idfa.org/reg/biotech/talking2.cfm - ↑ Kahan, Z et al., Elevated levels of circulating insulin-like growth factor-I, IGF-binding globulin-3 and testosterone predict hormone-dependent breast cancer in postmenopausal women: a case-control study. Int J Oncol. 2006 Jul;29(1):193-200. - ↑ Pacher, M. et al., Impact of constitutive IGF1/IGF2 stimulation on the transcriptional program of human breast cancer cells. Carcinogenesis. 2006 Jun 14 - ↑ International Scientific Committee Warns of Serious Risks of Breast and Prostate Cancer from Monsanto's Hormonal Milk. Press release of the Cancer Prevention Coalition. - ↑ Milk: Epstein, S., America's Health Problem. Web page of the Cancer Prevention Coalition. - ↑ http://www.fda.gov/bbs/topics/ANSWERS/ANS00564.html - ↑ http://en.wikipedia.org/wiki/Anaerobic_respiration - ↑ McGee, Harold (2004). On Food and Cooking: The Science and Lore of the Kitchen, Completely Revised and Updated. New York, NY: Scribner. p. 13. ISBN 9780684800011. - ↑ http://www.kt.iger.bbsrc.ac.uk/FACT%20sheet%20PDF%20files/kt21.pdf - ↑ http://books.google.com/books?id=qJgdAEhQvnMC&pg=PA226&lpg=PA226&dq=mastitis+and+milk+fat+levels&source=web&ots=PrguNhnHdm&sig=W_MS2A7FWTBksmBYvZZk38dRh4A - ↑ http://www.fda.gov/fdac/features/2004/504_milk.html - ↑ [3]

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

8471808e871dec0b434e77951e9683f29f0b1461

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Torr

Torr The torr (symbol: Torr) is a non-SI unit of pressure defined as 1/760 of an atmosphere. It was named after Evangelista Torricelli, an Italian physicist and mathematician who discovered the principle of the barometer in 1644. # History Torricelli attracted considerable attention when he demonstrated the first mercury barometer to the general public. He is credited with giving the first modern explanation of atmospheric pressure. Scientists at the time were familiar with small fluctuations in height that occurred in barometers. When these fluctuations were explained as a manifestation of changes in atmospheric pressure, the science of meteorology was born. Over time, 760 millimeters of mercury came to be regarded as the “standard” atmospheric pressure. The unit of barometric pressure (one millimeter of mercury, also written as 1 mm Hg) was named in honor of Torricelli. In 1954, the definition of atmosphere was revised by the 10e Conférence Générale des Poids et Mesures (10th CGPM) to the currently accepted definition: one atmosphere is equal to 101325 pascals. The torr was then re-defined as 1/760 of one atmosphere. This change in the definition of “torr” has been a source of confusion ever since. # SI units of pressure The SI unit of pressure is the pascal (symbol: Pa), defined as one newton per square meter. Other units of pressure are defined in terms of SI units. These include: - The bar (symbol: bar), defined as 105 Pa exactly. - The atmosphere (symbol: atm), defined as 101,325 Pa exactly. - The torr (symbol: Torr), defined as 1/760 atm exactly. These four SI-related pressure units are used in different settings. For example, the bar is used in meteorology to report atmospheric pressures. The torr, a more convenient unit for low pressures, is used in high-vacuum physics and engineering. # Manometric units of pressure Manometric units are units such as millimeters of mercury or centimeters of water that depend on an assumed density of a fluid and an assumed acceleration of gravity. These units are now regarded as obsolete, and their use is discouraged. Nevertheless, manometric units are used routinely in medicine and physiology, and they continue to be used in areas as diverse as weather reporting and scuba diving. The millimeter of mercury (symbol: mmHg) is defined as the pressure exerted at the base of a column of fluid exactly 1 mm high, when the density of the fluid is exactly 13.5951 g/cm³, at a place where the acceleration of gravity is exactly 9.80665 m/s². There are several things to notice about this definition: - A fluid density of 13.5951 g/cm³ was chosen for this definition because this is the approximate density of mercury at 0 °C. The definition, therefore, assumes a particular value for the density of mercury. This assumption limits the precision of any pressure measurement (in mmHg) to six significant digits. - The definition assumes a particular value for the acceleration of gravity: the standard acceleration gn = 9.80665 m/sec2. In practice, of course, measurements are made using local values. These assumptions limit both the validity and the precision of the mmHg as a unit of pressure. No metrology laboratory measures or calibrates pressure directly in these terms. It would be extremely difficult to find a fluid with exactly this density, and a place where g was exactly 9.80665 m/s². According to the UK’s National Physical Laboratory (NPL): The performance of modern transducers approaches the precision required to distinguish between the torr and the millimeter of mercury. The NPL concludes ## Manometric units in medicine and physiology In medicine, the mmHg (measured with a sphygmomanometer) is the gold standard for blood pressure measurement. In physiology, manometric units are used to measure Starling forces. Other applications include: - Intraocular pressure (tonometry) - CSF pressure - Intracranial pressure - Intramuscular pressure (compartment syndrome) - Central venous pressure - Pulmonary artery catheterization - Mechanical ventilation - Pulmonary gas pressure - Esophageal motility studies - Venous ulcer compression regime Manometric results in medicine are sometimes given in torr. This is usually incorrect, since the Torr and the mmHg are not the same thing. Pressures obtained with a manometer (or its transducer equivalent) should be reported in mmHg. # Conversion factors The mmHg is defined as 13.5951 x 9.80665 = 133.322387415 Pa. This is an exact number, although it is too long to be of any practical use. The torr is defined as 1/760 of one atmosphere, while the atmosphere is defined as 101,325 Pa. Therefore, one Torr is equal to 101325/760 of one Pa. The decimal form of this fraction (133.322368421...) is, unfortunately, an infinitely long, periodically repeating decimal. The relationship between the Torr and the mmHg is: The mmHg and the Torr differ from one another by less than 2 x 10-7 Torr. The difference between one atmosphere (101325 Pa) and 760 mmHg (101325.0144354 Pa) less than 0.2 μPa/Pa (less than 0.00002%). This small difference is negligible for most applications outside metrology. # Notes - ↑ Devices similar to the modern barometer, using water instead of mercury, were studied by a number of scientists in the early 1640s (). Torricelli’s explanation of the principle of the barometer appears in a letter to Michelangelo Ricci (/~guinta/torr.html) dated June 11, 1644. - ↑ Cohen ER et. al. Quantities, Units and Symbols in Physical Chemistry, 3rd ed. Royal Society of Chemistry, 2007. - ↑ DeVoe H. Thermodynamics and Chemistry. Prentice-Hall, Inc. 2001. - ↑ Note that a pressure of 1 bar (100,000 Pa) is slightly less than a pressure of 1 atmosphere (101,325 Pa). - ↑ National Physical Laboratory: Pressure units. . - ↑ Conventional millimeters of mercury. . - ↑ The density of mercury is now known to 6 decimal places (8 significant digits). See, for example, . - ↑ National Physical Laboratory: Pressure and vacuum.

Torr Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The torr (symbol: Torr) is a non-SI unit of pressure defined as 1/760 of an atmosphere. It was named after Evangelista Torricelli, an Italian physicist and mathematician who discovered the principle of the barometer in 1644.[1] # History Torricelli attracted considerable attention when he demonstrated the first mercury barometer to the general public. He is credited with giving the first modern explanation of atmospheric pressure. Scientists at the time were familiar with small fluctuations in height that occurred in barometers. When these fluctuations were explained as a manifestation of changes in atmospheric pressure, the science of meteorology was born. Over time, 760 millimeters of mercury came to be regarded as the “standard” atmospheric pressure. The unit of barometric pressure (one millimeter of mercury, also written as 1 mm Hg) was named in honor of Torricelli. In 1954, the definition of atmosphere was revised by the 10e Conférence Générale des Poids et Mesures (10th CGPM)[2] to the currently accepted definition: one atmosphere is equal to 101325 pascals. The torr was then re-defined as 1/760 of one atmosphere. This change in the definition of “torr” has been a source of confusion ever since. # SI units of pressure The SI unit of pressure is the pascal (symbol: Pa), defined as one newton per square meter. Other units of pressure are defined in terms of SI units.[3][4] These include: - The bar (symbol: bar), defined as 105 Pa exactly. - The atmosphere (symbol: atm), defined as 101,325 Pa exactly. - The torr (symbol: Torr), defined as 1/760 atm exactly. These four SI-related pressure units are used in different settings. For example, the bar is used in meteorology to report atmospheric pressures.[5] The torr, a more convenient unit for low pressures, is used in high-vacuum physics and engineering. Template:Pressure Units # Manometric units of pressure Manometric units are units such as millimeters of mercury or centimeters of water that depend on an assumed density of a fluid and an assumed acceleration of gravity. These units are now regarded as obsolete, and their use is discouraged.[6] Nevertheless, manometric units are used routinely in medicine and physiology, and they continue to be used in areas as diverse as weather reporting and scuba diving. The millimeter of mercury (symbol: mmHg) is defined as the pressure exerted at the base of a column of fluid exactly 1 mm high, when the density of the fluid is exactly 13.5951 g/cm³, at a place where the acceleration of gravity is exactly 9.80665 m/s².[7] There are several things to notice about this definition: - A fluid density of 13.5951 g/cm³ was chosen for this definition because this is the approximate density of mercury at 0 °C. The definition, therefore, assumes a particular value for the density of mercury. This assumption limits the precision of any pressure measurement (in mmHg) to six significant digits.[8] - The definition assumes a particular value for the acceleration of gravity: the standard acceleration gn = 9.80665 m/sec2. In practice, of course, measurements are made using local values. These assumptions limit both the validity and the precision of the mmHg as a unit of pressure. No metrology laboratory measures or calibrates pressure directly in these terms. It would be extremely difficult to find a fluid with exactly this density, and a place where g was exactly 9.80665 m/s². According to the UK’s National Physical Laboratory (NPL): The performance of modern transducers approaches the precision required to distinguish between the torr and the millimeter of mercury. The NPL concludes ## Manometric units in medicine and physiology In medicine, the mmHg (measured with a sphygmomanometer) is the gold standard for blood pressure measurement. In physiology, manometric units are used to measure Starling forces. Other applications include: - Intraocular pressure (tonometry) - CSF pressure - Intracranial pressure - Intramuscular pressure (compartment syndrome) - Central venous pressure - Pulmonary artery catheterization - Mechanical ventilation - Pulmonary gas pressure - Esophageal motility studies - Venous ulcer compression regime Manometric results in medicine are sometimes given in torr. This is usually incorrect, since the Torr and the mmHg are not the same thing. Pressures obtained with a manometer (or its transducer equivalent) should be reported in mmHg. # Conversion factors The mmHg is defined as 13.5951 x 9.80665 = 133.322387415 Pa. This is an exact number, although it is too long to be of any practical use. The torr is defined as 1/760 of one atmosphere, while the atmosphere is defined as 101,325 Pa. Therefore, one Torr is equal to 101325/760 of one Pa. The decimal form of this fraction (133.322368421...) is, unfortunately, an infinitely long, periodically repeating decimal. The relationship between the Torr and the mmHg is: The mmHg and the Torr differ from one another by less than 2 x 10-7 Torr. The difference between one atmosphere (101325 Pa) and 760 mmHg (101325.0144354 Pa) less than 0.2 μPa/Pa (less than 0.00002%). This small difference is negligible for most applications outside metrology. # Notes - ↑ Devices similar to the modern barometer, using water instead of mercury, were studied by a number of scientists in the early 1640s (http://www.strange-loops.com/scibarometer.html). Torricelli’s explanation of the principle of the barometer appears in a letter to Michelangelo Ricci (http://web.lemoyne.edu/~guinta/torr.html) dated June 11, 1644. - ↑ http://www.bipm.org/en/CGPM/db/10/4/ - ↑ Cohen ER et. al. Quantities, Units and Symbols in Physical Chemistry, 3rd ed. Royal Society of Chemistry, 2007. - ↑ DeVoe H. Thermodynamics and Chemistry. Prentice-Hall, Inc. 2001. - ↑ Note that a pressure of 1 bar (100,000 Pa) is slightly less than a pressure of 1 atmosphere (101,325 Pa). - ↑ National Physical Laboratory: Pressure units. http://www.npl.co.uk/pressure/punits.htm. - ↑ Conventional millimeters of mercury. http://www.sizes.com/units/mmHg.htms. - ↑ The density of mercury is now known to 6 decimal places (8 significant digits). See, for example, http://www.cstl.nist.gov/div836/836.05/papers/Strouse01TM_HG_TP_cells.pdf. - ↑ National Physical Laboratory: Pressure and vacuum. http://www.npl.co.uk/pressure/faqs/unitvalidity.html

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

68f9f44b4a45d12b9f0c9a9ba4293a55755f52f3

wikidoc

Mite

Mite Mites, along with ticks, belong to the subclass Acarina (also known as Acari) and the class Arachnida. Mites are among the most diverse and successful of all the invertebrate groups. They have exploited an incredible array of habitats, and because of their small size (most are microscopic) most go totally unnoticed. Many live freely in the soil or water, but there are also a large number of species that live as parasites on plants or animals and even some that feed on mold. Some of the plant pests include the so called spider mites (family Tetranychidae), thread-footed mites (family Tarsonemidae), and the gall mites (family Eriophyidae). Among the species that attack animals are members of the Sarcoptic Mange mites (family Sarcoptidae), which burrow under the skin. Demodex mites (family Demodicidae) are parasites that live in or near the hair follicles of mammals, including humans. Perhaps the best-known mite, though, is the house dust mite (family Pyroglyphidae). Insects may also have parasitic mites. Examples are Varroa destructor which attaches to the body of the honeybee, and Acarapis woodi (family Tarsonemidae), which lives in the tracheae of honey bees. There are hundreds of species of mites associated with other bee species, and most are poorly described and understood. Some are thought to be parasites, while others beneficial symbionts. There are over 45,000 described species of mites. Scientists believe that we have only found 5% of the total diversity of mites. Mites are believed to have existed for around 400 million years. The scientific discipline devoted to the study of ticks and mites is called acarology. The tropical species Archegozetes longisetosus is one of the strongest animals in the world, relative to its mass (100 μg): It lifts up to 1182 times its own weight, over five times more than would be expected of such a minute animal (Heethoff & Koerner 2007). # Systematics For the systematics of mites, see Acarina. # Allergy Mites cause several forms of allergic diseases, including hay fever, asthma and eczema and also aggrevates atopic dermatitis. Mites are usually found in warm and humid locations, including beds. It is thought that inhalation of mites during sleep exposes the human body to some antigens which eventually induce hypersensitivity reaction. Dust mite allergens are thought to be among the heaviest dust allergens. Like most of the other types of allergy, treatment of mite allergy starts with avoidance. There is a strong body of evidence showing that avoidance should be helpful in patients with atopic dermatitis triggered by exposure to mites. Regular washing of mattresses and blankets with hot water can help in this regard. Antihistamines are also useful; Cetirizine, for example, is shown to reduce allergic symptoms of patients.

Mite Mites, along with ticks, belong to the subclass Acarina (also known as Acari) and the class Arachnida. Mites are among the most diverse and successful of all the invertebrate groups. They have exploited an incredible array of habitats, and because of their small size (most are microscopic) most go totally unnoticed. Many live freely in the soil or water, but there are also a large number of species that live as parasites on plants or animals and even some that feed on mold. Some of the plant pests include the so called spider mites (family Tetranychidae), thread-footed mites (family Tarsonemidae), and the gall mites (family Eriophyidae). Among the species that attack animals are members of the Sarcoptic Mange mites (family Sarcoptidae), which burrow under the skin. Demodex mites (family Demodicidae) are parasites that live in or near the hair follicles of mammals, including humans. Perhaps the best-known mite, though, is the house dust mite (family Pyroglyphidae). Insects may also have parasitic mites. Examples are Varroa destructor which attaches to the body of the honeybee, and Acarapis woodi (family Tarsonemidae), which lives in the tracheae of honey bees. There are hundreds of species of mites associated with other bee species, and most are poorly described and understood. Some are thought to be parasites, while others beneficial symbionts. There are over 45,000 described species of mites[1]. Scientists believe that we have only found 5% of the total diversity of mites. Mites are believed to have existed for around 400 million years. The scientific discipline devoted to the study of ticks and mites is called acarology. The tropical species Archegozetes longisetosus is one of the strongest animals in the world, relative to its mass (100 μg): It lifts up to 1182 times its own weight, over five times more than would be expected of such a minute animal (Heethoff & Koerner 2007). # Systematics For the systematics of mites, see Acarina. # Allergy Mites cause several forms of allergic diseases, including hay fever, asthma and eczema and also aggrevates atopic dermatitis. [1] Mites are usually found in warm and humid locations, including beds. It is thought that inhalation of mites during sleep exposes the human body to some antigens which eventually induce hypersensitivity reaction.[2] Dust mite allergens are thought to be among the heaviest dust allergens.[3] Like most of the other types of allergy, treatment of mite allergy starts with avoidance. There is a strong body of evidence showing that avoidance should be helpful in patients with atopic dermatitis triggered by exposure to mites.[4] Regular washing of mattresses and blankets with hot water can help in this regard.[5] Antihistamines are also useful; Cetirizine, for example, is shown to reduce allergic symptoms of patients.[6]

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

37b76fd932a52dc0b8437d71f6ffd2c72b06ec14

wikidoc

Noni

Noni Morinda citrifolia, commonly known as Great morinda, Indian mulberry, Beach mulberry, Tahitian Noni, or since recently: Noni (from Hawaiian), Nono (in Tahitian), Mengkudu (from Malay), Nonu (in Tongan), and Ach (in Hindi), is a shrub or small tree in the family Rubiaceae. Morinda citrifolia is native to Southeast Asia but has been extensively spread by man throughout India and into the Pacific islands as far as the islands of French Polynesia, of which Tahiti is the most prominent. It can also be found in parts of the West Indies. Noni grows in shady forests as well as on open rocky or sandy shores. It reaches maturity in about 18 months and then yields between 4-8 kg of fruit every month throughout the year. It is tolerant of saline soils, drought conditions, and secondary soils. It is therefore found in a wide variety of habitats: volcanic terrains, lava-strewn coasts, and clearings or limestone outcrops. It can grow up to 9 m tall, and has large, simple, dark green, shiny and deeply veined leaves. The plant flowers and fruits all year round and prodces a small white flower. The fruit is a multiple fruit that has a pungent odor when ripening, and is hence also known as cheese fruit or even vomit fruit. It is oval and reaches 4-7 cm in size. At first green, the fruit turns yellow then almost white as it ripens. It contains many seeds. It is sometimes called starvation fruit. Despite its strong smell and bitter taste, the fruit is nevertheless eaten as a famine food and, in some Pacific islands, even a staple food, either raw or cooked. Southeast Asians and Australian Aborigines consume the fruit raw with salt or cook it with curry. The seeds are edible when roasted. The noni is especially attractive to weaver ants, which make nests out of the leaves of the tree. These ants protect the plant from some plant-parasitic insects. The smell of the fruit also attracts fruit bats, which aid in dispersing the seeds. # Nutrients Nutritional information for noni fruit is reported by the College of Tropical Agriculture, University of Hawaii at Mānoa who published analyses of fruit powder and pure juice. ## Macronutrients Analyzed as a whole fruit powder, noni fruit has excellent levels of carbohydrates and dietary fiber, providing 55% and 100% of the Dietary Reference Intakes, respectively, in a 100 g serving. A good source of protein (12% DRI), noni pulp is low in total fats (4% DRI). These macronutrients evidently reside in the fruit pulp, as noni juice has sparse amounts of macronutrients. ## Micronutrients The main micronutrient features of noni pulp powder include exceptional vitamin C content (10x DRI) and substantial amounts of niacin (vitamin B3), iron and potassium. Vitamin A, calcium and sodium are present in moderate amounts. When noni juice alone is analyzed and compared to pulp powder, only vitamin C is retained at a high level, 42% of DRI. Nutrient analyses for a major brand of noni juice (Tahitian Noni Juice™, TNJ) were published in 2002 by the Scientific Committee on Food of the European Commission on Health and Consumer Protection (ECHCP) during a test for public safety of TNJ. TNJ ingredients include noni purée and juice concentrates from grapes and blueberries. For antimicrobial purposes, TNJ must be subjected to the high temperatures of pasteurization which essentially nullifies most of the nutrient contents of the natural purée. As shown by the ECHCP analyses, excepting vitamin C content at 31% of DRI, TNJ bears no significant nutrition. Its macronutrient content provides just 8% of the DRI for carbohydrates, only traces of other macronutrients and low or trace levels of 10 essential vitamins, 7 essential dietary minerals and 18 amino acids. Although the most significant nutrient feature of noni pulp powder or juice is its high vitamin C content, this level in TNJ provides only about half the vitamin C of a raw navel orange. Sodium levels in TNJ (about 3% of DRI) are multiples of those in an orange. Although the potassium content appears relatively high for noni, this total is only about 3% of the Recommended Dietary Allowance and so would not be considered excessive. TNJ is otherwise similar in micronutrient content to a raw orange. ## Phytochemicals The history of published medical research on noni phytochemicals numbers only around a total of 120 reports which began appearing in the 1950s. Just since 2000, about 105 publications on noni have been published in medical literature, defining a relatively young research field (August, 2007). Nearly all noni research is at a preliminary stage, still in the laboratory as in vitro or basic animal experiments. Noni fruit contains phytochemicals for which there are no established DRI values. Examples: - oligo- and polysaccharides – long-chain sugar molecules that serve a prebiotic function as dietary fiber fermentable by colonic bacteria, yielding short chain fatty acids with numerous potential health properties not yet defined by scientific research on noni - glycosides – sugar-phenolic compounds including flavonoids such as rutin and asperulosidic acid, are common in several Rubiaceae plants; specifically named noni isolates called iridoides and morindoides have been reported, but are not well characterized to date - trisaccharide fatty-acid esters, "noniosides" - resulting from combination of an alcohol and an acid in noni fruit, noniosides are chemicals giving noni its noxious smell and taste - scopoletin – may have antibiotic activities; research is preliminary - beta-sitosterol – a plant sterol with potential for anti-cholesterol activity not yet proven in human research - damnacanthal – an anthraquinone having potential as an inhibitor of HIV viral proteins - alkaloids – naturally occurring amines from plants, often attributed to causing bitter tastes and so may contribute to the foul taste of noni. Some internet references mention xeronine or proxeronine as important noni constituents. However, as no reports on either of these substances exist in published medical literature, the terms are scientifically unrecognized. Although there is evidence from in vitro studies and laboratory models for bioactivity of each of the above phytochemicals, the research remains at best preliminary and too early to conclude anything about human health benefits provided by noni or its juice. Furthermore, nearly all these compounds exist in many plant foods, so are not unique to noni. # Uses Although noni has a reputation for uses in folk medicine extending over centuries, no medical applications as those discussed below have been verified by modern science. In China, Samoa, Japan, and Tahiti, various parts of the tree (leaves, flowers, fruits, bark, roots) serve as tonics and to contain fever, to treat eye and skin problems, gum and throat problems as well as constipation, stomach pain, or respiratory difficulties. In Malaysia, heated noni leaves applied to the chest are believed to relieve coughs, nausea, or colic. The noni fruit is taken, in Indochina especially, for asthma, lumbago, and dysentery. As for external uses, unripe fruits can be pounded, then mixed with salt and applied to cut or broken bones. In Hawaii, ripe fruits are applied to draw out pus from an infected boil. The green fruit, leaves and the root/rhizome have traditionally been used to treat menstrual cramps and irregularities, among other symptoms, while the root has also been used to treat urinary difficulties. The bark of the great morinda produces a brownish-purplish dye for batik making; on the Indonesian island of Java, the trees are cultivated for this purpose. In Hawaii, yellowish dye is extracted from its root in order to dye cloth. The fruit is used as a shampoo in Malaysia, where it is said to be helpful against head lice. There have been recent applications also for the use of oil from noni seeds. Noni seed oil is abundant in linoleic acid that may have useful properties when applied topically on skin, e.g., anti-inflammation, acne reduction, moisture retention. In Surinam and different other countries, the tree serves as a wind-break, as support for vines and as shade for coffee trees. # Noni juice ## The noni juice market Sold in capsule form, pulp powder was the first noni product brought to the commercial market in Hawaii by Herbert Moniz of Herb's Herbs in 1992 after patenting a unique noni dehydrating method. (US 5288491 ) In 1995, David Marcus, of Hawaiian Herbal Blessings Inc., began marketing the first traditionally fermented noni juice from Maui, Hawaii. There are now approximately 300 companies marketing noni juice in a global market estimated at more than $2 billion annually. In 1996, Morinda Inc. (now Tahitian Noni International with headquarters in Orem, Utah) acquired noni from French Polynesia to manufacture juice, capsule and personal care products for the western market, achieving $1 billion in sales over the next seven years. Today, raw materials for noni juices on the world market mainly come from Polynesia but most manufacturers are in the United States. ## Regulatory warnings and safety testing In August 2004, the US Food and Drug Administration issued a warning letter to Flora, Inc. for violating section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act (the Act) . Flora made twelve unfounded health claims about the purported benefits of noni juice as a medical product, in effect causing the juice to be evaluated as a drug. Under the Act, this necessitates all safety and clinical trial evidence for the juice providing such effects in humans. The FDA letter also cited 1) absent scientific evidence for health benefits of noni phytochemicals, scopoletin and damnacanthal, neither of which has been confirmed with biological activity in humans, and 2) lack of scientific foundation for health claims made by two proponents of noni juice, Dr. Isabella Abbot and Dr. Ralph Heinicke. Two other FDA letters have been issued for the same types of violations. In the European Union, after safety testing on one particular brand of noni juice (Tahitian Noni), approval was granted in 2002 as a novel food by the European Commission for Health and Consumer Protection Directorate-General. In their report, the European Commission's Scientific Committee made no endorsement of health claims. No noni products have achieved sufficient scientific foundation for being licensed as medicines or therapies. Companies today must still apply to the European Commission for Health and Consumer Protection Directorate-General to have their own brand of noni juice included as a novel food under the initial approval. ## Health and research issues In 2005, two scientific publications described incidents of acute hepatitis caused by ingesting noni. One study suggested the toxin to be anthraquinones, found in roots, leaves and fruit of the noni, while the other named juice as the delivery method. This was, however, followed by a publication showing that noni juice 1) was not toxic to the liver even when consumed in high doses, and 2) contained low quantities of anthraquinones which are potentially toxic to liver tissue.. The potential for toxicity caused by noni juices remains under surveillance by the European Food Safety Authority (EFSA), individual food safety authorities in France, Finland and Ireland, and medical investigators in Germany. The Physicians Desk Reference ("PDR") for Non-Prescription Drugs and Dietary Supplements lists only one particular commercial brand of noni juice, with no side-effects mentioned.Consumers of noni juice are advised to carefully check labels for warnings which may say, "Not safe for pregnant women" or "Keep out of reach of children." Some commercial brands of noni juice can be high in potassium. While potassium is a valuable nutrient in a normal diet, persons with advanced kidney disease cannot excrete it properly and should avoid noni juice which has been known to cause hyperkalemia.. Of related significance is a report showing high variability in mineral contents between various brands of noni juice. Athletes intending to use noni juice to supplement their diet should be aware that two brands of noni juice are listed on ConsumerLab.com's "Athletic Banned Substance Screening Program" as having been screened for substances on the World Anti-Doping Code Prohibited List.. ### Preliminary medical research Over the years since 1994, noni has increasingly stimulated the interest of medical science, with 114 papers published since then and 36 just in 2006-7 (search "noni"). Despite the large market for juice products and research developments, the nutrient and phytochemical profiles of noni have not been extensively studied. Furthermore, 1) numerous health claims made in noni juice marketing are not supported by scientific research and 2) in human clinical trials, only one cancer study completed under NIH peer-review in 2006 has been conducted, the results of which remain unpublished as of August 2007. Likewise, in a university-based clinical trial funded by the noni juice manufacturer, Tahitian Noni International, Inc., it was shown that noni juice consumption lowered blood cholesterol levels. Completed in 2006, however, the results of this study have not been published under peer-review and have met critical judgment by experts. Laboratory studies have investigated noni's effect on the growth of cancerous tissue in mice. One such study in vitro found that noni reduced growth of capillary vessels sprouting from human breast tumor explants and, at increased concentrations, caused existing vessels to degenerate. It remains unknown whether such effects occur in vivo in other animal models or in cancer patients. Another study showed noni juice to inhibit formation of cancer cells in rats (using detection methods of biochemical markers called DNA adducts). It further showed a reduced number of DNA adducts in rats induced with a carcinogen. The same study showed effective antioxidant properties of noni juice compared with those of vitamin C, grape seed powder, and pycnogenol. The results indicated reduced carcinogen-DNA adduct formation in this laboratory model and antioxidant activity that may be relevant to anti-cancer mechanisms. As such findings have neither been confirmed by other laboratory experiments nor demonstrated in expert-reviewed human clinical trials, no inference can be made about whether noni has anti-cancer properties.

Noni Morinda citrifolia, commonly known as Great morinda, Indian mulberry, Beach mulberry, Tahitian Noni, or since recently: Noni (from Hawaiian), Nono (in Tahitian), Mengkudu (from Malay), Nonu (in Tongan), and Ach (in Hindi), is a shrub or small tree in the family Rubiaceae. Morinda citrifolia is native to Southeast Asia but has been extensively spread by man throughout India and into the Pacific islands as far as the islands of French Polynesia, of which Tahiti is the most prominent. It can also be found in parts of the West Indies. Noni grows in shady forests as well as on open rocky or sandy shores. It reaches maturity in about 18 months and then yields between 4-8 kg of fruit every month throughout the year. It is tolerant of saline soils, drought conditions, and secondary soils. It is therefore found in a wide variety of habitats: volcanic terrains, lava-strewn coasts, and clearings or limestone outcrops. It can grow up to 9 m tall, and has large, simple, dark green, shiny and deeply veined leaves. The plant flowers and fruits all year round and prodces a small white flower. The fruit is a multiple fruit that has a pungent odor when ripening, and is hence also known as cheese fruit or even vomit fruit. It is oval and reaches 4-7 cm in size. At first green, the fruit turns yellow then almost white as it ripens. It contains many seeds. It is sometimes called starvation fruit. Despite its strong smell and bitter taste, the fruit is nevertheless eaten as a famine food[1] and, in some Pacific islands, even a staple food, either raw or cooked.[2] Southeast Asians and Australian Aborigines consume the fruit raw with salt or cook it with curry. The seeds are edible when roasted. The noni is especially attractive to weaver ants, which make nests out of the leaves of the tree. These ants protect the plant from some plant-parasitic insects. The smell of the fruit also attracts fruit bats, which aid in dispersing the seeds. # Nutrients Nutritional information for noni fruit is reported by the College of Tropical Agriculture, University of Hawaii at Mānoa who published analyses of fruit powder and pure juice. ## Macronutrients Analyzed as a whole fruit powder[3], noni fruit has excellent levels of carbohydrates and dietary fiber, providing 55% and 100% of the Dietary Reference Intakes, respectively, in a 100 g serving. A good source of protein (12% DRI), noni pulp is low in total fats (4% DRI). These macronutrients evidently reside in the fruit pulp, as noni juice has sparse amounts of macronutrients[4]. ## Micronutrients The main micronutrient features of noni pulp powder include exceptional vitamin C content (10x DRI) and substantial amounts of niacin (vitamin B3), iron and potassium[5]. Vitamin A, calcium and sodium are present in moderate amounts. When noni juice alone is analyzed and compared to pulp powder, only vitamin C is retained at a high level, 42% of DRI. Nutrient analyses for a major brand of noni juice (Tahitian Noni Juice™, TNJ) were published in 2002 by the Scientific Committee on Food of the European Commission on Health and Consumer Protection (ECHCP) [6] during a test for public safety of TNJ. TNJ ingredients include noni purée and juice concentrates from grapes and blueberries. For antimicrobial purposes, TNJ must be subjected to the high temperatures of pasteurization which essentially nullifies most of the nutrient contents of the natural purée. As shown by the ECHCP analyses, excepting vitamin C content at 31% of DRI, TNJ bears no significant nutrition. Its macronutrient content provides just 8% of the DRI for carbohydrates, only traces of other macronutrients and low or trace levels of 10 essential vitamins, 7 essential dietary minerals and 18 amino acids. Although the most significant nutrient feature of noni pulp powder or juice is its high vitamin C content, this level in TNJ provides only about half the vitamin C of a raw navel orange[7]. Sodium levels in TNJ (about 3% of DRI) are multiples of those in an orange. Although the potassium content appears relatively high for noni, this total is only about 3% of the Recommended Dietary Allowance and so would not be considered excessive. TNJ is otherwise similar in micronutrient content to a raw orange[8]. ## Phytochemicals The history of published medical research on noni phytochemicals numbers only around a total of 120 reports which began appearing in the 1950s. Just since 2000, about 105 publications on noni have been published in medical literature, defining a relatively young research field (August, 2007). Nearly all noni research is at a preliminary stage, still in the laboratory as in vitro or basic animal experiments. Noni fruit contains phytochemicals for which there are no established DRI values. Examples: - oligo- and polysaccharides – long-chain sugar molecules that serve a prebiotic function as dietary fiber fermentable by colonic bacteria, yielding short chain fatty acids with numerous potential health properties not yet defined by scientific research on noni - glycosides – sugar-phenolic compounds including flavonoids such as rutin and asperulosidic acid, are common in several Rubiaceae plants; specifically named noni isolates called iridoides and morindoides have been reported, but are not well characterized to date - trisaccharide fatty-acid esters, "noniosides" - resulting from combination of an alcohol and an acid in noni fruit, noniosides are chemicals giving noni its noxious smell and taste - scopoletin – may have antibiotic activities; research is preliminary - beta-sitosterol – a plant sterol with potential for anti-cholesterol activity not yet proven in human research - damnacanthal – an anthraquinone having potential as an inhibitor of HIV viral proteins - alkaloids – naturally occurring amines from plants, often attributed to causing bitter tastes and so may contribute to the foul taste of noni. Some internet references mention xeronine or proxeronine as important noni constituents. However, as no reports on either of these substances exist in published medical literature, the terms are scientifically unrecognized. Although there is evidence from in vitro studies and laboratory models for bioactivity of each of the above phytochemicals, the research remains at best preliminary and too early to conclude anything about human health benefits provided by noni or its juice. Furthermore, nearly all these compounds exist in many plant foods, so are not unique to noni. # Uses Although noni has a reputation for uses in folk medicine extending over centuries[9], no medical applications as those discussed below have been verified by modern science. In China, Samoa, Japan, and Tahiti, various parts of the tree (leaves, flowers, fruits, bark, roots) serve as tonics and to contain fever, to treat eye and skin problems, gum and throat problems as well as constipation, stomach pain, or respiratory difficulties.[citation needed] In Malaysia, heated noni leaves applied to the chest are believed to relieve coughs, nausea, or colic.[citation needed] The noni fruit is taken, in Indochina especially, for asthma, lumbago, and dysentery.[citation needed] As for external uses, unripe fruits can be pounded, then mixed with salt and applied to cut or broken bones.[citation needed] In Hawaii, ripe fruits are applied to draw out pus from an infected boil. The green fruit, leaves and the root/rhizome have traditionally been used to treat menstrual cramps and irregularities, among other symptoms, while the root has also been used to treat urinary difficulties.[10] The bark of the great morinda produces a brownish-purplish dye for batik making; on the Indonesian island of Java, the trees are cultivated for this purpose. In Hawaii, yellowish dye is extracted from its root in order to dye cloth.[11] The fruit is used as a shampoo in Malaysia, where it is said to be helpful against head lice.[citation needed] There have been recent applications also for the use of oil from noni seeds.[citation needed] Noni seed oil is abundant in linoleic acid that may have useful properties when applied topically on skin, e.g., anti-inflammation, acne reduction, moisture retention.[12] [13] [14] In Surinam and different other countries, the tree serves as a wind-break, as support for vines and as shade for coffee trees. # Noni juice ## The noni juice market Sold in capsule form, pulp powder was the first noni product brought to the commercial market in Hawaii by Herbert Moniz of Herb's Herbs in 1992 after patenting a unique noni dehydrating method. (US 5288491 ) In 1995, David Marcus, of Hawaiian Herbal Blessings Inc., began marketing the first traditionally fermented noni juice from Maui, Hawaii. There are now approximately 300 companies marketing noni juice in a global market estimated at more than $2 billion annually[15][16]. In 1996, Morinda Inc. (now Tahitian Noni International with headquarters in Orem, Utah) acquired noni from French Polynesia to manufacture juice, capsule and personal care products for the western market, achieving $1 billion in sales over the next seven years. Today, raw materials for noni juices on the world market mainly come from Polynesia but most manufacturers are in the United States. ## Regulatory warnings and safety testing In August 2004, the US Food and Drug Administration issued a warning letter to Flora, Inc. for violating section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 321(g)(1)]. Flora made twelve unfounded health claims about the purported benefits of noni juice as a medical product, in effect causing the juice to be evaluated as a drug. Under the Act, this necessitates all safety and clinical trial evidence for the juice providing such effects in humans. [17] The FDA letter also cited 1) absent scientific evidence for health benefits of noni phytochemicals, scopoletin and damnacanthal, neither of which has been confirmed with biological activity in humans, and 2) lack of scientific foundation for health claims made by two proponents of noni juice, Dr. Isabella Abbot and Dr. Ralph Heinicke[18]. Two other FDA letters have been issued for the same types of violations[19][20]. In the European Union, after safety testing on one particular brand of noni juice (Tahitian Noni), approval was granted in 2002 as a novel food by the European Commission for Health and Consumer Protection Directorate-General. [21] In their report, the European Commission's Scientific Committee made no endorsement of health claims. No noni products have achieved sufficient scientific foundation for being licensed as medicines or therapies. Companies today must still apply to the European Commission for Health and Consumer Protection Directorate-General to have their own brand of noni juice included as a novel food under the initial approval. ## Health and research issues In 2005, two scientific publications described incidents of acute hepatitis caused by ingesting noni. One study suggested the toxin to be anthraquinones, found in roots, leaves and fruit of the noni,[22] [23]while the other named juice as the delivery method.[24] This was, however, followed by a publication [25] showing that noni juice 1) was not toxic to the liver even when consumed in high doses, and 2) contained low quantities of anthraquinones which are potentially toxic to liver tissue.[26]. The potential for toxicity caused by noni juices remains under surveillance by the European Food Safety Authority (EFSA)[27], individual food safety authorities in France[28], Finland[29] and Ireland[30], and medical investigators in Germany[31]. The Physicians Desk Reference ("PDR") for Non-Prescription Drugs and Dietary Supplements lists only one particular commercial brand of noni juice, with no side-effects mentioned.[32]Consumers of noni juice are advised to carefully check labels for warnings which may say, "Not safe for pregnant women" or "Keep out of reach of children." Some commercial brands of noni juice can be high in potassium[citation needed]. While potassium is a valuable nutrient in a normal diet, persons with advanced kidney disease cannot excrete it properly and should avoid noni juice which has been known to cause hyperkalemia.[33]. Of related significance is a report showing high variability in mineral contents between various brands of noni juice.[34] Athletes intending to use noni juice to supplement their diet should be aware that two brands of noni juice are listed on ConsumerLab.com's "Athletic Banned Substance Screening Program" as having been screened for substances on the World Anti-Doping Code Prohibited List.[35]. ### Preliminary medical research Over the years since 1994, noni has increasingly stimulated the interest of medical science, with 114 papers published since then and 36 just in 2006-7[36] (search "noni"). Despite the large market for juice products and research developments, the nutrient and phytochemical profiles of noni have not been extensively studied. Furthermore, 1) numerous health claims made in noni juice marketing are not supported by scientific research[37][38] and 2) in human clinical trials, only one cancer study completed under NIH peer-review in 2006 has been conducted, the results of which remain unpublished[39] as of August 2007. Likewise, in a university-based clinical trial funded by the noni juice manufacturer, Tahitian Noni International, Inc., it was shown that noni juice consumption lowered blood cholesterol levels[40]. Completed in 2006, however, the results of this study have not been published under peer-review and have met critical judgment by experts[41][42]. Laboratory studies have investigated noni's effect on the growth of cancerous tissue in mice.[43] One such study in vitro found that noni reduced growth of capillary vessels sprouting from human breast tumor explants and, at increased concentrations, caused existing vessels to degenerate.[44] It remains unknown whether such effects occur in vivo in other animal models or in cancer patients. Another study showed noni juice to inhibit formation of cancer cells in rats (using detection methods of biochemical markers called DNA adducts). It further showed a reduced number of DNA adducts in rats induced with a carcinogen. The same study showed effective antioxidant properties of noni juice compared with those of vitamin C, grape seed powder, and pycnogenol. The results indicated reduced carcinogen-DNA adduct formation in this laboratory model and antioxidant activity that may be relevant to anti-cancer mechanisms.[45] As such findings have neither been confirmed by other laboratory experiments nor demonstrated in expert-reviewed human clinical trials, no inference can be made about whether noni has anti-cancer properties.

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

e502b5c51d25b809d3897a36c55495f8d9c060e3

wikidoc

Muon

Muon The muon (from the letter mu (μ)--used to represent it) is an elementary particle with negative electric charge and a spin of 1/2. It has a mean lifetime of 2.2μs, longer than any other unstable lepton, meson, or baryon except for the neutron. Together with the electron, the tau, and the neutrinos, it is classified as a lepton. Like all fundamental particles, the muon has an antimatter partner of opposite charge but equal mass and spin: the antimuon, also called a positive muon. Muons are denoted by μ− and antimuons by μ+. For historical reasons, muons are sometimes referred to as mu mesons, even though they are not classified as mesons by modern particle physicists (see History). Muons have a mass of 105.7 MeV/c2, which is 206.7 times the electron mass. Since their interactions are very similar to those of the electron, a muon can be thought of as a much heavier version of the electron. Due to their greater mass, muons do not emit as much bremsstrahlung radiation; consequently, they are highly penetrating, much more so than electrons. As with the case of the other charged leptons, there is a muon-neutrino which has the same flavor as the muon. Muon-neutrinos are denoted by νμ. # Muon sources Since the production of muons requires an available center of momentum frame energy of over 105 MeV, neither ordinary radioactive decay events nor nuclear fission and fusion events (such as those occurring in nuclear reactors and nuclear weapons) are energetic enough to produce muons. Only nuclear fission produces single-nuclear-event energies in this range, but due to conservation constraints, muons are not produced. On earth, all naturally occurring muons are apparently created by cosmic rays, which consist mostly of protons, many arriving from deep space at very high energy. About 10,000 muons reach every square meter of the earth's surface a minute; these charged particles form as by-products of cosmic rays colliding with molecules in the upper atmosphere. Traveling at relativistic speeds, muons can penetrate tens of meters into rocks and other matter before attenuating as a result of absorption or deflection by other atoms. When a cosmic ray proton impacts atomic nuclei of air atoms in the upper atmosphere, pions are created. These decay within a relatively short distance (meters) into muons (the pion's preferred decay product), and neutrinos. The muons from these high energy cosmic rays, generally continuing essentially in the same direction as the original proton, do so at very high velocities. Although their lifetime without relativistic effects would allow a half-survival distance of only about 0.66 km at most, the time dilation effect of special relativity allows cosmic ray secondary muons to survive the flight to the earth's surface. Indeed, since muons are unusually penetrative of ordinary matter, like neutrinos, they are also detectable deep underground and underwater, where they form a major part of the natural background ionizing radiation. Like cosmic rays, as noted, this secondary muon radiation is also directional. See the illustration above of the moon's cosmic ray shadow, detected when 700 m of soil and rock filters secondary radiation, but allows enough muons to form a crude image of the moon, in a directional detector. The same nuclear reaction described above (i.e., hadron-hadron impacts to produce pion beams, which then quickly decay to muon beams over short distances) is used by particle physicists to produce muon beams, such as the beam used for the muon g-2 gyromagnetic ratio experiment (see link below). In naturally-produced muons, the very high-energy protons to begin the process are thought to originate from acceleration by electromagnetic fields over long distances between stars or galaxies, in a manner somewhat analogous to the mechanism of proton acceleration used in laboratory particle accelerators. # Muon decays Muons are unstable elementary particles and are heavier than the electron and neutrinos but lighter than all other matter particles. They decay via the weak interaction to an electron, two neutrinos and possibly other particles with a net charge of zero. Nearly all of the time, they decay into an electron, an electron-antineutrino, and a muon-neutrino. Antimuons decay to a positron, an electron-neutrino, and a muon-antineutrino: The tree level muon decay width is A photon or electron-positron pair is also present in the decay products about 1.4% of the time. The mean lifetime of the muon is 2.197019±0.000021 μs. The equality of the muon and anti-muon lifetimes has been established to better than one part in 104. The decay distributions of the electron in muon decays have been parametrized using the so-called Michel parameters. The values of these five parameters can be predicted unambiguously in the Standard Model of particle physics—no deviation with respect to these predictions has yet been found. Certain neutrino-less decay modes are kinematically allowed but forbidden in the Standard Model. Examples are Observation of such decay modes would constitute clear evidence for physics beyond the Standard Model (BSM). Upper limits for the branching fractions of such decay modes are in the range 10−11 to 10−12. # Muonic atoms The muon was the first elementary particle discovered that does not appear in ordinary atoms. Negative muons can, however, form muonic atoms by replacing an electron in ordinary atoms. Muonic atoms are much smaller than typical atoms because the larger mass of the muon gives it a smaller ground-state wavefunction than the electron. A positive muon, when stopped in ordinary matter, can also bind an electron and form an exotic atom known as muonium (Mu) atom, in which the muon acts as the nucleus. The positive muon, in this context, can be considered a pseudo-isotope of hydrogen with one ninth of the mass of the proton. Because the reduced mass of muonium, and hence its Bohr radius, is very close to that of hydrogen, this short lived "atom" behaves chemically — to a first approximation — like hydrogen, deuterium and tritium. # Anomalous magnetic dipole moment The anomalous magnetic dipole moment is the difference between the experimentally observed value of the magnetic dipole moment and the theoretical value predicted by the Dirac equation. The measurement and prediction of this value is very important in the precision tests of QED (quantum electrodynamics). The E821 experiment at Brookhaven National Laboratory (BNL) studied the precession of muon and anti-muon in a constant external magnetic field as they circulated in a confining storage ring. The E821 Experiment reported the following average value (from the July 2007 review by Particle Data Group) where the first errors are statistical and the second systematic. The difference between the g-factors of the muon and the electron is due to their difference in mass. Because of the muon's larger mass, contributions to the theoretical calculation of its anomalous magnetic dipole moment from Standard Model weak interactions and from contributions involving hadrons are important at the current level of precision, whereas these effects are not important for the electron. The muon's anomalous magnetic dipole moment is also sensitive to contributions from new physics beyond the Standard Model, such as supersymmetry. For this reason, the muon's anomalous magnetic moment is normally used as a probe for new physics beyond the Standard Model rather than as a test of QED (Phys.Lett. B649, 173 (2007)). # History Muons were discovered by Carl D. Anderson in 1936 while he studied cosmic radiation. He had noticed particles that curved in a manner distinct from that of electrons and other known particles, when passed through a magnetic field. In particular, these new particles were negatively charged but curved to a smaller degree than electrons, but more sharply than protons, for particles of the same velocity. It was assumed that the magnitude of their negative electric charge was equal to that of the electron, and so to account for the difference in curvature, it was supposed that these particles were of intermediate mass (lying somewhere between that of an electron and that of a proton). For this reason, Anderson initially called the new particle a mesotron, adopting the prefix meso- from the Greek word for "mid-". Shortly thereafter, additional particles of intermediate mass were discovered, and the more general term meson was adopted to refer to any such particle. Faced with the need to differentiate between different types of mesons, the mesotron was in 1947 renamed the mu meson (with the Greek letter μ (mu) used to approximate the sound of the Latin letter m). However, it was soon found that the mu meson significantly differed from other mesons; for example, its decay products included a neutrino and an antineutrino, rather than just one or the other, as was observed in other mesons. Other mesons were eventually understood to be hadrons—that is, particles made of quarks—and thus subject to the residual strong force. In the quark model, a meson is composed of exactly two quarks (a quark and antiquark), unlike baryons which are composed of three quarks. Mu mesons, however, were found to be fundamental particles (leptons) like electrons, with no quark structure. Thus, mu mesons were not mesons at all (in the new sense and use of the term meson), and so the term mu meson was abandoned, and replaced with the modern term muon.

Muon Template:Infobox Particle The muon (from the letter mu (μ)--used to represent it) is an elementary particle with negative electric charge and a spin of 1/2. It has a mean lifetime of 2.2μs, longer than any other unstable lepton, meson, or baryon except for the neutron. Together with the electron, the tau, and the neutrinos, it is classified as a lepton. Like all fundamental particles, the muon has an antimatter partner of opposite charge but equal mass and spin: the antimuon, also called a positive muon. Muons are denoted by μ− and antimuons by μ+. For historical reasons, muons are sometimes referred to as mu mesons, even though they are not classified as mesons by modern particle physicists (see History). Muons have a mass of 105.7 MeV/c2, which is 206.7 times the electron mass. Since their interactions are very similar to those of the electron, a muon can be thought of as a much heavier version of the electron. Due to their greater mass, muons do not emit as much bremsstrahlung radiation; consequently, they are highly penetrating, much more so than electrons. As with the case of the other charged leptons, there is a muon-neutrino which has the same flavor as the muon. Muon-neutrinos are denoted by νμ. # Muon sources Since the production of muons requires an available center of momentum frame energy of over 105 MeV, neither ordinary radioactive decay events nor nuclear fission and fusion events (such as those occurring in nuclear reactors and nuclear weapons) are energetic enough to produce muons. Only nuclear fission produces single-nuclear-event energies in this range, but due to conservation constraints, muons are not produced. On earth, all naturally occurring muons are apparently created by cosmic rays, which consist mostly of protons, many arriving from deep space at very high energy. About 10,000 muons reach every square meter of the earth's surface a minute; these charged particles form as by-products of cosmic rays colliding with molecules in the upper atmosphere. Traveling at relativistic speeds, muons can penetrate tens of meters into rocks and other matter before attenuating as a result of absorption or deflection by other atoms. When a cosmic ray proton impacts atomic nuclei of air atoms in the upper atmosphere, pions are created. These decay within a relatively short distance (meters) into muons (the pion's preferred decay product), and neutrinos. The muons from these high energy cosmic rays, generally continuing essentially in the same direction as the original proton, do so at very high velocities. Although their lifetime without relativistic effects would allow a half-survival distance of only about 0.66 km at most, the time dilation effect of special relativity allows cosmic ray secondary muons to survive the flight to the earth's surface. Indeed, since muons are unusually penetrative of ordinary matter, like neutrinos, they are also detectable deep underground and underwater, where they form a major part of the natural background ionizing radiation. Like cosmic rays, as noted, this secondary muon radiation is also directional. See the illustration above of the moon's cosmic ray shadow, detected when 700 m of soil and rock filters secondary radiation, but allows enough muons to form a crude image of the moon, in a directional detector. The same nuclear reaction described above (i.e., hadron-hadron impacts to produce pion beams, which then quickly decay to muon beams over short distances) is used by particle physicists to produce muon beams, such as the beam used for the muon g-2 gyromagnetic ratio experiment (see link below). In naturally-produced muons, the very high-energy protons to begin the process are thought to originate from acceleration by electromagnetic fields over long distances between stars or galaxies, in a manner somewhat analogous to the mechanism of proton acceleration used in laboratory particle accelerators. # Muon decays Muons are unstable elementary particles and are heavier than the electron and neutrinos but lighter than all other matter particles. They decay via the weak interaction to an electron, two neutrinos and possibly other particles with a net charge of zero. Nearly all of the time, they decay into an electron, an electron-antineutrino, and a muon-neutrino. Antimuons decay to a positron, an electron-neutrino, and a muon-antineutrino: The tree level muon decay width is A photon or electron-positron pair is also present in the decay products about 1.4% of the time. The mean lifetime of the muon is 2.197019±0.000021 μs[1]. The equality of the muon and anti-muon lifetimes has been established to better than one part in 104. The decay distributions of the electron in muon decays have been parametrized using the so-called Michel parameters. The values of these five parameters can be predicted unambiguously in the Standard Model of particle physics—no deviation with respect to these predictions has yet been found. Certain neutrino-less decay modes are kinematically allowed but forbidden in the Standard Model. Examples are Observation of such decay modes would constitute clear evidence for physics beyond the Standard Model (BSM). Upper limits for the branching fractions of such decay modes are in the range 10−11 to 10−12. # Muonic atoms The muon was the first elementary particle discovered that does not appear in ordinary atoms. Negative muons can, however, form muonic atoms by replacing an electron in ordinary atoms. Muonic atoms are much smaller than typical atoms because the larger mass of the muon gives it a smaller ground-state wavefunction than the electron. A positive muon, when stopped in ordinary matter, can also bind an electron and form an exotic atom known as muonium (Mu) atom, in which the muon acts as the nucleus. The positive muon, in this context, can be considered a pseudo-isotope of hydrogen with one ninth of the mass of the proton. Because the reduced mass of muonium, and hence its Bohr radius, is very close to that of hydrogen, this short lived "atom" behaves chemically — to a first approximation — like hydrogen, deuterium and tritium. # Anomalous magnetic dipole moment The anomalous magnetic dipole moment is the difference between the experimentally observed value of the magnetic dipole moment and the theoretical value predicted by the Dirac equation. The measurement and prediction of this value is very important in the precision tests of QED (quantum electrodynamics). The E821 experiment at Brookhaven National Laboratory (BNL) studied the precession of muon and anti-muon in a constant external magnetic field as they circulated in a confining storage ring. The E821 Experiment reported the following average value (from the July 2007 review by Particle Data Group) where the first errors are statistical and the second systematic. The difference between the g-factors of the muon and the electron is due to their difference in mass. Because of the muon's larger mass, contributions to the theoretical calculation of its anomalous magnetic dipole moment from Standard Model weak interactions and from contributions involving hadrons are important at the current level of precision, whereas these effects are not important for the electron. The muon's anomalous magnetic dipole moment is also sensitive to contributions from new physics beyond the Standard Model, such as supersymmetry. For this reason, the muon's anomalous magnetic moment is normally used as a probe for new physics beyond the Standard Model rather than as a test of QED (Phys.Lett. B649, 173 (2007)). # History Template:Antimatter Muons were discovered by Carl D. Anderson in 1936 while he studied cosmic radiation. He had noticed particles that curved in a manner distinct from that of electrons and other known particles, when passed through a magnetic field. In particular, these new particles were negatively charged but curved to a smaller degree than electrons, but more sharply than protons, for particles of the same velocity. It was assumed that the magnitude of their negative electric charge was equal to that of the electron, and so to account for the difference in curvature, it was supposed that these particles were of intermediate mass (lying somewhere between that of an electron and that of a proton). For this reason, Anderson initially called the new particle a mesotron, adopting the prefix meso- from the Greek word for "mid-". Shortly thereafter, additional particles of intermediate mass were discovered, and the more general term meson was adopted to refer to any such particle. Faced with the need to differentiate between different types of mesons, the mesotron was in 1947 renamed the mu meson (with the Greek letter μ (mu) used to approximate the sound of the Latin letter m). However, it was soon found that the mu meson significantly differed from other mesons; for example, its decay products included a neutrino and an antineutrino, rather than just one or the other, as was observed in other mesons. Other mesons were eventually understood to be hadrons—that is, particles made of quarks—and thus subject to the residual strong force. In the quark model, a meson is composed of exactly two quarks (a quark and antiquark), unlike baryons which are composed of three quarks. Mu mesons, however, were found to be fundamental particles (leptons) like electrons, with no quark structure. Thus, mu mesons were not mesons at all (in the new sense and use of the term meson), and so the term mu meson was abandoned, and replaced with the modern term muon.

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

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MyoD

MyoD MyoD is a protein that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of proteins known as myogenic regulatory factors (MRFs). These bHLH (basic helix loop helix) transcription factors act sequentially in myogenic differentiation. MRF family members include MyoD, Myf5, myogenin, and MRF4 (Myf6). MyoD is one of the earliest markers of myogenic commitment. MyoD is expressed at extremely low and essentially undetectable levels in quiescent satellite cells, but expression of MyoD is activated in response to exercise or muscle tissue damage. The effect of MyoD on satellite cells is dose-dependent; high MyoD expression represses cell renewal, promotes terminal differentiation and can induce apoptosis. Although MyoD marks myoblast commitment, muscle development is not dramatically ablated in mouse mutants lacking the MyoD gene. This is likely due to functional redundancy from Myf5 and/or Mrf4. Nevertheless, the combination of MyoD and Myf5 is vital to the success of myogenesis. # History MyoD was cloned by an ingenious functional assay for muscle formation reported in Cell in 1987 by Davis, Weintraub, and Lassar. It was first described as a nuclear phosphoprotein in 1988 by Tapscott, Davis, Thayer, Cheng, Weintraub, and Lassar in Science. The researchers expressed the complementary DNA (cDNA) of the murine MyoD protein in a different cell lines (fibroblast and adipoblast) and found MyoD converted them to myogenic cells. The following year, the same research team performed several tests to determine both the structure and function of the protein, confirming their initial proposal that the active site of the protein consisted of the helix loop helix (now referred to as basic helix loop helix) for dimerization and a basic site upstream of this bHLH region facilitated DNA binding only once it became a protein dimer. MyoD has since been an active area of research as still relatively little is known concerning many aspects of its function. # Function The function of MyoD in development is to commit mesoderm cells to a skeletal myoblast lineage, and then to regulate that continued state. MyoD may also regulate muscle repair. MyoD mRNA levels are also reported to be elevated in aging skeletal muscle. One of the main actions of MyoD is to remove cells from the cell cycle (halt proliferation for terminal cell cycle arrest in differentiated myocytes) by enhancing the transcription of p21 and myogenin. MyoD is inhibited by cyclin dependent kinases (CDKs). CDKs are in turn inhibited by p21. Thus MyoD enhances its own activity in the cell in a feedforward manner. Sustained MyoD expression is necessary for retaining the expression of muscle-related genes. MyoD is also an important effector for the fast-twitch muscle fiber (types IIA, IIX, and IIB) phenotype. # Mechanisms MyoD is a transcription factor and can also direct chromatin remodelling through binding to a DNA motif known as the E-box. MyoD is known to have binding interactions with hundreds of muscular gene promoters and to permit myoblast proliferation. While not completely understood, MyoD is now thought to function as a major myogenesis controller in an on/off switch association mediated by KAP1 (KRAB -associated protein 1) phosphorylation. KAP1 is localized at muscle-related genes in myoblasts along with both MyoD and Mef2 (a myocyte transcription enhancer factor). Here, it serves as a scaffold and recruits the coactivators p300 and LSD1, in addition to several corepressors which include G9a and the Histone deacetylase HDAC1. The consequence of this coactivator/corepressor recruitment is silenced promoting regions on muscle genes. When the kinase MSK1 phosphorylates KAP1, the corepressors previously bound to the scaffold are released allowing MyoD and Mef2 to activate transcription. Once the "master controller" MyoD has become active, SETDB1 is required to maintain MyoD expression within the cell. Setdb1 appears to be necessary to maintain both MyoD expression and also genes that are specific to muscle tissues because reduction of Setdb1 expression results in a severe delay of myoblast differentiation and determination. In Setdb1 depleted myoblasts that are treated with exogenous MyoD, myoblastic differentiation is successfully restored. In one model of Setdb1 action on MyoD, Setdb1 represses an inhibitor of MyoD. This unidentified inhibitor likely acts competitively against MyoD during typical cellular proliferation. Evidence for this model is that reduction of Setdb1 results in direct inhibition of myoblast differentiation which may be caused by the release of the unknown MyoD inhibitor. MyoD has also been shown to function cooperatively with the tumor suppressor gene, Retinoblastoma (pRb) to cause cell cycle arrest in the terminally differentiated myoblasts. This is done through regulation of the Cyclin, Cyclin D1. Cell cycle arrest (in which myoblasts would indicate the conclusion of myogenesis) is dependent on the continuous and stable repression of the D1 cyclin. Both MyoD and pRb are necessary for the repression of cyclin D1, but rather than acting directly on cyclin D1, they act on Fra-1 which is immediately early of cyclin D1. MyoD and pRb are both necessary for repressing Fra-1 (and thus cyclin D1) as either MyoD or pRb on its own is not sufficient alone to induce cyclin D1 repression and thus cell cycle arrest. In an intronic enhancer of Fra-1 there were two conserved MyoD binding sites discovered. There is cooperative action of MyoD and pRb at the Fra-1 intronic enhancer that suppresses the enhancer, therefore suppressing cyclin D1 and ultimately resulting in cell cycle arrest for terminally differentiated myoblasts. # Role in the wnt signalling pathway The Wnt signalling pathway family refers to a group of secreted paracrine signaling proteins. Nineteen glycoproteins have been identified as members of this family. Wnts bind to the plasma membrane receptor Frizzled on the target cells. Several different intracellular pathways of signalling are activated by Wnts interacting with the Frizzled receptor. One of the most common is inhibition of glycogen synthase kinase 3β (GSK3β) which functions to destroy β-catenin. This inhibition allows β-catenin to accumulate in the cell cytoplasm and eventual translocation into the nucleus. In the canonical Wnt pathway, nuclear β-catenin forms a dimer with T-cell factor (TCF) and lympoid enhaner factor (LEF) on the gene promoter that is targeted. This initiates transcription and mediates the physiological response to the initial Wnt signal. Wnt-Frizzled pathways also are known to activate c-Jun N-terminal kinases (JNKs) in the cytoplasm. Wnts also drive the translocation of NFATs into the nucleus to initiate the transcription of the targeted genes. Proteins involved in the Wnt signalling pathway induce cells in somites and competent tissues that receive these wnt signals to actively express Pax3 and Pax7 in addition to myogenic regulatory factors, including Myf5 and MyoD. Specifically, Wnt3a is responsible for direct induction of MyoD expression via cis-element interactions with a distal enhancer and Wnt response element. In typical adult muscles in a resting condition (absence of physiological stress) the specific Wnt family proteins that are expressed are Wnt5a, Wnt5b, Wnt7a and Wnt4. When a muscle becomes injured (thus requiring regeneration) Wnt5a, Wnt5b, and Wnt7a are increased in expression. As the muscle completes repair Wnt7b and Wnt3a are increased as well. This patterning of Wnt signalling expression in muscle cell repair induces the differentiation of the progenitor cells, which reduces the number of available satellite cells. Wnt plays a crucial role in satellite cell regulation and skeletal muscle aging and also regeneration. Wnts are known to active the expression of Myf5 and MyoD by Wnt1 and Wnt7a. Wnt4, Wnt5, and Wnt6 function to increase the expression of both of the regulatory factors but at a more subtle level. Additionally, MyoD increases Wnt3a when myoblasts undergo differentiation. Whether MyoD is activated by Wnt via cis-regulation direct targeting or through indirect physiological pathways remains to be elucidated. # Coactivators and repressors IFRD1 is a positive cofactor of MyoD, as it cooperates with MyoD at inducing the transcriptional activity of MEF2C (by displacing HDAC4 from MEF2C); moreover IFRD1 also represses the transcriptional activity of NF-κB, which is known to inhibit MyoD mRNA accumulation. NFATc1 is a transcription factor that regulates composition of fiber type and the fast-to-slow twitch transition resulting from aerobic exercise requires the expression of NFATc1. MyoD expression is a key transcription factor in fast twitch fibers which is inhibited by NFATc1 in oxidative fiber types. NFATc1 works to inhibit MyoD via a physical interaction with the MyoD N-terminal activation domain resulting in inhibited recruitment of the necessary transcriptional coactivator p300. NFATc1 physically disrupts the interaction between MyoD and p300. This establishes the molecular mechanism by which fiber types transition in vivo through exercise with opposing roles for NFATc1 and MyoD. NFATc1 controls this balance by physical inhibition of MyoD in slow-twitch muscle fiber types. The histone deacetyltransferase p300 functions with MyoD in an interaction that is essential for the myotube generation from fibroblasts that is mediated by MyoD. Recruitment of p300 is the rate-limiting process in the conversion of fibroblasts to myotubes. In addition to p300, MyoD is also known to recruit Set7, H3K4me1, H3K27ac, and RNAP II to the enhancer that is bound with and this allows for the activation of muscle gene that is condition-specific and established by MyoD recruitment. Endogenous p300 though, is necessary for MyoD functioning by acting as an essential coactivator. MyoD associatively binds to the enhancer region in conjunction with a placeholding "putative pioneer factor" which helps to establish and maintain a both of them in a specific and inactive conformation. Upon the removal or inactivation on the placeholder protein bound to the enhancer, the recruitment of the additional group of transcription factors that help to positively regulate enhancer activity is permitted and this results in the MyoD-transcription factor-enhancer complex to assume a transcriptionally active state. # Interactions MyoD has been shown to interact with: - C-jun, - CREB-binding protein, - CSRP3, - Cyclin-dependent kinase 4, - Cyclin-dependent kinase inhibitor 1C, - EP300, - HDAC1, - ID1, - ID2, - MDFI, - MOS, - Retinoblastoma protein, - Retinoid X receptor alpha - STAT3, and - TCF3.

MyoD MyoD is a protein that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub,[1] belongs to a family of proteins known as myogenic regulatory factors (MRFs).[2] These bHLH (basic helix loop helix) transcription factors act sequentially in myogenic differentiation. MRF family members include MyoD, Myf5, myogenin, and MRF4 (Myf6). MyoD is one of the earliest markers of myogenic commitment. MyoD is expressed at extremely low and essentially undetectable levels in quiescent satellite cells, but expression of MyoD is activated in response to exercise or muscle tissue damage. The effect of MyoD on satellite cells is dose-dependent; high MyoD expression represses cell renewal, promotes terminal differentiation and can induce apoptosis. Although MyoD marks myoblast commitment, muscle development is not dramatically ablated in mouse mutants lacking the MyoD gene. This is likely due to functional redundancy from Myf5 and/or Mrf4. Nevertheless, the combination of MyoD and Myf5 is vital to the success of myogenesis.[3][4] # History MyoD was cloned by an ingenious functional assay for muscle formation reported in Cell in 1987 by Davis, Weintraub, and Lassar. It was first described as a nuclear phosphoprotein in 1988 by Tapscott, Davis, Thayer, Cheng, Weintraub, and Lassar in Science. The researchers expressed the complementary DNA (cDNA) of the murine MyoD protein in a different cell lines (fibroblast and adipoblast) and found MyoD converted them to myogenic cells.[1][5] The following year, the same research team performed several tests to determine both the structure and function of the protein, confirming their initial proposal that the active site of the protein consisted of the helix loop helix (now referred to as basic helix loop helix) for dimerization and a basic site upstream of this bHLH region facilitated DNA binding only once it became a protein dimer.[6] MyoD has since been an active area of research as still relatively little is known concerning many aspects of its function. # Function The function of MyoD in development is to commit mesoderm cells to a skeletal myoblast lineage, and then to regulate that continued state. MyoD may also regulate muscle repair. MyoD mRNA levels are also reported to be elevated in aging skeletal muscle. One of the main actions of MyoD is to remove cells from the cell cycle (halt proliferation for terminal cell cycle arrest in differentiated myocytes) by enhancing the transcription of p21 and myogenin. MyoD is inhibited by cyclin dependent kinases (CDKs). CDKs are in turn inhibited by p21. Thus MyoD enhances its own activity in the cell in a feedforward manner. Sustained MyoD expression is necessary for retaining the expression of muscle-related genes.[7] MyoD is also an important effector for the fast-twitch muscle fiber (types IIA, IIX, and IIB) phenotype.[8][9] # Mechanisms MyoD is a transcription factor and can also direct chromatin remodelling through binding to a DNA motif known as the E-box. MyoD is known to have binding interactions with hundreds of muscular gene promoters and to permit myoblast proliferation. While not completely understood, MyoD is now thought to function as a major myogenesis controller in an on/off switch association mediated by KAP1 (KRAB [Krüppel-like associated box]-associated protein 1) phosphorylation.[10] KAP1 is localized at muscle-related genes in myoblasts along with both MyoD and Mef2 (a myocyte transcription enhancer factor). Here, it serves as a scaffold and recruits the coactivators p300 and LSD1, in addition to several corepressors which include G9a and the Histone deacetylase HDAC1. The consequence of this coactivator/corepressor recruitment is silenced promoting regions on muscle genes. When the kinase MSK1 phosphorylates KAP1, the corepressors previously bound to the scaffold are released allowing MyoD and Mef2 to activate transcription.[11] Once the "master controller" MyoD has become active, SETDB1 is required to maintain MyoD expression within the cell. Setdb1 appears to be necessary to maintain both MyoD expression and also genes that are specific to muscle tissues because reduction of Setdb1 expression results in a severe delay of myoblast differentiation and determination.[12] In Setdb1 depleted myoblasts that are treated with exogenous MyoD, myoblastic differentiation is successfully restored. In one model of Setdb1 action on MyoD, Setdb1 represses an inhibitor of MyoD. This unidentified inhibitor likely acts competitively against MyoD during typical cellular proliferation. Evidence for this model is that reduction of Setdb1 results in direct inhibition of myoblast differentiation which may be caused by the release of the unknown MyoD inhibitor. MyoD has also been shown to function cooperatively with the tumor suppressor gene, Retinoblastoma (pRb) to cause cell cycle arrest in the terminally differentiated myoblasts.[13] This is done through regulation of the Cyclin, Cyclin D1. Cell cycle arrest (in which myoblasts would indicate the conclusion of myogenesis) is dependent on the continuous and stable repression of the D1 cyclin. Both MyoD and pRb are necessary for the repression of cyclin D1, but rather than acting directly on cyclin D1, they act on Fra-1 which is immediately early of cyclin D1. MyoD and pRb are both necessary for repressing Fra-1 (and thus cyclin D1) as either MyoD or pRb on its own is not sufficient alone to induce cyclin D1 repression and thus cell cycle arrest. In an intronic enhancer of Fra-1 there were two conserved MyoD binding sites discovered. There is cooperative action of MyoD and pRb at the Fra-1 intronic enhancer that suppresses the enhancer, therefore suppressing cyclin D1 and ultimately resulting in cell cycle arrest for terminally differentiated myoblasts.[14] # Role in the wnt signalling pathway The Wnt signalling pathway family refers to a group of secreted paracrine signaling proteins. Nineteen glycoproteins have been identified as members of this family. Wnts bind to the plasma membrane receptor Frizzled on the target cells. Several different intracellular pathways of signalling are activated by Wnts interacting with the Frizzled receptor. One of the most common is inhibition of glycogen synthase kinase 3β (GSK3β) which functions to destroy β-catenin. This inhibition allows β-catenin to accumulate in the cell cytoplasm and eventual translocation into the nucleus. In the canonical Wnt pathway, nuclear β-catenin forms a dimer with T-cell factor (TCF) and lympoid enhaner factor (LEF) on the gene promoter that is targeted. This initiates transcription and mediates the physiological response to the initial Wnt signal. Wnt-Frizzled pathways also are known to activate c-Jun N-terminal kinases (JNKs) in the cytoplasm. Wnts also drive the translocation of NFATs into the nucleus to initiate the transcription of the targeted genes.[15] Proteins involved in the Wnt signalling pathway induce cells in somites and competent tissues that receive these wnt signals to actively express Pax3 and Pax7 in addition to myogenic regulatory factors, including Myf5 and MyoD. Specifically, Wnt3a is responsible for direct induction of MyoD expression via cis-element interactions with a distal enhancer and Wnt response element.[16] In typical adult muscles in a resting condition (absence of physiological stress) the specific Wnt family proteins that are expressed are Wnt5a, Wnt5b, Wnt7a and Wnt4. When a muscle becomes injured (thus requiring regeneration) Wnt5a, Wnt5b, and Wnt7a are increased in expression. As the muscle completes repair Wnt7b and Wnt3a are increased as well. This patterning of Wnt signalling expression in muscle cell repair induces the differentiation of the progenitor cells, which reduces the number of available satellite cells. Wnt plays a crucial role in satellite cell regulation and skeletal muscle aging and also regeneration. Wnts are known to active the expression of Myf5 and MyoD by Wnt1 and Wnt7a. Wnt4, Wnt5, and Wnt6 function to increase the expression of both of the regulatory factors but at a more subtle level. Additionally, MyoD increases Wnt3a when myoblasts undergo differentiation. Whether MyoD is activated by Wnt via cis-regulation direct targeting or through indirect physiological pathways remains to be elucidated.[17] # Coactivators and repressors IFRD1 is a positive cofactor of MyoD, as it cooperates with MyoD at inducing the transcriptional activity of MEF2C (by displacing HDAC4 from MEF2C); moreover IFRD1 also represses the transcriptional activity of NF-κB, which is known to inhibit MyoD mRNA accumulation.[18][19] NFATc1 is a transcription factor that regulates composition of fiber type and the fast-to-slow twitch transition resulting from aerobic exercise requires the expression of NFATc1. MyoD expression is a key transcription factor in fast twitch fibers which is inhibited by NFATc1 in oxidative fiber types. NFATc1 works to inhibit MyoD via a physical interaction with the MyoD N-terminal activation domain resulting in inhibited recruitment of the necessary transcriptional coactivator p300. NFATc1 physically disrupts the interaction between MyoD and p300. This establishes the molecular mechanism by which fiber types transition in vivo through exercise with opposing roles for NFATc1 and MyoD. NFATc1 controls this balance by physical inhibition of MyoD in slow-twitch muscle fiber types.[20] The histone deacetyltransferase p300 functions with MyoD in an interaction that is essential for the myotube generation from fibroblasts that is mediated by MyoD. Recruitment of p300 is the rate-limiting process in the conversion of fibroblasts to myotubes.[21] In addition to p300, MyoD is also known to recruit Set7, H3K4me1, H3K27ac, and RNAP II to the enhancer that is bound with and this allows for the activation of muscle gene that is condition-specific and established by MyoD recruitment. Endogenous p300 though, is necessary for MyoD functioning by acting as an essential coactivator. MyoD associatively binds to the enhancer region in conjunction with a placeholding "putative pioneer factor" which helps to establish and maintain a both of them in a specific and inactive conformation. Upon the removal or inactivation on the placeholder protein bound to the enhancer, the recruitment of the additional group of transcription factors that help to positively regulate enhancer activity is permitted and this results in the MyoD-transcription factor-enhancer complex to assume a transcriptionally active state. # Interactions MyoD has been shown to interact with: - C-jun,[22] - CREB-binding protein,[23][24] - CSRP3,[25] - Cyclin-dependent kinase 4,[26][27] - Cyclin-dependent kinase inhibitor 1C,[28] - EP300,[24][29] - HDAC1,[30][31] - ID1,[32][33][34][35][36][37] - ID2,[33] - MDFI,[38] - MOS,[39] - Retinoblastoma protein,[31][40] - Retinoid X receptor alpha[41] - STAT3,[42] and - TCF3.[33][43]

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

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wikidoc

NAB2

NAB2 NGFI-A-binding protein 2 also known as EGR-1-binding protein 2 or melanoma-associated delayed early response protein (MADER) is a protein that in humans is encoded by the NAB2 gene. # Function This gene encodes a member of the family of NGFI-A binding (NAB) proteins, which function in the nucleus to repress or activate transcription induced by some members of the EGR (early growth response) family of transactivators. NAB proteins can homo- or hetero-multimerize with other EGR or NAB proteins through a conserved N-terminal domain, and repress transcription through two partially redundant C-terminal domains. Transcriptional repression by the encoded protein is mediated in part by interactions with the nucleosome remodeling and deactylase (NuRD) complex. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. # Pathology Recurrent somatic fusions of the two genes, NGFI-A–binding protein 2 (NAB2) and STAT6, located at chromosomal region 12q13, have been identified in solitary fibrous tumors.

NAB2 NGFI-A-binding protein 2 also known as EGR-1-binding protein 2 or melanoma-associated delayed early response protein (MADER) is a protein that in humans is encoded by the NAB2 gene.[1][2][3] # Function This gene encodes a member of the family of NGFI-A binding (NAB) proteins, which function in the nucleus to repress or activate transcription induced by some members of the EGR (early growth response) family of transactivators. NAB proteins can homo- or hetero-multimerize with other EGR or NAB proteins through a conserved N-terminal domain, and repress transcription through two partially redundant C-terminal domains. Transcriptional repression by the encoded protein is mediated in part by interactions with the nucleosome remodeling and deactylase (NuRD) complex. Alternatively spliced transcript variants have been described, but their biological validity has not been determined.[3] # Pathology Recurrent somatic fusions of the two genes, NGFI-A–binding protein 2 (NAB2) and STAT6, located at chromosomal region 12q13, have been identified in solitary fibrous tumors.[4]

https://www.wikidoc.org/index.php/NAB2

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wikidoc

NANS

NANS Sialic acid synthase is an enzyme that in humans is encoded by the NANS gene. This gene encodes an enzyme that functions in the biosynthetic pathways of sialic acids. In vitro, the encoded protein uses N-acetylmannosamine 6-phosphate and mannose 6-phosphate as substrates to generate phosphorylated forms of N-acetylneuraminic acid (Neu5Ac) and 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (KDN), respectively. However, it exhibits much higher activity toward the Neu5Ac phosphate product. In insect cells, expression of this gene results in Neu5Ac and KDN production. This gene is related to the E. coli sialic acid synthase gene neuB, and it can partially restore sialic acid synthase activity in an E. coli neuB-negative mutant.

NANS Sialic acid synthase is an enzyme that in humans is encoded by the NANS gene.[1][2] This gene encodes an enzyme that functions in the biosynthetic pathways of sialic acids. In vitro, the encoded protein uses N-acetylmannosamine 6-phosphate and mannose 6-phosphate as substrates to generate phosphorylated forms of N-acetylneuraminic acid (Neu5Ac) and 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (KDN), respectively. However, it exhibits much higher activity toward the Neu5Ac phosphate product. In insect cells, expression of this gene results in Neu5Ac and KDN production. This gene is related to the E. coli sialic acid synthase gene neuB, and it can partially restore sialic acid synthase activity in an E. coli neuB-negative mutant.[2]

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

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wikidoc

NCDN

NCDN Neurochondrin (also known as its murine homologue, Norbin) is a protein that in humans is encoded by the NCDN gene. This gene encodes a leucine-rich cytoplasmic protein, which is highly similar to a mouse protein norbin that negatively regulates Ca/calmodulin-dependent protein kinase II phosphorylation and may be essential for spatial learning processes. Several alternatively spliced transcript variants of this gene have been described. Norbin can modulate signaling activity and expression of metabotropic glutamate receptor 5; modulating mice with targeted deletion of NCDN in the brain have phenotypic traits usually found in the rodent models of schizophrenia, including disruptions in prepulse inhibition. Furthermore, norbin protein expression is altered in the schizophrenia brain.

NCDN Neurochondrin (also known as its murine homologue, Norbin) is a protein that in humans is encoded by the NCDN gene.[1][2] This gene encodes a leucine-rich cytoplasmic protein, which is highly similar to a mouse protein norbin that negatively regulates Ca/calmodulin-dependent protein kinase II phosphorylation and may be essential for spatial learning processes. Several alternatively spliced transcript variants of this gene have been described.[2] Norbin can modulate signaling activity and expression of metabotropic glutamate receptor 5; modulating mice with targeted deletion of NCDN in the brain have phenotypic traits usually found in the rodent models of schizophrenia, including disruptions in prepulse inhibition.[3] Furthermore, norbin protein expression is altered in the schizophrenia brain.[4]

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

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wikidoc

NCK1

NCK1 Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene. # Gene The Nck (non-catalytic region of tyrosine kinase adaptor protein 1) belongs to the adaptor family of proteins. The nck gene was initially isolated from a human melanoma cDNA library using a monoclonal antibody produced against the human melanoma-associated antigen. The Nck family has two known members in human cells (Nck-1/Nckalpha and NcK2/NcKbeta), two in mouse cells (mNckalpha and mNckbeta/Grb4) and one in drosophila (Dock means dreadlocks-ortholog). The two murine gene products exhibit 68% amino acid identity to one another, with most of the sequence variation being located to the linker regions between the SH3 and SH2 domains, and are 96% identical to their human counterparts. While human nck-1 gene has been localised to the 3q21 locus of chromosome 3, the nck-2 gene can be found on chromosome 2 at the 2q12 locus. # Function The protein encoded by this gene is one of the signaling and transforming proteins containing Src homology 2 and 3 (SH2 and SH3) domains. It is located in the cytoplasm and is an adaptor protein involved in transducing signals from receptor tyrosine kinases to downstream signal recipients such as RAS. Nck1 has been linked to glucose tolerance and insulin signaling within certain tissues, namely the liver, in obese mice. A deletion of the protein also causes a decrease of ER stress signaling within these obese cells, which is normally increased by the excessive fat. This stress causes expression of the unfolded protein response pathway, which leads to a decrease in glucose tolerance and inactivation of insulin signaling in certain cell types. This renewed glucose tolerance and insulin signaling is caused by the inhibition of the unfolded protein response pathway, particularly the protein IRE1alpha, and its subsequent phosphorylation of IRS-1 that causes insulin signaling to be blocked. IRE1alpha is involved with the JNK pathway that is responsible for the phosphorylation of IRS-1. Nck1 regulates the activation of IRE1alpha within the pathway and when removed from the pathway disrupts activation. This means that Nck1 has an interaction with the UPR and that a deletion can cause a decrease in the stress pathway from the ER in the mice. These deficient, obese mice also show increased insulin-induced phosphorylation of PKB within the liver but do not possess the same expression in adipose tissues or skeletal muscles. This evidence points to the pathway being ER stress induced within liver tissue. Nck1 has been shown to be associated with bone mass. A deficiency in Nck1, which is shown to reduce ER stress in obese mice, also accelerates unloading-induced osteoporosis caused by mechanical stress. This seems to suggest that would be a crucial protein involved with bone metabolism and that retention of bone tissue by a protein as yet unknown. Nck1 expression increased twofold when involved with nerectomy-based unloading osteoporosis. This then follows that in a deficient organism this upregulation would not be possible and thus the body would have increased bone loss due to the lack of expression of Nck1 to deal with the stress, which is what happens in vivo. This acceleration of bone loss leads researchers to believe that the pathway for bone metabolism is highly regulated by several proteins that have yet to be discovered or incorporated into a schema. Nck1 is involved with cellular remodeling via the WASp/Arp2/3 complex to coordinate actin cytoskeletal remodeling. The WASp binds to the SH3 domains within the N-terminus of the protein and after Nck1 has been activated by the signal from the ligand binding to a receptor tyrosine kinase and then uses the WASp/Arp2/3 complex to reorganize the actin cytoskeleton and cause the polarization of the cell as well as promote directional migration via pseudopodia. The reorganization of this cytoskeleton is caused by different Rho GTPases being moved to different locations within the cell, primarily to the leading edge, and strengthening the bonds with extracellular matrix components to induce motion. # Interactions NCK1 has been shown to interact with: - ABL1, - CBL, - DNM1, - DAG1, - EIF2B2, - EPHB1, - EGFR, - KHDRBS1, - LCP2, - MAP4K1, - MAP4K4, - MINK1, - NCKIPSD, - NEDD9, - PAK1, - PDGFRB, - PKN2, - PTK2, - RASA1, - RICS, - RRAS, - SOCS7, - SOS1, - TBK1, - WASL, - WIPF1, and - WAS.

NCK1 Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene.[1][2] # Gene The Nck (non-catalytic region of tyrosine kinase adaptor protein 1) belongs to the adaptor family of proteins. The nck gene was initially isolated from a human melanoma cDNA library using a monoclonal antibody produced against the human melanoma-associated antigen. The Nck family has two known members in human cells (Nck-1/Nckalpha and NcK2/NcKbeta), two in mouse cells (mNckalpha and mNckbeta/Grb4) and one in drosophila (Dock means dreadlocks-ortholog). The two murine gene products exhibit 68% amino acid identity to one another, with most of the sequence variation being located to the linker regions between the SH3 and SH2 domains, and are 96% identical to their human counterparts. While human nck-1 gene has been localised to the 3q21 locus of chromosome 3, the nck-2 gene can be found on chromosome 2 at the 2q12 locus. # Function The protein encoded by this gene is one of the signaling and transforming proteins containing Src homology 2 and 3 (SH2 and SH3) domains. It is located in the cytoplasm and is an adaptor protein involved in transducing signals from receptor tyrosine kinases to downstream signal recipients such as RAS.[3] Nck1 has been linked to glucose tolerance and insulin signaling within certain tissues, namely the liver, in obese mice. A deletion of the protein also causes a decrease of ER stress signaling within these obese cells, which is normally increased by the excessive fat. This stress causes expression of the unfolded protein response pathway, which leads to a decrease in glucose tolerance and inactivation of insulin signaling in certain cell types. This renewed glucose tolerance and insulin signaling is caused by the inhibition of the unfolded protein response pathway, particularly the protein IRE1alpha, and its subsequent phosphorylation of IRS-1 that causes insulin signaling to be blocked. IRE1alpha is involved with the JNK pathway that is responsible for the phosphorylation of IRS-1. Nck1 regulates the activation of IRE1alpha within the pathway and when removed from the pathway disrupts activation. This means that Nck1 has an interaction with the UPR and that a deletion can cause a decrease in the stress pathway from the ER in the mice. These deficient, obese mice also show increased insulin-induced phosphorylation of PKB within the liver but do not possess the same expression in adipose tissues or skeletal muscles. This evidence points to the pathway being ER stress induced within liver tissue.[4] Nck1 has been shown to be associated with bone mass. A deficiency in Nck1, which is shown to reduce ER stress in obese mice, also accelerates unloading-induced osteoporosis caused by mechanical stress. This seems to suggest that would be a crucial protein involved with bone metabolism and that retention of bone tissue by a protein as yet unknown. Nck1 expression increased twofold when involved with nerectomy-based unloading osteoporosis. This then follows that in a deficient organism this upregulation would not be possible and thus the body would have increased bone loss due to the lack of expression of Nck1 to deal with the stress, which is what happens in vivo. This acceleration of bone loss leads researchers to believe that the pathway for bone metabolism is highly regulated by several proteins that have yet to be discovered or incorporated into a schema.[5] Nck1 is involved with cellular remodeling via the WASp/Arp2/3 complex to coordinate actin cytoskeletal remodeling. The WASp binds to the SH3 domains within the N-terminus of the protein and after Nck1 has been activated by the signal from the ligand binding to a receptor tyrosine kinase and then uses the WASp/Arp2/3 complex to reorganize the actin cytoskeleton and cause the polarization of the cell as well as promote directional migration via pseudopodia. The reorganization of this cytoskeleton is caused by different Rho GTPases being moved to different locations within the cell, primarily to the leading edge, and strengthening the bonds with extracellular matrix components to induce motion.[6] # Interactions NCK1 has been shown to interact with: - ABL1,[7][8] - CBL,[7][9] - DNM1,[10] - DAG1,[11] - EIF2B2,[12] - EPHB1,[13] - EGFR,[14][15][15] - KHDRBS1,[14][16] - LCP2,[17][18] - MAP4K1,[19][20] - MAP4K4,[21] - MINK1,[22] - NCKIPSD,[23] - NEDD9,[24] - PAK1,[25][26][27] - PDGFRB,[15][25] - PKN2,[25][28] - PTK2,[24][29] - RASA1,[30] - RICS,[31] - RRAS,[32] - SOCS7,[13] - SOS1,[10][25][33][34] - TBK1,[35] - WASL,[36] - WIPF1,[37] and - WAS.[25][38][39][40]

https://www.wikidoc.org/index.php/NCK1

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wikidoc

NEK6

NEK6 Serine/threonine-protein kinase Nek6 is an enzyme that in humans is encoded by the NEK6 gene. # Function The Aspergillus nidulans 'never in mitosis A' (NIMA) gene encodes a serine/threonine kinase that controls initiation of mitosis. NIMA-related kinases (NEKs) are a group of protein kinases that are homologous to NIMA. Evidence suggests that NEKs perform functions similar to those of NIMA. It is a protein kinase which plays an important role in mitotic cell cycle progression. Required for chromosome segregation at metaphase-anaphase transition, robust mitotic spindle formation and cytokinesis. Phosphorylates ATF4, CIR1, PTN, RAD26L, RBBP6, RPS7, RPS6KB1, TRIP4, STAT3 and histones H1 and H3. Phosphorylates KIF11 to promote mitotic spindle formation. Involved in G2/M phase cell cycle arrest induced by DNA damage. Inhibition of activity results in apoptosis. May contribute to tumorigenesis by suppressing p53/TP53-induced cancer cell senescence. # Interactions NEK6 has been shown to interact with NEK9.

NEK6 Serine/threonine-protein kinase Nek6 is an enzyme that in humans is encoded by the NEK6 gene.[1][2] # Function The Aspergillus nidulans 'never in mitosis A' (NIMA) gene encodes a serine/threonine kinase that controls initiation of mitosis. NIMA-related kinases (NEKs) are a group of protein kinases that are homologous to NIMA. Evidence suggests that NEKs perform functions similar to those of NIMA.[2] It is a protein kinase which plays an important role in mitotic cell cycle progression. Required for chromosome segregation at metaphase-anaphase transition, robust mitotic spindle formation and cytokinesis. Phosphorylates ATF4, CIR1, PTN, RAD26L, RBBP6, RPS7, RPS6KB1, TRIP4, STAT3 and histones H1 and H3. Phosphorylates KIF11 to promote mitotic spindle formation. Involved in G2/M phase cell cycle arrest induced by DNA damage. Inhibition of activity results in apoptosis. May contribute to tumorigenesis by suppressing p53/TP53-induced cancer cell senescence.[3] # Interactions NEK6 has been shown to interact with NEK9.[4][5][6]

https://www.wikidoc.org/index.php/NEK6

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wikidoc

NEU1

NEU1 Sialidase 1 (lysosomal sialidase), also known as NEU1 is a mammalian lysosomal neuraminidase enzyme which in humans is encoded by the NEU1 gene. # Function The protein encoded by this gene encodes the lysosomal enzyme, which cleaves terminal sialic acid residues from substrates such as glycoproteins and glycolipids. In the lysosome, this enzyme is part of a heterotrimeric complex together with beta-galactosidase and cathepsin A (the latter also referred to as 'protective protein'). Mutations in this gene can lead to sialidosis. # Clinical significance Deficiencies in the human enzyme NEU1 leads to sialidosis, a rare lysosomal storage disease. Sialidase has also been shown to enhance recovery from spinal cord contusion injury when injected in rats. # Interactions NEU1 has been shown to interact with Cathepsin A.

NEU1 Sialidase 1 (lysosomal sialidase), also known as NEU1 is a mammalian lysosomal neuraminidase enzyme which in humans is encoded by the NEU1 gene.[1][2] # Function The protein encoded by this gene encodes the lysosomal enzyme, which cleaves terminal sialic acid residues from substrates such as glycoproteins and glycolipids. In the lysosome, this enzyme is part of a heterotrimeric complex together with beta-galactosidase and cathepsin A (the latter also referred to as 'protective protein'). Mutations in this gene can lead to sialidosis.[1] # Clinical significance Deficiencies in the human enzyme NEU1 leads to sialidosis, a rare lysosomal storage disease.[3] Sialidase has also been shown to enhance recovery from spinal cord contusion injury when injected in rats.[4] # Interactions NEU1 has been shown to interact with Cathepsin A.[5]

https://www.wikidoc.org/index.php/NEU1

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wikidoc

NFYA

NFYA Nuclear transcription factor Y subunit alpha is a protein that in humans is encoded by the NFYA gene. # Function The protein encoded by this gene is one subunit of a trimeric complex, forming a highly conserved transcription factor that binds to CCAAT motifs in the promoter regions in a variety of genes. Subunit A associates with a tight dimer composed of the B and C subunits, resulting in a trimer that binds to DNA with high specificity and affinity. The sequence specific interactions of the complex are made by the A subunit, suggesting a role as the regulatory subunit. In addition, there is evidence of post-transcriptional regulation in this gene product, either by protein degradation or control of translation. Further regulation is represented by alternative splicing in the glutamine-rich activation domain, with clear tissue-specific preferences for the two isoforms. # Interactions NFYA has been shown to interact with Serum response factor and ZHX1. NFYA, NFYB and NFYC form the NFY complex and it has been shown that the NFY complex serves as a pioneer factor by promoting chromatin accessibility to facilitate other co-localizing cell type-specific transcription factors.

NFYA Nuclear transcription factor Y subunit alpha is a protein that in humans is encoded by the NFYA gene.[1][2] # Function The protein encoded by this gene is one subunit of a trimeric complex, forming a highly conserved transcription factor that binds to CCAAT motifs in the promoter regions in a variety of genes. Subunit A associates with a tight dimer composed of the B and C subunits, resulting in a trimer that binds to DNA with high specificity and affinity. The sequence specific interactions of the complex are made by the A subunit, suggesting a role as the regulatory subunit. In addition, there is evidence of post-transcriptional regulation in this gene product, either by protein degradation or control of translation. Further regulation is represented by alternative splicing in the glutamine-rich activation domain, with clear tissue-specific preferences for the two isoforms.[3] # Interactions NFYA has been shown to interact with Serum response factor[4] and ZHX1.[4][5] NFYA, NFYB and NFYC form the NFY complex and it has been shown that the NFY complex serves as a pioneer factor by promoting chromatin accessibility to facilitate other co-localizing cell type-specific transcription factors.[6]

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

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wikidoc

NFYC

NFYC Nuclear transcription factor Y subunit gamma is a protein that in humans is encoded by the NFYC gene. # Function The protein encoded by this gene is one subunit of a trimeric complex, forming a highly conserved transcription factor that binds with high specificity to CCAAT motifs in the promoter regions in a variety of genes. This gene product, subunit C, forms a tight dimer with the B subunit (NFYB), a prerequisite for subunit A (NFYA) association. The resulting trimer binds to DNA with high specificity and affinity. Subunits B and C each contain a histone-like motif. Observation of the histone nature of these subunits is supported by two types of evidence; protein sequence alignments and experiments with mutants. Additional regulation, preliminarily supported by the EST database, may be represented by alternative splicing in this subunit. Two microRNAs; miR-30c and miR-30e are located within introns of the nfyc gene. These microRNAs are actively transcribed in human insulin-producing beta cells in the pancreatic islets that also show high expression of nfyc and CDH1 genes. The expression of these intronic microRNAs is essential for maintaining the differentiated phenotype of human islet beta cells. Inhibition of miR-30 family microRNAs induces epithelial-mesenchymal transition of human pancreatic islet cells. # Interactions NFYC has been shown to interact with Myc.

NFYC Nuclear transcription factor Y subunit gamma is a protein that in humans is encoded by the NFYC gene.[1][2][3] # Function The protein encoded by this gene is one subunit of a trimeric complex, forming a highly conserved transcription factor that binds with high specificity to CCAAT motifs in the promoter regions in a variety of genes. This gene product, subunit C, forms a tight dimer with the B subunit (NFYB), a prerequisite for subunit A (NFYA) association. The resulting trimer binds to DNA with high specificity and affinity. Subunits B and C each contain a histone-like motif. Observation of the histone nature of these subunits is supported by two types of evidence; protein sequence alignments and experiments with mutants. Additional regulation, preliminarily supported by the EST database, may be represented by alternative splicing in this subunit.[3] Two microRNAs; miR-30c and miR-30e are located within introns of the nfyc gene. These microRNAs are actively transcribed in human insulin-producing beta cells in the pancreatic islets that also show high expression of nfyc and CDH1 genes. The expression of these intronic microRNAs is essential for maintaining the differentiated phenotype of human islet beta cells. Inhibition of miR-30 family microRNAs induces epithelial-mesenchymal transition of human pancreatic islet cells.[4] # Interactions NFYC has been shown to interact with Myc.[5]

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

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wikidoc

NME4

NME4 Non-metastatic cells 4, protein expressed in, also known as NME4, is a protein which in humans is encoded by the NME4 gene. # Function The nucleoside diphosphate (NDP) kinases (EC 2.7.4.6) are ubiquitous enzymes that catalyze transfer of gamma-phosphates, via a phosphohistidine intermediate, between nucleoside and dioxynucleoside tri- and diphosphates. The enzymes are products of the nm23 gene family, which includes NME4. The first nm23 gene, nm23-H1 (NME1), was isolated based on its reduced expression in a highly metastatic murine melanoma cell line and was proposed to be a metastasis suppressing gene. The human equivalent was obtained by cDNA library screening using the murine gene as a probe and found to be homologous to the Drosophila awd gene. A second human gene, nm23-H2 (NME2), encoding a protein 88% identical to nm23-H1, was subsequently isolated. Both genes were localized on 17q21.3 and their gene products were formerly identified as the A and B subunits of NDP kinases. In mammals, functional NDP kinases are heterohexamers of the A and B monomers, which can combine at variable ratios to form different types of hybrids. These enzymes are highly expressed in tumors as compared with normal tissues. In some cell lines and in certain solid tumors, decreased expression of NME1 is associated with increased metastatic potential; moreover, when transfected into very aggressive cell lines, such as human breast carcinoma, NME1 decreased the metastatic potential. A third human gene, DR-nm23 (NME3), was identified and found to share high sequence similarity with the NME1 and NME2 genes. It is highly expressed in blast crisis transition of chronic myeloid leukemia. When overexpressed by transfection, NME3 suppressed granulocyte differentiation and induced apoptosis of myeloid precursor cells. # Model organisms Model organisms have been used in the study of NME4 function. A conditional knockout mouse line called Nme4tm1a(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

NME4 Non-metastatic cells 4, protein expressed in, also known as NME4, is a protein which in humans is encoded by the NME4 gene.[1][2] # Function The nucleoside diphosphate (NDP) kinases (EC 2.7.4.6) are ubiquitous enzymes that catalyze transfer of gamma-phosphates, via a phosphohistidine intermediate, between nucleoside and dioxynucleoside tri- and diphosphates. The enzymes are products of the nm23 gene family, which includes NME4. The first nm23 gene, nm23-H1 (NME1), was isolated based on its reduced expression in a highly metastatic murine melanoma cell line and was proposed to be a metastasis suppressing gene. The human equivalent was obtained by cDNA library screening using the murine gene as a probe and found to be homologous to the Drosophila awd gene. A second human gene, nm23-H2 (NME2), encoding a protein 88% identical to nm23-H1, was subsequently isolated. Both genes were localized on 17q21.3 and their gene products were formerly identified as the A and B subunits of NDP kinases. In mammals, functional NDP kinases are heterohexamers of the A and B monomers, which can combine at variable ratios to form different types of hybrids.[2] These enzymes are highly expressed in tumors as compared with normal tissues. In some cell lines and in certain solid tumors, decreased expression of NME1 is associated with increased metastatic potential; moreover, when transfected into very aggressive cell lines, such as human breast carcinoma, NME1 decreased the metastatic potential. A third human gene, DR-nm23 (NME3), was identified and found to share high sequence similarity with the NME1 and NME2 genes. It is highly expressed in blast crisis transition of chronic myeloid leukemia. When overexpressed by transfection, NME3 suppressed granulocyte differentiation and induced apoptosis of myeloid precursor cells.[1] # Model organisms Model organisms have been used in the study of NME4 function. A conditional knockout mouse line called Nme4tm1a(EUCOMM)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/NME4

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wikidoc

NME8

NME8 Thioredoxin domain-containing protein 3 (TXNDC3), also known as spermatid-specific thioredoxin-2 (Sptrx-2), is a protein that in humans is encoded by the NME8 gene (also known as the TXNDC3 gene) on chromosome 7. # Function This gene encodes a protein with an N-terminal thioredoxin domain and three C-terminal nucleoside diphosphate kinase (NDK) domains, but the NDK domains are thought to be catalytically inactive. The sea urchin ortholog of this gene encodes a component of sperm outer dynein arms, and the protein is implicated in ciliary function. # Clinical significance Mutations in the TXNDC3 gene are associated with primary ciliary dyskinesia.

NME8 Thioredoxin domain-containing protein 3 (TXNDC3), also known as spermatid-specific thioredoxin-2 (Sptrx-2), is a protein that in humans is encoded by the NME8 gene (also known as the TXNDC3 gene) on chromosome 7.[1][2] # Function This gene encodes a protein with an N-terminal thioredoxin domain and three C-terminal nucleoside diphosphate kinase (NDK) domains, but the NDK domains are thought to be catalytically inactive. The sea urchin ortholog of this gene encodes a component of sperm outer dynein arms, and the protein is implicated in ciliary function.[1] # Clinical significance Mutations in the TXNDC3 gene are associated with primary ciliary dyskinesia.[3]

https://www.wikidoc.org/index.php/NME8

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wikidoc

NOL1

NOL1 Putative ribosomal RNA methyltransferase NOP2 is an enzyme that in humans is encoded by the NOP2 gene. The protein encoded by this gene is a nucleolar antigen expressed in proliferating cells. It is not detectable in non-proliferating normal tissue but is detectable in many human tumors. Overexpression of p120 leads to malignant transformation of 3T3 cells while treatment with antisense p120 mRNA causes the transformed cells to revert to their original non-malignant phenotype. The p120 protein displays a dramatic increase in expression at the G1/S transition suggesting that p120 regulates the cell cycle and nucleolar activity that is required for cell proliferation. # Interactions NOL1 has been shown to interact with MCRS1.

NOL1 Putative ribosomal RNA methyltransferase NOP2 is an enzyme that in humans is encoded by the NOP2 gene.[1][2] The protein encoded by this gene is a nucleolar antigen expressed in proliferating cells. It is not detectable in non-proliferating normal tissue but is detectable in many human tumors.[3] Overexpression of p120 leads to malignant transformation of 3T3 cells while treatment with antisense p120 mRNA causes the transformed cells to revert to their original non-malignant phenotype.[4] The p120 protein displays a dramatic increase in expression at the G1/S transition suggesting that p120 regulates the cell cycle and nucleolar activity that is required for cell proliferation.[5] # Interactions NOL1 has been shown to interact with MCRS1.[6]

https://www.wikidoc.org/index.php/NOL1

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wikidoc

NOM1

NOM1 Nucleolar protein with MIF4G domain 1 is a protein that in humans is encoded by the NOM1 gene. Proteins that contain MIF4G (middle of eIF4G (MIM 600495)) and/or MA3 domains, such as NOM1, function in protein translation. These domains include binding sites for members of the EIF4A family of ATP-dependent DEAD box RNA helicases (see EIF4A1; MIM 602641) (Simmons et al., 2005 ).. # Model organisms Model organisms have been used in the study of NOM1 function. A conditional knockout mouse line, called Nom1tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and three significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and females had an abnormal hair cycle.

NOM1 Nucleolar protein with MIF4G domain 1 is a protein that in humans is encoded by the NOM1 gene.[1] Proteins that contain MIF4G (middle of eIF4G (MIM 600495)) and/or MA3 domains, such as NOM1, function in protein translation. These domains include binding sites for members of the EIF4A family of ATP-dependent DEAD box RNA helicases (see EIF4A1; MIM 602641) (Simmons et al., 2005 [PubMed 15715967]).[supplied by OMIM].[1] # Model organisms Model organisms have been used in the study of NOM1 function. A conditional knockout mouse line, called Nom1tm1a(KOMP)Wtsi[7] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[8][9][10] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][11] Twenty five tests were carried out on mutant mice and three significant abnormalities were observed.[5] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and females had an abnormal hair cycle.[5]

https://www.wikidoc.org/index.php/NOM1

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wikidoc

NOS1

NOS1 Nitric oxide synthase 1 (neuronal), also known as NOS1, is an enzyme that in humans is encoded by the NOS1 gene. # Function Nitric oxide synthases (EC 1.14.13.39) (NOSs) are a family of synthases that catalyze the production of nitric oxide (NO) from L-arginine. NO is a chemical messenger with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter and may be involved in long term potentiation. It is implicated in neurotoxicity associated with stroke and neurodegenerative diseases, neural regulation of smooth muscle, including peristalsis, and penile erection. NO is also responsible for endothelium-derived relaxing factor activity regulating blood pressure. In macrophages, NO mediates tumoricidal and bactericidal actions, as indicated by the fact that inhibitors of NO synthase (NOS) block these effects. Neuronal NOS and macrophage NOS are distinct isoforms. Both the neuronal and the macrophage forms are unusual among oxidative enzymes in requiring several electron donors: flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), NADPH, and tetrahydrobiopterin. # Clinical significance It has been implicated in asthma, schizophrenia and restless leg syndrome. It has also been investigated with respect to bipolar disorder and air pollution exposure. # Interactions NOS1 has been shown to interact with DLG4 and NOS1AP.

NOS1 Nitric oxide synthase 1 (neuronal), also known as NOS1, is an enzyme that in humans is encoded by the NOS1 gene.[1][2] # Function Nitric oxide synthases (EC 1.14.13.39) (NOSs) are a family of synthases that catalyze the production of nitric oxide (NO) from L-arginine. NO is a chemical messenger with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter and may be involved in long term potentiation. It is implicated in neurotoxicity associated with stroke and neurodegenerative diseases, neural regulation of smooth muscle, including peristalsis, and penile erection. NO is also responsible for endothelium-derived relaxing factor activity regulating blood pressure. In macrophages, NO mediates tumoricidal and bactericidal actions, as indicated by the fact that inhibitors of NO synthase (NOS) block these effects. Neuronal NOS and macrophage NOS are distinct isoforms.[3] Both the neuronal and the macrophage forms are unusual among oxidative enzymes in requiring several electron donors: flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), NADPH, and tetrahydrobiopterin.[4] # Clinical significance It has been implicated in asthma,[5][6] schizophrenia[7][8] and restless leg syndrome.[9] It has also been investigated with respect to bipolar disorder [10] and air pollution exposure.[11] # Interactions NOS1 has been shown to interact with DLG4[12][13] and NOS1AP.[12]

https://www.wikidoc.org/index.php/NOS1

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wikidoc

NOX2

NOX2 NADPH oxidase 2 (Nox2), also known as cytochrome b(558) subunit beta or Cytochrome b-245 heavy chain, is a protein that in humans is encoded by the NOX2 gene (also called CYBB gene). The protein is a super-oxide generating enzyme which forms reactive oxygen species (ROS). # Function Nox2, or Cytochrome b (-245) is composed of cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes. Nox2 is the catalytic, membrane-bound subunit of NADPH oxidase. It is inactive until it binds to the membrane-anchored p22phox, forming the heterodimer known as flavocytochrome b558. After activation, the regulatory subunits p67phox, p47phox, p40phox and a GTPase, typically Rac, are recruited to the complex to form NADPH oxidase on the plasma membrane or phagosomal membrane. Nox2 itself is composed of an N-terminal transmembrane domain that binds two heme groups, and a C-terminal domain that is able to bind to FAD and NADPH. There has been recent evidence that it plays an important role in atherosclerotic lesion development in the aortic arch, thoracic, and abdominal aorta. It has also been shown to play a part in determining the size of a myocardial infarction due to its connection to ROS, which play a role in myocardial reperfusion injury. This was a result of the relation between Nox2 and signaling necessary for neutrophil recruitment. Furthermore, it increases global post-reperfusion oxidative stress, likely due to decreased STAT3 and Erk phosphorylation. In addition, it appears that hippocampal oxidative stress is increased in septic animals due to the actions of Nox2. This connection also came about through the actions of the chemically active ROS, which work as one of the main components that help in the development of neuroinflammation associated with Sepsis-associated encephalopathy (SAE). Lastly, due to recent experiments, it seems that Nox2 also plays an important role in angiotensin II-mediated inward remodelling in cerebral arterioles due to the emittance of superoxides from Nox2-containing NADPH oxidases. # Clinical significance CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD). CGD is characterized by recurrent, severe infections to pathogens that are normally harmless to humans, such as the common mold Aspergillus niger, and can result from point mutations in the gene encoding Nox2. In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole. Since Nox2 was shown to play a huge part in determining the size of a myocardial infarction, this transforms the protein into a possible future target through drug medication due to its negative effect on myocardial reperfusion. Recent evidence highly suggests that Nox2 generates ROS which contribute to reduce flow-mediated dilation (FMD) in patients with periphery artery disease (PAD). Scientists have gone to conclude that administering an antioxidant helps with inhibiting Nox2 activity and allowing in the improvement of arterial dilation. Lastly, targeting Nox2 in the bone marrow could be a great therapeutic attempt at treating vascular injury during diabetic retinopathy (damage to the retina), because the Nox2-generated ROS which are produced by the bone-marrow derived cells & local retinal cells are accumulating the vascular injury in the diabetic retina area. # Interactions Nox2 has been shown to interact directly with podocyte TRPC6 channels.

NOX2 NADPH oxidase 2 (Nox2), also known as cytochrome b(558) subunit beta or Cytochrome b-245 heavy chain, is a protein that in humans is encoded by the NOX2 gene (also called CYBB gene).[1] The protein is a super-oxide generating enzyme which forms reactive oxygen species (ROS). # Function Nox2, or Cytochrome b (-245) is composed of cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes.[1] Nox2 is the catalytic, membrane-bound subunit of NADPH oxidase. It is inactive until it binds to the membrane-anchored p22phox, forming the heterodimer known as flavocytochrome b558.[2] After activation, the regulatory subunits p67phox, p47phox, p40phox and a GTPase, typically Rac, are recruited to the complex to form NADPH oxidase on the plasma membrane or phagosomal membrane.[3] Nox2 itself is composed of an N-terminal transmembrane domain that binds two heme groups, and a C-terminal domain that is able to bind to FAD and NADPH.[4] There has been recent evidence that it plays an important role in atherosclerotic lesion development in the aortic arch, thoracic, and abdominal aorta.[5] It has also been shown to play a part in determining the size of a myocardial infarction due to its connection to ROS, which play a role in myocardial reperfusion injury. This was a result of the relation between Nox2 and signaling necessary for neutrophil recruitment.[6] Furthermore, it increases global post-reperfusion oxidative stress, likely due to decreased STAT3 and Erk phosphorylation.[6] In addition, it appears that hippocampal oxidative stress is increased in septic animals due to the actions of Nox2. This connection also came about through the actions of the chemically active ROS, which work as one of the main components that help in the development of neuroinflammation associated with Sepsis-associated encephalopathy (SAE).[7] Lastly, due to recent experiments, it seems that Nox2 also plays an important role in angiotensin II-mediated inward remodelling in cerebral arterioles due to the emittance of superoxides from Nox2-containing NADPH oxidases.[8] # Clinical significance CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD). CGD is characterized by recurrent, severe infections to pathogens that are normally harmless to humans, such as the common mold Aspergillus niger, and can result from point mutations in the gene encoding Nox2. [4] In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole.[1] Since Nox2 was shown to play a huge part in determining the size of a myocardial infarction, this transforms the protein into a possible future target through drug medication due to its negative effect on myocardial reperfusion.[6] Recent evidence highly suggests that Nox2 generates ROS which contribute to reduce flow-mediated dilation (FMD) in patients with periphery artery disease (PAD). Scientists have gone to conclude that administering an antioxidant helps with inhibiting Nox2 activity and allowing in the improvement of arterial dilation.[9] Lastly, targeting Nox2 in the bone marrow could be a great therapeutic attempt at treating vascular injury during diabetic retinopathy (damage to the retina), because the Nox2-generated ROS which are produced by the bone-marrow derived cells & local retinal cells are accumulating the vascular injury in the diabetic retina area.[10] # Interactions Nox2 has been shown to interact directly with podocyte TRPC6 channels.[11]

https://www.wikidoc.org/index.php/NOX2

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wikidoc

NOX4

NOX4 NADPH oxidase 4 is an enzyme that in humans is encoded by the NOX4 gene, and is a member of the NOX family of NADPH oxidases. # Function Oxygen sensing is essential for homeostasis in all aerobic organisms. A phagocyte-type oxidase, similar to that responsible for the production of large amounts of reactive oxygen species (ROS) in neutrophil granulocytes, with resultant antimicrobial activity, has been postulated to function in the kidney as an oxygen sensor that regulates the synthesis of erythropoietin in the renal cortex. Nox4 protects the vasculature against inflammatory stress. Nox-dependent reactive oxygen species modulation by amino endoperoxides can induce apoptosis in high Nox4-expressing cancer cells.

NOX4 NADPH oxidase 4 is an enzyme that in humans is encoded by the NOX4 gene, and is a member of the NOX family of NADPH oxidases.[1] # Function Oxygen sensing is essential for homeostasis in all aerobic organisms. A phagocyte-type oxidase, similar to that responsible for the production of large amounts of reactive oxygen species (ROS) in neutrophil granulocytes, with resultant antimicrobial activity, has been postulated to function in the kidney as an oxygen sensor that regulates the synthesis of erythropoietin in the renal cortex.[1] Nox4 protects the vasculature against inflammatory stress.[2] Nox-dependent reactive oxygen species modulation by amino endoperoxides can induce apoptosis in high Nox4-expressing cancer cells.[3]

https://www.wikidoc.org/index.php/NOX4

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wikidoc

NPC1

NPC1 Niemann-Pick disease, type C1 (NPC1) is a disease of a membrane protein that mediates intracellular cholesterol trafficking in mammals. In humans the protein is encoded by the NPC1 gene (chromosome location 18q11). # Function NPC1 was identified as the gene that when mutated, results in Niemann-Pick disease, type C. Niemann-Pick disease, type C is a rare neurovisceral lipid storage disorder resulting from autosomal recessively inherited loss-of-function mutations in either NPC1 or NPC2. This disrupts intracellular lipid transport, leading to the accumulation of lipid products in the late endosomes and lysosomes. Approximately 95% of NPC patients are found to have mutations in the NPC1 gene. NPC1 encodes a putative integral membrane protein containing sequence motifs consistent with a role in intracellular transport of cholesterol to post-lysosomal destinations. # Clinical significance ## Obesity Mutations in the NPC1 gene have been strongly linked with obesity. A genome-wide association study identified NPC1 mutations as a risk factor in childhood obesity and adult morbid obesity, and 1,416 age-matched normal weight controls. Mutations in NPC1 were also correlated with ordinary weight gain in the population. Previous studies in mice have suggested that the NPC1 gene has a role in controlling appetite, as mice with a non-functioning NPC1 gene suffer late-onset weight loss and have poor food intake. NPC1 gene variant could account for around 10 per cent of all childhood obesity and about 14 per cent of adult morbid obesity cases. ## HIV-AIDS Cholesterol pathways play an important role at multiple stages during the HIV-1 infection cycle. HIV-1 fusion, entry, assembly, and budding occur at cholesterol-enriched microdomains called lipid rafts. The HIV-1 accessory protein, Nef, has been shown to induce many genes involved in cholesterol biosynthesis and homeostasis. Intracellular cholesterol trafficking pathways mediated by NPC1 are needed for efficient HIV-1 production. ## Ebola virus The human Niemann–Pick C1 (NPC1) cholesterol transporter appears to be essential for Ebola virus infection: a series of independent studies have presented evidence that Ebola virus enters human cells after binding to NPC1. When cells from Niemann Pick Type C patients lacking this transporter were exposed to Ebola virus in the laboratory, the cells survived and appeared impervious to the virus, further indicating that Ebola relies on NPC1 to enter cells. The same studies described similar results with Marburg virus, another filovirus, showing that it too needs NPC1 to enter cells. In one of the studies, NPC1 was shown to be critical to filovirus entry because it mediates infection by binding directly to the viral envelope glycoprotein. A later study confirmed the findings that NPC1 is a critical filovirus receptor that mediates infection by binding directly to the viral envelope glycoprotein and that the second lysosomal domain of NPC1 mediates this binding. In one of the original studies, a small molecule was shown to inhibit Ebola virus infection by preventing the virus glycoprotein from binding to NPC1. In the other study, mice that were heterozygous for NPC1 were shown to be protected from lethal challenge with mouse adapted Ebola virus. Together, these studies suggest NPC1 may be potential therapeutic target for an Ebola anti-viral drug. # Mechanisms in pathology In a mouse model carrying the underlying mutation for Niemann-Pick type C1 disease in the NPC1 protein, the expression of Myelin gene Regulatory Factor (MRF) has been shown to be significantly decreased. MRF is a transcription factor of critical importance in the development and maintenance of myelin sheaths. A perturbation of oligodendrocyte maturation and the myelination process might therefore be an underlying mechanism of the neurological deficits.

NPC1 Niemann-Pick disease, type C1 (NPC1) is a disease of a membrane protein that mediates intracellular cholesterol trafficking in mammals. In humans the protein is encoded by the NPC1 gene (chromosome location 18q11).[1][2] # Function NPC1 was identified as the gene that when mutated, results in Niemann-Pick disease, type C. Niemann-Pick disease, type C is a rare neurovisceral lipid storage disorder resulting from autosomal recessively inherited loss-of-function mutations in either NPC1 or NPC2. This disrupts intracellular lipid transport, leading to the accumulation of lipid products in the late endosomes and lysosomes. Approximately 95% of NPC patients are found to have mutations in the NPC1 gene. NPC1 encodes a putative integral membrane protein containing sequence motifs consistent with a role in intracellular transport of cholesterol to post-lysosomal destinations.[1][3] # Clinical significance ## Obesity Mutations in the NPC1 gene have been strongly linked with obesity.[4] A genome-wide association study identified NPC1 mutations as a risk factor in childhood obesity and adult morbid obesity, and 1,416 age-matched normal weight controls.[4] Mutations in NPC1 were also correlated with ordinary weight gain in the population. Previous studies in mice have suggested that the NPC1 gene has a role in controlling appetite, as mice with a non-functioning NPC1 gene suffer late-onset weight loss and have poor food intake. NPC1 gene variant could account for around 10 per cent of all childhood obesity and about 14 per cent of adult morbid obesity cases.[4] ## HIV-AIDS Cholesterol pathways play an important role at multiple stages during the HIV-1 infection cycle. HIV-1 fusion, entry, assembly, and budding occur at cholesterol-enriched microdomains called lipid rafts. The HIV-1 accessory protein, Nef, has been shown to induce many genes involved in cholesterol biosynthesis and homeostasis. Intracellular cholesterol trafficking pathways mediated by NPC1 are needed for efficient HIV-1 production.[5][6] ## Ebola virus The human Niemann–Pick C1 (NPC1) cholesterol transporter appears to be essential for Ebola virus infection: a series of independent studies have presented evidence that Ebola virus enters human cells after binding to NPC1.[7][8] When cells from Niemann Pick Type C patients lacking this transporter were exposed to Ebola virus in the laboratory, the cells survived and appeared impervious to the virus, further indicating that Ebola relies on NPC1 to enter cells.[8] The same studies described similar results with Marburg virus, another filovirus, showing that it too needs NPC1 to enter cells.[7][8] In one of the studies, NPC1 was shown to be critical to filovirus entry because it mediates infection by binding directly to the viral envelope glycoprotein.[8] A later study confirmed the findings that NPC1 is a critical filovirus receptor that mediates infection by binding directly to the viral envelope glycoprotein and that the second lysosomal domain of NPC1 mediates this binding.[9] In one of the original studies, a small molecule was shown to inhibit Ebola virus infection by preventing the virus glycoprotein from binding to NPC1.[8][10] In the other study, mice that were heterozygous for NPC1 were shown to be protected from lethal challenge with mouse adapted Ebola virus.[7] Together, these studies suggest NPC1 may be potential therapeutic target for an Ebola anti-viral drug. # Mechanisms in pathology In a mouse model carrying the underlying mutation for Niemann-Pick type C1 disease in the NPC1 protein, the expression of Myelin gene Regulatory Factor (MRF) has been shown to be significantly decreased.[11] MRF is a transcription factor of critical importance in the development and maintenance of myelin sheaths.[12] A perturbation of oligodendrocyte maturation and the myelination process might therefore be an underlying mechanism of the neurological deficits.[11]

https://www.wikidoc.org/index.php/NPC1

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wikidoc

NPM1

NPM1 Nucleophosmin (NPM), also known as nucleolar phosphoprotein B23 or numatrin, is a protein that in humans is encoded by the NPM1 gene. # Function NPM1 is associated with nucleolar ribonucleoprotein structures and binds single-stranded and double-stranded nucleic acids, but it binds preferentially G-quadruplex forming nucleic acids. It is involved in the biogenesis of ribosomes and may assist small basic proteins in their transport to the nucleolus. Its regulation through SUMOylation (by SENP3 and SENP5) is another facet of the proteins's regulation and cellular functions. It is located in the nucleolus, but it can be translocated to the nucleoplasm in case of serum starvation or treatment with anticancer drugs. The protein is phosphorylated. Nucleophosmin has multiple functions: - Histone chaperones - Ribosome biogenesis and transport - Genomic stability and DNA repair - Endoribonuclease activity - Centrosome duplication during cell cycle - Regulation of ARF-p53 tumor suppressor pathway - RNA helix destabilizing activity - Inhibition of caspase-activated DNase - Prevents apoptosis when located in nucleolus # Clinical significance NPM1 gene is up-regulated, mutated and chromosomally translocated in many tumor types. Chromosomal aberrations involving NPM1 were found in patients with non-Hodgkin lymphoma, acute promyelocytic leukemia, myelodysplastic syndrome, and acute myelogenous leukemia. Heterozygous mice for NPM1 are vulnerable to tumor development. In solid tumors NPM1 is frequently found overexpressed, and it is thought that NPM1 could promote tumor growth by inactivation of the tumor suppressor p53/ARF pathway; on the contrary, when expressed at low levels, NPM1 could suppress tumor growth by the inhibition of centrosome duplication. Of high importance is NPM involvement in acute myelogenous leukemia, where a mutated protein lacking a folded C-terminal domain (NPM1c+) has been found in the cytoplasm in patients. This aberrant localization has been linked to the development of the disease. Strategies against this subtype of acute myelogenous leukemia include the refolding of the C-terminal domain using pharmalogical chaperones and the displacement of the protein from nucleolus to nucleoplasm, which has been linked to apoptotic mechanisms. # Interactions NPM1 has been shown to interact with - AKT1, - BARD1, - BRCA1, and - nucleolin. Nucleophosmin has multiple binding partners: - rRNA - HIV Rev and Rex peptide - p53 tumor suppressor - ARF tumor suppressor - MDM2 (mouse double minute 2, ubiquitin ligase) - Ribosome protein S9 - Phosphatidylinositol 3,4,5-triphosphate (PIP3) - Exportin-1 (CRM1, chromosome region maintenance) - Nucleolin/C23 - Transcription target of myc oncogene

NPM1 Nucleophosmin (NPM), also known as nucleolar phosphoprotein B23 or numatrin, is a protein that in humans is encoded by the NPM1 gene.[1][2] # Function NPM1 is associated with nucleolar ribonucleoprotein structures and binds single-stranded and double-stranded nucleic acids, but it binds preferentially G-quadruplex forming nucleic acids. It is involved in the biogenesis of ribosomes and may assist small basic proteins in their transport to the nucleolus. Its regulation through SUMOylation (by SENP3 and SENP5) is another facet of the proteins's regulation and cellular functions. It is located in the nucleolus, but it can be translocated to the nucleoplasm in case of serum starvation or treatment with anticancer drugs. The protein is phosphorylated. Nucleophosmin has multiple functions:[3] - Histone chaperones - Ribosome biogenesis and transport - Genomic stability and DNA repair - Endoribonuclease activity - Centrosome duplication during cell cycle - Regulation of ARF-p53 tumor suppressor pathway - RNA helix destabilizing activity - Inhibition of caspase-activated DNase - Prevents apoptosis when located in nucleolus # Clinical significance NPM1 gene is up-regulated, mutated and chromosomally translocated in many tumor types. Chromosomal aberrations involving NPM1 were found in patients with non-Hodgkin lymphoma, acute promyelocytic leukemia, myelodysplastic syndrome, and acute myelogenous leukemia.[4] Heterozygous mice for NPM1 are vulnerable to tumor development. In solid tumors NPM1 is frequently found overexpressed, and it is thought that NPM1 could promote tumor growth by inactivation of the tumor suppressor p53/ARF pathway; on the contrary, when expressed at low levels, NPM1 could suppress tumor growth by the inhibition of centrosome duplication. Of high importance is NPM involvement in acute myelogenous leukemia,[5] where a mutated protein lacking a folded C-terminal domain (NPM1c+) has been found in the cytoplasm in patients. This aberrant localization has been linked to the development of the disease. Strategies against this subtype of acute myelogenous leukemia include the refolding of the C-terminal domain using pharmalogical chaperones and the displacement of the protein from nucleolus to nucleoplasm, which has been linked to apoptotic mechanisms. # Interactions NPM1 has been shown to interact with - AKT1,[6] - BARD1,[7] - BRCA1,[7] and - nucleolin.[8] Nucleophosmin has multiple binding partners:[3] - rRNA - HIV Rev and Rex peptide - p53 tumor suppressor - ARF tumor suppressor - MDM2 (mouse double minute 2, ubiquitin ligase) - Ribosome protein S9 - Phosphatidylinositol 3,4,5-triphosphate (PIP3) - Exportin-1 (CRM1, chromosome region maintenance) - Nucleolin/C23 - Transcription target of myc oncogene

https://www.wikidoc.org/index.php/NPM1

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wikidoc

NPR1

NPR1 Natriuretic peptide receptor A/guanylate cyclase A (atrionatriuretic peptide receptor A), also known as NPR1, is an atrial natriuretic peptide receptor. In humans it is encoded by the NPR1 gene. # Function NPR1 is a membrane-bound guanylate cyclase that serves as the receptor for both atrial and brain natriuretic peptides (ANP and BNP, respectively). It is localized in the kidney where it results in natriuresis upon binding to natriuretic peptides. However, it is found in even greater quantity in the lungs and adipocytes.

NPR1 Natriuretic peptide receptor A/guanylate cyclase A (atrionatriuretic peptide receptor A), also known as NPR1, is an atrial natriuretic peptide receptor. In humans it is encoded by the NPR1 gene. # Function NPR1 is a membrane-bound guanylate cyclase that serves as the receptor for both atrial and brain natriuretic peptides (ANP and BNP, respectively).[1] It is localized in the kidney[2] where it results in natriuresis upon binding to natriuretic peptides. However, it is found in even greater quantity in the lungs and adipocytes.[2]

https://www.wikidoc.org/index.php/NPR1

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wikidoc

NPTN

NPTN Neuroplastin is a protein that in humans is encoded by the NPTN gene. Neuroplastin is a type I transmembrane protein belonging to the Ig superfamily. The protein is believed to be involved in cell-cell interactions or cell-substrate interactions. The alpha and beta transcripts show differential localization within the brain. In 2014, in a study led by Dr. Sylvane Desrivières, of King's College London's Institute of Psychiatry found that "teenagers who had a highly functioning NPTN gene performed better in intelligence tests"

NPTN Neuroplastin is a protein that in humans is encoded by the NPTN gene.[1][2][3] Neuroplastin is a type I transmembrane protein belonging to the Ig superfamily. The protein is believed to be involved in cell-cell interactions or cell-substrate interactions. The alpha and beta transcripts show differential localization within the brain.[3] In 2014, in a study led by Dr. Sylvane Desrivières, of King's College London's Institute of Psychiatry found that "teenagers who had a highly functioning NPTN gene performed better in intelligence tests"[4][5][6]

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

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wikidoc

NRAP

NRAP Nebulin-related-anchoring protein (N-RAP) is a protein that in humans is encoded by the NRAP gene. N-RAP is a muscle-specific isoform belonging to the nebulin family of proteins. This family is composed of 5 members: N-RAP, nebulin, nebulette, LASP-1 and LASP-2. N-RAP is involved in both myofibrillar myogenesis during development and cell-cell connections in mature muscle. # Structure N-RAP is a 197 kDa protein composed of 1730 amino acids. As a member of the nebulin family of proteins, N-RAP is characterized by 35 amino acid stretches of ‘‘nebulin repeats’’, which are actin binding domains containing a conserved SDxxYK motif. Like nebulin, groups of seven single repeats within N-RAP form “super repeats”, which incorporate a single conserved motif WLKGIGW at the end of the third repeat. A unique feature of NRAP relative to nebulin is its N-terminal cysteine-rich LIM domain, a feature shared with LASP-1 and LASP-2. # Function An important role has been implicated for N-RAP in myofibrilar organization during cardiomyocyte development. It is clear that NRAP is critical for normal α-actinin-dependent organization of myofibrils in cardiomyocytes, as knock-down of N-RAP protein levels causes myofbrillar disassembly in embryonic cardiomyocytes. Specifically, studies suggest that NRAP super repeats may be an essential scaffold for organizing alpha-actinin and actin into sarcomereic I-Z-I complexes in premyofibrils, and dynamic imaging studies have shown that N-RAP departs from the I-Z-I complexes upon completion of actin thin filament assembly. In adult cardiac muscle, N-RAP colocalizes to intercalated discs, where it functions to anchor terminal actin filaments to the sarcolemma. It has been suggested that its role in adult muscle is force transduction from the sarcomere to the extracellular matrix. # Clinical significance Though no known direct link exists between N-RAP mutations and human cardiomyopathies, N-RAP has been shown to be significantly upregulated in murine models of dilated cardiomyopathy. This has been hypothesized to be an adaptive response to correct for disorganized actin thin filament architecture at intercalated disc junctions in cardiomyocytes during dilated cardiomyopathy.

NRAP Nebulin-related-anchoring protein (N-RAP) is a protein that in humans is encoded by the NRAP gene. N-RAP is a muscle-specific isoform belonging to the nebulin family of proteins. This family is composed of 5 members: N-RAP, nebulin, nebulette, LASP-1 and LASP-2. N-RAP is involved in both myofibrillar myogenesis during development and cell-cell connections in mature muscle.[1][2][3][4] # Structure N-RAP is a 197 kDa protein composed of 1730 amino acids.[5][6] As a member of the nebulin family of proteins, N-RAP is characterized by 35 amino acid stretches of ‘‘nebulin repeats’’, which are actin binding domains containing a conserved SDxxYK motif.[7] Like nebulin, groups of seven single repeats within N-RAP form “super repeats”, which incorporate a single conserved motif WLKGIGW at the end of the third repeat.[8] A unique feature of NRAP relative to nebulin is its N-terminal cysteine-rich LIM domain, a feature shared with LASP-1 and LASP-2.[4] # Function An important role has been implicated for N-RAP in myofibrilar organization during cardiomyocyte development. It is clear that NRAP is critical for normal α-actinin-dependent organization of myofibrils in cardiomyocytes, as knock-down of N-RAP protein levels causes myofbrillar disassembly in embryonic cardiomyocytes.[9] Specifically, studies suggest that NRAP super repeats may be an essential scaffold for organizing alpha-actinin and actin into sarcomereic I-Z-I complexes in premyofibrils,[10] and dynamic imaging studies have shown that N-RAP departs from the I-Z-I complexes upon completion of actin thin filament assembly.[11] In adult cardiac muscle, N-RAP colocalizes to intercalated discs,[12] where it functions to anchor terminal actin filaments to the sarcolemma. It has been suggested that its role in adult muscle is force transduction from the sarcomere to the extracellular matrix.[13] # Clinical significance Though no known direct link exists between N-RAP mutations and human cardiomyopathies, N-RAP has been shown to be significantly upregulated in murine models of dilated cardiomyopathy.[14][15] This has been hypothesized to be an adaptive response to correct for disorganized actin thin filament architecture at intercalated disc junctions in cardiomyocytes during dilated cardiomyopathy.

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

502e3228df0c754abf20662b910290313fb16319

wikidoc

NRF1

NRF1 Nuclear respiratory factor 1, also known as Nrf1, Nrf-1, NRF1 and NRF-1, encodes a protein that homodimerizes and functions as a transcription factor which activates the expression of some key metabolic genes regulating cellular growth and nuclear genes required for respiration, heme biosynthesis, and mitochondrial DNA transcription and replication. The protein has also been associated with the regulation of neurite outgrowth. Alternate transcriptional splice variants, which encode the same protein, have been characterized. Additional variants encoding different protein isoforms have been described but they have not been fully characterized. Confusion has occurred in bibliographic databases due to the shared symbol of NRF1 for this gene and for "nuclear factor (erythroid-derived 2)-like 1" which has an official symbol of NFE2L1. # Function Nrf1 functions as a transcription factor that activates the expression of some key metabolic genes regulating cellular growth and nuclear genes required for mitochondrial respiration, and mitochondrial DNA transcription and replication. Nrf1, together with Nrf2, mediates the biogenomic coordination between nuclear and mitochondrial genomes by directly regulating the expression of several nuclear-encoded ETC proteins, and indirectly regulating the three mitochondrial-encoded COX subunit genes by activating mtTFA, mtTFB1, and mtTFB2. Nrf1 is associated with the regulation of neurite outgrowth. Alternate transcriptional splice variants, which encode the same protein, have been characterized. Additional variants encoding different protein isoforms have been described but they have not been fully characterized. Cyclin D1-dependent kinase, through phosphorylating NRF-1 at S47, coordinates nuclear DNA synthesis and mitochondrial function. # Interactions NRF1 has been shown to interact with DYNLL1, PPARGC1A, and PPRC1.

NRF1 Nuclear respiratory factor 1, also known as Nrf1, Nrf-1, NRF1 and NRF-1, encodes a protein that homodimerizes and functions as a transcription factor which activates the expression of some key metabolic genes regulating cellular growth and nuclear genes required for respiration, heme biosynthesis, and mitochondrial DNA transcription and replication. The protein has also been associated with the regulation of neurite outgrowth. Alternate transcriptional splice variants, which encode the same protein, have been characterized. Additional variants encoding different protein isoforms have been described but they have not been fully characterized. Confusion has occurred in bibliographic databases due to the shared symbol of NRF1 for this gene and for "nuclear factor (erythroid-derived 2)-like 1" which has an official symbol of NFE2L1.[citation needed] # Function Nrf1 functions as a transcription factor that activates the expression of some key metabolic genes regulating cellular growth and nuclear genes required for mitochondrial respiration, and mitochondrial DNA transcription and replication. Nrf1, together with Nrf2, mediates the biogenomic coordination between nuclear and mitochondrial genomes by directly regulating the expression of several nuclear-encoded ETC proteins, and indirectly regulating the three mitochondrial-encoded COX subunit genes by activating mtTFA, mtTFB1, and mtTFB2. Nrf1 is associated with the regulation of neurite outgrowth.[1] Alternate transcriptional splice variants, which encode the same protein, have been characterized. Additional variants encoding different protein isoforms have been described but they have not been fully characterized.[2] Cyclin D1-dependent kinase, through phosphorylating NRF-1 at S47, coordinates nuclear DNA synthesis and mitochondrial function.[3] # Interactions NRF1 has been shown to interact with DYNLL1,[4] PPARGC1A,[5] and PPRC1.[6]

https://www.wikidoc.org/index.php/NRF1

48f03f9eab6d89154537c9f6ac8478422caf1874

wikidoc

NT5C

NT5C 5', 3'-nucleotidase, cytosolic, also known as 5'(3')-deoxyribonucleotidase, cytosolic type (cdN) or deoxy-5'-nucleotidase 1 (dNT-1), is an enzyme that in humans is encoded by the NT5C gene on chromosome 17. This gene encodes a nucleotidase that catalyzes the dephosphorylation of the 5' deoxyribonucleotides (dNTP) and 2'(3')-dNTP and ribonucleotides, but not 5' ribonucleotides. Of the different forms of nucleotidases characterized, this enzyme is unique in its preference for 5'-dNTP. It may be one of the enzymes involved in regulating the size of dNTP pools in cells. Alternatively spliced transcript variants have been found for this gene. # Structure cdN is one of seven 5' nucleotidases identified in humans, all of which differ in tissue specificity, subcellular location, primary structure and substrate specificity. Of the seven, the mitochondrial counterpart of cdN, mdN, is the most closely related to cdN. Their genes, NT5M and NT5C, share the same exon/intron organization, and their amino acid sequences are 52% identical. Both cdN and mdN share nearly identical catalytic phosphate binding sites with most members of the haloacid dehalogenase (HAD) superfamily. This enzyme forms a 45-kDa homodimer of two 22-kDa subunits composed of a core domain and cap domain. The core domain is an α/β Rossmann-like fold containing six antiparallel β-strands surrounded by α-helixes, and it spans residues 1-17 and 77-201 of the amino acid sequence. The cap domain is a 4-helix bundle spanning residues 18-76. The cleft formed by the core and cap domains acts as the enzyme’s active site, where three conserved motifs in the core domain plus the cofactor Mg2+ serve as the substrate binding site. Meanwhile, the residues Phe18, Phe44, Leu45, and Tyr65 in the cap domain form an aromatic, hydrophobic pocket that coordinates with the base of the nucleotide substrate and, thus, influences the enzyme’s substrate specificity. Its two main chain amides form hydrogen bonds with the 4-carbonyl group of dUMP and dTMP and with the 6-carbonyl group of dGMP and dIMP, while repelling the 4-amino group of dCMP and dAMP. The residue Asp43 is responsible for donating a proton to O5’ of the nucleotide during catalysis. # Function This enzyme functions in dephosphorylating nucleoside triphosphates, especially the 5′- and 2′(3′)-phosphates of uracil and thymine, as well as inosine and guanine, dNTPs (dUMPs, dTMPs, dIMPs, and dGMPs, respectively). Due to this function, cdN regulates the size of dNTP pools in cells, in conjunction with the cytosolic thymidine kinases, as part of the dNTP substrate cycle. The enzyme is ubiquitously expressed, though lymphoid cells display particularly high cdN activity. # Clinical Significance The protein cdN is essential to counteract accumulation of cellular dNTPs, as excess dNTPs have been linked to genetic disease. In addition, this enzyme's dephosphorylation function could be applied to anticancer and antiviral treatments which use nucleoside analogs. These treatments rely on the kinase activation of the analogs, which then are incorporated into the DNA of the tumor cell or virus to act as DNA chain terminators. cdN can be used to maintain the concentrations of nucleoside analogs at low levels to avoid cytotoxicity. Moreover, cdN may affect the sensitivity of acute myeloid leukemia (AML) patients to treatment with ara-C. as low cdN mRNA levels in leukemic blasts have been correlated with a worse clinical outcome. # Interactions cdN binds and dephosphorylates deoxyribonucleotides such as uracil, thymine, inosine, and guanine.

NT5C 5', 3'-nucleotidase, cytosolic, also known as 5'(3')-deoxyribonucleotidase, cytosolic type (cdN) or deoxy-5'-nucleotidase 1 (dNT-1), is an enzyme that in humans is encoded by the NT5C gene on chromosome 17.[1][2][3] This gene encodes a nucleotidase that catalyzes the dephosphorylation of the 5' deoxyribonucleotides (dNTP) and 2'(3')-dNTP and ribonucleotides, but not 5' ribonucleotides. Of the different forms of nucleotidases characterized, this enzyme is unique in its preference for 5'-dNTP. It may be one of the enzymes involved in regulating the size of dNTP pools in cells. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2011][2] # Structure cdN is one of seven 5' nucleotidases identified in humans, all of which differ in tissue specificity, subcellular location, primary structure and substrate specificity.[4][5] Of the seven, the mitochondrial counterpart of cdN, mdN, is the most closely related to cdN. Their genes, NT5M and NT5C, share the same exon/intron organization, and their amino acid sequences are 52% identical.[1][4][5] Both cdN and mdN share nearly identical catalytic phosphate binding sites with most members of the haloacid dehalogenase (HAD) superfamily.[5] This enzyme forms a 45-kDa homodimer of two 22-kDa subunits composed of a core domain and cap domain.[5][6] The core domain is an α/β Rossmann-like fold containing six antiparallel β-strands surrounded by α-helixes, and it spans residues 1-17 and 77-201 of the amino acid sequence. The cap domain is a 4-helix bundle spanning residues 18-76. The cleft formed by the core and cap domains acts as the enzyme’s active site, where three conserved motifs in the core domain plus the cofactor Mg2+ serve as the substrate binding site. Meanwhile, the residues Phe18, Phe44, Leu45, and Tyr65 in the cap domain form an aromatic, hydrophobic pocket that coordinates with the base of the nucleotide substrate and, thus, influences the enzyme’s substrate specificity. Its two main chain amides form hydrogen bonds with the 4-carbonyl group of dUMP and dTMP and with the 6-carbonyl group of dGMP and dIMP, while repelling the 4-amino group of dCMP and dAMP. The residue Asp43 is responsible for donating a proton to O5’ of the nucleotide during catalysis.[5] # Function This enzyme functions in dephosphorylating nucleoside triphosphates, especially the 5′- and 2′(3′)-phosphates of uracil and thymine, as well as inosine and guanine, dNTPs (dUMPs, dTMPs, dIMPs, and dGMPs, respectively).[1][4][5][7] Due to this function, cdN regulates the size of dNTP pools in cells, in conjunction with the cytosolic thymidine kinases, as part of the dNTP substrate cycle.[5][6][7][8] The enzyme is ubiquitously expressed, though lymphoid cells display particularly high cdN activity.[8] # Clinical Significance The protein cdN is essential to counteract accumulation of cellular dNTPs, as excess dNTPs have been linked to genetic disease.[6] In addition, this enzyme's dephosphorylation function could be applied to anticancer and antiviral treatments which use nucleoside analogs. These treatments rely on the kinase activation of the analogs, which then are incorporated into the DNA of the tumor cell or virus to act as DNA chain terminators.[8][9] cdN can be used to maintain the concentrations of nucleoside analogs at low levels to avoid cytotoxicity.[8] Moreover, cdN may affect the sensitivity of acute myeloid leukemia (AML) patients to treatment with ara-C. as low cdN mRNA levels in leukemic blasts have been correlated with a worse clinical outcome.[10] # Interactions cdN binds and dephosphorylates deoxyribonucleotides such as uracil, thymine, inosine, and guanine.[5]

https://www.wikidoc.org/index.php/NT5C

f62af9e4cec149ed4cb1bcb4aa1f9c2c50472096

wikidoc

NT5M

NT5M 5',3'-nucleotidase, mitochondrial, also known as 5'(3')-deoxyribonucleotidase, mitochondrial (mdN) or deoxy-5'-nucleotidase 2 (dNT-2), is an enzyme that in humans is encoded by the NT5M gene. This gene encodes a 5' nucleotidase that localizes to the mitochondrial matrix. This enzyme dephosphorylates the 5'- and 2'(3')-phosphates of uracil and thymine deoxyribonucleotides. The gene is located within the Smith-Magenis syndrome region on chromosome 17. # Structure The cDNA of mdN encodes a 25.9-kDa polypeptide, and the crystal structure of this enzymes reveals a 196-long amino acid sequence in the mature protein. The first 32 amino acids, which contain the mitochondrial targeting sequence, are removed during the processing of the premature protein for its import into the mitochondrial matrix. The enzyme is likely a dimer protein formed by the interaction of alpha and beta loops between the cores of the two monomers. Each monomer is composed of a large and small domain connected by two loops. The large domain forms an alpha/beta Rossmann fold as well as 2 helix loops in the fold, whereas the small domain forms a truncated four-helix bundle which is inserted between a beta strand and alpha-helix in the large domain. The active site is found in a cleft between the two domains and binds a magnesium ion that is coordinated by three exogenous ligands, a phosphate ion, and two water molecules in an octahedral shape. mdN is one of seven 5' nucleotidases identified in humans, all of which differ in tissue specificity, subcellular location, primary structure and substrate specificity. Of the seven, the cytosolic counterpart of mdN, cdN, is the most closely related to mdN. Their genes, NT5M and NT5C, share the same exon/intron organization, and their amino acid sequences are 52% identical. In addition, mdN structurally resembles members of the HAD family despite no significant sequence similarity. # Function This enzyme functions in dephosphorylating nucleoside triphosphates, especially the 5′- and 2′(3′)-phosphates of uracil and thymine deoxyribonucleotides (dUMPs and dTMPs). Due to this function, mdN regulates the size of pyrimidine deoxyribonucleotide pools within mitochondria, in conjunction with the mitochondrial thymidine kinase, as part of the thymidine (dTTP)/dTMP substrate cycle. Since excess dTTP leads to aberrant mitochondrial DNA replication, the regulatory role of mdN serves to maintain dTTP levels to ensure proper mitochondrial DNA replication. Similar to other mitochondrial enzymes, mdN mRNA is found in heart, brain, and muscle, and to a lesser degree in kidney and pancreas, while it is absent from placenta, liver, and lung. Though the enzyme is ubiquitous, mdN activity has only been detected in brain and heart tissue. # Clinical significance Since the NT5M gene is located in the Smith–Magenis syndrome region of chromosome 17, mutations in this gene could contribute to the disease. Moreover, its location may indicate that the disease involves a mitochondrial component. The protein mdN is essential to counteract dTTP accumulation, as excess dTTP has been linked to mitochondrial genetic disease. In addition, this enzyme's dephosphorylation function could be applied to anticancer and antiviral treatments which use nucleoside analogs. These treatments rely on the kinase activation of the analogs, which then are incorporated into the DNA of the tumor cell or virus to act as DNA chain terminators. mdN can be used to maintain the concentrations of nucleoside analogs at low levels to avoid mitochondrial toxicity. Thus, only analogs whose 5' phosphates are rapidly and specifically degraded by mdN should be used. # Interactions mdN binds and dephosphorylates uracil and thymine deoxyribonucleotides.

NT5M 5',3'-nucleotidase, mitochondrial, also known as 5'(3')-deoxyribonucleotidase, mitochondrial (mdN) or deoxy-5'-nucleotidase 2 (dNT-2), is an enzyme that in humans is encoded by the NT5M gene. This gene encodes a 5' nucleotidase that localizes to the mitochondrial matrix. This enzyme dephosphorylates the 5'- and 2'(3')-phosphates of uracil and thymine deoxyribonucleotides. The gene is located within the Smith-Magenis syndrome region on chromosome 17.[1][2] # Structure The cDNA of mdN encodes a 25.9-kDa polypeptide, and the crystal structure of this enzymes reveals a 196-long amino acid sequence in the mature protein.[3][4] The first 32 amino acids, which contain the mitochondrial targeting sequence, are removed during the processing of the premature protein for its import into the mitochondrial matrix. The enzyme is likely a dimer protein formed by the interaction of alpha and beta loops between the cores of the two monomers. Each monomer is composed of a large and small domain connected by two loops. The large domain forms an alpha/beta Rossmann fold as well as 2 helix loops in the fold, whereas the small domain forms a truncated four-helix bundle which is inserted between a beta strand and alpha-helix in the large domain. The active site is found in a cleft between the two domains and binds a magnesium ion that is coordinated by three exogenous ligands, a phosphate ion, and two water molecules in an octahedral shape.[4] mdN is one of seven 5' nucleotidases identified in humans, all of which differ in tissue specificity, subcellular location, primary structure and substrate specificity.[4][5] Of the seven, the cytosolic counterpart of mdN, cdN, is the most closely related to mdN. Their genes, NT5M and NT5C, share the same exon/intron organization, and their amino acid sequences are 52% identical.[3][4] In addition, mdN structurally resembles members of the HAD family despite no significant sequence similarity.[4] # Function This enzyme functions in dephosphorylating nucleoside triphosphates, especially the 5′- and 2′(3′)-phosphates of uracil and thymine deoxyribonucleotides (dUMPs and dTMPs).[3][4][6] Due to this function, mdN regulates the size of pyrimidine deoxyribonucleotide pools within mitochondria, in conjunction with the mitochondrial thymidine kinase, as part of the thymidine (dTTP)/dTMP substrate cycle. Since excess dTTP leads to aberrant mitochondrial DNA replication, the regulatory role of mdN serves to maintain dTTP levels to ensure proper mitochondrial DNA replication.[5][6] Similar to other mitochondrial enzymes, mdN mRNA is found in heart, brain, and muscle, and to a lesser degree in kidney and pancreas, while it is absent from placenta, liver, and lung.[3] Though the enzyme is ubiquitous, mdN activity has only been detected in brain and heart tissue.[3][4] # Clinical significance Since the NT5M gene is located in the Smith–Magenis syndrome region of chromosome 17, mutations in this gene could contribute to the disease. Moreover, its location may indicate that the disease involves a mitochondrial component.[3] The protein mdN is essential to counteract dTTP accumulation, as excess dTTP has been linked to mitochondrial genetic disease.[6] In addition, this enzyme's dephosphorylation function could be applied to anticancer and antiviral treatments which use nucleoside analogs.[4][5] These treatments rely on the kinase activation of the analogs, which then are incorporated into the DNA of the tumor cell or virus to act as DNA chain terminators.[5] mdN can be used to maintain the concentrations of nucleoside analogs at low levels to avoid mitochondrial toxicity. Thus, only analogs whose 5' phosphates are rapidly and specifically degraded by mdN should be used.[4][5] # Interactions mdN binds and dephosphorylates uracil and thymine deoxyribonucleotides.[3][4]

https://www.wikidoc.org/index.php/NT5M

1d59266e2c933e46c71687b9cebb3153a2e578a5

wikidoc

NUB1

NUB1 NEDD8 ultimate buster 1 is a protein that in humans is encoded by the NUB1 gene. # Function NUB1 interacts with and negatively regulates NEDD8 (MIM 603171), a ubiquitin-like protein that covalently conjugates to cullin (see MIM 603134) family members. # Interactions NUB1 has been shown to interact with NEDD8, UBD and AIPL1.

NUB1 NEDD8 ultimate buster 1 is a protein that in humans is encoded by the NUB1 gene.[1][2][3] # Function NUB1 interacts with and negatively regulates NEDD8 (MIM 603171), a ubiquitin-like protein that covalently conjugates to cullin (see MIM 603134) family members.[supplied by OMIM][3] # Interactions NUB1 has been shown to interact with NEDD8,[4][5] UBD[4] and AIPL1.[6]

https://www.wikidoc.org/index.php/NUB1

3dbaa6be5297053b6bd2d00acc6def0b5876e196

wikidoc

NXF1

NXF1 Nuclear RNA export factor 1, also known as NXF1 or TAP, is a protein which in humans is encoded by the NXF1 gene. # Function This gene is one member of a family of nuclear RNA export factor genes. Common domain features of this family are a noncanonical RNP-type RNA-binding domain (RBD), 4 leucine-rich repeats (LRRs), a nuclear transport factor 2 (NTF2)-like domain that allows heterodimerization with NTF2-related export protein-1 (NXT1), and a ubiquitin-associated domain that mediates interactions with nucleoporins. Alternative splicing results in transcript variants. The LRRs and NTF2-like domains are required for export activity. The encoded protein of this gene shuttles between the nucleus and the cytoplasm and binds in vivo to poly(A)+ RNA. It is the vertebrate homologue of the yeast protein Mex67p. The encoded protein overcomes the mRNA export block caused by the presence of saturating amounts of CTE (constitutive transport element) RNA of type D retroviruses. A variant allele of the homologous Nxf1 gene in mice suppresses a class of mutations caused by integration of an endogenous retrovirus (intracisternal A particle) into an intron. # Interactions NXF1 has been shown to interact with TNPO2, MAGOH, U2 small nuclear RNA auxiliary factor 1, DHX9, HuD and NUP214. # Tap protein In molecular biology, another name for the protein NXF1 is TAP. In particular this entry focuses on the C-terminal domain, which also contains the UBA(protein domain). This entry contains the NXF family of shuttling transport receptors for nuclear export of mRNA, which include: - vertebrate mRNA export factor TAP or nuclear RNA export factor 1 (NXF1). - Caenorhabditis elegans nuclear RNA export factor 1 (nxf-1). - yeast mRNA export factor MEX67. Members of the NXF family have a modular structure. A nuclear localization sequence and a noncanonical RNA recognition motif (RRM) (see PROSITEDOC) followed by four LRR repeats are located in its N-terminal half. The C-terminal half contains a NTF2 domain (see ) followed by a second domain, TAP-C. The TAP-C domain is important for binding to FG repeat-containing nuclear pore proteins (FG-nucleoporins) and is sufficient to mediate nuclear shuttling. The Tap-C domain is made of four alpha helices packed against each other. The arrangement of helices 1, 2 and 3 is similar to that seen in a UBA fold. and is joined to the next module by flexible 12-residue Pro-rich linker. # Function Nuclear export of mRNAs is mediated by the Tap protein. # Structure Tap can form a multimeric complex with itself and with other members of the NXF family. Three functional domains of Tap have been well characterized: the RNA-binding domain, the Nuclear Transport Factor 2 (NTF2)-like domain, and the ubiquitin-associated (UBA) domain.

NXF1 Nuclear RNA export factor 1, also known as NXF1 or TAP, is a protein which in humans is encoded by the NXF1 gene.[1][2] # Function This gene is one member of a family of nuclear RNA export factor genes. Common domain features of this family are a noncanonical RNP-type RNA-binding domain (RBD), 4 leucine-rich repeats (LRRs), a nuclear transport factor 2 (NTF2)-like domain that allows heterodimerization with NTF2-related export protein-1 (NXT1), and a ubiquitin-associated domain that mediates interactions with nucleoporins. Alternative splicing results in transcript variants. The LRRs and NTF2-like domains are required for export activity. The encoded protein of this gene shuttles between the nucleus and the cytoplasm and binds in vivo to poly(A)+ RNA. It is the vertebrate homologue of the yeast protein Mex67p.[2][3] The encoded protein overcomes the mRNA export block caused by the presence of saturating amounts of CTE (constitutive transport element) RNA of type D retroviruses.[4] A variant allele of the homologous Nxf1 gene in mice suppresses a class of mutations caused by integration of an endogenous retrovirus (intracisternal A particle) into an intron.[5][6] # Interactions NXF1 has been shown to interact with TNPO2,[7] MAGOH,[8] U2 small nuclear RNA auxiliary factor 1,[9] DHX9,[10] HuD[11] and NUP214.[12][13] # Tap protein In molecular biology, another name for the protein NXF1 is TAP. In particular this entry focuses on the C-terminal domain, which also contains the UBA(protein domain). This entry contains the NXF family of shuttling transport receptors for nuclear export of mRNA, which include: - vertebrate mRNA export factor TAP or nuclear RNA export factor 1 (NXF1). - Caenorhabditis elegans nuclear RNA export factor 1 (nxf-1). - yeast mRNA export factor MEX67. Members of the NXF family have a modular structure. A nuclear localization sequence and a noncanonical RNA recognition motif (RRM) (see PROSITEDOC) followed by four LRR repeats are located in its N-terminal half. The C-terminal half contains a NTF2 domain (see [href="http://expasy.org/prosite/PDOC50177 PROSITEDOC]) followed by a second domain, TAP-C. The TAP-C domain is important for binding to FG repeat-containing nuclear pore proteins (FG-nucleoporins) and is sufficient to mediate nuclear shuttling.[14][15] The Tap-C domain is made of four alpha helices packed against each other. The arrangement of helices 1, 2 and 3 is similar to that seen in a UBA fold. and is joined to the next module by flexible 12-residue Pro-rich linker.[14][15] # Function Nuclear export of mRNAs is mediated by the Tap protein. # Structure Tap can form a multimeric complex with itself and with other members of the NXF family. Three functional domains of Tap have been well characterized: the RNA-binding domain, the Nuclear Transport Factor 2 (NTF2)-like domain, and the ubiquitin-associated (UBA) domain.

https://www.wikidoc.org/index.php/NXF1

20e091308db0ff116e68a6144f4768d05aadadde

wikidoc

Neck

Neck # Overview The neck is the part of the body on many limbed vertebrates that distinguishes the head from the torso or trunk. # Anatomy of the human neck ## Bony anatomy: The cervical spine The cervical portion of the human spine comprises seven bony segments, typically referred to as C-1 to C-7, with cartilaginous disks between each vertebral body. The neck supports the weight of the head and protects the nerves that travel from the brain down to the rest of the body. In addition, the neck is highly flexible and allows the head to turn and flex in all directions. From top to bottom the cervical spine is gently curved in convex-forward fashion. It is the least marked of all the curves of the column. ## Soft tissue anatomy In the middle line below the chin can be felt the body of the hyoid bone, just below which is the prominence of the thyroid cartilage called "Adam's apple," better marked in men than in women. Still lower the cricoid cartilage is easily felt, while between this and the suprasternal notch the trachea and isthmus of the thyroid gland may be made out. At the side the outline of the sternomastoid muscle is the most striking mark; it divides the anterior triangle of the neck from the posterior. The upper part of the former contains the submaxillary gland also known as the parotid glands, which lies just below the posterior half of the body of the jaw. The line of the common and the external carotid arteries may be marked by joining the sterno-clavicular articulation to the angle of the jaw. The eleventh or spinal accessory nerve corresponds to a line drawn from a point midway between the angle of the jaw and the mastoid process to the middle of the posterior border of the sterno-mastoid muscle and thence across the posterior triangle to the deep surface of the trapezius. The external jugular vein can usually be seen through the skin; it runs in a line drawn from the angle of the jaw to the middle of the clavicle, and close to it are some small lymphatic glands. The anterior jugular vein is smaller, and runs down about half an inch from the middle line of the neck. The clavicle or collar-bone forms the lower limit of the neck, and laterally the outward slope of the neck to the shoulder is caused by the trapezius muscle. # Diagnostic Findings ## MRI (Images courtesy of RadsWiki) - MRI: Normal neck - MRI: Normal neck - MRI: Normal neck - MRI: Normal neck - MRI: Normal neck - MRI: Normal neck # Neck pain Disorders of the neck are a common source of pain. The neck has a great deal of functionality but is also subject to a lot of stress. Common sources of neck pain (and related pain syndromes, such as pain that radiates down the arm) include: - Whiplash, strained muscle or other soft tissue injury - Cervical herniated disc - Cervical spinal stenosis - Osteoarthritis - Vascular sources of pain, like arterial dissections or internal jugular vein thrombosis

Neck Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The neck is the part of the body on many limbed vertebrates that distinguishes the head from the torso or trunk. # Anatomy of the human neck ## Bony anatomy: The cervical spine The cervical portion of the human spine comprises seven bony segments, typically referred to as C-1 to C-7, with cartilaginous disks between each vertebral body. The neck supports the weight of the head and protects the nerves that travel from the brain down to the rest of the body. In addition, the neck is highly flexible and allows the head to turn and flex in all directions. From top to bottom the cervical spine is gently curved in convex-forward fashion. It is the least marked of all the curves of the column. ## Soft tissue anatomy In the middle line below the chin can be felt the body of the hyoid bone, just below which is the prominence of the thyroid cartilage called "Adam's apple," better marked in men than in women. Still lower the cricoid cartilage is easily felt, while between this and the suprasternal notch the trachea and isthmus of the thyroid gland may be made out. At the side the outline of the sternomastoid muscle is the most striking mark; it divides the anterior triangle of the neck from the posterior. The upper part of the former contains the submaxillary gland also known as the parotid glands, which lies just below the posterior half of the body of the jaw. The line of the common and the external carotid arteries may be marked by joining the sterno-clavicular articulation to the angle of the jaw. The eleventh or spinal accessory nerve corresponds to a line drawn from a point midway between the angle of the jaw and the mastoid process to the middle of the posterior border of the sterno-mastoid muscle and thence across the posterior triangle to the deep surface of the trapezius. The external jugular vein can usually be seen through the skin; it runs in a line drawn from the angle of the jaw to the middle of the clavicle, and close to it are some small lymphatic glands. The anterior jugular vein is smaller, and runs down about half an inch from the middle line of the neck. The clavicle or collar-bone forms the lower limit of the neck, and laterally the outward slope of the neck to the shoulder is caused by the trapezius muscle. # Diagnostic Findings ## MRI (Images courtesy of RadsWiki) - MRI: Normal neck - MRI: Normal neck - MRI: Normal neck - MRI: Normal neck - MRI: Normal neck - MRI: Normal neck # Neck pain Disorders of the neck are a common source of pain. The neck has a great deal of functionality but is also subject to a lot of stress. Common sources of neck pain (and related pain syndromes, such as pain that radiates down the arm) include: - Whiplash, strained muscle or other soft tissue injury - Cervical herniated disc - Cervical spinal stenosis - Osteoarthritis - Vascular sources of pain, like arterial dissections or internal jugular vein thrombosis

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Neon

Neon Neon (Template:PronEng) is the chemical element that has the symbol Ne and atomic number 10. A very common element in the universe, it is rare on Earth. A colorless, inert noble gas under standard conditions, neon gives a distinct reddish glow when used in vacuum discharge tubes and neon lamps. It is commercially extracted from air, in which it is found in trace amounts. # History Neon (Greek νέον(neon) meaning "new one") was discovered in 1898 by Scottish chemist William Ramsay (1852 - 1916) and English chemist Morris W. Travers in London, England. Neon was discovered when Ramsay chilled a sample of the atmosphere until it became a liquid, then warmed the liquid and captured the gases as they boiled off. The three gases were krypton, xenon, and neon. # Isotopes Neon has three stable isotopes: 20Ne (90.48%), 21Ne (0.27%) and 22Ne (9.25%). 21Ne and 22Ne are nucleogenic and their variations are well understood. In contrast, 20Ne is not known to be nucleogenic and the causes of its variation in the Earth have been hotly debated. The principal nuclear reactions which generate neon isotopes are neutron emission, alpha decay reactions on 24Mg and 25Mg, which produce 21Ne and 22Ne, respectively. The alpha particles are derived from uranium-series decay chains, while the neutrons are mostly produced by secondary reactions from alpha particles. The net result yields a trend towards lower 20Ne/22Ne and higher 21Ne/22Ne ratios observed in uranium-rich rocks such as granites. Isotopic analysis of exposed terrestrial rocks has demonstrated the cosmogenic production of 21Ne. This isotope is generated by spallation reactions on magnesium, sodium, silicon, and aluminium. By analyzing all three isotopes, the cosmogenic component can be resolved from magmatic neon and nucleogenic neon. This suggests that neon will be a useful tool in determining cosmic exposure ages of surficial rocks and meteorites. Similar to xenon, neon content observed in samples of volcanic gases are enriched in 20Ne, as well as nucleogenic 21Ne, relative to 22Ne content. The neon isotopic content of these mantle-derived samples represent a non-atmospheric source of neon. The 20Ne-enriched components are attributed to exotic primordial rare gas components in the Earth, possibly representing solar neon. Elevated 20Ne abundances are found in diamonds, further suggesting a solar neon reservoir in the Earth. # Notable characteristics Neon is the second-lightest noble gas, glows reddish-orange in a vacuum discharge tube and has over 40 times the refrigerating capacity of liquid helium and three times that of liquid hydrogen (on a per unit volume basis). In most applications it is a less expensive refrigerant than helium. Neon plasma has the most intense light discharge at normal voltages and currents of all the rare gases. The average color of this light to the human eye is red-orange; it contains a strong green line which is hidden, unless the visual components are dispersed by a spectroscope. # Occurrence Neon is actually abundant on a universal scale: the fifth most abundant chemical element in the universe by mass, after hydrogen, helium, oxygen, and carbon (see chemical element). Its relative rarity on Earth, like that of helium, is due to its relative lightness and chemical inertness, both properties keeping it from being trapped in the condensing gas and dust clouds of the formation of smaller and warmer solid planets like Earth. Mass abundance in the universe is about 1 part in 750 and in the Sun and presumably in the proto-solar system nebula, about 1 part in 600. The Galileo spacecraft atmospheric entry probe found that even in the upper atmosphere of Jupiter, neon is reduced by about a factor of 10, to 1 part in 6,000 by mass. This may indicate that even the ice-planetesmals which brought neon into Jupiter from the outer solar system, formed in a region which was too warm for them to have kept their neon (abundances of heavier inert gases on Jupiter are several times that found in the Sun). Neon is a monatomic gas at standard conditions. Neon is rare on Earth, found in the Earth's atmosphere at 1 part in 65,000 (by volume) or 1 part in 83,000 by mass. It is industrially produced by cryogenic fractional distillation of liquefied air. # Applications The reddish-orange color that neon emits in neon lights is widely used to make advertising signs and is used in long tubular strips in car modification. The word "neon" is used generically for these types of lights even though many other gases are used to produce different colors of light. Neon may also be used in vacuum tubes, high-voltage indicators, lightning arrestors, wave meter tubes, television tubes, and helium-neon lasers. Liquefied neon is commercially used as a cryogenic refrigerant in applications not requiring the lower temperature range attainable with more expensive liquid helium refrigeration. Neon's triple point temperature of 24.5561 K is a defining fixed point in the International Temperature Scale of 1990. # Compounds Neon is a noble gas, and therefore generally considered to be inert. However, the ions, Ne+, (NeAr)+, (NeH)+, and (HeNe+), have been observed from optical and mass spectrometric studies, and neon is also known to form an unstable hydrate.

Neon Template:Infobox neon Neon (Template:PronEng) is the chemical element that has the symbol Ne and atomic number 10. A very common element in the universe, it is rare on Earth. A colorless, inert noble gas under standard conditions, neon gives a distinct reddish glow when used in vacuum discharge tubes and neon lamps. It is commercially extracted from air, in which it is found in trace amounts. # History Template:Expand-section Neon (Greek νέον(neon) meaning "new one") was discovered in 1898 by Scottish chemist William Ramsay (1852 - 1916) and English chemist Morris W. Travers in London, England.[1] Neon was discovered when Ramsay chilled a sample of the atmosphere until it became a liquid, then warmed the liquid and captured the gases as they boiled off. The three gases were krypton, xenon, and neon.[2] # Isotopes Neon has three stable isotopes: 20Ne (90.48%), 21Ne (0.27%) and 22Ne (9.25%). 21Ne and 22Ne are nucleogenic and their variations are well understood. In contrast, 20Ne is not known to be nucleogenic and the causes of its variation in the Earth have been hotly debated. The principal nuclear reactions which generate neon isotopes are neutron emission, alpha decay reactions on 24Mg and 25Mg, which produce 21Ne and 22Ne, respectively. The alpha particles are derived from uranium-series decay chains, while the neutrons are mostly produced by secondary reactions from alpha particles. The net result yields a trend towards lower 20Ne/22Ne and higher 21Ne/22Ne ratios observed in uranium-rich rocks such as granites. Isotopic analysis of exposed terrestrial rocks has demonstrated the cosmogenic production of 21Ne. This isotope is generated by spallation reactions on magnesium, sodium, silicon, and aluminium. By analyzing all three isotopes, the cosmogenic component can be resolved from magmatic neon and nucleogenic neon. This suggests that neon will be a useful tool in determining cosmic exposure ages of surficial rocks and meteorites.[3] Similar to xenon, neon content observed in samples of volcanic gases are enriched in 20Ne, as well as nucleogenic 21Ne, relative to 22Ne content. The neon isotopic content of these mantle-derived samples represent a non-atmospheric source of neon. The 20Ne-enriched components are attributed to exotic primordial rare gas components in the Earth, possibly representing solar neon. Elevated 20Ne abundances are found in diamonds, further suggesting a solar neon reservoir in the Earth.[4] # Notable characteristics Neon is the second-lightest noble gas, glows reddish-orange in a vacuum discharge tube and has over 40 times the refrigerating capacity of liquid helium and three times that of liquid hydrogen (on a per unit volume basis).[5] In most applications it is a less expensive refrigerant than helium.[6] Neon plasma has the most intense light discharge at normal voltages and currents of all the rare gases. The average color of this light to the human eye is red-orange; it contains a strong green line which is hidden, unless the visual components are dispersed by a spectroscope.[7] # Occurrence Neon is actually abundant on a universal scale: the fifth most abundant chemical element in the universe by mass, after hydrogen, helium, oxygen, and carbon (see chemical element). Its relative rarity on Earth, like that of helium, is due to its relative lightness and chemical inertness, both properties keeping it from being trapped in the condensing gas and dust clouds of the formation of smaller and warmer solid planets like Earth. Mass abundance in the universe is about 1 part in 750 and in the Sun and presumably in the proto-solar system nebula, about 1 part in 600. The Galileo spacecraft atmospheric entry probe found that even in the upper atmosphere of Jupiter, neon is reduced by about a factor of 10, to 1 part in 6,000 by mass. This may indicate that even the ice-planetesmals which brought neon into Jupiter from the outer solar system, formed in a region which was too warm for them to have kept their neon (abundances of heavier inert gases on Jupiter are several times that found in the Sun).[8] Neon is a monatomic gas at standard conditions. Neon is rare on Earth, found in the Earth's atmosphere at 1 part in 65,000 (by volume) or 1 part in 83,000 by mass. It is industrially produced by cryogenic fractional distillation of liquefied air.[9] # Applications The reddish-orange color that neon emits in neon lights is widely used to make advertising signs and is used in long tubular strips in car modification. The word "neon" is used generically for these types of lights even though many other gases are used to produce different colors of light. Neon may also be used in vacuum tubes, high-voltage indicators, lightning arrestors, wave meter tubes, television tubes, and helium-neon lasers. Liquefied neon is commercially used as a cryogenic refrigerant in applications not requiring the lower temperature range attainable with more expensive liquid helium refrigeration. Neon's triple point temperature of 24.5561 K is a defining fixed point in the International Temperature Scale of 1990.[10] # Compounds Neon is a noble gas, and therefore generally considered to be inert. However, the ions, Ne+, (NeAr)+, (NeH)+, and (HeNe+), have been observed from optical and mass spectrometric studies, and neon is also known to form an unstable hydrate.[11]

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Nose

Nose # Overview Anatomically, a nose is a protuberance in vertebrates that houses the nostrils, or nares, which admit and expel air for respiration in conjunction with the mouth. In most humans, it also houses the nosehairs, which catch airborne particles and prevent them from reaching the lungs. Within and behind the nose is the olfactory mucosa and the sinuses. Behind the nasal cavity, air next passes through the pharynx, shared with the digestive system, and then into the rest of the respiratory system. In humans, the nose is located centrally on the face;on most other mammals, it is on the upper tip of the snout. As an interface between the body and the external world, the nose and associated structures frequently perform additional functions concerned with conditioning entering air (for instance, by warming and/or humidifying it, also for flicking if moving and by mostly reclaiming moisture from the air before it is exhaled (as occurs most efficiently in camels). In most mammals, the nose is the primary organ for smelling. As the animal sniffs, the air flows through the nose and over structures called turbinates in the nasal cavity. The turbulence caused by this disruption slows the air and directs it toward the olfactory epithelium. At the surface of the olfactory epithelium, odor molecules carried by the air contact olfactory receptor neurons which transduce the features of the molecule into non painful electrical impulses in the brain. In cetaceans, the nose has been reduced to the nostrils, which have migrated to the top of the head, producing a more streamlined body shape and the ability to breathe while mostly submerged. Conversely, the elephant's nose has become elaborated into a long, muscular, manipulative organ called the trunk.

Nose # Overview Anatomically, a nose is a protuberance in vertebrates that houses the nostrils, or nares, which admit and expel air for respiration in conjunction with the mouth. In most humans, it also houses the nosehairs, which catch airborne particles and prevent them from reaching the lungs. Within and behind the nose is the olfactory mucosa and the sinuses. Behind the nasal cavity, air next passes through the pharynx, shared with the digestive system, and then into the rest of the respiratory system. In humans, the nose is located centrally on the face;on most other mammals, it is on the upper tip of the snout. As an interface between the body and the external world, the nose and associated structures frequently perform additional functions concerned with conditioning entering air (for instance, by warming and/or humidifying it, also for flicking if moving and by mostly reclaiming moisture from the air before it is exhaled (as occurs most efficiently in camels). In most mammals, the nose is the primary organ for smelling. As the animal sniffs, the air flows through the nose and over structures called turbinates in the nasal cavity. The turbulence caused by this disruption slows the air and directs it toward the olfactory epithelium. At the surface of the olfactory epithelium, odor molecules carried by the air contact olfactory receptor neurons which transduce the features of the molecule into non painful electrical impulses in the brain. In cetaceans, the nose has been reduced to the nostrils, which have migrated to the top of the head, producing a more streamlined body shape and the ability to breathe while mostly submerged. Conversely, the elephant's nose has become elaborated into a long, muscular, manipulative organ called the trunk.

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76437a8f057e44c1e9945b88c6a77be17b15f40c

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Nuke

Nuke The word nuke, as a verb or a noun, can refer to multiple things: - A colloquialism for a nuclear weapon, or the use of one, or the equivalent destruction of the use of one (as an analogy) - A colloquialism for a nuclear power plant - A member of the United States Navy trained to operate a naval reactor (i.e. nuclear watch officer, nuclear Machinist Mate "MM", Electricians Mate "EM", or Electronics Technician "ET"). The enlisted ratings are found with an "N" after their ratings when taking promotion exams. - Nuke (computer), a denial-of-service attack - WinNuke, an exploit in some early versions of Microsoft Windows - For the meaning in the context of the warez scene, see Nuke (warez) - For the meaning in the context of role-playing games, see nuke (gaming) - Nuke (software), digital compositing software by The Foundry - A family of simple content management systems that provide basic functionality in the form of user management and news item editing, and add in more functionality, such as calendars and forums, through the use of modules. OpenPHPNuke PHP-Nuke PostNuke CPG-Nuke DotNetNuke Mambo (software) Joomla - OpenPHPNuke - PHP-Nuke - PostNuke - CPG-Nuke - DotNetNuke - Mambo (software) - Joomla - Nuke (Marvel Comics), an American Flag faced comic book Marvel Comics character - Nuke (Squadron Supreme), a superhero from Earth-712 in the fictional Marvel Universe - Fictional drug in RoboCop 2 - A portmonteau term (coming from "Noah" and "Luke") for the relationship between Luke Snyder and Noah Mayer on As the World Turns - Heating something in a microwave oven is sometimes referred to as "nuking" it - Nucleoside/Nucleotide Reverse Transcriptase Inhibitors, better known as nucleoside analogues or *Nukes were the first group of available antiretroviral drugs to treat HIV in 1987 de:Nuke

Nuke The word nuke, as a verb or a noun, can refer to multiple things: - A colloquialism for a nuclear weapon, or the use of one, or the equivalent destruction of the use of one (as an analogy) - A colloquialism for a nuclear power plant - A member of the United States Navy trained to operate a naval reactor (i.e. nuclear watch officer, nuclear Machinist Mate "MM", Electricians Mate "EM", or Electronics Technician "ET"). The enlisted ratings are found with an "N" after their ratings when taking promotion exams. - Nuke (computer), a denial-of-service attack - WinNuke, an exploit in some early versions of Microsoft Windows - For the meaning in the context of the warez scene, see Nuke (warez) - For the meaning in the context of role-playing games, see nuke (gaming) - Nuke (software), digital compositing software by The Foundry - A family of simple content management systems that provide basic functionality in the form of user management and news item editing, and add in more functionality, such as calendars and forums, through the use of modules. OpenPHPNuke PHP-Nuke PostNuke CPG-Nuke DotNetNuke Mambo (software) Joomla - OpenPHPNuke - PHP-Nuke - PostNuke - CPG-Nuke - DotNetNuke - Mambo (software) - Joomla - Nuke (Marvel Comics), an American Flag faced comic book Marvel Comics character - Nuke (Squadron Supreme), a superhero from Earth-712 in the fictional Marvel Universe - Fictional drug in RoboCop 2 - A portmonteau term (coming from "Noah" and "Luke") for the relationship between Luke Snyder and Noah Mayer on As the World Turns - Heating something in a microwave oven is sometimes referred to as "nuking" it - Nucleoside/Nucleotide Reverse Transcriptase Inhibitors, better known as nucleoside analogues or *Nukes were the first group of available antiretroviral drugs to treat HIV in 1987 Template:Disambig de:Nuke

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OCA2

OCA2 P protein, also known as melanocyte-specific transporter protein or pink-eyed dilution protein homolog, is a protein that in humans is encoded by the oculocutaneous albinism II (OCA2) gene. The P protein is believed to be an integral membrane protein involved in small molecule transport, specifically tyrosine - a precursor of melanin. Certain mutations in OCA2 result in type 2 oculocutaneous albinism. OCA2 encodes the human homologue of the mouse p (pink-eyed dilution) gene. The human OCA2 gene is located on the long arm (q) of chromosome 15, specifically from base pair 28,000,020 to base pair 28,344,457 on chromosome 15. # Function OCA2 provides instructions for making the protein called P protein which is located in melanocytes which are specialized cells that produce melanin. Melanin is responsible for giving color to the skin, hair, and eyes. Moreover, melanin is found in the light-sensitive tissue of the retina of the eye which plays a role in normal vision. The exact function of protein P is unknown, but it has been found that it is essential for the normal coloring of skin, eyes, and hair; and likely involved in melanin production. This gene seems to be the main determinant of eye color depending on the amount of melanin production in the iris stroma (large amounts giving rise to brown eyes; little to no melanin giving rise to blue eyes). # Clinical significance Mutations in the OCA2 gene cause a disruption in the normal production of melanin; therefore, causing vision problems and reductions in hair, skin, and eye color. Oculocutaneous albinism caused by mutations in the OCA2 gene is called oculocutaneous albinism type 2. The prevalence of OCA type 2 is estimated at 1/38,000-1/40,000 in most populations throughout the world, with a higher prevalence in the African population of 1/3,900-1/1,500. Other diseases associated with the deletion of the OCA2 gene are Angelman syndrome (light-colored hair and fair skin) and Prader-Willi syndrome (unusually light-colored hair and fair skin). With both these syndromes, the deletion often occurs in individuals with either syndrome. A mutation in the HERC2 gene adjacent to OCA2, affecting OCA2's expression in the human iris, is found common to nearly all people with blue eyes. It has been hypothesized that all blue-eyed humans share a single common ancestor with whom the mutation originated. The His615Arg allele of OCA2 is involved in the light skin tone and the derived allele is restricted to East Asia with high frequencies, with highest frequencies in Eastern East Asia (49-63%), midrange frequencies in Southeast Asia, and the lowest frequencies in Western China and some Eastern European populations.

OCA2 P protein, also known as melanocyte-specific transporter protein or pink-eyed dilution protein homolog, is a protein that in humans is encoded by the oculocutaneous albinism II (OCA2) gene.[1] The P protein is believed to be an integral membrane protein involved in small molecule transport, specifically tyrosine - a precursor of melanin. Certain mutations in OCA2 result in type 2 oculocutaneous albinism.[1] OCA2 encodes the human homologue of the mouse p (pink-eyed dilution) gene. The human OCA2 gene is located on the long arm (q) of chromosome 15, specifically from base pair 28,000,020 to base pair 28,344,457 on chromosome 15. # Function OCA2 provides instructions for making the protein called P protein which is located in melanocytes which are specialized cells that produce melanin. Melanin is responsible for giving color to the skin, hair, and eyes. Moreover, melanin is found in the light-sensitive tissue of the retina of the eye which plays a role in normal vision. The exact function of protein P is unknown, but it has been found that it is essential for the normal coloring of skin, eyes, and hair; and likely involved in melanin production. This gene seems to be the main determinant of eye color depending on the amount of melanin production in the iris stroma (large amounts giving rise to brown eyes; little to no melanin giving rise to blue eyes). # Clinical significance Mutations in the OCA2 gene cause a disruption in the normal production of melanin; therefore, causing vision problems and reductions in hair, skin, and eye color. Oculocutaneous albinism caused by mutations in the OCA2 gene is called oculocutaneous albinism type 2. The prevalence of OCA type 2 is estimated at 1/38,000-1/40,000 in most populations throughout the world, with a higher prevalence in the African population of 1/3,900-1/1,500.[2] Other diseases associated with the deletion of the OCA2 gene are Angelman syndrome (light-colored hair and fair skin) and Prader-Willi syndrome (unusually light-colored hair and fair skin). With both these syndromes, the deletion often occurs in individuals with either syndrome.[3][4] A mutation in the HERC2 gene adjacent to OCA2, affecting OCA2's expression in the human iris, is found common to nearly all people with blue eyes. It has been hypothesized that all blue-eyed humans share a single common ancestor with whom the mutation originated.[5][6][7] The His615Arg allele of OCA2 is involved in the light skin tone and the derived allele is restricted to East Asia with high frequencies, with highest frequencies in Eastern East Asia (49-63%), midrange frequencies in Southeast Asia, and the lowest frequencies in Western China and some Eastern European populations.[8][9]

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63c197843ee591595b4c61ad87d53e03cdbd4dcc

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OCLC

OCLC # Overview OCLC Online Computer Library Center, Inc. is a "nonprofit, membership, computer library service and research organization dedicated to the public purpose of furthering access to the world's information and reducing information costs", according to its website. It was founded in 1967 as the Ohio College Library Center. More than 60,000 libraries in 112 countries and territories around the world use OCLC services to locate, acquire, catalog, lend and preserve library materials. The organization was founded by Fred Kilgour, and its head office is located in Dublin, Ohio, United States. OCLC acquired NetLibrary, the largest electronic content provider, in 2002. OCLC owns 100% of the shares of OCLC PICA, a library automation systems and services company which has its headquarters in Leiden in the Netherlands and which was renamed "OCLC" at the end of 2007. In June 2006, the Research Libraries Group (RLG) merged into OCLC. On January 11, 2008, OCLC announced that it had purchased EZproxy. # Services OCLC provides bibliographic, abstract and full-text information to libraries, students, faculty, scholars, and other information seekers. OCLC and its member libraries cooperatively produce and maintain WorldCat—the OCLC Online Union Catalog, the largest OPAC (Online Public Access Catalog) in the world. WorldCat contains holding records from most public and private libraries worldwide. WorldCat is available through many libraries and university computer networks. The Open WorldCat program makes records of library-owned materials in OCLC's WorldCat database available to Web users on popular Internet search, bibliographic and bookselling sites. OCLC member libraries' catalogs are more accessible from the sites where many people start their search for information. In October 2005, the OCLC technical staff began a wiki-like project that allows readers and librarians to add commentary, and structured-field information, associated with any WorldCat record. OCLC owns a preservation microfilm and digitization operation called the OCLC Preservation Service Center, with its principal office in Bethlehem, Pennsylvania, U.S. Libraries, museums, historical societies, colleges and universities utilize the OCLC Preservation Services to preserve printed works, books, maps, manuscripts, newspapers, etc. in microfilm format for future generations due to its 500-year life expectancy. In addition OCLC Preservation Services converts print and microfilm to digital objects for computer access. # Online database OCLC maintains a database for cataloging and searching purposes which is used by librarians and the public. OCLC Passport was one of the computer programs used. Connexion was introduced in 2001 and replaced Passport when it was phased out in May 2005. This database contains records in MAchine Readable Cataloging (MARC standards) format contributed by library catalogers worldwide who use OCLC as a cataloging tool. These MARC format records are then downloaded into the libraries' local catalog systems. This allows libraries worldwide to find and download records for materials they want to add to their local catalog without having to go through the lengthy process of cataloging them each individually. As of February 2007, their database contained over 1.1 billion catalogued items. It remains the world's largest bibliographic database. Connexion is available to professional librarians both as a computer program or on the web at connexion.oclc.org. WorldCat is also available to the public for searching through a web-based service called FirstSearch, as well as through the Open WorldCat program. # Dewey Decimal System The Online Computer Library Center acquired the trademark and copyrights associated with the Dewey Decimal Classification System when it bought Forest Press in 1988. # WebJunction WebJunction is a division of OCLC funded by a grant from the Bill and Melinda Gates Foundation. # QuestionPoint QuestionPoint reference management service provides libraries with tools to communicate with users in multiple ways. This around-the-clock reference service is provided by a cooperative of participating global libraries. # Regional service providers Regional service providers contract with OCLC to provide support and training for OCLC services. This chart represents only OCLC services.

OCLC # Overview OCLC Online Computer Library Center, Inc. is a "nonprofit, membership, computer library service and research organization dedicated to the public purpose of furthering access to the world's information and reducing information costs", according to its website. It was founded in 1967 as the Ohio College Library Center. More than 60,000 libraries in 112 countries and territories around the world use OCLC services to locate, acquire, catalog, lend and preserve library materials.[1] The organization was founded by Fred Kilgour, and its head office is located in Dublin, Ohio, United States. OCLC acquired NetLibrary, the largest electronic content provider, in 2002. OCLC owns 100% of the shares of OCLC PICA, a library automation systems and services company which has its headquarters in Leiden in the Netherlands and which was renamed "OCLC" at the end of 2007.[2] In June 2006, the Research Libraries Group (RLG) merged into OCLC. On January 11, 2008, OCLC announced that it had purchased EZproxy. # Services OCLC provides bibliographic, abstract and full-text information to libraries, students, faculty, scholars, and other information seekers. OCLC and its member libraries cooperatively produce and maintain WorldCat—the OCLC Online Union Catalog, the largest OPAC (Online Public Access Catalog) in the world. WorldCat contains holding records from most public and private libraries worldwide. WorldCat is available through many libraries and university computer networks. The Open WorldCat program makes records of library-owned materials in OCLC's WorldCat database available to Web users on popular Internet search, bibliographic and bookselling sites. OCLC member libraries' catalogs are more accessible from the sites where many people start their search for information. In October 2005, the OCLC technical staff began a wiki-like project that allows readers and librarians to add commentary, and structured-field information, associated with any WorldCat record. OCLC owns a preservation microfilm and digitization operation called the OCLC Preservation Service Center, with its principal office in Bethlehem, Pennsylvania, U.S. Libraries, museums, historical societies, colleges and universities utilize the OCLC Preservation Services to preserve printed works, books, maps, manuscripts, newspapers, etc. in microfilm format for future generations due to its 500-year life expectancy. In addition OCLC Preservation Services converts print and microfilm to digital objects for computer access. # Online database OCLC maintains a database for cataloging and searching purposes which is used by librarians and the public. OCLC Passport was one of the computer programs used. Connexion was introduced in 2001 and replaced Passport when it was phased out in May 2005. This database contains records in MAchine Readable Cataloging (MARC standards) format contributed by library catalogers worldwide who use OCLC as a cataloging tool. These MARC format records are then downloaded into the libraries' local catalog systems. This allows libraries worldwide to find and download records for materials they want to add to their local catalog without having to go through the lengthy process of cataloging them each individually. As of February 2007, their database contained over 1.1 billion catalogued items. It remains the world's largest bibliographic database. Connexion is available to professional librarians both as a computer program or on the web at connexion.oclc.org. WorldCat is also available to the public for searching through a web-based service called FirstSearch, as well as through the Open WorldCat program. # Dewey Decimal System The Online Computer Library Center acquired the trademark and copyrights associated with the Dewey Decimal Classification System when it bought Forest Press in 1988. # WebJunction WebJunction is a division of OCLC funded by a grant from the Bill and Melinda Gates Foundation. # QuestionPoint QuestionPoint reference management service provides libraries with tools to communicate with users in multiple ways. This around-the-clock reference service is provided by a cooperative of participating global libraries. # Regional service providers Regional service providers contract with OCLC to provide support and training for OCLC services. This chart represents only OCLC services.

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

3ddadae7c6000bf286d8502de2be8f69ff0a5320

wikidoc

OCRL

OCRL Inositol polyphosphate 5-phosphatase OCRL-1 (INPP5F), also known as Lowe oculocerebrorenal syndrome protein, is an enzyme encoded by the OCRL gene located on the X chromosome in humans. This gene encodes a phosphatase enzyme involved in actin polymerization, and is found in the trans-Golgi network. Mutation in this gene are associated with oculocerebrorenal syndrome and also with Dent's disease.

OCRL Inositol polyphosphate 5-phosphatase OCRL-1 (INPP5F), also known as Lowe oculocerebrorenal syndrome protein, is an enzyme encoded by the OCRL gene located on the X chromosome in humans.[1] This gene encodes a phosphatase enzyme involved in actin polymerization, and is found in the trans-Golgi network.[1] Mutation in this gene are associated with oculocerebrorenal syndrome[2] and also with Dent's disease.[3][4]

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

71e8b0f67c522f6fe97fb9d4795e1ee92084371a

wikidoc

OGDH

OGDH Alpha-ketoglutarate dehydrogenase also known as 2-oxoglutarate dehydrogenase E1 component, mitochondrial is an enzyme that in humans is encoded by the OGDH gene. # Structure ## Gene The OGDH gene is located on the 7th chromosome, with the specific location being 7p14-p13. There are 26 exons located within the gene. ## Protein This gene encodes a subunit that catalyzes the oxidative decarboxylation of alpha-ketoglutarate to Succinyl-CoA at its active site in the fourth step of the metabolic citric acid cycle by acting as a base to facilitate the decarboxylation. The main residues responsible for the catalysis are thought to be His 260, Phe 227, Gln685, His 729, Ser302, and His 298. # Function This gene encodes one subunit of the 2-oxoglutarate dehydrogenase complex. This complex catalyzes the overall conversion of 2-oxoglutarate (alpha-ketoglutarate) to succinyl-CoA and CO2 during the citric acid cycle. The protein is located in the mitochondrial matrix and uses thiamine pyrophosphate as a cofactor. The overall complex furthers catalysis by keeping the necessary substrates for the reaction close within the enzyme, thus creating a situation in which it is more likely that the substrate will be in the favorable conformation and orientation. This enzyme is also part of a larger multienzyme complex that channels the intermediates in the catalysis between subunits of the complex thus minimizing unwanted side reactions. Not only do the subunits ferry products back and forth, but each of the subunits in the E1o homodimer are connected via a cavity lined with acidic residues, thus increasing the dimer's ability to act as a base. The orientation of the cavity allows for direct transfer of the intermediate to the E2o subunit. ## Mechanism The protein encoded by EGDH is thought to have a single active site. The enzyme also requires two cofactors in order for it to function properly, Thiamine diphosphate and a divalent magnesium ion. The specific mechanism of the subunit is currently unknown; however, there are several theories as to how it functions, among them is the Hexa Uni Ping Pong theory. Even though the mechanism isn't fully known the kinetic data have been calculated and are as follows: the Km is 0.14 ± 0.04 mM, and the Vmax is 9 ± 3 μmol/(min*mg). ## Regulation This subunit, known as E1o, catalyzes a rate-limiting step in the citric acid cycle and lies far from equilibrium; the total change in Gibbs free energy is ΔG = −33 kJ/mol. The significant energy change makes it a crucial point of regulation not only for the citric acid cycle, but also for the entire cellular respiration pathway. As such, E1o is inhibited by both NADH and Succinyl-CoA via non competitive feedback inhibition. # Clinical significance A congenital deficiency in 2-oxoglutarate dehydrogenase activity is believed to lead to hypotonia, metabolic acidosis, and hyperlactatemia. It is characterized by the buildup of a chemical called lactic acid in the body and a variety of neurological problems. Signs and symptoms of this condition usually first appear shortly after birth, and they can vary widely among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. Most have delayed development of mental abilities and motor skills such as sitting and walking. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking. Some affected individuals have abnormal brain structures, such as underdevelopment of the tissue connecting the left and right halves of the brain (corpus callosum), wasting away (atrophy) of the exterior part of the brain known as the cerebral cortex, or patches of damaged tissue (lesions) on some parts of the brain. Because of the severe health effects, many individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood. # 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}

OGDH Alpha-ketoglutarate dehydrogenase also known as 2-oxoglutarate dehydrogenase E1 component, mitochondrial is an enzyme that in humans is encoded by the OGDH gene.[1][2][3] # Structure ## Gene The OGDH gene is located on the 7th chromosome, with the specific location being 7p14-p13. There are 26 exons located within the gene.[3] ## Protein This gene encodes a subunit that catalyzes the oxidative decarboxylation of alpha-ketoglutarate to Succinyl-CoA at its active site in the fourth step of the metabolic citric acid cycle by acting as a base to facilitate the decarboxylation. The main residues responsible for the catalysis are thought to be His 260, Phe 227, Gln685, His 729, Ser302, and His 298.[4] # Function This gene encodes one subunit of the 2-oxoglutarate dehydrogenase complex. This complex catalyzes the overall conversion of 2-oxoglutarate (alpha-ketoglutarate) to succinyl-CoA and CO2 during the citric acid cycle. The protein is located in the mitochondrial matrix and uses thiamine pyrophosphate as a cofactor.[3] The overall complex furthers catalysis by keeping the necessary substrates for the reaction close within the enzyme, thus creating a situation in which it is more likely that the substrate will be in the favorable conformation and orientation. This enzyme is also part of a larger multienzyme complex that channels the intermediates in the catalysis between subunits of the complex thus minimizing unwanted side reactions. Not only do the subunits ferry products back and forth, but each of the subunits in the E1o homodimer are connected via a cavity lined with acidic residues, thus increasing the dimer's ability to act as a base. The orientation of the cavity allows for direct transfer of the intermediate to the E2o subunit.[5] ## Mechanism The protein encoded by EGDH is thought to have a single active site. The enzyme also requires two cofactors in order for it to function properly, Thiamine diphosphate and a divalent magnesium ion. The specific mechanism of the subunit is currently unknown; however, there are several theories as to how it functions, among them is the Hexa Uni Ping Pong theory.[6] Even though the mechanism isn't fully known the kinetic data have been calculated and are as follows: the Km is 0.14 ± 0.04 mM, and the Vmax is 9 ± 3 μmol/(min*mg).[7] ## Regulation This subunit, known as E1o, catalyzes a rate-limiting step in the citric acid cycle and lies far from equilibrium; the total change in Gibbs free energy is ΔG = −33 kJ/mol. The significant energy change makes it a crucial point of regulation not only for the citric acid cycle, but also for the entire cellular respiration pathway. As such, E1o is inhibited by both NADH and Succinyl-CoA via non competitive feedback inhibition.[4] # Clinical significance A congenital deficiency in 2-oxoglutarate dehydrogenase activity is believed to lead to hypotonia, metabolic acidosis, and hyperlactatemia. It is characterized by the buildup of a chemical called lactic acid in the body and a variety of neurological problems. Signs and symptoms of this condition usually first appear shortly after birth, and they can vary widely among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. Most have delayed development of mental abilities and motor skills such as sitting and walking. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking. Some affected individuals have abnormal brain structures, such as underdevelopment of the tissue connecting the left and right halves of the brain (corpus callosum), wasting away (atrophy) of the exterior part of the brain known as the cerebral cortex, or patches of damaged tissue (lesions) on some parts of the brain. Because of the severe health effects, many individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood.[3] # 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/OGDH

7dd70ca288f1306d3fbcaaceabbbab2b15ab1ce5

wikidoc

OGFr

OGFr Opioid growth factor receptor, also known as OGFr or the ζ-opioid receptor, is a protein which in humans is encoded by the OGFR gene. The protein encoded by this gene is a receptor for opioid growth factor (OGF), also known as -enkephalin. The endogenous ligand is thus a known opioid peptide, and OGFr was originally discovered and named as a new opioid receptor zeta (ζ). However it was subsequently found that it shares little sequence similarity with the other opioid receptors, and has quite different function. # Function The natural function of this receptor appears to be in regulation of tissue growth, and it has been shown to be important in embryonic development, wound repair, and certain forms of cancer. OGF is a negative regulator of cell proliferation and tissue organization in a variety of processes. The encoded unbound receptor for OGF has been localized to the outer nuclear envelope, where it binds OGF and is translocated into the nucleus. The coding sequence of this gene contains a polymorphic region of 60 nt tandem imperfect repeat units. Several transcripts containing between zero and eight repeat units have been reported. # Mechanism of activation The opioid growth factor receptor consists of a chain of 677 amino acids, which includes a nuclear localization sequence region. When OGF binds to the receptor, an OGF-OGFr complex is formed, which leads to the increase in the synthesis of the selective cyclin-dependent kinase (CDK) inhibitor proteins, p12 and p16. Retinoblastoma protein becomes activated through the phosphorylation from CDKs, and leads to the progression of the cell cycle from the G1 phase to the S phase. Because the activation of the OGF receptor, blocks the phosphorylation of retinoblastmoa proteins, retardation of the G1 phase occurs, which prevents the cell from further dividing. # Therapeutic applications Upregulation of OGFr and consequent stimulation of the OGF-OGFr system are important for the anti-proliferative effects of imidazoquinoline drugs like imiquimod and resiquimod, which are immune response modifiers with potent antiviral and antitumour effects, used as topical creams for the treatment of skin cancers and warts. # Structure OGF contains a conserved N-terminal domain followed by a series of imperfect repeats.

OGFr Opioid growth factor receptor, also known as OGFr or the ζ-opioid receptor, is a protein which in humans is encoded by the OGFR gene.[1][2] The protein encoded by this gene is a receptor for opioid growth factor (OGF), also known as [Met(5)]-enkephalin. The endogenous ligand is thus a known opioid peptide, and OGFr was originally discovered and named as a new opioid receptor zeta (ζ). However it was subsequently found that it shares little sequence similarity with the other opioid receptors, and has quite different function. # Function The natural function of this receptor appears to be in regulation of tissue growth,[3][4][5][6] and it has been shown to be important in embryonic development,[7] wound repair,[8] and certain forms of cancer.[9][10][11][12] OGF is a negative regulator of cell proliferation and tissue organization in a variety of processes. The encoded unbound receptor for OGF has been localized to the outer nuclear envelope, where it binds OGF and is translocated into the nucleus. The coding sequence of this gene contains a polymorphic region of 60 nt tandem imperfect repeat units. Several transcripts containing between zero and eight repeat units have been reported.[1] # Mechanism of activation The opioid growth factor receptor consists of a chain of 677 amino acids, which includes a nuclear localization sequence region. When OGF binds to the receptor, an OGF-OGFr complex is formed, which leads to the increase in the synthesis of the selective cyclin-dependent kinase (CDK) inhibitor proteins, p12 and p16. Retinoblastoma protein becomes activated through the phosphorylation from CDKs, and leads to the progression of the cell cycle from the G1 phase to the S phase. Because the activation of the OGF receptor, blocks the phosphorylation of retinoblastmoa proteins, retardation of the G1 phase occurs, which prevents the cell from further dividing.[13][14] # Therapeutic applications Upregulation of OGFr and consequent stimulation of the OGF-OGFr system are important for the anti-proliferative effects of imidazoquinoline drugs like imiquimod and resiquimod, which are immune response modifiers with potent antiviral and antitumour effects, used as topical creams for the treatment of skin cancers and warts.[15] # Structure OGF contains a conserved N-terminal domain followed by a series of imperfect repeats.[4]

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

20f36b5cfb3d8350958ea495917738b363d3cb10

wikidoc

OLR1

OLR1 Oxidized low-density lipoprotein receptor 1 (Ox-LDL receptor 1) also known as lectin-type oxidized LDL receptor 1 (LOX-1) is a protein that in humans is encoded by the OLR1 gene. LOX-1 is the main receptor for oxidized LDL on endothelial cells, macrophages, smooth muscle cells, and other cell types. But minimally oxidized LDL is more readily recognized by the TLR4 receptor, and highly oxidized LDL is more readily recognized by the CD36 receptor. # Function LOX-1 is a receptor protein which belongs to the C-type lectin superfamily. Its gene is regulated through the cyclic AMP signaling pathway. The protein binds, internalizes and degrades oxidized low-density lipoprotein. Normally, LOX-1 expression on endothelial cells is low, but tumor necrosis factor alpha, oxidized LDL, blood vessel sheer stress, and other atherosclerotic stimuli substantially increase LOX-1 expression. LOX-1 may be involved in the regulation of Fas-induced apoptosis. Oxidized LDL induces endothelial cell apoptosis through LOX-1 binding. Other ligands for LOX-1 include oxidized high-density lipoprotein, advanced glycation end-products, platelets, and apoptotic cells. The binding of platelets to LOX-1 causes a release of vasoconstrictive endothelin, which induces endothelial dysfunction. This protein may play a role as a scavenger receptor. # Clinical significance Binding of oxidized LDL to LOX-1 activates NF-κB, leading to monocyte adhesion to enthothelial cells (a pre-requisite for the macrophage foam cell formation of atherosclerosis). Macrophage affinity for unmodified LDL particles is low, but is greatly increased when the LDL particles are oxidized. LDL oxidation occurs in the sub-endothelial space, rather than in the circulation. But oxidized cholesterol from foods cooked at high temperature can also be a source of oxysterols. Mutations of the OLR1 gene have been associated with atherosclerosis, risk of myocardial infarction, and may modify the risk of Alzheimer's disease. When applied to human macrophage-derived foam cells in vitro, the dietary supplement berberine inhibits the expression of the ORL1 gene in response to oxidized low-density lipoprotein cholesterol, but this has not yet been demonstrated in a living animal or human.

OLR1 Oxidized low-density lipoprotein receptor 1 (Ox-LDL receptor 1) also known as lectin-type oxidized LDL receptor 1 (LOX-1) is a protein that in humans is encoded by the OLR1 gene.[1][2] LOX-1 is the main receptor for oxidized LDL on endothelial cells, macrophages, smooth muscle cells,[3] and other cell types.[4] But minimally oxidized LDL is more readily recognized by the TLR4 receptor, and highly oxidized LDL is more readily recognized by the CD36 receptor.[5] # Function LOX-1 is a receptor protein which belongs to the C-type lectin superfamily. Its gene is regulated through the cyclic AMP signaling pathway. The protein binds, internalizes and degrades oxidized low-density lipoprotein. Normally, LOX-1 expression on endothelial cells is low, but tumor necrosis factor alpha, oxidized LDL, blood vessel sheer stress, and other atherosclerotic stimuli substantially increase LOX-1 expression.[4][6] LOX-1 may be involved in the regulation of Fas-induced apoptosis. Oxidized LDL induces endothelial cell apoptosis through LOX-1 binding.[3] Other ligands for LOX-1 include oxidized high-density lipoprotein, advanced glycation end-products, platelets, and apoptotic cells.[3][6] The binding of platelets to LOX-1 causes a release of vasoconstrictive endothelin, which induces endothelial dysfunction.[6] This protein may play a role as a scavenger receptor.[2] # Clinical significance Binding of oxidized LDL to LOX-1 activates NF-κB, leading to monocyte adhesion to enthothelial cells (a pre-requisite for the macrophage foam cell formation of atherosclerosis).[4] Macrophage affinity for unmodified LDL particles is low, but is greatly increased when the LDL particles are oxidized.[7] LDL oxidation occurs in the sub-endothelial space, rather than in the circulation.[7] But oxidized cholesterol from foods cooked at high temperature can also be a source of oxysterols.[5] Mutations of the OLR1 gene have been associated with atherosclerosis, risk of myocardial infarction, and may modify the risk of Alzheimer's disease.[2] When applied to human macrophage-derived foam cells in vitro, the dietary supplement berberine inhibits the expression of the ORL1 gene in response to oxidized low-density lipoprotein cholesterol,[8] but this has not yet been demonstrated in a living animal or human.

https://www.wikidoc.org/index.php/OLR1

97b339ebfe3105e9ac836e90bcd914f106ccd308

wikidoc

OMA1

OMA1 Metalloendopeptidase OMA1, mitochondrial is an enzyme that in humans is encoded by the OMA1 gene. As a metalloprotease, this protein is a substantial component of the quality control system in the inner membrane of mitochondria. Being activated by enzyme Bax and Bak, mitochondrial protease OMA1 promotes cytochrome c release which subsequently induces apoptosis. # Structure ## Gene The gene OMA1 encodes a metalloprotease, a founding member of a conserved family of membrane-embedded metallopeptidases in mitochondria. The human gene has 9 exons and locates at chromosome band 1p32.2-p32.1 ## Protein The human protein metalloendopetidase OMA1, mitochondrial is 60.1 kDa in size and composed of 524 amino acids with mitochondrial transition peptide (position 1-13). The mature protein has a theoretical pI of 8.44. # Function The inner membrane of mitochondrial houses two AAA proteases and these membrane-embedded peptidases were termed m- and i-AAA proteases to indicate their different topology in the inner membrane. The m-AAA protease is facing the matrix and the i-AAA protease is facing the intermembrane space. OMA1 was shown to share an overlapping proteolytic activity with m-AAA protease. However, OMA1 doesn't completely regulate the turnover of a model substrate, Oxa1, as what the m-AAA protease does. On the contrary, Oma1 only generates N- and C-terminal proteolytic fragments. It has been showed that the mammalian mitochondrial inner membrane fusion protein OPA1 can be degraded by OMA1 when mitochondria lose membrane potential or adenosine triphosphate. Such inducible proteolysis acts as a regulatory mechanism to proteolytically inactivate OPA1, thus preventing the fusion of the mitochondrial network. # Clinical significance OMA1 seems to play role in neurodegeneration Several mutations in OMA1 were identified in Amyotrophic Lateral Sclerosis patients.

OMA1 Metalloendopeptidase OMA1, mitochondrial is an enzyme that in humans is encoded by the OMA1 gene.[1][2] As a metalloprotease, this protein is a substantial component of the quality control system in the inner membrane of mitochondria. Being activated by enzyme Bax and Bak, mitochondrial protease OMA1 promotes cytochrome c release which subsequently induces apoptosis.[3] # Structure ## Gene The gene OMA1 encodes a metalloprotease, a founding member of a conserved family of membrane-embedded metallopeptidases in mitochondria. The human gene has 9 exons and locates at chromosome band 1p32.2-p32.1 ## Protein The human protein metalloendopetidase OMA1, mitochondrial is 60.1 kDa in size and composed of 524 amino acids with mitochondrial transition peptide (position 1-13).[4] The mature protein has a theoretical pI of 8.44.[5] # Function The inner membrane of mitochondrial houses two AAA proteases and these membrane-embedded peptidases were termed m- and i-AAA proteases to indicate their different topology in the inner membrane. The m-AAA protease is facing the matrix and the i-AAA protease is facing the intermembrane space. OMA1 was shown to share an overlapping proteolytic activity with m-AAA protease. However, OMA1 doesn't completely regulate the turnover of a model substrate, Oxa1, as what the m-AAA protease does. On the contrary, Oma1 only generates N- and C-terminal proteolytic fragments.[2] It has been showed that the mammalian mitochondrial inner membrane fusion protein OPA1 can be degraded by OMA1 when mitochondria lose membrane potential or adenosine triphosphate. Such inducible proteolysis acts as a regulatory mechanism to proteolytically inactivate OPA1, thus preventing the fusion of the mitochondrial network.[6][7][8] # Clinical significance OMA1 seems to play role in neurodegeneration[9] Several mutations in OMA1 were identified in Amyotrophic Lateral Sclerosis patients.

https://www.wikidoc.org/index.php/OMA1

0b247d4c607a9a6617fee6edc1619e8b7648d3ab

wikidoc

OMIM

OMIM # Overview The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome and provides references for further research and tools for genomic analysis of a catalogued gene. # Versions It is available as a book named after the project, and it is currently in its 12th edition. The online version is called Online Mendelian Inheritance in Man™ (OMIM™), which can be accessed with the Entrez database searcher of the National Library of Medicine and is part of the NCBI project Education. # Collection process The information in this database is collected and processed under the leadership of Dr. Victor A. McKusick at Johns Hopkins University, assisted by a team of science writers and editors. Relevant articles are identified, discussed and written up in the relevant entries in the MIM database # The MIM code Every disease and gene is assigned a six digit number of which the first number classifies the method of inheritance. If the initial digit is 1, the trait is deemed autosomal dominant; if 2, autosomal recessive; if 3, X-linked. Wherever a trait defined in this dictionary has a MIM number, the number from the 12th edition of MIM, is given in square brackets with or without an asterisk (asterisks indicate that the mode of inheritance is known; a number symbol (#) before an entry number means that the phenotype can be caused by mutation in any of 2 or more genes) as appropriate e.g., Pelizaeus-Merzbacher disease is a well-established, autosomal, dominant, mendelian disorder.

OMIM Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome and provides references for further research and tools for genomic analysis of a catalogued gene. # Versions It is available as a book named after the project, and it is currently in its 12th edition. The online version is called Online Mendelian Inheritance in Man™ (OMIM™), which can be accessed with the Entrez database searcher of the National Library of Medicine and is part of the NCBI project Education. # Collection process The information in this database is collected and processed under the leadership of Dr. Victor A. McKusick at Johns Hopkins University, assisted by a team of science writers and editors. Relevant articles are identified, discussed and written up in the relevant entries in the MIM database # The MIM code Every disease and gene is assigned a six digit number of which the first number classifies the method of inheritance. If the initial digit is 1, the trait is deemed autosomal dominant; if 2, autosomal recessive; if 3, X-linked. Wherever a trait defined in this dictionary has a MIM number, the number from the 12th edition of MIM, is given in square brackets with or without an asterisk (asterisks indicate that the mode of inheritance is known; a number symbol (#) before an entry number means that the phenotype can be caused by mutation in any of 2 or more genes) as appropriate e.g., Pelizaeus-Merzbacher disease [MIM*169500] is a well-established, autosomal, dominant, mendelian disorder.

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

f08e19c07bead9027e09df6b5339edf8ecd9dc28

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OPN5

OPN5 Neuropsin is a protein that in humans is encoded by the OPN5 gene. It is a photoreceptor protein sensitive to ultraviolet (UV) light. The OPN5 gene was discovered in mouse and human genomes and its mRNA expression was also found in neural tissues. Neuropsin is bistable at 0 °C and activates a UV-sensitive, heterotrimeric G protein Gi-mediated pathway in mammalian and avian tissues. # Function Opsins are members of the G protein-coupled receptor superfamily. Human neuropsin is expressed in the eye, brain, testes, and spinal cord. Neuropsin belongs to the seven-exon subfamily of mammalian opsin genes that includes peropsin (RRH) and retinal G protein coupled receptor (RGR). Neuropsin has different isoforms created by alternative splicing. # Photochemistry When reconstituted with 11-cis-retinal, mouse and human neuropsins absorb maximally at 380 nm. When illuminated these neuropsins are converted into blue-absorbing photoproducts (470 nm), which are stable in the dark. The photoproducts are converted back to the UV-absorbing form, when they are illuminated with orange light (> 520 nm). # Phylogeny The neuropsins constitute one of the four subclades of the Go/RGR group of opsins, also known as RGR/Go or Group 4. Go/RGR is one of the four major subclades of type-II opsins, also known as metazoan or animal opsins. Go/RGR comprises Go-coupled, RGR, peropsins, and neuropsins. Type-II opsins comprise four subclades: C-opsins (ciliary), R-opsins (rhabdomeric), Cnidops (cnidarian), and Go/RGR. Three of these subclades occur only in Bilateria (all but Cnidops). However, the bilaterian clades constitute a parphyletic taxon without Cnidops. # Species Distribution Neuropsin and its orthologs have been found experimentally in a small number of animals, among them human, house mouse (Mus musculus), chicken (Gallus gallus domesticus), the Japanese quail (Coturnix japonica), the European brittle star Amphiura filiformis (related to starfish), the tardigrade water bear (Hypsibius dujardini), and the tadpole of Xenopus laevis. Searches of publicly available databases of genetic sequences have found putative neuropsin orthologs in both major branches of Bilateria: protostomes and deuterostomes. Among protostomes, putative neuropsins have been found in the molluscs owl limpet (Lottia gigantea) (a species of sea snail) and Pacific oyster (Crassostrea gigas), in the water flea (Daphnia pulex) (an arthropod), and in the annelid worm Capitella teleta.

OPN5 Neuropsin is a protein that in humans is encoded by the OPN5 gene.[1][2][3] It is a photoreceptor protein sensitive to ultraviolet (UV) light. The OPN5 gene was discovered in mouse and human genomes and its mRNA expression was also found in neural tissues. Neuropsin is bistable at 0 °C and activates a UV-sensitive, heterotrimeric G protein Gi-mediated pathway in mammalian and avian tissues.[4][5] # Function Opsins are members of the G protein-coupled receptor superfamily. Human neuropsin is expressed in the eye, brain, testes, and spinal cord. Neuropsin belongs to the seven-exon subfamily of mammalian opsin genes that includes peropsin (RRH) and retinal G protein coupled receptor (RGR). Neuropsin has different isoforms created by alternative splicing.[3] # Photochemistry When reconstituted with 11-cis-retinal, mouse and human neuropsins absorb maximally at 380 nm. When illuminated these neuropsins are converted into blue-absorbing photoproducts (470 nm), which are stable in the dark. The photoproducts are converted back to the UV-absorbing form, when they are illuminated with orange light (> 520 nm).[4] # Phylogeny The neuropsins constitute one of the four subclades of the Go/RGR group of opsins, also known as RGR/Go or Group 4. Go/RGR is one of the four major subclades of type-II opsins, also known as metazoan or animal opsins. Go/RGR comprises Go-coupled, RGR, peropsins, and neuropsins. Type-II opsins comprise four subclades: C-opsins (ciliary), R-opsins (rhabdomeric), Cnidops (cnidarian), and Go/RGR. Three of these subclades occur only in Bilateria (all but Cnidops). However, the bilaterian clades constitute a parphyletic taxon without Cnidops.[6][7] # Species Distribution Neuropsin and its orthologs have been found experimentally in a small number of animals, among them human, house mouse (Mus musculus),[1] chicken (Gallus gallus domesticus),[5][8] the Japanese quail (Coturnix japonica),[9] the European brittle star Amphiura filiformis (related to starfish),[10] the tardigrade water bear (Hypsibius dujardini),[11] and the tadpole of Xenopus laevis.[12] Searches of publicly available databases of genetic sequences have found putative neuropsin orthologs in both major branches of Bilateria: protostomes and deuterostomes. Among protostomes, putative neuropsins have been found in the molluscs owl limpet (Lottia gigantea) (a species of sea snail) and Pacific oyster (Crassostrea gigas), in the water flea (Daphnia pulex) (an arthropod), and in the annelid worm Capitella teleta.[11]

https://www.wikidoc.org/index.php/OPN5

6f1ca27d96e7b5a5012fe6f2bf9190c1ee577a61

wikidoc

ORC6

ORC6 Origin recognition complex subunit 6 is a protein that in humans is encoded by the ORC6 (ORC6L) gene. # Background The origin recognition complex (ORC) is a highly conserved six subunit protein complex essential for the initiation of the DNA replication in eukaryotic cells. Studies in yeast demonstrated that ORC binds specifically to origins of replication and serves as a platform for the assembly of additional initiation factors such as Cdc6 and Mcm proteins. # Function The protein encoded by this gene is a subunit of the ORC complex. It has been shown that this protein and ORC1 are loosely associated with the core complex consisting of ORC2, -3, -4 and -5. Gene silencing studies with small interfering RNA demonstrated that this protein plays an essential role in coordinating chromosome replication and segregation with cytokinesis. # Interactions ORC6 has been shown to interact with MCM5, ORC2, Replication protein A1, ORC4, DBF4, ORC3, CDC45-related protein, MCM4 and Cell division cycle 7-related protein kinase.

ORC6 Origin recognition complex subunit 6 is a protein that in humans is encoded by the ORC6 (ORC6L) gene.[1][2] # Background The origin recognition complex (ORC) is a highly conserved six subunit protein complex essential for the initiation of the DNA replication in eukaryotic cells. Studies in yeast demonstrated that ORC binds specifically to origins of replication and serves as a platform for the assembly of additional initiation factors such as Cdc6 and Mcm proteins. # Function The protein encoded by this gene is a subunit of the ORC complex. It has been shown that this protein and ORC1 are loosely associated with the core complex consisting of ORC2, -3, -4 and -5. Gene silencing studies with small interfering RNA demonstrated that this protein plays an essential role in coordinating chromosome replication and segregation with cytokinesis.[2] # Interactions ORC6 has been shown to interact with MCM5,[3] ORC2,[3][4] Replication protein A1,[3] ORC4,[3] DBF4,[3] ORC3,[3][4] CDC45-related protein,[3] MCM4[3] and Cell division cycle 7-related protein kinase.[3]

https://www.wikidoc.org/index.php/ORC6

408f197b62fb5783ea91b3138f66d79c282d81f7

wikidoc

OSBP

OSBP Oxysterol-binding protein 1 is a protein that in humans is encoded by the OSBP gene. # Function Oxysterol-binding protein (OSBP) is an intracellular protein that was identified as a cytosolic 25-hydroxycholesterol-binding protein. OSBP is a lipid transfer protein that controls cholesterol/PI4P exchange at ER-Golgi membrane contact sites. 25-hydroxycholesterol acts as a natural inhibitor of this exchange. OSBP regulates ER-Golgi membrane contact sites formation by bridging ER and Golgi membranes together. OSBP plays also a role as a sterol-regulated scaffolding protein for several cytosolic reactions including the phosphorylation of ERK 1/2. It has been shown that expression and maturation of SREBP-1c is controlled by OSBP. SREBP-1c is a major transcription factor for hepatic lipogenesis (fatty acids and triglycerides biosynthesis). OSBP expression levels in transgenic mice affect liver and serum TG levels. OSBP is thought to be an essential scaffolding compound of the protein complex that regulates the activation state of the ERK protein. OSBP also acts as a sterol-dependant scaffold for the JAK2 and STAT3 proteins. # Mechanism of action OSBP is a multi-domain protein consisting of an N-terminal pleckstrin homology (PH) domain, a central FFAT motif (two phenylalanines in an acidic track), and a C-terminal lipid transport domain (ORD). The PH domain binds the trans-Golgi membrane by contacting the lipid PI4P and the activated small G protein Arf1(-GTP), whereas the FFAT motif binds the type II ER membrane protein VAP-A. OSBP bridges the Golgi and the ER by establishing contacts with all of these determinants simultaneously. OSBP is thought to transport cholesterol from the ER to the Golgi, and to transport the phosphoinositide PI4P backward (from the Golgi to the ER). Then, PI4P can be hydrolyzed by the phosphatidylinositide phosphatase SAC1, which is an ER-resident protein. Therefore, OSBP acts as a negative regulator of its own attachment to the trans-Golgi (which requires the binding of its PH domain to PI4P). This negative feedback system might coordinate cholesterol transport out of the ER to PI4P level in the Golgi. # Regulation OSBP is regulated by PKD mediated phosphorylation, and by the oxysterol 25-hydroxycholesterol (25-OH), a high-affinity ligand for OSBP (~30 nM). Several proteins involved in cholesterol homeostasis, such as INSIG-1 or ACAT, also bind 25-OH. In fact 25-OH is a potent suppressor of sterol synthesis in cultured cells and accelerates cholesterol esterification. In cellular studies it has been shown that OSBP, initially cytosolic, relocates to ER-Golgi membrane contact sites in the presence of 25-OH. 25-OH acts as an inhibitor of sterol transport mediated by OSBP in vitro. # Isoforms OSBP is the founding member of the ORP (OSBP-related proteins) family of lipid transfer proteins. Mammals have 16 different ORPs, whereas the yeast S. cerevisiae genome encodes seven ORP homologues (Osh). ORP and Osh proteins contain a lipid transport domain called ORD (OSBP-related domain) encompassing the EQVSHHPP signature sequence. The ORD structure consists in a hydrophobic pocket. Because the EQVSHHPP sequence is crucial for PI4P binding to the ORD, but not for sterol binding, it has been proposed that PI4P transport is a common function of Osh/ORP proteins.

OSBP Oxysterol-binding protein 1 is a protein that in humans is encoded by the OSBP gene.[1] # Function Oxysterol-binding protein (OSBP) is an intracellular protein that was identified as a cytosolic 25-hydroxycholesterol-binding protein.[2] OSBP is a lipid transfer protein that controls cholesterol/PI4P exchange at ER-Golgi membrane contact sites.[3] 25-hydroxycholesterol acts as a natural inhibitor of this exchange. OSBP regulates ER-Golgi membrane contact sites formation by bridging ER and Golgi membranes together.[3] OSBP plays also a role as a sterol-regulated scaffolding protein for several cytosolic reactions including the phosphorylation of ERK 1/2.[4] It has been shown that expression and maturation of SREBP-1c is controlled by OSBP.[5] SREBP-1c is a major transcription factor for hepatic lipogenesis (fatty acids and triglycerides biosynthesis). OSBP expression levels in transgenic mice affect liver and serum TG levels. OSBP is thought to be an essential scaffolding compound of the protein complex that regulates the activation state of the ERK protein.[4] OSBP also acts as a sterol-dependant scaffold for the JAK2 and STAT3 proteins.[6] # Mechanism of action OSBP is a multi-domain protein consisting of an N-terminal pleckstrin homology (PH) domain, a central FFAT motif (two phenylalanines in an acidic track), and a C-terminal lipid transport domain (ORD). The PH domain binds the trans-Golgi membrane by contacting the lipid PI4P and the activated small G protein Arf1(-GTP), whereas the FFAT motif binds the type II ER membrane protein VAP-A.[7][8] OSBP bridges the Golgi and the ER by establishing contacts with all of these determinants simultaneously.[3] OSBP is thought to transport cholesterol from the ER to the Golgi, and to transport the phosphoinositide PI4P backward (from the Golgi to the ER).[3] Then, PI4P can be hydrolyzed by the phosphatidylinositide phosphatase SAC1, which is an ER-resident protein. Therefore, OSBP acts as a negative regulator of its own attachment to the trans-Golgi (which requires the binding of its PH domain to PI4P). This negative feedback system might coordinate cholesterol transport out of the ER to PI4P level in the Golgi. # Regulation OSBP is regulated by PKD mediated phosphorylation, and by the oxysterol 25-hydroxycholesterol (25-OH), a high-affinity ligand for OSBP (~30 nM).[2][9] Several proteins involved in cholesterol homeostasis, such as INSIG-1 or ACAT, also bind 25-OH.[10] In fact 25-OH is a potent suppressor of sterol synthesis in cultured cells and accelerates cholesterol esterification. In cellular studies it has been shown that OSBP, initially cytosolic, relocates to ER-Golgi membrane contact sites in the presence of 25-OH.[2] 25-OH acts as an inhibitor of sterol transport mediated by OSBP in vitro.[3] # Isoforms OSBP is the founding member of the ORP (OSBP-related proteins) family of lipid transfer proteins. Mammals have 16 different ORPs, whereas the yeast S. cerevisiae genome encodes seven ORP homologues (Osh). ORP and Osh proteins contain a lipid transport domain called ORD (OSBP-related domain) encompassing the EQVSHHPP signature sequence.[11] The ORD structure consists in a hydrophobic pocket. Because the EQVSHHPP sequence is crucial for PI4P binding to the ORD, but not for sterol binding, it has been proposed that PI4P transport is a common function of Osh/ORP proteins.[12]

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

70bc8a764a40dae299691afcce26a359c5a983f7

wikidoc

OSR1

OSR1 Protein odd-skipped-related 1 is a transcription factor that in humans is encoded by the OSR1 gene. The OSR1 and OSR2 transcription factors participate in the normal development of body parts such as the kidney. Protein odd-skipped related 1 is a zinc-finger transcription factor that, in humans, is encoded by the OSR1 gene found on chromosome 2 (2p24.1) and in mice is encoded by the Osr1 gene. In mammals, OSR1 is involved in the development of the kidneys, heart and in the palate and is often coexpressed with OSR2. OSR1 and OSR2 are homologous to the Odd-skipped class transcription factors in Drosophila, encoded by odd, bowl, sob and arm. # Structure OSR1 is a 266 amino-acid protein and contains three C2H2 zinc finger domains. OSR1 and OSR2 share 65% amino-acid sequence and 98% zinc finger domain similarity. # Function ## Early expression In mice, during gastrulation on embryological day 7.5, cells fated to become intermediate mesoderm show the mouse OSR1 homologue, Osr1, expression. A day later, it is expressed in the intermediate mesoderm, lateral to the neural plate. Osr1 expression weakens and shifts posteriorly, to the presumptive kidneys, by day 9.5. By day 10.5, the branchial arch and limbs also begin to express Osr1. ## Heart development Osr1 regulates atrial septum formation in the heart. Osr1 is expressed in the dorsal atrial wall, from which the primary atrial septum will emerge, and later in the septum and left venous valve leaflet. It is also present in the mesothelium of the thoracic cavity and the parietal pericardium. Embryos lacking Osr1 expression usually die before birth due to deformed atrioventricular junctions and hypoplastic venous valves; the ones that progress to term also have an incomplete parietal pericardium. These pathologies occur in the presence of other transcription factors important for atrial septum formation such as Nkx2.5, Pitx2 and Tbx5. ## Kidney development Osr1 is the earliest marker of the intermediate mesoderm, which will form the gonads and kidneys. This expression is not essential for the formation of intermediate mesoderm but for the differentiation towards renal and gonadal structures. Osr1 acts upstream of and causes expression of the transcription factors Lhx1, Pax2 and Wt1 which are involved in early urogenital development. In normal kidney development, activation of the Pax2-Eya1-Hox11 complex and subsequent activation of Six2 and Gdnf expression allows for branching of the ureteric bud and maintenance of the nephron-forming cap mesenchyme. Six2 maintains the self-renewing state of the cap mesenchyme. and Gdnf, via the Gdnf-Ret signalling pathway, is required for attraction and branching of the growing ureteric bud. Within the developing kidney, Osr1 expressing cells will become mesangial cells, pericytes, ureteric smooth muscle and the kidney capsule. The cell types that Osr1 expressing cells will differentiate into are determined by the timing of loss of expression – cells that will become part of the vasculature or ureteric epithelium lose expression of Osr1 early (E8.5), and those that become nephrons lose expression later (E11.5). All three stages of kidney formation are affected in mice lacking Osr1 expression and are similar to mice with reduced Wt1 and Pax2 expression – the Wollfian duct is abnormal, there are fewer mesonephric tubules and the kidney-forming metanephros and gonads are missing. In embryonic day 10.5, embryos lacking Osr1 expression fail to grow a ureteric bud that migrates into the uncompacted metanephric mesenchyme. The lack of inductive signals from the ureteric bud combined with a downstream reduction in Pax2 expression results in apoptosis and agenesis of the kidney. ## Limb formation Expression of Osr1 in the limb buds is initially restricted to the mesenchyme immediately below the endoderm, but shifts anteriorly and proximally by embryonic day 11.5. In mice, Osr1 is expressed in the interdigital mesenchyme and presumptive synovial joints during limb development. where it overlaps with expression of Gdf5, an early marker for joint formation. ## Other sites Osr1 is expressed in the first and second branchial arches, in the limb buds, mouth and nasal pits, in the trunk, the forebrain., developing somites, distal mandible and developing eye. # Regulation The expression of Osr1 is negatively regulated by Runx2 and Ikzf1. These genes are involved in osteoblast and lymphocyte differentiation through their interaction with the Osr1 promoter region. In human osteoblast and osteosarcoma cell lines, OSR1 is directly induced by 1,25-dihydroxyvitamin D3. # Clinical relevance ## Reduction of kidney size caused by variant allele A variant human OSR1 allele which does not produce a functional transcript and found in 6% of Caucasian populations, reduces the size of the newborn kidney by 11.8%. ## OSR1 methylation in cancer OSR1 is methylated and downregulated in 51.8% of gastric cancer cells and tissues. When expressed normally, OSR1 is anti-proliferative – it induces cell cycle arrest and induces apoptosis in gastric cancer cell. OSR1 is methylated in above 85% of squamous cell carcinomas.> # Orthologs

OSR1 Protein odd-skipped-related 1 is a transcription factor that in humans is encoded by the OSR1 gene.[1][2][3] The OSR1 and OSR2 transcription factors participate in the normal development of body parts such as the kidney.[4] Protein odd-skipped related 1 is a zinc-finger transcription factor that, in humans, is encoded by the OSR1 gene found on chromosome 2 (2p24.1) and in mice is encoded by the Osr1 gene. In mammals, OSR1 is involved in the development of the kidneys, heart and in the palate and is often coexpressed with OSR2. OSR1 and OSR2 are homologous to the Odd-skipped class transcription factors in Drosophila, encoded by odd,[1] bowl, sob[5] and arm.[6][7] # Structure OSR1 is a 266 amino-acid protein and contains three C2H2 zinc finger domains.[8] OSR1 and OSR2 share 65% amino-acid sequence and 98% zinc finger domain similarity.[9] # Function ## Early expression In mice, during gastrulation on embryological day 7.5, cells fated to become intermediate mesoderm show the mouse OSR1 homologue, Osr1, expression. A day later, it is expressed in the intermediate mesoderm, lateral to the neural plate. Osr1 expression weakens and shifts posteriorly, to the presumptive kidneys, by day 9.5. By day 10.5, the branchial arch and limbs also begin to express Osr1.[8][10] ## Heart development Osr1 regulates atrial septum formation in the heart. Osr1 is expressed in the dorsal atrial wall, from which the primary atrial septum will emerge, and later in the septum and left venous valve leaflet.[10] It is also present in the mesothelium of the thoracic cavity and the parietal pericardium.[10] Embryos lacking Osr1 expression usually die before birth due to deformed atrioventricular junctions and hypoplastic venous valves; the ones that progress to term also have an incomplete parietal pericardium.[10] These pathologies occur in the presence of other transcription factors important for atrial septum formation such as Nkx2.5, Pitx2 and Tbx5.[10] ## Kidney development Osr1 is the earliest marker of the intermediate mesoderm, which will form the gonads and kidneys. This expression is not essential for the formation of intermediate mesoderm but for the differentiation towards renal and gonadal structures.[10][11] Osr1 acts upstream of and causes expression of the transcription factors Lhx1, Pax2 and Wt1 which are involved in early urogenital development.[10] In normal kidney development, activation of the Pax2-Eya1-Hox11 complex and subsequent activation of Six2 and Gdnf expression allows for branching of the ureteric bud and maintenance of the nephron-forming cap mesenchyme.[12] Six2 maintains the self-renewing state of the cap mesenchyme.[13] and Gdnf, via the Gdnf-Ret signalling pathway, is required for attraction and branching of the growing ureteric bud.[14] Within the developing kidney, Osr1 expressing cells will become mesangial cells, pericytes, ureteric smooth muscle and the kidney capsule. The cell types that Osr1 expressing cells will differentiate into are determined by the timing of loss of expression – cells that will become part of the vasculature or ureteric epithelium lose expression of Osr1 early (E8.5), and those that become nephrons lose expression later (E11.5).[15] All three stages of kidney formation are affected in mice lacking Osr1 expression and are similar to mice with reduced Wt1 and Pax2 expression – the Wollfian duct is abnormal, there are fewer mesonephric tubules and the kidney-forming metanephros and gonads are missing.[10] In embryonic day 10.5, embryos lacking Osr1 expression fail to grow a ureteric bud that migrates into the uncompacted metanephric mesenchyme.[10] The lack of inductive signals from the ureteric bud combined with a downstream reduction in Pax2 expression results in apoptosis and agenesis of the kidney.[10] ## Limb formation Expression of Osr1 in the limb buds is initially restricted to the mesenchyme immediately below the endoderm, but shifts anteriorly and proximally by embryonic day 11.5.[8] In mice, Osr1 is expressed in the interdigital mesenchyme[8] and presumptive synovial joints during limb development.[16] where it overlaps with expression of Gdf5, an early marker for joint formation.[17] ## Other sites Osr1 is expressed in the first and second branchial arches, in the limb buds, mouth and nasal pits, in the trunk, the forebrain.,[8] developing somites, distal mandible and developing eye.[9] # Regulation The expression of Osr1 is negatively regulated by Runx2 and Ikzf1. These genes are involved in osteoblast and lymphocyte differentiation through their interaction with the Osr1 promoter region.[18] In human osteoblast and osteosarcoma cell lines, OSR1 is directly induced by 1,25-dihydroxyvitamin D3.[19] # Clinical relevance ## Reduction of kidney size caused by variant allele A variant human OSR1 allele which does not produce a functional transcript and found in 6% of Caucasian populations, reduces the size of the newborn kidney by 11.8%.[20] ## OSR1 methylation in cancer OSR1 is methylated and downregulated in 51.8% of gastric cancer cells and tissues.[21] When expressed normally, OSR1 is anti-proliferative – it induces cell cycle arrest and induces apoptosis in gastric cancer cell.[21] OSR1 is methylated in above 85% of squamous cell carcinomas.[22]> # Orthologs

https://www.wikidoc.org/index.php/OSR1

ba616a5f1401eb20dce567c3e01055070f14c5bf

wikidoc

Odor

Odor # Overview An odor or odour (see spelling differences) is a volatilized chemical compound, generally at a very low concentration, which humans and other animals perceive by the sense of olfaction. Odors are also called smells, which can refer to both pleasant and unpleasant odors. The terms fragrance, scent, or aroma are used primarily by the food and cosmetic industry to describe a pleasant odor, and is sometimes used to refer to perfumes. In contrast, stench, reek, and stink are used specifically to describe unpleasant odor. ## Basics Odor is a sensation caused by odorant molecules dissolved in the air. The widest range of odors consist of organic compounds, although some inorganic substances, such as hydrogen sulfide and ammonia, are also odorants. The perception of an odor effect is a two step process. First, there is the physiological part; the sense of the stimulus by receptors in the nose. After that, the psychological part follows. The stimuli are processed by the region of the human brain which is responsible for smelling. Because of this, an objective and analytical measure of odor is impossible. While odor feelings are very personal perceptions, individual reactions are related to gender, age, state of health, and private affectations. Common odors that people are used to, such as their own body odor, are less noticeable to individuals than external or uncommon odors. For most people, the process of smelling gives little information concerning the ingredients of a substance. It only offers information related to the emotional impact. Experienced people, however, such as flavorists and perfumers, can pick out individual chemicals in complex mixes through smell alone. ## Odor analysis The concentrations of odorant in Germany have been defined by the “Olfaktometrie” since the 1870’s, which helps to analyze the human sense of smell using the following parameters: odor substance concentration, intensity of odor, and hedonism assessment. To establish the odor concentration, an olfactometer is used which employs a panel of human noses as sensors. In the olfactometry testing procedure, a diluted odorous mixture and an odor-free gas (as a reference) are presented separately from sniffing ports to a group of panelists, which are housed in an odor neutral room. They are asked to compare the gases emitted from each sniffing port, after which the panelists are asked to report the presence of odor together with a confidence level such as guessing, inkling, or certainty of their assessment. The gas-diluting ratio is then decreased by a factor of two (i.e. chemical concentration is increased by a factor of two). The panelists are asked to repeat their judgment. This continues for a number of dilution levels. The responses of the panelists over a range of dilution settings are used to calculate the concentration of the odor in terms of European Odor Units (ouE/m³). The main panel calibration gas used is Butan-1-ol., which at a certain diluting gives 1 ouE/m³. ## General survey The analytic methods could be subdivided into the physical, the gas chromatographical, and the chemosensory method. When measuring odor, there is a difference between the emission and immission measurements. During the emission measurement, the odor concentration in the air is so high that the so called “Olfaktometer” is needed to thin the assay. Because of this, all measurement methods based on thinning assays are called “olfaktometrical methods.” On the contrary, an “Olfaktormeter” is seldom used during the immission measurement. The same measuring principals are used, but the judgment of the air assay happens without thinning the assay. # Measurement While no generally acceptable method for measuring odor exists, measurement of different aspects of odor can be attempted through a number of quantitative methods, for example: ## Odorant concentration This is the oldest method to define odor emission. Ledger of this method is the concentration of odor substrate at the odor threshold. This threshold is also called apperception barrier. The threshold has got an odorant concentration of 1 GEE/m³ and is subscribed with cod. To define the odorant concentration, it is necessary to dilute the air assay to the odor threshold with the help of the “Olfaktormeter.” The dilution factor Z, at the odor barrier, is the same number as the odor substance concentration. The European Union has with the introduction of the following standard: CEN EN 13725:2003, Air quality - Determination of odour concentration by dynamic olfactometry. standardized the odor concentration across Europe and odor concentration is now expressed in European Odor Units (ouE/m³). ## Odor intensity Odor intensity can be divided into the following categories according to intensity: If it is an emission measurement (diluted by the olfactometer), then the evaluation of an odor's intensity must be ranked by the olfactometer methods. A direct evaluation is used when the array is measured from the emission side. This method is most often applied by having a dilution series tested by a panel of independent observers who have been trained to differentiate intensity. ## Hedonic assessment The hedonic assessment is the process of scaling odors beginning with extremely unpleasant followed by neutral up to extremely pleasant. There is no difference between this process and the method of measuring the odor intensity. But the method of emission measurement is seldom used and that of emission measurement is not used. ## Odor type This is a verbal characterization of the sensed odor by the test person, such as disgusting, caustic, ruffling, etc. There are no more applications needed than a test person to run this method. The evaluation of the odor type could be an emission or an immission method. It has a great impact on evaluating the source of the odor emission. ## Emission measurement The following details have to be diffetentiated while the emission is measured: First there is the odor time slice (Result = Part of “odor hours per year” per area). Then there is the olfactory flag scope (Result = Current scope at actual meteorology situation). And last but not least there is the harassment exaltation by questionings (Result = differentiated acquisition harassments). ## Sampling technique There are two main odor sampling techniques, the direct odor sampling and the indirect odor sampling technique. Direct odor sampling. Air will be sampled at the source and fed straight into the olfactometer for assessment by an odor panel. The following problems can be associated with this technique: Odor panel members need to be seated in an odor neutral environment, thus they need to be housed in a separate area. This is difficult to achieve when assessing odor released from, for example factories, were the odor can be emitted from a stack on the end of a production line. This means that the odor sample collected needs to be transported from the stack to the unit were the odor panel sits. This can sometimes be on the other side of the factory plant. The sample then must therefore pass trough a very long sample line to the olfactometer. This can have influences on the sample quality, can have potential air blockages due to water condensation or other operational procedures. Therefore most odor annoyance assessment companies use the indirect air sampling method. Indirect odor sampling Indirect odor sampling is done with the use of odor (air) sampling bags, which are made from an odor neutral material e.g. Teflon. The odor sample bags are connected to an air sampling line which is then, for example, hooked up to a stack. The air stream is then sampled and stored in the odor sample bag and can then be analyzed in a suitable environment (e.g. in an odor laboratory). The indirect method is used to sample a wide variety of odor sources. From stacks on the end of a factory line, water surfaces or ambient air surroundings. Each odor source has its own set of problems when sampled; these problems need to be overcome in order to collect a representative sample of the odor source. The following problems can be encountered: - Vacuum. - High temperatures and moisture content. - High lethal gas concentrations. - Odor concentrations. - Large odor emitting surface (land or water). 1) Vacuum Vacuum can be overcome by placing the odor sample bag in vacuum container which can be placed under vacuum. If the vacuum is higher then the vacuum at the source, the odor sample will collect in the bag. 2) High temperatures and high moisture contents High temperatures and high moisture contents inside the odor source leads to complications when sampled. When the sample leaves the source, it will cool down and produce condensate in the sample line and or odor sample bag. This can lead to growth of bacteria or when drying out release more odor, thus alter the odor concentration of the sample. The same hold up when sampling in high moisture conditions. A way round the problem is to use a stack dilution probe trough which an inert gas (for example dry nitrogen) can be fed that dries the sample stream. This prevents the moisture condensing in the sample line and or the odor sample bag. 3) High lethal gas concentrations Sometimes odor sources emits a high concentration of gasses that are lethal to man. These samples must be diluted to a safe level, before being presented to the odor panel. This pre-dilution can be done in a stack-dilution probe, by the addition of an inert gas or on a dilution device for example an extra olfactometer. 4) Odor concentration More often than not, odor sampled at the source is higher then the ambient odor concentration. In a few cases the odor concentration can be so high that panelists will make a positive identification even if the olfactometer is diluting the odor sample in its upper dilution range. The sample must then be pre-diluted to make a sensible reading, this pre-dilution can again be done with a stack-dilution probe, by the addition of an inert gas or on a dilution device for example an extra olfactometer. 5) Large odor emitting surface (land or on water). When a large surface is emitting odor, for example a sewage treatment plant, a fixed dimension “hood” can be used. In one end of the hood, clean air is blown in at a know rate, and on the other end, a sample is collected via the indirect method. If a large land surface is emitting odor, for example a bio filter (a big concrete basin filled with wood chip trough which the factories waste air is pumped), a section can be cornered off with plastic (e.g. Teflon) (of which the dimensions are know). The air from the factory will inflate the plastic (lift it up) and an odor sample can be taken from under the plastic via the direct air method. All involved sampling parts have to be made out of olfactory neutral materials. Principally every sampling has to meet the logically requirements, has to be defined, standardized, meaningful and reproducible. This is needed to make different measurements comparable. Odorant concentrations scaled in either GG/m³ or ouE/m³ aren’t convincing while comparing different emissions of different plants. Because of this instead of comparing different concentrations, different emission mass currents of the emitted freight are compared. # Legislative provisions associated with odors In the beginning of legislating the environmental protection in Germany the question of evaluating different odors appeared. Since that time following laws had been made: - “refinery guideline” (early 1970s) - federal emission protection law (1974) - technical guideline to keep the air fresh - olfactory emission guideline (early 1980s until 1998) Controls at the point of the emission, like plurally vitrification against aircraft noise, drop out. Terms of transmission could be marginally changed by establishingramparts, plantings and so on, but the objective efficiency of those controls is likely minimal. But the subjective efficiency of a plantings is remarkable. The choice of the location is the most important control, that means keeping an adequate distance to the nearest receptor and paying attention to the meteorology conditions, such as the prevailing wind direction. Reduction of the emission, by way of dilution of a small emission concentration with large air flow volumes, could be an effective and economic alternative, instead of reducing the emission with different controls. Encapsulating of olfactory relevant asset areas is the best known method to reduce the emission, but it is not the most suitable one. Different matters need to be considered by encapsulation. Within an enclosure a damp and oppressive atmosphere can arise, so that the inner materials of the capsule produce a high degree of mechanical stress. Not to let the explosion hazard slide. In terms of encapsulation, you have to think about exhaust the spent air. When emission is avoided through capsuling, then odorants remain inside the medium and try to leak at the next suitable spot. By the way, capsuling is never really gas-proof, at some spots considerable higher concentrated substances could leak out. There are three different ways for treating exhausted air: - chemical treatment - physical treatment - biological treatment # Adsorption as separating process Adsorption is a thermo separation process, which is characterized by the removal of molecules out of a fluid phase at a solid surface. Molecules of a gas- or fluid mixture are taken up by a solid with a porous interface surface. The solid matter is called the adsorbant, the adsorbed fluid is called the adsorbate. There are two types of adsorption, physisorption and chemisorption. The type of force driving the adsorption process is different between the two. ## Physisorption A special type of adsorption is physisorption. The difference between physisorption and chemisorption is that the adsorbed molecule is tied up with the substrate by physical forces, defined here as forces which doesn’t cause chemical bonds. Such interactions are mostly unfocused in contrast to chemical bonds. “Van-Der-Waals” – forces are a special type of such physical forces. These forces are characterized by electrostatic interactions between induced, fluctuating dipoles. To be more specific you have to call those forces “London's Dispersal forces”. A so called dipole moment occurs because of fluctuations in the distribution of electrons around individual atoms. The temporary mean value of this force is however zero. Even though it’s only a mere transient dipole moment, this moment can cause a nonparallel dipole moment in an adjacent molecule. Operating forces of this nature are in inverse proportion to the sixth power of the distance between those molecules. These forces occur in almost every chemical system, but are relatively weak. Physisorption is an exothermic and reversible reaction. Obviously stronger strengths accrue through the interaction between solid dipoles at polar surfaces or reflexive loadings, appearing in electric conductive surfaces. Such interactions could be defined as a chemisorption because of their strength. ## Chemisorption Now the mediation of the chemisorption is to come. In many reactions, physisorption is a pre-cursor to chemisorption. Compared to physisorption, chemisorption is not reversible and requires a larger activation energy. Usually the bond energy is about 800 kJ/mol. For physisorption the bond energy is only about 80 kJ/mol. A monomolecular layer could be maximally adsorbed. Strong bonds between the adsorbative molecules and the substrate could lead to the point that their intermolecular bonds partly or completely detach. In such a case you have to call this a dissociation. Those molecules are in a highly reactive state. This is the basis of heterogeneous catalysis. The substrate is then called catalytic converter. The differences between Chemisorption and Physisorption extends beyond an increased activation energy. An important criteria for chemisorption is the chemical mutation of the absorbent. Thereby it is possible that you have to deal with a chemisorption in a few combinations with a relatively low bond energy, for example 80 kJ/mol, as a physisorption could be another combination with a bond energy even by 100 kJ/mol. The interaction with different adsorbative molecules is very different. The surface could be taken by substances, which point out a very high bond energy with the substrate, and as a consequence of this the wanted reaction is impossible. Because of that feature those substances are called catalytic converter venom. Heat is released during that process too. ## Loading of the adsorben During the adsorption of a molecule, energy - the heat of adsorption – is released. This energy is the difference of the enthalpy of the adsorben in the fluid or gaseous phase and the its corresponding enthalpy on the surface of the adsorbant. With an increase of the loading on the surface of the adsorbant the bond energy decreases in the area of the monomolecular covering. For higher loading this value approaches zero. This implies that there is a limit for the loading of an adsorbant. The procedure of turning back that process is called desorption. Adsorption as a separating process is a challenging process, in the case of finding the eligible adsorbents, which could link as multilateral as possible. # Types of odors Some odors such as perfumes and flowers are sought after, elite varieties commanding high prices. Whole industries have developed products to remove unpleasant odors (seedeodorant). The perception of odors is also very much dependent upon circumstance and culture. The odor of cooking processes may be pleasurable while cooking but not necessarily after the meal. The odor molecules send messages to the limbic system, the area of the brain that governs emotional responses. Some believe that these messages have the power to alter moods, evoke distant memories, raise their spirits, and boost self-confidence. This belief has led to the concept of “aromatherapy” wherein fragrances are claimed to cure a wide range of psychological and physical problems. Aromatherapy claims fragrances can positively affect sleep, stress, alertness, social interaction, and general feelings of well-being. However, the evidence for the effectiveness of aromatherapy consists mostly of anecdotes and lacks controlled scientific studies to back up its claims. With some fragrances, such as those found in perfume, scented shampoo, scented deodorant, or similar products, people can be allergic to the ingredients. The reaction, as with other chemical allergies, can be anywhere from a slight headache to anaphylactic shock, which can result in death. Unpleasant odors can arise from certain industrial processes, adversely affecting workers and even residents downwind of the industry. The most common sources of industrial odor arise from sewage treatment plants, refineries, certain animal rendering plants and industries processing chemicals (such as sulfur) which have odorous characteristics. Sometimes industrial odor sources are the subject of community controversy and scientific analysis. ## The study of odors The study of odors is a growing field but is a complex and difficult one. The human olfactory system can detect many thousands of scents based on only very minute airborne concentrations of a chemical. The sense of smell of many animals is even better. Some fragrant flowers give off odor plumes that move downwind and are detectable by bees more than a kilometer away. The study of odors can also get complicated because of the complex chemistry taking place at the moment of a smell sensation. For example iron metal objects are perceived to have an odor when touched although iron vapor pressure is negligible. According to a 2006 study this smell is the result of aldehydes (for example nonanal) and ketones (example: 1-octen-3-one) released from the human skin on contact with ferrous ions that are formed in the sweat-mediated corrosion of iron. The same chemicals are also associated with the smell of blood as ferrous iron in blood on skin produces the same reaction. ## Pheromones Pheromones are odors that are deliberately used for communication. A female moth may release a pheromone that can entice a male moth that is several kilometers away. Honeybee queens constantly release pheromones that regulate the activity of the hive. Workers can release such smells to call other bees into an appropriate cavity when a swarm moves in or to "sound" an alarm when the hive is threatened. In mammals some pathway of Pheromones identification lay in vomeronasal organ and some - in odor receptors. ## Advanced technology There are hopes that advanced smelling machines could do everything from test perfumes to help detect cancer or explosives by detecting certain scents, but as of yet artificial noses are still problematic. The complex nature of the human nose, its ability to detect even the most subtle of scents, is at the present moment difficult to replicate. Most artificial or electronic nose instruments work by combining output from an array of non-specific chemical sensors to produce a finger print of whatever volatile chemicals it is exposed to. Most electronic noses need to be "trained" to recognize whatever chemicals are of interest for the application in question before it can be used. The training involves exposure to chemicals with the response being recorded and statistically analyzed, often using multivariate analysis and neural network techniques, to "learn" the chemicals. Many current electronic nose instruments suffer from problems with reproducibility with varying ambient temperature and humidity.

Odor # Overview An odor or odour (see spelling differences) is a volatilized chemical compound, generally at a very low concentration, which humans and other animals perceive by the sense of olfaction. Odors are also called smells, which can refer to both pleasant and unpleasant odors. The terms fragrance, scent, or aroma are used primarily by the food and cosmetic industry to describe a pleasant odor, and is sometimes used to refer to perfumes. In contrast, stench, reek, and stink are used specifically to describe unpleasant odor. ## Basics Odor is a sensation caused by odorant molecules dissolved in the air. The widest range of odors consist of organic compounds, although some inorganic substances, such as hydrogen sulfide and ammonia, are also odorants. The perception of an odor effect is a two step process. First, there is the physiological part; the sense of the stimulus by receptors in the nose. After that, the psychological part follows. The stimuli are processed by the region of the human brain which is responsible for smelling. Because of this, an objective and analytical measure of odor is impossible. While odor feelings are very personal perceptions, individual reactions are related to gender, age, state of health, and private affectations. Common odors that people are used to, such as their own body odor, are less noticeable to individuals than external or uncommon odors. For most people, the process of smelling gives little information concerning the ingredients of a substance. It only offers information related to the emotional impact. Experienced people, however, such as flavorists and perfumers, can pick out individual chemicals in complex mixes through smell alone. ## Odor analysis The concentrations of odorant in Germany have been defined by the “Olfaktometrie” since the 1870’s, which helps to analyze the human sense of smell using the following parameters: odor substance concentration, intensity of odor, and hedonism assessment. To establish the odor concentration, an olfactometer is used which employs a panel of human noses as sensors. In the olfactometry testing procedure, a diluted odorous mixture and an odor-free gas (as a reference) are presented separately from sniffing ports to a group of panelists, which are housed in an odor neutral room. They are asked to compare the gases emitted from each sniffing port, after which the panelists are asked to report the presence of odor together with a confidence level such as guessing, inkling, or certainty of their assessment. The gas-diluting ratio is then decreased by a factor of two (i.e. chemical concentration is increased by a factor of two). The panelists are asked to repeat their judgment. This continues for a number of dilution levels. The responses of the panelists over a range of dilution settings are used to calculate the concentration of the odor in terms of European Odor Units (ouE/m³). The main panel calibration gas used is Butan-1-ol., which at a certain diluting gives 1 ouE/m³. ## General survey The analytic methods could be subdivided into the physical, the gas chromatographical, and the chemosensory method. When measuring odor, there is a difference between the emission and immission measurements. During the emission measurement, the odor concentration in the air is so high that the so called “Olfaktometer” is needed to thin the assay. Because of this, all measurement methods based on thinning assays are called “olfaktometrical methods.” On the contrary, an “Olfaktormeter” is seldom used during the immission measurement. The same measuring principals are used, but the judgment of the air assay happens without thinning the assay. # Measurement While no generally acceptable method for measuring odor exists, measurement of different aspects of odor can be attempted through a number of quantitative methods, for example: ## Odorant concentration This is the oldest method to define odor emission. Ledger of this method is the concentration of odor substrate at the odor threshold. This threshold is also called apperception barrier. The threshold has got an odorant concentration of 1 GEE/m³ and is subscribed with cod. To define the odorant concentration, it is necessary to dilute the air assay to the odor threshold with the help of the “Olfaktormeter.” The dilution factor Z, at the odor barrier, is the same number as the odor substance concentration. The European Union has with the introduction of the following standard: CEN EN 13725:2003, Air quality - Determination of odour concentration by dynamic olfactometry. standardized the odor concentration across Europe and odor concentration is now expressed in European Odor Units (ouE/m³). ## Odor intensity Odor intensity can be divided into the following categories according to intensity: If it is an emission measurement (diluted by the olfactometer), then the evaluation of an odor's intensity must be ranked by the olfactometer methods. A direct evaluation is used when the array is measured from the emission side. This method is most often applied by having a dilution series tested by a panel of independent observers who have been trained to differentiate intensity. ## Hedonic assessment The hedonic assessment is the process of scaling odors beginning with extremely unpleasant followed by neutral up to extremely pleasant. There is no difference between this process and the method of measuring the odor intensity. But the method of emission measurement is seldom used and that of emission measurement is not used. ## Odor type This is a verbal characterization of the sensed odor by the test person, such as disgusting, caustic, ruffling, etc. There are no more applications needed than a test person to run this method. The evaluation of the odor type could be an emission or an immission method. It has a great impact on evaluating the source of the odor emission. ## Emission measurement The following details have to be diffetentiated while the emission is measured: First there is the odor time slice (Result = Part of “odor hours per year” per area). Then there is the olfactory flag scope (Result = Current scope at actual meteorology situation). And last but not least there is the harassment exaltation by questionings (Result = differentiated acquisition harassments). ## Sampling technique There are two main odor sampling techniques, the direct odor sampling and the indirect odor sampling technique. Direct odor sampling. Air will be sampled at the source and fed straight into the olfactometer for assessment by an odor panel. The following problems can be associated with this technique: Odor panel members need to be seated in an odor neutral environment, thus they need to be housed in a separate area. This is difficult to achieve when assessing odor released from, for example factories, were the odor can be emitted from a stack on the end of a production line. This means that the odor sample collected needs to be transported from the stack to the unit were the odor panel sits. This can sometimes be on the other side of the factory plant. The sample then must therefore pass trough a very long sample line to the olfactometer. This can have influences on the sample quality, can have potential air blockages due to water condensation or other operational procedures. Therefore most odor annoyance assessment companies use the indirect air sampling method. Indirect odor sampling Indirect odor sampling is done with the use of odor (air) sampling bags, which are made from an odor neutral material e.g. Teflon. The odor sample bags are connected to an air sampling line which is then, for example, hooked up to a stack. The air stream is then sampled and stored in the odor sample bag and can then be analyzed in a suitable environment (e.g. in an odor laboratory). The indirect method is used to sample a wide variety of odor sources. From stacks on the end of a factory line, water surfaces or ambient air surroundings. Each odor source has its own set of problems when sampled; these problems need to be overcome in order to collect a representative sample of the odor source. The following problems can be encountered: - Vacuum. - High temperatures and moisture content. - High lethal gas concentrations. - Odor concentrations. - Large odor emitting surface (land or water). 1) Vacuum Vacuum can be overcome by placing the odor sample bag in vacuum container which can be placed under vacuum. If the vacuum is higher then the vacuum at the source, the odor sample will collect in the bag. 2) High temperatures and high moisture contents High temperatures and high moisture contents inside the odor source leads to complications when sampled. When the sample leaves the source, it will cool down and produce condensate in the sample line and or odor sample bag. This can lead to growth of bacteria or when drying out release more odor, thus alter the odor concentration of the sample. The same hold up when sampling in high moisture conditions. A way round the problem is to use a stack dilution probe trough which an inert gas (for example dry nitrogen) can be fed that dries the sample stream. This prevents the moisture condensing in the sample line and or the odor sample bag. 3) High lethal gas concentrations Sometimes odor sources emits a high concentration of gasses that are lethal to man. These samples must be diluted to a safe level, before being presented to the odor panel. This pre-dilution can be done in a stack-dilution probe, by the addition of an inert gas or on a dilution device for example an extra olfactometer. 4) Odor concentration More often than not, odor sampled at the source is higher then the ambient odor concentration. In a few cases the odor concentration can be so high that panelists will make a positive identification even if the olfactometer is diluting the odor sample in its upper dilution range. The sample must then be pre-diluted to make a sensible reading, this pre-dilution can again be done with a stack-dilution probe, by the addition of an inert gas or on a dilution device for example an extra olfactometer. 5) Large odor emitting surface (land or on water). When a large surface is emitting odor, for example a sewage treatment plant, a fixed dimension “hood” can be used. In one end of the hood, clean air is blown in at a know rate, and on the other end, a sample is collected via the indirect method. If a large land surface is emitting odor, for example a bio filter (a big concrete basin filled with wood chip trough which the factories waste air is pumped), a section can be cornered off with plastic (e.g. Teflon) (of which the dimensions are know). The air from the factory will inflate the plastic (lift it up) and an odor sample can be taken from under the plastic via the direct air method. All involved sampling parts have to be made out of olfactory neutral materials. Principally every sampling has to meet the logically requirements, has to be defined, standardized, meaningful and reproducible. This is needed to make different measurements comparable. Odorant concentrations scaled in either GG/m³ or ouE/m³ aren’t convincing while comparing different emissions of different plants. Because of this instead of comparing different concentrations, different emission mass currents of the emitted freight are compared. # Legislative provisions associated with odors In the beginning of legislating the environmental protection in Germany the question of evaluating different odors appeared. Since that time following laws had been made: - “refinery guideline” (early 1970s) - federal emission protection law (1974) - technical guideline to keep the air fresh - olfactory emission guideline (early 1980s until 1998) Controls at the point of the emission, like plurally vitrification against aircraft noise, drop out. Terms of transmission could be marginally changed by establishingramparts, plantings and so on, but the objective efficiency of those controls is likely minimal. But the subjective efficiency of a plantings is remarkable. The choice of the location is the most important control, that means keeping an adequate distance to the nearest receptor and paying attention to the meteorology conditions, such as the prevailing wind direction. Reduction of the emission, by way of dilution of a small emission concentration with large air flow volumes, could be an effective and economic alternative, instead of reducing the emission with different controls. Encapsulating of olfactory relevant asset areas is the best known method to reduce the emission, but it is not the most suitable one. Different matters need to be considered by encapsulation. Within an enclosure a damp and oppressive atmosphere can arise, so that the inner materials of the capsule produce a high degree of mechanical stress. Not to let the explosion hazard slide. In terms of encapsulation, you have to think about exhaust the spent air. When emission is avoided through capsuling, then odorants remain inside the medium and try to leak at the next suitable spot. By the way, capsuling is never really gas-proof, at some spots considerable higher concentrated substances could leak out. There are three different ways for treating exhausted air: - chemical treatment - physical treatment - biological treatment # Adsorption as separating process Adsorption is a thermo separation process, which is characterized by the removal of molecules out of a fluid phase at a solid surface. Molecules of a gas- or fluid mixture are taken up by a solid with a porous interface surface. The solid matter is called the adsorbant, the adsorbed fluid is called the adsorbate. There are two types of adsorption, physisorption and chemisorption. The type of force driving the adsorption process is different between the two. ## Physisorption A special type of adsorption is physisorption. The difference between physisorption and chemisorption is that the adsorbed molecule is tied up with the substrate by physical forces, defined here as forces which doesn’t cause chemical bonds. Such interactions are mostly unfocused in contrast to chemical bonds. “Van-Der-Waals” – forces are a special type of such physical forces. These forces are characterized by electrostatic interactions between induced, fluctuating dipoles. To be more specific you have to call those forces “London's Dispersal forces”. A so called dipole moment occurs because of fluctuations in the distribution of electrons around individual atoms. The temporary mean value of this force is however zero. Even though it’s only a mere transient dipole moment, this moment can cause a nonparallel dipole moment in an adjacent molecule. Operating forces of this nature are in inverse proportion to the sixth power of the distance between those molecules. These forces occur in almost every chemical system, but are relatively weak. Physisorption is an exothermic and reversible reaction. Obviously stronger strengths accrue through the interaction between solid dipoles at polar surfaces or reflexive loadings, appearing in electric conductive surfaces. Such interactions could be defined as a chemisorption because of their strength. ## Chemisorption Now the mediation of the chemisorption is to come. In many reactions, physisorption is a pre-cursor to chemisorption. Compared to physisorption, chemisorption is not reversible and requires a larger activation energy. Usually the bond energy is about 800 kJ/mol. For physisorption the bond energy is only about 80 kJ/mol. A monomolecular layer could be maximally adsorbed. Strong bonds between the adsorbative molecules and the substrate could lead to the point that their intermolecular bonds partly or completely detach. In such a case you have to call this a dissociation. Those molecules are in a highly reactive state. This is the basis of heterogeneous catalysis. The substrate is then called catalytic converter. The differences between Chemisorption and Physisorption extends beyond an increased activation energy. An important criteria for chemisorption is the chemical mutation of the absorbent. Thereby it is possible that you have to deal with a chemisorption in a few combinations with a relatively low bond energy, for example 80 kJ/mol, as a physisorption could be another combination with a bond energy even by 100 kJ/mol. The interaction with different adsorbative molecules is very different. The surface could be taken by substances, which point out a very high bond energy with the substrate, and as a consequence of this the wanted reaction is impossible. Because of that feature those substances are called catalytic converter venom. Heat is released during that process too. ## Loading of the adsorben During the adsorption of a molecule, energy - the heat of adsorption – is released. This energy is the difference of the enthalpy of the adsorben in the fluid or gaseous phase and the its corresponding enthalpy on the surface of the adsorbant. With an increase of the loading on the surface of the adsorbant the bond energy decreases in the area of the monomolecular covering. For higher loading this value approaches zero. This implies that there is a limit for the loading of an adsorbant. The procedure of turning back that process is called desorption. Adsorption as a separating process is a challenging process, in the case of finding the eligible adsorbents, which could link as multilateral as possible. # Types of odors Some odors such as perfumes and flowers are sought after, elite varieties commanding high prices. Whole industries have developed products to remove unpleasant odors (seedeodorant). The perception of odors is also very much dependent upon circumstance and culture. The odor of cooking processes may be pleasurable while cooking but not necessarily after the meal. The odor molecules send messages to the limbic system, the area of the brain that governs emotional responses. Some believe that these messages have the power to alter moods, evoke distant memories, raise their spirits, and boost self-confidence. This belief has led to the concept of “aromatherapy” wherein fragrances are claimed to cure a wide range of psychological and physical problems. Aromatherapy claims fragrances can positively affect sleep, stress, alertness, social interaction, and general feelings of well-being. However, the evidence for the effectiveness of aromatherapy consists mostly of anecdotes and lacks controlled scientific studies to back up its claims. With some fragrances, such as those found in perfume, scented shampoo, scented deodorant, or similar products, people can be allergic to the ingredients. The reaction, as with other chemical allergies, can be anywhere from a slight headache to anaphylactic shock, which can result in death. Unpleasant odors can arise from certain industrial processes, adversely affecting workers and even residents downwind of the industry. The most common sources of industrial odor arise from sewage treatment plants, refineries, certain animal rendering plants and industries processing chemicals (such as sulfur) which have odorous characteristics. Sometimes industrial odor sources are the subject of community controversy and scientific analysis. ## The study of odors The study of odors is a growing field but is a complex and difficult one. The human olfactory system can detect many thousands of scents based on only very minute airborne concentrations of a chemical. The sense of smell of many animals is even better. Some fragrant flowers give off odor plumes that move downwind and are detectable by bees more than a kilometer away. The study of odors can also get complicated because of the complex chemistry taking place at the moment of a smell sensation. For example iron metal objects are perceived to have an odor when touched although iron vapor pressure is negligible. According to a 2006 study[1] this smell is the result of aldehydes (for example nonanal) and ketones (example: 1-octen-3-one) released from the human skin on contact with ferrous ions that are formed in the sweat-mediated corrosion of iron. The same chemicals are also associated with the smell of blood as ferrous iron in blood on skin produces the same reaction. ## Pheromones Pheromones are odors that are deliberately used for communication. A female moth may release a pheromone that can entice a male moth that is several kilometers away. Honeybee queens constantly release pheromones that regulate the activity of the hive. Workers can release such smells to call other bees into an appropriate cavity when a swarm moves in or to "sound" an alarm when the hive is threatened. In mammals some pathway of Pheromones identification lay in vomeronasal organ and some - in odor receptors. ## Advanced technology There are hopes that advanced smelling machines could do everything from test perfumes to help detect cancer or explosives by detecting certain scents, but as of yet artificial noses are still problematic. The complex nature of the human nose, its ability to detect even the most subtle of scents, is at the present moment difficult to replicate. Most artificial or electronic nose instruments work by combining output from an array of non-specific chemical sensors to produce a finger print of whatever volatile chemicals it is exposed to. Most electronic noses need to be "trained" to recognize whatever chemicals are of interest for the application in question before it can be used. The training involves exposure to chemicals with the response being recorded and statistically analyzed, often using multivariate analysis and neural network techniques, to "learn" the chemicals. Many current electronic nose instruments suffer from problems with reproducibility with varying ambient temperature and humidity.

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Oklo

Oklo Oklo is a region near the town of Franceville, in the Haut-Ogooué province of the Central African state of Gabon. The discovery in September 1972 of several natural nuclear fission reactors in the uranium mines situated there has fired the imagination and aroused the curiosity of scientists. # History Gabon was a French colony when prospectors from the French nuclear energy commissariat (the industrial parts, which later became the COGEMA) discovered uranium in the remote region in 1956. France immediately opened mines operated by Comuf (Compagnie des Mines d'Uranium de Franceville) near Mounana village in order to exploit the vast mineral resources and the State of Gabon was given a minority share in the company. For forty years, France mined for uranium in Gabon. Once extracted, the uranium was used for electricity production in France and much of Europe. Gabon's miners half-joked that it was thanks to them that France's high-speed TGV trains could operate. Today, however, the uranium deposits are exhausted, and the mine is no longer worked. Currently, reclamation work is ongoing in the region affected by the mine operations. There is strong geochemical evidence that the Oklo uranium deposit behaved as a natural nuclear fission reactor in Precambrian times: Some of mined uranium was found to have a lower concentration of U235 than expected, as if it had already been in a reactor. Geologists found that it had been in a reactor before -- two billion years ago. At that time the natural uranium had a concentration of about 3% U235, and could have gone critical with natural water as neutron moderator.

Oklo Oklo is a region near the town of Franceville, in the Haut-Ogooué province of the Central African state of Gabon. The discovery in September 1972 of several natural nuclear fission reactors in the uranium mines situated there has fired the imagination and aroused the curiosity of scientists. # History Gabon was a French colony when prospectors from the French nuclear energy commissariat (the industrial parts, which later became the COGEMA) discovered uranium in the remote region in 1956. France immediately opened mines operated by Comuf (Compagnie des Mines d'Uranium de Franceville) near Mounana village in order to exploit the vast mineral resources and the State of Gabon was given a minority share in the company. For forty years, France mined for uranium in Gabon. Once extracted, the uranium was used for electricity production in France and much of Europe. Gabon's miners half-joked that it was thanks to them that France's high-speed TGV trains could operate. Today, however, the uranium deposits are exhausted, and the mine is no longer worked. Currently, reclamation work is ongoing in the region affected by the mine operations. There is strong geochemical evidence that the Oklo uranium deposit behaved as a natural nuclear fission reactor in Precambrian times: Some of mined uranium was found to have a lower concentration of U235 than expected, as if it had already been in a reactor. Geologists found that it had been in a reactor before -- two billion years ago. At that time the natural uranium had a concentration of about 3% U235, and could have gone critical with natural water as neutron moderator.

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f8fcf5936b39176e6b224a9d1f07f6c758eefbc7

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Okra

Okra Okra (American English: Template:IPA, British English Template:IPA), also known as lady's finger, bhindi and gumbo, is a flowering plant valued for its edible green fruits. Its scientific name is Abelmoschus esculentus. The species is an annual or perennial, growing to 2.5 m tall. The leaves are 10–20 cm long and broad, palmately lobed with 5–7 lobes. The flowers are 4–8 cm diameter, with five white to yellow petals, often with a red or purple spot at the base of each petal. The fruit is a capsule up to 20 cm long, containing numerous seeds. # Etymology, origin and distribution The name "okra" is of West African origin and is cognate with "ọ́kụ̀rụ̀" in Igbo, a language spoken in what is now known as Nigeria. In various Bantu languages, okra is called "kingombo" or a variant thereof, and this is the origin of its name in Portuguese, Spanish and French. The Arabic "Template:ArabDIN" is the basis of the names in the Middle East, the Balkans, Turkey, North Africa and Russia. In Southern Asia, its name is usually a variant of "bhindi". Okra is occasionally referred to by an early, now incorrect synonym, Hibiscus esculentus L. The species apparently originated in the Ethiopian Highlands, though the manner of distribution from there is undocumented. The Egyptians and Moors of the 12th and 13th centuries used the Arab word for the plant, suggesting that it had come from the east. The plant may thus have been taken across the Red Sea or the Bab-el-Mandeb strait to the Arabian Peninsula, rather than north across the Sahara. One of the earliest accounts is by a Spanish Moor who visited Egypt in 1216, who described the plant under cultivation by the locals who ate the tender, young pods with meal. From Arabia, the plant spread around the shores of the Mediterranean Sea and eastward. The lack of a word for okra in the ancient languages of India suggests that it arrived there after the beginning of the Common Era. The plant was introduced to the Americas by ships plying the Atlantic slave trade by 1658, when its presence was recorded in Brazil. It was further documented in Suriname in 1686. Okra may have been introduced to the southeastern North America in the early 18th century and gradually spread. It was being grown as far north as Philadelphia by 1748, while Thomas Jefferson noted that it was well established in Virginia by 1781. It was commonplace throughout the southern United States by 1800 and the first mention of different cultivars was in 1806. # Uses Abelmoschus esculentus is cultivated throughout the tropical and warm temperate regions of the world for its fibrous fruits or pods containing round, white seeds. The fruits are harvested when immature and eaten as a vegetable. In Iran, Egypt, Lebanon, Israel, Jordan, Iraq, Greece, Turkey and other parts of the eastern Mediterranean, okra is widely used in a thick stew made with vegetables and meat. In Indian cooking, it is sauteed or added to gravy-based preparations and is very popular in South India. It became a popular vegetable in Japanese cuisine towards the end of the 20th century, served with soy sauce and katsuobushi or as tempura. It is used as a thickening agent in Charleston gumbo. Breaded, deep fried okra is served in the southern United States. The immature pods may also be pickled. Okra leaves may be cooked in a similar manner as the greens of beets or dandelions. The leaves are also eaten raw in salads. Okra seeds may be roasted and ground to form a non-caffeinated substitute for coffee. As imports were disrupted by the American Civil War in 1861, the Austin State Gazette noted, "An acre of okra will produce seed enough to furnish a plantation of fifty negroes with coffee in every way equal to that imported from Rio." Okra forms part of several regional 'signature' dishes. Frango com quiabo (chicken with okra) is a Brazilian dish that is especially famous in the region of Minas Gerais. Gumbo, a hearty stew whose key ingredient is okra, is found throughout the Gulf Coast of the United States. The word "gumbo" is based on the Central Bantu word for okra, "kigombo", via the Caribbean Spanish "guingambó" or "qimbombó". It is also an expected ingredient in callaloo, a Caribbean dish and the national dish of Trinidad & Tobago. Okra oil is a pressed seed oil, extracted from the seeds of the okra. The greenish yellow edible oil has a pleasant taste and odor, and is high in unsaturated fats such as oleic acid and linoleic acid. The oil content of the seed is quite high at about 40%. Oil yields from okra crops are also high. At 794 kg/ha, the yield was exceeded only by that of sunflower oil in one trial. Unspecified parts of the plant reportedly possess diuretic properties. # Cultivation Abelmoschus esculentus is among the most heat- and drought-tolerant vegetable species in the world. It will tolerate poor soils with heavy clay and intermittent moisture. Severe frost can damage the pods. It is an annual crop in the southern United States. In cultivation, the seeds are soaked overnight prior to planting to a depth of 1-2 cm. Germination occurs between six days (soaked seeds) and three weeks. Seedlings require ample water. The seed pods rapidly become fibrous and woody and must be harvested within a week of the fruit being pollinated to be edible. The products of the plant are mucilaginous, resulting in the characteristic "goo" when the seed pods are cooked. In order to avoid this effect, okra pods are often stir fried, so the moisture is cooked away, or paired with slightly acidic ingredients, such as citrus or tomatoes. The cooked leaves are also a powerful soup thickener.

Okra Okra (American English: Template:IPA, British English Template:IPA), also known as lady's finger[1], bhindi and gumbo, is a flowering plant valued for its edible green fruits. Its scientific name is Abelmoschus esculentus. The species is an annual or perennial, growing to 2.5 m tall. The leaves are 10–20 cm long and broad, palmately lobed with 5–7 lobes. The flowers are 4–8 cm diameter, with five white to yellow petals, often with a red or purple spot at the base of each petal. The fruit is a capsule up to 20 cm long, containing numerous seeds. # Etymology, origin and distribution The name "okra" is of West African origin and is cognate with "ọ́kụ̀rụ̀" in Igbo, a language spoken in what is now known as Nigeria. In various Bantu languages, okra is called "kingombo" or a variant thereof, and this is the origin of its name in Portuguese, Spanish and French. The Arabic "Template:ArabDIN" is the basis of the names in the Middle East, the Balkans, Turkey, North Africa and Russia. In Southern Asia, its name is usually a variant of "bhindi". Okra is occasionally referred to by an early, now incorrect synonym, Hibiscus esculentus L. The species apparently originated in the Ethiopian Highlands, though the manner of distribution from there is undocumented. The Egyptians and Moors of the 12th and 13th centuries used the Arab word for the plant, suggesting that it had come from the east. The plant may thus have been taken across the Red Sea or the Bab-el-Mandeb strait to the Arabian Peninsula, rather than north across the Sahara. One of the earliest accounts is by a Spanish Moor who visited Egypt in 1216, who described the plant under cultivation by the locals who ate the tender, young pods with meal.[2] From Arabia, the plant spread around the shores of the Mediterranean Sea and eastward. The lack of a word for okra in the ancient languages of India suggests that it arrived there after the beginning of the Common Era. The plant was introduced to the Americas by ships plying the Atlantic slave trade[3] by 1658, when its presence was recorded in Brazil. It was further documented in Suriname in 1686. Okra may have been introduced to the southeastern North America in the early 18th century and gradually spread. It was being grown as far north as Philadelphia by 1748, while Thomas Jefferson noted that it was well established in Virginia by 1781. It was commonplace throughout the southern United States by 1800 and the first mention of different cultivars was in 1806.[2] # Uses Template:Nutritionalvalue Abelmoschus esculentus is cultivated throughout the tropical and warm temperate regions of the world for its fibrous fruits or pods containing round, white seeds. The fruits are harvested when immature and eaten as a vegetable. In Iran, Egypt, Lebanon, Israel, Jordan, Iraq, Greece, Turkey and other parts of the eastern Mediterranean, okra is widely used in a thick stew made with vegetables and meat. In Indian cooking, it is sauteed or added to gravy-based preparations and is very popular in South India. It became a popular vegetable in Japanese cuisine towards the end of the 20th century, served with soy sauce and katsuobushi or as tempura. It is used as a thickening agent in Charleston gumbo. Breaded, deep fried okra is served in the southern United States. The immature pods may also be pickled. Okra leaves may be cooked in a similar manner as the greens of beets or dandelions.[4] The leaves are also eaten raw in salads.[citation needed] Okra seeds may be roasted and ground to form a non-caffeinated substitute for coffee.[2] As imports were disrupted by the American Civil War in 1861, the Austin State Gazette noted, "An acre of okra will produce seed enough to furnish a plantation of fifty negroes with coffee in every way equal to that imported from Rio."[5] Okra forms part of several regional 'signature' dishes. Frango com quiabo (chicken with okra) is a Brazilian dish that is especially famous in the region of Minas Gerais. Gumbo, a hearty stew whose key ingredient is okra, is found throughout the Gulf Coast of the United States. The word "gumbo" is based on the Central Bantu word for okra, "kigombo", via the Caribbean Spanish "guingambó" or "qimbombó".[2] It is also an expected ingredient in callaloo, a Caribbean dish and the national dish of Trinidad & Tobago. Okra oil is a pressed seed oil, extracted from the seeds of the okra. The greenish yellow edible oil has a pleasant taste and odor, and is high in unsaturated fats such as oleic acid and linoleic acid.[6] The oil content of the seed is quite high at about 40%. Oil yields from okra crops are also high. At 794 kg/ha, the yield was exceeded only by that of sunflower oil in one trial.[7] Unspecified parts of the plant reportedly possess diuretic properties.[8][9] # Cultivation Abelmoschus esculentus is among the most heat- and drought-tolerant vegetable species in the world. It will tolerate poor soils with heavy clay and intermittent moisture. Severe frost can damage the pods.[citation needed] It is an annual crop in the southern United States. In cultivation, the seeds are soaked overnight prior to planting to a depth of 1-2 cm. Germination occurs between six days (soaked seeds) and three weeks. Seedlings require ample water.[citation needed] The seed pods rapidly become fibrous and woody and must be harvested within a week of the fruit being pollinated to be edible.[2] The products of the plant are mucilaginous, resulting in the characteristic "goo" when the seed pods are cooked. In order to avoid this effect, okra pods are often stir fried, so the moisture is cooked away, or paired with slightly acidic ingredients, such as citrus or tomatoes. The cooked leaves are also a powerful soup thickener.[citation needed]

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

cc3bac76e55b196cfb74e520498e795595578fc5

wikidoc

Olea

Olea # Overview Olea (/ˈoʊliːə/) is a genus of about 40 species in the family Oleaceae, native to warm temperate and tropical regions of southern Europe, Africa, southern Asia and Australasia. They are evergreen trees and shrubs, with small, opposite, entire leaves. The fruit is a drupe. Leaves of Olea contain Tricho sclereids. For humans, the most important species is by far the Olive (Olea europaea), native to the Mediterranean region. O. paniculata is a larger tree, attaining a height of 15–18 m in the forests of Queensland, and yielding a hard and tough timber. The yet harder wood of the Black Ironwood O. laurifolia, an inhabitant of Natal, is important in South Africa. Olea species are used as food plants by the larvae of some Lepidoptera species including Double-striped Pug. # Selected species - Olea ambrensis H.Perrier - Olea borneensis Boerl. - Olea brachiata (Lour.) Merr. - Olea capensis L. – Small Ironwood - Olea caudatilimba L.C.Chia - Olea chimanimani Kupicha - Olea chrysophylla Lam. - Olea cordatula H.L.Li - Olea dioica Roxb. - Olea europaea L. – Olive - Olea exasperata Jacq. - Olea gagnepainii Knobl. - Olea gamblei C.B.Clarke - Olea guangxiensis B.M.Miao - Olea hainanensis H.L.Li - Olea javanica (Blume) Knobl. - Olea lancea Lam. - Olea laurifolia Lam. – Black Ironwood - Olea laxiflora H.L.Li - Olea moluccensis Kiew - Olea neriifolia H.L.Li - Olea obovata (Merr.) Kiew - Olea oleaster Hoffmanns. & Link – Wild-olive - Olea palawanensis Kiew - Olea paniculata R.Br. - Olea parvilimba (Merr. & Chun) B.M.Miao - Olea polygama Wight - Olea rosea Craib - Olea rubrovenia (Elmer) Kiew - Olea salicifolia Wall. ex G.Don - Olea schliebenii Knobl. - Olea sylvestris Mill. - Olea tetragonoclada L.C.Chia - Olea tsoongii (Merr.) P.S.Green - Olea undulata (Sol.) Jacq. - Olea welwitschii (Knobl.) Gilg & G.Schellenb. - Olea wightiana Wall. ex G.Don - Olea woodiana Knobl. - Olea yuennanensis Hand.-Mazz. ## Formerly placed here - Chionanthus foveolatus (E.Mey.) Stearn (as O. foveolata E.Mey.) - Ligustrum compactum var. compactum (as O. compacta Wall. ex G.Don) - Nestegis cunninghamii (Hook.f.) L.A.S.Johnson (as O. cunninghamii Hook.f.) - Noronhia emarginata (Lam.) Thouars (as O. emarginata Lam.) - Osmanthus americanus (L.) Benth. & Hook.f. ex A.Gray (as O. americana L.) - Osmanthus heterophyllus (G. Don) P.S.Green (as O. aquifolium Siebold & Zucc. or O. ilicifolia Siebold ex Hassk.)

Olea Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Olea (/[invalid input: 'icon']ˈoʊliːə/)[2] is a genus of about 40 species in the family Oleaceae, native to warm temperate and tropical regions of southern Europe, Africa, southern Asia and Australasia. They are evergreen trees and shrubs, with small, opposite, entire leaves. The fruit is a drupe. Leaves of Olea contain Tricho sclereids. For humans, the most important species is by far the Olive (Olea europaea), native to the Mediterranean region. O. paniculata is a larger tree, attaining a height of 15–18 m in the forests of Queensland, and yielding a hard and tough timber. The yet harder wood of the Black Ironwood O. laurifolia, an inhabitant of Natal, is important in South Africa. Olea species are used as food plants by the larvae of some Lepidoptera species including Double-striped Pug. # Selected species - Olea ambrensis H.Perrier - Olea borneensis Boerl. - Olea brachiata (Lour.) Merr. - Olea capensis L. – Small Ironwood - Olea caudatilimba L.C.Chia - Olea chimanimani Kupicha - Olea chrysophylla Lam. - Olea cordatula H.L.Li - Olea dioica Roxb. - Olea europaea L. – Olive - Olea exasperata Jacq. - Olea gagnepainii Knobl. - Olea gamblei C.B.Clarke - Olea guangxiensis B.M.Miao - Olea hainanensis H.L.Li - Olea javanica (Blume) Knobl. - Olea lancea Lam. - Olea laurifolia Lam. – Black Ironwood - Olea laxiflora H.L.Li - Olea moluccensis Kiew - Olea neriifolia H.L.Li - Olea obovata (Merr.) Kiew - Olea oleaster Hoffmanns. & Link – Wild-olive - Olea palawanensis Kiew - Olea paniculata R.Br. - Olea parvilimba (Merr. & Chun) B.M.Miao - Olea polygama Wight - Olea rosea Craib - Olea rubrovenia (Elmer) Kiew - Olea salicifolia Wall. ex G.Don - Olea schliebenii Knobl. - Olea sylvestris Mill. - Olea tetragonoclada L.C.Chia - Olea tsoongii (Merr.) P.S.Green - Olea undulata (Sol.) Jacq. - Olea welwitschii (Knobl.) Gilg & G.Schellenb. - Olea wightiana Wall. ex G.Don - Olea woodiana Knobl. - Olea yuennanensis Hand.-Mazz. ## Formerly placed here - Chionanthus foveolatus (E.Mey.) Stearn (as O. foveolata E.Mey.) - Ligustrum compactum var. compactum (as O. compacta Wall. ex G.Don) - Nestegis cunninghamii (Hook.f.) L.A.S.Johnson (as O. cunninghamii Hook.f.) - Noronhia emarginata (Lam.) Thouars (as O. emarginata Lam.) - Osmanthus americanus (L.) Benth. & Hook.f. ex A.Gray (as O. americana L.) - Osmanthus heterophyllus (G. Don) P.S.Green (as O. aquifolium Siebold & Zucc. or O. ilicifolia Siebold ex Hassk.)

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Opal

Opal Opal is a mineraloid gel which is deposited at a relatively low temperature and may occur in the fissures of almost any kind of rock, being most commonly found with limonite, sandstone, rhyolite, and basalt. The water content is usually between three and ten percent, but can be as high as 20%. Opal ranges from clear through white, gray, red, orange, yellow, green, shore, blue, magenta, rose, pink, slate, olive, brown, and black. Of these hues, the reds against black are the most rare and dear, whereas white and greens are the most common; these are a function of growth size into the red and infrared wavelengths—see precious opal. Common opal is truly amorphous, but precious opal does have a structural element. The word opal comes from the Latin opalus, by Greek opallios, and is from the same root as Sanskrit upálá for "stone", originally a millstone with upárá for slab. (see Upal). Opals are also Australia's national gemstone. Opal is one of the mineraloids that can form or replace fossils. The resulting fossils, though not of any extra scientific interest, appeal to collectors. # Precious opal Precious opal shows a variable interplay of internal colors and does have an internal structure. At the micro scale precious opal is composed of silica spheres some 150 to 300 nm in diameter in a hexagonal or cubic closed-packed lattice. These ordered silica spheres produce the internal colors by causing the interference and diffraction of light passing through the microstructure of opal. It is the regularity of the sizes of the spheres, and of the packing of these spheres that determines the quality of precious opal. Where the distance between the regularly packed planes of spheres is approximately half the wavelength of a component of visible light, the light of that wavelength may be subject to diffraction from the grating created by the stacked planes. The spacing between the planes and the orientation of planes with respect to the incident light determines the colors observed. The process can be described by Bragg's Law of diffraction. Visible light of diffracted wavelengths cannot pass through large thicknesses of the opal. This is the basis of the optical band gap in a photonic crystal, of which opal is the best known natural example. In addition, microfractures may be filled with secondary silica and form thin lamellae inside the opal during solidification. The term opalescence is commonly and erroneously used to describe this unique and beautiful phenomenon, which is correctly termed play of color. Contrarily, opalescence is correctly applied to the milky, turbid appearance of common or potch opal. Potch does not show a play of color. The veins of opal displaying the play of color are often quite thin, and this has given rise to unusual methods of preparing the stone as a gem.  An opal doublet is a thin layer of opal, backed by a swart mineral such as ironstone, basalt, or obsidian.  The darker backing emphasizes the play of color, and results in a more attractive display than a lighter potch. Combined with modern technique of polishing, doublet opal produces similar effect of black or boulder opals at a mere fraction of the price. Doublet opal also has the added benefit of having genuine opal as the top visible and touchable layer, unlike triplet opals. The triplet cut backs the colored material with a dark backing, and then has a domed cap of clear quartz (rock crystal) or plastic on top, which takes a high polish, and acts as a protective layer for the relatively fragile opal. The top layer also acts as a magniflier, to emphasis the play of colour of the opal beneath, which are often of a lower quality. Triplet opals therefore have a more artificial feel to it and are not classed as precious opal. # Common opal Besides the gemstone varieties that show a play of color, there are other kinds of common opal such as the milk opal, milky bluish to greenish (which can sometimes be of gemstone quality); resin opal, honey-yellow with a resinous luster; wood opal, caused by the replacement of the organic material in wood with opal; menilite brown or grey; hyalite, a colorless glass-clear opal sometimes called Muller's Glass; geyserite, (siliceous sinter) deposited around hot springs or geysers; and diatomite or diatomaceous earth, the accumulations of diatom shells or tests. # Other varieties of opal Fire opal – Fire opals are transparent to translucent opals with warm body colors yellow, orange, orange-yellow or red and they do not show any play-of-color. The most famous source of fire opals is the state of Queretaro in Mexico and these opals are commonly called Mexican fire opals. Peruvian opal (also called blue opal) is a semi-opaque to opaque blue-green stone found in Peru which is often cut to include the matrix in the more opaque stones. It does not display pleochroism. # Sources of opal Australia produces around 97% of the world’s opal. 90% is called ‘light opal’ or white and crystal opal. White makes up 60% but not all the opal fields produce white opal; Crystal opal or pure hydrated silica makes up 30%; 8% is black and only 2% is boulder opal. The town of Coober Pedy in South Australia is a major source of opal. Andamooka in South Australia is also a major producer of matrix opal, crystal opal, and black opal. Another Australian town, Lightning Ridge in New South Wales, is the main source of black opal, opal containing a predominantly dark background (dark-gray to blue-black displaying the play of color). Boulder opal consists of concretions and fracture fillings in a dark siliceous ironstone matrix. It is found sporadically in western Queensland, from Kynuna in the north, to Yowah and Koroit in the south. The Virgin Valley opal fields of Humboldt County in northern Nevada produce a wide variety of black, crystal, white, and fire opal. The fire opal mined from this locality is designated as the official gemstone of the State of Nevada. Most precious opals are wood replacements. Many specimens have a high water content, and as a result, have a greater tendency to desiccate and crack than most precious opal. The largest black opal in the Smithsonian Museum comes from the Royal Peacock opal mine in the Virgin Valley. Another source of white base opal in the United States is Spencer, Idaho. A high percentage of the opal found there occurs in thin layers. As a result, most of the production goes into the making of doublets and triplets. Other significant deposits of precious opal around the world can be found in the Czech Republic, Slovakia, Hungary, Turkey, Indonesia, Brazil, Honduras, Guatemala, Nicaragua and Ethiopia. In late 2008, NASA announced that it had discovered opal deposits on Mars. # Synthetic opal As well as occurring naturally, opals of all varieties have been synthesized experimentally and commercially. The discovery of the ordered sphere structure of precious opal led to its synthesis by Pierre Gilson in 1974. The resulting material is distinguishable from natural opal by its regularity; under magnification, the patches of color are seen to be arranged in a "lizard skin" or "chicken wire" pattern. Synthetics are further distinguished from naturals by the former's lack of fluorescence under UV light. Synthetics are also generally lower in density and are often highly porous; some may even stick to the tongue. Two notable producers of synthetic opal are the companies Kyocera and Inamori of Japan. Most so-called synthetics, however, are more correctly termed imitations, as they contain substances not found in natural opal (e.g., plastic stabilizers). The imitation opals seen in vintage jewellery are often "Slocum Stone" consisting of laminated glass with bits of foil interspersed. # Local atomic structure of opals The lattice of spheres of opal that cause the interference with light are several hundred times larger than the fundamental structure of crystalline silica. As a mineraloid, there is no unit cell that describes the structure of opal. Nevertheless, opals can be roughly divided into those that show no signs of crystalline order—i.e., amorphous opal—and those that show signs of the beginning of crystalline order, commonly termed cryptocrystalline or microcrystalline opal. Dehydration experiments and infrared spectroscopy have shown that most of the H2O in the formula of SiO2·nH2O of opals is present in the familiar form of clusters of molecular water. Isolated water molecules, and silanols, structures such as Si-O-H, generally form a lesser proportion of the total and can reside near the surface or in defects inside the opal. The structure of low-pressure polymorphs of anhydrous silica consist of frameworks of fully-corner bonded tetrahedra of SiO4. The higher temperature polymorphs of silica cristobalite and tridymite are frequently the first to crystallize from amorphous anhydrous silica, and the local structures of microcrystalline opals also appear to be closer to that of cristobalite and tridymite than to quartz. The structures of tridymite and cristobalite are closely related and can be described as hexagonal and cubic close-packed layers. It is therefore possible to have intermediate structures in which the layers are not regularly stacked. ## Microcrystalline opal Opal-CT has been interpreted as consisting of clusters of stacking of cristobalite and tridymite over very short length scales. The spheres of opal in opal-CT are themselves made up of tiny microcrystalline blades of cristobalite and tridymite. Opal-CT has occasionally been further subdivided in the literature. Water content may be as high as 10 wt%. Lussatite is a synonym. Opal-C is interpreted as consisting of localized order of \alpha-cristobalite with a lot of stacking disorder. Typical water content is about 1.5wt%. Lussatine is a synonym. ## Non-crystalline opal Two broad categories of non-crystalline opals, sometimes just referred to as opal-A, have been proposed Opal-AG: Aggregated spheres of silica, with water filling the space in between. Precious opal and potch opal are generally varieties of this, the difference being in the regularity of the sizes of the spheres and their packing. Opal-AN: Water-containing amorphous silica-glass. Hyalite is a synonym. Non-crystalline silica in siliceous sediments is reported to gradually transform to opal-CT and then opal-C as a result of diagenesis, due to the increasing overburden pressure in sedimentary rocks, as some of the stacking disorder is removed. # Historical superstitions In the Middle Ages, opal was considered a stone that could provide great luck because it was believed to possess all the virtues of each gemstone whose color was represented in the color spectrum of the opal. However, modern superstition attributes bad luck to the stone, though some believe this is avoided if opal is the owner's birthstone (that is, the owner was born in October) or if the stone is a gift. Even under the last czar at the beginning of the 20th century, it was believed that when a Russian of any sex, of any rank, saw an opal, amongst other goods offered for sale, he or she would not buy anything more, since, in the judgement of subjects of the tzar, the opal embodied the evil eye. It's possible that the stone's extreme fragility (when compared to other gemstones) has contributed to this bad reputation. # Opals in popular culture The opal is the official gemstone of South Australia, The Commonwealth of Australia and Nevada. Opal is the traditional birthstone of the month of October. # Famous opals - The Andamooka Opal, presented to Queen Elizabeth II, also known as the Queen's Opal - The Aurora Australis Opal, considered to be the most valuable black opal - The Black Prince Opal, originally known as Harlequin Prince - The Empress of Australia Opal - The Fire Queen Opal - The Flame Queen Opal - The Flamingo Opal - The Halley's Comet Opal, the world's largest uncut black opal - The Jupiter Five Opal - The Olympic Australis Opal, reported to be the largest and most valuable uncut gem opal ever found - The Pride of Australia Opal, also known as the Red Emperor Opal - The Red Admiral Opal, also known as the Butterfly Stone

Opal Template:Alternateuses Template:Infobox mineral Opal is a mineraloid gel which is deposited at a relatively low temperature and may occur in the fissures of almost any kind of rock, being most commonly found with limonite, sandstone, rhyolite, and basalt. The water content is usually between three and ten percent, but can be as high as 20%. Opal ranges from clear through white, gray, red, orange, yellow, green, shore, blue, magenta, rose, pink, slate, olive, brown, and black. Of these hues, the reds against black are the most rare and dear, whereas white and greens are the most common; these are a function of growth size into the red and infrared wavelengths—see precious opal. Common opal is truly amorphous, but precious opal does have a structural element. The word opal comes from the Latin opalus, by Greek opallios, and is from the same root as Sanskrit upálá[s] for "stone", originally a millstone with upárá[s] for slab.[1] (see Upal). Opals are also Australia's national gemstone. Opal is one of the mineraloids that can form or replace fossils. The resulting fossils, though not of any extra scientific interest, appeal to collectors. # Precious opal Precious opal shows a variable interplay of internal colors and does have an internal structure. At the micro scale precious opal is composed of silica spheres some 150 to 300 nm in diameter in a hexagonal or cubic closed-packed lattice. These ordered silica spheres produce the internal colors by causing the interference and diffraction of light passing through the microstructure of opal.[2] It is the regularity of the sizes of the spheres, and of the packing of these spheres that determines the quality of precious opal. Where the distance between the regularly packed planes of spheres is approximately half the wavelength of a component of visible light, the light of that wavelength may be subject to diffraction from the grating created by the stacked planes. The spacing between the planes and the orientation of planes with respect to the incident light determines the colors observed. The process can be described by Bragg's Law of diffraction. Visible light of diffracted wavelengths cannot pass through large thicknesses of the opal. This is the basis of the optical band gap in a photonic crystal, of which opal is the best known natural example. In addition, microfractures may be filled with secondary silica and form thin lamellae inside the opal during solidification. The term opalescence is commonly and erroneously used to describe this unique and beautiful phenomenon, which is correctly termed play of color. Contrarily, opalescence is correctly applied to the milky, turbid appearance of common or potch opal. Potch does not show a play of color. The veins of opal displaying the play of color are often quite thin, and this has given rise to unusual methods of preparing the stone as a gem.  An opal doublet is a thin layer of opal, backed by a swart mineral such as ironstone, basalt, or obsidian.  The darker backing emphasizes the play of color, and results in a more attractive display than a lighter potch. Combined with modern technique of polishing, doublet opal produces similar effect of black or boulder opals at a mere fraction of the price. Doublet opal also has the added benefit of having genuine opal as the top visible and touchable layer, unlike triplet opals. The triplet cut backs the colored material with a dark backing, and then has a domed cap of clear quartz (rock crystal) or plastic on top, which takes a high polish, and acts as a protective layer for the relatively fragile opal. The top layer also acts as a magniflier, to emphasis the play of colour of the opal beneath, which are often of a lower quality. Triplet opals therefore have a more artificial feel to it and are not classed as precious opal. # Common opal Besides the gemstone varieties that show a play of color, there are other kinds of common opal such as the milk opal, milky bluish to greenish (which can sometimes be of gemstone quality); resin opal, honey-yellow with a resinous luster; wood opal, caused by the replacement of the organic material in wood with opal[3]; menilite brown or grey; hyalite, a colorless glass-clear opal sometimes called Muller's Glass; geyserite, (siliceous sinter) deposited around hot springs or geysers; and diatomite or diatomaceous earth, the accumulations of diatom shells or tests. # Other varieties of opal Fire opal – Fire opals are transparent to translucent opals with warm body colors yellow, orange, orange-yellow or red and they do not show any play-of-color. The most famous source of fire opals is the state of Queretaro in Mexico and these opals are commonly called Mexican fire opals. Peruvian opal (also called blue opal) is a semi-opaque to opaque blue-green stone found in Peru which is often cut to include the matrix in the more opaque stones. It does not display pleochroism. # Sources of opal Australia produces around 97% of the world’s opal. 90% is called ‘light opal’ or white and crystal opal. White makes up 60% but not all the opal fields produce white opal; Crystal opal or pure hydrated silica makes up 30%; 8% is black and only 2% is boulder opal.[citation needed] The town of Coober Pedy in South Australia is a major source of opal. Andamooka in South Australia is also a major producer of matrix opal, crystal opal, and black opal. Another Australian town, Lightning Ridge in New South Wales, is the main source of black opal, opal containing a predominantly dark background (dark-gray to blue-black displaying the play of color). Boulder opal consists of concretions and fracture fillings in a dark siliceous ironstone matrix. It is found sporadically in western Queensland, from Kynuna in the north, to Yowah and Koroit in the south.[4] The Virgin Valley opal fields of Humboldt County in northern Nevada produce a wide variety of black, crystal, white, and fire opal. The fire opal mined from this locality is designated as the official gemstone of the State of Nevada. Most precious opals are wood replacements. Many specimens have a high water content, and as a result, have a greater tendency to desiccate and crack than most precious opal. The largest black opal in the Smithsonian Museum comes from the Royal Peacock opal mine in the Virgin Valley.[citation needed] Another source of white base opal in the United States is Spencer, Idaho. A high percentage of the opal found there occurs in thin layers. As a result, most of the production goes into the making of doublets and triplets. Other significant deposits of precious opal around the world can be found in the Czech Republic, Slovakia, Hungary, Turkey, Indonesia, Brazil, Honduras, Guatemala, Nicaragua and Ethiopia. In late 2008, NASA announced that it had discovered opal deposits on Mars.[5] # Synthetic opal As well as occurring naturally, opals of all varieties have been synthesized experimentally and commercially. The discovery of the ordered sphere structure of precious opal led to its synthesis by Pierre Gilson in 1974.[2] The resulting material is distinguishable from natural opal by its regularity; under magnification, the patches of color are seen to be arranged in a "lizard skin" or "chicken wire" pattern. Synthetics are further distinguished from naturals by the former's lack of fluorescence under UV light. Synthetics are also generally lower in density and are often highly porous; some may even stick to the tongue. Two notable producers of synthetic opal are the companies Kyocera and Inamori of Japan. Most so-called synthetics, however, are more correctly termed imitations, as they contain substances not found in natural opal (e.g., plastic stabilizers). The imitation opals seen in vintage jewellery are often "Slocum Stone" consisting of laminated glass with bits of foil interspersed. # Local atomic structure of opals The lattice of spheres of opal that cause the interference with light are several hundred times larger than the fundamental structure of crystalline silica. As a mineraloid, there is no unit cell that describes the structure of opal. Nevertheless, opals can be roughly divided into those that show no signs of crystalline order—i.e., amorphous opal—and those that show signs of the beginning of crystalline order, commonly termed cryptocrystalline or microcrystalline opal.[6] Dehydration experiments and infrared spectroscopy have shown that most of the H2O in the formula of SiO2·nH2O of opals is present in the familiar form of clusters of molecular water. Isolated water molecules, and silanols, structures such as Si-O-H, generally form a lesser proportion of the total and can reside near the surface or in defects inside the opal. The structure of low-pressure polymorphs of anhydrous silica consist of frameworks of fully-corner bonded tetrahedra of SiO4. The higher temperature polymorphs of silica cristobalite and tridymite are frequently the first to crystallize from amorphous anhydrous silica, and the local structures of microcrystalline opals also appear to be closer to that of cristobalite and tridymite than to quartz. The structures of tridymite and cristobalite are closely related and can be described as hexagonal and cubic close-packed layers. It is therefore possible to have intermediate structures in which the layers are not regularly stacked. ## Microcrystalline opal Opal-CT has been interpreted as consisting of clusters of stacking of cristobalite and tridymite over very short length scales. The spheres of opal in opal-CT are themselves made up of tiny microcrystalline blades of cristobalite and tridymite. Opal-CT has occasionally been further subdivided in the literature. Water content may be as high as 10 wt%. Lussatite is a synonym. Opal-C is interpreted as consisting of localized order of <math>\alpha</math>-cristobalite with a lot of stacking disorder. Typical water content is about 1.5wt%. Lussatine is a synonym. ## Non-crystalline opal Two broad categories of non-crystalline opals, sometimes just referred to as opal-A, have been proposed Opal-AG: Aggregated spheres of silica, with water filling the space in between. Precious opal and potch opal are generally varieties of this, the difference being in the regularity of the sizes of the spheres and their packing. Opal-AN: Water-containing amorphous silica-glass. Hyalite is a synonym. Non-crystalline silica in siliceous sediments is reported to gradually transform to opal-CT and then opal-C as a result of diagenesis, due to the increasing overburden pressure in sedimentary rocks, as some of the stacking disorder is removed.[7] # Historical superstitions In the Middle Ages, opal was considered a stone that could provide great luck because it was believed to possess all the virtues of each gemstone whose color was represented in the color spectrum of the opal.[8] However, modern superstition attributes bad luck to the stone, though some believe this is avoided if opal is the owner's birthstone (that is, the owner was born in October) or if the stone is a gift. Even under the last czar at the beginning of the 20th century, it was believed that when a Russian of any sex, of any rank, saw an opal, amongst other goods offered for sale, he or she would not buy anything more, since, in the judgement of subjects of the tzar, the opal embodied the evil eye.[8] It's possible that the stone's extreme fragility (when compared to other gemstones) has contributed to this bad reputation. # Opals in popular culture The opal is the official gemstone of South Australia, The Commonwealth of Australia and Nevada. Opal is the traditional birthstone of the month of October. # Famous opals - The Andamooka Opal, presented to Queen Elizabeth II, also known as the Queen's Opal - The Aurora Australis Opal, considered to be the most valuable black opal - The Black Prince Opal, originally known as Harlequin Prince - The Empress of Australia Opal - The Fire Queen Opal - The Flame Queen Opal - The Flamingo Opal - The Halley's Comet Opal, the world's largest uncut black opal - The Jupiter Five Opal - The Olympic Australis Opal, reported to be the largest and most valuable uncut gem opal ever found - The Pride of Australia Opal, also known as the Red Emperor Opal - The Red Admiral Opal, also known as the Butterfly Stone

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

def4a42f50faaad8ae2168e91d1bca3508bf1cd4

wikidoc

Osha

Osha Osha (Ligusticum porteri) is a perennial herb used for its medicinal properties. Osha grows in parts of the Rocky Mountains especially in the North American Southwest. L. porteri (Osha) root or L. wallichii (Ligusticum) root can be steeped in ethanol (whisky, vodka, etc.) for at least a month. The resulting tincture is an effective, albeit pungent, liniment for sore muscles that can be stored (in a cool place) indefinitely. # Synonymy Osha is also known by the following names: - Osha root, Porter's Lovage, Porter's Licorice-root, Lovage, Wild Lovage, Porter's Wild Lovage, Loveroot, Porter's Ligusticum, Bear Medicine, Bear Root, Colorado Cough Root, Indian Root, Indian Parsley, Wild Parsley, Mountain Ginseng, Mountain Carrot, Nipo, Empress Of The Dark Forest, Chuchupate, Chuchupati, Chuchupaste, Chuchupatle, Guariaca, Hierba del cochino, Raíz del cochino, Washía (tarahumara), Yerba de cochino In the Jicarilla language, osha is called ha’ich’idéé. The White Mountain Apache (WMA)call it '"Ha 'il chii' gah". Osha is still commonly used widely by the Apaches and other native tribes. According to WMA Elders, they would use it as a snake and insect repellant:It has a strong smell. Apaches use this herb to aid in the curing of common colds, sore throats, cough, sinusitis, and other side effects of the winter season. It is said that when put in water over your woodstove, it will help in keeping you immune in winter times.

Osha Osha (Ligusticum porteri) is a perennial herb used for its medicinal properties. Osha grows in parts of the Rocky Mountains especially in the North American Southwest. L. porteri (Osha) root or L. wallichii (Ligusticum) root can be steeped in ethanol (whisky, vodka, etc.) for at least a month. The resulting tincture is an effective, albeit pungent, liniment for sore muscles that can be stored (in a cool place) indefinitely. # Synonymy Osha is also known by the following names: - Osha root, Porter's Lovage, Porter's Licorice-root, Lovage, Wild Lovage, Porter's Wild Lovage, Loveroot, Porter's Ligusticum, Bear Medicine, Bear Root, Colorado Cough Root, Indian Root, Indian Parsley, Wild Parsley, Mountain Ginseng, Mountain Carrot, Nipo, Empress Of The Dark Forest, Chuchupate, Chuchupati, Chuchupaste, Chuchupatle, Guariaca, Hierba del cochino, Raíz del cochino, Washía (tarahumara), Yerba de cochino In the Jicarilla language, osha is called ha’ich’idéé. The White Mountain Apache (WMA)call it '"Ha 'il chii' gah". Osha is still commonly used widely by the Apaches and other native tribes. According to WMA Elders, they would use it as a snake and insect repellant:It has a strong smell. Apaches use this herb to aid in the curing of common colds, sore throats, cough, sinusitis, and other side effects of the winter season. It is said that when put in water over your woodstove, it will help in keeping you immune in winter times. # External links - USDA page - Research to Determine Osha’s Economic Potential as a Sustainable Agricultural Crop - Ligusticum porteri Cult et Rose Template:Apiales-stub Template:WikiDoc Sources

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

abcdad4282fce824ba64d0a833cfadae951c7351

wikidoc

P4HB

P4HB Protein disulfide-isomerase, also known as the beta-subunit of prolyl 4-hydroxylase (P4HB), is an enzyme that in humans encoded by the P4HB gene. The human P4HB gene is localized in chromosome 17q25. Unlike other prolyl 4-hydroxylase family proteins, this protein is multifunctional and acts as an oxidoreductase for disulfide formation, breakage, and isomerization. The activity of P4HB is tightly regulated. Both dimer dissociation and substrate binding are likely to enhance its enzymatic activity during the catalysis process. # Structure P4HB has four thioredoxin domains (a, b, b’, and a’), with two CGHC active sites in the a and a’ domains. In both the reduced and oxidized state, these domains are arranged as a horseshoe shape. In reduced P4HB, domains a, b, and b' are in the same plane, while domain a' twists out at an ∼45° angle. When oxidized, the four domains stay in the same plane, and the distance between the active sites is larger than that in the reduced state. The oxidized form also exposes more hydrophobic areas and possesses a larger cleft to facilitate substrate binding. P4HB has been shown to dimerize in vivo via noncatalytic bb' domains. Formation of dimer blocks substrate-binding site and inhibits P4HB’s activity. # Function This gene encodes the beta subunit of prolyl 4-hydroxylase, a highly abundant multifunctional enzyme that belongs to the protein disulfide isomerase family. When present as a tetramer consisting of two alpha and two beta subunits, this enzyme is involved in hydroxylation of prolyl residues in preprocollagen. This enzyme is also a disulfide isomerase containing two thioredoxin domains that catalyze the formation, breakage and rearrangement of disulfide bonds. Other known functions include its ability to act as a chaperone that inhibits aggregation of misfolded proteins in a concentration-dependent manner, its ability to bind thyroid hormone, its role in both the influx and efflux of S-nitrosothiol-bound nitric oxide, and its function as a subunit of the microsomal triglyceride transfer protein complex. # Clinical significance P4HB is a risk factor of amyotrophic lateral sclerosis (ALS). Studies have shown significant genotypic associations for two SNPs in P4HB with FALS (familial ALS), rs876016 (P=0.0198) and rs2070872 (P=0.0046). Together with other ER stress markers, P4HB is greatly elevated in ALS spinal cord. P4HB can also be nitrosylated, and elevation of nitrosylated P4HB has been shown in Parkinson's and Alzheimer's disease brain tissue, as well as in transgenic mutant superoxide dismutase 1 mouse and human sporadic amyotrophic lateral sclerosis spinal cord tissues. In addition to neurodegenerative diseases, P4HB level is upregulated in glioblastoma multiforme (GBM) (brain tumor). Inhibition of P4HB attenuates resistance to temozolomide, a standard GBM chemotherapeutic agent, via the PERK arm of endoplasmic reticulum stress response pathway. Furthermore, heterozygous missense mutation in P4HB can cause Cole-Carpenter syndrome, a severe bone fragility disorder. # Interactions P4HB has been shown to interact with UBQLN1, ERO1LB and ERO1L.

P4HB Protein disulfide-isomerase, also known as the beta-subunit of prolyl 4-hydroxylase (P4HB), is an enzyme that in humans encoded by the P4HB gene. The human P4HB gene is localized in chromosome 17q25.[1][2][3][4] Unlike other prolyl 4-hydroxylase family proteins, this protein is multifunctional and acts as an oxidoreductase for disulfide formation, breakage, and isomerization.[5] The activity of P4HB is tightly regulated. Both dimer dissociation and substrate binding are likely to enhance its enzymatic activity during the catalysis process.[6][7] # Structure P4HB has four thioredoxin domains (a, b, b’, and a’), with two CGHC active sites in the a and a’ domains. In both the reduced and oxidized state, these domains are arranged as a horseshoe shape. In reduced P4HB, domains a, b, and b' are in the same plane, while domain a' twists out at an ∼45° angle. When oxidized, the four domains stay in the same plane, and the distance between the active sites is larger than that in the reduced state. The oxidized form also exposes more hydrophobic areas and possesses a larger cleft to facilitate substrate binding.[8][9] P4HB has been shown to dimerize in vivo via noncatalytic bb' domains. Formation of dimer blocks substrate-binding site and inhibits P4HB’s activity.[10] # Function This gene encodes the beta subunit of prolyl 4-hydroxylase, a highly abundant multifunctional enzyme that belongs to the protein disulfide isomerase family. When present as a tetramer consisting of two alpha and two beta subunits, this enzyme is involved in hydroxylation of prolyl residues in preprocollagen. This enzyme is also a disulfide isomerase containing two thioredoxin domains that catalyze the formation, breakage and rearrangement of disulfide bonds. Other known functions include its ability to act as a chaperone that inhibits aggregation of misfolded proteins in a concentration-dependent manner, its ability to bind thyroid hormone, its role in both the influx and efflux of S-nitrosothiol-bound nitric oxide, and its function as a subunit of the microsomal triglyceride transfer protein complex.[2] # Clinical significance P4HB is a risk factor of amyotrophic lateral sclerosis (ALS). Studies have shown significant genotypic associations for two SNPs in P4HB with FALS (familial ALS), rs876016 (P=0.0198) and rs2070872 (P=0.0046). Together with other ER stress markers, P4HB is greatly elevated in ALS spinal cord.[11] P4HB can also be nitrosylated, and elevation of nitrosylated P4HB has been shown in Parkinson's and Alzheimer's disease brain tissue, as well as in transgenic mutant superoxide dismutase 1 mouse and human sporadic amyotrophic lateral sclerosis spinal cord tissues.[12][13] In addition to neurodegenerative diseases, P4HB level is upregulated in glioblastoma multiforme (GBM) (brain tumor). Inhibition of P4HB attenuates resistance to temozolomide, a standard GBM chemotherapeutic agent, via the PERK arm of endoplasmic reticulum stress response pathway.[14] Furthermore, heterozygous missense mutation in P4HB can cause Cole-Carpenter syndrome, a severe bone fragility disorder.[15] # Interactions P4HB has been shown to interact with UBQLN1,[16] ERO1LB[17][18] and ERO1L.[17][18]

https://www.wikidoc.org/index.php/P4HB

f26735e3863cacc192dfb12c71abb41eb7fedbf7

wikidoc

PAG1

PAG1 Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 is a protein that in humans is encoded by the PAG1 gene. The protein encoded by this gene is a type III transmembrane adaptor protein that binds to the tyrosine kinase csk protein. It is thought to be involved in the regulation of T cell activation. # Interactions PAG1 has been shown to interact with FYN, C-src tyrosine kinase, Sodium-hydrogen antiporter 3 regulator 1 and Abl gene.

PAG1 Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 is a protein that in humans is encoded by the PAG1 gene.[1][2] The protein encoded by this gene is a type III transmembrane adaptor protein that binds to the tyrosine kinase csk protein. It is thought to be involved in the regulation of T cell activation.[2] # Interactions PAG1 has been shown to interact with FYN,[1] C-src tyrosine kinase,[1] Sodium-hydrogen antiporter 3 regulator 1[3] and Abl gene.[4]

https://www.wikidoc.org/index.php/PAG1

56d062b12e8d64e4ad10deab298e23b7d8032000

wikidoc

PAK1

PAK1 Serine/threonine-protein kinase PAK 1 is an enzyme that in humans is encoded by the PAK1 gene. PAK1 is one of six members of the PAK family of serine/threonine kinases which are broadly divided into group I (PAK1, PAK2 and PAK3) and group II (PAK4, PAK6 and PAK5/7). The PAKs are evolutionarily conserved. PAK1 localizes in distinct sub-cellular domains in the cytoplasm and nucleus. PAK1 regulates cytoskeleton remodeling, phenotypic signaling and gene expression, and affects a wide variety of cellular processes such as directional motility, invasion, metastasis, growth, cell cycle progression, angiogenesis. PAK1-signaling dependent cellular functions regulate both physiologic and disease processes, including cancer, as PAK1 is widely overexpressed and hyperstimulated in human cancer, at-large. # Discovery PAK1 was first discovered as an effector of the Rho GTPases in rat brain by Manser and colleagues in 1994. The human PAK1 was identified as a GTP-dependent interacting partner of Rac1 or Cdc42 in the cytosolic fraction from neutrophils, and its complementary DNA was cloned from a human placenta library by Martin and Colleagues in 1995. # Function PAK proteins are critical effectors that link the Rho family of GTPases (Rho GTPases) to cytoskeleton reorganization and nuclear signaling. PAK proteins, a family of serine/threonine p21-activated kinases, include PAK1, PAK2, PAK3 and PAK4. These proteins serve as targets for the small GTP binding proteins Cdc42 and Rac and have been implicated in a wide range of biological activities. PAK1 regulates cell motility and morphology. Alternative transcripts of this gene have been found, but their full-length natures have not been determined. Stimulation of PAK1 activity is accompanied by a series of cellular processes that are fundamental to living systems. Being a nodular signaling molecule, PAK1 operates to converging station of a large number of signals triggered by proteins on the cell surface as well as upstream activators, and translates into specific phenotypes. At the biochemical level, these activities are regulated by the ability of PAK1 to phosphorylate its effector interacting substrates, which in-turn set-up a cascade of biochemical events cumulating into a cellular phenotypic response. In addition, PAK1 action is also influenced by its scaffolding activity. Examples of PAK1-regulated cellular processes include dynamic of actin and microtubule fibers, critical steps during cell cycle progression, motility and invasion, redox and energy metabolism, cell survival, angiogenesis, DNA-repair, hormone sensitivity, and gene expression. Functional implications of the PAK1 signaling are exemplified by its role in oncogenesis, viral pathogenesis, cardiovascular dysregulation, and neurological disorders. # Gene and spliced variants The human PAK1 gene is 153-kb long and consists of 23 exons, six exons for 5’-UTR and 17 exons for protein coding (Gene from review). Alternative splicing of six exons generates 20 transcripts from 308-bp to 3.7-kb long; however, only 12 spliced transcripts have open reading frames and are predicted to code ten proteins and two polypeptides. The remaining 8 transcripts range are for non-coding long RNAs from 308-bp to 863-bp long. Unlike the human PAK1, murine PAK1 gene generates five transcripts: three protein-coding from 508-bp to 3.0-kb long, and two transcripts of about 900-bp for non-coding RNAs. # Protein domains The core domains of the PAK family include a kinase domain in the C-terminal region, a p21-binding domain (PBD), and an auto-inhibitory domain (AID) in group I PAKs. Group I PAKs exist in an inactive, closed homodimer conformation wherein AID of one molecule binds to the kinase domain of another molecule, and activated in both GTPase-dependent and -independent manners. # Activation/inhibition PAK1 contains an autoinhibitory domain that suppresses the catalytic activity of its kinase domain. PAK1 activators relieve this autoinhibition and initiate conformational rearrangements and autoPhosphorylation events leading to kinase activation. IPA-3 inhibits PAK1. Preactivated PAK1 is resistant to IPA-3. Inhibition in live cells supports a critical role for PAK in PDGF-stimulated ERK activation. Reversible covalent binding of IPA-3 to the PAK1 regulatory domain prevents GTPase docking and the subsequent switch to a catalytically active state. PAK1 knockdown in prostate cancer cells is associated with reduced motility, reduced MMP9 secretion and increased TGFβ expression, which in these cases, is growth inhibitory. However, IPA-3's pharmacokinetic properties as well as undesirable redox effects in cells, due to the continuous reduction of the sulfhydryl moiety, make it unsuitable for clinical development. ## Upstream activators PAK1 activity is stimulated by a large number of upstream activators and signals, ranging from EGF, heregulin-beta 1, VEGF, basic fibroblast growth factor, platelet-derived growth factor, estrogen, lysophosphatidic acid, phosphoinositides, ETK, AKT, JAK2, ERK, casein kinase II, Rac3, chemokine (C-X-C motif) ligand 1, breast cancer anti-estrogen resistance 3, Kaposi's sarcoma-associated herpesvirus-G protein-coupled receptor, ARG-binding protein 2γ, hepatitis B virus X protein, STE20-related kinase adaptor protein α, RhoI, Klotho, N-acetylglucosaminyl transferase V, B-Raf proto-oncogene, casein kinase 2-interacting protein 1, and filamin A. ## Downstream effector targets Functions of PAK1 are regulated by its ability to phosphorylate downstream effector substrates, scaffold activity, redistribution to distinct sub-cellular cellular sub-domains, stimulation or repression of expression of its genomic targets either directly or indirectly, or by all of these mechanisms. Representative PAK1 effector substrates in cancer cells include: Stathmin-S16, Merlin-S518, Vimentin-S25-S38-S50-S65-S72, Histone H3-S10, FilaminA-S2152, Estrogen receptor-alpha-S305, signal transducer and activator of transcription 5a-S779, C-terminal binding protein 1-S158, Raf1-S338, Arpc1b-T21, DLC1-S88, phosphoglucomutase 1-T466, SMART/HDAC1-associated repressor protein-S3486-T3568, Tubulin Cofactor B-S65-S128, Snail-S246 vascular endothelial-cadherin-S665, poly(RC) binding protein 1-T60-S246, integrin-linked kinase 1-T173-S246, epithelium-specific Ets transcription factor 1-S207, ErbB3 binding protein 1-T261, nuclear receptor-interacting factor 3-S28, SRC3-delta4-T56-S659-676, beta-catenin-S675, BAD-S111, BAD-S112,S136, MEK1-S298, CRKII-S41, MORC family CW-type zinc finger 2-S739, Paxillin-S258, and Paxillin-S273. ## Genomic targets PAK1 and/or PAK1-dependent signals modulate the expression of its genomic targets, including, vascular endothelial growth factor, Cyclin D1, phosphofructokinase-muscle isoform, nuclear factor of activated T-cell, Cyclin B1, Tissue Factor and tissue factor pathway inhibitor, Metalloproteinase 9, and fibronectin. # Interactions PAK1 has been shown to interact with: - ARHGEF2, - ARPC1B, - BMX, - C-Raf, - CDC42, - Cyclin-dependent kinase 5, - DYNLL1, - LIMK1, - NCK1, - PAK1IP1 and - RAC1. # Notes

PAK1 Serine/threonine-protein kinase PAK 1 is an enzyme that in humans is encoded by the PAK1 gene.[1][2] PAK1 is one of six members of the PAK family of serine/threonine kinases which are broadly divided into group I (PAK1, PAK2 and PAK3) and group II (PAK4, PAK6 and PAK5/7).[3][4] The PAKs are evolutionarily conserved.[5] PAK1 localizes in distinct sub-cellular domains in the cytoplasm and nucleus.[6] PAK1 regulates cytoskeleton remodeling, phenotypic signaling and gene expression, and affects a wide variety of cellular processes such as directional motility, invasion, metastasis, growth, cell cycle progression, angiogenesis.[6][7] PAK1-signaling dependent cellular functions regulate both physiologic and disease processes, including cancer, as PAK1 is widely overexpressed and hyperstimulated in human cancer, at-large.[6][8][9] # Discovery PAK1 was first discovered as an effector of the Rho GTPases in rat brain by Manser and colleagues in 1994.[3] The human PAK1 was identified as a GTP-dependent interacting partner of Rac1 or Cdc42 in the cytosolic fraction from neutrophils, and its complementary DNA was cloned from a human placenta library by Martin and Colleagues in 1995.[4] # Function PAK proteins are critical effectors that link the Rho family of GTPases (Rho GTPases) to cytoskeleton reorganization and nuclear signaling. PAK proteins, a family of serine/threonine p21-activated kinases, include PAK1, PAK2, PAK3 and PAK4. These proteins serve as targets for the small GTP binding proteins Cdc42 and Rac and have been implicated in a wide range of biological activities. PAK1 regulates cell motility and morphology. Alternative transcripts of this gene have been found, but their full-length natures have not been determined.[10] Stimulation of PAK1 activity is accompanied by a series of cellular processes that are fundamental to living systems. Being a nodular signaling molecule, PAK1 operates to converging station of a large number of signals triggered by proteins on the cell surface as well as upstream activators, and translates into specific phenotypes. At the biochemical level, these activities are regulated by the ability of PAK1 to phosphorylate its effector interacting substrates, which in-turn set-up a cascade of biochemical events cumulating into a cellular phenotypic response. In addition, PAK1 action is also influenced by its scaffolding activity. Examples of PAK1-regulated cellular processes include dynamic of actin and microtubule fibers, critical steps during cell cycle progression, motility and invasion, redox and energy metabolism, cell survival, angiogenesis, DNA-repair, hormone sensitivity, and gene expression. Functional implications of the PAK1 signaling are exemplified by its role in oncogenesis,[5] viral pathogenesis,[11][12] cardiovascular dysregulation,[13] and neurological disorders.[14] # Gene and spliced variants The human PAK1 gene is 153-kb long and consists of 23 exons, six exons for 5’-UTR and 17 exons for protein coding (Gene from review). Alternative splicing of six exons generates 20 transcripts from 308-bp to 3.7-kb long; however, only 12 spliced transcripts have open reading frames and are predicted to code ten proteins and two polypeptides. The remaining 8 transcripts range are for non-coding long RNAs from 308-bp to 863-bp long. Unlike the human PAK1, murine PAK1 gene generates five transcripts: three protein-coding from 508-bp to 3.0-kb long, and two transcripts of about 900-bp for non-coding RNAs. # Protein domains The core domains of the PAK family include a kinase domain in the C-terminal region, a p21-binding domain (PBD), and an auto-inhibitory domain (AID) in group I PAKs. Group I PAKs exist in an inactive, closed homodimer conformation wherein AID of one molecule binds to the kinase domain of another molecule, and activated in both GTPase-dependent and -independent manners.[9] # Activation/inhibition PAK1 contains an autoinhibitory domain that suppresses the catalytic activity of its kinase domain. PAK1 activators relieve this autoinhibition and initiate conformational rearrangements and autoPhosphorylation events leading to kinase activation. IPA-3 inhibits PAK1. Preactivated PAK1 is resistant to IPA-3. Inhibition in live cells supports a critical role for PAK in PDGF-stimulated ERK activation.[15] Reversible covalent binding of IPA-3 to the PAK1 regulatory domain prevents GTPase docking and the subsequent switch to a catalytically active state.[16] PAK1 knockdown in prostate cancer cells is associated with reduced motility, reduced MMP9 secretion and increased TGFβ expression, which in these cases, is growth inhibitory. However, IPA-3's pharmacokinetic properties as well as undesirable redox effects in cells, due to the continuous reduction of the sulfhydryl moiety, make it unsuitable for clinical development.[16] ## Upstream activators PAK1 activity is stimulated by a large number of upstream activators and signals, ranging from EGF,[17] heregulin-beta 1,[18] VEGF,[19] basic fibroblast growth factor,[20] platelet-derived growth factor,[21] estrogen,[22] lysophosphatidic acid,[23] phosphoinositides,[24] ETK,[25] AKT,[26] JAK2,[27] ERK,[28] casein kinase II,[29] Rac3,[30] chemokine (C-X-C motif) ligand 1,[31] breast cancer anti-estrogen resistance 3,[32] Kaposi's sarcoma-associated herpesvirus-G protein-coupled receptor,[33] ARG-binding protein 2γ,[34] hepatitis B virus X protein,[35] STE20-related kinase adaptor protein α,[36] RhoI,[37] Klotho,[38] N-acetylglucosaminyl transferase V,[39] B-Raf proto-oncogene,[40] casein kinase 2-interacting protein 1,[41] and filamin A.[42] ## Downstream effector targets Functions of PAK1 are regulated by its ability to phosphorylate downstream effector substrates, scaffold activity, redistribution to distinct sub-cellular cellular sub-domains, stimulation or repression of expression of its genomic targets either directly or indirectly, or by all of these mechanisms. Representative PAK1 effector substrates in cancer cells include: Stathmin-S16,[43] Merlin-S518,[44] Vimentin-S25-S38-S50-S65-S72,[45] Histone H3-S10,[46] FilaminA-S2152,[42] Estrogen receptor-alpha-S305,[47] signal transducer and activator of transcription 5a-S779,[48] C-terminal binding protein 1-S158,[49] Raf1-S338,[50] Arpc1b-T21,[51] DLC1-S88,[52] phosphoglucomutase 1-T466,[53] SMART/HDAC1-associated repressor protein-S3486-T3568,[54] Tubulin Cofactor B-S65-S128,[55] Snail-S246 [56] vascular endothelial-cadherin-S665,[57] poly(RC) binding protein 1-T60-S246,[58] integrin-linked kinase 1-T173-S246,[59] epithelium-specific Ets transcription factor 1-S207,[60] ErbB3 binding protein 1-T261,[61] nuclear receptor-interacting factor 3-S28,[62] SRC3-delta4-T56-S659-676,[63] beta-catenin-S675,[64] BAD-S111,[65] BAD-S112,S136,[66] MEK1-S298,[67][68] CRKII-S41,[69] MORC family CW-type zinc finger 2-S739,[70][71] Paxillin-S258,[11] and Paxillin-S273.[72] ## Genomic targets PAK1 and/or PAK1-dependent signals modulate the expression of its genomic targets,[5] including, vascular endothelial growth factor,[19] Cyclin D1,[73] phosphofructokinase-muscle isoform,[74] nuclear factor of activated T-cell,[74] Cyclin B1,[75] Tissue Factor and tissue factor pathway inhibitor,[76] Metalloproteinase 9,[77] and fibronectin.[78] # Interactions PAK1 has been shown to interact with: - ARHGEF2,[79] - ARPC1B,[80] - BMX,[25] - C-Raf,[81] - CDC42,[82][83] - Cyclin-dependent kinase 5,[84] - DYNLL1,[52] - LIMK1,[85] - NCK1,[86][87][88] - PAK1IP1[89] and - RAC1.[90][82][83] # Notes

https://www.wikidoc.org/index.php/PAK1

bae2e8a1cfd86974e6f4decea64451250800de3d

wikidoc

PAK2

PAK2 Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the PAK2 gene. PAK2 is one of three members of Group I PAK family of serine/threonine kinases. The PAKs are evolutionary conserved. PAK2 and its cleaved fragment localize in both the cytoplasmic or nuclear compartments. PAK2 signaling modulates apoptosis, endothelial lumen formation, viral pathogenesis, and cancer including, breast, hepatocarcinoma, and gastric and cancer, at-large. # Discovery The human PAK2 was identified as a downstream effector of Rac or Cdc42. # Gene and spliced variants The PAK2 gene is about 92.7-kb long. The gene contains 15 exons and generates three alternatively spliced transcripts - two of which code proteins of 524 amino acids and 221 amino acids, while the third one is a 371-bp non-coding RNA transcript(Gene from review) There are two transcripts generated from the murine PAK2 gene, a 5.7-kb transcript coding a 524 amino acids long polypeptide and a 1.2-kb long non-coding RNA transcript. # Protein domains Similar to PAK1, PAK2 contains a p21-binding domain (PBD) and an auto-inhibitory domain (AID) and exists in an inactive conformation. The p21 activated kinases (PAK) are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. The PAK proteins are a family of serine/threonine kinases that serve as targets for the small GTP binding proteins, CDC42 and RAC1, and have been implicated in a wide range of biological activities. The protein encoded by this gene is activated by proteolytic cleavage during caspase-mediated apoptosis, and may play a role in regulating the apoptotic events in the dying cell. # Function The p21 activated kinases (PAK) are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. The PAK proteins are a family of serine/threonine kinases that serve as targets for the small GTP binding proteins, CDC42 and RAC1, and have been implicated in a wide range of biological activities. The protein encoded by this gene is activated by proteolytic cleavage during caspase-mediated apoptosis, and may play a role in regulating the apoptotic events in the dying cell. # Upstream activators PAK2 kinase activity is stimulated by transforming growth factor β in fibroblasts, by proteinase inhibitor alpha2-macroglobulin binding to GRP78 in prostate cancer cells, by its phosphorylation by AMP-activated protein kinase in stem and cancer cells and eryptosis. PAK2 is cleaved through activated caspase-3 in fibroblast and cancer cells exposed to ultraviolet, hyperosmotic shock, and ionizing radiation. # Inhibitors The levels of PAK2 activation in experimental systems are inhibited by synthetic PAK-inhibitors and miRs. For example, FRAX1036 differentially inhibits PAK2 and PAK1 activities; FRAX597 suppresses PAK2 activity in neurofibromatosis type 2 (NF2)-associated tumorigenesis; and miR-23b and miR-137 inhibits PAK2 expression in tumor cells. Insulin stimulation of neuronal cells also antagonizes PAK2 kinase activity, leading to an increased glucose uptake. # Downstream targets PAK2-mediated phosphorylation of merlin at S518 modulates its tumor suppressor activity, c-Jun phosphorylation at T2, T8, T89, T93 and T286 contributes to the growth of growth factor-stimulated melanoma cells, Caspase-7 phosphorylation at S30, T173 and S239 inhibits apoptotic activity in breast cancer cells, Paxillin phosphorylation at S272 and S274 activates ADAM10 protease, and STAT5 phosphorylation at S779 modulates BCL-ABL-mediated leukemogenesis. PAK2 activity negatively regulates the function and expression of c-Myc: PAK2 phosphorylation of c-Myc at T358-S373-T400 inhibits its transactivation function and PAK2 depletion stimulates c-Myc expression during granulocyte-monocyte lineage. # Notes

PAK2 Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the PAK2 gene.[1][2] PAK2 is one of three members of Group I PAK family of serine/threonine kinases.[3][4] The PAKs are evolutionary conserved.[5] PAK2 and its cleaved fragment localize in both the cytoplasmic or nuclear compartments. PAK2 signaling modulates apoptosis,[6] endothelial lumen formation,[7] viral pathogenesis,[8] and cancer including, breast,[9] hepatocarcinoma,[10] and gastric [11] and cancer, at-large.[12] # Discovery The human PAK2 was identified as a downstream effector of Rac or Cdc42.[3][4] # Gene and spliced variants The PAK2 gene is about 92.7-kb long. The gene contains 15 exons and generates three alternatively spliced transcripts - two of which code proteins of 524 amino acids and 221 amino acids, while the third one is a 371-bp non-coding RNA transcript(Gene from review) There are two transcripts generated from the murine PAK2 gene, a 5.7-kb transcript coding a 524 amino acids long polypeptide and a 1.2-kb long non-coding RNA transcript. # Protein domains Similar to PAK1, PAK2 contains a p21-binding domain (PBD) and an auto-inhibitory domain (AID) and exists in an inactive conformation.[12] The p21 activated kinases (PAK) are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. The PAK proteins are a family of serine/threonine kinases that serve as targets for the small GTP binding proteins, CDC42 and RAC1, and have been implicated in a wide range of biological activities. The protein encoded by this gene is activated by proteolytic cleavage during caspase-mediated apoptosis, and may play a role in regulating the apoptotic events in the dying cell.[13] # Function The p21 activated kinases (PAK) are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. The PAK proteins are a family of serine/threonine kinases that serve as targets for the small GTP binding proteins, CDC42 and RAC1, and have been implicated in a wide range of biological activities. The protein encoded by this gene is activated by proteolytic cleavage during caspase-mediated apoptosis, and may play a role in regulating the apoptotic events in the dying cell.[14] # Upstream activators PAK2 kinase activity is stimulated by transforming growth factor β in fibroblasts,[15] by proteinase inhibitor alpha2-macroglobulin binding to GRP78 in prostate cancer cells,[16] by its phosphorylation by AMP-activated protein kinase in stem and cancer cells [17] and eryptosis.[18] PAK2 is cleaved through activated caspase-3 in fibroblast and cancer cells exposed to ultraviolet,[19] hyperosmotic shock,[20] and ionizing radiation.[21] # Inhibitors The levels of PAK2 activation in experimental systems are inhibited by synthetic PAK-inhibitors and miRs. For example, FRAX1036 differentially inhibits PAK2 and PAK1 activities;[22] FRAX597 suppresses PAK2 activity in neurofibromatosis type 2 (NF2)-associated tumorigenesis;[23] and miR-23b and miR-137 inhibits PAK2 expression in tumor cells.[24][25] Insulin stimulation of neuronal cells also antagonizes PAK2 kinase activity, leading to an increased glucose uptake.[26] # Downstream targets PAK2-mediated phosphorylation of merlin at S518 modulates its tumor suppressor activity,[27] c-Jun phosphorylation at T2, T8, T89, T93 and T286 contributes to the growth of growth factor-stimulated melanoma cells,[28] Caspase-7 phosphorylation at S30, T173 and S239 inhibits apoptotic activity in breast cancer cells,[9] Paxillin phosphorylation at S272 and S274 activates ADAM10 protease,[29] and STAT5 phosphorylation at S779 modulates BCL-ABL-mediated leukemogenesis.[30] PAK2 activity negatively regulates the function and expression of c-Myc: PAK2 phosphorylation of c-Myc at T358-S373-T400 inhibits its transactivation function [31] and PAK2 depletion stimulates c-Myc expression during granulocyte-monocyte lineage.[32] # Notes

https://www.wikidoc.org/index.php/PAK2

eadc9b5a7074354014355274caa83caea43fe511

wikidoc

PAK3

PAK3 PAK3 (p21-activated kinase 2, beta-PAK) is one of three members of Group I PAK family of evolutionary conserved serine/threonine kinases. PAK3 is preferentially expressed in neuronal cells and involved in synapse formation and plasticity and mental retardation. # Discovery PAK3 was initially cloned from a murine fibroblast cDNA library and from a murine embryo cDNA library. Like other group I PAKs, PAK3 is stimulated by activated Cdc42 and Rac1. # Gene and spliced variants The human PAK3 gene, the longest group I family member, is 283-kb long. The PAK3 gene is composed of 22 exons of which 6 exons are for 5’-UTR and generates 13 alternative spliced transcripts. Among PAK3 transcripts, 11 transcripts are for coding proteins ranging from 181- to 580-amino acids long, while remaining two transcripts are non-coding RNAs. The murine PAK3 gene contains 10 transcripts, coding six proteins from 544 amino acids and 559 amino acids long, and four smaller polypeptides from 23 to 366 amino acids. # Protein domains Similar to PAK1, PAK2 contains a p21-binding domain (PBD) and an auto-inhibitory domain (AID) and exists in an inactive conformation. # Activators and inhibitors PAK3 activity is stimulated by Dbl, Cdc42 and Cool-2, and by AP1 transcription factor. Stimulation of PAK3 activity by upstream stimulators such as Dbl or Cdc42 is inhibited by p50 (Cool-1) PAK3 activity is inhibited by FRAX597, a PAN inhibitor of PAKs. # Functions PAK3 is overexpressed in neuroendocrine/carcinoids tumors. PAK3 has been shown to be important for synapse formation and plasticity, and contribute to mental retardation. Further, a point mutation in PAK3 gene has been associated with nonsyndromic X-linked mental retardation. # Notes

PAK3 PAK3 (p21-activated kinase 2, beta-PAK) is one of three members of Group I PAK family of evolutionary conserved serine/threonine kinases.[1][2][3] PAK3 is preferentially expressed in neuronal cells [4][5] and involved in synapse formation and plasticity and mental retardation.[6][7] # Discovery PAK3 was initially cloned from a murine fibroblast cDNA library and from a murine embryo cDNA library.[4][5] Like other group I PAKs, PAK3 is stimulated by activated Cdc42 and Rac1. # Gene and spliced variants The human PAK3 gene, the longest group I family member, is 283-kb long. The PAK3 gene is composed of 22 exons of which 6 exons are for 5’-UTR and generates 13 alternative spliced transcripts. Among PAK3 transcripts, 11 transcripts are for coding proteins ranging from 181- to 580-amino acids long, while remaining two transcripts are non-coding RNAs.[8] The murine PAK3 gene contains 10 transcripts, coding six proteins from 544 amino acids and 559 amino acids long, and four smaller polypeptides from 23 to 366 amino acids. # Protein domains Similar to PAK1, PAK2 contains a p21-binding domain (PBD) and an auto-inhibitory domain (AID) and exists in an inactive conformation.[9] # Activators and inhibitors PAK3 activity is stimulated by Dbl, Cdc42 and Cool-2,[10][11] and by AP1 transcription factor.[12] Stimulation of PAK3 activity by upstream stimulators such as Dbl or Cdc42 is inhibited by p50 (Cool-1)[11] PAK3 activity is inhibited by FRAX597, a PAN inhibitor of PAKs.[13] # Functions PAK3 is overexpressed in neuroendocrine/carcinoids tumors.[14] PAK3 has been shown to be important for synapse formation and plasticity, and contribute to mental retardation.[6] Further, a point mutation in PAK3 gene has been associated with nonsyndromic X-linked mental retardation.[7] # Notes

https://www.wikidoc.org/index.php/PAK3

a8a769508dc937bf73ac27612a7a4b5d5eb7c18a

wikidoc

PAK4

PAK4 Serine/threonine-protein kinase PAK 4 is an enzyme that in humans is encoded by the PAK4 gene. PAK4 is one of six members of the PAK family of serine/threonine kinases which are divided into group I (PAK1, PAK2 and PAK3) and group II (PAK4, PAK6 and PAK5/7). PAK4 localizes in sub-cellular domains of the cytoplasm and nucleus. PAK4 regulates cytoskeleton remodeling, phenotypic signaling and gene expression, and affects directional motility, invasion, metastasis, and growth. Similar to PAK1, PAK4-signaling dependent cellular functions also regulate both physiologic and disease processes such as cancer as PAK4 is overexpressed and/or hyperstimulated in human cancer, at-large. # Discovery PAK4, the founding member of Group II PAK member, was cloned and identified by Minden A. and colleagues in 1998 using a PCR-based strategy from a cDNA library prepared from Jurkett cells. # Gene and spliced variants The group II PAKs have less coding exons compared with group I PAKs, highlights the potential structural and functional differences between two group of PAKs. The human PAK4 is about 57-kb in length with 13 exons. The PAK4 generates 12 transcripts of which 10 coding transcripts are predicted to code proteins of about 438 to 591 amino acids long, while remaining two transcripts are non-coding in nature. In contrast to human PAK4, murine PAK4 contains four transcripts - two coding for 593 amino acids long polypeptides and two are non-coding RNA transcripts. # Protein domains The core domains of PAK4 include, a kinase domain in the C-terminal region, a p21-binding domain (PBD), and a newly defined auto-inhibitory domain (AID) or an AID-like pseudosubstrate sequence (PS) domain. # Regulation PAK4 activity is stimulated by upstream activators and signals, including by HGF, PKD, PKA, CDK5RAP3, and SH3RF2. In addition to other mechanisms, PAK4 functions are mediated though phosphorylation of its effector proteins, including, LIMK1-Thr508, integrin β5-Ser759/Ser762, p120-catenin-Ser288, superior cervical ganglia 10 (SCG10)-Ser50, GEF-H1-Ser810 β-catenin-Ser675, and Smad2-Ser465. PAK4 and/or PAK4-dependent signals also modulate the expression of genomic targets, including MT1-MMP and p57Kip2. # Inhibitors The PAK4 activity and expression has been shown to be inhibited by chemical inhibitors such as PF-3758309, LCH-7749944, glaucarubinone, KY-04031, KY-04045, 1-phenanthryl-tetrahydroisoquinoline derivatives, (-)-β-hydrastine, Inka1, GL-1196, GNE-2861, and microRNAs such as miR-145, miR-433, and miR-126. # Function PAK proteins, a family of serine/threonine p21-activating kinases, include PAK1, PAK2, PAK3 and PAK4. PAK proteins are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. They serve as targets for the small GTP binding proteins Cdc42 and Rac and have been implicated in a wide range of biological activities. PAK4 interacts specifically with the GTP-bound form of Cdc42Hs and weakly activates the JNK family of MAP kinases. PAK4 is a mediator of filopodia formation and may play a role in the reorganization of the actin cytoskeleton. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. PAK4 has been shown to be repressed at translational level by miR-24. PAK4 regulates cellular processes by its scaffolding activity and/or by phosphorylation of effector substrates, which in-turn, set-up a cascades of biochemical events cumulating into a cellular phenotypic response. Examples of PAK4-regulated cellular processes include, dynamic reorganization of actin, and microtubule fibers, anchorage-independent growth, filopodium formation, and cell motility - ITGB5, cell survival embryonic development, supports stem cell-like phenotypes, and gene expression. Modulation of PAK4 signaling has been shown to lead to significant functional implications in a number of disease conditions, exemplified by oncogenesis, cancer cell invasion and metastasis. # Interactions PAK4 has been shown to interact with: - CDC42, - ITGB5, and - LIMK1. # Notes

PAK4 Serine/threonine-protein kinase PAK 4 is an enzyme that in humans is encoded by the PAK4 gene.[1][2][3] PAK4 is one of six members of the PAK family of serine/threonine kinases which are divided into group I (PAK1, PAK2 and PAK3) and group II (PAK4, PAK6 and PAK5/7).[4][5] PAK4 localizes in sub-cellular domains of the cytoplasm and nucleus.[4][6][7] PAK4 regulates cytoskeleton remodeling, phenotypic signaling and gene expression, and affects directional motility, invasion, metastasis, and growth.[8] Similar to PAK1, PAK4-signaling dependent cellular functions also regulate both physiologic and disease processes such as cancer as PAK4 is overexpressed and/or hyperstimulated in human cancer, at-large.[9][10] # Discovery PAK4, the founding member of Group II PAK member, was cloned and identified by Minden A. and colleagues in 1998 using a PCR-based strategy from a cDNA library prepared from Jurkett cells.[4] # Gene and spliced variants The group II PAKs have less coding exons compared with group I PAKs, highlights the potential structural and functional differences between two group of PAKs. The human PAK4 is about 57-kb in length with 13 exons. The PAK4 generates 12 transcripts of which 10 coding transcripts are predicted to code proteins of about 438 to 591 amino acids long, while remaining two transcripts are non-coding in nature. In contrast to human PAK4, murine PAK4 contains four transcripts - two coding for 593 amino acids long polypeptides and two are non-coding RNA transcripts. # Protein domains The core domains of PAK4 include, a kinase domain in the C-terminal region, a p21-binding domain (PBD), and a newly defined auto-inhibitory domain (AID) [11] or an AID-like pseudosubstrate sequence (PS) domain.[12] # Regulation PAK4 activity is stimulated by upstream activators and signals, including by HGF,[13] PKD,[14][15] PKA,[16] CDK5RAP3,[17] and SH3RF2.[18] In addition to other mechanisms, PAK4 functions are mediated though phosphorylation of its effector proteins, including, LIMK1-Thr508,[19] integrin β5-Ser759/Ser762,[20] p120-catenin-Ser288,[21] superior cervical ganglia 10 (SCG10)-Ser50,[22] GEF-H1-Ser810[7][23] β-catenin-Ser675,[6] and Smad2-Ser465.[24] PAK4 and/or PAK4-dependent signals also modulate the expression of genomic targets, including MT1-MMP[25] and p57Kip2.[26] # Inhibitors The PAK4 activity and expression has been shown to be inhibited by chemical inhibitors such as PF-3758309,[27] LCH-7749944,[28] glaucarubinone,[29] KY-04031,[30] KY-04045,[31] 1-phenanthryl-tetrahydroisoquinoline derivatives,[32] (-)-β-hydrastine,[33] Inka1,[34] GL-1196,[35] GNE-2861,[36] and microRNAs such as miR-145,[37] miR-433,[38] and miR-126.[39] # Function PAK proteins, a family of serine/threonine p21-activating kinases, include PAK1, PAK2, PAK3 and PAK4. PAK proteins are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. They serve as targets for the small GTP binding proteins Cdc42 and Rac and have been implicated in a wide range of biological activities. PAK4 interacts specifically with the GTP-bound form of Cdc42Hs and weakly activates the JNK family of MAP kinases. PAK4 is a mediator of filopodia formation and may play a role in the reorganization of the actin cytoskeleton. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[3] PAK4 has been shown to be repressed at translational level by miR-24.[40] PAK4 regulates cellular processes by its scaffolding activity and/or by phosphorylation of effector substrates, which in-turn, set-up a cascades of biochemical events cumulating into a cellular phenotypic response. Examples of PAK4-regulated cellular processes include, dynamic reorganization of actin,[19] and microtubule fibers,[22] anchorage-independent growth,[41] filopodium formation,[4] and cell motility</ref> - ITGB5,[42] cell survival[43] embryonic development,[44] supports stem cell-like phenotypes,[45] and gene expression.[6] Modulation of PAK4 signaling has been shown to lead to significant functional implications in a number of disease conditions, exemplified by oncogenesis,[24] cancer cell invasion and metastasis.[22][46] # Interactions PAK4 has been shown to interact with: - CDC42,[1][47][48] - ITGB5,[42] and - LIMK1.[49] # Notes

https://www.wikidoc.org/index.php/PAK4

7c7263788183d64437ce5a6867fbfb3e983e1529

wikidoc

PAK5

PAK5 Serine/threonine-protein kinase PAK 5 is an enzyme that in humans is encoded by the PAK5 gene. The PAK5 enzyme is one of three members of Group II PAK family of serine/threonine kinases, and evolutionary conserved across species. # Discovery The PAK5 was initially cloned as a brain-specific kinase with a predominant expression in brain with a suggested role in neurite growth in neuronal cells. Selectivity of PAK5 signaling was recognized by its ability to stimulate the JNK kinase but not p38 or ERK kinases. # Gene and spliced variants The PAK5 gene, the longest among the PAK family, contains a total of 12 exons of which four exons are for 5’-UTR and remaining 8 exons for protein coding(Gene from review). Alternative exon splicing of the PAK5 gene generates three transcripts, and one of the transcript encodes a 719 amino acids long protein(Gene from review). The exon splicing of the murine PAK5 gene generates three transcripts, two of which code an identical 719 amino acids long polypeptide while the 2.0-kb transcript is a non-coding RNA with retained intron. # Protein domains Similar to PAK4, PAK5 consists of a kinase, a CDC42/Rac1 interactive binding (CRIB) motif. # Function The protein encoded by this gene is a member of the PAK family of Ser/Thr protein kinases. PAK family members are known to be effectors of Rac/Cdc42 GTPases, which have been implicated in the regulation of cytoskeletal dynamics, proliferation, and cell survival signaling. This kinase contains a CDC42/Rac1 interactive binding (CRIB) motif, and has been shown to bind CDC42 in the presence of GTP. This kinase is predominantly expressed in brain. It is capable of promoting neurite outgrowth, and thus may play a role in neurite development. This kinase is associated with microtubule networks and induces microtubule stabilization. The subcellular localization of this kinase is tightly regulated during cell cycle progression. Alternatively spliced transcript variants encoding the same protein have been described. Genetic deletion of PAK5 with or without PAK6 deletion in mice has been shown to be associated with a defective locomotion, memory, and learning. PAK5 is co-expressed with DISC1, a psychosis risk gene, and the pathway is likely to be involved in modulating synapse plasticity. Physiological level of PAK5 is linked with an overall physical activity in mice as PAK5 deletion in mice has been shown to be associated with an increased activity upon amphetamine stimulation. PAK5 has been also thought to be one of genetic variants regulating gene expression (eQTL) and its expression associates with an inhibited glucose-regulated secretion of insulin in INS1 cells. # Upstream regulators PAK5 expression is positively regulated by Aurora-A and both PAK5 and Aurora-A are co-upregulated in esophageal squamous carcinoma. The levels of PAK5 are regulated by miR-129 in hepatocacinoma cancer cells, and by the binding of the long non-coding RNA Colorectal neoplasia differentially expressed (CRNDE) to miR-186 in glioma cells. # Downstream targets PAK5 phosphorylates Pacsin-1 and Synaptojanin-1 and regulates synaptic vesicle trafficking. PAK5-mediated phosphorylation of GATA1 at S161 and S187 contributes to Epithelial-mesenchymal transition. PAK5 phosphorylation of p120-catenin at S288 plays a role in cytoskeleton remodeling. In addition to the cytoplasm, the PAK5 also localizes in mitochondria and phosphorylates BAD at S112. PAK5 inhibits the MARK2/Par1 activity and modulates microtubules dynamics. # Clinical significance PAK5 levels are upregulated in osteosarcoma, hepatocellular carcinomas, gastric cancer, glioma, esophageal squamous cell cancer, colon cancer, ovarian cancer, and breast cancer. There are also examples of gain-of-function activating PAK5 mutations in non-small-cell lung cancer lung cancer. PAK5 promotes the cell survival and sensitivity of cancer cells to chemotherapy. # Notes

PAK5 Serine/threonine-protein kinase PAK 5 is an enzyme that in humans is encoded by the PAK5 gene.[1][2][3] The PAK5 enzyme is one of three members of Group II PAK family of serine/threonine kinases,[4][5] and evolutionary conserved across species.[6] # Discovery The PAK5 was initially cloned as a brain-specific kinase with a predominant expression in brain with a suggested role in neurite growth in neuronal cells.[4][5] Selectivity of PAK5 signaling was recognized by its ability to stimulate the JNK kinase but not p38 or ERK kinases.[5] # Gene and spliced variants The PAK5 gene, the longest among the PAK family, contains a total of 12 exons of which four exons are for 5’-UTR and remaining 8 exons for protein coding(Gene from review). Alternative exon splicing of the PAK5 gene generates three transcripts, and one of the transcript encodes a 719 amino acids long protein(Gene from review). The exon splicing of the murine PAK5 gene generates three transcripts, two of which code an identical 719 amino acids long polypeptide while the 2.0-kb transcript is a non-coding RNA with retained intron. # Protein domains Similar to PAK4, PAK5 consists of a kinase, a CDC42/Rac1 interactive binding (CRIB) motif.[7] # Function The protein encoded by this gene is a member of the PAK family of Ser/Thr protein kinases. PAK family members are known to be effectors of Rac/Cdc42 GTPases, which have been implicated in the regulation of cytoskeletal dynamics, proliferation, and cell survival signaling. This kinase contains a CDC42/Rac1 interactive binding (CRIB) motif, and has been shown to bind CDC42 in the presence of GTP. This kinase is predominantly expressed in brain. It is capable of promoting neurite outgrowth, and thus may play a role in neurite development. This kinase is associated with microtubule networks and induces microtubule stabilization. The subcellular localization of this kinase is tightly regulated during cell cycle progression. Alternatively spliced transcript variants encoding the same protein have been described.[3] Genetic deletion of PAK5 with or without PAK6 deletion in mice has been shown to be associated with a defective locomotion, memory, and learning.[8][9] PAK5 is co-expressed with DISC1, a psychosis risk gene, and the pathway is likely to be involved in modulating synapse plasticity.[10] Physiological level of PAK5 is linked with an overall physical activity in mice as PAK5 deletion in mice has been shown to be associated with an increased activity upon amphetamine stimulation.[11] PAK5 has been also thought to be one of genetic variants regulating gene expression (eQTL) and its expression associates with an inhibited glucose-regulated secretion of insulin in INS1 cells.[12] # Upstream regulators PAK5 expression is positively regulated by Aurora-A and both PAK5 and Aurora-A are co-upregulated in esophageal squamous carcinoma.[13] The levels of PAK5 are regulated by miR-129 in hepatocacinoma cancer cells,[14] and by the binding of the long non-coding RNA Colorectal neoplasia differentially expressed (CRNDE) to miR-186 in glioma cells.[15] # Downstream targets PAK5 phosphorylates Pacsin-1 and Synaptojanin-1 and regulates synaptic vesicle trafficking.[16] PAK5-mediated phosphorylation of GATA1 at S161 and S187 contributes to Epithelial-mesenchymal transition.[17] PAK5 phosphorylation of p120-catenin at S288 plays a role in cytoskeleton remodeling.[18] In addition to the cytoplasm, the PAK5 also localizes in mitochondria and phosphorylates BAD at S112.[19] PAK5 inhibits the MARK2/Par1 activity and modulates microtubules dynamics.[20] # Clinical significance PAK5 levels are upregulated in osteosarcoma,[21] hepatocellular carcinomas,[22] gastric cancer,[23] glioma,[24] esophageal squamous cell cancer,[25] colon cancer,[26] ovarian cancer,[27] and breast cancer.[28] There are also examples of gain-of-function activating PAK5 mutations in non-small-cell lung cancer lung cancer.[29] PAK5 promotes the cell survival and sensitivity of cancer cells to chemotherapy.[13][27][30][31] # Notes

https://www.wikidoc.org/index.php/PAK5

10a32b20b4a504648afcb4bc8ff9a58f13795725

wikidoc

PAK6

PAK6 Serine/threonine-protein kinase PAK 6 is an enzyme that in humans is encoded by the PAK6 gene. PAK6 belongs to the Group II PAK family members. Like other family members, PAK6 is also evolutionary conserved across species. # Discovery The PAK6 was originally cloned as an androgen receptor interacting kinase which can be stimulated by androgen receptor but not Rac or Cdc42, like other family members. # Gene and spliced variants The human PAK6 gene consists of 16 exons of which 8 exons are used for 5’-UTR splicing to generating 17 transcripts by alternative splicing, and the gene is about 38-kb long. Among PAK6 transcripts, 14 are protein coding RNAs to code four proteins of 681 and 636 amino acids while remaining PAK6 transcripts are non-coding RNAs. There are five transcripts in murine PAK6 gene, of which two transcripts are protein coding and other two non-coding RNAs(Gene from review). # Protein domains Following the general structural organization of the group II PAKs, PAK6 also contains a kinase, and a GTPase interacting domain. # Function This gene encodes a protein that shares a high degree of sequence similarity with p21-activated kinase (PAK) family members. The proteins of this family are Rac/Cdc42-associated Ste20-like Ser/Thr protein kinases, characterized by a highly conserved amino-terminal Cdc42/Rac interactive binding (CRIB) domain and a carboxyl-terminal kinase domain. PAK kinases are implicated in the regulation of a number of cellular processes, including cytoskeleton rearrangement, apoptosis and the MAP kinase signaling pathway. The protein encoded by this gene was found to interact with androgen receptor (AR), which is a steroid hormone-dependent transcription factor that is important for male sexual differentiation and development. The p21-activated protein kinase 6 gene was found to be highly expressed in testis and prostate tissues and the encoded protein was shown to cotranslocate into the nucleus with AR in response to androgen. Genetic deletion of PAK6 alone in mice leads to increased body mass. However, PAK6 deletion along with PAK5 impairs the ability of animals to learn and move. PAK6 expression is increased in a rat model of spinal cord injury. PAK6 is also considered a candidate gene for epileptic encephalopathy, and interacts with Parkinson associated gene product leucine-rich repeat kinase 2. PAK6 expression has been found to be overexpressed in prostate cancer, hepatocellular carcinoma, and colon cancer. PAK6 levels have been correlated well with therapeutic resistance to 5-flurouracil, docetaxel, and radiation. # Regulators and interactors PAK6 kinase activity is positively regulated by androgen receptor, p38MAPK, 5-fluorouracil and atypical Rho family GTPase Chp/RhoV. PAK6 expression is negatively regulated by miR-328, miR-429 and miR-23a. PAK6 interacts with junctional protein IQGAP1, E3 ligase Mdm2, and leucine-rich repeat kinase 2 (LRRK2). # Interactions PAK6 has been shown to interact with Androgen receptor. # Notes

PAK6 Serine/threonine-protein kinase PAK 6 is an enzyme that in humans is encoded by the PAK6 gene.[1][2] PAK6 belongs to the Group II PAK family members.[3] Like other family members, PAK6 is also evolutionary conserved across species.[4] # Discovery The PAK6 was originally cloned as an androgen receptor interacting kinase which can be stimulated by androgen receptor but not Rac or Cdc42, like other family members.[3] # Gene and spliced variants The human PAK6 gene consists of 16 exons of which 8 exons are used for 5’-UTR splicing to generating 17 transcripts by alternative splicing, and the gene is about 38-kb long. Among PAK6 transcripts, 14 are protein coding RNAs to code four proteins of 681 and 636 amino acids while remaining PAK6 transcripts are non-coding RNAs. There are five transcripts in murine PAK6 gene, of which two transcripts are protein coding and other two non-coding RNAs(Gene from review). # Protein domains Following the general structural organization of the group II PAKs, PAK6 also contains a kinase, and a GTPase interacting domain.[5][6] # Function This gene encodes a protein that shares a high degree of sequence similarity with p21-activated kinase (PAK) family members. The proteins of this family are Rac/Cdc42-associated Ste20-like Ser/Thr protein kinases, characterized by a highly conserved amino-terminal Cdc42/Rac interactive binding (CRIB) domain and a carboxyl-terminal kinase domain. PAK kinases are implicated in the regulation of a number of cellular processes, including cytoskeleton rearrangement, apoptosis and the MAP kinase signaling pathway. The protein encoded by this gene was found to interact with androgen receptor (AR), which is a steroid hormone-dependent transcription factor that is important for male sexual differentiation and development. The p21-activated protein kinase 6 gene was found to be highly expressed in testis and prostate tissues and the encoded protein was shown to cotranslocate into the nucleus with AR in response to androgen.[2] Genetic deletion of PAK6 alone in mice leads to increased body mass.[7] However, PAK6 deletion along with PAK5 impairs the ability of animals to learn and move.[7][8] PAK6 expression is increased in a rat model of spinal cord injury.[9] PAK6 is also considered a candidate gene for epileptic encephalopathy,[10] and interacts with Parkinson associated gene product leucine-rich repeat kinase 2.[11] PAK6 expression has been found to be overexpressed in prostate cancer,[12][13] hepatocellular carcinoma,[14] and colon cancer.[15] PAK6 levels have been correlated well with therapeutic resistance to 5-flurouracil,[15] docetaxel,[13] and radiation.[16] # Regulators and interactors PAK6 kinase activity is positively regulated by androgen receptor,[3][17] p38MAPK,[18] 5-fluorouracil[15] and atypical Rho family GTPase Chp/RhoV.[19] PAK6 expression is negatively regulated by miR-328, miR-429 and miR-23a.[20][21][22] PAK6 interacts with junctional protein IQGAP1,[23][24] E3 ligase Mdm2,[25] and leucine-rich repeat kinase 2 (LRRK2).[11] # Interactions PAK6 has been shown to interact with Androgen receptor.[1][3] # Notes

https://www.wikidoc.org/index.php/PAK6

5741a0d4c16926b92ed55144a4565b6d9694a2ec

wikidoc

PAPB

PAPB Polyaminopropyl biguanide (PAPB) is a preservative used in cleaning solutions for contact lenses. U.S. Pat. No. 4,758,595 to Ogunbiyi et al. discloses a contact-lens solution containing a Polyaminopropyl biguanide (PAPB), also known as polyhexamethylene biguanide (PHMB) or Polyhexanide, in combination with a borate buffer. These disinfecting and preservative solutions are claimed to have a broad spectrum of bactericidal and fungicidal activity at low concentrations coupled with very low toxicity when used with soft-type contact lenses. Some of the most popular products for disinfecting lenses are multipurpose solutions that can be used to clean, disinfect and wet contact lenses, followed by direct insertion (placement on the eye) without rinsing. Such a solution must be particularly gentle to the eye, because some of the solution will be on the lens when inserted and will come into contact with the eye.

PAPB Polyaminopropyl biguanide (PAPB) is a preservative used in cleaning solutions for contact lenses. U.S. Pat. No. 4,758,595 to Ogunbiyi et al. discloses a contact-lens solution containing a Polyaminopropyl biguanide (PAPB), also known as polyhexamethylene biguanide (PHMB) or Polyhexanide, in combination with a borate buffer. These disinfecting and preservative solutions are claimed to have a broad spectrum of bactericidal and fungicidal activity at low concentrations coupled with very low toxicity when used with soft-type contact lenses. Some of the most popular products for disinfecting lenses are multipurpose solutions that can be used to clean, disinfect and wet contact lenses, followed by direct insertion (placement on the eye) without rinsing. Such a solution must be particularly gentle to the eye, because some of the solution will be on the lens when inserted and will come into contact with the eye.

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

2ed108c3b75aef29722c07aab2c33359fa1e73a8

wikidoc

PARL

PARL Presenilins-associated rhomboid-like protein, mitochondrial also known as mitochondrial intramembrane cleaving protease PARL is an inner mitochondrial membrane protein that in humans is encoded by the PARL gene on chromosome 3. It is a member of the rhomboid family of intramembrane serine proteases. This protein is involved in signal transduction and apoptosis, as well as neurodegenerative diseases and type 2 diabetes. # Structure Rhomboid family members share a conserved core of six transmembrane helices (TMHs), with the Ser and His residues required to form the catalytic dyad embedded in TMH-4 and TMH-6, respectively. This dyad is found deep below the membrane surface, which indicates that the hydrolysis of peptide bonds occurs within the hydrophobic phospholipid bilayer membrane. As a member of the Parl subfamily, PARL has an additional N-terminal TMH which may form a loop to the catalytic core. # Function This gene encodes a mitochondrial integral membrane protein. Following proteolytic processing of this protein, a small peptide (P-beta) is formed and translocated to the nucleus. This gene may be involved in signal transduction via regulated intramembrane proteolysis of membrane-tethered precursor proteins. Variation in this gene has been associated with increased risk for type 2 diabetes. Alternative splicing results in multiple transcript variants encoding different isoforms. Additionally, PARL is involved in apoptosis through its interactions with the mitochondrial GTPase optic atrophy 1 (OPA1) and the Bcl-2 family-related protein HAX1. OPA1 mainly regulates mitochondrial fusion in the mitochondrial inner membrane, but after proteolytic cleavage by PARL, its short, soluble form contributes to inhibiting apoptosis by slowing down cytochrome c release, and thus, proapoptotic signaling. Alternatively, PARL can inhibit apoptosis by coordinating with HAX1 to activate HtrA2 protease, thus preventing the accumulation of the proapoptotic Bax. # Clinical significance It has been shown that the p.S77N presenilin-associated rhomboid-like protein mutation is not a frequent cause of early-onset Parkinson’s disease. Variation in presenilins-associated rhomboid-like protein (PSARL) sequence and/or expression may be an important new risk factor for type 2 diabetes and other components of the metabolic syndrome. Mutations in PARL may also be involved in Leber hereditary optic neuropathy by disrupting normal function of the mitochondria, thus promoting retinal ganglion cell death and neurodegeneration. # Interactions PARL has been shown to interact with: - PINK1, - OPA1, and - HAX1.

PARL Presenilins-associated rhomboid-like protein, mitochondrial also known as mitochondrial intramembrane cleaving protease PARL is an inner mitochondrial membrane protein that in humans is encoded by the PARL gene on chromosome 3.[1] It is a member of the rhomboid family of intramembrane serine proteases.[2] This protein is involved in signal transduction and apoptosis, as well as neurodegenerative diseases and type 2 diabetes.[1][3] # Structure Rhomboid family members share a conserved core of six transmembrane helices (TMHs), with the Ser and His residues required to form the catalytic dyad embedded in TMH-4 and TMH-6, respectively. This dyad is found deep below the membrane surface, which indicates that the hydrolysis of peptide bonds occurs within the hydrophobic phospholipid bilayer membrane. As a member of the Parl subfamily, PARL has an additional N-terminal TMH which may form a loop to the catalytic core. [4] # Function This gene encodes a mitochondrial integral membrane protein. Following proteolytic processing of this protein, a small peptide (P-beta) is formed and translocated to the nucleus. This gene may be involved in signal transduction via regulated intramembrane proteolysis of membrane-tethered precursor proteins. Variation in this gene has been associated with increased risk for type 2 diabetes. Alternative splicing results in multiple transcript variants encoding different isoforms.[1] Additionally, PARL is involved in apoptosis through its interactions with the mitochondrial GTPase optic atrophy 1 (OPA1) and the Bcl-2 family-related protein HAX1. OPA1 mainly regulates mitochondrial fusion in the mitochondrial inner membrane, but after proteolytic cleavage by PARL, its short, soluble form contributes to inhibiting apoptosis by slowing down cytochrome c release, and thus, proapoptotic signaling. Alternatively, PARL can inhibit apoptosis by coordinating with HAX1 to activate HtrA2 protease, thus preventing the accumulation of the proapoptotic Bax.[3] # Clinical significance It has been shown that the p.S77N presenilin-associated rhomboid-like protein mutation is not a frequent cause of early-onset Parkinson’s disease.[5] Variation in presenilins-associated rhomboid-like protein (PSARL) sequence and/or expression may be an important new risk factor for type 2 diabetes and other components of the metabolic syndrome.[6] Mutations in PARL may also be involved in Leber hereditary optic neuropathy by disrupting normal function of the mitochondria, thus promoting retinal ganglion cell death and neurodegeneration.[3] # Interactions PARL has been shown to interact with: - PINK1,[7] - OPA1,[3] and - HAX1.[3]

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

7957cd5059010feda9fac4a0eb819509d3218984

wikidoc

PAWR

PAWR PRKC, apoptosis, WT1, regulator, also known as PAWR or Prostate apoptosis response-4 (Par-4), is a human gene coding for a tumor-suppressor protein that induces apoptosis in cancer cells, but not in normal cells. # Function The tumor suppressor WT1 represses and activates transcription. The protein encoded by this gene is a WT1-interacting protein that itself functions as a transcriptional repressor. It contains a putative leucine zipper domain which interacts with the zinc finger DNA binding domain of WT1. This protein is specifically upregulated during apoptosis of prostate cells. The active domain of the Par-4 protein has been found to confer cancer resistance in transgenic mice without compromising normal viability or aging, and may have therapeutic significance. # Interactions PAWR has been shown to interact with: - Apoptosis antagonizing transcription factor, - DAPK3, - Protein kinase Mζ, - SLC5A1, - THAP1, and - WT1.

PAWR PRKC, apoptosis, WT1, regulator, also known as PAWR or Prostate apoptosis response-4 (Par-4), is a human gene coding for a tumor-suppressor protein that induces apoptosis in cancer cells, but not in normal cells. # Function The tumor suppressor WT1 represses and activates transcription. The protein encoded by this gene is a WT1-interacting protein that itself functions as a transcriptional repressor. It contains a putative leucine zipper domain which interacts with the zinc finger DNA binding domain of WT1. This protein is specifically upregulated during apoptosis of prostate cells.[1] The active domain of the Par-4 protein has been found to confer cancer resistance in transgenic mice without compromising normal viability or aging, and may have therapeutic significance.[2] # Interactions PAWR has been shown to interact with: - Apoptosis antagonizing transcription factor,[3] - DAPK3,[4] - Protein kinase Mζ,[5] - SLC5A1,[6] - THAP1,[7] and - WT1.[8]

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

2ff0e2dfa3ab304f2ec5b883e2c5fc898714a707

wikidoc

PAX2

PAX2 Paired box gene 2, also known as PAX2 is a protein which in humans is encoded by the PAX2 gene. # Function The Pax Genes, or Paired-Box Containing Genes, play important roles in the development and proliferation of multiple cell lines, development of organs, and development and organization of the central nervous system. The transcription factor gene Pax2 is important in the regionalized embryological development of the central nervous system. In mammals, the brain is developed in three regions: the forebrain, midbrain, and the hindbrain. Concentration gradients of fibroblast growth factor 8 (FGF8) and Wingless-Type MMTV Integration Site Family, Member 1 (Wnt1) control expression of Pax2 during development of the Mesencephalon, or midbrain. Similar patterning during embryological development can be observed in “basal chordates or ascidians,” in which organization of the central nervous system in ascidian larvae are also controlled by fibroblast growth factor genes. The Pax2 gene encodes for the transcription factor which appears to be essential in the organization of the midbrain and hindbrain regions, and at the earliest can be detected on either side of the sulcus limitans, which separates motor and sensory nerve nuclei. PAX2 encodes paired box gene 2, one of many human homologues of the Drosophila melanogaster gene prd. The central feature of this transcription factor gene family is the conserved DNA-binding paired box domain. PAX2 is believed to be a target of transcriptional suppression by the tumor suppressor gene WT1. Pax 2 is a transcription factor controlled by the signaling molecules Wnt1 and Fgf8. Pax2 along with other transcription factors Pax5, Pax8, En1, and En 2 are expressed across the Otx2-Gbx2 boundary in the mid-hindbrain region. These transcription factors work with the signaling molecules Wnt1 and Fgf8 to maintain the MHB organizer. The MHB controls midbrain and cerebellum development. Pax2 is the earliest known gene to be expressed across the Otx2-Gbx2 boundary. It is first expressed in the late primitive streak stage and is expressed in a narrow ring centered at the MHB during somitogenesis. Transgene expression of the mid-hindbrain and developing kidney is directed by Pax2. There are three distinct MHB-specific enhancers in the upstream region of Pax2. Expression at the MHB from the four-somite stage onwards is directed by the two late enhancers in the proximal and distal regions of Pax2. The early enhancer located in the intermediate region activates the mid-hindbrain region of late gastrula embryos. The activation of Pax2, Pax5, and Pax8 is a conserved feature of all vertebrates. # Clinical significance Pathologically, Pax2 has been demonstrated to activate hepatocyte growth factor (HGF) gene promoter, and both have been indicated as playing a role in human prostate cancers. Mutations within PAX2 have been shown to result in optic nerve colobomas and renal hypoplasia. Alternative splicing of this gene results in multiple transcript variants. Pax2 and Pax8 are also necessary for the formation of the pronephros and subsequent kidney structures. Pax2 and Pax8 regulate the expression of Gata3. Without these genes mutations in the urogenital system arise. Pax2 misexpression is frequently observed in proliferative disorders of the kidney. For example, Pax2 is highly expressed in polycystic kidney disease (PKD), Wilms' tumor (WT), and renal cell carcinoma (RCC). Pax2 expression in these diseases appears fuel cell cycling, inhibit cell death, and confer resistance to chemotherapy. Due to its role in these diseases, Pax2 is an attractive therapeutic target and a number of methods for inhibiting its activity have been investigated. In fact, a small-molecule was recently identified with the ability to disrupt Pax2 mediated transcription by blocking Pax2 from binding to DNA. # Interactions PAX2 has been shown to interact with PAXIP1.

PAX2 Paired box gene 2, also known as PAX2 is a protein which in humans is encoded by the PAX2 gene.[1][2] # Function The Pax Genes, or Paired-Box Containing Genes, play important roles in the development and proliferation of multiple cell lines, development of organs, and development and organization of the central nervous system.[3] The transcription factor gene Pax2 is important in the regionalized embryological development of the central nervous system. In mammals, the brain is developed in three regions: the forebrain, midbrain, and the hindbrain.[4] Concentration gradients of fibroblast growth factor 8 (FGF8) and Wingless-Type MMTV Integration Site Family, Member 1 (Wnt1) control expression of Pax2 during development of the Mesencephalon, or midbrain.[5] Similar patterning during embryological development can be observed in “basal chordates or ascidians,” in which organization of the central nervous system in ascidian larvae are also controlled by fibroblast growth factor genes.[4] The Pax2 gene encodes for the transcription factor which appears to be essential in the organization of the midbrain and hindbrain regions, and at the earliest can be detected on either side of the sulcus limitans, which separates motor and sensory nerve nuclei.[3][6] PAX2 encodes paired box gene 2, one of many human homologues of the Drosophila melanogaster gene prd. The central feature of this transcription factor gene family is the conserved DNA-binding paired box domain. PAX2 is believed to be a target of transcriptional suppression by the tumor suppressor gene WT1. Pax 2 is a transcription factor controlled by the signaling molecules Wnt1 and Fgf8. Pax2 along with other transcription factors Pax5, Pax8, En1, and En 2 are expressed across the Otx2-Gbx2 boundary in the mid-hindbrain region. These transcription factors work with the signaling molecules Wnt1 and Fgf8 to maintain the MHB organizer. The MHB controls midbrain and cerebellum development. Pax2 is the earliest known gene to be expressed across the Otx2-Gbx2 boundary. It is first expressed in the late primitive streak stage and is expressed in a narrow ring centered at the MHB during somitogenesis. Transgene expression of the mid-hindbrain and developing kidney is directed by Pax2. There are three distinct MHB-specific enhancers in the upstream region of Pax2. Expression at the MHB from the four-somite stage onwards is directed by the two late enhancers in the proximal and distal regions of Pax2. The early enhancer located in the intermediate region activates the mid-hindbrain region of late gastrula embryos. The activation of Pax2, Pax5, and Pax8 is a conserved feature of all vertebrates. # Clinical significance Pathologically, Pax2 has been demonstrated to activate hepatocyte growth factor (HGF) gene promoter, and both have been indicated as playing a role in human prostate cancers.[7] Mutations within PAX2 have been shown to result in optic nerve colobomas and renal hypoplasia. Alternative splicing of this gene results in multiple transcript variants.[8] Pax2 and Pax8 are also necessary for the formation of the pronephros and subsequent kidney structures. Pax2 and Pax8 regulate the expression of Gata3. Without these genes mutations in the urogenital system arise. Pax2 misexpression is frequently observed in proliferative disorders of the kidney. For example, Pax2 is highly expressed in polycystic kidney disease (PKD), Wilms' tumor (WT), and renal cell carcinoma (RCC).[9] Pax2 expression in these diseases appears fuel cell cycling, inhibit cell death, and confer resistance to chemotherapy.[9] Due to its role in these diseases, Pax2 is an attractive therapeutic target and a number of methods for inhibiting its activity have been investigated. In fact, a small-molecule was recently identified with the ability to disrupt Pax2 mediated transcription by blocking Pax2 from binding to DNA.[10] [11] # Interactions PAX2 has been shown to interact with PAXIP1.[12]

https://www.wikidoc.org/index.php/PAX2

7c8b202f6ecb26da44908872c491463e4118b806

wikidoc

PAX3

PAX3 The PAX3 (paired box gene 3) gene encodes a member of the paired box or PAX family of transcription factors. The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse Pax3 are present in a subfamily along with the highly homologous human PAX7 and mouse Pax7 genes. The human PAX3 gene is located in the 2q36.1 chromosomal region, and contains 10 exons within a 100 kb region. # Transcript splicing Alternative splicing and processing generates multiple PAX3 isoforms that have been detected at the mRNA level. PAX3e is the longest isoform and consists of 10 exons that encode a 505 amino acid protein. In other mammalian species, including mouse, the longest mRNAs correspond to the human PAX3c and PAX3d isoforms, which consist of the first 8 or 9 exons of the PAX3 gene, respectively. Shorter PAX3 isoforms include mRNAs that skip exon 8 (PAX3g and PAX3h) and mRNAs containing 4 or 5 exons (PAX3a and PAX3b). In limited studies comparing isoform expression, PAX3d is expressed at the highest levels. From a functional standpoint, PAX3c, PAX3d, and PAX3h stimulate activities such as cell growth whereas PAX3e and PAX3g inhibit these activities, and PAX3a and PAX3b show no activity or inhibit these endpoints. A common alternative splice affecting the PAX3 mRNA involves the sequence CAG at the 5’ end of exon 3. This splice either includes or excludes these three bases, thus resulting in the presence or absence of a glutamine residue in the paired box motif. Limited sequencing studies of full-length human cDNAs identified this splicing event as a variant of the PAX3d isoform, and this spliced isoform has been separately termed the PAX3i isoform. The Q+ and Q- isoforms of PAX3 are generally co-expressed in cells. At the functional level, the Q+ isoform shows similar or less DNA binding and transcriptional activation than the Q- isoform. # Protein structure and function PAX3 encodes a transcription factor with an N-terminal DNA binding domain consisting of a paired box (PD) encoded by exons 2, 3, and 4, and an octapeptide and complete homeodomain (HD) encoded by exons 5 and 6. In addition, the PAX3 protein has a C-terminal transcriptional activation domain encoded by exons 7 and 8. The highly conserved PD consists of a 128 amino acid region that binds to DNA sequences related to the TCACGC/G motif. The HD motif usually consists of 60 amino acids and binds to sequences containing a TAAT core motif. The combination of these two DNA binding domains enable the PAX3 protein to recognize longer sequences containing PD and HD binding sites. In the C-terminus of PAX3, there is a proline, serine and threonine (PST)-rich region measuring 78 amino acids that functions to stimulate transcriptional activity. There are also transcriptional repression domains in the HD and N-terminal region (including the first half of the PD) that repress the C-terminal transcriptional activation domain. PAX3 functions as a transcriptional activator for most target genes, but also may repress a smaller subset of target genes. These expression changes are effected through binding of PAX3 to specific recognition sites, which are situated in various genomic locations. Some binding sites are located in or near target genes, such as the 5’ promoter, first intron and 3’ untranslated region. A substantial number of PAX3 binding sites are located at larger distances upstream and downstream of target genes. Among the PAX3 target genes, there is one group associated with muscle development and a second group associated with neural and melanocyte development. The proteins encoded by these target genes regulate various functional activities in these lineages, including differentiation, proliferation, migration, adhesion, and apoptosis. PAX3 interacts with other nuclear proteins, which modulate PAX3 transcriptional activity. Dimerization of PAX3 with another PAX3 molecule or a PAX7 molecule enables binding to a palindromic HD binding site (TAATCAATTA). Interaction of PAX3 with other transcription factors (such as SOX10) or chromatin factors (such as PAX3/7BP) enables synergistic activation of PAX3 target genes. In contrast, binding of PAX3 to co-repressors, such as calmyrin, inhibits activation of PAX3 target genes. These co-repressors may function by altering chromatin structure at target genes, inhibiting PAX3 recognition of its DNA binding site or directly altering PAX3 transcriptional activity. Finally, PAX3 protein expression and function can be modulated by post-translational modifications. PAX3 can be phosphorylated at serines 201, 205 and 209 by kinases such as GSK3b, which in some settings will increase PAX3 protein stability. In addition, PAX3 can also undergo ubiquitination and acetylation at lysines 437 and 475, which regulates protein stability and function. Table 1. Representative PAX3 transcriptional target genes. # Expression during development During development, one of the major lineages expressing Pax3 is the skeletal muscle lineage. Pax3 expression is first seen in the pre-somitic paraxial mesoderm, and then ultimately becomes restricted to the dermomyotome, which forms from the dorsal region of the somites. To form skeletal muscle in central body segments, PAX3-expressing cells detach from the dermomyotome and then Pax3 expression is turned off as Myf5 and MyoD1 expression is activated. To form other skeletal muscles, Pax3-expressing cells detach from the dermomyotome and migrate to more distant sites, such as the limbs and diaphragm. A subset of these Pax3-expressing dermomyotome-derived cells also serves as an ongoing progenitor pool for skeletal muscle growth during fetal development. During later developmental stages, myogenic precursors expressing Pax3 and/or Pax7 form satellite cells within the skeletal muscle, which contribute to postnatal muscle growth and muscle regeneration. These adult satellite cells remain quiescent until injury occurs, and then are stimulated to divide and regenerate the injured muscle. Pax3 is also involved in the development of the nervous system. Expression of Pax3 is first detected in the dorsal region of the neural groove and, as this neural groove deepens to form the neural tube, Pax3 is expressed in the dorsal portion of the neural tube. As the neural tube enlarges, Pax3 expression is localized to proliferative cells in the inner ventricular zone and then this expression is turned off as these cells migrate to more superficial regions. Pax3 is expressed along the length of the neural tube and throughout much of the developing brain, and this expression is subsequently turned off during later developmental stages in a rostral to caudal direction. During early development, Pax3 expression also occurs at the lateral and posterior margins of the neural plate, which is the region from which the neural crest arises. Pax3 is later expressed by various cell types and structures arising from the neural crest, such as melanoblasts, Schwann cell precursors, and dorsal root ganglia. In addition, Pax3-expressing cells derived from the neural crest contribute to the formation of other structures, such as the inner ear, mandible and maxilla. # Germline mutations in disease Germline mutations of the Pax3 gene cause the splotch phenotype in mice. At the molecular level, this phenotype is caused by point mutations or deletions that alter or abolish Pax3 transcriptional function. In the heterozygous state, the splotch phenotype is characterized by white patches in the belly, tail and feet. These white spots are attributed to localized deficiencies in pigment-forming melanocytes resulting from neural crest cell defects. In the homozygous state, these Pax3 mutations cause embryonic lethality, which is associated with prominent neural tube closure defects and abnormalities of neural crest-derived structures, such as melanocytes, dorsal root ganglia and enteric ganglia. Heart malformations also result from the loss of cardiac neural crest cells, which normally contribute to the cardiac outflow tract and innervation of the heart. Finally, limb musculature does not develop in the homozygotes and axial musculature demonstrates varying abnormalities. These myogenic effects are caused by increased cell death of myogenic precursors in the dermomyotome and diminished migration from the dermomyotome. Germline mutations of the PAX3 gene occur in the human disease Waardenburg syndrome, which consists of four autosomal dominant genetic disorders (WS1, WS2, WS3 and WS4). Of the four subtypes, WS1 and WS3 are usually caused by PAX3 mutations. All four subtypes are characterized by hearing loss, eye abnormalities and pigmentation disorders. In addition, WS1 is frequently associated with a midfacial alteration called dystopia canthorum, while WS3 (Klein-Waardenburg syndrome) is frequently distinguished by musculoskeletal abnormalities affecting the upper limbs. Most WS1 cases are caused by heterozygous PAX3 mutations while WS3 is caused by either partial or total deletion of PAX3 and contiguous genes or by smaller PAX3 mutations in the heterozygous or homozygous state. These PAX3 mutations in WS1 and WS3 include missense, nonsense and splicing mutations; small insertions; and small or gross deletions. Though these changes are usually not recurrent, the mutations generally occur in exons 2 through 6 with exon 2 mutations being most common. As these exons encode the paired box and homeodomain, these mutations often affect DNA binding function. # Mutations in human cancer Alveolar rhabdomyosarcoma (ARMS) is an aggressive soft tissue sarcoma that occurs in children and is usually characterized by a recurrent t(2;13)(q35;q14) chromosomal translocation. This 2;13 translocation breaks and rejoins portions of the PAX3 and FOXO1 genes to generate a PAX3-FOXO1 fusion gene that expresses a PAX3-FOXO1 fusion transcript encoding a PAX3-FOXO1 fusion protein. PAX3 and FOXO1 encode transcription factors, and the translocation results in a fusion transcription factor containing the N-terminal PAX3 DNA-binding domain and the C-terminal FOXO1 transactivation domain. A smaller subset of ARMS cases is associated with less common fusions of PAX7 to FOXO1 or rare fusions of PAX3 to other transcription factors, such as NCOA1. Compared to the wild-type PAX3 protein, the PAX3-FOXO1 fusion protein more potently activates PAX3 target genes. In ARMS cells, PAX3-FOXO1 usually functions as a transcriptional activator and excessively increases expression of downstream target genes. In addition, PAX3-FOXO1 binds along with MYOD1, MYOG and MYCN as well as chromatin structural proteins, such as CHD4 and BRD4, to contribute to the formation of super enhancers in the vicinity of a subset of these target genes. These dysregulated target genes contribute to tumorigenesis by altering signaling pathways that affect proliferation, cell death, myogenic differentiation, and migration. A t(2;4)(q35;q31.1) chromosomal translocation that fuses the PAX3 and MAML3 genes occurs in biphenotypic sinonasal sarcoma (BSNS), a low-grade adult malignancy associated with both myogenic and neural differentiation. MAML3 encodes a transcriptional coactivator involved in Notch signaling. The PAX3-MAML3 fusion juxtaposes the N-terminal PAX3 DNA binding domain with the C-terminal MAML3 transactivation domain to create another potent activator of target genes with PAX3 binding sites. Of note, PAX3 is rearranged without MAML3 involvement in a smaller subset of BSNS cases, and some of these variant cases contain a PAX3-NCOA1 or PAX3-FOXO1 fusion. Though PAX3-FOXO1 and PAX3-NCOA1 fusions can be formed in both ARMS and BSNS, there are differences in the pattern of activated downstream target genes suggesting that the cell environment has an important role in modulating the output of these fusion transcription factors. In addition to tumors with PAX3-related fusion genes, there are several other tumor categories that express the wild-type PAX3 gene. The presence of PAX3 expression in some tumors can be explained by their derivation from developmental lineages normally expressing wild-type PAX3. For example, PAX3 is expressed in cancers associated with neural tube-derived lineages, (e.g., glioblastoma), neural crest-derived lineages (e.g., melanoma) and myogenic lineages (e.g., embryonal rhabdomyosarcoma). However, PAX3 is also expressed in other cancer types without a clear relationship to a PAX3-expressing developmental lineages, such as breast carcinoma and osteosarcoma. In these wild-type PAX3-expressing cancers, PAX3 function impacts on the control of proliferation, apoptosis, differentiation and motility. Therefore wild-type PAX3 exerts a regulatory role in tumorigenesis and tumor progression, which may be related to its role in normal development.

PAX3 The PAX3 (paired box gene 3) gene encodes a member of the paired box or PAX family of transcription factors.[1] The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse Pax3 are present in a subfamily along with the highly homologous human PAX7 and mouse Pax7 genes. The human PAX3 gene is located in the 2q36.1 chromosomal region, and contains 10 exons within a 100 kb region. # Transcript splicing Alternative splicing and processing generates multiple PAX3 isoforms that have been detected at the mRNA level.[2] PAX3e is the longest isoform and consists of 10 exons that encode a 505 amino acid protein. In other mammalian species, including mouse, the longest mRNAs correspond to the human PAX3c and PAX3d isoforms, which consist of the first 8 or 9 exons of the PAX3 gene, respectively. Shorter PAX3 isoforms include mRNAs that skip exon 8 (PAX3g and PAX3h) and mRNAs containing 4 or 5 exons (PAX3a and PAX3b). In limited studies comparing isoform expression, PAX3d is expressed at the highest levels. From a functional standpoint, PAX3c, PAX3d, and PAX3h stimulate activities such as cell growth whereas PAX3e and PAX3g inhibit these activities, and PAX3a and PAX3b show no activity or inhibit these endpoints. A common alternative splice affecting the PAX3 mRNA involves the sequence CAG at the 5’ end of exon 3.[3] This splice either includes or excludes these three bases, thus resulting in the presence or absence of a glutamine residue in the paired box motif. Limited sequencing studies of full-length human cDNAs identified this splicing event as a variant of the PAX3d isoform, and this spliced isoform has been separately termed the PAX3i isoform. The Q+ and Q- isoforms of PAX3 are generally co-expressed in cells. At the functional level, the Q+ isoform shows similar or less DNA binding and transcriptional activation than the Q- isoform. # Protein structure and function PAX3 encodes a transcription factor with an N-terminal DNA binding domain consisting of a paired box (PD) encoded by exons 2, 3, and 4, and an octapeptide and complete homeodomain (HD) encoded by exons 5 and 6.[4] In addition, the PAX3 protein has a C-terminal transcriptional activation domain encoded by exons 7 and 8. The highly conserved PD consists of a 128 amino acid region that binds to DNA sequences related to the TCACGC/G motif.[5] The HD motif usually consists of 60 amino acids and binds to sequences containing a TAAT core motif.[6] The combination of these two DNA binding domains enable the PAX3 protein to recognize longer sequences containing PD and HD binding sites.[7] In the C-terminus of PAX3, there is a proline, serine and threonine (PST)-rich region measuring 78 amino acids that functions to stimulate transcriptional activity.[8] There are also transcriptional repression domains in the HD and N-terminal region (including the first half of the PD) that repress the C-terminal transcriptional activation domain.[9] PAX3 functions as a transcriptional activator for most target genes, but also may repress a smaller subset of target genes.[10] These expression changes are effected through binding of PAX3 to specific recognition sites, which are situated in various genomic locations.[11] Some binding sites are located in or near target genes, such as the 5’ promoter, first intron and 3’ untranslated region. A substantial number of PAX3 binding sites are located at larger distances upstream and downstream of target genes. Among the PAX3 target genes, there is one group associated with muscle development and a second group associated with neural and melanocyte development. The proteins encoded by these target genes regulate various functional activities in these lineages, including differentiation, proliferation, migration, adhesion, and apoptosis. PAX3 interacts with other nuclear proteins, which modulate PAX3 transcriptional activity. Dimerization of PAX3 with another PAX3 molecule or a PAX7 molecule enables binding to a palindromic HD binding site (TAATCAATTA).[12] Interaction of PAX3 with other transcription factors (such as SOX10) or chromatin factors (such as PAX3/7BP) enables synergistic activation of PAX3 target genes.[13][14] In contrast, binding of PAX3 to co-repressors, such as calmyrin, inhibits activation of PAX3 target genes.[15] These co-repressors may function by altering chromatin structure at target genes, inhibiting PAX3 recognition of its DNA binding site or directly altering PAX3 transcriptional activity. Finally, PAX3 protein expression and function can be modulated by post-translational modifications. PAX3 can be phosphorylated at serines 201, 205 and 209 by kinases such as GSK3b, which in some settings will increase PAX3 protein stability.[16][17] In addition, PAX3 can also undergo ubiquitination and acetylation at lysines 437 and 475, which regulates protein stability and function.[18][19] Table 1. Representative PAX3 transcriptional target genes. # Expression during development During development, one of the major lineages expressing Pax3 is the skeletal muscle lineage.[20] Pax3 expression is first seen in the pre-somitic paraxial mesoderm, and then ultimately becomes restricted to the dermomyotome, which forms from the dorsal region of the somites. To form skeletal muscle in central body segments, PAX3-expressing cells detach from the dermomyotome and then Pax3 expression is turned off as Myf5 and MyoD1 expression is activated. To form other skeletal muscles, Pax3-expressing cells detach from the dermomyotome and migrate to more distant sites, such as the limbs and diaphragm. A subset of these Pax3-expressing dermomyotome-derived cells also serves as an ongoing progenitor pool for skeletal muscle growth during fetal development. During later developmental stages, myogenic precursors expressing Pax3 and/or Pax7 form satellite cells within the skeletal muscle, which contribute to postnatal muscle growth and muscle regeneration. These adult satellite cells remain quiescent until injury occurs, and then are stimulated to divide and regenerate the injured muscle. Pax3 is also involved in the development of the nervous system.[21] Expression of Pax3 is first detected in the dorsal region of the neural groove and, as this neural groove deepens to form the neural tube, Pax3 is expressed in the dorsal portion of the neural tube. As the neural tube enlarges, Pax3 expression is localized to proliferative cells in the inner ventricular zone and then this expression is turned off as these cells migrate to more superficial regions. Pax3 is expressed along the length of the neural tube and throughout much of the developing brain, and this expression is subsequently turned off during later developmental stages in a rostral to caudal direction. During early development, Pax3 expression also occurs at the lateral and posterior margins of the neural plate, which is the region from which the neural crest arises.[22] Pax3 is later expressed by various cell types and structures arising from the neural crest, such as melanoblasts, Schwann cell precursors, and dorsal root ganglia. In addition, Pax3-expressing cells derived from the neural crest contribute to the formation of other structures, such as the inner ear, mandible and maxilla.[23] # Germline mutations in disease Germline mutations of the Pax3 gene cause the splotch phenotype in mice.[24][25] At the molecular level, this phenotype is caused by point mutations or deletions that alter or abolish Pax3 transcriptional function. In the heterozygous state, the splotch phenotype is characterized by white patches in the belly, tail and feet. These white spots are attributed to localized deficiencies in pigment-forming melanocytes resulting from neural crest cell defects. In the homozygous state, these Pax3 mutations cause embryonic lethality, which is associated with prominent neural tube closure defects and abnormalities of neural crest-derived structures, such as melanocytes, dorsal root ganglia and enteric ganglia. Heart malformations also result from the loss of cardiac neural crest cells, which normally contribute to the cardiac outflow tract and innervation of the heart. Finally, limb musculature does not develop in the homozygotes and axial musculature demonstrates varying abnormalities. These myogenic effects are caused by increased cell death of myogenic precursors in the dermomyotome and diminished migration from the dermomyotome. Germline mutations of the PAX3 gene occur in the human disease Waardenburg syndrome,[26] which consists of four autosomal dominant genetic disorders (WS1, WS2, WS3 and WS4).[27] Of the four subtypes, WS1 and WS3 are usually caused by PAX3 mutations. All four subtypes are characterized by hearing loss, eye abnormalities and pigmentation disorders. In addition, WS1 is frequently associated with a midfacial alteration called dystopia canthorum, while WS3 (Klein-Waardenburg syndrome) is frequently distinguished by musculoskeletal abnormalities affecting the upper limbs. Most WS1 cases are caused by heterozygous PAX3 mutations while WS3 is caused by either partial or total deletion of PAX3 and contiguous genes or by smaller PAX3 mutations in the heterozygous or homozygous state. These PAX3 mutations in WS1 and WS3 include missense, nonsense and splicing mutations; small insertions; and small or gross deletions. Though these changes are usually not recurrent, the mutations generally occur in exons 2 through 6 with exon 2 mutations being most common. As these exons encode the paired box and homeodomain, these mutations often affect DNA binding function. # Mutations in human cancer Alveolar rhabdomyosarcoma (ARMS) is an aggressive soft tissue sarcoma that occurs in children and is usually characterized by a recurrent t(2;13)(q35;q14) chromosomal translocation.[28][29] This 2;13 translocation breaks and rejoins portions of the PAX3 and FOXO1 genes to generate a PAX3-FOXO1 fusion gene that expresses a PAX3-FOXO1 fusion transcript encoding a PAX3-FOXO1 fusion protein.[30] PAX3 and FOXO1 encode transcription factors, and the translocation results in a fusion transcription factor containing the N-terminal PAX3 DNA-binding domain and the C-terminal FOXO1 transactivation domain. A smaller subset of ARMS cases is associated with less common fusions of PAX7 to FOXO1 or rare fusions of PAX3 to other transcription factors, such as NCOA1.[31][32] Compared to the wild-type PAX3 protein, the PAX3-FOXO1 fusion protein more potently activates PAX3 target genes.[9] In ARMS cells, PAX3-FOXO1 usually functions as a transcriptional activator and excessively increases expression of downstream target genes.[33][34] In addition, PAX3-FOXO1 binds along with MYOD1, MYOG and MYCN as well as chromatin structural proteins, such as CHD4 and BRD4, to contribute to the formation of super enhancers in the vicinity of a subset of these target genes.[35] These dysregulated target genes contribute to tumorigenesis by altering signaling pathways that affect proliferation, cell death, myogenic differentiation, and migration. A t(2;4)(q35;q31.1) chromosomal translocation that fuses the PAX3 and MAML3 genes occurs in biphenotypic sinonasal sarcoma (BSNS), a low-grade adult malignancy associated with both myogenic and neural differentiation.[36] MAML3 encodes a transcriptional coactivator involved in Notch signaling. The PAX3-MAML3 fusion juxtaposes the N-terminal PAX3 DNA binding domain with the C-terminal MAML3 transactivation domain to create another potent activator of target genes with PAX3 binding sites. Of note, PAX3 is rearranged without MAML3 involvement in a smaller subset of BSNS cases, and some of these variant cases contain a PAX3-NCOA1 or PAX3-FOXO1 fusion.[37][38] Though PAX3-FOXO1 and PAX3-NCOA1 fusions can be formed in both ARMS and BSNS, there are differences in the pattern of activated downstream target genes suggesting that the cell environment has an important role in modulating the output of these fusion transcription factors. In addition to tumors with PAX3-related fusion genes, there are several other tumor categories that express the wild-type PAX3 gene. The presence of PAX3 expression in some tumors can be explained by their derivation from developmental lineages normally expressing wild-type PAX3. For example, PAX3 is expressed in cancers associated with neural tube-derived lineages, (e.g., glioblastoma), neural crest-derived lineages (e.g., melanoma) and myogenic lineages (e.g., embryonal rhabdomyosarcoma).[39][40][41][42] However, PAX3 is also expressed in other cancer types without a clear relationship to a PAX3-expressing developmental lineages, such as breast carcinoma and osteosarcoma.[43][44] In these wild-type PAX3-expressing cancers, PAX3 function impacts on the control of proliferation, apoptosis, differentiation and motility.[39][40] Therefore wild-type PAX3 exerts a regulatory role in tumorigenesis and tumor progression, which may be related to its role in normal development.

https://www.wikidoc.org/index.php/PAX3

8e221a16053631cd5b7999a50c2743a7da8ae9bc

wikidoc

PAX5

PAX5 Paired box protein Pax-5 is a protein that in humans is encoded by the PAX5 gene. # Function The PAX5 gene is a member of the paired box (PAX) family of transcription factors. The central feature of this gene family is a novel, highly conserved DNA-binding domain, known as the paired box. The PAX proteins are important regulators in early development, and alterations in the expression of their genes are thought to contribute to neoplastic transformation. The PAX5 gene encodes the B-cell lineage specific activator protein (BSAP) that is expressed at early, but not late stages of B-cell differentiation. Its expression has also been detected in developing CNS and testis, therefore, PAX5 gene product may not only play an important role in B-cell differentiation, but also in neural development and spermatogenesis. # Clinical significance The PAX5 gene is located in chromosome 9p13 region, which is involved in t(9;14)(p13;q32) translocations recurring in small lymphocytic lymphomas of the plasmacytoid subtype, and in derived large-cell lymphomas. This translocation brings the potent E-mu enhancer of the IgH gene locus into close proximity of the PAX5 promoters, suggesting that the deregulation of PAX5 gene transcription contributes to the pathogenesis of these lymphomas. Up to 97% of the Reed–Sternberg cells of Hodgkin's lymphoma express Pax-5. # Interactions PAX5 has been shown to interact with TLE4 and Death associated protein 6.

PAX5 Paired box protein Pax-5 is a protein that in humans is encoded by the PAX5 gene.[1][2][3] # Function The PAX5 gene is a member of the paired box (PAX) family of transcription factors. The central feature of this gene family is a novel, highly conserved DNA-binding domain, known as the paired box. The PAX proteins are important regulators in early development, and alterations in the expression of their genes are thought to contribute to neoplastic transformation. The PAX5 gene encodes the B-cell lineage specific activator protein (BSAP) that is expressed at early, but not late stages of B-cell differentiation. Its expression has also been detected in developing CNS and testis, therefore, PAX5 gene product may not only play an important role in B-cell differentiation, but also in neural development and spermatogenesis.[3] # Clinical significance The PAX5 gene is located in chromosome 9p13 region, which is involved in t(9;14)(p13;q32) translocations recurring in small lymphocytic lymphomas of the plasmacytoid subtype, and in derived large-cell lymphomas. This translocation brings the potent E-mu enhancer of the IgH gene locus into close proximity of the PAX5 promoters, suggesting that the deregulation of PAX5 gene transcription contributes to the pathogenesis of these lymphomas.[3] Up to 97% of the Reed–Sternberg cells of Hodgkin's lymphoma express Pax-5.[4] # Interactions PAX5 has been shown to interact with TLE4[5][6] and Death associated protein 6.[7]

https://www.wikidoc.org/index.php/PAX5

88caa960a5fba0007cd9107758ca9d4132b4894a

wikidoc

PAX6

PAX6 Paired box protein Pax-6, also known as aniridia type II protein (AN2) or oculorhombin, is a protein that in humans is encoded by the PAX6 gene. Pax6 is a transcription factor present during embryonic development. The encoded protein contains two different binding sites that are known to bind DNA and function as regulators of gene transcription. It is a key regulatory gene of eye and brain development. Within the brain, the protein is involved in development of the specialized cells that process smell. As a transcription factor, Pax6 activates and/or deactivates gene expression patterns to ensure for proper development of the tissue. Mutations of the Pax6 gene are known to cause various disorders of the eyes. Two common disorders associated with a mutation are: aniridia, the absence -f the iris, and Peters' anomaly, thinning and clouding of the cornea. Scientists have created a "tae" model using mice during which time the mouse does not express Pax6. The "knockout" model is eyeless or has very underdeveloped eyes further indicating Pax6 is required for proper eye development. # Function PAX6 is a member of the Pax gene family which is responsible for carrying the genetic information that will encode the Pax-6 protein. It acts as a "master control" gene for the development of eyes and other sensory organs, certain neural and epidermal tissues as well as other homologous structures, usually derived from ectodermal tissues. However it has been recognized that a suite of genes is necessary for eye development, and therefore the term of "master control" gene may be inaccurate. Pax-6 is expressed as a transcription factor when neural ectoderm receives a combination of weak Sonic hedgehog (SHH) and strong TGF-Beta signaling gradients. Expression is first seen in the forebrain, hindbrain, head ectoderm and spinal cord followed by later expression in midbrain. This transcription factor is most noted for its use in the interspecifically induced expression of ectopic eyes and is of medical importance because heterozygous mutants produce a wide spectrum of ocular defects such as Aniridia in humans. Pax6 serves as a regulator in the coordination and pattern formation required for differentiation and proliferation to successfully take place, ensuring that the processes of neurogenesis and oculogenesis are carried out successfully. As a transcription factor, Pax6 acts at the molecular level in the signaling and formation of the central nervous system. The characteristic paired DNA binding domain of Pax6 utilizes two DNA-binding domains, the paired domain (PD), and the paired-type homeodomain (HD). These domains function separately via utilization by Pax6 to carry out molecular signaling that regulates specific functions of Pax6. An example of this lies in HD’s regulatory involvement in the formation of the lens and retina throughout oculogenesis contrasted by the molecular mechanisms of control exhibited on the patterns of neurogenesis in brain development by PD. The HD and PD domains act in close coordination, giving Pax6 its multifunctional nature in directing molecular signaling in formation of the CNS. Although many functions of Pax6 are known, the molecular mechanisms of these functions remain largely unresolved. High-throughput studies uncovered many new target genes of the Pax6 transcription factors during lens development. They include the transcriptional activator BCL9, recently identified, together with Pygo2, to be downstream effectors of Pax6 functions. # Species distribution PAX6 protein function is highly conserved across bilaterian species. For instance, mouse PAX6 can trigger eye development in Drosophila melanogaster. Additionally, mouse and human PAX6 have identical amino acid sequences. Genomic organisation of the PAX6 locus varies considerably among species, including the number and distribution of exons, cis-regulatory elements, and transcription start sites. The first work on genomic organisation was performed in quail, but the picture of the mouse locus is the most complete to date. This consists of 2 confirmed promoters (P0 and P1), 16 exons, and at least 6 enhancers. The 16 confirmed exons are numbered 0 through 13 with the additions of exon α located between exons 4 and 5, and the alternatively spliced exon 5a. Each promoter is associated with its own proximal exon (exon 0 for P0, exon 1 for P1) resulting in transcripts which are alternatively spliced in the 5' un-translated region. Of the four Drosophila Pax6 orthologues, it is thought that the eyeless (ey) and twin of eyeless (toy) gene products share functional homology with the vertebrate canonical Pax6 isoform, while the eyegone (eyg) and twin of eyegone (toe) gene products share functional homology with the vertebrate Pax6(5a) isoform. Eyeless and eyegone were named for their respective mutant phenotypes. # Isoforms The vertebrate PAX6 locus encodes at least three different protein isoforms, these being the canonical PAX6, PAX6(5a), and PAX6(ΔPD). The canonical PAX6 protein contains an N-terminal paired domain, connected by a linker region to a paired-type homeodomain, and a proline/serine/threonine (P/S/T)-rich C-terminal domain. The paired domain and paired-type homeodomain each have DNA binding activities, while the P/S/T-rich domain possesses a transactivation function. PAX6(5a) is a product of the alternatively spliced exon 5a resulting in a 14 residue insertion in the paired domain which alters the specificity of this DNA binding activity. The nucleotide sequence corresponding to the linker region encodes a set of three alternative translation start codons from which the third PAX6 isoform originates. Collectively known as the PAX6(ΔPD) or pairedless isoforms, these three gene products all lack a paired domain. The pairedless proteins possess molecular weights of 43, 33, or 32kDa, depending on the particular start codon used. PAX6 transactivation function is attributed to the variable length C-terminal P/S/T-rich domain which stretches to 153 residues in human and mouse proteins. # Clinical significance Experiments in mice demonstrate that a deficiency in Pax-6 leads to decrease in brain size, brain structure abnormality leading to Autism, lack of iris formation or a thin cornea. Knockout experiments produced eyeless phenotypes reinforcing the gene’s role in eye development. # Mutations During embryological development the PAX6 gene, found on chromosome 2, can be seen expressed in multiple early structures such as the spinal cord, hindbrain, forebrain and eyes. Mutations of the PAX6 gene in mammalian species can produce a drastic effect on the phenotype of the organism. This can be seen in mice that contain homozygous mutations of the 422 amino acid long transcription factor encoded by PAX6 in which they do not develop eyes or nasal cavities termed ‘small eye’ mice (PAX10sey/sey). Deletion of PAX6 induces the same abnormal phenotypes indicating that mutations cause the protein to lose functionality. PAX6 is essential is the formation of the retina, lens and cornea due to its role in early cell determination when forming precursors of these structures such as the optic vesicle and overlying surface ectoderm. PAX10 mutations also hinder nasal cavity development due to the similar precursor structures that in small eye mice do not express PAX10 mRNA. Mice with the mutant genotype begin to be phenotypically differentiable from normal mouse embryos at about day 9 to 10 of gestation. The full elucidation of the precise mechanisms and molecular components by which the PAX6 gene influences eye, nasal and central nervous system development are still researched however, the study of PAX6 has brought more understanding to the development and genetic complexities of these mammalian body systems.

PAX6 Paired box protein Pax-6, also known as aniridia type II protein (AN2) or oculorhombin, is a protein that in humans is encoded by the PAX6 gene.[1] Pax6 is a transcription factor present during embryonic development. The encoded protein contains two different binding sites that are known to bind DNA and function as regulators of gene transcription. It is a key regulatory gene of eye and brain development. Within the brain, the protein is involved in development of the specialized cells that process smell. As a transcription factor, Pax6 activates and/or deactivates gene expression patterns to ensure for proper development of the tissue. Mutations of the Pax6 gene are known to cause various disorders of the eyes. Two common disorders associated with a mutation are: aniridia, the absence of the iris, and Peters' anomaly, thinning and clouding of the cornea. Scientists have created a "tae" model using mice during which time the mouse does not express Pax6. The "knockout" model is eyeless or has very underdeveloped eyes further indicating Pax6 is required for proper eye development.[2] # Function PAX6 is a member of the Pax gene family which is responsible for carrying the genetic information that will encode the Pax-6 protein. It acts as a "master control" gene for the development of eyes and other sensory organs, certain neural and epidermal tissues as well as other homologous structures, usually derived from ectodermal tissues.[citation needed] However it has been recognized that a suite of genes is necessary for eye development, and therefore the term of "master control" gene may be inaccurate.[3] Pax-6 is expressed as a transcription factor when neural ectoderm receives a combination of weak Sonic hedgehog (SHH) and strong TGF-Beta signaling gradients. Expression is first seen in the forebrain, hindbrain, head ectoderm and spinal cord followed by later expression in midbrain. This transcription factor is most noted for its use in the interspecifically induced expression of ectopic eyes and is of medical importance because heterozygous mutants produce a wide spectrum of ocular defects such as Aniridia in humans.[4] Pax6 serves as a regulator in the coordination and pattern formation required for differentiation and proliferation to successfully take place, ensuring that the processes of neurogenesis and oculogenesis are carried out successfully. As a transcription factor, Pax6 acts at the molecular level in the signaling and formation of the central nervous system. The characteristic paired DNA binding domain of Pax6 utilizes two DNA-binding domains, the paired domain (PD), and the paired-type homeodomain (HD). These domains function separately via utilization by Pax6 to carry out molecular signaling that regulates specific functions of Pax6. An example of this lies in HD’s regulatory involvement in the formation of the lens and retina throughout oculogenesis contrasted by the molecular mechanisms of control exhibited on the patterns of neurogenesis in brain development by PD. The HD and PD domains act in close coordination, giving Pax6 its multifunctional nature in directing molecular signaling in formation of the CNS. Although many functions of Pax6 are known, the molecular mechanisms of these functions remain largely unresolved.[5] High-throughput studies uncovered many new target genes of the Pax6 transcription factors during lens development.[6] They include the transcriptional activator BCL9, recently identified, together with Pygo2, to be downstream effectors of Pax6 functions.[7] # Species distribution PAX6 protein function is highly conserved across bilaterian species. For instance, mouse PAX6 can trigger eye development in Drosophila melanogaster. Additionally, mouse and human PAX6 have identical amino acid sequences.[8] Genomic organisation of the PAX6 locus varies considerably among species, including the number and distribution of exons, cis-regulatory elements, and transcription start sites.[citation needed] The first work on genomic organisation was performed in quail, but the picture of the mouse locus is the most complete to date. This consists of 2 confirmed promoters (P0 and P1), 16 exons, and at least 6 enhancers. The 16 confirmed exons are numbered 0 through 13 with the additions of exon α located between exons 4 and 5, and the alternatively spliced exon 5a. Each promoter is associated with its own proximal exon (exon 0 for P0, exon 1 for P1) resulting in transcripts which are alternatively spliced in the 5' un-translated region. Of the four Drosophila Pax6 orthologues, it is thought that the eyeless (ey) and twin of eyeless (toy) gene products share functional homology with the vertebrate canonical Pax6 isoform, while the eyegone (eyg) and twin of eyegone (toe) gene products share functional homology with the vertebrate Pax6(5a) isoform. Eyeless and eyegone were named for their respective mutant phenotypes. # Isoforms The vertebrate PAX6 locus encodes at least three different protein isoforms, these being the canonical PAX6, PAX6(5a), and PAX6(ΔPD). The canonical PAX6 protein contains an N-terminal paired domain, connected by a linker region to a paired-type homeodomain, and a proline/serine/threonine (P/S/T)-rich C-terminal domain. The paired domain and paired-type homeodomain each have DNA binding activities, while the P/S/T-rich domain possesses a transactivation function. PAX6(5a) is a product of the alternatively spliced exon 5a resulting in a 14 residue insertion in the paired domain which alters the specificity of this DNA binding activity. The nucleotide sequence corresponding to the linker region encodes a set of three alternative translation start codons from which the third PAX6 isoform originates. Collectively known as the PAX6(ΔPD) or pairedless isoforms, these three gene products all lack a paired domain. The pairedless proteins possess molecular weights of 43, 33, or 32kDa, depending on the particular start codon used. PAX6 transactivation function is attributed to the variable length C-terminal P/S/T-rich domain which stretches to 153 residues in human and mouse proteins. # Clinical significance Experiments in mice demonstrate that a deficiency in Pax-6 leads to decrease in brain size, brain structure abnormality leading to Autism, lack of iris formation or a thin cornea. Knockout experiments produced eyeless phenotypes reinforcing the gene’s role in eye development.[4] # Mutations During embryological development the PAX6 gene, found on chromosome 2, can be seen expressed in multiple early structures such as the spinal cord, hindbrain, forebrain and eyes.[9] Mutations of the PAX6 gene in mammalian species can produce a drastic effect on the phenotype of the organism. This can be seen in mice that contain homozygous mutations of the 422 amino acid long transcription factor encoded by PAX6 in which they do not develop eyes or nasal cavities termed ‘small eye’ mice (PAX10sey/sey).[9][10] Deletion of PAX6 induces the same abnormal phenotypes indicating that mutations cause the protein to lose functionality. PAX6 is essential is the formation of the retina, lens and cornea due to its role in early cell determination when forming precursors of these structures such as the optic vesicle and overlying surface ectoderm.[10] PAX10 mutations also hinder nasal cavity development due to the similar precursor structures that in small eye mice do not express PAX10 mRNA.[11] Mice with the mutant genotype begin to be phenotypically differentiable from normal mouse embryos at about day 9 to 10 of gestation.[12] The full elucidation of the precise mechanisms and molecular components by which the PAX6 gene influences eye, nasal and central nervous system development are still researched however, the study of PAX6 has brought more understanding to the development and genetic complexities of these mammalian body systems.

https://www.wikidoc.org/index.php/PAX6

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wikidoc

PAX7

PAX7 Paired box protein Pax-7 is a protein that in humans is encoded by the PAX7 gene. # Function Pax-7 plays a role in neural crest development and gastrulation, and it is an important factor in the expression of neural crest markers such as Slug, Sox9, Sox10 and HNK-1. PAX7 is expressed in the palatal shelf of the maxilla, Meckel's cartilage, mesencephalon, nasal cavity, nasal epithelium, nasal capsule and pons. Pax7 is a transcription factor that plays a role in myogenesis through regulation of muscle precursor cells proliferation. It can bind to DNA as an heterodimer with PAX3. Also interacts with PAXBP1; the interaction links PAX7 to a WDR5-containing histone methyltransferase complex By similarity. Interacts with DAXX too. PAX7 functions as a marker for a rare subset of spermatogonial stem cells, specifically a sub set of Asingle spermatogonia. These PAX7+ spermatogonia are rare in adult testis but are much more prevalent in newborns, making up 28% of germ cells in neonate testis. Unlike PAX7+ muscle satellite cells, PAX7+ spermatogonia rapidly proliferate and are not quiescent. PAX7+ spermatogonia are able to give rise to all stages of spermatogenesis and produce motile sperm. However, PAX7 is not required for spermatogenesis, as mice without PAX7+ spermatogonia show no deficits in fertility. PAX7 may also function in the recovery in spermatogenesis. Unlike other spermatogonia, PAX7+ spermatogonia are resistant to radiation and chemotherapy. The surviving PAX7+ spermatogonia are able to increase in number following these therapies and differentiate into the other forms of spermatogonia that did not survive. Additionally, mice lacking PAX7 had delayed recovery of spermatogenesis following exposure to busulfan when compared to control mice. # Clinical significance Pax proteins play critical roles during fetal development and cancer growth. The specific function of the paired box gene 7 is unknown but speculated to involve tumor suppression since fusion of this gene with a forkhead domain family member has been associated with alveolar rhabdomyosarcoma. Alternative splicing in this gene has produced two known products but the biological significance of the variants is unknown. Animal studies show that mutant mice have malformation of maxilla and the nose.

PAX7 Paired box protein Pax-7 is a protein that in humans is encoded by the PAX7 gene.[1][2][3] # Function Pax-7 plays a role in neural crest development and gastrulation, and it is an important factor in the expression of neural crest markers such as Slug, Sox9, Sox10 and HNK-1.[4] PAX7 is expressed in the palatal shelf of the maxilla, Meckel's cartilage, mesencephalon, nasal cavity, nasal epithelium, nasal capsule and pons. Pax7 is a transcription factor that plays a role in myogenesis through regulation of muscle precursor cells proliferation. It can bind to DNA as an heterodimer with PAX3. Also interacts with PAXBP1; the interaction links PAX7 to a WDR5-containing histone methyltransferase complex By similarity. Interacts with DAXX too.[5] PAX7 functions as a marker for a rare subset of spermatogonial stem cells, specifically a sub set of Asingle spermatogonia.[6] These PAX7+ spermatogonia are rare in adult testis but are much more prevalent in newborns, making up 28% of germ cells in neonate testis.[6] Unlike PAX7+ muscle satellite cells, PAX7+ spermatogonia rapidly proliferate and are not quiescent.[6][7] PAX7+ spermatogonia are able to give rise to all stages of spermatogenesis and produce motile sperm.[6] However, PAX7 is not required for spermatogenesis, as mice without PAX7+ spermatogonia show no deficits in fertility.[6] PAX7 may also function in the recovery in spermatogenesis. Unlike other spermatogonia, PAX7+ spermatogonia are resistant to radiation and chemotherapy.[6] The surviving PAX7+ spermatogonia are able to increase in number following these therapies and differentiate into the other forms of spermatogonia that did not survive.[6] Additionally, mice lacking PAX7 had delayed recovery of spermatogenesis following exposure to busulfan when compared to control mice.[6] # Clinical significance Pax proteins play critical roles during fetal development and cancer growth. The specific function of the paired box gene 7 is unknown but speculated to involve tumor suppression since fusion of this gene with a forkhead domain family member has been associated with alveolar rhabdomyosarcoma. Alternative splicing in this gene has produced two known products but the biological significance of the variants is unknown.[3] Animal studies show that mutant mice have malformation of maxilla and the nose.[8]

https://www.wikidoc.org/index.php/PAX7

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wikidoc

PAX8

PAX8 Paired box gene 8, also known as PAX8, is a protein which in humans is encoded by the PAX8 gene. # Function This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically encode proteins which contain a paired box domain, an octapeptide, and a paired-type homeodomain. The PAX gene family has an important role in the formation of tissues and organs during embryonic development and maintaining the normal function of some cells after birth. The PAX genes give instructions for making proteins that attach themselves to certain areas of DNA. This nuclear protein is involved in thyroid follicular cell development and expression of thyroid-specific genes. PAX8 releases the hormones important for regulating growth, brain development, and metabolism. Also functions in very early stages of kidney organogenesis, the müllerian system, and the thymus. Additionally, PAX8 is expressed in the renal excretory system, epithelial cells of the endocervix, endometrium, ovary, Fallopian tube, seminal vesicle, epididymis, pancreatic islet cells and lymphoid cells. PAX8 and other transcription factors play a role in binding to DNA and regulating the genes that drive thyroid hormone synthesis (Tg, TPO, Slc5a5 and Tshr). PAX8 (and PAX2) is one of the important regulators of urogenital system morphogenesis. They play a role in the specification of the first renal cells of the embryo and remain essential players throughout development. # Clinical significance Mutations in this gene have been associated with thyroid dysgenesis, thyroid follicular carcinomas and atypical follicular thyroid adenomas. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. The PAX8 gene is also associated congenital hypothyroidism due to thyroid dysgenesis because of its role in growth and development of the thyroid gland. A mutation in the PAX8 gene could prevent or disrupt normal development. These mutations can affect different functions of the protein including DNA biding, gene activation, protein stability, and cooperation with the co-activator p300. PAX gene deficiencies can result in development defects called Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). ## Cancer PAX8 is considered a "master regulator transcription factor". As a master regulator, it is possible that it regulates expression of genes other than thyroid-specific. Several known tumor suppressor genes like TP53 and WT1 have been identified as transcriptional targets in human astrocytoma cells. Over 90% of thyroid tumors arise from follicular thyroid cells. A fusion protein, PAX8-PPAR-γ, is implicated in some follicular thyroid carcinomas and follicular-variant papillary thyroid carcinoma. The mechanism for this transformation is not well understood, but there are several proposed possibilities. - Inhibition of normal PPAR y function by chimeric PAX8/PPARy protein through a dominant negative effect - Activation of normal PPARy targets due to the over expression of the chimeric protein that contain all functional domains of wild-type PPAR y - Deregulation of PAX8 function - Activation of a set of genes unrelated to both wild-type PPARy and wild-type PAX8 pathways The PAX 8 gene has some association with follicular thyroid tumors. PAX8/PPARy rearrangement account for 30-40% of conventional type follicular carcinomas and less than 5% of oncocytic carcinomas (aka Hurthle-Cell Neoplasms). Tumors expressing the PAX8/PPARy are usually present in at a young age, small in size, present in a solid/nested growth pattern and frequently involve vascular invasion. It has been observed that PAX8/PPAR y-positive tumors rarely express RAS mutations in combination. This suggests that follicular carcinomas develop in two distinct pathways either with PAX8/PPAR y or RAS. Some whole-genome sequencing studies have shown that PAX8 also targets BRCA1 (carcinogenesis), MAPK pathways (thyroid malignancies), and Ccnb1 and Ccnb2 (cell-cycle processes). PAX8 is shown to be involved in tumor cell proliferation and differentiation, signal transduction, apoptosis, cell polarity and transport, cell motility and adhesion. Expression of PAX8 is increased in neoplastic renal tissues, Wilms tumors, ovarian cancer and Müllerian carcinomas. For this reason, the immunodetection of PAX8 is widely used for diagnosing primary and metastatic renal tumors. Re-activation of PAX8 (or Pax2) expression has been reported in pediatric Wilms Tumors, almost all subtypes of renal cell carcinoma, nephrogenic adenomas, ovarian cancer cells, bladder, prostate, and endometrial carcinomas. The mechanism of switching on the genes is unknown. Some studies have suggested that the renal PAX genes act as pro-survival factors and allow tumor cells to resist apoptosis. Down regulation of the PAX gene expression inhibits cell growth and induces apoptosis. This could be a possible avenue for therapeutic targets in renal cancer. # Interactions PAX8 has been shown to interact with NK2 homeobox 1.

PAX8 Paired box gene 8, also known as PAX8, is a protein which in humans is encoded by the PAX8 gene.[1] # Function This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically encode proteins which contain a paired box domain, an octapeptide, and a paired-type homeodomain. The PAX gene family has an important role in the formation of tissues and organs during embryonic development and maintaining the normal function of some cells after birth. The PAX genes give instructions for making proteins that attach themselves to certain areas of DNA.[2] This nuclear protein is involved in thyroid follicular cell development and expression of thyroid-specific genes. PAX8 releases the hormones important for regulating growth, brain development, and metabolism. Also functions in very early stages of kidney organogenesis, the müllerian system, and the thymus.[3] Additionally, PAX8 is expressed in the renal excretory system, epithelial cells of the endocervix, endometrium, ovary, Fallopian tube, seminal vesicle, epididymis, pancreatic islet cells and lymphoid cells.[4] PAX8 and other transcription factors play a role in binding to DNA and regulating the genes that drive thyroid hormone synthesis (Tg, TPO, Slc5a5 and Tshr). PAX8 (and PAX2) is one of the important regulators of urogenital system morphogenesis. They play a role in the specification of the first renal cells of the embryo and remain essential players throughout development.[5] # Clinical significance Mutations in this gene have been associated with thyroid dysgenesis, thyroid follicular carcinomas and atypical follicular thyroid adenomas. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[1] The PAX8 gene is also associated congenital hypothyroidism due to thyroid dysgenesis because of its role in growth and development of the thyroid gland. A mutation in the PAX8 gene could prevent or disrupt normal development. These mutations can affect different functions of the protein including DNA biding, gene activation, protein stability, and cooperation with the co-activator p300. PAX gene deficiencies can result in development defects called Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). ## Cancer PAX8 is considered a "master regulator transcription factor".[4] As a master regulator, it is possible that it regulates expression of genes other than thyroid-specific. Several known tumor suppressor genes like TP53 and WT1 have been identified as transcriptional targets in human astrocytoma cells. Over 90% of thyroid tumors arise from follicular thyroid cells.[4] A fusion protein, PAX8-PPAR-γ, is implicated in some follicular thyroid carcinomas and follicular-variant papillary thyroid carcinoma.[6] The mechanism for this transformation is not well understood, but there are several proposed possibilities.[7][8][9] - Inhibition of normal PPAR y function by chimeric PAX8/PPARy protein through a dominant negative effect - Activation of normal PPARy targets due to the over expression of the chimeric protein that contain all functional domains of wild-type PPAR y - Deregulation of PAX8 function - Activation of a set of genes unrelated to both wild-type PPARy and wild-type PAX8 pathways The PAX 8 gene has some association with follicular thyroid tumors. PAX8/PPARy rearrangement account for 30-40% of conventional type follicular carcinomas[10] and less than 5% of oncocytic carcinomas (aka Hurthle-Cell Neoplasms).[11] Tumors expressing the PAX8/PPARy are usually present in at a young age, small in size, present in a solid/nested growth pattern and frequently involve vascular invasion. It has been observed that PAX8/PPAR y-positive tumors rarely express RAS mutations in combination. This suggests that follicular carcinomas develop in two distinct pathways either with PAX8/PPAR y or RAS. Some whole-genome sequencing studies have shown that PAX8 also targets BRCA1 (carcinogenesis), MAPK pathways (thyroid malignancies), and Ccnb1 and Ccnb2 (cell-cycle processes). PAX8 is shown to be involved in tumor cell proliferation and differentiation, signal transduction, apoptosis, cell polarity and transport, cell motility and adhesion.[4] Expression of PAX8 is increased in neoplastic renal tissues, Wilms tumors, ovarian cancer and Müllerian carcinomas. For this reason, the immunodetection of PAX8 is widely used for diagnosing primary and metastatic renal tumors. Re-activation of PAX8 (or Pax2) expression has been reported in pediatric Wilms Tumors, almost all subtypes of renal cell carcinoma, nephrogenic adenomas, ovarian cancer cells, bladder, prostate, and endometrial carcinomas.[5] The mechanism of switching on the genes is unknown. Some studies have suggested that the renal PAX genes act as pro-survival factors and allow tumor cells to resist apoptosis. Down regulation of the PAX gene expression inhibits cell growth and induces apoptosis. This could be a possible avenue for therapeutic targets in renal cancer. # Interactions PAX8 has been shown to interact with NK2 homeobox 1.[12]

https://www.wikidoc.org/index.php/PAX8

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wikidoc

PAX9

PAX9 Paired box gene 9, also known as PAX9, is a protein which in humans is encoded by the PAX9 gene. It is also found in other mammals. # Expression and function This gene is a member of the paired box (PAX) family of transcription factors. During mouse embryogenesis Pax9 expression starts from embryonic day 8.5 and becomes more evident by E9.5; at this stage its expression is restricted to the pharyngeal endoderm. Later on, Pax9 is also expressed in the axial skeleton. Pax9 is required for craniofacial, tooth and limb development, and may more generally involve development of stratified squamous epithelia as well as various organs and skeletal elements. PAX9 plays a role in the absence of wisdom teeth in some human populations (possibly along with the less well studied AXIN2 and MSX1). # Clinical significance This gene was found amplified in lung cancer. The amplification covers three tissue developmental genes - TTF1, NKX2-8, and PAX9. It appears that certain lung cancer cells select for DNA copy number amplification and increased RNA/protein expression of these three coamplified genes for functional advantages. ## Oligodontia Oligodontia is a genetic disorder caused by the mutation of the PAX 9 gene. This disorder results in the congenital absence of 6 or more permanent teeth, with the exception of the third molar. Also known as selective tooth agenesis (STHAG), it is the most common disorder in regard to human dentition, affecting a little less than one fourth of the population. The gene PAX 9 which can be found on chromosome 14 encodes a group of transcription factors that play an important role in early tooth development. In humans, a frameshift mutation in the paired domain of PAX 9 was discovered in those affected with oligodontia. Multiple mechanisms are possible by which the mutation may arise. Recently, a study involving the missense mutation of a PAX 9 gene suggests that the loss of function due to the absence DNA binding domain is a mechanism that causes oligodontia. Those who express the PAX 9 mutation and develop the disorder continue to have a normal life expectancy. Along with the mutation of the PAX 9 gene, MSX1 gene mutations have also shown to affect dental development in fetuses. # Interactions PAX9 has been shown to interact with JARID1B.

PAX9 Paired box gene 9, also known as PAX9, is a protein which in humans is encoded by the PAX9 gene.[1][2] It is also found in other mammals.[3] # Expression and function This gene is a member of the paired box (PAX) family of transcription factors. During mouse embryogenesis Pax9 expression starts from embryonic day 8.5 and becomes more evident by E9.5; at this stage its expression is restricted to the pharyngeal endoderm.[4][5] Later on, Pax9 is also expressed in the axial skeleton.[4] Pax9 is required for craniofacial, tooth and limb development,[3][4] and may more generally involve development of stratified squamous epithelia as well as various organs and skeletal elements.[1] PAX9 plays a role in the absence of wisdom teeth in some human populations (possibly along with the less well studied AXIN2 and MSX1).[3] # Clinical significance This gene was found amplified in lung cancer. The amplification covers three tissue developmental genes - TTF1, NKX2-8, and PAX9.[6] It appears that certain lung cancer cells select for DNA copy number amplification and increased RNA/protein expression of these three coamplified genes for functional advantages. ## Oligodontia Oligodontia is a genetic disorder caused by the mutation of the PAX 9 gene. This disorder results in the congenital absence of 6 or more permanent teeth, with the exception of the third molar.[7] Also known as selective tooth agenesis (STHAG), it is the most common disorder in regard to human dentition, affecting a little less than one fourth of the population.[7] The gene PAX 9 which can be found on chromosome 14 encodes a group of transcription factors that play an important role in early tooth development.[8] In humans, a frameshift mutation in the paired domain of PAX 9 was discovered in those affected with oligodontia.[9] Multiple mechanisms are possible by which the mutation may arise. Recently, a study involving the missense mutation of a PAX 9 gene suggests that the loss of function due to the absence DNA binding domain is a mechanism that causes oligodontia.[10] Those who express the PAX 9 mutation and develop the disorder continue to have a normal life expectancy. Along with the mutation of the PAX 9 gene, MSX1 gene mutations have also shown to affect dental development in fetuses.[10] # Interactions PAX9 has been shown to interact with JARID1B.[11]

https://www.wikidoc.org/index.php/PAX9

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wikidoc

PCA3

PCA3 Prostate cancer antigen 3 (PCA3, also referred to as DD3) is a gene that expresses a non-coding RNA. PCA3 is only expressed in human prostate tissue, and the gene is highly overexpressed in prostate cancer. Because of its restricted expression profile, the PCA3 RNA is useful as a tumor marker. # Use as biomarker The most frequently used biomarker for prostate cancer today is the serum level of prostate-specific antigen (PSA), or derived measurements. However, since PSA is prostate-specific but not cancer-specific, it is an imperfect biomarker. For example, PSA can increase in older men with benign prostatic hyperplasia. Several new biomarkers are being investigated to improve the diagnosis of prostate cancer. Some of these can be measured in urine samples, and it is possible that a combination of several urinary biomarkers will replace PSA in the future. Compared to serum PSA, PCA3 has a lower sensitivity but a higher specificity and a better positive and negative predictive value. It is independent of prostate volume, whereas PSA is not. It should be measured in the first portion of urine after prostate massage with digital rectal examination. PCA3 has been shown to be useful to predict the presence of malignancy in men undergoing repeat prostate biopsy. This means that it could be useful clinically for a patient for whom digital rectal examination and PSA suggest possible prostate cancer, but the first prostate biopsy returns a normal result. This occurs in approximately 60% of cases, and on repeat testing, 20-40% have an abnormal biopsy result. Other uses that are being studied for PCA3 include its correlation with adverse tumor features such as tumor volume, grading (Gleason score) or extracapsular extension. These studies have so far produced conflicting results. # Society and culture A commercial kit called the Progensa PCA3 test is marketed by the Californian company Gen-Probe. Gen-Probe acquired rights to the PCA3 test from Diagnocure in 2003. In April 2012, Hologic bought Gen-Probe for $3.75 billion by cash. # Discovery PCA3 was discovered to be highly expressed by prostate cancer cells in 1999.

PCA3 Prostate cancer antigen 3 (PCA3, also referred to as DD3) is a gene that expresses a non-coding RNA. PCA3 is only expressed in human prostate tissue, and the gene is highly overexpressed in prostate cancer.[1][2] Because of its restricted expression profile, the PCA3 RNA is useful as a tumor marker.[3] # Use as biomarker The most frequently used biomarker for prostate cancer today is the serum level of prostate-specific antigen (PSA), or derived measurements. However, since PSA is prostate-specific but not cancer-specific, it is an imperfect biomarker. For example, PSA can increase in older men with benign prostatic hyperplasia. Several new biomarkers are being investigated to improve the diagnosis of prostate cancer. Some of these can be measured in urine samples, and it is possible that a combination of several urinary biomarkers will replace PSA in the future.[4] Compared to serum PSA, PCA3 has a lower sensitivity but a higher specificity and a better positive and negative predictive value.[5] It is independent of prostate volume, whereas PSA is not.[6] It should be measured in the first portion of urine after prostate massage with digital rectal examination.[7] PCA3 has been shown to be useful to predict the presence of malignancy in men undergoing repeat prostate biopsy.[7][8] This means that it could be useful clinically for a patient for whom digital rectal examination and PSA suggest possible prostate cancer, but the first prostate biopsy returns a normal result. This occurs in approximately 60% of cases, and on repeat testing, 20-40% have an abnormal biopsy result.[9] Other uses that are being studied for PCA3 include its correlation with adverse tumor features such as tumor volume, grading (Gleason score) or extracapsular extension. These studies have so far produced conflicting results.[10][11][12] # Society and culture A commercial kit called the Progensa PCA3 test is marketed by the Californian company Gen-Probe.[citation needed] Gen-Probe acquired rights to the PCA3 test from Diagnocure in 2003.[citation needed] In April 2012, Hologic bought Gen-Probe for $3.75 billion by cash.[13] # Discovery PCA3 was discovered to be highly expressed by prostate cancer cells in 1999.[1][third-party source needed]

https://www.wikidoc.org/index.php/PCA3

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wikidoc

PCAF

PCAF P300/CBP-associated factor (PCAF), also known as K(lysine) acetyltransferase 2B (KAT2B), is a human gene and transcriptional coactivator associated with p53. # Structure Several domains of PCAF can act independently or in unison to enable its functions. PCAF has separate acetyltransferase and E3 ubiquitin ligase domains as well as a bromodomain for interaction with other proteins. PCAF also possesses sites for its own acetylation and ubiquitination. # Function CBP and p300 are large nuclear proteins that bind to many sequence-specific factors involved in cell growth and/or differentiation, including c-jun and the adenoviral oncoprotein E1A. The protein encoded by the PCAF gene associates with p300/CBP. It has in vitro and in vivo binding activity with CBP and p300, and competes with E1A for binding sites in p300/CBP. It has histone acetyl transferase activity with core histones and nucleosome core particles, indicating that this protein plays a direct role in transcriptional regulation. # Regulation The acetyltransferase activity and cellular location of PCAF are regulated through acetylation of PCAF itself. PCAF may be autoacetylated (acetylated by itself) or by p300. Acetylation leads to migration to the nucleus and enhances its acetyltransferase activity. PCAF interacts with and is deacetylated by HDAC3, leading to a reduction in PCAF acetyltransferase activity and cytoplasmic localisation. # Protein interactions PCAF forms complexes with numerous proteins that guide its activity. For example PCAF is recruited by ATF to acetylate histones and promote transcription of ATF4 target genes. # Targets There are various protein targets of PCAF's acetyltransferase activity including transcription factors such as Fli1, p53 and numerous histone residues. Hdm2, itself a ubiquitin ligase that targets p53, has also been demonstrated to be a target of the ubiquitin-ligase activity of PCAF. # Interactions PCAF has been shown to interact with: - BRCA2, - CTNNB1, - CREBBP, - EVI1, - HNF1A, - IRF1, - IRF2, - KLF13, - Mdm2 - Myc, - NCOA1, - POLR2A, - RBPJ, - TCF3, - TRRAP, and - TWIST1.

PCAF P300/CBP-associated factor (PCAF), also known as K(lysine) acetyltransferase 2B (KAT2B), is a human gene and transcriptional coactivator associated with p53. # Structure Several domains of PCAF can act independently or in unison to enable its functions. PCAF has separate acetyltransferase and E3 ubiquitin ligase domains as well as a bromodomain for interaction with other proteins. PCAF also possesses sites for its own acetylation and ubiquitination.[1] # Function CBP and p300 are large nuclear proteins that bind to many sequence-specific factors involved in cell growth and/or differentiation, including c-jun and the adenoviral oncoprotein E1A. The protein encoded by the PCAF gene associates with p300/CBP. It has in vitro and in vivo binding activity with CBP and p300, and competes with E1A for binding sites in p300/CBP. It has histone acetyl transferase activity with core histones and nucleosome core particles, indicating that this protein plays a direct role in transcriptional regulation.[2] # Regulation The acetyltransferase activity and cellular location of PCAF are regulated through acetylation of PCAF itself. PCAF may be autoacetylated (acetylated by itself) or by p300. Acetylation leads to migration to the nucleus and enhances its acetyltransferase activity.[3] PCAF interacts with and is deacetylated by HDAC3, leading to a reduction in PCAF acetyltransferase activity and cytoplasmic localisation.[4] # Protein interactions PCAF forms complexes with numerous proteins that guide its activity. For example PCAF is recruited by ATF[5] to acetylate histones and promote transcription of ATF4 target genes. # Targets There are various protein targets of PCAF's acetyltransferase activity including transcription factors such as Fli1,[6] p53[7] and numerous histone residues. Hdm2, itself a ubiquitin ligase that targets p53, has also been demonstrated to be a target of the ubiquitin-ligase activity of PCAF.[1] # Interactions PCAF has been shown to interact with: - BRCA2,[8][9] - CTNNB1,[10] - CREBBP,[11][12] - EVI1,[13] - HNF1A,[14] - IRF1,[15] - IRF2,[15][16] - KLF13,[17] - Mdm2[18] - Myc,[19] - NCOA1,[20] - POLR2A,[12] - RBPJ,[21] - TCF3,[22] - TRRAP,[19][23] and - TWIST1.[24]

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

435b537c1d49b76f19f1ee422208d56977cac5c8

wikidoc

PCK1

PCK1 Phosphoenolpyruvate carboxykinase 1 (soluble), also known as PCK1, is an enzyme which in humans is encoded by the PCK1 gene. # Function This enzyme is a main control point for the regulation of gluconeogenesis. The cytosolic enzyme encoded by this gene, along with GTP, catalyzes the formation of phosphoenolpyruvate from oxaloacetate, with the release of carbon dioxide and GDP. The expression of this gene can be regulated by insulin, glucocorticoids, glucagon, cAMP, and diet. A mitochondrial isozyme of the encoded protein also has been characterized. # 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}

PCK1 Phosphoenolpyruvate carboxykinase 1 (soluble), also known as PCK1, is an enzyme which in humans is encoded by the PCK1 gene.[1][2] # Function This enzyme is a main control point for the regulation of gluconeogenesis. The cytosolic enzyme encoded by this gene, along with GTP, catalyzes the formation of phosphoenolpyruvate from oxaloacetate, with the release of carbon dioxide and GDP. The expression of this gene can be regulated by insulin, glucocorticoids, glucagon, cAMP, and diet. A mitochondrial isozyme of the encoded protein also has been characterized.[1] # 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/PCK1

bfb5aceb67610b386daf742c32f7613bbcd4accd

wikidoc

PCK2

PCK2 Phosphoenolpyruvate carboxykinase 2, mitochondrial (PCK2, PEPCK-M), is an isozyme of phosphoenolpyruvate carboxykinase (PCK, PEPCK) that in humans is encoded by the PCK2 gene on chromosome 14. This gene encodes a mitochondrial enzyme that catalyzes the conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP) in the presence of guanosine triphosphate (GTP). A cytosolic form of this protein is encoded by a different gene and is the key enzyme of gluconeogenesis in the liver. Alternatively spliced transcript variants have been described. # Structure The PCK2 gene encodes the mitochondrial form of PCK and shares a 68% homology in DNA sequence with PCK1 and 70% homology in amino acid sequence with its encoded cytosolic form, PCK1. Moreover, PCK2 shares structural homology with PCK1, indicating that the genes originated from a common ancestor gene. Nonetheless, though both genes possess ten exons and nine introns, the sizes of their introns may differ by ~2 kb, with the largest intron in PCK2 spanning 2.5 kb. Altogether, the total length of the PCK2 gene spans ~10 kb. Another difference is the presence of Alu sequences in its introns that are absent in PCK1. PCK2 also contains an 18-residue mitochondrial targeting sequence at its N-terminal. Potential regulatory elements, including five GC boxes and three CCAAT boxes, lie 1819 bp upstream of the transcription start site. In addition, the proximal promoter region of PCK2 contains two putative ATF/CRE sequences which bind ATF4. # Function As a PCK, PCK2 catalyzes the GTP-driven conversion of OAA to PEP as a rate-limiting step in gluconeogenesis. This conversion step serves as a bridge between glycolytic and TCA cycle intermediates in the mitochondria. In pancreatic β-cells, PCK2 regulates glucose-stimulated insulin secretion by recycling GTP generated from the succinyl-CoA synthase reaction. This drives the TCA cycle, converting PEP to pyruvate to acetyl-CoA for the citrate synthase reaction. Since nearly all of the glycolytic reactions upstream of PEP and downstream of glucose-6-phosphate (G6P) are reversible, PCK2-mediated synthesis of PEP could fuel multiple biosynthetic processes, such as serine synthesis, glycerol synthesis, and nucleotide synthesis. Notably, PCK2 preferentially converts OAA derived from lactate and, thus, can promote biosynthesis even under low-glucose conditions. As a result, PCK2 activity contributes to cell growth and survival during stress. While PCK1 is mainly expressed in the liver and kidney, PCK2 is ubiquitously expressed in various cell types, including leukocytes and neurons, as well as in non-gluconeogenic tissues, including pancreas, brain, heart. Moreover, while PCK1 expression is regulated by hormones or nutrients involved in gluconeogenesis, PCK2 is constitutively expressed. These differences indicate that PCK2 may also perform non-gluconeogenic functions. # Clinical Significance PCK2 is associated with several cancers, including lung cancer, and promotes tumorigenesis through its gluconeogenic function. In low-glucose settings, stress to the endoplasmic reticulum upregulates ATF4, which then upregulates PCK2. As PCK2 allows cells to utilize alternative cataplerotic pathways to convert TCA cycle intermediates to glycolytic intermediates, PCK2 activity can enhance the survival tumor cells facing reduced glucose levels. Due to the gluconeogenic function of PCK2, PCK2 deficiency is expected to disrupt glucose homeostasis and result in hypoglycemia. However, though two cases have been documented, a subsequent study suggested that PCK2 deficiency may not have been the primary cause. # 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}

PCK2 Phosphoenolpyruvate carboxykinase 2, mitochondrial (PCK2, PEPCK-M), is an isozyme of phosphoenolpyruvate carboxykinase (PCK, PEPCK) that in humans is encoded by the PCK2 gene on chromosome 14. This gene encodes a mitochondrial enzyme that catalyzes the conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP) in the presence of guanosine triphosphate (GTP). A cytosolic form of this protein is encoded by a different gene and is the key enzyme of gluconeogenesis in the liver. Alternatively spliced transcript variants have been described.[provided by RefSeq, Apr 2014][1] # Structure The PCK2 gene encodes the mitochondrial form of PCK and shares a 68% homology in DNA sequence with PCK1 and 70% homology in amino acid sequence with its encoded cytosolic form, PCK1.[2][3] Moreover, PCK2 shares structural homology with PCK1, indicating that the genes originated from a common ancestor gene.[2] Nonetheless, though both genes possess ten exons and nine introns, the sizes of their introns may differ by ~2 kb, with the largest intron in PCK2 spanning 2.5 kb. Altogether, the total length of the PCK2 gene spans ~10 kb. Another difference is the presence of Alu sequences in its introns that are absent in PCK1.[2] PCK2 also contains an 18-residue mitochondrial targeting sequence at its N-terminal.[3] Potential regulatory elements, including five GC boxes and three CCAAT boxes, lie 1819 bp upstream of the transcription start site.[4] In addition, the proximal promoter region of PCK2 contains two putative ATF/CRE sequences which bind ATF4.[5] # Function As a PCK, PCK2 catalyzes the GTP-driven conversion of OAA to PEP as a rate-limiting step in gluconeogenesis. This conversion step serves as a bridge between glycolytic and TCA cycle intermediates in the mitochondria.[2][5] In pancreatic β-cells, PCK2 regulates glucose-stimulated insulin secretion by recycling GTP generated from the succinyl-CoA synthase reaction. This drives the TCA cycle, converting PEP to pyruvate to acetyl-CoA for the citrate synthase reaction.[5] Since nearly all of the glycolytic reactions upstream of PEP and downstream of glucose-6-phosphate (G6P) are reversible, PCK2-mediated synthesis of PEP could fuel multiple biosynthetic processes, such as serine synthesis, glycerol synthesis, and nucleotide synthesis.[6] Notably, PCK2 preferentially converts OAA derived from lactate and, thus, can promote biosynthesis even under low-glucose conditions.[2][5][6] As a result, PCK2 activity contributes to cell growth and survival during stress.[5] While PCK1 is mainly expressed in the liver and kidney, PCK2 is ubiquitously expressed in various cell types, including leukocytes and neurons, as well as in non-gluconeogenic tissues, including pancreas, brain, heart. Moreover, while PCK1 expression is regulated by hormones or nutrients involved in gluconeogenesis, PCK2 is constitutively expressed. These differences indicate that PCK2 may also perform non-gluconeogenic functions.[2][5] # Clinical Significance PCK2 is associated with several cancers, including lung cancer, and promotes tumorigenesis through its gluconeogenic function.[5][6] In low-glucose settings, stress to the endoplasmic reticulum upregulates ATF4, which then upregulates PCK2.[5] As PCK2 allows cells to utilize alternative cataplerotic pathways to convert TCA cycle intermediates to glycolytic intermediates, PCK2 activity can enhance the survival tumor cells facing reduced glucose levels.[5][6] Due to the gluconeogenic function of PCK2, PCK2 deficiency is expected to disrupt glucose homeostasis and result in hypoglycemia. However, though two cases have been documented, a subsequent study suggested that PCK2 deficiency may not have been the primary cause.[3][7] # 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/PCK2

2d2c38538bf6330c9b6533f8437997931108ffee

wikidoc

PCLO

PCLO Protein piccolo is a protein that in humans is encoded by the PCLO gene. # Function Synaptic vesicles dock and fuse in the active zone of the plasma membrane at chemical synapses. The presynaptic cytoskeletal matrix (PCM), which is associated with the active zone and is situated between synaptic vesicles, is thought to be involved in maintaining the neurotransmitter release site in register with the postsynaptic reception apparatus. The cycling of synaptic vesicles is a multistep process involving a number of proteins (see MIM 603215). Among the components of the PCM that orchestrate these events are Bassoon (BSN; MIM 604020), RIM (RIMS1; MIM 606629), Oboe (RIMS2; MIM 606630), and Piccolo (PCLO). # Interactions The protein product of PCLO called Piccolo has been shown to interact with number of proteins including GIT1, the F-actin-binding protein Abp1, PRA1, TRIO, DAAM1, and Profilin. # Clinical relevance Recurrent mutations in this gene have been associated to cases of diffuse large B-cell lymphoma. Recent evidence has shown that a homozygous, nonsense PCLO mutation is the genetic cause of the autosomal recessive neurodegenerative disorder, pontocerebellar hypoplasia type III (PCH3).

PCLO Protein piccolo is a protein that in humans is encoded by the PCLO gene.[1][2][3] # Function Synaptic vesicles dock and fuse in the active zone of the plasma membrane at chemical synapses. The presynaptic cytoskeletal matrix (PCM), which is associated with the active zone and is situated between synaptic vesicles, is thought to be involved in maintaining the neurotransmitter release site in register with the postsynaptic reception apparatus. The cycling of synaptic vesicles is a multistep process involving a number of proteins (see MIM 603215). Among the components of the PCM that orchestrate these events are Bassoon (BSN; MIM 604020), RIM (RIMS1; MIM 606629), Oboe (RIMS2; MIM 606630), and Piccolo (PCLO).[supplied by OMIM][3] # Interactions The protein product of PCLO called Piccolo has been shown to interact with number of proteins including GIT1,[4] the F-actin-binding protein Abp1,[5] PRA1,[6] TRIO,[7] DAAM1,[8] and Profilin.[9] # Clinical relevance Recurrent mutations in this gene have been associated to cases of diffuse large B-cell lymphoma.[10] Recent evidence has shown that a homozygous, nonsense PCLO mutation is the genetic cause of the autosomal recessive neurodegenerative disorder, pontocerebellar hypoplasia type III (PCH3).[11]

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

89857315c4e8d99cc6189706c686c80a64b650dc

wikidoc

PCNA

PCNA # Overview Proliferating Cell Nuclear Antigen, commonly known as PCNA, is a protein that acts as a processivity factor for DNA polymerase delta in eukaryotic cells. It achieves this processivity by encircling the DNA, thus creating a topological link to the genome. It is an example of a DNA clamp. The protein encoded by this gene is found in the nucleus and is a cofactor of DNA polymerase delta. The encoded protein acts as a homotrimer and helps increase the processivity of leading strand synthesis during DNA replication. In response to DNA damage, this protein is ubiquitinated and is involved in the RAD6-dependent DNA repair pathway. Two transcript variants encoding the same protein have been found for this gene. Pseudogenes of this gene have been described on chromosome 4 and on the X chromosome. # Expression in the nucleus during DNA synthesis PCNA was originally identified as an antigen that is expressed in the nuclei of cells during the DNA synthesis phase of the cell cycle . Part of the protein was sequenced and that sequence was used to allow isolation of a cDNA clone . PCNA helps hold DNA polymerase delta (Pol δ) to DNA. PCNA is clamped to DNA through the action of replication factor C (RFC) , which is a heteropentameric member of the AAA+ class of ATPases. Expression of PCNA is under the control of E2F transcription factor-containing complexes . # Role in DNA repair Since DNA polymerase delta is involved in resynthesis of excised damaged DNA strands during DNA repair, PCNA is important for both DNA synthesis and DNA repair . PCNA is also involved in the switch to DNA damage bypass translation synthesis.

PCNA Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Proliferating Cell Nuclear Antigen, commonly known as PCNA, is a protein that acts as a processivity factor for DNA polymerase delta in eukaryotic cells. It achieves this processivity by encircling the DNA, thus creating a topological link to the genome. It is an example of a DNA clamp. The protein encoded by this gene is found in the nucleus and is a cofactor of DNA polymerase delta. The encoded protein acts as a homotrimer and helps increase the processivity of leading strand synthesis during DNA replication. In response to DNA damage, this protein is ubiquitinated and is involved in the RAD6-dependent DNA repair pathway. Two transcript variants encoding the same protein have been found for this gene. Pseudogenes of this gene have been described on chromosome 4 and on the X chromosome.[1] # Expression in the nucleus during DNA synthesis PCNA was originally identified as an antigen that is expressed in the nuclei of cells during the DNA synthesis phase of the cell cycle [2]. Part of the protein was sequenced and that sequence was used to allow isolation of a cDNA clone [3]. PCNA helps hold DNA polymerase delta (Pol δ) to DNA. PCNA is clamped [4] to DNA through the action of replication factor C (RFC) [5], which is a heteropentameric member of the AAA+ class of ATPases. Expression of PCNA is under the control of E2F transcription factor-containing complexes [6]. # Role in DNA repair Since DNA polymerase delta is involved in resynthesis of excised damaged DNA strands during DNA repair, PCNA is important for both DNA synthesis and DNA repair [7]. PCNA is also involved in the switch to DNA damage bypass translation synthesis.

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

44c1a5c70954bcf0c9418d0a84410944abd3a02f

wikidoc

PCNT

PCNT Pericentrin (kendrin), also known as PCNT and pericentrin-B (PCNTB), is a protein which in humans is encoded by the PCNT gene on chromosome 21. This protein localizes to the centrosome and recruits proteins to the pericentriolar matrix (PCM) to ensure proper centrosome and mitotic spindle formation, and thus, uninterrupted cell cycle progression. This gene is implicated in many diseases and disorders, including congenital disorders such as microcephalic osteodysplastic primordial dwarfism type II (MOPDII) and Seckel syndrome. # Structure PCNT is a 360 kDa protein which contains a series of coiled coil domains and a highly conserved PCM targeting motif called the PACT domain near its C-terminus. The PACT domain is responsible for targeting the protein to the centrosomes and attaching it to the centriole walls during interphase. In addition, PCNT possesses five nuclear export sequences which all contribute to its nuclear export into the cytoplasm, as well as one nuclear localization signal composed of three clusters of basic amino acids, all of which contribute to the protein’s nuclear localization. PCNTB, a cDNA homolog of PCNT, was identified and described by Li et al. to share a sequence identity of 61% and similarity of 75%. However, compared to PCNT, PCNTB contains an additional coiled coil domain and unique 1000-residue C-terminus, suggesting that these two may be separate proteins in a new CPM superfamily. As with PCNT, the C-terminus of PCNTB contains functional domains for centriole localization and CEP215 binding. The N-terminus may also contain a functional domain that associates with the C-terminus domain, and this association is required for engagement with the centriole. # Function The protein encoded by this gene is expressed in the cytoplasm and centrosome throughout the cell cycle, and to a lesser extent, in the nucleus. It is an integral component of the PCM, which is a centrosome scaffold that anchors microtubule nucleating complexes and other centrosomal proteins. In one model, PCNT complexes with CEP215 and is phosphorylated by PLK1, leading to PCM component recruitment and organization, centrosome maturation, and spindle formation. The protein controls the nucleation of microtubules by interacting with the microtubule nucleation component γ-tubulin, thus anchoring the γ-tubulin ring complex to the centrosome, which is essential for bipolar spindle formation and chromosome assembly in early mitosis. This ensures normal function and organization of the centrosomes, mitotic spindles, and cytoskeleton, and by extension, regulation over cell cycle progression and checkpoints. Downregulation of PCNT disrupted mitotic checkpoints and arrested the cell at the G2/M checkpoint, leading to cell death. Moreover, microtubule functioning was also disrupted, resulting in mono- or multipolar spindles, chromosomal misalignment, premature sister chromatid separation, and aneuploidy. PCNT is highly abundant in skeletal muscle, indicating that it may be involved in muscle insulin action. PCNT is also involved in neuronal development through its interaction with DISC1 to regulate microtubule organization. # Clinical significance Mutations in the PCNT gene have been linked to Down syndrome (DS); two types of primordial dwarfism, MOPDII and Seckel syndrome; intrauterine growth retardation; cardiomyopathy; early onset type 2 diabetes; chronic myeloid leukemia (CML); bipolar affective disorder; and other congenital disorders . In particular, the short stature and small brain size characteristic of MOPDII and Seckel syndrome have been attributed to centrosome dysfunction and cell growth disruption as a result of PCNT malfunction. Additionally, premature aging, cerebral involution, inflammatory and immune responses are linked to DS associated with PCNT mutations, while severe insulin resistance, diabetes, and dyslipidemia are featured in MOPDII associated with PCNT mutations. # Interactions PCNT has been shown to interact with: - calmodulin, - separase, - CEP215, - CHD3/4, - protein kinase A, - protein kinase C, - DISC1, - γ-tubulin complex proteins, and - PCM1.

PCNT Pericentrin (kendrin), also known as PCNT and pericentrin-B (PCNTB), is a protein which in humans is encoded by the PCNT gene on chromosome 21.[1][2][3][4] This protein localizes to the centrosome and recruits proteins to the pericentriolar matrix (PCM) to ensure proper centrosome and mitotic spindle formation, and thus, uninterrupted cell cycle progression.[1][5][6][7][8] This gene is implicated in many diseases and disorders, including congenital disorders such as microcephalic osteodysplastic primordial dwarfism type II (MOPDII) and Seckel syndrome.[5][6] # Structure PCNT is a 360 kDa protein which contains a series of coiled coil domains and a highly conserved PCM targeting motif called the PACT domain near its C-terminus.[1][4][5][6][7][9][10] The PACT domain is responsible for targeting the protein to the centrosomes and attaching it to the centriole walls during interphase.[5][6] In addition, PCNT possesses five nuclear export sequences which all contribute to its nuclear export into the cytoplasm, as well as one nuclear localization signal composed of three clusters of basic amino acids, all of which contribute to the protein’s nuclear localization.[5] PCNTB, a cDNA homolog of PCNT, was identified and described by Li et al. to share a sequence identity of 61% and similarity of 75%. However, compared to PCNT, PCNTB contains an additional coiled coil domain and unique 1000-residue C-terminus, suggesting that these two may be separate proteins in a new CPM superfamily.[4] As with PCNT, the C-terminus of PCNTB contains functional domains for centriole localization and CEP215 binding. The N-terminus may also contain a functional domain that associates with the C-terminus domain, and this association is required for engagement with the centriole.[11] # Function The protein encoded by this gene is expressed in the cytoplasm and centrosome throughout the cell cycle, and to a lesser extent, in the nucleus. It is an integral component of the PCM, which is a centrosome scaffold that anchors microtubule nucleating complexes and other centrosomal proteins.[1][4][5][7][11][12] In one model, PCNT complexes with CEP215 and is phosphorylated by PLK1, leading to PCM component recruitment and organization, centrosome maturation, and spindle formation.[6][11] The protein controls the nucleation of microtubules by interacting with the microtubule nucleation component γ-tubulin, thus anchoring the γ-tubulin ring complex to the centrosome, which is essential for bipolar spindle formation and chromosome assembly in early mitosis.[1][5][6][7][8] This ensures normal function and organization of the centrosomes, mitotic spindles, and cytoskeleton, and by extension, regulation over cell cycle progression and checkpoints.[1][5][6][7][12] Downregulation of PCNT disrupted mitotic checkpoints and arrested the cell at the G2/M checkpoint, leading to cell death.[10][12] Moreover, microtubule functioning was also disrupted, resulting in mono- or multipolar spindles, chromosomal misalignment, premature sister chromatid separation, and aneuploidy.[6][12] PCNT is highly abundant in skeletal muscle, indicating that it may be involved in muscle insulin action.[7] PCNT is also involved in neuronal development through its interaction with DISC1 to regulate microtubule organization.[8] # Clinical significance Mutations in the PCNT gene have been linked to Down syndrome (DS); two types of primordial dwarfism, MOPDII and Seckel syndrome; intrauterine growth retardation; cardiomyopathy; early onset type 2 diabetes; chronic myeloid leukemia (CML); bipolar affective disorder; and other congenital disorders .[5][6][8][10][11][12][12] In particular, the short stature and small brain size characteristic of MOPDII and Seckel syndrome have been attributed to centrosome dysfunction and cell growth disruption as a result of PCNT malfunction.[5] Additionally, premature aging, cerebral involution, inflammatory and immune responses are linked to DS associated with PCNT mutations, while severe insulin resistance, diabetes, and dyslipidemia are featured in MOPDII associated with PCNT mutations.[7][10] # Interactions PCNT has been shown to interact with: - calmodulin,[1] - separase,[11] - CEP215,[6] - CHD3/4,[5] - protein kinase A,[5] - protein kinase C,[5] - DISC1,[5] - γ-tubulin complex proteins,[5] and - PCM1.[4][4][5]

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

89255d13060d30cfb1563a98182875d82e70d382

wikidoc

PDE1

PDE1 PDE1 (phosphodiesterase1) is a phosphodiesterase enzyme also known as calcium- and calmodulin-dependent phosphodiesterase. It is one of the 11 families of phosphodiesterase (PDE1-PDE11). PDE1 has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms. The various isoforms exhibit different affinities for cAMP and cGMP. # Discovery of PDE1 The existence of the Ca2+-stimulated PDE1 was first demonstrated by Cheung (1970), Kakiuchi and Yamazaki (1970) as a result of their research on bovine brain and rat brain respectively. . It has since been found to be widely distributed in various mammalian tissues as well as in other eukaryotes. It is now one of the most intensively studied member of the PDE superfamily of enzymes , which today represents 11 gene families , and the best characterized one as well . Further researches in the field along with increased availability of monoclonal antibodies have shown that various PDE1 isozymes exist and have been identified and purified. It is now known that PDE1 exists as tissue specific isozymes. # Structure of PDE1 The PDE1 isozyme family belongs to a Class I enzymes , which includes all vertebrate PDEs and some yeast enzymes. Class I enzymes all have a catalytic core of at least 250 amino acids whereas Class II enzymes lack such a common feature. Usually vertebrate PDEs are dimers of linear 50 – 150 kDa proteins. They consist of three functional domains; a conserved catalytic core, a regulatory N-terminus and a C-terminus . The proteins are chimeric and each domain is associated with their particular function . The regulatory N-terminus is substantially different in various PDE types. . They are flanked by the catalytic core and include regions that auto-inhibit the catalytic domains. They also target sequences that control subcellular localization. In PDE1 this region contains a calmodulin binding domain. The catalytic domains of PDE1 (and other types of PDEs) have three helical subdomains: an N-terminal cyclin-fold region, a linker region and a C-terminal helical bundle. A deep hydrophobic pocket is formed at the interface of these subdomains. It is composed of four subsites. They are: a metal binding site (M site), core pocket (Q pocket), hydrophobic pocket (H pocket) and lid region (L region). The M site is placed at the bottom of the hydrophobic pocket with several metal atoms. The metal atoms bind to residues that are completely conserved in all PDE family members. The identity of the metal atoms is not known with absolute certainty. However, some evidence indicate that at least one of the metals is zinc and the other is likely to be magnesium. The zinc coordination sphere is composed of three histidines, one aspartate and two water molecules. The magnesium coordination sphere involves the same aspartate along with five water molecules, one of which is shared with the zinc molecule. The reputed role of the metal ions include structure stabilization as well as activation of hydroxide to mediate catalysis. The domains are separated by ”hinge” regions where they can be experimentally separated by limited proteolysis. The PDE1 isozyme family (along with the PDE4 family) is the most diverse one and includes numerous splice variant PDE1 isoforms. It has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms. # Localization The localization of PDE1 isoforms in different tissues/cells and their location within the cells is as follows: Table 1. Various PDE1s location in tissues and within cells. Most PDE1 isoforms are reported to be cytosolic. However, there are instances of PDE1s being localized to subcellular regions but little is known about the molecular mechanisms responsible for such localization. It is thought to be likely that the unique N-terminal or C-terminal regions of the various isoforms allow the different proteins to be targeted to specific subcellular domains. # Functional role Intracellular second messengers such as cGMP and cAMP undergo rapid changes in concentration in a response to a wide variety of cell specific stimuli. The concentration of these second messengers is determined to a large extent by the relative synthetic activity of adenylate cyclase and degrative activity of cyclic nucleotide PDE. The role of PDE1 enzymes is to degrate both cGMP and cAMP. The various isoforms exhibit different affinities for cAMP and cGMP. PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C degrades both cAMP and cGMP with high affinity. For example in airway smooth muscles of humans and other species, generic PDE1 accounts for more than 50% of the hydrolytic activity of cyclic nucleotides . It has been demonstrated that deletion and overexpression of PDE1 produces strong effects on agonist-induced cAMP signalling but has little effect on the basal cAMP level. ## Pharmacology Because of in vitro regulation by Ca2+/calmodulin, PDE1s are believed to function as a mechanism for integrating cell signalling pathways mediated by cGMP and cAMP with pathways that regulate intracellular calcium levels. The precise function of PDE1 isozymes in various pathophysiological processes is not clear because most of the studies have been carried out in vitro. Therefore it is essential to direct further research to in vivo studies. PDE1 has been implicated to play a role in a number of physiological and pathological processes: PDE1A most likely serves to regulate vascular smooth muscle concentration and has been found to be up-regulated in rat aorta in response to chronic nitroglycerin treatment. It is also possible that it plays a role in sperm function. PDE1B knockout mice have increased locomotor activity and in some paradigms decreased memory and learning abilities. PDE1B is also involved in dopaminergic signalling and is induced in several types of activated immune cells. PDE1B mRNA is induced in PHA or anti-CD3/CD28-activated human T-lymphocytes and participates in IL-13 regulation implicated in allergic diseases. PDE1C has been shown to be a major regulator of smooth muscle proliferation, at least in human smooth muscle. Nonproliferating smooth muscle cells (SMC) exhibit only low levels of PDE1C expression but it is highly expressed in proliferating SMCs. It can therefore be speculated that inhibition of PDE1C could produce beneficial effects due to its putative inhibition of SMC proliferation, an event that contributes importantly to the pathophysiology of atherosclerosis. Another likely roles of PDE1C is in olfaction , to regulate sperm function and neuronal signaling. # Regulation The distinguishing feature of PDE1 as a family is their regulation by calcium (Ca2+) and calmodulin (CaM). Calmodulin has been shown to activate cyclic nucleotide PDE in a calcium-dependent manner and the cooperative binding of four Ca2+ to calmodulin is required to fully activate PDE1 . The binding of one Ca2+/CaM complex per monomer to binding sites near the N-terminus stimulates hydrolysis of cyclic nucleotides. In intact cells, PDE1 is almost exclusively activated by Ca2+ entering the cell from the extracellular space. The regulation of PDE1 by Ca2+ and CaM has been studied in vitro and these studies have shown that eight methionine residues within the hydrophobic clefts of Ca2+-CaM are required for the binding and activation of PDE1. Mutations in the N-terminal lobe of CaM affect its ability to activate PDE1 so it is believed that the C-terminal lobe of CaM serves to target CaM to PDE1, while the N-terminal lobe activates the enzyme. The presence of an aromatic residue, usually a tryptophan, in the CaM-binding region of Ca2+-CaM-regulated proteins may also be required for binding to PDE1. Between different PDE1 isozymes there is a significant difference in affinity for Ca2+/CaM. In general, the PDE1 enzymes have high affinity for the complex but the affinity can be affected by phosphorylation. Phosphorylation of PDE1A1 and PDE1A2 by protein kinase A and of PDE1B1 by CaM Kinase II decreases their sensitivity to calmodulin activation. This phosphorylation can be reversed by the phosphatase, calcineurin. The phosphorylation of the isozymes is accompanied by a decrease in the isozymes affinity towards CaM, as well as an increase in the Ca2+ concentrations required for CaM activation of the isozymes. # PDE1 inhibitors and their function PDEs have been pursued as therapeutic targets because of the basic pharmacological principle that regulation of degradation of any ligand or second messenger can often make a more rapid and larger percentage change in concentration than comparable rates of synthesis. Another reason is that PDEs do not have to compete with very high levels of endogenous substrate to be effective since the levels of cAMP and cGMP in most cells are typically in the micromolar range. The availability of high-resolution crystal structures of the catalytic domains of PDEs makes the development of highly potent and specific inhibitors possible. Many compounds reported as PDE1 inhibitors do not interact directly with the catalytic site of PDE1 but interact during activation, either at the level of calmodulin binding sites such as compound KS505a or directly on Ca2+/calmodulin such as bepril, flunarizine and amiodarone. Those inhibitors that interact with the catalytic site occupy part of the active site, primarily around the Q pocket and occasionally close to the M pocket. A major point of interaction is a conserved hydrophobic pocket that is involved in orienting the substrate purine ring for interaction with a glutamine residue that is crucial for the catalytic mechanism of the PDEs. The interactions of inhibitors can be split into three major types: interactions with the metal ions mediated through water, H-bond interactions with the protein residues involved in nucleotide recognition and most importantly the interaction with the hydrophobic residues lining the cavity of the active site. All known inhibitors seem to exploit these three types of interactions and hence these interactions should guide the design of new types of inhibitors. Initially PDE1 inhibitors were claimed to be effective vascular relaxants. With availability of purified cloned enzymes, however, it is now known that such inhibitors are in fact equally active against PDE5. Those inhibitors include e.g. zaprinast, 8-methoxymethyl IPMX and SCH 51866. All therapeutically effective PDE inhibitors must be incorporated into the cell because all PDEs are localized in the cytoplasm and/or on intracellular membranes. Today, there is no real and effective specific PDE1 inhibitor that can be used to assess the functional role of PD1 in tissues . ## Common PDE1 inhibitors Nimodipine (3,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 2-methoxyethyl 1-methylethyl ester ) is a dihydropyridine that antagonizes/blocks specifically L-type Ca2+-channel, and was first described as a PDE1 inhibitor. This effect is not related to its calcium antagonist property since it inhibits, in micromolar range, basal and calmodulin stimulated purified PDE1. Since nimodipine at lower concentrations blocks the L-type calcium channel, it can only be used to estimate PDE1 participation in tissue and cell homogenates . Vinpocetine was described as a specific inhibitor of basal and calmodulin-activated PDE1. This effect leads to an increase of cAMP over cGMP . It is mainly used as a pharmacological tool to implicate PDE1. Vinpocetine inhibits differently the various subtypes of PDE1 (IC50 from 8 to 50µm) and it is also able to inhibit PDE7B. It can not be used as a specific tool to investigate the functional role of PDE1 due to its direct activator effects on BK (Ca) channels. Vinpocetine crosses the blood-brain barrier and is taken up by cerebral tissue. It has been hypothesized that vinpocetine can effect voltage dependent calcium channels. IC224 inhibits PDE1 (IC50 = 0,08 µM) with a selective ratio of 127 (ratio of IC50 value for the next most sensitive PDE and for IC50 value for PDE1). It was developed by ICOS corporation. If IC224 similarly inhibits basal and calmodulin-activated PDE1 subtypes, this compound could be very helpful to characterize PDE1 activity and to clearly investigate the various roles of PDE1 in pathophysiology. # PDE1 inhibitors in diseases Nearly all the phosphodiesterases are expressed in the CNS, making this gene family an attractive source of new targets for the treatment of psychiatric and neurodegenerative disorders. PDE1A2 has a potential role in neurodegenerative diseases e.g.: Parkinsons Axonal neurofilament degradation Motorneuronal degradation Neuronal ischemia Alzheimer’s disease epilepsy PDE1C could have a role in the regulation of insulin release and may target proliferating smooth muscle cells in atherosclerotic lesions or during restenosis.

PDE1 PDE1 (phosphodiesterase1) is a phosphodiesterase enzyme also known as calcium- and calmodulin-dependent phosphodiesterase. It is one of the 11 families of phosphodiesterase (PDE1-PDE11). PDE1 has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms. The various isoforms exhibit different affinities for cAMP and cGMP.[1][2] # Discovery of PDE1 The existence of the Ca2+-stimulated PDE1 was first demonstrated by Cheung (1970), Kakiuchi and Yamazaki (1970) as a result of their research on bovine brain and rat brain respectively. [3] [1]. It has since been found to be widely distributed in various mammalian tissues as well as in other eukaryotes. It is now one of the most intensively studied member of the PDE superfamily of enzymes [3], which today represents 11 gene families [1][4], and the best characterized one as well [3]. Further researches in the field along with increased availability of monoclonal antibodies have shown that various PDE1 isozymes exist and have been identified and purified. It is now known that PDE1 exists as tissue specific isozymes[3]. # Structure of PDE1 The PDE1 isozyme family belongs to a Class I enzymes [2][5], which includes all vertebrate PDEs and some yeast enzymes. [5] Class I enzymes all have a catalytic core of at least 250 amino acids whereas Class II enzymes lack such a common feature.[5] Usually vertebrate PDEs are dimers of linear 50 – 150 kDa proteins[5]. They consist of three functional domains; a conserved catalytic core, a regulatory N-terminus and a C-terminus [3-5]. The proteins are chimeric and each domain is associated with their particular function [2]. The regulatory N-terminus is substantially different in various PDE types. [4][5]. They are flanked by the catalytic core and include regions that auto-inhibit the catalytic domains. They also target sequences that control subcellular localization. In PDE1 this region contains a calmodulin binding domain.[4] The catalytic domains of PDE1 (and other types of PDEs) have three helical subdomains: an N-terminal cyclin-fold region, a linker region and a C-terminal helical bundle. A deep hydrophobic pocket is formed at the interface of these subdomains. It is composed of four subsites. They are: a metal binding site (M site), core pocket (Q pocket), hydrophobic pocket (H pocket) and lid region (L region). The M site is placed at the bottom of the hydrophobic pocket with several metal atoms. The metal atoms bind to residues that are completely conserved in all PDE family members. The identity of the metal atoms is not known with absolute certainty. However, some evidence indicate that at least one of the metals is zinc and the other is likely to be magnesium. The zinc coordination sphere is composed of three histidines, one aspartate and two water molecules. The magnesium coordination sphere involves the same aspartate along with five water molecules, one of which is shared with the zinc molecule. The reputed role of the metal ions include structure stabilization as well as activation of hydroxide to mediate catalysis.[4] The domains are separated by ”hinge” regions where they can be experimentally separated by limited proteolysis.[2] The PDE1 isozyme family (along with the PDE4 family) is the most diverse one and includes numerous splice variant PDE1 isoforms. It has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms.[1][2] # Localization The localization of PDE1 isoforms in different tissues/cells and their location within the cells is as follows: Table 1. Various PDE1s location in tissues and within cells. Most PDE1 isoforms are reported to be cytosolic. However, there are instances of PDE1s being localized to subcellular regions but little is known about the molecular mechanisms responsible for such localization. It is thought to be likely that the unique N-terminal or C-terminal regions of the various isoforms allow the different proteins to be targeted to specific subcellular domains.[2] # Functional role Intracellular second messengers such as cGMP and cAMP undergo rapid changes in concentration in a response to a wide variety of cell specific stimuli. The concentration of these second messengers is determined to a large extent by the relative synthetic activity of adenylate cyclase and degrative activity of cyclic nucleotide PDE.[3] The role of PDE1 enzymes is to degrate both cGMP and cAMP.[7] The various isoforms exhibit different affinities for cAMP and cGMP. PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C degrades both cAMP and cGMP with high affinity. For example in airway smooth muscles of humans and other species, generic PDE1 accounts for more than 50% of the hydrolytic activity of cyclic nucleotides [8]. It has been demonstrated that deletion and overexpression of PDE1 produces strong effects on agonist-induced cAMP signalling but has little effect on the basal cAMP level.[9] ## Pharmacology Because of in vitro regulation by Ca2+/calmodulin, PDE1s are believed to function as a mechanism for integrating cell signalling pathways mediated by cGMP and cAMP with pathways that regulate intracellular calcium levels.[2] The precise function of PDE1 isozymes in various pathophysiological processes is not clear because most of the studies have been carried out in vitro. Therefore it is essential to direct further research to in vivo studies.[3] PDE1 has been implicated to play a role in a number of physiological and pathological processes: PDE1A most likely serves to regulate vascular smooth muscle concentration and has been found to be up-regulated in rat aorta in response to chronic nitroglycerin treatment. It is also possible that it plays a role in sperm function.[7] PDE1B knockout mice have increased locomotor activity and in some paradigms decreased memory and learning abilities. PDE1B is also involved in dopaminergic signalling and is induced in several types of activated immune cells.[7] PDE1B mRNA is induced in PHA or anti-CD3/CD28-activated human T-lymphocytes and participates in IL-13 regulation implicated in allergic diseases.[1] PDE1C has been shown to be a major regulator of smooth muscle proliferation, at least in human smooth muscle. Nonproliferating smooth muscle cells (SMC) exhibit only low levels of PDE1C expression but it is highly expressed in proliferating SMCs. It can therefore be speculated that inhibition of PDE1C could produce beneficial effects due to its putative inhibition of SMC proliferation, an event that contributes importantly to the pathophysiology of atherosclerosis.[7] Another likely roles of PDE1C is in olfaction [4], to regulate sperm function and neuronal signaling.[7] # Regulation The distinguishing feature of PDE1 as a family is their regulation by calcium (Ca2+) and calmodulin (CaM).[10] Calmodulin has been shown to activate cyclic nucleotide PDE in a calcium-dependent manner and the cooperative binding of four Ca2+ to calmodulin is required to fully activate PDE1 [2]. The binding of one Ca2+/CaM complex per monomer to binding sites near the N-terminus stimulates hydrolysis of cyclic nucleotides. In intact cells, PDE1 is almost exclusively activated by Ca2+ entering the cell from the extracellular space. The regulation of PDE1 by Ca2+ and CaM has been studied in vitro and these studies have shown that eight methionine residues within the hydrophobic clefts of Ca2+-CaM are required for the binding and activation of PDE1. Mutations in the N-terminal lobe of CaM affect its ability to activate PDE1 so it is believed that the C-terminal lobe of CaM serves to target CaM to PDE1, while the N-terminal lobe activates the enzyme. The presence of an aromatic residue, usually a tryptophan, in the CaM-binding region of Ca2+-CaM-regulated proteins may also be required for binding to PDE1.[10] Between different PDE1 isozymes there is a significant difference in affinity for Ca2+/CaM. In general, the PDE1 enzymes have high affinity for the complex but the affinity can be affected by phosphorylation. Phosphorylation of PDE1A1 and PDE1A2 by protein kinase A and of PDE1B1 by CaM Kinase II decreases their sensitivity to calmodulin activation.[1] This phosphorylation can be reversed by the phosphatase, calcineurin.[2] The phosphorylation of the isozymes is accompanied by a decrease in the isozymes affinity towards CaM, as well as an increase in the Ca2+ concentrations required for CaM activation of the isozymes.[3] # PDE1 inhibitors and their function PDEs have been pursued as therapeutic targets because of the basic pharmacological principle that regulation of degradation of any ligand or second messenger can often make a more rapid and larger percentage change in concentration than comparable rates of synthesis. Another reason is that PDEs do not have to compete with very high levels of endogenous substrate to be effective since the levels of cAMP and cGMP in most cells are typically in the micromolar range.[2] The availability of high-resolution crystal structures of the catalytic domains of PDEs makes the development of highly potent and specific inhibitors possible.[6] Many compounds reported as PDE1 inhibitors do not interact directly with the catalytic site of PDE1 but interact during activation, either at the level of calmodulin binding sites such as compound KS505a or directly on Ca2+/calmodulin such as bepril, flunarizine and amiodarone.[1] Those inhibitors that interact with the catalytic site occupy part of the active site, primarily around the Q pocket and occasionally close to the M pocket.[11] A major point of interaction is a conserved hydrophobic pocket that is involved in orienting the substrate purine ring for interaction with a glutamine residue that is crucial for the catalytic mechanism of the PDEs.[6] The interactions of inhibitors can be split into three major types: interactions with the metal ions mediated through water, H-bond interactions with the protein residues involved in nucleotide recognition and most importantly the interaction with the hydrophobic residues lining the cavity of the active site. All known inhibitors seem to exploit these three types of interactions and hence these interactions should guide the design of new types of inhibitors.[11] Initially PDE1 inhibitors were claimed to be effective vascular relaxants. With availability of purified cloned enzymes, however, it is now known that such inhibitors are in fact equally active against PDE5.[4] Those inhibitors include e.g. zaprinast, 8-methoxymethyl IPMX and SCH 51866.[1] All therapeutically effective PDE inhibitors must be incorporated into the cell because all PDEs are localized in the cytoplasm and/or on intracellular membranes.[7] Today, there is no real and effective specific PDE1 inhibitor that can be used to assess the functional role of PD1 in tissues [1]. ## Common PDE1 inhibitors Nimodipine (3,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 2-methoxyethyl 1-methylethyl ester [12]) is a dihydropyridine that antagonizes/blocks specifically L-type Ca2+-channel, and was first described as a PDE1 inhibitor. This effect is not related to its calcium antagonist property since it inhibits, in micromolar range, basal and calmodulin stimulated purified PDE1. Since nimodipine at lower concentrations blocks the L-type calcium channel, it can only be used to estimate PDE1 participation in tissue and cell homogenates [1]. Vinpocetine was described as a specific inhibitor of basal and calmodulin-activated PDE1. This effect leads to an increase of cAMP over cGMP [1] [13]. It is mainly used as a pharmacological tool to implicate PDE1. Vinpocetine inhibits differently the various subtypes of PDE1 (IC50 from 8 to 50µm) and it is also able to inhibit PDE7B. It can not be used as a specific tool to investigate the functional role of PDE1 due to its direct activator effects on BK (Ca) channels.[1] Vinpocetine crosses the blood-brain barrier and is taken up by cerebral tissue. It has been hypothesized that vinpocetine can effect voltage dependent calcium channels.[13] IC224 inhibits PDE1 (IC50 = 0,08 µM) with a selective ratio of 127 (ratio of IC50 value for the next most sensitive PDE and for IC50 value for PDE1). It was developed by ICOS corporation. If IC224 similarly inhibits basal and calmodulin-activated PDE1 subtypes, this compound could be very helpful to characterize PDE1 activity and to clearly investigate the various roles of PDE1 in pathophysiology.[1] # PDE1 inhibitors in diseases Nearly all the phosphodiesterases are expressed in the CNS, making this gene family an attractive source of new targets for the treatment of psychiatric and neurodegenerative disorders.[6] PDE1A2 has a potential role in neurodegenerative diseases e.g.:[4] Parkinsons Axonal neurofilament degradation Motorneuronal degradation Neuronal ischemia Alzheimer’s disease epilepsy PDE1C could have a role in the regulation of insulin release [5] and may target proliferating smooth muscle cells in atherosclerotic lesions or during restenosis.[4][14]

https://www.wikidoc.org/index.php/PDE1

7c3412711a66f0a2f6b2675a47137333a862d8cc

wikidoc

PDK2

PDK2 Pyruvate dehydrogenase kinase isoform 2 (PDK2) also known as pyruvate dehydrogenase lipoamide kinase isozyme 2, mitochondrial is an enzyme that in humans is encoded by the PDK2 gene. PDK2 is an isozyme of pyruvate dehydrogenase kinase. # Structure The protein encoded by the PDK2 gene has two sites, an active site and an allosteric site that allow for the activity and regulation of this enzyme. There are many structural motifs that are important to the regulation of this enzyme. Nov3r and AZ12 inhibitors bind at the lipoamide binding site that is located at one end of the R domain. Pfz3 binds in an extended site at the other end of the R domain. One inhibitor, dicholoroacetate (DCA), binds at the center of the R domain. Within the active site, there are three amino acid residues, R250, T302, and Y320, that make the kinase resistant to the inhibitor dichloroacetate, which uncouples the active site from the allosteric site. This supports the theory that R250, T302, and Y320 stabilize the "open" and "closed" conformations of the built-in lid that controls the access of a nucleotide into the nucleotide-binding cavity. This strongly suggests that the mobility of ATP lid is central to the allosteric regulation of PDHK2 activity serving as a conformational switch required for communication between the active site and allosteric sites in the kinase molecule. There is also a DW-motif that is crucial in mediating DCA, nucleotide, and lipoyl domain binding site communication. This network is responsible for rendering PDK2 locked in the closed, or inactive conformation. # Function The Pyruvate Dehydrogenase (PDH) complex must be tightly regulated due to its central role in general metabolism. Within the complex, there are three serine residues on the E1 component that are sites for phosphorylation; this phosphorylation inactivates the complex. In humans, there have been four isozymes of Pyruvate Dehydrogenase Kinase that have been shown to phosphorylate these three sites: PDK1, PDK2, PDK3, and PDK4. PDK2 has been identified as the most abundant isoform in human tissues. Through many studies, it has been made clear that the activity of this enzyme is essential, even at rest, to regulate glycolysis/carbodydrate oxidation and producing metabolites for oxidative phosphorylation and the electron transport chain. These studies have illustrated that the kinetics of the PDK isoform population, specifically PDK2, is more important in determining PDH activity than measuring PDK activity. ## Regulation As the primary regulators of a crucial step in the central metabolic pathway, the pyruvate dehydrogenase family is tightly regulated itself by a myriad of factors. PDK2 activity is modulated by low levels of hydrogen peroxide; this happens because the compound temporarily oxidizes the cysteine residues 45 and 392 on the enzyme, resulting in an inactive PDK2 and greater PDH activity. These conditions also inactivate the TCA cycle, the next step in aerobic respiration. This alludes to the fact that when there is a high level of O2 production in the mitochondria, which may occur because of nutrient excess, the increase in the products serve as a negative feedback that control mitochondria metabolism. PDK2, in conjunction with PDK3 and PDK4, are primary targets of Peroxisome proliferator-activated receptor delta or beta, with PDK2 having two elements that respond to these receptors. # Clinical significance All of the pyruvate dehydrogenase isozymes have been associated with various metabolic disorders, including diabetes. This is due to a mechanism by which consistently elevated free fatty acid levels stimulate the PDK enzymes, particularly, PDK2 and PDK4 in the liver. In stimulating this activity, there is less PDH activity, and therefore less glucose uptake. ## Cancer As the PDK enzymes are associated with central metabolism and growth, they are often associated with various mechanisms of cancer progression. Enhanced PDK2 activity leads to increased glycolysis and lactic acid production, known as the Warburg effect. In some studies, the wild-type form of tumor protein p53 prevents manifestation of tumorigenesis by regulating PDK2 activity. Additionally, inhibition of PDK2 subsequently inhibits HIF1A in cancer cells by both a prolyl-hydroxylase (PHD)-dependent mechanism and a PHD-independent mechanism. Therefore, mitochondria-targeting metabolic modulators increase pyruvate dehydrogenase activity, and suppress angiogenesis as well, normalizing the pseudo-hypoxic signals that lead to normoxic HIF1A activation in solid tumors.

PDK2 Pyruvate dehydrogenase kinase isoform 2 (PDK2) also known as pyruvate dehydrogenase lipoamide kinase isozyme 2, mitochondrial is an enzyme that in humans is encoded by the PDK2 gene.[1][2] PDK2 is an isozyme of pyruvate dehydrogenase kinase. # Structure The protein encoded by the PDK2 gene has two sites, an active site and an allosteric site that allow for the activity and regulation of this enzyme. There are many structural motifs that are important to the regulation of this enzyme. Nov3r and AZ12 inhibitors bind at the lipoamide binding site that is located at one end of the R domain. Pfz3 binds in an extended site at the other end of the R domain. One inhibitor, dicholoroacetate (DCA), binds at the center of the R domain.[3] Within the active site, there are three amino acid residues, R250, T302, and Y320, that make the kinase resistant to the inhibitor dichloroacetate, which uncouples the active site from the allosteric site. This supports the theory that R250, T302, and Y320 stabilize the "open" and "closed" conformations of the built-in lid that controls the access of a nucleotide into the nucleotide-binding cavity. This strongly suggests that the mobility of ATP lid is central to the allosteric regulation of PDHK2 activity serving as a conformational switch required for communication between the active site and allosteric sites in the kinase molecule.[4] There is also a DW-motif that is crucial in mediating DCA, nucleotide, and lipoyl domain binding site communication. This network is responsible for rendering PDK2 locked in the closed, or inactive conformation.[5] # Function The Pyruvate Dehydrogenase (PDH) complex must be tightly regulated due to its central role in general metabolism. Within the complex, there are three serine residues on the E1 component that are sites for phosphorylation; this phosphorylation inactivates the complex. In humans, there have been four isozymes of Pyruvate Dehydrogenase Kinase that have been shown to phosphorylate these three sites: PDK1, PDK2, PDK3, and PDK4.[6] PDK2 has been identified as the most abundant isoform in human tissues. Through many studies, it has been made clear that the activity of this enzyme is essential, even at rest, to regulate glycolysis/carbodydrate oxidation and producing metabolites for oxidative phosphorylation and the electron transport chain. These studies have illustrated that the kinetics of the PDK isoform population, specifically PDK2, is more important in determining PDH activity than measuring PDK activity.[7] ## Regulation As the primary regulators of a crucial step in the central metabolic pathway, the pyruvate dehydrogenase family is tightly regulated itself by a myriad of factors. PDK2 activity is modulated by low levels of hydrogen peroxide; this happens because the compound temporarily oxidizes the cysteine residues 45 and 392 on the enzyme, resulting in an inactive PDK2 and greater PDH activity. These conditions also inactivate the TCA cycle, the next step in aerobic respiration. This alludes to the fact that when there is a high level of O2 production in the mitochondria, which may occur because of nutrient excess, the increase in the products serve as a negative feedback that control mitochondria metabolism.[8] PDK2, in conjunction with PDK3 and PDK4, are primary targets of Peroxisome proliferator-activated receptor delta or beta, with PDK2 having two elements that respond to these receptors.[9] # Clinical significance All of the pyruvate dehydrogenase isozymes have been associated with various metabolic disorders, including diabetes. This is due to a mechanism by which consistently elevated free fatty acid levels stimulate the PDK enzymes, particularly, PDK2 and PDK4 in the liver. In stimulating this activity, there is less PDH activity, and therefore less glucose uptake.[10] ## Cancer As the PDK enzymes are associated with central metabolism and growth, they are often associated with various mechanisms of cancer progression. Enhanced PDK2 activity leads to increased glycolysis and lactic acid production, known as the Warburg effect. In some studies, the wild-type form of tumor protein p53 prevents manifestation of tumorigenesis by regulating PDK2 activity.[11] Additionally, inhibition of PDK2 subsequently inhibits HIF1A in cancer cells by both a prolyl-hydroxylase (PHD)-dependent mechanism and a PHD-independent mechanism. Therefore, mitochondria-targeting metabolic modulators increase pyruvate dehydrogenase activity, and suppress angiogenesis as well, normalizing the pseudo-hypoxic signals that lead to normoxic HIF1A activation in solid tumors.[12]

https://www.wikidoc.org/index.php/PDK2

4564f44350cc67cf70ddbe6fd5f2e2bfa13e81a2

wikidoc

PDK3

PDK3 Pyruvate dehydrogenase lipoamide kinase isozyme 3, mitochondrial is an enzyme that in humans is encoded by the PDK3 gene. It codes for an isozyme of pyruvate dehydrogenase kinase.The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO2. It provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle, and thus is one of the major enzymes responsible for the regulation of glucose metabolism. The enzymatic activity of PDH is regulated by a phosphorylation/dephosphorylation cycle, and phosphorylation results in inactivation of PDH. The protein encoded by this gene is one of the four pyruvate dehydrogenase kinases that inhibits the PDH complex by phosphorylation of the E1 alpha subunit. This gene is predominantly expressed in the heart and skeletal muscles. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. # Structure The structure of the PDK3/L2 complex has been elucidated, and there are several key features. When the L2 domain binds to PDK3, it induces a “cross-tail” conformation in PDK3, thereby stimulating activity. There are three crucial residues, Leu-140, Glu-170, and Glu-179, in the C-terminal domain that are crucial for this interaction. Structural studies have indicated that L2 binding stimulates activity by disrupting the closed conformation, or ATP lid, to remove product inhibition. The PDK3 subunits are in one of two conformations; one subunit exists as an “open” subunit, while the other subunit is “closed”. The open subunit is the configuration most crucial to the putative substrate-binding cleft, as it is where the target peptide can access the active center. The closed subunit blocks this target peptide because of a neighboring unwound alpha helix. Additionally, the ATP-binding loop in one PDK3 subunit adopts an open conformation, implying that the nucleotide loading into the active site is mediated by the inactive "pre-insertion" binding mode. This asymmetric complex represents a physiological state in which binding of a single L2-domain activates one of the PDHK subunits while inactivating another. Thus, the L2-domains likely act not only as the structural anchors but also modulate the catalytic cycle of PDK3. # Function The Pyruvate Dehydrogenase (PDH) complex must be tightly regulated due to its central role in general metabolism. Within the complex, there are three serine residues on the E1 component that are sites for phosphorylation; this phosphorylation inactivates the complex. In humans, there have been four isozymes of Pyruvate Dehydrogenase Kinase that have been shown to phosphorylate these three sites: PDK1, PDK2, PDK3, and PDK4. The PDK3 protein is primarily found in the kidney, brain, and testis. ## Regulation As the primary regulators of a crucial step in the central metabolic pathway, the pyruvate dehydrogenase family is tightly regulated itself by a myriad of factors. PDK3, in conjunction with PDK2 and PDK4, are primary targets of peroxisome proliferator-activated receptor delta/beta (PPAR beta/delta), with PDK3 having five elements that respond to these receptors. # Model organisms Model organisms have been used in the study of PDK3 function. A conditional knockout mouse line called Pdk3tm2a(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

PDK3 Pyruvate dehydrogenase lipoamide kinase isozyme 3, mitochondrial is an enzyme that in humans is encoded by the PDK3 gene.[1] [2] It codes for an isozyme of pyruvate dehydrogenase kinase.The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO2. It provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle, and thus is one of the major enzymes responsible for the regulation of glucose metabolism. The enzymatic activity of PDH is regulated by a phosphorylation/dephosphorylation cycle, and phosphorylation results in inactivation of PDH. The protein encoded by this gene is one of the four pyruvate dehydrogenase kinases that inhibits the PDH complex by phosphorylation of the E1 alpha subunit. This gene is predominantly expressed in the heart and skeletal muscles. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[2] # Structure The structure of the PDK3/L2 complex has been elucidated, and there are several key features. When the L2 domain binds to PDK3, it induces a “cross-tail” conformation in PDK3, thereby stimulating activity. There are three crucial residues, Leu-140, Glu-170, and Glu-179, in the C-terminal domain that are crucial for this interaction.[3] Structural studies have indicated that L2 binding stimulates activity by disrupting the closed conformation, or ATP lid, to remove product inhibition.[4] The PDK3 subunits are in one of two conformations; one subunit exists as an “open” subunit, while the other subunit is “closed”. The open subunit is the configuration most crucial to the putative substrate-binding cleft, as it is where the target peptide can access the active center. The closed subunit blocks this target peptide because of a neighboring unwound alpha helix. Additionally, the ATP-binding loop in one PDK3 subunit adopts an open conformation, implying that the nucleotide loading into the active site is mediated by the inactive "pre-insertion" binding mode. This asymmetric complex represents a physiological state in which binding of a single L2-domain activates one of the PDHK subunits while inactivating another.[5] Thus, the L2-domains likely act not only as the structural anchors but also modulate the catalytic cycle of PDK3. # Function The Pyruvate Dehydrogenase (PDH) complex must be tightly regulated due to its central role in general metabolism. Within the complex, there are three serine residues on the E1 component that are sites for phosphorylation; this phosphorylation inactivates the complex. In humans, there have been four isozymes of Pyruvate Dehydrogenase Kinase that have been shown to phosphorylate these three sites: PDK1, PDK2, PDK3, and PDK4.[6] The PDK3 protein is primarily found in the kidney, brain, and testis.[7] ## Regulation As the primary regulators of a crucial step in the central metabolic pathway, the pyruvate dehydrogenase family is tightly regulated itself by a myriad of factors. PDK3, in conjunction with PDK2 and PDK4, are primary targets of peroxisome proliferator-activated receptor delta/beta (PPAR beta/delta), with PDK3 having five elements that respond to these receptors.[8] # Model organisms Model organisms have been used in the study of PDK3 function. A conditional knockout mouse line called Pdk3tm2a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[9] Male and female animals underwent a standardized phenotypic screen[10] to determine the effects of deletion.[11][12][13][14] Additional screens performed: - In-depth immunological phenotyping[15]

https://www.wikidoc.org/index.php/PDK3

7827da4f1229cd248cb0fd3c61c2f3bf134a91d3

wikidoc

PDK4

PDK4 Pyruvate dehydrogenase lipoamide kinase isozyme 4, mitochondrial is an enzyme that in humans is encoded by the PDK4 gene. It codes for an isozyme of pyruvate dehydrogenase kinase. This gene is a member of the PDK/BCKDK protein kinase family and encodes a mitochondrial protein with a histidine kinase domain. This protein is located in the matrix of the mitochondria and inhibits the pyruvate dehydrogenase complex by phosphorylating one of its subunits, reducing the conversion of pyruvate, which is produced from the oxidation of glucose and amino acids, to acetyl-CoA and contributing to the regulation of glucose metabolism. Expression of this gene is regulated by glucocorticoids, retinoic acid and insulin. PDK4 is increased in hibernation and helps to decrease metabolism and conserve glucose by decreasing its conversion to acetyl-CoA, which enters the citric acid cycle and is converted to ATP. # Structure The mature protein encoded by the PDK4 gene contains 294 amino acids in its sequence. To form the active protein, two of the polypeptide chains come together to form an open conformation. Specifically, the two subunits come together to form a nucleotide-binding pocket; this pocket is targeted most often by inhibitors. # Function The Pyruvate Dehydrogenase (PDH) complex must be tightly regulated due to its central role in general metabolism. Within the complex, there are three serine residues on the E1 component that are sites for phosphorylation; this phosphorylation inactivates the complex. In humans, there have been four isozymes of Pyruvate Dehydrogenase Kinase that have been shown to phosphorylate these three sites: PDK1, PDK2, PDK3, and PDK4. PDK4 does not incorporate the most phosphate groups per catalytic event, because it can only phosphorylate site 1 and site 2; its rate of phosphorylation is less than PDK1, equal to PDK3, and more than PDK2. When the thiamine pyrophosphate (TPP) coenzyme is bound, the rates of phosphorylation by all four isozymes are drastically affected. Site 1 is the most affected, with the rate being significantly decreased. However, overall activity by PDK4 is not affected. ## Regulation As the primary regulators of a crucial step in the central metabolic pathway, the pyruvate dehydrogenase family is tightly regulated itself by a myriad of factors including transcription factors Sp1 and CCAAT box binding factor (CBF). Retinoic acid enhances PDK4 transcription by enabling Retinoic acid receptor family members to recruit transcriptional coactivators to retinoic acid response elements (RAREs) in the PDK4 promoter. Transcription is also increased by inhibiting inhibitory histone acetyltransferases (HATs) using trichostatin A (TSA). Rosiglitazone, a thiazolidinedione known to activate the glycerol biogenesis pathway, increases PDK4 mRNA transcription in white adipose tissue, but not in liver or muscle tissue. Farnesoid X receptor, or FXR, suppresses glycolysis and enhances fatty acid oxidation by increasing PDK4 expression and inactivating the PDH complex. Other factors, such as insulin, directly downregulate both PDK2 and PDK4 mRNA transcription. This is done through a proposed phosphatidylinositol 3-kinase (PI3K)-dependent pathway. In fact, even when cells are exposed to dexamethasone to increase mRNA expression, insulin blocks this effect. Peroxisome proliferator-activated receptors also regulate expression; PPAR alpha and delta were found to upregulate PDK4 mRNA, but PPAR gamma activation downregulated expression. # Clinical significance PDK4 is relevant in a variety of clinical conditions. Short-term fasting induces an increase in PDK4 transcription by about 10-fold. Upon refeeding, transcription of PDK4 increased further, a surprising outlook, by about 50-fold over levels before fasting began. This effect can be seen long term as well. PDK4 is overexpressed in skeletal muscle in type 2 diabetes, resulting in impaired glucose utilization. In post-obese patients, there is a significant decrease in PDK4 mRNA expression, in conjunction with increased glucose uptake; this is likely due to the downregulation of PDK4 by insulin. This corroborates the concept that a lowered availability of free fatty acids affects glucose metabolism by PDH complex regulation. In fact, it has been shown that insufficient downregulation of PDK mRNA in insulin-resistant individuals could be a cause of increased PDK expression leading to impaired glucose oxidation followed by increased fatty acid oxidation. Exercise has been shown to induce changes in this gene as well, and that transient changes can have a cumulative effect across many exercise sessions. The mRNA of PDK4, along with PPARGC1A, increase in both types of muscle tissue after exercise. These metabolic effects can be seen in other conditions. Hypoxia is shown to induce PDK4 gene expression through the ERR gamma mechanism. Conversely, PDK4 is downregulated in cardiac muscle tissue during heart failure. ## Cancer The ubiquitous role of this gene lends itself to being involved in a variety of disease pathologies, including cancer. One metabolite, butyrate, induces hyperacetylation of the histones around the PDK4 gene. This is associated with a greater transcription level of PDK4 mRNA, thereby reversing the downregulation of PDK4 in colon carcinoma cells. In human colon cancer cells, targeting and inactivating the PDH complex limits the metabolic rate and regulates glutamine metabolism, thereby partially inhibiting cell growth. However, PDK4 has also been shown to promote tumor genesis and proliferation through a different pathway, the CREB-RHEB-mTORC1 signaling cascade. # 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}

PDK4 Pyruvate dehydrogenase lipoamide kinase isozyme 4, mitochondrial is an enzyme that in humans is encoded by the PDK4 gene.[1][2] It codes for an isozyme of pyruvate dehydrogenase kinase. This gene is a member of the PDK/BCKDK protein kinase family and encodes a mitochondrial protein with a histidine kinase domain. This protein is located in the matrix of the mitochondria and inhibits the pyruvate dehydrogenase complex by phosphorylating one of its subunits, reducing the conversion of pyruvate, which is produced from the oxidation of glucose and amino acids, to acetyl-CoA and contributing to the regulation of glucose metabolism. Expression of this gene is regulated by glucocorticoids, retinoic acid and insulin.[2] PDK4 is increased in hibernation and helps to decrease metabolism and conserve glucose by decreasing its conversion to acetyl-CoA, which enters the citric acid cycle and is converted to ATP.[3] # Structure The mature protein encoded by the PDK4 gene contains 294 amino acids in its sequence. To form the active protein, two of the polypeptide chains come together to form an open conformation.[2] Specifically, the two subunits come together to form a nucleotide-binding pocket; this pocket is targeted most often by inhibitors.[4] # Function The Pyruvate Dehydrogenase (PDH) complex must be tightly regulated due to its central role in general metabolism. Within the complex, there are three serine residues on the E1 component that are sites for phosphorylation; this phosphorylation inactivates the complex. In humans, there have been four isozymes of Pyruvate Dehydrogenase Kinase that have been shown to phosphorylate these three sites: PDK1, PDK2, PDK3, and PDK4. PDK4 does not incorporate the most phosphate groups per catalytic event, because it can only phosphorylate site 1 and site 2; its rate of phosphorylation is less than PDK1, equal to PDK3, and more than PDK2. When the thiamine pyrophosphate (TPP) coenzyme is bound, the rates of phosphorylation by all four isozymes are drastically affected. Site 1 is the most affected, with the rate being significantly decreased. However, overall activity by PDK4 is not affected.[5] ## Regulation As the primary regulators of a crucial step in the central metabolic pathway, the pyruvate dehydrogenase family is tightly regulated itself by a myriad of factors including transcription factors Sp1 and CCAAT box binding factor (CBF). Retinoic acid enhances PDK4 transcription by enabling Retinoic acid receptor family members to recruit transcriptional coactivators to retinoic acid response elements (RAREs) in the PDK4 promoter. Transcription is also increased by inhibiting inhibitory histone acetyltransferases (HATs) using trichostatin A (TSA).[6] Rosiglitazone, a thiazolidinedione known to activate the glycerol biogenesis pathway, increases PDK4 mRNA transcription in white adipose tissue, but not in liver or muscle tissue.[7] Farnesoid X receptor, or FXR, suppresses glycolysis and enhances fatty acid oxidation by increasing PDK4 expression and inactivating the PDH complex.[8] Other factors, such as insulin, directly downregulate both PDK2 and PDK4 mRNA transcription. This is done through a proposed phosphatidylinositol 3-kinase (PI3K)-dependent pathway. In fact, even when cells are exposed to dexamethasone to increase mRNA expression, insulin blocks this effect.[9] Peroxisome proliferator-activated receptors also regulate expression; PPAR alpha and delta were found to upregulate PDK4 mRNA, but PPAR gamma activation downregulated expression.[10] # Clinical significance PDK4 is relevant in a variety of clinical conditions. Short-term fasting induces an increase in PDK4 transcription by about 10-fold.[11] Upon refeeding, transcription of PDK4 increased further, a surprising outlook, by about 50-fold over levels before fasting began.[12] This effect can be seen long term as well. PDK4 is overexpressed in skeletal muscle in type 2 diabetes, resulting in impaired glucose utilization.[13] In post-obese patients, there is a significant decrease in PDK4 mRNA expression, in conjunction with increased glucose uptake; this is likely due to the downregulation of PDK4 by insulin. This corroborates the concept that a lowered availability of free fatty acids affects glucose metabolism by PDH complex regulation.[14] In fact, it has been shown that insufficient downregulation of PDK mRNA in insulin-resistant individuals could be a cause of increased PDK expression leading to impaired glucose oxidation followed by increased fatty acid oxidation.[15] Exercise has been shown to induce changes in this gene as well, and that transient changes can have a cumulative effect across many exercise sessions. The mRNA of PDK4, along with PPARGC1A, increase in both types of muscle tissue after exercise.[16][17] These metabolic effects can be seen in other conditions. Hypoxia is shown to induce PDK4 gene expression through the ERR gamma mechanism.[18] Conversely, PDK4 is downregulated in cardiac muscle tissue during heart failure.[19] ## Cancer The ubiquitous role of this gene lends itself to being involved in a variety of disease pathologies, including cancer. One metabolite, butyrate, induces hyperacetylation of the histones around the PDK4 gene. This is associated with a greater transcription level of PDK4 mRNA, thereby reversing the downregulation of PDK4 in colon carcinoma cells. In human colon cancer cells, targeting and inactivating the PDH complex limits the metabolic rate and regulates glutamine metabolism, thereby partially inhibiting cell growth.[20] However, PDK4 has also been shown to promote tumor genesis and proliferation through a different pathway, the CREB-RHEB-mTORC1 signaling cascade.[21] # 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/PDK4

532294dcc9eee4a6d5b36098e6fe5c462baa1c96

wikidoc

PDPN

PDPN Podoplanin is a protein that in humans is encoded by the "PDPN" gene. # Structure and function Podoplanin is a mucin-type protein with a mass of 36- to 43-kDa. It is relatively well conserved between species, with homologues in humans, mice, rats, dogs and hamsters. This gene encodes a type-I, integral membrane, heavily O-glycosylated glycoprotein with diverse distribution in human tissues. The physiological function of this protein may be related to its mucin-type character. The homologous protein in other species has been described as a differentiation antigen and influenza-virus receptor. The specific function of this protein has not been determined but it has been proposed as a marker of lung injury. Alternatively spliced transcript variants encoding different isoforms have been identified. This protein has been found to have functions in lung alveolar cells, kidney podocytes, and lymphatic endothelial cells. More recently, this protein has been found in neural tissue in both mouse and human samples. In lymphatic endothelial cells, experimentation has indicated that podoplanin plays a role in proper formation of linkages between the cardiovascular system and the lymphatic systems, typically causing fatty liver disease in these mice. Although the exact function is unknown in many tissues, podoplanin is generally receptive to detection via immunofluorescent staining and has been shown to co-localize with the protein nestin, a type VI intermediate filament protein expressed almost primarily in neural tissues. Currently, the only protein known to interact with podoplanin physiologically is CLEC-2, a C-type lectin 2 expressed on platelets and on hematopoietic cells. Both serve a role in the proper formation of blood/lymphatic connections in embryonic development. # Clinical significance PDPN has been studied extensively in the cancer field. It is a specific lymphatic vessel marker, and since lymphangiogenesis levels are correlated with poor prognosis in cancer patients, it can be used as a diagnostic marker. It is often upregulated in certain types of cancer, including several types of squamous cell carcinomas, malignant mesothelioma and brain tumors. Moreover, it can be upregulated by cancer-associated fibroblasts (CAFs) in the tumor stroma, where it has been associated with poor prognosis. In squamous cell carcinomas, PDPN is believed to play a key role in the cancer cell invasiveness by controlling invadopodia, and thus mediating efficient ECM degradation.

PDPN Podoplanin is a protein that in humans is encoded by the "PDPN" gene.[1][2][3] # Structure and function Podoplanin is a mucin-type protein with a mass of 36- to 43-kDa. It is relatively well conserved between species, with homologues in humans, mice, rats, dogs and hamsters.[4] This gene encodes a type-I, integral membrane, heavily O-glycosylated glycoprotein with diverse distribution in human tissues. The physiological function of this protein may be related to its mucin-type character. The homologous protein in other species has been described as a differentiation antigen and influenza-virus receptor. The specific function of this protein has not been determined but it has been proposed as a marker of lung injury. Alternatively spliced transcript variants encoding different isoforms have been identified.[3] This protein has been found to have functions in lung alveolar cells, kidney podocytes, and lymphatic endothelial cells. More recently, this protein has been found in neural tissue in both mouse and human samples.[5] In lymphatic endothelial cells, experimentation has indicated that podoplanin plays a role in proper formation of linkages between the cardiovascular system and the lymphatic systems, typically causing fatty liver disease in these mice.[5] Although the exact function is unknown in many tissues, podoplanin is generally receptive to detection via immunofluorescent staining and has been shown to co-localize with the protein nestin, a type VI intermediate filament protein expressed almost primarily in neural tissues.[6] Currently, the only protein known to interact with podoplanin physiologically is CLEC-2, a C-type lectin 2 expressed on platelets and on hematopoietic cells.[7] Both serve a role in the proper formation of blood/lymphatic connections in embryonic development. # Clinical significance PDPN has been studied extensively in the cancer field. It is a specific lymphatic vessel marker, and since lymphangiogenesis levels are correlated with poor prognosis in cancer patients, it can be used as a diagnostic marker.[4] It is often upregulated in certain types of cancer, including several types of squamous cell carcinomas, malignant mesothelioma and brain tumors.[4] Moreover, it can be upregulated by cancer-associated fibroblasts (CAFs) in the tumor stroma,[4][8] where it has been associated with poor prognosis.[9] In squamous cell carcinomas, PDPN is believed to play a key role in the cancer cell invasiveness by controlling invadopodia, and thus mediating efficient ECM degradation.[10]

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

2456d9e315ca93f5b360d0f32c38e15cb6993fc6

wikidoc

PDPR

PDPR Pyruvate dehydrogenase phosphatase regulatory subunit is a protein that in humans is encoded by the PDPR gene. # Structure The complete cDNA of PDPR, which contains 2885 base pairs, has an open reading frame of 2634 nucleotides encoding a putative presequence of 31 amino acid residues and a mature protein of 847. Characteristics of native PDPR include ability to decrease the sensitivity of the catalytic subunit to Mg2+, and reversal of this inhibitory effect by the polyamine spermine. A BLAST search of protein databases revealed that PDPr is distantly related to the mitochondrial flavoprotein dimethylglycine dehydrogenase, which functions in choline degradation. # Function The mitochondrial pyruvate dehydrogenase complex (PDC) catalyzes the oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid (FA) synthesis. Knowledge of the mechanisms that regulate PDC activity is important, because PDC inactivation is crucial for glucose conservation when glucose is scarce, whereas adequate PDC activity is required to allow both ATP and FA production from glucose. The mechanisms that control mammalian PDC activity include its phosphorylation (inactivation) by a family of pyruvate dehydrogenase kinases (PDKs 1-4) and its dephosphorylation (activation, reactivation) by the pyruvate dehydrogenase phosphatases (PDPs 1 and 2). # Clinical significance As PDPR is involved in the regulation of the central metabolic pathway, its participation in disease pathophysiology is likely, but there has been no published research on this thus far.

PDPR Pyruvate dehydrogenase phosphatase regulatory subunit is a protein that in humans is encoded by the PDPR gene.[1] # Structure The complete cDNA of PDPR, which contains 2885 base pairs, has an open reading frame of 2634 nucleotides encoding a putative presequence of 31 amino acid residues and a mature protein of 847. Characteristics of native PDPR include ability to decrease the sensitivity of the catalytic subunit to Mg2+, and reversal of this inhibitory effect by the polyamine spermine. A BLAST search of protein databases revealed that PDPr is distantly related to the mitochondrial flavoprotein dimethylglycine dehydrogenase, which functions in choline degradation.[2] # Function The mitochondrial pyruvate dehydrogenase complex (PDC) catalyzes the oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid (FA) synthesis. Knowledge of the mechanisms that regulate PDC activity is important, because PDC inactivation is crucial for glucose conservation when glucose is scarce, whereas adequate PDC activity is required to allow both ATP and FA production from glucose. The mechanisms that control mammalian PDC activity include its phosphorylation (inactivation) by a family of pyruvate dehydrogenase kinases (PDKs 1-4) and its dephosphorylation (activation, reactivation) by the pyruvate dehydrogenase phosphatases (PDPs 1 and 2).[3] # Clinical significance As PDPR is involved in the regulation of the central metabolic pathway, its participation in disease pathophysiology is likely, but there has been no published research on this thus far.[1]

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

d3a954328c5c77e06e0576713722a76b766a9754

wikidoc

PDX1

PDX1 PDX1 (pancreatic and duodenal homeobox 1), also known as insulin promoter factor 1, is a transcription factor necessary for pancreatic development, including β-cell maturation, and duodenal differentiation. In humans this protein is encoded by the PDX1 gene, which was formerly known as IPF1. # Function ## Pancreatic development In pancreatic development, Pdx1 is expressed by a population of cells in the posterior foregut region of the definitive endoderm, and Pdx1+ epithelial cells give rise to the developing pancreatic buds, and eventually, the whole of the pancreas—its exocrine, endocrine, and ductal cell populations. Pancreatic Pdx1+ cells first arise at mouse embryonic day 8.5-9.0 (E8.5-9.0), and Pdx1 expression continues until E12.0-E12.5, after which Pdx1 expression decreases and the pancreas is formed—other transcription factors are expressed, controlling the fates of the cells of the newly formed pancreas. Homozygous Pdx1 knockout mice form pancreatic buds but fail to develop a pancreas, and transgenic mice in which tetracycline application results in death of Pdx1+ cells are almost completely apancreatic if doxycycline (tetracycline derivative) is administered throughout the pregnancy of these transgenic mice, illustrating the necessity of Pdx1+ cells in pancreatic development. ## β-cell maturation and survival Pdx1 is also necessary for β-cell maturation: developing β-cells co-express Pdx1, NKX6-1, and insulin, a process that results in the silencing of MafB and the expression of MafA, a necessary switch in maturation of β-cells. Pdx1 appears to also play a role in the fating of endocrine cells, encoding for insulin and somatostatin, two pancreatic endocrine products, while repressing glucagon. Thus, Pdx1 expression apparently favors the production of insulin+ β-cells and somatostatin+Δ-cells rather than glucagon+ α-cells. In addition to roles in beta-cell differentiation, Pdx1 is required for β-cell survival. Cells with reduced Pdx1 have an increased rate of apoptotic programmed cell death. ## Transcriptional network Pdx1+ pancreatic progenitor cells also co-express Hlxb9, Hnf6, Ptf1a and NKX6-1, and these progenitor cells form the initial pancreatic buds, which further proliferate and branch in response to FGF-10 signaling. Afterwards, fating of the pancreatic cells begins; a population of cells has Notch signaling inhibited, and subsequently, expresses Ngn3. This Ngn3+ population is a transient population of pancreatic endocrine progenitors that gives rise to the α, β, Δ, PP, and ε cells of the islets of Langerhans. Other cells will give rise to the exocrine and ductal pancreatic cell populations. ## Duodenum Pdx1 is necessary for the development of the proximal duodenum and maintenance of the gastro-duodenal junction. Duodenal enterocytes, Brunner's glands and entero-endocrine cells (including those in the gastric antrum) are dependent on Pdx1 expression. It is a ParaHox gene, which together with Sox2 and Cdx2, determines the correct cellular differentiation in the proximal gut. In mature mice duodenum, several genes have been identified which are dependent on Pdx1 expression and include some affecting lipid and iron absorption. # Pathology Mutations in the Pdx1 gene may be involved in several pancreatic pathologies, including diabetes mellitus, as shown, for example, by the study of the complete nuclear DNA genome of the sand rat, Psammomys obesus. Maturity onset diabetes of the young (Type 4) can be caused by heterozygous mutations in Pdx1 Expression is lost in gastric cancers, suggesting a role as a tumor suppressor. # Interactions Pdx1 has been shown to interact with MAFA.

PDX1 PDX1 (pancreatic and duodenal homeobox 1), also known as insulin promoter factor 1, is a transcription factor necessary for pancreatic development, including β-cell maturation, and duodenal differentiation. In humans this protein is encoded by the PDX1 gene, which was formerly known as IPF1.[1][2] # Function ## Pancreatic development In pancreatic development, Pdx1 is expressed by a population of cells in the posterior foregut region of the definitive endoderm, and Pdx1+ epithelial cells give rise to the developing pancreatic buds, and eventually, the whole of the pancreas—its exocrine, endocrine, and ductal cell populations.[3] Pancreatic Pdx1+ cells first arise at mouse embryonic day 8.5-9.0 (E8.5-9.0), and Pdx1 expression continues until E12.0-E12.5,[4] after which Pdx1 expression decreases and the pancreas is formed—other transcription factors are expressed, controlling the fates of the cells of the newly formed pancreas.[5] Homozygous Pdx1 knockout mice form pancreatic buds but fail to develop a pancreas,[5] and transgenic mice in which tetracycline application results in death of Pdx1+ cells are almost completely apancreatic if doxycycline (tetracycline derivative) is administered throughout the pregnancy of these transgenic mice, illustrating the necessity of Pdx1+ cells in pancreatic development.[4] ## β-cell maturation and survival Pdx1 is also necessary for β-cell maturation: developing β-cells co-express Pdx1, NKX6-1, and insulin, a process that results in the silencing of MafB and the expression of MafA, a necessary switch in maturation of β-cells.[3] Pdx1 appears to also play a role in the fating of endocrine cells, encoding for insulin and somatostatin, two pancreatic endocrine products, while repressing glucagon. Thus, Pdx1 expression apparently favors the production of insulin+ β-cells and somatostatin+Δ-cells rather than glucagon+ α-cells. In addition to roles in beta-cell differentiation, Pdx1 is required for β-cell survival. Cells with reduced Pdx1 have an increased rate of apoptotic programmed cell death.[6][7] ## Transcriptional network Pdx1+ pancreatic progenitor cells also co-express Hlxb9, Hnf6, Ptf1a and NKX6-1, and these progenitor cells form the initial pancreatic buds, which further proliferate and branch in response to FGF-10 signaling. Afterwards, fating of the pancreatic cells begins; a population of cells has Notch signaling inhibited, and subsequently, expresses Ngn3. This Ngn3+ population is a transient population of pancreatic endocrine progenitors that gives rise to the α, β, Δ, PP, and ε cells of the islets of Langerhans.[4] Other cells will give rise to the exocrine and ductal pancreatic cell populations. ## Duodenum Pdx1 is necessary for the development of the proximal duodenum and maintenance of the gastro-duodenal junction.[8] Duodenal enterocytes, Brunner's glands and entero-endocrine cells (including those in the gastric antrum) are dependent on Pdx1 expression. It is a ParaHox gene, which together with Sox2 and Cdx2, determines the correct cellular differentiation in the proximal gut.[8] In mature mice duodenum, several genes have been identified which are dependent on Pdx1 expression and include some affecting lipid and iron absorption.[9] # Pathology Mutations in the Pdx1 gene may be involved in several pancreatic pathologies, including diabetes mellitus, as shown, for example, by the study of the complete nuclear DNA genome of the sand rat, Psammomys obesus.[10] Maturity onset diabetes of the young (Type 4) can be caused by heterozygous mutations in Pdx1 [11][12] Expression is lost in gastric cancers, suggesting a role as a tumor suppressor.[13] # Interactions Pdx1 has been shown to interact with MAFA.[14]

https://www.wikidoc.org/index.php/PDX1

7464e6a3776f4ab03f25a8bc971bffdb98a09545

wikidoc

PEDF

PEDF Pigment epithelium-derived factor (PEDF) also known as serpin F1 (SERPINF1), is a multifunctional secreted protein that has anti-angiogenic, anti-tumorigenic, and neurotrophic functions. Found in vertebrates, this 50 kDa protein is being researched as a therapeutic candidate for treatment of such conditions as choroidal neovascularization, heart disease, and cancer. In humans, pigment epithelium-derived factor is encoded by the SERPINF1 gene. # Discovery Pigment epithelium-derived factor (PEDF) was originally discovered by Joyce Tombran-Tink and Lincoln Johnson in the late 1980s. This group was studying human retinal cell development by identifying secreted factors produced by the retinal pigmented epithelium (RPE), a layer of cells that supports the retina. Upon noticing RPE produced a factor that promoted the differentiation of primitive retinal cells into cells of a neuronal phenotype, they set out to determine the identity of the factor. They isolated proteins unique to RPE cells and tested the individual proteins for neurotrophic function, meaning promoting a neuronal phenotype. A neurotrophic protein around 50 kilodaltons (kDa) was identified and temporarily named RPE-54 before being officially termed pigment epithelium-derived factor. Soon thereafter, the same laboratory sequenced the PEDF protein and compared it to a human fetal eye library. They found that PEDF was a previously uncharacterized protein and a member of the serpin (serine protease inhibitor) family. # Gene The gene encoding human PEDF was localized to the 17th chromosome at position 17p13.1. The human PEDF gene is around 15.6kb, and the mRNA transcript is around 1.5kb. Immediately upstream of the PEDF gene lies a 200bp promoter region with putative binding sites for the transcription factors HNF4, CHOP, and USF. The PEDF gene consists of 8 exons and 7 introns. The PEDF gene is present in vertebrates from human to fish, but not present in sea squirts, worms, or fruit flies. Sea squirts express several serpin genes, suggesting that the PEDF gene may have arisen from another serpin family member after the evolution of vertebral animals. The gene most homologous to PEDF is its adjacent neighbor on chromosome 17, SerpinF2. # Protein The PEDF protein is a secreted protein of roughly 50kDa size and 418 amino acids in length. The N-terminus contains a leader sequence responsible for protein secretion out of the cell at residues 1-19. A 34-mer fragment of PEDF (residues 24-57) was shown to have antiangiogenic properties, and a 44-mer (residues 58-101) was shown to have neurotrophic properties. A BLAST search reveals a putative receptor binding site exists between residues 75-124. A nuclear localization sequence (NLS) exists about 150 amino acids into the protein. The additional molecular weight is partly due to a single glycosylation site at residue 285. Near the C-terminus at residues 365-390 lies the reactive center loop (RCL) which is normally involved in serine protease inhibitor activity; however, in PEDF this region does not retain the inhibitory function. In 2001, the crystal structure of PEDF was successfully generated. The PEDF structure includes 3 beta sheets and 10 alpha helices. This discovery demonstrated that PEDF has an asymmetrical charge distribution across the whole protein. One side of the protein is heavily basic and the other side is heavily acidic, leading to a polar 3-D structure. They proposed that the basic side of the protein contains a heparin binding site. # Signaling PEDF expression is upregulated by plasminogen kringle domains 1-4 (also known as angiostatin) and the kringle 5 (K5) domain. Hypoxia, or low oxygen conditions, leads to the downregulation of PEDF. This effect is due to hypoxic conditions causing matrix metalloproteinases (MMPs) to proteolytically degrade PEDF. In addition, amyloid beta has been shown to decrease PEDF mRNA levels. Secreted PEDF binds a receptor on the cell surface termed PEDF-R. PEDF-R has phospholipase A2 activity which liberates fatty acids from glycerolipids. PEDF enhances gamma-secretase activity, leading to the cleavage of the VEGF receptor 1 (VEGFR-1) transmembrane domain. This action interferes with VEGF signaling thereby inhibiting angiogenesis. Laminin receptor is also a target for PEDF, and the interaction occurs between residues 24-57 of PEDF, a region known to regulate antiangiogenic function. PEDF induces PPAR-gamma expression which in turn induces p53, a tumor suppressor gene involved in cell cycle regulation and apoptosis. Thrombospondin, an antiangiogenic protein, is upregulated by PEDF. PEDF stimulates several other well known signaling cascades such as the Ras pathway, the NF-κB pathway, and extrinsic apoptosis cascades. # Function PEDF has a variety of functions including antiangiogenic, antitumorigenic, and neurotrophic properties. Endothelial cell migration is inhibited by PEDF. PEDF suppresses retinal neovascularization and endothelial cell proliferation. The antiangiogenic residues 24-57 were shown to be sufficient at inhibiting angiogenesis. PEDF is also responsible for apoptosis of endothelial cells either through the p38 MAPK pathway or through the FAS/FASL pathway Antiangiogenic function is also conferred by PEDF through inhibition of both VEGFR-1 and VEGFR-2. The antitumorigenic effects of PEDF are not only due to inhibition of supporting vasculature, but also due to effects on the cancer cells themselves. PEDF was shown to inhibit cancer cell proliferation and increase apoptosis via the FAS/FASL pathway. VEGF expression by cancer cells is inhibited by PEDF. PEDF also displays neurotrophic functions. Retinoblastoma cells differentiate into neurons due to the presence of PEDF. Expression of PEDF in the human retina is found at 7.4 weeks of gestation, suggesting it may play a role in retinal neuron differentiation. # Clinical significance PEDF, a protein with many functions, has been suggested to play a clinical role in choroidal neovascularization, cardiovascular disease, diabetes, diabetic macular edema, osteogenesis imperfecta and cancer. As an antiangiogenic protein, PEDF may help suppress unwanted neovascularization of the eye. Molecules that shift the balance towards PEDF and away from VEGF may prove useful tools in both choroidal neovascularization and preventing cancer metastasis formation.

PEDF Pigment epithelium-derived factor (PEDF) also known as serpin F1 (SERPINF1), is a multifunctional secreted protein that has anti-angiogenic, anti-tumorigenic, and neurotrophic functions. Found in vertebrates, this 50 kDa protein is being researched as a therapeutic candidate for treatment of such conditions as choroidal neovascularization, heart disease, and cancer.[1] In humans, pigment epithelium-derived factor is encoded by the SERPINF1 gene.[2][3] # Discovery Pigment epithelium-derived factor (PEDF) was originally discovered by Joyce Tombran-Tink and Lincoln Johnson in the late 1980s.[4][5] This group was studying human retinal cell development by identifying secreted factors produced by the retinal pigmented epithelium (RPE), a layer of cells that supports the retina. Upon noticing RPE produced a factor that promoted the differentiation of primitive retinal cells into cells of a neuronal phenotype, they set out to determine the identity of the factor. They isolated proteins unique to RPE cells and tested the individual proteins for neurotrophic function, meaning promoting a neuronal phenotype. A neurotrophic protein around 50 kilodaltons (kDa) was identified and temporarily named RPE-54 before being officially termed pigment epithelium-derived factor. Soon thereafter, the same laboratory sequenced the PEDF protein and compared it to a human fetal eye library.[3] They found that PEDF was a previously uncharacterized protein and a member of the serpin (serine protease inhibitor) family. # Gene The gene encoding human PEDF was localized to the 17th chromosome at position 17p13.1.[6] The human PEDF gene is around 15.6kb, and the mRNA transcript is around 1.5kb.[7] Immediately upstream of the PEDF gene lies a 200bp promoter region with putative binding sites for the transcription factors HNF4, CHOP, and USF. The PEDF gene consists of 8 exons and 7 introns. The PEDF gene is present in vertebrates from human to fish, but not present in sea squirts, worms, or fruit flies.[7] Sea squirts express several serpin genes, suggesting that the PEDF gene may have arisen from another serpin family member after the evolution of vertebral animals. The gene most homologous to PEDF is its adjacent neighbor on chromosome 17, SerpinF2. # Protein The PEDF protein is a secreted protein of roughly 50kDa size and 418 amino acids in length.[1] The N-terminus contains a leader sequence responsible for protein secretion out of the cell at residues 1-19. A 34-mer fragment of PEDF (residues 24-57) was shown to have antiangiogenic properties, and a 44-mer (residues 58-101) was shown to have neurotrophic properties.[8] A BLAST search reveals a putative receptor binding site exists between residues 75-124. A nuclear localization sequence (NLS) exists about 150 amino acids into the protein. The additional molecular weight is partly due to a single glycosylation site at residue 285.[9] Near the C-terminus at residues 365-390 lies the reactive center loop (RCL) which is normally involved in serine protease inhibitor activity; however, in PEDF this region does not retain the inhibitory function.[1][10] In 2001, the crystal structure of PEDF was successfully generated.[11] The PEDF structure includes 3 beta sheets and 10 alpha helices. This discovery demonstrated that PEDF has an asymmetrical charge distribution across the whole protein. One side of the protein is heavily basic and the other side is heavily acidic, leading to a polar 3-D structure. They proposed that the basic side of the protein contains a heparin binding site. # Signaling PEDF expression is upregulated by plasminogen kringle domains 1-4 (also known as angiostatin) and the kringle 5 (K5) domain.[12][13] Hypoxia, or low oxygen conditions, leads to the downregulation of PEDF.[13] This effect is due to hypoxic conditions causing matrix metalloproteinases (MMPs) to proteolytically degrade PEDF.[14] In addition, amyloid beta has been shown to decrease PEDF mRNA levels.[15] Secreted PEDF binds a receptor on the cell surface termed PEDF-R.[16] PEDF-R has phospholipase A2 activity which liberates fatty acids from glycerolipids. PEDF enhances gamma-secretase activity, leading to the cleavage of the VEGF receptor 1 (VEGFR-1) transmembrane domain.[17] This action interferes with VEGF signaling thereby inhibiting angiogenesis. Laminin receptor is also a target for PEDF, and the interaction occurs between residues 24-57 of PEDF, a region known to regulate antiangiogenic function.[18] PEDF induces PPAR-gamma expression which in turn induces p53, a tumor suppressor gene involved in cell cycle regulation and apoptosis.[19] Thrombospondin, an antiangiogenic protein, is upregulated by PEDF.[20] PEDF stimulates several other well known signaling cascades such as the Ras pathway, the NF-κB pathway, and extrinsic apoptosis cascades.[21] # Function PEDF has a variety of functions including antiangiogenic, antitumorigenic, and neurotrophic properties.[22] Endothelial cell migration is inhibited by PEDF.[23] PEDF suppresses retinal neovascularization and endothelial cell proliferation.[24][25] The antiangiogenic residues 24-57 were shown to be sufficient at inhibiting angiogenesis.[26] PEDF is also responsible for apoptosis of endothelial cells either through the p38 MAPK pathway[27] or through the FAS/FASL pathway[28] Antiangiogenic function is also conferred by PEDF through inhibition of both VEGFR-1[17] and VEGFR-2.[29] The antitumorigenic effects of PEDF are not only due to inhibition of supporting vasculature, but also due to effects on the cancer cells themselves. PEDF was shown to inhibit cancer cell proliferation and increase apoptosis via the FAS/FASL pathway.[30] VEGF expression by cancer cells is inhibited by PEDF.[31] PEDF also displays neurotrophic functions. Retinoblastoma cells differentiate into neurons due to the presence of PEDF.[5] Expression of PEDF in the human retina is found at 7.4 weeks of gestation, suggesting it may play a role in retinal neuron differentiation.[32] # Clinical significance PEDF, a protein with many functions, has been suggested to play a clinical role in choroidal neovascularization, cardiovascular disease, diabetes, diabetic macular edema, osteogenesis imperfecta and cancer.[22][24][26][33][34] As an antiangiogenic protein, PEDF may help suppress unwanted neovascularization of the eye. Molecules that shift the balance towards PEDF and away from VEGF may prove useful tools in both choroidal neovascularization and preventing cancer metastasis formation.[12][35][36]

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

d0a30dcffe7f15fb7aa3673de2069bf54c8c316a

wikidoc

PEPD

PEPD Xaa-Pro dipeptidase, also known as prolidase, is an enzyme that in humans is encoded by the PEPD gene. # Function Xaa-Pro dipeptidase is a cytosolic dipeptidase that hydrolyzes dipeptides with proline or hydroxyproline at the carboxy terminus (but not Pro-Pro). It is important in collagen metabolism because of the high levels of imino acids. Mutations at the PEPD locus cause prolidase deficiency. This is characterised by Iminodipeptidurea, skin ulcers, mental retardation and recurrent infections. # Structure Prolidases fall under a subclass of metallopeptidases that involve binuclear active site metal clusters. This metal cluster facilitates catalysis by serving as a substrate binding site, activating nucleophiles, and stabilizing the transition state. Furthermore, prolidases are classified under a smaller family called “pita-bread” enzymes, which cleave amido-, imido-, and amidino- containing bonds. The “pita-bread” fold, containing a metal center flanked by two well-defined substrate binding pockets enabled prolidase to specifically cleave between any non-proline amino acid and proline. Prolidase cleavage of peptide to yield alanine and proline The first ever solved structure of prolidase came from the hyperthermophilic archaeon Pyrococcus furiosus (Pfprol). This dimer has a crystal structure shows two approximately symmetrical monomers that both have an N-terminal domain, made up of a six-stranded mixed β-sheet flanked by five α-helices, a helical linker, and C-terminal domain, consisting of a mixed six-stranded β-sheet flanked by four α-helices. The curved β-sheet of Domain II has a “pita-bread” fold. The active site lies on the inner surface of the β-sheet of Domain II, with a notable dinuclear Co cluster anchored by the side chains of two aspartate residues (Asp209 and Asp220), two glutamate residues (Glu313 and Glu327), and a histidine residue (His284). Carboxylate groups of aspartate and glutamine residues serve as bridges between the two Co atoms. In the crystallization process, the Co atoms are replaced with Zn, which hinders enzymatic activity. Unlike Pfprol, the structure of the human variant remains poorly understood. Sequence homology between human and Pfprol yield only 25% identity and 43% similarity. The two available structures of human prolidase available on the Protein Data Bank are homodimers contain either Na or Mn, which bind to similar amino acids as those in Pfprol: Glu412 (Glu313 in Pfprol), binds to the first ion, Asp276 (Asp209 in Pfprol) binds to the second ion, and Asp287 and Glu452 bind to both (Asp220 and Glu327 in Pfprol). # Function Due to proline’s cyclic structure, only few peptidases could cleave the bond between proline and other amino acids. Along with prolinase, prolidase are the only known enzymes that can break down dipeptides to yield free proline. Prolidase serve to hydrolyze both dietary and endogenous Xaa-Pro dipeptides. More specifically, it is essential in catalyzing the last step of the degradation of procollagen, collagen, and other proline-containing peptides into free amino acids to be used for cellular growth. Additionally, it also participates in the process of recycling proline from Xaa-Pro dipeptides for collagen resynthesis. Proline and hydroyxyproline make up a quarter of the amino acid residues in collagen, which is the most abundant protein in the body by mass and plays an important role in maintaining connective tissue in the body. # Mechanism The mechanism for prolidase catalytic activity remains largely uncharacterized. However, biochemical and structural analyses of aminopeptidase (APPro), methionine aminopeptidase (MetAP), and prolidase, all members of the “pita-bread” metalloenzymes, suggest that they share a common mechanism scheme. The main difference arises in the location of the carbonyl oxygen atom of the scissile peptide bond. The following mechanism shows a proposed scheme for a metal-dependent “pita-bread” enzyme with residue numbering corresponding to those found in methionine aminopeptidase from E. coli. As shown in Intermediate I of the figure, three potential acidic amino acid residues interact with the N-terminus of the substrate in a fashion that is yet to be determined. The carbonyl and amide groups of the scissile peptide bond interact with the first metal ion, M1, in addition to His178 and His79, respectively. M1 and Glu204 activate a water molecule to prepare it nucleophilic attack at the carbonyl carbon of the scissile peptide bond. Then, the tetrahedral intermediate (Intermediate II) becomes stabilized from interactions with M1 and His178. Lastly, Glu204 donates a proton to the amine of the leaving peptide (P1’). This leads to the breakdown of the intermediate (Intermediate III), which retains its interactions with M1 and His178. # Regulation Post-translational modifications of prolidase regulate its enzymatic abilities. Phosphorylation of prolidase has been shown to increase its activity while dephosphorylation leads to a decrease in enzyme activity. Analysis of known consensus sequence required for serine/threonine phosphorylation revealed that prolidase contains at least three potential sites for serine/threonine phosphorylation. Nitric oxide, both exogenously acquired and endogenously generated, was shown to increase prolidase activity in a time- and dose-dependent manner via phosphorylation at these serine and threonine sites. Additionally, prolidase may also be regulated at tyrosine phosphorylation sites, which are mediated by FAK and MAPK signaling pathways. # Disease relevance Deficiency in prolidase leads to a rare, severe autosomal recessive disorder (prolidase deficiency) that causes many chronic, debilitating health conditions in humans. These phenotypical symptoms vary and may include skin ulcerations, mental retardation, splenomegaly, recurrent infections, photosensitivity, hyperkeratosis, and unusual facial appearance. Furthermore, prolidase activity was found to be abnormal compared to healthy levels in various medical conditions including but limited to: bipolar disorder, breast cancer, endometrial cancer, keloid scar formation, erectile dysfunction, liver disease, lung cancer, hypertension, melanoma, and chronic pancreatitis. In some cancers with increased levels of prolidase activity, such as melanoma, the differential expression of prolidase and its substrate specificity for dipeptides with proline at the carboxyl end suggests the potential of prolidase in becoming a viable, selective endogenous enzyme target for proline prodrugs. Serum prolidase enzyme activity is also currently being explored as a possible, reliable marker for diseases including chronic hepatitis B and liver fibrosis. # Other applications Decontamination: Prolidase from the hyperthermophilic archaeon Pyrococcus furiosus (Pfprol) shows potential for application in decontamination of organophosphorus nerve agents in chemical warfare agents. Additionally, prolidase could also serve to detect fluorine-containing organophosphorus neurotoxins, like the G-type chemical warfare agents, and could antagonize organophosphorous intoxication and protect against the effects of diisopropylfluorophosphate when encapsulated in liposomes. # Model organisms Model organisms have been used in the study of PEPD function. A conditional knockout mouse line called Pepdtm1a(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

PEPD Xaa-Pro dipeptidase, also known as prolidase, is an enzyme that in humans is encoded by the PEPD gene.[1][2][3] # Function Xaa-Pro dipeptidase is a cytosolic dipeptidase that hydrolyzes dipeptides with proline or hydroxyproline at the carboxy terminus (but not Pro-Pro). It is important in collagen metabolism because of the high levels of imino acids.[3] Mutations at the PEPD locus cause prolidase deficiency. This is characterised by Iminodipeptidurea, skin ulcers, mental retardation and recurrent infections. # Structure Prolidases fall under a subclass of metallopeptidases that involve binuclear active site metal clusters.[4] This metal cluster facilitates catalysis by serving as a substrate binding site, activating nucleophiles, and stabilizing the transition state. Furthermore, prolidases are classified under a smaller family called “pita-bread” enzymes, which cleave amido-, imido-, and amidino- containing bonds.[5] The “pita-bread” fold, containing a metal center flanked by two well-defined substrate binding pockets enabled prolidase to specifically cleave between any non-proline amino acid and proline. Prolidase cleavage of peptide to yield alanine and proline The first ever solved structure of prolidase came from the hyperthermophilic archaeon Pyrococcus furiosus (Pfprol).[4] This dimer has a crystal structure shows two approximately symmetrical monomers that both have an N-terminal domain, made up of a six-stranded mixed β-sheet flanked by five α-helices, a helical linker, and C-terminal domain, consisting of a mixed six-stranded β-sheet flanked by four α-helices. The curved β-sheet of Domain II has a “pita-bread” fold. The active site lies on the inner surface of the β-sheet of Domain II, with a notable dinuclear Co cluster anchored by the side chains of two aspartate residues (Asp209 and Asp220), two glutamate residues (Glu313 and Glu327), and a histidine residue (His284). Carboxylate groups of aspartate and glutamine residues serve as bridges between the two Co atoms. In the crystallization process, the Co atoms are replaced with Zn, which hinders enzymatic activity. Unlike Pfprol, the structure of the human variant remains poorly understood. Sequence homology between human and Pfprol yield only 25% identity and 43% similarity.[6] The two available structures of human prolidase available on the Protein Data Bank are homodimers contain either Na or Mn, which bind to similar amino acids as those in Pfprol: Glu412 (Glu313 in Pfprol), binds to the first ion, Asp276 (Asp209 in Pfprol) binds to the second ion, and Asp287 and Glu452 bind to both (Asp220 and Glu327 in Pfprol). # Function Due to proline’s cyclic structure, only few peptidases could cleave the bond between proline and other amino acids.[7] Along with prolinase, prolidase are the only known enzymes that can break down dipeptides to yield free proline. Prolidase serve to hydrolyze both dietary and endogenous Xaa-Pro dipeptides. More specifically, it is essential in catalyzing the last step of the degradation of procollagen, collagen, and other proline-containing peptides into free amino acids to be used for cellular growth.[8] Additionally, it also participates in the process of recycling proline from Xaa-Pro dipeptides for collagen resynthesis. Proline and hydroyxyproline make up a quarter of the amino acid residues in collagen, which is the most abundant protein in the body by mass and plays an important role in maintaining connective tissue in the body.[8][9] # Mechanism The mechanism for prolidase catalytic activity remains largely uncharacterized.[10] However, biochemical and structural analyses of aminopeptidase (APPro), methionine aminopeptidase (MetAP), and prolidase, all members of the “pita-bread” metalloenzymes, suggest that they share a common mechanism scheme.[5] The main difference arises in the location of the carbonyl oxygen atom of the scissile peptide bond. The following mechanism shows a proposed scheme for a metal-dependent “pita-bread” enzyme with residue numbering corresponding to those found in methionine aminopeptidase from E. coli.[5] As shown in Intermediate I of the figure, three potential acidic amino acid residues interact with the N-terminus of the substrate in a fashion that is yet to be determined. The carbonyl and amide groups of the scissile peptide bond interact with the first metal ion, M1, in addition to His178 and His79, respectively. M1 and Glu204 activate a water molecule to prepare it nucleophilic attack at the carbonyl carbon of the scissile peptide bond. Then, the tetrahedral intermediate (Intermediate II) becomes stabilized from interactions with M1 and His178. Lastly, Glu204 donates a proton to the amine of the leaving peptide (P1’). This leads to the breakdown of the intermediate (Intermediate III), which retains its interactions with M1 and His178. # Regulation Post-translational modifications of prolidase regulate its enzymatic abilities. Phosphorylation of prolidase has been shown to increase its activity while dephosphorylation leads to a decrease in enzyme activity.[11] Analysis of known consensus sequence required for serine/threonine phosphorylation revealed that prolidase contains at least three potential sites for serine/threonine phosphorylation. Nitric oxide, both exogenously acquired and endogenously generated, was shown to increase prolidase activity in a time- and dose-dependent manner via phosphorylation at these serine and threonine sites.[12] Additionally, prolidase may also be regulated at tyrosine phosphorylation sites, which are mediated by FAK and MAPK signaling pathways.[11] # Disease relevance Deficiency in prolidase leads to a rare, severe autosomal recessive disorder (prolidase deficiency) that causes many chronic, debilitating health conditions in humans.[13] These phenotypical symptoms vary and may include skin ulcerations, mental retardation, splenomegaly, recurrent infections, photosensitivity, hyperkeratosis, and unusual facial appearance. Furthermore, prolidase activity was found to be abnormal compared to healthy levels in various medical conditions including but limited to: bipolar disorder, breast cancer, endometrial cancer, keloid scar formation, erectile dysfunction, liver disease, lung cancer, hypertension, melanoma, and chronic pancreatitis.[7] In some cancers with increased levels of prolidase activity, such as melanoma, the differential expression of prolidase and its substrate specificity for dipeptides with proline at the carboxyl end suggests the potential of prolidase in becoming a viable, selective endogenous enzyme target for proline prodrugs.[14] Serum prolidase enzyme activity is also currently being explored as a possible, reliable marker for diseases including chronic hepatitis B and liver fibrosis.[15][16][17] # Other applications Decontamination: Prolidase from the hyperthermophilic archaeon Pyrococcus furiosus (Pfprol) shows potential for application in decontamination of organophosphorus nerve agents in chemical warfare agents.[18] Additionally, prolidase could also serve to detect fluorine-containing organophosphorus neurotoxins, like the G-type chemical warfare agents, and could antagonize organophosphorous intoxication and protect against the effects of diisopropylfluorophosphate when encapsulated in liposomes.[19][20] # Model organisms Model organisms have been used in the study of PEPD function. A conditional knockout mouse line called Pepdtm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[21] Male and female animals underwent a standardized phenotypic screen[22] to determine the effects of deletion.[23][24][25][26] Additional screens performed: - In-depth immunological phenotyping[27]

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

0c0bc6bcd0b6b35e2aa84092a050e4320a159460

wikidoc

PER1

PER1 The PER1 gene encodes the period circadian protein homolog 1 protein in humans. # Function The PER1 protein is important to the maintenance of circadian rhythms in cells, and may also play a role in the development of cancer. This gene is a member of the period family of genes. It is expressed with a daily oscillating circadian rhythm, or an oscillation that cycles with a period of approximately 24 hours. PER1 is most notably expressed in the region of the brain called the suprachiasmatic nucleus (SCN), which is the primary circadian pacemaker in the mammalian brain. PER1 is also expressed throughout mammalian peripheral tissues. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. Circadian expression of PER1 in the suprachiasmatic nucleus will free-run in constant darkness, meaning that the 24-hour period of the cycle will persist without the aid of external light cues. Subsequently, a shift in the light/dark cycle evokes a proportional shift of gene expression in the suprachiasmatic nucleus. The time of gene expression is sensitive to light, as light during a mammal's subjective night results in a sudden increase in per expression and thus a shift in phase in the suprachiasmatic nucleus. Alternative splicing has been observed in this gene; however, these variants have not been fully described. There is some disagreement between experts over the occurrence of polymorphisms with functional significance. Many scientists state that there are no known polymorphisms of the human PER1 gene with significance at a population level that results in measurable behavioral or physiological changes. Still, some believe that even silent mutations can cause significant behavioral phenotypes,and result in major phase changes. Functional conservation of the PER gene is shown in a study by Shigeyoshi et al. 2002. In this study, mouse mPer1 and mPer2 genes were driven by Drosophila timeless promoter in Drosophila malanogaster. They found that both mPer constructs could restore rhythm to arrythmic flies (per01 flies). Thus mPer1 and mPer2 can function as clock components in flies and may have implications concerning the homology of per genes. ## Role in chronobiology The PER1 gene, also called rigui, is a characteristic circadian oscillator. PER1 is rhythmically transcribed in the SCN, keeping a period of approximately 24 hours. This rhythm is sustained in constant darkness, and can also be entrained to changing light cycles. PER1 is involved in generating circadian rhythms in the SCN, and also has an effect on other oscillations throughout the body. For example, PER1 knockouts affect food entrainable oscillators and methamphetamine-sensitive circadian oscillators, whose periods are altered in the absence of PER1. In addition, mice with knockouts in both the PER1 and PER2 genes show no circadian rhythmicity. Phase shifts in PER1 neurons can be induced by a strong, brief light stimulus to the SCN of rats. This light exposure causes increases in PER1 mRNA, suggesting that the PER1 gene plays an important role in entrainment of the mammalian biological clock to the light-dark cycle. ## Feedback mechanism The PER1 mRNA is expressed in all cells, acting as a part of a transcription-translation negative feedback mechanism, which creates a cell autonomous molecular clock. PER1 transcription is regulated by protein interactions with its five E-box and one D-box elements in its promoter region. Heterodimer CLOCK-BMAL1 activates E-box elements present in the PER1 promoter, as well activating the E box promoters of other components of the molecular clock such as PER2, CRY1, and CRY2. The phase of PER1 mRNA expression varies between tissues, The transcript leaves the nucleus and is translated into a protein with PAS domains, which enable protein-protein interactions. PER1 and PER2 are phosphorylated by CK1ε, which leads to increased ubiquitylation and degradation. This phosphorylation is counteracted by PP1 phosphatase, resulting in a more gradual increase in phosphorylated PER, and an additional control over the period of the molecular clock. Phosphorylation of PER1 can also lead to masking of its leucine-rich nuclear localization sequence and thus impeded heterodimer import. PER interacts with other PER proteins as well as the E-box regulated, clock controlled proteins CRY1 and CRY2 to create a heterodimer which translocates into the nucleus. There it inhibits CLOCK-BMAL activation. PER1 is not necessary for the creation circadian rhythms, but homozygous PER1 mutants display a shortened period of mRNA expression. While PER1 must be mutated in conjunction with PER2 to result in arhythmiticity, the two translated PER proteins have been shown to have slightly different roles, as PER1 acts preferentially through interaction with other clock proteins. # Clinical significance PER1 expression may have significant effects on the cell cycle. Cancer is often a result of unregulated cell growth and division, which can be controlled by circadian mechanisms. Therefore, a cell's circadian clock may play a large role in its likelihood of developing into a cancer cell. PER1 is a gene that plays an important role in such a circadian mechanism. Its overexpression, in particular, causes DNA-damage induced apoptosis. In addition, down-regulation of PER1 can enhance tumor growth in mammals. PER1 also interacts with proteins ATM and Chk2. These proteins are key checkpoint proteins in the cell cycle. Cancer patients have a lowered expression of per1. Gery, et al. suggests that regulation of PER1 expression may be useful for cancer treatment in the future. # Gene ## Orthologs The following is a list of some orthologs of the PER1 gene in other species: - PER1 (Rattus norvegicus) - PER1 (Mus musculus) - per1a (Danio rerio) - PER1 (Homo sapiens) - lin-42 (Caenorhabditis elegans) - PER1 (Bos taurus) - per1b (Danio rerio) - PER (Drosophila melanogaster) - PER1 (Xenopus tropicalis) - PER1 (Equus caballus) - PER1 (Macaca mulatta) - PER1 (Sus scrofa) ## Paralogs - PER2 - PER3 ## Location The human PER1 gene is located on chromosome 17 at the following location: - Start: 8,140,470 - Finish: 8,156,405 - Length: 15,936 - Exons: 24 PER1 has 19 transcripts (splice variants). # Discovery The PER1 ortholog was first discovered by Ronald Konopka and Seymour Benzer in 1971. During 1997, Period 1 (mPer1) and Period 2 (mPer2) genes were discovered (Sun et al., 1997 and Albretch et al., 1997). Through homology screens with the Drosophila per, these genes were discovered. It was independently discovered by Sun et al. 1997, naming it RIGUI and by Tei et al. 1997, who named it hper because of the protein sequence similarity with Drosophila per. They found that the mouse homolog had the properties of a circadian regulator. It had circadian expression in the suprachiasmatic nucleus (SCN), self-sustained oscillation, and entrainment of circadian expression by external light cues.

PER1 The PER1 gene encodes the period circadian protein homolog 1 protein in humans.[1] # Function The PER1 protein is important to the maintenance of circadian rhythms in cells, and may also play a role in the development of cancer. This gene is a member of the period family of genes. It is expressed with a daily oscillating circadian rhythm, or an oscillation that cycles with a period of approximately 24 hours. PER1 is most notably expressed in the region of the brain called the suprachiasmatic nucleus (SCN), which is the primary circadian pacemaker in the mammalian brain. PER1 is also expressed throughout mammalian peripheral tissues.[2] Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. Circadian expression of PER1 in the suprachiasmatic nucleus will free-run in constant darkness, meaning that the 24-hour period of the cycle will persist without the aid of external light cues. Subsequently, a shift in the light/dark cycle evokes a proportional shift of gene expression in the suprachiasmatic nucleus. The time of gene expression is sensitive to light, as light during a mammal's subjective night results in a sudden increase in per expression and thus a shift in phase in the suprachiasmatic nucleus.[3] Alternative splicing has been observed in this gene; however, these variants have not been fully described.[4] There is some disagreement between experts over the occurrence of polymorphisms with functional significance. Many scientists state that there are no known polymorphisms of the human PER1 gene with significance at a population level that results in measurable behavioral or physiological changes.[5] Still, some believe that even silent mutations can cause significant behavioral phenotypes,and result in major phase changes.[6] Functional conservation of the PER gene is shown in a study by Shigeyoshi et al. 2002. In this study, mouse mPer1 and mPer2 genes were driven by Drosophila timeless promoter in Drosophila malanogaster. They found that both mPer constructs could restore rhythm to arrythmic flies (per01 flies). Thus mPer1 and mPer2 can function as clock components in flies and may have implications concerning the homology of per genes.[7] ## Role in chronobiology The PER1 gene, also called rigui, is a characteristic circadian oscillator. PER1 is rhythmically transcribed in the SCN, keeping a period of approximately 24 hours. This rhythm is sustained in constant darkness, and can also be entrained to changing light cycles.[1] PER1 is involved in generating circadian rhythms in the SCN, and also has an effect on other oscillations throughout the body. For example, PER1 knockouts affect food entrainable oscillators and methamphetamine-sensitive circadian oscillators, whose periods are altered in the absence of PER1.[8] In addition, mice with knockouts in both the PER1 and PER2 genes show no circadian rhythmicity.[9] Phase shifts in PER1 neurons can be induced by a strong, brief light stimulus to the SCN of rats. This light exposure causes increases in PER1 mRNA, suggesting that the PER1 gene plays an important role in entrainment of the mammalian biological clock to the light-dark cycle.[10] ## Feedback mechanism The PER1 mRNA is expressed in all cells, acting as a part of a transcription-translation negative feedback mechanism, which creates a cell autonomous molecular clock. PER1 transcription is regulated by protein interactions with its five E-box and one D-box elements in its promoter region. Heterodimer CLOCK-BMAL1 activates E-box elements present in the PER1 promoter, as well activating the E box promoters of other components of the molecular clock such as PER2, CRY1, and CRY2. The phase of PER1 mRNA expression varies between tissues,[11] The transcript leaves the nucleus and is translated into a protein with PAS domains, which enable protein-protein interactions. PER1 and PER2 are phosphorylated by CK1ε, which leads to increased ubiquitylation and degradation.[12] This phosphorylation is counteracted by PP1 phosphatase, resulting in a more gradual increase in phosphorylated PER, and an additional control over the period of the molecular clock.[13] Phosphorylation of PER1 can also lead to masking of its leucine-rich nuclear localization sequence and thus impeded heterodimer import.[14] PER interacts with other PER proteins as well as the E-box regulated, clock controlled proteins CRY1 and CRY2 to create a heterodimer which translocates into the nucleus. There it inhibits CLOCK-BMAL activation.[15] PER1 is not necessary for the creation circadian rhythms, but homozygous PER1 mutants display a shortened period of mRNA expression.[9] While PER1 must be mutated in conjunction with PER2 to result in arhythmiticity, the two translated PER proteins have been shown to have slightly different roles, as PER1 acts preferentially through interaction with other clock proteins.[16] # Clinical significance PER1 expression may have significant effects on the cell cycle. Cancer is often a result of unregulated cell growth and division, which can be controlled by circadian mechanisms. Therefore, a cell's circadian clock may play a large role in its likelihood of developing into a cancer cell. PER1 is a gene that plays an important role in such a circadian mechanism. Its overexpression, in particular, causes DNA-damage induced apoptosis. In addition, down-regulation of PER1 can enhance tumor growth in mammals.[17] PER1 also interacts with proteins ATM and Chk2. These proteins are key checkpoint proteins in the cell cycle.[18] Cancer patients have a lowered expression of per1. Gery, et al. suggests that regulation of PER1 expression may be useful for cancer treatment in the future.[19] # Gene ## Orthologs The following is a list of some orthologs of the PER1 gene in other species:[20] - PER1 (Rattus norvegicus) - PER1 (Mus musculus) - per1a (Danio rerio) - PER1 (Homo sapiens) - lin-42 (Caenorhabditis elegans) - PER1 (Bos taurus) - per1b (Danio rerio) - PER (Drosophila melanogaster) - PER1 (Xenopus tropicalis) - PER1 (Equus caballus) - PER1 (Macaca mulatta) - PER1 (Sus scrofa) ## Paralogs - PER2 - PER3 ## Location The human PER1 gene is located on chromosome 17 at the following location:[21] - Start: 8,140,470 - Finish: 8,156,405 - Length: 15,936 - Exons: 24 PER1 has 19 transcripts (splice variants). # Discovery The PER1 ortholog was first discovered by Ronald Konopka and Seymour Benzer in 1971. During 1997, Period 1 (mPer1) and Period 2 (mPer2) genes were discovered (Sun et al., 1997 and Albretch et al., 1997). Through homology screens with the Drosophila per, these genes were discovered. It was independently discovered by Sun et al. 1997, naming it RIGUI and by Tei et al. 1997, who named it hper because of the protein sequence similarity with Drosophila per. They found that the mouse homolog had the properties of a circadian regulator. It had circadian expression in the suprachiasmatic nucleus (SCN), self-sustained oscillation, and entrainment of circadian expression by external light cues.[22]

https://www.wikidoc.org/index.php/PER1

cced77c8a96bb2f84a727871f4addef380ebd953

wikidoc

PER2

PER2 PER2 is a protein in mammals encoded by the PER2 gene. PER2 is noted for its major role in circadian rhythms. # Discovery The per gene was first discovered using forward genetics in Drosophilla melanogaster in 1971. This led to experiments in mammals that found Per2 in humans. Mammalian Per2 was discovered by Albrecht U et al. in 1997 through a search for homologous CDNA sequences to PER1. It is more similar to Drosophila per than its paralogs. # Function PER2 is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian clock, which regulates the daily rhythms of locomotor activity, metabolism, and behavior. Circadian expression of these genes and their encoded proteins in the suprachiasmatic nucleus. Human PER2 is involved human sleep disorder and cancer formation. Lowered PER2 expression is common in many tumors cells within the body, suggesting PER2 is integral for proper function and decreased levels promotes tumor progression. PER2 contains glucocorticoid response elements (GREs) and a GRE within the core clock gene PER2 is continuously occupied during rhythmic expression and essential for glucocorticoid regulation of PER2 in vivo. Mice with a genomic deletion spanning this GRE expressed elevated leptin levels and were protected from glucose intolerance and insulin resistance on glucocorticoid treatment but not from muscle wasting. PER2 is an integral component of a particular glucocorticoid regulatory pathway and that glucocorticoid regulation of the peripheral clock is selectively required for some actions of glucocorticoids. PER2 in mice is stabilized by exposure to strong light. PER2 in turn enhances oxygen-efficient glycolysis and hence provides cardioprotection from ischemia. Therefore, it is speculated that strong light may reduce the risk of heart attacks and decrease the damage after experiencing one. Moreover, PER2 has protective functions in liver diseases, as it antagonizes hepatitis C viral replication. Per2 knockout mice experience a free-running period of around 21.8 hours, compared to the normal mouse free-running period of 23.3 hours. Some of the Per2 knockout mice can also become arrhythmic under constant light conditions. PER2 has also been shown to be possibly important in the development of cancer. PER2 expression is significantly lower in human patients with lymphoma and acute myeloid leukemia. The PER2 protein seems to be important for the proliferation of osteoblasts, which aid in adding density to the bone through a pathway utilizing Myc and Ccnd1. Certain PER2 mutations have shown that they can increase the tolerance to the amount of alcohol that a mouse can intake through reduced uptake of glutamate. ## Main interactions In mammals, mPER2 forms a heterodimer with mPER1, mCRY1, and mCRY2 by binding to PAS domains. The heterodimer acts to inhibit their own transcription by suppressing the CLOCK/BMAL1 complex resulting in a negative feedback loop. This negative feedback loop is essential for maintaining a functioning circadian clock. A disruption of either both mPER1 and mPER2 genes together or both mCRY genes causes behavioural arrhythmicity when the double-knockout animals are placed in constant conditions. A third PER gene, mPer3, does not have a critical role in the maintenance of the core clock feedback loops. Molecular and behavioural rhythms are preserved in mice lacking mPer3. ## Interactions with CK1e PER2 has been shown to interact with a kinase called CK1e. CK1e phosphorylates PER2 in mammals. In Syrian hamster, a mutation called tau has been discovered in the CK1e, which increases phosphorylation of homologous PER2 leading to a faster degradation and a shortened period. Mutations in hPER2 can cause FASPS because of a lack of phosphorylation site in the mutated hPER2 protein. ## Interaction table # Clinical significance A genetic test from a cheek swab can use PER2 expression levels to tell whether a person is an early morning person or a "night owl". ## Familial Advanced Sleep Phase Familial advanced sleep phase (FASP) is characterized as a short period (e.g. 23.3 vs 24.3hr for population) in humans. A mutation in hPER2 decreases its phosphorylation by CK1d, which causes the phenotype seen in some FASP. The primary cause of these FASP is a mutation that changes amino acid 662 from serine to glycine (S662G) in PER2. The S662G mutation makes PER2 mutant protein a stronger repressor than normal PER2, decreasing cellular PER2 levels and therefore causing this form of FASP. The mutation also seems to cause an increase in the turnover rate of PER2 in the nucleus. # Gene The PER2 gene is located on the long (q) arm of chromosome 2 at position 37.3 and has 25 exons. Predicted human PER2 protein created from the PER2 gene shares 44% identity with human PER1 and 77% identity with mouse Per2. Northern blots analysis revealed that PER2 was expressed as a 7-kb mRNA in all tissues examined. An additional 1.8-kb transcript was also detected in some tissues. PER2 mRNA has been shown to peak at ZT 6 in the SCN.

PER2 PER2 is a protein in mammals encoded by the PER2 gene. PER2 is noted for its major role in circadian rhythms.[1][2] # Discovery The per gene was first discovered using forward genetics in Drosophilla melanogaster in 1971. This led to experiments in mammals that found Per2 in humans. Mammalian Per2 was discovered by Albrecht U et al. in 1997 through a search for homologous CDNA sequences to PER1.[3] It is more similar to Drosophila per than its paralogs.[4] # Function PER2 is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian clock, which regulates the daily rhythms of locomotor activity, metabolism, and behavior. Circadian expression of these genes and their encoded proteins in the suprachiasmatic nucleus. Human PER2 is involved human sleep disorder and cancer formation.[5] Lowered PER2 expression is common in many tumors cells within the body, suggesting PER2 is integral for proper function and decreased levels promotes tumor progression.[6][7] PER2 contains glucocorticoid response elements (GREs) and a GRE within the core clock gene PER2 is continuously occupied during rhythmic expression and essential for glucocorticoid regulation of PER2 in vivo. Mice with a genomic deletion spanning this GRE expressed elevated leptin levels and were protected from glucose intolerance and insulin resistance on glucocorticoid treatment but not from muscle wasting. PER2 is an integral component of a particular glucocorticoid regulatory pathway and that glucocorticoid regulation of the peripheral clock is selectively required for some actions of glucocorticoids.[8] PER2 in mice is stabilized by exposure to strong light. PER2 in turn enhances oxygen-efficient glycolysis and hence provides cardioprotection from ischemia. Therefore, it is speculated that strong light may reduce the risk of heart attacks and decrease the damage after experiencing one.[9] Moreover, PER2 has protective functions in liver diseases, as it antagonizes hepatitis C viral replication.[10] Per2 knockout mice experience a free-running period of around 21.8 hours, compared to the normal mouse free-running period of 23.3 hours. Some of the Per2 knockout mice can also become arrhythmic under constant light conditions. PER2 has also been shown to be possibly important in the development of cancer. PER2 expression is significantly lower in human patients with lymphoma and acute myeloid leukemia.[11] The PER2 protein seems to be important for the proliferation of osteoblasts, which aid in adding density to the bone through a pathway utilizing Myc and Ccnd1. Certain PER2 mutations have shown that they can increase the tolerance to the amount of alcohol that a mouse can intake through reduced uptake of glutamate.[12] ## Main interactions In mammals, mPER2 forms a heterodimer with mPER1, mCRY1, and mCRY2 by binding to PAS domains. The heterodimer acts to inhibit their own transcription by suppressing the CLOCK/BMAL1 complex resulting in a negative feedback loop.[13][14] This negative feedback loop is essential for maintaining a functioning circadian clock. A disruption of either both mPER1 and mPER2 genes together or both mCRY genes causes behavioural arrhythmicity when the double-knockout animals are placed in constant conditions. A third PER gene, mPer3, does not have a critical role in the maintenance of the core clock feedback loops. Molecular and behavioural rhythms are preserved in mice lacking mPer3.[15] ## Interactions with CK1e PER2 has been shown to interact with a kinase called CK1e. CK1e phosphorylates PER2 in mammals. In Syrian hamster, a mutation called tau has been discovered in the CK1e, which increases phosphorylation of homologous PER2 leading to a faster degradation and a shortened period.[16] Mutations in hPER2 can cause FASPS because of a lack of phosphorylation site in the mutated hPER2 protein. ## Interaction table # Clinical significance A genetic test from a cheek swab can use PER2 expression levels to tell whether a person is an early morning person or a "night owl".[17] ## Familial Advanced Sleep Phase Familial advanced sleep phase (FASP) is characterized as a short period (e.g. 23.3 vs 24.3hr for population) in humans. A mutation in hPER2 decreases its phosphorylation by CK1d, which causes the phenotype seen in some FASP.[18] The primary cause of these FASP is a mutation that changes amino acid 662 from serine to glycine (S662G) in PER2. The S662G mutation makes PER2 mutant protein a stronger repressor than normal PER2, decreasing cellular PER2 levels and therefore causing this form of FASP. The mutation also seems to cause an increase in the turnover rate of PER2 in the nucleus.[12] # Gene The PER2 gene is located on the long (q) arm of chromosome 2 at position 37.3 and has 25 exons.[5] Predicted human PER2 protein created from the PER2 gene shares 44% identity with human PER1 and 77% identity with mouse Per2. Northern blots analysis revealed that PER2 was expressed as a 7-kb mRNA in all tissues examined. An additional 1.8-kb transcript was also detected in some tissues.[19] PER2 mRNA has been shown to peak at ZT 6 in the SCN.[12]

https://www.wikidoc.org/index.php/PER2

ea0a9bd0b73a95e921d3c487b5828427e587f8ed

wikidoc

PER3

PER3 The PER3 gene encodes the period circadian protein homolog 3 protein in humans. PER3 is a paralog to the PER1 and PER2 genes. It is a circadian gene associate with delayed sleep phase syndrome in humans. # History The Per3 gene was independently cloned by two research groups (Kobe University School of Medicine and the Harvard Medical School) who both published their discovery in June 1988. The mammalian Per3 was discovered by searching for homologous cDNA sequences to Per2. The amino acid sequence of the mouse PERIOD3 protein (mPER3) is between 37-56% similar to the other two PER proteins. # Function This gene is a member of the Period family of genes. It is expressed in a circadian pattern in the suprachiasmatic nucleus (SCN), the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. Circadian expression in the SCN continues in constant darkness, and a shift in the light/dark cycle evokes a proportional shift of gene expression in the SCN. PER1 and PER2 are necessary for molecular timekeeping and light responsiveness in the master circadian clock in the SCN, but little data is shown on the concrete function for PER3. PER3 was found to be important for endogenous timekeeping in specific tissues and those tissue-specific changes in endogenous periods result in internal misalignment of circadian clocks in Per3 double knockout (-/-) mice. PER3 may have a stabilizing effect on PER1 and PER2, and this stabilizing effect may be reduced in the PER3-P415A/H417R polymorphism. # Role in chronobiology The RNA levels of mPer3 oscillate with a circadian rhythm in both the SCN and in the eyes, as well as in peripheral tissues, including the liver, skeletal muscle, and testis. Unlike Per1 and Per2, of which the mRNA is induced in response to light, Per3 mRNA in the SCN does not respond to light. This suggests that Per3 may be regulated differently than either Per1 or Per2. The mPER3 protein contains a PAS domain, similar to mPER1 and mPER2. Likely, mPER3 binds to other proteins using this domain. However, while PER1/2 have been shown to be important in the transcription-translation feedback loop involved in the intracellular circadian clock, the influence of PER3 in this loop has not yet been fully elucidated, given that mPER3 does not appear to be functionally redundant to mPER1 and mPER2. mPer3 may not be a member of the core clock loop at all. # Animal studies While the Per3 gene is a paralog to the PER1 and PER2 genes, studies in animals generally show that it does not contribute significantly to circadian rhythms. Functional Per3-/- animals experience only small changes in free-running period, and do not respond significantly differently to light pulses. Per1-/- and Per2-/- animals experience a significant change in free-running period; however, knocking out Per3 in addition to either Per1 or Per2 has little effect on free-running rhythms. Furthermore, Per1-/-Per2-/- mice are completely arrhythmic, indicating that these two genes have much more importance to the biological clock than Per3. Per3 knockout mice experience a slightly shortened period of locomotor activity (by 0.5 hr) and are less sensitive to light, in that they entrain more slowly to changes in the light-dark cycle. PER3 may be involved in the suppression of behavioral activity in response to light, although mPer3 expression is not necessary for circadian rhythms. # Clinical significance The PER3 “length” polymorphism in the 54-bp repeat sequence in exon 18 (GenBank accession no. AB047686) is a structural polymorphism due to an insertion or deletion of 18 amino acids in a region encoding a putative phosphorylation domain. The polymorphism has been associated with diurnal preference and delayed sleep phase syndrome. A longer allele polymorphism is associated with “morningness” and the short allele with “eveningness.” The short allele is also associated with delayed sleep phase syndrome. The length polymorphism has also been shown to inhibit adipogenesis and Per3 knockout mice were shown to have increased adipose tissue and decreased muscle tissue compared to wild type. Additionally, the presence of the length polymorphism has also been shown to be associated with type 2 diabetes mellitus (T2DM) patients as compared to non-diabetic control patients. The PER3-P415A/H417R polymorphism has been linked to familial advanced sleep phase syndrome in humans, as well as to seasonal affective disorder, though when knocked in to mice, the polymorphism causes a delayed sleep phase. # Gene ## Orthologs The following is a list of some orthologs of the PER3 gene in other species: - PER3 (P. troglodytes) - PER3 (M. mulatta) - PER3 (C. lupus) - PER3 (H. sapiens) - PER3 (B. taurus) - Per3 (M. musculus) - Per3 (R. norvegicus) - PER3 (G. gallus) - per3 (X. tropicalis) - per3 (D. rerio) ## Paralogs - PER1 - PER2 ## Gene location The human PER3 gene is located on chromosome 1 at the following location: - Start: 7,784,320 bp - Finish: 7,845,181 bp - Length: 60,862 bases - Exons: 25 PER3 has 19 transcripts (splice variants). ## Protein structure The PER3 protein has been identified to have the following features: - Size: 1201 amino acids - Molecular mass: 131888 Da - Quaternary structure: Homodimer ## Post translational modifications The following are some known post transcriptional modifications to the Per3 gene: - Phosphorylation by CSNK1E is weak and appears to require association with PER1 and translocation to the nucleus. - Ubiquitinated. - Modification sites at PhosphoSitePlus - Modification sites at neXtProt

PER3 The PER3 gene encodes the period circadian protein homolog 3 protein in humans.[1] PER3 is a paralog to the PER1 and PER2 genes. It is a circadian gene associate with delayed sleep phase syndrome in humans.[2] # History The Per3 gene was independently cloned by two research groups (Kobe University School of Medicine and the Harvard Medical School) who both published their discovery in June 1988.[3][4] The mammalian Per3 was discovered by searching for homologous cDNA sequences to Per2. The amino acid sequence of the mouse PERIOD3 protein (mPER3) is between 37-56% similar to the other two PER proteins.[4][3] # Function This gene is a member of the Period family of genes. It is expressed in a circadian pattern in the suprachiasmatic nucleus (SCN), the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. Circadian expression in the SCN continues in constant darkness, and a shift in the light/dark cycle evokes a proportional shift of gene expression in the SCN.[5] PER1 and PER2 are necessary for molecular timekeeping and light responsiveness in the master circadian clock in the SCN, but little data is shown on the concrete function for PER3. PER3 was found to be important for endogenous timekeeping in specific tissues and those tissue-specific changes in endogenous periods result in internal misalignment of circadian clocks in Per3 double knockout (-/-) mice.[6] PER3 may have a stabilizing effect on PER1 and PER2, and this stabilizing effect may be reduced in the PER3-P415A/H417R polymorphism.[7] # Role in chronobiology The RNA levels of mPer3 oscillate with a circadian rhythm in both the SCN and in the eyes, as well as in peripheral tissues, including the liver, skeletal muscle, and testis.[4] Unlike Per1 and Per2, of which the mRNA is induced in response to light, Per3 mRNA in the SCN does not respond to light. This suggests that Per3 may be regulated differently than either Per1 or Per2.[4] The mPER3 protein contains a PAS domain, similar to mPER1 and mPER2. Likely, mPER3 binds to other proteins using this domain.[4] However, while PER1/2 have been shown to be important in the transcription-translation feedback loop involved in the intracellular circadian clock, the influence of PER3 in this loop has not yet been fully elucidated, given that mPER3 does not appear to be functionally redundant to mPER1 and mPER2.[8] mPer3 may not be a member of the core clock loop at all.[8] # Animal studies While the Per3 gene is a paralog to the PER1 and PER2 genes, studies in animals generally show that it does not contribute significantly to circadian rhythms. Functional Per3-/- animals experience only small changes in free-running period,[8] and do not respond significantly differently to light pulses.[9] Per1-/- and Per2-/- animals experience a significant change in free-running period; however, knocking out Per3 in addition to either Per1 or Per2 has little effect on free-running rhythms.[8] Furthermore, Per1-/-Per2-/- mice are completely arrhythmic, indicating that these two genes have much more importance to the biological clock than Per3.[8] Per3 knockout mice experience a slightly shortened period of locomotor activity (by 0.5 hr[9]) and are less sensitive to light, in that they entrain more slowly to changes in the light-dark cycle. PER3 may be involved in the suppression of behavioral activity in response to light, although mPer3 expression is not necessary for circadian rhythms.[10][11] # Clinical significance The PER3 “length” polymorphism in the 54-bp repeat sequence in exon 18 (GenBank accession no. AB047686) is a structural polymorphism due to an insertion or deletion of 18 amino acids in a region encoding a putative phosphorylation domain. The polymorphism has been associated with diurnal preference and delayed sleep phase syndrome. A longer allele polymorphism is associated with “morningness” and the short allele with “eveningness.” The short allele is also associated with delayed sleep phase syndrome.[2] The length polymorphism has also been shown to inhibit adipogenesis and Per3 knockout mice were shown to have increased adipose tissue and decreased muscle tissue compared to wild type. Additionally, the presence of the length polymorphism has also been shown to be associated with type 2 diabetes mellitus (T2DM) patients as compared to non-diabetic control patients.[12] The PER3-P415A/H417R polymorphism has been linked to familial advanced sleep phase syndrome in humans, as well as to seasonal affective disorder, though when knocked in to mice, the polymorphism causes a delayed sleep phase.[7] # Gene ## Orthologs The following is a list of some orthologs of the PER3 gene in other species:[13] - PER3 (P. troglodytes) - PER3 (M. mulatta) - PER3 (C. lupus) - PER3 (H. sapiens) - PER3 (B. taurus) - Per3 (M. musculus) - Per3 (R. norvegicus) - PER3 (G. gallus) - per3 (X. tropicalis) - per3 (D. rerio) ## Paralogs - PER1 - PER2 ## Gene location The human PER3 gene is located on chromosome 1 at the following location:[14] - Start: 7,784,320 bp - Finish: 7,845,181 bp - Length: 60,862 bases - Exons: 25 PER3 has 19 transcripts (splice variants). ## Protein structure The PER3 protein has been identified to have the following features:[15] - Size: 1201 amino acids - Molecular mass: 131888 Da - Quaternary structure: Homodimer ## Post translational modifications The following are some known post transcriptional modifications to the Per3 gene:[15] - Phosphorylation by CSNK1E is weak and appears to require association with PER1 and translocation to the nucleus. - Ubiquitinated. - Modification sites at PhosphoSitePlus - Modification sites at neXtProt

https://www.wikidoc.org/index.php/PER3

c1ed4f0d9b2f8354c91f2f955d76b602c7834880

wikidoc

PETN

PETN # Overview Pentaerythritol tetranitrate (PETN), also known as PENT, PENTA, TEN, corpent, penthrite (or—rarely and primarily in German—as nitropenta), is the nitrate ester of pentaerythritol, and is structurally very similar to nitroglycerin. Penta refers to the five carbon atoms of the neopentane skeleton. PETN is best known as an explosive. It is one of the most powerful high explosives known, with a relative effectiveness factor of 1.66. PETN mixed with a plasticizer forms a plastic explosive. As a mixture with RDX and other minor additives, it forms another plastic explosive called Semtex as well. The compound was discovered in the bombs used by the 2001 Shoe Bomber, in the 2009 Christmas Day bomb plot, and in the 2010 cargo plane bomb plot. On 7 September 2011, a bomb suspected to have used PETN exploded near the High Court of Delhi in India claiming 13 lives and injuring more than 70. It is also used as a vasodilator drug to treat certain heart conditions, such as for management of angina. # History Penthrite was first synthesized in 1891 by Bernhard Tollens and P. Wigand by nitration of pentaerythritol. The production of PETN started in 1912, when it was patented by the German government. PETN was used by the German Army in World War I. # Properties PETN is practically insoluble in water (0.01 g/100 ml at 50 °C), weakly soluble in common nonpolar solvents such as aliphatic hydrocarbons (like gasoline) or tetrachloromethane, but soluble in some other organic solvents, particularly in acetone (about 15 g/100 g of the solution at 20 °C, 55 g/100 g at 60 °C) and dimethylformamide (40 g/100 g of the solution at 40 °C, 70 g/100 g at 70 °C). PETN forms eutectic mixtures with some liquid or molten aromatic nitro compounds, e.g. trinitrotoluene (TNT) or tetryl. Due to its highly symmetrical structure, PETN is resistant to attack by many chemical reagents; it does not hydrolyze in water at room temperature or in weaker alkaline aqueous solutions. Water at 100 °C or above causes hydrolysis to dinitrate; presence of 0.1% nitric acid accelerates the reaction. Addition of TNT and other aromatic nitro derivatives lowers thermal stability of PETN. The chemical stability of PETN is of interest, because of the use of PETN in aging stockpiles of weapons. A review has been published. Neutron radiation degrades PETN, producing carbon dioxide and some pentaerythritol dinitrate and trinitrate. Gamma radiation increases the thermal decomposition sensitivity of PETN, lowers melting point by few degrees Celsius, and causes swelling of the samples. Like other nitrate esters, the primary degradation mechanism is the loss of nitrogen dioxide; this reaction is autocatalytic. Studies were performed on thermal decomposition of PETN. In the environment, PETN undergoes biodegradation. Some bacteria denitrate PETN to trinitrate and then dinitrate, which is then further degraded. PETN has low volatility and low solubility in water, and therefore has low bioavailability for most organisms. Its toxicity is relatively low, and its transdermal absorption also seems to be low. It poses a threat for aquatic organisms. It can be degraded to pentaerythritol by iron metal. # Production Production is by the reaction of pentaerythritol with concentrated nitric acid to form a precipitate which can be recrystallized from acetone to give processable crystals. Variations of a method first published in a US Patent 2,370,437 by Acken and Vyverberg (1945 to Du Pont) forms the basis of all current commercial production. PETN is manufactured by numerous manufacturers as a powder about the consistency of fine popcorn salt, or together with nitrocellulose and plasticizer as thin plasticized sheets (e.g. Primasheet 1000 or Detasheet). PETN residues are easily detectable in hair of people handling it. The highest residue retention is on black hair; some residues remain present even after washing. # Medical Use Like nitroglycerin (glyceryl trinitrate) and other nitrates, PETN is also used medically as a vasodilator in the treatment of heart conditions. These drugs work by releasing the signaling gas nitric oxide in the body. The heart medicine Lentonitrat is nearly pure PETN. Monitoring of oral usage of the drug by patients has been performed by determination of plasma levels of several of its hydrolysis products, pentaerythritol dinitrate, pentaerythritol mononitrate and pentaerythritol, in plasma using gas chromatography-mass spectrometry. # See Also - Erythritol tetranitrate - Pentaerythritol - RDX

PETN Template:Explosivebox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Pentaerythritol tetranitrate (PETN), also known as PENT, PENTA, TEN, corpent, penthrite (or—rarely and primarily in German—as nitropenta), is the nitrate ester of pentaerythritol, and is structurally very similar to nitroglycerin. Penta refers to the five carbon atoms of the neopentane skeleton. PETN is best known as an explosive. It is one of the most powerful high explosives known, with a relative effectiveness factor of 1.66. PETN mixed with a plasticizer forms a plastic explosive. As a mixture with RDX and other minor additives, it forms another plastic explosive called Semtex as well. The compound was discovered in the bombs used by the 2001 Shoe Bomber, in the 2009 Christmas Day bomb plot, and in the 2010 cargo plane bomb plot. On 7 September 2011, a bomb suspected to have used PETN exploded near the High Court of Delhi in India claiming 13 lives and injuring more than 70. It is also used as a vasodilator drug to treat certain heart conditions, such as for management of angina.[1][2] # History Penthrite was first synthesized in 1891 by Bernhard Tollens and P. Wigand by nitration of pentaerythritol.[3] The production of PETN started in 1912, when it was patented by the German government. PETN was used by the German Army in World War I.[4] # Properties PETN is practically insoluble in water (0.01 g/100 ml at 50 °C), weakly soluble in common nonpolar solvents such as aliphatic hydrocarbons (like gasoline) or tetrachloromethane, but soluble in some other organic solvents, particularly in acetone (about 15 g/100 g of the solution at 20 °C, 55 g/100 g at 60 °C) and dimethylformamide (40 g/100 g of the solution at 40 °C, 70 g/100 g at 70 °C). PETN forms eutectic mixtures with some liquid or molten aromatic nitro compounds, e.g. trinitrotoluene (TNT) or tetryl. Due to its highly symmetrical structure, PETN is resistant to attack by many chemical reagents; it does not hydrolyze in water at room temperature or in weaker alkaline aqueous solutions. Water at 100 °C or above causes hydrolysis to dinitrate; presence of 0.1% nitric acid accelerates the reaction. Addition of TNT and other aromatic nitro derivatives lowers thermal stability of PETN. The chemical stability of PETN is of interest, because of the use of PETN in aging stockpiles of weapons. A review has been published. Neutron radiation degrades PETN, producing carbon dioxide and some pentaerythritol dinitrate and trinitrate. Gamma radiation increases the thermal decomposition sensitivity of PETN, lowers melting point by few degrees Celsius, and causes swelling of the samples. Like other nitrate esters, the primary degradation mechanism is the loss of nitrogen dioxide; this reaction is autocatalytic. Studies were performed on thermal decomposition of PETN. In the environment, PETN undergoes biodegradation. Some bacteria denitrate PETN to trinitrate and then dinitrate, which is then further degraded. PETN has low volatility and low solubility in water, and therefore has low bioavailability for most organisms. Its toxicity is relatively low, and its transdermal absorption also seems to be low. It poses a threat for aquatic organisms. It can be degraded to pentaerythritol by iron metal.[5] # Production Production is by the reaction of pentaerythritol with concentrated nitric acid to form a precipitate which can be recrystallized from acetone to give processable crystals. Variations of a method first published in a US Patent 2,370,437 by Acken and Vyverberg (1945 to Du Pont) forms the basis of all current commercial production. PETN is manufactured by numerous manufacturers as a powder about the consistency of fine popcorn salt, or together with nitrocellulose and plasticizer as thin plasticized sheets (e.g. Primasheet 1000 or Detasheet). PETN residues are easily detectable in hair of people handling it.[6] The highest residue retention is on black hair; some residues remain present even after washing.[7][8] # Medical Use Like nitroglycerin (glyceryl trinitrate) and other nitrates, PETN is also used medically as a vasodilator in the treatment of heart conditions.[1][2] These drugs work by releasing the signaling gas nitric oxide in the body. The heart medicine Lentonitrat is nearly pure PETN.[9] Monitoring of oral usage of the drug by patients has been performed by determination of plasma levels of several of its hydrolysis products, pentaerythritol dinitrate, pentaerythritol mononitrate and pentaerythritol, in plasma using gas chromatography-mass spectrometry.[10] # See Also - Erythritol tetranitrate - Pentaerythritol - RDX

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

58ff4e40ca5d5441e172636f394d7bd091b4ef06

wikidoc

PEX5

PEX5 Peroxisomal targeting signal 1 receptor (PTS1R) is a protein that in humans is encoded by the PEX5 gene. PTS1R is a peroxisomal targeting sequence involved in the specific transport of molecules for oxidation inside the peroxisome. SKL binds to PTS1R in the cytosol followed by binding to the Pex14p receptor allowing importation of the peroxisomal protein through the pexsubunit transporter. Diseases associated with dysfunctional PTS1R receptors include X-linked adrenoleukodystrophy and Zellweger syndrome. # Interactions PEX5 has been shown to interact with PEX12, PEX13 and PEX14.

PEX5 Peroxisomal targeting signal 1 receptor (PTS1R) is a protein that in humans is encoded by the PEX5 gene.[1] PTS1R is a peroxisomal targeting sequence involved in the specific transport of molecules for oxidation inside the peroxisome. SKL binds to PTS1R in the cytosol followed by binding to the Pex14p receptor allowing importation of the peroxisomal protein through the pexsubunit transporter. Diseases associated with dysfunctional PTS1R receptors include X-linked adrenoleukodystrophy and Zellweger syndrome. # Interactions PEX5 has been shown to interact with PEX12,[2][3] PEX13[4][5] and PEX14.[3][5][6]

https://www.wikidoc.org/index.php/PEX5

520c0eeac9740efdb9cd7619e388e45df9932886

wikidoc

PEX6

PEX6 Peroxisome assembly factor 2 is a protein that in humans is encoded by the PEX6 gene. PEX6 is an AAA ATPase that localizes to the peroxisome. PEX6 forms a hexamer with PEX1 and is recruited to the membrane by PEX26. # Function From yeast to plants to humans, there is only one verified function of PEX6; PEX6 (and PEX1) removes PEX5 from the peroxisomal membrane so that PEX5 may do additional rounds of peroxisomal import. Human PEX6 can genetically complement plant pex6 mutants, which highlights functional conservation. Work with pex6 mutants in Arabidopsis thaliana has shown that PEX6 may have a role in consuming oil body (plant-specific lipid droplets). Work with yeast pex6 mutants has shown that PEX6 is a key player in the autophagy of peroxisomes called pexophagy. # Related diseases Mutations in the genes encoding PEX6, along with PEX1, are the leading causes of peroxisomal biogenesis disorders, such as Zellweger Syndrome spectrum, infantile Refsum disease, and neonatal adrenoleukodystrophy. These genetic diseases are autosomal recessive and occur in 1 of every 50,000 births.

PEX6 Peroxisome assembly factor 2 is a protein that in humans is encoded by the PEX6 gene.[1][2] PEX6 is an AAA ATPase that localizes to the peroxisome. PEX6 forms a hexamer with PEX1[3][4] and is recruited to the membrane by PEX26.[5] # Function From yeast to plants to humans, there is only one verified function of PEX6; PEX6 (and PEX1) removes PEX5 from the peroxisomal membrane so that PEX5 may do additional rounds of peroxisomal import. Human PEX6 can genetically complement plant pex6 mutants, which highlights functional conservation.[6] Work with pex6 mutants in Arabidopsis thaliana has shown that PEX6 may have a role in consuming oil body (plant-specific lipid droplets).[7] Work with yeast pex6 mutants has shown that PEX6 is a key player in the autophagy of peroxisomes called pexophagy.[8] # Related diseases Mutations in the genes encoding PEX6, along with PEX1, are the leading causes of peroxisomal biogenesis disorders[9], such as Zellweger Syndrome spectrum, infantile Refsum disease, and neonatal adrenoleukodystrophy. These genetic diseases are autosomal recessive and occur in 1 of every 50,000 births.[10]

https://www.wikidoc.org/index.php/PEX6

0f44baaa30dd37d6f63b5682224e017d93d45bcf

wikidoc

PFKL

PFKL 6-phosphofructokinase, liver type (PFKL) is an enzyme that in humans is encoded by the PFKL gene on chromosome 21. This gene encodes the liver (L) subunit of an enzyme that catalyzes the conversion of D-fructose 6-phosphate to D-fructose 1,6-bisphosphate, which is a key step in glucose metabolism (glycolysis). This enzyme is a tetramer that may be composed of different subunits encoded by distinct genes in different tissues. Alternative splicing results in multiple transcript variants. # Structure ## Gene The PFKL mRNA sequence includes 55 nucleotides at the 5' and 515 nucleotides at the 3' noncoding regions, as well as 2,337 nucleotides in the coding region, encoding 779 amino acids. This coding region only shares a 68% similarity between PFKL and the muscle-type PFKM. ## Protein This 80-kDa protein is one of three subunit types that comprise the five tetrameric PFK isozymes. The liver PFK (PFK-5) contains solely PFKL, while the erythrocyte PFK includes five isozymes composed of different combinations of PFKL and the second subunit type, PFKM. The muscle isozyme (PFK-1) is composed solely of PFKM. These subunits evolved from a common prokaryotic ancestor via gene duplication and mutation events. Generally, the N-terminal of the subunits carries out their catalytic activity while the C-terminal contains allosteric ligand binding sites # Function This gene encodes one of three protein subunits of PFK, which are expressed and combined to form the tetrameric PFK in a tissue-specific manner. As a PFK subunit, PFKL is involved in catalyzing the phosphorylation of fructose 6-phosphate to fructose 1,6-bisphosphate. This irreversible reaction serves as the major rate-limiting step of glycolysis. Notably, knockdown of PFKL has been shown to impair glycolysis and promote metabolism via the pentose phosphate pathway. Moreover, PFKL regulates NADPH oxidase activity through the pentose phosphate pathway and according to NADPH levels. PFKL has also been detected in leukocytes, kidney, and brain. # Clinical significance As the erythrocyte PFK is composed of both PFKL and PFKM, this heterogeneic composition is attributed with the differential PFK activity and organ involvement observed in some inherited PFK deficiency states in which myopathy or hemolysis or both can occur, such as glycogenosis type VII (Tarui disease). Overexpression of PFKL has been associated with Down's syndrome (DS) erythrocytes and fibroblasts and attributed with biochemical changes in PFK that enhance its glycolytic function. Moreover, the PFKL gene maps to the triplicated region of chromosome 21 responsible for DS, indicating that this gene, too, has been triplicated. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} # Model organisms Model organisms have been used in the study of PFKL function. A conditional knockout mouse line, called Pfkltm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on mutant mice and three significant abnormalities were observed. Few homozygous mutant embryos were identified during gestation, and none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and a hair follicle degeneration phenotype was observed.

PFKL 6-phosphofructokinase, liver type (PFKL) is an enzyme that in humans is encoded by the PFKL gene on chromosome 21.[1] This gene encodes the liver (L) subunit of an enzyme that catalyzes the conversion of D-fructose 6-phosphate to D-fructose 1,6-bisphosphate, which is a key step in glucose metabolism (glycolysis). This enzyme is a tetramer that may be composed of different subunits encoded by distinct genes in different tissues. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014][1] # Structure ## Gene The PFKL mRNA sequence includes 55 nucleotides at the 5' and 515 nucleotides at the 3' noncoding regions, as well as 2,337 nucleotides in the coding region, encoding 779 amino acids. This coding region only shares a 68% similarity between PFKL and the muscle-type PFKM.[2] ## Protein This 80-kDa protein is one of three subunit types that comprise the five tetrameric PFK isozymes. The liver PFK (PFK-5) contains solely PFKL, while the erythrocyte PFK includes five isozymes composed of different combinations of PFKL and the second subunit type, PFKM.[3][4] The muscle isozyme (PFK-1) is composed solely of PFKM.[3][5][6] These subunits evolved from a common prokaryotic ancestor via gene duplication and mutation events. Generally, the N-terminal of the subunits carries out their catalytic activity while the C-terminal contains allosteric ligand binding sites[7] # Function This gene encodes one of three protein subunits of PFK, which are expressed and combined to form the tetrameric PFK in a tissue-specific manner. As a PFK subunit, PFKL is involved in catalyzing the phosphorylation of fructose 6-phosphate to fructose 1,6-bisphosphate. This irreversible reaction serves as the major rate-limiting step of glycolysis.[3][6][7][8] Notably, knockdown of PFKL has been shown to impair glycolysis and promote metabolism via the pentose phosphate pathway. Moreover, PFKL regulates NADPH oxidase activity through the pentose phosphate pathway and according to NADPH levels.[8] PFKL has also been detected in leukocytes, kidney, and brain.[5] # Clinical significance As the erythrocyte PFK is composed of both PFKL and PFKM, this heterogeneic composition is attributed with the differential PFK activity and organ involvement observed in some inherited PFK deficiency states in which myopathy or hemolysis or both can occur, such as glycogenosis type VII (Tarui disease).[3][4] Overexpression of PFKL has been associated with Down's syndrome (DS) erythrocytes and fibroblasts and attributed with biochemical changes in PFK that enhance its glycolytic function. Moreover, the PFKL gene maps to the triplicated region of chromosome 21 responsible for DS, indicating that this gene, too, has been triplicated.[9] # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. [§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} # Model organisms Model organisms have been used in the study of PFKL function. A conditional knockout mouse line, called Pfkltm1a(EUCOMM)Wtsi[14][15] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[16][17][18] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[12][19] Twenty six tests were carried out on mutant mice and three significant abnormalities were observed.[12] Few homozygous mutant embryos were identified during gestation, and none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and a hair follicle degeneration phenotype was observed.[12]

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

13e12c4ccb05e85f2a73fa1ba70ef39dfa7c893c

wikidoc

PFKP

PFKP Phosphofructokinase, platelet, also known as PFKP is an enzyme which in humans is encoded by the PFKP gene. # Function The PFKP gene encodes the platelet isoform of phosphofructokinase (PFK) (ATP:D-fructose-6-phosphate-1-phosphotransferase, EC 2.7.1.11). PFK catalyzes the irreversible conversion of fructose 6-phosphate to fructose 1,6-bisphosphate and is a key regulatory enzyme in glycolysis. The PFKP gene, which maps to chromosome 10p, is also expressed in fibroblasts. See also the muscle (PFKM) and liver (PFKL) isoforms of phosphofructokinase, which map to chromosomes 12q13 and 21q22, respectively. Full tetrameric phosphofructokinase enzyme expressed in platelets can be composed of subunits P4, P3L, and P2L2. # 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}

PFKP Phosphofructokinase, platelet, also known as PFKP is an enzyme which in humans is encoded by the PFKP gene.[1] # Function The PFKP gene encodes the platelet isoform of phosphofructokinase (PFK) (ATP:D-fructose-6-phosphate-1-phosphotransferase, EC 2.7.1.11). PFK catalyzes the irreversible conversion of fructose 6-phosphate to fructose 1,6-bisphosphate and is a key regulatory enzyme in glycolysis. The PFKP gene, which maps to chromosome 10p, is also expressed in fibroblasts. See also the muscle (PFKM) and liver (PFKL) isoforms of phosphofructokinase, which map to chromosomes 12q13 and 21q22, respectively. Full tetrameric phosphofructokinase enzyme expressed in platelets can be composed of subunits P4, P3L, and P2L2.[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: "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}

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PFN2

PFN2 Profilin-2 is a protein that in humans is encoded by the PFN2 gene. The protein encoded by this gene is a ubiquitous actin monomer-binding protein belonging to the profilin family. It is thought to regulate actin polymerization in response to extracellular signals. There are two alternatively spliced transcript variants encoding different isoforms described for this gene. # Interactions PFN2 has been shown to interact with ROCK1, Vasodilator-stimulated phosphoprotein, CCDC113 and FMNL1.

PFN2 Profilin-2 is a protein that in humans is encoded by the PFN2 gene.[1][2][3] The protein encoded by this gene is a ubiquitous actin monomer-binding protein belonging to the profilin family. It is thought to regulate actin polymerization in response to extracellular signals. There are two alternatively spliced transcript variants encoding different isoforms described for this gene.[3] # Interactions PFN2 has been shown to interact with ROCK1,[4] Vasodilator-stimulated phosphoprotein,[5][6] CCDC113[7] and FMNL1.[8]

https://www.wikidoc.org/index.php/PFN2

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pFPP

pFPP Parafluorophenylpiperazine (flippiperazine, fluoperazine, pFPP, 4-FPP) is a piperazine derivative with mildly hallucinogenic and euphoric effects which has been sold as an ingredient in legal recreational drugs known as "Party pills", initially in New Zealand and subsequently in other countries around the world. pFPP has been found in vitro to act mainly as a 5HT1A serotonin receptor agonist, with some affinity for 5HT2A and 5HT2C receptors. It also inhibits the reuptake of serotonin and norepinephrine. pFPP was originally discovered as a metabolite of the hypnotic antihistamine Niaprazine in 1982, but was subsequently re-discovered in 2003 as a potential recreational drug, and subsequently sold as an ingredient in "Party pills" in New Zealand, under brand names such as "The Big Grin","Mashed" and "Extreme Beans". pFPP has little stimulant effects, with its subjective effects derived mainly from its action as a 5HT1A agonist . Its effects have been described as similar to a cross between Fluoxetine and a very small dose of LSD, both of which have significant actions as 5HT1A agonists in addition to their primary mechanism of action. pFPP is active at doses between 20mg - 150mg, but higher doses cause a range of side effects including migraine headaches, muscle aches, anxiety, nausea and vomiting.

pFPP Parafluorophenylpiperazine (flippiperazine, fluoperazine, pFPP, 4-FPP) is a piperazine derivative with mildly hallucinogenic and euphoric effects[1][2] which has been sold as an ingredient in legal recreational drugs known as "Party pills", initially in New Zealand and subsequently in other countries around the world. pFPP has been found in vitro to act mainly as a 5HT1A serotonin receptor agonist, with some affinity for 5HT2A and 5HT2C receptors. It also inhibits the reuptake of serotonin and norepinephrine. pFPP was originally discovered as a metabolite of the hypnotic antihistamine Niaprazine in 1982[3], but was subsequently re-discovered in 2003 as a potential recreational drug, and subsequently sold as an ingredient in "Party pills" in New Zealand, under brand names such as "The Big Grin","Mashed" and "Extreme Beans". pFPP has little stimulant effects, with its subjective effects derived mainly from its action as a 5HT1A agonist [4]. Its effects have been described as similar to a cross between Fluoxetine and a very small dose of LSD[citation needed], both of which have significant actions as 5HT1A agonists in addition to their primary mechanism of action. pFPP is active at doses between 20mg - 150mg, but higher doses cause a range of side effects including migraine headaches, muscle aches, anxiety, nausea and vomiting.

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