id
stringlengths 40
40
| source
stringclasses 9
values | title
stringlengths 2
345
| clean_text
stringlengths 35
1.63M
| raw_text
stringlengths 4
1.63M
| url
stringlengths 4
498
| overview
stringlengths 0
10k
|
|---|---|---|---|---|---|---|
15efe4d9a68728b8790ae597d88566f85c407218 | wikidoc | miR-27 | miR-27
miR-27 is a family of microRNA precursors found in animals, including humans. MicroRNAs are typically transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a ~22 nucleotide product. The excised region or, mature product, of the miR-27 precursor is the microRNA mir-27.
Herpesvirus saimiri expresses several non-coding RNAs (HSURs) which have been found to significantly reduce the level of mir-27 in a host cell. It has been proposed that miR-27 operates together with miR-23 and mir-24 in a co-operative cluster.
# Regulation of adipocyte differentiation
miR-27 is one of a number of microRNAs implicated in cholesterol homeostasis and fatty acid metabolism. The miR-27 gene family has been shown to be downregulated during the differentiation of adipocytes. miR-27 inhibits adipocyte formation when overexpressed, acting by blocking the expression of two main regulators of adipogenesis. MicroRNAs miR-27a and -27b have been found to negatively regulate adipocyte differentiation through regulation of the peroxisome proliferator-activated receptor gamma (PPARγ) post-transcriptionally, as well as C/EBP alpha in the case of miR-27b. miR-27 can be identified both as an adipogenic inhibitor and as playing an important role in the development of obesity.
# Wnt signalling pathway
miR-27 is an activator of the Wnt signalling pathway, affecting the differentiation of mesenchymal stem cells into osteoblasts. miR-27 has been found to target and inhibit gene expression of the adenomatous polyposis coli (APC) protein, enabling it to regulate osteoblast differentiation. Expression levels of miR-27 are positively correlated with beta-catenin, a key protein in Wnt signalling. There is activation of Wnt signalling through nuclear accumulation of this protein, which is in response to inhibition of the beta-catenin destruction complex. This in turn is brought about by APC inhibition of miR-27.
# Cancer Regulation
miR-27 is known to regulate components involved in numerous types of cancer, including breast and ovarian. miR-27a has been identified as an oncogenic microRNA and, specifically, is highly expressed in breast cancer cells. mir-27b expression is associated with survival in triple negative breast cancer patients. Inhibition of miR-27 by antisense molecules decreases cell proliferation. Antisense RNA directed against miR-27a has been shown to decrease the percentage of cells in S phase whilst also increasing those in the G2-M phase.
The FOXO (Forkhead Box O) gene sub-family encodes tumour-suppressive transcription factors that regulate multiple aspects of cell cycle progression and survival. FOXO1 protein expression is down-regulated in breast tumour tissue samples; miR-27a has been identified as one of three miRNAS (along with miR-96 and miR-182) which directly target FOXO1 and regulate its endogenous expression. Suppression of miR-27a results in a FOXO1 protein increase and a consequent cell number decrease. | miR-27
miR-27 is a family of microRNA precursors found in animals, including humans.[1] MicroRNAs are typically transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a ~22 nucleotide product.[2] The excised region or, mature product, of the miR-27 precursor is the microRNA mir-27.
Herpesvirus saimiri expresses several non-coding RNAs (HSURs) which have been found to significantly reduce the level of mir-27 in a host cell.[3] It has been proposed that miR-27 operates together with miR-23 and mir-24 in a co-operative cluster.[4]
# Regulation of adipocyte differentiation
miR-27 is one of a number of microRNAs implicated in cholesterol homeostasis and fatty acid metabolism.[5] The miR-27 gene family has been shown to be downregulated during the differentiation of adipocytes. miR-27 inhibits adipocyte formation when overexpressed, acting by blocking the expression of two main regulators of adipogenesis.[6] MicroRNAs miR-27a and -27b have been found to negatively regulate adipocyte differentiation through regulation of the peroxisome proliferator-activated receptor gamma (PPARγ) post-transcriptionally, as well as C/EBP alpha in the case of miR-27b.[7] miR-27 can be identified both as an adipogenic inhibitor and as playing an important role in the development of obesity.[6]
# Wnt signalling pathway
miR-27 is an activator of the Wnt signalling pathway, affecting the differentiation of mesenchymal stem cells into osteoblasts.[8] miR-27 has been found to target and inhibit gene expression of the adenomatous polyposis coli (APC) protein, enabling it to regulate osteoblast differentiation. Expression levels of miR-27 are positively correlated with beta-catenin,[9] a key protein in Wnt signalling. There is activation of Wnt signalling through nuclear accumulation of this protein, which is in response to inhibition of the beta-catenin destruction complex. This in turn is brought about by APC inhibition of miR-27.[9]
# Cancer Regulation
miR-27 is known to regulate components involved in numerous types of cancer, including breast[10][11] and ovarian.[12] miR-27a has been identified as an oncogenic microRNA and, specifically, is highly expressed in breast cancer cells. mir-27b expression is associated with survival in triple negative breast cancer patients.[13] Inhibition of miR-27 by antisense molecules decreases cell proliferation.[14] Antisense RNA directed against miR-27a has been shown to decrease the percentage of cells in S phase whilst also increasing those in the G2-M phase.[15]
The FOXO (Forkhead Box O) gene sub-family encodes tumour-suppressive transcription factors that regulate multiple aspects of cell cycle progression and survival. FOXO1 protein expression is down-regulated in breast tumour tissue samples; miR-27a has been identified as one of three miRNAS (along with miR-96 and miR-182) which directly target FOXO1 and regulate its endogenous expression. Suppression of miR-27a results in a FOXO1 protein increase and a consequent cell number decrease.[15] | https://www.wikidoc.org/index.php/MiR-27 | |
dd1059ddc035e5070c2457b9c798bbe6d5febe5f | wikidoc | miR-33 | miR-33
miR-33 is a family of microRNA precursors, which are processed by the Dicer enzyme to give mature microRNAs. miR-33 is found in several animal species, including humans. In some species there is a single member of this family which gives the mature product mir-33. In humans there are two members of this family called mir-33a and mir-33b, which are located in intronic regions within two protein-coding genes for Sterol regulatory element-binding proteins (SREBP-2 and SREBP-1) respectively.
# Function
miR-33 plays a role in lipid metabolism; it downregulates a number of ABC transporters, including ABCA1 and ABCG1, which in turn regulate cholesterol and HDL generation. Further related roles of miR-33 have been proposed in fatty acid degradation and in macrophage response to low-density lipoprotein.
It has been suggested that miR-33a and miR-33b regulates genes Involved in fatty acid metabolism and insulin signalling.
Potential binding sites for mir-33 have been identified in the cDNA of tumour suppressor p53. Further, study has shown that miR-33 is able to repress p53 expression and p53-induced apoptosis. This function is thought to be related to hematopoietic stem cell renewal.
# Applications
miR-33, along with miR-122, could be used to diagnose or treat conditions related to metabolic disorders and cardiovascular disease. | miR-33
miR-33 is a family of microRNA precursors, which are processed by the Dicer enzyme to give mature microRNAs.[1] miR-33 is found in several animal species, including humans. In some species there is a single member of this family which gives the mature product mir-33. In humans there are two members of this family called mir-33a and mir-33b, which are located in intronic regions within two protein-coding genes for Sterol regulatory element-binding proteins (SREBP-2 and SREBP-1) respectively.[2]
# Function
miR-33 plays a role in lipid metabolism; it downregulates a number of ABC transporters, including ABCA1 and ABCG1, which in turn regulate cholesterol and HDL generation.[3][4] Further related roles of miR-33 have been proposed in fatty acid degradation and in macrophage response to low-density lipoprotein.[2]
It has been suggested that miR-33a and miR-33b regulates genes Involved in fatty acid metabolism and insulin signalling.[5]
Potential binding sites for mir-33 have been identified in the cDNA of tumour suppressor p53.[6] Further, study has shown that miR-33 is able to repress p53 expression and p53-induced apoptosis. This function is thought to be related to hematopoietic stem cell renewal.[7]
# Applications
miR-33, along with miR-122, could be used to diagnose or treat conditions related to metabolic disorders and cardiovascular disease.[2][8] | https://www.wikidoc.org/index.php/MiR-33 | |
581cbeb915cd658a5ec4c1a774d62b96f5ee2f86 | wikidoc | Midget | Midget
In the 19th century, midget was a medical term referring to an extremely short but normally proportioned person and was used in contrast to dwarf, which denoted disproportionate shortness. Like many other older medical terms, as it became part of popular language, it was usually used in a pejorative sense. When applied to a person who is very short, midget is now often considered offensive, an example of the euphemism treadmill.
The word "dwarf" has generally replaced "midget" even for proportionally short people, though the term "little person" is preferred. According to the Little People of America, dwarfism is "a medical or genetic condition that usually results in an adult height of 4'10" (147 cm) or shorter, among both men and women, although in some cases a person with a dwarfing condition may be slightly taller than that."
Modern terminology now distinguishes between the two types of dwarfism using the terms proportionate dwarfism, such as primordial dwarfism, and disproportionate dwarfism, such as achondroplasia. Proportionate dwarfism is often the result of a hormonal deficiency (such as human growth hormone), and it may be treated medically. | Midget
In the 19th century, midget was a medical term referring to an extremely short but normally proportioned person and was used in contrast to dwarf, which denoted disproportionate shortness. Like many other older medical terms, as it became part of popular language, it was usually used in a pejorative sense. When applied to a person who is very short, midget is now often considered offensive, an example of the euphemism treadmill.[1]
The word "dwarf" has generally replaced "midget" even for proportionally short people, though the term "little person" is preferred. According to the Little People of America, dwarfism is "a medical or genetic condition that usually results in an adult height of 4'10" (147 cm) or shorter, among both men and women, although in some cases a person with a dwarfing condition may be slightly taller than that."[2]
Modern terminology now distinguishes between the two types of dwarfism using the terms proportionate dwarfism, such as primordial dwarfism, and disproportionate dwarfism, such as achondroplasia. Proportionate dwarfism is often the result of a hormonal deficiency (such as human growth hormone), and it may be treated medically. | https://www.wikidoc.org/index.php/Midget | |
f1b867b58f2466674d4dbc66b3065a9b4fe5e4b5 | wikidoc | Midgut | Midgut
# Overview
The midgut is the portion of the embryo from which most of the intestines are derived. After it bends around the superior mesenteric artery, it is called the "midgut loop". It originates from the foregut at the opening of the bile duct into the duodenum and continues through the small intestine and much of the large intestine until the transition to the hindgut about two-thirds of the way through the transverse colon.
# Structures in the adult midgut
- Duodenum (3rd and 4th parts)
- Jejunum
- Ileum
- Cecum
- Appendix
- Ascending colon
- Hepatic flexure of colon.
- Transverse colon (proximal two-thirds)
# Vascular, lymphatics and innervation
Arterial supply to the midgut is from the superior mesenteric artery, an unpaired branch of the aorta. Venous drainage is to the portal venous system. Lymph from the midgut drains to prevertebral superior mesenteric nodes located at the origin of the superior mesenteric artery from the aorta. Portal drainage carries all non-lipid nutrients from digestion to the liver for processing and detoxification, while lymphatic drainage carries fatty chyle to the cisterna chyli. Autonomic innervation of the midgut is from the superior mesenteric plexus.
# Clinical notes
- Malrotation of the midgut during development can lead to volvulus.
- Pain in the midgut is referred to the umbilical region (around the belly button) | Midgut
# Overview
Template:Infobox Embryology
The midgut is the portion of the embryo from which most of the intestines are derived. After it bends around the superior mesenteric artery, it is called the "midgut loop". It originates from the foregut at the opening of the bile duct into the duodenum and continues through the small intestine and much of the large intestine until the transition to the hindgut about two-thirds of the way through the transverse colon.
# Structures in the adult midgut
- Duodenum (3rd and 4th parts)
- Jejunum
- Ileum
- Cecum
- Appendix
- Ascending colon
- Hepatic flexure of colon.
- Transverse colon (proximal two-thirds)
# Vascular, lymphatics and innervation
Arterial supply to the midgut is from the superior mesenteric artery, an unpaired branch of the aorta. Venous drainage is to the portal venous system. Lymph from the midgut drains to prevertebral superior mesenteric nodes located at the origin of the superior mesenteric artery from the aorta. Portal drainage carries all non-lipid nutrients from digestion to the liver for processing and detoxification, while lymphatic drainage carries fatty chyle to the cisterna chyli. Autonomic innervation of the midgut is from the superior mesenteric plexus.
# Clinical notes
- Malrotation of the midgut during development can lead to volvulus.
- Pain in the midgut is referred to the umbilical region (around the belly button) | https://www.wikidoc.org/index.php/Midgut | |
d5e5de3e300e7bdb665538aa39215ce0edfbc408 | wikidoc | Mildew | Mildew
Mildew refers to certain kinds of mold or fungus. In Old English, it meant honeydew (a substance secreted by aphids on leaves, formerly thought to distill from the air like dew), and later came to mean mildew in the modern senses.
- The term mildew is often used generically to refer to mold growth, usually with a flat growth habit. Molds can thrive on any organic matter, including clothing, leather, paper, and the ceilings, walls and floors of homes with moisture management problems. Mildew often lives on shower walls, windowsills, and other places where moisture levels are high. There are many species of molds. In unaired places, such as basements, they can produce a strong musty odor.
- What most horticulturalists and gardeners call mildew is more precisely called powdery mildew. It is caused by many different species of fungi in the order Erysiphales. Most species are specific to a narrow range of hosts, and all are obligate parasites of flowering plants. The species that affects roses is Sphaerotheca pannosa var. rosa.
- Another plant-associated type of mildew is downy mildew. Downy mildews are caused by fungus-like organisms in the family Peronosporaceae (Oomycota). They are obligate plant pathogens, and the many species are each parasitic on a narrow range of hosts. In agriculture, downy mildews are a particular problem for growers of potatoes, grapes, tobacco and cucurbits.
The English word was exported into French as mildiou and as mildiu in Spanish. | Mildew
Mildew refers to certain kinds of mold or fungus. In Old English, it meant honeydew (a substance secreted by aphids on leaves, formerly thought to distill from the air like dew), and later came to mean mildew in the modern senses.[1]
- The term mildew is often used generically to refer to mold growth, usually with a flat growth habit. Molds can thrive on any organic matter, including clothing, leather, paper, and the ceilings, walls and floors of homes with moisture management problems. Mildew often lives on shower walls, windowsills, and other places where moisture levels are high. There are many species of molds. In unaired places, such as basements, they can produce a strong musty odor.
- What most horticulturalists and gardeners call mildew is more precisely called powdery mildew. It is caused by many different species of fungi in the order Erysiphales. Most species are specific to a narrow range of hosts, and all are obligate parasites of flowering plants. The species that affects roses is Sphaerotheca pannosa var. rosa.
- Another plant-associated type of mildew is downy mildew. Downy mildews are caused by fungus-like organisms in the family Peronosporaceae (Oomycota). They are obligate plant pathogens, and the many species are each parasitic on a narrow range of hosts. In agriculture, downy mildews are a particular problem for growers of potatoes, grapes, tobacco and cucurbits.
The English word was exported into French as mildiou and as mildiu in Spanish. | https://www.wikidoc.org/index.php/Mildew | |
fe8a875a4811d89bc9b9aedfec26f50bbe7f4625 | wikidoc | Mirror | Mirror
A mirror is an object with a surface that has good specular reflection; that is, it is smooth enough to form an image. The most familiar type of mirror is the plane mirror, which has a flat surface. Curved mirrors are also used, to produce magnified or diminished images or focus light or simply distort the reflected image.
Mirrors are most commonly used for personal grooming (in which case the old-fashioned term "looking-glass" can be used), decoration, and architecture. Mirrors are also used in scientific apparatus such as telescopes and lasers, cameras, and industrial machinery. Most mirrors are designed for visible light; however, mirrors designed for other types of waves or other wavelengths of electromagnetic radiation are also used, especially in optical instruments.
# History
The earliest manufactured mirrors were pieces of polished stone such as obsidian, a naturally occurring volcanic glass. Examples of obsidian mirrors found in Anatolia (modern-day Turkey) have been dated to around 6000 BC. Polished stone mirrors from central and south America date from around 2000 BC onwards.
Mirrors of polished copper were crafted in Mesopotamia from 4000 BC, and in ancient Egypt from around 3000 BC. In China, bronze mirrors were manufactured from around 2000 BC.
Metal-coated glass mirrors are said to have been invented in Sidon (modern-day Lebanon) in the first century AD, and glass mirrors backed with gold leaf are mentioned by the Roman author Pliny in his Natural History, written in about 77 AD. The Romans also developed a technique for creating crude mirrors by coating blown glass with molten lead.
Some time during the early Renaissance, European manufacturers perfected a superior method of coating glass with a tin-mercury amalgam. The exact date and location of the discovery is unknown, but in the 16th century, Venice, a city famed for its glass-making expertise, became a centre of mirror production using this new technique. Glass mirrors from this period were extremely expensive luxuries. The Saint-Gobain factory, founded by royal initiative in France, was an important manufacturer, and Bohemian and German glass, often rather cheaper, was also important.
The invention of the silvered-glass mirror is credited to German chemist Justus von Liebig in 1835. His process involved the deposition of a thin layer of metallic silver onto glass through the chemical reduction of silver nitrate. This silvering process was adapted for mass manufacturing and led to the greater availability of affordable mirrors. Nowadays, mirrors are often produced by the vacuum deposition of aluminium (or sometimes silver) directly onto the glass substrate.
# Manufacturing
Most mirrors are made by applying a reflective coating to a suitable substrate. The most common such substrate is glass, due to its ease of fabrication, its rigidity, and its ability to take a smooth finish. The reflective coating is typically applied to the back surface of the glass, so that it is protected from corrosion and accidental damage. (Glass is much more scratch-resistant than most substrates.)
The substrate is shaped, polished and cleaned, and is then coated. Glass mirrors are most often coated with silver or aluminium, implemented by a series of coatings:
- tin
- silver
- chemical activator
- copper
- paint
The tin is applied because the silver will not bond with the glass. The activator causes the tin/silver to harden. Copper is added for long-term durability. The paint protects the coating on the back of the mirror from scratches and other accidental damage.
In some applications, generally those that are cost-sensitive or that require great durability, mirrors are instead made from a single, bulk material such as polished metal.
For technical applications such as laser mirrors, the reflective coating is typically applied by vacuum deposition on the front surface of the substrate. This eliminates double reflections and reduces absorption of light in the mirror. Cheaper technical mirrors use a silver, aluminium, or gold coating (the latter typically for infrared mirrors), and achieve reflectivities of 90–95% when new. A protective overcoat may be applied to prevent oxidation of the reflective layer. Applications requiring higher reflectivity or greater durability use dielectric coatings, which can achieve reflectivities as high as 99.999% over a narrow range of wavelengths.
# Effects
In a plane mirror, a parallel beam of light changes its direction as a whole, while still remaining parallel; the images formed by a plane mirror are virtual images, of the same size as the original object (see mirror image). There are also concave mirrors, where a parallel beam of light becomes a convergent beam, whose rays intersect in the focus of the mirror. Lastly, there are convex mirrors, where a parallel beam becomes divergent, with the rays appearing to diverge from a common intersection "behind" the mirror. Spherical concave and convex mirrors do not focus parallel rays to a single point due to spherical aberration. However, the ideal of focusing to a point is a commonly-used approximation. Parabolic reflectors resolve this, allowing incoming parallel rays (for example, light from a distant star) to be focused to a small spot; almost an ideal point. Parabolic reflectors are not suitable for imaging nearby objects because the light rays are not parallel.
A beam of light reflects off a mirror at an angle of reflection that is equal to its angle of incidence (if the size of a mirror is much larger than the wavelength of light). That is, if the beam of light is shining on a mirror's surface at a 30° angle from vertical, then it reflects from the point of incidence at a 30° angle from vertical in the opposite direction.
This law mathematically follows from the interference of a plane wave on a flat boundary (of much larger size than the wavelength).
# Applications
## Safety and easier viewing
Rear-view mirrors are widely used in and on vehicles (such as automobiles, or bicycles), to allow drivers to see other vehicles coming up behind them. Some motorcycle helmets have a built-in so-called MROS (Multiple Reflective Optic System): a set of reflective surfaces inside the helmet that together function as a rear-view mirror. There exist rear view sunglasses, of which the left end of the left glass and the right end of the right glass work as mirrors.
Convex mirrors are used to provide a wider field of view than a flat mirror. They are sometimes placed at road junctions, and corners of places such as parking lots to allow people to see around corners to avoid crashing into other vehicles or shopping carts. They are also sometimes used as part of security systems, so that a single video camera can show more than one angle at a time.
Mouth mirrors or "dental mirrors" are used by dentists to allow indirect vision and lighting within the mouth. Their reflective surfaces may be either flat or curved. Mouth mirrors are also commonly used by engineers to allow vision in tight spaces and around corners in equipment.
## Two-way mirrors
A two-way mirror, also sometimes referred to as a one-way mirror or one-way glass, reflects some percentage of the light and lets some other percentage pass. It is a sheet of glass coated with a layer of metal only a few dozen atoms thick, allowing some of the light through the surface (from both sides). It is used between a dark room and a brightly lit room. People on the brightly lit side see their own reflection — it looks like a normal mirror. People on the dark side see through it — it looks like a transparent window. It may be used to observe criminal suspects or customers. The same type of mirror, when used in an optical instrument, is called a half-silvered mirror or beam splitter. Its purpose is to split a beam of light so that half passes straight through, while the other half is reflected — this is useful for interferometry. The reality television program Big Brother makes extensive use of two-way mirrors throughout its set to allow cameramen in special black hallways to use movable cameras to videotape contestants without their coming in contact with the workers.
Contrary to popular belief, passive one-way mirrors that operate directionally between equally lit rooms do not exist. The laws of physics do not allow for real, passive one-way mirrors or windows (ones that do not need external energy); if such a device were possible, one could break the second law of thermodynamics and make energy flow from a cold object to a hot one, by placing such a mirror between them. One-way windows can be made to work with polarized light, however, without violating the second law. Optical isolators are one-way devices that are commonly used with lasers.
## Signalling
With the sun as light source, a mirror can be used to signal by variations in the orientation of the mirror. The signal can be used over long distances, possibly up to 60 kilometres on a clear day. This technique was used by Native American tribes and numerous militaries to transmit information between distant outposts.
Mirrors can also be used for rescue, especially to attract the attention of search and rescue helicopters. Specialised signalling mirrors are available and are often included in military survival kits.
## Technology
### Televisions and projectors
Microscopic mirrors are a core element of many of the largest high-definition televisions and video projectors. A common technology of this type is Texas Instruments' DLP. A DLP chip is a postage stamp-sized microchip whose surface is comprised of an array of millions of microscopic mirrors. The picture is created as the individual mirrors move to either reflect light toward the projection surface (pixel on), or toward a light absorbing surface (pixel off).
Other projection technologies involving mirrors include LCoS. Like a DLP chip, LCoS is a microchip of similar size, but rather than millions of individual mirrors, there is a single mirror that is actively shielded by a liquid crystal matrix with up to millions of pixels. The picture is formed as light is either reflected toward the projection surface (pixel on), or absorbed by the activated LCD pixels (pixel off). LCoS-based televisions and projectors often use 3 chips, one for each primary color.
Large mirrors are used in rear projection televisions. Light (for example from a DLP as mentioned above) is "folded" by one or more mirrors so that the television set is compact.
### Instruments
Telescopes and other precision instruments use front silvered or first surface mirrors, where the reflecting surface is placed on the front (or first) surface of the glass (this eliminates reflection from glass surface ordinary back mirrors have). Some of them use silver, but most are aluminum, which is more reflective at short wavelengths than silver.
All of these coatings are easily damaged and require special handling.
They reflect 90% to 95% of the incident light when new.
The coatings are typically applied by vacuum deposition.
A protective overcoat is usually applied before the mirror is removed from the vacuum, because the coating otherwise begins to corrode as soon as it is exposed to oxygen and humidity in the air. Front silvered mirrors have to be resurfaced occasionally to keep their quality.
The reflectivity of the mirror coating can be measured using a reflectometer and for a particular metal it will be different for different wavelengths of light. This is exploited in some optical work to make cold mirrors and hot mirrors. A cold mirror is made by using a transparent substrate and choosing a coating material that is more reflective to visible light and more transmissive to infrared light.
A hot mirror is the opposite, the coating preferentially reflects infrared. Mirror surfaces are sometimes given thin film overcoatings both to retard degradation of the surface and to increase their reflectivity in parts of the spectrum where they will be used. For instance, aluminum mirrors are commonly coated with silicon dioxide or magnesium fluoride. The reflectivity as a function of wavelength depends on both the thickness of the coating and on how it is applied.
For scientific optical work, dielectric mirrors are often used. These are glass (or sometimes other material) substrates on which one or more layers of dielectric material are deposited, to form an optical coating. By careful choice of the type and thickness of the dielectric layers, the range of wavelengths and amount of light reflected from the mirror can be specified. The best mirrors of this type can reflect >99.999% of the light (in a narrow range of wavelengths) which is incident on the mirror. Such mirrors are often used in lasers.
In astronomy, adaptive optics is a technique to measure variable image distortions and adapt a deformable mirror accordingly on a timescale of milliseconds, to compensate for the distortions.
Although the most of mirrors are designed to reflect visible light, surfaces reflecting other forms of electromagnetic radiation are also called "mirrors". The mirrors for other ranges of electromagnetic waves are used in
-ptics and astronomy. Mirrors for radio waves are important elements of radio telescopes.
A Mangin mirror is a combination lens and concave mirror and is widely used in optical instruments and even sometimes in cameras.
Some devices use two or more mirrors facing one another to generate multiple reflections:
- Fabry-Pérot interferometer
- Laser (which contains an optical cavity)
- some types of catoptric cistula
- momentum-enhanced solar sail
The reflected images between these mirrors give the appearance of an infinite regress.
### Military applications
It has been said that Archimedes used a large array of mirrors to burn Roman ships during an attack on Syracuse. This has never been proven or disproved; however, many have put it to the test. Recently, on a popular Discovery Channel show, MythBusters, a team from MIT tried to recreate the famous "Archimedes Death Ray". They were successful at starting a fire on a ship at 75 feet away; however, previous attempts to light the boat on fire using only the bronze mirrors available in Archimedes' time were unsuccessful, and the time taken to ignite the craft would have made its use impractical, resulting in the MythBusters team deeming the myth "busted". (However, see solar power tower for a practical use of this technique.)
### Seasonal lighting
Due to its location in a steep-sided valley, the Italian town of Viganella gets no direct sunlight for seven weeks each winter. In 2006 a €100,000 computer-controlled mirror, 8×5 m, was installed to reflect sunlight into the town's piazza. In early 2007 the similarly situated village of Bondo, Switzerland, was considering applying this solution as well.
## Leisure
### Decoration
Mirrors, typically large and unframed, are frequently used in interior decoration to create an illusion of space, and amplify the apparent size of a room.
Mirrors are used also in some schools of feng shui, an ancient Chinese practice of placement and arrangement of space to achieve harmony with the environment.
The softness of old mirrors is sometimes replicated by contemporary artisans for use in interior design. These reproduction antiqued mirrors are works of art and can bring color and texture to an otherwise hard, cold reflective surface. It is an artistic process that has been attempted by many and perfected by few.
A decorative reflecting sphere of thin metal-coated glass, working as a reducing wide-angle mirror, is sold as a Christmas ornament called a bauble.
### Entertainment
The hall of mirrors, commonly found in amusement parks, is an attraction in which a number of distorted mirrors are used to produce unusual reflections of the visitor. Mirror mazes, also found in amusement parks, contain large numbers of mirrors and sheets of glass. The idea is to navigate the disorientating array without bumping into the walls.
Mirrors are often used in magic to create an illusion. One effect is called Pepper's ghost. Illuminated rotating disco balls covered with small mirrors are used to cast moving spots of light around a dance floor. Mirrors are employed in kaleidoscopes, personal entertainment devices invented in Scotland by sir David Brewster.
### Art
Filippo Brunelleschi discovered linear perspective with the help of the mirror, Leonardo da Vinci called the mirror the "master of painters". He recommended. "When you wish to see whether your whole picture accords with what you have portrayed from nature take a mirror and reflect the actual object in it. Compare what is reflected with your painting and carefully consider whether both likenesses of the subject correspond, particularly in regard to the mirror. The mirror is the central device in some of the greatest of European paintings: Jan Van Eyck's Arnolfini Portrait, Diego Velazquez's Las Meninas and Edouard Manet’s A Bar at the Folies-Bergère. Without a mirror, the great self portraits by Dürer, Rembrandt, Van Gogh and Frida Kahlo could not have been painted. M. C. Escher used special shapes of mirrors in order to have a much more complete view of the surroundings than by direct observation (Hand with Reflecting Sphere). István Orosz’s anamorphic works are images distorted such way that they only become clearly visible when reflected in a suitably-shaped and positioned mirror. Some other contemporary artists use mirrors as the material of art, like in mirror-sculptures and paintings on mirror surfaces. Some artists build special mirror installations as the neon mirror cubes by Jeppe Hein.
Painters depicting someone in front of a mirror often also show the person's reflection. This is a kind of abstraction—in most cases the angle of view is such that the person's reflection should not be visible. Similarly, in movies and still photography an actor or actress is often shown ostensibly looking at him or herself in the mirror, and yet the reflection faces the camera. In reality, the actor or actress sees only the camera and its operator in this case, not their own reflection.
# Mirrors and superstition
It is a common superstition that someone who breaks a mirror will receive seven years of bad luck. One of the many reasons for this belief is that the mirror is believed to reflect part of the soul, therefore, breaking the mirror will break part of the soul. However, the soul is said to regenerate every seven years, thus coming back unbroken. To counter this one of many rituals has to be performed, the easiest of which is to stop the mirror from reflecting the broken soul by grinding it to dust. The belief might also simply originate from the high cost of mirrors in times gone past.
According to legend, a vampire has no reflection in mirrors because it is an undead creature and has already lost its soul.
Another superstition claims it is bad luck to have two mirrors facing each other.
# Mirrors and animals
Experiments have shown that only large-brained social animals are able to recognise that a mirror shows a reflection of themselves.
Animals that have shown they are able to use a mirror to study themselves:
- Asian elephants
- Bonobos
- Common chimpanzees
- Dolphins
- Orangutans
- Pigs
- Llamas
# Unusual types of mirror
Other types of reflecting device are also called "mirrors". For example metallic reflectors are used to reflect infrared light (such as in space heaters), or microwaves.
An acoustic mirror is a passive device used to reflect and perhaps to focus sound waves. Acoustic mirrors were used for selective detection of sound waves, especially during World War 2. They were used for detection of enemy aircraft prior to the development of radar. Acoustic mirrors are used for remote probing of the atmosphere; they can be used to form a narrow diffraction-limited beam. They can also be used for underwater "imaging".
Active mirrors are mirrors that amplify the light they reflect. They are used to make disk lasers. The amplification is typically over a narrow range of wavelengths, and requires an external source of power.
An atomic mirror is a device which reflects matter waves. Usually, atomic mirrors work at grazing incidence. Such a mirror can be used for atomic interferometry and atomic holography. It has been proposed that they can be used for non-destructive imaging systems with nanometer resolution.
Cold mirrors are dielectric mirrors that reflect the entire visible light spectrum while efficiently transmitting infrared wavelengths. Conversely, hot mirrors reflect infrared light while allowing visible light to pass. These can be used to separate useful light from unneeded infrared to reduce heating of components in an optical device. They can also be used as dichroic beamsplitters.
Corner reflectors use three flat mirrors to reflect light back towards its source. They are used for emergency location, and even laser ranging to the Moon.
X-ray mirrors produce specular reflection of X-rays. All known types work only at angles near grazing incidence, and only a small fraction of the rays are reflected. | Mirror
Template:Otheruses4
A mirror is an object with a surface that has good specular reflection; that is, it is smooth enough to form an image. The most familiar type of mirror is the plane mirror, which has a flat surface. Curved mirrors are also used, to produce magnified or diminished images or focus light or simply distort the reflected image.
Mirrors are most commonly used for personal grooming (in which case the old-fashioned term "looking-glass" can be used), decoration, and architecture. Mirrors are also used in scientific apparatus such as telescopes and lasers, cameras, and industrial machinery. Most mirrors are designed for visible light; however, mirrors designed for other types of waves or other wavelengths of electromagnetic radiation are also used, especially in optical instruments.
# History
The earliest manufactured mirrors were pieces of polished stone such as obsidian, a naturally occurring volcanic glass. Examples of obsidian mirrors found in Anatolia (modern-day Turkey) have been dated to around 6000 BC. Polished stone mirrors from central and south America date from around 2000 BC onwards.[1]
Mirrors of polished copper were crafted in Mesopotamia from 4000 BC,[1] and in ancient Egypt from around 3000 BC.[2] In China, bronze mirrors were manufactured from around 2000 BC.[3]
Metal-coated glass mirrors are said to have been invented in Sidon (modern-day Lebanon) in the first century AD,[4] and glass mirrors backed with gold leaf are mentioned by the Roman author Pliny in his Natural History, written in about 77 AD.[5] The Romans also developed a technique for creating crude mirrors by coating blown glass with molten lead.[6]
Some time during the early Renaissance, European manufacturers perfected a superior method of coating glass with a tin-mercury amalgam. The exact date and location of the discovery is unknown, but in the 16th century, Venice, a city famed for its glass-making expertise, became a centre of mirror production using this new technique. Glass mirrors from this period were extremely expensive luxuries.[7] The Saint-Gobain factory, founded by royal initiative in France, was an important manufacturer, and Bohemian and German glass, often rather cheaper, was also important.
The invention of the silvered-glass mirror is credited to German chemist Justus von Liebig in 1835. His process involved the deposition of a thin layer of metallic silver onto glass through the chemical reduction of silver nitrate. This silvering process was adapted for mass manufacturing and led to the greater availability of affordable mirrors. Nowadays, mirrors are often produced by the vacuum deposition of aluminium (or sometimes silver) directly onto the glass substrate.
# Manufacturing
Most mirrors are made by applying a reflective coating to a suitable substrate. The most common such substrate is glass, due to its ease of fabrication, its rigidity, and its ability to take a smooth finish. The reflective coating is typically applied to the back surface of the glass, so that it is protected from corrosion and accidental damage. (Glass is much more scratch-resistant than most substrates.)
The substrate is shaped, polished and cleaned, and is then coated. Glass mirrors are most often coated with silver or aluminium, implemented by a series of coatings:
- tin
- silver
- chemical activator
- copper
- paint
The tin is applied because the silver will not bond with the glass. The activator causes the tin/silver to harden. Copper is added for long-term durability.[8] The paint protects the coating on the back of the mirror from scratches and other accidental damage.
In some applications, generally those that are cost-sensitive or that require great durability, mirrors are instead made from a single, bulk material such as polished metal.
For technical applications such as laser mirrors, the reflective coating is typically applied by vacuum deposition on the front surface of the substrate. This eliminates double reflections and reduces absorption of light in the mirror. Cheaper technical mirrors use a silver, aluminium, or gold coating (the latter typically for infrared mirrors), and achieve reflectivities of 90–95% when new. A protective overcoat may be applied to prevent oxidation of the reflective layer. Applications requiring higher reflectivity or greater durability use dielectric coatings, which can achieve reflectivities as high as 99.999% over a narrow range of wavelengths.
# Effects
In a plane mirror, a parallel beam of light changes its direction as a whole, while still remaining parallel; the images formed by a plane mirror are virtual images, of the same size as the original object (see mirror image). There are also concave mirrors, where a parallel beam of light becomes a convergent beam, whose rays intersect in the focus of the mirror. Lastly, there are convex mirrors, where a parallel beam becomes divergent, with the rays appearing to diverge from a common intersection "behind" the mirror. Spherical concave and convex mirrors do not focus parallel rays to a single point due to spherical aberration. However, the ideal of focusing to a point is a commonly-used approximation. Parabolic reflectors resolve this, allowing incoming parallel rays (for example, light from a distant star) to be focused to a small spot; almost an ideal point. Parabolic reflectors are not suitable for imaging nearby objects because the light rays are not parallel.
A beam of light reflects off a mirror at an angle of reflection that is equal to its angle of incidence (if the size of a mirror is much larger than the wavelength of light). That is, if the beam of light is shining on a mirror's surface at a 30° angle from vertical, then it reflects from the point of incidence at a 30° angle from vertical in the opposite direction.
This law mathematically follows from the interference of a plane wave on a flat boundary (of much larger size than the wavelength).
# Applications
## Safety and easier viewing
Rear-view mirrors are widely used in and on vehicles (such as automobiles, or bicycles), to allow drivers to see other vehicles coming up behind them. Some motorcycle helmets have a built-in so-called MROS (Multiple Reflective Optic System): a set of reflective surfaces inside the helmet that together function as a rear-view mirror.[1] There exist rear view sunglasses, of which the left end of the left glass and the right end of the right glass work as mirrors.
Convex mirrors are used to provide a wider field of view than a flat mirror. They are sometimes placed at road junctions, and corners of places such as parking lots to allow people to see around corners to avoid crashing into other vehicles or shopping carts. They are also sometimes used as part of security systems, so that a single video camera can show more than one angle at a time.
Mouth mirrors or "dental mirrors" are used by dentists to allow indirect vision and lighting within the mouth. Their reflective surfaces may be either flat or curved. Mouth mirrors are also commonly used by engineers to allow vision in tight spaces and around corners in equipment.
## Two-way mirrors
A two-way mirror, also sometimes referred to as a one-way mirror or one-way glass, reflects some percentage of the light and lets some other percentage pass. It is a sheet of glass coated with a layer of metal only a few dozen atoms thick, allowing some of the light through the surface (from both sides). It is used between a dark room and a brightly lit room. People on the brightly lit side see their own reflection — it looks like a normal mirror. People on the dark side see through it — it looks like a transparent window. It may be used to observe criminal suspects or customers. The same type of mirror, when used in an optical instrument, is called a half-silvered mirror or beam splitter. Its purpose is to split a beam of light so that half passes straight through, while the other half is reflected — this is useful for interferometry. The reality television program Big Brother makes extensive use of two-way mirrors throughout its set to allow cameramen in special black hallways to use movable cameras to videotape contestants without their coming in contact with the workers.
Contrary to popular belief, passive one-way mirrors that operate directionally between equally lit rooms do not exist. The laws of physics do not allow for real, passive one-way mirrors or windows (ones that do not need external energy); if such a device were possible, one could break the second law of thermodynamics and make energy flow from a cold object to a hot one, by placing such a mirror between them. One-way windows can be made to work with polarized light, however, without violating the second law.[9][10] Optical isolators are one-way devices that are commonly used with lasers.
## Signalling
With the sun as light source, a mirror can be used to signal by variations in the orientation of the mirror. The signal can be used over long distances, possibly up to 60 kilometres on a clear day. This technique was used by Native American tribes and numerous militaries to transmit information between distant outposts.
Mirrors can also be used for rescue, especially to attract the attention of search and rescue helicopters. Specialised signalling mirrors are available and are often included in military survival kits.
## Technology
### Televisions and projectors
Microscopic mirrors are a core element of many of the largest high-definition televisions and video projectors. A common technology of this type is Texas Instruments' DLP. A DLP chip is a postage stamp-sized microchip whose surface is comprised of an array of millions of microscopic mirrors. The picture is created as the individual mirrors move to either reflect light toward the projection surface (pixel on), or toward a light absorbing surface (pixel off).
Other projection technologies involving mirrors include LCoS. Like a DLP chip, LCoS is a microchip of similar size, but rather than millions of individual mirrors, there is a single mirror that is actively shielded by a liquid crystal matrix with up to millions of pixels. The picture is formed as light is either reflected toward the projection surface (pixel on), or absorbed by the activated LCD pixels (pixel off). LCoS-based televisions and projectors often use 3 chips, one for each primary color.
Large mirrors are used in rear projection televisions. Light (for example from a DLP as mentioned above) is "folded" by one or more mirrors so that the television set is compact.
### Instruments
Telescopes and other precision instruments use front silvered or first surface mirrors, where the reflecting surface is placed on the front (or first) surface of the glass (this eliminates reflection from glass surface ordinary back mirrors have). Some of them use silver, but most are aluminum, which is more reflective at short wavelengths than silver.
All of these coatings are easily damaged and require special handling.
They reflect 90% to 95% of the incident light when new.
The coatings are typically applied by vacuum deposition.
A protective overcoat is usually applied before the mirror is removed from the vacuum, because the coating otherwise begins to corrode as soon as it is exposed to oxygen and humidity in the air. Front silvered mirrors have to be resurfaced occasionally to keep their quality.
The reflectivity of the mirror coating can be measured using a reflectometer and for a particular metal it will be different for different wavelengths of light. This is exploited in some optical work to make cold mirrors and hot mirrors. A cold mirror is made by using a transparent substrate and choosing a coating material that is more reflective to visible light and more transmissive to infrared light.
A hot mirror is the opposite, the coating preferentially reflects infrared. Mirror surfaces are sometimes given thin film overcoatings both to retard degradation of the surface and to increase their reflectivity in parts of the spectrum where they will be used. For instance, aluminum mirrors are commonly coated with silicon dioxide or magnesium fluoride. The reflectivity as a function of wavelength depends on both the thickness of the coating and on how it is applied.
For scientific optical work, dielectric mirrors are often used. These are glass (or sometimes other material) substrates on which one or more layers of dielectric material are deposited, to form an optical coating. By careful choice of the type and thickness of the dielectric layers, the range of wavelengths and amount of light reflected from the mirror can be specified. The best mirrors of this type can reflect >99.999% of the light (in a narrow range of wavelengths) which is incident on the mirror. Such mirrors are often used in lasers.
In astronomy, adaptive optics is a technique to measure variable image distortions and adapt a deformable mirror accordingly on a timescale of milliseconds, to compensate for the distortions.
Although the most of mirrors are designed to reflect visible light, surfaces reflecting other forms of electromagnetic radiation are also called "mirrors". The mirrors for other ranges of electromagnetic waves are used in
optics and astronomy. Mirrors for radio waves are important elements of radio telescopes.
A Mangin mirror is a combination lens and concave mirror and is widely used in optical instruments and even sometimes in cameras.[2] [3][4]
Some devices use two or more mirrors facing one another to generate multiple reflections:
- Fabry-Pérot interferometer
- Laser (which contains an optical cavity)
- some types of catoptric cistula
- momentum-enhanced solar sail[5]
The reflected images between these mirrors give the appearance of an infinite regress.
### Military applications
It has been said that Archimedes used a large array of mirrors to burn Roman ships during an attack on Syracuse. This has never been proven or disproved; however, many have put it to the test. Recently, on a popular Discovery Channel show, MythBusters, a team from MIT tried to recreate the famous "Archimedes Death Ray". They were successful at starting a fire on a ship at 75 feet away; however, previous attempts to light the boat on fire using only the bronze mirrors available in Archimedes' time were unsuccessful, and the time taken to ignite the craft would have made its use impractical, resulting in the MythBusters team deeming the myth "busted". (However, see solar power tower for a practical use of this technique.)
### Seasonal lighting
Due to its location in a steep-sided valley, the Italian town of Viganella gets no direct sunlight for seven weeks each winter. In 2006 a €100,000 computer-controlled mirror, 8×5 m, was installed to reflect sunlight into the town's piazza. In early 2007 the similarly situated village of Bondo, Switzerland, was considering applying this solution as well.[11][12]
## Leisure
### Decoration
Mirrors, typically large and unframed, are frequently used in interior decoration to create an illusion of space, and amplify the apparent size of a room.
Mirrors are used also in some schools of feng shui, an ancient Chinese practice of placement and arrangement of space to achieve harmony with the environment.
The softness of old mirrors is sometimes replicated by contemporary artisans for use in interior design. These reproduction antiqued mirrors are works of art and can bring color and texture to an otherwise hard, cold reflective surface. It is an artistic process that has been attempted by many and perfected by few.
A decorative reflecting sphere of thin metal-coated glass, working as a reducing wide-angle mirror, is sold as a Christmas ornament called a bauble.
### Entertainment
The hall of mirrors, commonly found in amusement parks, is an attraction in which a number of distorted mirrors are used to produce unusual reflections of the visitor. Mirror mazes, also found in amusement parks, contain large numbers of mirrors and sheets of glass. The idea is to navigate the disorientating array without bumping into the walls.
Mirrors are often used in magic to create an illusion. One effect is called Pepper's ghost. Illuminated rotating disco balls covered with small mirrors are used to cast moving spots of light around a dance floor. Mirrors are employed in kaleidoscopes, personal entertainment devices invented in Scotland by sir David Brewster.
### Art
Filippo Brunelleschi discovered linear perspective with the help of the mirror, Leonardo da Vinci called the mirror the "master of painters". He recommended. "When you wish to see whether your whole picture accords with what you have portrayed from nature take a mirror and reflect the actual object in it. Compare what is reflected with your painting and carefully consider whether both likenesses of the subject correspond, particularly in regard to the mirror. The mirror is the central device in some of the greatest of European paintings: Jan Van Eyck's Arnolfini Portrait, Diego Velazquez's Las Meninas and Edouard Manet’s A Bar at the Folies-Bergère. Without a mirror, the great self portraits by Dürer, Rembrandt, Van Gogh and Frida Kahlo could not have been painted. M. C. Escher used special shapes of mirrors in order to have a much more complete view of the surroundings than by direct observation (Hand with Reflecting Sphere). István Orosz’s anamorphic works are images distorted such way that they only become clearly visible when reflected in a suitably-shaped and positioned mirror. Some other contemporary artists use mirrors as the material of art, like in mirror-sculptures and paintings on mirror surfaces. Some artists build special mirror installations as the neon mirror cubes by Jeppe Hein.
Painters depicting someone in front of a mirror often also show the person's reflection. This is a kind of abstraction—in most cases the angle of view is such that the person's reflection should not be visible. Similarly, in movies and still photography an actor or actress is often shown ostensibly looking at him or herself in the mirror, and yet the reflection faces the camera. In reality, the actor or actress sees only the camera and its operator in this case, not their own reflection.
# Mirrors and superstition
It is a common superstition that someone who breaks a mirror will receive seven years of bad luck. One of the many reasons for this belief is that the mirror is believed to reflect part of the soul, therefore, breaking the mirror will break part of the soul. However, the soul is said to regenerate every seven years, thus coming back unbroken. To counter this one of many rituals has to be performed, the easiest of which is to stop the mirror from reflecting the broken soul by grinding it to dust.[citation needed] The belief might also simply originate from the high cost of mirrors in times gone past.
According to legend, a vampire has no reflection in mirrors because it is an undead creature and has already lost its soul.
Another superstition claims it is bad luck to have two mirrors facing each other.[citation needed]
# Mirrors and animals
Experiments have shown that only large-brained social animals are able to recognise that a mirror shows a reflection of themselves.[13]
Animals that have shown they are able to use a mirror to study themselves:
- Asian elephants
- Bonobos
- Common chimpanzees
- Dolphins
- Orangutans
- Pigs
- Llamas
# Unusual types of mirror
Other types of reflecting device are also called "mirrors". For example metallic reflectors are used to reflect infrared light (such as in space heaters), or microwaves.
An acoustic mirror is a passive device used to reflect and perhaps to focus sound waves. Acoustic mirrors were used for selective detection of sound waves, especially during World War 2. They were used for detection of enemy aircraft prior to the development of radar. Acoustic mirrors are used for remote probing of the atmosphere; they can be used to form a narrow diffraction-limited beam.[14] They can also be used for underwater "imaging".
Active mirrors are mirrors that amplify the light they reflect. They are used to make disk lasers.[15] The amplification is typically over a narrow range of wavelengths, and requires an external source of power.
An atomic mirror is a device which reflects matter waves. Usually, atomic mirrors work at grazing incidence. Such a mirror can be used for atomic interferometry and atomic holography. It has been proposed that they can be used for non-destructive imaging systems with nanometer resolution.[16]
Cold mirrors are dielectric mirrors that reflect the entire visible light spectrum while efficiently transmitting infrared wavelengths. Conversely, hot mirrors reflect infrared light while allowing visible light to pass. These can be used to separate useful light from unneeded infrared to reduce heating of components in an optical device. They can also be used as dichroic beamsplitters.
Corner reflectors use three flat mirrors to reflect light back towards its source. They are used for emergency location, and even laser ranging to the Moon.
X-ray mirrors produce specular reflection of X-rays. All known types work only at angles near grazing incidence, and only a small fraction of the rays are reflected.[17] | https://www.wikidoc.org/index.php/Mirror | |
8a4852daee73e37f5be4403e55ec4f7e528eb069 | wikidoc | Moesin | Moesin
Moesin is a protein that in humans is encoded by the MSN gene.
Moesin (for membrane-organizing extension spike protein) is a member of the ERM protein family which includes ezrin and radixin. ERM proteins appear to function as cross-linkers between plasma membranes and actin-based cytoskeletons.
Moesin is localized to filopodia and other membranous protrusions that are important for cell–cell recognition and signaling and for cell movement.
# Interactions
Moesin has been shown to interact with:
- CD43
- ICAM3
- Neutrophil cytosolic factor 1,
- Neutrophil cytosolic factor 4
- VCAM-1
- EZR | Moesin
Moesin is a protein that in humans is encoded by the MSN gene.[1][2]
Moesin (for membrane-organizing extension spike protein) is a member of the ERM protein family which includes ezrin and radixin. ERM proteins appear to function as cross-linkers between plasma membranes and actin-based cytoskeletons.[3]
Moesin is localized to filopodia and other membranous protrusions that are important for cell–cell recognition and signaling and for cell movement.[3]
# Interactions
Moesin has been shown to interact with:
- CD43[4][5]
- ICAM3[6][7]
- Neutrophil cytosolic factor 1,[8]
- Neutrophil cytosolic factor 4[8]
- VCAM-1[9]
- EZR[10][11][12] | https://www.wikidoc.org/index.php/Moesin | |
f48ac1fb9e9325401073a27caaea6359ba9ad3a5 | wikidoc | Monera | Monera
Monera was a kingdom biological kingdom]] of the five-kingdom system of biological classification. It comprised most organisms with a prokaryotic cell organization. For this reason the kingdom was sometimes called Prokaryota or Prokaryotae. Prior to its creation these were treated as two separate divisions of plants: the Schizomycetes (bacteria) were considered fungi, and the Cyanophyta were considered blue-green algae. The latter are now considered a group of bacteria, typically called the cyanobacteria and are now known not to be closely related to plants, fungi, or animals.
Recent DNA and RNA sequence analyses has demonstrated that there are two major groups of prokaryotes, the Bacteria and Archaea, which do not appear to be closer in relationship to each other than they are to the Eukaryotes. Thus, Monera has since been divided into Archaea and Bacteria, forming the more recent six-kingdom system and three-domain system. All new schemes abandon the Monera and now treat the Bacteria, Archaea, and Eukarya as separate domains or kingdoms.
# History
Traditionally organisms were classified as animal, vegetable, or mineral as in Systema Naturae. After the discovery of microscopy, attempts were made to fit microscopic organisms into either the plant or animal kingdom. In 1866 Ernst Haeckel proposed a three kingdom system which added Protista as a new kingdom that contained most microscopic organisms. One of his eight major divisions of Protista was called Moneres. Haeckel's Moneres subcategory included known bacterial groups such as Vibrio. Haeckel's Protista kingdom also included eukaryotic organisms now classified as Protist. It was later decided that Haeckel's Protista kingdom had proven to be too diverse to be seriously considered one single kingdom.
In 1969, Robert Whittaker published a proposed five kingdom system for classification of living organisms. Whittaker's system placed most single celled organisms into either the prokaryotic Monera or the eukaryotic Protista. The other three kingdoms in his system were the eukaryotic Fungi, Animalia, and Plantae.
# Further Classification
Based on molecular phylogeny studies, Carl Woese proposed that the prokaryotes (monerans) be divided into two separate groups: Bacteria and Archaea. In Carl Woese's 1990 proposed phylogeny, these three kingdoms are all rooted in a universal common ancestor and this is the most widely accepted categorical phylogeny accepted today. However, the most modern interpretation for these three kingdoms is the "Universal and Eukaryote Phylogenetic Tree" based on 16s rDNA, as presented in the Tree of Life Web Project.
## Bacteria and Archaea
Eubacteria and Archaebacteria differ most noticeably in the environments they are able to inhabit. Eubacteria encompass the vast majority of bacteria with which humans come into contact. The bacteria that live within and around humans, such as Escherichia coli and those of the genus Salmonella, are Eubacteria. Archaebacteria live in much harsher conditions, such as in acidic hot springs and at depths of a mile below the arctic ice.
These groups were later renamed to Bacteria and Archaea, which might lead to some confusing situations, as the common use of the word "bacteria" in the English language (originally) simply refers to prokaryote microorganisms, or in other words monerans.
# Summary | Monera
Monera was a kingdom biological kingdom]] of the five-kingdom system of biological classification. It comprised most organisms with a prokaryotic cell organization. For this reason the kingdom was sometimes called Prokaryota or Prokaryotae. Prior to its creation these were treated as two separate divisions of plants: the Schizomycetes (bacteria) were considered fungi, and the Cyanophyta were considered blue-green algae. The latter are now considered a group of bacteria, typically called the cyanobacteria and are now known not to be closely related to plants, fungi, or animals.
Recent DNA and RNA sequence analyses has demonstrated that there are two major groups of prokaryotes, the Bacteria and Archaea, which do not appear to be closer in relationship to each other than they are to the Eukaryotes. Thus, Monera has since been divided into Archaea and Bacteria, forming the more recent six-kingdom system and three-domain system. All new schemes abandon the Monera and now treat the Bacteria, Archaea, and Eukarya as separate domains or kingdoms.
# History
Traditionally organisms were classified as animal, vegetable, or mineral as in Systema Naturae. After the discovery of microscopy, attempts were made to fit microscopic organisms into either the plant or animal kingdom. In 1866 Ernst Haeckel proposed a three kingdom system which added Protista as a new kingdom that contained most microscopic organisms.[1] One of his eight major divisions of Protista was called Moneres. Haeckel's Moneres subcategory included known bacterial groups such as Vibrio. Haeckel's Protista kingdom also included eukaryotic organisms now classified as Protist. It was later decided that Haeckel's Protista kingdom had proven to be too diverse to be seriously considered one single kingdom.
In 1969, Robert Whittaker published a proposed five kingdom system for classification of living organisms.[2] Whittaker's system placed most single celled organisms into either the prokaryotic Monera or the eukaryotic Protista. The other three kingdoms in his system were the eukaryotic Fungi, Animalia, and Plantae.
# Further Classification
Based on molecular phylogeny studies, Carl Woese proposed that the prokaryotes (monerans) be divided into two separate groups: Bacteria and Archaea. In Carl Woese's 1990 proposed phylogeny[3], these three kingdoms are all rooted in a universal common ancestor and this is the most widely accepted categorical phylogeny accepted today. However, the most modern interpretation for these three kingdoms is the "Universal and Eukaryote Phylogenetic Tree" based on 16s rDNA, as presented in the Tree of Life Web Project.[4]
## Bacteria and Archaea
Eubacteria and Archaebacteria differ most noticeably in the environments they are able to inhabit. Eubacteria encompass the vast majority of bacteria with which humans come into contact. The bacteria that live within and around humans, such as Escherichia coli and those of the genus Salmonella, are Eubacteria. Archaebacteria live in much harsher conditions, such as in acidic hot springs and at depths of a mile below the arctic ice.
These groups were later renamed to Bacteria and Archaea, which might lead to some confusing situations, as the common use of the word "bacteria" in the English language (originally) simply refers to prokaryote microorganisms, or in other words monerans.
# Summary
Template:Biological systems | https://www.wikidoc.org/index.php/Monera | |
a8d0931b91470bf1b33d944de0e5c07a9d0b48b1 | wikidoc | Morgue | Morgue
A morgue or mortuary is a building or room (as in a hospital) used for the storage of human remains.
Morgue is predominantly used in North American English, whilst mortuary is more common in British English. (Mortuary is also often synonymous with funeral home in American English.) The euphemisms "Rose Cottage" and "Rainbow room" (for children) are widely used in British hospitals to enable discussion in front of patients. The term morgue is derived from French morguer, which means 'to look at solemnly, to defy'. The term was first used to describe the inner wicket of a prison, where prisoners were kept for some time, during which the jailers and turnkeys would spend time looking at the prisoners so that they would be able to recognize them. Relating to dead people, the name was first given to a building in Paris, which, in the middle of the fifth century, was part of the Châtelet and was used for the keeping and identification of unknown corpses.
The person responsible for handling and washing the bodies is the Diener.
Probably because it is in a sense where the dead bodies are kept, the term morgue is also used in the United States to refer to the room in which newspaper or magazine publishers keep their back issues and other historical references.
Morgue - Morgue or mortuary cold chamber
There are two types of mortuary cold chambers:
- Morgue - Positive temperature
+2/+4 °C which is the most usual for keeping the bodies a few days or a few weeks, but does not prevent decomposition of the corpse, which continues, albeit at a slow rate.
- Morgue - Negative temperature
-15°C/-25 °C which is usual in forensic institutes, especially for bodies which have not yet been identified. At these temperatures, the body is completely frozen and decomposition totally halted.
# Usage
The mortuary cold chamber is used to keep the deceased as long as is necessary for identification purposes, post-mortem examination, or while awaiting burial.
In many countries, the family of the deceased must make the burial within 72 hours of death, but in some countries (in parts of Africa, for example) it is usual that the burial take place some weeks or some months after the death. This is why some corpses are kept as long as one or two years at a hospital or in a funeral home. When the family has enough money to organize the ceremony, they take the corpse from the cold chamber for burial.
In some funeral homes, the morgue is in the same room, or directly adjacent to, the specially designed ovens, known as retorts, that are used in funerary cremation. Some religions dictate that, should a body be cremated, the family must witness its incineration. To honor these religious rights, many funeral homes install a viewing window, which allows the family to watch as the body is inserted into the retort. In this way, the family can honor their customs without entering the morgue.
In many countries, the body of the deceased is embalmed, which makes refrigeration unnecessary.
## Waiting Mortuary
A Waiting Mortuary is a mortuary building designed specifically for the purpose of confirming that deceased persons are truly deceased. Prior to the advent of modern methods of verifying death, people feared that they would be buried alive. To alleviate such fears, the recently deceased were housed for a time in waiting mortuaries, where attendants would watch for signs of life. The corpses would be allowed to decompose partially prior to burial. Waiting mortuaries were most popular in 19th century Germany, and were often large ornate halls.
A bell was strung to the corpses to alert attendants of any motion. Although there is no documented case of a person being saved from accidental burial in this way,
it is sometimes erroneously believed that this was the origin of the phrase "Saved by the bell", whilst in fact, the phrase originates from the sport of boxing. | Morgue
A morgue or mortuary is a building or room (as in a hospital) used for the storage of human remains.
Morgue is predominantly used in North American English, whilst mortuary is more common in British English. (Mortuary is also often synonymous with funeral home in American English.) The euphemisms "Rose Cottage" and "Rainbow room" (for children) are widely used in British hospitals to enable discussion in front of patients. The term morgue is derived from French morguer, which means 'to look at solemnly, to defy'. The term was first used to describe the inner wicket of a prison, where prisoners were kept for some time, during which the jailers and turnkeys would spend time looking at the prisoners so that they would be able to recognize them. Relating to dead people, the name was first given to a building in Paris, which, in the middle of the fifth century, was part of the Châtelet and was used for the keeping and identification of unknown corpses.
The person responsible for handling and washing the bodies is the Diener.
Probably because it is in a sense where the dead bodies are kept, the term morgue is also used in the United States to refer to the room in which newspaper or magazine publishers keep their back issues and other historical references.
Morgue - Morgue or mortuary cold chamber
There are two types of mortuary cold chambers:
- Morgue - Positive temperature
+2/+4 °C which is the most usual for keeping the bodies a few days or a few weeks, but does not prevent decomposition of the corpse, which continues, albeit at a slow rate.
- Morgue - Negative temperature
-15°C/-25 °C which is usual in forensic institutes, especially for bodies which have not yet been identified. At these temperatures, the body is completely frozen and decomposition totally halted.
# Usage
The mortuary cold chamber is used to keep the deceased as long as is necessary for identification purposes, post-mortem examination, or while awaiting burial.
In many countries, the family of the deceased must make the burial within 72 hours of death, but in some countries (in parts of Africa, for example) it is usual that the burial take place some weeks or some months after the death. This is why some corpses are kept as long as one or two years at a hospital or in a funeral home. When the family has enough money to organize the ceremony, they take the corpse from the cold chamber for burial.
In some funeral homes, the morgue is in the same room, or directly adjacent to, the specially designed ovens, known as retorts, that are used in funerary cremation. Some religions dictate that, should a body be cremated, the family must witness its incineration. To honor these religious rights, many funeral homes install a viewing window, which allows the family to watch as the body is inserted into the retort. In this way, the family can honor their customs without entering the morgue.
In many countries, the body of the deceased is embalmed, which makes refrigeration unnecessary.
## Waiting Mortuary
A Waiting Mortuary is a mortuary building designed specifically for the purpose of confirming that deceased persons are truly deceased. Prior to the advent of modern methods of verifying death, people feared that they would be buried alive. To alleviate such fears, the recently deceased were housed for a time in waiting mortuaries, where attendants would watch for signs of life. The corpses would be allowed to decompose partially prior to burial. Waiting mortuaries were most popular in 19th century Germany, and were often large ornate halls.
A bell was strung to the corpses to alert attendants of any motion. Although there is no documented case of a person being saved from accidental burial in this way,[1]
it is sometimes erroneously believed that this was the origin of the phrase "Saved by the bell", whilst in fact, the phrase originates from the sport of boxing.[2] | https://www.wikidoc.org/index.php/Morgue | |
9145294e8db581d9f271b6da27c0c00706c9c16b | wikidoc | Morula | Morula
A morula (Latin "morus", mulberry) is an embryo at an early stage of embryonic development, consisting of approximately 12-32 cells (called blastomeres) in a solid ball contained within the zona pellucida.
# Production
The morula is produced by embryonic cleavage, the rapid division of the zygote. After reaching the 16-cell stage, the cells of the morula differentiate. The inner blastomeres will become the inner cell mass and the blastomeres on the surface will later flatten to form the trophoblast. As this process begins, the blastomeres change their shape and tightly align themselves against each other to form a compact ball of cells. This is called compaction and is likely mediated by cell surface adhesion glycoproteins.
# Development
In mammals the morula travels to the uterus around 3-4 days after fertilization, and at about 4 days after fertilization a fluid-filled space called the blastocoel cavity appears and the morula becomes a blastocyst.
# Additional images
- Morula, 8 cell stage
bg:Морула
cs:Morula
de:Morula
it:Morula
lt:Morulė
sk:Morula
sv:Morula | Morula
Template:Infobox Embryology
A morula (Latin "morus", mulberry) is an embryo at an early stage of embryonic development, consisting of approximately 12-32 cells (called blastomeres) in a solid ball contained within the zona pellucida.
# Production
The morula is produced by embryonic cleavage, the rapid division of the zygote. After reaching the 16-cell stage, the cells of the morula differentiate. The inner blastomeres will become the inner cell mass and the blastomeres on the surface will later flatten to form the trophoblast. As this process begins, the blastomeres change their shape and tightly align themselves against each other to form a compact ball of cells. This is called compaction and is likely mediated by cell surface adhesion glycoproteins.
# Development
In mammals the morula travels to the uterus around 3-4 days after fertilization, and at about 4 days after fertilization a fluid-filled space called the blastocoel cavity appears and the morula becomes a blastocyst.
# Additional images
- Morula, 8 cell stage
Template:Developmental-biology-stub
Template:Embryology
bg:Морула
cs:Morula
de:Morula
it:Morula
lt:Morulė
sk:Morula
sv:Morula | https://www.wikidoc.org/index.php/Morula | |
f4247d49c25b5675e5049d6f65ddea9b25ace7dd | wikidoc | Muscle | Muscle
Muscle (from Latin musculus, diminutive of mus "mouse") is contractile tissue of the body and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. It is classified as skeletal, cardiac, or smooth muscle, and its function is to produce force and cause motion, either locomotion or movement within internal organs. Much of muscle contraction occurs without conscious thought and is necessary for survival, like the contraction of the heart, or peristalsis (which pushes food through the digestive system). Voluntary muscle contraction is used to move the body, and can be finely controlled, like movements of the eye, or gross movements like the quadriceps muscle of the thigh. There are two broad types of voluntary muscle fibers, slow twitch and fast twitch. Slow twitch fibers contract for long periods of time but with little force while fast twitch fibers contract quickly and powerfully but fatigue very rapidly.
# Types
There are three types of muscle:
- Skeletal muscle or "voluntary muscle" is anchored by tendons to bone and is used to affect skeletal movement such as locomotion and in maintaining posture. Though this postural control is generally maintained as a subconscious reflex, the muscles responsible react to conscious control like non-postural muscles. An average adult male is made up of 40–50% of skeletal muscle and an average adult female is made up of 30–40%.
- Smooth muscle or "involuntary muscle" is found within the walls of organs and structures such as the esophagus, stomach, intestines, bronchi, uterus, urethra, bladder, and blood vessels, and unlike skeletal muscle, smooth muscle is not under conscious control.
- Cardiac muscle is also an "involuntary muscle" but is more akin in structure to skeletal muscle, and is found only in the heart.
Cardiac and skeletal muscles are "striated" in that they contain sarcomeres and are packed into highly-regular arrangements of bundles; smooth muscle has neither. While skeletal muscles are arranged in regular, parallel bundles, cardiac muscle connects at branching, irregular angles (called intercalated discs). Striated muscle contracts and relaxes in short, intense bursts, whereas smooth muscle sustains longer or even near-permanent contractions.
Skeletal muscle is further divided into several subtypes:
- Type I, slow oxidative, slow twitch, or "red" muscle is dense with capillaries and is rich in mitochondria and myoglobin, giving the muscle tissue its characteristic red color. It can carry more oxygen and sustain aerobic activity.
- Type II, fast twitch muscle, has three major kinds that are, in order of increasing contractile speed:
Type IIa, which, like slow muscle, is aerobic, rich in mitochondria and capillaries and appears red.
Type IIx (also known as type IId), which is less dense in mitochondria and myoglobin. This is the fastest muscle type in humans. It can contract more quickly and with a greater amount of force than oxidative muscle, but can sustain only short, anaerobic bursts of activity before muscle contraction becomes painful (often incorrectly attributed to a build-up of lactic acid). N.B. in some books and articles this muscle in humans was, confusingly, called type IIB.
Type IIb, which is anaerobic, glycolytic, "white" muscle that is even less dense in mitochondria and myoglobin. In small animals like rodents this is the major fast muscle type, explaining the pale color of their flesh.
- Type IIa, which, like slow muscle, is aerobic, rich in mitochondria and capillaries and appears red.
- Type IIx (also known as type IId), which is less dense in mitochondria and myoglobin. This is the fastest muscle type in humans. It can contract more quickly and with a greater amount of force than oxidative muscle, but can sustain only short, anaerobic bursts of activity before muscle contraction becomes painful (often incorrectly attributed to a build-up of lactic acid). N.B. in some books and articles this muscle in humans was, confusingly, called type IIB.
- Type IIb, which is anaerobic, glycolytic, "white" muscle that is even less dense in mitochondria and myoglobin. In small animals like rodents this is the major fast muscle type, explaining the pale color of their flesh.
# Anatomy
The anatomy of muscles includes both gross anatomy, comprising all the muscles of an organism, and, on the other hand, microanatomy, which comprises the structures of a single muscle.
## Gross anatomy
The gross anatomy of a muscle is the single most important indicator of its role in the body. The action a muscle generates is determined by the origin and insertion locations. The cross-sectional area of a muscle (rather than volume or length) determines the amount of force it can generate by defining the number of sarcomeres which can operate in parallel. The amount of force applied to the external environment is determined by lever mechanics, specifically the ratio of in-lever to out-lever. For example, moving the insertion point of the biceps more distally on the radius (farther from the joint of rotation) would increase the force generated during flexion (and, as a result, the maximum weight lifted in this movement), but decrease the maximum speed of flexion. Moving the insertion point proximally (closer to the joint of rotation) would result in decreased force but increased velocity. This can be most easily seen by comparing the limb of a mole to a horse - in the former, the insertion point is positioned to maximize force (for digging), while in the latter, the insertion point is positioned to maximize speed (for running).
One particularly important aspect of gross anatomy of muscles is pennation or lack thereof. In most muscles, all the fibers are oriented in the same direction, running in a line from the origin to the insertion. In pennate muscles, the individual fibers are oriented at an angle relative to the line of action, attaching to the origin and insertion tendons at each end. Because the contracting fibers are pulling at an angle to the overall action of the muscle, the change in length is smaller, but this same orientation allows for more fibers (thus more force) in a muscle of a given size. Pennate muscles are usually found where their length change is less important than maximum force, such as the rectus femoris.
There are approximately 639 skeletal muscles in the human body. However, the exact number is difficult to define because different sources group muscles differently.
Following are some major muscles and their basic features:
## Microanatomy
Muscle is mainly composed of muscle cells. Within the cells are myofibrils; myofibrils contain sarcomeres, which are composed of actin and myosin. Individual muscle fibres are surrounded by endomysium. Muscle fibers are bound together by perimysium into bundles called fascicles; the bundles are then grouped together to form muscle, which is enclosed in a sheath of epimysium. Muscle spindles are distributed throughout the muscles and provide sensory feedback information to the central nervous system.
Skeletal muscle is muscle attached to skeletal tissue, distinct from heart or smooth muscle. It is arranged in discrete muscles, an example of which is the biceps brachii. It is connected by tendons to processes of the skeleton. In contrast, smooth muscle occurs at various scales in almost every organ, from the skin (in which it controls erection of body hair) to the blood vessels and digestive tract (in which it controls the caliber of the lumen and peristalsis). Cardiac muscle is the muscle tissue of the heart, and is similar to skeletal muscle in both composition and action, being comprised of myofibrils of sarcomeres. Cardiac muscle is anatomically different in that the muscle fibers are typically branched like a tree branch, and connect to other cardiac muscle fibers through intercalcated discs, and form the appearance of a syncytium.
# Physiology
The three (skeletal, cardiac and smooth) types of muscle have significant differences. However, all three use the movement of actin against myosin to create contraction. In skeletal muscle, contraction is stimulated by electrical impulses transmitted by the nerves, the motor nerves and motoneurons in particular. Cardiac and smooth muscle contractions are stimulated by internal pacemaker cells which regularly contract, and propagate contractions to other muscle cells they are in contact with. All skeletal muscle and many smooth muscle contractions are facilitated by the neurotransmitter acetylcholine.
Muscular activity accounts for much of the body's energy consumption. All muscle cells produce adenosine triphosphate (ATP) molecules which are used to power the movement of the myosin heads. Muscles conserve energy in the form of creatine phosphate which is generated from ATP and can regenerate ATP when needed with creatine kinase. Muscles also keep a storage form of glucose in the form of glycogen. Glycogen can be rapidly converted to glucose when energy is required for sustained, powerful contractions. Within the voluntary skeletal muscles, the glucose molecule can be metabolized anaerobically in a process called glycolysis which produces two ATP and two lactic acid molecules in the process (note that in aerobic conditions, lactate is not formed; instead pyruvate is formed and transmitted through the citric acid cycle). Muscle cells also contain globules of fat, which are used for energy during aerobic exercise. The aerobic energy systems take longer to produce the ATP and reach peak efficiency, and requires many more biochemical steps, but produces significantly more ATP than anaerobic glycolysis. Cardiac muscle on the other hand, can readily consume any of the three macronutrients (protein, glucose and fat) aerobically without a 'warm up' period and always extracts the maximum ATP yield from any molecule involved. The heart, liver and red blood cells will also consume lactic acid produced and excreted by skeletal muscles during exercise.
# Nervous control
## Efferent leg
The efferent leg of the peripheral nervous system is responsible for conveying commands to the muscles and glands, and is ultimately responsible for voluntary movement. Nerves move muscles in response to voluntary and autonomic (involuntary) signals from the brain. Deep muscles, superficial muscles, muscles of the face and internal muscles all correspond with dedicated regions in the primary motor cortex of the brain, directly anterior to the central sulcus that divides the frontal and parietal lobes.
In addition, muscles react to reflexive nerve stimuli that do not always send signals all the way to the brain. In this case, the signal from the afferent fiber does not reach the brain, but produces the reflexive movement by direct connections with the efferent nerves in the spine. However, the majority of muscle activity is volitional, and the result of complex interactions between various areas of the brain.
Nerves that control skeletal muscles in mammals correspond with neuron groups along the primary motor cortex of the brain's cerebral cortex. Commands are routed though the basal ganglia and are modified by input from the cerebellum before being relayed through the pyramidal tract to the spinal cord and from there to the motor end plate at the muscles. Along the way, feedback, such as that of the extrapyramidal system contribute signals to influence muscle tone and response.
Deeper muscles such as those involved in posture often are controlled from nuclei in the brain stem and basal ganglia.
## Afferent leg
The afferent leg of the peripheral nervous system is responsible for conveying sensory information to the brain, primarily from the sense organs like the skin. In the muscles, the muscle spindles convey information about the degree of muscle length and stretch to the central nervous system to assist in maintaining posture and joint position. The sense of where our bodies are in space is called proprioception, the perception of body awareness. More easily demonstrated than explained, proprioception is the "unconscious" awareness of where the various regions of the body are located at any one time. This can be demonstrated by anyone closing their eyes and waving their hand around. Assuming proper proprioceptive function, at no time will the person lose awareness of where the hand actually is, even though it is not being detected by any of the other senses.
Several areas in the brain coordinate movement and position with the feedback information gained from proprioception. The cerebellum and red nucleus in particular continuously sample position against movement and make minor corrections to assure smooth motion.
# Exercise
Exercise is often recommended as a means of improving motor skills, fitness, muscle and bone strength, and joint function. Exercise has several effects upon muscles, connective tissue, bone, and the nerves that stimulate the muscles.
Various exercises require a predominance of certain muscle fiber utilization over another. Aerobic exercise involves long, low levels of exertion in which the muscles are used at well below their maximal contraction strength for long periods of time (the most classic example being the marathon). Aerobic events, which rely primarily on the aerobic (with oxygen) system, use a higher percentage of Type I (or slow-twitch) muscle fibers, consume a mixture of fat, protein and carbohydrates for energy, consume large amounts of oxygen and produce little lactic acid. Anaerobic exercise involves short bursts of higher intensity contractions at a much greater percentage of their maximum contraction strength. Examples of anaerobic exercise include sprinting and weight lifting. The anaerobic energy delivery system uses predominantly Type II or fast-twitch muscle fibers, relies mainly on ATP or glucose for fuel, consumes relatively little oxygen, protein and fat, produces large amounts of lactic acid and can not be sustained for as long a period as aerobic exercise. The presence of lactic acid has an inhibitory effect on ATP generation within the muscle; though not producing fatigue, it can inhibit or even stop performance if the intracellular concentration becomes too high. However, long-term training causes neovascularization within the muscle, increasing the ability to move waste products out of the muscles and maintain contraction. Once moved out of muscles with high concentrations within the sarcomere, lactic acid can be used by other muscles or body tissues as a source of energy, or transported to the liver where it is converted back to pyruvate. The ability of the body to export lactic acid and use it as a source of energy depends on training level.
Humans are genetically predisposed with a larger percentage of one type of muscle group over another. An individual born with a greater percentage of Type I muscle fibers would theoretically be more suited to endurance events, such as triathlons, distance running, and long cycling events, whereas a human born with a greater percentage of Type II muscle fibers would be more likely to excel at anaerobic events such as a 200 meter dash, or weightlifting. People with high overall musculation and balanced muscle type percentage engage in sports such as rugby or boxing and often engage in other sports to increase their performance in the former.
Delayed onset muscle soreness is pain or discomfort that may be felt one to three days after exercising and subsides generally within two to three days later. Once thought to be caused by lactic acid buildup, a more recent theory is that it is caused by tiny tears in the muscle fibres caused by eccentric contraction, or unaccustomed training levels. Since lactic acid disperses fairly rapidly, it could not explain pain experienced days after exercise.
# Disease
Symptoms of muscle diseases may include weakness, spasticity, myoclonus and myalgia. Diagnostic procedures that may reveal muscular disorders include testing creatine kinase levels in the blood and electromyography (measuring electrical activity in muscles). In some cases, muscle biopsy may be done to identify a myopathy, as well as genetic testing to identify DNA abnormalities associated with specific myopathies and dystrophies.
Neuromuscular diseases are those that affect the muscles and/or their nervous control. In general, problems with nervous control can cause spasticity or paralysis, depending on the location and nature of the problem. A large proportion of neurological disorders leads to problems with movement, ranging from cerebrovascular accident (stroke) and Parkinson's disease to Creutzfeldt-Jakob disease.
A non-invasive elastography technique that measures muscle noise is undergoing experimentation to provide a way of monitoring neuromuscular disease. The sound produced by a muscle comes from the shortening of actomyosin filaments along the axis of the muscle. During contraction, the muscle shortens along its longitudinal axis and expands across the transverse axis, producing vibrations at the surface.
## Atrophy
There are many diseases and conditions which cause a decrease in muscle mass, known as muscle atrophy. Example include cancer and AIDS, which induce a body wasting syndrome called cachexia. Other syndromes or conditions which can induce skeletal muscle atrophy are congestive heart disease and some diseases of the liver.
During aging, there is a gradual decrease in the ability to maintain skeletal muscle function and mass, known as sarcopenia. The exact cause of sarcopenia is unknown, but it may be due to a combination of the gradual failure in the "satellite cells" which help to regenerate skeletal muscle fibers, and a decrease in sensitivity to or the availability of critical secreted growth factors which are necessary to maintain muscle mass and satellite cell survival. Sarcopenia is a normal aspect of aging, and is not actually a disease state.
# Strength
A display of "strength" (e.g lifting a weight) is a result of three factors that overlap; Physiological strength (muscle size, cross sectional area, available crossbridging, responses to training), neurological strength (how strong or weak is the signal that tells the muscle to contract), and mechanical strength (muscle's force angle on the lever, moment arm length, joint capabilities). Contrary to popular belief, the number of muscle fibres cannot be increased through exercise; instead the muscle cells simply get bigger. Muscle fibres have a limited capacity for growth through hypertrophy and some believe they split through hyperplasia if subject to increased demand.
## The "strongest" human muscle
Since three factors affect muscular strength simultaneously and muscles never work individually, it is unrealistic to compare strength in individual muscles, and state that one is the "strongest". But below are several muscles whose strength is noteworthy for different reasons.
- In ordinary parlance, muscular "strength" usually refers to the ability to exert a force on an external object—for example, lifting a weight. By this definition, the masseter or jaw muscle is the strongest. The 1992 Guinness Book of Records records the achievement of a bite strength of 4337 N (975 bf) for 2 seconds. What distinguishes the masseter is not anything special about the muscle itself, but its advantage in working against a much shorter lever arm than other muscles.
- If "strength" refers to the force exerted by the muscle itself, e.g., on the place where it inserts into a bone, then the strongest muscles are those with the largest cross-sectional area. This is because the tension exerted by an individual skeletal muscle fiber does not vary much. Each fiber can exert a force on the order of 0.3 micronewton. By this definition, the strongest muscle of the body is usually said to be the quadriceps femoris or the gluteus maximus.
- A shorter muscle will be stronger "pound for pound" (i.e., by weight) than a longer muscle. The myometrial layer of the uterus may be the strongest muscle by weight in the human body. At the time when an infant is delivered, the entire human uterus weighs about 1.1 kg (40 oz). During childbirth, the uterus exerts 100 to 400 N (25 to 100 lbf) of downward force with each contraction.
- The external muscles of the eye are conspicuously large and strong in relation to the small size and weight of the eyeball. It is frequently said that they are "the strongest muscles for the job they have to do" and are sometimes claimed to be "100 times stronger than they need to be." However, eye movements (particularly saccades used on facial scanning and reading) do require high speed movements, and eye muscles are exercised nightly during Rapid eye movement.
- The statement that "the tongue is the strongest muscle in the body" appears frequently in lists of surprising facts, but it is difficult to find any definition of "strength" that would make this statement true. Note that the tongue consists of sixteen muscles, not one.
- The heart has a claim to being the muscle that performs the largest quantity of physical work in the course of a lifetime. Estimates of the power output of the human heart range from 1 to 5 watts. This is much less than the maximum power output of other muscles; for example, the quadriceps can produce over 100 watts, but only for a few minutes. The heart does its work continuously over an entire lifetime without pause, and thus does "outwork" other muscles. An output of one watt continuously for seventy years yields a total work output of two to three gigajoules.
# Efficiency
The efficiency of human muscle has been measured (in the context of rowing and cycling) at 14% to 27%. The efficiency is defined as the ratio of mechanical work output to the total metabolic cost.
# Body building
Bodybuilding is the process of maximizing muscle hypertrophy through the combination of weight training, sufficient caloric intake, and rest - often utilising extraneous hormones. Someone who engages in this activity is referred to as a bodybuilder. The muscles are revealed through a combination of fat loss, oils, and tanning (or tanning lotions) which combined with lighting make the definition of the muscle group more distinct.
# Muscle evolution
Evolutionarily, specialized forms of skeletal and cardiac muscles predated the divergence of the vertebrate/arthropod evolutionary line. This indicates that these types of muscle developed in a common ancestor sometime before 700 million years ago (mya). Vertebrate smooth muscle (smooth muscle found in humans) was found to have evolved independently from the skeletal and cardiac muscles. | Muscle
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Muscle (from Latin musculus, diminutive of mus "mouse"[1]) is contractile tissue of the body and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. It is classified as skeletal, cardiac, or smooth muscle, and its function is to produce force and cause motion, either locomotion or movement within internal organs. Much of muscle contraction occurs without conscious thought and is necessary for survival, like the contraction of the heart, or peristalsis (which pushes food through the digestive system). Voluntary muscle contraction is used to move the body, and can be finely controlled, like movements of the eye, or gross movements like the quadriceps muscle of the thigh. There are two broad types of voluntary muscle fibers, slow twitch and fast twitch. Slow twitch fibers contract for long periods of time but with little force while fast twitch fibers contract quickly and powerfully but fatigue very rapidly.
# Types
There are three types of muscle:
- Skeletal muscle or "voluntary muscle" is anchored by tendons to bone and is used to affect skeletal movement such as locomotion and in maintaining posture. Though this postural control is generally maintained as a subconscious reflex, the muscles responsible react to conscious control like non-postural muscles. An average adult male is made up of 40–50% of skeletal muscle and an average adult female is made up of 30–40%.
- Smooth muscle or "involuntary muscle" is found within the walls of organs and structures such as the esophagus, stomach, intestines, bronchi, uterus, urethra, bladder, and blood vessels, and unlike skeletal muscle, smooth muscle is not under conscious control.
- Cardiac muscle is also an "involuntary muscle" but is more akin in structure to skeletal muscle, and is found only in the heart.
Cardiac and skeletal muscles are "striated" in that they contain sarcomeres and are packed into highly-regular arrangements of bundles; smooth muscle has neither. While skeletal muscles are arranged in regular, parallel bundles, cardiac muscle connects at branching, irregular angles (called intercalated discs). Striated muscle contracts and relaxes in short, intense bursts, whereas smooth muscle sustains longer or even near-permanent contractions.
Skeletal muscle is further divided into several subtypes:
- Type I, slow oxidative, slow twitch, or "red" muscle is dense with capillaries and is rich in mitochondria and myoglobin, giving the muscle tissue its characteristic red color. It can carry more oxygen and sustain aerobic activity.
- Type II, fast twitch muscle, has three major kinds that are, in order of increasing contractile speed:[2]
Type IIa, which, like slow muscle, is aerobic, rich in mitochondria and capillaries and appears red.
Type IIx (also known as type IId), which is less dense in mitochondria and myoglobin. This is the fastest muscle type in humans. It can contract more quickly and with a greater amount of force than oxidative muscle, but can sustain only short, anaerobic bursts of activity before muscle contraction becomes painful (often incorrectly attributed to a build-up of lactic acid). N.B. in some books and articles this muscle in humans was, confusingly, called type IIB.[3]
Type IIb, which is anaerobic, glycolytic, "white" muscle that is even less dense in mitochondria and myoglobin. In small animals like rodents this is the major fast muscle type, explaining the pale color of their flesh.
- Type IIa, which, like slow muscle, is aerobic, rich in mitochondria and capillaries and appears red.
- Type IIx (also known as type IId), which is less dense in mitochondria and myoglobin. This is the fastest muscle type in humans. It can contract more quickly and with a greater amount of force than oxidative muscle, but can sustain only short, anaerobic bursts of activity before muscle contraction becomes painful (often incorrectly attributed to a build-up of lactic acid). N.B. in some books and articles this muscle in humans was, confusingly, called type IIB.[3]
- Type IIb, which is anaerobic, glycolytic, "white" muscle that is even less dense in mitochondria and myoglobin. In small animals like rodents this is the major fast muscle type, explaining the pale color of their flesh.
# Anatomy
The anatomy of muscles includes both gross anatomy, comprising all the muscles of an organism, and, on the other hand, microanatomy, which comprises the structures of a single muscle.
## Gross anatomy
The gross anatomy of a muscle is the single most important indicator of its role in the body. The action a muscle generates is determined by the origin and insertion locations. The cross-sectional area of a muscle (rather than volume or length) determines the amount of force it can generate by defining the number of sarcomeres which can operate in parallel. The amount of force applied to the external environment is determined by lever mechanics, specifically the ratio of in-lever to out-lever. For example, moving the insertion point of the biceps more distally on the radius (farther from the joint of rotation) would increase the force generated during flexion (and, as a result, the maximum weight lifted in this movement), but decrease the maximum speed of flexion. Moving the insertion point proximally (closer to the joint of rotation) would result in decreased force but increased velocity. This can be most easily seen by comparing the limb of a mole to a horse - in the former, the insertion point is positioned to maximize force (for digging), while in the latter, the insertion point is positioned to maximize speed (for running).
One particularly important aspect of gross anatomy of muscles is pennation or lack thereof. In most muscles, all the fibers are oriented in the same direction, running in a line from the origin to the insertion. In pennate muscles, the individual fibers are oriented at an angle relative to the line of action, attaching to the origin and insertion tendons at each end. Because the contracting fibers are pulling at an angle to the overall action of the muscle, the change in length is smaller, but this same orientation allows for more fibers (thus more force) in a muscle of a given size. Pennate muscles are usually found where their length change is less important than maximum force, such as the rectus femoris.
There are approximately 639 skeletal muscles in the human body. However, the exact number is difficult to define because different sources group muscles differently.
Following are some major muscles[4] and their basic features:
## Microanatomy
Muscle is mainly composed of muscle cells. Within the cells are myofibrils; myofibrils contain sarcomeres, which are composed of actin and myosin. Individual muscle fibres are surrounded by endomysium. Muscle fibers are bound together by perimysium into bundles called fascicles; the bundles are then grouped together to form muscle, which is enclosed in a sheath of epimysium. Muscle spindles are distributed throughout the muscles and provide sensory feedback information to the central nervous system.
Skeletal muscle is muscle attached to skeletal tissue, distinct from heart or smooth muscle. It is arranged in discrete muscles, an example of which is the biceps brachii. It is connected by tendons to processes of the skeleton. In contrast, smooth muscle occurs at various scales in almost every organ, from the skin (in which it controls erection of body hair) to the blood vessels and digestive tract (in which it controls the caliber of the lumen and peristalsis). Cardiac muscle is the muscle tissue of the heart, and is similar to skeletal muscle in both composition and action, being comprised of myofibrils of sarcomeres. Cardiac muscle is anatomically different in that the muscle fibers are typically branched like a tree branch, and connect to other cardiac muscle fibers through intercalcated discs, and form the appearance of a syncytium.
# Physiology
The three (skeletal, cardiac and smooth) types of muscle have significant differences. However, all three use the movement of actin against myosin to create contraction. In skeletal muscle, contraction is stimulated by electrical impulses transmitted by the nerves, the motor nerves and motoneurons in particular. Cardiac and smooth muscle contractions are stimulated by internal pacemaker cells which regularly contract, and propagate contractions to other muscle cells they are in contact with. All skeletal muscle and many smooth muscle contractions are facilitated by the neurotransmitter acetylcholine.
Muscular activity accounts for much of the body's energy consumption. All muscle cells produce adenosine triphosphate (ATP) molecules which are used to power the movement of the myosin heads. Muscles conserve energy in the form of creatine phosphate which is generated from ATP and can regenerate ATP when needed with creatine kinase. Muscles also keep a storage form of glucose in the form of glycogen. Glycogen can be rapidly converted to glucose when energy is required for sustained, powerful contractions. Within the voluntary skeletal muscles, the glucose molecule can be metabolized anaerobically in a process called glycolysis which produces two ATP and two lactic acid molecules in the process (note that in aerobic conditions, lactate is not formed; instead pyruvate is formed and transmitted through the citric acid cycle). Muscle cells also contain globules of fat, which are used for energy during aerobic exercise. The aerobic energy systems take longer to produce the ATP and reach peak efficiency, and requires many more biochemical steps, but produces significantly more ATP than anaerobic glycolysis. Cardiac muscle on the other hand, can readily consume any of the three macronutrients (protein, glucose and fat) aerobically without a 'warm up' period and always extracts the maximum ATP yield from any molecule involved. The heart, liver and red blood cells will also consume lactic acid produced and excreted by skeletal muscles during exercise.
# Nervous control
## Efferent leg
The efferent leg of the peripheral nervous system is responsible for conveying commands to the muscles and glands, and is ultimately responsible for voluntary movement. Nerves move muscles in response to voluntary and autonomic (involuntary) signals from the brain. Deep muscles, superficial muscles, muscles of the face and internal muscles all correspond with dedicated regions in the primary motor cortex of the brain, directly anterior to the central sulcus that divides the frontal and parietal lobes.
In addition, muscles react to reflexive nerve stimuli that do not always send signals all the way to the brain. In this case, the signal from the afferent fiber does not reach the brain, but produces the reflexive movement by direct connections with the efferent nerves in the spine. However, the majority of muscle activity is volitional, and the result of complex interactions between various areas of the brain.
Nerves that control skeletal muscles in mammals correspond with neuron groups along the primary motor cortex of the brain's cerebral cortex. Commands are routed though the basal ganglia and are modified by input from the cerebellum before being relayed through the pyramidal tract to the spinal cord and from there to the motor end plate at the muscles. Along the way, feedback, such as that of the extrapyramidal system contribute signals to influence muscle tone and response.
Deeper muscles such as those involved in posture often are controlled from nuclei in the brain stem and basal ganglia.
## Afferent leg
The afferent leg of the peripheral nervous system is responsible for conveying sensory information to the brain, primarily from the sense organs like the skin. In the muscles, the muscle spindles convey information about the degree of muscle length and stretch to the central nervous system to assist in maintaining posture and joint position. The sense of where our bodies are in space is called proprioception, the perception of body awareness. More easily demonstrated than explained, proprioception is the "unconscious" awareness of where the various regions of the body are located at any one time. This can be demonstrated by anyone closing their eyes and waving their hand around. Assuming proper proprioceptive function, at no time will the person lose awareness of where the hand actually is, even though it is not being detected by any of the other senses.
Several areas in the brain coordinate movement and position with the feedback information gained from proprioception. The cerebellum and red nucleus in particular continuously sample position against movement and make minor corrections to assure smooth motion.
# Exercise
Exercise is often recommended as a means of improving motor skills, fitness, muscle and bone strength, and joint function. Exercise has several effects upon muscles, connective tissue, bone, and the nerves that stimulate the muscles.
Various exercises require a predominance of certain muscle fiber utilization over another. Aerobic exercise involves long, low levels of exertion in which the muscles are used at well below their maximal contraction strength for long periods of time (the most classic example being the marathon). Aerobic events, which rely primarily on the aerobic (with oxygen) system, use a higher percentage of Type I (or slow-twitch) muscle fibers, consume a mixture of fat, protein and carbohydrates for energy, consume large amounts of oxygen and produce little lactic acid. Anaerobic exercise involves short bursts of higher intensity contractions at a much greater percentage of their maximum contraction strength. Examples of anaerobic exercise include sprinting and weight lifting. The anaerobic energy delivery system uses predominantly Type II or fast-twitch muscle fibers, relies mainly on ATP or glucose for fuel, consumes relatively little oxygen, protein and fat, produces large amounts of lactic acid and can not be sustained for as long a period as aerobic exercise. The presence of lactic acid has an inhibitory effect on ATP generation within the muscle; though not producing fatigue, it can inhibit or even stop performance if the intracellular concentration becomes too high. However, long-term training causes neovascularization within the muscle, increasing the ability to move waste products out of the muscles and maintain contraction. Once moved out of muscles with high concentrations within the sarcomere, lactic acid can be used by other muscles or body tissues as a source of energy, or transported to the liver where it is converted back to pyruvate. The ability of the body to export lactic acid and use it as a source of energy depends on training level.
Humans are genetically predisposed with a larger percentage of one type of muscle group over another. An individual born with a greater percentage of Type I muscle fibers would theoretically be more suited to endurance events, such as triathlons, distance running, and long cycling events, whereas a human born with a greater percentage of Type II muscle fibers would be more likely to excel at anaerobic events such as a 200 meter dash, or weightlifting. People with high overall musculation and balanced muscle type percentage engage in sports such as rugby or boxing and often engage in other sports to increase their performance in the former.
Delayed onset muscle soreness is pain or discomfort that may be felt one to three days after exercising and subsides generally within two to three days later. Once thought to be caused by lactic acid buildup, a more recent theory is that it is caused by tiny tears in the muscle fibres caused by eccentric contraction, or unaccustomed training levels. Since lactic acid disperses fairly rapidly, it could not explain pain experienced days after exercise.[5]
# Disease
Symptoms of muscle diseases may include weakness, spasticity, myoclonus and myalgia. Diagnostic procedures that may reveal muscular disorders include testing creatine kinase levels in the blood and electromyography (measuring electrical activity in muscles). In some cases, muscle biopsy may be done to identify a myopathy, as well as genetic testing to identify DNA abnormalities associated with specific myopathies and dystrophies.
Neuromuscular diseases are those that affect the muscles and/or their nervous control. In general, problems with nervous control can cause spasticity or paralysis, depending on the location and nature of the problem. A large proportion of neurological disorders leads to problems with movement, ranging from cerebrovascular accident (stroke) and Parkinson's disease to Creutzfeldt-Jakob disease.
A non-invasive elastography technique that measures muscle noise is undergoing experimentation to provide a way of monitoring neuromuscular disease. The sound produced by a muscle comes from the shortening of actomyosin filaments along the axis of the muscle. During contraction, the muscle shortens along its longitudinal axis and expands across the transverse axis, producing vibrations at the surface.[6]
## Atrophy
There are many diseases and conditions which cause a decrease in muscle mass, known as muscle atrophy. Example include cancer and AIDS, which induce a body wasting syndrome called cachexia. Other syndromes or conditions which can induce skeletal muscle atrophy are congestive heart disease and some diseases of the liver.
During aging, there is a gradual decrease in the ability to maintain skeletal muscle function and mass, known as sarcopenia. The exact cause of sarcopenia is unknown, but it may be due to a combination of the gradual failure in the "satellite cells" which help to regenerate skeletal muscle fibers, and a decrease in sensitivity to or the availability of critical secreted growth factors which are necessary to maintain muscle mass and satellite cell survival. Sarcopenia is a normal aspect of aging, and is not actually a disease state.
# Strength
A display of "strength" (e.g lifting a weight) is a result of three factors that overlap; Physiological strength (muscle size, cross sectional area, available crossbridging, responses to training), neurological strength (how strong or weak is the signal that tells the muscle to contract), and mechanical strength (muscle's force angle on the lever, moment arm length, joint capabilities). Contrary to popular belief, the number of muscle fibres cannot be increased through exercise; instead the muscle cells simply get bigger. Muscle fibres have a limited capacity for growth through hypertrophy and some believe they split through hyperplasia if subject to increased demand.
## The "strongest" human muscle
Since three factors affect muscular strength simultaneously and muscles never work individually, it is unrealistic to compare strength in individual muscles, and state that one is the "strongest". But below are several muscles whose strength is noteworthy for different reasons.
- In ordinary parlance, muscular "strength" usually refers to the ability to exert a force on an external object—for example, lifting a weight. By this definition, the masseter or jaw muscle is the strongest. The 1992 Guinness Book of Records records the achievement of a bite strength of 4337 N (975 bf) for 2 seconds. What distinguishes the masseter is not anything special about the muscle itself, but its advantage in working against a much shorter lever arm than other muscles.
- If "strength" refers to the force exerted by the muscle itself, e.g., on the place where it inserts into a bone, then the strongest muscles are those with the largest cross-sectional area. This is because the tension exerted by an individual skeletal muscle fiber does not vary much. Each fiber can exert a force on the order of 0.3 micronewton. By this definition, the strongest muscle of the body is usually said to be the quadriceps femoris or the gluteus maximus.
- A shorter muscle will be stronger "pound for pound" (i.e., by weight) than a longer muscle. The myometrial layer of the uterus may be the strongest muscle by weight in the human body. At the time when an infant is delivered, the entire human uterus weighs about 1.1 kg (40 oz). During childbirth, the uterus exerts 100 to 400 N (25 to 100 lbf) of downward force with each contraction.
- The external muscles of the eye are conspicuously large and strong in relation to the small size and weight of the eyeball. It is frequently said that they are "the strongest muscles for the job they have to do" and are sometimes claimed to be "100 times stronger than they need to be." However, eye movements (particularly saccades used on facial scanning and reading) do require high speed movements, and eye muscles are exercised nightly during Rapid eye movement.
- The statement that "the tongue is the strongest muscle in the body" appears frequently in lists of surprising facts, but it is difficult to find any definition of "strength" that would make this statement true. Note that the tongue consists of sixteen muscles, not one.
- The heart has a claim to being the muscle that performs the largest quantity of physical work in the course of a lifetime. Estimates of the power output of the human heart range from 1 to 5 watts. This is much less than the maximum power output of other muscles; for example, the quadriceps can produce over 100 watts, but only for a few minutes. The heart does its work continuously over an entire lifetime without pause, and thus does "outwork" other muscles. An output of one watt continuously for seventy years yields a total work output of two to three gigajoules.
# Efficiency
The efficiency of human muscle has been measured (in the context of rowing and cycling) at 14% to 27%. The efficiency is defined as the ratio of mechanical work output to the total metabolic cost.
# Body building
Bodybuilding is the process of maximizing muscle hypertrophy through the combination of weight training, sufficient caloric intake, and rest - often utilising extraneous hormones. Someone who engages in this activity is referred to as a bodybuilder. The muscles are revealed through a combination of fat loss, oils, and tanning (or tanning lotions) which combined with lighting make the definition of the muscle group more distinct.
# Muscle evolution
Evolutionarily, specialized forms of skeletal and cardiac muscles predated the divergence of the vertebrate/arthropod evolutionary line.[7] This indicates that these types of muscle developed in a common ancestor sometime before 700 million years ago (mya). Vertebrate smooth muscle (smooth muscle found in humans) was found to have evolved independently from the skeletal and cardiac muscles. | https://www.wikidoc.org/index.php/Motor_system | |
ceea5db7660e87110be217f96af8b7306d18a09d | wikidoc | Mutant | Mutant
A mutant is an individual, organism, or new genetic character arising or resulting from an instance of mutation, which is a sudden structural change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or trait not found in the wildtype. In an organism or individual, the new character or trait may or may not be trivial, may occasionally be beneficial, but will usually result in either a genetic disorder or have no phenotypic effect whatsoever. The natural occurrence of genetic mutations is integral to the process of evolution. A more general term for mutant is sport, which includes individuals who vary from type due to mutation, as well as those who vary from type due to other reasons.
Developmental abnormalities not due to genetic change, are frequently referred to as mutants by non-experts. The difference between a developmental abnormality and a mutation is that the former is non-hereditable as the DNA is unchanged. Such abnormalities include extra limbs and occur when a genetically normal embryo develops abnormally.
Occasionally, a body cell in a healthy organism may acquire a mutation caused by a genetic error occurring during routine cell division. This is also known as a "somatic mutation." Such an error may result in cancer.
Creatures with visibly obvious mutations are often regarded as objects of curiosity. Examples include rare blue lobsters. albinos of many species and animals with extra digits. A well-known mutation in fruit flies causes the flies to have legs in place of antennas. An American aquarium even displays what it calls a "double mutant" snake that is both albino and has two heads, though calling this a double mutation is a misnomer as the two-headed condition is a developmental abnormality and not a genetic mutation.
Similarly striking human mutations also occur occasionally. People who are completely covered in a fur-like coat of hair are one example (see hypertrichosis). There are also cases of newborn babies having an extended tailbone or a sixth finger.
Purely internal, less obvious mutations are more common; a small fraction of these cause serious medical conditions or death. (The ratio is probably under 1.5%, as only about 1.5% of the genome encodes protein genes)
# Wild type
Wild type (sometimes written wildtype, wild-type or +) is the genetic term used in texts for the typical form of an organism, strain, gene, or characteristic as it was first observed in nature. . Wild type refers to the most common phenotype in the natural population, however this may, over a period of time, be replaced by a mutant form, which then becomes the new wildtype. The phenotype can be dominant or recessive. Naturally occurring mutant phenotypes play a role in evolution. | Mutant
A mutant is an individual, organism, or new genetic character arising or resulting from an instance of mutation, which is a sudden structural change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or trait not found in the wildtype. In an organism or individual, the new character or trait may or may not be trivial, may occasionally be beneficial, but will usually result in either a genetic disorder or have no phenotypic effect whatsoever. The natural occurrence of genetic mutations is integral to the process of evolution. A more general term for mutant is sport, which includes individuals who vary from type due to mutation, as well as those who vary from type due to other reasons.
Developmental abnormalities not due to genetic change, are frequently referred to as mutants by non-experts. The difference between a developmental abnormality and a mutation is that the former is non-hereditable as the DNA is unchanged. Such abnormalities include extra limbs and occur when a genetically normal embryo develops abnormally.
Occasionally, a body cell in a healthy organism may acquire a mutation caused by a genetic error occurring during routine cell division. This is also known as a "somatic mutation." Such an error may result in cancer.
Creatures with visibly obvious mutations are often regarded as objects of curiosity. Examples include rare blue lobsters.[1] albinos of many species[2][3] and animals with extra digits.[4] A well-known mutation in fruit flies causes the flies to have legs in place of antennas.[5] An American aquarium even displays what it calls a "double mutant" snake that is both albino and has two heads[6], though calling this a double mutation is a misnomer as the two-headed condition is a developmental abnormality and not a genetic mutation.
Similarly striking human mutations also occur occasionally. People who are completely covered in a fur-like coat of hair are one example (see hypertrichosis). There are also cases of newborn babies having an extended tailbone or a sixth finger.
Purely internal, less obvious mutations are more common; a small fraction of these cause serious medical conditions or death. (The ratio is probably under 1.5%, as only about 1.5% of the genome encodes protein genes)[7]
# Wild type
Wild type (sometimes written wildtype, wild-type or +) is the genetic term used in texts for the typical form of an organism, strain, gene, or characteristic as it was first observed in nature. [8][9]. Wild type refers to the most common phenotype in the natural population, however this may, over a period of time, be replaced by a mutant form, which then becomes the new wildtype. The phenotype can be dominant or recessive. Naturally occurring mutant phenotypes play a role in evolution. | https://www.wikidoc.org/index.php/Mutant | |
c80e16b3aa98576680e93f0035a8368a5cff762e | wikidoc | Myosin | Myosin
# Overview
Myosins are a large family of motor proteins found in eukaryotic tissues. They are responsible for actin-based motility.
# Structure and Function
## Domains
Most myosin molecules are composed of both a head and a tail domain.
- The head domain binds the filamentous actin, and uses ATP hydrolysis to generate force and to "walk" along the filament towards the (+) end (with the exception of one family member, myosin VI, which moves towards the (-) end).
- The tail domain generally mediates interaction with cargo molecules and/or other myosin subunits.
## Myosin I
Myosin I's function is unknown, but it is believed to be responsible for vesicle transport or the contraction vacuole of cells.
## Myosin II
Myosin II, responsible for skeletal muscle contraction, is perhaps the best-studied example of these properties.
- Myosin II contains two heavy chains, each about 2000 amino acids in length, which constitute the head and tail domains. Each of these heavy chains contains the N-terminal head domain, while the C-terminal tails take on a coiled-coil morphology, holding the two heavy chains together (imagine two snakes wrapped around each other, such as in a caduceus). Thus, myosin II has two heads.
- It also contains 4 light chains (2 per head), which bind the heavy chains in the "neck" region between the head and tail.
In muscle cells, it is myosin II that is responsible for producing the contractile force. Here, the long coiled-coil tails of the individual myosin molecules join together, forming the thick filaments of the sarcomere. The force-producing head domains stick out from the side of the thick filament, ready to walk along the adjacent actin-based thin filaments in response to the proper chemical signals.
# Evolution and Family Tree
Myosin II, the most conspicuous of the myosin superfamily due to its abundance in muscle fibers, was the first to be discovered. However, beginning in the 1970s researchers began to discover new myosin variants, with one head (as opposed to myosin II's two) and largely divergent tail domains. These new superfamily members have been grouped according to their structural similarities, with each subfamily being assigned a Roman numeral. The now diverse array of myosins has evolved from an ancestral precursor (see picture).
Analysis of the amino acid sequences of different myosins shows great variability among the tail domains but almost perfect retention of the same head sequence. Presumably this is so the myosins may interact, via their tails, with a large number of different cargoes, while the goal in each case - to move along actin filaments - remains the same and therefore requires the same machinery in the motor. For example, the human genome contains over 40 different myosin genes.
These differences in shape also determine the speed at which myosins can move along actin filaments. The hydrolysis of ATP and the subsequent release of the phosphate group causes the "power stroke," in which the "lever arm" or "neck" region of the heavy chain is dragged forward. Since the power stroke always moves the lever arm by the same angle, the length of the lever arm determines how fast the cargo will move. A longer lever arm will cause the cargo to traverse a greater distance even though the lever arm undergoes the same angular displacement - just as a person with longer legs can move farther with each individual step. Myosin V, for example, has a much longer neck region than myosin II, and therefore moves 30-40 nanometers with each stroke as opposed to only 5-10.
# Genes in humans
Note that not all of these genes are active.
- Family I: MYO1A, MYO1B, MYO1C, MYO1D, MYO1E, MYO1F, MYO1G, MYO1H
- Family III: MYO3A, MYO3B
- Family V: MYO5A, MYO5B, MYO5C
- Family VI: MYO6
- Family VII: MYO7A, MYO7B
- Family IX: MYO9A, MYO9B, MYO10
- Family XV: MYO15A
- Family XVIII: MYO18A, MYO18B
- Heavy chain: MYH1, MYH2, MYH3, MYH4, MYH6, MYH7, MYH7B, MYH8, MYH9, MYH10, MYH11, MYH13, MYH14, MYH15, MYH16. See also MYH7.
- Light chain: MYL1, MYL2, MYL3, MYL4, MYL5, MYL6, MYL6B, MYL7, MYL9, MYLIP, MYLK, MYLK2, MYLL1 | Myosin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Myosins are a large family of motor proteins found in eukaryotic tissues. They are responsible for actin-based motility.
# Structure and Function
## Domains
Most myosin molecules are composed of both a head and a tail domain.
- The head domain binds the filamentous actin, and uses ATP hydrolysis to generate force and to "walk" along the filament towards the (+) end (with the exception of one family member, myosin VI, which moves towards the (-) end).
- The tail domain generally mediates interaction with cargo molecules and/or other myosin subunits.
## Myosin I
Myosin I's function is unknown, but it is believed to be responsible for vesicle transport or the contraction vacuole of cells.[1]
## Myosin II
Myosin II, responsible for skeletal muscle contraction, is perhaps the best-studied example of these properties.
- Myosin II contains two heavy chains, each about 2000 amino acids in length, which constitute the head and tail domains. Each of these heavy chains contains the N-terminal head domain, while the C-terminal tails take on a coiled-coil morphology, holding the two heavy chains together (imagine two snakes wrapped around each other, such as in a caduceus). Thus, myosin II has two heads.
- It also contains 4 light chains (2 per head), which bind the heavy chains in the "neck" region between the head and tail.
In muscle cells, it is myosin II that is responsible for producing the contractile force. Here, the long coiled-coil tails of the individual myosin molecules join together, forming the thick filaments of the sarcomere. The force-producing head domains stick out from the side of the thick filament, ready to walk along the adjacent actin-based thin filaments in response to the proper chemical signals.
# Evolution and Family Tree
Myosin II, the most conspicuous of the myosin superfamily due to its abundance in muscle fibers, was the first to be discovered. However, beginning in the 1970s researchers began to discover new myosin variants, with one head (as opposed to myosin II's two) and largely divergent tail domains. These new superfamily members have been grouped according to their structural similarities, with each subfamily being assigned a Roman numeral. The now diverse array of myosins has evolved from an ancestral precursor (see picture).
Analysis of the amino acid sequences of different myosins shows great variability among the tail domains but almost perfect retention of the same head sequence. Presumably this is so the myosins may interact, via their tails, with a large number of different cargoes, while the goal in each case - to move along actin filaments - remains the same and therefore requires the same machinery in the motor. For example, the human genome contains over 40 different myosin genes.
These differences in shape also determine the speed at which myosins can move along actin filaments. The hydrolysis of ATP and the subsequent release of the phosphate group causes the "power stroke," in which the "lever arm" or "neck" region of the heavy chain is dragged forward. Since the power stroke always moves the lever arm by the same angle, the length of the lever arm determines how fast the cargo will move. A longer lever arm will cause the cargo to traverse a greater distance even though the lever arm undergoes the same angular displacement - just as a person with longer legs can move farther with each individual step. Myosin V, for example, has a much longer neck region than myosin II, and therefore moves 30-40 nanometers with each stroke as opposed to only 5-10.
# Genes in humans
Note that not all of these genes are active.
- Family I: MYO1A, MYO1B, MYO1C, MYO1D, MYO1E, MYO1F, MYO1G, MYO1H
- Family III: MYO3A, MYO3B
- Family V: MYO5A, MYO5B, MYO5C
- Family VI: MYO6
- Family VII: MYO7A, MYO7B
- Family IX: MYO9A, MYO9B, MYO10
- Family XV: MYO15A
- Family XVIII: MYO18A, MYO18B
- Heavy chain: MYH1, MYH2, MYH3, MYH4, MYH6, MYH7, MYH7B, MYH8, MYH9, MYH10, MYH11, MYH13, MYH14, MYH15, MYH16. See also MYH7.
- Light chain: MYL1, MYL2, MYL3, MYL4, MYL5, MYL6, MYL6B, MYL7, MYL9, MYLIP, MYLK, MYLK2, MYLL1 | https://www.wikidoc.org/index.php/Myosin | |
bce904b92c0aff6a1f0885f32003b9b29462c02e | wikidoc | NBEAL1 | NBEAL1
NBEAL1 is a protein that in humans is encoded by the NBEAL1 gene. It is found on chromosome 2q33.2 of Homo sapiens.
Through the different domains of this protein, the function of NBEAL1 is predicted to be involved in the following cellular mechanisms: vesicle trafficking, membrane dynamics, receptor signaling, pre-mRNA processing, signal transduction and cytoskeleton assembly. NBEAL1 is also known as Amytorophic Lateral Sclerosis 2 Chromosomal Region, ALS2CR16 and ALS2CR17.
# Protein Properties
## Transcript
The mRNA for this protein consists of 9058 base pairs in a linear sequence with the coding sequence begins at base pair number 334 and extends until base pair number 8418. The translated protein is a total 56 exons that constitute a final length of 2694 amino acids. There are currently 9 known isoforms within humans.
### Domains
Neurobeachin-like1 contains five domains: DUF4704, DUF4800, PH_BEACH, Beach, and WD40 repeats.
DUF4704 is a domain of unknown function. While the function of this domain is unknown, it is conserved within neurobeachin proteins in eukaryotes. It begins at amino acid 859 and spans until number 1115.
DUF4800 is a domain of unknown function. It begins at amino acid 1580, spanning until 1833. While it is uncharacterized in function, it is found within eukaryotes.
Spanning from amino acid 1886 until amino acid 1983, this domain is referred to as a Pleckstrin Homology domain in the BEACH domain. It has a PH because the fold of this domain is similar to the PH domain, but is not identical in the sequence of the canonical PH domains. The PH_BEACH domain is not able to bind phospholipids.
The Beige and Chediak-Higashi (BEACH) domain is one of the most significant domains within this protein. This domain is highly conserved roughly 280 amino acid domain, present in nine different human BEACH domains. It located after the PH_BEACH domain in the sequence. While not much is understood on the exact function of BDCP proteins within the BEACH domain, it is known that they serve many purposes within cellular mechanisms: vesicular transport, apoptosis, membrane dynamics and receptor signaling. This protein family is of great clinical importance currently because mutations in this domain have been identified in multiple human disorders. For example, neurobeachin-like1 is upregulated in glioma: as the pathological grade of the glioma increases, the expression of neurobeachin-like1 is decreased. In NBEAL1, this follows the PH_BEACH domain, beginning at amino acid 2005 and ending at amino acid 2284.
NBEAL1 has one WD40 domain within NBEAL1. From amino acid 2409 to 2682 is the entire WD40 domain. Within the domain, from 2406 to 2439, there is a structural motif WD40 repeat. The WD40 domain is found in a number of eukaryotic proteins that have multiple functions. These include, but are not limited to, adaptor/regulatory modules in signal transduction, pre-mRNA processing, and cytoskeleton assembly.
## Properties
- Molecular weight of 307.3 kilo Daltons
- Predicted to be localized to the mitochondria
# Structure
## Secondary
The secondary structure of NBEAL1 is predicted to be a combination of alpha helices, beta sheets and random coils.
## Tertiary
I-TASSER was used to predict a 3D structure of NBEAL1. Since NBEAL1 is longer in amino acid length than allowed for input, it was split in half to predict the structure of the whole protein.
## Post-Translational Modifications
The following document illustrates the different post-translational modifications.
# Expression
Using the EST abundance profile through Unigene, NBEAL1 expression was discovered based on both body sites and health states. NBEAL1 shows expression in the brain, embryonic tissue, eye, intestine, kidney, liver, lung, mammary glands, ovaries, pancreas, pharynx, placenta, prostate, skin, stomach, testis, thyroid, and trachea. Based on transcripts per million, expression is highest in the stomach at 62 transcripts per million, with pancreas and trachea being next with their transcripts per million being 37 and 38, respectively. The lowest transcripts per million in the brain, eye, placenta and testis, all at 4 per million. When looking at the breakdown by different health states, NBEAL1 is highly expressed in multiple tumors. Again, the abundance was highest in gastrointestinal tumors, correlating to the high expression of NBEAL1 within the stomach. However, NBEAL1 expression is not seen in pancreatic tumors, which may signify something about its function within the pancreas. The abundance also differs in developmental stages, the highest being the fetal stage with 21 transcripts per million and the adult at 14 transcripts per million.
# Function
The function of NBEAL1 is not yet well understood by the scientific community. However, given the function of the different domains and disease associations, it is predicted that the NBEAL1 protein may be involved in a variety of functions. As of now they include, but are not limited to, protein-protein interactions, vesicle trafficking, membrane dynamics, receptor signaling, apoptosis, adaptor/regulatory modules in signal transduction, pre-mRNA processing, and cytoskeleton assembly.
# Clinical Significance
This protein has been associated with NBEAL1 are Amyotrophic Lateral Sclerosis, Juvenile and Adenocarcinoma, although the function in these diseases has not yet been identified.
# Homology
Neurobeachin-like1 is a highly conserved protein. It has orthologs found in many life forms, including but not limited to: reptiles, birds, amphibians, mammals, fish, and a few invertebrates. The following table presents some of the orthologs found using searches in BLAST and BLAT.
## Paralogs
According to GeneCards, NBEAL1 has a few paralogs: NBEAL2, WDFY3, NBEA, LRBA, Lysosomal trafficking regulator (LYST), and WDFY3. The table below summarizes the paralogs of NBEAL1. | NBEAL1
NBEAL1 is a protein that in humans is encoded by the NBEAL1 gene.[1] It is found on chromosome 2q33.2 of Homo sapiens.
Through the different domains of this protein, the function of NBEAL1 is predicted to be involved in the following cellular mechanisms: vesicle trafficking, membrane dynamics, receptor signaling, pre-mRNA processing, signal transduction and cytoskeleton assembly.[2][3][4] NBEAL1 is also known as Amytorophic Lateral Sclerosis 2 Chromosomal Region, ALS2CR16 and ALS2CR17.[1]
# Protein Properties
## Transcript
The mRNA for this protein consists of 9058 base pairs in a linear sequence with the coding sequence begins at base pair number 334 and extends until base pair number 8418.[5] The translated protein is a total 56 exons that constitute a final length of 2694 amino acids.[6] There are currently 9 known isoforms within humans.[3]
### Domains
Neurobeachin-like1 contains five domains: DUF4704, DUF4800, PH_BEACH, Beach, and WD40 repeats.[6]
DUF4704 is a domain of unknown function. While the function of this domain is unknown, it is conserved within neurobeachin proteins in eukaryotes.[4] It begins at amino acid 859 and spans until number 1115.[3]
DUF4800 is a domain of unknown function. It begins at amino acid 1580, spanning until 1833.[3] While it is uncharacterized in function, it is found within eukaryotes.[7]
Spanning from amino acid 1886 until amino acid 1983, this domain is referred to as a Pleckstrin Homology domain in the BEACH domain.[8] It has a PH because the fold of this domain is similar to the PH domain, but is not identical in the sequence of the canonical PH domains. The PH_BEACH domain is not able to bind phospholipids.[9]
The Beige and Chediak-Higashi (BEACH) domain is one of the most significant domains within this protein. This domain is highly conserved roughly 280 amino acid domain, present in nine different human BEACH domains.[10] It located after the PH_BEACH domain in the sequence. While not much is understood on the exact function of BDCP proteins within the BEACH domain, it is known that they serve many purposes within cellular mechanisms: vesicular transport, apoptosis, membrane dynamics and receptor signaling.[10] This protein family is of great clinical importance currently because mutations in this domain have been identified in multiple human disorders. For example, neurobeachin-like1 is upregulated in glioma: as the pathological grade of the glioma increases, the expression of neurobeachin-like1 is decreased.[2] In NBEAL1, this follows the PH_BEACH domain, beginning at amino acid 2005 and ending at amino acid 2284.[3]
NBEAL1 has one WD40 domain within NBEAL1. From amino acid 2409 to 2682 is the entire WD40 domain. Within the domain, from 2406 to 2439, there is a structural motif WD40 repeat. The WD40 domain is found in a number of eukaryotic proteins that have multiple functions. These include, but are not limited to, adaptor/regulatory modules in signal transduction, pre-mRNA processing, and cytoskeleton assembly.[3]
## Properties
- Molecular weight of 307.3 kilo Daltons[11]
- Predicted to be localized to the mitochondria[12]
# Structure
## Secondary
The secondary structure of NBEAL1 is predicted to be a combination of alpha helices, beta sheets and random coils.[13]
## Tertiary
I-TASSER was used to predict a 3D structure of NBEAL1.[14] Since NBEAL1 is longer in amino acid length than allowed for input, it was split in half to predict the structure of the whole protein.
## Post-Translational Modifications
The following document illustrates the different post-translational modifications.
# Expression
Using the EST abundance profile through Unigene, NBEAL1 expression was discovered based on both body sites and health states.[15] NBEAL1 shows expression in the brain, embryonic tissue, eye, intestine, kidney, liver, lung, mammary glands, ovaries, pancreas, pharynx, placenta, prostate, skin, stomach, testis, thyroid, and trachea. Based on transcripts per million, expression is highest in the stomach at 62 transcripts per million, with pancreas and trachea being next with their transcripts per million being 37 and 38, respectively. The lowest transcripts per million in the brain, eye, placenta and testis, all at 4 per million. When looking at the breakdown by different health states, NBEAL1 is highly expressed in multiple tumors.[15] Again, the abundance was highest in gastrointestinal tumors, correlating to the high expression of NBEAL1 within the stomach. However, NBEAL1 expression is not seen in pancreatic tumors, which may signify something about its function within the pancreas. The abundance also differs in developmental stages, the highest being the fetal stage with 21 transcripts per million and the adult at 14 transcripts per million.
# Function
The function of NBEAL1 is not yet well understood by the scientific community. However, given the function of the different domains and disease associations, it is predicted that the NBEAL1 protein may be involved in a variety of functions. As of now they include, but are not limited to, protein-protein interactions, vesicle trafficking, membrane dynamics, receptor signaling, apoptosis, adaptor/regulatory modules in signal transduction, pre-mRNA processing, and cytoskeleton assembly.[3][2]
# Clinical Significance
This protein has been associated with NBEAL1 are Amyotrophic Lateral Sclerosis, Juvenile and Adenocarcinoma,[1] although the function in these diseases has not yet been identified.
# Homology
Neurobeachin-like1 is a highly conserved protein. It has orthologs found in many life forms, including but not limited to: reptiles, birds, amphibians, mammals, fish, and a few invertebrates. The following table presents some of the orthologs found using searches in BLAST[16] and BLAT.[17]
## Paralogs
According to GeneCards, NBEAL1 has a few paralogs: NBEAL2, WDFY3, NBEA, LRBA, Lysosomal trafficking regulator (LYST), and WDFY3.[19] The table below summarizes the paralogs of NBEAL1. | https://www.wikidoc.org/index.php/NBEAL1 | |
eb38f43285a1844751dcd95d0bde507c87f180ae | wikidoc | NBEAL2 | NBEAL2
Neurobeachin-like 2 is a protein that in humans is encoded by the NBEAL2 gene.
# Function
The protein encoded by this gene contains a beige and Chediak-Higashi (BEACH) domain and multiple WD40 domains, and may play a role in megakaryocyte alpha-granule biogenesis.
# Clinical relevance
Mutation in this gene have been shown to cause gray platelet syndrome. | NBEAL2
Neurobeachin-like 2 is a protein that in humans is encoded by the NBEAL2 gene.[1]
# Function
The protein encoded by this gene contains a beige and Chediak-Higashi (BEACH) domain and multiple WD40 domains, and may play a role in megakaryocyte alpha-granule biogenesis.[1]
# Clinical relevance
Mutation in this gene have been shown to cause gray platelet syndrome.[2] | https://www.wikidoc.org/index.php/NBEAL2 | |
80fe86fc922f4db811874a2c20796fd39743a22d | wikidoc | NBPF10 | NBPF10
Neuroblastoma breakpoint family member 10 is a protein that in Homo sapiens is encoded by the NBPF10 gene.
The full gene is 75,313 bp, with the major isoform of mRNA being 10,697 bp long. The gene is located at 1q21.1. NBPF contains what is known as the DUF1220 repeats. The highly conserved, repeated region is believed to be originated from MGC8902. The NBPF family has been linked to primate evolution. It is assumed to be related to the 1q21.1 deletion syndrome and 1q21.1 duplication syndrome.
# Homology
Paralogs of NBPF10 includes other NBPF family members.
Orthologs of NBPF10 are found in other primates; distant orthologs are found in bovine, equine, and canine
NBPF10 paralogs and orthologs unrooted phylogenetic tree
# Functional role
Although NBPF10's function is unknown, there is reason to believe that NBPF10 is an important biomarker for the Odontoblast Phenotype
# Gene Neighborhood
NOTCH2NL, SEC22B, HFE2, TXNIP are close neighbors of NBPF10. All of these neighboring genes are well studied in their own right.
NBPF10's chromosomal location
# Post-translational modification
NBPF10 has extremely low threonine content which may make the protein less susceptible to post-translational modification. | NBPF10
Neuroblastoma breakpoint family member 10 is a protein that in Homo sapiens is encoded by the NBPF10 gene.[1][2]
The full gene is 75,313 bp, with the major isoform of mRNA being 10,697 bp long. The gene is located at 1q21.1. NBPF contains what is known as the DUF1220 repeats. The highly conserved, repeated region is believed to be originated from MGC8902. The NBPF family has been linked to primate evolution.[2] It is assumed to be related to the 1q21.1 deletion syndrome and 1q21.1 duplication syndrome.[3]
# Homology
Paralogs of NBPF10 includes other NBPF family members.
Orthologs of NBPF10 are found in other primates; distant orthologs are found in bovine, equine, and canine
NBPF10 paralogs and orthologs unrooted phylogenetic tree
# Functional role
Although NBPF10's function is unknown, there is reason to believe that NBPF10 is an important biomarker for the Odontoblast Phenotype[4]
# Gene Neighborhood
NOTCH2NL, SEC22B, HFE2, TXNIP are close neighbors of NBPF10. All of these neighboring genes are well studied in their own right.
NBPF10's chromosomal location
# Post-translational modification
NBPF10 has extremely low threonine content which may make the protein less susceptible to post-translational modification.[citation needed] | https://www.wikidoc.org/index.php/NBPF10 | |
5df3c27fc0ff41479288b412303ceac8e7a5c6d9 | wikidoc | NBPF16 | NBPF16
Neuroblastoma Breakpoint Family, Member 16, also known as NBPF16, is a protein which in humans is encoded by the NBPF16 gene. The gene is 18762 bp long, with mRNA that is 3837 bp long. The gene is located on chromosome 1q21.1. Its sub-cellular location is predicted to be in the nucleus and cytoplasm. It contains what is known as the NBPF repeat, which is a two exon stretch of sequence that is characteristic of all 21 members of the NBPF gene family. The repeat is considered the ancestral exons, and the NBPF family has been linked to primate evolution.
# Function
The function of NBPF16 is not fully understood. It is a member of the NBPF family of proteins, which have been linked to possible roles in oncogenesis and tumor suppressor genes.
# Protein
The protein is composed of 670 amino acids. The gene contains five domains of unknown function, called DUF1220. DUF1220 domains are found in all members of the NBPF gene family, although the number differs between each member. Repetitive structure with high intergenic and intragenic sequence conservation, both in coding and noncoding regions. Makes it possible for homologous recombination to occur easily between different alleles. The repetitiveness of it, and the other members of the NBPF gene family is thought to have arisen from segmental duplications on chromosome 1.
## Predicted properties
Properties of NBPF16 that were predicted using Bioinformatics tools:
- Molecular Weight: 76 kD
- Isoelectric point: 4.43
- Post-translational modification: None predicted.
- No predicted Signal Peptide or signal peptide cleavage site.
- No interacting proteins or binding partners.
## Expression
There is little to no expression data available for the gene, but most indications point to it being ubiquitously expressed throughout the body.
# Homology
## Orthologs
There exists no great orthologs outside of primates. These orthologs were gathered from BLAT. and BLAST searches
## Paralogs
Due to there being 21 other members of the NBPF gene family, there are 21 paralogs of NBPF16. They all show high conservation and repetitive structures. | NBPF16
Neuroblastoma Breakpoint Family, Member 16, also known as NBPF16, is a protein which in humans is encoded by the NBPF16 gene.[1] The gene is 18762 bp long, with mRNA that is 3837 bp long. The gene is located on chromosome 1q21.1. Its sub-cellular location is predicted to be in the nucleus and cytoplasm.[2] It contains what is known as the NBPF repeat, which is a two exon stretch of sequence that is characteristic of all 21 members of the NBPF gene family. The repeat is considered the ancestral exons, and the NBPF family has been linked to primate evolution.[3]
# Function
The function of NBPF16 is not fully understood. It is a member of the NBPF family of proteins, which have been linked to possible roles in oncogenesis and tumor suppressor genes.[3]
# Protein
The protein is composed of 670 amino acids. The gene contains five domains of unknown function, called DUF1220. DUF1220 domains are found in all members of the NBPF gene family, although the number differs between each member. Repetitive structure with high intergenic and intragenic sequence conservation, both in coding and noncoding regions. Makes it possible for homologous recombination to occur easily between different alleles. The repetitiveness of it, and the other members of the NBPF gene family is thought to have arisen from segmental duplications on chromosome 1.[3]
## Predicted properties
Properties of NBPF16 that were predicted using Bioinformatics tools:
- Molecular Weight: 76 kD[4]
- Isoelectric point: 4.43[5]
- Post-translational modification: None predicted.
- No predicted Signal Peptide or signal peptide cleavage site.[6]
- No interacting proteins or binding partners.
## Expression
There is little to no expression data available for the gene, but most indications point to it being ubiquitously expressed throughout the body.
# Homology
## Orthologs
There exists no great orthologs outside of primates. These orthologs were gathered from BLAT.[7] and BLAST searches[8]
## Paralogs
Due to there being 21 other members of the NBPF gene family, there are 21 paralogs of NBPF16. They all show high conservation and repetitive structures. | https://www.wikidoc.org/index.php/NBPF16 | |
ac6a39e770d2d2945dd47144827176a21a5b6798 | wikidoc | NBPF19 | NBPF19
Neuroblastoma breakpoint family member 19, or NBPF19, is a protein that in humans is encoded by the NBPF19 gene. This protein is included in the neuroblastoma breakpoint family of proteins.
# Gene
The NBPF19 gene is a protein-encoding gene in humans. It is composed of 80,464 bases including all introns and exons. It is located on the positive strand of chromosome 1 at locus 1q21.2.
## Expression
EST profiling of NBPF19 shows it to be ubiquitously expressed in most human tissues at unremarkable amounts. It is expressed in relatively higher amounts in the skin, lymphoid organs (lymph nodes, spleen) and the gonads (ovary, testes).
## Transcript
The mRNA transcript of NBPF19 in humans is 13,190 bases long. There are 2 predicted alternative splicing isoforms, although none have been experimentally observed.
# Protein
The protein product of the NBPF19 transcript is composed of 3,843 amino acids and weights 440.5 kD. It contains 45 DUF1220 domains of unknown function but that have been linked to evolutionary changes and generally decrease in number in species increasingly evolutionarily distant from humans.
## Structure
NBPF19 is expected to undergo many post-translational modifications, most notably phosphorylation and sumoylation. The protein is extensively phosphorylated on serine, threonine and tyrosine residues in a repetitive pattern seen in the figure to the left. There are 14 predicted repeats within the protein sequence likely to be sites of sumoylation.
The tertiary structure of NBPF19 is predicted to be roughly 50% coiled-coil and 40% alpha helical. There is no presence of a signal peptide or any transmembrane domains. NBPF19 is likely localized to the nucleus due to the presence of a nuclear localization signal near its 5' terminus.
# Homology
NBPF19 is one of 26 identified members of the neuroblastoma breakpoint family of proteins in humans. Sequence similarity among these proteins is largely limited to conservation of DUF1220 domains. The most highly-similar paralogs are listed below:
NBPF19 is not well conserved outside of humans and any notable conservation does not extend past primates and mammals. Select species possess short sequences of similarity and are listed below:
- Pan troglodytes (common chimpanzee)
- Pongo abelii (Sumatran orangutan)
- Piliocolobus tephrosceles (Ugandan red colobus)
- Bos taurus (cow)
- Felis catus (cat)
- Camelus ferus (Bactrian camel)
- Sus scrofa (wild boar)
- Equus asinus (donkey) | NBPF19
Neuroblastoma breakpoint family member 19, or NBPF19, is a protein that in humans is encoded by the NBPF19 gene.[1] This protein is included in the neuroblastoma breakpoint family of proteins.[2]
# Gene
The NBPF19 gene is a protein-encoding gene in humans. It is composed of 80,464 bases including all introns and exons. It is located on the positive strand of chromosome 1 at locus 1q21.2.[3]
## Expression
EST profiling of NBPF19 shows it to be ubiquitously expressed in most human tissues at unremarkable amounts. It is expressed in relatively higher amounts in the skin, lymphoid organs (lymph nodes, spleen) and the gonads (ovary, testes).[3]
## Transcript
The mRNA transcript of NBPF19 in humans is 13,190 bases long.[5] There are 2 predicted alternative splicing isoforms, although none have been experimentally observed.[6]
# Protein
The protein product of the NBPF19 transcript is composed of 3,843 amino acids and weights 440.5 kD.[6][7] It contains 45 DUF1220 domains of unknown function but that have been linked to evolutionary changes and generally decrease in number in species increasingly evolutionarily distant from humans.[8]
## Structure
NBPF19 is expected to undergo many post-translational modifications, most notably phosphorylation and sumoylation. The protein is extensively phosphorylated on serine, threonine and tyrosine residues in a repetitive pattern seen in the figure to the left.[9] There are 14 predicted repeats within the protein sequence likely to be sites of sumoylation.[10]
The tertiary structure of NBPF19 is predicted to be roughly 50% coiled-coil and 40% alpha helical.[11] There is no presence of a signal peptide or any transmembrane domains.[12] NBPF19 is likely localized to the nucleus due to the presence of a nuclear localization signal near its 5' terminus.[13]
# Homology
NBPF19 is one of 26 identified members of the neuroblastoma breakpoint family of proteins in humans. Sequence similarity among these proteins is largely limited to conservation of DUF1220 domains.[6] The most highly-similar paralogs are listed below:
NBPF19 is not well conserved outside of humans and any notable conservation does not extend past primates and mammals.[14] Select species possess short sequences of similarity and are listed below:
- Pan troglodytes (common chimpanzee)
- Pongo abelii (Sumatran orangutan)
- Piliocolobus tephrosceles (Ugandan red colobus)
- Bos taurus (cow)
- Felis catus (cat)
- Camelus ferus (Bactrian camel)
- Sus scrofa (wild boar)
- Equus asinus (donkey) | https://www.wikidoc.org/index.php/NBPF19 | |
580007a90ef881781c7518ad33c0f815aac664d4 | wikidoc | NDUFA2 | NDUFA2
NADH dehydrogenase 1 alpha subcomplex subunit 2 is a protein that in humans is encoded by the NDUFA2 gene. The NDUFA2 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in the NDUFA2 gene are associated with Leigh's syndrome.
# Structure
The NDUFA2 gene is located on the long (q) arm of chromosome 5 at position 31.2 and it spans 2,422 base pairs. The NDUFA2 gene produces an 11 kDa protein composed of 99 amino acids. NDUFA2 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. NDUFA2 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH:ubiquinone oxidoreductase complex at the inner mitochondrial membrane.
# Function
The human NDUFA2 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. NDUFA2 is an accessory subunit of Complex I that is believed not to be involved in catalysis but may be involved in regulating Complex I activity or its assembly via assistance in redox processes. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.
# Clinical significance
Mutations in the NDUFA2 gene can result in Leigh's syndrome, a severe neurological disorder that typically arises in the first year of life. One such mutation interferes with normal splicing patterns and results in exon 2 being skipped. This causes a reduction in Complex I activity and disturbs its assembly. The NDUFA2 mutation is also associated with the depolarization of the mitochondria.
# Interactions
NDUFA2 has many protein interactions, including interactions with other members of the NADH dehydrogenase 1 alpha subcomplex, other subunits of Complex I as well as with redox proteins. This may be due to its potential role in Complex I assembly and assistance in redox processes. | NDUFA2
NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 is a protein that in humans is encoded by the NDUFA2 gene.[1][2] The NDUFA2 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[3] Mutations in the NDUFA2 gene are associated with Leigh's syndrome.[2]
# Structure
The NDUFA2 gene is located on the long (q) arm of chromosome 5 at position 31.2 and it spans 2,422 base pairs.[2] The NDUFA2 gene produces an 11 kDa protein composed of 99 amino acids.[4][5] NDUFA2 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[3] NDUFA2 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH:ubiquinone oxidoreductase complex at the inner mitochondrial membrane.[2]
# Function
The human NDUFA2 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. NDUFA2 is an accessory subunit of Complex I that is believed not to be involved in catalysis but may be involved in regulating Complex I activity or its assembly via assistance in redox processes.[2][6] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[3]
# Clinical significance
Mutations in the NDUFA2 gene can result in Leigh's syndrome, a severe neurological disorder that typically arises in the first year of life.[2] One such mutation interferes with normal splicing patterns and results in exon 2 being skipped. This causes a reduction in Complex I activity and disturbs its assembly. The NDUFA2 mutation is also associated with the depolarization of the mitochondria.[7]
# Interactions
NDUFA2 has many protein interactions, including interactions with other members of the NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, other subunits of Complex I as well as with redox proteins. This may be due to its potential role in Complex I assembly and assistance in redox processes.[2] | https://www.wikidoc.org/index.php/NDUFA2 | |
4fe0333db6b019050c0670db4fa92e84b371ad5f | wikidoc | NDUFA3 | NDUFA3
NADH dehydrogenase 1 alpha subcomplex subunit 3 is a protein that in humans is encoded by the NDUFA3 gene. The NDUFA3 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.
# Structure
The NDUFA3 gene is located on the q arm of chromosome 19 at position 13.42, and it has a total span of 4,123 base pairs. The NDUFA3 gene produces an 9.3 kDa protein composed of 84 amino acids. NDUFA3 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. NDUFA3 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH:ubiquinone oxidoreductase complex at the inner mitochondrial membrane.
# Function
The human NDUFA3 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. However, NDUFA3 is an accessory subunit of the complex that is believed not to be involved in catalysis. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.
# Interactions
NDUFA3 has been shown to interact with ubiquitin C, a polyubiquitin precursor. | NDUFA3
NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3 is a protein that in humans is encoded by the NDUFA3 gene.[1] The NDUFA3 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[2]
# Structure
The NDUFA3 gene is located on the q arm of chromosome 19 at position 13.42, and it has a total span of 4,123 base pairs.[1] The NDUFA3 gene produces an 9.3 kDa protein composed of 84 amino acids.[3][4] NDUFA3 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[2] NDUFA3 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH:ubiquinone oxidoreductase complex at the inner mitochondrial membrane.[1]
# Function
The human NDUFA3 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone.[1] However, NDUFA3 is an accessory subunit of the complex that is believed not to be involved in catalysis.[5] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[2]
# Interactions
NDUFA3 has been shown to interact with ubiquitin C, a polyubiquitin precursor.[1][6] | https://www.wikidoc.org/index.php/NDUFA3 | |
271a53fb61d79b57ab5a31fbcaed1d37c230f488 | wikidoc | NDUFA4 | NDUFA4
NDUFA4, mitochondrial complex associated is a protein that in humans is encoded by the NDUFA4 gene. The NDUFA3 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in the NDUFA4 gene are associated with Leigh's syndrome.
# Structure
The NDUFA4 gene is located on the p arm of chromosome 7 at position 21.3 with a total length of 8,234 base pairs. The NDUFA4 gene produces a 9.4 kDa protein composed of 81 amino acids.
NDUFA4 has traditionally been defined as a subunit of the enzyme NADH dehydrogenase (ubiquinone) (Complex I), the largest of the respiratory complexes. The structure of Complex I is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH:ubiquinone oxidoreductase complex at the inner mitochondrial membrane.
More recent research has demonstrated that no perturbation of Complex I occurs upon NDUFA4 deletion, calling into question its role in this complex. It has been demonstrated that NDUFA4 plays a role in Complex IV function and biogenesis, however, with some authors suggesting that the NDUFA4 gene be renamed and the structure of both Complex I and Complex IV be re-evaluated.
# Function
The human NDUFA1 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. Mammalian complex I of mitochondrial respiratory chain is composed of 45 different subunits; the protein encoded by this gene belongs to the complex I 9kDa subunit family and it has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.
# Clinical significance
Mutations in the NDUFA4 gene can result in Leigh's syndrome, a severe neurological disorder that typically arises in the first year of life. Disruption of Complex IV, also called cytochrome c oxidase or COX, is the most common cause of Leigh syndrome. Given that NDUFA4 has only recently been identified as a subunit of Complex IV rather than Complex I, patients with previously unexplained COX deficiencies could be genetically tested for NDUFA4 mutations.
# Interactions
NDUFA4 has many protein-protein interactions, including ubiquitin proteins such as ubiquitin C and UBL4A, as well as CUL3 and PARK7. | NDUFA4
NDUFA4, mitochondrial complex associated is a protein that in humans is encoded by the NDUFA4 gene.[1] The NDUFA3 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[2] Mutations in the NDUFA4 gene are associated with Leigh's syndrome.[1]
# Structure
The NDUFA4 gene is located on the p arm of chromosome 7 at position 21.3 with a total length of 8,234 base pairs.[1] The NDUFA4 gene produces a 9.4 kDa protein composed of 81 amino acids.[3][4]
NDUFA4 has traditionally been defined as a subunit of the enzyme NADH dehydrogenase (ubiquinone) (Complex I), the largest of the respiratory complexes. The structure of Complex I is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[2] It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH:ubiquinone oxidoreductase complex at the inner mitochondrial membrane.[1]
More recent research has demonstrated that no perturbation of Complex I occurs upon NDUFA4 deletion, calling into question its role in this complex. It has been demonstrated that NDUFA4 plays a role in Complex IV function and biogenesis, however, with some authors suggesting that the NDUFA4 gene be renamed and the structure of both Complex I and Complex IV be re-evaluated.[5]
# Function
The human NDUFA1 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. Mammalian complex I of mitochondrial respiratory chain is composed of 45 different subunits; the protein encoded by this gene belongs to the complex I 9kDa subunit family and it has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain.[1] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[2]
# Clinical significance
Mutations in the NDUFA4 gene can result in Leigh's syndrome, a severe neurological disorder that typically arises in the first year of life. Disruption of Complex IV, also called cytochrome c oxidase or COX, is the most common cause of Leigh syndrome. Given that NDUFA4 has only recently been identified as a subunit of Complex IV rather than Complex I, patients with previously unexplained COX deficiencies could be genetically tested for NDUFA4 mutations.[1][6][7]
# Interactions
NDUFA4 has many protein-protein interactions, including ubiquitin proteins such as ubiquitin C and UBL4A, as well as CUL3 and PARK7.[1] | https://www.wikidoc.org/index.php/NDUFA4 | |
8e84ea6bed6482a1fdb4decf44c58d5c622f5ea6 | wikidoc | NDUFA5 | NDUFA5
NADH dehydrogenase 1 alpha subcomplex subunit 5 is an enzyme that in humans is encoded by the NDUFA5 gene. The NDUFA5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.
# Structure
The NDUFA5 gene is located on the q arm of chromosome 7 and it spans 64,655 base pairs. The gene produces a 13.5 kDa protein composed of 116 amino acids. NDUFA5 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane. NDUFA5 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. The protein localizes to the inner mitochondrial membrane as part of the 7 component-containing, water-soluble iron-sulfur protein (IP) fraction of complex I, although its specific role is unknown. It is assumed to undergo post-translational removal of the initiator methionine and N-acetylation of the next amino acid. The predicted secondary structure is primarily alpha helix, but the carboxy-terminal half of the protein has high potential to adopt a coiled-coil form. The amino-terminal part contains a putative beta sheet rich in hydrophobic amino acids that may serve as mitochondrial import signal. Related pseudogenes have also been identified on four other chromosomes.
# Function
The human NDUFA5 gene codes for the B13 subunit of complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. The NDUFA5 protein localizes to the mitochondrial inner membrane and it is thought to aid in this transfer of electrons. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix. The high degree of conservation of NDUFA5 extending to plants and fungi indicates its functional significance in the enzyme complex.
# Clinical significance
NDUFA5, ATP5A1 and ATP5A1 all show consistently reduced expression in brains of autism patients. Mitochondrial dysfunction and impaired ATP synthesis can result in oxidative stress, which may play a role in the development of autism.
# Interactions
NDUFA5 has many protein-protein interactions, such as ubiquitin C and with members of the NADH dehydrogenase 1 beta subcomplex, including NDUFB1, NDUFB9 and NDUFB10. | NDUFA5
NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5 is an enzyme that in humans is encoded by the NDUFA5 gene.[1] The NDUFA5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[2]
# Structure
The NDUFA5 gene is located on the q arm of chromosome 7 and it spans 64,655 base pairs.[1] The gene produces a 13.5 kDa protein composed of 116 amino acids.[3][4] NDUFA5 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[2] It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane. NDUFA5 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. The protein localizes to the inner mitochondrial membrane as part of the 7 component-containing, water-soluble iron-sulfur protein (IP) fraction of complex I, although its specific role is unknown. It is assumed to undergo post-translational removal of the initiator methionine and N-acetylation of the next amino acid. The predicted secondary structure is primarily alpha helix, but the carboxy-terminal half of the protein has high potential to adopt a coiled-coil form. The amino-terminal part contains a putative beta sheet rich in hydrophobic amino acids that may serve as mitochondrial import signal. Related pseudogenes have also been identified on four other chromosomes.[1][5]
# Function
The human NDUFA5 gene codes for the B13 subunit of complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. The NDUFA5 protein localizes to the mitochondrial inner membrane and it is thought to aid in this transfer of electrons.[1] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[2] The high degree of conservation of NDUFA5 extending to plants and fungi indicates its functional significance in the enzyme complex.[6]
# Clinical significance
NDUFA5, ATP5A1 and ATP5A1 all show consistently reduced expression in brains of autism patients. Mitochondrial dysfunction and impaired ATP synthesis can result in oxidative stress, which may play a role in the development of autism.[7][8]
# Interactions
NDUFA5 has many protein-protein interactions, such as ubiquitin C and with members of the NADH dehydrogenase [ubiquinone] 1 beta subcomplex, including NDUFB1, NDUFB9 and NDUFB10.[1] | https://www.wikidoc.org/index.php/NDUFA5 | |
8adb8db92335292819fc89180223601a41fd8890 | wikidoc | NDUFA6 | NDUFA6
NADH dehydrogenase 1 alpha subcomplex subunit 6 is an enzyme that in humans is encoded by the NDUFA6 gene. The NDUFA6 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.
# Structure
The NDUFA6 gene is located on the q arm of chromosome 22 in position 13.2 and spans 5,359 base pairs. The gene produces an 18 kDa protein composed of 154 amino acids. NDUFA6 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane. NDUFA6 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. The predicted secondary structure is primarily alpha helix, but the carboxy-terminal half of the protein has high potential to adopt a coiled-coil form. The amino-terminal part contains a putative beta sheet rich in hydrophobic amino acids that may serve as mitochondrial import signal. Related pseudogenes have also been identified on four other chromosomes.
# Function
The human NDUFA6 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix. | NDUFA6
NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6 is an enzyme that in humans is encoded by the NDUFA6 gene.[1] The NDUFA6 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[2]
# Structure
The NDUFA6 gene is located on the q arm of chromosome 22 in position 13.2 and spans 5,359 base pairs.[1] The gene produces an 18 kDa protein composed of 154 amino acids.[3][4] NDUFA6 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[2] It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane. NDUFA6 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. The predicted secondary structure is primarily alpha helix, but the carboxy-terminal half of the protein has high potential to adopt a coiled-coil form. The amino-terminal part contains a putative beta sheet rich in hydrophobic amino acids that may serve as mitochondrial import signal. Related pseudogenes have also been identified on four other chromosomes.[1][5][6][7]
# Function
The human NDUFA6 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone.[1] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[2] | https://www.wikidoc.org/index.php/NDUFA6 | |
6664015a94b2c5a40d79403614e355949ed96267 | wikidoc | NDUFA7 | NDUFA7
NADH dehydrogenase 1 alpha subcomplex subunit 7 is an enzyme that in humans is encoded by the NDUFA7 gene. The NDUFA7 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.
# Structure
The NDUFA7 gene is located on the p arm of chromosome 19 in position 13.2 and spans 12,618 base pairs. The gene produces a 12.5 kDa protein composed of 113 amino acids. NDUFA7 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane. NDUFA7 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. The predicted secondary structure is primarily alpha helix, but the carboxy-terminal half of the protein has high potential to adopt a coiled-coil form. The amino-terminal part contains a putative beta sheet rich in hydrophobic amino acids that may serve as mitochondrial import signal. Related pseudogenes have also been identified on four other chromosomes.
# Function
The human NDUFA7 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix. | NDUFA7
NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7 is an enzyme that in humans is encoded by the NDUFA7 gene.[1] The NDUFA7 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[2]
# Structure
The NDUFA7 gene is located on the p arm of chromosome 19 in position 13.2 and spans 12,618 base pairs.[1] The gene produces a 12.5 kDa protein composed of 113 amino acids.[3][4] NDUFA7 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[2] It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane. NDUFA7 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. The predicted secondary structure is primarily alpha helix, but the carboxy-terminal half of the protein has high potential to adopt a coiled-coil form. The amino-terminal part contains a putative beta sheet rich in hydrophobic amino acids that may serve as mitochondrial import signal. Related pseudogenes have also been identified on four other chromosomes.[1][5][6][7]
# Function
The human NDUFA7 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone.[1] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[2] | https://www.wikidoc.org/index.php/NDUFA7 | |
ff3bbc3249d0e7b45deaf0504bffe129ac81820e | wikidoc | NDUFA8 | NDUFA8
NADH dehydrogenase 1 alpha subcomplex subunit 8 is an enzyme that in humans is encoded by the NDUFA8 gene. The NDUFA8 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.
# Structure
The NDUFA8 gene is located on the q arm of chromosome 9 in position 33.2 and spans 27,354 base pairs. The gene produces a 20 kDa protein composed of 172 amino acids. NDUFA8 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane. NDUFA8 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. The predicted secondary structure is primarily alpha helix, but the carboxy-terminal half of the protein has high potential to adopt a coiled-coil form. The amino-terminal part contains a putative beta sheet rich in hydrophobic amino acids that may serve as mitochondrial import signal. Related pseudogenes have also been identified on four other chromosomes.
# Function
The human NDUFA8 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix. | NDUFA8
NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8 is an enzyme that in humans is encoded by the NDUFA8 gene.[1] The NDUFA8 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[2][3]
# Structure
The NDUFA8 gene is located on the q arm of chromosome 9 in position 33.2 and spans 27,354 base pairs.[1] The gene produces a 20 kDa protein composed of 172 amino acids.[4][5] NDUFA8 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[2] It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane. NDUFA8 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. The predicted secondary structure is primarily alpha helix, but the carboxy-terminal half of the protein has high potential to adopt a coiled-coil form. The amino-terminal part contains a putative beta sheet rich in hydrophobic amino acids that may serve as mitochondrial import signal. Related pseudogenes have also been identified on four other chromosomes.[1][3][6][7]
# Function
The human NDUFA8 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone.[1] NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[2] | https://www.wikidoc.org/index.php/NDUFA8 | |
d047570f1607e596cd6b7e4ddfd823155b49b089 | wikidoc | NDUFA9 | NDUFA9
NADH dehydrogenase 1 alpha subcomplex subunit 9 is an enzyme that in humans is encoded by the NDUFA9 gene. The NDUFA9 protein is a subunit of NADH:ubiquinone oxidoreductase (Complex I of the electron transport chain), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in NADH dehydrogenase (ubiquinone), also known as Complex I, frequently lead to complex neurodegenerative diseases such as Leigh's syndrome. In the case of NDUFA9, a mutation to the MT-ND3 gene might interrupt their interaction and formation of subcomplexes, compromising Complex I function and leading to disease.
# Structure
The NDUFA9 gene is located on the p arm of chromosome 12 in position 13.3 and spans 45,222 base pairs. The gene produces a 42.5 kDa protein composed of 377 amino acids. NDUFA9 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane. NDUFA9 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I, but it is an accessory subunit that is believed not to be involved in catalysis. The predicted secondary structure is primarily alpha helix, but the carboxy-terminal half of the protein has high potential to adopt a coiled-coil form. The amino-terminal part contains a putative beta sheet rich in hydrophobic amino acids that may serve as mitochondrial import signal.
# Function
The human NDUFA9 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.
# Clinical significance
Decreased expression of NDUFA9 is associated with Leigh's syndrome, a severe neurological disorder that typically arises in the first year of life, is characterized by progressive loss of mental and movement abilities, and typically results in death within a couple of years, usually due to respiratory failure. A mutation in the MT-ND3 gene (tyrosine to cytosine at the 10191 position) results in a substitution of serine for proline, which may introduce instability of Complex I due to the inability form subcomplexes between MT-ND3 and NDUFA9. However, this genetic identification may not be suitable for prenatal testing because of the mutation's age and tissue dependence.
# Interactions
NDUFA9 has been shown to have 135 binary protein-protein interactions including 112 co-complex interactions. NDUFA9 appears to interact with BLOC1S1, NDUFS1, NOA1, CYSRT1, KRTAP6-2, CIAO1, MT-ND3, TSC22D1, DNAJA3, SIRT3, MAGED1, and SSR1. | NDUFA9
NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9 is an enzyme that in humans is encoded by the NDUFA9 gene.[1][2][3] The NDUFA9 protein is a subunit of NADH:ubiquinone oxidoreductase (Complex I of the electron transport chain), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[4][5] Mutations in NADH dehydrogenase (ubiquinone), also known as Complex I, frequently lead to complex neurodegenerative diseases such as Leigh's syndrome. In the case of NDUFA9, a mutation to the MT-ND3 gene might interrupt their interaction and formation of subcomplexes, compromising Complex I function and leading to disease.[6]
# Structure
The NDUFA9 gene is located on the p arm of chromosome 12 in position 13.3 and spans 45,222 base pairs.[1] The gene produces a 42.5 kDa protein composed of 377 amino acids.[7][8] NDUFA9 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[4] It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane. NDUFA9 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I, but it is an accessory subunit that is believed not to be involved in catalysis.[9] The predicted secondary structure is primarily alpha helix, but the carboxy-terminal half of the protein has high potential to adopt a coiled-coil form. The amino-terminal part contains a putative beta sheet rich in hydrophobic amino acids that may serve as mitochondrial import signal.[1][5][10]
# Function
The human NDUFA9 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone.[1] NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[4]
# Clinical significance
Decreased expression of NDUFA9 is associated with Leigh's syndrome, a severe neurological disorder that typically arises in the first year of life, is characterized by progressive loss of mental and movement abilities, and typically results in death within a couple of years, usually due to respiratory failure. A mutation in the MT-ND3 gene (tyrosine to cytosine at the 10191 position) results in a substitution of serine for proline, which may introduce instability of Complex I due to the inability form subcomplexes between MT-ND3 and NDUFA9. However, this genetic identification may not be suitable for prenatal testing because of the mutation's age and tissue dependence.[6]
# Interactions
NDUFA9 has been shown to have 135 binary protein-protein interactions including 112 co-complex interactions. NDUFA9 appears to interact with BLOC1S1, NDUFS1, NOA1, CYSRT1, KRTAP6-2, CIAO1, MT-ND3, TSC22D1, DNAJA3, SIRT3, MAGED1, and SSR1.[11] | https://www.wikidoc.org/index.php/NDUFA9 | |
8439c26a3f4024c22ecc9ccad86ea8bc48c3a51e | wikidoc | NDUFB1 | NDUFB1
NADH dehydrogenase 1 beta subcomplex subunit 1 is an enzyme that in humans is encoded by the NDUFB1 gene. NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 1, 7kDa is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.
# Structure
The NDUFB1 gene, located on the q arm of chromosome 14 in position 32.12, is 5,687 base pairs long. The NDUFB1 protein weighs 7 kDa and is composed of 58 amino acids. NDUFB1 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. NDUFB1 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.
# Function
The human NDUFB1 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. However, NDUFB1 is an accessory subunit of the complex that is believed not to be involved in catalysis. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix. | NDUFB1
NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1 is an enzyme that in humans is encoded by the NDUFB1 gene.[1][2] NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 1, 7kDa is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.[3]
# Structure
The NDUFB1 gene, located on the q arm of chromosome 14 in position 32.12, is 5,687 base pairs long. The NDUFB1 protein weighs 7 kDa and is composed of 58 amino acids.[4][5] NDUFB1 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[3] NDUFB1 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.[2]
# Function
The human NDUFB1 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone.[2] However, NDUFB1 is an accessory subunit of the complex that is believed not to be involved in catalysis.[6] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[3] | https://www.wikidoc.org/index.php/NDUFB1 | |
0011ce80b53cb293ba9d1018772c553b99b32eb5 | wikidoc | NDUFB2 | NDUFB2
NADH dehydrogenase 1 beta subcomplex subunit 2, mitochondrial is an enzyme that in humans is encoded by the NDUFB2 gene. NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 2, 8kDa is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.
# Structure
The NDUFB2 gene, located on the q arm of chromosome 7 in position 34, is 9,966 base pairs long and is composed of 4 exons. The NDUFB2 protein weighs 12 kDa and is composed of 105 amino acids. NDUFB2 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. NDUFB3 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane. Hydropathy analysis revealed that this subunit and 4 other subunits have an overall hydrophilic pattern, even though they are found within the hydrophobic protein (HP) fraction of complex I.
# Function
The human NDUFB2 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. However, NDUFB2 is an accessory subunit of the complex that is believed not to be involved in catalysis. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix. | NDUFB2
NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial is an enzyme that in humans is encoded by the NDUFB2 gene.[1][2][3] NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 2, 8kDa is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.[4]
# Structure
The NDUFB2 gene, located on the q arm of chromosome 7 in position 34, is 9,966 base pairs long and is composed of 4 exons.[3] The NDUFB2 protein weighs 12 kDa and is composed of 105 amino acids.[5][6] NDUFB2 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[4] NDUFB3 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane. Hydropathy analysis revealed that this subunit and 4 other subunits have an overall hydrophilic pattern, even though they are found within the hydrophobic protein (HP) fraction of complex I.[3]
# Function
The human NDUFB2 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone.[3] However, NDUFB2 is an accessory subunit of the complex that is believed not to be involved in catalysis.[7] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[4] | https://www.wikidoc.org/index.php/NDUFB2 | |
d61f49682885860992a7d80a6b262abb271cdf9b | wikidoc | NDUFB3 | NDUFB3
NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3, 12kDa is a protein that in humans is encoded by the NDUFB3 gene. NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3, 12kDa is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain. Mutations in this gene contribute to mitochondrial complex I deficiency.
# Structure
The NDUFB3 gene, located on the q arm of chromosome 2 in position 31.3, is 14,012 base pairs long. The NDUFB3 protein weighs 11.4 kDa and is composed of 98 amino acids. NDUFB3 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. NDUFB3 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. This protein localizes to the inner membrane of the mitochondrion as a single-pass membrane protein. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.
# Function
The human NDUFB3 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. However, NDUFB3 is an accessory subunit of the complex that is believed not to be involved in catalysis. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.
# Clinical significance
Mutations in the NDUFB3 gene have been implicated in the pathogenicity of human oxidative phosphorylation disease, characterized by a biochemical defect in the respiratory chain. | NDUFB3
NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3, 12kDa is a protein that in humans is encoded by the NDUFB3 gene. NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3, 12kDa is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.[1] Mutations in this gene contribute to mitochondrial complex I deficiency.[2]
# Structure
The NDUFB3 gene, located on the q arm of chromosome 2 in position 31.3, is 14,012 base pairs long. The NDUFB3 protein weighs 11.4 kDa and is composed of 98 amino acids.[3][4] NDUFB3 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[1] NDUFB3 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. This protein localizes to the inner membrane of the mitochondrion as a single-pass membrane protein. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.[2]
# Function
The human NDUFB3 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone.[2] However, NDUFB3 is an accessory subunit of the complex that is believed not to be involved in catalysis.[5] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[1]
# Clinical significance
Mutations in the NDUFB3 gene have been implicated in the pathogenicity of human oxidative phosphorylation disease, characterized by a biochemical defect in the respiratory chain.[6] | https://www.wikidoc.org/index.php/NDUFB3 | |
be430cf4121f601062936f2fb96632a94097b6b3 | wikidoc | NDUFB4 | NDUFB4
NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 4, 15kDa is a protein that in humans is encoded by the NDUFB4 gene. The NDUFB4 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.
# Structure
The NDUFB4 gene, located on the q arm of chromosome 3 in position 13.33, is 6,130 base pairs long. The NDUFB4 protein weighs 15 kDa and is composed of 129 amino acids. NDUFB4 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. NDUFB4 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I and is of the non-catalytic subunits of the complex. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.
# Function
The human NDUFB4 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. However, NDUFB4 is an accessory subunit of the complex that is believed not to be involved in catalysis. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein complex has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix. | NDUFB4
NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 4, 15kDa is a protein that in humans is encoded by the NDUFB4 gene.[1] The NDUFB4 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[2]
# Structure
The NDUFB4 gene, located on the q arm of chromosome 3 in position 13.33, is 6,130 base pairs long. The NDUFB4 protein weighs 15 kDa and is composed of 129 amino acids.[3][4] NDUFB4 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[2] NDUFB4 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I and is of the non-catalytic subunits of the complex. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.[1]
# Function
The human NDUFB4 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone.[1] However, NDUFB4 is an accessory subunit of the complex that is believed not to be involved in catalysis.[5] Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein complex has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.[1] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[2] | https://www.wikidoc.org/index.php/NDUFB4 | |
4ced0b0b1ff4f4f38475986e35e303716b20df47 | wikidoc | NDUFB5 | NDUFB5
NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 5, 16kDa is a protein that in humans is encoded by the NDUFB5 gene. The NDUFB5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.
# Structure
The NDUFB5 gene, located on the q arm of chromosome 3 in position 26.33, is 19,713 base pairs long. The NDUFB5 protein weighs 21.7 kDa and is composed of 189 amino acids. NDUFB5 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. NDUFB5 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I and is of the non-catalytic subunits of the complex. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.
# Function
The human NDUFB5 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. However, NDUFB5 is an accessory subunit of the complex that is believed not to be involved in catalysis. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix. | NDUFB5
NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 5, 16kDa is a protein that in humans is encoded by the NDUFB5 gene.[1] The NDUFB5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[2]
# Structure
The NDUFB5 gene, located on the q arm of chromosome 3 in position 26.33, is 19,713 base pairs long. The NDUFB5 protein weighs 21.7 kDa and is composed of 189 amino acids.[3][4] NDUFB5 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[2] NDUFB5 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I and is of the non-catalytic subunits of the complex. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.[1]
# Function
The human NDUFB5 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone.[1] However, NDUFB5 is an accessory subunit of the complex that is believed not to be involved in catalysis.[5] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[2] | https://www.wikidoc.org/index.php/NDUFB5 | |
b3a307e94feb11f06bb8c8e675411afe940960a9 | wikidoc | NDUFB6 | NDUFB6
NADH dehydrogenase 1 beta subcomplex subunit 6, also known as complex I-B17, is a protein that in humans is encoded by the NDUFB6 gene. NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 6, is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.
# Gene
The NDUFB6 gene is located on the p arm of chromosome 9 in position 21.1 and is 19,659 base pairs long.
# Structure
The NDUFB6 protein weighs 15.5 kDa and is composed of 128 amino acids. NDUFB6 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.
# Function
The protein encoded by this gene is an accessory subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I) that is not directly involved in catalysis. However, NDUFB6 is required for electron transfer activity. Mammalian complex I is composed of 44 different subunits. It locates at the mitochondrial inner membrane. This protein complex has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.
# Clinical significance
Decreased expression of genes involved in oxidative phosphorylation, including NDUFB6, is associated with insulin resistance and type 2 diabetes. A polymorphism in the promoter region of the NDFUB6 gene resulting in an adenine to guanine shift at rs629566 was shown to create a DNA methylation site that is associated with a decline in NDUFB6 expression in muscle of aging patients. | NDUFB6
NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6, also known as complex I-B17, is a protein that in humans is encoded by the NDUFB6 gene.[1][2][3] NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 6, is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.[4]
# Gene
The NDUFB6 gene is located on the p arm of chromosome 9 in position 21.1 and is 19,659 base pairs long.[5][6]
# Structure
The NDUFB6 protein weighs 15.5 kDa and is composed of 128 amino acids.[5][6] NDUFB6 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[4] It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.[3]
# Function
The protein encoded by this gene is an accessory subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I) that is not directly involved in catalysis.[3] However, NDUFB6 is required for electron transfer activity.[7] Mammalian complex I is composed of 44 different subunits. It locates at the mitochondrial inner membrane. This protein complex has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified.[3] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[4]
# Clinical significance
Decreased expression of genes involved in oxidative phosphorylation, including NDUFB6, is associated with insulin resistance and type 2 diabetes. A polymorphism in the promoter region of the NDFUB6 gene resulting in an adenine to guanine shift at rs629566 was shown to create a DNA methylation site that is associated with a decline in NDUFB6 expression in muscle of aging patients.[8] | https://www.wikidoc.org/index.php/NDUFB6 | |
b5313eda3f02428762b86423de9a06857309a0c5 | wikidoc | NDUFB7 | NDUFB7
NADH dehydrogenase 1 beta subcomplex subunit 7, also known as complex I-B18, is an enzyme that in humans is encoded by the NDUFB7 gene. NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 7 is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.
# Gene
The NDUFB7 gene is located on the p arm of chromosome 19 in position 13.12 and is 6,000 base pairs long.
# Structure
The NDUFB7 protein weighs 16.4 kDa and is composed of 137 amino acids. NDUFB7 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. NDUFB7 and NDUFB8 have been shown to localize at the intermembrane surface of complex I. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.
# Function
The protein encoded by this gene is an accessory subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I) that is not directly involved in catalysis. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein complex has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix. | NDUFB7
NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7, also known as complex I-B18, is an enzyme that in humans is encoded by the NDUFB7 gene.[1][2][3] NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 7 is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.[4]
# Gene
The NDUFB7 gene is located on the p arm of chromosome 19 in position 13.12 and is 6,000 base pairs long.[5][6]
# Structure
The NDUFB7 protein weighs 16.4 kDa and is composed of 137 amino acids.[5][6] NDUFB7 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[4] NDUFB7 and NDUFB8 have been shown to localize at the intermembrane surface of complex I.[7] It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.[3]
# Function
The protein encoded by this gene is an accessory subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I) that is not directly involved in catalysis. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein complex has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified.[3] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[4] | https://www.wikidoc.org/index.php/NDUFB7 | |
fa08b5ab6635d1d9ee4062aee841ee3972c792eb | wikidoc | NDUFB8 | NDUFB8
NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial is an enzyme that in humans is encoded by the NDUFB8 gene. NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8 is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.
# Gene
The NDUFB8 gene is located on the q arm of chromosome 10 in position 24.31 and is 6,194 base pairs long.
# Structure
The NDUFB8 protein weighs 22 kDa and is composed of 186 amino acids. NDUFB8 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. NDUFB7 and NDUFB8 have been shown to localize at the intermembrane surface of complex I. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.
# Function
The protein encoded by this gene is an accessory subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I) that is not directly involved in catalysis. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein complex has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.
# Model organisms
Model organisms have been used in the study of NDUFB8 function. A conditional knockout mouse line called Ndufb8tm1a(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 | NDUFB8
NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial is an enzyme that in humans is encoded by the NDUFB8 gene.[1][2] NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8 is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.[3]
# Gene
The NDUFB8 gene is located on the q arm of chromosome 10 in position 24.31 and is 6,194 base pairs long.[4][5]
# Structure
The NDUFB8 protein weighs 22 kDa and is composed of 186 amino acids.[4][5] NDUFB8 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[3] NDUFB7 and NDUFB8 have been shown to localize at the intermembrane surface of complex I.[6] It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.[2]
# Function
The protein encoded by this gene is an accessory subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I) that is not directly involved in catalysis. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein complex has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified.[2] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[3]
# Model organisms
Model organisms have been used in the study of NDUFB8 function. A conditional knockout mouse line called Ndufb8tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[7] Male and female animals underwent a standardized phenotypic screen[8] to determine the effects of deletion.[9][10][11][12] Additional screens performed: - In-depth immunological phenotyping[13] | https://www.wikidoc.org/index.php/NDUFB8 | |
00d3d7e723b79affb70039960074ad0882902b9c | wikidoc | NDUFB9 | NDUFB9
NADH dehydrogenase 1 beta subcomplex subunit 9 is an enzyme that in humans is encoded by the NDUFB9 gene. NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 9 is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.
# Structure
The NDUFB9 gene is located on the q arm of chromosome 8 in position 13.3 and is 10,884 base pairs long. The NDUFB9 protein weighs 22 kDa and is composed of 179 amino acids. NDUFB9 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.
# Function
The protein encoded by this gene is an accessory subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I) that is not directly involved in catalysis. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein complex has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.
# Clinical significance
A mutation in NDUFB9 resulting in reduction in NDUFB9 protein and both amount and activity of complex I has been shown to be a causal mutation leading to Complex I deficiency. | NDUFB9
NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 is an enzyme that in humans is encoded by the NDUFB9 gene.[1][2] NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 9 is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.[3]
# Structure
The NDUFB9 gene is located on the q arm of chromosome 8 in position 13.3 and is 10,884 base pairs long. The NDUFB9 protein weighs 22 kDa and is composed of 179 amino acids.[4][5] NDUFB9 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[3] It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.[2]
# Function
The protein encoded by this gene is an accessory subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I) that is not directly involved in catalysis. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein complex has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified.[2] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[3]
# Clinical significance
A mutation in NDUFB9 resulting in reduction in NDUFB9 protein and both amount and activity of complex I has been shown to be a causal mutation leading to Complex I deficiency.[6] | https://www.wikidoc.org/index.php/NDUFB9 | |
5e3bc03aa060c05696ae1b5112b64eb191b29939 | wikidoc | NDUFS1 | NDUFS1
NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1) is an enzyme that in humans is encoded by the NDUFS1 gene. The encoded protein, NDUFS1, is the largest subunit of complex I, located on the inner mitochondrial membrane, and is important for mitochondrial oxidative phosphorylation. Mutations in this gene are associated with complex I deficiency.
# Structure
NDUFS1 is located on the q arm of chromosome 2 in position 33.3 and has 20 exons. The NDUFS1 gene produces a 79.5 kDa protein composed of 727 amino acids. NDUFS1, the protein encoded by this gene, is a member of the complex I 75 kDa subunit family. It contains a transit peptide, 10 turns, 19 beta strands, 27 alpha helixes, and cofactor binding sites for and clusters. The cluster domains consist of a 79 amino acid 2Fe-2S ferredoxin-type from positions 30-108, a 40 amino acid 4Fe-4S His(Cys)3-ligated-type from positions 108-147, and a 57 amino acid 4Fe-4S Mo/W bis-MGD-type from positions 245-301. Several transcript variants encoding different isoforms have been found for this gene.
# Function
The protein encoded by this gene belongs to the complex I 75 kDa subunit family. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. This protein is the largest subunit of complex I and it is a component of the iron-sulfur (IP) fragment of the enzyme. It may form part of the active site crevice where NADH is oxidized.
# Clinical significance
Mutations in the NDUFS1 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders. Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible. However, the majority of cases are caused by mutations in nuclear-encoded genes. It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.
# Interactions
NDUFS1 has been shown to have 124 binary protein-protein interactions including 110 co-complex interactions. NDUFS1 appears to interact with SOAT1, NDUFA9, HLA-B, ECE2, C1QTNF9, GPAA1, STOM, GDI1, ACAP2, EHBP1, MBOAT7, PIGS. | NDUFS1
NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1) is an enzyme that in humans is encoded by the NDUFS1 gene.[1] The encoded protein, NDUFS1, is the largest subunit of complex I, located on the inner mitochondrial membrane, and is important for mitochondrial oxidative phosphorylation. Mutations in this gene are associated with complex I deficiency.[2]
# Structure
NDUFS1 is located on the q arm of chromosome 2 in position 33.3 and has 20 exons.[3] The NDUFS1 gene produces a 79.5 kDa protein composed of 727 amino acids.[4][5] NDUFS1, the protein encoded by this gene, is a member of the complex I 75 kDa subunit family. It contains a transit peptide, 10 turns, 19 beta strands, 27 alpha helixes, and cofactor binding sites for [2Fe-2S] and [4Fe-4S] clusters. The cluster domains consist of a 79 amino acid 2Fe-2S ferredoxin-type from positions 30-108, a 40 amino acid 4Fe-4S His(Cys)3-ligated-type from positions 108-147, and a 57 amino acid 4Fe-4S Mo/W bis-MGD-type from positions 245-301.[6][7] Several transcript variants encoding different isoforms have been found for this gene.[2]
# Function
The protein encoded by this gene belongs to the complex I 75 kDa subunit family. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. This protein is the largest subunit of complex I and it is a component of the iron-sulfur (IP) fragment of the enzyme. It may form part of the active site crevice where NADH is oxidized.[2]
# Clinical significance
Mutations in the NDUFS1 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders.[8][9] Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible.[10] However, the majority of cases are caused by mutations in nuclear-encoded genes.[11][12] It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.[13]
# Interactions
NDUFS1 has been shown to have 124 binary protein-protein interactions including 110 co-complex interactions. NDUFS1 appears to interact with SOAT1, NDUFA9, HLA-B, ECE2, C1QTNF9, GPAA1, STOM, GDI1, ACAP2, EHBP1, MBOAT7, PIGS.[14] | https://www.wikidoc.org/index.php/NDUFS1 | |
aea08b787fb23ef95776826b28fa6214b4e7e54e | wikidoc | NDUFS2 | NDUFS2
NADH dehydrogenase iron-sulfur protein 2, mitochondrial (NDUFS2) also known as NADH-ubiquinone oxidoreductase 49 kDa subunit is an enzyme that in humans is encoded by the NDUFS2 gene. The protein encoded by this gene is a core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Mutations in this gene are associated with mitochondrial complex I deficiency.
# Structure
NDUFS2 is located on the q arm of chromosome 1 in position 23.3 and has 15 exons. The NDUFS2 gene produces a 52.5 kDa protein composed of 463 amino acids. NDUFS2, the protein encoded by this gene, is a member of the complex I 49 kDa subunit family. It is a peripheral membrane protein on the matrix side of the inner mitochondrial membrane. It contains a cofactor binding site for a cluster, a transit peptide, 5 turns, 11 beta strands, and 18 alpha helixes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.
# Function
Mitochondrial complex I is the first multimeric complex of the respiratory chain that catalyzes the NADH oxidation with concomitant ubiquinone reduction and proton ejection out of the mitochondria. Mammalian mitochondrial complex I is an assembly of at least 43 different subunits. Seven of the subunits are encoded by the mitochondrial genome; the remainder are the products of nuclear genes. The iron-sulfur protein (IP) fraction of complex I is made up of 7 subunits, including NDUFS2. Dimethylation at Arg-118 by NDUFAF7 takes place after NDUFS2 assembles into the complex I, leading to the stabilization of the early intermediate complex.
# Clinical significance
Mutations in the NDUFS2 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders. Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible. However, the majority of cases are caused by mutations in nuclear-encoded genes. It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.
# Interactions
NDUFS2 has been shown to have 121 binary protein-protein interactions including 112 co-complex interactions. NDUFS2 appears to interact with NDUFS3, MKLN1, EGR2, HMOX2, CENPU, and TNFRSF14. | NDUFS2
NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial (NDUFS2) also known as NADH-ubiquinone oxidoreductase 49 kDa subunit is an enzyme that in humans is encoded by the NDUFS2 gene.[1][2] The protein encoded by this gene is a core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Mutations in this gene are associated with mitochondrial complex I deficiency.[3]
# Structure
NDUFS2 is located on the q arm of chromosome 1 in position 23.3 and has 15 exons.[3] The NDUFS2 gene produces a 52.5 kDa protein composed of 463 amino acids.[4][5] NDUFS2, the protein encoded by this gene, is a member of the complex I 49 kDa subunit family. It is a peripheral membrane protein on the matrix side of the inner mitochondrial membrane. It contains a cofactor binding site for a [4Fe-4S] cluster, a transit peptide, 5 turns, 11 beta strands, and 18 alpha helixes.[6][7] Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[3]
# Function
Mitochondrial complex I is the first multimeric complex of the respiratory chain that catalyzes the NADH oxidation with concomitant ubiquinone reduction and proton ejection out of the mitochondria. Mammalian mitochondrial complex I is an assembly of at least 43 different subunits. Seven of the subunits are encoded by the mitochondrial genome; the remainder are the products of nuclear genes. The iron-sulfur protein (IP) fraction of complex I is made up of 7 subunits, including NDUFS2.[3] Dimethylation at Arg-118 by NDUFAF7 takes place after NDUFS2 assembles into the complex I, leading to the stabilization of the early intermediate complex.[8][9][6][7]
# Clinical significance
Mutations in the NDUFS2 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders.[10][11] Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible.[12] However, the majority of cases are caused by mutations in nuclear-encoded genes.[13][14] It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.[15]
# Interactions
NDUFS2 has been shown to have 121 binary protein-protein interactions including 112 co-complex interactions. NDUFS2 appears to interact with NDUFS3, MKLN1, EGR2, HMOX2, CENPU, and TNFRSF14.[16] | https://www.wikidoc.org/index.php/NDUFS2 | |
a69bb82607c76d17d8699e0c6b5e007d42597f2b | wikidoc | NDUFS3 | NDUFS3
NADH dehydrogenase iron-sulfur protein 3, mitochondrial is an enzyme that in humans is encoded by the NDUFS3 gene on chromosome 11. This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone oxidoreductase (complex I). Mutations in this gene are associated with Leigh syndrome resulting from mitochondrial complex I deficiency.
# Structure
The NDUFS3 gene encodes a protein subunit consisting of 263 amino acids. This protein is synthesized in the cytoplasm and then transported to the mitochondria via a signal peptide. Two mutations that occur in its highly conserved C-terminal region, T145I and R199W, are causally linked to Leigh syndrome and optic atrophy. Nonetheless, despite its crucial biological role, the human NDUFS3 remains structurally poorly understood.
# Function
This gene encodes one of the iron-sulfur protein (IP) components of complex I. The 45-subunit NADH:ubiquinone oxidoreductase (complex I) is the first enzyme complex in the electron transport chain of mitochondria. As a catalytic subunit, NDUFS3 plays a vital role in the proper assembly of complex I and is recruited to the inner mitochondrial membrane to form an early assembly intermediate with NDUFS2. It initiates the assembly of complex I in the mitochondrial matrix.
Cleavage of NDUFS3 by GzmA has been observed to activate a programmed cell death pathway which results in mitochondrial dysfunction and reactive oxygen species (ROS) generation.
# Clinical significance
Mutations in the NDUFS3 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders. Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible. However, the majority of cases are caused by mutations in nuclear-encoded genes. It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.
NDUFS3 has also been implicated in breast cancer and ductal carcinoma and, thus, may serve as a novel biomarker for tracking cancer progression and invasiveness.
# Model organisms
Model organisms have been used in the study of NDUFS3 function. A conditional knockout mouse line, called Ndufs3tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.
Twenty five tests were carried out on mutant mice and six 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; males had an increased lean body mass and heart weight, and a decrease in some plasma chemistry and haematology parameters. | NDUFS3
NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial is an enzyme that in humans is encoded by the NDUFS3 gene on chromosome 11.[1][2] This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone oxidoreductase (complex I). Mutations in this gene are associated with Leigh syndrome resulting from mitochondrial complex I deficiency.[2]
# Structure
The NDUFS3 gene encodes a protein subunit consisting of 263 amino acids. This protein is synthesized in the cytoplasm and then transported to the mitochondria via a signal peptide. Two mutations that occur in its highly conserved C-terminal region, T145I and R199W, are causally linked to Leigh syndrome and optic atrophy. Nonetheless, despite its crucial biological role, the human NDUFS3 remains structurally poorly understood.[3]
# Function
This gene encodes one of the iron-sulfur protein (IP) components of complex I.[2] The 45-subunit NADH:ubiquinone oxidoreductase (complex I) is the first enzyme complex in the electron transport chain of mitochondria.[2][4] As a catalytic subunit, NDUFS3 plays a vital role in the proper assembly of complex I and is recruited to the inner mitochondrial membrane to form an early assembly intermediate with NDUFS2.[4][5] It initiates the assembly of complex I in the mitochondrial matrix.[3]
Cleavage of NDUFS3 by GzmA has been observed to activate a programmed cell death pathway which results in mitochondrial dysfunction and reactive oxygen species (ROS) generation.
[6]
# Clinical significance
Mutations in the NDUFS3 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders.[7][8] Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible.[9] However, the majority of cases are caused by mutations in nuclear-encoded genes.[10][11] It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.[12]
NDUFS3 has also been implicated in breast cancer and ductal carcinoma and, thus, may serve as a novel biomarker for tracking cancer progression and invasiveness.[4]
# Model organisms
Model organisms have been used in the study of NDUFS3 function. A conditional knockout mouse line, called Ndufs3tm1a(EUCOMM)Wtsi[21][22] 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.[23][24][25]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[19][26]
Twenty five tests were carried out on mutant mice and six significant abnormalities were observed.[19] 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; males had an increased lean body mass and heart weight, and a decrease in some plasma chemistry and haematology parameters.[19] | https://www.wikidoc.org/index.php/NDUFS3 | |
6125d8f0754082c302a82a9a1b053672b6528a28 | wikidoc | NDUFS4 | NDUFS4
NADH dehydrogenase iron-sulfur protein 4, mitochondrial (NDUFS4) also known as NADH-ubiquinone oxidoreductase 18 kDa subunit is an enzyme that in humans is encoded by the NDUFS4 gene. This gene encodes an nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome.
# Structure
NDUFS4 is located on the q arm of chromosome 5 in position 11.2 and has 8 exons. The NDUFS4 gene produces a 20.1 kDa protein composed of 175 amino acids. NDUFS4, the protein encoded by this gene, is a member of the complex I NDUFS4 subunit family. It is a peripheral membrane protein located on the matrix side of the inner mitochondrial membrane. NDUFS4 is a component of the iron-sulfur (IP) fragment of the enzyme and contains a transit peptide domain, 4 turns, 6 beta strands, and 4 alpha helixes. Alternative splicing results in multiple transcript variants.
# Function
Complex I, or NADH:ubiquinone oxidoreductase, the first multisubunit enzyme complex of the mitochondrial respiratory chain, plays a vital role in cellular ATP production, the primary source of energy for many crucial processes in living cells. It removes electrons from NADH and passes them by a series of different protein-coupled redox centers to the electron acceptor ubiquinone. In well-coupled mitochondria, the electron flux leads to ATP generation via the building of a proton gradient across the inner membrane. Complex I is composed of at least 41 subunits, of which 7 are encoded by the mitochondrial genome (ND1-6, ND4L) and the remainder by nuclear genes.
# Clinical significance
Mutations in the NDUFS4 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders. Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible. However, the majority of cases are caused by mutations in nuclear-encoded genes. It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. Complex I deficiency with autosomal recessive inheritance results from mutation in nuclear-encoded subunit genes, including NDUFV1, NDUFV2, NDUFS1, NDUFS2, NDUFS3, NDUFS6, NDUFS7, NDUFS8, NDUFA2, NDUFA11, NDUFAF3, NDUFAF10, NDUFB3, NDUFB9, ACAD9, FOXRED1, and MTFMT.
# Interactions
NDUFS4 has been shown to have 58 binary protein-protein interactions including 57 co-complex interactions. NDUFS4 appears to interact with UBE2G2. | NDUFS4
NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial (NDUFS4) also known as NADH-ubiquinone oxidoreductase 18 kDa subunit is an enzyme that in humans is encoded by the NDUFS4 gene.[1][2] This gene encodes an nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome.[3]
# Structure
NDUFS4 is located on the q arm of chromosome 5 in position 11.2 and has 8 exons.[4] The NDUFS4 gene produces a 20.1 kDa protein composed of 175 amino acids.[5][6] NDUFS4, the protein encoded by this gene, is a member of the complex I NDUFS4 subunit family. It is a peripheral membrane protein located on the matrix side of the inner mitochondrial membrane. NDUFS4 is a component of the iron-sulfur (IP) fragment of the enzyme and contains a transit peptide domain, 4 turns, 6 beta strands, and 4 alpha helixes.[7][8] Alternative splicing results in multiple transcript variants.[3]
# Function
Complex I, or NADH:ubiquinone oxidoreductase, the first multisubunit enzyme complex of the mitochondrial respiratory chain, plays a vital role in cellular ATP production, the primary source of energy for many crucial processes in living cells. It removes electrons from NADH and passes them by a series of different protein-coupled redox centers to the electron acceptor ubiquinone. In well-coupled mitochondria, the electron flux leads to ATP generation via the building of a proton gradient across the inner membrane. Complex I is composed of at least 41 subunits, of which 7 are encoded by the mitochondrial genome (ND1-6, ND4L) and the remainder by nuclear genes.[1][3]
# Clinical significance
Mutations in the NDUFS4 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders.[9][10] Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible.[11] However, the majority of cases are caused by mutations in nuclear-encoded genes.[12][13] It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.[14] Complex I deficiency with autosomal recessive inheritance results from mutation in nuclear-encoded subunit genes, including NDUFV1, NDUFV2, NDUFS1, NDUFS2, NDUFS3, NDUFS6, NDUFS7, NDUFS8, NDUFA2, NDUFA11, NDUFAF3, NDUFAF10, NDUFB3, NDUFB9, ACAD9, FOXRED1, and MTFMT.
# Interactions
NDUFS4 has been shown to have 58 binary protein-protein interactions including 57 co-complex interactions. NDUFS4 appears to interact with UBE2G2.[15] | https://www.wikidoc.org/index.php/NDUFS4 | |
f3d4e85b47c9c456f56301587773c244636d1966 | wikidoc | NDUFS6 | NDUFS6
NADH dehydrogenase iron-sulfur protein 6, mitochondrial is an enzyme that in humans is encoded by the NDUFS6 gene.
# Function
The multisubunit NADH:ubiquinone oxidoreductase (complex I) is the first enzyme complex in the electron transport chain of mitochondria. The iron-sulfur protein (IP) fraction is made up of 7 subunits, including NDUFS6.
# Clinical significance
Mutations in the NDUFS6 gene are associated with mitochondrial Complex I deficiency, and are inherited in an autosomal recessive manner. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders. Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible. However, the majority of cases are caused by mutations in nuclear-encoded genes. It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.
In NDUFS6 mutations the presentation is typically a neonatal lactic acidosis that is swiftly fatal, coupled with multi-system failure. | NDUFS6
NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial is an enzyme that in humans is encoded by the NDUFS6 gene.[1][2]
# Function
The multisubunit NADH:ubiquinone oxidoreductase (complex I) is the first enzyme complex in the electron transport chain of mitochondria. The iron-sulfur protein (IP) fraction is made up of 7 subunits, including NDUFS6.[2]
# Clinical significance
Mutations in the NDUFS6 gene are associated with mitochondrial Complex I deficiency, and are inherited in an autosomal recessive manner. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders.[3][4] Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible.[5] However, the majority of cases are caused by mutations in nuclear-encoded genes.[6][7] It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease[8].
In NDUFS6 mutations the presentation is typically a neonatal lactic acidosis that is swiftly fatal, coupled with multi-system failure[3][5][8]. | https://www.wikidoc.org/index.php/NDUFS6 | |
3dbfa68403a23c1b60ce433358e231468c8c6284 | wikidoc | NDUFS7 | NDUFS7
NADH dehydrogenase iron-sulfur protein 7, mitochondrial, also knowns as NADH-ubiquinone oxidoreductase 20 kDa subunit, Complex I-20kD (CI-20kD), or PSST subunit is an enzyme that in humans is encoded by the NDUFS7 gene. The NDUFS7 protein is a subunit of NADH dehydrogenase (ubiquinone) also known as Complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.
# Structure
The NDUFS7 gene is located on the p arm of chromosome 19 in position 13.3. The NDUFS7 gene produces a 25 kDa protein composed of 238 amino acids. The PSST subunit is highly conserved across evolutionary distances. Crystal structures and mutational studies indicate that it is one of the ubiquinone binding sites of Complex I, together with the TYKY (NDUFS8) subunit. It has been proposed that PSST, along with TYKY, 49 kDa, ND1 and ND5 subunits interact with iron-sulfur clusters as part of the catalytic core of NADH dehydrogenase (ubiquinone).
# Function
The PSST subunit encoded by the NDUSF7 gene is one of over 40 subunits involved in the transfer of electrons from NADH to ubiquinone. Specifically, it is thought that the PSST subunit directly couples electron transfer between the iron-sulfur cluster N2 and ubiquinone, along with ubiquinone-binding ND1. Functional evidence for the importance of PSST has been garnered from mutational studies in the obligate aerobic yeast, Yarrow lipolytic, which elucidated a central role in proton translocation that was reduced in mutant forms of the subunit.
# Clinical Significance
Mitochondrial complex I deficiency (MT-C1D) is caused by mutations affecting the NDUFS7 gene. Complex I deficiency is a disorder of the mitochondrial respiratory chain that causes a wide range of clinical manifestations, from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber's hereditary optic neuropathy, and some forms of Parkinson's disease. Leigh syndrome is an early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord, and is the most common mitochondrial encephalomyopathy. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, dysphagia, and lactic acidosis.
# Interactions
In addition to co-subunits for complex I, NDUFS7 has protein-protein interactions with ENO2 and ARRB2. | NDUFS7
NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial, also knowns as NADH-ubiquinone oxidoreductase 20 kDa subunit, Complex I-20kD (CI-20kD), or PSST subunit is an enzyme that in humans is encoded by the NDUFS7 gene.[1][2][3] The NDUFS7 protein is a subunit of NADH dehydrogenase (ubiquinone) also known as Complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[4]
# Structure
The NDUFS7 gene is located on the p arm of chromosome 19 in position 13.3.[2] The NDUFS7 gene produces a 25 kDa protein composed of 238 amino acids.[5][6] The PSST subunit is highly conserved across evolutionary distances. Crystal structures and mutational studies indicate that it is one of the ubiquinone binding sites of Complex I, together with the TYKY (NDUFS8) subunit.[7] It has been proposed that PSST, along with TYKY, 49 kDa, ND1 and ND5 subunits interact with iron-sulfur clusters as part of the catalytic core of NADH dehydrogenase (ubiquinone).[8]
# Function
The PSST subunit encoded by the NDUSF7 gene is one of over 40 subunits involved in the transfer of electrons from NADH to ubiquinone. Specifically, it is thought that the PSST subunit directly couples electron transfer between the iron-sulfur cluster N2 and ubiquinone, along with ubiquinone-binding ND1.[8] Functional evidence for the importance of PSST has been garnered from mutational studies in the obligate aerobic yeast, Yarrow lipolytic, which elucidated a central role in proton translocation that was reduced in mutant forms of the subunit.[9]
# Clinical Significance
Mitochondrial complex I deficiency (MT-C1D) is caused by mutations affecting the NDUFS7 gene. Complex I deficiency is a disorder of the mitochondrial respiratory chain that causes a wide range of clinical manifestations, from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber's hereditary optic neuropathy, and some forms of Parkinson's disease. Leigh syndrome is an early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord, and is the most common mitochondrial encephalomyopathy. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, dysphagia, and lactic acidosis.[10][3][11]
# Interactions
In addition to co-subunits for complex I, NDUFS7 has protein-protein interactions with ENO2 and ARRB2.[12][13] | https://www.wikidoc.org/index.php/NDUFS7 | |
78d983c2d3ae5a4b023bc74a8048fa75b6f5b305 | wikidoc | NDUFS8 | NDUFS8
NADH dehydrogenase iron-sulfur protein 8, mitochondrial also known as NADH-ubiquinone oxidoreductase 23 kDa subunit, Complex I-23kD (CI-23kD), or TYKY subunit is an enzyme that in humans is encoded by the NDUFS8 gene. The NDUFS8 protein is a subunit of NADH dehydrogenase (ubiquinone) also known as Complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in this gene have been associated with Leigh syndrome.
# Structure
NDUFS8 is located on the q arm of chromosome 11 in position 13.2. The NDUFS8 gene produces a 23.7 kDa protein composed of 210 amino acids. The encoded protein, TYKY, contains two 4Fe4S ferredoxin consensus patterns which are believed to be iron-sulfur cluster N-2 binding sites. Studies of other subunits of Complex I have suggested that the subunits TYKY, PSST, 49 kDa, ND1, and ND5 interact with iron-sulfur clusters to form the catalytic core of NADH dehydrogenase (ubiquinone).
# Function
This gene encodes a subunit of mitochondrial NADH:ubiquinone oxidoreductase, or Complex I, a multimeric enzyme of the respiratory chain responsible for NADH oxidation, ubiquinone reduction, and the ejection of protons from mitochondria. The encoded protein is involved in the binding of two of the six to eight iron-sulfur clusters of Complex I and, as such, is required in the electron transfer process.
# Clinical significance
Mutations in NDUFS8 have been associated with mitochondrial diseases, which can cause any one of a clinically heterogeneous group of disorders arising from dysfunction of the mitochondrial respiratory chain. The phenotypic spectrum ranges from isolated diseases affecting single organs to severe multisystem disorders. Common clinical features include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, encephalopathy, seizures, stroke-like episodes, ataxia, spasticity and lactic acidosis. Mitochondrial disorders can be caused by mutations of mitochondrial DNA or nuclear DNA that either affect oxidative phosphorylation proteins directly, or affect respiratory chain function by impacting the production of the complex machinery needed to run this process.
NDUFS8 mutations have also been associated with Leigh syndrome. Leigh syndrome is an early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, dysphagia and lactic acidosis. One case report of a pathogenic mutation in NDUFS8 found that it resulted in complex I mitochondrial deficiency and a diagnosis of Leigh syndrome. The patient’s symptoms included apnea, cyanosis, hypercarbia, hypotonia, brisk tendon reflexes, ankle clonus, and erratic seizures. Further analysis revealed increased lactate, cerebral lesions, and a hypertrophic obstructive cardiomyopathy.
# Interactions
In addition to co-subunits for complex I, NDUFS8 has protein-protein interactions with MLH1 and GEM. | NDUFS8
NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial also known as NADH-ubiquinone oxidoreductase 23 kDa subunit, Complex I-23kD (CI-23kD), or TYKY subunit is an enzyme that in humans is encoded by the NDUFS8 gene.[1][2][3][4] The NDUFS8 protein is a subunit of NADH dehydrogenase (ubiquinone) also known as Complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[5] Mutations in this gene have been associated with Leigh syndrome.[3]
# Structure
NDUFS8 is located on the q arm of chromosome 11 in position 13.2.[3] The NDUFS8 gene produces a 23.7 kDa protein composed of 210 amino acids.[6][7] The encoded protein, TYKY, contains two 4Fe4S ferredoxin consensus patterns which are believed to be iron-sulfur cluster N-2 binding sites.[8] Studies of other subunits of Complex I have suggested that the subunits TYKY, PSST, 49 kDa, ND1, and ND5 interact with iron-sulfur clusters to form the catalytic core of NADH dehydrogenase (ubiquinone).[9]
# Function
This gene encodes a subunit of mitochondrial NADH:ubiquinone oxidoreductase, or Complex I, a multimeric enzyme of the respiratory chain responsible for NADH oxidation, ubiquinone reduction, and the ejection of protons from mitochondria. The encoded protein is involved in the binding of two of the six to eight iron-sulfur clusters of Complex I and, as such, is required in the electron transfer process.[3]
# Clinical significance
Mutations in NDUFS8 have been associated with mitochondrial diseases, which can cause any one of a clinically heterogeneous group of disorders arising from dysfunction of the mitochondrial respiratory chain. The phenotypic spectrum ranges from isolated diseases affecting single organs to severe multisystem disorders. Common clinical features include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, encephalopathy, seizures, stroke-like episodes, ataxia, spasticity and lactic acidosis. Mitochondrial disorders can be caused by mutations of mitochondrial DNA or nuclear DNA that either affect oxidative phosphorylation proteins directly, or affect respiratory chain function by impacting the production of the complex machinery needed to run this process.[4]
NDUFS8 mutations have also been associated with Leigh syndrome. Leigh syndrome is an early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, dysphagia and lactic acidosis.[4] One case report of a pathogenic mutation in NDUFS8 found that it resulted in complex I mitochondrial deficiency and a diagnosis of Leigh syndrome. The patient’s symptoms included apnea, cyanosis, hypercarbia, hypotonia, brisk tendon reflexes, ankle clonus, and erratic seizures. Further analysis revealed increased lactate, cerebral lesions, and a hypertrophic obstructive cardiomyopathy.[8]
# Interactions
In addition to co-subunits for complex I, NDUFS8 has protein-protein interactions with MLH1 and GEM.[10][11] | https://www.wikidoc.org/index.php/NDUFS8 | |
4c655b588145b57966785aa95c1a5d62c19c9039 | wikidoc | NDUFV1 | NDUFV1
NADH dehydrogenase flavoprotein 1, mitochondrial (NDUFV1) is an enzyme that in humans is encoded by the NDUFV1 gene. The NDUFV1 gene encodes the 51-kD subunit of complex I (NADH:ubiquinone oxidoreductase) of the mitochondrial respiratory chain. Defects in complex I are a common cause of mitochondrial dysfunction. Mitochondrial complex I deficiency is linked to myopathies, encephalomyopathies, and neurodegenerative disorders such as Parkinson's disease and Leigh syndrome.
# Structure
NDUFV1 is located on the q arm of chromosome 11 in position 13.2 and has 10 exons. The NDUFV1 gene produces a 50.8 kDa protein composed of 464 amino acids. NDUFV1, the protein encoded by this gene, is a member of the complex I 51 kDa subunit family. This subunit carries the NADH-binding site as well as flavin mononucleotide (FMN)- and Fe-S-binding sites. It also contains a transit peptide domain and is composed of 6 turns, 14 beta strands, and 19 alpha helixes.
# Function
Complex I is composed of 45 different subunits. NDUFV1 is a component of the flavoprotein-sulfur (FP) fragment of the enzyme. NDUFV1 is an oxidoreductase and core subunit of complex I that is thought to be required for assembly and catalysis. It is a peripheral membrane protein located on the matrix side of the mitochondrion inner membrane.
## Catalytic Activity
NADH + ubiquinone + 5 H+(In) = NAD+ + ubiquinol + 4 H+(Out).
NADH + acceptor = NAD+ + reduced acceptor.
# Clinical significance
Mutations in the NDUFV1 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders. Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible. However, the majority of cases are caused by mutations in nuclear-encoded genes. It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. Clinical manifestations can include lactic acidosis, cerebral degeneration, ophthalmoplegia, ataxia, spasticity, and dystonia resulting from mutations in NDUFV1.
# Interactions
NDUFV1 has been shown to have 103 binary protein-protein interactions including 97 co-complex interactions. NDUFV1 appears to interact with EWSR1, CREB1, NCOR1, and VDAC1. | NDUFV1
NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial (NDUFV1) is an enzyme that in humans is encoded by the NDUFV1 gene.[1] The NDUFV1 gene encodes the 51-kD subunit of complex I (NADH:ubiquinone oxidoreductase) of the mitochondrial respiratory chain. Defects in complex I are a common cause of mitochondrial dysfunction. Mitochondrial complex I deficiency is linked to myopathies, encephalomyopathies, and neurodegenerative disorders such as Parkinson's disease and Leigh syndrome.[2]
# Structure
NDUFV1 is located on the q arm of chromosome 11 in position 13.2 and has 10 exons.[2] The NDUFV1 gene produces a 50.8 kDa protein composed of 464 amino acids.[3][4] NDUFV1, the protein encoded by this gene, is a member of the complex I 51 kDa subunit family. This subunit carries the NADH-binding site as well as flavin mononucleotide (FMN)- and Fe-S-binding sites.[2] It also contains a transit peptide domain and is composed of 6 turns, 14 beta strands, and 19 alpha helixes.[5][6]
# Function
Complex I is composed of 45 different subunits. NDUFV1 is a component of the flavoprotein-sulfur (FP) fragment of the enzyme.[7] NDUFV1 is an oxidoreductase and core subunit of complex I that is thought to be required for assembly and catalysis. It is a peripheral membrane protein located on the matrix side of the mitochondrion inner membrane.[5][6]
## Catalytic Activity
NADH + ubiquinone + 5 H+(In) = NAD+ + ubiquinol + 4 H+(Out).
NADH + acceptor = NAD+ + reduced acceptor.[5][6]
# Clinical significance
Mutations in the NDUFV1 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders.[8][9] Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible.[10] However, the majority of cases are caused by mutations in nuclear-encoded genes.[11][12] It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.[13] Clinical manifestations can include lactic acidosis, cerebral degeneration, ophthalmoplegia, ataxia, spasticity, and dystonia resulting from mutations in NDUFV1.[14][15]
# Interactions
NDUFV1 has been shown to have 103 binary protein-protein interactions including 97 co-complex interactions. NDUFV1 appears to interact with EWSR1, CREB1, NCOR1, and VDAC1.[16] | https://www.wikidoc.org/index.php/NDUFV1 | |
d75cebbbd495f1f661e720f931c385c04b39a288 | wikidoc | NDUFV2 | NDUFV2
NADH dehydrogenase flavoprotein 2, mitochondrial (NDUFV2) is an enzyme that in humans is encoded by the NDUFV2 gene. The encoded protein, NDUFV2, is a subunit of complex I of the mitochondrial respiratory chain, which is located on the inner mitochondrial membrane and involved in oxidative phosphorylation. Mutations in this gene are implicated in Parkinson's disease, bipolar disorder, schizophrenia, and have been found in one case of early onset hypertrophic cardiomyopathy and encephalopathy.
# Structure
NDUFV2 is located on the p arm of chromosome 18 in position 11.22 and has 9 exons. The NDUFV2 gene produces a 27.4 kDa protein composed of 249 amino acids. NDUFV2, the protein encoded by this gene, is a member of the complex I 24 kDa subunit family. It contains a cofactor binding site for a 2Fe-2S cluster and a transit peptide domain. The protein consists of 2 turns, 3 beta strands, and 7 alpha helixes. A non-transcribed pseudogene of this locus is found on chromosome 19.
# Function
The NADH-ubiquinone oxidoreductase complex (complex I) of the mitochondrial respiratory chain catalyzes the transfer of electrons from NADH to ubiquinone, and consists of at least 43 subunits. The complex is located in the inner mitochondrial membrane. This gene encodes the 24 kDa subunit of complex I, and is involved in electron transfer. NDUFV2 is an oxidoreductase and a component of the flavoprotein-sulfur (FP) fragment of the enzyme. It is thought to be required for assembly and catalysis.
## Catalytic activity
NADH + ubiquinone + 5 H+(In) = NAD+ + ubiquinol + 4 H+(Out).
NADH + acceptor = NAD+ + reduced acceptor.
# Clinical significance
Mutations in the NDUFV2 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders. Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible. However, the majority of cases are caused by mutations in nuclear-encoded genes. It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.
# Interactions
NDUFV2 has been shown to have 102 binary protein-protein interactions including 80 co-complex interactions. NDUFV2 appears to interact with HSCB, CCNC, GOLM1, FAM114A2, CRMP1, KAT5, SP110. | NDUFV2
NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial (NDUFV2) is an enzyme that in humans is encoded by the NDUFV2 gene.[1][2] The encoded protein, NDUFV2, is a subunit of complex I of the mitochondrial respiratory chain, which is located on the inner mitochondrial membrane and involved in oxidative phosphorylation. Mutations in this gene are implicated in Parkinson's disease, bipolar disorder, schizophrenia, and have been found in one case of early onset hypertrophic cardiomyopathy and encephalopathy.[3]
# Structure
NDUFV2 is located on the p arm of chromosome 18 in position 11.22 and has 9 exons.[3] The NDUFV2 gene produces a 27.4 kDa protein composed of 249 amino acids.[4][5] NDUFV2, the protein encoded by this gene, is a member of the complex I 24 kDa subunit family. It contains a cofactor binding site for a 2Fe-2S cluster and a transit peptide domain. The protein consists of 2 turns, 3 beta strands, and 7 alpha helixes.[6][7] A non-transcribed pseudogene of this locus is found on chromosome 19.[3]
# Function
The NADH-ubiquinone oxidoreductase complex (complex I) of the mitochondrial respiratory chain catalyzes the transfer of electrons from NADH to ubiquinone, and consists of at least 43 subunits. The complex is located in the inner mitochondrial membrane. This gene encodes the 24 kDa subunit of complex I, and is involved in electron transfer.[3] NDUFV2 is an oxidoreductase and a component of the flavoprotein-sulfur (FP) fragment of the enzyme.[8] It is thought to be required for assembly and catalysis.[6][7]
## Catalytic activity
NADH + ubiquinone + 5 H+(In) = NAD+ + ubiquinol + 4 H+(Out).
NADH + acceptor = NAD+ + reduced acceptor.[6][7]
# Clinical significance
Mutations in the NDUFV2 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders.[9][10] Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible.[11] However, the majority of cases are caused by mutations in nuclear-encoded genes.[12][13] It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.[14]
# Interactions
NDUFV2 has been shown to have 102 binary protein-protein interactions including 80 co-complex interactions. NDUFV2 appears to interact with HSCB, CCNC, GOLM1, FAM114A2, CRMP1, KAT5, SP110.[15] | https://www.wikidoc.org/index.php/NDUFV2 | |
84f74bdf7bd8c0cef5095b9dcb6bdee53f07d45b | wikidoc | NEDD4L | NEDD4L
Neural precursor cell expressed developmentally downregulated gene 4-like (NEDD4L) or NEDD4-2 (NEDD4-2) is an enzyme (ubiquitin ligase) of the NEDD4 family.
In human the protein is encoded by the NEDD4L gene. In mouse the protein is commonly known as NEDD4-2 and the gene Nedd4-2.
NEDD4-2 has been shown to ubiquitinate and therefore down regulate the epithelial sodium channel (ENaC) in the collecting ducts of the kidneys, therefore opposing the actions of aldosterone and increasing salt excretion. In Liddle's Syndrome NEDD4 is unable to bind to the ENaC and lead to salt retention and hypertension occur.
NEDD4L belongs to the NEDD4 family of E3 HECT domain ubiquitin ligases. It is the closest homologue of NEDD4, the prototypic member of the family and probably arose as a result of gene duplication. While NEDD4 orthologues are present in all eukaryotes, NEDD4L proteins are limited to vertebrates. NEDD4L proteins are known to be involved in regulating many membrane proteins via ubiquitination and endocytosis.
NEDD4L protein is expressed widely. The primary targets of NEDD4-2 include the epithelial sodium channel (ENaC), the Na+-Cl- co-transporter (NCC), and the voltage gated sodium channels (Navs), although additional targets are predicted from in vitro studies. NEDD4-2 gene in mice is essential for animal survival and the polymorphisms in NEDD4L are associated with human hypertension.
# Protein architecture
The NEDD4-2 protein consists of an amino-terminal Ca2+-phospholipid binding domain (C2), 4 WW domains (protein-protein interaction domains) and the carboxyl-terminal HECT domain (ubiquitin ligase domain). The WW domains in the protein are responsible for binding the substrates, regulatory proteins and adaptors. These domains generally recognize PPxY (or similar) motifs in the target proteins.
# Expression
Human NEDD4L gene is located on chromosome 18q12.31 with 38 exons that transcribe multiple splice variants of NEDD4L. The protein expressed in the brain, lung, heart and the kidney contains a C2 domain. Three predominant forms of NEDD4L are isoform I containing a novel C2 domain with a start codon in exon1, isoform II with an intact conserved C2 domain consisting of an alternate start codon in exon 1 upstream of the actual start codon of the isoform 1, and isoform III lacking a C2 domain due to exon 2a–3 splicing. Isoform 1 is found to be abundant in kidney and adrenal gland whereas isoform 2 is predominantly found in the lungs. The antibodies specific to NEDD4-2 recognize two species of ~110-115 kDa in most tissues, with one being variable depending on the tissue.
# Function
NEDD4L is a ubiquitin-protein ligase (E3) that accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then transfers it to specific substrates.
In vivo NEDD4-2 regulates ENaC in the lung and kidney, the renal NCC and several Navs.
It has also been shown to regulate EGFR, TGFβ receptor and WNT signalling.
NEDD4L has been implicated in viral budding and viral latency processes via ubiquitination of viral proteins.
In vitro data implicate NEDD4-2 in the regulation of many other proteins, including several ion channels and transporters. However most of these results have not been validated in vivo.
# Regulation of NEDD4-2
NDFIP1 and NDFIP2 proteins bind NEDD4-2 and regulate its activity and/or interaction with substrates.
NEDD4-2 phosphorylation by kinases SGK1 and AKT in response to insulin and aldosterone signaling results in its interaction with 14-3-3 proteins. 14-3-3 binding to NEDD4-2 inhibits its ability to bind and ubiquitinate its substrates (such the ENaC subunits).
Autoubiquitination and deubiquitylation of NEDD4-2 by USP2-45 are also known to maintain NEDD4-2 protein stability.
# Clinical significance
NEDD4L is a critical regulator of renal ENaC and NCC and malfunction of this pathway has been linked to hypertension, as in Liddle's syndrome, a genetic disorder where mutations in the ENaC subunits abrogate NEDD4L binding.
In mouse, NEDD4-2 deletion leads to increased cell surface expression and activity of ENaC in the lung, resulting in premature clearance of lung fluid, airway drying, lung inflammation and perinatal lethality.
Specific deletion of NEDD4-2 in mouse renal tubules leads to increased expression of ENaC and NCC. Consistent with the critical function in ENaC and NCC regulation, NEDDL polymorphisms are linked to essential hypertension in certain human populations. Specific deletion of NEDD4-2 in mouse neurons results in axonal branching defects. Isolated fetal cortical neurons from NEDD4-2 knockout mice show defective regulation of voltage-gated sodium currents, and in animal models of neuropathic pain NEDD4-2 expression has been found to be downregulated. Also NEDD4-2-deficiency results in hyperexcitability of DRG neurons and contributes to pathological pain
# Interactions
NEDD4L has been shown to interact with SCNN1A. | NEDD4L
Neural precursor cell expressed developmentally downregulated gene 4-like (NEDD4L) or NEDD4-2 (NEDD4-2) is an enzyme (ubiquitin ligase) of the NEDD4 family.
In human the protein is encoded by the NEDD4L gene.[1][2][3][4] In mouse the protein is commonly known as NEDD4-2 and the gene Nedd4-2.
NEDD4-2 has been shown to ubiquitinate and therefore down regulate the epithelial sodium channel (ENaC) in the collecting ducts of the kidneys, therefore opposing the actions of aldosterone and increasing salt excretion. In Liddle's Syndrome NEDD4 is unable to bind to the ENaC and lead to salt retention and hypertension occur.[5]
NEDD4L belongs to the NEDD4 family of E3 HECT domain ubiquitin ligases.[6][7][8][9] It is the closest homologue of NEDD4, the prototypic member of the family and probably arose as a result of gene duplication.[8] While NEDD4 orthologues are present in all eukaryotes, NEDD4L proteins are limited to vertebrates. NEDD4L proteins are known to be involved in regulating many membrane proteins via ubiquitination and endocytosis.[6]
NEDD4L protein is expressed widely. The primary targets of NEDD4-2 include the epithelial sodium channel (ENaC), the Na+-Cl- co-transporter (NCC), and the voltage gated sodium channels (Navs), although additional targets are predicted from in vitro studies. NEDD4-2 gene in mice is essential for animal survival and the polymorphisms in NEDD4L are associated with human hypertension.[7][9]
# Protein architecture
The NEDD4-2 protein consists of an amino-terminal Ca2+-phospholipid binding domain (C2), 4 WW domains (protein-protein interaction domains) and the carboxyl-terminal HECT domain (ubiquitin ligase domain). The WW domains in the protein are responsible for binding the substrates, regulatory proteins and adaptors. These domains generally recognize PPxY (or similar) motifs in the target proteins.[6][7][8][9]
# Expression
Human NEDD4L gene is located on chromosome 18q12.31 with 38 exons that transcribe multiple splice variants of NEDD4L.[10][11] The protein expressed in the brain, lung, heart and the kidney contains a C2 domain. Three predominant forms of NEDD4L are isoform I containing a novel C2 domain with a start codon in exon1, isoform II with an intact conserved C2 domain consisting of an alternate start codon in exon 1 upstream of the actual start codon of the isoform 1, and isoform III lacking a C2 domain due to exon 2a–3 splicing. Isoform 1 is found to be abundant in kidney and adrenal gland whereas isoform 2 is predominantly found in the lungs.[11][12] The antibodies specific to NEDD4-2 recognize two species of ~110-115 kDa in most tissues, with one being variable depending on the tissue.[11][13]
# Function
NEDD4L is a ubiquitin-protein ligase (E3) that accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then transfers it to specific substrates.[7][8][9]
In vivo NEDD4-2 regulates ENaC in the lung and kidney, the renal NCC and several Navs.[12][12][14][15][16]
It has also been shown to regulate EGFR, TGFβ receptor and WNT signalling.[17][18]
NEDD4L has been implicated in viral budding and viral latency processes via ubiquitination of viral proteins.[7][9][19]
In vitro data implicate NEDD4-2 in the regulation of many other proteins, including several ion channels and transporters. However most of these results have not been validated in vivo.[8][9]
# Regulation of NEDD4-2
NDFIP1 and NDFIP2 proteins bind NEDD4-2 and regulate its activity and/or interaction with substrates.[20][21]
NEDD4-2 phosphorylation by kinases SGK1 and AKT in response to insulin and aldosterone signaling results in its interaction with 14-3-3 proteins. 14-3-3 binding to NEDD4-2 inhibits its ability to bind and ubiquitinate its substrates (such the ENaC subunits).[22][23][24][25]
Autoubiquitination and deubiquitylation of NEDD4-2 by USP2-45 are also known to maintain NEDD4-2 protein stability.[26][27]
# Clinical significance
NEDD4L is a critical regulator of renal ENaC and NCC and malfunction of this pathway has been linked to hypertension, as in Liddle's syndrome, a genetic disorder where mutations in the ENaC subunits abrogate NEDD4L binding.[13][28][29]
In mouse, NEDD4-2 deletion leads to increased cell surface expression and activity of ENaC in the lung, resulting in premature clearance of lung fluid, airway drying, lung inflammation and perinatal lethality.[28][30]
Specific deletion of NEDD4-2 in mouse renal tubules leads to increased expression of ENaC and NCC. Consistent with the critical function in ENaC and NCC regulation, NEDDL polymorphisms are linked to essential hypertension in certain human populations.[31][32] Specific deletion of NEDD4-2 in mouse neurons results in axonal branching defects.[33] Isolated fetal cortical neurons from NEDD4-2 knockout mice show defective regulation of voltage-gated sodium currents,[34] and in animal models of neuropathic pain NEDD4-2 expression has been found to be downregulated.[35] Also NEDD4-2-deficiency results in hyperexcitability of DRG neurons and contributes to pathological pain[36]
# Interactions
NEDD4L has been shown to interact with SCNN1A.[2][37] | https://www.wikidoc.org/index.php/NEDD4L | |
ef7d87e85552d1f521605b674708aab3f2385138 | wikidoc | NFATC2 | NFATC2
Nuclear factor of activated T-cells, cytoplasmic 2 is a protein that in humans is encoded by the NFATC2 gene.
# Function
This gene is a member of the nuclear factor of activated T cells (NFAT) family. The product of this gene is a DNA-binding protein with a REL-homology region (RHR) and an NFAT-homology region (NHR). This protein is present in the cytosol and only translocates to the nucleus upon T cell receptor (TCR) stimulation, where it becomes a member of the nuclear factors of activated T cells transcription complex. This complex plays a central role in inducing gene transcription during the immune response. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.
# Clinical significance
NFAT transcription factors are implicated in breast cancer, more specifically in the process of cell motility at the basis of metastasis formation. Indeed, NFAT1 (NFATC2) is pro-invasive and pro-migratory in breast carcinoma.
To increase cell motility NFAT1 up-regulates the gene of the Lipocalin 2 expression and modulate the TWEAKR/TWEAK axis.
Translocation forming an in frame fusions product between EWSR1 gene and the NFATc2 gene has been described in bone tumor with a Ewing sarcoma-like clinical appearance. The translocation breakpoint led to the loss of the controlling elements of the NFATc2 protein and the fusion of the N terminal region of the EWSR1 gene conferred constant activation of the protein.
# Interactions
NFATC2 has been shown to interact with MEF2D, EP300, IRF4 and Protein kinase Mζ. | NFATC2
Nuclear factor of activated T-cells, cytoplasmic 2 is a protein that in humans is encoded by the NFATC2 gene.[1]
# Function
This gene is a member of the nuclear factor of activated T cells (NFAT) family. The product of this gene is a DNA-binding protein with a REL-homology region (RHR) and an NFAT-homology region (NHR). This protein is present in the cytosol and only translocates to the nucleus upon T cell receptor (TCR) stimulation, where it becomes a member of the nuclear factors of activated T cells transcription complex. This complex plays a central role in inducing gene transcription during the immune response. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[2]
# Clinical significance
NFAT transcription factors are implicated in breast cancer, more specifically in the process of cell motility at the basis of metastasis formation. Indeed, NFAT1 (NFATC2) is pro-invasive and pro-migratory in breast carcinoma.[3][4]
To increase cell motility NFAT1 up-regulates the gene of the Lipocalin 2 expression and modulate the TWEAKR/TWEAK axis.[5]
Translocation forming an in frame fusions product between EWSR1 gene and the NFATc2 gene has been described in bone tumor with a Ewing sarcoma-like clinical appearance. The translocation breakpoint led to the loss of the controlling elements of the NFATc2 protein and the fusion of the N terminal region of the EWSR1 gene conferred constant activation of the protein.[6]
# Interactions
NFATC2 has been shown to interact with MEF2D,[7] EP300,[8] IRF4[9] and Protein kinase Mζ.[10] | https://www.wikidoc.org/index.php/NFATC2 | |
e302a1fc327b1f65abf84eaa9850673f8c207858 | wikidoc | NFATC4 | NFATC4
Nuclear factor of activated T-cells, cytoplasmic 4 is a protein that in humans is encoded by the NFATC4 gene.
# Function
The product of this gene is a member of the nuclear factors of activated T cells DNA-binding transcription complex. This complex consists of at least two components: a preexisting cytosolic component that translocates to the nucleus upon T cell receptor (TCR) stimulation and an inducible nuclear component. Other members of this family of nuclear factors of activated T cells also participate in the formation of this complex. The product of this gene plays a role in the inducible expression of cytokine genes in T cells, especially in the induction of the IL-2 and IL-4.
NFAT transcription factors are implicated in breast cancer, more specifically in the process of cell motility at the basis of metastasis formation. Indeed, NFAT3 (NFATc4) is an inhibitor of cell motility by blocking the expression of LCN2.
# Interactions
NFATC4 has been shown to interact with CREB-binding protein. | NFATC4
Nuclear factor of activated T-cells, cytoplasmic 4 is a protein that in humans is encoded by the NFATC4 gene.[1][2]
# Function
The product of this gene is a member of the nuclear factors of activated T cells DNA-binding transcription complex. This complex consists of at least two components: a preexisting cytosolic component that translocates to the nucleus upon T cell receptor (TCR) stimulation and an inducible nuclear component. Other members of this family of nuclear factors of activated T cells also participate in the formation of this complex. The product of this gene plays a role in the inducible expression of cytokine genes in T cells, especially in the induction of the IL-2 and IL-4.[2]
NFAT transcription factors are implicated in breast cancer, more specifically in the process of cell motility at the basis of metastasis formation. Indeed, NFAT3 (NFATc4) is an inhibitor of cell motility by blocking the expression of LCN2.[3]
# Interactions
NFATC4 has been shown to interact with CREB-binding protein.[4] | https://www.wikidoc.org/index.php/NFATC4 | |
4b29af2721860ddaa648d0d9826bc09356c4ac31 | wikidoc | NFE2L1 | NFE2L1
Nuclear factor erythroid 2-related factor 1 (Nrf1) also known as nuclear factor erythroid-2-like 1 (NFE2L1) is a protein that in humans is encoded by the NFE2L1 gene. Since NFE2L1 is referred to as Nrf1, it is often confused with nuclear respiratory factor 1 (Nrf1).
NFE2L1 is a cap ‘n’ collar, basic-leucine zipper (bZIP) transcription factor. Several isoforms of NFE2L1 have been described for both human and mouse genes. NFE2L1 was first cloned in yeast using a genetic screening method. NFE2L1 is ubiquitously expressed, and high levels of transcript are detected in the heart, kidney, skeletal muscle, fat, and brain. Four separate regions — an asparagine/serine/threonine, acidic domains near the N-terminus, and a serine-rich domain located near the CNC motif — are required for full transactivation function of NFE2L1. NFE2L1 is a key regulator of cellular functions including oxidative stress response, differentiation, inflammatory response, metabolism, cholesterol handling and maintaining proteostasis.
# Interactions
NFE2L1 binds DNA as heterodimers with one of small Maf proteins (MAFF, MAFG, MAFK). NFE2L1 has been shown to interact with C-jun.
# Cellular homeostasis
NFE2L1 regulates a wide variety of cellular responses, several of which are related to important aspects of protection from stress stimuli. NFE2L1 is involved in providing cellular protection against oxidative stress through the induction of antioxidant genes. The glutathione synthesis pathway is catalyzed by glutamate-cysteine ligase, which contains the catalytic GCLC and regulatory GCLM, and glutathione synthetase (GSS). Nfe2l1 was found to regulate Gclm and Gss expression in mouse fibroblasts. Gclm was found to be a direct target of Nfe2l1, and Nfe2l1 also regulates Gclc expression through an indirect mechanism. Nfe2l1 knockout mice also exhibit down-regulation of Gpx1 and Hmox1, and Nfe2l1 (this gene)-deficient hepatocytes from liver-specific Nfe2l1 knockout mice showed decreased expression of various Gst genes. Metallothioenein-1 and Metallothioenein-2 genes, which protect cells against cytotoxicity induced by toxic metals, are also direct targets of Nfe2l1.
Nfe2l1 is also involved in maintaining proteostasis. Brains of mice with conditional knockout of Nfe2l1 in neuronal cells showed decreased proteasome activity and accumulation of ubiquitin-conjugated proteins, and down regulation of genes encoding the 20S core and 19S regulatory sub-complexes of the 26S proteasome. A similar effect on proteasome gene expression and function was observed in livers of mice with Nfe2l1 conditional knockout in hepatocytes. Induction of proteasome genes was also lost in brains and livers of Nfe2l1 conditional knockout mice. Re-establishment of Nfe2l1 function in Nfe2l1 null cells rescued proteasome expression and function, indicating Nfe2l1 was necessary for induction of proteasome genes (bounce-back response) in response to proteasome inhibition. This compensatory up-regulation of proteasome genes in response to proteasome inhibition has also been demonstrated to be Nfe2l1-dependent in various other cell types. NFE2L1 was shown to directly bind and activate expression of the PsmB6 gene, which encodes a catalytic subunit of the 20S core. Nfe2l1 was also shown to regulate expression of Herpud1 and Vcp/p97, which are components of the ER-associated degradation pathway.
Nfe2l1 also plays a role in metabolic processes. Loss of hepatic Nfe2l1 has been shown to result in lipid accumulation, hepatocellular damage, cysteine accumulation, and altered fatty acid composition. Glucose homeostasis and insulin secretion have also been found to be under the control of Nfe2l1. Insulin-regulated glycolytic genes—Gck, Aldob, Pgk1, and Pklr, hepatic glucose transporter gene — SLC2A2, and gluconeogenic genes — Fbp1 and Pck1 were repressed in livers of Nfe2l1 transgenic mice. Nfe2l1 may also play a role in maintaining chromosomal stability and genomic integrity by inducing expression of genes encoding components of the spindle assembly and kinetochore. Nfe2l1 has also been shown to sense and respond to excess cholesterol in the ER.
# Regulation
NFE2L1 is an ER membrane protein. Its N-terminal domain (NTD) anchors the protein to the membrane. Specifically, amino acid residues 7 to 24 are known to be a hydrophobic domain that serves as a transmembrane region. The concerted mechanism of HRD1, a member of E3-ubiquitin ligase family, and p97/VCP1 was found to play an important role in the degradation of NFE2L1 through the ER Associated Degradation (ERAD) pathway and the release of NFE2L1 from the ER membrane. NFE2L1 is also regulated by other ubiquitin ligases and kinases. FBXW7, a member of the SCF ubiquitin ligase family, targets NFE2L1 for proteolytic degradation by the proteasome. FBXW7 requires the Cdc4 phosphodegron domain within NFE2L1 to be phosphorylated via Glycogen Kinase 3. Casein Kinase 2 was shown to phosphorylate Ser497 of NFE2L1, which attenuates the activity of NFE2L1 on proteasome gene expression. NFE2L1 also interacts with another member of the SCF ligase ubiquitin family known as β-TrCP. β-TrCP also binds to the DSGLC motif, a highly conserved region of CNC-bZIP proteins, in order to poly-ubiquitinate NFE2L1 prior to its proteolytic degradation. Phosphorylation of Ser599 by protein kinase A enables NFE2L1 and C/EBP-β to dimerize to repress DSPP expression during odontoblast differentiation. NFE2L1 expression and activation is also controlled by cellular stresses. Oxidative stress induced by arsenic and t-butyl hydroquinone leads to accumulation of NFE2L1 protein inside the nucleus as well as higher activation on antioxidant genes. Treatment with an ER stress inducer tunicamycin was shown to induce accumulation of NFE2L1 inside the nucleus; however, it was not associated with increased activity, suggesting further investigation is needed to elucidate the role of ER stress on NFE2L1. Hypoxia was also shown to increase the expression of NFE2L1 while attenuating expression of the p65 isoform of NFE2L1. Growth factors affect expression of NFE2L1 through a mTORC and SREBP-1 mediated pathway. Growth factors induce higher activity of mTORC, which then promotes activity of its downstream protein SREBP-1, a transcription factor for NFE2L1.
# Animal studies
Loss and gain of function studies in mice showed that dysregulation of Nfe2l1 leads to pathological states that could have relevance in human diseases. Nfe2l1 is crucial for embryonic development and survival of hepatocytes during development. Loss of Nfe2l1 in mouse hepatocytes leads to steatosis, inflammation, and tumorigenesis. Nfe2l1 is also necessary for neuronal homeostasis. Loss of Nfe2l1 function is also associated with insulin resistance. Mice with conditional deletion of Nfe2l1 in pancreatic β-cells exhibited severe fasting hyperinsulinemia and glucose intolerance, suggesting that Nfe2l1 may play a role in the development of type-2 diabetes Future studies may provide therapeutic efforts involving Nfe2l1 for cancer, neurodegeneration, and metabolic diseases. | NFE2L1
Nuclear factor erythroid 2-related factor 1 (Nrf1) also known as nuclear factor erythroid-2-like 1 (NFE2L1) is a protein that in humans is encoded by the NFE2L1 gene.[1][2][3] Since NFE2L1 is referred to as Nrf1, it is often confused with nuclear respiratory factor 1 (Nrf1).
NFE2L1 is a cap ‘n’ collar, basic-leucine zipper (bZIP) transcription factor. Several isoforms of NFE2L1 have been described for both human and mouse genes. NFE2L1 was first cloned in yeast using a genetic screening method. NFE2L1 is ubiquitously expressed, and high levels of transcript are detected in the heart, kidney, skeletal muscle, fat, and brain.[1] Four separate regions — an asparagine/serine/threonine, acidic domains near the N-terminus, and a serine-rich domain located near the CNC motif — are required for full transactivation function of NFE2L1.[4][5][6] NFE2L1 is a key regulator of cellular functions including oxidative stress response, differentiation, inflammatory response, metabolism, cholesterol handling[7] and maintaining proteostasis.
# Interactions
NFE2L1 binds DNA as heterodimers with one of small Maf proteins (MAFF, MAFG, MAFK).[8][9][6] NFE2L1 has been shown to interact with C-jun.[10]
# Cellular homeostasis
NFE2L1 regulates a wide variety of cellular responses, several of which are related to important aspects of protection from stress stimuli. NFE2L1 is involved in providing cellular protection against oxidative stress through the induction of antioxidant genes. The glutathione synthesis pathway is catalyzed by glutamate-cysteine ligase, which contains the catalytic GCLC and regulatory GCLM, and glutathione synthetase (GSS).[11] Nfe2l1 was found to regulate Gclm and Gss expression in mouse fibroblasts.[12] Gclm was found to be a direct target of Nfe2l1, and Nfe2l1 also regulates Gclc expression through an indirect mechanism.[13][14] Nfe2l1 knockout mice also exhibit down-regulation of Gpx1 and Hmox1, and Nfe2l1 (this gene)-deficient hepatocytes from liver-specific Nfe2l1 knockout mice showed decreased expression of various Gst genes.[15][16] Metallothioenein-1 and Metallothioenein-2 genes, which protect cells against cytotoxicity induced by toxic metals, are also direct targets of Nfe2l1.[17]
Nfe2l1 is also involved in maintaining proteostasis. Brains of mice with conditional knockout of Nfe2l1 in neuronal cells showed decreased proteasome activity and accumulation of ubiquitin-conjugated proteins, and down regulation of genes encoding the 20S core and 19S regulatory sub-complexes of the 26S proteasome.[18] A similar effect on proteasome gene expression and function was observed in livers of mice with Nfe2l1 conditional knockout in hepatocytes.[19] Induction of proteasome genes was also lost in brains and livers of Nfe2l1 conditional knockout mice. Re-establishment of Nfe2l1 function in Nfe2l1 null cells rescued proteasome expression and function, indicating Nfe2l1 was necessary for induction of proteasome genes (bounce-back response) in response to proteasome inhibition.[20] This compensatory up-regulation of proteasome genes in response to proteasome inhibition has also been demonstrated to be Nfe2l1-dependent in various other cell types.[21][22] NFE2L1 was shown to directly bind and activate expression of the PsmB6 gene, which encodes a catalytic subunit of the 20S core.[18][20] Nfe2l1 was also shown to regulate expression of Herpud1 and Vcp/p97, which are components of the ER-associated degradation pathway.[23][22]
Nfe2l1 also plays a role in metabolic processes. Loss of hepatic Nfe2l1 has been shown to result in lipid accumulation, hepatocellular damage, cysteine accumulation, and altered fatty acid composition.[16][24] Glucose homeostasis and insulin secretion have also been found to be under the control of Nfe2l1.[25] Insulin-regulated glycolytic genes—Gck, Aldob, Pgk1, and Pklr, hepatic glucose transporter gene — SLC2A2, and gluconeogenic genes — Fbp1 and Pck1 were repressed in livers of Nfe2l1 transgenic mice.[26] Nfe2l1 may also play a role in maintaining chromosomal stability and genomic integrity by inducing expression of genes encoding components of the spindle assembly and kinetochore.[27] Nfe2l1 has also been shown to sense and respond to excess cholesterol in the ER.[7]
# Regulation
NFE2L1 is an ER membrane protein. Its N-terminal domain (NTD) anchors the protein to the membrane. Specifically, amino acid residues 7 to 24 are known to be a hydrophobic domain that serves as a transmembrane region.[28] The concerted mechanism of HRD1, a member of E3-ubiquitin ligase family, and p97/VCP1 was found to play an important role in the degradation of NFE2L1 through the ER Associated Degradation (ERAD) pathway and the release of NFE2L1 from the ER membrane.[21][29][30] NFE2L1 is also regulated by other ubiquitin ligases and kinases. FBXW7, a member of the SCF ubiquitin ligase family, targets NFE2L1 for proteolytic degradation by the proteasome.[31] FBXW7 requires the Cdc4 phosphodegron domain within NFE2L1 to be phosphorylated via Glycogen Kinase 3.[32] Casein Kinase 2 was shown to phosphorylate Ser497 of NFE2L1, which attenuates the activity of NFE2L1 on proteasome gene expression.[33] NFE2L1 also interacts with another member of the SCF ligase ubiquitin family known as β-TrCP. β-TrCP also binds to the DSGLC motif, a highly conserved region of CNC-bZIP proteins, in order to poly-ubiquitinate NFE2L1 prior to its proteolytic degradation.[29] Phosphorylation of Ser599 by protein kinase A enables NFE2L1 and C/EBP-β to dimerize to repress DSPP expression during odontoblast differentiation.[34] NFE2L1 expression and activation is also controlled by cellular stresses. Oxidative stress induced by arsenic and t-butyl hydroquinone leads to accumulation of NFE2L1 protein inside the nucleus as well as higher activation on antioxidant genes.[5][35] Treatment with an ER stress inducer tunicamycin was shown to induce accumulation of NFE2L1 inside the nucleus; however, it was not associated with increased activity, suggesting further investigation is needed to elucidate the role of ER stress on NFE2L1.[36][5] Hypoxia was also shown to increase the expression of NFE2L1 while attenuating expression of the p65 isoform of NFE2L1.[37] Growth factors affect expression of NFE2L1 through a mTORC and SREBP-1 mediated pathway. Growth factors induce higher activity of mTORC, which then promotes activity of its downstream protein SREBP-1, a transcription factor for NFE2L1.[38][39]
# Animal studies
Loss and gain of function studies in mice showed that dysregulation of Nfe2l1 leads to pathological states that could have relevance in human diseases. Nfe2l1 is crucial for embryonic development and survival of hepatocytes during development.[2][15] Loss of Nfe2l1 in mouse hepatocytes leads to steatosis, inflammation, and tumorigenesis.[16] Nfe2l1 is also necessary for neuronal homeostasis.[18] Loss of Nfe2l1 function is also associated with insulin resistance. Mice with conditional deletion of Nfe2l1 in pancreatic β-cells exhibited severe fasting hyperinsulinemia and glucose intolerance, suggesting that Nfe2l1 may play a role in the development of type-2 diabetes[25] Future studies may provide therapeutic efforts involving Nfe2l1 for cancer, neurodegeneration, and metabolic diseases. | https://www.wikidoc.org/index.php/NFE2L1 | |
d1220ddadfa10bad5fa93f99222603e9ec5ddb6a | wikidoc | NFE2L2 | NFE2L2
Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a transcription factor that in humans is encoded by the NFE2L2 gene. Nrf2 is a basic leucine zipper (bZIP) protein that regulates the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation. Several drugs that stimulate the NFE2L2 pathway are being studied for treatment of diseases that are caused by oxidative stress.
# Function
NFE2L2 and other genes, such as NFE2, NFE2L1 and NFE2L3, encode basic leucine zipper (bZIP) transcription factors. They share highly conserved regions that are distinct from other bZIP families, such as JUN and FOS, although remaining regions have diverged considerably from each other.
Under normal or unstressed conditions, Nrf2 is kept in the cytoplasm by a cluster of proteins that degrade it quickly. Under oxidative stress, Nrf2 is not degraded, but instead travels to the nucleus where it binds to a DNA promoter and initiates transcription of antioxidative genes and their proteins.
Nrf2 is kept in the cytoplasm by Kelch like-ECH-associated protein 1 (KEAP1) and Cullin 3 which degrade Nrf2 by ubiquitination. Cullin 3 ubiquitinates Nrf2, while Keap1 is a substrate adaptor protein that facilitates the reaction. Once Nrf2 is ubiquitinated, it is transported to the proteasome, where it is degraded and its components recycled. Under normal conditions Nrf2 has a half-life of only 20 minutes. Oxidative stress or electrophilic stress disrupts critical cysteine residues in Keap1, disrupting the Keap1-Cul3 ubiquitination system. When Nrf2 is not ubiquitinated, it builds up in the cytoplasm, and translocates into the nucleus. In the nucleus, it combines (forms a heterodimer) with one of small Maf proteins (MAFF, MAFG, MAFK) and binds to the antioxidant response element (ARE) in the upstream promoter region of many antioxidative genes, and initiates their transcription.
# Target genes
Activation of Nrf2 results in the induction of many cytoprotective proteins. These include, but are not limited to, the following:
- NAD(P)H quinone oxidoreductase 1 (Nqo1) is a prototypical Nrf2 target gene that catalyzes the reduction and detoxification of highly reactive quinones that can cause redox cycling and oxidative stress.
- Glutamate-cysteine ligase, catalytic (Gclc) and glutamate-cysteine ligase, modifier (GCLM) subunits form a heterodimer, which is the rate-limiting step in the synthesis of glutathione (GSH), a very powerful endogenous antioxidant. Both Gclc and Gclm are characteristic Nrf2 target genes, which establish Nrf2 as a regulator of glutathione, one of the most important antioxidants in the body.
- Sulfiredoxin 1 (SRXN1) and Thioredoxin reductase 1 (TXNRD1) support the reduction and recovery of peroxiredoxins, proteins important in the detoxification of highly reactive peroxides, including hydrogen peroxide and peroxynitrite.
- Heme oxygenase-1 (HMOX1, HO-1) is an enzyme that catalyzes the breakdown of heme into the antioxidant biliverdin, the anti-inflammatory agent carbon monoxide, and iron. HO-1 is a Nrf2 target gene that has been shown to protect from a variety of pathologies, including sepsis, hypertension, atherosclerosis, acute lung injury, kidney injury, and pain. In a recent study, however, induction of HO-1 has been shown to exacerbate early brain injury after intracerebral hemorrhage.
- The glutathione S-transferase (GST) family includes cytosolic, mitochondrial, and microsomal enzymes that catalyze the conjugation of GSH with endogenous and xenobiotic electrophiles. After detoxification by glutathione (GSH) conjugation catalyzed by GSTs, the body can eliminate potentially harmful and toxic compounds. GSTs are induced by Nrf2 activation and represent an important route of detoxification.
- The UDP-glucuronosyltransferase (UGT) family catalyze the conjugation of a glucuronic acid moiety to a variety of endogenous and exogenous substances, making them more water-soluble and readily excreted. Important substrates for glucuronidation include bilirubin and acetaminophen. Nrf2 has been shown to induce UGT1A1 and UGT1A6.
- Multidrug resistance-associated proteins (Mrps) are important membrane transporters that efflux various compounds from various organs and into bile or plasma, with subsequent excretion in the feces or urine, respectively. Mrps have been shown to be upregulated by Nrf2 and alteration in their expression can dramatically alter the pharmacokinetics and toxicity of compounds.
# Structure
Nrf2 is a basic leucine zipper (bZip) transcription factor with a Cap “n” Collar (CNC) structure. Nrf2 possesses six highly conserved domains called Nrf2-ECH homology (Neh) domains. The Neh1 domain is a CNC-bZIP domain that allows Nrf2 to heterodimerize with small Maf proteins (MAFF, MAFG, MAFK). The Neh2 domain allows for binding of Nrf2 to its cytosolic repressor Keap1.
The Neh3 domain may play a role in Nrf2 protein stability and may act as a transactivation domain, interacting with component of the transcriptional apparatus.
The Neh4 and Neh5 domains also act as transactivation domains, but bind to a different protein called cAMP Response Element Binding Protein (CREB), which possesses intrinsic histone acetyltransferase activity.
The Neh6 domain may contain a degron that is involved in the degradation of Nrf2, even in stressed cells, where the half-life of Nrf2 protein is longer than in unstressed conditions.
# Tissue distribution
Nrf2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain.
# Clinical drug target
Dimethyl fumarate, marketed as Tecfidera by Biogen Idec, was approved by the Food and Drug Administration in March 2013 following the conclusion of Phase 3 clinical trials which demonstrated that the drug reduced relapse rates and increased time to progression of disability in people with multiple sclerosis. The mechanism by which it exerts its therapeutic effect is unknown. Dimethyl fumarate (and its metabolite, monomethyl fumarate) activates the Nrf2 pathway and has been identified as a nicotinic acid receptor agonist in vitro. The label includes warnings about the risk of anaphylaxis and angioedema, progressive multifocal leukoencephalopathy (PML), lymphopenia, and liver damage; other adverse effects include flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain.
The dithiolethiones are a class of organosulfur compounds, of which oltipraz, an NRF2 inducer, is the best studied. Oltipraz inhibits cancer formation in rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue. However, clinical trials of oltipraz have not demonstrated efficacy and have shown significant side effects, including neurotoxicity and gastrointestinal toxicity. Oltipraz also generates superoxide radical, which can be toxic.
# Potential adverse effects of NRF2 activation
Genetic activation of NRF2 may promote the development of de novo cancerous tumors as well as the development of atherosclerosis by raising plasma cholesterol levels and cholesterol content in the liver. It has been suggested that the latter effect may overshadow the potential benefits of antioxidant induction afforded by NRF2 activation.
# Interactions
NFE2L2 has been shown to interact with MAFF, MAFG, MAFK, C-jun, CREBBP, EIF2AK3, KEAP1, and UBC. | NFE2L2
Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a transcription factor that in humans is encoded by the NFE2L2 gene.[1] Nrf2 is a basic leucine zipper (bZIP) protein that regulates the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation.[2] Several drugs that stimulate the NFE2L2 pathway are being studied for treatment of diseases that are caused by oxidative stress.
# Function
NFE2L2 and other genes, such as NFE2, NFE2L1 and NFE2L3, encode basic leucine zipper (bZIP) transcription factors. They share highly conserved regions that are distinct from other bZIP families, such as JUN and FOS, although remaining regions have diverged considerably from each other.[3][4]
Under normal or unstressed conditions, Nrf2 is kept in the cytoplasm by a cluster of proteins that degrade it quickly. Under oxidative stress, Nrf2 is not degraded, but instead travels to the nucleus where it binds to a DNA promoter and initiates transcription of antioxidative genes and their proteins.
Nrf2 is kept in the cytoplasm by Kelch like-ECH-associated protein 1 (KEAP1) and Cullin 3 which degrade Nrf2 by ubiquitination.[5] Cullin 3 ubiquitinates Nrf2, while Keap1 is a substrate adaptor protein that facilitates the reaction. Once Nrf2 is ubiquitinated, it is transported to the proteasome, where it is degraded and its components recycled. Under normal conditions Nrf2 has a half-life of only 20 minutes.[6] Oxidative stress or electrophilic stress disrupts critical cysteine residues in Keap1, disrupting the Keap1-Cul3 ubiquitination system. When Nrf2 is not ubiquitinated, it builds up in the cytoplasm,[7][8] and translocates into the nucleus. In the nucleus, it combines (forms a heterodimer) with one of small Maf proteins (MAFF, MAFG, MAFK) and binds to the antioxidant response element (ARE) in the upstream promoter region of many antioxidative genes, and initiates their transcription.[9]
# Target genes
Activation of Nrf2 results in the induction of many cytoprotective proteins. These include, but are not limited to, the following:
- NAD(P)H quinone oxidoreductase 1 (Nqo1) is a prototypical Nrf2 target gene that catalyzes the reduction and detoxification of highly reactive quinones that can cause redox cycling and oxidative stress.[10]
- Glutamate-cysteine ligase, catalytic (Gclc) and glutamate-cysteine ligase, modifier (GCLM) subunits form a heterodimer, which is the rate-limiting step in the synthesis of glutathione (GSH), a very powerful endogenous antioxidant. Both Gclc and Gclm are characteristic Nrf2 target genes, which establish Nrf2 as a regulator of glutathione, one of the most important antioxidants in the body.[11]
- Sulfiredoxin 1 (SRXN1) and Thioredoxin reductase 1 (TXNRD1) support the reduction and recovery of peroxiredoxins, proteins important in the detoxification of highly reactive peroxides, including hydrogen peroxide and peroxynitrite.[12][13]
- Heme oxygenase-1 (HMOX1, HO-1) is an enzyme that catalyzes the breakdown of heme into the antioxidant biliverdin, the anti-inflammatory agent carbon monoxide, and iron. HO-1 is a Nrf2 target gene that has been shown to protect from a variety of pathologies, including sepsis, hypertension, atherosclerosis, acute lung injury, kidney injury, and pain.[14] In a recent study, however, induction of HO-1 has been shown to exacerbate early brain injury after intracerebral hemorrhage.[15]
- The glutathione S-transferase (GST) family includes cytosolic, mitochondrial, and microsomal enzymes that catalyze the conjugation of GSH with endogenous and xenobiotic electrophiles. After detoxification by glutathione (GSH) conjugation catalyzed by GSTs, the body can eliminate potentially harmful and toxic compounds. GSTs are induced by Nrf2 activation and represent an important route of detoxification.[16]
- The UDP-glucuronosyltransferase (UGT) family catalyze the conjugation of a glucuronic acid moiety to a variety of endogenous and exogenous substances, making them more water-soluble and readily excreted. Important substrates for glucuronidation include bilirubin and acetaminophen. Nrf2 has been shown to induce UGT1A1 and UGT1A6.[17]
- Multidrug resistance-associated proteins (Mrps) are important membrane transporters that efflux various compounds from various organs and into bile or plasma, with subsequent excretion in the feces or urine, respectively. Mrps have been shown to be upregulated by Nrf2 and alteration in their expression can dramatically alter the pharmacokinetics and toxicity of compounds.[18][19]
# Structure
Nrf2 is a basic leucine zipper (bZip) transcription factor with a Cap “n” Collar (CNC) structure.[1] Nrf2 possesses six highly conserved domains called Nrf2-ECH homology (Neh) domains. The Neh1 domain is a CNC-bZIP domain that allows Nrf2 to heterodimerize with small Maf proteins (MAFF, MAFG, MAFK).[20] The Neh2 domain allows for binding of Nrf2 to its cytosolic repressor Keap1.[21]
The Neh3 domain may play a role in Nrf2 protein stability and may act as a transactivation domain, interacting with component of the transcriptional apparatus.[22]
The Neh4 and Neh5 domains also act as transactivation domains, but bind to a different protein called cAMP Response Element Binding Protein (CREB), which possesses intrinsic histone acetyltransferase activity.[21]
The Neh6 domain may contain a degron that is involved in the degradation of Nrf2, even in stressed cells, where the half-life of Nrf2 protein is longer than in unstressed conditions.[23]
# Tissue distribution
Nrf2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain.[1]
# Clinical drug target
Dimethyl fumarate, marketed as Tecfidera by Biogen Idec, was approved by the Food and Drug Administration in March 2013 following the conclusion of Phase 3 clinical trials which demonstrated that the drug reduced relapse rates and increased time to progression of disability in people with multiple sclerosis. The mechanism by which it exerts its therapeutic effect is unknown. Dimethyl fumarate (and its metabolite, monomethyl fumarate) activates the Nrf2 pathway and has been identified as a nicotinic acid receptor agonist in vitro.[24] The label includes warnings about the risk of anaphylaxis and angioedema, progressive multifocal leukoencephalopathy (PML), lymphopenia, and liver damage; other adverse effects include flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain.[24]
The dithiolethiones are a class of organosulfur compounds, of which oltipraz, an NRF2 inducer, is the best studied.[25] Oltipraz inhibits cancer formation in rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue.[26] However, clinical trials of oltipraz have not demonstrated efficacy and have shown significant side effects, including neurotoxicity and gastrointestinal toxicity.[26] Oltipraz also generates superoxide radical, which can be toxic.[27]
# Potential adverse effects of NRF2 activation
Genetic activation of NRF2 may promote the development of de novo cancerous tumors[28][29] as well as the development of atherosclerosis by raising plasma cholesterol levels and cholesterol content in the liver.[30] It has been suggested that the latter effect may overshadow the potential benefits of antioxidant induction afforded by NRF2 activation.[30][31]
# Interactions
NFE2L2 has been shown to interact with MAFF, MAFG, MAFK, C-jun,[32] CREBBP,[33] EIF2AK3,[34] KEAP1,[35][34][36][37] and UBC.[36][38] | https://www.wikidoc.org/index.php/NFE2L2 | |
7aaf3421f1554c630d534e976cc5526e7cda13a1 | wikidoc | NFE2L3 | NFE2L3
Nuclear Factor (Erythroid 2) - Like Factor 3, also known as NFE2L3 or 'NRF3', is a transcription factor that in humans is encoded by the Nfe2l3 gene.
This protein is a basic leucine zipper transcription factor belonging to the Cap ‘n’ Collar (CNC) family of proteins. In 1989, the first CNC transcription factor was identified, namely NFE2L2. After that, several other protein members have also been identified over the years like NRF1 and NRF3 in different organisms like humans, mice and zebrafish. These proteins are specifically encoded in the humans by Nfe2l1 and Nfe2l3 genes respectively.
# Gene
The mapping of Nfe2l3 gene by Fluorescence In-Situ Hybridisation (FISH) technique revealed its chromosomal location being 7p15-p14. It covers 34.93 kB from 26191830 to 26226754 on the direct DNA strand with an exon count of 4. The gene maps near the HOXA gene cluster which is similar to the genetic loci of p45 NFE2, NFE2L1 and NFE2L2 and are further clustered around HOXC, HOXB and HOXD genes respectively. This information tells us that all these genes have been derived from a single ancestral gene which is closely localised to HOX cluster and from there, these genes have diverged to four closely related transcription factors.
The human NFE2L3 encodes for a 694 base pairs amino acid protein. From Bioinformatics analysis, it has been observed that NFE2L3 protein shows a high degree of conservation through its evolutionary pathway from zebrafish to humans having key domains like N-terminal Homology Box 1 (NHB1), N-terminal Homology Box 2 (NHB2) and CNC domain. These conserved domains help to identify the functional properties of this protein.
# Sub-Cellular Location
NFE2L3 is a membrane bound glycoprotein that is targeted specifically to the endoplasmic reticulum (ER) and the nuclear membrane. From biochemical studies, it has been seen that there are three different migrating endogenous forms of NFE2L3 protein which are essentially short lived - the first one being migrating "A" form, the second one being an intermediate "B" form and the third one being a fast migrating "C" form. Using PNGase F and Endoglycosidase H enzymes, it was revealed that "A" form is glycosylated whereas "B" and "C" forms are unglycosylated. In total, seven potential sites of N-linked glycosylation has been observed in the centre portion of this NFE2L3 protein, however the exact information on each of the forms are yet to be identified.
# Protein Expression Levels
The expression levels of NFE2L3 proteins are found to be highest in placenta. more specifically in the chorionic villi (at week 12 of gestation period) The expression levels are more common in primary placental cytotrophoblast, but not in placental fibroblasts. Along with the placenta, the expression of this protein has also been observed in human choriocarcinoma cell lines which have been derived from trophoblastic tumours found in the placenta. Other variety of tissue regions that have experienced the expression of NFE2L3 protein has been Heart, Brain, Lungs, Kidney, Pancreas, Colon, Thymus, Leukocytes as well as Spleen. Very low levels of expression were found in case of Human Megakaryocytes and Erythrocytes whereas no expression was found in case of reproductive organs found in both the sexes.
# Function
The specific functions of NFE2L3 protein are still unknown, but since the structural information has been found to be similar to that of NFE2L1 protein, some functional properties can be deciphered from that.
This encoded protein NFE2L3 heterodimerizes with small musculo-aponeurotic fibro-sarcoma (MAF Genes) factors to bind antioxidant response elements in target genes. Several in vivo data has revealed that NFE2L3 is known to protect the body against carcinogen-induced lymphomagenesis. But, not enough information has been derived and researchers are still working on it.
Recently, a few reports have opened new avenues for NFE2L3 protein. But, all these proposals are still in its niche stage and needs concrete evidences to reveal its actual functionality.
# Associated diseases
A series of Gene chip analysis array data of NFE2L3 has shown its involvement in various malignancies with over-expressions like Hodgkin Lymphoma, Non-Hodgkin lymphoma cell lineages and Mantle cell lymphoma. Along with that, there has also been an up-regulation of mRNA levels in human breast cancer cells and testicular carcinoma tissues which reveals that NFE2L3 plays a role in inducing carcinogenesis. | NFE2L3
Nuclear Factor (Erythroid 2) - Like Factor 3, also known as NFE2L3 or 'NRF3', is a transcription factor that in humans is encoded by the Nfe2l3 gene.[1][2]
This protein is a basic leucine zipper transcription factor belonging to the Cap ‘n’ Collar (CNC) family of proteins.[3] In 1989, the first CNC transcription factor was identified, namely NFE2L2. After that, several other protein members have also been identified over the years like NRF1 and NRF3 in different organisms like humans, mice and zebrafish.[4] These proteins are specifically encoded in the humans by Nfe2l1 and Nfe2l3 genes respectively.[5][6]
# Gene
The mapping of Nfe2l3 gene by Fluorescence In-Situ Hybridisation (FISH) technique revealed its chromosomal location being 7p15-p14.[5] It covers 34.93 kB from 26191830 to 26226754 on the direct DNA strand with an exon count of 4. The gene maps near the HOXA gene cluster which is similar to the genetic loci of p45 NFE2, NFE2L1 and NFE2L2 and are further clustered around HOXC, HOXB and HOXD genes respectively.[3][5] This information tells us that all these genes have been derived from a single ancestral gene which is closely localised to HOX cluster and from there, these genes have diverged to four closely related transcription factors.[5]
The human NFE2L3 encodes for a 694 base pairs amino acid protein.[3][5] From Bioinformatics analysis, it has been observed that NFE2L3 protein shows a high degree of conservation through its evolutionary pathway from zebrafish to humans having key domains like N-terminal Homology Box 1 (NHB1), N-terminal Homology Box 2 (NHB2) and CNC domain. These conserved domains help to identify the functional properties of this protein.[7]
# Sub-Cellular Location
NFE2L3 is a membrane bound glycoprotein that is targeted specifically to the endoplasmic reticulum (ER) and the nuclear membrane.[5] From biochemical studies, it has been seen that there are three different migrating endogenous forms of NFE2L3 protein which are essentially short lived - the first one being migrating "A" form, the second one being an intermediate "B" form and the third one being a fast migrating "C" form.[5] Using PNGase F and Endoglycosidase H enzymes, it was revealed that "A" form is glycosylated whereas "B" and "C" forms are unglycosylated.[3][5] In total, seven potential sites of N-linked glycosylation [3] has been observed in the centre portion of this NFE2L3 protein, however the exact information on each of the forms are yet to be identified.
# Protein Expression Levels
The expression levels of NFE2L3 proteins are found to be highest in placenta.[8] more specifically in the chorionic villi (at week 12 of gestation period) [9] The expression levels are more common in primary placental cytotrophoblast, but not in placental fibroblasts. Along with the placenta, the expression of this protein has also been observed in human choriocarcinoma cell lines which have been derived from trophoblastic tumours found in the placenta. Other variety of tissue regions that have experienced the expression of NFE2L3 protein has been Heart, Brain, Lungs, Kidney, Pancreas, Colon, Thymus, Leukocytes as well as Spleen.[10] Very low levels of expression were found in case of Human Megakaryocytes and Erythrocytes whereas no expression was found in case of reproductive organs found in both the sexes.[5][11]
# Function
The specific functions of NFE2L3 protein are still unknown, but since the structural information has been found to be similar to that of NFE2L1 protein, some functional properties can be deciphered from that.
This encoded protein NFE2L3 heterodimerizes with small musculo-aponeurotic fibro-sarcoma (MAF Genes) factors to bind antioxidant response elements in target genes.[12] Several in vivo data has revealed that NFE2L3 is known to protect the body against carcinogen-induced lymphomagenesis. But, not enough information has been derived and researchers are still working on it.
Recently, a few reports have opened new avenues for NFE2L3 protein. But, all these proposals are still in its niche stage and needs concrete evidences to reveal its actual functionality.
# Associated diseases
A series of Gene chip analysis array data of NFE2L3 has shown its involvement in various malignancies with over-expressions like Hodgkin Lymphoma, Non-Hodgkin lymphoma cell lineages and Mantle cell lymphoma.[13] Along with that, there has also been an up-regulation of mRNA levels in human breast cancer cells and testicular carcinoma tissues which reveals that NFE2L3 plays a role in inducing carcinogenesis.[14] | https://www.wikidoc.org/index.php/NFE2L3 | |
0408021514f812dda428073fa83487d50b6b99d9 | wikidoc | NFKBID | NFKBID
Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, delta also known as IκBNS is a protein in humans that is encoded by the NFKBID gene.
IκBNS is a member of the atypical inhibitors of NF-κB (also called the nuclear IκBs). NF-κB is a transcription factor, which regulates the expression of its target genes, depending on intracellular and extracellular signals. As NFKBID influences the impact of NF-κB on several genes, it is involved in cellular responses to stimuli such as stress and bacterial or viral antigens.
# Structure
NFKBID is a nuclear protein with 327 amino acids. It contains six ankyrin repeats (ANKs), that are surrounded by a nuclear localization signal sequence (NLS) at the N-terminus and a short C-terminus. The ANKs are characteristic for all IκB proteins. The NLS is an additional characteristic structural element of only atypical IκB proteins, which is responsible for the localization of the protein into the nucleus. In contrast, classical inhibitors, e.g. IκBα and IκBβ, are located in the cytoplasm. A high resolution structure of NFKBID is not available yet.
# Function
It seems that NFKBID acts as an inhibitor of the NF-κB cascade. By its functions, including promotion of germinal center reactions and its requirement in imunosuppressive regulatory T cell generation, NFKBID regulates homeostasis of the immune system and has further different consequences on it. Furthermore, NFKBID influences B cells and plasma cells substantially, concerning their functions and development.
The expression of NFKBID is precisely regulated. After NF-κB activation atypical IκBs are induced by the transcription factor Atypical IκBs, in turn, can regulate the NF-κB transcription as either inducers or inhibitors. In contrast, the classical proteins can only repress NF-κB transcription.
In mature T cells (CD4+), T cell receptor (TCR) stimulation can induce the expression of NFKBID, whereas in macrophages, TLR ligands take on this task.
To influence the transcription of genes, NFKBID has some interaction protein partners. It was reported that NFKBID interacts with p50, which is a subunit of NF-κB, p52, p65, RelB, and c-Rel. NFKBID binds these proteins only in the nucleus, except for p50, which can be bound both in the cytoplasm and in the nucleus
Researchers suggest that apart from this, NFKBID can also interact with homo- and heterodimers consisting of some of these subunits, e.g. p50/p50 and p65/p50. Depending on the target gene and on which protein is bound by NFKBID, it can function as both repressor and activator. | NFKBID
Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, delta also known as IκBNS is a protein in humans that is encoded by the NFKBID gene.[1]
IκBNS is a member of the atypical inhibitors of NF-κB (also called the nuclear IκBs). NF-κB is a transcription factor, which regulates the expression of its target genes, depending on intracellular and extracellular signals. As NFKBID influences the impact of NF-κB on several genes, it is involved in cellular responses to stimuli such as stress and bacterial or viral antigens.
# Structure
NFKBID is a nuclear protein with 327 amino acids. It contains six ankyrin repeats (ANKs), that are surrounded by a nuclear localization signal sequence (NLS) at the N-terminus and a short C-terminus.[2][3] The ANKs are characteristic for all IκB proteins. The NLS is an additional characteristic structural element of only atypical IκB proteins, which is responsible for the localization of the protein into the nucleus. In contrast, classical inhibitors, e.g. IκBα and IκBβ, are located in the cytoplasm. A high resolution structure of NFKBID is not available yet.
# Function
It seems that NFKBID acts as an inhibitor of the NF-κB cascade. By its functions, including promotion of germinal center reactions and its requirement in imunosuppressive regulatory T cell generation, NFKBID regulates homeostasis of the immune system and has further different consequences on it.[2] Furthermore, NFKBID influences B cells and plasma cells substantially, concerning their functions and development.[4]
The expression of NFKBID is precisely regulated. After NF-κB activation atypical IκBs are induced by the transcription factor [3] Atypical IκBs, in turn, can regulate the NF-κB transcription as either inducers or inhibitors. In contrast, the classical proteins can only repress NF-κB transcription.[2]
In mature T cells (CD4+), T cell receptor (TCR) stimulation can induce the expression of NFKBID, whereas in macrophages, TLR ligands take on this task.[5][6]
To influence the transcription of genes, NFKBID has some interaction protein partners. It was reported that NFKBID interacts with p50, which is a subunit of NF-κB, p52, p65, RelB, and c-Rel. NFKBID binds these proteins only in the nucleus, except for p50, which can be bound both in the cytoplasm and in the nucleus [7][8]
Researchers suggest that apart from this, NFKBID can also interact with homo- and heterodimers consisting of some of these subunits, e.g. p50/p50 and p65/p50.[9] Depending on the target gene and on which protein is bound by NFKBID, it can function as both repressor and activator. | https://www.wikidoc.org/index.php/NFKBID | |
b95ae0bc456cfa3ce8f8691471a12d3dadd239bf | wikidoc | NFKBIE | NFKBIE
Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, epsilon, also known as NFKBIE, is a protein which in humans is encoded by the NFKBIE gene.
# Function
NFKBIE protein expression is up-regulated following NF-κB activation and during myelopoiesis. NFKBIE is able to inhibit NF-κB-directed transactivation via cytoplasmic retention of REL proteins.
NFKB1 or NFKB2 is bound to REL, RELA, or RELB to form the NF-κB transcription factor complex. The NF-κB complex is inhibited by I-kappa-B proteins (NFKBIA or NFKBIB), which inactivate NF-kappa-B by trapping it in the cytoplasm. Phosphorylation of serine residues on the I-kappa-B proteins by kinases (IKBKA, or IKBKB) marks them for destruction via the ubiquitination pathway, thereby allowing activation of the NF-kappa-B complex. Activated NF-κB complex translocates into the nucleus and binds DNA at kappa-B-binding motifs such as 5-prime GGGRNNYYCC 3-prime or 5-prime HGGARNYYCC 3-prime (where H is A, C, or T; R is an A or G purine; and Y is a C or T pyrimidine). For some genes, activation requires NF-κB interaction with other transcription factors, such as STAT (see STAT6), AP-1 (JUN), and NFAT (see NFATC1).
# Interactions
NFKBIE has been shown to interact with NFKB2, RELA, NFKB1 and REL. | NFKBIE
Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, epsilon, also known as NFKBIE, is a protein which in humans is encoded by the NFKBIE gene.[1][2]
# Function
NFKBIE protein expression is up-regulated following NF-κB activation and during myelopoiesis. NFKBIE is able to inhibit NF-κB-directed transactivation via cytoplasmic retention of REL proteins.[2]
NFKB1 or NFKB2 is bound to REL, RELA, or RELB to form the NF-κB transcription factor complex. The NF-κB complex is inhibited by I-kappa-B proteins (NFKBIA or NFKBIB), which inactivate NF-kappa-B by trapping it in the cytoplasm. Phosphorylation of serine residues on the I-kappa-B proteins by kinases (IKBKA, or IKBKB) marks them for destruction via the ubiquitination pathway, thereby allowing activation of the NF-kappa-B complex. Activated NF-κB complex translocates into the nucleus and binds DNA at kappa-B-binding motifs such as 5-prime GGGRNNYYCC 3-prime or 5-prime HGGARNYYCC 3-prime (where H is A, C, or T; R is an A or G purine; and Y is a C or T pyrimidine). For some genes, activation requires NF-κB interaction with other transcription factors, such as STAT (see STAT6), AP-1 (JUN), and NFAT (see NFATC1).[1]
# Interactions
NFKBIE has been shown to interact with NFKB2,[3] RELA,[3] NFKB1[3] and REL.[3][4][5] | https://www.wikidoc.org/index.php/NFKBIE | |
e085dcb4efc45b22bd59e0fc32e318d3f5ae3a05 | wikidoc | NKX2-2 | NKX2-2
Homeobox protein Nkx-2.2 is a protein that in humans is encoded by the NKX2-2 gene.
Homeobox protein Nkx-2.2 contains a homeobox domain and may be involved in the morphogenesis of the central nervous system. This gene is found on chromosome 20 near NKX2-4, and these two genes appear to be duplicated on chromosome 14 in the form of TITF1 and NKX2-8. The encoded protein is likely to be a nuclear transcription factor.
The expression of Nkx2-2 is regulated by an antisense RNA called Nkx2-2as.
In the developing spinal cord, Nkx-2.2 regulates IRX3 thereby contributing to the proper differentiation of the ventral horn neurons. | NKX2-2
Homeobox protein Nkx-2.2 is a protein that in humans is encoded by the NKX2-2 gene.[1][2][3]
Homeobox protein Nkx-2.2 contains a homeobox domain and may be involved in the morphogenesis of the central nervous system. This gene is found on chromosome 20 near NKX2-4, and these two genes appear to be duplicated on chromosome 14 in the form of TITF1 and NKX2-8. The encoded protein is likely to be a nuclear transcription factor.[3]
The expression of Nkx2-2 is regulated by an antisense RNA called Nkx2-2as.[4]
In the developing spinal cord, Nkx-2.2 regulates IRX3 thereby contributing to the proper differentiation of the ventral horn neurons.[5] | https://www.wikidoc.org/index.php/NKX2-2 | |
442d0f32d53ac98ef270bc407b0024132afddb71 | wikidoc | NKX3-1 | NKX3-1
Homeobox protein Nkx-3.1, also known as NKX3-1, NKX3, BAPX2, NKX3A and NKX3.1 is a protein that in humans is encoded by the NKX3-1 gene located on chromosome 8p. NKX3-1 is a prostatic tumor suppressor gene.
NKX3-1 is an androgen-regulated, prostate-specific homeobox gene whose expression is predominantly localized to prostate epithelium. It acts as a transcription factor that has critical function in prostate development and tumor suppression. It is a negative regulator of epithelial cell growth in prostate tissue. The NKX3-1 homeobox protein is encoded by the NKX3-1 gene.
# Function
The homeodomain-containing transcription factor NKX3A is a putative prostate tumor suppressor that is expressed in a largely prostate-specific and androgen-regulated manner. Loss of NKX3A protein expression is a common finding in human prostate carcinomas and prostatic intraepithelial neoplasia.
# Gene
In humans, the NKX3-1 gene is located on chromosome 8p21.2 with 4 exons. The 8p chromosome is a region that is frequently reported to undergo a loss of heterozygosity (LOH) associated with tissue dedifferentiation and loss of androgen responsiveness during the progression of prostate cancer. LOH has been reported to be observed in 12-89% of high-grade prostatic intraepithelial neoplasia (PIN) and 35-86% of prostatic adenocarcinomas. The frequency of loss of heterozygosity on chromosome 8p is seen to increase with advanced prostate cancer grade and stage.
# Structure
NKX3-1 contains two exons encoding a 234 amino acid protein including a homeodomain. The 234 amino acids are 35-38 kDa. One N-terminal domain one homeodomain and one C-terminal domain are present. The observed interaction between NKX3-1 and Serum Response Factor (SRF)indicate that amino-terminal domains participate in the interaction. The synergistic transcriptional activation requires both interactions at multiple protein-protein interfaces and protein-DNA interactions. This indicates that one mechanism of NKX3-1 dependent transcriptional activation in prostate epithelia requires combinatorial interactions with other factors expressed within those cells
In 2000, full length NKX3-1 cDNA was obtained from a human prostate cDNA library. Korkmaz et al. identified 3 splice variants with deletions in the N-terminal region as well as a variant at position 137 within the homeobox domain. NKX3-1 expression was visualized using Fluorescence microscopy, utilizing GFP-NKX3-1 in the nucleus.
# Function
NKX3-1 expression acts as a transcription factor that has been found to play a main role in prostate development and tumor suppression. The loss of NKX3-1 expression is frequently observed in prostate tumorigenesis and has been seen to be a result of allelic loss, methylation, and post transcriptional silencing. NKX3-1 expression is seen in prostate epithelium, testis, ureter, and pulmonary bronchial mucous glands.
NKX3-1 binds to DNA to suppress transcription as well as interacts with transcription factors such as serum response factor, to enhance transcriptional activation.
Wang et al. demonstrated that NKX3-1 marks a stem cell population that functions during prostate regeneration. Genetic lineage marking demonstrated that rare luminal cells that express NKX3-1 in the absence of testicular androgens are bipotential and can self-renew in vivo. Single-cell transplantation assays showed that castration-resistant NKX3-1 expressing cells (CARNs) can reconstitute prostate ducts in renal grafts. Functional assays of NKX3-1 mutant mice in serial prostate regeneration suggested that NKX3-1 is required for stem cell maintenance. Furthermore, targeted deletion of PTEN gene in CARNs resulted in rapid carcinoma formation after androgen-mediated regeneration. This indicates that CARNs represent a new luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer.
It has also been found to be essential in pluripotency of stem cells using Yamanaka factors.
# Regulation
In 2010 it was shown that NKX3-1 was controlled by ERG and ESE3 both directly and through induction of EZH2 (Polycomb group pcg).
# Discovery
Using a random cDNA sequencing approach, He et al. cloned a novel prostate-specific gene that encoded a homeobox-containing protein. The gene which they symbolized NKX3-1 encoded a 234-amino acid polypeptide with greatest homology to the Drosophila NK3 gene. Northern blot analysis showed that NKX3.1 had a uniquely restricted tissue expression pattern with mRNA being abundant in the prostate, lower levels in the testis and absent from all other tissues tested. The NKX3-1 protein expression was detected a hormone-responsive, androgen receptor-positive prostate cancer cell line, but was absent from androgen receptor-negative prostate cancer cell lines as well as other cell lines of varied origins. The link between androgen stimulation and NKX3-1 was discovered through the use of an androgen-dependent carcinoma line. The researchers suggested that the NKX3-1 gene plays a role in androgen-driven differentiation of prostatic tissue as well as in loss of differentiation during the progression of prostate cancer.
# Role in disease
Prostate cancer is the most commonly diagnosed cancer in American men and the second leading cause of cancer related deaths. Prostate cancer predominantly occurs in the peripheral zone of the human prostate, with fewer than 10% of cases found in the central zone. The disease develops as a result of the temporal and spatial loss of the basal epithelial compartment as well as increased proliferation and dedifferentiation of the luminal (secretory) epithelial cells. Prostate cancer is typically found in men of ages older than 60 and its incidence increases with increasing age.
NKX3-1 plays an essential role in normal murine prostate development. Loss of function of NKX3-1 leads to defects in prostatic protein secretions as well as ductal morphogenesis. Loss of function also contributes to prostate carcinogenesis.
NKX3-1 has been established as a marker for identifying metastatic tumors. Furthermore, anti-NKX3-1 antibodies are a more sensitive and specific method for diagnosing metastatic prostatic adenocarcinomas in distant sites.
# Interactions
NKX3-1 has been shown to interact with SPDEF.
The stability of NKX3-1 protein has been shown to be regulated by phosphorylation. | NKX3-1
Homeobox protein Nkx-3.1, also known as NKX3-1, NKX3, BAPX2, NKX3A and NKX3.1 is a protein that in humans is encoded by the NKX3-1 gene located on chromosome 8p.[1] NKX3-1 is a prostatic tumor suppressor gene.
NKX3-1 is an androgen-regulated, prostate-specific homeobox gene whose expression is predominantly localized to prostate epithelium. It acts as a transcription factor that has critical function in prostate development and tumor suppression. It is a negative regulator of epithelial cell growth in prostate tissue. The NKX3-1 homeobox protein is encoded by the NKX3-1 gene.[1]
# Function
The homeodomain-containing transcription factor NKX3A is a putative prostate tumor suppressor that is expressed in a largely prostate-specific and androgen-regulated manner. Loss of NKX3A protein expression is a common finding in human prostate carcinomas and prostatic intraepithelial neoplasia.[2]
# Gene
In humans, the NKX3-1 gene is located on chromosome 8p21.2 with 4 exons.[3] The 8p chromosome is a region that is frequently reported to undergo a loss of heterozygosity (LOH) associated with tissue dedifferentiation and loss of androgen responsiveness during the progression of prostate cancer. LOH has been reported to be observed in 12-89% of high-grade prostatic intraepithelial neoplasia (PIN) and 35-86% of prostatic adenocarcinomas. The frequency of loss of heterozygosity on chromosome 8p is seen to increase with advanced prostate cancer grade and stage.[4]
# Structure
NKX3-1 contains two exons encoding a 234 amino acid protein including a homeodomain. The 234 amino acids are 35-38 kDa. One N-terminal domain one homeodomain and one C-terminal domain are present. The observed interaction between NKX3-1 and Serum Response Factor (SRF)indicate that amino-terminal domains participate in the interaction. The synergistic transcriptional activation requires both interactions at multiple protein-protein interfaces and protein-DNA interactions. This indicates that one mechanism of NKX3-1 dependent transcriptional activation in prostate epithelia requires combinatorial interactions with other factors expressed within those cells[5]
In 2000, full length NKX3-1 cDNA was obtained from a human prostate cDNA library. Korkmaz et al.[6] identified 3 splice variants with deletions in the N-terminal region as well as a variant at position 137 within the homeobox domain. NKX3-1 expression was visualized using Fluorescence microscopy, utilizing GFP-NKX3-1 in the nucleus.
# Function
NKX3-1 expression acts as a transcription factor that has been found to play a main role in prostate development and tumor suppression. The loss of NKX3-1 expression is frequently observed in prostate tumorigenesis and has been seen to be a result of allelic loss, methylation, and post transcriptional silencing.[7] NKX3-1 expression is seen in prostate epithelium, testis, ureter, and pulmonary bronchial mucous glands.
NKX3-1 binds to DNA to suppress transcription as well as interacts with transcription factors such as serum response factor, to enhance transcriptional activation.
Wang et al.[8] demonstrated that NKX3-1 marks a stem cell population that functions during prostate regeneration. Genetic lineage marking demonstrated that rare luminal cells that express NKX3-1 in the absence of testicular androgens are bipotential and can self-renew in vivo. Single-cell transplantation assays showed that castration-resistant NKX3-1 expressing cells (CARNs) can reconstitute prostate ducts in renal grafts. Functional assays of NKX3-1 mutant mice in serial prostate regeneration suggested that NKX3-1 is required for stem cell maintenance. Furthermore, targeted deletion of PTEN gene in CARNs resulted in rapid carcinoma formation after androgen-mediated regeneration. This indicates that CARNs represent a new luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer.
It has also been found to be essential in pluripotency of stem cells using Yamanaka factors.[9]
# Regulation
In 2010 it was shown that NKX3-1 was controlled by ERG and ESE3 both directly and through induction of EZH2 (Polycomb group pcg).[10]
# Discovery
Using a random cDNA sequencing approach, He et al.[11] cloned a novel prostate-specific gene that encoded a homeobox-containing protein. The gene which they symbolized NKX3-1 encoded a 234-amino acid polypeptide with greatest homology to the Drosophila NK3 gene. Northern blot analysis showed that NKX3.1 had a uniquely restricted tissue expression pattern with mRNA being abundant in the prostate, lower levels in the testis and absent from all other tissues tested. The NKX3-1 protein expression was detected a hormone-responsive, androgen receptor-positive prostate cancer cell line, but was absent from androgen receptor-negative prostate cancer cell lines as well as other cell lines of varied origins. The link between androgen stimulation and NKX3-1 was discovered through the use of an androgen-dependent carcinoma line. The researchers suggested that the NKX3-1 gene plays a role in androgen-driven differentiation of prostatic tissue as well as in loss of differentiation during the progression of prostate cancer.
# Role in disease
Prostate cancer is the most commonly diagnosed cancer in American men and the second leading cause of cancer related deaths.[12] Prostate cancer predominantly occurs in the peripheral zone of the human prostate, with fewer than 10% of cases found in the central zone. The disease develops as a result of the temporal and spatial loss of the basal epithelial compartment as well as increased proliferation and dedifferentiation of the luminal (secretory) epithelial cells. Prostate cancer is typically found in men of ages older than 60 and its incidence increases with increasing age.
NKX3-1 plays an essential role in normal murine prostate development. Loss of function of NKX3-1 leads to defects in prostatic protein secretions as well as ductal morphogenesis. Loss of function also contributes to prostate carcinogenesis.
NKX3-1 has been established as a marker for identifying metastatic tumors.[4] Furthermore, anti-NKX3-1 antibodies are a more sensitive and specific method for diagnosing metastatic prostatic adenocarcinomas in distant sites.[13]
# Interactions
NKX3-1 has been shown to interact with SPDEF.[14]
The stability of NKX3-1 protein has been shown to be regulated by phosphorylation.[15] | https://www.wikidoc.org/index.php/NKX3-1 | |
90c664b2dbdfb99f66a671c2a4d6bb89bdabbf61 | wikidoc | NMNAT1 | NMNAT1
Nicotinamide mononucleotide adenylyltransferase 1 is an enzyme that in humans is encoded by the NMNAT1 gene. It is a member of the nicotinamide-nucleotide adenylyltransferases.
# Function
The coenzyme NAD and its derivatives are involved in hundreds of metabolic redox reactions and are utilized in protein ADP-ribosylation, histone deacetylation, and in some Ca2+ signaling pathways. NMNAT (EC 2.7.7.1) is a central enzyme in NAD biosynthesis, catalyzing the condensation of nicotinamide mononucleotide (NMN) or nicotinic acid mononucleotide (NaMN) with the AMP moiety of ATP to form NAD or NaAD.
NMNAT1 is the most widely expressed of three orthologous genes with nicotinamide-nucleotide adenylyltransferase (NMNAT) activity. Genetically engineered mice lacking NMNAT1 die during early embryogenesis, indicating a critical role of this gene in organismal viability. In contrast, mice lacking NMNAT2, which is expressed predominantly in neural tissues, complete development but die shortly after birth. However, NMNAT1 is dispensable for cell viability, as homozygous deletion of this gene occurs in glioblastoma tumors and cell lines. NMNAT enzymatic activity is probably essential at the cellular level, as complete ablation of NMNAT activity in model organisms leads to cellular inviability.
# Clinical relevance
Mutations in this gene have been shown associated to retinal degeneration pathologies, like Leber's congenital amaurosis. | NMNAT1
Nicotinamide mononucleotide adenylyltransferase 1 is an enzyme that in humans is encoded by the NMNAT1 gene.[1][2][3] It is a member of the nicotinamide-nucleotide adenylyltransferases.
# Function
The coenzyme NAD and its derivatives are involved in hundreds of metabolic redox reactions and are utilized in protein ADP-ribosylation, histone deacetylation, and in some Ca2+ signaling pathways. NMNAT (EC 2.7.7.1) is a central enzyme in NAD biosynthesis, catalyzing the condensation of nicotinamide mononucleotide (NMN) or nicotinic acid mononucleotide (NaMN) with the AMP moiety of ATP to form NAD or NaAD.[3]
NMNAT1 is the most widely expressed of three orthologous genes with nicotinamide-nucleotide adenylyltransferase (NMNAT) activity. Genetically engineered mice lacking NMNAT1 die during early embryogenesis, indicating a critical role of this gene in organismal viability.[citation needed] In contrast, mice lacking NMNAT2, which is expressed predominantly in neural tissues, complete development but die shortly after birth. However, NMNAT1 is dispensable for cell viability, as homozygous deletion of this gene occurs in glioblastoma tumors and cell lines. NMNAT enzymatic activity is probably essential at the cellular level, as complete ablation of NMNAT activity in model organisms leads to cellular inviability.[4]
# Clinical relevance
Mutations in this gene have been shown associated to retinal degeneration pathologies, like Leber's congenital amaurosis.[5] | https://www.wikidoc.org/index.php/NMNAT1 | |
91dd29ea5f200dbe9f193bfc98548ba5444051ad | wikidoc | NPC1L1 | NPC1L1
Niemann-Pick C1-Like 1 (NPC1L1) is a gene associated with NPC1, mutation of which results in Niemann-Pick disease. It codes for Niemann-Pick C1-like protein 1, found on the gastrointestinal tract epithelial cells as well as in hepatocytes. Specifically, it appears to bind to a critical mediator of cholesterol absorption.
The drug ezetimibe blocks NPC1L1 causing a reduction in cholesterol absorption, resulting in a blood cholesterol reduction of between 15-20%. Polymorphic variations in NPC1L1 gene could be associated with non-response to ezetimibe treatment.
NPC1L1 has been shown to be an accessory receptor for hepatitis C virus entry into cells, and thus ezetimibe might be used as a therapeutic strategy.
As cancer appeared more frequently in patients treated with simvastatin-ezetimibe combination therapy in one clinical trial, it had been hypothesized that NPC1L1 by ezetimibe might be associated with an increase cancer risk. However a meta-analysis of ezetimibe clinical data showed no increased risk of cancer from treatment with ezetimibe. | NPC1L1
Niemann-Pick C1-Like 1 (NPC1L1) is a gene associated with NPC1, mutation of which results in Niemann-Pick disease. It codes for Niemann-Pick C1-like protein 1, found on the gastrointestinal tract epithelial cells[1] as well as in hepatocytes.[2] Specifically, it appears to bind to a critical mediator of cholesterol absorption.
The drug ezetimibe blocks NPC1L1 causing a reduction in cholesterol absorption, resulting in a blood cholesterol reduction of between 15-20%.[3] Polymorphic variations in NPC1L1 gene could be associated with non-response to ezetimibe treatment.[4]
NPC1L1 has been shown to be an accessory receptor for hepatitis C virus entry into cells, and thus ezetimibe might be used as a therapeutic strategy.[5]
As cancer appeared more frequently in patients treated with simvastatin-ezetimibe combination therapy in one clinical trial,[6] it had been hypothesized that NPC1L1 by ezetimibe might be associated with an increase cancer risk.[7] However a meta-analysis of ezetimibe clinical data showed no increased risk of cancer from treatment with ezetimibe.[8] | https://www.wikidoc.org/index.php/NPC1L1 | |
b2045c18bddbe58bfc6cb2aa91cef589bca667a2 | wikidoc | NPEPPS | NPEPPS
Puromycin-sensitive amino peptidase also known as cytosol alanyl aminopeptidase or alanine aminopeptidase (AAP) (EC 3.4.11.14) is an enzyme that in humans is encoded by the NPEPPS gene. It is used as a biomarker to detect damage to the kidneys, and that may be used to help diagnose certain kidney disorders. It is found at high levels in the urine when there are kidney problems.
# Function
This gene encodes the puromycin-sensitive aminopeptidase, a zinc metallopeptidase which hydrolyzes amino acids from the N-terminus of its substrate. The protein has been localized to both the cytoplasm and to cellular membranes. This enzyme degrades enkephalins in the brain, and studies in mouse suggest that it is involved in proteolytic events regulating the cell cycle. It has been identified as a novel modifier of TAU-induced neurodegeneration with neuroprotective effects via direct proteolysis of TAU protein. The loss of NPEPPS function exacerbates neurodegeneration.
# Structure
## Gene
The NPEPPS gene is located at chromosome 17q21, consisting of 25 exons and spanning 40 kb.
## Protein
NPEPPS is a ubiquitous , 100 kDa, Zn2+ metallopeptidase highly expressed in the brain. Two isozymes have been found and they are expressed differently in the nervous system. Glu 309 is one of the active site glutamates, and its mutation could convert the enzyme into an inactive binding protein.
# Function
NPEPPS has been proposed to function in a variety of processes, including metabolism of neuropeptidase, regulation of the cell cycle, and hydrolysis of proteasomal products to amino acids. NPEPPS is a major protease to digest SOD1, similar to its role in TAU-induced neurodegeneration. NPEPPS is also reported to play a role in creating and destroying MHC class Ⅰ-presented peptides and in limiting MHC class Ⅰ Ag presentation in dendritic cells.
# Clinical significance
NPEPPS is induced in neurons expressing mutant huntingtin and is critical in preventing the accumulation of polyglutamine in normal cells. It has been reported as the major peptidase digesting polyglutamine sequences in neurodegenerative diseases, such as Huntington’s disease. It has been shown that elevation of NPEPPS activity in vivo could effectively block accumulation of hyperphosphorylated TAU protein and thus slow down the disease progression, suggesting increasing NPEPPS activity may be a feasible therapeutic approach to eliminate accumulation of toxic substrates, which are involved in neurodegenerative diseases.
# Interactions
- Cyclin-dependent kinase 5
- SOD1
- TAU
- Tetrahydropyridine
- β-amyloid | NPEPPS
Puromycin-sensitive amino peptidase also known as cytosol alanyl aminopeptidase or alanine aminopeptidase (AAP) (EC 3.4.11.14) is an enzyme that in humans is encoded by the NPEPPS gene.[1][2][3] It is used as a biomarker to detect damage to the kidneys, and that may be used to help diagnose certain kidney disorders. It is found at high levels in the urine when there are kidney problems.[4]
# Function
This gene encodes the puromycin-sensitive aminopeptidase, a zinc metallopeptidase which hydrolyzes amino acids from the N-terminus of its substrate. The protein has been localized to both the cytoplasm and to cellular membranes. This enzyme degrades enkephalins in the brain, and studies in mouse suggest that it is involved in proteolytic events regulating the cell cycle.[3] It has been identified as a novel modifier of TAU-induced neurodegeneration with neuroprotective effects via direct proteolysis of TAU protein.[5][6] The loss of NPEPPS function exacerbates neurodegeneration.[7]
# Structure
## Gene
The NPEPPS gene is located at chromosome 17q21, consisting of 25 exons and spanning 40 kb.
## Protein
NPEPPS is a ubiquitous , 100 kDa, Zn2+ metallopeptidase highly expressed in the brain.[8] Two isozymes have been found and they are expressed differently in the nervous system.[9] Glu 309 is one of the active site glutamates, and its mutation could convert the enzyme into an inactive binding protein.[10]
# Function
NPEPPS has been proposed to function in a variety of processes, including metabolism of neuropeptidase, regulation of the cell cycle, and hydrolysis of proteasomal products to amino acids.[11][12][13] NPEPPS is a major protease to digest SOD1, similar to its role in TAU-induced neurodegeneration.[6][14] NPEPPS is also reported to play a role in creating and destroying MHC class Ⅰ-presented peptides and in limiting MHC class Ⅰ Ag presentation in dendritic cells.[15]
# Clinical significance
NPEPPS is induced in neurons expressing mutant huntingtin and is critical in preventing the accumulation of polyglutamine in normal cells. It has been reported as the major peptidase digesting polyglutamine sequences in neurodegenerative diseases, such as Huntington’s disease.[16] It has been shown that elevation of NPEPPS activity in vivo could effectively block accumulation of hyperphosphorylated TAU protein and thus slow down the disease progression, suggesting increasing NPEPPS activity may be a feasible therapeutic approach to eliminate accumulation of toxic substrates, which are involved in neurodegenerative diseases.[17]
# Interactions
- Cyclin-dependent kinase 5 [18]
- SOD1 [14]
- TAU [6]
- Tetrahydropyridine [19]
- β-amyloid [20] | https://www.wikidoc.org/index.php/NPEPPS | |
afee0589a3f1e41d6336852af08c6f1d4e030841 | wikidoc | NPLOC4 | NPLOC4
Nuclear protein localization protein 4 homolog is a protein that in humans is encoded by the NPLOC4 gene.
# Model organisms
Model organisms have been used in the study of NPLOC4 function. A conditional knockout mouse line, called Nploc4tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out and two phenotypes were reported. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals.
# Interactions
NPLOC4 has been shown to interact with UFD1L. | NPLOC4
Nuclear protein localization protein 4 homolog is a protein that in humans is encoded by the NPLOC4 gene.[1][2][3]
# Model organisms
Model organisms have been used in the study of NPLOC4 function. A conditional knockout mouse line, called Nploc4tm1a(EUCOMM)Wtsi[8][9] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[10][11][12]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty six tests were carried out and two phenotypes were reported. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals.[6]
# Interactions
NPLOC4 has been shown to interact with UFD1L.[1][14] | https://www.wikidoc.org/index.php/NPLOC4 | |
d4232310b91bcef11de297f9e7d9a74d9a19b039 | wikidoc | NUDT15 | NUDT15
Nudix hydrolase 15 is a protein that in humans is encoded by the NUDT15 gene.
# Function
This gene encodes an enzyme that belongs to the Nudix hydrolase superfamily. Members of this superfamily catalyze the hydrolysis of nucleoside diphosphates, including substrates like 8-oxo-dGTP, which are a result of oxidative damage, and can induce base mispairing during DNA replication, causing transversions. The encoded enzyme is a negative regulator of thiopurine activation and toxicity. Mutations in this gene result in poor metabolism of thiopurines, and are associated with thiopurine-induced early leukopenia. Multiple pseudogenes of this gene have been identified.
NUDT15 germline variants (e.g., a missense SNP:rs116855232, inducing R139C) have been linked to clinical usage of thiopurines (e.g., mercaptopurine) in acute lymphoblastic leukemia as well as inflammatory bowel diseases to avoid thiopurine-induced leukopenia. These variants also exhibit ethnicity-specific (e.g.,variant allele of rs116855232 is high is East Asians and Hispanics but low in Caucasians and Africans). Rare functional variants even singletons in this gene have also been identified to be related to thiopurine-induced myelotoxicity, suggesting the whole gene screening should be taken to determine the initial dosage using of thiopurine. | NUDT15
Nudix hydrolase 15 is a protein that in humans is encoded by the NUDT15 gene.[1]
# Function
This gene encodes an enzyme that belongs to the Nudix hydrolase superfamily. Members of this superfamily catalyze the hydrolysis of nucleoside diphosphates, including substrates like 8-oxo-dGTP, which are a result of oxidative damage, and can induce base mispairing during DNA replication, causing transversions. The encoded enzyme is a negative regulator of thiopurine activation and toxicity. Mutations in this gene result in poor metabolism of thiopurines, and are associated with thiopurine-induced early leukopenia. Multiple pseudogenes of this gene have been identified.
NUDT15 germline variants (e.g., a missense SNP:rs116855232, inducing R139C) have been linked to clinical usage of thiopurines (e.g., mercaptopurine) in acute lymphoblastic leukemia[2][3] as well as inflammatory bowel diseases to avoid thiopurine-induced leukopenia.[4][5] These variants also exhibit ethnicity-specific (e.g.,variant allele of rs116855232 is high is East Asians and Hispanics but low in Caucasians and Africans). Rare functional variants even singletons in this gene have also been identified to be related to thiopurine-induced myelotoxicity,[6] suggesting the whole gene screening should be taken to determine the initial dosage using of thiopurine. | https://www.wikidoc.org/index.php/NUDT15 | |
158632b0cb05532d87686a54772bd8d6ad62fb4d | wikidoc | Nabidh | Nabidh
Nabidh was an intoxicating beverage.
Narrated Abu Hurayrah:
I knew that the Apostle of Allah (peace_be_upon_him) used to keep fast. I waited for the day when he did not fast to present him the drink (nabidh) which I made in a pumpkin. I then brought it to him while it fermented. He said: Throw it to this wall, for this is a drink of the one who does not believe in Allah and the Last Day.
"Whilst on his deathbed, Umar became deeply affected by the wound and his physician asked Umar 'Which alcohol would you like to drink?' Umar said 'alcohol called nabidh is my preferred choice. This drink was then administered to Umar".
Yahya related to me from Malik from Yahya ibn Said from Abd ar-Rahman ibn al-Qasim that Aslam, the mawla of Umar ibn al-Khattab informed him that he had visited Abdullah ibn Ayyash al-Makhzumi. He saw that he had some nabidh with him and he was at that moment on the way to Makka. Aslam said to him, Umar ibn al-Khattab loves this drink." Abdullah ibn Ayyash therefore carried a great drinking bowl and brought it to Umar ibn al-Khattab and placed it before him. Umar brought it near to him and then raised his head. Umar said, "This drink is good," so he drank some of it and then passed it to a man on his right.
# Ibn Fadlan
Muslim writer Ibn Fadlan states that it was drunken by the Vikings .
Brewed for ten days, nabidh was probably alcohol-based and may have included henbane, cannabis, and/or opium .
Fadlan describes the drink being given to a female slave who was sacrificed, by strangulation and stabbing, during a ship burial ceremony . | Nabidh
Nabidh was an intoxicating beverage.
Narrated Abu Hurayrah:
I knew that the Apostle of Allah (peace_be_upon_him) used to keep fast. I waited for the day when he did not fast to present him the drink (nabidh) which I made in a pumpkin. I then brought it to him while it fermented. He said: Throw it to this wall, for this is a drink of the one who does not believe in Allah and the Last Day.
[1]
"Whilst on his deathbed, Umar became deeply affected by the wound and his physician asked Umar 'Which alcohol would you like to drink?' Umar said 'alcohol called nabidh is my preferred choice. This drink was then administered to Umar".[2]
Yahya related to me from Malik from Yahya ibn Said from Abd ar-Rahman ibn al-Qasim that Aslam, the mawla of Umar ibn al-Khattab informed him that he had visited Abdullah ibn Ayyash al-Makhzumi. He saw that he had some nabidh with him and he was at that moment on the way to Makka. Aslam said to him, Umar ibn al-Khattab loves this drink." Abdullah ibn Ayyash therefore carried a great drinking bowl and brought it to Umar ibn al-Khattab and placed it before him. Umar brought it near to him and then raised his head. Umar said, "This drink is good," so he drank some of it and then passed it to a man on his right.[3]
# Ibn Fadlan
Muslim writer Ibn Fadlan states that it was drunken by the Vikings [4].
Brewed for ten days, nabidh was probably alcohol-based and may have included henbane, cannabis, and/or opium [4].
Fadlan describes the drink being given to a female slave who was sacrificed, by strangulation and stabbing, during a ship burial ceremony [4]. | https://www.wikidoc.org/index.php/Nabidh | |
c73a002415bfa696da94493185e2a912d782271e | wikidoc | Nanobe | Nanobe
# Overview
Nanobes are tiny filamental structures first found in some rocks and sediments. Some hypothesize that they are the smallest form of life, ten times smaller than the smallest known bacteria.
Nanobes were discovered in 1996 (published in American Minerologist, vol 83., 1998) by Philipa Uwins, University of Queensland, Australia.
The smallest are just 20 nanometers in diameter. Some researchers believe them to be merely crystal growths, but a purported find of DNA in nanobe samples may prove otherwise. They are similar to the life-like structures found in ALH84001, the famous Mars meteorite from the Antarctic. Recently there has been some interest amongst bio-tech companies in commercial application of nanobes in utilization of plastics. Some researchers believe nanobe-like organisms might be implicated in a number of diseases. They might be responsible for the formation of some types of renal stones. They might even explain mysterious calcification of teeth in the human mouth, and thus actually be a useful or necessary symbiont (like Acidophilus).
Nanobes and nanobacteria are both controversial and unproven concepts; however, these two should not be confused. Nanobacteria are supposed to be walled organisms, while nanobes are hypothesized to be a previously unknown form of life. The origins of discovery, naming, and research methods also differ.
# Claims
- It is a living organism (contains DNA or some analogue, and reproduces).
- Has a morphology similar to Actinomycetes and Fungi.
- No article or research states that nanobes are nanobacteria.
- Nanobes are 20 nm in length which biological conventional wisdom assumes is too small to contain the basic elements for an organism to exist (DNA, plasmids, etc.), suggesting that they may reproduce via some unconventional means, like RNA instead of DNA.
- The Martian meteorite ALH84001, discovered in 1996 in the Antarctic, contained similar tubular structures which some astrobiologists suggest could be proof of life at an earlier time on Mars. | Nanobe
# Overview
Nanobes are tiny filamental structures first found in some rocks and sediments. Some hypothesize that they are the smallest form of life, ten times smaller than the smallest known bacteria.
Nanobes were discovered in 1996 (published in American Minerologist, vol 83., 1998) by Philipa Uwins, University of Queensland, Australia.
The smallest are just 20 nanometers in diameter. Some researchers believe them to be merely crystal growths, but a purported find of DNA in nanobe samples [1] may prove otherwise. They are similar to the life-like structures found in ALH84001, the famous Mars meteorite from the Antarctic. Recently there has been some interest amongst bio-tech companies in commercial application of nanobes in utilization of plastics. Some researchers believe nanobe-like organisms might be implicated in a number of diseases. They might be responsible for the formation of some types of renal stones. They might even explain mysterious calcification of teeth in the human mouth, and thus actually be a useful or necessary symbiont (like Acidophilus).
Nanobes and nanobacteria are both controversial and unproven concepts; however, these two should not be confused. Nanobacteria are supposed to be walled organisms, while nanobes are hypothesized to be a previously unknown form of life. The origins of discovery, naming, and research methods also differ.
# Claims
- It is a living organism (contains DNA or some analogue, and reproduces).
- Has a morphology similar to Actinomycetes and Fungi.
- No article or research states that nanobes are nanobacteria.
- Nanobes are 20 nm in length which biological conventional wisdom assumes is too small to contain the basic elements for an organism to exist (DNA, plasmids, etc.), suggesting that they may reproduce via some unconventional means, like RNA instead of DNA.
- The Martian meteorite ALH84001, discovered in 1996 in the Antarctic, contained similar tubular structures which some astrobiologists suggest could be proof of life at an earlier time on Mars. | https://www.wikidoc.org/index.php/Nanobe | |
7b5f8a137936bab4f13721f0e97c2b540503c847 | wikidoc | Napalm | Napalm
Napalm is the name given to any of a number of flammable liquids used in warfare, often jellied gasoline. Napalm is actually the thickener in such liquids, which when mixed with gasoline makes a sticky incendiary gel. Developed by the U.S. in World War II by a team of Harvard chemists led by Louis Fieser, its name is a combination of the names of its original ingredients, coprecipitated aluminium salts of naphthenic and palmitic acids. These were added to the flammable substance to cause it to gel.
One of the major problems of early incendiary fluids was that they splashed and drained too easily. The U.S. found that a gasoline gel increased both the range and effectiveness of flamethrowers, but was difficult to manufacture because it used natural rubber, which was in high demand and expensive. Napalm provided a far cheaper alternative, solving the issues involved with rubber-based incendiaries.
Modern napalm is composed primarily of benzene and polystyrene, and is known as napalm-B.
Napalm 878 was used in flamethrowers and bombs by the U.S. and Allied forces, to increase effectiveness of flammable liquids. The substance is formulated to burn at a specific rate and adhere to materials. Napalm is mixed with gasoline in various proportions to achieve this. Another useful (and dangerous) effect, primarily involving its use in bombs, was that napalm "rapidly deoxygenates the available air" as well as creating large amounts of carbon monoxide causing suffocation. Napalm bombs were also used in the Vietnam War.
Though napalm was a 20th century invention, it is part of a long history of incendiary materials in warfare. However, historically, it was primarily liquids that were used (see Greek fire). An infantry-based flammable liquid fuel weapon, the flamethrower, was introduced in World War I by the Germans, variations of which were soon developed by other nations in the conflict.
# Usage in warfare
On July 17, 1944, napalm incendiary bombs were dropped for the first time by American P-38 pilots on a fuel depot at Coutances, near St. Lô, France. Howard Zinn relates how he participated in a napalm bombing of German soldiers (and French civilians) who were awaiting the end of WWII in France about two weeks before the end of the war. Napalm bombs were first used in the Pacific Theatre during the Battle of Tinian by Marine aviators; however, its use was complicated by problems with mixing, fusing and the release mechanisms. In World War II, The USAAF bombed cities in Japan with napalm, and used it in bombs and flamethrowers in Germany and the Japanese-held islands. It was used by the Greek National army against the Democratic Army of Greece (DSE) during the Greek Civil War, by United Nations forces in Korea, by France against the Viet Minh in the First Indochina War, by Mexico in the late 1960s against guerrilla fighters in Guerrero and by the United States during the Vietnam War.
The most well-known method of delivering napalm is from air-dropped incendiary bombs. A lesser-known method is the flame throwers used by combat infantry. Flame throwers use a thinner version of the same jellied gasoline to destroy gun emplacements, bunkers and cave hideouts. U.S. Marines fighting on Guadalcanal found them very effective against Japanese positions. The Marines used fire as both a casualty weapon as well as a psychological weapon. They found that Japanese soldiers would abandon positions in which they fought to the death against other weapons. Prisoners of war confirmed that they feared napalm more than any other weapon utilised against them.
Pilots returning from the war zone often remarked they would rather have a couple of droppable gasoline tanks full of napalm than any other weapon, bombs, rockets or guns. The U.S. Air Force and Navy used napalm with great effect against all manner of targets to include troops, tanks, buildings and even railroad tunnels. The demoralizing effect napalm had on the enemy became apparent when scores of North Korean troops began to surrender to aircraft flying overhead. Pilots noted that they saw surviving enemy troops waving white flags on subsequent passes after dropping napalm. The pilots radioed to ground troops and the North Koreans were captured.
Napalm has been used recently in wartime by or against: Morocco (1976), Iran (1980–88), Israel (1967, 1982), Nigeria (1969), India & Pakistan (1965 & 1971), Brazil (1972), Egypt (1973), Cyprus (1964, 1974), Argentina (1982), Iraq (1980–88, 1991, 2003 - present), Serbia (1994),1993 Angola, France during the First Indochina War (1946-1954) and the Algerian War (1954-1962 ), and the United States.
Napalm can kill or wound by immolation and by asphyxiation. Immolation produces rapid loss of blood pressure, unconsciousness and death in a short time. 3rd degree burns are typically not painful at the time, because only the skin nerves respond to heat and 3rd degree burns kill the nerves. Burn victims do not experience 1st degree burns due to the adhesive properties of napalm that stick to the skin. Severe 2nd degree burns, likely to be suffered by someone hit with a small splash of napalm are severely painful and produce hideous scars called keloids, which can also bring about motor disturbances.
"Napalm is the most terrible pain you can imagine," said Kim Phúc, a napalm bombing survivor known from a famous Vietnam War photograph. "Water boils at 100 degrees Celsius. Napalm generates extremely high temperatures upon oxidation on the skin
Phúc sustained third-degree burns to half her body and was not expected to live after the attack by South Vietnamese aircraft. But thanks to assistance from South Vietnamese photographer Nick Ut and American doctors, and after surviving a 14-month hospital stay and 17 operations, she became an outspoken peace activist.
International law does not necessarily prohibit the use of napalm or other incendiaries against military targets, but use against civilian populations was banned by the United Nations Convention on Certain Conventional Weapons, (often referred to as the CCW) in 1980. Protocol III of the CCW restricts the use of incendiary weapons (not only napalm), but a number of states have not acceded to all of the protocols of the CCW. According to the Stockholm International Peace Research Institute (SIPRI), states are considered a party to the convention, which entered into force as international law in December 1983, if they ratify at least two of the five protocols. The United States, for example, is a party to the CCW but did not sign protocol III.
Reports by the Sydney Morning Herald suggested the usage of napalm in the Iraq War by US forces. This was denied by the U.S. Department of Defense. In August 2003, the San Diego Union Tribune alleged that U.S. Marine pilots and their commanders confirmed the use of Mark 77 firebombs on Iraqi Republican Guards during the initial stages of combat. Official denials of the use of 'napalm' were, however, disingenuous, as the Mk 77 bomb that is currently in service at this time, the Mk 77 Mod 5, does not use actual napalm (for example, napalm-B). The last U.S. bomb to use actual napalm was the Mark 77 Mod 4, the last of which were destroyed in March 2001. The substance used now is a different incendiary mixture, but sufficiently analogous in its effects that it is still a controversial incendiary, and can still be referred to colloquially as 'napalm.'
"We napalmed both those (bridge) approaches," said Col. Randolph Alles in a recent interview. "Unfortunately, there were people there because you could see them in the (cockpit) video." (...) "They were Iraqi soldiers there. It's no great way to die," he added. (...) The generals love napalm. ... It has a big psychological effect." - San Diego Union-Tribune, August 2003
These bombs did not actually contain napalm. The napalm-B (super napalm) used in Vietnam was gasoline based. The Mk-77 firebombs used in the Gulf were kerosene based. It is, however, a napalm-like liquid in its effect.
# Composition
Napalm is usually a mixture of gasoline with suitable thickening agents. The earliest thickeners were soaps, aluminium, and magnesium palmitates and stearates. Depending on the amount of added thickener, the resulting viscosity may range between syrupy liquid and thick rubbery gel. The content of long hydrocarbon chains makes the material highly hydrophobic (resistant to wetting with water), making it more difficult to extinguish. Thickened fuel also rebounds better from surfaces, making it more useful for operations in urban terrain.
There are two types of napalm: oil-based with aluminium soap thickener, and oil-based with polymeric thickener ("napalm-B").
The United States military uses three kinds of thickeners: M1, M2, and M4.
- The M1 Thickener (MIL-T-589A), chemically a mixture of 25% wt. aluminium naphthenate, 25% aluminium oleate, and 50% aluminium laurate, (or, according to other sources, aluminium stearate soap) is a highly hygroscopic coarse tan-colored powder. As the water content impairs the quality of napalm, thickener from partially used open containers should not be used later. It is not maintained in the US Army inventory any more as it was replaced with M4.
- The M2 Thickener (MIL-T-0903025B) is a whitish powder similar to M1, with added devolatilized silica and anticaking agent.
- The M4 flame fuel thickening compound (MIL-T-50009A), hydroxyl aluminium bis(2-ethylhexanoate) with anti-caking agent, is a fine white powder. It is less hygroscopic than M1 and opened containers can be resealed and used within one day. About half the amount of M4 is needed for the same effect as of M1.
A later variant, napalm-B, also called "super napalm", is a mixture of low-octane gasoline with benzene and polystyrene. It was used in the Vietnam War. Unlike conventional napalm, which burns for only 15–30 seconds, napalm B burns for up to 10 minutes with fewer fireballs, sticks better to surfaces, and offers improved destruction effects. It is not as easy to ignite, which reduces the number of accidents caused by soldiers smoking. When it burns, it develops a characteristic smell.
Starting in the early 1990s, various websites including The Anarchist Cookbook advertised recipes for homemade napalm. These recipes were predominantly equal parts gasoline and styrofoam. This mixture closely resembles that of napalm-B, but lacks a percentage of benzene.
Napalm reaches burning temperatures of approximately 1,200 °C (2,200 °F). Other additives can be added, eg. powdered aluminium or magnesium, or white phosphorus.
In the early 1950s, Norway developed its own napalm, based on fatty acids in whale oil. The reason for this development was that the American-produced thickening agent performed rather poorly in the cold Norwegian climate. The product was known as Northick II.
Some weapons utilize a pyrophoric variant, known as TPA (thickened pyrophoric agent). Chemically it is a triethylaluminium thickened with polyisobutylene.
# In popular culture
Napalm itself became well-known by the American public after its use in the Vietnam war. Since then, it has been mentioned in the media and arts on numerous occasions. In the film Apocalypse Now, Airmobile Infantry Colonel Kilgore declared "I love the smell of napalm in the morning... It smells like... victory" following a nearby napalm strike. In An Officer and a Gentleman, Sgt. Foley led a quick-step march with a cadence call that had the chorus, "Cause napalm sticks to kids!", representing a cadence call common in the U.S. military at the time. | Napalm
Napalm is the name given to any of a number of flammable liquids used in warfare, often jellied gasoline. Napalm is actually the thickener in such liquids, which when mixed with gasoline makes a sticky incendiary gel. Developed by the U.S. in World War II by a team of Harvard chemists led by Louis Fieser, its name is a combination of the names of its original ingredients, coprecipitated aluminium salts of naphthenic and palmitic acids. These were added to the flammable substance to cause it to gel.[1]
One of the major problems of early incendiary fluids was that they splashed and drained too easily. The U.S. found that a gasoline gel increased both the range and effectiveness of flamethrowers, but was difficult to manufacture because it used natural rubber, which was in high demand and expensive. Napalm provided a far cheaper alternative, solving the issues involved with rubber-based incendiaries.[1]
Modern napalm is composed primarily of benzene and polystyrene, and is known as napalm-B.[1]
Napalm 878 was used in flamethrowers and bombs by the U.S. and Allied forces, to increase effectiveness of flammable liquids. The substance is formulated to burn at a specific rate and adhere to materials. Napalm is mixed with gasoline in various proportions to achieve this. Another useful (and dangerous) effect, primarily involving its use in bombs, was that napalm "rapidly deoxygenates the available air" as well as creating large amounts of carbon monoxide causing suffocation. Napalm bombs were also used in the Vietnam War.[1]
Though napalm was a 20th century invention, it is part of a long history of incendiary materials in warfare. However, historically, it was primarily liquids that were used (see Greek fire). An infantry-based flammable liquid fuel weapon, the flamethrower, was introduced in World War I by the Germans, variations of which were soon developed by other nations in the conflict.[1]
# Usage in warfare
On July 17, 1944, napalm incendiary bombs were dropped for the first time by American P-38 pilots on a fuel depot at Coutances, near St. Lô, France.[citation needed] Howard Zinn relates how he participated in a napalm bombing of German soldiers (and French civilians) who were awaiting the end of WWII in France about two weeks before the end of the war.[2] Napalm bombs were first used in the Pacific Theatre during the Battle of Tinian by Marine aviators; however, its use was complicated by problems with mixing, fusing and the release mechanisms.[3] In World War II, The USAAF bombed cities in Japan with napalm, and used it in bombs and flamethrowers in Germany and the Japanese-held islands. It was used by the Greek National army against the Democratic Army of Greece (DSE) during the Greek Civil War, by United Nations forces in Korea, by France against the Viet Minh in the First Indochina War, by Mexico in the late 1960s against guerrilla fighters in Guerrero and by the United States during the Vietnam War.
The most well-known method of delivering napalm is from air-dropped incendiary bombs. A lesser-known method is the flame throwers used by combat infantry. Flame throwers use a thinner version of the same jellied gasoline to destroy gun emplacements, bunkers and cave hideouts. U.S. Marines fighting on Guadalcanal found them very effective against Japanese positions. The Marines used fire as both a casualty weapon as well as a psychological weapon. They found that Japanese soldiers would abandon positions in which they fought to the death against other weapons. Prisoners of war confirmed that they feared napalm more than any other weapon utilised against them.
Pilots returning from the war zone often remarked they would rather have a couple of droppable gasoline tanks full of napalm than any other weapon, bombs, rockets or guns. The U.S. Air Force and Navy used napalm with great effect against all manner of targets to include troops, tanks, buildings and even railroad tunnels. The demoralizing effect napalm had on the enemy became apparent when scores of North Korean troops began to surrender to aircraft flying overhead. Pilots noted that they saw surviving enemy troops waving white flags on subsequent passes after dropping napalm. The pilots radioed to ground troops and the North Koreans were captured. [4]
Napalm has been used recently in wartime by or against: Morocco (1976), Iran (1980–88), Israel (1967, 1982), Nigeria (1969), India & Pakistan (1965 & 1971), Brazil (1972), Egypt (1973), Cyprus (1964, 1974), Argentina (1982), Iraq (1980–88, 1991, 2003 - present), Serbia (1994),1993 Angola, France during the First Indochina War (1946-1954) and the Algerian War (1954-1962 [5]), and the United States.
Napalm can kill or wound by immolation and by asphyxiation. Immolation produces rapid loss of blood pressure, unconsciousness and death in a short time. 3rd degree burns are typically not painful at the time, because only the skin nerves respond to heat and 3rd degree burns kill the nerves. Burn victims do not experience 1st degree burns due to the adhesive properties of napalm that stick to the skin. Severe 2nd degree burns, likely to be suffered by someone hit with a small splash of napalm are severely painful and produce hideous scars called keloids, which can also bring about motor disturbances.[1]
"Napalm is the most terrible pain you can imagine," said Kim Phúc, a napalm bombing survivor known from a famous Vietnam War photograph. "Water boils at 100 degrees Celsius. Napalm generates extremely high temperatures upon oxidation on the skin[6]
Phúc sustained third-degree burns to half her body and was not expected to live after the attack by South Vietnamese aircraft. But thanks to assistance from South Vietnamese photographer Nick Ut and American doctors, and after surviving a 14-month hospital stay and 17 operations, she became an outspoken peace activist.
International law does not necessarily prohibit the use of napalm or other incendiaries against military targets,[6] but use against civilian populations was banned by the United Nations Convention on Certain Conventional Weapons, (often referred to as the CCW) in 1980. Protocol III of the CCW restricts the use of incendiary weapons (not only napalm), but a number of states have not acceded to all of the protocols of the CCW. According to the Stockholm International Peace Research Institute (SIPRI), states are considered a party to the convention, which entered into force as international law in December 1983, if they ratify at least two of the five protocols. The United States, for example, is a party to the CCW but did not sign protocol III.[7]
Reports by the Sydney Morning Herald suggested the usage of napalm in the Iraq War by US forces.[8] This was denied by the U.S. Department of Defense. In August 2003, the San Diego Union Tribune alleged that U.S. Marine pilots and their commanders confirmed the use of Mark 77 firebombs on Iraqi Republican Guards during the initial stages of combat. Official denials of the use of 'napalm' were, however, disingenuous, as the Mk 77 bomb that is currently in service at this time, the Mk 77 Mod 5, does not use actual napalm (for example, napalm-B). The last U.S. bomb to use actual napalm was the Mark 77 Mod 4, the last of which were destroyed in March 2001.[9] The substance used now is a different incendiary mixture, but sufficiently analogous in its effects that it is still a controversial incendiary, and can still be referred to colloquially as 'napalm.'
"We napalmed both those (bridge) approaches," said Col. Randolph Alles in a recent interview. "Unfortunately, there were people there because you could see them in the (cockpit) video." (...) "They were Iraqi soldiers there. It's no great way to die," he added. (...) The generals love napalm. ... It has a big psychological effect." - San Diego Union-Tribune, August 2003[10]
These bombs did not actually contain napalm. The napalm-B (super napalm) used in Vietnam was gasoline based. The Mk-77 firebombs used in the Gulf were kerosene based. It is, however, a napalm-like liquid in its effect.[1]
# Composition
Napalm is usually a mixture of gasoline with suitable thickening agents. The earliest thickeners were soaps, aluminium, and magnesium palmitates and stearates. Depending on the amount of added thickener, the resulting viscosity may range between syrupy liquid and thick rubbery gel. The content of long hydrocarbon chains makes the material highly hydrophobic (resistant to wetting with water), making it more difficult to extinguish. Thickened fuel also rebounds better from surfaces, making it more useful for operations in urban terrain.
There are two types of napalm: oil-based with aluminium soap thickener, and oil-based with polymeric thickener ("napalm-B").
The United States military uses three kinds of thickeners: M1, M2, and M4.
- The M1 Thickener (MIL-T-589A), chemically a mixture of 25% wt. aluminium naphthenate, 25% aluminium oleate, and 50% aluminium laurate, (or, according to other sources, aluminium stearate soap) is a highly hygroscopic coarse tan-colored powder. As the water content impairs the quality of napalm, thickener from partially used open containers should not be used later. It is not maintained in the US Army inventory any more as it was replaced with M4.
- The M2 Thickener (MIL-T-0903025B) is a whitish powder similar to M1, with added devolatilized silica and anticaking agent.
- The M4 flame fuel thickening compound (MIL-T-50009A), hydroxyl aluminium bis(2-ethylhexanoate) with anti-caking agent, is a fine white powder. It is less hygroscopic than M1 and opened containers can be resealed and used within one day. About half the amount of M4 is needed for the same effect as of M1.
A later variant, napalm-B, also called "super napalm", is a mixture of low-octane gasoline with benzene and polystyrene. It was used in the Vietnam War. Unlike conventional napalm, which burns for only 15–30 seconds, napalm B burns for up to 10 minutes with fewer fireballs, sticks better to surfaces, and offers improved destruction effects. It is not as easy to ignite, which reduces the number of accidents caused by soldiers smoking. When it burns, it develops a characteristic smell.
Starting in the early 1990s, various websites including The Anarchist Cookbook advertised recipes for homemade napalm. These recipes were predominantly equal parts gasoline and styrofoam. This mixture closely resembles that of napalm-B, but lacks a percentage of benzene.
Napalm reaches burning temperatures of approximately 1,200 °C (2,200 °F). Other additives can be added, eg. powdered aluminium or magnesium, or white phosphorus.
In the early 1950s, Norway developed its own napalm, based on fatty acids in whale oil. The reason for this development was that the American-produced thickening agent performed rather poorly in the cold Norwegian climate. The product was known as Northick II.[11]
Some weapons utilize a pyrophoric variant, known as TPA (thickened pyrophoric agent). Chemically it is a triethylaluminium thickened with polyisobutylene.
# In popular culture
Napalm itself became well-known by the American public after its use in the Vietnam war. Since then, it has been mentioned in the media and arts on numerous occasions. In the film Apocalypse Now, Airmobile Infantry Colonel Kilgore declared "I love the smell of napalm in the morning... It smells like... victory" following a nearby napalm strike. In An Officer and a Gentleman, Sgt. Foley led a quick-step march with a cadence call that had the chorus, "Cause napalm sticks to kids!", representing a cadence call common in the U.S. military at the time. | https://www.wikidoc.org/index.php/Napalm | |
d8b7ffed3f41348c7f69714ab9235e25ec50c800 | wikidoc | Natron | Natron
Natron is a naturally occurring mixture of hydrated sodium carbonate (soda ash, Na2CO3·10 H2O) and about 17% sodium bicarbonate (baking soda, NaHCO3) along with small quantities of household salt (sodium chloride) and sodium sulfate. Natron is white to colorless when pure, varying to gray or yellow with impurities. Natron deposits occur naturally as a part of saline lake beds in arid environments. Historically natron had many practical applications which still resonate in the wide modern use of its constituent mineral components.
# Etymology
The English word natron is a French cognate derived from the Spanish natrón through the Arabic natrun from Greek nitron. The modern chemical symbol for sodium, Na, is an abbreviation of that element's new Latin name natrium, which was derived from natron.
# Chemical properties
Natron has a specific gravity of 1.42 to 1.47 and a Mohs hardness of 1. It crystallizes in the monoclinic crystal system, typically forming efflorescences and encrustations. Natron effloresces (loses water) in dry air and is partially transformed into the monohydrate thermonatrite, Na2(CO3)·(H2O). The mineral is often found in association with thermonatrite, trona, mirabilite, gaylussite, gypsum and calcite.
# Importance in antiquity
Natron was harvested directly from dry lake beds in ancient Egypt and has been used for thousands of years as a cleaning product for both the home and body. Blended with oil, it was an early form of soap. It softens water whilst removing oil, grease and alcohol stains. Undiluted, natron was a cleanser for the teeth and an early mouthwash. The mineral was mixed into early antiseptics for wounds and minor cuts. Natron can be used to dry and preserve fish and meat. It was also an ancient household insecticide.
The mineral was used in Egyptian mummification because it absorbs water and behaves as a drying agent. Moreover, when exposed to moisture the bicarbonate in natron increases pH, which creates a hostile environment for bacteria. Culturally, natron was generally thought to enhance spiritual safety for both the living and the dead. Natron was added to castor oil to make a smokeless fuel which allowed Egyptian artisans to paint elaborate artworks inside ancient tombs without staining them with soot.
Natron is an ingredient for the making of a distinct color called Egyptian blue. It was used along with sand in ceramic and glass making by the Romans and others at least until 640 CE. The mineral was also employed as a flux to solder precious metals together.
## Declining use
Most of natron's uses both in the home and by industry were gradually replaced with often closely related sodium compounds and minerals. Natron's detergent properties are now commercially supplied by soda ash (the compound's chief ingredient) and other chemicals. Soda ash also replaced natron in glassmaking. Many of its ancient household roles are now filled by ordinary baking soda, natron's secondary ingredient.
# Geological occurrence
- Quebec, Canada
Rouville County
Mont-Saint-Hilaire
- Rouville County
- Mont-Saint-Hilaire
- Interior British Columbia, Canada
- Wadi Natrum, Egypt
- Showa Province, Ethiopia
- Hungary
Bács-Kiskun County, (Great Hungarian Plain)
Szabolcs-Szatmár-Bereg County (Great Hungarian Plain)
- Bács-Kiskun County, (Great Hungarian Plain)
- Szabolcs-Szatmár-Bereg County (Great Hungarian Plain)
- Campania, Italy
Province of Naples
Somma-Vesuvius Complex
- Province of Naples
- Somma-Vesuvius Complex
- Russia (Northern Region)
Murmanskaja Oblast
Kola Peninsula
Khibiny Massif
Lovozero Massif
Alluaiv Mountain
Umbozero Mine
Kedykverpakhk Mountain
- Murmanskaja Oblast
- Kola Peninsula
- Khibiny Massif
- Lovozero Massif
- Alluaiv Mountain
- Umbozero Mine
- Kedykverpakhk Mountain
- England, UK
Cornwall
St Just District
Botallack - Pendeen Area
Botallack, and Botallack Mine
- Cornwall
- St Just District
- Botallack - Pendeen Area
- Botallack, and Botallack Mine
- California, USA
Inyo County
- Inyo County
- Nevada, USA
Churchill County (Soda Lake District)
Humboldt County
Mineral County
- Churchill County (Soda Lake District)
- Humboldt County
- Mineral County
- Oregon, USA
Lake County
- Lake County
- Washington, USA
Okanogan County
- Okanogan County | Natron
Natron is a naturally occurring mixture of hydrated sodium carbonate (soda ash, Na2CO3·10 H2O) and about 17% sodium bicarbonate (baking soda, NaHCO3) along with small quantities of household salt (sodium chloride) and sodium sulfate. Natron is white to colorless when pure, varying to gray or yellow with impurities. Natron deposits occur naturally as a part of saline lake beds in arid environments. Historically natron had many practical applications which still resonate in the wide modern use of its constituent mineral components.
# Etymology
The English word natron is a French cognate derived from the Spanish natrón through the Arabic natrun from Greek nitron. The modern chemical symbol for sodium, Na, is an abbreviation of that element's new Latin name natrium, which was derived from natron.
# Chemical properties
Natron has a specific gravity of 1.42 to 1.47 and a Mohs hardness of 1. It crystallizes in the monoclinic crystal system, typically forming efflorescences and encrustations. Natron effloresces (loses water) in dry air and is partially transformed into the monohydrate thermonatrite, Na2(CO3)·(H2O). The mineral is often found in association with thermonatrite, trona, mirabilite, gaylussite, gypsum and calcite.
# Importance in antiquity
Natron was harvested directly from dry lake beds in ancient Egypt and has been used for thousands of years as a cleaning product for both the home and body. Blended with oil, it was an early form of soap. It softens water whilst removing oil, grease and alcohol stains. Undiluted, natron was a cleanser for the teeth and an early mouthwash. The mineral was mixed into early antiseptics for wounds and minor cuts. Natron can be used to dry and preserve fish and meat. It was also an ancient household insecticide.
The mineral was used in Egyptian mummification because it absorbs water and behaves as a drying agent. Moreover, when exposed to moisture the bicarbonate in natron increases pH, which creates a hostile environment for bacteria. Culturally, natron was generally thought to enhance spiritual safety for both the living and the dead. Natron was added to castor oil to make a smokeless fuel which allowed Egyptian artisans to paint elaborate artworks inside ancient tombs without staining them with soot.
Natron is an ingredient for the making of a distinct color called Egyptian blue. It was used along with sand in ceramic and glass making by the Romans and others at least until 640 CE. The mineral was also employed as a flux to solder precious metals together.
## Declining use
Most of natron's uses both in the home and by industry were gradually replaced with often closely related sodium compounds and minerals. Natron's detergent properties are now commercially supplied by soda ash (the compound's chief ingredient) and other chemicals. Soda ash also replaced natron in glassmaking. Many of its ancient household roles are now filled by ordinary baking soda, natron's secondary ingredient.
# Geological occurrence
- Quebec, Canada
Rouville County
Mont-Saint-Hilaire
- Rouville County
- Mont-Saint-Hilaire
- Interior British Columbia, Canada
- Wadi Natrum, Egypt
- Showa Province, Ethiopia
- Hungary
Bács-Kiskun County, (Great Hungarian Plain)
Szabolcs-Szatmár-Bereg County (Great Hungarian Plain)
- Bács-Kiskun County, (Great Hungarian Plain)
- Szabolcs-Szatmár-Bereg County (Great Hungarian Plain)
- Campania, Italy
Province of Naples
Somma-Vesuvius Complex
- Province of Naples
- Somma-Vesuvius Complex
- Russia (Northern Region)
Murmanskaja Oblast
Kola Peninsula
Khibiny Massif
Lovozero Massif
Alluaiv Mountain
Umbozero Mine
Kedykverpakhk Mountain
- Murmanskaja Oblast
- Kola Peninsula
- Khibiny Massif
- Lovozero Massif
- Alluaiv Mountain
- Umbozero Mine
- Kedykverpakhk Mountain
- England, UK
Cornwall
St Just District
Botallack - Pendeen Area
Botallack, and Botallack Mine
- Cornwall
- St Just District
- Botallack - Pendeen Area
- Botallack, and Botallack Mine
- California, USA
Inyo County
- Inyo County
- Nevada, USA
Churchill County (Soda Lake District)
Humboldt County
Mineral County
- Churchill County (Soda Lake District)
- Humboldt County
- Mineral County
- Oregon, USA
Lake County
- Lake County
- Washington, USA
Okanogan County
- Okanogan County | https://www.wikidoc.org/index.php/Natron | |
6658c4a06e4ccc2b496ce355d69dc735008d1f14 | wikidoc | Nav1.1 | Nav1.1
Nav1.1, also known as the sodium channel, voltage-gated, type I, alpha subunit (SCN1A), is a protein which in humans is encoded by the SCN1A gene.
# Function
The vertebrate sodium channel is a voltage-gated ion channel essential for the generation and propagation of action potentials, chiefly in nerve and muscle. Voltage-sensitive sodium channels are heteromeric complexes consisting of a large central pore-forming glycosylated alpha subunit and 2 smaller auxiliary beta subunits. Functional studies have indicated that the transmembrane alpha subunit of the brain sodium channels is sufficient for expression of functional sodium channels. Brain sodium channel alpha subunits form a gene subfamily with several structurally distinct isoforms clustering on chromosome 2q24, types I, II (Nav1.2), and III (Nav1.3). There are also several distinct sodium channel alpha subunit isoforms in skeletal and cardiac muscle (Nav1.4 and Nav1.5, respectively).
# Clinical significance
Mutations in the SCN1A gene cause inherited febrile seizures and GEFS+, type 2.
# Patent controversy
On 29 November 2008, The Sydney Morning Herald reported the first evidence of private intellectual property rights over human DNA having adversely affected medical care. The Melbourne company Genetic Technologies (GTG) controls rights to the gene, and requires royalties for tests on the gene, which can help identify Dravet syndrome. Doctors on the Children's Hospital in Westmead, Australia have told journalists that they would test 50% more infants for the gene, if they could conduct the test on site.
# Interactions
Nav1.1 has been shown to interact with syntrophin, alpha 1. | Nav1.1
Nav1.1, also known as the sodium channel, voltage-gated, type I, alpha subunit (SCN1A), is a protein which in humans is encoded by the SCN1A gene.[1][2][3][4]
# Function
The vertebrate sodium channel is a voltage-gated ion channel essential for the generation and propagation of action potentials, chiefly in nerve and muscle. Voltage-sensitive sodium channels are heteromeric complexes consisting of a large central pore-forming glycosylated alpha subunit and 2 smaller auxiliary beta subunits. Functional studies have indicated that the transmembrane alpha subunit of the brain sodium channels is sufficient for expression of functional sodium channels.[5] Brain sodium channel alpha subunits form a gene subfamily with several structurally distinct isoforms clustering on chromosome 2q24, types I, II (Nav1.2), and III (Nav1.3). There are also several distinct sodium channel alpha subunit isoforms in skeletal and cardiac muscle (Nav1.4[6] and Nav1.5,[7] respectively).
# Clinical significance
Mutations in the SCN1A gene cause inherited febrile seizures and GEFS+, type 2.[8][9][10][11]
# Patent controversy
On 29 November 2008, The Sydney Morning Herald reported the first evidence of private intellectual property rights over human DNA[12] having adversely affected medical care. The Melbourne company Genetic Technologies (GTG) controls rights to the gene, and requires royalties for tests on the gene, which can help identify Dravet syndrome. Doctors on the Children's Hospital in Westmead, Australia have told journalists that they would test 50% more infants for the gene, if they could conduct the test on site.
# Interactions
Nav1.1 has been shown to interact with syntrophin, alpha 1.[13] | https://www.wikidoc.org/index.php/Nav1.1 | |
5847e8146c6634e60ef95641e742cf61ec241ef8 | wikidoc | Nav1.2 | Nav1.2
Navα1.2, also known as the sodium channel, voltage-gated, type II, alpha subunit is a protein that in humans is encoded by the SCN2A gene. Functional sodium channels contain an ion conductive alpha subunit and one or more regulatory beta subunits. Sodium channels which contain the Navα1.2 subunit are called Nav1.2 channels.
# Function
Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four domains including 24 transmembrane segments and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is heterogeneously expressed in the brain, and mutations in this gene have been linked to several seizure disorders. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.
# Clinical significance
Mutations in this gene have been implicated in cases of autism, infantile spasms and bitemporal glucose hypometabolism. | Nav1.2
Navα1.2, also known as the sodium channel, voltage-gated, type II, alpha subunit is a protein that in humans is encoded by the SCN2A gene.[1] Functional sodium channels contain an ion conductive alpha subunit and one or more regulatory beta subunits. Sodium channels which contain the Navα1.2 subunit are called Nav1.2 channels.
# Function
Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four domains including 24 transmembrane segments and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is heterogeneously expressed in the brain, and mutations in this gene have been linked to several seizure disorders. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.[1]
# Clinical significance
Mutations in this gene have been implicated in cases of autism,[2] infantile spasms and bitemporal glucose hypometabolism.[3] | https://www.wikidoc.org/index.php/Nav1.2 | |
200a9b3f1c4eeeac86d9218ad867156be1a45f34 | wikidoc | Nav1.4 | Nav1.4
Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.
The Nav1.4 voltage-gated sodium channel is encoded by the SCN4A gene. Mutations in the gene are associated with hypokalemic periodic paralysis, hyperkalemic periodic paralysis, paramyotonia congenita, and potassium-aggravated myotonia.
# Function
Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders.
# Clinical significance
## Periodic paralysis
In hypokalemic periodic paralysis, arginine residues making up the voltage sensor of Nav1.4 are mutated. The voltage sensor comprises the S4 alpha helix of each of the four transmembrane domains (I-IV) of the protein, and contains basic residues that only allow entry of the positive sodium ions at appropriate membrane voltages by blocking or opening the channel pore. In patients with these mutations, the channel has a reduced excitability and signals from the central nervous system are unable to depolarise muscle. As a result, the muscle cannot contract efficiently, causing paralysis. The condition is hypokalemic because a low extracellular potassium ion concentration will cause the muscle to repolarise to the resting potential more quickly, so even if calcium conductance does occur it cannot be sustained. It becomes more difficult to reach the calcium threshold at which the muscle can contract, and even if this is reached then the muscle is more likely to relax. Because of this, the severity would be reduced if potassium ion concentrations are kept high.
In hyperkalemic periodic paralysis, mutations occur in residues between transmembrane domains III and IV which make up the fast inactivation gate of Nav1.4. Mutations have also been found on the cytoplasmic loops between the S4 and S5 helices of domains II, III and IV, which are the binding sites of the inactivation gate.
In patients with these the channel is unable to inactivate, sodium conductance is sustained and the muscle remains permanently tense. Since the motor end plate is depolarized, further signals to contract have no effect (paralysis). The condition is hyperkalemic because a high extracellular potassium ion concentration will make it even more unfavourable for potassium to leave the cell in order to repolarise it to the resting potential, and this further prolongs the sodium conductance and keeps the muscle contracted. Hence, the severity would be reduced if extracellular (serum) potassium ion concentrations are kept low.
## Myotonia
The same types of mutations cause myotonia and paralysis, however the difference between these phenotypes depends on the level of sodium current that persists. If the conductance fluctuates below the voltage threshold for Nav1.4, then the sodium channels will eventually be able to close, and be depolarised again. Thus, the muscle merely remains contracted for longer than normal (myotonia) but will relax and be able to contract again within a short period. If the conductance settles at a steady state with the sodium pore open and unable to inactivate, then the muscle is unable to relax at all and motor control is completely lost (paralysis). | Nav1.4
Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.[1][2][3][4]
The Nav1.4 voltage-gated sodium channel is encoded by the SCN4A gene. Mutations in the gene are associated with hypokalemic periodic paralysis, hyperkalemic periodic paralysis, paramyotonia congenita, and potassium-aggravated myotonia.
# Function
Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders.[4]
# Clinical significance
## Periodic paralysis
In hypokalemic periodic paralysis, arginine residues making up the voltage sensor of Nav1.4 are mutated. The voltage sensor comprises the S4 alpha helix of each of the four transmembrane domains (I-IV) of the protein, and contains basic residues that only allow entry of the positive sodium ions at appropriate membrane voltages by blocking or opening the channel pore. In patients with these mutations, the channel has a reduced excitability and signals from the central nervous system are unable to depolarise muscle. As a result, the muscle cannot contract efficiently, causing paralysis. The condition is hypokalemic because a low extracellular potassium ion concentration will cause the muscle to repolarise to the resting potential more quickly, so even if calcium conductance does occur it cannot be sustained. It becomes more difficult to reach the calcium threshold at which the muscle can contract, and even if this is reached then the muscle is more likely to relax. Because of this, the severity would be reduced if potassium ion concentrations are kept high.[5][6]
In hyperkalemic periodic paralysis, mutations occur in residues between transmembrane domains III and IV which make up the fast inactivation gate of Nav1.4. Mutations have also been found on the cytoplasmic loops between the S4 and S5 helices of domains II, III and IV, which are the binding sites of the inactivation gate.[7][8]
In patients with these the channel is unable to inactivate, sodium conductance is sustained and the muscle remains permanently tense. Since the motor end plate is depolarized, further signals to contract have no effect (paralysis). The condition is hyperkalemic because a high extracellular potassium ion concentration will make it even more unfavourable for potassium to leave the cell in order to repolarise it to the resting potential, and this further prolongs the sodium conductance and keeps the muscle contracted. Hence, the severity would be reduced if extracellular (serum) potassium ion concentrations are kept low.[6]
## Myotonia
The same types of mutations cause myotonia and paralysis, however the difference between these phenotypes depends on the level of sodium current that persists. If the conductance fluctuates below the voltage threshold for Nav1.4, then the sodium channels will eventually be able to close, and be depolarised again. Thus, the muscle merely remains contracted for longer than normal (myotonia) but will relax and be able to contract again within a short period. If the conductance settles at a steady state with the sodium pore open and unable to inactivate, then the muscle is unable to relax at all and motor control is completely lost (paralysis). | https://www.wikidoc.org/index.php/Nav1.4 | |
99ee4620f3f465ffabcb21076fe4081ce1f2c6c6 | wikidoc | Nav1.5 | Nav1.5
NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of Na+-ions (INa) across the cell membrane, resulting in the fast depolarization phase of the cardiac action potential. As such, it plays a major role in impulse propagation through the heart. A vast number of cardiac diseases is associated with mutations in NaV1.5 (see paragraph genetics). SCN5A is the gene that encodes the cardiac sodium channel NaV1.5.
# Gene structure
SCN5A is a highly conserved gene located on human chromosome 3, where it spans more than 100 kb. The gene consists of 28 exons, of which exon 1 and in part exon 2 form the 5’ untranslated region (5’UTR) and exon 28 the 3’ untranslated region (3’UTR) of the RNA. SCN5A is part of a family of 10 genes that encode different types of sodium channels, i.e. brain-type (NaV1.1, NaV1.2, NaV1.3, NaV1.6), neuronal channels (NaV1.7, NaV1.8 and NaV1.9), skeletal muscle channels (NaV1.4) and the cardiac sodium channel NaV1.5.
## Expression pattern
SCN5A is mainly expressed in the heart, where expression is abundant in working myocardium and conduction tissue. In contrast, expression is low in the sinoatrial node and atrioventricular node. Within the heart, a transmural expression gradient from subendocardium to subsendocardium is present, with higher expression of SCN5A in the endocardium as compared to the epicardium
## Splice variants
More than 10 different splice isoforms have been described for SCN5A, of which several harbour different functional properties. In the heart, two isoforms are mainly expressed (ratio 1:2), of which the least predominant one contains an extra glutamine at position 1077 (1077Q). Moreover, different isoforms are expressed during fetal life and adult, differing in the inclusion of an alternative exon 6.
# Protein structure and function
NaV1.5 is a large transmembrane protein with 4 repetitive transmembrane domains (DI-DIV), containing 6 transmembrane spanning sections each (S1-S6). The pore region of the channels, through which Na+-ions flow, are formed by the segments S5 and S6 of the 4 domains. Voltage sensing is mediated by the remaining segments, of which the positively charged S4 segments plays a fundamental role.
NaV1.5 channels predominantly mediate the sodium current (INa) in cardiac cells. INa is responsible for the fast upstroke of the action potential, and as such plays a crucial role in impulse propagation through the heart. The conformational state of the channel, which is both voltage and time-dependent, determines whether the channel is opened or closed. At the resting membrane potential (around -85 mV), NaV1.5 channels are closed. Upon a stimulus (through conduction by a neighboring cell), the membrane depolarizes and NaV1.5 channels open through the outward movement of the S4 segments, leading to the initiation of the action potential. Simultaneously, a process called ‘fast inactivation’ results in closure of the channels within 1 ms. In physiological conditions, when inactivated, channels remain in closed state until the cell membrane repolarizes, where a recovery from inactivation is necessary before they become available for activation again. During the action potential, a very small fraction of sodium current persists and does not inactivate completely. This current is called ‘sustained current’, ‘late current’ or ‘INa,L’.
Also, some channels may reactivate during the repolarizing phase of the action potential at a range of potentials where inactivation is not complete and shows overlap with activation, generating the so-called “window current”.
## Sub-units and protein interaction partners
Trafficking, function and structure of NaV1.5 can be affected by the many protein interaction partners that have been identified to date (for an extensive review, see Abriel et al. 2010). Of these, the 4 sodium channel beta-subunits, encoded by the genes SCN1B, SCN2B, SCN3B and SCN4B, form an important category. In general, beta-subunits increase function of NaV1.5, either by change in intrinsic properties or by affecting the process of trafficking to the cell surface.
Apart from the beta-subunits, other proteins, such as calmodulin, calmodulin kinase II δc, ankyrin-G and plakophilin-2, are known to interact and modulate function of NaV1.5. Some of these have also been linked to genetic and acquired cardiac diseases.
# Genetics
Mutations in SCN5A, which could result in a loss and/or a gain-of-function of the channel, are associated with a spectrum of cardiac diseases. Pathogenic mutations generally exhibit an autosomal dominant inheritance pattern, although recessive forms of SCN5A mutations are also described. Also, mutations may act as a disease modifier, especially in families where lack of direct causality is reflected by complex inheritance patterns. It is important to note that a significant number of individuals (2-7%) in the general population carry a rare (population frequency <1%), protein-altering variant in the gene, highlighting the complexity of linking mutations directly with observed phenotypes. Mutations that result in the same biophysical effect can give rise to different diseases.
To date, loss-of-function mutations have been associated with Brugada syndrome (BrS), progressive cardiac conduction disease (Lev-Lenègre disease), dilated cardiomyopathy (DCM), sick sinus syndrome, and atrial fibrillation.
Mutations resulting in a gain-of-function are causal for Long QT syndrome type 3 and are also more recently implicated in multifocal ectopic Purkinje-related premature contractions (MEPPC) Some gain-of-function mutations are also associated with AF and DCM. Gain-of-function of NaV1.5 is generally reflected by an increase in INa,L, a slowed rate of inactivation or a shift in voltage dependence of activation or inactivation (resulting in an increased window-current).
SCN5A mutations are believed to be found in a disproportionate number of people who have Irritable Bowel Syndrome, particularly the constipation-predominant variant (IBS-C). The resulting defect leads to disruption in bowel function, by affecting the Nav1.5 channel, in smooth muscle of the colon and pacemaker cells. Researchers managed to treat a case of IBS-C with mexiletine to restore Nav1.5 channels, reversing constipation and abdominal pain.
## SCN5A variations in the general population
Genetic variations in SCN5A, i.e. single nucleotide polymorphisms (SNPs) have been described in both coding and non-coding regions of the gene. These variations are typically present at relatively high frequencies within the general population. Genome Wide Association Studies (GWAS) have used this type of common genetic variation to identify genetic loci associated with variability in phenotypic traits. In the cardiovascular field this powerful technique has been used to detect loci involved in variation in electrocardiographic parameters (i.e. PR-, QRS- and QTc-interval duration) in the general population. The rationale behind this technique is that common genetic variation present in the general population can influence cardiac conduction in non-diseased individuals. these studies consistently identified the SCN5A-SCN10A genomic region on chromosome 3 to be associated with variation in QTc-interval, QRS duration and PR-interval. These results indicate that genetic variation at the SCN5A locus is not only involved in disease genetics but also plays a role in the variation in cardiac function between individuals in the general population.
# NaV1.5 as a pharmacological target
The cardiac sodium channel NaV1.5 has long been a common target in the pharmacologic treatment of arrhythmic events. Classically, sodium channel blockers that block the peak sodium current are classified as Class I anti-arrhythmic agents and further subdivided in class IA, IB and IC, depending on their ability to change the length of the cardiac action potential. Use of such sodium channel blockers is among others indicated in patients with ventricular reentrant tachyarrhythmia in the setting of cardiac ischemia and in patients with atrial fibrillation in absence of structural heart disease. | Nav1.5
NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of Na+-ions (INa) across the cell membrane, resulting in the fast depolarization phase of the cardiac action potential. As such, it plays a major role in impulse propagation through the heart. A vast number of cardiac diseases is associated with mutations in NaV1.5 (see paragraph genetics). SCN5A is the gene that encodes the cardiac sodium channel NaV1.5.
# Gene structure
SCN5A is a highly conserved gene[1] located on human chromosome 3, where it spans more than 100 kb. The gene consists of 28 exons, of which exon 1 and in part exon 2 form the 5’ untranslated region (5’UTR) and exon 28 the 3’ untranslated region (3’UTR) of the RNA. SCN5A is part of a family of 10 genes that encode different types of sodium channels, i.e. brain-type (NaV1.1, NaV1.2, NaV1.3, NaV1.6), neuronal channels (NaV1.7, NaV1.8 and NaV1.9), skeletal muscle channels (NaV1.4) and the cardiac sodium channel NaV1.5.
## Expression pattern
SCN5A is mainly expressed in the heart, where expression is abundant in working myocardium and conduction tissue. In contrast, expression is low in the sinoatrial node and atrioventricular node.[2] Within the heart, a transmural expression gradient from subendocardium to subsendocardium is present, with higher expression of SCN5A in the endocardium as compared to the epicardium[2]
## Splice variants
More than 10 different splice isoforms have been described for SCN5A, of which several harbour different functional properties. In the heart, two isoforms are mainly expressed (ratio 1:2), of which the least predominant one contains an extra glutamine at position 1077 (1077Q). Moreover, different isoforms are expressed during fetal life and adult, differing in the inclusion of an alternative exon 6.[3]
# Protein structure and function
NaV1.5 is a large transmembrane protein with 4 repetitive transmembrane domains (DI-DIV), containing 6 transmembrane spanning sections each (S1-S6). The pore region of the channels, through which Na+-ions flow, are formed by the segments S5 and S6 of the 4 domains. Voltage sensing is mediated by the remaining segments, of which the positively charged S4 segments plays a fundamental role.[1][4]
NaV1.5 channels predominantly mediate the sodium current (INa) in cardiac cells. INa is responsible for the fast upstroke of the action potential, and as such plays a crucial role in impulse propagation through the heart. The conformational state of the channel, which is both voltage and time-dependent, determines whether the channel is opened or closed. At the resting membrane potential (around -85 mV), NaV1.5 channels are closed. Upon a stimulus (through conduction by a neighboring cell), the membrane depolarizes and NaV1.5 channels open through the outward movement of the S4 segments, leading to the initiation of the action potential. Simultaneously, a process called ‘fast inactivation’ results in closure of the channels within 1 ms. In physiological conditions, when inactivated, channels remain in closed state until the cell membrane repolarizes, where a recovery from inactivation is necessary before they become available for activation again. During the action potential, a very small fraction of sodium current persists and does not inactivate completely. This current is called ‘sustained current’, ‘late current’ or ‘INa,L’.[5][6]
Also, some channels may reactivate during the repolarizing phase of the action potential at a range of potentials where inactivation is not complete and shows overlap with activation, generating the so-called “window current”.[7]
## Sub-units and protein interaction partners
Trafficking, function and structure of NaV1.5 can be affected by the many protein interaction partners that have been identified to date (for an extensive review, see Abriel et al. 2010).[8] Of these, the 4 sodium channel beta-subunits, encoded by the genes SCN1B, SCN2B, SCN3B and SCN4B, form an important category. In general, beta-subunits increase function of NaV1.5, either by change in intrinsic properties or by affecting the process of trafficking to the cell surface.
Apart from the beta-subunits, other proteins, such as calmodulin, calmodulin kinase II δc, ankyrin-G and plakophilin-2, are known to interact and modulate function of NaV1.5.[8] Some of these have also been linked to genetic and acquired cardiac diseases.[9][10]
# Genetics
Mutations in SCN5A, which could result in a loss and/or a gain-of-function of the channel, are associated with a spectrum of cardiac diseases. Pathogenic mutations generally exhibit an autosomal dominant inheritance pattern, although recessive forms of SCN5A mutations are also described. Also, mutations may act as a disease modifier, especially in families where lack of direct causality is reflected by complex inheritance patterns. It is important to note that a significant number of individuals (2-7%) in the general population carry a rare (population frequency <1%),[11] protein-altering variant in the gene, highlighting the complexity of linking mutations directly with observed phenotypes. Mutations that result in the same biophysical effect can give rise to different diseases.
To date, loss-of-function mutations have been associated with Brugada syndrome (BrS),[12][13][14] progressive cardiac conduction disease (Lev-Lenègre disease),[15][16] dilated cardiomyopathy (DCM),[17][18] sick sinus syndrome,[19] and atrial fibrillation.[20]
Mutations resulting in a gain-of-function are causal for Long QT syndrome type 3[14][21] and are also more recently implicated in multifocal ectopic Purkinje-related premature contractions (MEPPC)[18][22] Some gain-of-function mutations are also associated with AF and DCM.[23] Gain-of-function of NaV1.5 is generally reflected by an increase in INa,L, a slowed rate of inactivation or a shift in voltage dependence of activation or inactivation (resulting in an increased window-current).
SCN5A mutations are believed to be found in a disproportionate number of people who have Irritable Bowel Syndrome, particularly the constipation-predominant variant (IBS-C).[24][25] The resulting defect leads to disruption in bowel function, by affecting the Nav1.5 channel, in smooth muscle of the colon and pacemaker cells.[24] Researchers managed to treat a case of IBS-C with mexiletine to restore Nav1.5 channels, reversing constipation and abdominal pain.[26][unreliable medical source][27]
## SCN5A variations in the general population
Genetic variations in SCN5A, i.e. single nucleotide polymorphisms (SNPs) have been described in both coding and non-coding regions of the gene. These variations are typically present at relatively high frequencies within the general population. Genome Wide Association Studies (GWAS) have used this type of common genetic variation to identify genetic loci associated with variability in phenotypic traits. In the cardiovascular field this powerful technique has been used to detect loci involved in variation in electrocardiographic parameters (i.e. PR-, QRS- and QTc-interval duration) in the general population.[11] The rationale behind this technique is that common genetic variation present in the general population can influence cardiac conduction in non-diseased individuals. these studies consistently identified the SCN5A-SCN10A genomic region on chromosome 3 to be associated with variation in QTc-interval, QRS duration and PR-interval.[11] These results indicate that genetic variation at the SCN5A locus is not only involved in disease genetics but also plays a role in the variation in cardiac function between individuals in the general population.
# NaV1.5 as a pharmacological target
The cardiac sodium channel NaV1.5 has long been a common target in the pharmacologic treatment of arrhythmic events. Classically, sodium channel blockers that block the peak sodium current are classified as Class I anti-arrhythmic agents and further subdivided in class IA, IB and IC, depending on their ability to change the length of the cardiac action potential.[28][29] Use of such sodium channel blockers is among others indicated in patients with ventricular reentrant tachyarrhythmia in the setting of cardiac ischemia and in patients with atrial fibrillation in absence of structural heart disease.[29] | https://www.wikidoc.org/index.php/Nav1.5 | |
83ad149572a53c8f2523dbf3617a8cec95f4fa3f | wikidoc | Nav1.7 | Nav1.7
Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene. It is usually expressed at high levels in two types of neurons: the nociceptive (pain) neurons at dorsal root ganglion (DRG) and trigeminal ganglion and sympathetic ganglion neurons, which are part of the autonomic (involuntary) nervous system.
# Function
Nav1.7 is a voltage-gated sodium channel and plays a critical role in the generation and conduction of action potentials and is thus important for electrical signaling by most excitable cells. Nav1.7 is present at the endings of pain-sensing nerves, the nociceptors, close to the region where the impulse is initiated. Stimulation of the nociceptor nerve endings produces "generator potentials", which are small changes in the voltage across the neuronal membranes. The Nav1.7 channel amplifies these membrane depolarizations, and when the membrane potential difference reaches a specific threshold, the neuron fires. In sensory neurons, multiple voltage-dependent sodium currents can be differentiated by their voltage dependence and by sensitivity to the voltage-gated sodium-channel blocker tetrodotoxin. The Nav1.7 channel produces a rapidly activating and inactivating current which is sensitive to the level of tetrodotoxin. Nav1.7 is important in the early phases of neuronal electrogenesis. Nav1.7 activity consists of a slow transition of the channel into an inactive state when it is depolarized, even to a minor degree. This property allows these channels to remain available for activation with even small or slowly developing depolarizations. Stimulation of the nociceptor nerve endings produces "generator potentials", small changes in the voltage across the neuronal membranes. This brings neurons to a voltage that stimulate Nav1.8, which has a more depolarized activation threshold that produces most of the transmembrane current responsible for the depolarizing phase of action potentials.
# Clinical significance
## Animal studies
The critical role of Nav1.7 in nociception and pain was originally shown using Cre-Lox recombination tissue specific knockout mice. These transgenic mice specifically lack Nav1.7 in Nav1.8 positive nociceptors and showed reduced behavioural responses, specifically to acute mechanical and inflammatory pain assays. At the same time, behavioural responses to acute thermal and neuropathic pain assays remained intact. However, the expression of Nav1.7 is not restricted to Nav1.8 positive DRG neurons. Further work examining the behavioural response of two other transgenic mouse strains; one lacking Nav1.7 in all DRG neurons and the other lacking Nav1.7 in all DRG neurons as well as all sympathetic neurons, has revealed distinct sets of modality specific peripheral neurons. Therefore, Nav1.7 expressed in Nav1.8 positive DRG neurons is critical for normal responses to acute mechanical and inflammatory pain assays. Whilst Nav1.7 expressed in Nav1.8 negative DRG neurons is critical for normal responses to acute thermal pain assays. Finally, Nav1.7 expressed in sympathetic neurons is critical for normal behavioural responses to neuropathic pain assays.
## Primary erythromelalgia
Mutation in Nav1.7 may result in primary erythromelalgia (PE), an autosomal dominant, inherited disorder which is characterized by attacks or episodes of symmetrical burning pain of the feet, lower legs, and sometimes hands, elevated skin temperature of affected areas, and reddened extremities. The mutation causes excessive channel activity which suggests that Nav1.7 sets the gain on pain signaling in humans. It was observed that a missense mutation in the SCN9A gene affected conserved residues in the pore-forming α subunit of the Nav1.7 channel. Multiple studies have found a dozen SCN9A mutations in multiple families as causing erythromelagia. All of the observed erythromelalgia mutations that are observed are missense mutations that change important and highly conserved amino acid residues of the Nav1.7 protein. The majority of mutations that cause PE are located in cytoplasmic linkers of the Nav1.7 channel, however some mutations are present in transmembrane domains of the channel. The PE mutations cause a hyperpolarizing shift in the voltage dependence of channel activation, which allows the channel to be activated by smaller than normal depolarizations, thus enhancing the activity of Nav1.7. Moreover, the majority of the PE mutations also slow deactivation, thus keeping the channel open longer once it is activated. In addition, in response to a slow, depolarizing stimulus, most mutant channels will generate a larger than normal sodium current. Each of these alterations in activation and deactivation can contribute to the hyperexcitability of pain-signaling DRG neurons expressing these mutant channels, thus causing extreme sensitivity to pain (hyperalgesia). While the expression of PE Nav1.7 mutations produces hyperexcitability in DRG neurons, studies on cultured rat in sympathetic ganglion neurons indicate that expression of these same PE mutations results in reduction of excitability of these cells. This occurs because Nav1.8 channels, which are selectively expressed in addition to Nav1.7 in DRG neurons, are not present within sympathetic ganglion neurons. Thus lack of Nav1.7 results in inactivation of the sodium channels results in reduced excitability. Thus physiological interaction of Nav1.7 and Nav1.8 can explain the reason that PE presents with pain due to hyperexcitability of nociceptors and with sympathetic dysfunction that is most likely due to hypoexcitability of sympathetic ganglion neurons.
Recent studies have associated a defect in SCN9A with congenital insensitivity to pain.
## Paroxysmal extreme pain disorder
Paroxysmal extreme pain disorder (PEPD) is another rare, extreme pain disorder. Like primary erythromelalgia, PEPD is similarly the result of a gain-of-function mutation in the gene encoding the Nav1.7 channel.
## Congenital insensitivity to pain
Individuals with congenital insensitivity to pain have painless injuries beginning in infancy but otherwise normal sensory responses upon examination. Patients frequently have bruises and cuts, and are often only diagnosed because of limping or lack of use of a limb. Individuals have been reported to be able to walk over burning coals and to insert knives and drive spikes through their arms. It has been observed that the insensitivity to pain does not appear to be due to axonal degeneration.
A mutation that causes loss of Nav1.7 function has been detected in three consanguineous families from northern Pakistan. All mutations observed were nonsense mutation, with the majority of affected patients having a homozygous mutation in the SCN9A gene. This discovery linked loss of Nav1.7 function with the inability to experience pain. This is in contrast with the genetic basis of primary erythromelalgia in which the disorder results from gain-of-function mutations.
## Clinical analgesics
Local anesthetics such as lidocaine, but also the anticonvulsant phenytoin, mediate their analgesic effects by non-selectively blocking voltage-gated sodium channels. Nav1.7, as well as Nav1.3, Nav1.8, and Nav1.9, are the specific channels that have been implicated in pain signaling. Thus, the blockade of these specific channels is likely to underlie the analgesia of local anesthetics and anticonvulsants such as phenytoin. In addition, inhibition of these channels is also likely responsible for the analgesic efficacy of certain tricyclic antidepressants, and of mexiletine.
## Itch
Mutations of Nav1.7 have been linked to itching (pruritus), and genetic knockouts of Nav1.7 and an antibody that inhibits Nav1.7 also appear to inhibit itching.
## Future prospects
As the Nav1.7 channel appears to be a highly important component in nociception, with null activity conferring total analgesia, there has been immense interest in developing selective Nav1.7 channel blockers as potential novel analgesics. Since Nav1.7 is not present in heart tissue or the central nervous system, selective blockers of Nav1.7, unlike non-selective blockers such as local anesthetics, could be safely used systemically for pain relief. Moreover, selective Nav1.7 blockers may prove to be far more effective analgesics, and with fewer undesirable effects, relative to current pharmacotherapies.
A number of selective Nav1.7 (and/or Nav1.8) blockers are in clinical development, including funapide (TV-45070, XEN402), PF-05089771, DSP-2230, NKTR-171, GDC-0276, and RG7893 (GDC-0287). Ralfinamide (formerly NW-1029, FCE-26742A, PNU-0154339E) is a multimodal, non-selective Nav channel blocker which is under development for the treatment of pain.
Surprisingly, many potent Nav1.7 blockers have been found to be clinically effective but only relatively weak analgesics. Recently, it has been elucidated that congenital loss of Navv1.7 results in a dramatic increase in the levels of endogenous enkephalins, and it was found that blocking these opioids with the opioid antagonist naloxone allowed for pain sensitivity both in Navv1.7 null mice and in a woman with a defective Navv1.7 gene and associated congenital insensitivity to pain. Development of the venom-derived peptide, JNJ63955 allowed for selective inhibition of Nav1.7 only while it was in the closed state, which produced results, in mice, much more similar to knock-out models. It is possible that channel blockade is maximal only when the channel is inhibited in its closed state. It appears that complete inactivation of Nav 1.7-mediated sodium efflux is necessary to upregulate enkephalin expression enough to achieve complete analgesia. Prior to the development of JNJ63955, the most potent antagonists had failed in regards to achieving the same degree of analgesia as congenital Nav 1.7 inactivity. The proposed mechanism also suggests that the analgesic effects of Nav1.7 blockers may be greatly potentiated by the co-administration of exogenous opioids or enkephalinase inhibitors. Supporting this idea, a strong analgesic synergy between local anesthetics and topical opioids has already been observed in clinical research.
An additional implication of the aforementioned findings is that congenital insensitivity to pain may be clinically treatable with opioid antagonists. | Nav1.7
Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene.[1][2][3] It is usually expressed at high levels in two types of neurons: the nociceptive (pain) neurons at dorsal root ganglion (DRG) and trigeminal ganglion and sympathetic ganglion neurons, which are part of the autonomic (involuntary) nervous system.[4][5]
# Function
Nav1.7 is a voltage-gated sodium channel and plays a critical role in the generation and conduction of action potentials and is thus important for electrical signaling by most excitable cells. Nav1.7 is present at the endings of pain-sensing nerves, the nociceptors, close to the region where the impulse is initiated. Stimulation of the nociceptor nerve endings produces "generator potentials", which are small changes in the voltage across the neuronal membranes. The Nav1.7 channel amplifies these membrane depolarizations, and when the membrane potential difference reaches a specific threshold, the neuron fires. In sensory neurons, multiple voltage-dependent sodium currents can be differentiated by their voltage dependence and by sensitivity to the voltage-gated sodium-channel blocker tetrodotoxin. The Nav1.7 channel produces a rapidly activating and inactivating current which is sensitive to the level of tetrodotoxin.[6] Nav1.7 is important in the early phases of neuronal electrogenesis. Nav1.7 activity consists of a slow transition of the channel into an inactive state when it is depolarized, even to a minor degree.[7] This property allows these channels to remain available for activation with even small or slowly developing depolarizations. Stimulation of the nociceptor nerve endings produces "generator potentials", small changes in the voltage across the neuronal membranes.[7] This brings neurons to a voltage that stimulate Nav1.8, which has a more depolarized activation threshold that produces most of the transmembrane current responsible for the depolarizing phase of action potentials.[8]
# Clinical significance
## Animal studies
The critical role of Nav1.7 in nociception and pain was originally shown using Cre-Lox recombination tissue specific knockout mice. These transgenic mice specifically lack Nav1.7 in Nav1.8 positive nociceptors and showed reduced behavioural responses, specifically to acute mechanical and inflammatory pain assays. At the same time, behavioural responses to acute thermal and neuropathic pain assays remained intact.[9] However, the expression of Nav1.7 is not restricted to Nav1.8 positive DRG neurons. Further work examining the behavioural response of two other transgenic mouse strains; one lacking Nav1.7 in all DRG neurons and the other lacking Nav1.7 in all DRG neurons as well as all sympathetic neurons, has revealed distinct sets of modality specific peripheral neurons.[10] Therefore, Nav1.7 expressed in Nav1.8 positive DRG neurons is critical for normal responses to acute mechanical and inflammatory pain assays. Whilst Nav1.7 expressed in Nav1.8 negative DRG neurons is critical for normal responses to acute thermal pain assays. Finally, Nav1.7 expressed in sympathetic neurons is critical for normal behavioural responses to neuropathic pain assays.
## Primary erythromelalgia
Mutation in Nav1.7 may result in primary erythromelalgia (PE), an autosomal dominant, inherited disorder which is characterized by attacks or episodes of symmetrical burning pain of the feet, lower legs, and sometimes hands, elevated skin temperature of affected areas, and reddened extremities. The mutation causes excessive channel activity which suggests that Nav1.7 sets the gain on pain signaling in humans. It was observed that a missense mutation in the SCN9A gene affected conserved residues in the pore-forming α subunit of the Nav1.7 channel. Multiple studies have found a dozen SCN9A mutations in multiple families as causing erythromelagia.[11][12] All of the observed erythromelalgia mutations that are observed are missense mutations that change important and highly conserved amino acid residues of the Nav1.7 protein. The majority of mutations that cause PE are located in cytoplasmic linkers of the Nav1.7 channel, however some mutations are present in transmembrane domains of the channel. The PE mutations cause a hyperpolarizing shift in the voltage dependence of channel activation, which allows the channel to be activated by smaller than normal depolarizations, thus enhancing the activity of Nav1.7. Moreover, the majority of the PE mutations also slow deactivation, thus keeping the channel open longer once it is activated.[13] In addition, in response to a slow, depolarizing stimulus, most mutant channels will generate a larger than normal sodium current. Each of these alterations in activation and deactivation can contribute to the hyperexcitability of pain-signaling DRG neurons expressing these mutant channels, thus causing extreme sensitivity to pain (hyperalgesia). While the expression of PE Nav1.7 mutations produces hyperexcitability in DRG neurons, studies on cultured rat in sympathetic ganglion neurons indicate that expression of these same PE mutations results in reduction of excitability of these cells. This occurs because Nav1.8 channels, which are selectively expressed in addition to Nav1.7 in DRG neurons, are not present within sympathetic ganglion neurons. Thus lack of Nav1.7 results in inactivation of the sodium channels results in reduced excitability. Thus physiological interaction of Nav1.7 and Nav1.8 can explain the reason that PE presents with pain due to hyperexcitability of nociceptors and with sympathetic dysfunction that is most likely due to hypoexcitability of sympathetic ganglion neurons.[5]
Recent studies have associated a defect in SCN9A with congenital insensitivity to pain.[14]
## Paroxysmal extreme pain disorder
Paroxysmal extreme pain disorder (PEPD) is another rare, extreme pain disorder.[15][16] Like primary erythromelalgia, PEPD is similarly the result of a gain-of-function mutation in the gene encoding the Nav1.7 channel.[15][16]
## Congenital insensitivity to pain
Individuals with congenital insensitivity to pain have painless injuries beginning in infancy but otherwise normal sensory responses upon examination. Patients frequently have bruises and cuts,[17] and are often only diagnosed because of limping or lack of use of a limb. Individuals have been reported to be able to walk over burning coals and to insert knives and drive spikes through their arms. It has been observed that the insensitivity to pain does not appear to be due to axonal degeneration.
A mutation that causes loss of Nav1.7 function has been detected in three consanguineous families from northern Pakistan. All mutations observed were nonsense mutation, with the majority of affected patients having a homozygous mutation in the SCN9A gene. This discovery linked loss of Nav1.7 function with the inability to experience pain. This is in contrast with the genetic basis of primary erythromelalgia in which the disorder results from gain-of-function mutations.[14]
## Clinical analgesics
Local anesthetics such as lidocaine, but also the anticonvulsant phenytoin, mediate their analgesic effects by non-selectively blocking voltage-gated sodium channels.[18][19] Nav1.7, as well as Nav1.3, Nav1.8, and Nav1.9, are the specific channels that have been implicated in pain signaling.[18][20] Thus, the blockade of these specific channels is likely to underlie the analgesia of local anesthetics and anticonvulsants such as phenytoin.[18] In addition, inhibition of these channels is also likely responsible for the analgesic efficacy of certain tricyclic antidepressants, and of mexiletine.[21][22]
## Itch
Mutations of Nav1.7 have been linked to itching (pruritus),[23][24] and genetic knockouts of Nav1.7[25] and an antibody that inhibits Nav1.7 also appear to inhibit itching.[26][27][28]
## Future prospects
As the Nav1.7 channel appears to be a highly important component in nociception, with null activity conferring total analgesia,[16] there has been immense interest in developing selective Nav1.7 channel blockers as potential novel analgesics.[29] Since Nav1.7 is not present in heart tissue or the central nervous system, selective blockers of Nav1.7, unlike non-selective blockers such as local anesthetics, could be safely used systemically for pain relief. Moreover, selective Nav1.7 blockers may prove to be far more effective analgesics, and with fewer undesirable effects, relative to current pharmacotherapies.[29][30][31]
A number of selective Nav1.7 (and/or Nav1.8) blockers are in clinical development, including funapide (TV-45070, XEN402), PF-05089771, DSP-2230, NKTR-171, GDC-0276, and RG7893 (GDC-0287).[32][33][34] Ralfinamide (formerly NW-1029, FCE-26742A, PNU-0154339E) is a multimodal, non-selective Nav channel blocker which is under development for the treatment of pain.[35]
Surprisingly, many potent Nav1.7 blockers have been found to be clinically effective but only relatively weak analgesics.[36] Recently, it has been elucidated that congenital loss of Navv1.7 results in a dramatic increase in the levels of endogenous enkephalins, and it was found that blocking these opioids with the opioid antagonist naloxone allowed for pain sensitivity both in Navv1.7 null mice and in a woman with a defective Navv1.7 gene and associated congenital insensitivity to pain.[36] Development of the venom-derived peptide, JNJ63955 allowed for selective inhibition of Nav1.7 only while it was in the closed state, which produced results, in mice, much more similar to knock-out models.[37][unreliable medical source] It is possible that channel blockade is maximal only when the channel is inhibited in its closed state. It appears that complete inactivation of Nav 1.7-mediated sodium efflux is necessary to upregulate enkephalin expression enough to achieve complete analgesia. Prior to the development of JNJ63955, the most potent [Nav 1.7] antagonists had failed in regards to achieving the same degree of analgesia as congenital Nav 1.7 inactivity.[36] The proposed mechanism also suggests that the analgesic effects of Nav1.7 blockers may be greatly potentiated by the co-administration of exogenous opioids or enkephalinase inhibitors.[36] Supporting this idea, a strong analgesic synergy between local anesthetics and topical opioids has already been observed in clinical research.[36]
An additional implication of the aforementioned findings is that congenital insensitivity to pain may be clinically treatable with opioid antagonists.[36] | https://www.wikidoc.org/index.php/Nav1.7 | |
2a4e0fc4dd5aaa65cf179126b9ef921c357cca2e | wikidoc | Nav1.8 | Nav1.8
Nav1.8 is a sodium ion channel subtype that in humans is encoded by the SCN10A gene.
Nav1.8-containing channels are tetrodotoxin (TTX)-resistant voltage-gated channels. Nav1.8 is expressed specifically in the dorsal root ganglion (DRG), in unmyelinated, small-diameter sensory neurons called C-fibres, and is involved in nociception. C-fibres can be activated by noxious thermal or mechanical stimuli and thus can carry pain messages.
The specific location of Nav1.8 in sensory neurons of the DRG may make it a key therapeutic target for the development of new analgesics and the treatment of chronic pain.
# Function
Voltage-gated sodium ion channels (VGSC) are essential in producing and propagating action potentials. Tetrodotoxin, a toxin found in pufferfish, is able to block some VGSCs and therefore is used to distinguish the different subtypes. There are three TTX-resistant VGSC: Nav1.5, Nav1.8 and Nav1.9. Nav1.8 and Nav1.9 are both expressed in nociceptors (damage-sensing neurons). Nav1.7, Nav1.8 and Nav1.9 are found in the DRG and help mediate chronic inflammatory pain. Nav1.8 is an α-type channel subunit consisting of four homologous domains, each with six transmembrane regions, of which one is a voltage sensor.
Voltage clamp methods have demonstrated that NaV1.8 is unique, among sodium channels, in exhibiting relatively depolarized steady-state inactivation. Thus, NaV1.8 remains available to operate, when neurons are depolarized to levels that inactivate other sodium channels. Voltage clamp has been used to show how action potentials in DRG cells are shaped by TTX-resistant sodium channels. Nav1.8 contributes the most to sustaining the depolarizing stage of action repetitive high-frequency potentials in nociceptive sensory neurons because it activates quickly and remaining activated after detecting a noxious stimulus. Therefore, Nav1.8 contributes to hyperalgesia (increased sensitivity to pain) and allodynia (pain from stimuli that do not usually cause it), which are elements of chronic pain. Nav1.8 knockout mice studies have shown that the channel is associated with inflammatory and neuropathic pain. Moreover, Nav1.8 plays a crucial role in cold pain. Reducing the temperature from 30 °C to 10 °C slows the activation of VGSCs and hence decreases the current. However, Nav1.8 is cold-resistant and is able to generate action potentials in the cold to carry information from nociceptors to the central nervous system (CNS). Furthermore, Nav1.8-null mice failed to produce action potentials, indicating that Nav1.8 is essential to the perception of pain in cold temperatures.
Although the early studies on the biophysics of NaV1.8 channels were carried out in rodent channels, more recent studies have examined the properties of human NaV1.8 channels. Notably, human NaV1.8 channels exhibit an inactivation voltage-dependence that is even more depolarized than that in rodents, and it also exhibits a larger persistent current. Thus, the influence of human NaV1.8 channels on firing of sensory neurons may be even larger than that of rodent NaV1.8 channels.
Gain-of-function mutations of NaV1.8, identified in patients with painful peripheral neuropathies, have been found to make DRG neurons hyper excitable, and thus are causes of pain. Although NaV1.8 is not normally expressed within the cerebellum, its expression is up-regulated in cerebellar Purkinje cells in animal models of MS (Multiple Sclerosis), and in human MS. The presence of NaV1.8 channels within these cerebellar neurons, where it is not normally present, increases their excitability and alters their firing pattern in vitro, and in rodents with experimental autoimmune encephalomyelitis, a model of MS. At a behavioral level, the ectopic expression of NaV1.8 within cerebellar Purkinje neurons has been shown to impair motor performance in a transgenic model.
# Clinical significance
## Pain signalling pathways
Nociceptors are different from other sensory neurons in that they have a low activating threshold and consequently increase their response to constant stimuli. Therefore, nociceptors are easily sensitised by agents such as bradykinin and nerve growth factor, which are released at the site of tissue injury, ultimately causing changes to ion channel conductance. VGSCs have been shown to increase in density after nerve injury. Therefore, VGSCs can be modulated by many different hyperalgesic agents that are released after nerve injury. Further examples include prostaglandin E2 (PGE2), serotonin and adenosine, which all act to increase the current through Nav1.8.
Prostaglandins such as PGE2 can sensitise nociceptors to thermal, chemical and mechanical stimuli and increase the excitability of DRG sensory neurons. This occurs because PGE2 modulates the trafficking of Nav1.8 by binding to G-protein-coupled EP2 receptor, which in turn activates protein kinase A. Protein kinase A phosphorylates Nav1.8 at intracellular sites, resulting in increased sodium ion currents. Evidence for a link between PGE2 and hyperalgesia comes from an antisense deoxynucleotide knockdown of Nav1.8 in the DRG of rats. Another modulator of Nav1.8 is the ε isoform of PKC. This isoform is activated by the inflammatory mediator bradykinin and phosphorylates Nav1.8, causing an increase in sodium current in the sensory neurons, which promotes mechanical hyperalgesia.
## Brugada syndrome
Mutations in SCN10A are associated to Brugada syndrome .
## Membrane trafficking
Nerve growth factor levels in inflamed or injured tissues are increased creating an increased sensitivity to pain (hyperalgesia). The increased levels of nerve growth factor and tumour necrosis factor-α (TNF-α) causes the upregulation of Nav1.8 in sensory neurons via the accessory protein p11 (annexin II light chain). It has been shown using the yeast-two hybrid screening method that p11 binds to a 28-amino-acid fragment at the N terminus of Nav1.8 and promotes its translocation to the plasma membrane. This contributes to the hyperexcitability of sensory neurons during pain. p11-null nociceptive sensory neurons in mice, created using the Cre-loxP recombinase system, show a decrease in Nav1.8 expression at the plasma membrane. Therefore, disrupting the interactions between p11 and Nav1.8 may be a good therapeutic target for lowering pain.
In myelinated fibres, VGSCs are located at the nodes of Ranvier; however, in unmyelinated fibres, the exact location of VGSCs has not been determined. Nav1.8 in unmyelinated fibres has been found in clusters associated with lipid rafts along DRG fibers both in vitro and in vivo. Lipid rafts organise the cell membrane, which includes trafficking and localising ion channels. Removal of lipid rafts in the membrane using MβCD, which depletes cholesterol from the plasma membrane, leads to a shift of Nav1.8 to a non-raft portion of the membrane, causing reduced action potential firing and propagation.
## Painful peripheral neuropathies
Painful peripheral neuropathies or small-fibre neuropathies are disorders of unmyelinated nociceptive C-fibres causing neuropathic pain; in some cases there is no known cause. Genetic screening of patients with these idiopathic neuropathies has uncovered mutations in the SCN9A gene, encoding the related channel Nav1.7. A gain-of-function mutation in Nav1.7 located in the DRG sensory neurons was found in 30% of patients. This gain-of-function mutation causes an increase in excitability (hyperexcitability) of DRG sensory neurons and thus an increase in pain. Nav1.7 thus been shown to be linked to human pain; Nav1.8, by contrast, had only been associated to pain in animal studies until recently. A gain-of-function mutation was found in the Nav1.8-encoding SCN10A gene in patients with painful peripheral neuropathy. A study of 104 patients with idiopathic peripheral neuropathies who did not have the mutation in SCN9A used voltage clamp and current clamp methods, along with predictive algorithms, and yielded two gain-of-function mutations in SCN10A in three patients. Both mutations cause increased excitability in DRG sensory neurons and hence contribute to pain, but the mechanism by which they do so is not understood. | Nav1.8
Nav1.8 is a sodium ion channel subtype that in humans is encoded by the SCN10A gene.[1][2][3][4]
Nav1.8-containing channels are tetrodotoxin (TTX)-resistant voltage-gated channels. Nav1.8 is expressed specifically in the dorsal root ganglion (DRG), in unmyelinated, small-diameter sensory neurons called C-fibres, and is involved in nociception.[5][6] C-fibres can be activated by noxious thermal or mechanical stimuli and thus can carry pain messages.
The specific location of Nav1.8 in sensory neurons of the DRG may make it a key therapeutic target for the development of new analgesics[7] and the treatment of chronic pain.[8]
# Function
Voltage-gated sodium ion channels (VGSC) are essential in producing and propagating action potentials. Tetrodotoxin, a toxin found in pufferfish, is able to block some VGSCs and therefore is used to distinguish the different subtypes. There are three TTX-resistant VGSC: Nav1.5, Nav1.8 and Nav1.9. Nav1.8 and Nav1.9 are both expressed in nociceptors (damage-sensing neurons). Nav1.7, Nav1.8 and Nav1.9 are found in the DRG and help mediate chronic inflammatory pain.[9] Nav1.8 is an α-type channel subunit consisting of four homologous domains, each with six transmembrane regions, of which one is a voltage sensor.
Voltage clamp methods have demonstrated that NaV1.8 is unique, among sodium channels, in exhibiting relatively depolarized steady-state inactivation. Thus, NaV1.8 remains available to operate, when neurons are depolarized to levels that inactivate other sodium channels. Voltage clamp has been used to show how action potentials in DRG cells are shaped by TTX-resistant sodium channels. Nav1.8 contributes the most to sustaining the depolarizing stage of action repetitive high-frequency potentials in nociceptive sensory neurons because it activates quickly and remaining activated after detecting a noxious stimulus.[10][11] Therefore, Nav1.8 contributes to hyperalgesia (increased sensitivity to pain) and allodynia (pain from stimuli that do not usually cause it), which are elements of chronic pain.[12] Nav1.8 knockout mice studies have shown that the channel is associated with inflammatory and neuropathic pain.[5][13][14] Moreover, Nav1.8 plays a crucial role in cold pain.[15] Reducing the temperature from 30 °C to 10 °C slows the activation of VGSCs and hence decreases the current. However, Nav1.8 is cold-resistant and is able to generate action potentials in the cold to carry information from nociceptors to the central nervous system (CNS). Furthermore, Nav1.8-null mice failed to produce action potentials, indicating that Nav1.8 is essential to the perception of pain in cold temperatures.[15]
Although the early studies on the biophysics of NaV1.8 channels were carried out in rodent channels, more recent studies have examined the properties of human NaV1.8 channels. Notably, human NaV1.8 channels exhibit an inactivation voltage-dependence that is even more depolarized than that in rodents, and it also exhibits a larger persistent current.[16] Thus, the influence of human NaV1.8 channels on firing of sensory neurons may be even larger than that of rodent NaV1.8 channels.
Gain-of-function mutations of NaV1.8, identified in patients with painful peripheral neuropathies, have been found to make DRG neurons hyper excitable, and thus are causes of pain.[17][18] Although NaV1.8 is not normally expressed within the cerebellum, its expression is up-regulated in cerebellar Purkinje cells in animal models of MS (Multiple Sclerosis), and in human MS.[19] The presence of NaV1.8 channels within these cerebellar neurons, where it is not normally present, increases their excitability and alters their firing pattern in vitro,[20] and in rodents with experimental autoimmune encephalomyelitis, a model of MS.[21] At a behavioral level, the ectopic expression of NaV1.8 within cerebellar Purkinje neurons has been shown to impair motor performance in a transgenic model.[22]
# Clinical significance
## Pain signalling pathways
Nociceptors are different from other sensory neurons in that they have a low activating threshold and consequently increase their response to constant stimuli. Therefore, nociceptors are easily sensitised by agents such as bradykinin and nerve growth factor, which are released at the site of tissue injury, ultimately causing changes to ion channel conductance. VGSCs have been shown to increase in density after nerve injury.[23] Therefore, VGSCs can be modulated by many different hyperalgesic agents that are released after nerve injury. Further examples include prostaglandin E2 (PGE2), serotonin and adenosine, which all act to increase the current through Nav1.8.[24]
Prostaglandins such as PGE2 can sensitise nociceptors to thermal, chemical and mechanical stimuli and increase the excitability of DRG sensory neurons. This occurs because PGE2 modulates the trafficking of Nav1.8 by binding to G-protein-coupled EP2 receptor, which in turn activates protein kinase A.[25][26] Protein kinase A phosphorylates Nav1.8 at intracellular sites, resulting in increased sodium ion currents. Evidence for a link between PGE2 and hyperalgesia comes from an antisense deoxynucleotide knockdown of Nav1.8 in the DRG of rats.[27] Another modulator of Nav1.8 is the ε isoform of PKC. This isoform is activated by the inflammatory mediator bradykinin and phosphorylates Nav1.8, causing an increase in sodium current in the sensory neurons, which promotes mechanical hyperalgesia.[28]
## Brugada syndrome
Mutations in SCN10A are associated to Brugada syndrome .[29]
## Membrane trafficking
Nerve growth factor levels in inflamed or injured tissues are increased creating an increased sensitivity to pain (hyperalgesia).[30] The increased levels of nerve growth factor and tumour necrosis factor-α (TNF-α) causes the upregulation of Nav1.8 in sensory neurons via the accessory protein p11 (annexin II light chain). It has been shown using the yeast-two hybrid screening method that p11 binds to a 28-amino-acid fragment at the N terminus of Nav1.8 and promotes its translocation to the plasma membrane. This contributes to the hyperexcitability of sensory neurons during pain.[31] p11-null nociceptive sensory neurons in mice, created using the Cre-loxP recombinase system, show a decrease in Nav1.8 expression at the plasma membrane.[32] Therefore, disrupting the interactions between p11 and Nav1.8 may be a good therapeutic target for lowering pain.
In myelinated fibres, VGSCs are located at the nodes of Ranvier; however, in unmyelinated fibres, the exact location of VGSCs has not been determined. Nav1.8 in unmyelinated fibres has been found in clusters associated with lipid rafts along DRG fibers both in vitro and in vivo.[33] Lipid rafts organise the cell membrane, which includes trafficking and localising ion channels. Removal of lipid rafts in the membrane using MβCD, which depletes cholesterol from the plasma membrane, leads to a shift of Nav1.8 to a non-raft portion of the membrane, causing reduced action potential firing and propagation.[33]
## Painful peripheral neuropathies
Painful peripheral neuropathies or small-fibre neuropathies are disorders of unmyelinated nociceptive C-fibres causing neuropathic pain; in some cases there is no known cause.[34] Genetic screening of patients with these idiopathic neuropathies has uncovered mutations in the SCN9A gene, encoding the related channel Nav1.7. A gain-of-function mutation in Nav1.7 located in the DRG sensory neurons was found in 30% of patients.[35] This gain-of-function mutation causes an increase in excitability (hyperexcitability) of DRG sensory neurons and thus an increase in pain. Nav1.7 thus been shown to be linked to human pain; Nav1.8, by contrast, had only been associated to pain in animal studies until recently. A gain-of-function mutation was found in the Nav1.8-encoding SCN10A gene in patients with painful peripheral neuropathy.[17] A study of 104 patients with idiopathic peripheral neuropathies who did not have the mutation in SCN9A used voltage clamp and current clamp methods, along with predictive algorithms, and yielded two gain-of-function mutations in SCN10A in three patients. Both mutations cause increased excitability in DRG sensory neurons and hence contribute to pain, but the mechanism by which they do so is not understood. | https://www.wikidoc.org/index.php/Nav1.8 | |
5d6abb0820bafc7e8259959fb2caf511e4bebb19 | wikidoc | Nav1.9 | Nav1.9
Sodium channel, voltage-gated, type XI, alpha subunit also known as SCN11A or Nav1.9 is a voltage-gated sodium ion channel protein which is encoded by the SCN11A gene on chromosome 3 in humans. Like Nav1.7 and Nav1.8, Nav1.9 plays a role in pain perception. This channel is largely expressed in small-diameter nociceptors of the dorsal root ganglion and trigeminal ganglion neurons, but is also found in intrinsic myenteric neurons.
# Function
Voltage-gated sodium channels are membrane protein complexes that play a fundamental role in the rising phase of the action potential in most excitable cells. Alpha subunits, such as SCN11A, mediate voltage-dependent gating and conductance, while auxiliary beta subunits regulate the kinetic properties of the channel and facilitate membrane localization of the complex. Aberrant expression patterns or mutations of alpha subunits underlie a number of disorders. Each alpha subunit consists of 4 domains connected by 3 intracellular loops; each domain consists of 6 transmembrane segments and intra- and extracellular linkers. The 4th transmembrane segment of each domain is the voltage-sensing region of the channel. Following depolarization of the cell, voltage-gated sodium channels become inactivated through a change in conformation in which the 4th segments in each domain move into the pore region in response to the highly positive voltage expressed at the peak of the action potential. This effectively blocks the Na+ pore and prevents further influx of Na+, therefore preventing further depolarization. Similarly, when the cell reaches its minimum (most negative) voltage during hyperpolarization, the 4th segments respond by moving outward, thus reopening the pore and allowing Na+ to flow into the cell.
Nav1.9 is known to play a role in nociception, having been linked to the perception of inflammatory, neuropathic, and cold-related pain. It does this primarily through its ability to lower the threshold potential of the neuron, allowing for an increase in action potential firing that leads to hyperexcitability of the neuron and increased pain perception. Because of this role in altering the threshold potential, Nav1.9 is considered a threshold channel. Though most sodium channels are blocked by tetrodotoxin, Nav1.9 is tetrodotoxin-resistant due to the presence of serine on an extracellular linker that plays a role in the selectivity of the pore for Na+. This property is found in similar channels, namely Nav1.8, and has been associated with slower channel kinetics than the tetrodotoxin-sensitive sodium channels. In Nav1.9, this is mostly associated with the slower speed at which channel inactivation occurs.
# Animal models of pain
Both Nav1.8 and Nav1.9 have been shown to play a role in bone cancer associated pain using a rat model of bone cancer. The dorsal root ganglion of lumbar 4-5 of rats with bone cancer were shown to have up-regulation of Nav1.8 and Nav1.9 mRNA expression as well as an increase in total number of these alpha subunits. These results suggest that tetrodotoxin-resistant voltage gated sodium channels are involved in the development and maintenance of bone cancer pain.
The role of Nav1.9 in chronic inflammatory joint pain has been demonstrated in rat models of chronic inflammatory knee pain. Expression of Nav1.9 in the afferent neurons of the dorsal root ganglion was found to be elevated as many as four weeks after the onset of the inflammatory pain. These results indicated that this alpha subunit plays some role in the maintenance of chronic inflammatory pain.
# Clinical significance
## Gain-of-function mutations
There are currently many known gain-of-function mutations in the human SCN11A gene that are associated with various pain abnormalities. The majority of these mutations lead to the experience of episodic pain, mainly in the joints of the extremities. In some of these mutants, the pain symptoms began in early childhood and diminished somewhat with age, but some of the mutants were asymptomatic until later in adulthood. Many of these conditions are also accompanied by gastrointestinal disturbances such as constipation and diarrhea. Additionally, one gain-of-function mutation on SCN11A has been linked with a congenital inability to experience pain.
## As a drug target for pain relief
The role of Nav1.9 in inflammatory and neuropathic pain has made it a potential drug target for pain relief. It is thought that a drug that targets Nav1.9 could be used to decrease pain effectively while avoiding the many side effects associated with other high-strength analgesics. Topical menthol blocks both Nav1.8 and Nav1.9 channels in the dorsal root ganglion. Menthol inhibits action potentials by dampening the Na+ channel activity without affecting normal neural activity in the affected area. Nav1.9 has also been proposed as a target to treat oxaliplatin induced cold-associated pain side effects. | Nav1.9
Sodium channel, voltage-gated, type XI, alpha subunit also known as SCN11A or Nav1.9 is a voltage-gated sodium ion channel protein which is encoded by the SCN11A gene on chromosome 3 in humans.[1][2] Like Nav1.7 and Nav1.8, Nav1.9 plays a role in pain perception. This channel is largely expressed in small-diameter nociceptors of the dorsal root ganglion and trigeminal ganglion neurons,[1][3] but is also found in intrinsic myenteric neurons.[4]
# Function
Voltage-gated sodium channels are membrane protein complexes that play a fundamental role in the rising phase of the action potential in most excitable cells. Alpha subunits, such as SCN11A, mediate voltage-dependent gating and conductance, while auxiliary beta subunits regulate the kinetic properties of the channel and facilitate membrane localization of the complex. Aberrant expression patterns or mutations of alpha subunits underlie a number of disorders. Each alpha subunit consists of 4 domains connected by 3 intracellular loops; each domain consists of 6 transmembrane segments and intra- and extracellular linkers.[5] The 4th transmembrane segment of each domain is the voltage-sensing region of the channel. Following depolarization of the cell, voltage-gated sodium channels become inactivated through a change in conformation in which the 4th segments in each domain move into the pore region in response to the highly positive voltage expressed at the peak of the action potential. This effectively blocks the Na+ pore and prevents further influx of Na+, therefore preventing further depolarization. Similarly, when the cell reaches its minimum (most negative) voltage during hyperpolarization, the 4th segments respond by moving outward, thus reopening the pore and allowing Na+ to flow into the cell.[6]
Nav1.9 is known to play a role in nociception, having been linked to the perception of inflammatory, neuropathic,[3] and cold-related pain.[7] It does this primarily through its ability to lower the threshold potential of the neuron, allowing for an increase in action potential firing that leads to hyperexcitability of the neuron and increased pain perception. Because of this role in altering the threshold potential, Nav1.9 is considered a threshold channel.[8][9] Though most sodium channels are blocked by tetrodotoxin, Nav1.9 is tetrodotoxin-resistant due to the presence of serine on an extracellular linker that plays a role in the selectivity of the pore for Na+.[3] This property is found in similar channels, namely Nav1.8,[6] and has been associated with slower channel kinetics than the tetrodotoxin-sensitive sodium channels.[10] In Nav1.9, this is mostly associated with the slower speed at which channel inactivation occurs.[3]
# Animal models of pain
Both Nav1.8 and Nav1.9 have been shown to play a role in bone cancer associated pain using a rat model of bone cancer. The dorsal root ganglion of lumbar 4-5 of rats with bone cancer were shown to have up-regulation of Nav1.8 and Nav1.9 mRNA expression as well as an increase in total number of these alpha subunits. These results suggest that tetrodotoxin-resistant voltage gated sodium channels are involved in the development and maintenance of bone cancer pain.[11]
The role of Nav1.9 in chronic inflammatory joint pain has been demonstrated in rat models of chronic inflammatory knee pain. Expression of Nav1.9 in the afferent neurons of the dorsal root ganglion was found to be elevated as many as four weeks after the onset of the inflammatory pain. These results indicated that this alpha subunit plays some role in the maintenance of chronic inflammatory pain.[12]
# Clinical significance
## Gain-of-function mutations
There are currently many known gain-of-function mutations in the human SCN11A gene that are associated with various pain abnormalities. The majority of these mutations lead to the experience of episodic pain, mainly in the joints of the extremities. In some of these mutants, the pain symptoms began in early childhood and diminished somewhat with age,[13][14][15] but some of the mutants were asymptomatic until later in adulthood.[16][17] Many of these conditions are also accompanied by gastrointestinal disturbances such as constipation and diarrhea.[13][16] Additionally, one gain-of-function mutation on SCN11A has been linked with a congenital inability to experience pain.[18]
## As a drug target for pain relief
The role of Nav1.9 in inflammatory and neuropathic pain has made it a potential drug target for pain relief. It is thought that a drug that targets Nav1.9 could be used to decrease pain effectively while avoiding the many side effects associated with other high-strength analgesics.[3] Topical menthol blocks both Nav1.8 and Nav1.9 channels in the dorsal root ganglion. Menthol inhibits action potentials by dampening the Na+ channel activity without affecting normal neural activity in the affected area.[19] Nav1.9 has also been proposed as a target to treat oxaliplatin induced cold-associated pain side effects.[7] | https://www.wikidoc.org/index.php/Nav1.9 | |
cf5409c35d7a1fcc4c86139d5fd045aacd671d54 | wikidoc | Neroli | Neroli
Neroli oil is a plant oil similar in scent to bergamot produced from the blossom of the bitter orange tree (Citrus aurantium var. amara or Bigaradia).
The blossoms are gathered, usually by hand, in late April to early May. The oil is produced by water distillation, as the blossom is too fragile to endure steam distillation.
By the end of the 17th century, Anne Marie Orsini, duchess of Bracciano and princess of Nerola, introduced the essence of bitter orange tree as a fashionable fragrance by using it to perfume her gloves and her bath. Since then, the name of Neroli has been used to describe this essence. Neroli has a refreshing and distinctive, spicy aroma with sweet and flowery notes. It is one of the most widely used floral oils in perfumery. It is a non-toxic, non-irritant, non-sensitizing, non-photo-toxic substance. More than 12% of all modern quality perfumes use Neroli as their principal ingredient. It blends well with any citrus oil, various floral absolutes, and most of the synthetic components available on the market. Neroli oil is a classic element in fragrance design and one of the most commonly used in the industry. It is also used in flavors (alimentary) where it has a limited use.
As an essential oil, used in aromatherapy and massage, Neroli is considered to have a soothing effect on the nervous system. Traditionally, neroli oil was used not only to relieve tension and anxiety, but also in increase circulation and heal thread vein scars. A solution is made by adding three or four drops of the essential oil to one cup of either sweet almond oil or wheat germ oil. The oil is then fixed by adding grapefruit seed extract, but if the solution is to be used on children or pregnant women, only half the quantity of essential oil should be used. | Neroli
Neroli oil is a plant oil similar in scent to bergamot produced from the blossom of the bitter orange tree (Citrus aurantium var. amara or Bigaradia).
The blossoms are gathered, usually by hand, in late April to early May. The oil is produced by water distillation, as the blossom is too fragile to endure steam distillation.
By the end of the 17th century, Anne Marie Orsini, duchess of Bracciano and princess of Nerola, introduced the essence of bitter orange tree as a fashionable fragrance by using it to perfume her gloves and her bath. Since then, the name of Neroli has been used to describe this essence. Neroli has a refreshing and distinctive, spicy aroma with sweet and flowery notes. It is one of the most widely used floral oils in perfumery. It is a non-toxic, non-irritant, non-sensitizing, non-photo-toxic substance. More than 12% of all modern quality perfumes use Neroli as their principal ingredient. It blends well with any citrus oil, various floral absolutes, and most of the synthetic components available on the market. Neroli oil is a classic element in fragrance design and one of the most commonly used in the industry. It is also used in flavors (alimentary) where it has a limited use.
As an essential oil, used in aromatherapy and massage, Neroli is considered to have a soothing effect on the nervous system. Traditionally, neroli oil was used not only to relieve tension and anxiety, but also in increase circulation and heal thread vein scars. A solution is made by adding three or four drops of the essential oil to one cup of either sweet almond oil or wheat germ oil. The oil is then fixed by adding grapefruit seed extract, but if the solution is to be used on children or pregnant women, only half the quantity of essential oil should be used. | https://www.wikidoc.org/index.php/Neroli | |
4947ced415fbf93727e53dce45a250b744817c47 | wikidoc | Neuron | Neuron
Neurons (also known as neurones and nerve cells) are electrically excitable cells in the nervous system that process and transmit information. In vertebrate animals, neurons are the core components of the brain, spinal cord and peripheral nerves.
# Overview
Neurons are usually amitotic, but some, such as the olfactory sensory neurons, undergo adult neurogenesis.
Neurons are typically composed of a soma, or cell body, a dendritic tree and an axon. The majority of vertebrate neurons receive input on the cell body and dendritic tree, and transmit output via the axon. However, there is great heterogeneity throughout the nervous system and the animal kingdom, in the size, shape and function of neurons.
Neurons communicate via chemical and electrical synapses, in a process known as synaptic transmission. The fundamental process that triggers synaptic transmission is the action potential, a propagating electrical signal that is generated by exploiting the electrically excitable membrane of the neuron. This is also known as a wave of depolarization.
# History
The neuron's place as the primary functional unit of the nervous system was first recognized in the early 20th century through the work of the Spanish anatomist Santiago Ramón y Cajal.Cajal proposed that neurons were discrete cells that communicated with each other via specialized junctions, or spaces, between cells. This became known as the neuron doctrine, one of the central tenets of modern neuroscience. To observe the structure of individual neurons, Cajal used a silver staining method developed by his rival, Camillo Golgi. The Golgi stain is an extremely useful method for neuroanatomical investigations because, for reasons unknown, it stains a very small percentage of cells in a tissue, so one is able to see the complete microstructure of individual neurons without much overlap from other cells in the densely packed brain.
# Anatomy and histology
Neurons are highly specialized for the processing and transmission of cellular signals. Given the diversity of functions performed by neurons in different parts of the nervous system, there is, as expected, a wide variety in the shape, size, and electrochemical properties of neurons. For instance, the soma of a neuron can vary from 4 to 100 micrometers in diameter.
- The soma is the central part of the neuron. It contains the nucleus of the cell, and therefore is where most protein synthesis occurs. The nucleus ranges from 3 to 18 micrometers in diameter.
- The dendrites of a neuron are cellular extensions with many branches, and metaphorically this overall shape and structure is referred to as a dendritic tree. This is where the majority of input to the neuron occurs. Information outflow (i.e. from dendrites to other neurons) can also occur, but not across chemical synapses; there, the backflow of a nerve impulse is inhibited by the fact that an axon does not possess chemoreceptors and dendrites cannot secrete neurotransmitter chemicals. This unidirectionality of a chemical synapse explains why nerve impulses are conducted only in one direction.
- The axon is a finer, cable-like projection which can extend tens, hundreds, or even tens of thousands of times the diameter of the soma in length. The axon carries nerve signals away from the soma (and also carry some types of information back to it). Many neurons have only one axon, but this axon may - and usually will - undergo extensive branching, enabling communication with many target cells. The part of the axon where it emerges from the soma is called the 'axon hillock'. Besides being an anatomical structure, the axon hillock is also the part of the neuron that has the greatest density of voltage-dependent sodium channels. This makes it the most easily-excited part of the neuron and the spike initiation zone for the axon: in neurological terms it has the most negative hyperpolarized action potential threshold. While the axon and axon hillock are generally involved in information outflow, this region can also receive input from other neurons.
- The axon terminal is a specialized structure at the end of the axon that is used to release neurotransmitter chemicals and communicate with target neurons.
Although the canonical view of the neuron attributes dedicated functions to its various anatomical components, dendrites and axons often act in ways contrary to their so-called main function.
Axons and dendrites in the central nervous system are typically only about one micrometer thick, while some in the peripheral nervous system are much thicker. The soma is usually about 10–25 micrometers in diameter and often is not much larger than the cell nucleus it contains. The longest axon of a human motoneuron can be over a meter long, reaching from the base of the spine to the toes. Sensory neurons have axons that run from the toes to the dorsal columns, over 1.5 meters in adults. Giraffes have single axons several meters in length running along the entire length of their necks. Much of what is known about axonal function comes from studying the squid giant axon, an ideal experimental preparation because of its relatively immense size (0.5–1 millimeters thick, several centimeters long).
# Classes
File:GFPneuron.png
## Structural classification
### Polarity
Most neurons can be anatomically characterized as:
- Unipolar or pseudounipolar: dendrite and axon emerging from same process.
- Bipolar: single axon and single dendrite on opposite ends of the soma.
- Multipolar: more than two dendrites:
Golgi I: neurons with long-projecting axonal processes; examples are pyramidal cells, Purkinje cells, and anterior horn cells.
Golgi II: neurons whose axonal process projects locally; the best example are the granule cells.
- Golgi I: neurons with long-projecting axonal processes; examples are pyramidal cells, Purkinje cells, and anterior horn cells.
- Golgi II: neurons whose axonal process projects locally; the best example are the granule cells.
### Other
Furthermore, some unique neuronal types can be identified according to their location in the nervous system and distinct shape. Some examples are:
- Basket cells, neurons with dilated and knotty dendrites in the cerebellum.
- Betz cells, large motor neurons.
- Medium spiny neurons, most neurons in the corpus striatum.
- Purkinje cells, huge neurons in the cerebellum, a type of Golgi I multipolar neuron.
- pyramidal cells, neurons with triangular soma, a type of Golgi I.
- Renshaw cells, neurons with both ends linked to alpha motor neurons.
- Granule cells, a type of as Golgi II neuron.
- anterior horn cells, motoneurons located in the spinal cord.
## Functional classification
### Direction
- Afferent neurons convey information from tissues and organs into the central nervous system and are sometimes also called sensory neurons.
- Efferent neurons transmit signals from the central nervous system to the effector cells and are sometimes called motor neurons.
- Interneurons connect neurons within specific regions of the central nervous system.
Afferent and efferent can also refer generally to neurons which, respectively, bring information to or send information from the brain region.
### Action on other neurons
- Excitatory neurons excite their target neurons. Excitatory neurons in the central nervous system, including the brain, are often glutamatergic. Neurons of the peripheral nervous system, such as spinal motoneurons that synapse onto muscle cells, often use acetylcholine as their excitatory neurotransmitter. However, this is just a general rule that is not always true. It is not the neurotransmitter that decides excitatory or inhibitory action, but rather it is the postsynaptic receptor that is responsible for the action of the neurotransmitter.
- Inhibitory neurons inhibit their target neurons. Inhibitory neurons are often interneurons. The output of some brain structures (neostriatum, globus pallidus, cerebellum) are inhibitory. The primary inhibitory neurotransmitters are GABA and glycine.
- Modulatory neurons evoke more complex effects termed neuromodulation. These neurons use such neurotransmitters as dopamine, acetylcholine, serotonin and others.
### Discharge patterns
Neurons can be classified according to their electrophysiological characteristics:
- Tonic or regular spiking. Some neurons are typically constantly (or tonically) active. Example: interneurons in neurostriatum.
- Phasic or bursting. Neurons that fire in bursts are called phasic.
- Fast spiking. Some neurons are notable for their fast firing rates, for example some types of cortical inhibitory interneurons, cells in globus pallidus.
- Thin-spike. Action potentials of some neurons are more narrow compared to the others. For example, interneurons in prefrontal cortex are thin-spike neurons.
### Neurotransmitter released
Some examples are cholinergic, GABAergic, glutamatergic and dopaminergic neurons.
# Connectivity
Neurons communicate with one another via synapses, where the axon terminal of one cell impinges upon a dendrite or soma of another (or less commonly to an axon). Neurons such as Purkinje cells in the cerebellum can have over 1000 dendritic branches, making connections with tens of thousands of other cells; other neurons, such as the magnocellular neurons of the supraoptic nucleus, have only one or two dendrites, each of which receives thousands of synapses. Synapses can be excitatory or inhibitory and will either increase or decrease activity in the target neuron. Some neurons also communicate via electrical synapses, which are direct, electrically-conductive junctions between cells.
In a chemical synapse, the process of synaptic transmission is as follows: when an action potential reaches the axon terminal, it opens voltage-gated calcium channels, allowing calcium ions to enter the terminal. Calcium causes synaptic vesicles filled with neurotransmitter molecules to fuse with the membrane, releasing their contents into the synaptic cleft. The neurotransmitters diffuse across the synaptic cleft and activate receptors on the postsynaptic neuron.
The human brain has a huge number of synapses. Each of the 1011 (one hundred billion) neurons has on average 7,000 synaptic connections to other neurons. It has been estimated that the brain of a three-year-old child has about 1016 synapses (10 quadrillion). This number declines with age, stabilizing by adulthood. Estimates vary for an adult, ranging from 1015 to 5 x 1015 synapses (1 to 5 quadrillion).
# Mechanisms for propagating action potentials
The cell membrane in the axon and soma contain voltage-gated ion channels which allow the neuron to generate and propagate an electrical impulse (an action potential).
Substantial early knowledge of neuron electrical activity came from experiments with squid giant axons. In 1937, John Zachary Young suggested that the giant squid axon can be used to study neuronal electrical properties. As they are much larger than human neurons, but similar in nature, it was easier to study them with the technology of that time. By inserting electrodes into the giant squid axons, accurate measurements could be made of the membrane potential.
Electrical activity can be produced in neurons by a number of stimuli. Pressure, stretch, chemical transmitters, and electrical current passing across the nerve membrane as a result of a difference in voltage can all initiate nerve activity.
The narrow cross-section of axons lessens the metabolic expense of carrying action potentials, but thicker axons convey impulses more rapidly. To minimize metabolic expense while maintaining rapid conduction, many neurons have insulating sheaths of myelin around their axons. The sheaths are formed by glial cells: oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. The sheath enables action potentials to travel faster than in unmyelinated axons of the same diameter, whilst using less energy. The myelin sheath in peripheral nerves normally runs along the axon in sections about 1 mm long, punctuated by unsheathed nodes of Ranvier which contain a high density of voltage-gated ion channels. Multiple sclerosis is a neurological disorder that results from demyelination of axons in the central nervous system.
Some neurons do not generate action potentials, but instead generate a graded electrical signal, which in turn causes graded neurotransmitter release. Such nonspiking neurons tend to be sensory neurons or interneurons, because they cannot carry signals long distances.
# Histology and internal structure
Nerve cell bodies stained with basophilic dyes show numerous microscopic clumps of Nissl substance (named after German psychiatrist and neuropathologist Franz Nissl, 1860–1919), which consists of rough endoplasmic reticulum and associated ribosomes. The prominence of the Nissl substance can be explained by the fact that nerve cells are metabolically very active, and hence are involved in large amounts of protein synthesis.
The cell body of a neuron is supported by a complex meshwork of structural proteins called neurofilaments, which are assembled into larger neurofibrils. Some neurons also contain pigment granules, such as neuromelanin (a brownish-black pigment, byproduct of synthesis of catecholamines) and lipofuscin (yellowish-brown pigment that accumulates with age).
There are different internal structural characteristics between axons and dendrites. Axons typically almost never contain ribosomes, except some in the initial segment. Dendrites contain granular endoplasmic reticulum or ribosomes, with diminishing amounts with distance from the cell body.
# The neuron doctrine
The neuron doctrine is the now fundamental idea that neurons are the basic structural and functional units of the nervous system. The theory was put forward by Santiago Ramón y Cajal in the late 19th century. It held that neurons are discrete cells (not connected in a meshwork), acting as metabolically distinct units. Cajal further extended this to the Law of Dynamic Polarization, which states that neural transmission goes only in one direction, from dendrites toward axons.
As with all doctrines, there are some exceptions. For example glial cells may also play a role in information processing. Also, electrical synapses are more common than previously thought, meaning that there are direct-cytoplasmic connections between neurons. In fact, there are examples of neurons forming even tighter coupling; the squid giant axon arises from the fusion of multiple neurons that retain individual cell bodies and the crayfish giant axon consists of a series of neurons with high conductance septate junctions. The Law of Dynamic Polarization also has important exceptions; dendrites can serve as synaptic output sites of neurons and axons can receive synaptic inputs.
# Neurons in the brain
The number of neurons in the brain varies dramatically from species to species. One estimate puts the human brain at about 100 billion (10^{11}) neurons and 100 trillion (10^{14}) synapses. By contrast, the nematode worm (Caenorhabditis elegans) has just 302 neurons making it an ideal experimental subject as scientists have been able to map all of the organism's neurons. By contrast, Drosophila melanogaster (the fruit fly) has around 300,000 neurons (which do spike) and exhibits many complex behaviors. Many properties of neurons, from the type of neurotransmitters used to ion channel composition, are maintained across species, allowing scientists to study processes occurring in more complex organisms in much simpler experimental systems. | Neuron
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5]
Neurons (also known as neurones and nerve cells) are electrically excitable cells in the nervous system that process and transmit information. In vertebrate animals, neurons are the core components of the brain, spinal cord and peripheral nerves.
# Overview
Neurons are usually amitotic, but some, such as the olfactory sensory neurons, undergo adult neurogenesis.[1][2][3]
Neurons are typically composed of a soma, or cell body, a dendritic tree and an axon. The majority of vertebrate neurons receive input on the cell body and dendritic tree, and transmit output via the axon. However, there is great heterogeneity throughout the nervous system and the animal kingdom, in the size, shape and function of neurons.
Neurons communicate via chemical and electrical synapses, in a process known as synaptic transmission. The fundamental process that triggers synaptic transmission is the action potential, a propagating electrical signal that is generated by exploiting the electrically excitable membrane of the neuron. This is also known as a wave of depolarization.
# History
The neuron's place as the primary functional unit of the nervous system was first recognized in the early 20th century through the work of the Spanish anatomist Santiago Ramón y Cajal.[4]Cajal proposed that neurons were discrete cells that communicated with each other via specialized junctions, or spaces, between cells.[4] This became known as the neuron doctrine, one of the central tenets of modern neuroscience.[4] To observe the structure of individual neurons, Cajal used a silver staining method developed by his rival, Camillo Golgi.[4] The Golgi stain is an extremely useful method for neuroanatomical investigations because, for reasons unknown, it stains a very small percentage of cells in a tissue, so one is able to see the complete microstructure of individual neurons without much overlap from other cells in the densely packed brain.[5]
# Anatomy and histology
Template:Neuron map
Neurons are highly specialized for the processing and transmission of cellular signals. Given the diversity of functions performed by neurons in different parts of the nervous system, there is, as expected, a wide variety in the shape, size, and electrochemical properties of neurons. For instance, the soma of a neuron can vary from 4 to 100 micrometers in diameter.[6]
- The soma is the central part of the neuron. It contains the nucleus of the cell, and therefore is where most protein synthesis occurs. The nucleus ranges from 3 to 18 micrometers in diameter.[7]
- The dendrites of a neuron are cellular extensions with many branches, and metaphorically this overall shape and structure is referred to as a dendritic tree. This is where the majority of input to the neuron occurs. Information outflow (i.e. from dendrites to other neurons) can also occur, but not across chemical synapses; there, the backflow of a nerve impulse is inhibited by the fact that an axon does not possess chemoreceptors and dendrites cannot secrete neurotransmitter chemicals. This unidirectionality of a chemical synapse explains why nerve impulses are conducted only in one direction.
- The axon is a finer, cable-like projection which can extend tens, hundreds, or even tens of thousands of times the diameter of the soma in length. The axon carries nerve signals away from the soma (and also carry some types of information back to it). Many neurons have only one axon, but this axon may - and usually will - undergo extensive branching, enabling communication with many target cells. The part of the axon where it emerges from the soma is called the 'axon hillock'. Besides being an anatomical structure, the axon hillock is also the part of the neuron that has the greatest density of voltage-dependent sodium channels. This makes it the most easily-excited part of the neuron and the spike initiation zone for the axon: in neurological terms it has the most negative hyperpolarized action potential threshold. While the axon and axon hillock are generally involved in information outflow, this region can also receive input from other neurons.
- The axon terminal is a specialized structure at the end of the axon that is used to release neurotransmitter chemicals and communicate with target neurons.
Although the canonical view of the neuron attributes dedicated functions to its various anatomical components, dendrites and axons often act in ways contrary to their so-called main function.
Axons and dendrites in the central nervous system are typically only about one micrometer thick, while some in the peripheral nervous system are much thicker. The soma is usually about 10–25 micrometers in diameter and often is not much larger than the cell nucleus it contains. The longest axon of a human motoneuron can be over a meter long, reaching from the base of the spine to the toes. Sensory neurons have axons that run from the toes to the dorsal columns, over 1.5 meters in adults. Giraffes have single axons several meters in length running along the entire length of their necks. Much of what is known about axonal function comes from studying the squid giant axon, an ideal experimental preparation because of its relatively immense size (0.5–1 millimeters thick, several centimeters long).
# Classes
File:GFPneuron.png
## Structural classification
### Polarity
Most neurons can be anatomically characterized as:
- Unipolar or pseudounipolar: dendrite and axon emerging from same process.
- Bipolar: single axon and single dendrite on opposite ends of the soma.
- Multipolar: more than two dendrites:
Golgi I: neurons with long-projecting axonal processes; examples are pyramidal cells, Purkinje cells, and anterior horn cells.
Golgi II: neurons whose axonal process projects locally; the best example are the granule cells.
- Golgi I: neurons with long-projecting axonal processes; examples are pyramidal cells, Purkinje cells, and anterior horn cells.
- Golgi II: neurons whose axonal process projects locally; the best example are the granule cells.
### Other
Furthermore, some unique neuronal types can be identified according to their location in the nervous system and distinct shape. Some examples are:
- Basket cells, neurons with dilated and knotty dendrites in the cerebellum.
- Betz cells, large motor neurons.
- Medium spiny neurons, most neurons in the corpus striatum.
- Purkinje cells, huge neurons in the cerebellum, a type of Golgi I multipolar neuron.
- pyramidal cells, neurons with triangular soma, a type of Golgi I.
- Renshaw cells, neurons with both ends linked to alpha motor neurons.
- Granule cells, a type of as Golgi II neuron.
- anterior horn cells, motoneurons located in the spinal cord.
## Functional classification
### Direction
- Afferent neurons convey information from tissues and organs into the central nervous system and are sometimes also called sensory neurons.
- Efferent neurons transmit signals from the central nervous system to the effector cells and are sometimes called motor neurons.
- Interneurons connect neurons within specific regions of the central nervous system.
Afferent and efferent can also refer generally to neurons which, respectively, bring information to or send information from the brain region.
### Action on other neurons
- Excitatory neurons excite their target neurons. Excitatory neurons in the central nervous system, including the brain, are often glutamatergic. Neurons of the peripheral nervous system, such as spinal motoneurons that synapse onto muscle cells, often use acetylcholine as their excitatory neurotransmitter. However, this is just a general rule that is not always true. It is not the neurotransmitter that decides excitatory or inhibitory action, but rather it is the postsynaptic receptor that is responsible for the action of the neurotransmitter.
- Inhibitory neurons inhibit their target neurons. Inhibitory neurons are often interneurons. The output of some brain structures (neostriatum, globus pallidus, cerebellum) are inhibitory. The primary inhibitory neurotransmitters are GABA and glycine.
- Modulatory neurons evoke more complex effects termed neuromodulation. These neurons use such neurotransmitters as dopamine, acetylcholine, serotonin and others.
### Discharge patterns
Neurons can be classified according to their electrophysiological characteristics:
- Tonic or regular spiking. Some neurons are typically constantly (or tonically) active. Example: interneurons in neurostriatum.
- Phasic or bursting. Neurons that fire in bursts are called phasic.
- Fast spiking. Some neurons are notable for their fast firing rates, for example some types of cortical inhibitory interneurons, cells in globus pallidus.
- Thin-spike. Action potentials of some neurons are more narrow compared to the others. For example, interneurons in prefrontal cortex are thin-spike neurons.
### Neurotransmitter released
Some examples are cholinergic, GABAergic, glutamatergic and dopaminergic neurons.
# Connectivity
Neurons communicate with one another via synapses, where the axon terminal of one cell impinges upon a dendrite or soma of another (or less commonly to an axon). Neurons such as Purkinje cells in the cerebellum can have over 1000 dendritic branches, making connections with tens of thousands of other cells; other neurons, such as the magnocellular neurons of the supraoptic nucleus, have only one or two dendrites, each of which receives thousands of synapses. Synapses can be excitatory or inhibitory and will either increase or decrease activity in the target neuron. Some neurons also communicate via electrical synapses, which are direct, electrically-conductive junctions between cells.
In a chemical synapse, the process of synaptic transmission is as follows: when an action potential reaches the axon terminal, it opens voltage-gated calcium channels, allowing calcium ions to enter the terminal. Calcium causes synaptic vesicles filled with neurotransmitter molecules to fuse with the membrane, releasing their contents into the synaptic cleft. The neurotransmitters diffuse across the synaptic cleft and activate receptors on the postsynaptic neuron.
The human brain has a huge number of synapses. Each of the 1011 (one hundred billion) neurons has on average 7,000 synaptic connections to other neurons. It has been estimated that the brain of a three-year-old child has about 1016 synapses (10 quadrillion). This number declines with age, stabilizing by adulthood. Estimates vary for an adult, ranging from 1015 to 5 x 1015 synapses (1 to 5 quadrillion).[8]
# Mechanisms for propagating action potentials
The cell membrane in the axon and soma contain voltage-gated ion channels which allow the neuron to generate and propagate an electrical impulse (an action potential).
Substantial early knowledge of neuron electrical activity came from experiments with squid giant axons. In 1937, John Zachary Young suggested that the giant squid axon can be used to study neuronal electrical properties.[9] As they are much larger than human neurons, but similar in nature, it was easier to study them with the technology of that time. By inserting electrodes into the giant squid axons, accurate measurements could be made of the membrane potential.
Electrical activity can be produced in neurons by a number of stimuli. Pressure, stretch, chemical transmitters, and electrical current passing across the nerve membrane as a result of a difference in voltage can all initiate nerve activity.[10]
The narrow cross-section of axons lessens the metabolic expense of carrying action potentials, but thicker axons convey impulses more rapidly. To minimize metabolic expense while maintaining rapid conduction, many neurons have insulating sheaths of myelin around their axons. The sheaths are formed by glial cells: oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. The sheath enables action potentials to travel faster than in unmyelinated axons of the same diameter, whilst using less energy. The myelin sheath in peripheral nerves normally runs along the axon in sections about 1 mm long, punctuated by unsheathed nodes of Ranvier which contain a high density of voltage-gated ion channels. Multiple sclerosis is a neurological disorder that results from demyelination of axons in the central nervous system.
Some neurons do not generate action potentials, but instead generate a graded electrical signal, which in turn causes graded neurotransmitter release. Such nonspiking neurons tend to be sensory neurons or interneurons, because they cannot carry signals long distances.
# Histology and internal structure
Nerve cell bodies stained with basophilic dyes show numerous microscopic clumps of Nissl substance (named after German psychiatrist and neuropathologist Franz Nissl, 1860–1919), which consists of rough endoplasmic reticulum and associated ribosomes. The prominence of the Nissl substance can be explained by the fact that nerve cells are metabolically very active, and hence are involved in large amounts of protein synthesis.
The cell body of a neuron is supported by a complex meshwork of structural proteins called neurofilaments, which are assembled into larger neurofibrils. Some neurons also contain pigment granules, such as neuromelanin (a brownish-black pigment, byproduct of synthesis of catecholamines) and lipofuscin (yellowish-brown pigment that accumulates with age).
There are different internal structural characteristics between axons and dendrites. Axons typically almost never contain ribosomes, except some in the initial segment. Dendrites contain granular endoplasmic reticulum or ribosomes, with diminishing amounts with distance from the cell body.
# The neuron doctrine
The neuron doctrine is the now fundamental idea that neurons are the basic structural and functional units of the nervous system. The theory was put forward by Santiago Ramón y Cajal in the late 19th century. It held that neurons are discrete cells (not connected in a meshwork), acting as metabolically distinct units. Cajal further extended this to the Law of Dynamic Polarization, which states that neural transmission goes only in one direction, from dendrites toward axons[11].
As with all doctrines, there are some exceptions. For example glial cells may also play a role in information processing[12]. Also, electrical synapses are more common than previously thought,[13] meaning that there are direct-cytoplasmic connections between neurons. In fact, there are examples of neurons forming even tighter coupling; the squid giant axon arises from the fusion of multiple neurons that retain individual cell bodies and the crayfish giant axon consists of a series of neurons with high conductance septate junctions. The Law of Dynamic Polarization also has important exceptions; dendrites can serve as synaptic output sites of neurons[14] and axons can receive synaptic inputs.
# Neurons in the brain
The number of neurons in the brain varies dramatically from species to species.[15] One estimate puts the human brain at about 100 billion (<math>10^{11}</math>) neurons and 100 trillion (<math>10^{14}</math>) synapses.[15] By contrast, the nematode worm (Caenorhabditis elegans) has just 302 neurons making it an ideal experimental subject as scientists have been able to map all of the organism's neurons. By contrast, Drosophila melanogaster (the fruit fly) has around 300,000 neurons (which do spike) and exhibits many complex behaviors. Many properties of neurons, from the type of neurotransmitters used to ion channel composition, are maintained across species, allowing scientists to study processes occurring in more complex organisms in much simpler experimental systems. | https://www.wikidoc.org/index.php/Nerve_cell | |
ed1ab8fad6523b67ebf47d1d9c668b4bbe01b794 | wikidoc | Retina | Retina
The retina is a thin layer of neural cells that lines the back of the eyeball of vertebrates and some cephalopods. It is comparable to the film in a camera. In vertebrate embryonic development, the retina and the optic nerve originate as outgrowths of the developing brain. Hence, the retina is part of the central nervous system (CNS). It is the only part of the CNS that can be imaged directly.
The vertebrate retina contains photoreceptor cells (rods and cones) that respond to light; the resulting neural signals then undergo complex processing by other neurons of the retina. The retinal output takes the form of action potentials in retinal ganglion cells whose axons form the optic nerve. Several important features of visual perception can be traced to the retinal encoding and processing of light.
The unique structure of the blood vessels in the retina has been used for biometric identification.
# Anatomy of vertebrate retina
The vertebrate retina has ten distinct layers. From innermost to outermost, they include:
- Inner limiting membrane - Müller cell footplates
- Nerve fiber layer
- Ganglion cell layer - Layer that contains nuclei of ganglion cells and gives rise to optic nerve fibers.
- Inner plexiform layer
- Inner nuclear layer
- Outer plexiform layer - In the macular region, this is known as the Fiber layer of Henle.
- Outer nuclear layer
- External limiting membrane - Layer that separates the inner segment portions of the photoreceptors from their cell nuclei.
- Photoreceptor layer - Rods / Cones
- Retinal pigment epithelium
# Physical structure of human retina
In adult humans the entire retina is 72% of a sphere about 22 mm in diameter. An area of the retina is the optic disc, sometimes known as "the blind spot" because it lacks photoreceptors. It appears as an oval white area of 3 mm². Temporal (in the direction of the temples) to this disc is the macula. At its center is the fovea, a pit that is most sensitive to light and is responsible for our sharp central vision. Human and non-human primates possess one fovea as opposed to certain bird species such as hawks who actually are bifoviate and dogs and cats who possess no fovea but a central band known as the visual streak. Around the fovea extends the central retina for about 6 mm and then the peripheral retina. The edge of the retina is defined by the ora serrata. The length from one ora to the other (or macula), the most sensitive area along the horizontal meridian is about 3.2 mm.
In section the retina is no more than 0.5 mm thick. It has three layers of nerve cells and two of synapses. The optic nerve carries the ganglion cell axons to the brain and the blood vessels that open into the retina. As a byproduct of evolution, the ganglion cells lie innermost in the retina while the photoreceptive cells lie outermost. Because of this arrangement, light must first pass through the thickness of the retina before reaching the rods and cones. However it does not pass through the epithelium or the choroid (both of which are opaque).
The white blood cells in the capillaries in front of the photoreceptors can be perceived as tiny bright moving dots when looking into blue light. This is known as the blue field entoptic phenomenon (or Scheerer's phenomenon).
Between the ganglion cell layer and the rods and cones there are two layers of neuropils where synaptic contacts are made. The neuropil layers are the outer plexiform layer and the inner plexiform layer. In the outer the rod and cones connect to the vertically running bipolar cells and the horizontally oriented horizontal cells connect to ganglion cells.
The central retina is cone-dominated and the peripheral retina is rod-dominated. In total there are about seven million cones and a hundred million rods. At the centre of the macula is the foveal pit where the cones are smallest and in a hexagonal mosaic, the most efficient and highest density. Below the pit the other retina layers are displaced, before building up along the foveal slope until the rim of the fovea or parafovea which is the thickest portion of the retina. The macula has a yellow pigmentation from screening pigments and is known as the macula lutea.
## Difference between vertebrate and cephalopod retinas
The vertebrate retina is inverted in the sense that the light sensing cells sit at the back side of the retina, so that light has to pass through a layer of neurons before it reaches the photoreceptors. By contrast, the cephalopod retina is everted: the photoreceptors are located at the front side of the retina, with processing neurons behind them. Because of this, cephalopods do not have a blind spot.
The cephalopod retina does not originate as an outgrowth of the brain, as the vertebrate one does. This shows that vertebrate and cephalopod eyes are not homologous but have evolved separately.
# Physiology
An image is produced by the "patterned excitation" of the retinal receptors, the cones and rods. The excitation is processed by the neuronal system and various parts of the brain working in parallel to form a representation of the external environment in the brain.
The cones respond to bright light and mediate high-resolution vision and colour vision. The rods respond to dim light and mediate lower-resolution, black-and-white, night vision. It is a lack of cones sensitive to red, blue, or green light that causes individuals to have deficiencies in colour vision or various kinds of colour blindness. Humans and old world monkeys have three different types of cones (trichromatic vision) while other mammals lack cones with red sensitive pigment and therefore have poorer (dichromatic) colour vision.
When light falls on a receptor it sends a proportional response synaptically to bipolar cells which in turn signal the retinal ganglion cells. The receptors are also 'cross-linked' by horizontal cells and amacrine cells, which modify the synaptic signal before the ganglion cells. Rod and cone signals are intermixed and combine, although rods are mostly active in very poorly lit conditions and saturate in broad daylight, while cones function in brighter lighting because they are not sensitive enough to work at very low light levels.
Despite the fact that all are nerve cells, only the retinal ganglion cells and few amacrine cells create action potentials. In the photoreceptors, exposure to light hyperpolarizes the membrane in a series of graded shifts. The outer cell segment contains a photopigment. Inside the cell the normal levels of cGMP keeps the Na+ channel open and thus in the resting state the cell is depolarised. The photon causes the retinal bound to the receptor protein to isomerise to trans-retinal. This causes receptor to activate multiple G-proteins. This in turn causes the Ga-subunit of the protein to bind and degrade cGMP inside the cell which then cannot bind to the CNG Na+ channels. Thus the cell is hyperpolarised. The amount of neurotransmitter released is reduced in bright light and increases as light levels fall. The actual photopigment is bleached away in bright light and only replaced as a chemical process, so in a transition from bright light to darkness the eye can take up to thirty minutes to reach full sensitivity (see dark adaptation).
In the retinal ganglion cells there are two types of response, depending on the receptive field of the cell. The receptive fields of retinal ganglion cells comprise a central approximately circular area, where light has one effect on the firing of the cell, and an annular surround, where light has the opposite effect on the firing of the cell. In ON cells, an increment in light intensity in the centre of the receptive field causes the firing rate to increase. In OFF cells, it makes it decrease. Beyond this simple difference ganglion cells are also differentiated by chromatic sensitivity and the type of spatial summation. Cells showing linear spatial summation are termed X cells (also called "parvocellular", "P", or "midget" ganglion cells), and those showing non-linear summation are Y cells (also called "magnocellular, "M", or "parasol" retinal ganglion cells), although the correspondence between X and Y cells (in the cat retina) and P and M cells (in the primate retina) is not as simple as it once seemed.
In the transfer of signal to the brain, the visual pathway, the retina is vertically divided in two, a temporal half and a nasal half. The axons from the nasal half cross the brain at the optic chiasma to join with axons from the temporal half of the other eye before passing into the lateral geniculate body.
Although there are more than 130 million retinal receptors, there are only approximately 1.2 million fibres (axons) in the optic nerve so a large amount of pre-processing is performed within the retina. The fovea produces the most accurate information. Despite occupying about 0.01% of the visual field (less than 2° of visual angle), about 10% of axons in the optic nerve are devoted to the fovea. The resolution limit of the fovea has been determined at around 10,000 points. The information capacity is estimated at 500,000 bits per second (for more information on bits, see information theory) without colour or around 600,000 bits per second including colour.
## Spatial Encoding
The retina, unlike a camera, does not simply relay a picture to the brain, it first spatially encodes the image to fit the limited capacity of the optic nerve (there are 100 times less ganglion cells than photoreceptors). The retina employs spatial encoding (which involves sampling every region in the image, recording its value/colour), but it also aims to decorrelate incoming spatial images. This is carried out by the center surround inhibition of the bipolar and ganglion cells, which is based on the assumption that neighboring areas on an image are more likely to be the same colour/intensity. Once spatially encoded, the signal is sent to the LGN where it will be temporally encoded.
# Diseases and disorders
There are many inherited and acquired diseases or disorders that may affect the retina. Some of them include:
- Retinitis pigmentosa is a group of genetic diseases that affect the retina and causes the loss of night vision and peripheral vision.
- Macular degeneration describes a group of diseases characterized by loss of central vision because of death or impairment of the cells in the macula.
- Cone-rod dystrophy (CORD) describes a number of diseases where vision loss is caused by deterioration of the cones and/or rods in the retina.
- In retinal separation, the retina detaches from the back of the eyeball. Ignipuncture is an outdated treatment method.
- Both hypertension and diabetes mellitus can cause damage to the tiny blood vessels that supply the retina, leading to hypertensive retinopathy and diabetic retinopathy.
- Retinoblastoma is a cancer of the retina.
- Retinal diseases in dogs include retinal dysplasia, progressive retinal atrophy, and sudden acquired retinal degeneration.
# Diagnosis and treatment
A number of different instruments are available for the diagnosis of diseases and disorders affecting the retina. An ophthalmoscope is used to examine the retina. Recently, adaptive optics has been used to image individual rods and cones in the living human retina.
The electroretinogram is used to measure non-invasively the retina's electrical activity, which is affected by certain diseases. A relatively new technology, now becoming widely available, is optical coherence tomography (OCT). This non-invasive technique allows one to obtain a 3D volumetric or high resolution cross-sectional tomogram of the retinal fine structure with histologic-quality.
Treatment depends upon the nature of the disease or disorder. Transplantation of retinas has been attempted, but without much success. At MIT, The University of Southern California, and the University of New South Wales, an "artificial retina" is under development: an implant which will bypass the photoreceptors of the retina and stimulate the attached nerve cells directly, with signals from a digital camera.
# Research
George Wald, Haldan Keffer Hartline and Ragnar Granit won the 1967 Nobel Prize in Physiology or Medicine for their scientific research on the retina.
A recent University of Pennsylvania study calculated the approximate bandwidth of human retinas is 8.75 megabits per second, whereas a guinea pig retinas transfer at 875 kilobits.
Robert MacLaren and colleagues at University College London and Moorfields Eye Hospital in London showed in 2006 that photoreceptor cells could be transplanted successfully in the mouse retina if donor cells were at a critical developmental stage. | Retina
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The retina is a thin layer of neural cells that lines the back of the eyeball of vertebrates and some cephalopods. It is comparable to the film in a camera. In vertebrate embryonic development, the retina and the optic nerve originate as outgrowths of the developing brain. Hence, the retina is part of the central nervous system (CNS). It is the only part of the CNS that can be imaged directly.
The vertebrate retina contains photoreceptor cells (rods and cones) that respond to light; the resulting neural signals then undergo complex processing by other neurons of the retina. The retinal output takes the form of action potentials in retinal ganglion cells whose axons form the optic nerve. Several important features of visual perception can be traced to the retinal encoding and processing of light.
The unique structure of the blood vessels in the retina has been used for biometric identification.
# Anatomy of vertebrate retina
The vertebrate retina has ten distinct layers.[1] From innermost to outermost, they include:
- Inner limiting membrane - Müller cell footplates
- Nerve fiber layer
- Ganglion cell layer - Layer that contains nuclei of ganglion cells and gives rise to optic nerve fibers.
- Inner plexiform layer
- Inner nuclear layer
- Outer plexiform layer - In the macular region, this is known as the Fiber layer of Henle.
- Outer nuclear layer
- External limiting membrane - Layer that separates the inner segment portions of the photoreceptors from their cell nuclei.
- Photoreceptor layer - Rods / Cones
- Retinal pigment epithelium
# Physical structure of human retina
In adult humans the entire retina is 72% of a sphere about 22 mm in diameter. An area of the retina is the optic disc, sometimes known as "the blind spot" because it lacks photoreceptors. It appears as an oval white area of 3 mm². Temporal (in the direction of the temples) to this disc is the macula. At its center is the fovea, a pit that is most sensitive to light and is responsible for our sharp central vision. Human and non-human primates possess one fovea as opposed to certain bird species such as hawks who actually are bifoviate and dogs and cats who possess no fovea but a central band known as the visual streak. Around the fovea extends the central retina for about 6 mm and then the peripheral retina. The edge of the retina is defined by the ora serrata. The length from one ora to the other (or macula), the most sensitive area along the horizontal meridian is about 3.2 mm.
In section the retina is no more than 0.5 mm thick. It has three layers of nerve cells and two of synapses. The optic nerve carries the ganglion cell axons to the brain and the blood vessels that open into the retina. As a byproduct of evolution, the ganglion cells lie innermost in the retina while the photoreceptive cells lie outermost. Because of this arrangement, light must first pass through the thickness of the retina before reaching the rods and cones. However it does not pass through the epithelium or the choroid (both of which are opaque).
The white blood cells in the capillaries in front of the photoreceptors can be perceived as tiny bright moving dots when looking into blue light. This is known as the blue field entoptic phenomenon (or Scheerer's phenomenon).
Between the ganglion cell layer and the rods and cones there are two layers of neuropils where synaptic contacts are made. The neuropil layers are the outer plexiform layer and the inner plexiform layer. In the outer the rod and cones connect to the vertically running bipolar cells and the horizontally oriented horizontal cells connect to ganglion cells.
The central retina is cone-dominated and the peripheral retina is rod-dominated. In total there are about seven million cones and a hundred million rods. At the centre of the macula is the foveal pit where the cones are smallest and in a hexagonal mosaic, the most efficient and highest density. Below the pit the other retina layers are displaced, before building up along the foveal slope until the rim of the fovea or parafovea which is the thickest portion of the retina. The macula has a yellow pigmentation from screening pigments and is known as the macula lutea.
## Difference between vertebrate and cephalopod retinas
The vertebrate retina is inverted in the sense that the light sensing cells sit at the back side of the retina, so that light has to pass through a layer of neurons before it reaches the photoreceptors. By contrast, the cephalopod retina is everted: the photoreceptors are located at the front side of the retina, with processing neurons behind them. Because of this, cephalopods do not have a blind spot.
The cephalopod retina does not originate as an outgrowth of the brain, as the vertebrate one does. This shows that vertebrate and cephalopod eyes are not homologous but have evolved separately.
# Physiology
An image is produced by the "patterned excitation" of the retinal receptors, the cones and rods. The excitation is processed by the neuronal system and various parts of the brain working in parallel to form a representation of the external environment in the brain.
The cones respond to bright light and mediate high-resolution vision and colour vision. The rods respond to dim light and mediate lower-resolution, black-and-white, night vision. It is a lack of cones sensitive to red, blue, or green light that causes individuals to have deficiencies in colour vision or various kinds of colour blindness. Humans and old world monkeys have three different types of cones (trichromatic vision) while other mammals lack cones with red sensitive pigment and therefore have poorer (dichromatic) colour vision.
When light falls on a receptor it sends a proportional response synaptically to bipolar cells which in turn signal the retinal ganglion cells. The receptors are also 'cross-linked' by horizontal cells and amacrine cells, which modify the synaptic signal before the ganglion cells. Rod and cone signals are intermixed and combine, although rods are mostly active in very poorly lit conditions and saturate in broad daylight, while cones function in brighter lighting because they are not sensitive enough to work at very low light levels.
Despite the fact that all are nerve cells, only the retinal ganglion cells and few amacrine cells create action potentials. In the photoreceptors, exposure to light hyperpolarizes the membrane in a series of graded shifts. The outer cell segment contains a photopigment. Inside the cell the normal levels of cGMP keeps the Na+ channel open and thus in the resting state the cell is depolarised. The photon causes the retinal bound to the receptor protein to isomerise to trans-retinal. This causes receptor to activate multiple G-proteins. This in turn causes the Ga-subunit of the protein to bind and degrade cGMP inside the cell which then cannot bind to the CNG Na+ channels. Thus the cell is hyperpolarised. The amount of neurotransmitter released is reduced in bright light and increases as light levels fall. The actual photopigment is bleached away in bright light and only replaced as a chemical process, so in a transition from bright light to darkness the eye can take up to thirty minutes to reach full sensitivity (see dark adaptation).
In the retinal ganglion cells there are two types of response, depending on the receptive field of the cell. The receptive fields of retinal ganglion cells comprise a central approximately circular area, where light has one effect on the firing of the cell, and an annular surround, where light has the opposite effect on the firing of the cell. In ON cells, an increment in light intensity in the centre of the receptive field causes the firing rate to increase. In OFF cells, it makes it decrease. Beyond this simple difference ganglion cells are also differentiated by chromatic sensitivity and the type of spatial summation. Cells showing linear spatial summation are termed X cells (also called "parvocellular", "P", or "midget" ganglion cells), and those showing non-linear summation are Y cells (also called "magnocellular, "M", or "parasol" retinal ganglion cells), although the correspondence between X and Y cells (in the cat retina) and P and M cells (in the primate retina) is not as simple as it once seemed.
In the transfer of signal to the brain, the visual pathway, the retina is vertically divided in two, a temporal half and a nasal half. The axons from the nasal half cross the brain at the optic chiasma to join with axons from the temporal half of the other eye before passing into the lateral geniculate body.
Although there are more than 130 million retinal receptors, there are only approximately 1.2 million fibres (axons) in the optic nerve so a large amount of pre-processing is performed within the retina. The fovea produces the most accurate information. Despite occupying about 0.01% of the visual field (less than 2° of visual angle), about 10% of axons in the optic nerve are devoted to the fovea. The resolution limit of the fovea has been determined at around 10,000 points. The information capacity is estimated at 500,000 bits per second (for more information on bits, see information theory) without colour or around 600,000 bits per second including colour.
## Spatial Encoding
The retina, unlike a camera, does not simply relay a picture to the brain, it first spatially encodes the image to fit the limited capacity of the optic nerve (there are 100 times less ganglion cells than photoreceptors). The retina employs spatial encoding (which involves sampling every region in the image, recording its value/colour), but it also aims to decorrelate incoming spatial images. This is carried out by the center surround inhibition of the bipolar and ganglion cells, which is based on the assumption that neighboring areas on an image are more likely to be the same colour/intensity. Once spatially encoded, the signal is sent to the LGN where it will be temporally encoded.
# Diseases and disorders
There are many inherited and acquired diseases or disorders that may affect the retina. Some of them include:
- Retinitis pigmentosa is a group of genetic diseases that affect the retina and causes the loss of night vision and peripheral vision.
- Macular degeneration describes a group of diseases characterized by loss of central vision because of death or impairment of the cells in the macula.
- Cone-rod dystrophy (CORD) describes a number of diseases where vision loss is caused by deterioration of the cones and/or rods in the retina.
- In retinal separation, the retina detaches from the back of the eyeball. Ignipuncture is an outdated treatment method.
- Both hypertension and diabetes mellitus can cause damage to the tiny blood vessels that supply the retina, leading to hypertensive retinopathy and diabetic retinopathy.
- Retinoblastoma is a cancer of the retina.
- Retinal diseases in dogs include retinal dysplasia, progressive retinal atrophy, and sudden acquired retinal degeneration.
# Diagnosis and treatment
A number of different instruments are available for the diagnosis of diseases and disorders affecting the retina. An ophthalmoscope is used to examine the retina. Recently, adaptive optics has been used to image individual rods and cones in the living human retina.
The electroretinogram is used to measure non-invasively the retina's electrical activity, which is affected by certain diseases. A relatively new technology, now becoming widely available, is optical coherence tomography (OCT). This non-invasive technique allows one to obtain a 3D volumetric or high resolution cross-sectional tomogram of the retinal fine structure with histologic-quality.
Treatment depends upon the nature of the disease or disorder. Transplantation of retinas has been attempted, but without much success. At MIT, The University of Southern California, and the University of New South Wales, an "artificial retina" is under development: an implant which will bypass the photoreceptors of the retina and stimulate the attached nerve cells directly, with signals from a digital camera.
# Research
George Wald, Haldan Keffer Hartline and Ragnar Granit won the 1967 Nobel Prize in Physiology or Medicine for their scientific research on the retina.
A recent University of Pennsylvania study calculated the approximate bandwidth of human retinas is 8.75 megabits per second, whereas a guinea pig retinas transfer at 875 kilobits. [2]
Robert MacLaren and colleagues at University College London and Moorfields Eye Hospital in London showed in 2006 that photoreceptor cells could be transplanted successfully in the mouse retina if donor cells were at a critical developmental stage. [3] | https://www.wikidoc.org/index.php/Nervous_tunic | |
9ea5be5af71a1ef8b2a8f784d64109acbccc6812 | wikidoc | Nettle | Nettle
Nettle is the common name for any of between 30-45 species of flowering plants of the genus Urtica in the family Urticaceae, with a cosmopolitan though mainly temperate distribution. They are mostly herbaceous perennial plants, but some are annual and a few are shrubby.
The most prominent member of the genus is the stinging nettle Urtica dioica, native to Europe, north Africa, Asia, and North America. The genus also contains a number of other species with similar properties, listed below. However, a large number of species names that will be encountered in this genus in the older literature (about 100 species have been described) are now recognised as synonyms of Urtica dioica. Some of these taxa are still recognised as subspecies.
Most of the species listed below share the property of having stinging hairs, and can be expected to have very similar medicinal uses to the stinging nettle. The stings of Urtica ferox, the ongaonga or tree nettle of New Zealand, have been known to kill horses, dogs and at least one human.
The nature of the toxin secreted by nettles is not settled. The stinging hairs of most nettle species contain formic acid, serotonin and histamine; however recent studies of Urtica thunbergiana (Fu et al, 2006) implicate oxalic acid and tartaric acid rather than any of those substances, at least in that species.
# Species of nettle
Species in the genus Urtica, and their primary natural ranges, include:
- Urtica angustifolia Fisch. ex Hornem. 1819. China, Japan, Korea.
- Urtica ardens. China.
- Urtica atrichocaulis. Himalaya, southwestern China.
- Urtica atrovirens. Western Mediterranean region.
- Urtica cannabina L. 1753. Western Asia from Siberia to Iran.
- Urtica chamaedryoides (heartleaf nettle). Southeastern North America.
- Urtica dioica L. 1753 (stinging nettle or bull nettle). Europe, Asia, North America.
- Urtica dubia (large-leaved nettle). Canada.
- Urtica ferox (ongaonga or tree nettle). New Zealand.
- Urtica fissa. China.
- Urtica galeopsifolia Wierzb. ex Opiz, 1825. Central and eastern Europe.
- Urtica gracilenta (mountain nettle). Arizona, New Mexico, west Texas, northern Mexico.
- Urtica hyperborea. Himalaya from Pakistan to Bhutan, Mongolia and Tibet, high altitudes.
- Urtica incisa (scrub nettle). Australia.
- Urtica kioviensis Rogow. 1843. Eastern Europe.
- Urtica laetivirens Maxim. 1877. Japan, Manchuria.
- Urtica mairei. Himalaya, southwestern China, northeastern India, Myanmar.
- Urtica membranacea. Mediterranean region, Azores.
- Urtica morifolia. Canary Islands (endemic).
- Urtica parviflora. Himalaya (lower altitudes).
- Urtica pilulifera (Roman nettle). Southern Europe.
- Urtica platyphylla Wedd. 1856-1857. China, Japan.
- Urtica pubescens Ledeb. 1833. Southwestern Russia east to central Asia.
- Urtica rupestris. Sicily (endemic).
- Urtica sondenii (Simmons) Avrorin ex Geltman, 1988. Northeastern Europe, northern Asia.
- Urtica taiwaniana. Taiwan.
- Urtica thunbergiana. Japan, Taiwan.
- Urtica triangularis
- Urtica urens L. 1753 (dwarf nettle or annual nettle). Europe, North America.
The family Urticaceae also contains some other plants called nettles that are not members of the genus Urtica. These include the wood nettle Laportea canadensis, found in eastern North America from Nova Scotia to Florida, and the false nettle Boehmeria cylindrica, found in most of the United States east of the Rockies. As its name implies, the false nettle does not sting.
There are many unrelated organisms called nettle, such as:
- Dead-nettle (Lamium spp.) and hedge-nettle (Stachys spp.) which are in the Lamiaceae or mint family.
- Devil's nettle, which is another name for yarrow.
- Carolina horsenettle (Solanum carolinense) in the Solanaceae.
- Spurge-nettle (Cnidolscolus stimulosus) in the Euphorbiaceae.
- Sea nettle (Chtysaora quinquecirrha) which is a jellyfish.
Nettles are the exclusive larval food plant for several species of butterfly, such as the Peacock Butterfly or the Small Tortoiseshell, and are also eaten by the larvae of some moths including Angle Shades, Buff Ermine, Dot Moth, The Flame, The Gothic, Grey Chi, Grey Pug, Lesser Broad-bordered Yellow Underwing, Mouse Moth, Setaceous Hebrew Character and Small Angle Shades. The roots are sometimes eaten by the larva of the Ghost Moth Hepialus humuli.
# Uses
## Culinary
The tops of growing nettles are a popular cooked green in many areas. Some cooks throw away a first water to get rid of the stinging compounds, while others retain the water and cook the nettles straight. Nettle tops are sold in some farmers' markets and natural food stores.
## Tea
The fresh or dried leaves of nettle can be used to make a tea and commercial tea bags are commonly sold in natural food stores.
## Medical
Nettle is believed to be a galactagogue and a clinical trial has shown that the juice is diuretic in patients with congestive heart failure.
Urtication, or flogging with nettles, is the process of deliberately applying stinging nettles to the skin in order to provoke inflammation. An agent thus used is known as a rubefacient (i.e. something that causes redness). This is done as a folk remedy for rheumatism, as it provides temporary relief from pain. They may also be used as a suppository, although this can be very painful and will not stop much skin irritation.
Extracts can be used to treat arthritis, anemia, hay fever, kidney problems, and pain. Nettle is used in hair shampoos to control dandruff, and is said to make hair more glossy, which is why some farmers include a handful of nettles with cattle feed.
Nettle root extracts have been extensively studied in human clinical trials as a treatment for symptoms of benign prostatic hyperplasia (BPH). These extracts have been shown to help relieve symptoms compared to placebo both by themselves and when combined with other herbal medicines.
Because it contains 3,4-divanillyltetrahydrofuran, certain extracts of the nettle are used by bodybuilders in an effort to increase free testosterone by occupying sex-hormone binding globulin.
Fresh nettle, specifically Urtica Dioica, is used in folk remedies to stop all types of bleeding, due to its high Vitamin K content. Meanwhile, in dry Urtica Dioica, the Vitamin K is practically non-existent, and so is used as a blood thinner.
## Paper
Nettle stems are a popular raw material used in small-scale papermaking.
## Textiles
Nettle fibre has been used in textiles. This is more experimental than mass-market. Unlike cotton, nettles grow easily without pesticides. The fibres are coarser however.
As well being the fibre, Nettles were also used as a dye-stuff in the medieval period.
# Safety
Though the fresh leaves can cause painful stings and acute urticaria, these are rarely seriously harmful (but see remarks in the introductory section re the U. ferox, ongaonga or tree nettle of New Zealand). Otherwise most species of nettles are extremely safe and some are even eaten as vegetables after being steamed to remove the stingers.
Nettles can be picked painlessly by wearing a standard pair of washing-up gloves. Another common recommendation is to firmly grasp the nettle with the bare hand, crushing the stingers instead of allowing them to penetrate the skin. Done properly, this is effective in practice, however due to a natural hesitancy when grabbing a nettle, first time practitioners close their hand too gently and slowly and so get stung. A traditional verse goes "Tenderly you stroke a Nettle, and it stings you for your pains. Grasp it like a man of mettle, and it soft as silk remains."
The traditional remedy for nettle stings is rubbing with the crushed leaf of the dock plant, Rumex obtusifolius, which often grows beside nettles in the wild and has a milky substance which can cause dermatitis. Plantain is another traditional remedy. The alkalinity of the sap may counteract the nettle's acids. Nettle itself will release alkaline sap when macerated While there is no scientific proof that this remedy works, searching for and using a dock leaf at least takes the mind off the stinging pain somewhat. Though unproven, some claim that dabbing mud on the affected area, allowing it to dry, and rubbing it off can remove the stingers. Another disputed claim is that the spores of certain ferns can lessen the pain by rubbing the underside of fern leaves, where the spores are located in rows of round, orange lumps, on the affected area.
The nettle stingers can be removed from the skin quickly and effectively by wiping your skin with a chamois (same as used for drying cars). The inside of a leather glove works similarly. The nettle hairs stick to these textures more readily than your skin and a simple single wiping removes them from your skin.
# Popular culture
- The Bottle Inn, a pub in Marshwood, Dorset, England, holds an annual World Stinging Nettle Eating Championship. The women's title is currently held by Jo Carter, of Weymouth, who ate the leaves from 34 feet of raw stinging nettles in the 2006 competition. The men's title is held by veteran competitor Simon Sleigh, who chomped the leaves from more than 74 feet of stinging nettles in an hour.
- "Grasp the Nettle" is an old term meaning to approach a diffcult or problematic situation without hesitation. | Nettle
Nettle is the common name for any of between 30-45 species of flowering plants of the genus Urtica in the family Urticaceae, with a cosmopolitan though mainly temperate distribution. They are mostly herbaceous perennial plants, but some are annual and a few are shrubby.
The most prominent member of the genus is the stinging nettle Urtica dioica, native to Europe, north Africa, Asia, and North America. The genus also contains a number of other species with similar properties, listed below. However, a large number of species names that will be encountered in this genus in the older literature (about 100 species have been described) are now recognised as synonyms of Urtica dioica. Some of these taxa are still recognised as subspecies.
Most of the species listed below share the property of having stinging hairs, and can be expected to have very similar medicinal uses to the stinging nettle. The stings of Urtica ferox, the ongaonga or tree nettle of New Zealand, have been known to kill horses, dogs and at least one human.[1]
The nature of the toxin secreted by nettles is not settled. The stinging hairs of most nettle species contain formic acid, serotonin and histamine; however recent studies of Urtica thunbergiana (Fu et al, 2006) implicate oxalic acid and tartaric acid rather than any of those substances, at least in that species.
# Species of nettle
Species in the genus Urtica, and their primary natural ranges, include:
- Urtica angustifolia Fisch. ex Hornem. 1819. China, Japan, Korea.
- Urtica ardens. China.
- Urtica atrichocaulis. Himalaya, southwestern China.
- Urtica atrovirens. Western Mediterranean region.
- Urtica cannabina L. 1753. Western Asia from Siberia to Iran.
- Urtica chamaedryoides (heartleaf nettle). Southeastern North America.
- Urtica dioica L. 1753 (stinging nettle or bull nettle). Europe, Asia, North America.
- Urtica dubia (large-leaved nettle). Canada.
- Urtica ferox (ongaonga or tree nettle). New Zealand.
- Urtica fissa. China.
- Urtica galeopsifolia Wierzb. ex Opiz, 1825. Central and eastern Europe.
- Urtica gracilenta (mountain nettle). Arizona, New Mexico, west Texas, northern Mexico.
- Urtica hyperborea. Himalaya from Pakistan to Bhutan, Mongolia and Tibet, high altitudes.
- Urtica incisa (scrub nettle). Australia.
- Urtica kioviensis Rogow. 1843. Eastern Europe.
- Urtica laetivirens Maxim. 1877. Japan, Manchuria.
- Urtica mairei. Himalaya, southwestern China, northeastern India, Myanmar.
- Urtica membranacea. Mediterranean region, Azores.
- Urtica morifolia. Canary Islands (endemic).
- Urtica parviflora. Himalaya (lower altitudes).
- Urtica pilulifera (Roman nettle). Southern Europe.
- Urtica platyphylla Wedd. 1856-1857. China, Japan.
- Urtica pubescens Ledeb. 1833. Southwestern Russia east to central Asia.
- Urtica rupestris. Sicily (endemic).
- Urtica sondenii (Simmons) Avrorin ex Geltman, 1988. Northeastern Europe, northern Asia.
- Urtica taiwaniana. Taiwan.
- Urtica thunbergiana. Japan, Taiwan.
- Urtica triangularis
- Urtica urens L. 1753 (dwarf nettle or annual nettle). Europe, North America.
The family Urticaceae also contains some other plants called nettles that are not members of the genus Urtica. These include the wood nettle Laportea canadensis, found in eastern North America from Nova Scotia to Florida, and the false nettle Boehmeria cylindrica, found in most of the United States east of the Rockies. As its name implies, the false nettle does not sting.
There are many unrelated organisms called nettle, such as:
- Dead-nettle (Lamium spp.) and hedge-nettle (Stachys spp.) which are in the Lamiaceae or mint family.
- Devil's nettle, which is another name for yarrow.
- Carolina horsenettle (Solanum carolinense) in the Solanaceae.
- Spurge-nettle (Cnidolscolus stimulosus) in the Euphorbiaceae.
- Sea nettle (Chtysaora quinquecirrha) which is a jellyfish.
Nettles are the exclusive larval food plant for several species of butterfly, such as the Peacock Butterfly[2] or the Small Tortoiseshell, and are also eaten by the larvae of some moths including Angle Shades, Buff Ermine, Dot Moth, The Flame, The Gothic, Grey Chi, Grey Pug, Lesser Broad-bordered Yellow Underwing, Mouse Moth, Setaceous Hebrew Character and Small Angle Shades. The roots are sometimes eaten by the larva of the Ghost Moth Hepialus humuli.
# Uses
## Culinary
The tops of growing nettles are a popular cooked green in many areas. Some cooks throw away a first water to get rid of the stinging compounds, while others retain the water and cook the nettles straight. Nettle tops are sold in some farmers' markets and natural food stores.
## Tea
The fresh or dried leaves of nettle can be used to make a tea and commercial tea bags are commonly sold in natural food stores.
## Medical
Nettle is believed to be a galactagogue[3] and a clinical trial has shown that the juice is diuretic in patients with congestive heart failure.
Urtication, or flogging with nettles, is the process of deliberately applying stinging nettles to the skin in order to provoke inflammation. An agent thus used is known as a rubefacient (i.e. something that causes redness). This is done as a folk remedy for rheumatism, as it provides temporary relief from pain. They may also be used as a suppository, although this can be very painful and will not stop much skin irritation.
Extracts can be used to treat arthritis, anemia, hay fever, kidney problems, and pain. Nettle is used in hair shampoos to control dandruff, and is said to make hair more glossy, which is why some farmers include a handful of nettles with cattle feed.[4]
Nettle root extracts have been extensively studied in human clinical trials as a treatment for symptoms of benign prostatic hyperplasia (BPH). These extracts have been shown to help relieve symptoms compared to placebo both by themselves and when combined with other herbal medicines.[5]
Because it contains 3,4-divanillyltetrahydrofuran, certain extracts of the nettle are used by bodybuilders in an effort to increase free testosterone by occupying sex-hormone binding globulin.[citation needed]
Fresh nettle, specifically Urtica Dioica, is used in folk remedies to stop all types of bleeding, due to its high Vitamin K content. Meanwhile, in dry Urtica Dioica, the Vitamin K is practically non-existent, and so is used as a blood thinner.
## Paper
Nettle stems are a popular raw material used in small-scale papermaking.
## Textiles
Nettle fibre has been used in textiles. This is more experimental than mass-market. Unlike cotton, nettles grow easily without pesticides. The fibres are coarser however. [6]
As well being the fibre, Nettles were also used as a dye-stuff in the medieval period.[citation needed]
# Safety
Template:Contradict-other
Though the fresh leaves can cause painful stings and acute urticaria, these are rarely seriously harmful (but see remarks in the introductory section re the U. ferox, ongaonga or tree nettle of New Zealand). Otherwise most species of nettles are extremely safe and some are even eaten as vegetables after being steamed to remove the stingers.
Nettles can be picked painlessly by wearing a standard pair of washing-up gloves. Another common recommendation is to firmly grasp the nettle with the bare hand, crushing the stingers instead of allowing them to penetrate the skin. Done properly, this is effective in practice, however due to a natural hesitancy when grabbing a nettle, first time practitioners close their hand too gently and slowly and so get stung. A traditional verse goes "Tenderly you stroke a Nettle, and it stings you for your pains. Grasp it like a man of mettle, and it soft as silk remains."
The traditional remedy for nettle stings is rubbing with the crushed leaf of the dock plant, Rumex obtusifolius, which often grows beside nettles in the wild and has a milky substance which can cause dermatitis. Plantain is another traditional remedy. The alkalinity of the sap may counteract the nettle's acids. Nettle itself will release alkaline sap when macerated[7] While there is no scientific proof that this remedy works, searching for and using a dock leaf at least takes the mind off the stinging pain somewhat. Though unproven, some claim that dabbing mud on the affected area, allowing it to dry, and rubbing it off can remove the stingers. Another disputed claim is that the spores of certain ferns can lessen the pain by rubbing the underside of fern leaves, where the spores are located in rows of round, orange lumps, on the affected area.
The nettle stingers can be removed from the skin quickly and effectively by wiping your skin with a chamois (same as used for drying cars). The inside of a leather glove works similarly. The nettle hairs stick to these textures more readily than your skin and a simple single wiping removes them from your skin.[citation needed]
# Popular culture
- The Bottle Inn, a pub in Marshwood, Dorset, England, holds an annual World Stinging Nettle Eating Championship. The women's title is currently held by Jo Carter, of Weymouth, who ate the leaves from 34 feet of raw stinging nettles in the 2006 competition. The men's title is held by veteran competitor Simon Sleigh, who chomped the leaves from more than 74 feet of stinging nettles in an hour.
- "Grasp the Nettle" is an old term meaning to approach a diffcult or problematic situation without hesitation. | https://www.wikidoc.org/index.php/Nettle | |
82fc263a36ce088b1bca5457c0e1293cab3cc5b9 | wikidoc | Newton | Newton
The newton (symbol: N) is the SI derived unit of force, named after Sir Isaac Newton in recognition of his work on classical mechanics.
# Definition
The newton is the unit of force derived in the SI system; it is equal to the amount of force required to give a mass of one kilogram an acceleration of one meter per second squared . Algebraically:
# Examples
- 1 N is the force of earth's gravity on an object with a mass of about 102 g (1⁄9.8 kg) (such as a small apple).
- On Earth's surface, a mass of 1 kg exerts a force of approximately 9.81 N (or 1 kgf). The approximation of 1 kg corresponding to 10 N is sometimes used as a rule of thumb in everyday life and in engineering.
- The decanewton (daN) = 10 N is increasingly used when specifying load bearing capacity of items such as ropes and anti-vibration mounts, being approximately equivalent to the more familiar non-SI unit of force, the kgf.
- The force of Earth's gravity on a human being with a mass of 70 kg is approximately 687 N.
- The scalar product of force and distance is energy. Thus, in SI units, a force of 1 N exerted over a distance of 1 m is 1 N·m = 1 joule, the SI unit of energy.
- Because a newton is a small force, it is common to see forces expressed in kilonewtons or kN, where 1 kN = 1 000 N.
- A metric tonne (1 000 kg) exerts a force of 9.8 kN (or 1 000 kgf) under standard gravity conditions on Earth.
# Notes | Newton
The newton (symbol: N) is the SI derived unit of force, named after Sir Isaac Newton in recognition of his work on classical mechanics.
# Definition
The newton is the unit of force derived in the SI system; it is equal to the amount of force required to give a mass of one kilogram an acceleration of one meter per second squared . Algebraically:
-
-
-
-
# Examples
- 1 N is the force of earth's gravity on an object with a mass of about 102 g (1⁄9.8 kg) (such as a small apple).
- On Earth's surface, a mass of 1 kg exerts a force of approximately 9.81 N [down] (or 1 kgf). The approximation of 1 kg corresponding to 10 N is sometimes used as a rule of thumb in everyday life and in engineering.
- The decanewton (daN) = 10 N is increasingly used when specifying load bearing capacity of items such as ropes and anti-vibration mounts, being approximately equivalent to the more familiar non-SI unit of force, the kgf.
- The force of Earth's gravity on a human being with a mass of 70 kg is approximately 687 N.
- The scalar product of force and distance is energy. Thus, in SI units, a force of 1 N exerted over a distance of 1 m is 1 N·m = 1 joule, the SI unit of energy.
- Because a newton is a small force, it is common to see forces expressed in kilonewtons or kN, where 1 kN = 1 000 N.
- A metric tonne (1 000 kg) exerts a force of 9.8 kN (or 1 000 kgf) under standard gravity conditions on Earth.
# Notes
Template:Units of force
Template:GravEngAbs | https://www.wikidoc.org/index.php/Newton | |
c775e12f767bc6c59084836790b0213799b4c358 | wikidoc | Nibrin | Nibrin
Nibrin, also known as NBN or NBS1, is a protein which in humans is encoded by the NBN gene.
# Function
Nibrin is a protein associated with the repair of double strand breaks (DSBs) which pose serious damage to a genome. It is a 754 amino acid protein identified as a member of the NBS1/hMre11/RAD50(N/M/R, more commonly referred to as MRN) double strand DNA break repair complex. This complex recognizes DNA damage and rapidly relocates to DSB sites and forms nuclear foci. It also has a role in regulation of N/M/R (MRN) protein complex activity which includes end-processing of both physiological and mutagenic DNA double strand breaks (DSBs).
# Cellular response to DSBs
Cellular response is performed by damage sensors, effectors of lesion repair and signal transduction. The central role is carried out by ataxia telangiectasia mutated (ATM) by activating the DSB signaling cascade, phosphorylating downstream substrates such as histone H2AX and NBS1. NBS1 relocates to DSB sites by interaction of FHA/BRCT domains with phosphorylated histone H2AX. Once it interacts with nibrin c-terminal hMre11-binding domain, hMre11 and hRad50 relocate from the cytoplasm to the nucleus then to sites of DSBs. They finally relocate to N/M/R where they form the foci at the site of damage.
# Double strand breaks (DSBs)
DSBs occur during V(D)J recombination during early B and T cell development. This is at the point when the cells of the immune system are developing and the DSBs affect the development of lymphoid cells. DSBs also occur in immunoglobulin class switch in mature B cells. More frequently, however, DSBs are caused by mutagenic agents like radiomimetic chemicals and ionizing radiation(IR).
# DSB mutations
As mentioned, DSBs cause extreme damage to DNA. Mutations that cause defective repair of DSBs tend to accumulate un-repaired DSBs. One such mutation is associated with Nijmegen breakage syndrome (NBS), a radiation hyper-sensitive disease. It is a rare inherited autosomal recessive condition of chrosomal instability. It has been linked to mutations within exons 6-10 in the NBS1 gene which results in a truncated protein. Characteristics of NBS include microcephaly, cranial characteristics, growth retardation, impaired sexual maturation, immunodeficiency/recurring infections and a predisposition to cancer. This predisposition to cancer may be linked to the DSBs occurring at the development of lymphoid cells.
# Fertility
Two adult siblings, both heterozygous for two particular NBS1 nonsense mutations displayed cellular sensitivity to radiation, chromosome instability and fertility defects, but not the developmental defects that are typically found in other NBS patients. These individuals appear to be primarily defective in homologous recombination, a process that accurately repairs double-strand breaks, both in somatic cells and during meiosis.
Orthologs of NBS1 have been studied in mice and the plant arabidopsis. NBS1 mutant mice display cellular radiation sensitivity and female mice are sterile due to oogenesis failure. Studies of NBS1 mutants in Arabidopsis revealed that NBS1 has a role in recombination during early stages of meiosis.
# NBS1 over-expression in cancer
NBS1 has a role in microhomology-mediated end joining (MMEJ) repair of double strand breaks. It is one of 6 enzymes required for this error prone DNA repair pathway. NBS1 is often over-expressed in prostate cancer, in liver cancer, in esophageal squamous cell carcinoma,
in non-small cell lung carcinoma, hepatoma, and esophageal cancer, in head and neck cancer, and in squamous cell carcinoma of the oral cavity.
Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes). (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers. (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, NBS1 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.
# Herpes virus
HSV-1 infects more than 90% of adults over the age of 50. Alphaherpesviruses alone can cause the host to have mild symptoms, but these viruses can be associated with severe disease when they are transferred to a new species. Humans can even pass and also get an HSV-1 infection from other primate species. However, because of evolutionary differences between primate species, only some species can pass HSV-1 in an interspecies interaction. Also, though HSV-1 transmission from humans to other species primates can occur, there is no known sustained transmission chains that have resulted from constant transmission. A study found that Nbs1 is the most diverged in DNA sequence in the MRN complex between different primate species and that there is a high degree of species specificity, causing variability in promotion of the HSV-1 life cycle. The same study found that Nbs1 interacts with HSV-1's ICP0 proteins in an area of structural disorder of the nibrin. This suggests that in general, viruses commonly interact in intrinsically disordered domains in host proteins. It is possible that there are differences in the mammalian genomes that create unique environments for the viruses. Host proteins that are specific to the species might determine how the viruses must adapt to be able to ignite an infection in a new species. The evolution of increased disorder in nibrin benefits the host in decreasing ICP0 interaction and virus hijack. Nbs1 may not be the only host protein that evolves this way.
HSV-1-infection has been shown to result from the phosphorylation of Nbs1. It has been shown in studies that activation of the MRN complex and ATM biochemical cascade is consistent for a resulting HSV-1 infection. When there is an HSV-1 infection, the nucleus is reorganized causing the formation of RCs (replication compartments) where gene expression and DNA replication occurs. Proteins in the host used for DNA repair and damage response are needed for virus production. ICP8, which is a viral single-strand binding protein, is known to interact with several DNA repair proteins, such as Rad50, Mre11, BRG1, and DNA-PKcs. Ul12 and ICP8 viral proteins function together as a recombinase, possibly showing that while working with the host's recombination factors, work to form a concatemer by stimulating homologous recombination. These proteins may move the MRN complex towards the viral genome so it is able to promote homologous recombination, and to prevent non-homologous recombination as non-homologous recombination can have anti-viral effects. This possibly shows that the reaction between UL12 and MRN regulates the complex in a way that benefits the herpes virus.
# Interactions
Nibrin has been shown to interact with:
- Ataxia telangiectasia mutated,
- BRCA1,
- H2AFX,
- MRE11A,
- Rad50, and
- TERF2 | Nibrin
Nibrin, also known as NBN or NBS1, is a protein which in humans is encoded by the NBN gene.[1][2][3]
# Function
Nibrin is a protein associated with the repair of double strand breaks (DSBs) which pose serious damage to a genome. It is a 754 amino acid protein identified as a member of the NBS1/hMre11/RAD50(N/M/R, more commonly referred to as MRN) double strand DNA break repair complex.[4] This complex recognizes DNA damage and rapidly relocates to DSB sites and forms nuclear foci. It also has a role in regulation of N/M/R (MRN) protein complex activity which includes end-processing of both physiological and mutagenic DNA double strand breaks (DSBs).[5]
# Cellular response to DSBs
Cellular response is performed by damage sensors, effectors of lesion repair and signal transduction. The central role is carried out by ataxia telangiectasia mutated (ATM) by activating the DSB signaling cascade, phosphorylating downstream substrates such as histone H2AX and NBS1. NBS1 relocates to DSB sites by interaction of FHA/BRCT domains with phosphorylated histone H2AX. Once it interacts with nibrin c-terminal hMre11-binding domain, hMre11 and hRad50 relocate from the cytoplasm to the nucleus then to sites of DSBs. They finally relocate to N/M/R where they form the foci at the site of damage.[6]
# Double strand breaks (DSBs)
DSBs occur during V(D)J recombination during early B and T cell development. This is at the point when the cells of the immune system are developing and the DSBs affect the development of lymphoid cells. DSBs also occur in immunoglobulin class switch in mature B cells.[5] More frequently, however, DSBs are caused by mutagenic agents like radiomimetic chemicals and ionizing radiation(IR).
# DSB mutations
As mentioned, DSBs cause extreme damage to DNA. Mutations that cause defective repair of DSBs tend to accumulate un-repaired DSBs. One such mutation is associated with Nijmegen breakage syndrome (NBS), a radiation hyper-sensitive disease.[7] It is a rare inherited autosomal recessive condition of chrosomal instability. It has been linked to mutations within exons 6-10 in the NBS1 gene which results in a truncated protein.[5] Characteristics of NBS include microcephaly, cranial characteristics, growth retardation, impaired sexual maturation, immunodeficiency/recurring infections and a predisposition to cancer. This predisposition to cancer may be linked to the DSBs occurring at the development of lymphoid cells.
# Fertility
Two adult siblings, both heterozygous for two particular NBS1 nonsense mutations displayed cellular sensitivity to radiation, chromosome instability and fertility defects, but not the developmental defects that are typically found in other NBS patients.[8] These individuals appear to be primarily defective in homologous recombination, a process that accurately repairs double-strand breaks, both in somatic cells and during meiosis.
Orthologs of NBS1 have been studied in mice[9] and the plant arabidopsis.[10] NBS1 mutant mice display cellular radiation sensitivity and female mice are sterile due to oogenesis failure.[9] Studies of NBS1 mutants in Arabidopsis revealed that NBS1 has a role in recombination during early stages of meiosis.[10]
# NBS1 over-expression in cancer
NBS1 has a role in microhomology-mediated end joining (MMEJ) repair of double strand breaks. It is one of 6 enzymes required for this error prone DNA repair pathway.[11] NBS1 is often over-expressed in prostate cancer,[12] in liver cancer,[13] in esophageal squamous cell carcinoma,[14]
in non-small cell lung carcinoma, hepatoma, and esophageal cancer,[15] in head and neck cancer,[16] and in squamous cell carcinoma of the oral cavity.[17]
Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes).[18] (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers.[18] (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, NBS1 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.
# Herpes virus
HSV-1 infects more than 90% of adults over the age of 50. Alphaherpesviruses alone can cause the host to have mild symptoms, but these viruses can be associated with severe disease when they are transferred to a new species. Humans can even pass and also get an HSV-1 infection from other primate species. However, because of evolutionary differences between primate species, only some species can pass HSV-1 in an interspecies interaction. Also, though HSV-1 transmission from humans to other species primates can occur, there is no known sustained transmission chains that have resulted from constant transmission. A study found that Nbs1 is the most diverged in DNA sequence in the MRN complex between different primate species and that there is a high degree of species specificity, causing variability in promotion of the HSV-1 life cycle. The same study found that Nbs1 interacts with HSV-1's ICP0 proteins in an area of structural disorder of the nibrin. This suggests that in general, viruses commonly interact in intrinsically disordered domains in host proteins. It is possible that there are differences in the mammalian genomes that create unique environments for the viruses. Host proteins that are specific to the species might determine how the viruses must adapt to be able to ignite an infection in a new species. The evolution of increased disorder in nibrin benefits the host in decreasing ICP0 interaction and virus hijack. Nbs1 may not be the only host protein that evolves this way.[19]
HSV-1-infection has been shown to result from the phosphorylation of Nbs1. It has been shown in studies that activation of the MRN complex and ATM biochemical cascade is consistent for a resulting HSV-1 infection. When there is an HSV-1 infection, the nucleus is reorganized causing the formation of RCs (replication compartments) where gene expression and DNA replication occurs. Proteins in the host used for DNA repair and damage response are needed for virus production. ICP8, which is a viral single-strand binding protein, is known to interact with several DNA repair proteins, such as Rad50, Mre11, BRG1, and DNA-PKcs. Ul12 and ICP8 viral proteins function together as a recombinase, possibly showing that while working with the host's recombination factors, work to form a concatemer by stimulating homologous recombination. These proteins may move the MRN complex towards the viral genome so it is able to promote homologous recombination, and to prevent non-homologous recombination as non-homologous recombination can have anti-viral effects. This possibly shows that the reaction between UL12 and MRN regulates the complex in a way that benefits the herpes virus.[20]
# Interactions
Nibrin has been shown to interact with:
- Ataxia telangiectasia mutated,[21][22]
- BRCA1,[21][23][24]
- H2AFX,[25]
- MRE11A,[21][26][27][28][29]
- Rad50,[21][26][27][29] and
- TERF2[30] | https://www.wikidoc.org/index.php/Nibrin | |
ca21a8615a52a59d06a71e974d498ab03843c200 | wikidoc | Nickel | Nickel
Nickel (IPA: Template:IPA) is a metallic chemical element in the periodic table that has the symbol Ni and atomic number 28.
# Characteristics
Nickel is a silvery white metal that takes on a high polish. It belongs to the transition metals, and is hard and ductile. It occurs most usually in combination with sulfur and iron in pentlandite, with sulfur in millerite, with arsenic in the mineral nickeline, and with arsenic and sulfur in nickel glance.
It is clear that in common with massive forms of chromium, aluminium and titanium metal that nickel is very slow to react with air, but it is a very reactive element.
Because of its permanence in air and its inertness to oxidation, it is used in coins, for plating iron, brass, etc., for chemical apparatus, and in certain alloys, such as German silver. It is magnetic, and is very frequently accompanied by cobalt, both being found in meteoric iron. It is chiefly valuable for the alloys it forms, especially many superalloys, and particularly stainless steel.
Nickel is one of the five ferromagnetic elements. However, the U.S. "nickel" coin is not magnetic, because it actually is mostly (75%) copper. The Canadian nickel minted at various periods between 1922-81 was 99.9% nickel, and these are magnetic.
The most common oxidation state of nickel is +2, though 0, +1, +3 and +4 Ni complexes are observed. It is also thought that a +6 oxidation state may exist, however, results are inconclusive.
The unit cell of nickel is a face centred cube with a lattice parameter of 0.356 nm giving a radius of the atom of 0.126 nm.
Nickel-62 is the most stable nuclide of all the existing elements; it is more stable even than Iron-56.
# History
The use of nickel is ancient, and can be traced back as far as 3500 BC. Bronzes from what is now Syria had a nickel content of up to 2%. Further, there are Chinese manuscripts suggesting that "white copper" (i.e. baitung) was used in the Orient between 1700 and 1400 BC. However, because the ores of nickel were easily mistaken for ores of silver, any understanding of this metal and its use dates to more contemporary times.
Minerals containing nickel (e.g. kupfernickel, meaning copper of the devil ("Nick"), or false copper) were of value for colouring glass green. In 1751, Baron Axel Fredrik Cronstedt was attempting to extract copper from kupfernickel (now called niccolite), and obtained instead a white metal that he called nickel.
In the United States, the term "nickel" or "nick" was originally applied to the copper-nickel Indian cent coin introduced in 1859. Later, the name designated the three-cent coin introduced in 1865, and the following year the five-cent shield nickel appropriated the designation, which has remained ever since. Coins of pure nickel were first used in 1881 in Switzerland.
# Biological role
Although not recognized until the 1970s, nickel plays numerous roles in biology. In fact urease (an enzyme which assists in the hydrolysis of urea) contains nickel. The NiFe-hydrogenases contain nickel in addition to iron-sulfur clusters. Such -hydrogenases characteristically oxidise H2. A nickel-tetrapyrrole coenzyme, F430, is present in the methyl coenzyme M reductase which powers methanogenic archaea.
One of the carbon monoxide dehydrogenase enzymes consists of an Fe-Ni-S cluster.
Other nickel-containing enzymes include a class of superoxide dismutase and a glyoxalase.
# Occurrence
The bulk of the nickel mined comes from two types of ore deposits. The first are laterites where the principal ore minerals are nickeliferous limonite: (Fe, Ni)O(OH) and garnierite (a hydrous nickel silicate): (Ni, Mg)3Si2O5(OH). The second are magmatic sulfide deposits where the principal ore mineral is pentlandite: (Ni, Fe)9S8.
- see Ore genesis, Category:Nickel minerals
In terms of supply, the Sudbury region of Ontario, Canada, produces about 30 percent of the world's supply of nickel. The Sudbury Basin deposit is theorized to have been created by a massive meteorite impact event early in the geologic history of Earth. Russia contains about 40% of the world's known resources at the massive Norilsk deposit in Siberia. The Russian mining company MMC Norilsk Nickel mines this for the world market, as well as the associated palladium. Other major deposits of nickel are found in New Caledonia, Australia, Cuba, and Indonesia. The deposits in tropical areas are typically laterites which are produced by the intense weathering of ultramafic igneous rocks and the resulting secondary concentration of nickel bearing oxide and silicate minerals. A recent development has been the exploitation of a deposit in western Turkey, especially convenient for European smelters, steelmakers and factories. The one locality in the United States where nickel is commercially mined is Riddle, Oregon, where several square miles of nickel-bearing garnierite surface deposits are located.
Based on geophysical evidence, most of the nickel on Earth is postulated to be concentrated in the Earth's core.
# Applications
Nickel is used in many industrial and consumer products, including stainless steel, magnets, coinage, and special alloys. It is also used for plating and as a green tint in glass. Nickel is pre-eminently an alloy metal, and its chief use is in the nickel steels and nickel cast irons, of which there are innumberable varieties. It is also widely used for many other alloys, such as nickel brasses and bronzes, and alloys with copper, chromium, aluminum, lead, cobalt, silver, and gold.
Nickel consumption can be summarized as: nickel steels (60%), nickel-copper alloys and nickel silver (14%), malleable nickel, nickel clad and Inconel (9%), plating (6%), nickel cast irons (3%), heat and electric resistance alloys (3%), nickel brasses and bronzes (2%), others (3%).
In the laboratory, nickel is frequently used as a catalyst for hydrogenation, most often using Raney nickel, a finely divided form of the metal.
# Extraction and purification
Nickel can be recovered using extractive metallurgy. Most sulfide ores have traditionally been processed using pyrometallurgical techniques to produce a matte for further refining. Recent advances in hydrometallurgy have resulted in recent nickel processing operations being developed using these processes. Most sulphide deposits have traditionally been processed by concentration through a froth flotation process followed by pyrometallurgical extraction. Recent advances in hydrometallurgical processing of sulphides has led to some recent projects being built around this technology.
Nickel is extracted from its ores by conventional roasting and reduction processes which yield a metal of >75% purity. Final purification in the Mond process to >99.99% purity This process was patented by L. Mond and was used in South Wales in the 20th century. Nickel is reacted with carbon monoxide at around 50 degrees Celsius to form volatile nickel carbonyl. Any impurities remain solid. The nickel carbonyl gas is passed into a large chamber at high temperatures which tens of thousands of nickel spheres are maintained in constant motion. The nickel carbonyl decomposes depositing pure nickel onto the nickel spheres (known as pellets). Alternatively, the nickel carbonyl may be decomposed in a smaller chamber at 230 degrees Celsius to create fine powders. The resultant carbon monoxide is re-circulated through the process. The highly pure nickel produced by this process is known as carbonyl nickel. A second common form of refining involves the leaching of the metal matte followed by the electro-winning of the nickel from solution by plating it onto a cathode. In many stainless steel applications, the nickel can be taken directly in the 75% purity form, depending on the presence of any impurities.
In 2005, Russia was the largest producer of nickel with about one-fifth world share closely followed by Canada, Australia and Indonesia, reports the British Geological Survey.
# Compounds
- Kamacite is a naturally occurring alloy of iron and nickel, usually in the proportion of 90:10 to 95:5 although impurities such as cobalt or carbon may be present. Kamacite occurs in nickel-iron meteorites.
See also nickel compounds.
# Isotopes
Naturally occurring nickel is composed of 5 stable isotopes; 58Ni, 60Ni, 61Ni, 62Ni and 64Ni with 58Ni being the most abundant (68.077% natural abundance). 18 radioisotopes have been characterised with the most stable being 59Ni with a half-life of 76,000 years, 63Ni with a half-life of 100.1 years, and 56Ni with a half-life of 6.077 days. All of the remaining radioactive isotopes have half-lives that are less than 60 hours and the majority of these have half-lives that are less than 30 seconds. This element also has 1 meta state.
Nickel-56 is produced in large quantities in type Ia supernovae and the shape of the light curve of these supernovae corresponds to the decay via beta radiation of nickel-56 to cobalt-56 and then to iron-56.
Nickel-59 is a long-lived cosmogenic radionuclide with a half-life of 76,000 years. 59Ni has found many applications in isotope geology. 59Ni has been used to date the terrestrial age of meteorites and to determine abundances of extraterrestrial dust in ice and sediment.
Nickel-60 is the daughter product of the extinct radionuclide 60Fe (half-life = 1.5 Myr). Because the extinct radionuclide 60Fe had such a long half-life, its persistence in materials in the solar system at high enough concentrations may have generated observable variations in the isotopic composition of 60Ni. Therefore, the abundance of 60Ni present in extraterrestrial material may provide insight into the origin of the solar system and its early history.
Nickel-62 has the highest binding energy per nucleon of any isotope for any element. Isotopes heavier than 62Ni cannot be formed by nuclear fusion without losing energy.
Nickel-48, discovered in 1999, is the most proton-rich nickel isotope known . With 28 protons and 20 neutrons 48Ni is "doubly magic" (like 208Pb) and therefore unusually stable
The isotopes of nickel range in atomic weight from 48 u (48-Ni) to 78 u (78-Ni). Nickel-78's half-life was recently measured to be 110 milliseconds and is believed to be an important isotope involved in supernova nucleosynthesis of elements heavier than iron.
# Precautions
Exposure to nickel metal and soluble compounds should not exceed 0.05 mg/cm³ in nickel equivalents per 40-hour work week. Nickel sulfide fume and dust is believed to be carcinogenic, and various other nickel compounds may be as well.
Nickel carbonyl, , is an extremely toxic gas. The toxicity of metal carbonyls is a function of both the toxicity of a metal as well as the carbonyl's ability to give off highly toxic carbon monoxide gas, and this one is no exception. It is explosive in air.
Sensitised individuals may show an allergy to nickel affecting their skin. The amount of nickel which is allowed in products which come into contact with human skin is regulated by the European Union. In 2002 researchers found amounts of nickel being emitted by 1 and 2 Euro coins far in excess of those standards. This is believed to be due to a galvanic reaction.
# Metal Value
As of April 5, 2007 nickel was trading at 52,300 $US/mt (52.30 $US/kg, 23.51 $US/lb or 1.47 $US/oz), . Interestingly, the US nickel coin contains 0.04 oz (1.25 g) of nickel, which at this new price is worth 6.5 cents, along with 3.75 grams of copper worth about 3 cents, making the metal value over 9 cents. Since a nickel is worth 5 cents, this made it an attractive target for melting by people wanting to sell the metals at a profit. However, the United States Mint, in anticipation of this practice, implemented new interim rules on December 14, 2006, subject to public comment for 30 days, which criminalize the melting and export of cents and nickels. Violators can be punished with a fine of up to US$10,000 and/or imprisoned for a maximum of five years. | Nickel
Template:Infobox nickel
Nickel (IPA: Template:IPA) is a metallic chemical element in the periodic table that has the symbol Ni and atomic number 28.
# Characteristics
Nickel is a silvery white metal that takes on a high polish. It belongs to the transition metals, and is hard and ductile. It occurs most usually in combination with sulfur and iron in pentlandite, with sulfur in millerite, with arsenic in the mineral nickeline, and with arsenic and sulfur in nickel glance.[1][2][3]
It is clear that in common with massive forms of chromium, aluminium and titanium metal that nickel is very slow to react with air, but it is a very reactive element.
Because of its permanence in air and its inertness to oxidation, it is used in coins, for plating iron, brass, etc., for chemical apparatus, and in certain alloys, such as German silver. It is magnetic, and is very frequently accompanied by cobalt, both being found in meteoric iron. It is chiefly valuable for the alloys it forms, especially many superalloys, and particularly stainless steel.
Nickel is one of the five ferromagnetic elements. However, the U.S. "nickel" coin is not magnetic, because it actually is mostly (75%) copper. The Canadian nickel minted at various periods between 1922-81 was 99.9% nickel, and these are magnetic.
The most common oxidation state of nickel is +2, though 0, +1, +3 and +4 Ni complexes are observed. It is also thought that a +6 oxidation state may exist, however, results are inconclusive.
The unit cell of nickel is a face centred cube with a lattice parameter of 0.356 nm giving a radius of the atom of 0.126 nm.[citation needed]
Nickel-62 is the most stable nuclide of all the existing elements; it is more stable even than Iron-56.
# History
The use of nickel is ancient, and can be traced back as far as 3500 BC. Bronzes from what is now Syria had a nickel content of up to 2%. Further, there are Chinese manuscripts suggesting that "white copper" (i.e. baitung) was used in the Orient between 1700 and 1400 BC. However, because the ores of nickel were easily mistaken for ores of silver, any understanding of this metal and its use dates to more contemporary times.
Minerals containing nickel (e.g. kupfernickel, meaning copper of the devil ("Nick"), or false copper) were of value for colouring glass green. In 1751, Baron Axel Fredrik Cronstedt was attempting to extract copper from kupfernickel (now called niccolite), and obtained instead a white metal that he called nickel.
In the United States, the term "nickel" or "nick" was originally applied to the copper-nickel Indian cent coin introduced in 1859. Later, the name designated the three-cent coin introduced in 1865, and the following year the five-cent shield nickel appropriated the designation, which has remained ever since. Coins of pure nickel were first used in 1881 in Switzerland. [1]
# Biological role
Although not recognized until the 1970s, nickel plays numerous roles in biology. In fact urease (an enzyme which assists in the hydrolysis of urea) contains nickel. The NiFe-hydrogenases contain nickel in addition to iron-sulfur clusters. Such [NiFe]-hydrogenases characteristically oxidise H2. A nickel-tetrapyrrole coenzyme, F430, is present in the methyl coenzyme M reductase which powers methanogenic archaea.
One of the carbon monoxide dehydrogenase enzymes consists of an Fe-Ni-S cluster.[4]
Other nickel-containing enzymes include a class of superoxide dismutase[5] and a glyoxalase.[6]
# Occurrence
The bulk of the nickel mined comes from two types of ore deposits. The first are laterites where the principal ore minerals are nickeliferous limonite: (Fe, Ni)O(OH) and garnierite (a hydrous nickel silicate): (Ni, Mg)3Si2O5(OH). The second are magmatic sulfide deposits where the principal ore mineral is pentlandite: (Ni, Fe)9S8.
- see Ore genesis, Category:Nickel minerals
In terms of supply, the Sudbury region of Ontario, Canada, produces about 30 percent of the world's supply of nickel. The Sudbury Basin deposit is theorized to have been created by a massive meteorite impact event early in the geologic history of Earth. Russia contains about 40% of the world's known resources at the massive Norilsk deposit in Siberia. The Russian mining company MMC Norilsk Nickel mines this for the world market, as well as the associated palladium. Other major deposits of nickel are found in New Caledonia, Australia, Cuba, and Indonesia. The deposits in tropical areas are typically laterites which are produced by the intense weathering of ultramafic igneous rocks and the resulting secondary concentration of nickel bearing oxide and silicate minerals. A recent development has been the exploitation of a deposit in western Turkey, especially convenient for European smelters, steelmakers and factories. The one locality in the United States where nickel is commercially mined is Riddle, Oregon, where several square miles of nickel-bearing garnierite surface deposits are located.
Based on geophysical evidence, most of the nickel on Earth is postulated to be concentrated in the Earth's core.
# Applications
Nickel is used in many industrial and consumer products, including stainless steel, magnets, coinage, and special alloys. It is also used for plating and as a green tint in glass. Nickel is pre-eminently an alloy metal, and its chief use is in the nickel steels and nickel cast irons, of which there are innumberable varieties. It is also widely used for many other alloys, such as nickel brasses and bronzes, and alloys with copper, chromium, aluminum, lead, cobalt, silver, and gold.
Nickel consumption can be summarized as: nickel steels (60%), nickel-copper alloys and nickel silver (14%), malleable nickel, nickel clad and Inconel (9%), plating (6%), nickel cast irons (3%), heat and electric resistance alloys (3%), nickel brasses and bronzes (2%), others (3%).
In the laboratory, nickel is frequently used as a catalyst for hydrogenation, most often using Raney nickel, a finely divided form of the metal.
# Extraction and purification
Nickel can be recovered using extractive metallurgy. Most sulfide ores have traditionally been processed using pyrometallurgical techniques to produce a matte for further refining. Recent advances in hydrometallurgy have resulted in recent nickel processing operations being developed using these processes. Most sulphide deposits have traditionally been processed by concentration through a froth flotation process followed by pyrometallurgical extraction. Recent advances in hydrometallurgical processing of sulphides has led to some recent projects being built around this technology.
Nickel is extracted from its ores by conventional roasting and reduction processes which yield a metal of >75% purity. Final purification in the Mond process to >99.99% purity This process was patented by L. Mond and was used in South Wales in the 20th century. Nickel is reacted with carbon monoxide at around 50 degrees Celsius to form volatile nickel carbonyl. Any impurities remain solid. The nickel carbonyl gas is passed into a large chamber at high temperatures which tens of thousands of nickel spheres are maintained in constant motion. The nickel carbonyl decomposes depositing pure nickel onto the nickel spheres (known as pellets). Alternatively, the nickel carbonyl may be decomposed in a smaller chamber at 230 degrees Celsius to create fine powders. The resultant carbon monoxide is re-circulated through the process. The highly pure nickel produced by this process is known as carbonyl nickel. A second common form of refining involves the leaching of the metal matte followed by the electro-winning of the nickel from solution by plating it onto a cathode. In many stainless steel applications, the nickel can be taken directly in the 75% purity form, depending on the presence of any impurities.
In 2005, Russia was the largest producer of nickel with about one-fifth world share closely followed by Canada, Australia and Indonesia, reports the British Geological Survey.
# Compounds
- Kamacite is a naturally occurring alloy of iron and nickel, usually in the proportion of 90:10 to 95:5 although impurities such as cobalt or carbon may be present. Kamacite occurs in nickel-iron meteorites.
See also nickel compounds.
# Isotopes
Naturally occurring nickel is composed of 5 stable isotopes; 58Ni, 60Ni, 61Ni, 62Ni and 64Ni with 58Ni being the most abundant (68.077% natural abundance). 18 radioisotopes have been characterised with the most stable being 59Ni with a half-life of 76,000 years, 63Ni with a half-life of 100.1 years, and 56Ni with a half-life of 6.077 days. All of the remaining radioactive isotopes have half-lives that are less than 60 hours and the majority of these have half-lives that are less than 30 seconds. This element also has 1 meta state.
Nickel-56 is produced in large quantities in type Ia supernovae and the shape of the light curve of these supernovae corresponds to the decay via beta radiation of nickel-56 to cobalt-56 and then to iron-56.
Nickel-59 is a long-lived cosmogenic radionuclide with a half-life of 76,000 years. 59Ni has found many applications in isotope geology. 59Ni has been used to date the terrestrial age of meteorites and to determine abundances of extraterrestrial dust in ice and sediment.
Nickel-60 is the daughter product of the extinct radionuclide 60Fe (half-life = 1.5 Myr). Because the extinct radionuclide 60Fe had such a long half-life, its persistence in materials in the solar system at high enough concentrations may have generated observable variations in the isotopic composition of 60Ni. Therefore, the abundance of 60Ni present in extraterrestrial material may provide insight into the origin of the solar system and its early history.
Nickel-62 has the highest binding energy per nucleon of any isotope for any element. Isotopes heavier than 62Ni cannot be formed by nuclear fusion without losing energy.
Nickel-48, discovered in 1999, is the most proton-rich nickel isotope known . With 28 protons and 20 neutrons 48Ni is "doubly magic" (like 208Pb) and therefore unusually stable
[7].
The isotopes of nickel range in atomic weight from 48 u (48-Ni) to 78 u (78-Ni). Nickel-78's half-life was recently measured to be 110 milliseconds and is believed to be an important isotope involved in supernova nucleosynthesis of elements heavier than iron. [2]
# Precautions
Exposure to nickel metal and soluble compounds should not exceed 0.05 mg/cm³ in nickel equivalents per 40-hour work week. Nickel sulfide fume and dust is believed to be carcinogenic, and various other nickel compounds may be as well.[8][9]
Nickel carbonyl, [Ni(CO)4], is an extremely toxic gas. The toxicity of metal carbonyls is a function of both the toxicity of a metal as well as the carbonyl's ability to give off highly toxic carbon monoxide gas, and this one is no exception. It is explosive in air.[citation needed]
Sensitised individuals may show an allergy to nickel affecting their skin. The amount of nickel which is allowed in products which come into contact with human skin is regulated by the European Union. In 2002 researchers found amounts of nickel being emitted by 1 and 2 Euro coins far in excess of those standards. This is believed to be due to a galvanic reaction.[10]
# Metal Value
As of April 5, 2007 nickel was trading at 52,300 $US/mt (52.30 $US/kg, 23.51 $US/lb or 1.47 $US/oz), [3] [4]. Interestingly, the US nickel coin contains 0.04 oz (1.25 g) of nickel, which at this new price is worth 6.5 cents, along with 3.75 grams of copper worth about 3 cents, making the metal value over 9 cents. Since a nickel is worth 5 cents, this made it an attractive target for melting by people wanting to sell the metals at a profit. However, the United States Mint, in anticipation of this practice, implemented new interim rules on December 14, 2006, subject to public comment for 30 days, which criminalize the melting and export of cents and nickels.[5] Violators can be punished with a fine of up to US$10,000 and/or imprisoned for a maximum of five years. | https://www.wikidoc.org/index.php/Nickel | |
9cdd79c72f5904f4400d61f695a00eec8c0bd377 | wikidoc | Nitrox | Nitrox
Nitrox refers to any gas mixture composed (excluding trace gases) of nitrogen and oxygen; this includes normal air which is approximately 78% nitrogen, 21% oxygen, and 1% other gases, primarily argon. However, in SCUBA diving, nitrox is normally differentiated and handled differently from air. The most common use of nitrox mixtures containing higher than normal levels of oxygen is in SCUBA, where the reduced percentage of nitrogen is advantageous in reducing nitrogen take up in the body's tissues and so extending the possible dive time, and/or reducing the risk of decompression sickness (also known as the bends).
# Purpose
Enriched Air Nitrox, Nitrox with an oxygen content above 21%, is mainly used in scuba diving to reduce the proportion of nitrogen in the breathing gas mixture. Reducing the proportion of nitrogen by increasing the proportion of oxygen reduces the risk of decompression sickness, allowing extended dive times without increasing the need for decompression stops. Nitrox is not a safer gas than compressed air in all respects; although its use reduces the risk of decompression sickness, it increases the risk of oxygen toxicity and fire, which are further discussed below.
Breathing nitrox is not thought to reduce the effects of narcosis, as oxygen seems to have equally narcotic properties under pressure as nitrogen; thus one should not expect a reduction in narcotic effects due only to the use of nitrox. Nonetheless, there remains a body of the diving community that insists that they feel reduced narcotic effects at depths breathing nitrox.
This may be due to a dissociation of the subjective and behavioural effects of narcosis. However, it should be noted that because of risks associated with oxygen toxicity, divers tend not to utilize nitrox at greater depths where more pronounced narcosis symptoms are more likely to occur. For a reduction in narcotic effects trimix or heliox gases which also contain helium are generally used by divers.
There is anecdotal evidence that the use of nitrox reduces post-dive fatigue, particularly in older and or obese divers; however the only known double-blind study to test this found no statistically significant reduction in reported fatigue. There has, however, been some suggestion that post dive fatigue is due to sub-clinical decompression sickness (DCS) (i.e. micro bubbles in the blood insufficient to cause symptoms of DCS); the fact that the study mentioned was conducted in a dry chamber with an ideal decompression profile may have been sufficient to reduce sub-clinical DCS and prevent fatigue in both nitrox and air divers.
Further studies with a number of different dive profiles, and also different levels of exertion, would be necessary to fully investigate this issue. For example, there is much better scientific evidence that breathing high-oxygen gases increase exercise tolerance, during aerobic exertion. Though even moderate exertion while breathing from the regulator is a relatively uncommon occurrence in scuba, as divers usually try to minimize it in order to conserve gas, episodes of exertion while regulator-breathing do occasionally occur in sport diving. Examples are surface-swimming a distance to a boat or beach after surfacing, where residual "safety" cylinder gas is often used freely, since the remainder will be wasted anyway when the dive is completed. It is possible that these so-far un-studied situations have contributed to some of the positive reputation of nitrox.
# Naming
Nitrox is known by many names: Enhanced Air Nitrox, Oxygen Enriched Air, Nitrox, EANx or Safe Air. The name "nitrox" may be capitalized when referring to specific mixtures such as Nitrox32, which contains 68% nitrogen and 32% oxygen. When one figure is stated, it refers to the oxygen percentage, not the nitrogen percentage. The original convention, Nitrox68/32 became shortened as the second figure is redundant.
Although "nitrox" usually refers to a mixture of nitrogen and oxygen with more than 21% oxygen, it can refer to mixtures that are leaner in oxygen than air. "Enriched Air Nitrox", "Enriched Air" or "EAN" are used to emphasise richer than air mixtures. In "EANx", the "x" indicates the percentage of oxygen in the mix and is replaced by a number when the percentage is known; for example a 40% EANx mix is called EAN40. The two most popular blends are EAN32 and EAN36 (also named Nitrox I and Nitrox II, respectively, or Nitrox68/32 and Nitrox64/36).
In its early days of introduction to non-technical divers, nitrox has occasionally also been known by detractors by less complimentary terms, such as "devil gas" or "voodoo gas" (a term now sometimes used with pride).
These percentages are what the gas blender aims for in partial-pressure blending, but the final actual mix in such cases will be unique, and so a small flow of gas from the cylinder must be measured with a handheld oxygen analyzer, before the diver breathes from the cylinder underwater.
# Richness of mix
The two most common recreational diving nitrox mixes contain 32% and 36% oxygen, which have maximum operating depths (MODs) of 34 metres (111.5485566 ft) and 29 metres (95.1443571 ft) respectively when limited to a maximum partial pressure of oxygen of 1.4 (Expression error: Missing operand for *. ). EAN32 is common because it is the mixture with the maximum concentration of oxygen that allows the diver to go to the full depth of recreational diving's "No Decompression Limit" for air. Divers may calculate an equivalent air depth to determine their decompression requirements or may use nitrox tables or a nitrox-capable dive computer.
Nitrox with more than 40% oxygen is uncommon within recreational diving. There are two main reasons for this: the first is that all pieces of diving equipment that come into contact with mixes containing higher proportions of oxygen, particularly at high pressure, need special cleaning and servicing to reduce the risk of fire. The second reason is that richer mixes extend the time the diver can stay underwater without needing decompression stops far further than the duration of typical diving cylinders. For example, based on the PADI nitrox recommendations, the maximum operating depth for EAN45 would be 21 metres (68.8976379 ft) and the maximum dive time available at this depth even with EAN36 is nearly 1 hour 15 minutes: a diver with a breathing rate of 20 litres per minute using twin 10 litre, 230 bar (about double 85 cu. ft.) cylinders would have completely emptied the cylinders after 1 hour 14 minutes at this depth.
Nitrox containing 50% to 100% oxygen is common in technical diving as a decompression gas, which eliminates inert gases such as nitrogen and helium from the tissues more quickly than leaner oxygen mixtures.
In deep open circuit technical diving, where hypoxic gases are breathed during the bottom portion of the dive, a Nitrox mix with 50% or less oxygen called a "travel mix" is sometimes breathed during the beginning of the descent in order to avoid hypoxia. Normally, however, the most oxygen-lean of the diver's decompression gases would be used for this purpose, since descent time spent reaching a depth where bottom mix is no longer hypoxic is normally small, and the distance between this depth and the MOD of any nitrox decompression gas is likely to be very short, if it occurs at all.
# Cylinder markings
Any cylinder containing any blend of gas other than the standard air content is required by most diving training organizations to be clearly marked. Some organizations, e.g. GUE, argue that it does not make sense to have a permanent marking on a gas tank that can be filled with any gas.
The standard nitrox cylinder is yellow in color and marked with a green band around the shoulder of the tank, with "Nitrox" or "Enriched air" marked in white or yellow letters inside.
Tanks of any other color are generally marked with six inch band around the shoulder, with a one inch yellow band on the top and bottom, with four inches of green in the middle. This green band will also have the designation of "NITROX" or something similar inside, in yellow or white letters.
Every nitrox cylinder should also have a sticker stating whether or not the cylinder is oxygen clean and suitable for partial pressure blending. Any oxygen clean cylinder may have any mix up to 100% oxygen inside. If by some accident an oxygen clean cylinder is filled at a station which does not supply gas to oxygen-clean standards it is then considered contaminated and must be re-cleaned before a gas containing more than 40% oxygen may again be added. Cylinders marked as not-oxygen clean may only be filled with enriched oxygen mixtures from membrane or stick blending systems where the gas is mixed before being added to the cylinder.
Finally, all nitrox cylinders should have a tag that, at minimum, states the oxygen content of the cylinder, the date it was blended, the gas blender's name, and the maximum operating depth along with the partial pressure this depth was calculated with. Other requirements may be made as to what is marked on the cylinder, but these markings are considered standard and safe by the diving community, and any cylinders lacking these markings should be considered possibly unsafe. Training for nitrox certification suggests this tag be verified by the diver himself by using an oxygen analyzer.
# Dangers
## Oxygen toxicity
Diving and handling nitrox raises a number of potentially fatal dangers due to the high partial pressure of oxygen (ppO2). Nitrox is not a deep-diving gas mixture owing to the increased proportion of oxygen, which becomes toxic when breathed at high pressure. For example, the maximum operating depth of nitrox with 36% oxygen, a popular recreational diving mix, is 29 metres (95.1443571 ft) to ensure a maximum ppO2 of no more than 1.4 (Expression error: Missing operand for *. ). The exact value of the maximum allowed ppO2 and maximum operating depth varies depending on factors such as the training agency, the type of dive, the breathing equipment and the level of surface support, with professional divers sometimes being allowed to breath higher ppO2 than those recommended to recreational divers.
To dive safely with nitrox, the diver must learn good buoyancy control, a vital part of scuba diving in its own right, and a disciplined approach to preparing, planning and executing a dive to ensure that the ppO2 is known, and the maximum operating depth is not exceeded. Reputable dive operators and gas blenders insist on the diver having recognised nitrox training (which appears as an extra notation on a certification card) before selling nitrox to divers.
Some training agencies teach the use of two depth limits to protect against oxygen toxicity. The shallower depth is called the "maximum operating depth" and is reached when the partial pressure of oxygen in the breathing gas reaches 1.4 (Expression error: Missing operand for *. ). The second deeper depth, called the "contingency depth", is reached when the partial pressure reaches 1.6 (Expression error: Missing operand for *. ). Diving at or beyond this level exposes the diver to the risk of central nervous system (CNS) oxygen toxicity. This can be extremely dangerous since its onset is often without warning and can lead to drowning, as the regulator may be spat out during convulsions which occur in conjunction with sudden unconsciousness (general seizure induced by oxygen toxicity).
Divers trained to use nitrox memorise the acronym VENTID (which stands for Vision (blurriness), Ears (ringing sound), Nausea, Twitching, Irritability and Dizziness), which indicate some of the possible warning signs of onsetting convulsions. However, evidence from non-fatal oxygen convulsions indicates that most convulsions are not preceded by any warning symptoms at all. Further, many of the suggested warning signs are also symptoms of nitrogen narcosis, and so may lead to misdiagnosis by a diver.
# Precautionary procedures at the fill station
Many training agencies such as PADI, CMAS, SSI and NAUI train their divers to personally check the oxygen percentage content of each nitrox cylinder before every dive. If the oxygen percentage deviates by more than 1% from the value written on the cylinder by the gas blender, the scuba diver must either recalculate his or her bottom times with the new mix, or else abort the dive to remain safe and avoid oxygen toxicity or decompression sickness. Under IANTD and ANDI rules for use of nitrox, which are followed by most dive resorts around the world, filled nitrox cylinders are signed out personally in a gas blender log book, which contains, for each cylinder and fill, the cylinder number, the measured oxygen percent composition, the signature of the receiving diver (who should have personally measured the oxygen percent with an instrument at the fill-shop), and finally a calculation of the maximum operating depth for that fill/cylinder. All of these steps minimize danger but increase complexity of operations (for example, personalized cylinders for each diver must generally be kept track of on dive boats with nitrox, which is not the case with generic compressed air cylinders).
## Fire and toxic cylinder contamination from oxygen reactions
Diving cylinders are usually filled with nitrox by a gas blending technique such as partial pressure blending or premix decanting (in which a nitrox mix is supplied to the filler in pressurized larger cylinders). A few facilities have begun to fill cylinders with air which has been enriched with oxygen by a pre-mixing process, so that it is pressurized as nitrox for the first time in the diving cylinder. The pre-mixing is accomplished either by a membrane system which removes nitrogen from the air during compression or by a 'stick' blending technique where pure oxygen is mixed with air in a baffled chamber attached to the compressor intake.
With the use of pure oxygen during "partial pressure blending" (where pure oxygen is added from a large oxygen cylinder to the nearly empty dive cylinder until it reaches 300 (Expression error: Unexpected round operator. ) before air is added by compressor) there is an especially increased risk of fire. Partial blending using pure oxygen is often used to provide nitrox for multiple dives on live-aboard dive boats, but it is also used in some smaller diver shops.
However, any gas which contains a significantly larger percentage of oxygen than air is a fire hazard. Furthermore, such gases can also react with hydrocarbons or incorrect lubricants inside a dive cylinder to produce carbon monoxide, even if a recognized fire does not happen. At present, there is some discussion over whether or not mixtures of gas which contain less than 40% oxygen may sometimes be exempt from oxygen clean standards. Some of the controversy comes from a single U.S. regulation intended for commercial divers (not recreational divers) years ago. However, the U.S. Compressed Gas Association (CGA) and two international nitrox teaching agencies (IANTD and ANDI) now support the standard that any gas containing more than 23.5% oxygen should be treated as nitrox (which is to say, no differently from pure oxygen) for purposes of oxygen cleanliness and oxygen compatibility (i.e., oxygen "servicability"). However, the largest training agency - PADI - is still teaching that pre-mixed nitrox (i.e. nitrox which is mixed before being put into the cylinder) below 40% oxygen does not require a specially cleaned cylinder or other equipment. Most nitrox fill stations which supply pre-mixed nitrox will fill non-oxygen clean cylinders with mixtures below 40%. For a history of this controversy see Luxfer cylinders.
# History
In the 1920s or 1930's Draeger of Germany made a nitrox backpack independent air supply for a standard diving suit.
In World War II or soon after, British commando frogmen and work divers started sometimes diving with oxygen rebreathers adapted for semi-closed-circuit nitrox (which they called "mixture") diving by fitting larger cylinders and carefully setting the gas flow rate using a flow meter. These developments were kept secret until independently duplicated by civilians in the 1960s.
In the 1950s the United States Navy (USN) documented enriched oxygen gas procedures for military use of what we today call nitrox, in the USN Diving Manual.
In 1970, Dr. Morgan Wells, who was the first director of the National Oceanographic and Atmospheric Administration (NOAA) Diving Center, began instituting diving procedures for oxygen-enriched air. He also developed a process for mixing oxygen and air which he called a continuous blending system. For many years Dr. Wells' invention was the only practical alternative to partial pressure blending. In 1979 NOAA published Wells' procedures for the scientific use of nitrox in the NOAA Diving Manual.
In 1985 Dick Rutkowski, a former NOAA diving safety officer, formed IAND (International Association of Nitrox Divers) and began teaching nitrox use for recreational diving. This was considered dangerous by some, and met with heavy skepticism by the diving community. In 1992 the name was changed to the International Association of Nitrox and Technical Divers (IANTD), the T being added when the European Association of Technical Divers (EATD) merged with IAND. In the early 1990s, the agencies teaching nitrox were not the main scuba agencies. New organizations, including Ed Betts' American Nitrox Divers International (ANDI) - which invented the term "Safe Air" for marketing purposes - and Bret Gilliam's Technical Diving International (TDI) gave scientific credence to nitrox.
Meanwhile, diving stores were finding a purely economic reason to offer nitrox: not only was an entire new course and certification needed to use it, but instead of cheap or free tank fills with compressed air, dive shops found they could charge premium amounts of money for custom-gas blending of nitrox to their ordinary moderately experienced divers. With the new dive computers which could be programmed to allow for the longer bottom-times and shorter residual nitrogen times which nitrox gave, the incentive for the sport diver to use the gas increased. An intersection of economics and scientific validity had occurred.
In 1996, the Professional Association of Diving Instructors (PADI) announced full educational support for nitrox. While other main line scuba organizations had announced their support of nitrox earlier, it was PADI's endorsement that put nitrox over the top as a standard sport diving "option."
# Nitrox in nature
Sometimes in the geologic past the Earth's atmosphere contained much more than 20% oxygen: e.g. up to 35% in the Upper Carboniferous. This let animals absorb oxygen more easily and influenced evolution. | Nitrox
Nitrox refers to any gas mixture composed (excluding trace gases) of nitrogen and oxygen; this includes normal air which is approximately 78% nitrogen, 21% oxygen, and 1% other gases, primarily argon.[1][2][3] However, in SCUBA diving, nitrox is normally differentiated and handled differently from air.[3] The most common use of nitrox mixtures containing higher than normal levels of oxygen is in SCUBA, where the reduced percentage of nitrogen is advantageous in reducing nitrogen take up in the body's tissues and so extending the possible dive time, and/or reducing the risk of decompression sickness (also known as the bends).
# Purpose
Enriched Air Nitrox, Nitrox with an oxygen content above 21%, is mainly used in scuba diving to reduce the proportion of nitrogen in the breathing gas mixture. Reducing the proportion of nitrogen by increasing the proportion of oxygen reduces the risk of decompression sickness, allowing extended dive times without increasing the need for decompression stops. Nitrox is not a safer gas than compressed air in all respects; although its use reduces the risk of decompression sickness, it increases the risk of oxygen toxicity and fire, which are further discussed below.
Breathing nitrox is not thought to reduce the effects of narcosis, as oxygen seems to have equally narcotic properties under pressure as nitrogen; thus one should not expect a reduction in narcotic effects due only to the use of nitrox.[4][5][note 1] Nonetheless, there remains a body of the diving community that insists that they feel reduced narcotic effects at depths breathing nitrox.[note 2]
This may be due to a dissociation of the subjective and behavioural effects of narcosis.[6] However, it should be noted that because of risks associated with oxygen toxicity, divers tend not to utilize nitrox at greater depths where more pronounced narcosis symptoms are more likely to occur. For a reduction in narcotic effects trimix or heliox gases which also contain helium are generally used by divers.
There is anecdotal evidence that the use of nitrox reduces post-dive fatigue, particularly in older and or obese divers; however the only known double-blind study to test this found no statistically significant reduction in reported fatigue.[1][7] There has, however, been some suggestion that post dive fatigue is due to sub-clinical decompression sickness (DCS) (i.e. micro bubbles in the blood insufficient to cause symptoms of DCS); the fact that the study mentioned was conducted in a dry chamber with an ideal decompression profile may have been sufficient to reduce sub-clinical DCS and prevent fatigue in both nitrox and air divers.
Further studies with a number of different dive profiles, and also different levels of exertion, would be necessary to fully investigate this issue. For example, there is much better scientific evidence that breathing high-oxygen gases increase exercise tolerance, during aerobic exertion.[8] Though even moderate exertion while breathing from the regulator is a relatively uncommon occurrence in scuba, as divers usually try to minimize it in order to conserve gas, episodes of exertion while regulator-breathing do occasionally occur in sport diving. Examples are surface-swimming a distance to a boat or beach after surfacing, where residual "safety" cylinder gas is often used freely, since the remainder will be wasted anyway when the dive is completed. It is possible that these so-far un-studied situations have contributed to some of the positive reputation of nitrox.
# Naming
Nitrox is known by many names: Enhanced Air Nitrox, Oxygen Enriched Air, Nitrox, EANx or Safe Air.[3][9] The name "nitrox" may be capitalized when referring to specific mixtures such as Nitrox32, which contains 68% nitrogen and 32% oxygen. When one figure is stated, it refers to the oxygen percentage, not the nitrogen percentage. The original convention, Nitrox68/32 became shortened as the second figure is redundant.[citation needed]
Although "nitrox" usually refers to a mixture of nitrogen and oxygen with more than 21% oxygen, it can refer to mixtures that are leaner in oxygen than air.[3] "Enriched Air Nitrox", "Enriched Air" or "EAN" are used to emphasise richer than air mixtures.[3] In "EANx", the "x" indicates the percentage of oxygen in the mix and is replaced by a number when the percentage is known; for example a 40% EANx mix is called EAN40. The two most popular blends are EAN32 and EAN36 (also named Nitrox I and Nitrox II, respectively, or Nitrox68/32 and Nitrox64/36).[2][3]
In its early days of introduction to non-technical divers, nitrox has occasionally also been known by detractors by less complimentary terms, such as "devil gas" or "voodoo gas" (a term now sometimes used with pride).[citation needed]
These percentages are what the gas blender aims for in partial-pressure blending, but the final actual mix in such cases will be unique, and so a small flow of gas from the cylinder must be measured with a handheld oxygen analyzer, before the diver breathes from the cylinder underwater.[10]
# Richness of mix
The two most common recreational diving nitrox mixes contain 32% and 36% oxygen, which have maximum operating depths (MODs) of 34 metres (111.5485566 ft) and 29 metres (95.1443571 ft) respectively when limited to a maximum partial pressure of oxygen of 1.4 (Expression error: Missing operand for *. ). EAN32 is common because it is the mixture with the maximum concentration of oxygen that allows the diver to go to the full depth of recreational diving's "No Decompression Limit" for air[citation needed]. Divers may calculate an equivalent air depth to determine their decompression requirements or may use nitrox tables or a nitrox-capable dive computer.[2][3][11][12]
Nitrox with more than 40% oxygen is uncommon within recreational diving. There are two main reasons for this: the first is that all pieces of diving equipment that come into contact with mixes containing higher proportions of oxygen, particularly at high pressure, need special cleaning and servicing to reduce the risk of fire.[2][3] The second reason is that richer mixes extend the time the diver can stay underwater without needing decompression stops far further than the duration of typical diving cylinders. For example, based on the PADI nitrox recommendations, the maximum operating depth for EAN45 would be 21 metres (68.8976379 ft) and the maximum dive time available at this depth even with EAN36 is nearly 1 hour 15 minutes: a diver with a breathing rate of 20 litres per minute using twin 10 litre, 230 bar (about double 85 cu. ft.) cylinders would have completely emptied the cylinders after 1 hour 14 minutes at this depth.
Nitrox containing 50% to 100% oxygen is common in technical diving as a decompression gas, which eliminates inert gases such as nitrogen and helium from the tissues more quickly than leaner oxygen mixtures.
In deep open circuit technical diving, where hypoxic gases are breathed during the bottom portion of the dive, a Nitrox mix with 50% or less oxygen called a "travel mix" is sometimes breathed during the beginning of the descent in order to avoid hypoxia. Normally, however, the most oxygen-lean of the diver's decompression gases would be used for this purpose, since descent time spent reaching a depth where bottom mix is no longer hypoxic is normally small, and the distance between this depth and the MOD of any nitrox decompression gas is likely to be very short, if it occurs at all.
# Cylinder markings
Any cylinder containing any blend of gas other than the standard air content is required by most diving training organizations to be clearly marked. Some organizations, e.g. GUE, argue that it does not make sense to have a permanent marking on a gas tank that can be filled with any gas.
The standard nitrox cylinder is yellow in color and marked with a green band around the shoulder of the tank, with "Nitrox" or "Enriched air" marked in white or yellow letters inside.
Tanks of any other color are generally marked with six inch band around the shoulder, with a one inch yellow band on the top and bottom, with four inches of green in the middle. This green band will also have the designation of "NITROX" or something similar inside, in yellow or white letters.
Every nitrox cylinder should also have a sticker stating whether or not the cylinder is oxygen clean and suitable for partial pressure blending. Any oxygen clean cylinder may have any mix up to 100% oxygen inside. If by some accident an oxygen clean cylinder is filled at a station which does not supply gas to oxygen-clean standards it is then considered contaminated and must be re-cleaned before a gas containing more than 40% oxygen may again be added. Cylinders marked as not-oxygen clean may only be filled with enriched oxygen mixtures from membrane or stick blending systems where the gas is mixed before being added to the cylinder.
Finally, all nitrox cylinders should have a tag that, at minimum, states the oxygen content of the cylinder, the date it was blended, the gas blender's name, and the maximum operating depth along with the partial pressure this depth was calculated with. Other requirements may be made as to what is marked on the cylinder, but these markings are considered standard and safe by the diving community, and any cylinders lacking these markings should be considered possibly unsafe. Training for nitrox certification suggests this tag be verified by the diver himself by using an oxygen analyzer.
# Dangers
## Oxygen toxicity
Diving and handling nitrox raises a number of potentially fatal dangers due to the high partial pressure of oxygen (ppO2).[2][3] Nitrox is not a deep-diving gas mixture owing to the increased proportion of oxygen, which becomes toxic when breathed at high pressure. For example, the maximum operating depth of nitrox with 36% oxygen, a popular recreational diving mix, is 29 metres (95.1443571 ft) to ensure a maximum ppO2 of no more than 1.4 (Expression error: Missing operand for *. ). The exact value of the maximum allowed ppO2 and maximum operating depth varies depending on factors such as the training agency, the type of dive, the breathing equipment and the level of surface support, with professional divers sometimes being allowed to breath higher ppO2 than those recommended to recreational divers.
To dive safely with nitrox, the diver must learn good buoyancy control, a vital part of scuba diving in its own right, and a disciplined approach to preparing, planning and executing a dive to ensure that the ppO2 is known, and the maximum operating depth is not exceeded. Reputable dive operators and gas blenders insist on the diver having recognised nitrox training (which appears as an extra notation on a certification card) before selling nitrox to divers.
Some training agencies teach the use of two depth limits to protect against oxygen toxicity. The shallower depth is called the "maximum operating depth" and is reached when the partial pressure of oxygen in the breathing gas reaches 1.4 (Expression error: Missing operand for *. ). The second deeper depth, called the "contingency depth", is reached when the partial pressure reaches 1.6 (Expression error: Missing operand for *. ). Diving at or beyond this level exposes the diver to the risk of central nervous system (CNS) oxygen toxicity. This can be extremely dangerous since its onset is often without warning and can lead to drowning, as the regulator may be spat out during convulsions which occur in conjunction with sudden unconsciousness (general seizure induced by oxygen toxicity).
Divers trained to use nitrox memorise the acronym VENTID (which stands for Vision (blurriness), Ears (ringing sound), Nausea, Twitching, Irritability and Dizziness), which indicate some of the possible warning signs of onsetting convulsions. However, evidence from non-fatal oxygen convulsions indicates that most convulsions are not preceded by any warning symptoms at all. Further, many of the suggested warning signs are also symptoms of nitrogen narcosis, and so may lead to misdiagnosis by a diver.
# Precautionary procedures at the fill station
Many training agencies such as PADI[13], CMAS, SSI and NAUI train their divers to personally check the oxygen percentage content of each nitrox cylinder before every dive. If the oxygen percentage deviates by more than 1% from the value written on the cylinder by the gas blender, the scuba diver must either recalculate his or her bottom times with the new mix, or else abort the dive to remain safe and avoid oxygen toxicity or decompression sickness. Under IANTD and ANDI[14] rules for use of nitrox, which are followed by most dive resorts around the world, filled nitrox cylinders are signed out personally in a gas blender log book, which contains, for each cylinder and fill, the cylinder number, the measured oxygen percent composition, the signature of the receiving diver (who should have personally measured the oxygen percent with an instrument at the fill-shop), and finally a calculation of the maximum operating depth for that fill/cylinder. All of these steps minimize danger but increase complexity of operations (for example, personalized cylinders for each diver must generally be kept track of on dive boats with nitrox, which is not the case with generic compressed air cylinders).
## Fire and toxic cylinder contamination from oxygen reactions
Diving cylinders are usually filled with nitrox by a gas blending technique such as partial pressure blending or premix decanting (in which a nitrox mix is supplied to the filler in pressurized larger cylinders). A few facilities have begun to fill cylinders with air which has been enriched with oxygen by a pre-mixing process, so that it is pressurized as nitrox for the first time in the diving cylinder. The pre-mixing is accomplished either by a membrane system which removes nitrogen from the air during compression or by a 'stick' blending technique where pure oxygen is mixed with air in a baffled chamber attached to the compressor intake.
With the use of pure oxygen during "partial pressure blending" (where pure oxygen is added from a large oxygen cylinder to the nearly empty dive cylinder until it reaches 300 (Expression error: Unexpected round operator. ) before air is added by compressor) there is an especially increased risk of fire. Partial blending using pure oxygen is often used to provide nitrox for multiple dives on live-aboard dive boats, but it is also used in some smaller diver shops.
However, any gas which contains a significantly larger percentage of oxygen than air is a fire hazard. Furthermore, such gases can also react with hydrocarbons or incorrect lubricants inside a dive cylinder to produce carbon monoxide, even if a recognized fire does not happen. At present, there is some discussion over whether or not mixtures of gas which contain less than 40% oxygen may sometimes be exempt from oxygen clean standards.[15] Some of the controversy comes from a single U.S. regulation intended for commercial divers (not recreational divers) years ago.[3] However, the U.S. Compressed Gas Association (CGA) and two international nitrox teaching agencies (IANTD and ANDI) now support the standard that any gas containing more than 23.5% oxygen should be treated as nitrox (which is to say, no differently from pure oxygen) for purposes of oxygen cleanliness and oxygen compatibility (i.e., oxygen "servicability"). However, the largest training agency - PADI - is still teaching that pre-mixed nitrox (i.e. nitrox which is mixed before being put into the cylinder) below 40% oxygen does not require a specially cleaned cylinder or other equipment.[2][3][13] Most nitrox fill stations which supply pre-mixed nitrox will fill non-oxygen clean cylinders with mixtures below 40%. For a history of this controversy[3] see Luxfer cylinders.
# History
In the 1920s or 1930's Draeger of Germany made a nitrox backpack independent air supply for a standard diving suit.
In World War II or soon after, British commando frogmen and work divers started sometimes diving with oxygen rebreathers adapted for semi-closed-circuit nitrox (which they called "mixture") diving by fitting larger cylinders and carefully setting the gas flow rate using a flow meter. These developments were kept secret until independently duplicated by civilians in the 1960s.
In the 1950s the United States Navy (USN) documented enriched oxygen gas procedures for military use of what we today call nitrox, in the USN Diving Manual.[16]
In 1970, Dr. Morgan Wells, who was the first director of the National Oceanographic and Atmospheric Administration (NOAA) Diving Center, began instituting diving procedures for oxygen-enriched air. He also developed a process for mixing oxygen and air which he called a continuous blending system. For many years Dr. Wells' invention was the only practical alternative to partial pressure blending. In 1979 NOAA published Wells' procedures for the scientific use of nitrox in the NOAA Diving Manual.[2][3]
In 1985 Dick Rutkowski, a former NOAA diving safety officer, formed IAND (International Association of Nitrox Divers) and began teaching nitrox use for recreational diving. This was considered dangerous by some, and met with heavy skepticism by the diving community. In 1992 the name was changed to the International Association of Nitrox and Technical Divers (IANTD), the T being added when the European Association of Technical Divers (EATD) merged with IAND. In the early 1990s, the agencies teaching nitrox were not the main scuba agencies. New organizations, including Ed Betts' American Nitrox Divers International (ANDI) - which invented the term "Safe Air" for marketing purposes - and Bret Gilliam's Technical Diving International (TDI) gave scientific credence to nitrox.
Meanwhile, diving stores were finding a purely economic reason to offer nitrox: not only was an entire new course and certification needed to use it, but instead of cheap or free tank fills with compressed air, dive shops found they could charge premium amounts of money for custom-gas blending of nitrox to their ordinary moderately experienced divers. With the new dive computers which could be programmed to allow for the longer bottom-times and shorter residual nitrogen times which nitrox gave, the incentive for the sport diver to use the gas increased. An intersection of economics and scientific validity had occurred.
In 1996, the Professional Association of Diving Instructors (PADI) announced full educational support for nitrox.[13] While other main line scuba organizations had announced their support of nitrox earlier[17], it was PADI's endorsement that put nitrox over the top as a standard sport diving "option."[18]
# Nitrox in nature
Sometimes in the geologic past the Earth's atmosphere contained much more than 20% oxygen: e.g. up to 35% in the Upper Carboniferous. This let animals absorb oxygen more easily and influenced evolution. | https://www.wikidoc.org/index.php/Nitrox | |
883505f3064e78deaed8e27523affe536380deb9 | wikidoc | Norrin | Norrin
Norrin, also known as Norrie disease protein or X-linked exudative vitreoretinopathy 2 protein (EVR2) is a protein that in humans is encoded by the NDP gene. Mutations in the NDP gene are associated with the Norrie disease.
# Function
Signaling induced by the protein Norrin regulates vascular development of vertebrate retina and controls important blood vessels in the ear. Norrin binds with high affinity to Frizzled 4, and Frizzled 4 knockout mice exhibit abnormal vascular development of the retina.
# Clinical significance
NDP is the genetic locus identified as harboring mutations that result in Norrie disease. Norrie disease is a rare genetic disorder characterized by bilateral congenital blindness that is caused by a vascularized mass behind each lens due to a maldeveloped retina (pseudoglioma). | Norrin
Norrin, also known as Norrie disease protein or X-linked exudative vitreoretinopathy 2 protein (EVR2) is a protein that in humans is encoded by the NDP gene.[1] Mutations in the NDP gene are associated with the Norrie disease.
# Function
Signaling induced by the protein Norrin regulates vascular development of vertebrate retina and controls important blood vessels in the ear.[1] Norrin binds with high affinity to Frizzled 4, and Frizzled 4 knockout mice exhibit abnormal vascular development of the retina.
# Clinical significance
NDP is the genetic locus identified as harboring mutations that result in Norrie disease. Norrie disease is a rare genetic disorder characterized by bilateral congenital blindness that is caused by a vascularized mass behind each lens due to a maldeveloped retina (pseudoglioma).[1] | https://www.wikidoc.org/index.php/Norrin | |
44e2a1cd1130b4ecbb66d98f0ab9dcffa22973df | wikidoc | Poison | Poison
# Overview
In the context of biology, poisons are substances that can cause damage, illness, or death to organisms, usually by chemical reaction or other activity on the molecular scale, when a sufficient quantity is absorbed by an organism. Paracelsus, the father of toxicology, once wrote: "Everything is poison, there is poison in everything. Only the dose makes a thing not a poison".
In medicine (particularly veterinary) and in zoology, a poison is often distinguished from a toxin and a venom. Toxins are poisons produced via some biological function in nature, and venoms are usually defined as biologic toxins that are injected by a bite or sting to cause their effect, while other poisons are generally defined as substances which are absorbed through epithelial linings such as the skin or gut.
# Terminology
Some poisons are also toxins, usually referring to naturally produced substances, such as the bacterial proteins that cause tetanus and botulism. A distinction between the two terms is not always observed, even among scientists.
Animal toxins that are delivered subcutaneously (e.g. by sting or bite) are also called venom. In normal usage, a poisonous organism is one that is harmful to consume, but a venomous organism uses poison to defend itself while still alive. A single organism can be both venomous and poisonous.
The derivative forms "toxic" and "poisonous" are synonymous.
Within chemistry and physics, a poison is a substance that obstructs or inhibits a reaction, for example by binding to a catalyst. For example, see nuclear poison.
The phrase "poison" is often used colloquially to describe any harmful substance, particularly corrosive substances, carcinogens, mutagens, teratogens and harmful pollutants, and to exaggerate the dangers of chemicals. The legal definition of "poison" is stricter.
# Classification
The majority of this section is sorted by ICD-10 code, which classifies poisons based upon the nature of the poison itself. However, it is also possible to classify poisons based upon the effect the poison has (for example, "Metabolic poisons" such as Antimycin, Malonate, and2,4-Dinitrophenol act by adversely disrupting the normal metabolism of an organism.)
(T36-T50) Poisoning by drugs, medicaments and biological substances
(T36) Poisoning by systemic antibiotics
(T37) Poisoning by other systemic anti-infectives and antiparasitics
(T38) Poisoning by hormones and their synthetic substitutes and antagonists, not elsewhere classified
(T39) Poisoning by nonopiod analgesics, antipyretics and antirheumatics
(T40) Poisoning by narcotics and psychodysleptics (hallucinogens)
(T41) Poisoning by anaesthetics and therapeutic gases
(T42) Poisoning by antiepileptic, sedative-hypnotic and antiparkinsonism drugs
(T43) Poisoning by psychotropic drugs, not elsewhere classified
(T44) Poisoning by drugs primarily affecting the autonomic nervous system
Neurotoxins interfere with nervous system functions and often lead to near-instant paralysis followed by rapid death. They include mostspider and snake venoms, as well as many modern chemical weapons. One class of toxins of interest to neurochemical researchers are the various cone snail toxins known as conotoxins.
- Atropine
- Poison hemlock
Anticholinesterases (T44.0)
- Fasciculin
- Nerve agents
Acetylcholine antagonists
- Curare
- Pancuronium
Cell membrane disrupters
Others
- Nicotine - not strictly a neurotoxin, but capable in large doses of causing heart attack
(T45) Poisoning by primarily systemic and haematological agents, not elsewhere classified
- Phytohaemagglutinin (Red kidney bean poisoning)
(T46) Poisoning by agents primarily affecting the cardiovascular system
- Digitoxin
- Digoxin
- Ouabain
(T47) Poisoning by agents primarily affecting the gastrointestinal system
- Solanine
- Hyoscyamine
(T48) Poisoning by agents primarily acting on smooth and skeletal muscles and the respiratory system
- Strychnine
- Aconite
(T49) Poisoning by topical agents primarily affecting skin and mucous membrane and by ophthalmological,otorhinolaryngological and dental drugs
(T50) Poisoning by diuretics and other unspecified drugs, medicaments and biological substances
(T51-T65) Toxic effects of substances chiefly nonmedicinal as to source
(T51) Toxic effect of alcohol
- (T51.0) Ethanol
- (T51.1) Methanol
(T52) Toxic effect of organic solvents
(T53) Toxic effect of halogen derivatives of aliphatic and aromatic hydrocarbons
(T54) Toxic effect of corrosive substances
Corrosives mechanically damage biological systems on contact. Both the sensation and injury caused by contact with a corrosive resembles a burn injury.
- Acids and bases, corrosives
Various light metal oxides, hydroxides, superoxides
Bleach, some pool chemicals, other hypochlorates (acidic and oxydizing effect)
Hydrofluoric acid
- Various light metal oxides, hydroxides, superoxides
- Bleach, some pool chemicals, other hypochlorates (acidic and oxydizing effect)
- Hydrofluoric acid
Acids (T54.2)
Strong inorganic acids, such as concentrated sulfuric acid, nitric acid or hydrochloric acid, destroy any biological tissue with which they come in contact within seconds.
Bases (T54.3)
Strong inorganic bases, such as lye, gradually dissolve skin on contact but can cause serious damage to eyes or mucous membranes much more rapidly. Ammonia is a far weaker base than lye, but has the distinction of being a gas and thus may more easily come into contact with the sensitive mucous membranes of the respiratory system. Quicklime, which has household uses, is a particularly common cause of poisoning. Some of the light metals, if handled carelessly, can not only cause thermal burns, but also produce very strongly basic solutions in sweat.
(T55) Toxic effect of soaps and detergents
(T56) Toxic effect of metals
A common trait shared by toxic metals is the chronic nature of their toxicity (a notable exception would be bismuth, which is considered entirely non-toxic). Low levels of toxic metal salts ingested over time accumulate in the body until toxic levels are reached. Toxic metals are often inaccurately referred to as "heavy metals", although not all heavy metals are necessarily harmful and not all toxic metals are heavy metals.
Toxic metals are generally far more toxic when ingested in the form of soluble salts than in elemental form. For example, metallic mercury passes through the human digestive tract without interaction and is commonly used in dental fillings—even though mercury salts and inhaled mercury vapor are highly toxic.
Examples:
- (T56.0) Lead poisoning
- (T56.1) Mercury
- (T56.2) Chromium
- (T56.3) Cadmium
- (T56.7) Beryllium (a highly but subtly toxic light metal)
- Antimony
- Barium
- Thallium
- Uranium
(T57) Toxic effect of other inorganic substances
- (T57.0) Arsenic (see arsenic poisoning)
Arsenic compounds
Arsenic trioxide
Fowler's solution
- Arsenic compounds
Arsenic trioxide
Fowler's solution
- Arsenic trioxide
- Fowler's solution
Reducing agents
- (T57.1) The most notable substance in this class is phosphorus.
(T58) Toxic effect of carbon monoxide
- (T58) By far the most notable metabolic poison is carbon monoxide, which blocks the ability of red blood cells to transport oxygen.
(T59) Toxic effect of other gases, fumes and vapours
- Formaldehyde (T59.2)
- Phosgene
- Phosphine
- Hydrogen sulfide
Oxidizers
Poisons of this class are generally not very harmful to higher life forms such as humans (for whom the outer layer of cells are more or less disposable), but lethal to microorganisms such as bacteria. Typical examples are ozone and chlorine (T59.4), either of which is added to nearly every municipal water supply in order to kill any harmful microorganisms present.
All halogens are strong oxidizing agents, fluorine (T59.5) being the strongest of all.
(T60) Toxic effect of pesticides
- Pesticide poisoning
- Fluoroacetate is a metabolic poison that blocks a vital step in the citric acid cycle.
- Rotenone is a metabolic poison that disrupts electron transport in cellular respiration.
(T61) Toxic effect of noxious substances eaten as seafood
- Ciguatera poisoning
- Scombroid poisoning
- Shellfish toxins (PSP, DSP, NSP, ASP )
- Domoic acid (or Amnesic shellfish poisoning, ASP)
- Tetrodotoxin
(T62) Toxic effect of other noxious substances eaten as food
- Food poisoning
- Botulin toxin
- Hemlock water dropwort
- Grayanotoxin (Honey intoxication)
- Tetanospasmin (Tetanos Toxin)
(T63) Toxic effect of venomous animals
- Snake and spider venoms
(T64) Toxic effect of aflatoxin and other mycotoxin food contaminants
- Fungal toxins
Amanita toxin, see Amanita phalloides
Muscarine
Aflatoxins
- Amanita toxin, see Amanita phalloides
- Muscarine
- Aflatoxins
(T65) Toxic effect of other and unspecified substances
- (T65.0) Cyanide is a metabolic poison that bonds with an enzyme involved in ATP production.
# Warning Symbols
Poisons have been known to be symbolized by the skull and crossbones, indicating lethal potential. This is the UN standard symbol, used in the European Union and in the Globally Harmonized System. However, it can be considered a liability for marketing. In the United States, other symbols such as Mr. Yuk have been suggested to replace the skull and crossbones. Proponents of the Mr. Yuk argue that the skull-and-crossbones symbols attracts children because of its association to pirates, and assert that Mr. Yuk does not. However, the Globally Harmonized System will be enforced also in the United States, including the skull-and-crossbones symbol.
Chemicals with non-lethal hazards, such as corrosivity, mild toxicity and harmfulness, may be informally referred to as "poisons", but are not usually marked with the skull-and-crossbones symbol. To contrast, see also the definitions of corrosive, harmful, environmentally hazardous and irritant. The UN standard symbol for harmful and irritant substances is a St Andrew's cross on an orange background, which is being replaced by an exclamation mark (or carcinogen symbol when applicable) in the Globally Harmonized System. This is applied to materials with non-lethal hazards as well as to potentially lethal materials.
# Uses of Poison
Poisons are usually not used for their toxicity, but may be used for their other properties. The property of toxicity itself has limited applications: mainly for controlling pests and weeds, and for preserving building materials and food stuffs. Where possible, specific agents which are less poisonous to humans have come to be preferred, but exceptions such as phosphine continue in use.
Throughout human history, intentional application of poison has been used as a method of assassination, murder, suicide and execution. As a method of execution, poison has been ingested, as the ancient Athenians did (see Socrates), inhaled, as with carbon monoxide or hydrogen cyanide (see gas chamber), or injected (see lethal injection). Many languages describe lethal injection with their corresponding words for "poison shot". Poison was also employed in gunpowder warfare. For example, the 14th century Chinese text of the Huo Long Jing written by Jiao Yu outlined the use of a poisonous gunpowder mixture to fill cast iron grenade bombs.
Poisonous materials are often used for their chemical or physical properties other than being poisonous. The most effective, easiest, safest, or cheapest option for use in a chemical synthesis may be a poisonous material. Particularly in experimental laboratory syntheses a specific reactivity is used, despite the toxicity of the reagent. Chromic acid is an example of such a "simple to use" reagent. Many technical applications call for some specific physical properties; a toxic substance may possess these properties and therefore be superior. Reactivity, in particular, is important. Hydrogen fluoride, for example, is poisonous and extremely corrosive. However, it has a high affinity for silicon, which is exploited by using HF to etch glass or to manufacture silicon semiconductor chips.
# Biological Poisoning
Acute poisoning is exposure to a poison on one occasion or during a short period of time. Symptoms develop in close relation to the exposure. Absorption of a poison is necessary for systemic poisoning. In contrast, substances that destroy tissue but do not absorb, such as lye, are classified as corrosives rather than poisons.
Chronic poisoning is long-term repeated or continuous exposure to a poison where symptoms do not occur immediately or after each exposure. The patient gradually becomes ill, or becomes ill after a long latent period. Chronic poisoning most commonly occurs following exposure to poisons that bioaccumulate such as mercury and lead.
Contact or absorption of poisons can cause rapid death or impairment. Agents that act on the nervous system can paralyze in seconds or less, and include both biologically derived neurotoxins and so-called nerve gases, which may be synthesized for warfare or industry.
Inhaled or ingested cyanide as used as method of execution on US gas chambers almost instantly starves the body of energy by inhibiting the enzymes in mitochondria that make ATP. Intravenous injection of an unnaturally high concentration of potassium chloride, such as in the execution of prisoners in parts of the United States, quickly stops the heart by eliminating the cell potential necessary for muscle contraction.
Most (but not all) biocides, including pesticides, are created to act as poisons to target organisms, although acute or less observable chronic poisoning can also occur in non-target organism, including the humans who apply the biocides and other beneficial organisms. For example, the herbicide 2,4-D imitates the action of a plant hormone, to the effect that the lethal toxicity is specific to plants. Indeed, 2,4-D is not a poison, but classified as "harmful" (EU).
Many substances regarded as poisons are toxic only indirectly, by toxication. An example is "wood alcohol" or methanol, which is not poisonous itself, but is chemically converted to toxic formaldehyde and formic acid in the liver. Many drug molecules are made toxic in the liver, and the genetic variability of certain liver enzymes makes the toxicity of many compounds differ between individuals.
The study of the symptoms, mechanisms, treatment and diagnosis of biological poisoning is known as toxicology.
Exposure to radioactive substances can produce radiation poisoning, an unrelated phenomenon.
# Treatment
- Poison Control Centers (In the US reachable at 1-800-222-1222 at all hours) provide immediate, free, and expert treatment advice and assistance over the telephone in case of suspected exposure to poisons or toxic substances.
## General First Aid
- If the poison is an inhalant, remove the patient from the area and to fresh air.
- If the poisoning is affecting the skin, remove the clothing and wash the skin thoroughly unless a dry powder is the cause of the poisoning.
- If the poison is in the eye, flush the eye thoroughly with water for at least 15 minutes.
- Following ingestion, do not induce vomiting or administer anything without medical advice.
- Contact a poison control center for advice on what to do next.
## Initial Medical Management
- Initial management for all poisonings includes ensuring adequate cardiopulmonary function and providing treatment for any symptoms such as seizures, shock, and pain.
## Decontamination
- If the toxin was recently ingested, absorption of the substance may be able to be decreased through gastric decontamination. This may be achieved using activated charcoal, gastric lavage, whole bowel irrigation, or nasogastric aspiration. Routine use of emetics (syrup of Ipecac) and cathartics are no longer recommended.
Activated charcoal is the treatment of choice to prevent absorption of the poison. It is usually administered when the patient is in the emergency room. However, charcoal is ineffective against metals, Na, K, alcohols, glycols, acids, and alkalis.
Whole bowel irrigation cleanses the bowel, this is achieved by giving the patient large amounts of a polyethylene glycol solution. The osmotically balanced polyethylene glycol solution is not absorbed into the body, having the effect of flushing out the entire gastrointestinal tract. Its major uses are following ingestion of sustained release drugs, toxins that are not absorbed by activated charcoal (i.e. lithium, iron), and for the removal of ingested packets of drugs (body packing/smuggling).
Gastric lavage, commonly known as a stomach pump, is the insertion of a tube into the stomach, followed by administration of water or saline down the tube. The liquid is then removed along with the contents of the stomach. Lavage has been used for many years as a common treatment for poisoned patients. However, a recent review of the procedure in poisonings suggests no benefit. It is still sometimes used if it can be performed within 1 h of ingestion and the exposure is potentially life threatening.
Nasogastric aspiration involves the placement of a tube via the nose down into the stomach, the stomach contents are then removed via suction. This procedure is mainly used for liquid ingestions where activated charcoal is ineffective, i.e. ethylene glycol.
Emesis (i.e. induced by ipecac) is no longer recommended in poisoning situations.
Cathartics were postulated to decrease absorption by increasing the expulsion of the poison from the gastrointestinal tract. There are two types of cathartics used in poisoned patients; saline cathartics (sodium sulfate, magnesium citrate, magnesium sulfate) and saccharide cathartics (sorbitol). They do not appear to improve patient outcome and are no longer recommended.
- Activated charcoal is the treatment of choice to prevent absorption of the poison. It is usually administered when the patient is in the emergency room. However, charcoal is ineffective against metals, Na, K, alcohols, glycols, acids, and alkalis.
- Whole bowel irrigation cleanses the bowel, this is achieved by giving the patient large amounts of a polyethylene glycol solution. The osmotically balanced polyethylene glycol solution is not absorbed into the body, having the effect of flushing out the entire gastrointestinal tract. Its major uses are following ingestion of sustained release drugs, toxins that are not absorbed by activated charcoal (i.e. lithium, iron), and for the removal of ingested packets of drugs (body packing/smuggling).
- Gastric lavage, commonly known as a stomach pump, is the insertion of a tube into the stomach, followed by administration of water or saline down the tube. The liquid is then removed along with the contents of the stomach. Lavage has been used for many years as a common treatment for poisoned patients. However, a recent review of the procedure in poisonings suggests no benefit. It is still sometimes used if it can be performed within 1 h of ingestion and the exposure is potentially life threatening.
- Nasogastric aspiration involves the placement of a tube via the nose down into the stomach, the stomach contents are then removed via suction. This procedure is mainly used for liquid ingestions where activated charcoal is ineffective, i.e. ethylene glycol.
- Emesis (i.e. induced by ipecac) is no longer recommended in poisoning situations.
- Cathartics were postulated to decrease absorption by increasing the expulsion of the poison from the gastrointestinal tract. There are two types of cathartics used in poisoned patients; saline cathartics (sodium sulfate, magnesium citrate, magnesium sulfate) and saccharide cathartics (sorbitol). They do not appear to improve patient outcome and are no longer recommended.
## Antidotes
Some poisons have specific antidotes:
## Enhanced Excretion
- In some situations elimination of the poison can be enhanced using diuresis, hemodialysis, hemoperfusion, peritoneal dialysis, or exchange transfusion.
## Further Treatment
- In the majority of poisonings the mainstay of management is providing supportive care for the patient, i.e. treating the symptoms rather than the poison. | Poison
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
In the context of biology, poisons are substances that can cause damage, illness, or death to organisms, usually by chemical reaction or other activity on the molecular scale, when a sufficient quantity is absorbed by an organism. Paracelsus, the father of toxicology, once wrote: "Everything is poison, there is poison in everything. Only the dose makes a thing not a poison".
In medicine (particularly veterinary) and in zoology, a poison is often distinguished from a toxin and a venom. Toxins are poisons produced via some biological function in nature, and venoms are usually defined as biologic toxins that are injected by a bite or sting to cause their effect, while other poisons are generally defined as substances which are absorbed through epithelial linings such as the skin or gut.
# Terminology
Some poisons are also toxins, usually referring to naturally produced substances, such as the bacterial proteins that cause tetanus and botulism. A distinction between the two terms is not always observed, even among scientists.
Animal toxins that are delivered subcutaneously (e.g. by sting or bite) are also called venom. In normal usage, a poisonous organism is one that is harmful to consume, but a venomous organism uses poison to defend itself while still alive. A single organism can be both venomous and poisonous.
The derivative forms "toxic" and "poisonous" are synonymous.
Within chemistry and physics, a poison is a substance that obstructs or inhibits a reaction, for example by binding to a catalyst. For example, see nuclear poison.
The phrase "poison" is often used colloquially to describe any harmful substance, particularly corrosive substances, carcinogens, mutagens, teratogens and harmful pollutants, and to exaggerate the dangers of chemicals. The legal definition of "poison" is stricter.
# Classification
The majority of this section is sorted by ICD-10 code, which classifies poisons based upon the nature of the poison itself. However, it is also possible to classify poisons based upon the effect the poison has (for example, "Metabolic poisons" such as Antimycin, Malonate, and2,4-Dinitrophenol act by adversely disrupting the normal metabolism of an organism.)
(T36-T50) Poisoning by drugs, medicaments and biological substances
(T36) Poisoning by systemic antibiotics
(T37) Poisoning by other systemic anti-infectives and antiparasitics
(T38) Poisoning by hormones and their synthetic substitutes and antagonists, not elsewhere classified
(T39) Poisoning by nonopiod analgesics, antipyretics and antirheumatics
(T40) Poisoning by narcotics and psychodysleptics (hallucinogens)
(T41) Poisoning by anaesthetics and therapeutic gases
(T42) Poisoning by antiepileptic, sedative-hypnotic and antiparkinsonism drugs
(T43) Poisoning by psychotropic drugs, not elsewhere classified
(T44) Poisoning by drugs primarily affecting the autonomic nervous system
Neurotoxins interfere with nervous system functions and often lead to near-instant paralysis followed by rapid death. They include mostspider and snake venoms, as well as many modern chemical weapons. One class of toxins of interest to neurochemical researchers are the various cone snail toxins known as conotoxins.
- Atropine
- Poison hemlock
Anticholinesterases (T44.0)
- Fasciculin
- Nerve agents
Acetylcholine antagonists
- Curare
- Pancuronium
Cell membrane disrupters
Others
- Nicotine - not strictly a neurotoxin, but capable in large doses of causing heart attack
(T45) Poisoning by primarily systemic and haematological agents, not elsewhere classified
- Phytohaemagglutinin (Red kidney bean poisoning)
(T46) Poisoning by agents primarily affecting the cardiovascular system
- Digitoxin
- Digoxin
- Ouabain
(T47) Poisoning by agents primarily affecting the gastrointestinal system
- Solanine
- Hyoscyamine
(T48) Poisoning by agents primarily acting on smooth and skeletal muscles and the respiratory system
- Strychnine
- Aconite
(T49) Poisoning by topical agents primarily affecting skin and mucous membrane and by ophthalmological,otorhinolaryngological and dental drugs
(T50) Poisoning by diuretics and other unspecified drugs, medicaments and biological substances
(T51-T65) Toxic effects of substances chiefly nonmedicinal as to source
(T51) Toxic effect of alcohol
- (T51.0) Ethanol
- (T51.1) Methanol
(T52) Toxic effect of organic solvents
(T53) Toxic effect of halogen derivatives of aliphatic and aromatic hydrocarbons
(T54) Toxic effect of corrosive substances
Corrosives mechanically damage biological systems on contact. Both the sensation and injury caused by contact with a corrosive resembles a burn injury.
- Acids and bases, corrosives
Various light metal oxides, hydroxides, superoxides
Bleach, some pool chemicals, other hypochlorates (acidic and oxydizing effect)
Hydrofluoric acid
- Various light metal oxides, hydroxides, superoxides
- Bleach, some pool chemicals, other hypochlorates (acidic and oxydizing effect)
- Hydrofluoric acid
Acids (T54.2)
Strong inorganic acids, such as concentrated sulfuric acid, nitric acid or hydrochloric acid, destroy any biological tissue with which they come in contact within seconds.
Bases (T54.3)
Strong inorganic bases, such as lye, gradually dissolve skin on contact but can cause serious damage to eyes or mucous membranes much more rapidly. Ammonia is a far weaker base than lye, but has the distinction of being a gas and thus may more easily come into contact with the sensitive mucous membranes of the respiratory system. Quicklime, which has household uses, is a particularly common cause of poisoning. Some of the light metals, if handled carelessly, can not only cause thermal burns, but also produce very strongly basic solutions in sweat.
(T55) Toxic effect of soaps and detergents
(T56) Toxic effect of metals
A common trait shared by toxic metals is the chronic nature of their toxicity (a notable exception would be bismuth, which is considered entirely non-toxic). Low levels of toxic metal salts ingested over time accumulate in the body until toxic levels are reached. Toxic metals are often inaccurately referred to as "heavy metals", although not all heavy metals are necessarily harmful and not all toxic metals are heavy metals.
Toxic metals are generally far more toxic when ingested in the form of soluble salts than in elemental form. For example, metallic mercury passes through the human digestive tract without interaction and is commonly used in dental fillings—even though mercury salts and inhaled mercury vapor are highly toxic.
Examples:
- (T56.0) Lead poisoning
- (T56.1) Mercury
- (T56.2) Chromium
- (T56.3) Cadmium
- (T56.7) Beryllium (a highly but subtly toxic light metal)
- Antimony
- Barium
- Thallium
- Uranium
(T57) Toxic effect of other inorganic substances
- (T57.0) Arsenic (see arsenic poisoning)
Arsenic compounds
Arsenic trioxide
Fowler's solution
- Arsenic compounds
Arsenic trioxide
Fowler's solution
- Arsenic trioxide
- Fowler's solution
Reducing agents
- (T57.1) The most notable substance in this class is phosphorus.
(T58) Toxic effect of carbon monoxide
- (T58) By far the most notable metabolic poison is carbon monoxide, which blocks the ability of red blood cells to transport oxygen.
(T59) Toxic effect of other gases, fumes and vapours
- Formaldehyde (T59.2)
- Phosgene
- Phosphine
- Hydrogen sulfide
Oxidizers
Poisons of this class are generally not very harmful to higher life forms such as humans (for whom the outer layer of cells are more or less disposable), but lethal to microorganisms such as bacteria. Typical examples are ozone and chlorine (T59.4), either of which is added to nearly every municipal water supply in order to kill any harmful microorganisms present.
All halogens are strong oxidizing agents, fluorine (T59.5) being the strongest of all.
(T60) Toxic effect of pesticides
- Pesticide poisoning
- Fluoroacetate is a metabolic poison that blocks a vital step in the citric acid cycle.
- Rotenone is a metabolic poison that disrupts electron transport in cellular respiration.
(T61) Toxic effect of noxious substances eaten as seafood
- Ciguatera poisoning
- Scombroid poisoning
- Shellfish toxins (PSP, DSP, NSP, ASP )
- Domoic acid (or Amnesic shellfish poisoning, ASP)
- Tetrodotoxin
(T62) Toxic effect of other noxious substances eaten as food
- Food poisoning
- Botulin toxin
- Hemlock water dropwort
- Grayanotoxin (Honey intoxication)
- Tetanospasmin (Tetanos Toxin)
(T63) Toxic effect of venomous animals
- Snake and spider venoms
(T64) Toxic effect of aflatoxin and other mycotoxin food contaminants
- Fungal toxins
Amanita toxin, see Amanita phalloides
Muscarine
Aflatoxins
- Amanita toxin, see Amanita phalloides
- Muscarine
- Aflatoxins
(T65) Toxic effect of other and unspecified substances
- (T65.0) Cyanide is a metabolic poison that bonds with an enzyme involved in ATP production.
# Warning Symbols
Poisons have been known to be symbolized by the skull and crossbones, indicating lethal potential. This is the UN standard symbol, used in the European Union and in the Globally Harmonized System. However, it can be considered a liability for marketing. In the United States, other symbols such as Mr. Yuk have been suggested to replace the skull and crossbones. Proponents of the Mr. Yuk argue that the skull-and-crossbones symbols attracts children because of its association to pirates, and assert that Mr. Yuk does not. However, the Globally Harmonized System will be enforced also in the United States, including the skull-and-crossbones symbol.
Chemicals with non-lethal hazards, such as corrosivity, mild toxicity and harmfulness, may be informally referred to as "poisons", but are not usually marked with the skull-and-crossbones symbol. To contrast, see also the definitions of corrosive, harmful, environmentally hazardous and irritant. The UN standard symbol for harmful and irritant substances is a St Andrew's cross on an orange background, which is being replaced by an exclamation mark (or carcinogen symbol when applicable) in the Globally Harmonized System. This is applied to materials with non-lethal hazards as well as to potentially lethal materials.
# Uses of Poison
Poisons are usually not used for their toxicity, but may be used for their other properties. The property of toxicity itself has limited applications: mainly for controlling pests and weeds, and for preserving building materials and food stuffs. Where possible, specific agents which are less poisonous to humans have come to be preferred, but exceptions such as phosphine continue in use.
Throughout human history, intentional application of poison has been used as a method of assassination, murder, suicide and execution. [1][2] As a method of execution, poison has been ingested, as the ancient Athenians did (see Socrates), inhaled, as with carbon monoxide or hydrogen cyanide (see gas chamber), or injected (see lethal injection). Many languages describe lethal injection with their corresponding words for "poison shot". Poison was also employed in gunpowder warfare. For example, the 14th century Chinese text of the Huo Long Jing written by Jiao Yu outlined the use of a poisonous gunpowder mixture to fill cast iron grenade bombs.[3]
Poisonous materials are often used for their chemical or physical properties other than being poisonous. The most effective, easiest, safest, or cheapest option for use in a chemical synthesis may be a poisonous material. Particularly in experimental laboratory syntheses a specific reactivity is used, despite the toxicity of the reagent. Chromic acid is an example of such a "simple to use" reagent. Many technical applications call for some specific physical properties; a toxic substance may possess these properties and therefore be superior. Reactivity, in particular, is important. Hydrogen fluoride, for example, is poisonous and extremely corrosive. However, it has a high affinity for silicon, which is exploited by using HF to etch glass or to manufacture silicon semiconductor chips.
# Biological Poisoning
Acute poisoning is exposure to a poison on one occasion or during a short period of time. Symptoms develop in close relation to the exposure. Absorption of a poison is necessary for systemic poisoning. In contrast, substances that destroy tissue but do not absorb, such as lye, are classified as corrosives rather than poisons.
Chronic poisoning is long-term repeated or continuous exposure to a poison where symptoms do not occur immediately or after each exposure. The patient gradually becomes ill, or becomes ill after a long latent period. Chronic poisoning most commonly occurs following exposure to poisons that bioaccumulate such as mercury and lead.
Contact or absorption of poisons can cause rapid death or impairment. Agents that act on the nervous system can paralyze in seconds or less, and include both biologically derived neurotoxins and so-called nerve gases, which may be synthesized for warfare or industry.
Inhaled or ingested cyanide as used as method of execution on US gas chambers almost instantly starves the body of energy by inhibiting the enzymes in mitochondria that make ATP. Intravenous injection of an unnaturally high concentration of potassium chloride, such as in the execution of prisoners in parts of the United States, quickly stops the heart by eliminating the cell potential necessary for muscle contraction.
Most (but not all) biocides, including pesticides, are created to act as poisons to target organisms, although acute or less observable chronic poisoning can also occur in non-target organism, including the humans who apply the biocides and other beneficial organisms. For example, the herbicide 2,4-D imitates the action of a plant hormone, to the effect that the lethal toxicity is specific to plants. Indeed, 2,4-D is not a poison, but classified as "harmful" (EU).
Many substances regarded as poisons are toxic only indirectly, by toxication. An example is "wood alcohol" or methanol, which is not poisonous itself, but is chemically converted to toxic formaldehyde and formic acid in the liver. Many drug molecules are made toxic in the liver, and the genetic variability of certain liver enzymes makes the toxicity of many compounds differ between individuals.
The study of the symptoms, mechanisms, treatment and diagnosis of biological poisoning is known as toxicology.
Exposure to radioactive substances can produce radiation poisoning, an unrelated phenomenon.
# Treatment
- Poison Control Centers (In the US reachable at 1-800-222-1222 at all hours) provide immediate, free, and expert treatment advice and assistance over the telephone in case of suspected exposure to poisons or toxic substances.
## General First Aid
- If the poison is an inhalant, remove the patient from the area and to fresh air.
- If the poisoning is affecting the skin, remove the clothing and wash the skin thoroughly unless a dry powder is the cause of the poisoning.
- If the poison is in the eye, flush the eye thoroughly with water for at least 15 minutes.
- Following ingestion, do not induce vomiting or administer anything without medical advice.
- Contact a poison control center for advice on what to do next.
## Initial Medical Management
- Initial management for all poisonings includes ensuring adequate cardiopulmonary function and providing treatment for any symptoms such as seizures, shock, and pain.
## Decontamination
- If the toxin was recently ingested, absorption of the substance may be able to be decreased through gastric decontamination. This may be achieved using activated charcoal, gastric lavage, whole bowel irrigation, or nasogastric aspiration. Routine use of emetics (syrup of Ipecac) and cathartics are no longer recommended.
Activated charcoal is the treatment of choice to prevent absorption of the poison. It is usually administered when the patient is in the emergency room. However, charcoal is ineffective against metals, Na, K, alcohols, glycols, acids, and alkalis.
Whole bowel irrigation cleanses the bowel, this is achieved by giving the patient large amounts of a polyethylene glycol solution. The osmotically balanced polyethylene glycol solution is not absorbed into the body, having the effect of flushing out the entire gastrointestinal tract. Its major uses are following ingestion of sustained release drugs, toxins that are not absorbed by activated charcoal (i.e. lithium, iron), and for the removal of ingested packets of drugs (body packing/smuggling).[4]
Gastric lavage, commonly known as a stomach pump, is the insertion of a tube into the stomach, followed by administration of water or saline down the tube. The liquid is then removed along with the contents of the stomach. Lavage has been used for many years as a common treatment for poisoned patients. However, a recent review of the procedure in poisonings suggests no benefit.[5] It is still sometimes used if it can be performed within 1 h of ingestion and the exposure is potentially life threatening.
Nasogastric aspiration involves the placement of a tube via the nose down into the stomach, the stomach contents are then removed via suction. This procedure is mainly used for liquid ingestions where activated charcoal is ineffective, i.e. ethylene glycol.
Emesis (i.e. induced by ipecac) is no longer recommended in poisoning situations.[6]
Cathartics were postulated to decrease absorption by increasing the expulsion of the poison from the gastrointestinal tract. There are two types of cathartics used in poisoned patients; saline cathartics (sodium sulfate, magnesium citrate, magnesium sulfate) and saccharide cathartics (sorbitol). They do not appear to improve patient outcome and are no longer recommended.[7]
- Activated charcoal is the treatment of choice to prevent absorption of the poison. It is usually administered when the patient is in the emergency room. However, charcoal is ineffective against metals, Na, K, alcohols, glycols, acids, and alkalis.
- Whole bowel irrigation cleanses the bowel, this is achieved by giving the patient large amounts of a polyethylene glycol solution. The osmotically balanced polyethylene glycol solution is not absorbed into the body, having the effect of flushing out the entire gastrointestinal tract. Its major uses are following ingestion of sustained release drugs, toxins that are not absorbed by activated charcoal (i.e. lithium, iron), and for the removal of ingested packets of drugs (body packing/smuggling).[4]
- Gastric lavage, commonly known as a stomach pump, is the insertion of a tube into the stomach, followed by administration of water or saline down the tube. The liquid is then removed along with the contents of the stomach. Lavage has been used for many years as a common treatment for poisoned patients. However, a recent review of the procedure in poisonings suggests no benefit.[5] It is still sometimes used if it can be performed within 1 h of ingestion and the exposure is potentially life threatening.
- Nasogastric aspiration involves the placement of a tube via the nose down into the stomach, the stomach contents are then removed via suction. This procedure is mainly used for liquid ingestions where activated charcoal is ineffective, i.e. ethylene glycol.
- Emesis (i.e. induced by ipecac) is no longer recommended in poisoning situations.[6]
- Cathartics were postulated to decrease absorption by increasing the expulsion of the poison from the gastrointestinal tract. There are two types of cathartics used in poisoned patients; saline cathartics (sodium sulfate, magnesium citrate, magnesium sulfate) and saccharide cathartics (sorbitol). They do not appear to improve patient outcome and are no longer recommended.[7]
## Antidotes
Some poisons have specific antidotes:
## Enhanced Excretion
- In some situations elimination of the poison can be enhanced using diuresis, hemodialysis, hemoperfusion, peritoneal dialysis, or exchange transfusion.
## Further Treatment
- In the majority of poisonings the mainstay of management is providing supportive care for the patient, i.e. treating the symptoms rather than the poison. | https://www.wikidoc.org/index.php/Noxious | |
54e89a1fd4e58c83785fd5d47a8c055b3b7d6b82 | wikidoc | Nutmeg | Nutmeg
The nutmegs Myristica are a genus of evergreen trees indigenous to tropical southeast Asia and Australasia. They are important for two spices derived from the fruit, nutmeg and mace.
Nutmeg is the actual seed of the tree, roughly egg-shaped and about 20–30 mm long and 15–18 mm wide, and weighing between 5 and 10 grams dried, while mace is the dried "lacy" reddish covering or arillus of the seed.
Several other commercial products are also produced from the trees, including essential oils, extracted oleoresins, and nutmeg butter (see below).
The outer surface of the nutmeg bruises easily.
The pericarp (fruit/pod) is used in Grenada to make a jam called Morne Delice. In Indonesia, the fruit is sliced finely, cooked and crystallised to make a fragrant candy called manisan pala ("nutmeg sweets").
The most important species commercially is the Common or Fragrant Nutmeg Myristica fragrans, native to the Banda Islands of Indonesia; it is also grown in the Caribbean, especially in Grenada. Other species include Papuan Nutmeg M. argentea from New Guinea, and Bombay Nutmeg M. malabarica from India; both are used as adulterants of M. fragrans products.
# Culinary uses
Nutmeg and mace have similar taste qualities, nutmeg having a slightly sweeter and mace a more delicate flavor. Mace is often preferred in light-coloured dishes for the bright orange, saffron-like colour it imparts. Nutmeg is a flavorsome addition to cheese sauces and is best grated fresh (see nutmeg grater).
In Indian cuisine, nutmeg powder is used almost exclusively in sweet dishes. It is known as Jaiphal in most parts of India. It may also be used in small quantities in garam masala.
In Middle Eastern cuisine, nutmeg powder is often used as a spice for savoury dishes. In Arabic, nutmeg is called Jawz at-Tiyb.
In European cuisine, nutmeg and mace are used especially in potato dishes and in processed meat products; they are also used in soups, sauces and baked goods.
Japanese varieties of curry powder include nutmeg as an ingredient.
Nutmeg is a traditional ingredient in mulled cider, mulled wine, and eggnog.
# Essential oils
The essential oil is obtained by the steam distillation of ground nutmeg and is used heavily in the perfumery and pharmaceutical industries.
The oil is colourless or light yellow and smells and tastes of nutmeg. It contains numerous components of interest to the oleochemical industry, and is used as a natural food flavouring in baked goods, syrups (e.g. Coca Cola), beverages, sweets etc. It replaces ground nutmeg as it leaves no particles in the food. The essential oil is also used in the cosmetic and pharmaceutical industries for instance in tooth paste and as major ingredient in some cough syrups. In traditional medicine nutmeg and nutmeg oil were used for illnesses related to the nervous and digestive systems. Myristicin and elemicin are believed to be the chemical constituents responsible for the subtle hallucinogenic properties of nutmeg oil. Other known chemical ingredients of the oil are α-pinene, sabinene, γ-terpinene and safrole.
Externally, the oil is used for rheumatic pain and, like clove oil, can be applied as an emergency treatment to dull toothache. Put 1–2 drops on a cotton swab, and apply to the gums around an aching tooth until dental treatment can be obtained. In France, it is given in drop doses in honey for digestive upsets and used for bad breath. Use 3–5 drops on a sugar lump or in a teaspoon of honey for nausea, gastroenteritis, chronic diarrhea, and indigestion.
Alternatively a massage oil can be created by diluting 10 drops in 10 ml almond oil. This can be used for muscular pains associated with rheumatism or overexertion. It can also be combined with thyme or rosemary essential oils. To prepare for childbirth, massaging the abdomen daily in the three weeks before the baby is due with a mixture of 5 drops nutmeg oil and no more than 5 drops sage oil in 25 ml almond oil has been suggested.
# Nutmeg butter
Nutmeg butter is obtained from the nut by expression. It is semi solid and reddish brown in colour and tastes and smells of nutmeg. Approximately 75% (by weight) of nutmeg butter is trimyristin which can be turned into myristic acid, a 14-carbon fatty acid which can be used as replacement for cocoa butter, can be mixed with other fats like cottonseed oil or palm oil, and has applications as an industrial lubricant.
# History
There is some evidence that Roman priests may have burned nutmeg as a form of incense, although this is disputed. It is known to have been used as a prized and costly spice in medieval cuisine. Saint Theodore the Studite ( ca. 758 – ca. 826), was famous for allowing his monks to sprinkle nutmeg on their pease pudding when required to eat it. In Elizabethan times it was believed that nutmeg could ward off the plague, so nutmeg was very popular. Nutmeg was traded by Arabs during the Middle Ages in the profitable Indian Ocean trade.
In the late 15th century, Portugal started trading in the Indian Ocean, including nutmeg, under the Treaty of Tordesillas with Spain and a separate treaty with the sultan of Ternate. But full control of this trade was not possible and they remained largely participants, rather than overlords since the authority Ternate held over the nutmeg-growing centre of the Banda Islands was quite limited, therefore the Portuguese failed to gain a foothold in the islands themselves.
The trade in nutmeg later became dominated by the Dutch in the 17th century. The British and Dutch engaged in prolonged struggles and intrigue to gain control of Run island, then the only source of nutmegs. At the end of the Second Anglo-Dutch War the Dutch gained control of Run in exchange for the British controlling New Amsterdam (New York) in North America.
The Dutch managed to establish control over the Banda Islands after an extended military campaign that culminated in the massacre or expulsion of most of the islands' inhabitants in 1621. Thereafter, the Banda Islands were run as a series of plantation estates, with the Dutch mounting annual expeditions in local war-vessels to extirpate nutmeg trees planted elsewhere.
As a result of the Dutch interregnum during the Napoleonic Wars, the English took temporary control of the Banda Islands from the Dutch and transplanted nutmeg trees to their own colonial holdings elsewhere, notably Zanzibar and Grenada. Today, a stylised split-open nutmeg fruit is found on the national flag of Grenada.
Connecticut gets its nickname ("the Nutmeg State", "Nutmegger") from the legend that some unscrupulous Connecticut traders would whittle "nutmeg" out of wood, creating a "wooden nutmeg" (a term which came to mean any fraud) .
# World production
World production of nutmeg is estimated to average between 10,000 and 12,000 tonnes per year with annual world demand estimated at 9,000 tonnes; production of mace is estimated at 1,500 to 2,000 tonnes. Indonesia and Grenada dominate production and exports of both products with a world market share of 75% and 20% respectively. Other producers include India, Malaysia, Papua New Guinea, Sri Lanka and Caribbean islands such as St. Vincent. The principal import markets are the European Community, the United States, Japan and India. Singapore and the Netherlands are major re-exporters.
At one time, nutmeg was one of the most valuable spices. It has been said that in England, several hundred years ago, a few nutmeg nuts could be sold for enough money to enable financial independence for life.
The first harvest of nutmeg trees takes place 7–9 years after planting and the trees reach their full potential after 20 years.
# Risks and toxicity
In low doses, nutmeg produces no noticeable physiological or neurological response. Large doses of 30 g (~6 teaspoons) or more are dangerous, potentially inducing convulsions, palpitations, nausea, eventual dehydration, and generalized body pain "BMJ"..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} In amounts of 5–20 g (~1-4 teaspoons) it is a mild to medium hallucinogen, producing visual distortions and a mild euphoria. It is a common misconception that nutmeg contains monoamine oxidase inhibitors (MAOIs). While this is untrue, nutmeg taken in combination with MAOIs may elevate risks. A test was carried out on the substance that showed that, when ingested in large amounts, nutmeg takes on a similar chemical make-up to MDMA (ecstasy). However, use of nutmeg as a recreational drug is unpopular due to its unpleasant taste and its side effects, including dizziness, flushes, dry mouth, accelerated heartbeat, temporary constipation, difficulty in urination, nausea, and panic. A user will not experience a peak until approximately six hours after ingestion, and effects can linger for up to three days afterwards.
A risk in any large-quantity (over 25 g, ~5 teaspoons) ingestion of nutmeg is the onset of 'nutmeg poisoning', an acute psychiatric disorder marked by thought disorder, a sense of impending death, and agitation. Some cases have resulted in hospitalization.
Fatal doses in children are significantly lower, with approximately 15g being sufficient to cause one of only two recorded nutmeg toxicity deaths, in an eight year old child."BMJ".
Nutmeg is an abortifacient, and as such any significant doses should be avoided by pregnant women."BMJ".
# Nutmeg in literature
Nutmeg appeared to fascinate the 16th-century Europeans, as reflected in this nursery rhyme:
I had a little nut tree,Nothing would it bearBut a silver nutmeg,And a golden pear;The King of Spain's daughterCame to visit me,And all for the sakeOf my little nut tree.Her dress was made of crimson,Jet black was her hair,She asked me for my nut treeAnd my golden pear.I said, "So fair a princessNever did I see,I'll give you all the fruitFrom my little nut tree.
This nursery rhyme is believed to refer to the 1506 visit of the Royal House of Spain to King Henry VII's English court. The 'King of Spain's daughter' refers to the daughter of King Ferdinand and Queen Isabella of Spain. The princess is probably Katherine of Aragon who was betrothed to Prince Arthur, the heir to the English throne. He died, thus Katherine married King Henry VIII. Prince Arthur was reputed to have deformed genitals (his little nut tree would bear nothing) and the 'silver nutmeg' refers to England's spice trade with the East, while the 'golden pear' refers to trade with the West (the golden pear is the ancient Greek Symbol for the Hesperides or West). The Spanish were hoping to gain these by marriage of the Spanish Princess to the English prince, though they were aware there would be no children from the marriage. The last verse is therefore ironic.
Another version has a different ending:
I had a little nut tree,Nothing would it bearBut a silver nutmegAnd a golden pear.The King of Spain’s daughterCame to visit me,And all for the sakeOf my little nut tree.I skipped over ocean,I danced over sea,And all the birds in the airCouldn’t catch me.
The last verse in this version is supposed to refer to Prince Arthur's death shortly after he married the Spanish princess.
The 'Benway' chapter of William Burroughs' Naked Lunch devotes a paragraph to Nutmeg use, quoting the British Journal of Addiction and stating among other things: "Result vaguely similar to marijuana with side effects of headache and nausea".
In a June 2007 issue of an underground, anti-Internet magazine called Magazine X (distributed at punk concerts in New York City) states that regular recreational users of nutmeg in New York City refer to themselves as "Nutheads." | Nutmeg
The nutmegs Myristica are a genus of evergreen trees indigenous to tropical southeast Asia and Australasia. They are important for two spices derived from the fruit, nutmeg and mace.
Nutmeg is the actual seed of the tree, roughly egg-shaped and about 20–30 mm long and 15–18 mm wide, and weighing between 5 and 10 grams dried, while mace is the dried "lacy" reddish covering or arillus of the seed.
Several other commercial products are also produced from the trees, including essential oils, extracted oleoresins, and nutmeg butter (see below).
The outer surface of the nutmeg bruises easily.
The pericarp (fruit/pod) is used in Grenada to make a jam called Morne Delice. In Indonesia, the fruit is sliced finely, cooked and crystallised to make a fragrant candy called manisan pala ("nutmeg sweets").
The most important species commercially is the Common or Fragrant Nutmeg Myristica fragrans, native to the Banda Islands of Indonesia; it is also grown in the Caribbean, especially in Grenada. Other species include Papuan Nutmeg M. argentea from New Guinea, and Bombay Nutmeg M. malabarica from India; both are used as adulterants of M. fragrans products.
# Culinary uses
Nutmeg and mace have similar taste qualities, nutmeg having a slightly sweeter and mace a more delicate flavor. Mace is often preferred in light-coloured dishes for the bright orange, saffron-like colour it imparts. Nutmeg is a flavorsome addition to cheese sauces and is best grated fresh (see nutmeg grater).
In Indian cuisine, nutmeg powder is used almost exclusively in sweet dishes. It is known as Jaiphal in most parts of India. It may also be used in small quantities in garam masala.
In Middle Eastern cuisine, nutmeg powder is often used as a spice for savoury dishes. In Arabic, nutmeg is called Jawz at-Tiyb.
In European cuisine, nutmeg and mace are used especially in potato dishes and in processed meat products; they are also used in soups, sauces and baked goods.
Japanese varieties of curry powder include nutmeg as an ingredient.
Nutmeg is a traditional ingredient in mulled cider, mulled wine, and eggnog.
# Essential oils
The essential oil is obtained by the steam distillation of ground nutmeg and is used heavily in the perfumery and pharmaceutical industries.
The oil is colourless or light yellow and smells and tastes of nutmeg. It contains numerous components of interest to the oleochemical industry, and is used as a natural food flavouring in baked goods, syrups (e.g. Coca Cola[citation needed]), beverages, sweets etc. It replaces ground nutmeg as it leaves no particles in the food. The essential oil is also used in the cosmetic and pharmaceutical industries for instance in tooth paste and as major ingredient in some cough syrups. In traditional medicine nutmeg and nutmeg oil were used for illnesses related to the nervous and digestive systems. Myristicin and elemicin are believed to be the chemical constituents responsible for the subtle hallucinogenic properties of nutmeg oil. Other known chemical ingredients of the oil are α-pinene, sabinene, γ-terpinene and safrole.
Externally, the oil is used for rheumatic pain and, like clove oil, can be applied as an emergency treatment to dull toothache. Put 1–2 drops on a cotton swab, and apply to the gums around an aching tooth until dental treatment can be obtained. In France, it is given in drop doses in honey for digestive upsets and used for bad breath. Use 3–5 drops on a sugar lump or in a teaspoon of honey for nausea, gastroenteritis, chronic diarrhea, and indigestion.
Alternatively a massage oil can be created by diluting 10 drops in 10 ml almond oil. This can be used for muscular pains associated with rheumatism or overexertion. It can also be combined with thyme or rosemary essential oils. To prepare for childbirth, massaging the abdomen daily in the three weeks before the baby is due with a mixture of 5 drops nutmeg oil and no more than 5 drops sage oil in 25 ml almond oil has been suggested.
# Nutmeg butter
Nutmeg butter is obtained from the nut by expression. It is semi solid and reddish brown in colour and tastes and smells of nutmeg. Approximately 75% (by weight) of nutmeg butter is trimyristin which can be turned into myristic acid, a 14-carbon fatty acid which can be used as replacement for cocoa butter, can be mixed with other fats like cottonseed oil or palm oil, and has applications as an industrial lubricant.
# History
There is some evidence that Roman priests may have burned nutmeg as a form of incense, although this is disputed. It is known to have been used as a prized and costly spice in medieval cuisine. Saint Theodore the Studite ( ca. 758 – ca. 826), was famous for allowing his monks to sprinkle nutmeg on their pease pudding when required to eat it. In Elizabethan times it was believed that nutmeg could ward off the plague, so nutmeg was very popular. Nutmeg was traded by Arabs during the Middle Ages in the profitable Indian Ocean trade.
In the late 15th century, Portugal started trading in the Indian Ocean, including nutmeg, under the Treaty of Tordesillas with Spain and a separate treaty with the sultan of Ternate. But full control of this trade was not possible and they remained largely participants, rather than overlords since the authority Ternate held over the nutmeg-growing centre of the Banda Islands was quite limited, therefore the Portuguese failed to gain a foothold in the islands themselves.
The trade in nutmeg later became dominated by the Dutch in the 17th century. The British and Dutch engaged in prolonged struggles and intrigue to gain control of Run island, then the only source of nutmegs. At the end of the Second Anglo-Dutch War the Dutch gained control of Run in exchange for the British controlling New Amsterdam (New York) in North America.
The Dutch managed to establish control over the Banda Islands after an extended military campaign that culminated in the massacre or expulsion of most of the islands' inhabitants in 1621. Thereafter, the Banda Islands were run as a series of plantation estates, with the Dutch mounting annual expeditions in local war-vessels to extirpate nutmeg trees planted elsewhere.
As a result of the Dutch interregnum during the Napoleonic Wars, the English took temporary control of the Banda Islands from the Dutch and transplanted nutmeg trees to their own colonial holdings elsewhere, notably Zanzibar and Grenada. Today, a stylised split-open nutmeg fruit is found on the national flag of Grenada.
Connecticut gets its nickname ("the Nutmeg State", "Nutmegger") from the legend that some unscrupulous Connecticut traders would whittle "nutmeg" out of wood, creating a "wooden nutmeg" (a term which came to mean any fraud) [1].
# World production
World production of nutmeg is estimated to average between 10,000 and 12,000 tonnes per year with annual world demand estimated at 9,000 tonnes; production of mace is estimated at 1,500 to 2,000 tonnes. Indonesia and Grenada dominate production and exports of both products with a world market share of 75% and 20% respectively. Other producers include India, Malaysia, Papua New Guinea, Sri Lanka and Caribbean islands such as St. Vincent. The principal import markets are the European Community, the United States, Japan and India. Singapore and the Netherlands are major re-exporters.
At one time, nutmeg was one of the most valuable spices. It has been said that in England, several hundred years ago, a few nutmeg nuts could be sold for enough money to enable financial independence for life.
The first harvest of nutmeg trees takes place 7–9 years after planting and the trees reach their full potential after 20 years.
# Risks and toxicity
In low doses, nutmeg produces no noticeable physiological or neurological response. Large doses of 30 g (~6 teaspoons) or more are dangerous, potentially inducing convulsions, palpitations, nausea, eventual dehydration, and generalized body pain "BMJ"..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} In amounts of 5–20 g (~1-4 teaspoons) it is a mild to medium hallucinogen, producing visual distortions and a mild euphoria. It is a common misconception that nutmeg contains monoamine oxidase inhibitors (MAOIs). While this is untrue, nutmeg taken in combination with MAOIs may elevate risks.[1] A test was carried out on the substance that showed that, when ingested in large amounts, nutmeg takes on a similar chemical make-up to MDMA (ecstasy). However, use of nutmeg as a recreational drug is unpopular due to its unpleasant taste and its side effects, including dizziness, flushes, dry mouth, accelerated heartbeat, temporary constipation, difficulty in urination, nausea, and panic. A user will not experience a peak until approximately six hours after ingestion, and effects can linger for up to three days afterwards.
A risk in any large-quantity (over 25 g, ~5 teaspoons) ingestion of nutmeg is the onset of 'nutmeg poisoning', an acute psychiatric disorder marked by thought disorder, a sense of impending death, and agitation. Some cases have resulted in hospitalization.
Fatal doses in children are significantly lower, with approximately 15g being sufficient to cause one of only two recorded nutmeg toxicity deaths, in an eight year old child."BMJ".
Nutmeg is an abortifacient, and as such any significant doses should be avoided by pregnant women."BMJ".
# Nutmeg in literature
Nutmeg appeared to fascinate the 16th-century Europeans, as reflected in this nursery rhyme:
I had a little nut tree,Nothing would it bearBut a silver nutmeg,And a golden pear;The King of Spain's daughterCame to visit me,And all for the sakeOf my little nut tree.Her dress was made of crimson,Jet black was her hair,She asked me for my nut treeAnd my golden pear.I said, "So fair a princessNever did I see,I'll give you all the fruitFrom my little nut tree.
This nursery rhyme is believed to refer to the 1506 visit of the Royal House of Spain to King Henry VII's English court. The 'King of Spain's daughter' refers to the daughter of King Ferdinand and Queen Isabella of Spain. The princess is probably Katherine of Aragon who was betrothed to Prince Arthur, the heir to the English throne. He died, thus Katherine married King Henry VIII. Prince Arthur was reputed to have deformed genitals (his little nut tree would bear nothing) and the 'silver nutmeg' refers to England's spice trade with the East, while the 'golden pear' refers to trade with the West (the golden pear is the ancient Greek Symbol for the Hesperides or West). The Spanish were hoping to gain these by marriage of the Spanish Princess to the English prince, though they were aware there would be no children from the marriage. The last verse is therefore ironic.
Another version has a different ending:
I had a little nut tree,Nothing would it bearBut a silver nutmegAnd a golden pear.The King of Spain’s daughterCame to visit me,And all for the sakeOf my little nut tree.I skipped over ocean,I danced over sea,And all the birds in the airCouldn’t catch me.
The last verse in this version is supposed to refer to Prince Arthur's death shortly after he married the Spanish princess.
The 'Benway' chapter of William Burroughs' Naked Lunch devotes a paragraph to Nutmeg use, quoting the British Journal of Addiction and stating among other things: "Result vaguely similar to marijuana with side effects of headache and nausea".
In a June 2007 issue of an underground, anti-Internet magazine called Magazine X (distributed at punk concerts in New York City) states that regular recreational users of nutmeg in New York City refer to themselves as "Nutheads." | https://www.wikidoc.org/index.php/Nutmeg | |
b6f62855fde8837d5d3399bbe1117cf2991239e4 | wikidoc | OPN1LW | OPN1LW
OPN1LW is a gene on the X chromosome that encodes for long wave sensitive (LWS) opsin, or red cone photopigment. It is responsible for perception of visible light in the yellow-green range on the visible spectrum (around 500-570nm). The gene contains 6 exons with variability that induces shifts in the spectral range. OPN1LW is subject to homologous recombination with OPN1MW, as the two have very similar genomes. These recombinations can lead to various vision problems, such as red-green colourblindness and blue monochromacy. The protein encoded is a G-protein coupled receptor with embedded 11-cis-retinal, whose light excitation causes a cis-trans conformational change that begins the process of chemical signalling to the brain.
# Gene
OPN1LW produces red-sensitive opsin, while it's counterparts, OPN1MW and OPN1SW, produce green-sensitive and blue-sensitive opsin respectively. OPN1LW and OPN1MW are on the X chromosome at position Xq28. They are in a tandem array, composed of a single OPN1LW gene which is followed by one or more OPN1MW genes.The locus control region (LCR) regulates expression of both genes, with only the OPN1LW gene and nearby adjacent OPN1MW genes being expressed and contributing to the colour vision phenotype. The LCR can not reach further than the first or second OPN1MW genes in the array. The slight difference in OPN1LW and OPN1MW absorption spectra is due to a handful of amino acid differences between the two highly similar genes.
## Exons
OPN1LW and OPN1MW both have six exons. Amino acid dimorphisms on exon 5 at positions 277 and 285 are the most influential on the spectral differences observed between LWS and MWS pigments. There are 3 amino acid changes on exon 5 for OPN1LW and OPN1MW that contribute to the spectral shift seen between their respective opsin: OPN1MW has phenylalanine at positions 277 and 309, and alanine at 285; OPN1LW have tyrosine at position 277 and 309, and threonine at position 285. The identity of the amino acids at these positions in exon 5 is what determines the gene as being M class or L class. On exon 3 at position 180 both genes can contain serine or alanine, but the presence of serine produces longer wavelength sensitivity. Exon 4 has two spectral tuning positions: 230 for isoleucine (longer peak wavelength) or threonine, and 233 for alanine (longer peak wavelength) or isoleucine.
## Homologous recombination
The arrangement of OPN1LW and OPN1MW, as well as the high similarity of the two genes, allows for frequent recombination between the two. Unequal recombination between female X chromosomes during meiosis is the main cause of the varying number of OPN1LW genes and OPN1MW genes among individuals, as well as being the cause of inherited colour vision deficiencies. Recombination events usually begin with misalignment of an OPN1LW gene with an OPN1MW gene and are followed by a certain type of crossover, which can result in many different gene abnormalities. Crossover in regions between OPN1LW and OPN1MW genes can produce chromosome products with extra OPN1LW or OPN1MW genes on one chromosome and reduced OPN1LW or OPN1MW genes on the other chromosome. If crossover occurs within the misaligned genes of OPN1LW and OPN1MW, then a new array will be produced on each chromosome consisting of only partial pieces of the two genes. This would create colour vision deficiencies if either chromosome were passed onto a male offspring.
# Protein
The LWS type I opsin is a G-protein coupled receptor (GPCR) protein with embedded 11-cis retinal. It is a transmembrane protein that has seven membrane domains, with the N-terminal being extracellular and the C-terminal being cytoplasmic. The LWS pigment has a maximum absorption of about 564nm, with an absorption range of around 500-570 nm. This opsin is known as the red opsin because it is the most sensitive to red light out of the three cone opsin types, not because its peak sensitivity is for red light. The peak absorption of 564nm actually falls in the yellow-green section of the visible light spectrum. When the protein comes in contact with light at a wavelength within its spectral range, the 11-cis-retinal chromophore becomes excited. The amount of energy in the light breaks the pi bond that holds the chromophore in its cis configuration, which causes photoisomerization and a shift to the trans configuration. This shift is what begins the chemical reaction sequence responsible for getting the LWS cone signal to the brain.
# Function
LWS opsin resides in disks of the outer segment of LWS cone cells, which mediate photopic vision along with MWS and SWS cones. Cone representation in the retina is substantially smaller than rod representation, with the majority of cones localizing in the fovea. When light within the LWS opsin spectral range reaches the retina, the 11-cis-retinal chromophore within the opsin protein becomes excited. This excitation causes a conformational change in the protein and triggers a series of chemical reactions. This reaction series passes from the LWS cone cells into horizontal cells, bipolar cells, amacrine cells, and finally ganglion cells before continuing to the brain via the optic nerve. Ganglion cells compile the signal from the LWS cones with all other cone signals that occurred in response to the light that was seen, and pass the overall signal into the optic nerve. The cones themselves do not process colour, it is the brain that decides what colour is being seen by the signal combination it receives from the ganglion cells.
# Evolutionary history
Before humans evolved to be a trichromatic species, our vision was dichromatic and consisted of only the OPN1LW and OPN1SW genes. OPN1LW is thought to have undergone a duplication event that lead to an extra copy of the gene, which then evolved independently to become OPN1MW. OPN1LW and OPN1MW share almost all of their DNA sequences, whereas OPN1LW and OPN1SW share less than half, suggesting that the long wave and medium wave genes diverged from each other much more recently than with OPN1SW. The emergence of OPN1MW is directly associated with dichromacy evolving to trichromacy. The presence of both LSW and MSW opsins improves colour recognition time, memorization for coloured objects, and distance-dependent discrimination, giving trichromatic organisms an evolutionary advantage over dichromatic organisms when searching for nutrient-rich food sources.
Cone pigments are the product of ancestral visual pigments, which consisted of only cone cells and no rod cells. These ancestral cones evolved to become the cone cells we know today (LWS, MWS, SWS), as well as rod cells.
# Vision impairments
## Red-green colour blindness
Many genetic changes of the OPN1LW and/or OPN1MW genes can cause red-green colourblindness. The majority of these genetic changes involve recombination events between the highly similar genes of OPN1LW and OPN1MW, which can result in deletion of one or both of these genes. Recombination can also result in the creation of many different OPN1LW and OPN1MW chimeras, which are genes that are similar to the original, but have different spectral properties. Single base-pair changes in OPN1LW can also inflict red-green colourblindness, but this is uncommon. The severity of vision loss in a red-green colourblind individual is influenced by the Ser180Ala polymorphism.
### Protanopia
Protanopia is caused by defective or total loss of the OPN1LW gene function, causing vision that is entirely dependent on OPN1MW and OPN1SW. Affected individuals have dichromatic vision, with the inability to fully differentiate between green, yellow, and red colour.
### Protanomaly
Protanomaly occurs when a partially functional hybrid OPN1LW gene replaces the normal gene. Opsins made from these hybrid genes have abnormal spectral shifts that impair colour perception for colours in the OPN1LW spectrum. Protanomaly is one form of anomalous trichromacy.
## Blue cone monochromacy
Blue cone monochromacy is caused by a loss of function of both OPN1LW and OPN1MW. This is commonly caused by mutations in the LCR, which would result in no expression of OPN1LW or OPN1MW. With this visual impairment, the individual can only see colours in the spectrum for SWS opsins, which fall in the blue range of light. | OPN1LW
OPN1LW is a gene on the X chromosome that encodes for long wave sensitive (LWS) opsin, or red cone photopigment.[1] It is responsible for perception of visible light in the yellow-green range on the visible spectrum (around 500-570nm).[2][3] The gene contains 6 exons with variability that induces shifts in the spectral range.[4] OPN1LW is subject to homologous recombination with OPN1MW, as the two have very similar genomes.[4] These recombinations can lead to various vision problems, such as red-green colourblindness and blue monochromacy.[5] The protein encoded is a G-protein coupled receptor with embedded 11-cis-retinal, whose light excitation causes a cis-trans conformational change that begins the process of chemical signalling to the brain.[6]
# Gene
OPN1LW produces red-sensitive opsin, while it's counterparts, OPN1MW and OPN1SW, produce green-sensitive and blue-sensitive opsin respectively.[3] OPN1LW and OPN1MW are on the X chromosome at position Xq28.[7] They are in a tandem array, composed of a single OPN1LW gene which is followed by one or more OPN1MW genes.[7]The locus control region (LCR) regulates expression of both genes, with only the OPN1LW gene and nearby adjacent OPN1MW genes being expressed and contributing to the colour vision phenotype.[7] The LCR can not reach further than the first or second OPN1MW genes in the array.[7] The slight difference in OPN1LW and OPN1MW absorption spectra is due to a handful of amino acid differences between the two highly similar genes.[4]
## Exons
OPN1LW and OPN1MW both have six exons.[4] Amino acid dimorphisms on exon 5 at positions 277 and 285 are the most influential on the spectral differences observed between LWS and MWS pigments.[4] There are 3 amino acid changes on exon 5 for OPN1LW and OPN1MW that contribute to the spectral shift seen between their respective opsin: OPN1MW has phenylalanine at positions 277 and 309, and alanine at 285; OPN1LW have tyrosine at position 277 and 309, and threonine at position 285.[4] The identity of the amino acids at these positions in exon 5 is what determines the gene as being M class or L class.[4] On exon 3 at position 180 both genes can contain serine or alanine, but the presence of serine produces longer wavelength sensitivity.[4] Exon 4 has two spectral tuning positions: 230 for isoleucine (longer peak wavelength) or threonine, and 233 for alanine (longer peak wavelength) or isoleucine.[4]
## Homologous recombination
The arrangement of OPN1LW and OPN1MW, as well as the high similarity of the two genes, allows for frequent recombination between the two.[4] Unequal recombination between female X chromosomes during meiosis is the main cause of the varying number of OPN1LW genes and OPN1MW genes among individuals, as well as being the cause of inherited colour vision deficiencies.[4] Recombination events usually begin with misalignment of an OPN1LW gene with an OPN1MW gene and are followed by a certain type of crossover, which can result in many different gene abnormalities. Crossover in regions between OPN1LW and OPN1MW genes can produce chromosome products with extra OPN1LW or OPN1MW genes on one chromosome and reduced OPN1LW or OPN1MW genes on the other chromosome.[4] If crossover occurs within the misaligned genes of OPN1LW and OPN1MW, then a new array will be produced on each chromosome consisting of only partial pieces of the two genes.[4] This would create colour vision deficiencies if either chromosome were passed onto a male offspring.[4]
# Protein
The LWS type I opsin is a G-protein coupled receptor (GPCR) protein with embedded 11-cis retinal.[7] It is a transmembrane protein that has seven membrane domains, with the N-terminal being extracellular and the C-terminal being cytoplasmic.[1] The LWS pigment has a maximum absorption of about 564nm, with an absorption range of around 500-570 nm.[2] This opsin is known as the red opsin because it is the most sensitive to red light out of the three cone opsin types, not because its peak sensitivity is for red light.[3] The peak absorption of 564nm actually falls in the yellow-green section of the visible light spectrum.[3] When the protein comes in contact with light at a wavelength within its spectral range, the 11-cis-retinal chromophore becomes excited.[6] The amount of energy in the light breaks the pi bond that holds the chromophore in its cis configuration, which causes photoisomerization and a shift to the trans configuration.[6] This shift is what begins the chemical reaction sequence responsible for getting the LWS cone signal to the brain.[6]
# Function
LWS opsin resides in disks of the outer segment of LWS cone cells, which mediate photopic vision along with MWS and SWS cones.[6][8] Cone representation in the retina is substantially smaller than rod representation, with the majority of cones localizing in the fovea.[8] When light within the LWS opsin spectral range reaches the retina, the 11-cis-retinal chromophore within the opsin protein becomes excited.[6] This excitation causes a conformational change in the protein and triggers a series of chemical reactions.[6] This reaction series passes from the LWS cone cells into horizontal cells, bipolar cells, amacrine cells, and finally ganglion cells before continuing to the brain via the optic nerve.[6] Ganglion cells compile the signal from the LWS cones with all other cone signals that occurred in response to the light that was seen, and pass the overall signal into the optic nerve.[2] The cones themselves do not process colour, it is the brain that decides what colour is being seen by the signal combination it receives from the ganglion cells.[6]
# Evolutionary history
Before humans evolved to be a trichromatic species, our vision was dichromatic and consisted of only the OPN1LW and OPN1SW genes.[4] OPN1LW is thought to have undergone a duplication event that lead to an extra copy of the gene, which then evolved independently to become OPN1MW.[4] OPN1LW and OPN1MW share almost all of their DNA sequences, whereas OPN1LW and OPN1SW share less than half, suggesting that the long wave and medium wave genes diverged from each other much more recently than with OPN1SW.[7] The emergence of OPN1MW is directly associated with dichromacy evolving to trichromacy.[2] The presence of both LSW and MSW opsins improves colour recognition time, memorization for coloured objects, and distance-dependent discrimination, giving trichromatic organisms an evolutionary advantage over dichromatic organisms when searching for nutrient-rich food sources.[2]
Cone pigments are the product of ancestral visual pigments, which consisted of only cone cells and no rod cells.[6] These ancestral cones evolved to become the cone cells we know today (LWS, MWS, SWS), as well as rod cells.[6]
# Vision impairments
## Red-green colour blindness
Many genetic changes of the OPN1LW and/or OPN1MW genes can cause red-green colourblindness.[5] The majority of these genetic changes involve recombination events between the highly similar genes of OPN1LW and OPN1MW, which can result in deletion of one or both of these genes.[5] Recombination can also result in the creation of many different OPN1LW and OPN1MW chimeras, which are genes that are similar to the original, but have different spectral properties.[9] Single base-pair changes in OPN1LW can also inflict red-green colourblindness, but this is uncommon.[5] The severity of vision loss in a red-green colourblind individual is influenced by the Ser180Ala polymorphism.[9]
### Protanopia
Protanopia is caused by defective or total loss of the OPN1LW gene function, causing vision that is entirely dependent on OPN1MW and OPN1SW.[4] Affected individuals have dichromatic vision, with the inability to fully differentiate between green, yellow, and red colour.[4]
### Protanomaly
Protanomaly occurs when a partially functional hybrid OPN1LW gene replaces the normal gene.[5] Opsins made from these hybrid genes have abnormal spectral shifts that impair colour perception for colours in the OPN1LW spectrum.[5] Protanomaly is one form of anomalous trichromacy.[4]
## Blue cone monochromacy
Blue cone monochromacy is caused by a loss of function of both OPN1LW and OPN1MW.[5] This is commonly caused by mutations in the LCR, which would result in no expression of OPN1LW or OPN1MW.[5] With this visual impairment, the individual can only see colours in the spectrum for SWS opsins, which fall in the blue range of light.[5] | https://www.wikidoc.org/index.php/OPN1LW | |
f77105be391ed5d5a66ee560338cb3cf0e2bded7 | wikidoc | OR10K1 | OR10K1
Olfactory receptor 10K1 is a protein that in humans is encoded by the OR10K1 gene.
Olfactory receptors interact with odorant molecules in the nose, to initiate a neuronal response that triggers the perception of a smell. The olfactory receptor proteins are members of a large family of G-protein-coupled receptors (GPCR) arising from single coding-exon genes. Olfactory receptors share a 7-transmembrane domain structure with many neurotransmitter and hormone receptors and are responsible for the recognition and G protein-mediated transduction of odorant signals. The olfactory receptor gene family is the largest in the genome. The nomenclature assigned to the olfactory receptor genes and proteins for this organism is independent of other organisms.
# Amino acid sequence
MEQVNKTVVR EFVVLGFSSL ARLQQLLFVI FLLLYLFTLG TNAIIISTIV LDRALHTPMY FFLAILSCSE ICYTFVIVPK MLVDLLSQKK TISFLGCAIQ MFSFLFFGSS HSFLLAAMGY DRYMAICNPL RYSVLMGHGV CMGLMAAACA CGFTVSLVTT SLVFHLPFHS SNQLHHFFCD ISPVLKLASQ HSGFSQLVIF MLGVFALVIP LLLILVSYIR IISAILKIPS SVGRYKTFST CASHLIVVTV HYSCASFIYL RPKTNYTSSQ DTLISVSYTI LTPLFNPMIY SLRNKEFKSA LRRTIGQTFY PLS | OR10K1
Olfactory receptor 10K1 is a protein that in humans is encoded by the OR10K1 gene.[1]
Olfactory receptors interact with odorant molecules in the nose, to initiate a neuronal response that triggers the perception of a smell. The olfactory receptor proteins are members of a large family of G-protein-coupled receptors (GPCR) arising from single coding-exon genes. Olfactory receptors share a 7-transmembrane domain structure with many neurotransmitter and hormone receptors and are responsible for the recognition and G protein-mediated transduction of odorant signals. The olfactory receptor gene family is the largest in the genome. The nomenclature assigned to the olfactory receptor genes and proteins for this organism is independent of other organisms.[1]
# Amino acid sequence
MEQVNKTVVR EFVVLGFSSL ARLQQLLFVI FLLLYLFTLG TNAIIISTIV LDRALHTPMY FFLAILSCSE ICYTFVIVPK MLVDLLSQKK TISFLGCAIQ MFSFLFFGSS HSFLLAAMGY DRYMAICNPL RYSVLMGHGV CMGLMAAACA CGFTVSLVTT SLVFHLPFHS SNQLHHFFCD ISPVLKLASQ HSGFSQLVIF MLGVFALVIP LLLILVSYIR IISAILKIPS SVGRYKTFST CASHLIVVTV HYSCASFIYL RPKTNYTSSQ DTLISVSYTI LTPLFNPMIY SLRNKEFKSA LRRTIGQTFY PLS
[2] | https://www.wikidoc.org/index.php/OR10K1 | |
65b6126064efd83735a843784318472f7ccc9725 | wikidoc | OR2T11 | OR2T11
Olfactory receptor 2T11 is a protein that in humans is encoded by the OR2T11 gene.
Olfactory receptors interact with odorant molecules in the nose, to initiate a neuronal response that triggers the perception of a smell. The olfactory receptor proteins are members of a large family of G-protein-coupled receptors (GPCR) arising from single coding-exon genes. Olfactory receptors share a 7-transmembrane domain structure with many neurotransmitter and hormone receptors and are responsible for the recognition and G protein-mediated transduction of odorant signals. The olfactory receptor gene family is the largest in the genome. The nomenclature assigned to the olfactory receptor genes and proteins for this organism is independent of other organisms.
# Ligands
- tert-Butylthiol (the response is enhanced by the presence of ionic copper)
- Ethanethiol (the response is enhanced by the presence of ionic copper)
- 2-Propenethiol (allyl mercaptan) (the response is enhanced by the presence of ionic copper)
- Thietane (the response is enhanced by the presence of ionic copper) | OR2T11
Olfactory receptor 2T11 is a protein that in humans is encoded by the OR2T11 gene.[1]
Olfactory receptors interact with odorant molecules in the nose, to initiate a neuronal response that triggers the perception of a smell. The olfactory receptor proteins are members of a large family of G-protein-coupled receptors (GPCR) arising from single coding-exon genes. Olfactory receptors share a 7-transmembrane domain structure with many neurotransmitter and hormone receptors and are responsible for the recognition and G protein-mediated transduction of odorant signals. The olfactory receptor gene family is the largest in the genome. The nomenclature assigned to the olfactory receptor genes and proteins for this organism is independent of other organisms.[1]
# Ligands
- tert-Butylthiol (the response is enhanced by the presence of ionic copper)[2]
- Ethanethiol (the response is enhanced by the presence of ionic copper)[2]
- 2-Propenethiol (allyl mercaptan) (the response is enhanced by the presence of ionic copper)[2]
- Thietane (the response is enhanced by the presence of ionic copper)[2] | https://www.wikidoc.org/index.php/OR2T11 | |
eb01cc6cefec451e64b2748ee5e8392ca6077e62 | wikidoc | OSBPL3 | OSBPL3
Oxysterol-binding protein-related protein 3 is a protein that in humans is encoded by the OSBPL3 gene.
# Function
This gene encodes a member of the oxysterol-binding protein (OSBP) family, a group of intracellular lipid receptors. Most members contain an N-terminal pleckstrin homology domain and a highly conserved C-terminal OSBP-like sterol-binding domain. Several transcript variants encoding different isoforms have been identified.
# Model organisms
Model organisms have been used in the study of OSBPL3 function. A conditional knockout mouse line called Osbpl3tm1a(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 | OSBPL3
Oxysterol-binding protein-related protein 3 is a protein that in humans is encoded by the OSBPL3 gene.[1][2]
# Function
This gene encodes a member of the oxysterol-binding protein (OSBP) family, a group of intracellular lipid receptors. Most members contain an N-terminal pleckstrin homology domain and a highly conserved C-terminal OSBP-like sterol-binding domain. Several transcript variants encoding different isoforms have been identified.[2]
# Model organisms
Model organisms have been used in the study of OSBPL3 function. A conditional knockout mouse line called Osbpl3tm1a(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/OSBPL3 | |
54d662d57a10313b317ac55621c7e51b43ed069c | wikidoc | OSBPL9 | OSBPL9
Oxysterol binding protein-like 9 is a protein that in humans is encoded by the OSBPL9 gene.
This gene encodes a member of the oxysterol-binding protein (OSBP) family, a group of intracellular lipid receptors. Most members contain an N-terminal pleckstrin homology domain and a highly conserved C-terminal OSBP-like sterol-binding domain, although some members contain only the sterol-binding domain. This family member functions as a cholesterol transfer protein that regulates Golgi structure and function. Multiple transcript variants, most of which encode distinct isoforms, have been identified. Related pseudogenes have been identified on chromosomes 3, 11 and 12.
# Model organisms
Model organisms have been used in the study of OSBPL9 function. A conditional knockout mouse line, called Osbpl9tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed. | OSBPL9
Oxysterol binding protein-like 9 is a protein that in humans is encoded by the OSBPL9 gene.[1]
This gene encodes a member of the oxysterol-binding protein (OSBP) family, a group of intracellular lipid receptors. Most members contain an N-terminal pleckstrin homology domain and a highly conserved C-terminal OSBP-like sterol-binding domain, although some members contain only the sterol-binding domain. This family member functions as a cholesterol transfer protein that regulates Golgi structure and function. Multiple transcript variants, most of which encode distinct isoforms, have been identified. Related pseudogenes have been identified on chromosomes 3, 11 and 12.[1]
# Model organisms
Model organisms have been used in the study of OSBPL9 function. A conditional knockout mouse line, called Osbpl9tm1a(KOMP)Wtsi[6][7] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[8][9][10]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[4][11] Twenty four tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed.[4] | https://www.wikidoc.org/index.php/OSBPL9 | |
7e0c53c6d0f3c9bbd2278c66b1b67aa86ad4af98 | wikidoc | OTUD6B | OTUD6B
OTU domain containing 6B is a protein that in humans is encoded by the OTUD6B gene.
OTUD6B is a functional deubiquitinating enzyme, a class of protease that specifically cleaves ubiquitin linkages, negating the action of ubiquitin ligases. OTUD6B, also known as DUBA5, belongs to a DUB subfamily characterized by an ovarian tumor domain (OTU). OTUD6B function may be connected to growth and proliferation. This hypothesis is supported by a recent study indicating that OTUD6B knock out mice, obtained through exon 4 deletion, are subviable and smaller in size. In humans, OTUD6B mutations have been connected to an intellectual disability syndrome associated with dysmorphic features.
Previous studies on model organisms (see below) cannot be verified by this editor.
Model organisms have been used in the study of OTUD6B function. A conditional knockout mouse line, called Otud6btm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed. | OTUD6B
OTU domain containing 6B is a protein that in humans is encoded by the OTUD6B gene.[1]
OTUD6B is a functional deubiquitinating enzyme, a class of protease that specifically cleaves ubiquitin linkages, negating the action of ubiquitin ligases. OTUD6B, also known as DUBA5, belongs to a DUB subfamily characterized by an ovarian tumor domain (OTU).[1] OTUD6B function may be connected to growth and proliferation.[2][3] This hypothesis is supported by a recent study indicating that OTUD6B knock out mice, obtained through exon 4 deletion, are subviable and smaller in size.[4] In humans, OTUD6B mutations have been connected to an intellectual disability syndrome associated with dysmorphic features.[4]
Previous studies on model organisms (see below) cannot be verified by this editor.
Model organisms have been used in the study of OTUD6B function. A conditional knockout mouse line, called Otud6btm1a(EUCOMM)Wtsi[9][10] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[11][12][13]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[7][14] Twenty five tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed.[7] | https://www.wikidoc.org/index.php/OTUD6B | |
3c91556b036887972ca341d838e288984f049959 | wikidoc | Occult | Occult
# Overview
The word occult comes from the Latin word occultus (clandestine, hidden, secret), referring to "knowledge of the hidden". In the medical sense it is used to refer to a structure or process that is hidden, e.g. an "occult bleed" may be one detected indirectly by the presence of otherwise unexplained anaemia.
- ↑ Crabb, G. (1927). English synonyms explained, in alphabetical order, with copious illustrations and examples drawn from the best writers. New York: Thomas Y. Crowell Co.
- ↑ Harvard Medical School Family Health Guide. Harvard Medical School 2005. 1272 pages ISBN 0684863731 | Occult
# Overview
The word occult comes from the Latin word occultus (clandestine, hidden, secret), referring to "knowledge of the hidden".[1] In the medical sense it is used to refer to a structure or process that is hidden, e.g. an "occult bleed"[2] may be one detected indirectly by the presence of otherwise unexplained anaemia.
- ↑ Crabb, G. (1927). English synonyms explained, in alphabetical order, with copious illustrations and examples drawn from the best writers. New York: Thomas Y. Crowell Co.
- ↑ Harvard Medical School Family Health Guide. Harvard Medical School 2005. 1272 pages ISBN 0684863731 | https://www.wikidoc.org/index.php/Occult | |
a45f152a34be2263ba6fd54c67e6a020c0d20815 | wikidoc | -omics | -omics
Informally, the English-language neologism omics refers to a field of study in biology ending in the suffix -omics such as genomics or proteomics. The related neologism omes addresses the objects of study of such fields, such as the genome or proteome respectively. Users of the suffix “-om-” frequently take it as referring to totality of some sort.
# Origin
The suffix “-om-” originated as a back-formation from “genome”, a word formed in analogy with “chromosome”. The word “chromosome” comes from the Greek stems “χρωμ(ατ)-” (colour) and “σωμ(ατ)-” (body). (Thus, had this word been well-formed, it would instead be “chromatosome”.) Because “genome” refers to the complete genetic makeup of an organism, some people have made the inference that there exists some root, *“-ome-”, of Greek origin referring to wholeness or to completion, but such root is unknown to most or all scholars..
Because of the success of large-scale quantitative biology projects such as genome sequencing, the suffix "-om-" has migrated to a host of other contexts. Bioinformaticians and molecular biologists figured amongst the first scientists to start to apply the "-ome" suffix widely.
## Omes and Omics people
Bioinformatists and molecular biologists figured amongst the first scientists to start to apply the "-ome" suffix widely. Some early advocates were bioinformatists in Cambridge, UK where there have been many early bioinformatics and omics related labs such as MRC centre, Sanger centre, EBI(European Bioinformatics Institute), Cavendish lab, genetics, and biochemistry departments. For example, MRC centre is where the first genome and proteome projects were carried out. EBI members were some of the earliest bioinformatists. For example, Christos Ouzounis's lab used the term textome. In the USA, due to the expansion of the internet, there were perhaps the largest number of bioinformatics and biology researchers who coined and used various omics such as phenome, physiome, metabolome, and so on.
In the mid 1990s, many scientists were not serious about omes and omics trend and jokingly talked about or playfully coined new omes and omics'. While some younger researchers took the terms seriously enough to organize and produce conceptual omes and omics en masse. This trend coupled by the trend of attaching bio- prefix to various biological and programming terms such as Bioperl and Biojava. There were a group of locally and internationally networked researchers who were proposing open and free style sharing information and programs. Jong Bhak was one of the enthusiastic takers of bio-, omes, and omics trend in Cambridge. Steve Brenner, George Fuellen, Ewan Birney, Chris Dagdigian, and several others were the young students who took up such Bio- projects and produced internationally collaborative bio- projects that affected the omics growth. Dan Bolser has advocated the concept of omics in complex systems perspective through interaction network research. In USA, George Church lab in Harvard medical school was an early advocate of conceptualizing omes and omics as shown in their web pages. In Yale, Mark Gerstein (who received his Ph.D. in MRC centre in Cambridge UK) was active in that trend, too. The historical observation showed one trend.
As research scientists increasingly sought to integrate biology with information science, they took up the use of omics. For biologists -omics easily conveyed a key concept, the implications of a complex systems approach, an approach that is closely tied to study of networks, emergent properties and encapsulation concepts of theoretical computer science. Information savvy biologists took up the ideas of Stuart Alan Kauffman's work. In 1999 and early 2000s, physicists and computer scientists produced some debatable papers on scale-free network properties in biological systems. These also contributed significantly in the expansion of the use of omics as a way to describe heterogeneous networks of objects.
# Acceptance
Some “-ome” are becoming useful, beyond the original “genome”. “Proteomics” has become well-established as a term for studying proteins. Researchers have proposed other “-omes” which are becoming accepted within biology field. Omes and omics concepts provide a distinct knowledge layer for biologists, especially when they become interested in high throughput experimental analyses. Modern biology is becoming an information science and such omes and omics classification can provide skeletons for various previously less well defined fields. For example, the term genetic study in the past could mean many different things for many different scientists while interactome study clearly sub divides a genetic study to the gene-gene, protein-protein, or protein-ligand interactions in terms of large scale information processing to find some networked functional information. Omes and omics is one of the most convenient and extensive reformations of biology since evolution and inheritance concepts were proposed in mid 1800s and molecular sequences and structures were deciphered in 1960s and 1970s. Researchers are taking up the omes and omics very rapidly as shown in the use of the terms in Pubmed in the last decade.
# Some of the new "omes"
- The transcriptome, the mRNA complement of an entire organism, tissue type, or cell; with its associated field transcriptomics
- The metabolome, the totality of metabolites in an organism; with its associated field metabolomics
- The metallome, the totality of metal and metalloid species; with its associated field metallomics
- The lipidome, the totality of lipids; with its associated field Lipidomics
- The glycome, the totality of glycans, carbohydrate structures of an organism, a cell or tissue type. Glycomics: The associated field of study. See .
- The interactome, the totality of the molecular interactions in an organism; a once proposed field of interactomics has generally become known as systems biology
- The spliceome (see spliceosome), the totality of the alternative splicing protein isoforms; with its associated field spliceomics.
- The ORFeome refers to the totality of DNA sequences that begin with the initiation codon ATG, end with a nonsense codon, and contain no stop codon. Such sequences may therefore encode part or all of a protein.
- The speechome. (BBC article on the Speechome Project)
- The mechanome refers to the force and mechanical systems at work within an organism.
- The Phenome - the organism itself. The Phenome is to the genome what the phenotype is to the genotype. Also, the complete list of phenotypic mutants available for a species.
- The Exposome - the collection of an individual's environmental exposures.
# Speculative "omics" and "omes"
- Textome: The body of scientific literature which text mining can analyse. Textomics: The study of the textome.
- Kinome: The totality of protein kinases in a cell. Kinomics: The study of the kinome. Publications exist.
- Physiome: Related to physiology. Physiomics: The associated field of study.
- Neurome: The complete neural makeup of an organism. A word which a neurobiologist might utter in the future. Neuromics: The study of the neurome.
Note: Neurome and Neuromics are now the names of Biotech companies. The term 'Neurome' has been used by NeuronBank.org, which is an attempt to develop an approach to catalog the Neurome.
- Note: Neurome and Neuromics are now the names of Biotech companies. The term 'Neurome' has been used by NeuronBank.org, which is an attempt to develop an approach to catalog the Neurome.
- Cytome: The cellular composition of a tissue. This term is associated to cell sorting techniques.
- Predictome: A complete set of predictions.
- Omeome: A complete set of "omes", Omeomics will be the cataloguing of all "omics"
- Reactome: A knowledge base of biological processes.
- Connectome: The connections between neurons. A Technicolour Approach to the Connectome (Nature)
# Unrelated words in -omics
Note that “comic” does not exemplify this suffix; it derives from Greek “κωμ(ο)-” (merriment) + “-ικ(ο)-” (an adjectival suffix), rather than presenting a truncation of “σωμ(ατ)-”.
Similarly, the word “economy” is assembled from Greek “οικ(ο)-” (household) + “νομ(ο)-” (law or custom), and “economic(s)” from “οικ(ο)-” + “νομ(ο)-” + “-ικ(ο)-”. The suffix -omics is sometimes used to create portmanteau words to refer to schools of economics such as Reaganomics. | -omics
Template:Inappropriate tone
Informally, the English-language neologism omics refers to a field of study in biology ending in the suffix -omics such as genomics or proteomics. The related neologism omes addresses the objects of study of such fields, such as the genome or proteome respectively. Users of the suffix “-om-” frequently take it as referring to totality of some sort.
# Origin
The suffix “-om-” originated as a back-formation from “genome”, a word formed in analogy with “chromosome”.[1] The word “chromosome” comes from the Greek stems “χρωμ(ατ)-” (colour) and “σωμ(ατ)-” (body).[1] (Thus, had this word been well-formed, it would instead be “chromatosome”.[2]) Because “genome” refers to the complete genetic makeup of an organism, some people have made the inference that there exists some root, *“-ome-”, of Greek origin referring to wholeness or to completion, but such root is unknown to most or all scholars.[3].
Because of the success of large-scale quantitative biology projects such as genome sequencing, the suffix "-om-" has migrated to a host of other contexts. Bioinformaticians and molecular biologists figured amongst the first scientists to start to apply the "-ome" suffix widely.[citation needed]
## Omes and Omics people
Template:Unreferencedsection
Bioinformatists and molecular biologists figured amongst the first scientists to start to apply the "-ome" suffix widely. Some early advocates were bioinformatists in Cambridge, UK where there have been many early bioinformatics and omics related labs such as MRC centre, Sanger centre, EBI(European Bioinformatics Institute), Cavendish lab, genetics, and biochemistry departments. For example, MRC centre is where the first genome and proteome projects were carried out. EBI members were some of the earliest bioinformatists. For example, Christos Ouzounis's lab used the term textome. In the USA, due to the expansion of the internet, there were perhaps the largest number of bioinformatics and biology researchers who coined and used various omics such as phenome, physiome, metabolome, and so on.
In the mid 1990s, many scientists were not serious about omes and omics trend and jokingly talked about or playfully coined new omes and omics'. While some younger researchers took the terms seriously enough to organize and produce conceptual omes and omics en masse. This trend coupled by the trend of attaching bio- prefix to various biological and programming terms such as Bioperl and Biojava. There were a group of locally and internationally networked researchers who were proposing open and free style sharing information and programs. Jong Bhak was one of the enthusiastic takers of bio-, omes, and omics trend in Cambridge. Steve Brenner, George Fuellen, Ewan Birney, Chris Dagdigian, and several others were the young students who took up such Bio- projects and produced internationally collaborative bio- projects that affected the omics growth. Dan Bolser has advocated the concept of omics in complex systems perspective through interaction network research. In USA, George Church lab in Harvard medical school was an early advocate of conceptualizing omes and omics as shown in their web pages. In Yale, Mark Gerstein (who received his Ph.D. in MRC centre in Cambridge UK) was active in that trend, too. The historical observation showed one trend.
As research scientists increasingly sought to integrate biology with information science, they took up the use of omics. For biologists -omics easily conveyed a key concept, the implications of a complex systems approach, an approach that is closely tied to study of networks, emergent properties and encapsulation concepts of theoretical computer science. Information savvy biologists took up the ideas of Stuart Alan Kauffman's work. In 1999 and early 2000s, physicists and computer scientists produced some debatable papers on scale-free network properties in biological systems. These also contributed significantly in the expansion of the use of omics as a way to describe heterogeneous networks of objects.
# Acceptance
Some “-ome” are becoming useful, beyond the original “genome”. “Proteomics” has become well-established as a term for studying proteins. Researchers have proposed other “-omes” which are becoming accepted within biology field. Omes and omics concepts provide a distinct knowledge layer for biologists, especially when they become interested in high throughput experimental analyses. Modern biology is becoming an information science and such omes and omics classification can provide skeletons for various previously less well defined fields. For example, the term genetic study in the past could mean many different things for many different scientists while interactome study clearly sub divides a genetic study to the gene-gene, protein-protein, or protein-ligand interactions in terms of large scale information processing to find some networked functional information. Omes and omics is one of the most convenient and extensive reformations of biology since evolution and inheritance concepts were proposed in mid 1800s and molecular sequences and structures were deciphered in 1960s and 1970s. Researchers are taking up the omes and omics very rapidly as shown in the use of the terms in Pubmed in the last decade.
# Some of the new "omes"
- The transcriptome, the mRNA complement of an entire organism, tissue type, or cell; with its associated field transcriptomics[1]
- The metabolome, the totality of metabolites in an organism; with its associated field metabolomics[2]
- The metallome, the totality of metal and metalloid species; with its associated field metallomics
- The lipidome, the totality of lipids; with its associated field Lipidomics [3]
- The glycome, the totality of glycans, carbohydrate structures of an organism, a cell or tissue type. Glycomics: The associated field of study. See http://www.functionalglycomics.org.
- The interactome, the totality of the molecular interactions in an organism[4]; a once proposed field of interactomics[5] has generally become known as systems biology
- The spliceome (see spliceosome), the totality of the alternative splicing protein isoforms;[6] with its associated field spliceomics.
- The ORFeome refers to the totality of DNA sequences that begin with the initiation codon ATG, end with a nonsense codon, and contain no stop codon. Such sequences may therefore encode part or all of a protein.[7][8]
- The speechome. (BBC article on the Speechome Project)
- The mechanome refers to the force and mechanical systems at work within an organism.
- The Phenome - the organism itself. The Phenome is to the genome what the phenotype is to the genotype. Also, the complete list of phenotypic mutants available for a species.
- The Exposome - the collection of an individual's environmental exposures.[4]
# Speculative "omics" and "omes"
- Textome: The body of scientific literature which text mining can analyse. Textomics: The study of the textome.
- Kinome: The totality of protein kinases in a cell. Kinomics: The study of the kinome. Publications exist.
- Physiome: Related to physiology. Physiomics: The associated field of study.
- Neurome: The complete neural makeup of an organism. A word which a neurobiologist might utter in the future. Neuromics: The study of the neurome.
Note: Neurome[9] and Neuromics[10] are now the names of Biotech companies. The term 'Neurome' has been used by NeuronBank.org[11], which is an attempt to develop an approach to catalog the Neurome.
- Note: Neurome[9] and Neuromics[10] are now the names of Biotech companies. The term 'Neurome' has been used by NeuronBank.org[11], which is an attempt to develop an approach to catalog the Neurome.
- Cytome: The cellular composition of a tissue. This term is associated to cell sorting techniques.
- Predictome: A complete set of predictions.[12]
- Omeome: A complete set of "omes", Omeomics will be the cataloguing of all "omics"
- Reactome: A knowledge base of biological processes.[13]
- Connectome: The connections between neurons. A Technicolour Approach to the Connectome (Nature)
# Unrelated words in -omics
Note that “comic” does not exemplify this suffix; it derives from Greek “κωμ(ο)-” (merriment) + “-ικ(ο)-” (an adjectival suffix), rather than presenting a truncation of “σωμ(ατ)-”.
Similarly, the word “economy” is assembled from Greek “οικ(ο)-” (household) + “νομ(ο)-” (law or custom), and “economic(s)” from “οικ(ο)-” + “νομ(ο)-” + “-ικ(ο)-”. The suffix -omics is sometimes used to create portmanteau words to refer to schools of economics such as Reaganomics. | https://www.wikidoc.org/index.php/Omics | |
582d06a31dc5175c5e2d51d7d23d85ecc93fca05 | wikidoc | Oolong | Oolong
Oolong (Template:Zh-c → wūlóng) is a traditional Chinese tea somewhere between green and black in oxidation. It ranges from 10% to 70% oxidation.
In Chinese tea culture, semi-oxidized oolong teas are collectively grouped as qīngchá (Template:Zh-cl). Oolong has a taste more akin to green tea than to black tea: it lacks the rosy, sweet aroma of black tea but it likewise does not have the stridently grassy vegetal notes that typify green tea. It is commonly brewed to be strong, with the bitterness leaving a sweet aftertaste. Several subvarieties of oolong, including those produced in the Wuyi Mountains of northern Fujian and in the central mountains of Taiwan, are among the most famous Chinese teas.
Oolong tea leaves are processed in two different ways. Some teas are rolled into long curly leaves, while some are pressed into a ball-like form similar to gunpowder tea. The former method of processing is the older of the two.
# Etymology
The name oolong tea comes into the English language from the Chinese name (烏龍茶), which is pronounced as O·-liông tê in the Min Nan spoken variant. The Chinese name means "black dragon tea". There are three widely accepted explanations on how this Chinese name came about.
According to the "tribute tea" theory, oolong tea was a direct descendant of Dragon-Phoenix Tea Cake tribute tea. Oolong tea replaced it when loose tea came into fashion. Since it was dark, long and curly, it was called the Black Dragon tea.
According to the "Wuyi" theory, oolong tea first existed in Wuyi Mountain. This is evidenced by Qing dynasty poems such as Wuyi Tea Song (Wuyi Chage) and Tea Tale (Chashuo). It was said that oolong tea was named after the part of Wuyi mountain it was originally produced.
According to the "Anxi" theory, oolong tea had its origin in the Anxi oolong tea plant. A man named Sulong, Wulong or Wuliang discovered it.
Another tale tells of a man named Wu Liang (later corrupted to Wu Long, or Oolong) who discovered oolong tea by accident when he was distracted by a deer after a hard day's tea-picking, and by the time he remembered about the tea it had already started to oxidize.
# Processing of Oolong
Oolong tea undergoes a few delicate processes in order to produce the unique aroma and taste. Typical Oolong tea is processed according to the following steps:
- Wilting (萎凋; wěidiāo): Sun dry or air dry to remove moisture partly.
- Cooling: Cool off in shaded area.
- Yaoqing (摇青; yáoqīng): Gently tossing leaves to bruise the edge of leaves to create more contacting surface for oxidation.
- Cooling and Yaoqing are repeated multiple times.
- Shaqing (杀青; shāqīng): The procedure is to stop oxidation with high heat. Premium leaves are usually stir fried in a large pan over high heat, large productions are done by machine.
- Rouqing (揉青; róuqīng): The tea leaves are rolled into strands or nuggets before dehydration.
- Roasting: Roasting with low heat to dehydrate tea leaves, this step can be repeated with temperature variations to produce flavors of choice.
- Grading
- Packaging
# Classification and grade
Tea connoisseurs classify the tea by its aroma (often floral or fruity), taste and aftertaste (often melony). Oolongs comes in either roasted (炭焙) or light (密香 or 清香). While most oolongs can be consumed immediately postproduction, like pu-erh tea, many oolong can benefit from long aging with regular light roasting with a low charcoal fire (烘培, pinyin:hōngpeì, literally: bake cultivation or 焙火, pinyin:peìhǔo, dry roasting by fire). Before roasting, Oolong tea leaves are rolled and bruised to break open cell walls and stimulate enzymatic activity. The process of roasting removes unwanted odours from the tea and reduces any sour or astringent tastes; in addition, the process is believed to make the oolong tea more gentle on the stomach.
# Varieties of Oolong Tea
### Wǔyí cliff tea (武夷岩茶) from Fújiàn province
The most famous and expensive Oolong teas are made here but the production is still usually accredited as organic. A lot of Shuǐ Xiān is grown elsewhere in Fujian.
Some of the better known yán chá are:
### Fújiàn province
### Guangdong province
As the name implies, Dancong ("single bush") teas are clonal or single-bush productions.
### Taiwan
Tea cultivation only began in Taiwan in the mid 19th century. Since then, many of the teas which are grown in Fujian province have also been grown in Taiwan. Since the 1970s the tea industry in Taiwan has grown at a rapid rate, in line with the rest of Taiwan's economy. Due to high domestic demand and a strong tea culture, the majority of Taiwanese tea is bought and consumed by the Taiwanese.
As the weather in Taiwan is highly variable, quality of tea may differ from season to season. Although the island is not particularly large, it is geographically varied, with high, steep mountains rising quickly from low-lying coastal plains. The different weather patterns, temperatures, altitudes and soil ultimately result in differences in appearance, aroma and flavour of the tea grown in Taiwan. In some mountainous areas, teas have been cultivated at ever higher elevations to produce a unique sweet taste that fetches a premium price.
## Other oolong teas
- Darjeeling Oolong: Darjeeling tea made according to Chinese methods.
- Vietnamese Oolong
- Thai Oolong
- African Oolong: made in Malawi and in Kenya
# Brewing
Generally, 2.25 grams of tea per 6 ounces of water, or about two teaspoons of oolong tea per cup, should be used. Oolong teas should be prepared with 180°F to 190°F (82°C-87°C) water (not boiling) and steeped 3-4 minutes. | Oolong
Template:Chinese
Oolong (Template:Zh-c → wūlóng) is a traditional Chinese tea somewhere between green and black in oxidation. It ranges from 10% to 70% oxidation.[1]
In Chinese tea culture, semi-oxidized oolong teas are collectively grouped as qīngchá (Template:Zh-cl).[2] Oolong has a taste more akin to green tea than to black tea: it lacks the rosy, sweet aroma of black tea but it likewise does not have the stridently grassy vegetal notes that typify green tea. It is commonly brewed to be strong, with the bitterness leaving a sweet aftertaste. Several subvarieties of oolong, including those produced in the Wuyi Mountains of northern Fujian and in the central mountains of Taiwan, are among the most famous Chinese teas.
Oolong tea leaves are processed in two different ways. Some teas are rolled into long curly leaves, while some are pressed into a ball-like form similar to gunpowder tea.[1] The former method of processing is the older of the two.
# Etymology
Template:Unreliablesources
The name oolong tea comes into the English language from the Chinese name (烏龍茶), which is pronounced as O·-liông tê in the Min Nan spoken variant. The Chinese name means "black dragon tea". There are three widely accepted explanations on how this Chinese name came about.[3]
According to the "tribute tea" theory, oolong tea was a direct descendant of Dragon-Phoenix Tea Cake tribute tea. Oolong tea replaced it when loose tea came into fashion. Since it was dark, long and curly, it was called the Black Dragon tea.
According to the "Wuyi" theory, oolong tea first existed in Wuyi Mountain. This is evidenced by Qing dynasty poems such as Wuyi Tea Song (Wuyi Chage) and Tea Tale (Chashuo). It was said that oolong tea was named after the part of Wuyi mountain it was originally produced.
According to the "Anxi" theory, oolong tea had its origin in the Anxi oolong tea plant. A man named Sulong, Wulong or Wuliang discovered it.
Another tale tells of a man named Wu Liang (later corrupted to Wu Long, or Oolong) who discovered oolong tea by accident when he was distracted by a deer after a hard day's tea-picking, and by the time he remembered about the tea it had already started to oxidize.[4]
# Processing of Oolong
Oolong tea undergoes a few delicate processes in order to produce the unique aroma and taste. Typical Oolong tea is processed according to the following steps:[5]
- Wilting (萎凋; wěidiāo): Sun dry or air dry to remove moisture partly.
- Cooling: Cool off in shaded area.
- Yaoqing (摇青; yáoqīng): Gently tossing leaves to bruise the edge of leaves to create more contacting surface for oxidation.
- Cooling and Yaoqing are repeated multiple times.
- Shaqing (杀青; shāqīng): The procedure is to stop oxidation with high heat. Premium leaves are usually stir fried in a large pan over high heat, large productions are done by machine.
- Rouqing (揉青; róuqīng): The tea leaves are rolled into strands or nuggets before dehydration.
- Roasting: Roasting with low heat to dehydrate tea leaves, this step can be repeated with temperature variations to produce flavors of choice.
- Grading
- Packaging
# Classification and grade
Tea connoisseurs classify the tea by its aroma (often floral or fruity), taste and aftertaste (often melony). Oolongs comes in either roasted (炭焙) or light (密香 or 清香).[6][7] While most oolongs can be consumed immediately postproduction, like pu-erh tea, many oolong can benefit from long aging with regular light roasting with a low charcoal fire (烘培, pinyin:hōngpeì, literally: bake cultivation or 焙火, pinyin:peìhǔo, dry roasting by fire).[5] Before roasting, Oolong tea leaves are rolled and bruised to break open cell walls and stimulate enzymatic activity. The process of roasting removes unwanted odours from the tea and reduces any sour or astringent tastes; in addition, the process is believed to make the oolong tea more gentle on the stomach.[7]
# Varieties of Oolong Tea
### Wǔyí cliff tea (武夷岩茶) from Fújiàn province
The most famous and expensive Oolong teas are made here but the production is still usually accredited as organic. A lot of Shuǐ Xiān is grown elsewhere in Fujian.
Some of the better known yán chá are:
### Fújiàn province
### Guangdong province
As the name implies, Dancong ("single bush") teas are clonal or single-bush productions.
### Taiwan
Tea cultivation only began in Taiwan in the mid 19th century. Since then, many of the teas which are grown in Fujian province have also been grown in Taiwan[6]. Since the 1970s the tea industry in Taiwan has grown at a rapid rate, in line with the rest of Taiwan's economy. Due to high domestic demand and a strong tea culture, the majority of Taiwanese tea is bought and consumed by the Taiwanese.
As the weather in Taiwan is highly variable, quality of tea may differ from season to season. Although the island is not particularly large, it is geographically varied, with high, steep mountains rising quickly from low-lying coastal plains. The different weather patterns, temperatures, altitudes and soil ultimately result in differences in appearance, aroma and flavour of the tea grown in Taiwan. In some mountainous areas, teas have been cultivated at ever higher elevations to produce a unique sweet taste that fetches a premium price.[6]
## Other oolong teas
- Darjeeling Oolong: Darjeeling tea made according to Chinese methods.
- Vietnamese Oolong
- Thai Oolong
- African Oolong: made in Malawi and in Kenya
# Brewing
Generally, 2.25 grams of tea per 6 ounces of water, or about two teaspoons of oolong tea per cup, should be used. Oolong teas should be prepared with 180°F to 190°F (82°C-87°C) water (not boiling) and steeped 3-4 minutes.[9] | https://www.wikidoc.org/index.php/Oolong | |
09f6856fd49130bd04c7cace1dfd4375775c60dd | wikidoc | Operon | Operon
# Overview
An operon is a functioning unit of key nucleotide sequences including an operator, a common promoter, and one or more structural genes, which is controlled as a unit to produce messenger RNA (mRNA), in the process of protein transcription.
# Overview
Operons occur primarily in prokaryotes but also in some eukaryotes, including nematodes. Although it may not be located in the operon gene, a "Regulator" gene is present which codes for the production of a repressor or corepressor protein. The location and condition of the regulator, promoter, operator and structural DNA sequences can determine the effects of common mutations.
The first operon to be described was the lac-operon in Escherichia coli, by F. Jacob, D. Perrin, C. Sanchez and J. Monod in the "Comptes rendus hebdomadaires des séances de l'Académie des sciences" in 1960.
Operons are related to regulons and stimulons. Whereas operons contain a set of genes regulated by the same operator, regulons contain a set of genes under regulation by a single regulatory protein, and stimulons contain a set of genes under regulation by a single cell stimulus.
# The operon as a unit of transcription
An operon contains one or more structural genes which are transcribed into one polycistronic mRNA: a single mRNA molecule that codes for more than one protein. Upstream of the structural genes lies a promoter sequence which provides a site for RNA polymerase to bind and initiate transcription. Close to the promoter lies a section of DNA called an operator. The operon may also contain regulatory genes such as a repressor gene which codes for a regulatory protein that binds to the operator and inhibits transcription. Regulatory genes need not be part of the operon itself, but may be located elsewhere in the genome. The repressor molecule will reach the operator to block the transcription of the structural genes.
# Promoter
A promoter is a DNA sequence that enables a gene to be transcribed. The promoter is recognized by RNA polymerase, which then initiates transcription. In RNA synthesis, promoters indicate which genes should be used for messenger RNA creation - and, by extension, control which proteins the cell manufactures.
# Operator
An operator is a segment of DNA which regulates the activity of the structural genes of the operon that it is linked to, by interacting with a specific repressor or activator. It is a regulatory sequence for shutting a gene down or turning it "on".
# Operon gene regulation
Control of operon genes is a type of gene regulation that enables organisms to regulate the expression of various genes depending on environmental conditions. Operon regulation can be either negative or positive.
Negative regulation involves the binding of a repressor to the operator to prevent transcription.
- In negative inducible operons, a regulatory repressor protein is normally bound to the operator and it prevents the transcription of the genes on the operon. If an inducer molecule is present, it binds to the repressor and changes its conformation so that it is unable to bind to the operator. This allows for the transcription of the genes on the operator.
- In negative repressible operons, transcription of the genes on the operon normally takes place. Repressor proteins are produced by a regulator gene but they are unable to bind to the operator in their normal conformation. However certain molecules called corepressors can bind to the repressor protein and change its conformation so that it can bind to the operator. The activated repressor protein binds to the operator and prevents transcription.
Operons can also be positively controlled. With positive control, an activator protein stimulates transcription by binding to DNA (usually at a site other than the operator).
- In positive inducible operons, activator proteins are normally unable to bind to the pertinent DNA. However, certain substrate molecules can bind to the activator proteins and change their conformations so that they can bind to the DNA and enable transcription to take place.
- In positive repressible operons, the activator proteins are normally bound to the pertinent DNA segment. However, certain molecules can bind to the activator and prevent it from binding to DNA. This prevents transcription.
# The lac operon
The lac operon of the model bacterium Escherichia coli was the first operon to be discovered and provides a typical example of operon function. It consists of three adjacent structural genes, a promoter, a terminator, and an operator. The lac operon is regulated by several factors including the availability of glucose and lactose.
# The trp operon
Discovered in 1953 by Jacques Monod and colleagues, the trp operon in E. coli was the first repressible operon to be discovered. While the lac operon can be activated by a chemical (lactose), the tryptophan (Trp) operon is inhibited by a chemical (tryptophan). This operon contains five structural genes: trp E, trp D, trp C, trp B, and trp A, which encodes tryptophan synthetase. It also contains a promoter which binds to RNA polymerase and an operator which blocks transcription when bound to the protein synthesized by the repressor gene (trp R) that binds to the operator. In the lac operon, lactose binds to the repressor protein and prevents it from repressing gene transcription, while in the trp operon, tryptophan binds to the repressor protein and enables it to repress gene transcription. Also different between the trp operon and the lac operon, the trp operon contains a leader peptide and an attenuator sequence which allows for graded regulation.
# Predicting the number and organization of operons
The number and organization of operons has been studied most critically in E. coli. As a result, predictions can be made based on an organism's genomic sequence.
One prediction method uses the intergenic distance between reading frames as a primary predictor of the number of operons in the genome. The separation merely changes the frame and guarantees that the read through is efficient. Longer stretches exist where operons start and stop, often up to 40-50 bases .
Operon prediction is even more accurate if the functional class of the molecules is considered. Bacteria have clustered their reading frames into units, sequestered by co-involvement in protein complexes, common pathways, or shared substrates and transporters. Thus, accurate prediction would involve all of these data, a difficult task indeed. | Operon
# Overview
An operon is a functioning unit of key nucleotide sequences including an operator, a common promoter, and one or more structural genes, which is controlled as a unit to produce messenger RNA (mRNA), in the process of protein transcription.
# Overview
Operons occur primarily in prokaryotes but also in some eukaryotes, including nematodes. Although it may not be located in the operon gene, a "Regulator" gene is present which codes for the production of a repressor or corepressor protein. The location and condition of the regulator, promoter, operator and structural DNA sequences can determine the effects of common mutations.
The first operon to be described was the lac-operon in Escherichia coli, by F. Jacob, D. Perrin, C. Sanchez and J. Monod in the "Comptes rendus hebdomadaires des séances de l'Académie des sciences" in 1960[2].
Operons are related to regulons and stimulons. Whereas operons contain a set of genes regulated by the same operator, regulons contain a set of genes under regulation by a single regulatory protein, and stimulons contain a set of genes under regulation by a single cell stimulus.
# The operon as a unit of transcription
An operon contains one or more structural genes which are transcribed into one polycistronic mRNA: a single mRNA molecule that codes for more than one protein. Upstream of the structural genes lies a promoter sequence which provides a site for RNA polymerase to bind and initiate transcription. Close to the promoter lies a section of DNA called an operator. The operon may also contain regulatory genes such as a repressor gene which codes for a regulatory protein that binds to the operator and inhibits transcription. Regulatory genes need not be part of the operon itself, but may be located elsewhere in the genome. The repressor molecule will reach the operator to block the transcription of the structural genes.
# Promoter
A promoter is a DNA sequence that enables a gene to be transcribed. The promoter is recognized by RNA polymerase, which then initiates transcription. In RNA synthesis, promoters indicate which genes should be used for messenger RNA creation - and, by extension, control which proteins the cell manufactures.
# Operator
An operator is a segment of DNA which regulates the activity of the structural genes of the operon that it is linked to, by interacting with a specific repressor or activator. It is a regulatory sequence for shutting a gene down or turning it "on".
# Operon gene regulation
Control of operon genes is a type of gene regulation that enables organisms to regulate the expression of various genes depending on environmental conditions. Operon regulation can be either negative or positive.
Negative regulation involves the binding of a repressor to the operator to prevent transcription.
- In negative inducible operons, a regulatory repressor protein is normally bound to the operator and it prevents the transcription of the genes on the operon. If an inducer molecule is present, it binds to the repressor and changes its conformation so that it is unable to bind to the operator. This allows for the transcription of the genes on the operator.
- In negative repressible operons, transcription of the genes on the operon normally takes place. Repressor proteins are produced by a regulator gene but they are unable to bind to the operator in their normal conformation. However certain molecules called corepressors can bind to the repressor protein and change its conformation so that it can bind to the operator. The activated repressor protein binds to the operator and prevents transcription.
Operons can also be positively controlled. With positive control, an activator protein stimulates transcription by binding to DNA (usually at a site other than the operator).
- In positive inducible operons, activator proteins are normally unable to bind to the pertinent DNA. However, certain substrate molecules can bind to the activator proteins and change their conformations so that they can bind to the DNA and enable transcription to take place.
- In positive repressible operons, the activator proteins are normally bound to the pertinent DNA segment. However, certain molecules can bind to the activator and prevent it from binding to DNA. This prevents transcription.
# The lac operon
The lac operon of the model bacterium Escherichia coli was the first operon to be discovered and provides a typical example of operon function. It consists of three adjacent structural genes, a promoter, a terminator, and an operator. The lac operon is regulated by several factors including the availability of glucose and lactose.
# The trp operon
Discovered in 1953 by Jacques Monod and colleagues, the trp operon in E. coli was the first repressible operon to be discovered. While the lac operon can be activated by a chemical (lactose), the tryptophan (Trp) operon is inhibited by a chemical (tryptophan). This operon contains five structural genes: trp E, trp D, trp C, trp B, and trp A, which encodes tryptophan synthetase. It also contains a promoter which binds to RNA polymerase and an operator which blocks transcription when bound to the protein synthesized by the repressor gene (trp R) that binds to the operator. In the lac operon, lactose binds to the repressor protein and prevents it from repressing gene transcription, while in the trp operon, tryptophan binds to the repressor protein and enables it to repress gene transcription. Also different between the trp operon and the lac operon, the trp operon contains a leader peptide and an attenuator sequence which allows for graded regulation.[1]
# Predicting the number and organization of operons
The number and organization of operons has been studied most critically in E. coli. As a result, predictions can be made based on an organism's genomic sequence.
One prediction method uses the intergenic distance between reading frames as a primary predictor of the number of operons in the genome. The separation merely changes the frame and guarantees that the read through is efficient. Longer stretches exist where operons start and stop, often up to 40-50 bases [2].
Operon prediction is even more accurate if the functional class of the molecules is considered. Bacteria have clustered their reading frames into units, sequestered by co-involvement in protein complexes, common pathways, or shared substrates and transporters. Thus, accurate prediction would involve all of these data, a difficult task indeed. | https://www.wikidoc.org/index.php/Operator_(biology) | |
4a8f502244b54bbc08565a9edccef47ab27d2d14 | wikidoc | Opiate | Opiate
# Overview
In medicine, the term opiate describes any of the narcotic alkaloids found in opium.
The main opiates derived from opium are morphine, codeine, thebaine, and Papaverine. Noscapine, narceine and approximately 25 other alkaloids are also present, but have essentially little to no effect on the central nervous system, and are not usually considered to be opiates. The drug opium is mostly produced in Asia.
# The alkaloids
## Morphine
Morphine is by far the most prevalent alkaloid in opium, making up anywhere from 10% to 16% of the total mass, and is responsible for many of its potentially harmful effects, such as pulmonary edema, respiratory depression, coma, cardiac and/or respiratory failure, with a normal lethal dose of 120 to 250 mg. (approximately two grams of opium.) However, the occurrence of pulmonary edema is uncommon. The most frequently-reported occurrences of opiate-induced pulmonary edema are among recreational heroin users. Although uncommon, reports of morphine-induced pulmonary edema are not unheard of. The primary difference being the more careful supervision of morphine administration compared to the lack of supervision and medical expertise among illicit heroin users. On the other hand, morphine may also be used in the treatment of pulmonary edema. Despite morphine's being the most medically-significant alkaloid, larger quantities of the milder codeine — most of it manufactured from morphine — are consumed medically.
The expression of the morphine content of opium as a percentage depends in part on the moisture content. When the government purchases the opium, as soon as practicable after it is collected, the moisture content is then usually about 30%. Commercial opium usually has around 10% to 15% moisture. Opium dried at ordinary temperatures still retains considerable moisture — usually about six percent — which can be driven off at about 103 degrees Celsius.
The quantity of morphine produced by poppy plants in the form of opium depends on two factors: the percentage of morphine in the opium, and the quantity of opium produced. The latter factor, in turn, depends in part on whether each capsule is bled several times, or just once. In Turkey, Bulgaria, Greece, and the Balkans, each capsule is bled only once, but, in most other opium-producing countries, like Iran, India, and Afghanistan, the capsules are incised repeatedly, often four or five times on different days, until they will yield no more latex. The quantity of latex falls off rapidly with later incisions, and so does the morphine content. Usually, all the opium obtained is mixed together. This is probably the chief reason for the often lower morphine content of Iranian and Indian opiums as compared with Turkish and Balkan opiums, although it must also be recognized that there are low-yielding and high-yielding strains of the poppy, one or the other of which may predominate in a given region.
Samples of opium assaying some 15% morphine from Japan, Indochina, and Afghanistan, as well as from Turkey, Greece, and the Balkans have been examined by the United Nations Secretariat. Afghanistan at one time exported two grades of opium, one of about 15% morphine and the other about 10%. The morphine content of dry capsule-chaff is about 0.25% to 0.5%, when not washed out by rain. Here again there are low-yielding and high-yielding varieties, but proper agricultural selection of poppies for morphine production means taking into account not only the percentage yield of morphine, but also the total weight of capsule-chaff produced per hectare, the poppy seed production per hectare, and other factors.
Most of the licit morphine is used to manufacture codeine through O-methylation. Morphine is also used to manufacture other drugs, such as heroin, dihydromorphine, hydromorphone, and many others. Of these, the conversion of morphine to heroin is particularly noteworthy due to heroin's unusual pharmacological properties. The acetylation of morphine's two hydroxyl groups results in a different drug in chemical structure, but nearly identical with regard to pharmacological properties, the principal difference being lipid solubility. This increase in lipid solubility allows heroin to enter the brain more rapidly than morphine.
As heroin is not pharmacologically active it must first be metabolized. The active metabolites of heroin are morphine, 6-monoacetylmorphine and 3-monoacetylmorphine.
## Codeine
The codeine content of opium is related inversely to the morphine content, but only in a general way. Codeine yield is closely related to the type of opium produced in a given district or even in some cases in an entire country. The opiums of the principal exporting countries have approximately the following percentages of codeine: Balkans 1.25%; Turkey 1.25%; Iran 3.4%; India 3.0%.
The highest percentages of codeine obtained by the United Nations Secretariat (averaging about 4.3%) were found in opium samples that came from north-eastern Asia (Korea, northern China).
The manufacturers’ statistics do not ordinarily show all the codeine obtained from opium. Some of it co-precipitates with the morphine, and there is no necessity of purifying the morphine completely of its codeine content, especially if it is to be used to manufacture more codeine.
Codeine is used to manufacture dihydrocodeine, hydrocodone, and others. It may also be used to manufacture the drugs ordinarily made by conversion of thebaine.
## Thebaine and Papaverine
The United Nations Secretariat is currently engaged in a survey, the most extensive ever attempted in this field, of opium samples from different regions for their thebaine and papaverine percentages. As yet, it is premature for general conclusions. However, the highest thebaine percentages found (nearly 5%) were in some samples from Indochina, which at the same time had virtually no papaverine. Both thebaine and papaverine have been high in most Iranian samples run. Papaverine is low in some Afghan and Indian opiums.
Thebaine is the most poisonous opium alkaloid and is scarcely used for medical purposes . It is even omitted from some of the preparations of mixed opium alkaloids that are used as soluble substitutes for opium. However, it is converted into several other narcotics that have medical use: hydrocodone, acetyldihydrocodeine, oxycodone, and the highly-potent and powerful narcotic oxymorphone .
Papaverine has a considerable medical use, so much so that supplies available from opium have sometimes run short. It is then manufactured synthetically.
# Terminology
In the traditional sense, opiate has referred to not only the alkaloids in opium but also the natural and semi-synthetic derivatives of morphine (itself an opiate). The term is often incorrectly used to refer to all drugs with opium- or morphine-like pharmacological action, which are more properly classified under the broader term opioid. | Opiate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In medicine, the term opiate describes any of the narcotic alkaloids found in opium.
The main opiates derived from opium are morphine, codeine, thebaine, and Papaverine. Noscapine, narceine and approximately 25 other alkaloids are also present, but have essentially little to no effect on the central nervous system, and are not usually considered to be opiates. The drug opium is mostly produced in Asia.[citation needed]
# The alkaloids
## Morphine
Morphine is by far the most prevalent alkaloid in opium, making up anywhere from 10% to 16% of the total mass, and is responsible for many of its potentially harmful effects, such as pulmonary edema, respiratory depression, coma, cardiac and/or respiratory failure, with a normal lethal dose of 120 to 250 mg.[1] (approximately two grams of opium.[2]) However, the occurrence of pulmonary edema is uncommon. The most frequently-reported occurrences of opiate-induced pulmonary edema are among recreational heroin users.[3][4] Although uncommon, reports of morphine-induced pulmonary edema are not unheard of.[5] The primary difference being the more careful supervision of morphine administration compared to the lack of supervision and medical expertise among illicit heroin users. On the other hand, morphine may also be used in the treatment of pulmonary edema.[6][7] Despite morphine's being the most medically-significant alkaloid, larger quantities of the milder codeine — most of it manufactured from morphine — are consumed medically.
The expression of the morphine content of opium as a percentage depends in part on the moisture content. When the government purchases the opium, as soon as practicable after it is collected, the moisture content is then usually about 30%. Commercial opium usually has around 10% to 15% moisture. Opium dried at ordinary temperatures still retains considerable moisture — usually about six percent — which can be driven off at about 103 degrees Celsius.
The quantity of morphine produced by poppy plants in the form of opium depends on two factors: the percentage of morphine in the opium, and the quantity of opium produced. The latter factor, in turn, depends in part on whether each capsule is bled several times, or just once. In Turkey, Bulgaria, Greece, and the Balkans, each capsule is bled only once, but, in most other opium-producing countries, like Iran, India, and Afghanistan, the capsules are incised repeatedly, often four or five times on different days, until they will yield no more latex. The quantity of latex falls off rapidly with later incisions, and so does the morphine content.[8] Usually, all the opium obtained is mixed together. This is probably the chief reason for the often lower morphine content of Iranian and Indian opiums as compared with Turkish and Balkan opiums, although it must also be recognized that there are low-yielding and high-yielding strains of the poppy, one or the other of which may predominate in a given region.
Samples of opium assaying some 15% morphine from Japan, Indochina, and Afghanistan, as well as from Turkey, Greece, and the Balkans have been examined by the United Nations Secretariat. Afghanistan at one time exported two grades of opium, one of about 15% morphine and the other about 10%. The morphine content of dry capsule-chaff is about 0.25% to 0.5%, when not washed out by rain. Here again there are low-yielding and high-yielding varieties, but proper agricultural selection of poppies for morphine production means taking into account not only the percentage yield of morphine, but also the total weight of capsule-chaff produced per hectare, the poppy seed production per hectare, and other factors.
Most of the licit morphine is used to manufacture codeine through O-methylation. Morphine is also used to manufacture other drugs, such as heroin, dihydromorphine, hydromorphone, and many others. Of these, the conversion of morphine to heroin is particularly noteworthy due to heroin's unusual pharmacological properties. The acetylation of morphine's two hydroxyl groups results in a different drug in chemical structure, but nearly identical with regard to pharmacological properties, the principal difference being lipid solubility. This increase in lipid solubility allows heroin to enter the brain more rapidly than morphine.[2]
As heroin is not pharmacologically active it must first be metabolized. The active metabolites of heroin are morphine, 6-monoacetylmorphine and 3-monoacetylmorphine.
## Codeine
The codeine content of opium is related inversely to the morphine content, but only in a general way. Codeine yield is closely related to the type of opium produced in a given district or even in some cases in an entire country. The opiums of the principal exporting countries have approximately the following percentages of codeine: Balkans 1.25%; Turkey 1.25%; Iran 3.4%; India 3.0%.
The highest percentages of codeine obtained by the United Nations Secretariat (averaging about 4.3%) were found in opium samples that came from north-eastern Asia (Korea, northern China).
The manufacturers’ statistics do not ordinarily show all the codeine obtained from opium. Some of it co-precipitates with the morphine, and there is no necessity of purifying the morphine completely of its codeine content, especially if it is to be used to manufacture more codeine.
Codeine is used to manufacture dihydrocodeine, hydrocodone, and others. It may also be used to manufacture the drugs ordinarily made by conversion of thebaine.[3]
## Thebaine and Papaverine
The United Nations Secretariat is currently engaged in a survey, the most extensive ever attempted in this field, of opium samples from different regions for their thebaine and papaverine percentages. As yet, it is premature for general conclusions. However, the highest thebaine percentages found (nearly 5%) were in some samples from Indochina, which at the same time had virtually no papaverine. Both thebaine and papaverine have been high in most Iranian samples run. Papaverine is low in some Afghan and Indian opiums.
Thebaine is the most poisonous opium alkaloid and is scarcely used for medical purposes [citation needed]. It is even omitted from some of the preparations of mixed opium alkaloids that are used as soluble substitutes for opium. However, it is converted into several other narcotics that have medical use: hydrocodone, acetyldihydrocodeine, oxycodone, and the highly-potent and powerful narcotic oxymorphone [citation needed].
Papaverine has a considerable medical use, so much so that supplies available from opium have sometimes run short. It is then manufactured synthetically.[4]
# Terminology
In the traditional sense, opiate has referred to not only the alkaloids in opium but also the natural and semi-synthetic derivatives of morphine (itself an opiate). The term is often incorrectly used to refer to all drugs with opium- or morphine-like pharmacological action, which are more properly classified under the broader term opioid. | https://www.wikidoc.org/index.php/Opiate | |
e3c0686e4eb6485e008f2bc00e11fdf98cd4db35 | wikidoc | Orgone | Orgone
Orgone energy is a term coined by psychoanalyst Wilhelm Reich for the "universal life energy" which he claimed to have discovered in published experiments in the late 1930s. Reich claimed that orgone energy was a "life energy" which filled all space, was blue in color, and that certain forms of illness were the consequence of depletion or blockages of the energy within the body. These theories are considered pseudoscience.
# Modern usage
Psychotherapists and Medical practitioners have occasionally used Reich's emotion-release methods, and even his orgone accumulator as part of their therapy. But its use is exceedingly rare, and limited to therapists who have been trained by "Reichian" institutions such as the American College of Orgonomy.
# Wilhelm Reich's theories
Reich claimed that life was founded upon bioenergetic phenomena, and characterized by the pulsation of bioenergy, as with heart-beat, respiration, and bladder functions. Emotions and sexuality, he argued, also followed a similar basic bioenergetic pulsation, and optimal health necessitated open emotional expression and periodic sexual release of accumulated bio-energy. He measured bioelectrical signatures of emotional-sexual human subjective experiences, using sensitive millivoltmeters, interpreting these as expressions of a specific "bio-electric" life-energy. He later observed and developed objective measures to identify energetic fields around humans and other living forms, including microbes, and claimed the same bio-energy also charged non-living matter, and existed in a free form in the atmosphere. He argued the "orgone" bore a similarity to the older concept of cosmological ether of space. The orgone accumulator was developed as a means to objectively capture this energy from the atmosphere, and later was claimed to have both anomalous biological and physical effects. Reich also designed a device called the "cloudbuster", which he claimed could disperse clouds and produce rain.
## Criticism
Reich's orgone theory is frequently noted as a typical example of pseudoscience in discussions of that subject and has been dismissed or ignored completely by most working within mainstream science. Critics also assert that the experiments may have followed scientific protocol, but how the results of the experiments were interpreted is also crucial. His measurements of "bio-energy" could equally have been merely millivolts of electricity generated by normal biological processes (such as, but not limited to, the galvanic skin response).
Some of his critics, meanwhile, insist that Reich's many experiments were seriously flawed in design; that his results have proved unrepeatable when the experiments are properly designed; and that his conclusions were, therefore, untenable. As of 2007, the National Institutes of Health database PubMed, and the Web of Science database, contained only 4 or 5 peer-reviewed scientific papers published since 1968 dealing with orgone therapy. Reich's work and name has become anathema within the academic world. Medical societies and the FDA, eager to prevent alleged health-fraud, lead to a court decision to burn Reich's books which mentioned orgone and discouraged application of his methods by health practitioners. However, starting in the 1960s and increasingly over the next several decades, the growing "alternative health" and "natural healing" movements provided shelter for the belief in orgone.
## Response to critics
Some of his advocates counter that Reich's observations and claims should be regarded as a protoscience rather than a pseudoscience, and assert that Reich's experiments followed the scientific method. Some of Reich's advocates are outright insistent that Reich's experiments are sound, reproducible on the original protocols, and made solid and important scientific discoveries. Comparisons have been made by orgone-advocates to "dark matter" in space, or between Reich's bions and archaea/protocells in microbiology. They state that his findings have been unfairly maligned by non-scientific attackers in the popular press and organized "pseudo-skeptic" organizations (see section below).
Advocates argue that evaluations of Reich's claims require evaluations of the original experiments by persons trained in the natural sciences, in the nature of verification studies, to see if they yield the same results as Reich claimed, and if so, that better-known explanations are ruled out. Along these lines, Reich's supporters point to an accumulating body of experimental evidence. Most of this material is published in non-mainstream research journals, or self-published sources.
Regarding the lack of citations from reliable sources, it is claimed, without evidence, that such large "mainstream" bibliographical indexes routinely exclude these same Reich-oriented journals. An on-line "Bibliography on Orgonomy" developed by orgone-advocate James DeMeo. Most of those citations focus upon Reich's psychotherapy methods, but approximately half of them address experimentally the biophysical aspects of his claims, such as the microscopical bions, the orgone energy accumulator (studies on lab animals, plant and human clinical studies), various aspects of orgone physics (such as the thermal anomaly in the orgone accumulator, which was dismissed as "solved" by Albert Einstein), and field experiments with the cloudbuster. DeMeo also provides a separate listing of unpublished dissertations and theses as supportive of Reich's theories.
Even the more outlandish of Reich's claims occasionally came under scientific study within mainstream universities. For example the Master's thesis of James DeMeo at the University of Kansas reports positive outcomes from field experiments on one of Reich's most controversial claims, regarding the cloudbuster. His results reportedly demonstrate systematic changes in Kansas weather when it was used according to the original protocols of Reich. A German-language thesis from Stefan Muschenich and Rainer Gebauer at the University of Marburg, replicated effects of the orgone accumulator on test subjects in keeping with Reich's original descriptions, while a control "dummy box" showed no such effects. A follow-up 1995 study, was undertaken at the University of Vienna, by Guenter Hebenstreit, with similar positive results in favor of Reich's claims.
# Orgone energy in popular culture
- An Orgone Accumulator is featured in the Jack Kerouac novel On the Road.
- Orgone energy was featured as a means of controlling weather in the Lupin III anime Da Capo of Love: Fujiko's Unlucky Days.
- There is a song called Orgone Accumulator in the album Space Ritual by Hawkwind 1973
- "Cloudbusting" is a song by Kate Bush which features the Reich's cloudbuster, a machine which could affect cloud formations, capture 'Orgone' and, to all intents and purposes, make clouds rain. Kate wrote "Cloudbusting" after reading A Book Of Dreams, a memoir by Reich's son Peter. In the music video for "Cloudbusting", a sentimental story told through the eyes of Wilhelm Reich's son, Kate Bush plays the young Peter Reich, who is seen being shown a cloudbuster by his father, Wilhelm Reich, who is portrayed by the celebrated Canadian film actor Donald Sutherland.
- The main character robots from the game Super Robot Wars J are powered by Orgone Energy
- In Hal Duncan's series "The Book of All Hours", a character styling himself Jack Flash uses "Orgone Bombs" as weapons.
- Harvey Pekar mistakes a green house for an orgone box in his 1989 short American Splendor story "The Greenhouse Effect" (Collected in The New American Splendor Anthology)
- In the second issue of Matt Fraction's "Casanova", the villain's island lair was powered by Orgone.
# Fictional accounts
## William S. Burroughs
Though thought of as a pseudoscience by many professionals, the study of orgones was heavily supported and researched by the beat generation author, William S. Burroughs, who is known for surreal imagery in his novels dealing mostly with his life with narcotics, especially heroin. The topic of orgones interested Burroughs not because he had cancer, but because he believed that the method in which the orgones supposedly helped cure cancer-sick patients could also help alleviates the harsh withdrawal symptoms from heroin, which Burroughs calls "junk sickness."
Burroughs compares cancer to a junkie trying to kick the habit in the novel Junky, where he also speaks of orgone accumulators. He writes:
“Cancer is rot of tissue in a living organism. In junk sickness the junk dependent cells die and are replaced. Cancer is a premature death process. The cancer patient shrinks. A junkie shrinks ¬¬– I have lost up to fifteen pounds in three days. So I figure if the accumulator is a therapy for cancer, it should be therapy for the after-effects of junk sickness.”
At the time that Burroughs was writing, there was only one source to get an accumulator. It was from the Orgone Institute in New York. They didn’t sell or rent these machines, instead, a ten dollar a moth donation was required. Burroughs decided to build an accumulator of his own. He substituted rock wool for the sheet iron, but still achieved the desired effect. Burroughs writes about what occurred once he started using the accumulator:
“Constant use of junk of the years has given me the habit of directing attention inward. When I went into the accumulator and sat down I noticed a special silence that you sometimes feel in deep woods, sometimes on a city street, a hum that is more rhythmic vibration than a sound. My skin prickled and I experienced an aphrodisiac effect similar to good strong weed. No doubt about it, orgones are as definite a force as electricity. After using the accumulator for several days my energy came back to normal. I began to eat and could not sleep more than eight hours. I was out of the post cure drag.”
## Jack Kerouac
The orgone accumulator was primarily used as a sex drive boost in Jack Kerouac’s popular beat novel, On The Road, when his character, Sal Paradise along with others visit Old Bull Lee, William Burroughs’s character, in New Orleans:
“‘Say, why don’t you fellows try my orgone accumulator? Put some juice in your bones. I always rush up and take off ninety miles an hour for the nearest whorehouse, hor-hor-hor!’ said Bull Lee… The orgone accumulator is an ordinary box big enough for a man to sit inside on a chair: a layer of wood, a layer of metal, and another layer of wood gather in orgones from the atmosphere and hold them captive long enough for a human to absorb more than a usual share. According the Reich, orgones are vibratory atmospheric atoms of the life-principle. People get cancer because they run out of orgones. Old Bull thought his orgone accumulator would be improved if the wood he used was as organic as possible, so he tied bushy bayou leaves and twigs to his mystical outhouse. It stood there in the hot, flat yard, an exfoliate machine clustered and bedecked with maniacal contrivances. Old Bull slipped off his clothes and went to sit and moon over his navel.” | Orgone
Orgone energy is a term coined by psychoanalyst Wilhelm Reich for the "universal life energy" which he claimed to have discovered in published experiments in the late 1930s. Reich claimed that orgone energy was a "life energy" which filled all space, was blue in color, and that certain forms of illness were the consequence of depletion or blockages of the energy within the body. These theories are considered pseudoscience.[1][2][3]
# Modern usage
Psychotherapists and Medical practitioners have occasionally used Reich's emotion-release methods, and even his orgone accumulator as part of their therapy.[4] But its use is exceedingly rare, and limited to therapists who have been trained by "Reichian" institutions such as the American College of Orgonomy.
# Wilhelm Reich's theories
Reich claimed that life was founded upon bioenergetic phenomena, and characterized by the pulsation of bioenergy, as with heart-beat, respiration, and bladder functions. Emotions and sexuality, he argued, also followed a similar basic bioenergetic pulsation, and optimal health necessitated open emotional expression and periodic sexual release of accumulated bio-energy. He measured bioelectrical signatures of emotional-sexual human subjective experiences, using sensitive millivoltmeters, interpreting these as expressions of a specific "bio-electric" life-energy. He later observed and developed objective measures to identify energetic fields around humans and other living forms, including microbes, and claimed the same bio-energy also charged non-living matter, and existed in a free form in the atmosphere. He argued the "orgone" bore a similarity to the older concept of cosmological ether of space. The orgone accumulator was developed as a means to objectively capture this energy from the atmosphere, and later was claimed to have both anomalous biological and physical effects. Reich also designed a device called the "cloudbuster", which he claimed could disperse clouds and produce rain.
## Criticism
Reich's orgone theory is frequently noted as a typical example of pseudoscience in discussions of that subject and has been dismissed or ignored completely by most working within mainstream science.[5] Critics also assert that the experiments may have followed scientific protocol, but how the results of the experiments were interpreted is also crucial. His measurements of "bio-energy" could equally have been merely millivolts of electricity generated by normal biological processes (such as, but not limited to, the galvanic skin response).
Some of his critics, meanwhile, insist that Reich's many experiments were seriously flawed in design; that his results have proved unrepeatable when the experiments are properly designed; and that his conclusions were, therefore, untenable. As of 2007, the National Institutes of Health database PubMed, and the Web of Science database, contained only 4 or 5 peer-reviewed scientific papers published since 1968 dealing with orgone therapy. Reich's work and name has become anathema within the academic world. Medical societies and the FDA, eager to prevent alleged health-fraud, lead to a court decision to burn Reich's books which mentioned orgone and discouraged application of his methods by health practitioners. However, starting in the 1960s and increasingly over the next several decades, the growing "alternative health" and "natural healing" movements provided shelter for the belief in orgone.
## Response to critics
Some of his advocates counter that Reich's observations and claims should be regarded as a protoscience rather than a pseudoscience, and assert that Reich's experiments followed the scientific method. Some of Reich's advocates[citation needed] are outright insistent that Reich's experiments are sound, reproducible on the original protocols, and made solid and important scientific discoveries. Comparisons have been made by orgone-advocates to "dark matter" in space, or between Reich's bions and archaea/protocells in microbiology.[citation needed] They state that his findings have been unfairly maligned by non-scientific attackers in the popular press and organized "pseudo-skeptic" organizations (see section below).
Advocates argue that evaluations of Reich's claims require evaluations of the original experiments by persons trained in the natural sciences, in the nature of verification studies, to see if they yield the same results as Reich claimed, and if so, that better-known explanations are ruled out. Along these lines, Reich's supporters point to an accumulating body of experimental evidence. Most of this material is published in non-mainstream research journals, or self-published sources.
Regarding the lack of citations from reliable sources, it is claimed, without evidence, that such large "mainstream" bibliographical indexes routinely exclude these same Reich-oriented journals. An on-line "Bibliography on Orgonomy" developed by orgone-advocate James DeMeo. Most of those citations focus upon Reich's psychotherapy methods, but approximately half of them address experimentally the biophysical aspects of his claims, such as the microscopical bions, the orgone energy accumulator (studies on lab animals, plant and human clinical studies), various aspects of orgone physics (such as the thermal anomaly in the orgone accumulator, which was dismissed as "solved" by Albert Einstein), and field experiments with the cloudbuster. DeMeo also provides a separate listing of unpublished dissertations and theses as supportive of Reich's theories.
Even the more outlandish of Reich's claims occasionally came under scientific study within mainstream universities. For example the Master's thesis of James DeMeo at the University of Kansas[6] reports positive outcomes from field experiments on one of Reich's most controversial claims, regarding the cloudbuster. His results reportedly demonstrate systematic changes in Kansas weather when it was used according to the original protocols of Reich. A German-language thesis from Stefan Muschenich and Rainer Gebauer at the University of Marburg,[7] replicated effects of the orgone accumulator on test subjects in keeping with Reich's original descriptions, while a control "dummy box" showed no such effects. A follow-up 1995 study, was undertaken at the University of Vienna, by Guenter Hebenstreit,[8] with similar positive results in favor of Reich's claims.
# Orgone energy in popular culture
- An Orgone Accumulator is featured in the Jack Kerouac novel On the Road.
- Orgone energy was featured as a means of controlling weather in the Lupin III anime Da Capo of Love: Fujiko's Unlucky Days.
- There is a song called Orgone Accumulator in the album Space Ritual by Hawkwind 1973
- "Cloudbusting" is a song by Kate Bush which features the Reich's cloudbuster, a machine which could affect cloud formations, capture 'Orgone' and, to all intents and purposes, make clouds rain. Kate wrote "Cloudbusting" after reading A Book Of Dreams, a memoir by Reich's son Peter. In the music video for "Cloudbusting", a sentimental story told through the eyes of Wilhelm Reich's son, Kate Bush plays the young Peter Reich, who is seen being shown a cloudbuster by his father, Wilhelm Reich, who is portrayed by the celebrated Canadian film actor Donald Sutherland.
- The main character robots from the game Super Robot Wars J are powered by Orgone Energy
- In Hal Duncan's series "The Book of All Hours", a character styling himself Jack Flash uses "Orgone Bombs" as weapons.
- Harvey Pekar mistakes a green house for an orgone box in his 1989 short American Splendor story "The Greenhouse Effect" (Collected in The New American Splendor Anthology)
- In the second issue of Matt Fraction's "Casanova", the villain's island lair was powered by Orgone.
# Fictional accounts
## William S. Burroughs
Though thought of as a pseudoscience by many professionals, the study of orgones was heavily supported and researched by the beat generation author, William S. Burroughs, who is known for surreal imagery in his novels dealing mostly with his life with narcotics, especially heroin. The topic of orgones interested Burroughs not because he had cancer, but because he believed that the method in which the orgones supposedly helped cure cancer-sick patients could also help alleviates the harsh withdrawal symptoms from heroin, which Burroughs calls "junk sickness."
Burroughs compares cancer to a junkie trying to kick the habit in the novel Junky, where he also speaks of orgone accumulators. He writes:
“Cancer is rot of tissue in a living organism. In junk sickness the junk dependent cells die and are replaced. Cancer is a premature death process. The cancer patient shrinks. A junkie shrinks ¬¬– I have lost up to fifteen pounds in three days. So I figure if the accumulator is a therapy for cancer, it should be therapy for the after-effects of junk sickness.”
At the time that Burroughs was writing, there was only one source to get an accumulator. It was from the Orgone Institute in New York. They didn’t sell or rent these machines, instead, a ten dollar a moth donation was required. Burroughs decided to build an accumulator of his own. He substituted rock wool for the sheet iron, but still achieved the desired effect. Burroughs writes about what occurred once he started using the accumulator:
“Constant use of junk of the years has given me the habit of directing attention inward. When I went into the accumulator and sat down I noticed a special silence that you sometimes feel in deep woods, sometimes on a city street, a hum that is more rhythmic vibration than a sound. My skin prickled and I experienced an aphrodisiac effect similar to good strong weed. No doubt about it, orgones are as definite a force as electricity. After using the accumulator for several days my energy came back to normal. I began to eat and could not sleep more than eight hours. I was out of the post cure drag.”
## Jack Kerouac
The orgone accumulator was primarily used as a sex drive boost in Jack Kerouac’s popular beat novel, On The Road, when his character, Sal Paradise along with others visit Old Bull Lee, William Burroughs’s character, in New Orleans:
“‘Say, why don’t you fellows try my orgone accumulator? Put some juice in your bones. I always rush up and take off ninety miles an hour for the nearest whorehouse, hor-hor-hor!’ said Bull Lee… The orgone accumulator is an ordinary box big enough for a man to sit inside on a chair: a layer of wood, a layer of metal, and another layer of wood gather in orgones from the atmosphere and hold them captive long enough for a human to absorb more than a usual share. According the Reich, orgones are vibratory atmospheric atoms of the life-principle. People get cancer because they run out of orgones. Old Bull thought his orgone accumulator would be improved if the wood he used was as organic as possible, so he tied bushy bayou leaves and twigs to his mystical outhouse. It stood there in the hot, flat yard, an exfoliate machine clustered and bedecked with maniacal contrivances. Old Bull slipped off his clothes and went to sit and moon over his navel.” | https://www.wikidoc.org/index.php/Orgone | |
d63c3a953463d581ac7f2e8dd060b246f926651b | wikidoc | Ostium | Ostium
# Overview
An ostium is a small opening or orifice, as in a body organ or passage.
# Anatomy
- Ostium of Fallopian tube.
- Ostium primum or foramen ovale (ostium secundum) of the developing heart.
- Ostium maxillare of the Maxillary Sinus
- Ostium of uterus
- Ostium vaginae (vaginal orifice)
- Coronary ostium (Opening of coronary arteries at root of aorta, superior to aortic valve)
# Ostial Disease
Ostial disease refer to diseases involving the ostium of a body organ, passage or vessel. In particular, ostial stenosis is a narrowing in a ostium. It can refer to:
- Coronary ostial stenosis
- Renal ostial stenosis | Ostium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
An ostium is a small opening or orifice, as in a body organ or passage.
# Anatomy
- Ostium of Fallopian tube.
- Ostium primum or foramen ovale (ostium secundum) of the developing heart.
- Ostium maxillare of the Maxillary Sinus
- Ostium of uterus
- Ostium vaginae (vaginal orifice)
- Coronary ostium (Opening of coronary arteries at root of aorta, superior to aortic valve)
# Ostial Disease
Ostial disease refer to diseases involving the ostium of a body organ, passage or vessel. In particular, ostial stenosis is a narrowing in a ostium. It can refer to:
- Coronary ostial stenosis
- Renal ostial stenosis
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Ostial | |
960621a30941d6fec7403b7762cab51a41e2012e | wikidoc | Oxamyl | Oxamyl
# Overview
Oxamyl is a chemical used as a pesticide that comes in two forms: granulated and liquid. The granulated form has been banned in the United States.
# Structure and uses
Oxamyl is a carbamate pesticide. According to the WHO Food and Agriculture Organization, "Oxamyl is a colourless crystalline solid with a melting point of 100-102 °C changing to a dimorphic form with a melting point of 108-110 °C. It has a slightly sulfurous odour. Oxamyl is non-corrosive. It has a specific gravity of 0.97 (25°/4°)."
According to the United Nations Environment Programme, "This product is efficient in controlling most nematode species in addition to a large number of sucking and chewing insects such as aphids and thrips." Oxamyl is extremely toxic to humans whether ingested, inhaled, or contact with the skin. Its overuse can also lead to residue accumulation in food, though its chemical composition--once coming into contact with the soil--rapidly degrades. Signs of Oxamyl poisoning include: Malaise, muscle weakness, dizziness, sweating, Headache, salivation, nausea, vomiting, abdominal pain, Miosis with blurred vision, incoordination, muscle twitching and slurred speech--though symptoms can worsen with severe poisoning. According to the Food and Agriculture Organization, "Contact with the skin, inhalation of dust or spray, or swallowing may be fatal."
Because of its toxicity, its use is restricted in the EU/UK with maximum residue limits for apples and oranges being 0.01 mg/kg and this amount is only allowed because this is the limit of detection. | Oxamyl
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Oxamyl is a chemical used as a pesticide that comes in two forms: granulated and liquid. The granulated form has been banned in the United States.[2]
# Structure and uses
Oxamyl is a carbamate pesticide.[3] According to the WHO Food and Agriculture Organization, "Oxamyl is a colourless crystalline solid with a melting point of 100-102 °C changing to a dimorphic form with a melting point of 108-110 °C. It has a slightly sulfurous odour. Oxamyl is non-corrosive. It has a specific gravity of 0.97 (25°/4°)."[1]
According to the United Nations Environment Programme, "This product is efficient in controlling most nematode species in addition to a large number of sucking and chewing insects such as aphids and thrips." Oxamyl is extremely toxic to humans whether ingested, inhaled, or contact with the skin. Its overuse can also lead to residue accumulation in food,[2] though its chemical composition--once coming into contact with the soil--rapidly degrades.[4] Signs of Oxamyl poisoning include: Malaise, muscle weakness, dizziness, sweating, Headache, salivation, nausea, vomiting, abdominal pain, Miosis with blurred vision, incoordination, muscle twitching and slurred speech--though symptoms can worsen with severe poisoning.[3] According to the Food and Agriculture Organization, "Contact with the skin, inhalation of dust or spray, or swallowing may be fatal."[1]
Because of its toxicity, its use is restricted in the EU/UK with maximum residue limits for apples and oranges being 0.01 mg/kg[citation needed] and this amount is only allowed because this is the limit of detection. | https://www.wikidoc.org/index.php/Oxamyl | |
8a949492cc27ad6dcf4dc0195eae95b278c2da86 | wikidoc | P wave | P wave
# Overview
During normal atrial depolarization, the main electrical vector is directed from the SA node towards the AV node, and spreads from the right atrium to the left atrium. This turns into the P wave on the ECG, which is upright in II, III, and aVF (since the general electrical activity is going toward the positive electrode in those leads), and inverted in aVR (since it is going away from the positive electrode for that lead). The P-wave morphology is best determined in leads II and V1 during sinus rhythm.
# The P Wave Morphology
- The P wave represents atrial depolarization (stimulation).
- At either slow or normal heart rates, the small, rounded P wave is clearly visible just before the taller, more peaked QRS complex.
- At more rapid rates, however, the P wave may merge with the preceding T wave and become difficult to identify. Sinus node depolarization is too small in amplitude to be recorded from the body surface so it is not seen.
### Steps in the evaluation of the P wave
- 1. Examination of the P wave contour:
The P wave contour is normally smooth, and is either entirely positive or entirely negative wave (monophasic wave) in all leads except V1.
- The P wave contour is normally smooth, and is either entirely positive or entirely negative wave (monophasic wave) in all leads except V1.
- 2. Measurement of the P wave duration:
The P wave duration is normally less than 0.12 seconds.
- The P wave duration is normally less than 0.12 seconds.
- 3. Measurement of the maximal P wave amplitude:
The maximal P-wave amplitude is normally no more than 0.2 mV in the frontal plane leads and no more than 0.1 mV in the transverse plane leads.
- The maximal P-wave amplitude is normally no more than 0.2 mV in the frontal plane leads and no more than 0.1 mV in the transverse plane leads.
- 4. Estimation of the P wave axis:
The P wave normally appears entirely upright on leftward and inferiorly oriented leads such as I, II, aVF, and V4 to V6. It is negative in aVR because of the rightward orientation of that lead, and it is variable in the other standard leads. The normal limits of the P wave axis are 0 degrees and +75 degrees.
- The P wave normally appears entirely upright on leftward and inferiorly oriented leads such as I, II, aVF, and V4 to V6. It is negative in aVR because of the rightward orientation of that lead, and it is variable in the other standard leads. The normal limits of the P wave axis are 0 degrees and +75 degrees.
# The P Wave in Normal Sinus Rhythm
- A P wave must be upright in leads II and aVF and inverted in lead aVR to designate a cardiac rhythm as normal sinus rhythm. The relationship between P waves and QRS complexes helps distinguish various cardiac arrhythmias.
If the P wave is inverted, then the origin of the rhythm may be in the low atrial region.
Widened P waves can be a sign of Class Ia antiarrhythmic drugs intoxication (quinidine, etc.)
Small or absent P waves can be a sign of hyperkalemia.
- If the P wave is inverted, then the origin of the rhythm may be in the low atrial region.
- Widened P waves can be a sign of Class Ia antiarrhythmic drugs intoxication (quinidine, etc.)
- Small or absent P waves can be a sign of hyperkalemia.
# Abnormal P Wave Examples
- Elevation or depression of the PTa segment (the part between the p wave and the beginning of the QRS complex) can result from atrial infarction or pericarditis.
- Altered P wave morphology is seen in left or right atrial enlargement. If the p-wave is enlarged, the atria are enlarged.
# The P Wave in Left Atrial Enlargement
- The shape and duration of the P waves may indicate atrial enlargement. Left atrial enlargement may be observed among patients with mitral insufficiency.
- Left atrial enlargement is defined as either:
P wave with a broad (>0.04 sec or 1 small suare) and deeply negative (>1 mm) terminal part in V1 (P mitrale)
P wave duration >0.12 sec in leads I and / or II
- P wave with a broad (>0.04 sec or 1 small suare) and deeply negative (>1 mm) terminal part in V1 (P mitrale)
- P wave duration >0.12 sec in leads I and / or II
- Left atrial enlargement
- Left atrial enlargement with ECG.
- Left atrial enlargement as seen in lead V1.
- Left atrial enlargement, a 12 lead ECG
## Differential Diagnosis of Left Atrial Enlargement
In alphabetical order
- Atrial aneurysm
- Infective endocarditis
- Left heart failure
- Mitral regurgitation
- Mitral stenosis
- Mitral valve prolapse
- Myxedma
- Patent Ductus Arteriosus
- Ventricular septal defect
# The P Wave in Right Atrial Enlargement
- Right atrial enlargement can result from increased right-sided pressures such as those related to valvular lesions and after pulmonary embolism.
- A positive part of the biphasic P wave in lead V1 larger than the negative part indicates right atrial enlargement.
- The width of the P wave is not part of the criteria for right atrial enlargement.
- Right atrial enlargement is defined as either:
P is taller than 2.5 mm in II / III and / or aVF (P pulmonale)
P >1.5 mm in V1
- P is taller than 2.5 mm in II / III and / or aVF (P pulmonale)
- P >1.5 mm in V1
- Right atrial enlargement
- Right atrial enlargement
## Differential Diagnosis of Right Atrial Enlargement
In alphabetical order
- Atrial aneurysm
- Atrial septal defect
- Ebstein's anomaly
- Pulmonic stenosis
- Right heart failure
- Tricuspid prolapse
- Tricuspid regurgitation
- Tricuspid stenosis
- Tumor
# Differential Diagnosis of Inverted P Waves in I and aVL
- It is possible to distinguish lead reversal and dextrocardia by watching the precordial leads. Dextrocardia will show an R wave inversion, whereas lead reversal will not.
- This bottom EKG shows marked right axis deviation and loss of voltage across the precordium. There are also inverted P waves in leads I and aVL. The differential for inverted P waves in lead I and aVL is Dextrocardia vs Reversed Arm Leads. Since there is loss of voltage across the precordium this is Dextrocardia.
- If the P waves are inverted in the other leads, then this may indicate that there is a low atrial focus to the origin of the rhythm.
# Inverted P Wave in the Inferior Leads
## Causes
- P waves are inverted in the inferior leads in the setting of a low atrial focus as the origin of the rhythm.
# Sources
- Copyleft images obtained courtesy of ECGpedia, :NewFiles&dir=prev&offset=20080806182927&limit=500 | P wave
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor(s)-in-Chief: Rim Halaby
# Overview
During normal atrial depolarization, the main electrical vector is directed from the SA node towards the AV node, and spreads from the right atrium to the left atrium. This turns into the P wave on the ECG, which is upright in II, III, and aVF (since the general electrical activity is going toward the positive electrode in those leads), and inverted in aVR (since it is going away from the positive electrode for that lead). The P-wave morphology is best determined in leads II and V1 during sinus rhythm.
# The P Wave Morphology
- The P wave represents atrial depolarization (stimulation).
- At either slow or normal heart rates, the small, rounded P wave is clearly visible just before the taller, more peaked QRS complex.
- At more rapid rates, however, the P wave may merge with the preceding T wave and become difficult to identify. Sinus node depolarization is too small in amplitude to be recorded from the body surface so it is not seen.
### Steps in the evaluation of the P wave
- 1. Examination of the P wave contour:
The P wave contour is normally smooth, and is either entirely positive or entirely negative wave (monophasic wave) in all leads except V1.
- The P wave contour is normally smooth, and is either entirely positive or entirely negative wave (monophasic wave) in all leads except V1.
- 2. Measurement of the P wave duration:
The P wave duration is normally less than 0.12 seconds.
- The P wave duration is normally less than 0.12 seconds.
- 3. Measurement of the maximal P wave amplitude:
The maximal P-wave amplitude is normally no more than 0.2 mV in the frontal plane leads and no more than 0.1 mV in the transverse plane leads.
- The maximal P-wave amplitude is normally no more than 0.2 mV in the frontal plane leads and no more than 0.1 mV in the transverse plane leads.
- 4. Estimation of the P wave axis:
The P wave normally appears entirely upright on leftward and inferiorly oriented leads such as I, II, aVF, and V4 to V6. It is negative in aVR because of the rightward orientation of that lead, and it is variable in the other standard leads. The normal limits of the P wave axis are 0 degrees and +75 degrees.
- The P wave normally appears entirely upright on leftward and inferiorly oriented leads such as I, II, aVF, and V4 to V6. It is negative in aVR because of the rightward orientation of that lead, and it is variable in the other standard leads. The normal limits of the P wave axis are 0 degrees and +75 degrees.
# The P Wave in Normal Sinus Rhythm
- A P wave must be upright in leads II and aVF and inverted in lead aVR to designate a cardiac rhythm as normal sinus rhythm. The relationship between P waves and QRS complexes helps distinguish various cardiac arrhythmias.
If the P wave is inverted, then the origin of the rhythm may be in the low atrial region.
Widened P waves can be a sign of Class Ia antiarrhythmic drugs intoxication (quinidine, etc.)
Small or absent P waves can be a sign of hyperkalemia.
- If the P wave is inverted, then the origin of the rhythm may be in the low atrial region.
- Widened P waves can be a sign of Class Ia antiarrhythmic drugs intoxication (quinidine, etc.)
- Small or absent P waves can be a sign of hyperkalemia.
# Abnormal P Wave Examples
- Elevation or depression of the PTa segment (the part between the p wave and the beginning of the QRS complex) can result from atrial infarction or pericarditis.
- Altered P wave morphology is seen in left or right atrial enlargement. If the p-wave is enlarged, the atria are enlarged.
# The P Wave in Left Atrial Enlargement
- The shape and duration of the P waves may indicate atrial enlargement. Left atrial enlargement may be observed among patients with mitral insufficiency.
- Left atrial enlargement is defined as either:
P wave with a broad (>0.04 sec or 1 small suare) and deeply negative (>1 mm) terminal part in V1 (P mitrale)
P wave duration >0.12 sec in leads I and / or II
- P wave with a broad (>0.04 sec or 1 small suare) and deeply negative (>1 mm) terminal part in V1 (P mitrale)
- P wave duration >0.12 sec in leads I and / or II
- Left atrial enlargement
- Left atrial enlargement with ECG.
- Left atrial enlargement as seen in lead V1.
- Left atrial enlargement, a 12 lead ECG
## Differential Diagnosis of Left Atrial Enlargement
In alphabetical order
- Atrial aneurysm
- Infective endocarditis
- Left heart failure
- Mitral regurgitation
- Mitral stenosis
- Mitral valve prolapse
- Myxedma
- Patent Ductus Arteriosus
- Ventricular septal defect
# The P Wave in Right Atrial Enlargement
- Right atrial enlargement can result from increased right-sided pressures such as those related to valvular lesions and after pulmonary embolism.
- A positive part of the biphasic P wave in lead V1 larger than the negative part indicates right atrial enlargement.
- The width of the P wave is not part of the criteria for right atrial enlargement.
- Right atrial enlargement is defined as either:
P is taller than 2.5 mm in II / III and / or aVF (P pulmonale)
P >1.5 mm in V1
- P is taller than 2.5 mm in II / III and / or aVF (P pulmonale)
- P >1.5 mm in V1
- Right atrial enlargement
- Right atrial enlargement
## Differential Diagnosis of Right Atrial Enlargement
In alphabetical order
- Atrial aneurysm
- Atrial septal defect
- Ebstein's anomaly
- Pulmonic stenosis
- Right heart failure
- Tricuspid prolapse
- Tricuspid regurgitation
- Tricuspid stenosis
- Tumor
# Differential Diagnosis of Inverted P Waves in I and aVL
- It is possible to distinguish lead reversal and dextrocardia by watching the precordial leads. Dextrocardia will show an R wave inversion, whereas lead reversal will not.
- This bottom EKG shows marked right axis deviation and loss of voltage across the precordium. There are also inverted P waves in leads I and aVL. The differential for inverted P waves in lead I and aVL is Dextrocardia vs Reversed Arm Leads. Since there is loss of voltage across the precordium this is Dextrocardia.
- If the P waves are inverted in the other leads, then this may indicate that there is a low atrial focus to the origin of the rhythm.
# Inverted P Wave in the Inferior Leads
## Causes
- P waves are inverted in the inferior leads in the setting of a low atrial focus as the origin of the rhythm.
# Sources
- Copyleft images obtained courtesy of ECGpedia, http://en.ecgpedia.org/index.php?title=Special:NewFiles&dir=prev&offset=20080806182927&limit=500 | https://www.wikidoc.org/index.php/P-wave | |
bb414c668d9e711d5080228145a802a5bd5c855d | wikidoc | p14arf | p14arf
p14ARF (also called ARF tumor suppressor, ARF, p14ARF) is an alternate reading frame protein product of the CDKN2A locus (i.e. INK4a/ARF locus). p14ARF is induced in response to elevated mitogenic stimulation, such as aberrant growth signaling from MYC and Ras (protein). It accumulates mainly in the nucleolus where it forms stable complexes with NPM or Mdm2. These interactions allow p14ARF to act as a tumor suppressor by inhibiting ribosome biogenesis or initiating p53-dependent cell cycle arrest and apoptosis, respectively. p14ARF is an atypical protein, in terms of its transcription, its amino acid composition, and its degradation: it is transcribed in an alternate reading frame of a different protein, it is highly basic, and it is polyubiquinated at the N-terminus.
Both p16INK4a and p14ARF are involved in cell cycle regulation. p14ARF inhibits mdm2, thus promoting p53, which promotes p21 activation, which then binds and inactivates certain cyclin-CDK complexes, which would otherwise promote transcription of genes that would carry the cell through the G1/S checkpoint of the cell cycle. Loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene will lead to elevated levels in mdm2 and, therefore, loss of p53 function and cell cycle control.
The equivalent in mice is p19ARF.
# Background
The p14ARF transcript was first identified in humans in 1995, and its protein product confirmed in mice that same year. Its gene locus is on the short arm of chromosome 9 in humans, and on a corresponding location on chromosome 4 in mice. It is located near the genes for the tandem repeats INK4a and INK4b, which are 16 kDa (p16INK4a) and 15 kDa (p15INK4b) proteins, respectively. These INK4 proteins directly inhibit the cyclin D-dependent kinases CDK4 and CDK6. There are other INK4 genes on other chromosomes, however these are not linked to cancer, and so their functions are not likely to be overlapping. An important cyclin-dependent substrate is the retinoblastoma protein Rb, which is phosphorylated in late gap 1 phase (G1 phase), allowing G1 exit. The Rb protein limits cell proliferation by blocking the activity of E2F transcription factors, which activate the transcription of genes needed for DNA replication. When Rb is phosphorylated by cyclin D and E-dependent kinases during the G1 phase of the cell cycle, Rb can not block E2F-dependent transcription, and the cell can progress to the DNA synthetic phase(S phase). Therefore, INK4a and INK4b serve as tumor suppressors by restricting proliferation though the inhibition of the CDKs responsible for Rb phosphorylation.
In addition to the INK4a protein, the unrelated protein, ARF, is transcribed from an alternate reading frame at the INK4a/ARF locus. INK4a and p14ARF mRNA each consist of three exons. They share exons 2 and 3, but there are two different exon 1 transcripts, α and β. Exon 1β (E1β) is intercalated between the genes for INK4a and INK4b. Although exon 1α (E1α) and E1β are about the same in terms of content and size, the 5’ AUG (start codon) of exon 1β has its own promoter and opens an alternative reading frame in exon 2, hence the name p14ARF (ARF exon 3 is not translated). Because of this, INK4a and p14ARF have unrelated amino acid sequences despite overlapping coding regions, and have distinct functions. This dual use of coding sequences is not commonly seen in mammals, making p14ARF an unusual protein. When the ARF β-transcript was found, it was thought that it probably would not encode a protein. In humans, ARF is translated into the 14kDa, 132 amino acid ] protein, and in mice, it is translated into the 19kDa, 169 amino acid p19Arf. The E1β protein segment of mouse and human ARF are 45% identical, with an overall ARF identity of 50%, compared to a 72% identity between mouse and human INK4a E1α segment, and a 65% overall identity.
Although the INK4a and ARF proteins are structurally and functionally different, they are both involved in cell cycle progression. Together, their broad inhibitory role may help counter oncogenic signals. As mentioned above, INK4a inhibits proliferation by indirectly allowing Rb to remain associated with E2F transcription factors. ARF is involved in p53 activation by inhibiting Mdm2 (HDM2 in humans). Mdm2 binds to p53, inhibiting its transcriptional activity. Mdm2 also has E3 ubiquitin ligase activity toward p53, and promotes its exportation from the cell nucleus to the cytoplasm for degradation. By antagonizing Mdm2, ARF permits the transcriptional activity of p53 that would lead to cell cycle arrest or apoptosis. A loss of ARF or p53, therefore, would give cells a survival advantage.
The function of ARF has primarily been attributed to its Mdm2/p53 mechanism. ARF does, however, also inhibit proliferation in cells lacking p53 or p53 and Mdm2. It has recently been found that one of ARF’s p53-independent functions involves its binding to nucleophosmin/B23 (NPM). NPM is an acidic ribosomal chaperone (protein) involved in preribosomal processing and nuclear exportation independent of p53, and oligomerizes with itself and p14ARF. Nearly half of p14ARF is found in NPM-containing complexes with high molecular mass (2 to 5 MDa). Enforced expression of ARF retards early 47S/45S rRNA precursor processing and inhibits 32S rRNA cleavage. This suggests that p14ARF can bind to NPM, inhibiting rRNA processing. ARF-null cells have increased nucleolar area, increased ribosome biogenesis, and a corresponding increase in protein synthesis. The larger size resulting from more ribosomes and protein is not associated with increased proliferation, however, and this ARF-null phenotype occurs even though the normal basal levels of Arf are usually low. Knocking down ARF with siRNA to exon 1β results in increased rRNA transcripts, rRNA processing, and ribosome nuclear export. The unrestrained ribosome biogenesis seen when NPM is not bound to ARF does not occur if NPM is also absent. Although the induction of ARF in response to oncogenic signals is considered to be of primary importance, the low levels of ARF seen in interphase cells also has a considerable effect in terms of keeping cell growth in check. Therefore, the function of basal level ARF in the NPM/ARF complex appears to be to monitor steady-state ribosome biogenesis and growth independently of preventing proliferation.
# Role in Disease
Very commonly, cancer is associated with a loss of function of INK4a, ARF, Rb, or p53. Without INK4a, Cdk4/6 can inappropriately phosphorylate Rb, leading to increased E2F-dependent transcription. Without ARF, Mdm2 can inappropriately inhibit p53, leading to increased cell survival.
The INK4a/ARF locus is found to be deleted or silenced in many kinds of tumors. For example, of the 100 primary breast carcinomas, approximately 41% have p14ARF defects. In a separate study, 32% of colorectal adenomas (non-cancerous tumors) were found to have p14ARF inactivation due to hypermethylation of the promoter. Mouse models lacking p19Arf, p53, and Mdm2 are more prone to tumor development than mice without Mdm2 and p53, alone. This suggests that p19Arf has Mdm2- and p53-independent effects, as well. Investigating this idea lead to the recent discovery of smARF.
Homozygous deletions and other mutations of CDK2NA (ARF) have been found to be associated with glioblastoma.
# smARF
Until recently, the two known effects of ARF were growth inhibition by NPM interactions and apoptosis induction by Mdm2 interactions. The function of ARF involving p53-independent death, has now been attributed to the small mitochondrial isoform of ARF, smARF. While full-length ARF inhibits cell growth by cell cycle arrest or type I apoptotic death, smARF kills cells by type II autophagic death. Like ARF, the expression of smARF increases when there are aberrant proliferation signals. When smARF is overexpressed, it localizes to the mitochondrial matrix, damaging the mitochondria membrane potential and structure, and leading to autophagic cell death.
The translation of the truncated ARF, smARF, is initiated at an internal methionine (M45) of the ARF transcript in human and mouse cells. SmARF is also detected in rat, even though an internal methionine is not present in the rat transcript. This suggests that there is an alternate mechanism to form smARF, underscoring the importance of this isoform. The role of smARF is distinct from that of ARF, as it lacks the nuclear localization signal (NLS) and cannot bind to Mdm2 or NPM. In some cell types, however, full-length ARF can also localize to the mitochondria and induce type II cell death, suggesting that in addition to autophagy being a starvation or other environmental response, it may also be involved in responding to oncogene activation.
# Biochemistry
ARF expression is regulated by oncogenic signaling. Aberrant mitogenic stimulation, such as by MYC or Ras (protein), will increase its expression, as will an amplification of mutated p53 or Mdm2, or p53 loss. ARF can also be induced by enforced E2F expression. Although E2F expression is increased during the cell cycle, ARF expression probably is not because the activation of a second, unknown transcription factor might be needed to prevent an ARF response to transient E2F increases. ARF is negatively regulated by Rb-E2F complexes and by amplified p53 activation. Aberrant growth signals also increase smARF expression.
ARF is a highly basic (pI>12) and hydrophobic protein. Its basic nature is attributed to its arginine content; more than 20% of its amino acids are arginine, and it contains little or no lysine. Due to these characteristics, ARF is likely to be unstructured unless it is bound to other targets. It reportedly complexes with more than 25 proteins, although the significance of each of these interactions is not known. One of these interactions results in sumoylating activity, suggesting that ARF may modify proteins to which it binds. The SUMO protein is a small ubiquitin-like modifier, which is added to lysly ε-amino groups. This process involves a three-enzyme cascade similar to the way ubiquitylation occurs. E1 is an activating enzyme, E2 is a conjugation enzyme, and E3 is a ligase. ARF associates with UBC9, the only SUMO E2 known, suggesting ARF facilitates SUMO conjugation. The importance of this role is unknown, as sumoylation is involved in different functions, such as protein trafficking, ubiquitylation interference, and gene expression changes.
The half-life of ARF is about 6 hours, while the half-life of smARF is less than 1 hour. Both isoforms are degraded in the proteasome. ARF is targeted for the proteasome by N-terminus ubiquitylation. Proteins are usually ubiquinated at lysine residues. Human ], however, does not contain any lysines, and mouse p19Arf only contains one lysine. If the mouse lysine is replaced with arginine, there is no effect on its degradation, suggesting it is also ubiquinated at the N-terminus. This adds to the uniqueness of the ARF proteins, because most eukaryotic proteins are acetylated at the N-terminus, preventing ubiquination at this location. Penultimate residues affect the efficiency of acetylation, in that acetylation is promoted by acidic residues and inhibited by basic ones. The N-terminal amino acid sequences of p19Arf (Met-Gly-Arg) and p14ARF (Met-Val-Arg) would be processed by methionine aminopeptidase but would not be acetylated, allowing ubiquination to proceed. The sequence of smARF, however, predicts that the initiating methionine would not be cleaved by methionine aminopeptidase and would probably be acetylated, and so is degraded by the proteasome without ubiquination.
Full-length nucleolar ARF appears to be stabilized by NPM. The NPM-ARF complex does not block the N-terminus of ARF, but likely protects ARF from being accessed by degradation machinery. The mitochondrial matrix protein p32 stabilizes smARF. This protein binds various cellular and viral proteins, but its exact function is unknown. Knocking down p32 dramatically decreases smARF levels by increasing its turnover. The levels of p19Arf are not affected by p32 knockdown, and so p32 specifically stabilizes smARF, possibly by protecting it from the proteasome or from mitochondrial proteases. | p14arf
p14ARF (also called ARF tumor suppressor, ARF, p14ARF) is an alternate reading frame protein product of the CDKN2A locus (i.e. INK4a/ARF locus).[1] p14ARF is induced in response to elevated mitogenic stimulation, such as aberrant growth signaling from MYC and Ras (protein).[2] It accumulates mainly in the nucleolus where it forms stable complexes with NPM or Mdm2. These interactions allow p14ARF to act as a tumor suppressor by inhibiting ribosome biogenesis or initiating p53-dependent cell cycle arrest and apoptosis, respectively.[3] p14ARF is an atypical protein, in terms of its transcription, its amino acid composition, and its degradation: it is transcribed in an alternate reading frame of a different protein, it is highly basic,[1] and it is polyubiquinated at the N-terminus.[4]
Both p16INK4a and p14ARF are involved in cell cycle regulation. p14ARF inhibits mdm2, thus promoting p53, which promotes p21 activation, which then binds and inactivates certain cyclin-CDK complexes, which would otherwise promote transcription of genes that would carry the cell through the G1/S checkpoint of the cell cycle. Loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene will lead to elevated levels in mdm2 and, therefore, loss of p53 function and cell cycle control.
The equivalent in mice is p19ARF.
# Background
The p14ARF transcript was first identified in humans in 1995,[5][6] and its protein product confirmed in mice that same year.[7] Its gene locus is on the short arm of chromosome 9 in humans, and on a corresponding location on chromosome 4 in mice.[1] It is located near the genes for the tandem repeats INK4a and INK4b, which are 16 kDa (p16INK4a) and 15 kDa (p15INK4b) proteins, respectively. These INK4 proteins directly inhibit the cyclin D-dependent kinases CDK4 and CDK6. There are other INK4 genes on other chromosomes, however these are not linked to cancer, and so their functions are not likely to be overlapping. An important cyclin-dependent substrate is the retinoblastoma protein Rb, which is phosphorylated in late gap 1 phase (G1 phase), allowing G1 exit. The Rb protein limits cell proliferation by blocking the activity of E2F transcription factors, which activate the transcription of genes needed for DNA replication. When Rb is phosphorylated by cyclin D and E-dependent kinases during the G1 phase of the cell cycle, Rb can not block E2F-dependent transcription, and the cell can progress to the DNA synthetic phase(S phase).[8] Therefore, INK4a and INK4b serve as tumor suppressors by restricting proliferation though the inhibition of the CDKs responsible for Rb phosphorylation.[7]
In addition to the INK4a protein, the unrelated protein, ARF, is transcribed from an alternate reading frame at the INK4a/ARF locus.[1] INK4a and p14ARF mRNA each consist of three exons. They share exons 2 and 3, but there are two different exon 1 transcripts, α and β. Exon 1β (E1β) is intercalated between the genes for INK4a and INK4b.[1] Although exon 1α (E1α) and E1β are about the same in terms of content and size, the 5’ AUG (start codon) of exon 1β has its own promoter and opens an alternative reading frame in exon 2, hence the name p14ARF (ARF exon 3 is not translated). Because of this, INK4a and p14ARF have unrelated amino acid sequences despite overlapping coding regions, and have distinct functions. This dual use of coding sequences is not commonly seen in mammals, making p14ARF an unusual protein.[1] When the ARF β-transcript was found, it was thought that it probably would not encode a protein.[5][6] In humans, ARF is translated into the 14kDa, 132 amino acid [[p14ARF]] protein, and in mice, it is translated into the 19kDa, 169 amino acid p19Arf.[1] The E1β protein segment of mouse and human ARF are 45% identical, with an overall ARF identity of 50%, compared to a 72% identity between mouse and human INK4a E1α segment, and a 65% overall identity.[7]
Although the INK4a and ARF proteins are structurally and functionally different, they are both involved in cell cycle progression. Together, their broad inhibitory role may help counter oncogenic signals. As mentioned above, INK4a inhibits proliferation by indirectly allowing Rb to remain associated with E2F transcription factors. ARF is involved in p53 activation by inhibiting Mdm2 (HDM2 in humans).[8] Mdm2 binds to p53, inhibiting its transcriptional activity. Mdm2 also has E3 ubiquitin ligase activity toward p53, and promotes its exportation from the cell nucleus to the cytoplasm for degradation. By antagonizing Mdm2, ARF permits the transcriptional activity of p53 that would lead to cell cycle arrest or apoptosis. A loss of ARF or p53, therefore, would give cells a survival advantage.[1]
The function of ARF has primarily been attributed to its Mdm2/p53 mechanism. ARF does, however, also inhibit proliferation in cells lacking p53 or p53 and Mdm2.[9] It has recently been found that one of ARF’s p53-independent functions involves its binding to nucleophosmin/B23 (NPM).[9] NPM is an acidic ribosomal chaperone (protein) involved in preribosomal processing and nuclear exportation independent of p53, and oligomerizes with itself and p14ARF. Nearly half of p14ARF is found in NPM-containing complexes with high molecular mass (2 to 5 MDa). Enforced expression of ARF retards early 47S/45S rRNA precursor processing and inhibits 32S rRNA cleavage. This suggests that p14ARF can bind to NPM, inhibiting rRNA processing.[9] ARF-null cells have increased nucleolar area, increased ribosome biogenesis, and a corresponding increase in protein synthesis.[10] The larger size resulting from more ribosomes and protein is not associated with increased proliferation, however, and this ARF-null phenotype occurs even though the normal basal levels of Arf are usually low. Knocking down ARF with siRNA to exon 1β results in increased rRNA transcripts, rRNA processing, and ribosome nuclear export. The unrestrained ribosome biogenesis seen when NPM is not bound to ARF does not occur if NPM is also absent. Although the induction of ARF in response to oncogenic signals is considered to be of primary importance, the low levels of ARF seen in interphase cells also has a considerable effect in terms of keeping cell growth in check. Therefore, the function of basal level ARF in the NPM/ARF complex appears to be to monitor steady-state ribosome biogenesis and growth independently of preventing proliferation.[10]
# Role in Disease
Very commonly, cancer is associated with a loss of function of INK4a, ARF, Rb, or p53.[11] Without INK4a, Cdk4/6 can inappropriately phosphorylate Rb, leading to increased E2F-dependent transcription. Without ARF, Mdm2 can inappropriately inhibit p53, leading to increased cell survival.
The INK4a/ARF locus is found to be deleted or silenced in many kinds of tumors. For example, of the 100 primary breast carcinomas, approximately 41% have p14ARF defects.[12] In a separate study, 32% of colorectal adenomas (non-cancerous tumors) were found to have p14ARF inactivation due to hypermethylation of the promoter. Mouse models lacking p19Arf, p53, and Mdm2 are more prone to tumor development than mice without Mdm2 and p53, alone. This suggests that p19Arf has Mdm2- and p53-independent effects, as well.[13] Investigating this idea lead to the recent discovery of smARF.[14]
Homozygous deletions and other mutations of CDK2NA (ARF) have been found to be associated with glioblastoma.[15]
# smARF
Until recently, the two known effects of ARF were growth inhibition by NPM interactions and apoptosis induction by Mdm2 interactions. The function of ARF involving p53-independent death, has now been attributed to the small mitochondrial isoform of ARF, smARF.[14] While full-length ARF inhibits cell growth by cell cycle arrest or type I apoptotic death, smARF kills cells by type II autophagic death. Like ARF, the expression of smARF increases when there are aberrant proliferation signals. When smARF is overexpressed, it localizes to the mitochondrial matrix, damaging the mitochondria membrane potential and structure, and leading to autophagic cell death.[16]
The translation of the truncated ARF, smARF, is initiated at an internal methionine (M45) of the ARF transcript in human and mouse cells. SmARF is also detected in rat, even though an internal methionine is not present in the rat transcript. This suggests that there is an alternate mechanism to form smARF, underscoring the importance of this isoform.[14] The role of smARF is distinct from that of ARF, as it lacks the nuclear localization signal (NLS) and cannot bind to Mdm2 or NPM.[3] In some cell types, however, full-length ARF can also localize to the mitochondria and induce type II cell death, suggesting that in addition to autophagy being a starvation or other environmental response, it may also be involved in responding to oncogene activation.[2]
# Biochemistry
ARF expression is regulated by oncogenic signaling. Aberrant mitogenic stimulation, such as by MYC or Ras (protein), will increase its expression, as will an amplification of mutated p53 or Mdm2, or p53 loss.[8] ARF can also be induced by enforced E2F expression. Although E2F expression is increased during the cell cycle, ARF expression probably is not because the activation of a second, unknown transcription factor might be needed to prevent an ARF response to transient E2F increases.[11] ARF is negatively regulated by Rb-E2F complexes [11] and by amplified p53 activation.[8] Aberrant growth signals also increase smARF expression.[16]
ARF is a highly basic (pI>12) and hydrophobic protein.[8] Its basic nature is attributed to its arginine content; more than 20% of its amino acids are arginine, and it contains little or no lysine. Due to these characteristics, ARF is likely to be unstructured unless it is bound to other targets. It reportedly complexes with more than 25 proteins, although the significance of each of these interactions is not known.[1] One of these interactions results in sumoylating activity, suggesting that ARF may modify proteins to which it binds. The SUMO protein is a small ubiquitin-like modifier, which is added to lysly ε-amino groups. This process involves a three-enzyme cascade similar to the way ubiquitylation occurs. E1 is an activating enzyme, E2 is a conjugation enzyme, and E3 is a ligase. ARF associates with UBC9, the only SUMO E2 known, suggesting ARF facilitates SUMO conjugation. The importance of this role is unknown, as sumoylation is involved in different functions, such as protein trafficking, ubiquitylation interference, and gene expression changes.[1]
The half-life of ARF is about 6 hours,[4] while the half-life of smARF is less than 1 hour.[3] Both isoforms are degraded in the proteasome.[1][4] ARF is targeted for the proteasome by N-terminus ubiquitylation.[4] Proteins are usually ubiquinated at lysine residues. Human [[p14ARF]], however, does not contain any lysines, and mouse p19Arf only contains one lysine. If the mouse lysine is replaced with arginine, there is no effect on its degradation, suggesting it is also ubiquinated at the N-terminus. This adds to the uniqueness of the ARF proteins, because most eukaryotic proteins are acetylated at the N-terminus, preventing ubiquination at this location. Penultimate residues affect the efficiency of acetylation, in that acetylation is promoted by acidic residues and inhibited by basic ones. The N-terminal amino acid sequences of p19Arf (Met-Gly-Arg) and p14ARF (Met-Val-Arg) would be processed by methionine aminopeptidase but would not be acetylated, allowing ubiquination to proceed. The sequence of smARF, however, predicts that the initiating methionine would not be cleaved by methionine aminopeptidase and would probably be acetylated, and so is degraded by the proteasome without ubiquination.[1]
Full-length nucleolar ARF appears to be stabilized by NPM. The NPM-ARF complex does not block the N-terminus of ARF, but likely protects ARF from being accessed by degradation machinery.[4] The mitochondrial matrix protein p32 stabilizes smARF.[16] This protein binds various cellular and viral proteins, but its exact function is unknown. Knocking down p32 dramatically decreases smARF levels by increasing its turnover. The levels of p19Arf are not affected by p32 knockdown, and so p32 specifically stabilizes smARF, possibly by protecting it from the proteasome or from mitochondrial proteases.[16] | https://www.wikidoc.org/index.php/P14arf | |
3352dc33c77e66b7033be5996511da876b8b5f6b | wikidoc | PABPC1 | PABPC1
Polyadenylate-binding protein 1 is a protein that in humans is encoded by the PABPC1 gene. The protein PABP1 binds mRNA and facilitates a variety of functions such as transport out of the nucleus, degradation, translation, and stability. There are two separate PABP1 proteins, one which is located in the nucleus (PABPN1) and the other which is found in the cytoplasm (PABPC1). The location of PABP1 affects the role of that protein and its function with RNA.
# Function
The poly(A)-binding protein (PAB or PABP), which is found complexed to the 3' poly(A) tail of eukaryotic mRNA, is required for poly(A) shortening and translation initiation. In humans, the PABPs comprise a small nuclear isoform and a conserved gene family that displays at least 3 functional proteins: PABP1 (PABPC1), inducible PABP (iPABP, or PABPC4; MIM 603407), and PABP3 (PABPC3; MIM 604680). In addition, there are at least 4 pseudogenes, PABPCP1 to PABPCP4.
PABPC1 is usually diffused within the cytoplasm and concentrated at sites of high mRNA concentration such as stress granules, processing bodies, and locations of high translational activity. PABPC1 is also associated with nonsense-mediated mRNA decay (NMD). PABPC1 binds to the poly(A) tail and interact with eIF4G, which stabilizes the circularization of mRNAs. This structure is required for the prevention of mRNA degradation via NMD.
In the nucleus PABP1 binds to the poly(A) tails of pre-mRNAs to facilitate stability, export, transport, and degradation. PABP1 binding is also required for nuclear-mediated degradation. PABPC1 contains four RNA-recognition motifs (RRMs). The first two, RRM1 and RRM2, bind both α-importin and the poly(A) tail of processed mRNA. This feature prevents mRNA from going back into the nucleus.
# Interactions
PABPC1 has been shown to interact with:
- ANAPC5,
- CNOT7,
- EIF4G3,
- EIF4G1,
- GSPT2,
- PAIP1, and
- PAIP2. | PABPC1
Polyadenylate-binding protein 1 is a protein that in humans is encoded by the PABPC1 gene.[1] The protein PABP1 binds mRNA and facilitates a variety of functions such as transport out of the nucleus, degradation, translation, and stability. There are two separate PABP1 proteins, one which is located in the nucleus (PABPN1) and the other which is found in the cytoplasm (PABPC1). The location of PABP1 affects the role of that protein and its function with RNA.[2]
# Function
The poly(A)-binding protein (PAB or PABP), which is found complexed to the 3' poly(A) tail of eukaryotic mRNA, is required for poly(A) shortening and translation initiation. In humans, the PABPs comprise a small nuclear isoform and a conserved gene family that displays at least 3 functional proteins: PABP1 (PABPC1), inducible PABP (iPABP, or PABPC4; MIM 603407), and PABP3 (PABPC3; MIM 604680). In addition, there are at least 4 pseudogenes, PABPCP1 to PABPCP4.[supplied by OMIM][3]
PABPC1 is usually diffused within the cytoplasm and concentrated at sites of high mRNA concentration such as stress granules, processing bodies, and locations of high translational activity. PABPC1 is also associated with nonsense-mediated mRNA decay (NMD). PABPC1 binds to the poly(A) tail and interact with eIF4G, which stabilizes the circularization of mRNAs. This structure is required for the prevention of mRNA degradation via NMD.[4]
In the nucleus PABP1 binds to the poly(A) tails of pre-mRNAs to facilitate stability, export, transport, and degradation. PABP1 binding is also required for nuclear-mediated degradation. PABPC1 contains four RNA-recognition motifs (RRMs). The first two, RRM1 and RRM2, bind both α-importin and the poly(A) tail of processed mRNA. This feature prevents mRNA from going back into the nucleus.[2]
# Interactions
PABPC1 has been shown to interact with:
- ANAPC5,[5]
- CNOT7,[6]
- EIF4G3,[7]
- EIF4G1,[7]
- GSPT2,[8]
- PAIP1,[9][10] and
- PAIP2.[11] | https://www.wikidoc.org/index.php/PABPC1 | |
6448a1113068245cc6cea5997cb077b97d3e0a16 | wikidoc | PABPC4 | PABPC4
Polyadenylate-binding protein 4 (PABPC4) is a protein that in humans is encoded by the PABPC4 gene.
# Function
Poly(A)-binding proteins (PABPs) bind to the poly(A) tail present at the 3-prime ends of most eukaryotic mRNAs. PABPC4 or IPABP (inducible PABP) was isolated as an activation-induced T-cell mRNA encoding a protein. Activation of T cells increased PABPC4 mRNA levels in T cells approximately 5-fold. PABPC4 contains 4 RNA-binding domains and proline-rich C terminus. PABPC4 is localized primarily to the cytoplasm. It is suggested that PABPC4 might be necessary for regulation of stability of labile mRNA species in activated T cells. PABPC4 was also identified as an antigen, APP1 (activated-platelet protein-1), expressed on thrombin-activated rabbit platelets. PABPC4 may also be involved in the regulation of protein translation in platelets and megakaryocytes or may participate in the binding or stabilization of polyadenylates in platelet dense granules.
# Model organisms
Model organisms have been used in the study of PABPC4 function. A conditional knockout mouse line, called Pabpc4tm1a(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 tests were carried out on mutant mice and one significant abnormality was observed: female homozygous mutants displayed impaired glucose tolerance.
# Interactions
PABPC4 has been shown to interact with PHLDA1. | PABPC4
Polyadenylate-binding protein 4 (PABPC4) is a protein that in humans is encoded by the PABPC4 gene.[1][2]
# Function
Poly(A)-binding proteins (PABPs) bind to the poly(A) tail present at the 3-prime ends of most eukaryotic mRNAs. PABPC4 or IPABP (inducible PABP) was isolated as an activation-induced T-cell mRNA encoding a protein. Activation of T cells increased PABPC4 mRNA levels in T cells approximately 5-fold. PABPC4 contains 4 RNA-binding domains and proline-rich C terminus. PABPC4 is localized primarily to the cytoplasm. It is suggested that PABPC4 might be necessary for regulation of stability of labile mRNA species in activated T cells. PABPC4 was also identified as an antigen, APP1 (activated-platelet protein-1), expressed on thrombin-activated rabbit platelets. PABPC4 may also be involved in the regulation of protein translation in platelets and megakaryocytes or may participate in the binding or stabilization of polyadenylates in platelet dense granules.[2]
# Model organisms
Model organisms have been used in the study of PABPC4 function. A conditional knockout mouse line, called Pabpc4tm1a(KOMP)Wtsi[6][7] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[8][9][10]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[4][11] Twenty tests were carried out on mutant mice and one significant abnormality was observed: female homozygous mutants displayed impaired glucose tolerance.[4]
# Interactions
PABPC4 has been shown to interact with PHLDA1.[12] | https://www.wikidoc.org/index.php/PABPC4 | |
8c7c7aa76775fe3672b95bd1fd4c8c98c3e5f9ce | wikidoc | PANDAS | PANDAS
# Background
PANDAS is an abbreviation for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections. This diagnosis is used to describe a set of children who are thought to have developed obsessive-compulsive disorder (OCD) and/or tic disorders such as Tourette syndrome following group A beta-hemolytic streptococcal (GABHS) infections such as "strep throat" and scarlet fever. Whether this condition exists is controversial and has been disputed, as some scientists think this sub-set of patients do not differ in any significant way from the remainder of the patient population and that infections do not increase the risk of Tourette syndrome. Consequently, the PANDAS model is a complex and rapidly-moving area of medical research. PANDAS is currently not listed as a diagnosis in the ICD or DSM.
# Identification
Children with PANDAS are clinically identified by dramatic, "overnight" onset of symptoms, including motor or vocal tics, obsessions, and/or compulsions, although this has not been consistent in all studies. Indeed some studies have shown no acute motor exacerbations among clinically defined PANDAS subjects whilst others have shown a profound one.
In addition to the motor symptoms, it is also thought that children may have psychiatric manifestations, becoming moody, irritable or show concerns about separating from parents or loved ones. In the PANDAS model, this abrupt onset is thought to be preceded by a strep throat infection. As the clinical spectrum of PANDAS appears to resemble that of Tourette's syndrome, some researchers hypothesize that PANDAS and Tourette's may be associated. This idea is controversial and a focus for current research.
Concerns have been raised that PANDAS may be overdiagnosed, as nearly a third of patients diagnosed with PANDAS by community physicians did not meet the criteria when examined by specialists, suggesting that the PANDAS diagnosis is conferred by community physicians without scientific evidence.
# Proposed mechanism
At present, whether the group of patients diagnosed with PANDAS have developed tics and OCD through a different mechanism (pathophysiology) than seen in other people diagnosed with Tourette syndrome is unclear. However, researchers at the NIMH are pursuing a hypothesis that the mechanism is similar to that of rheumatic fever, an autoimmune disorder triggered by streptococcal infections, where antibodies attack the brain and cause neuropsychiatric conditions.
In every bacterial infection, the body produces antibodies against the invading bacteria, and the antibodies help eliminate the bacteria from the body. However in rheumatic fever, the antibodies mistakenly recognize and "attack" the heart valves, joints, and/or certain parts of the brain. This phenomenon is called "molecular mimicry", which means that antigens on the cell wall of the strep. bacteria are similar in some way to the proteins of the heart valve, joints, or brain. Because the antibodies set off an immune reaction which damages those tissues, the child with rheumatic fever can get heart disease (especially mitral valve regurgitation), arthritis, and/or abnormal movements known as Sydenham's chorea or "St. Vitus Dance". In PANDAS, it is believed that Tourette syndrome is produced in a similar manner. One part of the brain that may be affected in PANDAS is the basal ganglia, which is believed to be responsible for movement and behavior. Thus, the antibodies damage the brain to cause the tics and OCD that characterize Tourette syndrome, instead of Sydenham's chorea. However, current data neither disprove nor support this hypothesis, indeed one recent study found no association between streptococcal infections and the risk of PANDAS symptoms.
# Experimental treatments
As both the PANDAS diagnosis and the hypothesis that symptoms in this subgroup of patients are caused by infection are controversial, anti-infective treatments for Tourette syndrome are experimental. According to the Advisory Boards of the Tourette Syndrome Association and the NIH, this diagnosis has engendered the use of dangerous and unproven treatment methodologies for children with tics and OCD, such as intravenous immunoglobulin (IVIG), plasma exchange, and the use of prophylactic antibiotics for the prevention of streptococcal infections.
The results from these experimental treatments have been mixed, although an initial study with 37 children found no effect of antibiotic treatment on either infection rate or obsessive-compulsive or tic symptom severity, a smaller study on twenty-three children later suggested that antibiotics were beneficial. However, the methods in the latter study have been criticized. | PANDAS
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
PANDAS is an abbreviation for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections. This diagnosis is used to describe a set of children who are thought to have developed obsessive-compulsive disorder (OCD) and/or tic disorders such as Tourette syndrome following group A beta-hemolytic streptococcal (GABHS) infections such as "strep throat" and scarlet fever.[1] Whether this condition exists is controversial and has been disputed, as some scientists think this sub-set of patients do not differ in any significant way from the remainder of the patient population and that infections do not increase the risk of Tourette syndrome. Consequently, the PANDAS model is a complex and rapidly-moving area of medical research. PANDAS is currently not listed as a diagnosis in the ICD or DSM.
# Identification
Children with PANDAS are clinically identified by dramatic, "overnight" onset of symptoms, including motor or vocal tics, obsessions, and/or compulsions,[1] although this has not been consistent in all studies. Indeed some studies have shown no acute motor exacerbations among clinically defined PANDAS subjects[2][3] whilst others have shown a profound one.
In addition to the motor symptoms, it is also thought that children may have psychiatric manifestations, becoming moody, irritable or show concerns about separating from parents or loved ones.[1] In the PANDAS model, this abrupt onset is thought to be preceded by a strep throat infection. As the clinical spectrum of PANDAS appears to resemble that of Tourette's syndrome, some researchers hypothesize that PANDAS and Tourette's may be associated. This idea is controversial and a focus for current research.
Concerns have been raised that PANDAS may be overdiagnosed, as nearly a third of patients diagnosed with PANDAS by community physicians did not meet the criteria when examined by specialists, suggesting that the PANDAS diagnosis is conferred by community physicians without scientific evidence.[4]
# Proposed mechanism
At present, whether the group of patients diagnosed with PANDAS have developed tics and OCD through a different mechanism (pathophysiology) than seen in other people diagnosed with Tourette syndrome is unclear.[5][2] However, researchers at the NIMH are pursuing a hypothesis that the mechanism is similar to that of rheumatic fever, an autoimmune disorder triggered by streptococcal infections, where antibodies attack the brain and cause neuropsychiatric conditions.[1]
In every bacterial infection, the body produces antibodies against the invading bacteria, and the antibodies help eliminate the bacteria from the body. However in rheumatic fever, the antibodies mistakenly recognize and "attack" the heart valves, joints, and/or certain parts of the brain.[6] This phenomenon is called "molecular mimicry", which means that antigens on the cell wall of the strep. bacteria are similar in some way to the proteins of the heart valve, joints, or brain. Because the antibodies set off an immune reaction which damages those tissues, the child with rheumatic fever can get heart disease (especially mitral valve regurgitation), arthritis, and/or abnormal movements known as Sydenham's chorea or "St. Vitus Dance".[7] In PANDAS, it is believed that Tourette syndrome is produced in a similar manner. One part of the brain that may be affected in PANDAS is the basal ganglia, which is believed to be responsible for movement and behavior. Thus, the antibodies damage the brain to cause the tics and OCD that characterize Tourette syndrome, instead of Sydenham's chorea.[1][5] However, current data neither disprove nor support this hypothesis, indeed one recent study found no association between streptococcal infections and the risk of PANDAS symptoms.[8]
# Experimental treatments
As both the PANDAS diagnosis and the hypothesis that symptoms in this subgroup of patients are caused by infection are controversial, anti-infective treatments for Tourette syndrome are experimental.[2][9] According to the Advisory Boards of the Tourette Syndrome Association and the NIH,[10] this diagnosis has engendered the use of dangerous and unproven treatment methodologies for children with tics and OCD, such as intravenous immunoglobulin (IVIG),[11] plasma exchange, and the use of prophylactic antibiotics for the prevention of streptococcal infections.
The results from these experimental treatments have been mixed, although an initial study with 37 children found no effect of antibiotic treatment on either infection rate or obsessive-compulsive or tic symptom severity,[12] a smaller study on twenty-three children later suggested that antibiotics were beneficial.[13] However, the methods in the latter study have been criticized.[14] | https://www.wikidoc.org/index.php/PANDAS |
Subsets and Splits
No saved queries yet
Save your SQL queries to embed, download, and access them later. Queries will appear here once saved.