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
|
|---|---|---|---|---|---|---|
151a50e18f0aac234803e31a6082afcc191fcfce | wikidoc | Maize | Maize
Maize pronounced Template:IPA) (Zea mays L. ssp. mays; principally known as corn) is a cereal grain that was domesticated in Mesoamerica and then spread throughout the American continents. Maize spread to the rest of the world after European contact with the Americas in the late 15th century and early 16th century. The term maize derives from the Spanish form (maíz) of the Arawak Native American term for the plant. However, it is commonly called corn in the United States, Canada and Australia. Corn is a shortened form of "Indian corn", i.e. the Indian grain. The English word "corn" originally referred to a granular particle, most commonly cereal grains. Hybrid maize is preferred by farmers over conventional varieties for its high grain yield, due to heterosis ("hybrid vigour"). Maize is the largest crop in all of the Americas (270 million metric tons annually in the U.S. alone).
While some maize varieties grow 7 metres (23 ft) tall at certain locations, commercial maize has been bred for a height of 2.5 metres (8 ft). Sweetcorn is usually shorter than field-corn varieties.
# Maize physiology
The stems superficially resemble bamboo canes and the joints (nodes) can reach 20–30 centimetres (8–12 in) apart. Maize has a very distinct growth form; the lower leaves being like broad flags, 50–100 centimetres long and 5–10 centimetres wide (2–4 ft by 2–4 in); the stems are erect, conventionally 2–3 metres (7–10 ft) in height, with many nodes, casting off flag-leaves at every node. Under these leaves and close to the stem grow the ears. They grow about 3 centimetres a day.
The ears are female inflorescences, tightly covered over by several layers of leaves, and so closed-in by them to the stem that they do not show themselves easily until the emergence of the pale yellow silks from the leaf whorl at the end of the ear. The silks are elongated stigmas that look like tufts of hair, at first green, and later red or yellow. Plantings for silage are even denser, and achieve an even lower percentage of ears and more plant matter. Certain varieties of maize have been bred to produce many additional developed ears, and these are the source of the "baby corn" that is used as a vegetable in Asian cuisine.
Maize is a facultative long-night plant and flowers in a certain number of growing degree days > 50 °F (10 °C) in the environment to which it is adapted. Photoperiodicity can be eccentric in tropical cultivars, where in the long days at higher latitudes the plants will grow so tall that they will not have enough time to produce seed before they are killed by frost. The magnitude of the influence that long-nights have on the number of days that must pass before maize flowers is genetically prescribed and regulated by the phytochrome system.
The apex of the stem ends in the tassel, an inflorescence of male flowers. Each silk may become pollinated to produce one kernel of corn. Young ears can be consumed raw, with the cob and silk, but as the plant matures (usually during the summer months) the cob becomes tougher and the silk dries to inedibility. By the end of the growing season, the kernels dry out and become difficult to chew without cooking them tender first in boiling water. Modern farming techniques in developed countries usually rely on dense planting, which produces on average only about 0.9 ears per stalk because it stresses the plants.
The kernel of corn has a pericarp of the fruit fused with the seed coat, typical of the grasses. It is close to a multiple fruit in structure, except that the individual fruits (the kernels) never fuse into a single mass. The grains are about the size of peas, and adhere in regular rows round a white pithy substance, which forms the ear. An ear contains from 200 to 400 kernels, and is from 10–25 centimetres (4–10 inches) in length. They are of various colors: blackish, bluish-gray, red, white and yellow. When ground into flour, maize yields more flour, with much less bran, than wheat does. However, it lacks the protein gluten of wheat and therefore makes baked goods with poor rising capability.
A genetic variation that accumulates more sugar and less starch in the ear is consumed as a vegetable and is called sweetcorn.
Immature maize shoots accumulate a powerful antibiotic substance, DIMBOA (2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one). DIMBOA is a member of a group of hydroxamic acids (also known as benzoxazinoids) that serve as a natural defense against a wide range of pests including insects, pathogenic fungi and bacteria. DIMBOA is also found in related grasses, particularly wheat. A maize mutant (bx) lacking DIMBOA is highly susceptible to be attacked by aphids and fungi. DIMBOA is also responsible for the relative resistance of immature maize to the European corn borer (family Crambidae). As maize matures, DIMBOA levels and resistance to the corn borer decline.
# Genetics
Many forms of maize are used for food, sometimes classified as various subspecies:
- Flour corn — Zea mays var. amylacea
- Popcorn — Zea mays var. everta
- Dent corn — Zea mays var. indentata
- Flint corn — Zea mays var. indurata
- Sweetcorn — Zea mays var. saccharata and Zea mays var. rugosa
- Waxy corn — Zea mays var. ceratina
- Amylomaize — Zea mays
- Pod corn — Zea mays var. tunicata Larrañaga ex A. St. Hil.
- Striped maize - Zea mays var. japonica
This system has been replaced (though not entirely displaced) over the last 60 years by multi-variable classifications based on ever more data. Agronomic data was supplemented by botanical traits for a robust initial classification, then genetic, cytological, protein and DNA evidence was added. Now the categories are forms (little used), races, racial complexes, and recently branches.
Maize has 10 chromosomes (n=10). The combined length of the chromosomes is 1500 cM. Some of the maize chromosomes have what are known as "chromosomal knobs": highly repetitive heterochromatic domains that stain darkly. Individual knobs are polymorphic among strains of both maize and teosinte. Barbara McClintock used these knob markers to prove her transposon theory of "jumping genes", for which she won the 1983 Nobel Prize in Physiology or Medicine. Maize is still an important model organism for genetics and developmental biology today.
There is a stock center of maize mutants, The Maize Genetics Cooperation — Stock Center, funded by the USDA Agricultural Research Service and located in the Department of Crop Sciences at the University of Illinois at Urbana-Champaign. The total collection has nearly 80,000 samples. The bulk of the collection consists of several hundred named genes, plus additional gene combinations and other heritable variants. There are about 1000 chromosomal aberrations (e.g., translocations and inversions) and stocks with abnormal chromosome numbers (e.g., tetraploids). Genetic data describing the maize mutant stocks as well as myriad other data about maize genetics can be accessed at MaizeGDB, the Maize Genetics and Genomics Database.
In 2005, the U.S. National Science Foundation (NSF), Department of Agriculture (USDA) and the Department of Energy (DOE) formed a consortium to sequence the maize genome. The resulting DNA sequence data will be deposited immediately into GenBank, a public repository for genome-sequence data. Sequencing the corn genome has been considered difficult because of its large size and complex genetic arrangements. The genome has 50,000–60,000 genes scattered among the 2.5 billion bases – molecules that form DNA – that make up its 10 chromosomes. (By comparison, the human genome contains about 2.9 billion bases and 26,000 genes.)
# Origin
There are several theories about the specific origin of maize in Mesoamerica:
- It is a direct domestication of a Mexican annual teosinte, Zea mays ssp. parviglumis, native to the Balsas River valley of southern Mexico, with up to 12% of its genetic material obtained from Zea mays ssp. mexicana through introgression;
- It derives from hybridization between a small domesticated maize (a slightly changed form of a wild maize) and a teosinte of section Luxuriantes, either Z. luxurians or Z. diploperennis;
- It underwent two or more domestications either of a wild maize or of a teosinte;
- It evolved from a hybridization of Z. diploperennis by Tripsacum dactyloides. (The term "teosinte" describes all species and subspecies in the genus Zea, excluding Zea mays ssp. mays.) In the late 1930s, Paul Mangelsdorf suggested that domesticated maize was the result of a hybridization event between an unknown wild maize and a species of Tripsacum, a related genus. However, the proposed role of tripsacum (gama grass) in the origins of maize has been refuted by modern genetic analysis, negating Mangelsdorf’s model and the fourth listed above.
The third model (actually a group of hypotheses) is unsupported. The second parsimoniously explains many conundrums but is dauntingly complex. The first model was proposed by Nobel Prize winner George Beadle in 1939. Though it has experimental support, it has not explained a number of problems, among them:
- how the immense diversity of the species of sect. Zea originated,
- how the tiny archaeological specimens of 3500–2700 BCE (uncorrected) could have been selected from a teosinte, and
- how domestication could have proceeded without leaving remains of teosinte or maize with teosintoid traits until ca. 1100 BCE.
The domestication of maize is of particular interest to researchers—archaeologists, geneticists, ethnobotanists, geographers, etc. The process is thought by some to have started 7,500 to 12,000 years ago (corrected for solar variations). Recent genetic evidence suggests that maize domestication occurred 9000 years ago in central Mexico, perhaps in the highlands between Oaxaca and Jalisco. The wild teosinte most similar to modern maize grows in the area of the Balsas River. Archaeological remains of early maize ears, found at Guila Naquitz Cave in the Oaxaca Valley, date back roughly 6,250 years (corrected; 3450 BCE, uncorrected); the oldest ears from caves near Tehuacan, Puebla, date ca. 2750 BCE. Little change occurred in ear form until ca. 1100 BCE when great changes appeared in ears from Mexican caves: maize diversity rapidly increased and archaeological teosinte was first deposited.
Perhaps as early as 1500 BCE, maize began to spread widely and rapidly. As it was introduced to new cultures, new uses were developed and new varieties selected to better serve in those preparations. Maize was the staple food, or a major staple, of most the pre-Columbian North American, Mesoamerican, South American, and Caribbean cultures. The Mesoamerican civilization was strengthened upon the field crop of maize; through harvesting it, its religious and spiritual importance and how it impacted their diet. Maize formed the Mesoamerican people’s identity. During the 1st millennium CE (AD), maize cultivation spread from Mexico into the Southwest and a millennium later into Northeast and southeastern Canada, transforming the landscape as Native Americans cleared large forest and grassland areas for the new crop.
It is unknown what precipitated its domestication, because the edible portion of the wild variety is too small and hard to obtain to be eaten directly, as each kernel is enclosed in a very hard bi-valve shell. However, George Beadle demonstrated that the kernels of teosinte are readily "popped" for human consumption, like modern popcorn. Some have argued that it would have taken too many generations of selective breeding in order to produce large compressed ears for efficient cultivation. However, studies of the hybrids readily made by intercrossing teosinte and modern maize suggest that this objection is not well-founded.
In 2005, research by the USDA Forest Service indicated that the rise in maize cultivation 500 to 1,000 years ago in the southeastern United States contributed to the decline of freshwater mussels, which are very sensitive to environmental changes.
# Cultivation
Maize is widely cultivated throughout the world, and a greater weight of maize is produced each year than any other grain. While the United States produces almost half of the world's harvest, other top producing countries are as widespread as China, Brazil, France, Indonesia, India and South Africa. Worldwide production was over 600 million metric tons in 2003 — just slightly more than rice or wheat. In 2004, close to 33 million hectares of maize were planted worldwide, with a production value of more than $23 billion.
Because it is cold-intolerant, in the temperate zones maize must be planted in the spring. Its root system is generally shallow, so the plant is dependent on soil moisture. As a C4 plant (a plant that uses C4 photosynthesis), maize is a considerably more water-efficient crop than C3 plants like the small grains, alfalfa and soybeans. Maize is most sensitive to drought at the time of silk emergence, when the flowers are ready for pollination. In the United States, a good harvest was traditionally predicted if the corn was "knee-high by the Fourth of July", although modern hybrids generally exceed this growth rate. Maize used for silage is harvested while the plant is green and the fruit immature. Sweet corn is harvested in the "milk stage", after pollination but before starch has formed, between late summer and early to mid-autumn. Field corn is left in the field very late in the autumn in order to thoroughly dry the grain, and may, in fact, sometimes not be harvested until winter or even early spring. The importance of sufficient soil moisture is shown in many parts of Africa, where periodic drought regularly causes famine by causing maize crop failure.
Maize was planted by the Native Americans in hills, in a complex system known to some as the Three Sisters: beans used the corn plant for support, and squashes provided ground cover to stop weeds. This method was replaced by single species hill planting where each hill 60–120 cm (2–4 ft) apart was planted with 3 or 4 seeds, a method still used by home gardeners. A later technique was checked corn where hills were placed 40 inches apart in each direction, allowing cultivators to run through the field in two directions. In more arid lands this was altered and seeds were planted in the bottom of 10–12 cm (4–5 in) deep furrows to collect water. Modern technique plants maize in rows which allows for cultivation while the plant is young, although the hill technique is still used in the cornfields of some Native American reservations.
In North America, fields are often planted in a two-crop rotation with a nitrogen-fixing crop, often alfalfa in cooler climates and soybeans in regions with longer summers. Sometimes a third crop, winter wheat, is added to the rotation. Fields are usually plowed each year, although no-till farming is increasing in use. Many of the maize varieties grown in the United States and Canada are hybrids. Over half of the corn area planted in the United States has been genetically modified using biotechnology to express agronomic traits such as pest resistance or herbicide resistance.
Before about World War II, most maize in North America was harvested by hand (as it still is in most of the other countries where it is grown). This often involved large numbers of workers and associated social events. Some one- and two-row mechanical pickers were in use but the corn combine was not adopted until after the War. By hand or mechanical picker, the entire ear is harvested which then requires a separate operation of a corn sheller to remove the kernels from the ear. Whole ears of corn were often stored in corn cribs and these whole ears are a sufficient form for some livestock feeding use. Few modern farms store maize in this manner. Most harvest the grain from the field and store it in bins. The combine with a corn head (with points and snap rolls instead of a reel) does not cut the stalk; it simply pulls the stalk down. The stalk continues downward and is crumpled in to a mangled pile on the ground. The ear of corn is too large to pass through a slit in a plate and the snap rolls pull the ear of corn from the stalk so that only the ear and husk enter the machinery. The combine separates out the husk and the cob, keeping only the kernels.
# Pellagra
When maize was first introduced outside of the Americas it was generally welcomed with enthusiasm by farmers everywhere for its productivity. However, a widespread problem of malnutrition soon arose wherever maize was introduced. This was a mystery since these types of malnutrition were not seen among the indigenous Americans under normal circumstances.
It was eventually discovered that the indigenous Americans learned long ago to add alkali — in the form of ashes among North Americans and lime (calcium carbonate) among Mesoamericans — to corn meal to liberate the B-vitamin niacin, the lack of which was the underlying cause of the condition known as pellagra. This alkali process is known by its Nahuatl (Aztec)-derived name: nixtamalization.
Besides the lack of niacin, pellagra was also characterized by protein deficiency, a result of the inherent lack of two key amino acids in pre-modern maize, lysine and tryptophan. Nixtamalisation was also found to increase the lysine and tryptophan content of maize to some extent, but more importantly, the indigenous Americans had learned long ago to balance their consumption of maize with beans and other protein sources such as amaranth and chia, as well as meat and fish, in order to acquire the complete range of amino acids for normal protein synthesis.
Since maize had been introduced into the diet of non-indigenous Americans without the necessary cultural knowledge acquired over thousands of years in the Americas, the reliance on maize elsewhere was often tragic. In the late 19th century pellagra reached endemic proportions in parts of the deep southern U.S., as medical researchers debated two theories for its origin: the deficiency theory (eventually shown to be true) posited that pellagra was due to a deficiency of some nutrient, and the germ theory posited that pellagra was caused by a germ transmitted by stable flies. In 1914 the U.S. government officially endorsed the germ theory of pellagra, but rescinded this endorsement several years later as evidence grew against it. By the mid-1920s the deficiency theory of pellagra was becoming scientific consensus, and the theory was proved in 1932 when niacin deficiency was determined to be the cause of the illness.
Once alkali processing and dietary variety was understood and applied, pellagra disappeared. The development of high lysine maize and the promotion of a more balanced diet has also contributed to its demise.
# Pests of maize
## Insect pests
- Corn earworm (Helicoverpa zea)
- Fall armyworm (Spodoptera frugiperda)
- Common armyworm (Pseudaletia unipuncta)
- Stalk borer (Papaipema nebris)
- Corn leaf aphid (Rhopalosiphum maidis)
- European corn borer (Ostrinia nubilalis) (ECB)
- Corn silkfly (Euxesta stigmatis)
- Lesser cornstalk borer (Elasmopalpus lignosellus)
- Corn delphacid (Peregrinus maidis)
- Western corn rootworm (Diabrotica virgifera virgifera LeConte)
The susceptibility of maize to the European corn borer, and the resulting large crop losses, led to the development of transgenic expressing the Bacillus thuringiensis toxin. "Bt corn" is widely grown in the United States and has been approved for release in Europe.
## Diseases
- Corn smut or common smut (Ustilago maydis): a fungal disease, known in Mexico as huitlacoche, which is prized by some as a gourmet delicacy in itself.
- Maize Dwarf Mosaic Virus
- Stewart's Wilt (Pantoea stewartii)
- Common Rust (Puccinia sorghi)
- Goss's Wilt (Clavibacter michiganese)
- Grey Leaf Spot
- Mal de Río Cuarto Virus (MRCV)
- Stalk and Kernal Rot
# Uses for maize
In the United States and Canada, the primary use for maize is as a feed for livestock, forage, silage or grain. "Feed corn" is also being increasingly used for heating; specialized corn stoves (similar to wood stoves) are available and use either feed corn or wood pellets to generate heat. Silage is made by fermentation of chopped green cornstalks. The grain also has many industrial uses, including transformation into plastics and fabrics. Some is hydrolyzed and enzymatically treated to produce syrups, particularly high fructose corn syrup, a sweetener, and some is fermented and distilled to produce grain alcohol. Grain alcohol from maize is traditionally the source of bourbon whiskey. Increasingly ethanol is being used at low concentrations (10% or less) as an additive in gasoline (gasohol) for motor fuels to increase the octane rating, lower pollutants, and reduce petroleum use.
Human consumption of corn and cornmeal constitutes a staple food in many regions of the world. Corn meal is made into a thick porridge in many cultures: from the polenta of Italy, the angu of Brazil, the mămăligă of Romania, to mush in the U.S. or the food called sadza, nshima, ugali and mealie pap in Africa. It is the main ingredient for tortillas, atole and many other dishes of Mexican food, and for chicha, a fermented beverage of Central and South America. The eating of corn on the cob varies culturally. It is common in the United States but virtually unheard of in some European countries.
Sweetcorn is a genetic variation that is high in sugars and low in starch that is served like a vegetable. Popcorn is kernels of certain varieties that explode when heated, forming fluffy pieces that are eaten as a snack.
Maize can also be prepared as hominy, in which the kernels are bleached with lye; or grits, which are coarsely ground corn. These are commonly eaten in the Southeastern United States, foods handed down from Native Americans. Another common food made from maize is corn flakes. The floury meal of maize (cornmeal or masa) is used to make cornbread and Mexican tortillas. Teosinte is used as fodder, and can also be popped as popcorn.
Some forms of the plant are occasionally grown for ornamental use in the garden. For this purpose, variegated and coloured leaf forms as well as those with colourful ears are used. Additionally, size-superlative varieties, having reached 31 ft (9.4m) tall, or with ears 24 inches (60cm) long, have been popular for at least a century.
Corncobs can be hollowed out and treated to make inexpensive smoking pipes, first manufactured in the United States in 1869. Corncobs are also used as a biomass fuel source. Maize is relatively cheap and home-heating furnaces have been developed which use maize kernels as a fuel. They feature a large hopper which feeds the uniformly sized corn kernels (or wood pellets or cherry pits) into the fire.
An unusual use for maize is to create a Maize Maze as a tourist attraction. This is a maze cut into a field of maize. The idea of a Maize Maze was introduced by Adrian Fisher, one of the most prolific designer of modern mazes, with The American Maze Company who created a maze in Pennsylvania in 1993. Traditional mazes are most commonly grown using yew hedges, but these take several years to mature. The rapid growth of a field of maize allows a maze to be laid out using GPS at the start of a growing season and for the maize to grow tall enough to obstruct a visitor's line of sight by the start of the summer. In Canada and the U.S., these are called "corn mazes" and are popular in many farming communities.
Maize is increasingly used as a biomass fuel, such as ethanol, which as researchers search for innovative ways to reduce fuel costs has unintentionally caused a rapid rise in food costs. This has led to the 2007 harvest being one of the most profitable corn crops in modern history for farmers. A biomass gasification power plant in Strem near Güssing, Burgenland, Austria was begun in 2005. Research is being done to make diesel out of the biogas by the Fischer Tropsch method.
Maize is also used as fish bait called "dough balls". It is particularly popular in Europe for coarse fishing.
Stigmas from female corn flowers, known popularly as corn silk, are sold as herbal supplements.
Corn kernels can be used in place of sand in a sandbox-like enclosure for children's play.
# Maize and art
Maize has been an essential crop in the Andes since the pre-Columbian Era. The Moche culture from Northern Peru made ceramics from earth, water, and fire. This pottery was a sacred substance, formed in significant shapes and used to represent important themes. Maize represented anthropomorphically as well as naturally. | Maize
Template:This
Maize pronounced Template:IPA) (Zea mays L. ssp. mays; principally known as corn[1][2][3]) is a cereal grain that was domesticated in Mesoamerica and then spread throughout the American continents. Maize spread to the rest of the world after European contact with the Americas in the late 15th century and early 16th century. The term maize derives from the Spanish form (maíz) of the Arawak Native American term for the plant. However, it is commonly called corn in the United States, Canada and Australia. Corn is a shortened form of "Indian corn", i.e. the Indian grain. The English word "corn" originally referred to a granular particle, most commonly cereal grains. Hybrid maize is preferred by farmers over conventional varieties for its high grain yield, due to heterosis ("hybrid vigour"). Maize is the largest crop in all of the Americas (270 million metric tons annually in the U.S. alone).
While some maize varieties grow 7 metres (23 ft) tall at certain locations,[4] commercial maize has been bred for a height of 2.5 metres (8 ft). Sweetcorn is usually shorter than field-corn varieties.
# Maize physiology
The stems superficially resemble bamboo canes and the joints (nodes) can reach 20–30 centimetres (8–12 in) apart. Maize has a very distinct growth form; the lower leaves being like broad flags, 50–100 centimetres long and 5–10 centimetres wide (2–4 ft by 2–4 in); the stems are erect, conventionally 2–3 metres (7–10 ft) in height, with many nodes, casting off flag-leaves at every node. Under these leaves and close to the stem grow the ears. They grow about 3 centimetres a day.
The ears are female inflorescences, tightly covered over by several layers of leaves, and so closed-in by them to the stem that they do not show themselves easily until the emergence of the pale yellow silks from the leaf whorl at the end of the ear. The silks are elongated stigmas that look like tufts of hair, at first green, and later red or yellow. Plantings for silage are even denser, and achieve an even lower percentage of ears and more plant matter. Certain varieties of maize have been bred to produce many additional developed ears, and these are the source of the "baby corn" that is used as a vegetable in Asian cuisine.
Maize is a facultative long-night plant and flowers in a certain number of growing degree days > 50 °F (10 °C) in the environment to which it is adapted.[5] Photoperiodicity can be eccentric in tropical cultivars, where in the long days at higher latitudes the plants will grow so tall that they will not have enough time to produce seed before they are killed by frost. The magnitude of the influence that long-nights have on the number of days that must pass before maize flowers is genetically prescribed and regulated by the phytochrome system.[6]
The apex of the stem ends in the tassel, an inflorescence of male flowers. Each silk may become pollinated to produce one kernel of corn. Young ears can be consumed raw, with the cob and silk, but as the plant matures (usually during the summer months) the cob becomes tougher and the silk dries to inedibility. By the end of the growing season, the kernels dry out and become difficult to chew without cooking them tender first in boiling water. Modern farming techniques in developed countries usually rely on dense planting, which produces on average only about 0.9 ears per stalk because it stresses the plants. [7]
The kernel of corn has a pericarp of the fruit fused with the seed coat, typical of the grasses. It is close to a multiple fruit in structure, except that the individual fruits (the kernels) never fuse into a single mass. The grains are about the size of peas, and adhere in regular rows round a white pithy substance, which forms the ear. An ear contains from 200 to 400 kernels, and is from 10–25 centimetres (4–10 inches) in length. They are of various colors: blackish, bluish-gray, red, white and yellow. When ground into flour, maize yields more flour, with much less bran, than wheat does. However, it lacks the protein gluten of wheat and therefore makes baked goods with poor rising capability.
A genetic variation that accumulates more sugar and less starch in the ear is consumed as a vegetable and is called sweetcorn.
Immature maize shoots accumulate a powerful antibiotic substance, DIMBOA (2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one). DIMBOA is a member of a group of hydroxamic acids (also known as benzoxazinoids) that serve as a natural defense against a wide range of pests including insects, pathogenic fungi and bacteria. DIMBOA is also found in related grasses, particularly wheat. A maize mutant (bx) lacking DIMBOA is highly susceptible to be attacked by aphids and fungi. DIMBOA is also responsible for the relative resistance of immature maize to the European corn borer (family Crambidae). As maize matures, DIMBOA levels and resistance to the corn borer decline.
# Genetics
Many forms of maize are used for food, sometimes classified as various subspecies:
- Flour corn — Zea mays var. amylacea
- Popcorn — Zea mays var. everta
- Dent corn — Zea mays var. indentata
- Flint corn — Zea mays var. indurata
- Sweetcorn — Zea mays var. saccharata and Zea mays var. rugosa
- Waxy corn — Zea mays var. ceratina
- Amylomaize — Zea mays
- Pod corn — Zea mays var. tunicata Larrañaga ex A. St. Hil.
- Striped maize - Zea mays var. japonica
This system has been replaced (though not entirely displaced) over the last 60 years by multi-variable classifications based on ever more data. Agronomic data was supplemented by botanical traits for a robust initial classification, then genetic, cytological, protein and DNA evidence was added. Now the categories are forms (little used), races, racial complexes, and recently branches.
Maize has 10 chromosomes (n=10). The combined length of the chromosomes is 1500 cM. Some of the maize chromosomes have what are known as "chromosomal knobs": highly repetitive heterochromatic domains that stain darkly. Individual knobs are polymorphic among strains of both maize and teosinte. Barbara McClintock used these knob markers to prove her transposon theory of "jumping genes", for which she won the 1983 Nobel Prize in Physiology or Medicine. Maize is still an important model organism for genetics and developmental biology today.
There is a stock center of maize mutants, The Maize Genetics Cooperation — Stock Center, funded by the USDA Agricultural Research Service and located in the Department of Crop Sciences at the University of Illinois at Urbana-Champaign. The total collection has nearly 80,000 samples. The bulk of the collection consists of several hundred named genes, plus additional gene combinations and other heritable variants. There are about 1000 chromosomal aberrations (e.g., translocations and inversions) and stocks with abnormal chromosome numbers (e.g., tetraploids). Genetic data describing the maize mutant stocks as well as myriad other data about maize genetics can be accessed at MaizeGDB, the Maize Genetics and Genomics Database.[8]
In 2005, the U.S. National Science Foundation (NSF), Department of Agriculture (USDA) and the Department of Energy (DOE) formed a consortium to sequence the maize genome. The resulting DNA sequence data will be deposited immediately into GenBank, a public repository for genome-sequence data. Sequencing the corn genome has been considered difficult because of its large size and complex genetic arrangements. The genome has 50,000–60,000 genes scattered among the 2.5 billion bases – molecules that form DNA – that make up its 10 chromosomes. (By comparison, the human genome contains about 2.9 billion bases and 26,000 genes.)
# Origin
There are several theories about the specific origin of maize in Mesoamerica:
- It is a direct domestication of a Mexican annual teosinte, Zea mays ssp. parviglumis, native to the Balsas River valley of southern Mexico, with up to 12% of its genetic material obtained from Zea mays ssp. mexicana through introgression;
- It derives from hybridization between a small domesticated maize (a slightly changed form of a wild maize) and a teosinte of section Luxuriantes, either Z. luxurians or Z. diploperennis;
- It underwent two or more domestications either of a wild maize or of a teosinte;
- It evolved from a hybridization of Z. diploperennis by Tripsacum dactyloides. (The term "teosinte" describes all species and subspecies in the genus Zea, excluding Zea mays ssp. mays.) In the late 1930s, Paul Mangelsdorf suggested that domesticated maize was the result of a hybridization event between an unknown wild maize and a species of Tripsacum, a related genus. However, the proposed role of tripsacum (gama grass) in the origins of maize has been refuted by modern genetic analysis, negating Mangelsdorf’s model and the fourth listed above.
The third model (actually a group of hypotheses) is unsupported.[citation needed] The second parsimoniously explains many conundrums but is dauntingly complex.[citation needed] The first model was proposed by Nobel Prize winner George Beadle in 1939. Though it has experimental support, it has not explained a number of problems, among them:
- how the immense diversity of the species of sect. Zea originated,
- how the tiny archaeological specimens of 3500–2700 BCE (uncorrected) could have been selected from a teosinte, and
- how domestication could have proceeded without leaving remains of teosinte or maize with teosintoid traits until ca. 1100 BCE.
The domestication of maize is of particular interest to researchers—archaeologists, geneticists, ethnobotanists, geographers, etc. The process is thought by some to have started 7,500 to 12,000 years ago (corrected for solar variations). Recent genetic evidence suggests that maize domestication occurred 9000 years ago in central Mexico, perhaps in the highlands between Oaxaca and Jalisco.[9] The wild teosinte most similar to modern maize grows in the area of the Balsas River. Archaeological remains of early maize ears, found at Guila Naquitz Cave in the Oaxaca Valley, date back roughly 6,250 years (corrected; 3450 BCE, uncorrected); the oldest ears from caves near Tehuacan, Puebla, date ca. 2750 BCE. Little change occurred in ear form until ca. 1100 BCE when great changes appeared in ears from Mexican caves: maize diversity rapidly increased and archaeological teosinte was first deposited.
Perhaps as early as 1500 BCE, maize began to spread widely and rapidly. As it was introduced to new cultures, new uses were developed and new varieties selected to better serve in those preparations. Maize was the staple food, or a major staple, of most the pre-Columbian North American, Mesoamerican, South American, and Caribbean cultures. The Mesoamerican civilization was strengthened upon the field crop of maize; through harvesting it, its religious and spiritual importance and how it impacted their diet. Maize formed the Mesoamerican people’s identity. During the 1st millennium CE (AD), maize cultivation spread from Mexico into the Southwest and a millennium later into Northeast and southeastern Canada, transforming the landscape as Native Americans cleared large forest and grassland areas for the new crop.
It is unknown what precipitated its domestication, because the edible portion of the wild variety is too small and hard to obtain to be eaten directly, as each kernel is enclosed in a very hard bi-valve shell. However, George Beadle demonstrated that the kernels of teosinte are readily "popped" for human consumption, like modern popcorn. Some have argued that it would have taken too many generations of selective breeding in order to produce large compressed ears for efficient cultivation. However, studies of the hybrids readily made by intercrossing teosinte and modern maize suggest that this objection is not well-founded.
In 2005, research by the USDA Forest Service indicated that the rise in maize cultivation 500 to 1,000 years ago in the southeastern United States contributed to the decline of freshwater mussels, which are very sensitive to environmental changes.[10]
# Cultivation
Template:Agricultural production box
Maize is widely cultivated throughout the world, and a greater weight of maize is produced each year than any other grain. While the United States produces almost half of the world's harvest, other top producing countries are as widespread as China, Brazil, France, Indonesia, India and South Africa. Worldwide production was over 600 million metric tons in 2003 — just slightly more than rice or wheat. In 2004, close to 33 million hectares of maize were planted worldwide, with a production value of more than $23 billion.
Because it is cold-intolerant, in the temperate zones maize must be planted in the spring. Its root system is generally shallow, so the plant is dependent on soil moisture. As a C4 plant (a plant that uses C4 photosynthesis), maize is a considerably more water-efficient crop than C3 plants like the small grains, alfalfa and soybeans. Maize is most sensitive to drought at the time of silk emergence, when the flowers are ready for pollination. In the United States, a good harvest was traditionally predicted if the corn was "knee-high by the Fourth of July", although modern hybrids generally exceed this growth rate. Maize used for silage is harvested while the plant is green and the fruit immature. Sweet corn is harvested in the "milk stage", after pollination but before starch has formed, between late summer and early to mid-autumn. Field corn is left in the field very late in the autumn in order to thoroughly dry the grain, and may, in fact, sometimes not be harvested until winter or even early spring. The importance of sufficient soil moisture is shown in many parts of Africa, where periodic drought regularly causes famine by causing maize crop failure.
Maize was planted by the Native Americans in hills, in a complex system known to some as the Three Sisters: beans used the corn plant for support, and squashes provided ground cover to stop weeds. This method was replaced by single species hill planting where each hill 60–120 cm (2–4 ft) apart was planted with 3 or 4 seeds, a method still used by home gardeners. A later technique was checked corn where hills were placed 40 inches apart in each direction, allowing cultivators to run through the field in two directions. In more arid lands this was altered and seeds were planted in the bottom of 10–12 cm (4–5 in) deep furrows to collect water. Modern technique plants maize in rows which allows for cultivation while the plant is young, although the hill technique is still used in the cornfields of some Native American reservations.
In North America, fields are often planted in a two-crop rotation with a nitrogen-fixing crop, often alfalfa in cooler climates and soybeans in regions with longer summers. Sometimes a third crop, winter wheat, is added to the rotation. Fields are usually plowed each year, although no-till farming is increasing in use. Many of the maize varieties grown in the United States and Canada are hybrids. Over half of the corn area planted in the United States has been genetically modified using biotechnology to express agronomic traits such as pest resistance or herbicide resistance.
Before about World War II, most maize in North America was harvested by hand (as it still is in most of the other countries where it is grown). This often involved large numbers of workers and associated social events. Some one- and two-row mechanical pickers were in use but the corn combine was not adopted until after the War. By hand or mechanical picker, the entire ear is harvested which then requires a separate operation of a corn sheller to remove the kernels from the ear. Whole ears of corn were often stored in corn cribs and these whole ears are a sufficient form for some livestock feeding use. Few modern farms store maize in this manner. Most harvest the grain from the field and store it in bins. The combine with a corn head (with points and snap rolls instead of a reel) does not cut the stalk; it simply pulls the stalk down. The stalk continues downward and is crumpled in to a mangled pile on the ground. The ear of corn is too large to pass through a slit in a plate and the snap rolls pull the ear of corn from the stalk so that only the ear and husk enter the machinery. The combine separates out the husk and the cob, keeping only the kernels.
# Pellagra
When maize was first introduced outside of the Americas it was generally welcomed with enthusiasm by farmers everywhere for its productivity. However, a widespread problem of malnutrition soon arose wherever maize was introduced. This was a mystery since these types of malnutrition were not seen among the indigenous Americans under normal circumstances.[11]
It was eventually discovered that the indigenous Americans learned long ago to add alkali — in the form of ashes among North Americans and lime (calcium carbonate) among Mesoamericans — to corn meal to liberate the B-vitamin niacin, the lack of which was the underlying cause of the condition known as pellagra. This alkali process is known by its Nahuatl (Aztec)-derived name: nixtamalization.
Besides the lack of niacin, pellagra was also characterized by protein deficiency, a result of the inherent lack of two key amino acids in pre-modern maize, lysine and tryptophan. Nixtamalisation was also found to increase the lysine and tryptophan content of maize to some extent, but more importantly, the indigenous Americans had learned long ago to balance their consumption of maize with beans and other protein sources such as amaranth and chia, as well as meat and fish, in order to acquire the complete range of amino acids for normal protein synthesis.
Since maize had been introduced into the diet of non-indigenous Americans without the necessary cultural knowledge acquired over thousands of years in the Americas, the reliance on maize elsewhere was often tragic. In the late 19th century pellagra reached endemic proportions in parts of the deep southern U.S., as medical researchers debated two theories for its origin: the deficiency theory (eventually shown to be true) posited that pellagra was due to a deficiency of some nutrient, and the germ theory posited that pellagra was caused by a germ transmitted by stable flies. In 1914 the U.S. government officially endorsed the germ theory of pellagra, but rescinded this endorsement several years later as evidence grew against it. By the mid-1920s the deficiency theory of pellagra was becoming scientific consensus, and the theory was proved in 1932 when niacin deficiency was determined to be the cause of the illness.
Once alkali processing and dietary variety was understood and applied, pellagra disappeared. The development of high lysine maize and the promotion of a more balanced diet has also contributed to its demise.
# Pests of maize
## Insect pests
- Corn earworm (Helicoverpa zea)
- Fall armyworm (Spodoptera frugiperda)
- Common armyworm (Pseudaletia unipuncta)
- Stalk borer (Papaipema nebris)
- Corn leaf aphid (Rhopalosiphum maidis)
- European corn borer (Ostrinia nubilalis) (ECB)
- Corn silkfly (Euxesta stigmatis)
- Lesser cornstalk borer (Elasmopalpus lignosellus)
- Corn delphacid (Peregrinus maidis)
- Western corn rootworm (Diabrotica virgifera virgifera LeConte)
The susceptibility of maize to the European corn borer, and the resulting large crop losses, led to the development of transgenic expressing the Bacillus thuringiensis toxin. "Bt corn" is widely grown in the United States and has been approved for release in Europe.
## Diseases
- Corn smut or common smut (Ustilago maydis): a fungal disease, known in Mexico as huitlacoche, which is prized by some as a gourmet delicacy in itself.
- Maize Dwarf Mosaic Virus
- Stewart's Wilt (Pantoea stewartii)
- Common Rust (Puccinia sorghi)
- Goss's Wilt (Clavibacter michiganese)
- Grey Leaf Spot
- Mal de Río Cuarto Virus (MRCV)
- Stalk and Kernal Rot
# Uses for maize
In the United States and Canada, the primary use for maize is as a feed for livestock, forage, silage or grain. "Feed corn" is also being increasingly used for heating; specialized corn stoves (similar to wood stoves) are available and use either feed corn or wood pellets to generate heat. Silage is made by fermentation of chopped green cornstalks. The grain also has many industrial uses, including transformation into plastics and fabrics. Some is hydrolyzed and enzymatically treated to produce syrups, particularly high fructose corn syrup, a sweetener, and some is fermented and distilled to produce grain alcohol. Grain alcohol from maize is traditionally the source of bourbon whiskey. Increasingly ethanol is being used at low concentrations (10% or less) as an additive in gasoline (gasohol) for motor fuels to increase the octane rating, lower pollutants, and reduce petroleum use.
Human consumption of corn and cornmeal constitutes a staple food in many regions of the world. Corn meal is made into a thick porridge in many cultures: from the polenta of Italy, the angu of Brazil, the mămăligă of Romania, to mush in the U.S. or the food called sadza, nshima, ugali and mealie pap in Africa. It is the main ingredient for tortillas, atole and many other dishes of Mexican food, and for chicha, a fermented beverage of Central and South America. The eating of corn on the cob varies culturally. It is common in the United States but virtually unheard of in some European countries.
Template:Nutritionalvalue
Sweetcorn is a genetic variation that is high in sugars and low in starch that is served like a vegetable. Popcorn is kernels of certain varieties that explode when heated, forming fluffy pieces that are eaten as a snack.
Maize can also be prepared as hominy, in which the kernels are bleached with lye; or grits, which are coarsely ground corn. These are commonly eaten in the Southeastern United States, foods handed down from Native Americans. Another common food made from maize is corn flakes. The floury meal of maize (cornmeal or masa) is used to make cornbread and Mexican tortillas. Teosinte is used as fodder, and can also be popped as popcorn.
Some forms of the plant are occasionally grown for ornamental use in the garden. For this purpose, variegated and coloured leaf forms as well as those with colourful ears are used. Additionally, size-superlative varieties, having reached 31 ft (9.4m) tall, or with ears 24 inches (60cm) long, have been popular for at least a century.[12][13]
Corncobs can be hollowed out and treated to make inexpensive smoking pipes, first manufactured in the United States in 1869. Corncobs are also used as a biomass fuel source. Maize is relatively cheap and home-heating furnaces have been developed which use maize kernels as a fuel. They feature a large hopper which feeds the uniformly sized corn kernels (or wood pellets or cherry pits) into the fire.
An unusual use for maize is to create a Maize Maze as a tourist attraction. This is a maze cut into a field of maize. The idea of a Maize Maze was introduced by Adrian Fisher, one of the most prolific designer of modern mazes, with The American Maze Company who created a maze in Pennsylvania in 1993. Traditional mazes are most commonly grown using yew hedges, but these take several years to mature. The rapid growth of a field of maize allows a maze to be laid out using GPS at the start of a growing season and for the maize to grow tall enough to obstruct a visitor's line of sight by the start of the summer. In Canada and the U.S., these are called "corn mazes" and are popular in many farming communities.
Maize is increasingly used as a biomass fuel, such as ethanol, which as researchers search for innovative ways to reduce fuel costs has unintentionally caused a rapid rise in food costs. This has led to the 2007 harvest being one of the most profitable corn crops in modern history for farmers. A biomass gasification power plant in Strem near Güssing, Burgenland, Austria was begun in 2005. Research is being done to make diesel out of the biogas by the Fischer Tropsch method.
Maize is also used as fish bait called "dough balls". It is particularly popular in Europe for coarse fishing.
Stigmas from female corn flowers, known popularly as corn silk, are sold as herbal supplements.
Corn kernels can be used in place of sand in a sandbox-like enclosure for children's play.[14]
# Maize and art
Maize has been an essential crop in the Andes since the pre-Columbian Era. The Moche culture from Northern Peru made ceramics from earth, water, and fire. This pottery was a sacred substance, formed in significant shapes and used to represent important themes. Maize represented anthropomorphically as well as naturally.[15] | https://www.wikidoc.org/index.php/Maize | |
87e9d02721b6b51b14041afc842e0344b5b3c1e7 | wikidoc | Mamba | Mamba
# Overview
Mambas, of the genus Dendroaspis, are fast-moving tree-dwelling snakes of Africa. ("Dendroaspis" is literally "tree snake".) They belong to the family of Elapidae which includes cobras, coral snakes, kraits and, debatably, sea snakes, all of which can be extremely deadly. The black mamba is the longest venomous snake in Africa, with an extremely potent neurotoxic venom that attacks the nervous system, and cardiotoxins which attack the heart; the bite is often fatal to humans without access to proper first aid and subsequent antivenin treatment, because it shuts down the lungs and heart. Prior to the availability of antivenom, envenomations by members of this genus carried a nearly 100% fatality rate. However, with antivenom being much more available today, fatalities have become much more rare.
The Western green mamba (D. viridis) and Eastern green mamba, (D. angusticeps), possess venom that is roughly equal in potency to that of the Black mamba (D. polylepis). However, they are not nearly as aggressive.
They are slightly smaller, and are arboreal, whereas the latter is primarily terrestrial.
The black mamba is not named for the colour of its body (which is usually a shade of grey or charcoal), but for the highly pigmented interior of its mouth, which it will display to the predator in hopes it will leave it alone. Many people believe that the Black Mamba will actually chase and attack humans. This is a myth, and is probably fueled by the great speed with which this species can move. Humans are actually their predators, rather than their prey. For that reason, mambas generally avoid contact with humans. However, if a mamba feels threatened by a human, it may defend itself fiercely.
In contrast to all other species in this genus, which are arboreal, black mambas reside in hollow insect mounds, abandoned burrows, and rock crevices. They are diurnal. During the day they actively hunt their prey of small mammals, birds and lizards. They return to the same lair nightly.
Mambas are related to the cobras (Elapids), as can be seen during their threat display, when they stretch a slightly smaller 'hood' while gaping their mouth. Unlike most other snakes mambas will strike repeatedly if cornered, and have been reported to bring down a giraffe and a lion with their venom.
# Mamba toxin
Mamba toxin is in fact several components, with different targets. Examples are:
- Mamba toxin 3, which inhibits M4 receptors.
- Mamba toxin 7, which inhibits M1 receptors. | Mamba
# Overview
Mambas, of the genus Dendroaspis, are fast-moving tree-dwelling snakes of Africa. ("Dendroaspis" is literally "tree snake".) They belong to the family of Elapidae which includes cobras, coral snakes, kraits and, debatably, sea snakes, all of which can be extremely deadly. The black mamba is the longest venomous snake in Africa, with an extremely potent neurotoxic venom that attacks the nervous system, and cardiotoxins which attack the heart; the bite is often fatal to humans without access to proper first aid and subsequent antivenin treatment, because it shuts down the lungs and heart. Prior to the availability of antivenom, envenomations by members of this genus carried a nearly 100% fatality rate. However, with antivenom being much more available today, fatalities have become much more rare.
The Western green mamba (D. viridis) and Eastern green mamba, (D. angusticeps), possess venom that is roughly equal in potency to that of the Black mamba (D. polylepis). However, they are not nearly as aggressive.
They are slightly smaller, and are arboreal, whereas the latter is primarily terrestrial.
The black mamba is not named for the colour of its body (which is usually a shade of grey or charcoal), but for the highly pigmented interior of its mouth, which it will display to the predator in hopes it will leave it alone. Many people believe that the Black Mamba will actually chase and attack humans. This is a myth, and is probably fueled by the great speed with which this species can move. Humans are actually their predators, rather than their prey. For that reason, mambas generally avoid contact with humans. However, if a mamba feels threatened by a human, it may defend itself fiercely.
In contrast to all other species in this genus, which are arboreal, black mambas reside in hollow insect mounds, abandoned burrows, and rock crevices. They are diurnal. During the day they actively hunt their prey of small mammals, birds and lizards. They return to the same lair nightly.
Mambas are related to the cobras (Elapids), as can be seen during their threat display, when they stretch a slightly smaller 'hood' while gaping their mouth. Unlike most other snakes mambas will strike repeatedly if cornered, and have been reported to bring down a giraffe and a lion with their venom.
# Mamba toxin
Mamba toxin is in fact several components, with different targets. Examples are:
- Mamba toxin 3, which inhibits M4 receptors. [1]
- Mamba toxin 7, which inhibits M1 receptors.[1] | https://www.wikidoc.org/index.php/Mamba | |
660bd48c78d3599be5b17070386871d5bf554519 | wikidoc | Mango | Mango
The mango (plural mangoes or mangos) is a tropical fruit of the mango tree. Mangoes belong to the genus Mangifera which consists of about 30 species of tropical fruiting trees in the flowering plant family Anacardiaceae. The exact origins of the mango are unknown, but most believe that it is native to Southern and Southeast Asia owing to the wide range of genetic diversity in the region and fossil records dating back 25 to 30 million years.
Mangoes retain a special significance in the culture of South Asia where they have been cultivated for millennia. It has been the national symbol of the Philippines. Reference to mangoes as the "food of the gods" can be found in the Hindu Vedas and the leaves are ritually used for floral decorations at Hindu marriages and religious ceremonies.
# Etymology
The name 'mango' is from the the Malayalam word "Manga", which was popularized by the Portuguese after their Indian exploration (hence Portuguese 'manga').
# Description
Mango trees ( Mangifera indica ) are large, reaching 35-40 m in height, with a crown radius of 10 m. The leaves are evergreen, alternate, simple, 15-35 cm long and 6-16 cm broad; when the leaves are young they are orange-pink, rapidly changing to a dark glossy red, then dark green as they mature. The flowers are produced in terminal panicles 10-40 cm long; each flower is small and white with five petals 5-10 mm long, with a mild sweet odor suggestive of lily of the valley. After the flowers finish, the fruit takes from three to six months to ripen.
The mango fruit is a drupe; when mature, it hangs from the tree on long stems. They are variable in size, from 10-25 cm long and 7-12 cm diameter, and may weigh up to 2.5 kg. The ripe fruit is variably colored yellow, orange and red, reddest on the side facing the sun and yellow where shaded; green usually indicates that the fruit is not yet ripe, but this depends on the cultivar. When ripe, the unpeeled fruit gives off a distinctive resinous slightly sweet smell. In the center of the fruit is a single flat, oblong seed (as big as a large stone) that can be fibrous or hairless on the surface, depending on cultivar. Inside the shell, which is 1-2 mm thick, is a paper-thin lining covering a single seed, 4-7 cm long, 3-4 cm wide, 1 cm thick. One variety, recently available in Hong Kong is quite large compared to common ones as shown in the photo below.
# Cultivation and uses
The mango is now widely cultivated as a fruit tree in frost-free tropical and warmer subtropical climates throughout the Indian subcontinent, North, South and Central America, the Caribbean, south and central Africa, Australia and Southeast Asia. It is easily cultivated and there are now more than 1,000 cultivars, ranging from the turpentine mango (from the strong taste of turpentine, which according to the Oxford Companion to Food some varieties actually contain) to the huevos de toro ("bull's balls", from the shape and size). The mango is reputed to be the most commonly eaten fresh fruit worldwide. Mangos also readily naturalize in tropical climates. Some lowland forests in the Hawaiian Islands are dominated by introduced mangos and it is a common backyard fruit tree in South Florida where it has also escaped from cultivation.
The mango is a popular fruit with people around the world. However, many mango farmers receive a low price for their produce. This has led to mangoes being available as a fair trade item in some countries.
There is a unique pigment that cannot be synthesized called euxanthin or euxanthine, and usually known as Indian Yellow, which is produced in the urine of cows fed on mango leaves. Their urine was once collected and evaporated and the pigment then used in oil paint. The practice was outlawed in 1908 due to malnutrition of the cows (the leaves have a mildly toxic substance related to that in poison ivy) and the color is now produced synthetically by mixing other pigments.
## Diseases
## Usage as food
The fruit flesh of a ripe mango is very sweet, with a unique taste. The texture of the flesh varies markedly between different cultivars; some have quite a soft and pulpy texture similar to an over-ripe plum, while others have a firmer flesh much like that of a cantaloupe or avocado, and in some cultivars the flesh can contain fibrous material. Mangoes are very juicy; the sweet taste and high water content make them refreshing to eat.
Mangoes are widely used in chutney, which in the West is often very sweet, but in the Indian subcontinent is usually made with sour, raw mangoes and hot chilis or limes. In India, ripe mango is often cut into thin layers, desiccated , folded, and then cut and sold as bars that are very chewy. These bars, known as amavat or halva in Hindi, are similar to dried guava fruit bars available in Colombia. In many parts of India, people eat squeezed mango juice (called Ras), the thickness of which depends on the type of mango, with variety of bread items and is part of the meal rather than a dessert. Many people like to eat unripe mangoes with salt (which are extremely sour; much more than lemon), and in regions where food is hotter, with salt and chili.
The fruit is also widely used as a key ingredient in a variety of cereal products, in particular muesli and oat granola.
In the Philippines, unripe mango is eaten with bagoong. Dried strips of sweet, ripe mangoes have also gained popularity both inside and outside the country, with those produced in Cebu making it to export markets around the world.
In other parts of South-east Asia, mangoes are very popular pickled with fish sauce and rice vinegar.
Mango is also used to make juices, both in ripe and unripe form. Pieces of fruit can be mashed and used in ice cream; they can be substituted for peaches in a peach (now mango) pie; or blended with milk and ice to make thick milkshakes. In Thailand and other South East Asian countries, sweet glutinous rice is flavoured with coconut then served with sliced mango on top as a dessert.
Dried unripe mango used as a spice and is known as amchur (sometimes spelled amchoor) in India and ambi in Urdu. Aam is a Hindi/Urdu word for mango, and choor for powder, hence the word Amchoor for mango powder.
Note: The Sweet Bell Pepper (capsicum) was once known as mango in parts of the midwestern United States With the advent of fresh fruit importers exposing individuals to the tropical fruit, the colloquial use of this alternative name for the Sweet Bell Pepper has become archaic, although occasionally midwestern menus will still offer stuffed mangoes as an entree.
### Serving Raw, Ripe Fruit
It is best done with a spoon and a knife. Make an incision with the knife around the longest circumference, which usually includes the stem. Making the incision deep to the stone will prevent making a cut of the largest doughnut shape possible. Use the spoon to peel the skin away from the flesh. Cut the remainder from the stone according to taste in spears, dice, or other shapes.
## Medicinal and nutritional properties
The mango is an excellent nutritional source, containing many vitamins, minerals, and antioxidants, as well as enzymes such as magneferin and lactase which aid in digestion and intestinal health. It is also used in some parts of southeast Asia and the Muslim world as a supplement for sexual potency.
The mango is in the same family as poison sumac and contains urushiol, though much less than poison sumac. Some people get dermatitis from touching mango peel or sap. Persons showing an allergic reaction after handling a mango can usually enjoy the fruit if someone else first removes the skin. It is very rare to develop a rash on your hands however. While the peel is typically considered inedible, recent study has shown that it yields considerable extracts that can be used in antioxidant food supplements. Consuming the peel itself is generally not advised as a painful rash or swelling may appear on the lips and face. If you are not allergic to the Urushiol within Ivy, Oak, and Sumac; enjoy the benefits of the peel. However, continued exposure to Urushiol can lead to a reaction. The amount of time it takes depends on genetic structure of the individual person.
## Cultural context
Mango leaves are used to decorate the entrance of a household amongst Hindus. Mango leaves are also used in Indian prayers (poojas) to propitiate the gods. The mango is also a common motif in Indian textiles, known as the paisley design.
# Production and consumption
India is by far the largest producer, with an area of 16,000 km² with an annual production of 10.8 million tonnes, which accounted for 57.18% of the total world production. Within India, the southern state of Andhra Pradesh is the largest producer of Mangoes, with 3,500 km² under cultivation (2004 data). In the country's north, Uttar Pradesh state dominates the mango production tables.
Langra , Alphonso and Himsagar are considered among the most superior types of mangoes in India. Both of these varieties are produced in East and North India, especially in Uttar Pradesh state and in Multan and Sindh in Pakistan. The main production of Langra happens in a small town of West Bengal, Malda. Both of these varieties are not suitable for long preservation and thus not usually exported. The variety Alphonso is considered another superior variety of mango. Grown exclusively in the Konkan region of Maharashtra, the Alphonso mango that is commonly exported. Alphonso is named after Afonso De Albuquerque, who reputedly brought the drupe on his journeys to Goa. The locals took to calling this Aphoos in Konkani and in Maharashtra the pronunciation got further corrupted to Hapoos. This variety then was taken to the Konkan region of Maharashtra and other parts of India. Banganapalli from Andhra Pradesh, Ratnagiri and Devgad Hapoos from Maharashtra are among the most prized varieties in south India. Lucknow and Varanasi Certain Mango varieties are picked raw and turned into spicy pickles. Andhra Pradesh and Karnataka states in the south, and Gujarat and Uttar Pradesh in the north are major producers of pickle-variety mangoes and specialize in making a variety of mango pickles. These pickles can be very spicy, and tend to have large regional differences in taste.
Generally, once ripe, mangoes are quite juicy and can be very messy to eat. However, those exported to temperate regions are, like most tropical fruit, picked under-ripe. Although they are ethylene producers and ripen in transit, they do not have the same juiciness or flavour as the fresh fruit. A ripe mango will have an orange-yellow or reddish skin. To allow a mango to continue to ripen after purchase, it should be stored in a cool, dark place, but not in a refrigerator as this will slow the ripening process.
Ripe mangoes are extremely popular throughout Latin America. In Mexico, sliced mango is eaten with chili powder and/or salt. Street vendors sometimes sell whole mangoes on a stick, dipped in the chili-salt mixture. In Indonesia, green mango is sold by street vendors with sugar and salt and/or chili. Green mango may be used in the sour salad called rujak in Indonesia, and rojak in Malaysia and Singapore. In Guatemala, Ecuador, Nicaragua, Honduras and El Salvador, small, green mangoes are popular; they have a sharp, brisk flavour like a Granny Smith apple. Vendors sell slices of peeled green mango on the streets of these countries, often served with salt. In Hawai'i it is common to pickle green mango slices. Ayurveda considers ripe mango sweet and heating, balancing all the three doshas(humors) and acts as an energizer.
Pakistani varieties of mango include Chaunsa, Sindhri, Qalmi, Langra, Desi and Anwar Latore, most of which are produced in the areas of Multan Division and Sindh province. While these types of mangoes are well known in their tastes and smells within the country, they have not yet received a lot of exposure abroad.
Raw mangoes are used in making pickles and condiments due to its peculiar sweet and sour taste. Dried and powdered raw mango is sometimes also used as a condiment in Indian cuisine.
# Cultivars
Many hundreds of named mango cultivars exist. In mango orchards, several cultivars are often intermixed to improve cross-pollination. In Maharashtra, the most common cultivar is Alphonso (known in Asia under the original name, Hapoos). Alphonso is very popular outside Indian subcontinent and one of the important export product of India. The best Alphonso mangos are reputed to come from the town of Ratnagiri and Devgad in Maharashtra. In Uttar Pradesh, Dasheri from Lucknow is famous for its aroma. Langra from Varanasi in eastern UP is another variety which is extremely sought after for its fine flavour and aroma, but is not suitable for export because of the perishable nature. Banganapalli (also called Banesha or Began Phali) of Andhra Pradesh is one of the most sought after cultivars. Maldah is one of the most sought after cultivars in Bihar. Notably, cultivars which excel in one climate fail to achieve their potential in other climates. Thus the cultivar Julie, a Jamaican favourite, and Alphonso have never found great success in South Florida, Israel or Australia.
Currently, the world market is dominated by the cultivar Tommy Atkins, a seedling of Haden which first fruited in 1940 in Southern Florida, USA. Despite being initially rejected commercially by Florida researchers, Tommy Atkins quickly became an export favourite worldwide. For example, 80% of mangos in UK supermarkets are Tommy Atkins. Despite its fibrous flesh and fair taste, growers world-wide have embraced the cultivar for its exceptional production and disease resistance, the shelf-life of its fruit, their transportability as well as their size and beautiful color. Tommy Atkins is predominant in the USA as well, although other cultivars, such Kent, Keitt, the Haitian grown Madame Francis and the Mexican grown Champagne are widely available.
In urban areas of southern Florida, small gardens, or lack thereof, have fueled the desire for dwarf Mango trees. The Fairchild Tropical Botanic Garden has led the charge for the "condo mango" by identifying cultivars which can be productive while maintained at a height below 2-2.5 m.
A list of additional leading cultivars can be found at the cultivar list link in the external links below.
There is an Australian variety of mango known as R2-E2, a name based on the orchard row location of the original plant. | Mango
The mango (plural mangoes or mangos) is a tropical fruit of the mango tree. Mangoes belong to the genus Mangifera which consists of about 30 species of tropical fruiting trees in the flowering plant family Anacardiaceae. The exact origins of the mango are unknown, but most believe that it is native to Southern and Southeast Asia owing to the wide range of genetic diversity in the region and fossil records dating back 25 to 30 million years.[1]
Mangoes retain a special significance in the culture of South Asia where they have been cultivated for millennia. It has been the national symbol of the Philippines. Reference to mangoes as the "food of the gods" can be found in the Hindu Vedas and the leaves are ritually used for floral decorations at Hindu marriages and religious ceremonies.
# Etymology
The name 'mango' is from the the Malayalam word "Manga", which was popularized by the Portuguese after their Indian exploration (hence Portuguese 'manga').
# Description
Mango trees ( Mangifera indica ) are large, reaching 35-40 m in height, with a crown radius of 10 m. The leaves are evergreen, alternate, simple, 15-35 cm long and 6-16 cm broad; when the leaves are young they are orange-pink, rapidly changing to a dark glossy red, then dark green as they mature. The flowers are produced in terminal panicles 10-40 cm long; each flower is small and white with five petals 5-10 mm long, with a mild sweet odor suggestive of lily of the valley. After the flowers finish, the fruit takes from three to six months to ripen.
The mango fruit is a drupe; when mature, it hangs from the tree on long stems. They are variable in size, from 10-25 cm long and 7-12 cm diameter, and may weigh up to 2.5 kg. The ripe fruit is variably colored yellow, orange and red, reddest on the side facing the sun and yellow where shaded; green usually indicates that the fruit is not yet ripe, but this depends on the cultivar. When ripe, the unpeeled fruit gives off a distinctive resinous slightly sweet smell. In the center of the fruit is a single flat, oblong seed (as big as a large stone) that can be fibrous or hairless on the surface, depending on cultivar. Inside the shell, which is 1-2 mm thick, is a paper-thin lining covering a single seed, 4-7 cm long, 3-4 cm wide, 1 cm thick. One variety, recently available in Hong Kong is quite large compared to common ones as shown in the photo below.
# Cultivation and uses
The mango is now widely cultivated as a fruit tree in frost-free tropical and warmer subtropical climates throughout the Indian subcontinent, North, South and Central America, the Caribbean, south and central Africa, Australia and Southeast Asia. It is easily cultivated and there are now more than 1,000 cultivars, ranging from the turpentine mango (from the strong taste of turpentine, which according to the Oxford Companion to Food some varieties actually contain) to the huevos de toro ("bull's balls", from the shape and size). The mango is reputed to be the most commonly eaten fresh fruit worldwide. Mangos also readily naturalize in tropical climates. Some lowland forests in the Hawaiian Islands are dominated by introduced mangos and it is a common backyard fruit tree in South Florida where it has also escaped from cultivation.
The mango is a popular fruit with people around the world. However, many mango farmers receive a low price for their produce. This has led to mangoes being available as a fair trade item in some countries.
There is a unique pigment that cannot be synthesized called euxanthin or euxanthine, and usually known as Indian Yellow, which is produced in the urine of cows fed on mango leaves. Their urine was once collected and evaporated and the pigment then used in oil paint.[2] The practice was outlawed in 1908 due to malnutrition of the cows (the leaves have a mildly toxic substance related to that in poison ivy) and the color is now produced synthetically by mixing other pigments.
## Diseases
## Usage as food
The fruit flesh of a ripe mango is very sweet, with a unique taste. The texture of the flesh varies markedly between different cultivars; some have quite a soft and pulpy texture similar to an over-ripe plum, while others have a firmer flesh much like that of a cantaloupe or avocado, and in some cultivars the flesh can contain fibrous material. Mangoes are very juicy; the sweet taste and high water content make them refreshing to eat.
Mangoes are widely used in chutney, which in the West is often very sweet, but in the Indian subcontinent is usually made with sour, raw mangoes and hot chilis or limes. In India, ripe mango is often cut into thin layers, desiccated , folded, and then cut and sold as bars that are very chewy. These bars, known as amavat or halva in Hindi, are similar to dried guava fruit bars available in Colombia. In many parts of India, people eat squeezed mango juice (called Ras), the thickness of which depends on the type of mango, with variety of bread items and is part of the meal rather than a dessert. Many people like to eat unripe mangoes with salt (which are extremely sour; much more than lemon), and in regions where food is hotter, with salt and chili.
The fruit is also widely used as a key ingredient in a variety of cereal products, in particular muesli and oat granola.
In the Philippines, unripe mango is eaten with bagoong. Dried strips of sweet, ripe mangoes have also gained popularity both inside and outside the country, with those produced in Cebu making it to export markets around the world.
In other parts of South-east Asia, mangoes are very popular pickled with fish sauce and rice vinegar.
Mango is also used to make juices, both in ripe and unripe form. Pieces of fruit can be mashed and used in ice cream; they can be substituted for peaches in a peach (now mango) pie; or blended with milk and ice to make thick milkshakes. In Thailand and other South East Asian countries, sweet glutinous rice is flavoured with coconut then served with sliced mango on top as a dessert.
Dried unripe mango used as a spice and is known as amchur (sometimes spelled amchoor) in India and ambi in Urdu. Aam is a Hindi/Urdu word for mango, and choor for powder, hence the word Amchoor for mango powder.
Note: The Sweet Bell Pepper (capsicum) was once known as mango in parts of the midwestern United States [3] With the advent of fresh fruit importers exposing individuals to the tropical fruit, the colloquial use of this alternative name for the Sweet Bell Pepper has become archaic, although occasionally midwestern menus will still offer stuffed mangoes as an entree.
### Serving Raw, Ripe Fruit
It is best done with a spoon and a knife. Make an incision with the knife around the longest circumference, which usually includes the stem. Making the incision deep to the stone will prevent making a cut of the largest doughnut shape possible. Use the spoon to peel the skin away from the flesh. Cut the remainder from the stone according to taste in spears, dice, or other shapes.
## Medicinal and nutritional properties
The mango is an excellent nutritional source, containing many vitamins, minerals, and antioxidants, as well as enzymes such as magneferin and lactase which aid in digestion and intestinal health.[4] It is also used in some parts of southeast Asia and the Muslim world as a supplement for sexual potency.[5]
Template:Nutritionalvalue
The mango is in the same family as poison sumac and contains urushiol, though much less than poison sumac. Some people get dermatitis from touching mango peel or sap. Persons showing an allergic reaction after handling a mango can usually enjoy the fruit if someone else first removes the skin. It is very rare to develop a rash on your hands however. While the peel is typically considered inedible, recent study has shown that it yields considerable extracts that can be used in antioxidant food supplements.[6] Consuming the peel itself is generally not advised as a painful rash or swelling may appear on the lips and face.[7] If you are not allergic to the Urushiol within Ivy, Oak, and Sumac; enjoy the benefits of the peel. However, continued exposure to Urushiol can lead to a reaction. The amount of time it takes depends on genetic structure of the individual person.
## Cultural context
Mango leaves are used to decorate the entrance of a household amongst Hindus. Mango leaves are also used in Indian prayers (poojas) to propitiate the gods. The mango is also a common motif in Indian textiles, known as the paisley design.
# Production and consumption
India is by far the largest producer, with an area of 16,000 km² with an annual production of 10.8 million tonnes, which accounted for 57.18% of the total world production. Within India, the southern state of Andhra Pradesh is the largest producer of Mangoes, with 3,500 km² under cultivation (2004 data). In the country's north, Uttar Pradesh state dominates the mango production tables.
Langra , Alphonso and Himsagar are considered among the most superior types of mangoes in India. Both of these varieties are produced in East and North India, especially in Uttar Pradesh state and in Multan and Sindh in Pakistan. The main production of Langra happens in a small town of West Bengal, Malda. Both of these varieties are not suitable for long preservation and thus not usually exported. The variety Alphonso is considered another superior variety of mango. Grown exclusively in the Konkan region of Maharashtra, the Alphonso mango that is commonly exported. Alphonso is named after Afonso De Albuquerque, who reputedly brought the drupe on his journeys to Goa. The locals took to calling this Aphoos in Konkani and in Maharashtra the pronunciation got further corrupted to Hapoos. This variety then was taken to the Konkan region of Maharashtra and other parts of India. Banganapalli from Andhra Pradesh, Ratnagiri and Devgad Hapoos from Maharashtra are among the most prized varieties in south India. Lucknow and Varanasi Certain Mango varieties are picked raw and turned into spicy pickles. Andhra Pradesh and Karnataka states in the south, and Gujarat and Uttar Pradesh in the north are major producers of pickle-variety mangoes and specialize in making a variety of mango pickles. These pickles can be very spicy, and tend to have large regional differences in taste.
Generally, once ripe, mangoes are quite juicy and can be very messy to eat. However, those exported to temperate regions are, like most tropical fruit, picked under-ripe. Although they are ethylene producers and ripen in transit, they do not have the same juiciness or flavour as the fresh fruit. A ripe mango will have an orange-yellow or reddish skin. To allow a mango to continue to ripen after purchase, it should be stored in a cool, dark place, but not in a refrigerator as this will slow the ripening process.
Ripe mangoes are extremely popular throughout Latin America. In Mexico, sliced mango is eaten with chili powder and/or salt. Street vendors sometimes sell whole mangoes on a stick, dipped in the chili-salt mixture. In Indonesia, green mango is sold by street vendors with sugar and salt and/or chili. Green mango may be used in the sour salad called rujak in Indonesia, and rojak in Malaysia and Singapore. In Guatemala, Ecuador, Nicaragua, Honduras and El Salvador, small, green mangoes are popular; they have a sharp, brisk flavour like a Granny Smith apple. Vendors sell slices of peeled green mango on the streets of these countries, often served with salt. In Hawai'i it is common to pickle green mango slices. Ayurveda considers ripe mango sweet and heating, balancing all the three doshas(humors) and acts as an energizer.
Pakistani varieties of mango include Chaunsa, Sindhri, Qalmi, Langra, Desi and Anwar Latore, most of which are produced in the areas of Multan Division and Sindh province. While these types of mangoes are well known in their tastes and smells within the country, they have not yet received a lot of exposure abroad.
Raw mangoes are used in making pickles and condiments due to its peculiar sweet and sour taste. Dried and powdered raw mango is sometimes also used as a condiment in Indian cuisine.
# Cultivars
Many hundreds of named mango cultivars exist. In mango orchards, several cultivars are often intermixed to improve cross-pollination. In Maharashtra, the most common cultivar is Alphonso (known in Asia under the original name, Hapoos). Alphonso is very popular outside Indian subcontinent and one of the important export product of India. The best Alphonso mangos are reputed to come from the town of Ratnagiri and Devgad in Maharashtra. In Uttar Pradesh, Dasheri from Lucknow is famous for its aroma. Langra from Varanasi in eastern UP is another variety which is extremely sought after for its fine flavour and aroma, but is not suitable for export because of the perishable nature. Banganapalli (also called Banesha or Began Phali) of Andhra Pradesh is one of the most sought after cultivars. Maldah is one of the most sought after cultivars in Bihar. Notably, cultivars which excel in one climate fail to achieve their potential in other climates. Thus the cultivar Julie, a Jamaican favourite, and Alphonso have never found great success in South Florida, Israel or Australia.
Currently, the world market is dominated by the cultivar Tommy Atkins, a seedling of Haden which first fruited in 1940 in Southern Florida, USA. Despite being initially rejected commercially by Florida researchers[citation needed], Tommy Atkins quickly became an export favourite worldwide. For example, 80% of mangos in UK supermarkets are Tommy Atkins. Despite its fibrous flesh and fair taste, growers world-wide have embraced the cultivar for its exceptional production and disease resistance, the shelf-life of its fruit, their transportability as well as their size and beautiful color. Tommy Atkins is predominant in the USA as well, although other cultivars, such Kent, Keitt, the Haitian grown Madame Francis and the Mexican grown Champagne are widely available.
In urban areas of southern Florida, small gardens, or lack thereof, have fueled the desire for dwarf Mango trees. The Fairchild Tropical Botanic Garden has led the charge for the "condo mango" by identifying cultivars which can be productive while maintained at a height below 2-2.5 m.[citation needed]
A list of additional leading cultivars can be found at the cultivar list link in the external links below.
There is an Australian variety of mango known as R2-E2, a name based on the orchard row location of the original plant. | https://www.wikidoc.org/index.php/Mango | |
47b0feec38766472afdd20e786c3dd4f98c562e2 | wikidoc | Maple | Maple
# Overview
Acer (/ˈeɪsər/) is a genus of trees or shrubs commonly known as maple.
Maples are variously classified in a family of their own, the Aceraceae, or together with the Hippocastanaceae included in the family Sapindaceae. Modern classifications, including the Angiosperm Phylogeny Group system, favour inclusion in Sapindaceae. The type species of the genus is Acer pseudoplatanus (Sycamore maple).
There are approximately 128 species, most of which are native to Asia, with a number also appearing in Europe, northern Africa, and North America. Only one species, the poorly studied Acer laurinum, is native to the Southern Hemisphere. Fifty-four species of maples meet the International Union for Conservation of Nature criteria for being under threat of extinction in their native habitat.
The word Acer derives from a Latin word meaning "sharp" (compare "acerbic"), referring to the characteristic points on maple leaves. It was first applied to the genus by the French botanist Joseph Pitton de Tournefort in 1700. The earliest known fossil maple is Acer alaskense, from the Latest Paleocene of Alaska. | Maple
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Acer (/[invalid input: 'icon']ˈeɪsər/)[1] is a genus of trees or shrubs commonly known as maple.
Maples are variously classified in a family of their own, the Aceraceae, or together with the Hippocastanaceae included in the family Sapindaceae. Modern classifications, including the Angiosperm Phylogeny Group system, favour inclusion in Sapindaceae. The type species of the genus is Acer pseudoplatanus (Sycamore maple).[2]
There are approximately 128 species, most of which are native to Asia,[3] with a number also appearing in Europe, northern Africa, and North America. Only one species, the poorly studied Acer laurinum, is native to the Southern Hemisphere.[4] Fifty-four species of maples meet the International Union for Conservation of Nature criteria for being under threat of extinction in their native habitat.[4]
The word Acer derives from a Latin word meaning "sharp" (compare "acerbic"), referring to the characteristic points on maple leaves. It was first applied to the genus by the French botanist Joseph Pitton de Tournefort in 1700. The earliest known fossil maple is Acer alaskense, from the Latest Paleocene of Alaska. | https://www.wikidoc.org/index.php/Maple | |
8a6c5882997e0a1bb630d75fd962c23459fd43f1 | wikidoc | Marsh | Marsh
In geography, a marsh, or morass, is a type of wetland which is subject to frequent or continuous inundation. Typically a marsh features grasses, rushes, reeds, typhas, sedges, and other herbaceous plants (possibly with low-growing woody plants) in a context of shallow water. A marsh is different from a swamp, which has a greater proportion of open water surface, and is generally deeper than a marsh. In North America, the term swamp is used for wetland dominated by trees rather than grasses and low herbs.
The water of a marsh can be fresh, brackish or saline. Coastal marshes may be associated with estuaries and along waterways between coastal barrier islands and the inner coast. The estuarine marsh, or tidal marsh, is often based on soils consisting of sandy bottoms or bay muds. An example is the Tantramar Marsh of eastern Canada.
Below water decomposition processes often produce marsh gas, which may through self-ignition manifest as Will o' the wisps (aka. Jack-a-lanterns or spirites).
Marshes are critically important wildlife habitats, often serving as breeding grounds for a wide variety of animal life.
Constructed wetlands featuring surface-flow design are usually in the form of a marsh.
# Images
- Marsh in Point Pelee, Ontario, Canada
Marsh in Point Pelee, Ontario, Canada
- Marsh in Long Point, Ontario, Canada
Marsh in Long Point, Ontario, Canada | Marsh
Template:Otheruses4
In geography, a marsh, or morass, is a type of wetland which is subject to frequent or continuous inundation.[1] Typically a marsh features grasses, rushes, reeds, typhas, sedges, and other herbaceous plants (possibly with low-growing woody plants) in a context of shallow water. A marsh is different from a swamp, which has a greater proportion of open water surface, and is generally deeper than a marsh. In North America, the term swamp is used for wetland dominated by trees rather than grasses and low herbs.
The water of a marsh can be fresh, brackish or saline. Coastal marshes may be associated with estuaries and along waterways between coastal barrier islands and the inner coast. The estuarine marsh, or tidal marsh, is often based on soils consisting of sandy bottoms or bay muds. An example is the Tantramar Marsh of eastern Canada.
Below water decomposition processes often produce marsh gas, which may through self-ignition manifest as Will o' the wisps (aka. Jack-a-lanterns or spirites).
Marshes are critically important wildlife habitats, often serving as breeding grounds for a wide variety of animal life.
Constructed wetlands featuring surface-flow design are usually in the form of a marsh.
# Images
- Marsh in Point Pelee, Ontario, Canada
Marsh in Point Pelee, Ontario, Canada
- Marsh in Long Point, Ontario, Canada
Marsh in Long Point, Ontario, Canada | https://www.wikidoc.org/index.php/Marsh | |
3ca092217bf99fcf363cfe8018315c622c6cfbb8 | wikidoc | MeNZB | MeNZB
MeNZB is a vaccine against a specific strain of group B meningococcus, currently being used to control an epidemic of meningococcal disease in New Zealand. Most people are able to carry the meningococcus bacteria safely with no ill effects. However, meningococcal disease can cause meningitis and septicaemia, resulting in brain damage, failure of various organs, severe skin and soft-tissue damage, and death.
Immunisation with MeNZB requires three doses, administered approximately six weeks apart (except in newborns, who have them in conjunction with their 6-week, 3-month and 5-month injections). People who have been fully immunised may still carry the meningococcus bacteria and may still contract meningococcal disease.
Each dose is 0.5 ml and contains:
- 25 mcg of outer membrane vesicles from the Neisseria meningitidis group B strain NZ98/245
- 1.65 mg of aluminium hydroxide (an adjuvant)
- histidine (to stabilise the pH)
- normal saline
The vaccine does not contain any whole bacteria (alive or dead). The "outer membrane vesicles" it contains are a small part of the "skin" of the bacteria that let the immune system recognise and prepare for being infected with the real thing.
MeNZB vaccine does not contain any human, blood, or bovine (cow)products, egg products, neomycin or the preservative thiomersal (mercury). There are no live meningococcal bacteria in the vaccine and it is not possible to catch the disease or become a carrier of the disease from the vaccine.
The immune system will normally not mount an immune response to the outer membrane vesicles if they are presented alone. The presence of the adjuvant forces the immune system to respond to the membrane vesicles by acting to prevent their breakdown and elimination, while causing local tissue damage to provoke the desired immune reaction.
The histidine pH buffer is to ensure the vaccine stays as close as possible to the pH of human body fluids. This is to ensure the immune system does not waste time trying to neutralise the vaccine instead of responding to the outer membrane vesicles.
The saline (sterile salt and water) is also like packaging. It is required so that all of the above can be dissolved into a solution that can be injected. It is the same salinity (saltiness) as normal human body fluid.
The antigen in MeNZB is prepared from B:4:P1.7b,4 (NZ 98/254 ) N. meningitidis strain, grown in a fermentor. The bacteria are grown in a synthetic culture medium containing sugar, essential amino acids and essential elements such as iron and potassium. The fermentation does not use bovine or porcine products. The cellular outer membranes are extracted with the detergent deoxycholate, which kills the bacteria. Outer membrane vesicles are purified out of the culture medium by ultracentrifugation, stabilised by histidine and then adsorbed to aluminium hydroxide Al(OH)3 as an adjuvant. Purification is achieved by ultrafiltration/diafiltration.
Since its introduction the vaccine has had a dramatic impact on the epidemic.
The vaccine, originally developed in Norway was never released for widespread use in that country because the norwegian epidemic was finishing before it was released. However, Norwegian authorities never approved their variant of the vaccine for use on infants and babies. | MeNZB
MeNZB is a vaccine against a specific strain of group B meningococcus, currently being used to control an epidemic of meningococcal disease in New Zealand. Most people are able to carry the meningococcus bacteria safely with no ill effects. However, meningococcal disease can cause meningitis and septicaemia, resulting in brain damage, failure of various organs, severe skin and soft-tissue damage, and death.
Immunisation with MeNZB requires three doses, administered approximately six weeks apart (except in newborns, who have them in conjunction with their 6-week, 3-month and 5-month injections). People who have been fully immunised may still carry the meningococcus bacteria and may still contract meningococcal disease.
Each dose is 0.5 ml and contains:
- 25 mcg of outer membrane vesicles from the Neisseria meningitidis group B strain NZ98/245
- 1.65 mg of aluminium hydroxide (an adjuvant)
- histidine (to stabilise the pH)
- normal saline
The vaccine does not contain any whole bacteria (alive or dead). The "outer membrane vesicles" it contains are a small part of the "skin" of the bacteria that let the immune system recognise and prepare for being infected with the real thing.
MeNZB vaccine does not contain any human, blood, or bovine (cow)products, egg products, neomycin or the preservative thiomersal (mercury). There are no live meningococcal bacteria in the vaccine and it is not possible to catch the disease or become a carrier of the disease from the vaccine.
The immune system will normally not mount an immune response to the outer membrane vesicles if they are presented alone. The presence of the adjuvant forces the immune system to respond to the membrane vesicles by acting to prevent their breakdown and elimination, while causing local tissue damage to provoke the desired immune reaction.
The histidine pH buffer is to ensure the vaccine stays as close as possible to the pH of human body fluids. This is to ensure the immune system does not waste time trying to neutralise the vaccine instead of responding to the outer membrane vesicles.
The saline (sterile salt and water) is also like packaging. It is required so that all of the above can be dissolved into a solution that can be injected. It is the same salinity (saltiness) as normal human body fluid.
The antigen in MeNZB is prepared from B:4:P1.7b,4 (NZ 98/254 ) N. meningitidis strain, grown in a fermentor. The bacteria are grown in a synthetic culture medium containing sugar, essential amino acids and essential elements such as iron and potassium. The fermentation does not use bovine or porcine products. The cellular outer membranes are extracted with the detergent deoxycholate, which kills the bacteria. Outer membrane vesicles are purified out of the culture medium by ultracentrifugation, stabilised by histidine and then adsorbed to aluminium hydroxide Al(OH)3 as an adjuvant. Purification is achieved by ultrafiltration/diafiltration.
Since its introduction the vaccine has had a dramatic impact on the epidemic.[citation needed]
The vaccine, originally developed in Norway was never released for widespread use in that country because the norwegian epidemic was finishing before it was released. However, Norwegian authorities never approved their variant of the vaccine for use on infants and babies. | https://www.wikidoc.org/index.php/MeNZB | |
24abd3307057b704703fc6f7e676d3a98f7a325e | wikidoc | Thiol | Thiol
# Overview
In organic chemistry, a thiol is a compound that contains the functional group composed of a sulfur atom and a hydrogen atom (-SH). Being the sulfur analogue of an alcohol group (-OH), this functional group is referred to either as a thiol group or a sulfhydryl group. More traditionally, thiols are often referred to as mercaptans.
# Nomenclature
When a thiol group is a substituent on an alkane, there are several ways of naming the resulting thiol:
- The preferred method (used by the IUPAC) is to add the suffix -thiol to the name of the alkane. The method is nearly identical to naming an alcohol. Example: CH3SH would be methanethiol.
- An older method, the word mercaptan replaces alcohol in the name of the equivalent alcohol compound. Example: CH3SH would be methyl mercaptan. (CH3OH would be methyl alcohol)
- As a prefix, the term mercapto- is used. Example: mercaptopurine.
# Etymology
The term mercaptan comes from the Latin mercurius captans, meaning 'laying hold of mercury,' because the –SH group binds tightly to the element mercury.
# Physical Properties
## Odor
Many thiols are colorless liquids having an odor resembling that of garlic. The odor of thiols is often strong and repulsive, particularly for those of low molecular weight. Thiols bind strongly to skin proteins, and are responsible for the intolerable, persistent odor produced by the spraying of skunks. Natural gas distributors began adding various forms of pungent thiols, usually ethanethiol, to natural gas, which is naturally odorless, after the deadly 1937 New London School explosion in New London, Texas. Thiols are also responsible for a class of wine faults caused by an unintended reaction between sulfur and yeast. However, not all thiols have unpleasant odors. For example, grapefruit mercaptan, a monoterpenoid thiol, is responsible for the characteristic scent of grapefruit.
## Boiling points and solubility
Due to the small electronegativity difference between sulfur and hydrogen, an S-H bond is practically nonpolar covalent. Therefore, the S-H bond in the thiols have a lower dipole moment as compared to the alcohol's O-H bond. Thiols show little association by hydrogen bonding, with both water molecules and among themselves. Hence, they have lower boiling points and are less soluble in water and other polar solvents than alcohols of similar molecular weight. Thiols are as soluble and have similar boiling points to isomeric sulfides.
# Chemical Properties
## Synthesis
The methods used in making thiols are analogous to those used to make alcohols and ethers. The reactions are quicker and higher yielding because sulfur anions are better nucleophiles than oxygen atoms.
Thiols are formed when a halogenoalkane is heated with a solution of sodium hydrosulfide
In addition, disulfides can be readily reduced by reducing agents such as lithium aluminium hydride in dry ether to form two thiols.
## Reactions
The thiol group is the sulfur analog of the hydroxyl group (-OH) found in alcohols. Since sulfur and oxygen belong to the same periodic table group, they share some similar chemical bonding properties. Like alcohol, in general, the deprotonated form RS− (called a thiolate) is more chemically reactive than the protonated thiol form RSH
The chemistry of thiols is thus related to the chemistry of alcohols: thiols form thioethers, thioacetals and thioesters, which are analogous to ethers, acetals, and esters. Furthermore, a thiol group can react with an alkene to create a thioether. (In fact, biochemically, thiol groups may react with vinyl groups to form a thioether linkage.)
## Acidity
The sulfur atom of a thiol is quite nucleophilic, rather more so than the oxygen atom of an alcohol. The thiol group is fairly acidic with a usual pKa around 10 to 11. In the presence of a base, a thiolate anion is formed which is a very powerful nucleophile. The group and its corresponding anion are readily oxidized by reagents such as bromine to give an organic disulfide (R-S-S-R).
Oxidation by more powerful reagents such as sodium hypochlorite or hydrogen peroxide yield sulfonic acids (RSO3H).
# Biological importance
As the functional group of the amino acid cysteine, the thiol group plays an important role in biological systems. When the thiol groups of two cysteine residues (as in monomers or constituent units) are brought near each other in the course of protein folding, an oxidation reaction can create a cystine unit with a disulfide bond (-S-S-). Disulfide bonds can contribute to a protein's tertiary structure if the cysteines are part of the same peptide chain, or contribute to the quaternary structure of multi-unit proteins by forming fairly strong covalent bonds between different peptide chains. The heavy and light chains of antibodies are held together by disulfide bridges. Also, the kinks in curly hair are a product of cystine formation. Permanents take advantage of the oxidizability of cysteine residues. The chemicals used in hair straightening are reductants that reduce cystine disulfide bridges to free cysteine sulfhydryl groups, while chemicals used in hair curling are oxidants that oxidize cysteine sulfhydryl groups to form cystine disulfide bridges. Sulfhydryl groups in the active site of an enzyme can form noncovalent bonds with the enzyme's substrate as well, contributing to catalytic activity. Active site cysteine residues are the functional unit in cysteine proteases.
# Examples of thiols
- Methanethiol - CH3SH
- Ethanethiol - C2H5SH
- Coenzyme A
- Lipoamide
- Glutathione
- Cysteine
- Dithiothreitol/dithioerythritol (an epimeric pair)
- 2-Mercaptoindole | Thiol
# Overview
In organic chemistry, a thiol is a compound that contains the functional group composed of a sulfur atom and a hydrogen atom (-SH). Being the sulfur analogue of an alcohol group (-OH), this functional group is referred to either as a thiol group or a sulfhydryl group. More traditionally, thiols are often referred to as mercaptans.
# Nomenclature
When a thiol group is a substituent on an alkane, there are several ways of naming the resulting thiol:
- The preferred method (used by the IUPAC) is to add the suffix -thiol to the name of the alkane. The method is nearly identical to naming an alcohol. Example: CH3SH would be methanethiol.
- An older method, the word mercaptan replaces alcohol in the name of the equivalent alcohol compound. Example: CH3SH would be methyl mercaptan. (CH3OH would be methyl alcohol)
- As a prefix, the term mercapto- is used. Example: mercaptopurine.
# Etymology
The term mercaptan comes from the Latin mercurius captans, meaning 'laying hold of mercury,' because the –SH group binds tightly to the element mercury.
# Physical Properties
## Odor
Many thiols are colorless liquids having an odor resembling that of garlic. The odor of thiols is often strong and repulsive, particularly for those of low molecular weight. Thiols bind strongly to skin proteins, and are responsible for the intolerable, persistent odor produced by the spraying of skunks. Natural gas distributors began adding various forms of pungent thiols, usually ethanethiol, to natural gas, which is naturally odorless, after the deadly 1937 New London School explosion in New London, Texas. Thiols are also responsible for a class of wine faults caused by an unintended reaction between sulfur and yeast. However, not all thiols have unpleasant odors. For example, grapefruit mercaptan, a monoterpenoid thiol, is responsible for the characteristic scent of grapefruit.
## Boiling points and solubility
Due to the small electronegativity difference between sulfur and hydrogen, an S-H bond is practically nonpolar covalent. Therefore, the S-H bond in the thiols have a lower dipole moment as compared to the alcohol's O-H bond. Thiols show little association by hydrogen bonding, with both water molecules and among themselves. Hence, they have lower boiling points and are less soluble in water and other polar solvents than alcohols of similar molecular weight. Thiols are as soluble and have similar boiling points to isomeric sulfides.
# Chemical Properties
## Synthesis
The methods used in making thiols are analogous to those used to make alcohols and ethers. The reactions are quicker and higher yielding because sulfur anions are better nucleophiles than oxygen atoms.
Thiols are formed when a halogenoalkane is heated with a solution of sodium hydrosulfide
In addition, disulfides can be readily reduced by reducing agents such as lithium aluminium hydride in dry ether to form two thiols.
## Reactions
The thiol group is the sulfur analog of the hydroxyl group (-OH) found in alcohols. Since sulfur and oxygen belong to the same periodic table group, they share some similar chemical bonding properties. Like alcohol, in general, the deprotonated form RS− (called a thiolate) is more chemically reactive than the protonated thiol form RSH
The chemistry of thiols is thus related to the chemistry of alcohols: thiols form thioethers, thioacetals and thioesters, which are analogous to ethers, acetals, and esters. Furthermore, a thiol group can react with an alkene to create a thioether. (In fact, biochemically, thiol groups may react with vinyl groups to form a thioether linkage.)
## Acidity
The sulfur atom of a thiol is quite nucleophilic, rather more so than the oxygen atom of an alcohol. The thiol group is fairly acidic with a usual pKa around 10 to 11. In the presence of a base, a thiolate anion is formed which is a very powerful nucleophile. The group and its corresponding anion are readily oxidized by reagents such as bromine to give an organic disulfide (R-S-S-R).
Oxidation by more powerful reagents such as sodium hypochlorite or hydrogen peroxide yield sulfonic acids (RSO3H).
# Biological importance
As the functional group of the amino acid cysteine, the thiol group plays an important role in biological systems. When the thiol groups of two cysteine residues (as in monomers or constituent units) are brought near each other in the course of protein folding, an oxidation reaction can create a cystine unit with a disulfide bond (-S-S-). Disulfide bonds can contribute to a protein's tertiary structure if the cysteines are part of the same peptide chain, or contribute to the quaternary structure of multi-unit proteins by forming fairly strong covalent bonds between different peptide chains. The heavy and light chains of antibodies are held together by disulfide bridges. Also, the kinks in curly hair are a product of cystine formation. Permanents take advantage of the oxidizability of cysteine residues. The chemicals used in hair straightening are reductants that reduce cystine disulfide bridges to free cysteine sulfhydryl groups, while chemicals used in hair curling are oxidants that oxidize cysteine sulfhydryl groups to form cystine disulfide bridges. Sulfhydryl groups in the active site of an enzyme can form noncovalent bonds with the enzyme's substrate as well, contributing to catalytic activity. Active site cysteine residues are the functional unit in cysteine proteases.
# Examples of thiols
- Methanethiol - CH3SH
- Ethanethiol - C2H5SH
- Coenzyme A
- Lipoamide
- Glutathione
- Cysteine
- Dithiothreitol/dithioerythritol (an epimeric pair)
- 2-Mercaptoindole | https://www.wikidoc.org/index.php/Mercaptan | |
222c168e445a8f7f771c9ef2acd622e380c321fc | wikidoc | Metal | Metal
# Overview
In chemistry, a metal (Greek: Metallon) is an element that readily loses electrons to form positive ions (cations) and has metallic bonds between metal atoms. Metals form ionic bonds with non-metals. They are sometimes described as a lattice of positive ions surrounded by a cloud of delocalized electrons. The metals are one of the three groups of elements as distinguished by their ionization and bonding properties, along with the metalloids and nonmetals. On the periodic table, a diagonal line drawn from boron (B) to polonium (Po) separates the metals from the nonmetals. Most elements on this line are metalloids, sometimes called semi-metals; elements to the lower left are metals; elements to the upper right are nonmetals.
An alternative definition of metals is that they have overlapping conduction bands and valence bands in their electronic structure. This definition opens up the category for metallic polymers and other organic metals, which have been made by researchers and employed in high-tech devices. These synthetic materials often have the characteristic silvery-grey reflectiveness (luster) of elemental metals.
The traditional definition focuses on the bulk properties of metals. They tend to be lustrous, ductile, malleable, and good conductors of electricity, while nonmetals are generally brittle (if solid), lack luster, and are insulators.
# Chemical properties
Most metals are chemically reactive, reacting with oxygen in the air to form oxides over changing timescales (for example iron rusts over years and potassium burns in seconds). The alkali metals react quickest followed by the alkaline earth metals, found in the leftmost two groups of the periodic table.
Examples:
The transition metals take much longer to oxidize (such as iron, copper, zinc, nickel). Others, like palladium, platinum and gold, do not react with the atmosphere at all. Some metals form a barrier layer of oxide on their surface which cannot be penetrated by further oxygen molecules and thus retain their shiny appearance and good conductivity for many decades (like aluminium, some steels, and titanium). The oxides of metals are basic (as opposed to those of nonmetals, which are acidic), although this may be considered a rule of thumb, rather than a fact.
Painting, anodising or plating metals are good ways to prevent their corrosion. However, a more reactive metal in the electrochemical series must be chosen for coating, especially when chipping of the coating is expected. Water and the two metals form an electrochemical cell, and if the coating is less reactive than the coatee, the coating actually promotes corrosion.
# Physical properties
Traditionally, metals have certain characteristic physical properties: they are usually shiny (they have metallic luster), have a high density, are ductile and malleable, have a high melting point, are hard, are usually a solid at room temperature and conduct electricity, heat and sound well. While there are several metals that are low density, soft, and have low melting points, these (the alkali and alkaline earth metals) are extremely reactive, and are rarely encountered in their elemental, metallic form.
The electrical and thermal conductivity of metals originate from the fact that in the metallic bond the outer electrons of the metal atoms form a gas of nearly free electrons, moving as an electron gas in a background of positive charge formed by the ion cores. Good mathematical predictions for electrical conductivity, as well as the electrons' contribution to the heat capacity and heat conductivity of metals can be calculated from the free electron model, which does not take the detailed structure of the ion lattice into account.
When considering the exact band structure and binding energy of a metal, it is necessary to take into account the positive potential caused by the specific arrangement of the ion cores - which is periodic in crystals. The most important consequence of the periodic potential is the formation of a small band gap at the boundary of the brillouin zone. Mathematically, the potential of the ion cores is treated in the nearly-free electron model.
# Alloys
An alloy is a mixture of two or more elements in solid solution in which the major component is a metal. Most pure metals are either too soft, brittle or chemically reactive for practical use. Combining different ratios of metals as alloys modify the properties of pure metals to produce desirable characteristics. The aim of making alloys is generally to make them less brittle, harder, resistant to corrosion, or have a more desirable color and luster. Examples of alloys are steel (iron and carbon), brass (copper and zinc), bronze (copper and tin), and duralumin (aluminium and copper). Alloys specially designed for highly demanding applications, such as jet engines, may contain more than ten elements.
# Categories
## Base metal
In chemistry, the term 'base metal' is used informally to refer to a metal that oxidizes or corrodes relatively easily, and reacts variably with dilute hydrochloric acid (HCl) to form hydrogen. Examples include iron, nickel, lead and zinc. Copper is considered a base metal as it oxidizes relatively easily, although it does not react with HCl. It is commonly used in opposition to noble metal.
In alchemy, a base metal was a common and inexpensive metal, as opposed to precious metals, mainly gold and silver. A longtime goal of the alchemists was the transmutation of base metals into precious metals.
In numismatics, coins used to derive their value primarily from the precious metal content. Most modern currencies are fiat currency, allowing the coins to be made of base metal.
## Ferrous metal
The term "ferrous" is derived from the latin word meaning "containing iron". This can include pure iron, such as wrought iron, or an alloy such as steel. Ferrous metals are often magnetic, but not exclusively.
## Noble metal
Noble metals are metals that are resistant to corrosion or oxidation, unlike most base metals. They tend to be precious metals, often due to perceived rarity. Examples include tantalum, gold, platinum, and rhodium.
## Precious metal
A precious metal is a rare metallic chemical element of high economic value.
Chemically, the precious metals are less reactive than most elements, have high luster and high electrical conductivity. Historically, precious metals were important as currency, but are now regarded mainly as investment and industrial commodities. Gold, silver, platinum and palladium each have an ISO 4217 currency code. The best-known precious metals are gold and silver. While both have industrial uses, they are better known for their uses in art, jewelry, and coinage. Other precious metals include the platinum group metals: ruthenium, rhodium, palladium, osmium, iridium, and platinum, of which platinum is the most widely traded. Plutonium and uranium could also be considered precious metals.
The demand for precious metals is driven not only by their practical use, but also by their role as investments and a store of value. Palladium was, as of summer 2006, valued at a little under half the price of gold, and platinum at around twice that of gold. Silver is substantially less expensive than these metals, but is often traditionally considered a precious metal for its role in coinage and jewelry.
# Extraction
Metals are often extracted from the Earth by means of mining, resulting in ores that are relatively rich sources of the requisite elements. Ore is located by prospecting techniques, followed by the exploration and examination of deposits. Mineral sources are generally divided into surface mines, which are mined by excavation using heavy equipment, and subsurface mines.
Once the ore is mined, the metals must be extracted, usually by chemical or electrolytic reduction. Pyrometallurgy uses high temperatures to convert ore into raw metals, while hydrometallurgy employs aqueous chemistry for the same purpose. The methods used depend on the metal and their contaminants.
# Metallurgy
Metallurgy is a domain of materials science that studies the physical and chemical behavior of metallic elements, their intermetallic compounds, and their mixtures, which are called alloys.
# Applications
Some metals and metal alloys possess high structural strength per unit mass, making them useful materials for carrying large loads or resisting impact damage. Metal alloys can be engineered to have high resistance to shear, torque and deformation. However the same metal can also be vulnerable to fatigue damage through repeated use, or from sudden stress failure when a load capacity is exceeded. The strength and resilience of metals has led to their frequent use in high-rise building and bridge construction, as well as most vehicles, many appliances, tools, pipes, non-illuminated signs and railroad tracks.
Metals are good conductors, making them valuable in electrical appliances and for carrying an electric current over a distance with little energy lost. Electrical power grids rely on metal cables to distribute electricity. Home electrical systems, for the most part, are wired with copper wire for its good conducting properties.
The thermal conductivity of metal is useful for containers to heat materials over a flame. Metal is also used for heat sinks to protect sensitive equipment from overheating.
The high reflectivity of some metals is important in the construction of mirrors, including precision astronomical instruments. This last property can also make metallic jewelry aesthetically appealing.
Some metals have specialized uses; Radioactive metals such as Uranium and Plutonium are used in nuclear power plants to produce energy via nuclear fission. Mercury is a liquid at room temperature and is used in switches to complete a circuit when it flows over the switch contacts. Shape memory alloy is used for applications such as pipes, fasteners and vascular stents. However they are very good at conducting electricity and heat.
# Trade
The World Bank reports that China was the top importer of ores and metals in 2005 followed by the U.S.A. and Japan.
# Astronomy
In the specialised usage of astronomy and astrophysics, the term "metal" is often used to refer to any element other than hydrogen or helium, including substances as chemically non-metallic as neon, fluorine, and oxygen. Nearly all the hydrogen and helium in the Universe was created in Big Bang nucleosynthesis, whereas all the "metals" were produced by nucleosynthesis in stars or supernovae. The Sun and the Milky Way Galaxy are composed of roughly 70% hydrogen, 30% helium, and 2% "metals" by mass. | Metal
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In chemistry, a metal (Greek: Metallon) is an element that readily loses electrons to form positive ions (cations) and has metallic bonds between metal atoms. Metals form ionic bonds with non-metals. They are sometimes described as a lattice of positive ions surrounded by a cloud of delocalized electrons. The metals are one of the three groups of elements as distinguished by their ionization and bonding properties, along with the metalloids and nonmetals. On the periodic table, a diagonal line drawn from boron (B) to polonium (Po) separates the metals from the nonmetals. Most elements on this line are metalloids, sometimes called semi-metals; elements to the lower left are metals; elements to the upper right are nonmetals.
An alternative definition of metals is that they have overlapping conduction bands and valence bands in their electronic structure. This definition opens up the category for metallic polymers and other organic metals, which have been made by researchers and employed in high-tech devices. These synthetic materials often have the characteristic silvery-grey reflectiveness (luster) of elemental metals.
The traditional definition focuses on the bulk properties of metals. They tend to be lustrous, ductile, malleable, and good conductors of electricity, while nonmetals are generally brittle (if solid), lack luster, and are insulators.
# Chemical properties
Most metals are chemically reactive, reacting with oxygen in the air to form oxides over changing timescales (for example iron rusts over years and potassium burns in seconds). The alkali metals react quickest followed by the alkaline earth metals, found in the leftmost two groups of the periodic table.
Examples:
The transition metals take much longer to oxidize (such as iron, copper, zinc, nickel). Others, like palladium, platinum and gold, do not react with the atmosphere at all. Some metals form a barrier layer of oxide on their surface which cannot be penetrated by further oxygen molecules and thus retain their shiny appearance and good conductivity for many decades (like aluminium, some steels, and titanium). The oxides of metals are basic (as opposed to those of nonmetals, which are acidic), although this may be considered a rule of thumb, rather than a fact.
Painting, anodising or plating metals are good ways to prevent their corrosion. However, a more reactive metal in the electrochemical series must be chosen for coating, especially when chipping of the coating is expected. Water and the two metals form an electrochemical cell, and if the coating is less reactive than the coatee, the coating actually promotes corrosion.
# Physical properties
Traditionally, metals have certain characteristic physical properties: they are usually shiny (they have metallic luster), have a high density, are ductile and malleable, have a high melting point, are hard, are usually a solid at room temperature and conduct electricity, heat and sound well. While there are several metals that are low density, soft, and have low melting points, these (the alkali and alkaline earth metals) are extremely reactive, and are rarely encountered in their elemental, metallic form.
The electrical and thermal conductivity of metals originate from the fact that in the metallic bond the outer electrons of the metal atoms form a gas of nearly free electrons, moving as an electron gas in a background of positive charge formed by the ion cores. Good mathematical predictions for electrical conductivity, as well as the electrons' contribution to the heat capacity and heat conductivity of metals can be calculated from the free electron model, which does not take the detailed structure of the ion lattice into account.
When considering the exact band structure and binding energy of a metal, it is necessary to take into account the positive potential caused by the specific arrangement of the ion cores - which is periodic in crystals. The most important consequence of the periodic potential is the formation of a small band gap at the boundary of the brillouin zone. Mathematically, the potential of the ion cores is treated in the nearly-free electron model.
# Alloys
An alloy is a mixture of two or more elements in solid solution in which the major component is a metal. Most pure metals are either too soft, brittle or chemically reactive for practical use. Combining different ratios of metals as alloys modify the properties of pure metals to produce desirable characteristics. The aim of making alloys is generally to make them less brittle, harder, resistant to corrosion, or have a more desirable color and luster. Examples of alloys are steel (iron and carbon), brass (copper and zinc), bronze (copper and tin), and duralumin (aluminium and copper). Alloys specially designed for highly demanding applications, such as jet engines, may contain more than ten elements.
# Categories
## Base metal
In chemistry, the term 'base metal' is used informally to refer to a metal that oxidizes or corrodes relatively easily, and reacts variably with dilute hydrochloric acid (HCl) to form hydrogen. Examples include iron, nickel, lead and zinc. Copper is considered a base metal as it oxidizes relatively easily, although it does not react with HCl. It is commonly used in opposition to noble metal.
In alchemy, a base metal was a common and inexpensive metal, as opposed to precious metals, mainly gold and silver. A longtime goal of the alchemists was the transmutation of base metals into precious metals.
In numismatics, coins used to derive their value primarily from the precious metal content. Most modern currencies are fiat currency, allowing the coins to be made of base metal.
## Ferrous metal
The term "ferrous" is derived from the latin word meaning "containing iron". This can include pure iron, such as wrought iron, or an alloy such as steel. Ferrous metals are often magnetic, but not exclusively.
## Noble metal
Noble metals are metals that are resistant to corrosion or oxidation, unlike most base metals. They tend to be precious metals, often due to perceived rarity. Examples include tantalum, gold, platinum, and rhodium.
## Precious metal
A precious metal is a rare metallic chemical element of high economic value.
Chemically, the precious metals are less reactive than most elements, have high luster and high electrical conductivity. Historically, precious metals were important as currency, but are now regarded mainly as investment and industrial commodities. Gold, silver, platinum and palladium each have an ISO 4217 currency code. The best-known precious metals are gold and silver. While both have industrial uses, they are better known for their uses in art, jewelry, and coinage. Other precious metals include the platinum group metals: ruthenium, rhodium, palladium, osmium, iridium, and platinum, of which platinum is the most widely traded. Plutonium and uranium could also be considered precious metals.
The demand for precious metals is driven not only by their practical use, but also by their role as investments and a store of value. Palladium was, as of summer 2006, valued at a little under half the price of gold, and platinum at around twice that of gold. Silver is substantially less expensive than these metals, but is often traditionally considered a precious metal for its role in coinage and jewelry.
# Extraction
Metals are often extracted from the Earth by means of mining, resulting in ores that are relatively rich sources of the requisite elements. Ore is located by prospecting techniques, followed by the exploration and examination of deposits. Mineral sources are generally divided into surface mines, which are mined by excavation using heavy equipment, and subsurface mines.
Once the ore is mined, the metals must be extracted, usually by chemical or electrolytic reduction. Pyrometallurgy uses high temperatures to convert ore into raw metals, while hydrometallurgy employs aqueous chemistry for the same purpose. The methods used depend on the metal and their contaminants.
Template:Sect-stub
# Metallurgy
Metallurgy is a domain of materials science that studies the physical and chemical behavior of metallic elements, their intermetallic compounds, and their mixtures, which are called alloys.
# Applications
Some metals and metal alloys possess high structural strength per unit mass, making them useful materials for carrying large loads or resisting impact damage. Metal alloys can be engineered to have high resistance to shear, torque and deformation. However the same metal can also be vulnerable to fatigue damage through repeated use, or from sudden stress failure when a load capacity is exceeded. The strength and resilience of metals has led to their frequent use in high-rise building and bridge construction, as well as most vehicles, many appliances, tools, pipes, non-illuminated signs and railroad tracks.
Metals are good conductors, making them valuable in electrical appliances and for carrying an electric current over a distance with little energy lost. Electrical power grids rely on metal cables to distribute electricity. Home electrical systems, for the most part, are wired with copper wire for its good conducting properties.
The thermal conductivity of metal is useful for containers to heat materials over a flame. Metal is also used for heat sinks to protect sensitive equipment from overheating.
The high reflectivity of some metals is important in the construction of mirrors, including precision astronomical instruments. This last property can also make metallic jewelry aesthetically appealing.
Some metals have specialized uses; Radioactive metals such as Uranium and Plutonium are used in nuclear power plants to produce energy via nuclear fission. Mercury is a liquid at room temperature and is used in switches to complete a circuit when it flows over the switch contacts. Shape memory alloy is used for applications such as pipes, fasteners and vascular stents. However they are very good at conducting electricity and heat.
# Trade
The World Bank reports that China was the top importer of ores and metals in 2005 followed by the U.S.A. and Japan.
# Astronomy
In the specialised usage of astronomy and astrophysics, the term "metal" is often used to refer to any element other than hydrogen or helium, including substances as chemically non-metallic as neon, fluorine, and oxygen. Nearly all the hydrogen and helium in the Universe was created in Big Bang nucleosynthesis, whereas all the "metals" were produced by nucleosynthesis in stars or supernovae. The Sun and the Milky Way Galaxy are composed of roughly 70% hydrogen, 30% helium, and 2% "metals" by mass.[1] | https://www.wikidoc.org/index.php/Metal | |
c435c05258bd0a6f5aecb51eee151827a7bfd87d | wikidoc | Model | Model
# Overview
A model is a pattern, plan, representation, or description designed to show the structure or workings of an object, system, or concept. And also it is a study of a miniature of the actual.
Model may also refer to:
Abstractions, concepts, and theories:
- Model (abstract), an abstraction or conceptual object used in the creation of a predictive formula
- Causal model, an abstract model that uses cause and effect logic
- Mathematical model, an abstract model that uses mathematical language
- Computer model, a computer program which attempts to simulate an abstract model of a particular system
- Data model, a description of the structure of a database
- Model (economics)
- Scientific modelling, the process of generating abstract models
- An in vitro model of a biological process, used in biological or medical research
- Model Driven Engineering, the systematic use of models in engineering
- Molecular modelling, methods and techniques to model the behaviour of molecules
- Geologic modelling, the applied science of creating computerized models of geologic features
- Morphological modelling, a problem-solving technique used for problems with which causal modelling does not function well
- The Standard Model, the theory in particle physics which describes certain fundamental forces and particles
- Model building (particle physics), the construction of new models beyond the Standard Model in particle physics
- Meta-modeling, a model of a model
- Business model
- Model theory, study of the representation of mathematical concepts
- Similitude (model), in engineering, used in the scientific testing of physical models
- Working Model, engineering software.
As representations of objects:
- Model (physical), a physical representation of an object
- Solid modeling, study of unambiguous representations of the solid parts of an object
- Scale model, a replica or prototype of an object
- Model building, a hobby centered around construction of material replicas
- 3D model, a 3D polygonal representation of an object, usually displayed with a computer
In human and animal behavior
- An organism (or set of signals originating from it) that is mimicked by another.
- Mental model, a person's cognitive representation of an idea or thought process
- Modeling (NLP), a process in neuro-linguistic programming
- Modelling (psychology), learning by imitating or observing a person's behavior
- Role model, a person who serves as a behavioural or moral example to others
In occupations:
- Model (person), a person whose occupation is to function as a living prop, often to display products, e.g. a fashion model (see also supermodel) or promotional model.
- Model (art), a person who poses for purposes of art, for example in art school
- Fetish model, a model who wears the clothing and/or devices of sexual fetishes
In history and culture:
- Walther Model, German field marshal in World War II
- Movement for Democracy in Liberia, MoDeL
- Models (band), an alternative rock group from Australia
- Model (manhwa), a manhwa series by Lee So Young
- "Model," a song by Avail from their 1994 album Dixie
In lighting:
- Modeling means how a key light reveals the three dimensional form of a subject
- Modeling light,a continuous lightsource that visualizes the effect of a photographic flash
In geography:
- Model, Colorado, an unincorporated town in the United States
- Model (Poland) - a village in Poland in Masovia Voivodeship in gostyniński county in Pacyna commune | Model
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Template:Wiktionarypar
A model is a pattern, plan, representation, or description designed to show the structure or workings of an object, system, or concept. And also it is a study of a miniature of the actual.
Model may also refer to:
Abstractions, concepts, and theories:
- Model (abstract), an abstraction or conceptual object used in the creation of a predictive formula
- Causal model, an abstract model that uses cause and effect logic
- Mathematical model, an abstract model that uses mathematical language
- Computer model, a computer program which attempts to simulate an abstract model of a particular system
- Data model, a description of the structure of a database
- Model (economics)
- Scientific modelling, the process of generating abstract models
- An in vitro model of a biological process, used in biological or medical research
- Model Driven Engineering, the systematic use of models in engineering
- Molecular modelling, methods and techniques to model the behaviour of molecules
- Geologic modelling, the applied science of creating computerized models of geologic features
- Morphological modelling, a problem-solving technique used for problems with which causal modelling does not function well
- The Standard Model, the theory in particle physics which describes certain fundamental forces and particles
- Model building (particle physics), the construction of new models beyond the Standard Model in particle physics
- Meta-modeling, a model of a model
- Business model
- Model theory, study of the representation of mathematical concepts
- Similitude (model), in engineering, used in the scientific testing of physical models
- Working Model, engineering software.
As representations of objects:
- Model (physical), a physical representation of an object
- Solid modeling, study of unambiguous representations of the solid parts of an object
- Scale model, a replica or prototype of an object
- Model building, a hobby centered around construction of material replicas
- 3D model, a 3D polygonal representation of an object, usually displayed with a computer
In human and animal behavior
- An organism (or set of signals originating from it) that is mimicked by another.
- Mental model, a person's cognitive representation of an idea or thought process
- Modeling (NLP), a process in neuro-linguistic programming
- Modelling (psychology), learning by imitating or observing a person's behavior
- Role model, a person who serves as a behavioural or moral example to others
In occupations:
- Model (person), a person whose occupation is to function as a living prop, often to display products, e.g. a fashion model (see also supermodel) or promotional model.
- Model (art), a person who poses for purposes of art, for example in art school
- Fetish model, a model who wears the clothing and/or devices of sexual fetishes
In history and culture:
- Walther Model, German field marshal in World War II
- Movement for Democracy in Liberia, MoDeL
- Models (band), an alternative rock group from Australia
- Model (manhwa), a manhwa series by Lee So Young
- "Model," a song by Avail from their 1994 album Dixie
In lighting:
- Modeling means how a key light reveals the three dimensional form of a subject
- Modeling light,a continuous lightsource that visualizes the effect of a photographic flash
In geography:
- Model, Colorado, an unincorporated town in the United States
- Model (Poland) - a village in Poland in Masovia Voivodeship in gostyniński county in Pacyna commune | https://www.wikidoc.org/index.php/Model | |
a2ca7de922119c2e786c35c2deb8b86a7d50dfc3 | wikidoc | Moles | Moles
# Overview
Moles are growths on the skin. They happen when cells in the skin, called melanocytes, grow in a cluster with the surrounding tissue. Moles are very common. Most people have between 10 and 40 moles. A person may develop new moles from time to time, usually until about the age of 40.
Moles are usually pink, tan or brown. They can be flat or raised. They are usually round or oval and no larger than a pencil eraser.
About one out of every ten people has at least one unusual (or atypical) mole that looks different from an ordinary mole. The medical term for these unusual moles is dysplastic nevi. They may be more likely than ordinary moles to develop into melanoma, a type of skin cancer. Because of this, you should have a healthcare professional check your moles if they look unusual, grow larger, change in color or outline, or in any other way. | Moles
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]
# Overview
Moles are growths on the skin. They happen when cells in the skin, called melanocytes, grow in a cluster with the surrounding tissue. Moles are very common. Most people have between 10 and 40 moles. A person may develop new moles from time to time, usually until about the age of 40.
Moles are usually pink, tan or brown. They can be flat or raised. They are usually round or oval and no larger than a pencil eraser.
About one out of every ten people has at least one unusual (or atypical) mole that looks different from an ordinary mole. The medical term for these unusual moles is dysplastic nevi. They may be more likely than ordinary moles to develop into melanoma, a type of skin cancer. Because of this, you should have a healthcare professional check your moles if they look unusual, grow larger, change in color or outline, or in any other way. | https://www.wikidoc.org/index.php/Moles | |
e13a7eb63534c2acd9201189e75c613d5fc793fe | wikidoc | Mucin | Mucin
# Overview
Mucins are a family of large, heavily glycosylated proteins. Although some mucins are membrane-bound due to the presence of a hydrophobic membrane-spanning domain that favors retention in the plasma membrane, the concentration here is on those mucins that are secreted on mucosal surfaces and saliva.
# Glycosylation and aggregation
Mucin genes encode mucin monomers that are synthesized as rod-shape apomucin cores that are post-translationally modified by exceptionally abundant glycosylation.
The dense "sugar coating" of mucins gives them considerable water-holding capacity and also makes them resistant to proteolysis, which may be important in maintaining mucosal barriers.
Mucins are secreted as massive aggregates of proteins with molecular masses of roughly 1 to 10 million Da. Within these aggregates, monomers are linked to one another mostly by non-covalent interactions, although intermolecular disulfide bonds may also play a role in this process.
# Regions
Two distinctly different regions are found in mature mucins:
- The amino- and carboxy-terminal regions are very lightly glycosylated, but rich in cysteines, which are likely involved in establishing disulfide linkages within and among mucin monomers.
- A large central region formed of multiple tandem repeats of 10 to 80 residue sequences in which up to half of the amino acids are serine or threonine. This area becomes saturated with hundreds of O-linked oligosaccharides. N-linked oligosaccharides are also found on mucins, but much less abundantly.
# Genes
At least 19 human mucin genes have been distinguished by cDNA cloning--MUC1, 2, 3A, 3B, 4, 5AC, 5B, 6-9, 11-13, and 15-19.
The major secreted airway mucins are MUC5AC and MUC5B, while MUC2 is secreted mostly in the intestine but also in the airway.
# Clinical significance
Increased mucin production occurs in many adenocarcinomas, including cancer of the pancreas, lung, breast, ovary, colon, etc. Mucins are also overexpressed in lung diseases such as asthma, bronchitis, COPD or cystic fibrosis. Two membrane mucins, MUC1 and MUC4 have been extensively studied in relation to their pathological implication in the disease process. Moreover, mucins are also being investigated for their potential as diagnostic markers. | Mucin
# Overview
Mucins are a family of large, heavily glycosylated proteins. Although some mucins are membrane-bound due to the presence of a hydrophobic membrane-spanning domain that favors retention in the plasma membrane, the concentration here is on those mucins that are secreted on mucosal surfaces and saliva.
# Glycosylation and aggregation
Mucin genes encode mucin monomers that are synthesized as rod-shape apomucin cores that are post-translationally modified by exceptionally abundant glycosylation.
The dense "sugar coating" of mucins gives them considerable water-holding capacity and also makes them resistant to proteolysis, which may be important in maintaining mucosal barriers.
Mucins are secreted as massive aggregates of proteins with molecular masses of roughly 1 to 10 million Da. Within these aggregates, monomers are linked to one another mostly by non-covalent interactions, although intermolecular disulfide bonds may also play a role in this process.
# Regions
Two distinctly different regions are found in mature mucins:
- The amino- and carboxy-terminal regions are very lightly glycosylated, but rich in cysteines, which are likely involved in establishing disulfide linkages within and among mucin monomers.
- A large central region formed of multiple tandem repeats of 10 to 80 residue sequences in which up to half of the amino acids are serine or threonine. This area becomes saturated with hundreds of O-linked oligosaccharides. N-linked oligosaccharides are also found on mucins, but much less abundantly.
# Genes
At least 19 human mucin genes have been distinguished by cDNA cloning--MUC1, 2, 3A, 3B, 4, 5AC, 5B, 6-9, 11-13, and 15-19.
The major secreted airway mucins are MUC5AC and MUC5B, while MUC2 is secreted mostly in the intestine but also in the airway.
# Clinical significance
Increased mucin production occurs in many adenocarcinomas, including cancer of the pancreas, lung, breast, ovary, colon, etc. Mucins are also overexpressed in lung diseases such as asthma, bronchitis, COPD or cystic fibrosis. Two membrane mucins, MUC1 and MUC4 have been extensively studied in relation to their pathological implication in the disease process. Moreover, mucins are also being investigated for their potential as diagnostic markers. | https://www.wikidoc.org/index.php/Mucin | |
99f00247e374cdccd172282d2248db674edc8fcb | wikidoc | Mucus | Mucus
# Overview
Mucus is a slippery secretion of the lining of the mucous membranes in the body. It is a viscous colloid containing antiseptic enzymes (such as lysozyme) and immunoglobulins. Mucus is produced by goblet cells in the mucous membranes that cover the surfaces of the membranes. It is made up of mucins and inorganic salts suspended in water. Phlegm is a type of mucus that is restricted to the respiratory tract, while the term mucus refers to secretions of the nasal passages as well.Mucus can be found in your nose.
# Functions
Mucus serves many different functions within the processes in an animal's body:
## Respiratory system
In the respiratory system, mucus traps particles such as bacteria and dust, helping to prevent them from entering the body; this occurs especially in the nose. Mucus aids in the protection of the lungs by trapping foreign particles that enter the nose during normal breathing. Additionally, it prevents tissues from drying out.
Increased mucus production in the respiratory tract is a symptom of many common illnesses, such as the common cold. The presence of mucus in the nose and throat is normal, but increased quantities can impede comfortable breathing and must be cleared by blowing the nose or expectorating phlegm from the throat. Among the components of nasal mucus are tears.
Dried nasal mucus (vulgarly or colloquially called "snot", "booger(s)", "boogie(s)" (US) or "bogey" (UK)) is partially solidified mucus from the nose. Dried nasal mucus forms when the mucus traps dust and other particles in the air. Mucus dries around the particle and hardens, somewhat like a pearl forming in an oyster. Since catching foreign particles is one of the main functions of nasal mucus, the presence of dried nasal mucus is a good indicator of a properly functioning nose.
### Mucin
Mucus is produced by submucosal cells as well as goblet cells in the respiratory system. It consists of mucin, a highly glycosylated peptide. Upon stimulation, MARPKs (myrastine-alanine rich protein kinases) signal the binding of mucin filled vesicles to the plasma membrane. The fusion of the vesicles causes the release of the mucin, which as it exchanges Ca2+ for Na+ expands up to 600 fold. The result is a viscoelastic product of interwoven molecules called mucus.
## Digestive system
In the digestive system, mucus is used as a lubricant for materials which must pass over membranes, e.g., food passing down the esophagus. A layer of mucus along the inner walls of the stomach is vital to protect the cell linings of that organ from the highly acidic environment within it.
## Reproductive system
In the female reproductive system, cervical mucus prevents infection and helps the movement of the penis during sexual intercourse. When thin, cervical mucus helps the movement of spermatozoa. The consistency of cervical mucus varies depending on the stage of a woman's menstrual cycle. At ovulation cervical mucus is clear, runny, and conducive to sperm; post-ovulation, mucus becomes thicker and is more likely to block sperm.
In the male reproductive system, the seminal vesicles located behind the bladder contribute up to 60% of the total volume of the semen and contain mucus, amino acids, and fructose as the main energy source for the sperm.
## Nasal mucus
Nasal mucus is mucus produced by the nasal mucosa. It serves to protect the respiratory tract and trap foreign objects such as dust and pollen before they enter the remainder of the respiratory tract. Nasal mucus is produced continually, and most of it is swallowed unconsciously.
# Diseases involving mucus
Generally mucus is clear and thin, serving to filter air during inhalation. During times of infection, mucus can change color to yellow or green either as a result of trapped bacteria, or due to the body's reaction to viral infection.
In the case of bacterial infection, the bacterium becomes trapped in already clogged sinuses, breeding in the moist, nutrient-rich environment. In this case, the clogged sinuses are a result of some other condition (such as allergies) and the bacterial infection is secondary to this original cause. When two different colors of common bacteria become mixed (such as yellow Staphylococcus aureus and blue Pseudomonas aeruginosa) the resulting shade is often green. Antibiotics may be used fruitfully to treat the secondary infection in these cases, but will generally not help with the original cause.
In the case of a viral infection such as cold or flu, the first stage of infection causes the production of a clear, thin mucus in the nose or back of the throat. As the body begins to react to the virus (generally one to three days), mucus thickens and may turn yellow or green. In these cases, antibiotics will not be useful, and are a major source of misuse. Treatment is generally symptom-based; the only cure is to allow the immune system to fight off the virus over time.
## Cystic fibrosis
Cystic fibrosis is an inherited disease that affects the entire body, but symptoms begin mostly in the lungs with excess production of mucus which is difficult to expel.
# Cold weather and mucus
During cold weather, the cilia which normally sweep mucus away from the nostrils and towards the back of the throat (see respiratory epithelium) become sluggish or completely cease functioning. This results in mucus running down the nose and dripping (a runny nose). Mucus also thickens in cold weather; when an individual comes in from the cold, the mucus thaws and begins to run before the cilia begin to work again.
## As a medical symptom
Increased mucus production in the respiratory tract is a symptom of many common diseases, such as the common cold. The presence of mucus in the nose and throat is normal, but increased quantities can hinder comfortable breathing and may be cleared by blowing the nose or expectorating excess mucus from the back of the throat. Nasal mucus may also be removed by using traditional methods of nasal irrigation. Excess mucus, as with a cold or allergies may be treated cautiously with decongestant drugs. Excess mucus in the bronchial tubes, as which occurs in asthma or bronchitis, may be treated with anti-inflammatory drugs to reduce the mucus production. Thickening of mucus by decongestant drugs may produce problems of drainage and circumstances that promote infection. Mucus with any color other than clear or white is generally an indicator of an infection of the nasal mucosa or the paranasal sinus.
# Dried mucus
Dried mucus forms when the mucus traps dust and other particles in the air and becomes desiccated. Mucus dries around the particle and hardens into a solid or semi-solid sticky object, resulting in the particle's eventual expulsion from the body. Since catching foreign particles is one of the main functions of nasal mucus, the presence of dried mucus formations is a good indicator of a properly functioning nose (as opposed to a "runny nose", which can indicate illness).
## Rhinolith
A rhinolith is sometimes mistaken for dried mucus but is actually a medical condition caused by salt deposition with the nasal cavity.
## Slang terms
A "loogie" is a slang expression used in North America to refer to a mass of sputum that is ejected from the mouth after being expelled from the throat of a person with nasal congestion. The expression "hocking a loogie" refers to expelling the phlegm in an obviously noisy manner involving violent vibrations of the uvular, producing a low, guttural, rumbling sound. "Hock" (alternate spelling "hawk") is derived from the archaic word "hough," pronounced the same way, meaning to clear one's throat. The word "loogie" arose as early as 1970, and appears to be a conjunction of the older slang "lung-er" (meaning an expectoration or a tuberculosis patient) and the word "booger" or "boogie." This practice may have other names in other countries and within the medical community. In the UK, the mass can be referred to as a 'flob', a portmanteau of the phonetic pronunciation of phlegm and 'gob', a slang term for saliva.
A "snot rocket" is a slang term referencing the act of holding one nostril while forcefully exhaling through the other mucous filled nostril resulting in a "rocket"-like projection of mucus from the nose and sinuses. This is also known as a "dustman's flick", "air hanky", "farmer's blow", "nose gob" or "farmer's hanky" or more offensively as a "guinea hankerchief" and "dutch hanky."
Dried nasal mucus is often removed by nose-picking. The social taboos regarding nasal mucus have also led to a wide variety of slang terms for nasal mucus. These include "snot", or "snotter" (Scottish), for nasal mucus; and "boogers" (U.S.), "boogies" (U.S.), or "bogies" (UK) for dried nasal mucus. | Mucus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Mucus is a slippery secretion of the lining of the mucous membranes in the body. It is a viscous colloid containing antiseptic enzymes (such as lysozyme) and immunoglobulins. Mucus is produced by goblet cells in the mucous membranes that cover the surfaces of the membranes. It is made up of mucins and inorganic salts suspended in water. Phlegm is a type of mucus that is restricted to the respiratory tract, while the term mucus refers to secretions of the nasal passages as well.Mucus can be found in your nose.
# Functions
Mucus serves many different functions within the processes in an animal's body:
## Respiratory system
In the respiratory system, mucus traps particles such as bacteria and dust, helping to prevent them from entering the body; this occurs especially in the nose. Mucus aids in the protection of the lungs by trapping foreign particles that enter the nose during normal breathing. Additionally, it prevents tissues from drying out.
Increased mucus production in the respiratory tract is a symptom of many common illnesses, such as the common cold. The presence of mucus in the nose and throat is normal, but increased quantities can impede comfortable breathing and must be cleared by blowing the nose or expectorating phlegm from the throat. Among the components of nasal mucus are tears.
Dried nasal mucus (vulgarly or colloquially called "snot", "booger(s)", "boogie(s)" (US) or "bogey" (UK)) is partially solidified mucus from the nose. Dried nasal mucus forms when the mucus traps dust and other particles in the air. Mucus dries around the particle and hardens, somewhat like a pearl forming in an oyster. Since catching foreign particles is one of the main functions of nasal mucus, the presence of dried nasal mucus is a good indicator of a properly functioning nose.
### Mucin
Mucus is produced by submucosal cells as well as goblet cells in the respiratory system. It consists of mucin, a highly glycosylated peptide. Upon stimulation, MARPKs (myrastine-alanine rich protein kinases) signal the binding of mucin filled vesicles to the plasma membrane. The fusion of the vesicles causes the release of the mucin, which as it exchanges Ca2+ for Na+ expands up to 600 fold. The result is a viscoelastic product of interwoven molecules called mucus.
## Digestive system
In the digestive system, mucus is used as a lubricant for materials which must pass over membranes, e.g., food passing down the esophagus. A layer of mucus along the inner walls of the stomach is vital to protect the cell linings of that organ from the highly acidic environment within it.
## Reproductive system
In the female reproductive system, cervical mucus prevents infection and helps the movement of the penis during sexual intercourse. When thin, cervical mucus helps the movement of spermatozoa. The consistency of cervical mucus varies depending on the stage of a woman's menstrual cycle. At ovulation cervical mucus is clear, runny, and conducive to sperm; post-ovulation, mucus becomes thicker and is more likely to block sperm.
In the male reproductive system, the seminal vesicles located behind the bladder contribute up to 60% of the total volume of the semen and contain mucus, amino acids, and fructose as the main energy source for the sperm.
## Nasal mucus
Nasal mucus is mucus produced by the nasal mucosa. It serves to protect the respiratory tract and trap foreign objects such as dust and pollen before they enter the remainder of the respiratory tract. Nasal mucus is produced continually, and most of it is swallowed unconsciously.
# Diseases involving mucus
Generally mucus is clear and thin, serving to filter air during inhalation. During times of infection, mucus can change color to yellow or green either as a result of trapped bacteria, or due to the body's reaction to viral infection.
In the case of bacterial infection, the bacterium becomes trapped in already clogged sinuses, breeding in the moist, nutrient-rich environment. In this case, the clogged sinuses are a result of some other condition (such as allergies) and the bacterial infection is secondary to this original cause. When two different colors of common bacteria become mixed (such as yellow Staphylococcus aureus and blue Pseudomonas aeruginosa) the resulting shade is often green. Antibiotics may be used fruitfully to treat the secondary infection in these cases, but will generally not help with the original cause.
In the case of a viral infection such as cold or flu, the first stage of infection causes the production of a clear, thin mucus in the nose or back of the throat. As the body begins to react to the virus (generally one to three days), mucus thickens and may turn yellow or green. In these cases, antibiotics will not be useful, and are a major source of misuse. Treatment is generally symptom-based; the only cure is to allow the immune system to fight off the virus over time.
## Cystic fibrosis
Cystic fibrosis is an inherited disease that affects the entire body, but symptoms begin mostly in the lungs with excess production of mucus which is difficult to expel.
# Cold weather and mucus
During cold weather, the cilia which normally sweep mucus away from the nostrils and towards the back of the throat (see respiratory epithelium) become sluggish or completely cease functioning. This results in mucus running down the nose and dripping (a runny nose). Mucus also thickens in cold weather; when an individual comes in from the cold, the mucus thaws and begins to run before the cilia begin to work again.
## As a medical symptom
Increased mucus production in the respiratory tract is a symptom of many common diseases, such as the common cold. The presence of mucus in the nose and throat is normal, but increased quantities can hinder comfortable breathing and may be cleared by blowing the nose or expectorating excess mucus from the back of the throat. Nasal mucus may also be removed by using traditional methods of nasal irrigation. Excess mucus, as with a cold or allergies may be treated cautiously with decongestant drugs. Excess mucus in the bronchial tubes, as which occurs in asthma or bronchitis, may be treated with anti-inflammatory drugs to reduce the mucus production. Thickening of mucus by decongestant drugs may produce problems of drainage and circumstances that promote infection. Mucus with any color other than clear or white is generally an indicator of an infection of the nasal mucosa or the paranasal sinus.
# Dried mucus
Dried mucus forms when the mucus traps dust and other particles in the air and becomes desiccated. Mucus dries around the particle and hardens into a solid or semi-solid sticky object, resulting in the particle's eventual expulsion from the body. Since catching foreign particles is one of the main functions of nasal mucus, the presence of dried mucus formations is a good indicator of a properly functioning nose (as opposed to a "runny nose", which can indicate illness).
## Rhinolith
A rhinolith is sometimes mistaken for dried mucus but is actually a medical condition caused by salt deposition with the nasal cavity.
## Slang terms
A "loogie" is a slang expression used in North America to refer to a mass of sputum that is ejected from the mouth after being expelled from the throat of a person with nasal congestion. The expression "hocking a loogie" refers to expelling the phlegm in an obviously noisy manner involving violent vibrations of the uvular, producing a low, guttural, rumbling sound. "Hock" (alternate spelling "hawk") is derived from the archaic word "hough," pronounced the same way, meaning to clear one's throat. The word "loogie" arose as early as 1970, and appears to be a conjunction of the older slang "lung-er" (meaning an expectoration or a tuberculosis patient) and the word "booger" or "boogie." This practice may have other names in other countries and within the medical community. In the UK, the mass can be referred to as a 'flob', a portmanteau of the phonetic pronunciation of phlegm and 'gob', a slang term for saliva.
A "snot rocket" is a slang term referencing the act of holding one nostril while forcefully exhaling through the other mucous filled nostril resulting in a "rocket"-like projection of mucus from the nose and sinuses. This is also known as a "dustman's flick", "air hanky", "farmer's blow", "nose gob" or "farmer's hanky" or more offensively as a "guinea hankerchief" and "dutch hanky."
Dried nasal mucus is often removed by nose-picking. The social taboos regarding nasal mucus have also led to a wide variety of slang terms for nasal mucus. These include "snot", or "snotter" (Scottish), for nasal mucus; and "boogers" (U.S.), "boogies" (U.S.), or "bogies" (UK) for dried nasal mucus. | https://www.wikidoc.org/index.php/Mucinous | |
26e60292c28178f54e2fed3ebe25fb0225610779 | wikidoc | Spasm | Spasm
A spasm is a sudden, involuntary contraction of a muscle, a group of muscles, or a hollow organ, or a similarly sudden contraction of an orifice. It is sometimes accompanied by a sudden burst of pain, but is usually harmless and ceases after a few minutes. Spasmodic muscle contraction may also be due to a large number of medical conditions, however, including the dystonias.
By extension, a spasm is also a sudden and temporary burst of energy, activity, or emotion.
A subtype of spasms is colic, an episodic pain due to spasms of smooth muscle in a particular organ (e.g. the bile duct). A characteristic of colic is the sensation of having to move about, and the pain may induce nausea or vomiting if severe. Series of spasms or permanent spasms are called a spasmism.
In very severe cases, the spasm can induce muscular contractions that are more forceful than the sufferer could generate under normal circumstances. This can lead to torn tendons and ligaments.
Some argue that hysterical strength is a type of spasm induced by the brain under extreme circumstances.
# Causes
## Drug Side Effect
- Eribulin
- Ixabepilone
- Lacosamide
- Ospemifene
- Ramucirumab
- Tiagabine | Spasm
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A spasm is a sudden, involuntary contraction of a muscle, a group of muscles, or a hollow organ, or a similarly sudden contraction of an orifice. It is sometimes accompanied by a sudden burst of pain, but is usually harmless and ceases after a few minutes. Spasmodic muscle contraction may also be due to a large number of medical conditions, however, including the dystonias.
By extension, a spasm is also a sudden and temporary burst of energy, activity, or emotion.
A subtype of spasms is colic, an episodic pain due to spasms of smooth muscle in a particular organ (e.g. the bile duct). A characteristic of colic is the sensation of having to move about, and the pain may induce nausea or vomiting if severe. Series of spasms or permanent spasms are called a spasmism.
In very severe cases, the spasm can induce muscular contractions that are more forceful than the sufferer could generate under normal circumstances. This can lead to torn tendons and ligaments.
Some argue that hysterical strength is a type of spasm induced by the brain under extreme circumstances.
## Causes
### Drug Side Effect
- Eribulin
- Ixabepilone
- Lacosamide
- Ospemifene
- Ramucirumab
- Tiagabine | https://www.wikidoc.org/index.php/Muscle_spasms | |
b9ef3e5d9531ca02194713d290b17e53f55ec6f1 | wikidoc | N-Myc | N-Myc
N-myc proto-oncogene protein also known as N-Myc or basic helix-loop-helix protein 37 (bHLHe37), is a protein that in humans is encoded by the MYCN gene.
# Function
The MYCN gene is a member of the MYC family of transcription factors and encodes a protein with a basic helix-loop-helix (bHLH) domain. This protein is located in the cell nucleus and must dimerize with another bHLH protein in order to bind DNA. N-Myc is highly expressed in the fetal brain and is critical for normal brain development.
The MYCN gene has an antisense RNA, N-cym or MYCNOS, transcribed from the opposite strand which can be translated to form a protein product. N-Myc and MYCNOS are co-regulated both in normal development and in tumor cells, so it is possible that the two transcripts are functionally related. It has been shown that the antisense RNA encodes for a protein, named NCYM, that has originated de novo and is specific to human and chimpanzee. This NCYM protein inhibits GSK3b and thus prevents MYCN degradation. Transgenic mice that harbor human MYCN/NCYM pair often show neuroblastomas with distant metastasis, which are atypical for normal mice. Thus NCYM represents a rare example of a de novo gene that has acquired molecular function and plays a major role in oncogenesis.
# Clinical significance
Amplification and overexpression of N-Myc can lead to tumorigenesis. Excess N-Myc is associated with a variety of tumors, most notably neuroblastomas where patients with amplification of the N-Myc gene tend to have poor outcomes. MYCN can also be activated in neuroblastoma and other cancers through somatic mutation.
# Interactions
N-Myc has been shown to interact with MAX.
N-Myc is also stabilized by aurora A which protects it from degradation. Drugs that target this interaction are under development, and are designed to change the conformation of aurora A. Conformational change in Aurora A leads to release of N-Myc, which is then degraded in a ubiquitin-dependent manner. | N-Myc
N-myc proto-oncogene protein also known as N-Myc or basic helix-loop-helix protein 37 (bHLHe37), is a protein that in humans is encoded by the MYCN gene.
# Function
The MYCN gene is a member of the MYC family of transcription factors and encodes a protein with a basic helix-loop-helix (bHLH) domain. This protein is located in the cell nucleus and must dimerize with another bHLH protein in order to bind DNA.[1] N-Myc is highly expressed in the fetal brain and is critical for normal brain development.[2]
The MYCN gene has an antisense RNA, N-cym or MYCNOS, transcribed from the opposite strand which can be translated to form a protein product.[3] N-Myc and MYCNOS are co-regulated both in normal development and in tumor cells, so it is possible that the two transcripts are functionally related.[4] It has been shown that the antisense RNA encodes for a protein, named NCYM, that has originated de novo and is specific to human and chimpanzee. This NCYM protein inhibits GSK3b and thus prevents MYCN degradation. Transgenic mice that harbor human MYCN/NCYM pair often show neuroblastomas with distant metastasis, which are atypical for normal mice. Thus NCYM represents a rare example of a de novo gene that has acquired molecular function and plays a major role in oncogenesis.[5]
# Clinical significance
Amplification and overexpression of N-Myc can lead to tumorigenesis. Excess N-Myc is associated with a variety of tumors, most notably neuroblastomas where patients with amplification of the N-Myc gene tend to have poor outcomes.[6][7][8] MYCN can also be activated in neuroblastoma and other cancers through somatic mutation.[9]
# Interactions
N-Myc has been shown to interact with MAX.[10][11]
N-Myc is also stabilized by aurora A which protects it from degradation.[12] Drugs that target this interaction are under development, and are designed to change the conformation of aurora A. Conformational change in Aurora A leads to release of N-Myc, which is then degraded in a ubiquitin-dependent manner.[13] | https://www.wikidoc.org/index.php/N-Myc | |
c13631334f3da8ea08a3a7ec846956867b29eb75 | wikidoc | NAA15 | NAA15
N-alpha-acetyltransferase 15, NatA auxiliary subunit also known as gastric cancer antigen Ga19 (GA19), NMDA receptor-regulated protein 1 (NARG1), and Tbdn100 is a protein that in humans is encoded by the NAA15 gene. NARG1 is the auxiliary subunit of the NatA (Nα-acetyltransferase A) complex.
This NatA complex can associate with the ribosome and catalyzes the transfer of an acetyl group to the Nα-terminal amino group of proteins as they emerge from the exit tunnel.
# Gene and transcripts
Human NAA15 is located on chromosome 4q31.1 and contains 23 exons. Initially, 2 mRNA species were identified, of size 4.6 and 5.8 kb, both harboring the same open reading frame encoding a putative protein of 866 amino acids (~105 kDa) protein that can be detected in most human adult tissues. According to RefSeq/NCBI, only one human transcript variant exists, although 2 more isoforms are predicted. In addition to full length Naa15, an N-terminally truncated variant of Naa15 (named tubedown-1), Naa15273-865 has been described; however, in mouse only full length Naa15 is widely expressed, whereas smaller transcripts seem to visualized only in heart and testis.
In addition to this, a NAA15 gene duplication, NAA16, has been identified, and the encoded protein shares 70% sequence identity to hNaa15 and is expressed in a variety of human cell lines, but is generally less abundant as compared to hNaa15. Three isoforms of Naa16 are validated so far (NCBI RefSeq). Mouse NAA15 is located on chromosome 2 D and contains 20 exons, whereas mouse NAA16 is located on chromosome 14 D3 and consists of 21 exons.
In principle, NatA can assemble from all the Naa10 and Naa15 isoforms in human and mouse, creating a more complex and flexible system for Nα-terminal acetylation as compared to lower eukaryotes.
# Structure
The X-ray crystal structure of the holo-NatA complex (Naa10/Naa15) from S. pombe revealed that Naa15 is composed of 13 conserved helical bundle tetratricopeptide repeat (TPR) motifs and adopts a ring-like topology that wraps around the catalytic subunit of NatA, Naa10.
This interaction induces conformational changes in the catalytic center of Naa10 that allows the acetylation of conventional NatA substrates. The crystal structure of human NatA bound to the protein HYPK has also been solved.
Because TPR motifs mediate protein–protein interactions, it has been postulated that this domain may facilitate the interaction with other NatA-binding partners such as the ribosome and Naa50/NatE.
Naa15 harbors a putative NLS between residues 612-628 (KKNAEKEKQQRNQKKKK); however, analysis of the nuclear localization of Naa15 revealed discrepant results.
# Function
Naa15, together with its catalytic subunit Naa10, constitutes the evolutionarily conserved NatA (Nα-acetyltransferase A) complex, which acetylates the α-amino group of the first amino acid residue of proteins starting with small side chains like serine, glycine, alanine, threonine and cysteine, after the initiator methionine has been cleaved by methionine aminopeptidases.
Both, Naa15 and Naa16 interact with the ribosome in yeast (via the ribosomal proteins, uL23 and uL29), humans and rat, thereby linking the NatA/Naa10 to the ribosome and facilitating co-translational acetylation of nascent polypeptide chains as they emerges from the exit tunnel. Furthermore, Naa15 might act as a scaffold for other factors, including the chaperone like protein HYPK (Huntingtin Interacting Protein K) and Naa50, the catalytic acetyltransferase subunit of NatE
In S. cerevisiae, NAA15Δ and NAA10Δ knockout cells exhibit the same phenotype, and biochemical data indicate that uncomplexed Naa15 is unstable and gets degraded. Therefore, Naa15 function has been closely linked to the acetyltransferase activity of Naa10 as part of the NatA complex.
NatA may also regulate co-translational protein folding and protein targeting to the endoplasmic reticulum, possibly through competition with SRP and NAC for the same ribosomal binding sites or through yet unknown interference with other ribosome-associated protein biogenesis factors, such as the MetAPs, the chaperones Hsp70/Hsp40, SRP and NAC, which act on newly synthesized proteins as soon as they emerge from the ribosome exit tunnel. However, the exact mechanism of such action is obscure. Apart from this, Naa15 has been linked to many cellular processes, including the maintenance of a healthy retina, endothelial cell permeability, tumor progression, generation and differentiation of neurons apoptosis and transcriptional regulation; however, it is not well understood whether these are NatA-independent or -dependent functions of Naa15.
# Disease
Two damaging de novo NAA15 mutations were reported by exome sequencing in parent-offspring trios with congenital heart disease. Patient 1 harbors a frameshift mutation (p. Lys335fs) and displays heterotaxy (dextrocardia, total anomalous pulmonary venous return, left superior vena cava, hypoplastic TV, double outlet right ventricle, hypoplastic RV, D-transposition of the great arteries, pulmonic stenosis) and hydronephrosis, asplenia, malrotation and abnormal neuro-development, the second patient harbors a nonsense mutation (p.S761X) and displays conotruncal defects (tetralogy of Fallot, single left coronary artery).
# Notes | NAA15
N-alpha-acetyltransferase 15, NatA auxiliary subunit also known as gastric cancer antigen Ga19 (GA19), NMDA receptor-regulated protein 1 (NARG1), and Tbdn100 is a protein that in humans is encoded by the NAA15 gene.[1] NARG1 is the auxiliary subunit of the NatA (Nα-acetyltransferase A) complex.
This NatA complex can associate with the ribosome and catalyzes the transfer of an acetyl group to the Nα-terminal amino group of proteins as they emerge from the exit tunnel.
# Gene and transcripts
Human NAA15 is located on chromosome 4q31.1 and contains 23 exons. Initially, 2 mRNA species were identified, of size 4.6 and 5.8 kb, both harboring the same open reading frame encoding a putative protein of 866 amino acids (~105 kDa) protein that can be detected in most human adult tissues.[1] According to RefSeq/NCBI, only one human transcript variant exists, although 2 more isoforms are predicted.[2] In addition to full length Naa15, an N-terminally truncated variant of Naa15 (named tubedown-1), Naa15273-865 has been described; however, in mouse only full length Naa15 is widely expressed, whereas smaller transcripts seem to visualized only in heart and testis.[3][4]
In addition to this, a NAA15 gene duplication, NAA16, has been identified, and the encoded protein shares 70% sequence identity to hNaa15 and is expressed in a variety of human cell lines, but is generally less abundant as compared to hNaa15.[5] Three isoforms of Naa16 are validated so far (NCBI RefSeq). Mouse NAA15 is located on chromosome 2 D and contains 20 exons, whereas mouse NAA16 is located on chromosome 14 D3 and consists of 21 exons.
In principle, NatA can assemble from all the Naa10 and Naa15 isoforms in human and mouse, creating a more complex and flexible system for Nα-terminal acetylation as compared to lower eukaryotes.[5][6][7]
# Structure
The X-ray crystal structure of the holo-NatA complex (Naa10/Naa15) from S. pombe revealed that Naa15 is composed of 13 conserved helical bundle tetratricopeptide repeat (TPR) motifs and adopts a ring-like topology that wraps around the catalytic subunit of NatA, Naa10.[8]
This interaction induces conformational changes in the catalytic center of Naa10 that allows the acetylation of conventional NatA substrates.[8] The crystal structure of human NatA bound to the protein HYPK has also been solved.[9]
Because TPR motifs mediate protein–protein interactions, it has been postulated that this domain may facilitate the interaction with other NatA-binding partners such as the ribosome and Naa50/NatE.[8]
Naa15 harbors a putative NLS between residues 612-628 (KKNAEKEKQQRNQKKKK); however, analysis of the nuclear localization of Naa15 revealed discrepant results.[4][10]
# Function
Naa15, together with its catalytic subunit Naa10, constitutes the evolutionarily conserved NatA (Nα-acetyltransferase A) complex, which acetylates the α-amino group of the first amino acid residue of proteins starting with small side chains like serine, glycine, alanine, threonine and cysteine, after the initiator methionine has been cleaved by methionine aminopeptidases.[10][11][12][13][14][15][16]
Both, Naa15 and Naa16 interact with the ribosome in yeast (via the ribosomal proteins, uL23 and uL29), humans and rat, thereby linking the NatA/Naa10 to the ribosome and facilitating co-translational acetylation of nascent polypeptide chains as they emerges from the exit tunnel.[5][17][18][19][20][21] Furthermore, Naa15 might act as a scaffold for other factors, including the chaperone like protein HYPK (Huntingtin Interacting Protein K) and Naa50, the catalytic acetyltransferase subunit of NatE[18][19][22][23]
In S. cerevisiae, NAA15Δ and NAA10Δ knockout cells exhibit the same phenotype, and biochemical data indicate that uncomplexed Naa15 is unstable and gets degraded.[8][24][25][26] Therefore, Naa15 function has been closely linked to the acetyltransferase activity of Naa10 as part of the NatA complex.
NatA may also regulate co-translational protein folding and protein targeting to the endoplasmic reticulum, possibly through competition with SRP and NAC for the same ribosomal binding sites or through yet unknown interference with other ribosome-associated protein biogenesis factors, such as the MetAPs, the chaperones Hsp70/Hsp40, SRP and NAC, which act on newly synthesized proteins as soon as they emerge from the ribosome exit tunnel.[17][20][27][28][29][30][31] However, the exact mechanism of such action is obscure. Apart from this, Naa15 has been linked to many cellular processes, including the maintenance of a healthy retina,[32][33][34] endothelial cell permeability,[34] tumor progression,[1][35] generation and differentiation of neurons[11][36][37] apoptosis[5][38] and transcriptional regulation;[4] however, it is not well understood whether these are NatA-independent or -dependent functions of Naa15.
# Disease
Two damaging de novo NAA15 mutations were reported by exome sequencing in parent-offspring trios with congenital heart disease.[39] Patient 1 harbors a frameshift mutation (p. Lys335fs) and displays heterotaxy (dextrocardia, total anomalous pulmonary venous return, left superior vena cava, hypoplastic TV, double outlet right ventricle, hypoplastic RV, D-transposition of the great arteries, pulmonic stenosis) and hydronephrosis, asplenia, malrotation and abnormal neuro-development, the second patient harbors a nonsense mutation (p.S761X) and displays conotruncal defects (tetralogy of Fallot, single left coronary artery).
# Notes | https://www.wikidoc.org/index.php/NAA15 | |
ec481c318232e4b7623a8e6911982193929456dc | wikidoc | NAGLU | NAGLU
N-acetylglucosaminidase, alpha is a protein that in humans is encoded by the NAGLU gene.
# Function
This gene encodes an enzyme that degrades heparan sulfate by hydrolysis of terminal N-acetyl-D-glucosamine residues in N-acetyl-alpha-D-glucosaminides.
# Clinical significance
Defects in this gene are the cause of mucopolysaccharidosis type IIIB (MPS-IIIB), also known as Sanfilippo syndrome B. This disease is characterized by the lysosomal accumulation and urinary excretion of heparan sulfate. | NAGLU
N-acetylglucosaminidase, alpha is a protein that in humans is encoded by the NAGLU gene.[1]
# Function
This gene encodes an enzyme that degrades heparan sulfate by hydrolysis of terminal N-acetyl-D-glucosamine residues in N-acetyl-alpha-D-glucosaminides.
# Clinical significance
Defects in this gene are the cause of mucopolysaccharidosis type IIIB (MPS-IIIB), also known as Sanfilippo syndrome B. This disease is characterized by the lysosomal accumulation and urinary excretion of heparan sulfate.[1] | https://www.wikidoc.org/index.php/NAGLU | |
ccaeeebcd1aa62469bd2cd03ac52c5a8f0a5b747 | wikidoc | NALP3 | NALP3
NACHT, LRR and PYD domains-containing protein 3 (NALP3), also known as cryopyrin, is a protein that in humans is encoded by the NLRP3 gene located on the long arm of chromosome 1.
NALP3 is expressed predominantly in macrophages and as a component of the inflammasome,:436 detects products of damaged cells such as extracellular ATP and crystalline uric acid. Activated NALP3 in turn triggers an immune response. Mutations in the NLRP3 gene are associated with a number of organ specific autoimmune diseases.
# Nomenclature
NACHT, LRR, and PYD are respectively acronyms for:
- NACHT – NAIP (neuronal apoptosis inhibitor protein), C2TA [class 2 transcription activator, of the MHC, HET-E (heterokaryon incompatibility) and TP1 (telomerase-associated protein 1)
- LRR – "leucine-rich repeat" and is synonymous with NLR, for or nucleotide-binding domain, leucine-rich repeat"
- PYD – "PYRIN domain," after the pyrin proteins The NLRP3 gene name abbreviates "NLR family, pyrin domain containing 3," where NLR refers to "nucleotide-binding domain, leucine-rich repeat."
The NACHT, LRR and PYD domains-containing protein 3 is also called:
- cold induced autoinflammatory syndrome 1 (CIAS1),
- caterpiller-like receptor 1.1 (CLR1.1), and
- PYRIN-containing APAF1-like protein 1 (PYPAF1).
# Structure
This gene encodes a pyrin-like protein which contains a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. This protein interacts with pyrin domain (PYD) of apoptosis-associated speck-like protein containing a CARD (ASC). Proteins which contain the caspase recruitment domain, CARD, have been shown to be involved in inflammation and immune response.
# Function
NALP3 is a component of the innate immune system that functions as a pathogen recognition receptor (PRR) that recognizes pathogen-associated molecular patterns (PAMPs). NALP3 belongs to the NOD-like receptor (NLR) subfamily of PRRs and NALP3 together with the adaptor ASC protein PYCARD forms a caspase-1 activating complex known as the NALP3 inflammasome. NALP3 in the absence of activating signal is kept in an inactive state complexed with HSP90 and SGT1 in the cytoplasm. NALP3 inflammasome detects danger signals such as crystalline uric acid and extracellular ATP released by damaged cells. These signals release HSP90 and SGT1 from and recruit ASC protein and caspase-1 to the inflammasome complex. Caspase-1 within the activated NALP3 inflammasome complex in turn activates the inflammatory cytokine, IL-1β.
The NALP3 inflammasome appears to be activated by changes in intracellular potassium caused by potassium efflux from mechanosensitive ion channels located in the cell membrane. It appears that NALP3 is also regulated by reactive oxygen species (ROS), though the precise mechanisms of such regulation has not been determined.
# Pathology
Mutations in the NLRP3 gene have been associated with a spectrum of dominantly inherited autoinflammatory diseases called cryopyrin-associated periodic syndrome (CAPS). This includes familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, neonatal onset multisystem inflammatory disease (NOMID), and keratoendotheliitis fugax hereditaria.
Defects in this gene have also been linked to familial Mediterranean fever. In addition, the NALP3 inflammasome has a role in the pathogenesis of gout and neuroinflammation occurring in protein-misfolding diseases, such as Alzheimer's, Parkinson's, and prion diseases. Amelioration of mouse models of many diseases has been shown to occur by deletion of the NLRP3 inflammasome, including gout, type 2 diabetes, multiple sclerosis, Alzheimer's disease, and atherosclerosis. The ketone β-Hydroxybutyrate has been shown to block NLRP3 activation, and thus may be of benefit for many of these diseases.
Deregulation of NALP3 has been connected with carcinogenesis. For example, all the components of the NALP3 inflammasome are downregulated or completely lost in human hepatocellular carcinoma.
# References and notes
- ↑ Jump up to: 1.0 1.1 1.2 Anon. (2015). "Entrez Gene: NLRP3 NLR family, pyrin domain containing 3 , Gene ID: 114548 (updated on 13-Nov-2015)". Bethesda, MD, USA: National Center for Biotechnology Information, National Library of Medicine. Retrieved 13 November 2015..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}
- ↑ Hoffman HM, Wright FA, Broide DH, Wanderer AA, Kolodner RD (May 2000). "Identification of a locus on chromosome 1q44 for familial cold urticaria". American Journal of Human Genetics. 66 (5): 1693–8. doi:10.1086/302874. PMC 1378006. PMID 10741953.
- ↑ Tao JH, Zhang Y, Li XP (Dec 2013). "P2X7R: a potential key regulator of acute gouty arthritis". review. Seminars in Arthritis and Rheumatism. 43 (3): 376–80. doi:10.1016/j.semarthrit.2013.04.007. PMID 23786870.
- ↑ Lu A, Wu H (Feb 2015). "Structural mechanisms of inflammasome assembly". review. The FEBS Journal. 282 (3): 435–44. doi:10.1111/febs.13133. PMID 25354325.
- ↑ Koonin EV, Aravind L (May 2000). "The NACHT family - a new group of predicted NTPases implicated in apoptosis and MHC transcription activation". Trends in Biochemical Sciences. 25 (5): 223–4. doi:10.1016/S0968-0004(00)01577-2. PMID 10782090.
- ↑ Pueyo I, Jiménez JR, Hernández J, Brugarolas A, García-Morán M, García-Muñiz JL, Arroyo F (Sep 1978). "Carcinoid syndrome treated by hepatic embolization". AJR. American Journal of Roentgenology. 131 (3): 511–3. doi:10.2214/ajr.131.3.511. PMID 99001.
- ↑ Jha S, Ting JP (Dec 2009). "Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases". Journal of Immunology. 183 (12): 7623–9. doi:10.4049/jimmunol.0902425. PMC 3666034. PMID 20007570.
- ↑ Bertin J, DiStefano PS (Dec 2000). "The PYRIN domain: a novel motif found in apoptosis and inflammation proteins". review. Cell Death and Differentiation. 7 (12): 1273–4. doi:10.1038/sj.cdd.4400774. PMID 11270363.
- ↑ Jha S, Ting JP (Dec 2009). "Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases". review. Journal of Immunology. 183 (12): 7623–9. doi:10.4049/jimmunol.0902425. PMC 3666034. PMID 20007570.
- ↑ Q96P20
- ↑ Jump up to: 11.0 11.1 11.2 Martinon F (Mar 2008). "Detection of immune danger signals by NALP3". review. Journal of Leukocyte Biology. 83 (3): 507–11. doi:10.1189/jlb.0607362. PMID 17982111.
- ↑ Hari A, Zhang Y, Tu Z, Detampel P, Stenner M, Ganguly A, Shi Y (2014). "Activation of NLRP3 inflammasome by crystalline structures via cell surface contact". Scientific Reports. 4: 7281. doi:10.1038/srep07281. PMC 4250918. PMID 25445147.
- ↑ Haneklaus M, O'Neill LA, Coll RC (Feb 2013). "Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments". review. Current Opinion in Immunology. 25 (1): 40–45. doi:10.1016/j.coi.2012.12.004. PMID 23305783.
- ↑ Turunen JA, Wedenoja J, Repo P, Järvinen RS, Jäntti JE, Mörtenhumer S, Riikonen AS, Lehesjoki AE, Majander A, Kivelä TT (Jan 2018). "Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene". American Journal of Ophthalmology. 184. doi:10.1016/j.ajo.2018.01.017. PMID 29366613.
- ↑ Church LD, Cook GP, McDermott MF (Jan 2008). "Primer: inflammasomes and interleukin 1beta in inflammatory disorders". review. Nature Clinical Practice Rheumatology. 4 (1): 34–42. doi:10.1038/ncprheum0681. PMID 18172447.
- ↑ Liu-Bryan R (Jan 2010). "Intracellular innate immunity in gouty arthritis: role of NALP3 inflammasome". review. Immunology and Cell Biology. 88 (1): 20–3. doi:10.1038/icb.2009.93. PMC 4337950. PMID 19935768.
- ↑ Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (Jan 2013). "NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice". Nature. 493 (7434): 674–8. doi:10.1038/nature11729. PMC 3812809. PMID 23254930.
- ↑ Shi F, Kouadir M, Yang Y (Aug 2015). "NALP3 inflammasome activation in protein misfolding diseases". review. Life Sciences. 135: 9–14. doi:10.1016/j.lfs.2015.05.011. PMID 26037399.
- ↑ Levy M, Thaiss CA, Elinav E (2015). "Taming the inflammasome" (PDF). Nature Medicine. 21 (3): 213–215. doi:10.1038/nm.3808. PMID 25742454.
- ↑ Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD (2015). "The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease". Nature Medicine. 21 (3): 263–269. doi:10.1038/nm.3804. PMC 4352123. PMID 25686106.
- ↑ Wei Q, Mu K, Li T, Zhang Y, Yang Z, Jia X, Zhao W, Huai W, Guo P, Han L (Jan 2014). "Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression". Laboratory Investigation. 94 (1): 52–62. doi:10.1038/labinvest.2013.126. PMID 24166187. | NALP3
NACHT, LRR and PYD domains-containing protein 3 (NALP3), also known as cryopyrin, is a protein that in humans is encoded by the NLRP3 gene[1] located on the long arm of chromosome 1.[2]
NALP3 is expressed predominantly in macrophages and as a component of the inflammasome,[3][4]:436 detects products of damaged cells such as extracellular ATP and crystalline uric acid. Activated NALP3 in turn triggers an immune response. Mutations in the NLRP3 gene are associated with a number of organ specific autoimmune diseases.
# Nomenclature
NACHT, LRR, and PYD are respectively acronyms for:
- NACHT – NAIP (neuronal apoptosis inhibitor protein), C2TA [class 2 transcription activator, of the MHC, HET-E (heterokaryon incompatibility) and TP1 (telomerase-associated protein 1)
- LRR – "leucine-rich repeat" [5][6] and is synonymous with NLR, for or nucleotide-binding domain, leucine-rich repeat"[7]
- PYD – "PYRIN domain," after the pyrin proteins[8] The NLRP3 gene name abbreviates "NLR family, pyrin domain containing 3," where NLR refers to "nucleotide-binding domain, leucine-rich repeat."[9]
The NACHT, LRR and PYD domains-containing protein 3 is also called:
- cold induced autoinflammatory syndrome 1 (CIAS1),
- caterpiller-like receptor 1.1 (CLR1.1), and
- PYRIN-containing APAF1-like protein 1 (PYPAF1).[10]
# Structure
This gene encodes a pyrin-like protein which contains a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. This protein interacts with pyrin domain (PYD) of apoptosis-associated speck-like protein containing a CARD (ASC). Proteins which contain the caspase recruitment domain, CARD, have been shown to be involved in inflammation and immune response.[1]
# Function
NALP3 is a component of the innate immune system that functions as a pathogen recognition receptor (PRR) that recognizes pathogen-associated molecular patterns (PAMPs).[11] NALP3 belongs to the NOD-like receptor (NLR) subfamily of PRRs and NALP3 together with the adaptor ASC protein PYCARD forms a caspase-1 activating complex known as the NALP3 inflammasome. NALP3 in the absence of activating signal is kept in an inactive state complexed with HSP90 and SGT1 in the cytoplasm. NALP3 inflammasome detects danger signals such as crystalline uric acid and extracellular ATP released by damaged cells. These signals release HSP90 and SGT1 from and recruit ASC protein and caspase-1 to the inflammasome complex. Caspase-1 within the activated NALP3 inflammasome complex in turn activates the inflammatory cytokine, IL-1β.[11]
The NALP3 inflammasome appears to be activated by changes in intracellular potassium caused by potassium efflux from mechanosensitive ion channels located in the cell membrane.[12] It appears that NALP3 is also regulated by reactive oxygen species (ROS), though the precise mechanisms of such regulation has not been determined.[13]
# Pathology
Mutations in the NLRP3 gene have been associated with a spectrum of dominantly inherited autoinflammatory diseases called cryopyrin-associated periodic syndrome (CAPS). This includes familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, neonatal onset multisystem inflammatory disease (NOMID), and keratoendotheliitis fugax hereditaria.[1][14]
Defects in this gene have also been linked to familial Mediterranean fever.[15] In addition, the NALP3 inflammasome has a role in the pathogenesis of gout[11] and neuroinflammation occurring in protein-misfolding diseases, such as Alzheimer's, Parkinson's, and prion diseases.[16][17][18] Amelioration of mouse models of many diseases has been shown to occur by deletion of the NLRP3 inflammasome, including gout, type 2 diabetes, multiple sclerosis, Alzheimer's disease, and atherosclerosis.[19] The ketone β-Hydroxybutyrate has been shown to block NLRP3 activation, and thus may be of benefit for many of these diseases.[20]
Deregulation of NALP3 has been connected with carcinogenesis. For example, all the components of the NALP3 inflammasome are downregulated or completely lost in human hepatocellular carcinoma.[21]
# References and notes
- ↑ Jump up to: 1.0 1.1 1.2 Anon. (2015). "Entrez Gene: NLRP3 NLR family, pyrin domain containing 3 [Homo sapiens (human)], Gene ID: 114548 (updated on 13-Nov-2015)". Bethesda, MD, USA: National Center for Biotechnology Information, National Library of Medicine. Retrieved 13 November 2015..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}
- ↑ Hoffman HM, Wright FA, Broide DH, Wanderer AA, Kolodner RD (May 2000). "Identification of a locus on chromosome 1q44 for familial cold urticaria". American Journal of Human Genetics. 66 (5): 1693–8. doi:10.1086/302874. PMC 1378006. PMID 10741953.
- ↑ Tao JH, Zhang Y, Li XP (Dec 2013). "P2X7R: a potential key regulator of acute gouty arthritis". review. Seminars in Arthritis and Rheumatism. 43 (3): 376–80. doi:10.1016/j.semarthrit.2013.04.007. PMID 23786870.
- ↑ Lu A, Wu H (Feb 2015). "Structural mechanisms of inflammasome assembly". review. The FEBS Journal. 282 (3): 435–44. doi:10.1111/febs.13133. PMID 25354325.
- ↑ Koonin EV, Aravind L (May 2000). "The NACHT family - a new group of predicted NTPases implicated in apoptosis and MHC transcription activation". Trends in Biochemical Sciences. 25 (5): 223–4. doi:10.1016/S0968-0004(00)01577-2. PMID 10782090.
- ↑ Pueyo I, Jiménez JR, Hernández J, Brugarolas A, García-Morán M, García-Muñiz JL, Arroyo F (Sep 1978). "Carcinoid syndrome treated by hepatic embolization". AJR. American Journal of Roentgenology. 131 (3): 511–3. doi:10.2214/ajr.131.3.511. PMID 99001.
- ↑ Jha S, Ting JP (Dec 2009). "Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases". Journal of Immunology. 183 (12): 7623–9. doi:10.4049/jimmunol.0902425. PMC 3666034. PMID 20007570.
- ↑ Bertin J, DiStefano PS (Dec 2000). "The PYRIN domain: a novel motif found in apoptosis and inflammation proteins". review. Cell Death and Differentiation. 7 (12): 1273–4. doi:10.1038/sj.cdd.4400774. PMID 11270363.
- ↑ Jha S, Ting JP (Dec 2009). "Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases". review. Journal of Immunology. 183 (12): 7623–9. doi:10.4049/jimmunol.0902425. PMC 3666034. PMID 20007570.
- ↑ Q96P20
- ↑ Jump up to: 11.0 11.1 11.2 Martinon F (Mar 2008). "Detection of immune danger signals by NALP3". review. Journal of Leukocyte Biology. 83 (3): 507–11. doi:10.1189/jlb.0607362. PMID 17982111.
- ↑ Hari A, Zhang Y, Tu Z, Detampel P, Stenner M, Ganguly A, Shi Y (2014). "Activation of NLRP3 inflammasome by crystalline structures via cell surface contact". Scientific Reports. 4: 7281. doi:10.1038/srep07281. PMC 4250918. PMID 25445147.
- ↑ Haneklaus M, O'Neill LA, Coll RC (Feb 2013). "Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments". review. Current Opinion in Immunology. 25 (1): 40–45. doi:10.1016/j.coi.2012.12.004. PMID 23305783.
- ↑ Turunen JA, Wedenoja J, Repo P, Järvinen RS, Jäntti JE, Mörtenhumer S, Riikonen AS, Lehesjoki AE, Majander A, Kivelä TT (Jan 2018). "Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene". American Journal of Ophthalmology. 184. doi:10.1016/j.ajo.2018.01.017. PMID 29366613.
- ↑ Church LD, Cook GP, McDermott MF (Jan 2008). "Primer: inflammasomes and interleukin 1beta in inflammatory disorders". review. Nature Clinical Practice Rheumatology. 4 (1): 34–42. doi:10.1038/ncprheum0681. PMID 18172447.
- ↑ Liu-Bryan R (Jan 2010). "Intracellular innate immunity in gouty arthritis: role of NALP3 inflammasome". review. Immunology and Cell Biology. 88 (1): 20–3. doi:10.1038/icb.2009.93. PMC 4337950. PMID 19935768.
- ↑ Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (Jan 2013). "NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice". Nature. 493 (7434): 674–8. doi:10.1038/nature11729. PMC 3812809. PMID 23254930.
- ↑ Shi F, Kouadir M, Yang Y (Aug 2015). "NALP3 inflammasome activation in protein misfolding diseases". review. Life Sciences. 135: 9–14. doi:10.1016/j.lfs.2015.05.011. PMID 26037399.
- ↑ Levy M, Thaiss CA, Elinav E (2015). "Taming the inflammasome" (PDF). Nature Medicine. 21 (3): 213–215. doi:10.1038/nm.3808. PMID 25742454.
- ↑ Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD (2015). "The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease". Nature Medicine. 21 (3): 263–269. doi:10.1038/nm.3804. PMC 4352123. PMID 25686106.
- ↑ Wei Q, Mu K, Li T, Zhang Y, Yang Z, Jia X, Zhao W, Huai W, Guo P, Han L (Jan 2014). "Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression". Laboratory Investigation. 94 (1): 52–62. doi:10.1038/labinvest.2013.126. PMID 24166187. | https://www.wikidoc.org/index.php/NALP3 | |
a7e96009f1d75de6aaeef156b3bcd2583ad81e31 | wikidoc | NBPF1 | NBPF1
Neuroblastoma Breakpoint Family, Member 1, or NBPF1 is a protein that is encoded by the gene NBPF1 in humans. This protein is member of the neuroblastoma breakpoint family proteins, a group of proteins that are thought to be involved in the development of the nervous system.
# Gene
The NBPF1 gene in humans is located on the minus strand of 1p36.3 in humans and is 51179 base pairs long including exons and introns. It is located between the protein coding genes NECAP2 and CROCC. NBPF1 is one of the 26 known members of the Neuroblastoma Breakpoint Family genes and pseudogenes. The NBPF2 pseudogene and NBPF3 gene are the most similar genes located close to NBPF1 and they reside on the chromosomal location 1p36.12. Most members of the NBPF gene family are located on chromosomal location 1q21.1-1q23.3 in humans, and these genes are more similar to each other in sequence than they are to NBPF1.
## Transcript
The transcript for NBPF1 in humans is a 6183 base pair mRNA that is made of 28 exons. There are more than 14 alternative splicing forms of NBPF1 predicted, but only seven of the splice forms have been observed. Out of all of the possible transcripts, only two are known to code proteins. One of these transcripts is 1139 amino acids long with 23 coding exons, while and the other is 1095 amino acids long and 23 coding exons. The noncoding transcripts are processed, but their function is unknown.
# Protein
NBPF1 is a 1214 amino acid long protein in humans that weighs 139 kD and has an isoelectric point of around 5. A feature about this protein's composition is that it is much richer than most other proteins in both glutamine and glutamic acid residues. Additionally, it contains amino acid repeats that are present in humans, other primates, and even armadillos. Another feature is that the NBPF1 protein contains residues that are predicted to have post-translational modifications, including glycation, N-linked glycosylation, O-GlcNAc attachment, O-linked glycosylation, Phosphorylation, and Sumoylation. The two most important domain types in the NBPF1 protein are the coiled coil domains and DUF1220 domains. NBPF1 contains three coiled coil domains and nine DUF1220 domains in humans. The coiled coil domains are 60-100 amino acids long, while the DUF1220 domains are approximately 65 base pairs long with high sequence similarity.
# = Interactions
Human NBPF1 has been shown to interact with Ubiquitin C via both protein complex immunoprecipitation and affinity chromatography. Two-hybrid screening assays have shown that NBPF1 interacts with the coiled coil domains of CBY1, a repressor for the Beta-catenin, a protein that is involved in Wnt signaling for cell proliferation. Additionally, two hybrid screen have shown that NBPF1 interacted with bacterial proteins, such as an Oxidoreductase iron/ascorbate family protein from the bacterium Francisella tularensis and an uncharacterized protein from the bacterium Bacillus anthracis.
## Functional and clinical significance
Although the function of the NBPF1 protein in unknown, its physical and chemical properties can give insight about its function. Like other NBPF proteins, the NBPF1 protein product contains a repeated domain called DUF1220, a domain of unknown function that is thought to be related to human brain complexity. First, NBPF1 is predicted to be a nuclear protein, as it contains positively charged nuclear localization signals. These nuclear localization signals in NBPF1 and a conserved DNA binding domain similar to the transcription factor STAT3/dna complex or STAT1/dna complex suggests that it could act as a transcription factor
Second, genes like NBPF1 with DUF1220 genes are expressed during human neurogenesis. The number of DUF1220 domains present in the human genome correlates with both brain size and the amount of neurons present in the brain. Additionally, higher copy numbers of the DUF1220 domain are associated with increasing Autism severity, which often results from an excess of neurons that do not under synaptic pruning.
The NBPF1 protein is also found to be disrupted by a chromosomal translocation between chromosomes 1 and 17 with in some cases of human neuroblastoma. Additional studies show that NBPF1 is possibly a tumor suppressor gene because adding it to cell cultures lowers the incidence of foci formation. Additionally, NBPF1 contains three coiled coil structures are commonly involved in oligomerization with other proteins. Based on the interactions listed above, NBPF1 is shown to interact with the coiled coil domain of CBY1, which represses Wnt signaling. Aberrant Wnt signaling in the brain is a common cause of tumor growth and drug resistance in neuroblastomas, further suggesting that NBPF1 could act as a tumor suppressor gene in the brain if it directly affects this pathway.
NBPF1 seems to be involved in proliferation during human neurogenesis, and growth suppression during adulthood, showing that the DUF1220 and coiled coil domains may be important during different life stages. The DUF1220 domains are important in neurogenesis, while the coiled coil domains involved with the binding of cell proliferation inhibitors. Although there are no known differences between Autism and neuroblastoma rates are known, a study has shown the existence of comorbid microcephaly and neuroblastoma conditions, although more research is needed to show this. Based on these predictions, the lack of NBPF1 during could prevent fetal neurogenesis and postnatal tumor suppression in the brain, although this connection is not well understood.
# Expression
NBPF1 is ubiquitously expressed in all tissues in humans, but shows the highest levels of expression in the bone marrow, skeletal muscle, brain, and spinal cord. It is expressed at slightly lower levels in other tissues such as the pancreas, kidney, and lung. In the brain, NBPF1 expression is the highest in the frontal, temporal, and parietal lobes, and it lowest in the ventricles and cerebellum. Based on protein composition, NBPF1 in humans and its orthologs in related species is most likely to be localized in the nucleus.
Predicted Localization of NBPF1 and its Orthologs
Expression studies have shown changes in NBPF1 under different experimental conditions in vitro. First, the depletion of nervous system transcription factor SOX11 causes a slight increase in NBPF1 expression. Additionally, the inactivation of Far upstream element-binding protein 1 causes a decrease in NBPF1, while the inactivation of Far Upstream Binding Elements 2 and 3 causes an increase in NBPF1 expression. Far upstream binding elements are involved in transcriptional regulation using gene enhancers, each having different binding sites. The overexpression of CLDN1, a protein that forms tight junctions such as those of the blood-brain barrier, causes a sharp decline in NBPF1 expression
# Homology and evolution
## Orthologs
Although NBPF1 itself only exists in primates, a wide variety of NBPF like protein orthologs exist in other mammals such as cattle, felines, and cetaceans. In non-primate mammals, the gene sequences of NBPF-like genes have little similarity to the primate NBPF genes. These genes appear to be entirely absent in model mammals such as mice and rats. The large amount of NBPF genes in the human genome is most likely due to recent duplications because all of the NBPF genes are so similar and repetitive that they easily recombine with each other, causing duplications. Variation in the number of repetitive sequences in the NBPF genes also varies even within humans.
DUF1220 domains also vary greatly from humans in other species in their NBPF proteins.The further away a species is from humans, the fewer DUF1220 domains the species has. Humans have on average 272 DUF1220 domains in their NBPF genes, while chimpanzees have 125, macaques have 35, and dolphins only have 4.
Selected Orthologs of NBPF1
## Paralogs
The paralogs for NBPF1 are other members of the NBPF protein family. The high similariy between these paralogs further shows evidence of gene duplication during human evolution.
Selected Paralogs of NBPF1 | NBPF1
Neuroblastoma Breakpoint Family, Member 1, or NBPF1 is a protein that is encoded by the gene NBPF1 in humans. This protein is member of the neuroblastoma breakpoint family proteins, a group of proteins that are thought to be involved in the development of the nervous system.[1]
# Gene
The NBPF1 gene in humans is located on the minus strand of 1p36.3 in humans and is 51179 base pairs long including exons and introns. It is located between the protein coding genes NECAP2 and CROCC. NBPF1 is one of the 26 known members of the Neuroblastoma Breakpoint Family genes and pseudogenes. The NBPF2 pseudogene and NBPF3 gene are the most similar genes located close to NBPF1 and they reside on the chromosomal location 1p36.12. Most members of the NBPF gene family are located on chromosomal location 1q21.1-1q23.3 in humans, and these genes are more similar to each other in sequence than they are to NBPF1.[2]
## Transcript
The transcript for NBPF1 in humans is a 6183 base pair mRNA that is made of 28 exons. There are more than 14 alternative splicing forms of NBPF1 predicted, but only seven of the splice forms have been observed. Out of all of the possible transcripts, only two are known to code proteins. One of these transcripts is 1139 amino acids long with 23 coding exons, while and the other is 1095 amino acids long and 23 coding exons. The noncoding transcripts are processed, but their function is unknown.[1][3][4]
# Protein
NBPF1 is a 1214 amino acid long protein in humans that weighs 139 kD and has an isoelectric point of around 5. A feature about this protein's composition is that it is much richer than most other proteins in both glutamine and glutamic acid residues. Additionally, it contains amino acid repeats that are present in humans, other primates, and even armadillos.[5] Another feature is that the NBPF1 protein contains residues that are predicted to have post-translational modifications, including glycation, N-linked glycosylation, O-GlcNAc attachment, O-linked glycosylation, Phosphorylation, and Sumoylation.[6] The two most important domain types in the NBPF1 protein are the coiled coil domains and DUF1220 domains. NBPF1 contains three coiled coil domains and nine DUF1220 domains in humans. The coiled coil domains are 60-100 amino acids long, while the DUF1220 domains are approximately 65 base pairs long with high sequence similarity.[7]
# = Interactions
=
Human NBPF1 has been shown to interact with Ubiquitin C via both protein complex immunoprecipitation[8] and affinity chromatography.[9] Two-hybrid screening assays have shown that NBPF1 interacts with the coiled coil domains of CBY1, a repressor for the Beta-catenin, a protein that is involved in Wnt signaling for cell proliferation.[10] Additionally, two hybrid screen have shown that NBPF1 interacted with bacterial proteins, such as an Oxidoreductase iron/ascorbate family protein from the bacterium Francisella tularensis and an uncharacterized protein from the bacterium Bacillus anthracis.[11]
## Functional and clinical significance
Although the function of the NBPF1 protein in unknown, its physical and chemical properties can give insight about its function. Like other NBPF proteins, the NBPF1 protein product contains a repeated domain called DUF1220, a domain of unknown function that is thought to be related to human brain complexity.[12] First, NBPF1 is predicted to be a nuclear protein, as it contains positively charged nuclear localization signals. These nuclear localization signals in NBPF1 and a conserved DNA binding domain similar to the transcription factor STAT3/dna complex or STAT1/dna complex suggests that it could act as a transcription factor[13]
Second, genes like NBPF1 with DUF1220 genes are expressed during human neurogenesis. The number of DUF1220 domains present in the human genome correlates with both brain size and the amount of neurons present in the brain.[14] Additionally, higher copy numbers of the DUF1220 domain are associated with increasing Autism severity, which often results from an excess of neurons that do not under synaptic pruning.[15]
The NBPF1 protein is also found to be disrupted by a chromosomal translocation between chromosomes 1 and 17 with in some cases of human neuroblastoma.[16] Additional studies show that NBPF1 is possibly a tumor suppressor gene because adding it to cell cultures lowers the incidence of foci formation. Additionally, NBPF1 contains three coiled coil structures are commonly involved in oligomerization with other proteins.[17] Based on the interactions listed above, NBPF1 is shown to interact with the coiled coil domain of CBY1, which represses Wnt signaling.[16] Aberrant Wnt signaling in the brain is a common cause of tumor growth and drug resistance in neuroblastomas,[18] further suggesting that NBPF1 could act as a tumor suppressor gene in the brain if it directly affects this pathway.
NBPF1 seems to be involved in proliferation during human neurogenesis, and growth suppression during adulthood, showing that the DUF1220 and coiled coil domains may be important during different life stages. The DUF1220 domains are important in neurogenesis, while the coiled coil domains involved with the binding of cell proliferation inhibitors. Although there are no known differences between Autism and neuroblastoma rates are known, a study has shown the existence of comorbid microcephaly and neuroblastoma conditions, although more research is needed to show this.[19] Based on these predictions, the lack of NBPF1 during could prevent fetal neurogenesis and postnatal tumor suppression in the brain, although this connection is not well understood.
# Expression
NBPF1 is ubiquitously expressed in all tissues in humans, but shows the highest levels of expression in the bone marrow, skeletal muscle, brain, and spinal cord. It is expressed at slightly lower levels in other tissues such as the pancreas, kidney, and lung.[20] In the brain, NBPF1 expression is the highest in the frontal, temporal, and parietal lobes, and it lowest in the ventricles and cerebellum.[21] Based on protein composition, NBPF1 in humans and its orthologs in related species is most likely to be localized in the nucleus.[22]
Predicted Localization of NBPF1 and its Orthologs[22]
Expression studies have shown changes in NBPF1 under different experimental conditions in vitro. First, the depletion of nervous system transcription factor SOX11 causes a slight increase in NBPF1 expression.[23] Additionally, the inactivation of Far upstream element-binding protein 1 causes a decrease in NBPF1, while the inactivation of Far Upstream Binding Elements 2 and 3 causes an increase in NBPF1 expression.[24] Far upstream binding elements are involved in transcriptional regulation using gene enhancers, each having different binding sites.[25] The overexpression of CLDN1, a protein that forms tight junctions such as those of the blood-brain barrier, causes a sharp decline in NBPF1 expression[26]
# Homology and evolution
## Orthologs
Although NBPF1 itself only exists in primates, a wide variety of NBPF like protein orthologs exist in other mammals such as cattle, felines, and cetaceans. In non-primate mammals, the gene sequences of NBPF-like genes have little similarity to the primate NBPF genes. These genes appear to be entirely absent in model mammals such as mice and rats. The large amount of NBPF genes in the human genome is most likely due to recent duplications because all of the NBPF genes are so similar and repetitive that they easily recombine with each other, causing duplications. Variation in the number of repetitive sequences in the NBPF genes also varies even within humans.[27]
DUF1220 domains also vary greatly from humans in other species in their NBPF proteins.The further away a species is from humans, the fewer DUF1220 domains the species has. Humans have on average 272 DUF1220 domains in their NBPF genes, while chimpanzees have 125, macaques have 35, and dolphins only have 4.[28]
Selected Orthologs of NBPF1[29][30]
## Paralogs
The paralogs for NBPF1 are other members of the NBPF protein family. The high similariy between these paralogs further shows evidence of gene duplication during human evolution.
Selected Paralogs of NBPF1 | https://www.wikidoc.org/index.php/NBPF1 | |
04a622410b07a7b9786bde46de46dbc4d998dce2 | wikidoc | NBPF3 | NBPF3
Neuroblastoma breakpoint family, member 3, also known as NBPF3, is a human gene of the neuroblastoma breakpoint family, which resides on chromosome 1 of the human genome. NBPF3 is located at 1p36.12, immediately upstream of genes ALPL and RAP1GAP.
# Protein sequence
The NBPF3 gene is 633 amino acids long and contains five DUF1220 domains, which are highlighted in the image below. DUF1220 domains are found in all other members of the neuroblastoma breakpoint family. The protein has a very repetitive structure, since, along with the remaining members of its protein family, it likely arose form segmental duplications on chromosome 1.
The domains are located at residues 236-298, 322-385, 394-460, 469-535, and 544-610.
The protein sequence is rich in three amino acids that are polar and negatively charged at physiological pH: glutamic acid, aspartic acid and glutamine. The isoelectric point of the protein is 4.21, the acidity of which may be attributed to the abundance of these amino acids.
# Isoforms and sequence characteristics
There are four known isoforms of the NPBF3 gene. While isoform 1 is the dominant form of the gene, each other isoform has unique changes to the protein sequence that may affect the structure, expression or function of the gene product:
These isoforms are represented in the following schematic, along with additional sequence characteristics which include Poly-Glu compositional biases and a potential coiled coil.
# Function
The function of the neuroblastoma breakpoint family proteins, including NPBF3, is not yet understood by the scientific community. Because of the repetitive composition of this family of genes as well as their amplification in primates, it has been suggested that the family is involved in cognitive development and the evolution of primates.
It has also been suggested that there is a connection between the neuroblastoma breakpoint family and oncogenesis. Due to the up-regulation of NBPF genes in some tumor tissues, proteins of this family have been hypothesized to be oncogenes. It has also been suggested that members of the neuroblastoma breakpoint family are tumor suppressor genes, due to a loss of heterozygosity in tumor tissue in the region of chromosome 1 where NBPF3 and other NBPF proteins are located.
# Homology
Orthologs of NBPF3 are found primarily in primate species, though orthologous sequences can be found in cow, horse, and dog species. There is no mouse ortholog of NPBF3.
NPBF3 has many human paralogs because it is a member of a gene family.
Both orthologs and paralogs of NBPF3 were found using the databases BLAT. and BLAST
# Protein interactions
NPBF3 interacts with three other proteins: C1orf19, Ankyrin-1 (ANK1) and Ewing Sarcoma Breakpoint region 1 (EWSR1). It is not known how these proteins interact or what the product of these interactions may be. | NBPF3
Neuroblastoma breakpoint family, member 3, also known as NBPF3, is a human gene of the neuroblastoma breakpoint family, which resides on chromosome 1 of the human genome. NBPF3 is located at 1p36.12, immediately upstream of genes ALPL and RAP1GAP.[1]
# Protein sequence
The NBPF3 gene is 633 amino acids long and contains five DUF1220 domains, which are highlighted in the image below. DUF1220 domains are found in all other members of the neuroblastoma breakpoint family. The protein has a very repetitive structure, since, along with the remaining members of its protein family, it likely arose form segmental duplications on chromosome 1.
The domains are located at residues 236-298, 322-385, 394-460, 469-535, and 544-610.
The protein sequence is rich in three amino acids that are polar and negatively charged at physiological pH: glutamic acid, aspartic acid and glutamine. The isoelectric point of the protein is 4.21, the acidity of which may be attributed to the abundance of these amino acids.
# Isoforms and sequence characteristics
There are four known isoforms of the NPBF3 gene. While isoform 1 is the dominant form of the gene, each other isoform has unique changes to the protein sequence that may affect the structure, expression or function of the gene product:[2]
These isoforms are represented in the following schematic, along with additional sequence characteristics which include Poly-Glu compositional biases and a potential coiled coil.
# Function
The function of the neuroblastoma breakpoint family proteins, including NPBF3, is not yet understood by the scientific community. Because of the repetitive composition of this family of genes as well as their amplification in primates, it has been suggested that the family is involved in cognitive development and the evolution of primates.
It has also been suggested that there is a connection between the neuroblastoma breakpoint family and oncogenesis. Due to the up-regulation of NBPF genes in some tumor tissues, proteins of this family have been hypothesized to be oncogenes. It has also been suggested that members of the neuroblastoma breakpoint family are tumor suppressor genes, due to a loss of heterozygosity in tumor tissue in the region of chromosome 1 where NBPF3 and other NBPF proteins are located.[3]
# Homology
Orthologs of NBPF3 are found primarily in primate species, though orthologous sequences can be found in cow, horse, and dog species. There is no mouse ortholog of NPBF3.
NPBF3 has many human paralogs because it is a member of a gene family.
Both orthologs and paralogs of NBPF3 were found using the databases BLAT.[4] and BLAST [5]
# Protein interactions
NPBF3 interacts with three other proteins: C1orf19, Ankyrin-1 (ANK1) and Ewing Sarcoma Breakpoint region 1 (EWSR1).[6] It is not known how these proteins interact or what the product of these interactions may be. | https://www.wikidoc.org/index.php/NBPF3 | |
ba44b5632b19e746ecf9df4cfe01ff58801da0f4 | wikidoc | NCAPH | NCAPH
Condensin complex subunit 2 also known as chromosome-associated protein H (CAP-H) or non-SMC condensin I complex subunit H (NCAPH) is a protein that in humans is encoded by the NCAPH gene. CAP-H is a subunit of condensin I, a large protein complex involved in chromosome condensation
# Function
CAP-H is a member of the barr protein family and a regulatory subunit of the condensin complex. This complex is required for the conversion of interphase chromatin into condensed chromosomes. CAP-H is associated with mitotic chromosomes, except during the early phase of chromosome condensation. During interphase, the protein has a distinct punctate nucleolar localization.
# Model organisms
Model organisms have been used in the study of NCAPH function. A conditional knockout mouse line, called Ncaphtm1a(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 four tests were carried out on mutant mice and three significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and an increased susceptibility to bacterial infection was observed in male animals. | NCAPH
Condensin complex subunit 2 also known as chromosome-associated protein H (CAP-H) or non-SMC condensin I complex subunit H (NCAPH) is a protein that in humans is encoded by the NCAPH gene.[1][2] CAP-H is a subunit of condensin I, a large protein complex involved in chromosome condensation
# Function
CAP-H is a member of the barr protein family and a regulatory subunit of the condensin complex. This complex is required for the conversion of interphase chromatin into condensed chromosomes. CAP-H is associated with mitotic chromosomes, except during the early phase of chromosome condensation. During interphase, the protein has a distinct punctate nucleolar localization.[2]
# Model organisms
Model organisms have been used in the study of NCAPH function. A conditional knockout mouse line, called Ncaphtm1a(EUCOMM)Wtsi[7][8] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[9][10][11]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty four tests were carried out on mutant mice and three significant abnormalities were observed.[5] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and an increased susceptibility to bacterial infection was observed in male animals.[5] | https://www.wikidoc.org/index.php/NCAPH | |
1377af8d6d9dbcb835184f3172c5168baff40f98 | wikidoc | NCEH1 | NCEH1
Neutral cholesterol ester hydrolase 1 (NCEH) also known as arylacetamide deacetylase-like 1 (AADACL1) or KIAA1363 is an enzyme that in humans is encoded by the NCEH1 gene.
NCEH is an enzyme located in the endoplasmic reticulum. NCEH hydrolyzes 2-acetyl monoalkylglycerol ether, as part of an enzymatic pathway regulating the levels of platelet activating factor and lysophospholipids that may be involved in cancer development.
# Function
The enzymatic reaction catalyzed by NCEH is:
- 2-acetyl monoalkylglycerol ether → monoalkylglycerol ether
Monoalkylglycerol ethers (MAGEs) can then be converted to lysophospholipids alkyl-lysophosphatidic acid (alkyl-LPA) and alkyl-lysophosphatidylcholine (alkyl-LPC).
Controversial studies by one group also implicate the protein in the hydrolysis of cholesterol esters. However, loss of the protein in mice selectively reduces 2-acetyl monoalkylglycerol ether activity throughout the body.
# Clinical significance
Evidence suggests a role for NCEH in cancer. Cancer cell lines contain unusually high levels of the protein. Reduction of the amount of NCEH1 in cancer cells reduces tumor migration and growth in mice and addition of alkyl-LPA restores these processes.
NCEH can break down organophosphates like the pesticide metabolite chlorpyrifos oxon. Conversely, enzymatic activity can be inhibited by organophosphates.
# Structure
NCEH is a serine hydrolase that contains an N-terminal transmembrane domain, a central catalytic domain and a lipid-binding domain at its C-terminus. The protein exists in three isoforms that result from differences in mRNA splicing. Transcripts encode a protein for isoform a of 448, b of 440 and c of 275 amino acids long. | NCEH1
Neutral cholesterol ester hydrolase 1 (NCEH) also known as arylacetamide deacetylase-like 1 (AADACL1) or KIAA1363 is an enzyme that in humans is encoded by the NCEH1 gene.[1]
NCEH is an enzyme located in the endoplasmic reticulum. NCEH hydrolyzes 2-acetyl monoalkylglycerol ether, as part of an enzymatic pathway regulating the levels of platelet activating factor and lysophospholipids that may be involved in cancer development.[2][3]
# Function
The enzymatic reaction catalyzed by NCEH is:[2]
- 2-acetyl monoalkylglycerol ether → monoalkylglycerol ether
Monoalkylglycerol ethers (MAGEs) can then be converted to lysophospholipids alkyl-lysophosphatidic acid (alkyl-LPA) and alkyl-lysophosphatidylcholine (alkyl-LPC).
Controversial studies by one group also implicate the protein in the hydrolysis of cholesterol esters.[4] However, loss of the protein in mice selectively reduces 2-acetyl monoalkylglycerol ether activity throughout the body.[3]
# Clinical significance
Evidence suggests a role for NCEH in cancer. Cancer cell lines contain unusually high levels of the protein.[5] Reduction of the amount of NCEH1 in cancer cells reduces tumor migration and growth in mice and addition of alkyl-LPA restores these processes.[2]
NCEH can break down organophosphates like the pesticide metabolite chlorpyrifos oxon.[6] Conversely, enzymatic activity can be inhibited by organophosphates.[7]
# Structure
NCEH is a serine hydrolase that contains an N-terminal transmembrane domain, a central catalytic domain and a lipid-binding domain at its C-terminus.[8] The protein exists in three isoforms that result from differences in mRNA splicing. Transcripts encode a protein for isoform a of 448, b of 440 and c of 275 amino acids long. | https://www.wikidoc.org/index.php/NCEH1 | |
d493758338925f3c761cbd549f3e52dc8565b930 | wikidoc | NDC80 | NDC80
Kinetochore protein NDC80 homolog is a protein that in humans is encoded by the NDC80 gene.
# Function
Ndc80 is one of the proteins of outer kinetochore. It forms a heterotetramer with proteins NUF2, SPC25, and SPC24. This protein complex has microtubule-binding domains.
HEC is one of several proteins involved in spindle checkpoint signaling. This surveillance mechanism assures correct segregation of chromosomes during cell division by detecting unaligned chromosomes and causing prometaphase arrest until the proper bipolar attachment of chromosomes is achieved.
# Interactions
NDC80 has been shown to interact with MIS12, NEK2 and PSMC2. | NDC80
Kinetochore protein NDC80 homolog is a protein that in humans is encoded by the NDC80 gene.[1][2][3]
# Function
Ndc80 is one of the proteins of outer kinetochore. It forms a heterotetramer with proteins NUF2, SPC25[4], and SPC24. This protein complex has microtubule-binding domains.[5]
HEC is one of several proteins involved in spindle checkpoint signaling. This surveillance mechanism assures correct segregation of chromosomes during cell division by detecting unaligned chromosomes and causing prometaphase arrest until the proper bipolar attachment of chromosomes is achieved.[supplied by OMIM][3]
# Interactions
NDC80 has been shown to interact with MIS12,[6][7] NEK2[8][9] and PSMC2.[9] | https://www.wikidoc.org/index.php/NDC80 | |
2d8b1b1f4fcb7ad0b3421f9ff8ce68774b7b0e1b | wikidoc | NDEL1 | NDEL1
Nuclear distribution protein nudE-like 1 is a protein that in humans is encoded by the NDEL1 gene.
This gene encodes a thiol-activated oligopeptidase that is phosphorylated in M phase of the cell cycle. Phosphorylation regulates the cell cycle-dependent distribution of this protein, with a fraction of the protein bound strongly to centrosomes in interphase and localized to mitotic spindles in early M phase. Overall, this protein plays a role in nervous system development. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.
# Interactions
NDEL1 has been shown to interact with Cyclin-dependent kinase 5, YWHAE, PAFAH1B1 and DISC1. | NDEL1
Nuclear distribution protein nudE-like 1 is a protein that in humans is encoded by the NDEL1 gene.[1][2][3]
This gene encodes a thiol-activated oligopeptidase that is phosphorylated in M phase of the cell cycle. Phosphorylation regulates the cell cycle-dependent distribution of this protein, with a fraction of the protein bound strongly to centrosomes in interphase and localized to mitotic spindles in early M phase. Overall, this protein plays a role in nervous system development. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[3]
# Interactions
NDEL1 has been shown to interact with Cyclin-dependent kinase 5,[1] YWHAE,[4] PAFAH1B1[1][4] and DISC1.[5][6] | https://www.wikidoc.org/index.php/NDEL1 | |
cf5cbb92855188f1f74a77cd21c85b380a38672c | wikidoc | NDRG1 | NDRG1
Protein NDRG1 is a protein that in humans is encoded by the NDRG1 gene.
This gene is a member of the N-myc downregulated gene family which belongs to the alpha/beta hydrolase superfamily. The protein encoded by this gene is a cytoplasmic protein involved in stress responses, hormone responses, cell growth, and differentiation. Mutations in this gene have been reported to be causative the autosomal-recessive version of Charcot-Marie-Tooth disease known as CMT4D.
It has been reported that NDRG1 localizes to the endosomes and is a Rab4a effector involved in vesicular recycling.
As reviewed by Fang et al., NDRG1 is involved in embryogenesis and development, cell growth and differentiation, lipid biosynthesis and myelination, stress responses, immunity, DNA repair and cell adhesion among other functions. NDRG1 is localised in the cytoplasm, nucleus and mitochondrion, at probabilities of 47.8%, 26.1% and 8.7%, respectively. In response to DNA damage NDRG1 translocates from the cytoplasm to the nucleus, where it may inhibit cell growth and promote DNA repair mechanisms. It is suggested that NDRG1 acts as a stress response gene or potentially as a transcription factor.
# Functions in cancer and metastasis
As reviewed by Kovacevic et al., NDRG1 is a potent, iron-regulated growth and metastasis suppressor that was found to be negatively correlated with cancer progression in a number of tumors, including prostate, pancreatic, breast, and colon cancers. NDRG1 has marked anti-oncogenic activity, being associated with decreased cell proliferation, migration, invasion, and angiogenesis. The molecular functions of NDRG1 affect numerous signaling pathways that regulate cancer cell proliferation, invasion, angiogenesis, and migration. Specifically, NDRG1 inhibits the oncogenic RAS, c-Src, phosphatidylinositol 3-kinase (PI3K), WNT, ROCK1/pMLC2, and nuclear factor-light chain enhancer of activated B cell (NF-B) pathways, while promoting expression of key tumor-suppressive molecules including phosphatase and tensin homolog, E-cadherin, and mothers against decapentaplegic homolog 4 (SMAD4). Through its effects on E-cadherin and beta-catenin, which form the adherens junction and promote cell adhesion, NDRG1 also inhibits the epithelial to mesenchymal transition, an initial key step in metastasis.
# Functions in DNA repair and aging
In one of its functions at a molecular level, NDRG1 binds and stabilizes methyltransferases, chiefly O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein. Thus, higher expression of NDRG1 can promote MGMT protein stability and activity. Dominick et al. showed NDRG1 and MGMT protein expression was increased by 2-fold to 3-fold for each of three strains of mice (Snell, GHKRO, and PAPPA-KO) with increased longevity. These authors strongly suggest a link between the increase in the MGMT DNA repair pathway and a delay in the aging process in these mouse strains. This is consistent with the DNA damage theory of aging. | NDRG1
Protein NDRG1 is a protein that in humans is encoded by the NDRG1 gene.[1][2][3][4]
This gene is a member of the N-myc downregulated gene family which belongs to the alpha/beta hydrolase superfamily. The protein encoded by this gene is a cytoplasmic protein involved in stress responses, hormone responses, cell growth, and differentiation[citation needed]. Mutations in this gene have been reported to be causative the autosomal-recessive version of Charcot-Marie-Tooth disease known as CMT4D.[4]
It has been reported that NDRG1 localizes to the endosomes and is a Rab4a effector involved in vesicular recycling.[5]
As reviewed by Fang et al.,[6] NDRG1 is involved in embryogenesis and development, cell growth and differentiation, lipid biosynthesis and myelination, stress responses, immunity, DNA repair and cell adhesion among other functions. NDRG1 is localised in the cytoplasm, nucleus and mitochondrion, at probabilities of 47.8%, 26.1% and 8.7%, respectively. In response to DNA damage NDRG1 translocates from the cytoplasm to the nucleus, where it may inhibit cell growth and promote DNA repair mechanisms. It is suggested that NDRG1 acts as a stress response gene or potentially as a transcription factor.
# Functions in cancer and metastasis
As reviewed by Kovacevic et al.,[7] NDRG1 is a potent, iron-regulated growth and metastasis suppressor that was found to be negatively correlated with cancer progression in a number of tumors, including prostate, pancreatic, breast, and colon cancers. NDRG1 has marked anti-oncogenic activity, being associated with decreased cell proliferation, migration, invasion, and angiogenesis. The molecular functions of NDRG1 affect numerous signaling pathways that regulate cancer cell proliferation, invasion, angiogenesis, and migration. Specifically, NDRG1 inhibits the oncogenic RAS, c-Src, phosphatidylinositol 3-kinase (PI3K), WNT, ROCK1/pMLC2, and nuclear factor-light chain enhancer of activated B cell (NF-B) pathways, while promoting expression of key tumor-suppressive molecules including phosphatase and tensin homolog, E-cadherin, and mothers against decapentaplegic homolog 4 (SMAD4). Through its effects on E-cadherin and beta-catenin, which form the adherens junction and promote cell adhesion, NDRG1 also inhibits the epithelial to mesenchymal transition, an initial key step in metastasis.
# Functions in DNA repair and aging
In one of its functions at a molecular level, NDRG1 binds and stabilizes methyltransferases, chiefly O-6-methylguanine-DNA methyltransferase (MGMT),[8] a DNA repair protein. Thus, higher expression of NDRG1 can promote MGMT protein stability and activity. Dominick et al.[9] showed NDRG1 and MGMT protein expression was increased by 2-fold to 3-fold for each of three strains of mice (Snell, GHKRO, and PAPPA-KO) with increased longevity. These authors strongly suggest a link between the increase in the MGMT DNA repair pathway and a delay in the aging process in these mouse strains. This is consistent with the DNA damage theory of aging. | https://www.wikidoc.org/index.php/NDRG1 | |
9cfdbb150b95e7d154eb85c6af94b517cbdb95e1 | wikidoc | NEAT1 | NEAT1
Nuclear Enriched Abundant Transcript 1 (NEAT1) is a ~3.2 kb novel nuclear long non-coding RNA (RIKEN cDNA 2310043N10Rik). It is also known as Virus Inducible NonCoding RNA (VINC) or MEN epsilon RNA. It is transcribed from the multiple endocrine neoplasia locus.
Expression of NEAT1 is induced in mouse brains during infection by Japanese encephalitis virus and rabies virus. NEAT1 is constitutively expressed in a number of non-neuronal tissues and cell lines.
NEAT1 localizes to specific nuclear structures called paraspeckles. NEAT1 RNA interacts with a paraspeckle protein known as P54nrb or NONO and it is essential for paraspeckle formation. Some studies demonstrate that NEAT1 RNA is essential for the formation and maintenance of paraspeckles. Thus, this novel noncoding RNA appears to have an important structural role in the nuclear paraspeckles. | NEAT1
Nuclear Enriched Abundant Transcript 1 (NEAT1) is a ~3.2 kb novel nuclear long non-coding RNA (RIKEN cDNA 2310043N10Rik). It is also known as Virus Inducible NonCoding RNA (VINC) or MEN epsilon RNA. It is transcribed from the multiple endocrine neoplasia locus.[1][2][3][4]
Expression of NEAT1 is induced in mouse brains during infection by Japanese encephalitis virus and rabies virus. NEAT1 is constitutively expressed in a number of non-neuronal tissues and cell lines.
NEAT1 localizes to specific nuclear structures called paraspeckles.[5] NEAT1 RNA interacts with a paraspeckle protein known as P54nrb or NONO and it is essential for paraspeckle formation. Some studies demonstrate that NEAT1 RNA is essential for the formation and maintenance of paraspeckles. Thus, this novel noncoding RNA appears to have an important structural role in the nuclear paraspeckles.[6][7] | https://www.wikidoc.org/index.php/NEAT1 | |
4f2c56eb61af10fd8ba746995bdae64c275f8051 | wikidoc | NEDD4 | NEDD4
E3 ubiquitin-protein ligase NEDD4 also known as neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4) is an enzyme that in humans is encoded by the NEDD4 gene.
NEDD4 is an E3 ubiquitin ligase enzyme that targets proteins for ubiquitination. NEDD4 is a highly conserved gene in eukaryotes, and is the founding member of the NEDD4 family of E3 HECT ubiquitin ligases, consisting of 9 members in humans . NEDD4 regulates a large number of membrane proteins, such as ion channels and membrane receptors, via ubiquitination and endocytosis.
NEDD4 protein is widely expressed, and a large number of proteins have been predicted or demonstrated to bind in vitro. In vivo NEDD4 is involved in the regulation of a diverse range of processes, including insulin-like growth factor signalling, neuronal architecture and viral budding. NEDD4 is an essential protein for animal development and survival.
# Structure
The NEDD4 protein has a modular structure that is shared among the NEDD4 family, consisting of an amino-terminal C2 calcium-dependent phospholipid binding domain, 3-4 WW protein-protein interaction domains, and a carboxyl-terminal catalytic HECT ubiquitin ligase domain. The C2 domain targets proteins to the phospholipid membrane, and can also be involved in targeting substrates. The WW domains interact with proline rich PPxY motifs in target proteins to mediate interactions with substrates and adaptors. The catalytic HECT domain forms a thioester bond with activated ubiquitin transferred from an E2 ubiquitin conjugating enzyme, before transferring ubiquitin directly to a specific substrate.
# Expression
The human NEDD4 gene is located on chromosome 15q21.3, and consists of 30 exons that transcribe five protein variants of NEDD4, all of which vary in the C2 domain but share 100% identity from the first WW domain through to the end of the protein. The mouse Nedd4 gene is located on chromosome 9. NEDD4 is a 120kDa protein that is expressed in most tissues, including brain, heart, lung, kidney, and skeletal muscle. The NEDD4 protein localizes to the cytoplasm, mainly in the perinuclear region and cytoplasmic periphery.
# Function
In vitro, NEDD4 has been shown to bind and ubiquitinate a number of ion channels and membrane transporters resulting in their subsequent endocytosis and degradation by the proteasome, including the epithelial sodium channel (ENaC), voltage-gated calcium and voltage-gated sodium channels.
NEDD4 mediates ubiquitination and subsequent down-regulation of components of the epidermal growth factor (EGF) signalling pathway, such as HER3 and HER4 EGF receptors, and ACK.
The fibroblast growth factor receptor 1 (FGFR1) undergoes NEDD4 mediated ubiquitination and down-regulation, and contains a novel site (VL*PSR) that binds the C2 and WW3 domain of NEDD4.
There is a role for NEDD4 in viral budding via ubiquitination of viral matrix proteins for a number of viruses, and NEDD4 also interacts with components of the endocytic machinery required for budding.
NEDD4 can also function independently of its ubiquitin ligase activity. NEDD4 interacts with VEGFR2, leading to the degradation of VEGFR2 irrespective of whether the HECT domain is catalytically active.
NEDD4 can bind and ubiquitinate the epithelial sodium channel (ENaC), leading to down-regulation of sodium channel activity. However, in vivo studies have implicated the NEDD4 family member NEDD4-2 as the main ligase responsible for ENaC regulation.
# Regulation
NEDD4 activity can be regulated by auto-inhibition, whereby the C2 domain binds to the HECT domain to create an inhibitory conformation of the protein. This auto-inhibitory conformation can be disrupted by the presence of calcium, by proteins that bind to NEDD4 to prevent this conformation, or by phosphorylation of NEDD4 at specific tyrosine residues to activate NEDD4 ubiquitin ligase activity.
The NDFIP1 and NDFIP2 proteins function as adaptor proteins that can facilitate NEDD4 binding to substrates that lack PY motifs, as well as a role in binding NEDD4 to abrogate auto-inhibition. NDFIP1 may also regulate NEDD4 recruitment to exosomes for secretion.
Oxidative stress induces the activation of NEDD4 transcription via the FOXM1B transcription factor. Ras signalling also up-regulates NEDD4 transcription.
# Physiological significance
In vivo, NEDD4 is involved in the regulation of insulin and insulin-like growth factor (IGF-1) signalling by regulating the amount of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) on the cell surface.
The deletion of NEDD4 in mice leads to a reduced number of effector T-cells, and a slower T-cell response to antigen, suggesting that NEDD4 may function to convert naïve T-cells into activated T-cells.
NEDD4 plays an important role in neuronal development, and is responsible for the formation and arborisation of dendrites in neurons by forming a signalling complex with TINK and Rap2A. It is also required for proper formation and function of neuromuscular junctions, and normal numbers of cranial neural crest cells, motor neurons and axons.
NEDD4 has been shown to interact with and ubiquitinate the tumour suppressor protein PTEN in vitro, resulting in PTEN proteasomal degradation or trafficking. The in vivo role of NEDD4 in PTEN regulation is less clear. There is some evidence from NEDD4 deficient mice that NEDD4 does not target PTEN for degradation or trafficking. However, in other in vivo models, and in many human cancer cell lines, NEDD4 does appear responsible for the degradation of PTEN. NEDD4 regulation of PTEN may only occur in specific biological contexts.
The role of NEDD4 in negatively regulating tumour suppressor proteins is consistent with the frequent overexpression of NEDD4 in many different types of human cancers. Decreased levels of NEDD4 have also been associated with some cancers, including neuroblastoma and pancreatic cancer where the NEDD4 directly targets the respective oncoproteins N-Myc and c-Myc associated with these cancers for degradation. | NEDD4
E3 ubiquitin-protein ligase NEDD4 also known as neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4) is an enzyme that in humans is encoded by the NEDD4 gene.[1][2]
NEDD4 is an E3 ubiquitin ligase enzyme that targets proteins for ubiquitination. NEDD4 is a highly conserved gene in eukaryotes, and is the founding member of the NEDD4 family of E3 HECT ubiquitin ligases, consisting of 9 members in humans [NEDD4 (this gene), NEDD4-2 (NEDD4L), ITCH, SMURF1, SMURF2, WWP1, WWP2, NEDL1 (HECW1) and NEDDL2 (HECW2)].[3][4][5] NEDD4 regulates a large number of membrane proteins, such as ion channels and membrane receptors, via ubiquitination and endocytosis.
NEDD4 protein is widely expressed, and a large number of proteins have been predicted or demonstrated to bind in vitro. In vivo NEDD4 is involved in the regulation of a diverse range of processes, including insulin-like growth factor signalling, neuronal architecture and viral budding. NEDD4 is an essential protein for animal development and survival.[6]
# Structure
The NEDD4 protein has a modular structure that is shared among the NEDD4 family, consisting of an amino-terminal C2 calcium-dependent phospholipid binding domain, 3-4 WW protein-protein interaction domains, and a carboxyl-terminal catalytic HECT ubiquitin ligase domain.[7] The C2 domain targets proteins to the phospholipid membrane, and can also be involved in targeting substrates.[8] The WW domains interact with proline rich PPxY motifs in target proteins to mediate interactions with substrates and adaptors.[9] The catalytic HECT domain forms a thioester bond with activated ubiquitin transferred from an E2 ubiquitin conjugating enzyme, before transferring ubiquitin directly to a specific substrate.[3]
# Expression
The human NEDD4 gene is located on chromosome 15q21.3, and consists of 30 exons that transcribe five protein variants of NEDD4, all of which vary in the C2 domain but share 100% identity from the first WW domain through to the end of the protein.[10] The mouse Nedd4 gene is located on chromosome 9.[1] NEDD4 is a 120kDa protein that is expressed in most tissues, including brain, heart, lung, kidney, and skeletal muscle.[11] The NEDD4 protein localizes to the cytoplasm, mainly in the perinuclear region and cytoplasmic periphery.[1][11]
# Function
In vitro, NEDD4 has been shown to bind and ubiquitinate a number of ion channels and membrane transporters resulting in their subsequent endocytosis and degradation by the proteasome, including the epithelial sodium channel (ENaC), voltage-gated calcium and voltage-gated sodium channels.[12][13][14][15]
NEDD4 mediates ubiquitination and subsequent down-regulation of components of the epidermal growth factor (EGF) signalling pathway, such as HER3 and HER4 EGF receptors, and ACK.[16][17][18]
The fibroblast growth factor receptor 1 (FGFR1) undergoes NEDD4 mediated ubiquitination and down-regulation, and contains a novel site (VL***PSR) that binds the C2 and WW3 domain of NEDD4.[19]
There is a role for NEDD4 in viral budding via ubiquitination of viral matrix proteins for a number of viruses,[5] and NEDD4 also interacts with components of the endocytic machinery required for budding.[20]
NEDD4 can also function independently of its ubiquitin ligase activity. NEDD4 interacts with VEGFR2, leading to the degradation of VEGFR2 irrespective of whether the HECT domain is catalytically active.[21]
NEDD4 can bind and ubiquitinate the epithelial sodium channel (ENaC), leading to down-regulation of sodium channel activity.[13] However, in vivo studies have implicated the NEDD4 family member NEDD4-2 as the main ligase responsible for ENaC regulation.[22][23][24]
# Regulation
NEDD4 activity can be regulated by auto-inhibition, whereby the C2 domain binds to the HECT domain to create an inhibitory conformation of the protein.[25] This auto-inhibitory conformation can be disrupted by the presence of calcium, by proteins that bind to NEDD4 to prevent this conformation, or by phosphorylation of NEDD4 at specific tyrosine residues to activate NEDD4 ubiquitin ligase activity.[25][26]
The NDFIP1 and NDFIP2 proteins function as adaptor proteins that can facilitate NEDD4 binding to substrates that lack PY motifs, as well as a role in binding NEDD4 to abrogate auto-inhibition.[27][28] NDFIP1 may also regulate NEDD4 recruitment to exosomes for secretion.[29]
Oxidative stress induces the activation of NEDD4 transcription via the FOXM1B transcription factor.[30] Ras signalling also up-regulates NEDD4 transcription.[31]
# Physiological significance
In vivo, NEDD4 is involved in the regulation of insulin and insulin-like growth factor (IGF-1) signalling by regulating the amount of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) on the cell surface.[6][32]
The deletion of NEDD4 in mice leads to a reduced number of effector T-cells, and a slower T-cell response to antigen, suggesting that NEDD4 may function to convert naïve T-cells into activated T-cells.[33]
NEDD4 plays an important role in neuronal development, and is responsible for the formation and arborisation of dendrites in neurons by forming a signalling complex with TINK and Rap2A.[34] It is also required for proper formation and function of neuromuscular junctions, and normal numbers of cranial neural crest cells, motor neurons and axons.[35][36]
NEDD4 has been shown to interact with and ubiquitinate the tumour suppressor protein PTEN in vitro, resulting in PTEN proteasomal degradation or trafficking.[37][38] The in vivo role of NEDD4 in PTEN regulation is less clear. There is some evidence from NEDD4 deficient mice that NEDD4 does not target PTEN for degradation or trafficking.[6][39][40] However, in other in vivo models, and in many human cancer cell lines, NEDD4 does appear responsible for the degradation of PTEN.[31][41][42][43][44] NEDD4 regulation of PTEN may only occur in specific biological contexts.
The role of NEDD4 in negatively regulating tumour suppressor proteins is consistent with the frequent overexpression of NEDD4 in many different types of human cancers.[45][46] Decreased levels of NEDD4 have also been associated with some cancers, including neuroblastoma and pancreatic cancer where the NEDD4 directly targets the respective oncoproteins N-Myc and c-Myc associated with these cancers for degradation.[47] | https://www.wikidoc.org/index.php/NEDD4 | |
42e00fdcb5236c30b1454e495605e07b9dce97aa | wikidoc | NEDD8 | NEDD8
NEDD8 is a protein that in humans is encoded by the NEDD8 gene. (In Saccharomyces cerevisiae this protein is known as Rub1.) This ubiquitin-like protein (ULP), becomes covalently conjugated to a limited number of cellular proteins in a manner analogous to ubiquitination. Human NEDD8 shares 60% amino acid sequence identity to ubiquitin. The primary known substrates of NEDD8 modification are the Cullin subunits of Cullin-based E3 ubiquitin ligases, which are active only when neddylated. Their NEDDylation is critical for the recruitment of E2 to the ligase complex, thus facilitating ubiquitin conjugation. NEDD8 modification has therefore been implicated in cell cycle progression and cytoskeletal regulation.
# Activation and conjugation
As with ubiquitin and SUMO, NEDD8 is conjugated to cellular proteins after its C-terminal tail is processed. The NEDD8 activating E1 enzyme is a heterodimer composed of APPBP1 and UBA3 subunits. The APPBP1/UBA3 enzyme has homology to the N- and C-terminal halves of the ubiquitin E1 enzyme, respectively. The UBA3 subunit contains the catalytic center and activates NEDD8 in an ATP-dependent reaction by forming a high-energy thiolester intermediate. The activated NEDD8 is subsequently transferred to the UbcH12 E2 enzyme, and is then conjugated to specific substrates in the presence of the appropriate E3 ligases.
# Substrates for NEDD8
As reviewed by Brown et al., the best-characterized activated-NEDD8 substrates are the cullins (CUL1, 2, 3, 4A, 4B, 5, and 7 and PARC in human cells), that serve as molecular scaffolds for cullin-RING ubiquitin ligases (CRLs). Neddylation results in covalent conjugation of a NEDD8 moiety onto a conserved cullin lysine residue. Cullin neddylation increases CRL ubiquitylation activity via conformational changes that optimize ubiquitin transfer to target proteins
# Removal
There are several different proteases which can remove NEDD8 from protein conjugates. UCHL1, UCHL3 and USP21 proteases have dual specificity for NEDD8 and ubiquitin. Proteases specific for NEDD8 removal are the COP9 signalosome which removes NEDD8 from the CUL1 subunit of SCF ubiquitin ligases, and NEDP1 (or DEN1, SENP8).
# Role in DNA repair
As shown by Brown et al., NEDD8 accumulation at DNA-damage sites is a highly dynamic process. Neddylation is needed during a short period of the global genome repair (GGR) sub-pathway of DNA nucleotide excision repair (NER). In GGR of NER, after DNA damage is caused by UV irradiation, Cul4A in the DNA damage binding protein 2 (DDB2) complex is activated by NEDD8, and this allows GGR-NER to proceed to remove the damage.
Neddylation also has a role in repair of double-strand breaks. Non-homologous end joining(NHEJ) is a DNA repair pathway frequently used to repair DNA double-strand breaks. The first step in this pathway depends on the Ku70/Ku80 heterodimer that forms a highly stable ring structure encircling DNA ends. But the Ku heterodimer needs to be removed when NHEJ is completed, or it blocks transcription or replication. The Ku heterodimer is ubiquitylated in a DNA-damage and neddylation-dependent manner to promote the release of Ku and other NHEJ factors from the site of repair after the process is completed.
# In cancer chemotherapy
As discussed by Jin and Roberston in their review, silencing of a DNA repair gene by hypermethylation of its promoter may be a very early step in progression to cancer. Gene silencing of a DNA repair gene at the transcription level is proposed to act similarly to a germ-line mutation in a DNA repair gene. Loss of DNA repair capability by either mechanism introduces genome instability and predisposes the cell and its descendants to progression to cancer. Epigenetically silenced DNA repair genes occur frequently in the 17 most common cancers (see e.g. Frequency of hypermethylation of DNA repair genes in cancer).
As discussed above, activated-NEDD8 is needed in two DNA repair pathways: NER and NHEJ. If activation of NEDD8 is inhibited, cells with induced deficiency of NER or NHEJ may then die because of deficient DNA repair leading to accumulation of DNA damages. The effect of NEDD8 inhibition may be greater for cancer cells than for normal cells if the cancer cells are independently deficient in DNA repair due to prior epigenetic silencing of DNA repair genes active in alternative pathways (see synthetic lethality).
Pevonedistat (MLN4924), a drug inhibiting activation of NEDD8, has shown a significant therapeutic effect in four Phase I clinical cancer trials in 2015-2016. These include pevonedistat trials against acute myeloid leukemia and myelodysplastic syndromes, relapsed/refractory multiple myeloma or lymphoma, metastatic melanoma, and advanced solid tumors.
# In preclinical studies
## PPARγ neddylation
PPARγ has a crucial role in adipogenesis and lipid accumulation within adipocytes (fat cells). Activated NEDD8 stabilizes PPARγ, allowing increased adipogenesis. In experiments with mice, Pevonedistat, a drug inhibiting activation of NEDD8, prevented high-fat diet-induced obesity and glucose intolerance.
## NF-κB and NEDD8
The transcriptional activity of NF-κB is primarily regulated by physical interaction with inhibitory IκB proteins (IκBα and IκBβ), which prevents its nuclear translocation. Degradation of the IκBα subunit of IκB is mediated by ubiquitination, and this ubiquitination depends on neddylation. Pevonedistat (MLN4924) inhibits activation of NEDD8, that then inhibits ubiquitination of IκBα, and this inhibits NF-κB translocation to the nucleus.
Pevonedistat, through its effects on NF-κB and a target of NF-κB (microRNA-155), prolonged the survival of mice engrafted with leukemic cells.
## Colorectal cancer
Inhibition of NEDD8 activation by pevonedistat was found to induce growth arrest and apoptosis in 16/122 (13%) colorectal cancer (CRC) cell lines. Further analyses in patient-derived tumor xenografts revealed that pevonedistat is effective on poorly differentiated, high-grade mucinous CRC.
# Interactions
NEDD8 has been shown to interact with:
- Aryl hydrocarbon receptor,
- NUB1,
- UBE1C,
- UBE2M, and
- UCHL3. | NEDD8
NEDD8 is a protein that in humans is encoded by the NEDD8 gene.[1][2] (In Saccharomyces cerevisiae this protein is known as Rub1.) This ubiquitin-like protein (ULP), becomes covalently conjugated to a limited number of cellular proteins in a manner analogous to ubiquitination. Human NEDD8 shares 60% amino acid sequence identity to ubiquitin. The primary known substrates of NEDD8 modification are the Cullin subunits of Cullin-based E3 ubiquitin ligases, which are active only when neddylated. Their NEDDylation is critical for the recruitment of E2 to the ligase complex, thus facilitating ubiquitin conjugation. NEDD8 modification has therefore been implicated in cell cycle progression and cytoskeletal regulation.
# Activation and conjugation
As with ubiquitin and SUMO, NEDD8 is conjugated to cellular proteins after its C-terminal tail is processed. The NEDD8 activating E1 enzyme is a heterodimer composed of APPBP1 and UBA3 subunits.[3] The APPBP1/UBA3 enzyme has homology to the N- and C-terminal halves of the ubiquitin E1 enzyme, respectively. The UBA3 subunit contains the catalytic center and activates NEDD8 in an ATP-dependent reaction by forming a high-energy thiolester intermediate. The activated NEDD8 is subsequently transferred to the UbcH12 E2 enzyme, and is then conjugated to specific substrates in the presence of the appropriate E3 ligases.
# Substrates for NEDD8
As reviewed by Brown et al.,[4] the best-characterized activated-NEDD8 substrates are the cullins (CUL1, 2, 3, 4A, 4B, 5, and 7 and PARC in human cells), that serve as molecular scaffolds for cullin-RING ubiquitin ligases (CRLs). Neddylation results in covalent conjugation of a NEDD8 moiety onto a conserved cullin lysine residue.[5] Cullin neddylation increases CRL ubiquitylation activity via conformational changes that optimize ubiquitin transfer to target proteins
# Removal
There are several different proteases which can remove NEDD8 from protein conjugates. UCHL1, UCHL3 and USP21 proteases have dual specificity for NEDD8 and ubiquitin. Proteases specific for NEDD8 removal are the COP9 signalosome which removes NEDD8 from the CUL1 subunit of SCF ubiquitin ligases, and NEDP1 (or DEN1, SENP8).[6]
# Role in DNA repair
As shown by Brown et al.,[4] NEDD8 accumulation at DNA-damage sites is a highly dynamic process. Neddylation is needed during a short period of the global genome repair (GGR) sub-pathway of DNA nucleotide excision repair (NER). In GGR of NER, after DNA damage is caused by UV irradiation, Cul4A in the DNA damage binding protein 2 (DDB2) complex is activated by NEDD8, and this allows GGR-NER to proceed to remove the damage.[7]
Neddylation also has a role in repair of double-strand breaks.[4] Non-homologous end joining(NHEJ) is a DNA repair pathway frequently used to repair DNA double-strand breaks. The first step in this pathway depends on the Ku70/Ku80 heterodimer that forms a highly stable ring structure encircling DNA ends.[8] But the Ku heterodimer needs to be removed when NHEJ is completed, or it blocks transcription or replication. The Ku heterodimer is ubiquitylated in a DNA-damage and neddylation-dependent manner to promote the release of Ku and other NHEJ factors from the site of repair after the process is completed.[4]
# In cancer chemotherapy
As discussed by Jin and Roberston in their review,[9] silencing of a DNA repair gene by hypermethylation of its promoter may be a very early step in progression to cancer. Gene silencing of a DNA repair gene at the transcription level is proposed to act similarly to a germ-line mutation in a DNA repair gene. Loss of DNA repair capability by either mechanism introduces genome instability and predisposes the cell and its descendants to progression to cancer. Epigenetically silenced DNA repair genes occur frequently in the 17 most common cancers (see e.g. Frequency of hypermethylation of DNA repair genes in cancer).[10][9]
As discussed above, activated-NEDD8 is needed in two DNA repair pathways: NER and NHEJ. If activation of NEDD8 is inhibited, cells with induced deficiency of NER or NHEJ may then die because of deficient DNA repair leading to accumulation of DNA damages. The effect of NEDD8 inhibition may be greater for cancer cells than for normal cells if the cancer cells are independently deficient in DNA repair due to prior epigenetic silencing of DNA repair genes active in alternative pathways (see synthetic lethality).
Pevonedistat (MLN4924), a drug inhibiting activation of NEDD8, has shown a significant therapeutic effect in four Phase I clinical cancer trials in 2015-2016. These include pevonedistat trials against acute myeloid leukemia and myelodysplastic syndromes,[11] relapsed/refractory multiple myeloma or lymphoma,[12] metastatic melanoma,[13] and advanced solid tumors.[14]
# In preclinical studies
## PPARγ neddylation
PPARγ has a crucial role in adipogenesis and lipid accumulation within adipocytes (fat cells).[15] Activated NEDD8 stabilizes PPARγ, allowing increased adipogenesis. In experiments with mice, Pevonedistat, a drug inhibiting activation of NEDD8, prevented high-fat diet-induced obesity and glucose intolerance.[15]
## NF-κB and NEDD8
The transcriptional activity of NF-κB is primarily regulated by physical interaction with inhibitory IκB proteins (IκBα and IκBβ), which prevents its nuclear translocation.[16] Degradation of the IκBα subunit of IκB is mediated by ubiquitination, and this ubiquitination depends on neddylation.[17] Pevonedistat (MLN4924) inhibits activation of NEDD8, that then inhibits ubiquitination of IκBα, and this inhibits NF-κB translocation to the nucleus.[16]
Pevonedistat, through its effects on NF-κB and a target of NF-κB (microRNA-155), prolonged the survival of mice engrafted with leukemic cells.[16]
## Colorectal cancer
Inhibition of NEDD8 activation by pevonedistat was found to induce growth arrest and apoptosis in 16/122 (13%) colorectal cancer (CRC) cell lines. Further analyses in patient-derived tumor xenografts revealed that pevonedistat is effective on poorly differentiated, high-grade mucinous CRC. [18]
# Interactions
NEDD8 has been shown to interact with:
- Aryl hydrocarbon receptor,[19]
- NUB1,[20][21]
- UBE1C,[22]
- UBE2M,[22] and
- UCHL3.[23] | https://www.wikidoc.org/index.php/NEDD8 | |
b2c11e6b11cc2810531646010d0f02c377057e7c | wikidoc | NEDD9 | NEDD9
Neural precursor cell expressed developmentally down-regulated protein 9 (NEDD-9) is a protein that in humans is encoded by the NEDD9 gene. NEDD-9 is also known as enhancer of filamentation 1 (EF1), CRK-associated substrate-related protein (CAS-L), and Cas scaffolding protein family member 2 (CASS2). An important paralog of this gene is BCAR1.
# Discovery
In 1992, Kumar, et al., first described a sequence tag corresponding to the NEDD9 3′ untranslated region based on the cloning of a group of genes predominantly expressed in the brain of embryonic, but not adult mice, a group of genes designated neural precursor cell expressed, developmentally down-regulated. In 1996, two groups independently described the complete sequence of the NEDD9 gene, and provided initial functional analysis of NEDD9 protein. Law et al. overexpressed a human cDNA library in S. cerevisiae, and screened for genes that simultaneously affected cell cycle and cell polarity controls, inducing a filamentous yeast budding phenotype, and thus identified the HEF1 protein (Human Enhancer of Filamentation 1). This study identified HEF1/NEDD9 as an interactive partner for focal adhesion kinase (FAK), connecting it to integrin signaling. Separately, Minegishi et al. cloned the gene encoding a protein hyperphosphorylated following ligation of β1-integrins in T cells and hypothesized to play a role in the process of T cell costimulation, designating this gene Cas-L (Crk-associated substrate-related protein, Lymphocyte type).
# Gene
The genomic coordinates of the NEDD9 gene are 6:11,183,530-11,382,580 in the GRCh37 assembly, or 6:11,183,298-11,382,348 in the GRCh38 assembly. The gene is on the minus strand. The cytogenetic location is 6p25-p24, based on the nomenclature developed by the Human Genome Organization (HUGO) gene nomenclature committee (HGNC). NEDD9 is the HGNC approved symbol. Official IDs are 7733 (HGNC), 4739 (Entrez Gene), and ENSG00000111859 (Ensembl). CAS-L, CASL, HEF1, dJ49G10.2, dJ761I2.1, CAS2, CASS2 are alias symbols. The NEDD9 gene is conserved in Rhesus monkeys, dogs, cows, mice, rats, chickens, zebrafish, and frogs. In vertebrates, it is a member of a 4-gene family, with the other paralogous genes known as BCAR1 (p130Cas), EFS (Sin), and CASS4 (HEPL)
The NEDD9 promoter has 2 transcriptional start sites. The transcript variants NM_006403.3 and NM_001142393.1 encode proteins that have distinct N-termini (MKYK and MWTR, respectively). In mouse, the two alternative first exons are MKYK and MWAR. Their function is not known. NM_001142393 initiates translation at an upstream location compared to NM_006403.3, but both transcripts have 7 exons. Shorter transcripts with missing exons or an alternative 3' terminal exon have been detected in various studies; however, their role in the cell is unclear.
The 5' region of the NEDD9 promoter is regulated by all-trans retinoic acid (ATRA), and contains a retinoic acid response element (RARE) that is specifically bound by a retinoid X receptor (RXR)/retinoic acid receptor (RAR) heterodimer. NEDD9 is also induced by the environmental pollutant dioxin, based on regulation through the aryl hydrocarbon receptor (AhR). One study has found NEDD9 repressed by estrogen, based on binding of the SAFB1 co-repressor. NEDD9 is induced by Wnt signaling in colon cancer, based on binding to T-cell factor (TCF) factors in the promoter region. NEDD9 is induced by hypoxia and loss of VHL, based on binding of hypoxia-induced factor (HIF) transcription factors to the NEDD9 promoter. Prostaglandin E2 induces NEDD9 transcription. The Fox transcription factor Forkhead box C1 (FoxC1) and PAX5 transcription factor have been reported to induce NEDD9 transcription. TGF-beta induces NEDD9 transcription. Based on inspection of sequence, the NEDD9 promoter also has potential binding sites for a number of additional transcription factors, including STAT5A and NF-kappa B.
In the 3'UTR of NEDD9 is a match to positions 2-8 of mature miR-145. NEDD9-binding regions in the miR-145 locus would allow the direct binding of the NEDD9 3'UTR to the genomic region of miR-145, and some studies suggests this miR regulates NEDD9 in glioblastoma prostate cancer, and renal cell carcinoma cells. A non-coding RNA, named B2, extending from 10 kb upstream of NEDD9 exon 1 to exon 4 has been described, but the functional role for this ncRNA is not yet clear. NEDD9 is highly expressed in the embryonal brain, and in numerous tissues in the embryo and adult organism. Elevated expression is associated with cancer, as discussed below.
# Protein family
NEDD9 is a member of the CAS (Crk-associated substrate) protein family, which has 4 members in vertebrates. The other paralogous genes are known BCAR1 (p130Cas), EFS (Sin), and CASS4 (HEPL). There is no detectable NEDD9-related gene in bacteria, yeast, or C. elegans. A single family member exists in D. Melanogaster, termed DCas.
# Structure
In humans, NEDD9 is 834 amino acids long. NEDD9 is a noncatalytic scaffolding protein that contains docking sites for proteins involved in multiple signal transduction pathways, regulating magnitude and duration of cell signaling cascades The overall structure of NEDD9 is represented graphically in Figure 1.
These domains include:
In terms of post-translational modifications, NEDD9 is subject to significant phosphorylation based on growth conditions. In most actively growing adherent cells, NEDD9 migrates as a doublet of 115 and 105 kDa. Serine/threonine hyper-phosphorylated p115 NEDD9 is more common in G2/M phase cells, suggesting these modifications are associated with increased localization to centrosome and mitotic spindle. One study indicated the conversion of p115 into p105 is activated by cell detachment through cytoskeletal regulation of phosphatase PP2A, although other work has found conflicting results.
# Synthesis and degradation
NEDD9 is present throughout cell cycle, but most abundant in G2/M phase cells. NEDD9 is subject to both caspase cleavage and proteasomal degradation. In conditions of cell detachment, and particularly in early stages of anoikis or apoptosis, NEDD9 is rapidly cleaved by caspases 3 and/or 7 at a DLVD site (residue 363), and at a DDYD site (residue 630) to form N-terminal 55 KDa and C-terminal 28 KDa fragments forms. This cleavage is prevented by focal adhesion formation, which suggests NEDD9 as a sensor of altered adhesion states. Overexpression of p28 in cells causes cellular rounding and detachment, and induces apoptosis, probably because of a dominant-negative effect on survival-promoting signaling complexes at focal adhesions. Together this data suggests that production of different NEDD9 posttranslational modifications is regulated by cell de/attachment, which, in turn, allows regulation of NEDD9 turnover and participation in distinct cellular processes.
P115 is the primary target for proteasomal degradation of NEDD9. Proteasomal degradation of NEDD9 is triggered by a number of stimuli, including induction of TGF-beta signaling. An effector of the TGFbeta receptor, Smad3, may interact directly with APC subunit APC10 and thus recruit the APC complex. CDH1 subunit of the APC complex recognizes NEDD9 and regulates ubiquitination and subsequent degradation of NEDD9. NEDD9 is also degraded by the proteasome at the end of mitosis, following completion of activities with Aurora-A that support mitotic progression.
# Tissue distribution and intracellular localization
In interphase cells, the majority of NEDD9 localizes to focal adhesions. However, some of the protein is also cytoplasmic, and small pools localize to the centrosome and the basal body of cilia. At mitotic entry NEDD9 moves along mitotic spindle, eventually localizing at midbody at cytokinesis.
# Function
NEDD9 is an intermediate in a number of important signaling pathways relevant to the cellular processes of proliferation, survival, migration, and others (see figure to the right).
## Integrin, FAK/RAFTK, and SRC kinases
Integrin signaling, which control cell movement, spreading and adhesion to extracellular matrix (ECM), and survival, is the best established signaling pathway for NEDD9. Integrins are transmembrane proteins that nucleate focal adhesions, structures that provide bi-directional signaling between ECM and actin cytoskeleton. NEDD9 stabilizes formation and regulates turnover of focal adhesions, influencing cell motility and the invasion and metastasis of cancer cells. In response to integrin activation, FAK or the related kinase RAFTK recruits NEDD9 into a focal adhesion site, binds it via the N-terminal SH3 domain and phosphorylates the NEDD9 Src-binding site. This allows SRC or SRC family kinase to bind NEDD9 via its SH2 domain. Phosphorylation of the NEDD9 substrate domain by Src and other kinases results in the creation of binding sites for Crk and other adaptors that associate with SH2 binding motifs. NEDD9 Crk complexes activate Rho and Ras family GTPases via the recruitment of their nucleotide exchange factors (GEFs), such as DOCK1, DOCK3 DOCK180 and C3G.
These GTPases regulate cell motility, proliferation and also contribute to tumor progression and invasion. In many cell types, NEDD9 overexpression increases spreading and crescent morphology (an indicator of high motility). However, in fibroblasts, some work has found that absence of NEDD9 leads to more rapid focal adhesion turnover, which led to increase of migration in NEDD9-/- compared to wild type.
In cancer cells, NEDD9 can drive mesenchymal-type movement by activating RAC1 GTPase and WAVE in complex with its GEF DOCK3, which in turn cause inhibition of GTPase Rho and amoeboid movement. Invasion is accompanied by proteolysis of the ECM through activation of MMP14, MMP2 and MMP9 metalloproteinases.
## Chemokine receptors, TCR, BCR/ABL, Fyn, Lck kinases
NEDD9 is involved in chemokine-induced T cell migration and T cell receptor (TCR)–mediated integrin activation. In lymphocytes, integrin or TCR signaling induces NEDD9 phosphorylation by tyrosine kinases Fyn and Lck (SRC family kinases), which is essential for T cell migration. In addition, in response to chemokine signals, Abl family kinases promote GTPase RAP1 activation by phosphorylating of NEDD9; NEDD9 associates with the transducer protein Chat-H/SHEP1/NSP3, a member of the NSP protein family, further supporting RAP1 activation, cell migration, and adhesion. In B cells, NEDD9 association with NSP3 enhances integrin-mediated NEDD9 serine/threonine hyperphosphorylation following B cell receptor (BCR) ligation, promoting B lymphocyte adhesion, motility and homing into marginal zones of spleen
Estrogen Receptor. The NEDD9 interactors p130/CAS and the NSP protein NSP2/BCAR3 are implicated in antiestrogen resistance and breast cancer progression Some data suggests a role for NEDD9 in the cellular response to estrogen, including the progression to anti-estrogen resistance, breast cancer progression and invasion
RTKs (EGFR). NEDD9 also contributes to the transduction of signals downstream receptor tyrosine kinases (RTKs). A role for NEDD9 in signaling crosstalk between epidermal growth factor receptor (EGFR) and integrins was established in non-small lung cancer (NSLC). It was shown that inhibition of EGFR reduces the tyrosine phosphorylation of NEDD9. Nedd9 interacts directly with the EGFR effector protein Shc, positioning it to affect downstream signaling relevant to EGFR; mice lacking Nedd9 have depressed activity of the EGFR effectors ERK and AKT. NSP proteins are also multidomain scaffolds, which bind activated RTKs in response to extracellular stimuli and recruit both NEDD9 and BCAR1 to assist in integrating signaling between RTKs and integrins. NEDD9 is also activated by PDGF and other RTKs, although more study is required.
## TGF-beta
TGF-beta is a regulator of tissue remodeling and epithelial-mesenchymal transition (EMT) in development, and promotes metastasis in cancer. A number of studies have identified NEDD9 as a downstream effector in the TGF-beta signaling pathway, essential for promoting EMT. In MCF-7 cells, NEDD9 negatively regulates expression of the epithelial protein E-cadherin, preventing association of E-cadherin with cell membrane and activating SRC-kinase. Activated SRC provides internalization and lysosomal degradation of E-cadherin. Consistent with these findings is a study demonstrating downregulation of epithelial markers (E-cadherin, occludin, β-catenin) and concurrent upregulation of mesenchymal markers (N-cadherin, vimentin, fibronectin) in response to NEDD9 overexpression in MCF-10 cells.
## Aurora-A
NEDD9 binds directly to the Aurora-A mitotic kinase at the centrosome, and promotes its activity, allowing cells to enter mitosis. Degradation of NEDD9 at the end of mitosis contributes to timely Aurora-A degradation. Cells overexpressing NEDD9 exhibit deficient cytokinesis resulting in the accumulation of multipolar mitotic spindles and abnormal numbers of centrosomes. On the other hand, cells with depleted NEDD9 have prematurely separated centrosomes and are deficient in microtubule organizing activity during mitosis, leading to an abundance of monopolar or asymmetric spindles, preventing cells from entering mitosis. NEDD9 also regulates Aurora-A activation at the basal body of cilia as cells resorb cilia during early G1. Cilia are small organelles that protrude from the surface of adherent cells that are the obligate site of action for proteins such as Hedgehog, and the polycystins: by influencing ciliary stability, NEDD9 is positioned to affect these signaling systems. Interaction of NEDD9 with Aurora A kinase may also play a role in tumor invasion. NEDD9 binds to and regulates acetylation of cortactin (CTTN) in an Aurora A kinase (AURKA)/HDAC6–dependent manner. The knockdown of NEDD9 or AURKA results in an increase in the amount of acetylated CTTN and a decrease in the binding of CTTN to F-actin. Overexpression of the deacetylation mimicking (9KR) mutant of CTTN is sufficient to restore actin dynamics at the leading edge and migration proficiency of the tumor cells. Inhibition of AURKA and HDAC6 activity by alisertib and tubastatin A in xenograft models of breast cancer has led to a decrease in the number of pulmonary metastases.
# Clinical significance
Transgenic mice with homozygous depletion of NEDD9 are vital and fertile, but have immunological abnormalities that result in pre-malignant conditions later in life, defects are initially subtle, but increase in later life; B cell homing to the spleen and lymphocyte trafficking are deficient.
## Alzheimer's disease
The NEDD9 rs760678 SNP located in an intronic region, has been studied for a possible association with late onset Alzheimer's disease (LOAD). However, in 2012, Wang et al., performed a meta-analysis and concluded that more studies are required for solid conclusions. This SNP and relevant signaling is discussed more fully in.
## Cancer
Altered (typically elevated) expression of NEDD9 is strongly associated with cancer. NEDD9 is rarely if ever mutated, but frequently show altered expression or phosphorylation (associated with increased activity) in pathological conditions including immune cell dysfunction and cancer. NEDD9 overexpression is documented to occur and in some cases linked the process of tumorigenesis of many different malignances. Besides examples in breast cancer discussed above, these malignancies include colon, pancreatic, head and neck, ovarian, gastric, lung, genitourinary (including prostate), liver, and kidney cancer, gastrointestinal stromal tumors, glioblastoma, and neuroblastoma.
## Other disease
Nedd9 expression may be important for recovery from stroke. Nedd9 is upregulated in the neurons of the cerebral cortex and hippocampus after transient global ischemia in rats. Induced Nedd9 is tyrosine phosphorylated, bound to FAK in dendrite and soma of neurons, and promotes neurite outgrowth, contributing into recovery of neurologic function after cerebral ischemia. Nedd9 has recently been implicated in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). NEDD9 expression is elevated in human autosomal dominant polycystic kidney disease (ADPKD) and in mouse ADPKD models, and ADPKD-prone mice lacking NEDD9 developed a more severe form of ADPKD than those with normal NEDD9.
## Therapeutic potential
Because of its roles in cancer, several studies have considered the potential value of NEDD9 as a therapeutic target or therapeutic guide. Because of lack of a kinase domain, or any defined catalytic domain, and because it is entirely intracellular, NEDD9 is a difficult molecule to target.
Because NEDD9 serves as a scaffolding molecule for other signaling proteins that play significant roles in cancer development, the effects of NEDD9 overexpression in supporting metastasis could in theory be mitigated by inhibition of its downstream targets. In one study, deletion of Nedd9 in MMTV-neu mammary tumors increased their sensitivity to inhbitiors of FAK and SRC. NEDD9 depletion sensitizes breast tumor cell lines to the Aurora A inhibitor alisertib. Consideration of NEDD9 as a biomarker for therapeutic response is a promising research direction.
# Interactions
NEDD9 has been shown to interact with:
- ABL1,
- AURKA,
- CDH1,
- CRK,
- CRKL,
- ID2,
- LYN,
- MICAL1,
- NCK1,
- NSP,
- PTK2,
- SMAD3, and
- SRC.
# Notes | NEDD9
Neural precursor cell expressed developmentally down-regulated protein 9 (NEDD-9) is a protein that in humans is encoded by the NEDD9 gene.[1] NEDD-9 is also known as enhancer of filamentation 1 (EF1), CRK-associated substrate-related protein (CAS-L), and Cas scaffolding protein family member 2 (CASS2). An important paralog of this gene is BCAR1.
# Discovery
In 1992, Kumar, et al., first described a sequence tag corresponding to the NEDD9 3′ untranslated region based on the cloning of a group of genes predominantly expressed in the brain of embryonic, but not adult mice, a group of genes designated neural precursor cell expressed, developmentally down-regulated.[2] In 1996, two groups independently described the complete sequence of the NEDD9 gene, and provided initial functional analysis of NEDD9 protein. Law et al. overexpressed a human cDNA library in S. cerevisiae, and screened for genes that simultaneously affected cell cycle and cell polarity controls, inducing a filamentous yeast budding phenotype, and thus identified the HEF1 protein (Human Enhancer of Filamentation 1).[3] This study identified HEF1/NEDD9 as an interactive partner for focal adhesion kinase (FAK), connecting it to integrin signaling. Separately, Minegishi et al. cloned the gene encoding a protein hyperphosphorylated following ligation of β1-integrins in T cells and hypothesized to play a role in the process of T cell costimulation, designating this gene Cas-L (Crk-associated substrate-related protein, Lymphocyte type).[4]
# Gene
The genomic coordinates of the NEDD9 gene are 6:11,183,530-11,382,580 in the GRCh37 assembly, or 6:11,183,298-11,382,348 in the GRCh38 assembly. The gene is on the minus strand. The cytogenetic location is 6p25-p24, based on the nomenclature developed by the Human Genome Organization (HUGO) gene nomenclature committee (HGNC). NEDD9 is the HGNC approved symbol. Official IDs are 7733 (HGNC), 4739 (Entrez Gene), and ENSG00000111859 (Ensembl). CAS-L, CASL, HEF1, dJ49G10.2, dJ761I2.1, CAS2, CASS2 are alias symbols. The NEDD9 gene is conserved in Rhesus monkeys, dogs, cows, mice, rats, chickens, zebrafish, and frogs. In vertebrates, it is a member of a 4-gene family, with the other paralogous genes known as BCAR1 (p130Cas), EFS (Sin), and CASS4 (HEPL)
The NEDD9 promoter has 2 transcriptional start sites. The transcript variants NM_006403.3 and NM_001142393.1 encode proteins that have distinct N-termini (MKYK and MWTR, respectively). In mouse, the two alternative first exons are MKYK and MWAR. Their function is not known. NM_001142393 initiates translation at an upstream location compared to NM_006403.3, but both transcripts have 7 exons. Shorter transcripts with missing exons or an alternative 3' terminal exon have been detected in various studies; however, their role in the cell is unclear.
The 5' region of the NEDD9 promoter is regulated by all-trans retinoic acid (ATRA), and contains a retinoic acid response element (RARE) that is specifically bound by a retinoid X receptor (RXR)/retinoic acid receptor (RAR) heterodimer.[5][6][7] NEDD9 is also induced by the environmental pollutant dioxin, based on regulation through the aryl hydrocarbon receptor (AhR).[8] One study has found NEDD9 repressed by estrogen, based on binding of the SAFB1 co-repressor.[9] NEDD9 is induced by Wnt signaling in colon cancer, based on binding to T-cell factor (TCF) factors in the promoter region.[10] NEDD9 is induced by hypoxia and loss of VHL, based on binding of hypoxia-induced factor (HIF) transcription factors to the NEDD9 promoter.[11][12][13] Prostaglandin E2 induces NEDD9 transcription.[14] The Fox transcription factor Forkhead box C1 (FoxC1)[15] and PAX5 transcription factor [16] have been reported to induce NEDD9 transcription. TGF-beta induces NEDD9 transcription.[17] Based on inspection of sequence, the NEDD9 promoter also has potential binding sites for a number of additional transcription factors, including STAT5A and NF-kappa B.
In the 3'UTR of NEDD9 is a match to positions 2-8 of mature miR-145. NEDD9-binding regions in the miR-145 locus would allow the direct binding of the NEDD9 3'UTR to the genomic region of miR-145, and some studies suggests this miR regulates NEDD9 in glioblastoma [18] prostate cancer,[19] and renal cell carcinoma cells.[20] A non-coding RNA, named B2, extending from 10 kb upstream of NEDD9 exon 1 to exon 4 has been described, but the functional role for this ncRNA is not yet clear.[21] NEDD9 is highly expressed in the embryonal brain,[22] and in numerous tissues in the embryo and adult organism. Elevated expression is associated with cancer, as discussed below.
# Protein family
NEDD9 is a member of the CAS (Crk-associated substrate) protein family, which has 4 members in vertebrates. The other paralogous genes are known BCAR1 (p130Cas),[23] EFS (Sin),[24][25] and CASS4 (HEPL).[26] There is no detectable NEDD9-related gene in bacteria, yeast, or C. elegans. A single family member exists in D. Melanogaster, termed DCas.[27][28]
# Structure
In humans, NEDD9 is 834 amino acids long. NEDD9 is a noncatalytic scaffolding protein that contains docking sites for proteins involved in multiple signal transduction pathways, regulating magnitude and duration of cell signaling cascades [29][30][31][32] The overall structure of NEDD9 is represented graphically in Figure 1.
These domains include:
In terms of post-translational modifications, NEDD9 is subject to significant phosphorylation based on growth conditions. In most actively growing adherent cells, NEDD9 migrates as a doublet of 115 and 105 kDa. Serine/threonine hyper-phosphorylated p115 NEDD9 is more common in G2/M phase cells,[46] suggesting these modifications are associated with increased localization to centrosome and mitotic spindle. One study indicated the conversion of p115 into p105 is activated by cell detachment through cytoskeletal regulation of phosphatase PP2A,[47] although other work has found conflicting results.[48]
# Synthesis and degradation
NEDD9 is present throughout cell cycle, but most abundant in G2/M phase cells.[46] NEDD9 is subject to both caspase cleavage and proteasomal degradation.[30][31] In conditions of cell detachment, and particularly in early stages of anoikis or apoptosis, NEDD9 is rapidly cleaved by caspases 3 and/or 7 at a DLVD site (residue 363), and at a DDYD site (residue 630) [49] to form N-terminal 55 KDa and C-terminal 28 KDa fragments forms. This cleavage is prevented by focal adhesion formation, which suggests NEDD9 as a sensor of altered adhesion states.[46][50] Overexpression of p28 in cells causes cellular rounding and detachment, and induces apoptosis,[50] probably because of a dominant-negative effect on survival-promoting signaling complexes at focal adhesions. Together this data suggests that production of different NEDD9 posttranslational modifications is regulated by cell de/attachment, which, in turn, allows regulation of NEDD9 turnover and participation in distinct cellular processes.
P115 is the primary target for proteasomal degradation of NEDD9.[47] Proteasomal degradation of NEDD9 is triggered by a number of stimuli, including induction of TGF-beta signaling.[51] An effector of the TGFbeta receptor, Smad3, may interact directly with APC subunit APC10 and thus recruit the APC complex. CDH1 subunit of the APC complex recognizes NEDD9 and regulates ubiquitination and subsequent degradation of NEDD9.[52] NEDD9 is also degraded by the proteasome at the end of mitosis, following completion of activities with Aurora-A that support mitotic progression.[46]
# Tissue distribution and intracellular localization
In interphase cells, the majority of NEDD9 localizes to focal adhesions. However, some of the protein is also cytoplasmic, and small pools localize to the centrosome [39] and the basal body of cilia.[53] At mitotic entry NEDD9 moves along mitotic spindle, eventually localizing at midbody at cytokinesis.[39]
# Function
NEDD9 is an intermediate in a number of important signaling pathways relevant to the cellular processes of proliferation, survival, migration, and others (see figure to the right).[29][30][31]
## Integrin, FAK/RAFTK, and SRC kinases
Integrin signaling, which control cell movement, spreading and adhesion to extracellular matrix (ECM), and survival, is the best established signaling pathway for NEDD9. Integrins are transmembrane proteins that nucleate focal adhesions, structures that provide bi-directional signaling between ECM and actin cytoskeleton. NEDD9 stabilizes formation and regulates turnover of focal adhesions, influencing cell motility and the invasion and metastasis of cancer cells.[54] In response to integrin activation, FAK or the related kinase RAFTK recruits NEDD9 into a focal adhesion site, binds it via the N-terminal SH3 domain and phosphorylates the NEDD9 Src-binding site. This allows SRC or SRC family kinase to bind NEDD9 via its SH2 domain. Phosphorylation of the NEDD9 substrate domain by Src and other kinases results in the creation of binding sites for Crk and other adaptors that associate with SH2 binding motifs. NEDD9 Crk complexes activate Rho and Ras family GTPases via the recruitment of their nucleotide exchange factors (GEFs), such as DOCK1, DOCK3 [32] DOCK180 and C3G.[55]
These GTPases regulate cell motility, proliferation and also contribute to tumor progression and invasion. In many cell types, NEDD9 overexpression increases spreading and crescent morphology (an indicator of high motility).[50] However, in fibroblasts, some work has found that absence of NEDD9 leads to more rapid focal adhesion turnover, which led to increase of migration in NEDD9-/- compared to wild type.[54]
In cancer cells, NEDD9 can drive mesenchymal-type movement by activating RAC1 GTPase and WAVE in complex with its GEF DOCK3, which in turn cause inhibition of GTPase Rho and amoeboid movement.[56] Invasion is accompanied by proteolysis of the ECM through activation of MMP14, MMP2 and MMP9 metalloproteinases.[57]
## Chemokine receptors, TCR, BCR/ABL, Fyn, Lck kinases
NEDD9 is involved in chemokine-induced T cell migration and T cell receptor (TCR)–mediated integrin activation. In lymphocytes, integrin or TCR signaling induces NEDD9 phosphorylation by tyrosine kinases Fyn and Lck (SRC family kinases), which is essential for T cell migration.[58] In addition, in response to chemokine signals, Abl family kinases promote GTPase RAP1 activation by phosphorylating of NEDD9;[59] NEDD9 associates with the transducer protein Chat-H/SHEP1/NSP3, a member of the NSP protein family, further supporting RAP1 activation, cell migration, and adhesion.[60] In B cells, NEDD9 association with NSP3 enhances integrin-mediated NEDD9 serine/threonine hyperphosphorylation following B cell receptor (BCR) ligation, promoting B lymphocyte adhesion, motility and homing into marginal zones of spleen [61]
Estrogen Receptor. The NEDD9 interactors p130/CAS and the NSP protein NSP2/BCAR3 are implicated in antiestrogen resistance [62][63] and breast cancer progression [64] Some data suggests a role for NEDD9 in the cellular response to estrogen, including the progression to anti-estrogen resistance, breast cancer progression and invasion [65][66][67]
RTKs (EGFR). NEDD9 also contributes to the transduction of signals downstream receptor tyrosine kinases (RTKs). A role for NEDD9 in signaling crosstalk between epidermal growth factor receptor (EGFR) and integrins was established in non-small lung cancer (NSLC). It was shown that inhibition of EGFR reduces the tyrosine phosphorylation of NEDD9.[68] Nedd9 interacts directly with the EGFR effector protein Shc, positioning it to affect downstream signaling relevant to EGFR; mice lacking Nedd9 have depressed activity of the EGFR effectors ERK and AKT.[69] NSP proteins are also multidomain scaffolds, which bind activated RTKs in response to extracellular stimuli and recruit both NEDD9 and BCAR1 to assist in integrating signaling between RTKs and integrins. NEDD9 is also activated by PDGF [70] and other RTKs, although more study is required.
## TGF-beta
TGF-beta is a regulator of tissue remodeling and epithelial-mesenchymal transition (EMT) in development, and promotes metastasis in cancer. A number of studies have identified NEDD9 as a downstream effector in the TGF-beta signaling pathway, essential for promoting EMT.[17][51][71][72][73] In MCF-7 cells, NEDD9 negatively regulates expression of the epithelial protein E-cadherin, preventing association of E-cadherin with cell membrane and activating SRC-kinase.[74] Activated SRC provides internalization and lysosomal degradation of E-cadherin.[74] Consistent with these findings is a study demonstrating downregulation of epithelial markers (E-cadherin, occludin, β-catenin) and concurrent upregulation of mesenchymal markers (N-cadherin, vimentin, fibronectin) in response to NEDD9 overexpression in MCF-10 cells.[75]
## Aurora-A
NEDD9 binds directly to the Aurora-A mitotic kinase at the centrosome, and promotes its activity, allowing cells to enter mitosis.[39][76] Degradation of NEDD9 at the end of mitosis contributes to timely Aurora-A degradation.[39][76][77] Cells overexpressing NEDD9 exhibit deficient cytokinesis resulting in the accumulation of multipolar mitotic spindles and abnormal numbers of centrosomes. On the other hand, cells with depleted NEDD9 have prematurely separated centrosomes and are deficient in microtubule organizing activity during mitosis, leading to an abundance of monopolar or asymmetric spindles,[39] preventing cells from entering mitosis. NEDD9 also regulates Aurora-A activation at the basal body of cilia as cells resorb cilia during early G1.[53] Cilia are small organelles that protrude from the surface of adherent cells that are the obligate site of action for proteins such as Hedgehog, and the polycystins: by influencing ciliary stability, NEDD9 is positioned to affect these signaling systems. Interaction of NEDD9 with Aurora A kinase may also play a role in tumor invasion. NEDD9 binds to and regulates acetylation of cortactin (CTTN) in an Aurora A kinase (AURKA)/HDAC6–dependent manner. The knockdown of NEDD9 or AURKA results in an increase in the amount of acetylated CTTN and a decrease in the binding of CTTN to F-actin. Overexpression of the deacetylation mimicking (9KR) mutant of CTTN is sufficient to restore actin dynamics at the leading edge and migration proficiency of the tumor cells. Inhibition of AURKA and HDAC6 activity by alisertib and tubastatin A in xenograft models of breast cancer has led to a decrease in the number of pulmonary metastases.[78]
# Clinical significance
Transgenic mice with homozygous depletion of NEDD9 are vital and fertile, but have immunological abnormalities that result in pre-malignant conditions later in life, defects are initially subtle, but increase in later life; B cell homing to the spleen and lymphocyte trafficking are deficient.[69][79]
## Alzheimer's disease
The NEDD9 rs760678 SNP located in an intronic region, has been studied for a possible association with late onset Alzheimer's disease (LOAD).[80][81][82][83][84] However, in 2012, Wang et al., performed a meta-analysis and concluded that more studies are required for solid conclusions.[83] This SNP and relevant signaling is discussed more fully in.[85]
## Cancer
Altered (typically elevated) expression of NEDD9 is strongly associated with cancer. NEDD9 is rarely if ever mutated, but frequently show altered expression or phosphorylation (associated with increased activity) in pathological conditions including immune cell dysfunction and cancer. NEDD9 overexpression is documented to occur and in some cases linked the process of tumorigenesis of many different malignances. Besides examples in breast cancer discussed above, these malignancies include colon,[10][11][14][86] pancreatic,[87] head and neck,[88] ovarian,[89] gastric,[90] lung,[91] genitourinary (including prostate),[19][92] liver,[15] and kidney cancer,[13][20] gastrointestinal stromal tumors,[93] glioblastoma,[18][70][94] and neuroblastoma.[5][6][54]
## Other disease
Nedd9 expression may be important for recovery from stroke. Nedd9 is upregulated in the neurons of the cerebral cortex and hippocampus after transient global ischemia in rats. Induced Nedd9 is tyrosine phosphorylated, bound to FAK in dendrite and soma of neurons, and promotes neurite outgrowth, contributing into recovery of neurologic function after cerebral ischemia.[95] Nedd9 has recently been implicated in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). NEDD9 expression is elevated in human autosomal dominant polycystic kidney disease (ADPKD) and in mouse ADPKD models, and ADPKD-prone mice lacking NEDD9 developed a more severe form of ADPKD than those with normal NEDD9.[96]
## Therapeutic potential
Because of its roles in cancer, several studies have considered the potential value of NEDD9 as a therapeutic target or therapeutic guide. Because of lack of a kinase domain, or any defined catalytic domain, and because it is entirely intracellular, NEDD9 is a difficult molecule to target.
Because NEDD9 serves as a scaffolding molecule for other signaling proteins that play significant roles in cancer development, the effects of NEDD9 overexpression in supporting metastasis could in theory be mitigated by inhibition of its downstream targets. In one study, deletion of Nedd9 in MMTV-neu mammary tumors increased their sensitivity to inhbitiors of FAK and SRC.[97] NEDD9 depletion sensitizes breast tumor cell lines to the Aurora A inhibitor alisertib.[77] Consideration of NEDD9 as a biomarker for therapeutic response is a promising research direction.
# Interactions
NEDD9 has been shown to interact with:
- ABL1,[98][99]
- AURKA,[39][76]
- CDH1,[100]
- CRK,[98][101]
- CRKL,[102][103][104][105]
- ID2,[106]
- LYN,[102]
- MICAL1,[107]
- NCK1,[98]
- NSP,[60]
- PTK2,[32][99]
- SMAD3,[100][108][109] and
- SRC.[32]
# Notes | https://www.wikidoc.org/index.php/NEDD9 | |
04b28a8ff27b111598a43c26e45c67905125e769 | wikidoc | NEIL1 | NEIL1
Endonuclease VIII-like 1 is an enzyme that in humans is encoded by the NEIL1 gene.
NEIL1 belongs to a class of DNA glycosylases homologous to the bacterial Fpg/Nei family. These glycosylases initiate the first step in base excision repair by cleaving bases damaged by reactive oxygen species (ROS) and introducing a DNA strand break via the associated lyase reaction.
# Targets
NEIL1 recognizes (targets) and removes certain ROS-damaged bases and then incises the abasic site via β,δ elimination, leaving 3′ and 5′ phosphate ends. NEIL1 recognizes oxidized pyrimidines, formamidopyrimidines, thymine residues oxidized at the methyl group, and both stereoisomers of thymine glycol. The best substrates for human NEIL1 appear to be the hydantoin lesions, guanidinohydantoin, and spiroiminodihydantoin that are further oxidation products of 8-oxoG. NEIL1 is also capable of removing lesions from single-stranded DNA as well as from bubble and forked DNA structures. Because the expression of NEIL1 is cell-cycle dependent, and because it acts on forked DNA structures and interacts with PCNA and FEN-1, it has been proposed that NEIL1 functions in replication associated DNA repair.
# Deficiency in cancer
NEIL1 is one of the DNA repair genes most frequently hypermethylated in head and neck squamous cell carcinoma (HNSCC). When 160 human DNA repair genes were evaluated for aberrant methylation in HNSCC tumors, 62% of tumors were hypermethylated in the NEIL1 promoter region, causing NEIL1 messenger RNA and NEIL1 protein to be repressed. When 8 DNA repair genes were evaluated in non-small cell lung cancer (NSCLC) tumors, 42% were hypermethylated in the NEIL1 promoter region. This was the most frequent DNA repair deficiency found among the 8 DNA repair genes tested. NEIL1 was also one of six DNA repair genes found to be hypermethylated in their promoter regions in colorectal cancer.
While other DNA repair genes, such as MGMT and MLH1, are often evaluated for epigenetic repression in many types of cancer, epigenetic deficiency of NEIL1 is usually not evaluated, but might be of importance in such cancers as well.
DNA damage appears to be the primary underlying cause of cancer. If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutational errors during DNA replication due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair. Such mutations and epigenetic alterations may give rise to cancer (see malignant neoplasms).
In colon cancer, germ line mutations in DNA repair genes cause only 2–5% of cases. However, methylation of the promoter region of DNA repair genes (including NEIL1), are frequently associated with colon cancers and may be an important causal factor for these cancers. | NEIL1
Endonuclease VIII-like 1 is an enzyme that in humans is encoded by the NEIL1 gene.[1][2]
NEIL1 belongs to a class of DNA glycosylases homologous to the bacterial Fpg/Nei family. These glycosylases initiate the first step in base excision repair by cleaving bases damaged by reactive oxygen species (ROS) and introducing a DNA strand break via the associated lyase reaction.[2]
# Targets
NEIL1 recognizes (targets) and removes certain ROS-damaged bases and then incises the abasic site via β,δ elimination, leaving 3′ and 5′ phosphate ends. NEIL1 recognizes oxidized pyrimidines, formamidopyrimidines, thymine residues oxidized at the methyl group, and both stereoisomers of thymine glycol.[3] The best substrates for human NEIL1 appear to be the hydantoin lesions, guanidinohydantoin, and spiroiminodihydantoin that are further oxidation products of 8-oxoG. NEIL1 is also capable of removing lesions from single-stranded DNA as well as from bubble and forked DNA structures. Because the expression of NEIL1 is cell-cycle dependent, and because it acts on forked DNA structures and interacts with PCNA and FEN-1, it has been proposed that NEIL1 functions in replication associated DNA repair.
# Deficiency in cancer
NEIL1 is one of the DNA repair genes most frequently hypermethylated in head and neck squamous cell carcinoma (HNSCC).[4] When 160 human DNA repair genes were evaluated for aberrant methylation in HNSCC tumors, 62% of tumors were hypermethylated in the NEIL1 promoter region, causing NEIL1 messenger RNA and NEIL1 protein to be repressed. When 8 DNA repair genes were evaluated in non-small cell lung cancer (NSCLC) tumors,[5] 42% were hypermethylated in the NEIL1 promoter region. This was the most frequent DNA repair deficiency found among the 8 DNA repair genes tested. NEIL1 was also one of six DNA repair genes found to be hypermethylated in their promoter regions in colorectal cancer.[6]
While other DNA repair genes, such as MGMT and MLH1, are often evaluated for epigenetic repression in many types of cancer,[7] epigenetic deficiency of NEIL1 is usually not evaluated, but might be of importance in such cancers as well.
DNA damage appears to be the primary underlying cause of cancer.[7][8] If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutational errors during DNA replication due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair.[9][10] Such mutations and epigenetic alterations may give rise to cancer (see malignant neoplasms).
In colon cancer, germ line mutations in DNA repair genes cause only 2–5% of cases.[11] However, methylation of the promoter region of DNA repair genes (including NEIL1[6]), are frequently associated with colon cancers and may be an important causal factor for these cancers.[7] | https://www.wikidoc.org/index.php/NEIL1 | |
c58216f0ed38f4e0c476cfe45b73b01be74fc261 | wikidoc | NELL1 | NELL1
Protein kinase C-binding protein NELL1 also known as NEL-like protein 1 (NELL1) or Nel-related protein 1 (NRP1) is a protein that in humans is encoded by the NELL1 gene.
# Function
This gene encodes a cytoplasmic protein that contains epidermal growth factor (EGF) -like repeats. The encoded heterotrimeric protein may be involved in cell growth regulation and differentiation. A similar protein in rodents is involved in craniosynostosis. An alternative splice variant has been described but its full-length sequence has not been determined.
Recent study by UCLA researchers shows that administering the protein NELL-1 intravenously stimulates significant bone formation through the regenerative ability of stem cells. | NELL1
Protein kinase C-binding protein NELL1 also known as NEL-like protein 1 (NELL1) or Nel-related protein 1 (NRP1) is a protein that in humans is encoded by the NELL1 gene.[1][2][3]
# Function
This gene encodes a cytoplasmic protein that contains epidermal growth factor (EGF) -like repeats. The encoded heterotrimeric protein may be involved in cell growth regulation and differentiation. A similar protein in rodents is involved in craniosynostosis. An alternative splice variant has been described but its full-length sequence has not been determined.[2]
Recent study by UCLA researchers shows that administering the protein NELL-1 intravenously stimulates significant bone formation through the regenerative ability of stem cells.[3] | https://www.wikidoc.org/index.php/NELL1 | |
3c38e9852c625c51282239dacd430a89ca366111 | wikidoc | NF-kB | NF-kB
# Overview
NF-κB (nuclear factor-kappa B) is a protein complex which is a transcription factor. NF-κB is found in all cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Consistent with this role, incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.
# Discovery
NF-κB was first discovered in the lab of Nobel Prize laureate David Baltimore via its interaction with an 11-base pair sequence in the immunoglobulin light-chain enhancer in B cells.
# Characterization
NF-κB family members share structural homology with the retroviral oncoprotein v-Rel, resulting in their classification as NF-κB/Rel proteins.
There are five proteins in the mammalian NF-κB family:
- NF-κB1 (also called p50) - NFKB1
- NF-κB2 (also called p52) - NFKB2
- RelA (also named p65) - RELA
- RelB - RELB
- c-Rel REL
In addition, there are NF-κB proteins in lower organisms, such as the fruit fly Drosophila, sea urchins, sea anemones and sponges.
All proteins of the NF-κB family share a Rel homology domain in their N-terminal halves. A subfamily of NF-κB proteins, including RelA, RelB and c-Rel, have a transactivation domain in their C-termini. In contrast, the NF-κB1 and NF-κB2 proteins are synthesized as large precursors, p105 and p100, which undergo processing to generate the mature NF-κB subunits, p50 and p52, respectively. The processing of p105 and p100 is mediated by the ubiquitin/proteasome pathway and involves selective degradation of their C-terminal region containing ankyrin repeats. While the generation of p52 from p100 is a tightly regulated process, p50 is produced from constitutive processing of p105.
# Activation of NF-κB
Part of NF-κB's importance in regulating cellular responses is that it belongs to the category of "rapid-acting" primary transcription factors---i.e., transcription factors which are present in cells in an inactive state and do not require new protein synthesis to be activated (other members of this family include transcription factors such as c-Jun, STATs and nuclear hormone receptors). This allows NF-κB to act as a "first responder" to harmful cellular stimuli. Stimulation of a wide variety of cell-surface receptors, such as RANK, TNFR, IL1R leads directly to NF-κB activation and fairly rapid changes in gene expression.
Many bacterial products can activate NF-κB. The identification of Toll-like receptors (TLRs) as specific pattern recognition molecules and the finding that stimulation of TLRs leads to activation of NF-κB improved our understanding of how different pathogens activate NF-κB. For example, studies have identified TLR4 as the receptor for the LPS component of Gram-Negative bacteria. TLRs are key regulators of both innate and adaptive immune responses.
Unlike RelA, RelB, and c-Rel, the p50 and p52 NF-κB subunits do not contain transactivation domains in their C terminal halves. Nevertheless, the p50 and p52 NF-κB members play critical roles in modulating the specificity of NF-κB function. Although homodimers of p50 and p52 are generally repressors of κB site transcription, both p50 and p52 participate in target gene transactivation by forming heterodimers with RelA, RelB or c-Rel. Additionally, p50 and p52 homodimers also bind to the nuclear protein Bcl-3, and such complexes can function as transcriptional activators.
# Inhibitors of NF-κB
In unstimulated cells, the NF-κB dimers are sequestered in the cytoplasm by a family of inhibitors, called IκBs (Inhibitor of kappa B), which are proteins that contain multiple copies of a sequence called ankyrin repeats. By virtue of their ankyrin repeat domains, the IκB proteins mask the nuclear localization signals (NLS) of NF-κB proteins and keep them sequestered in an inactive state in the cytoplasm.
IκBs are a family of related proteins that have an N-terminal regulatory domain, followed by six or more ankyrin repeats and a PEST domain near their C terminus. Although the IκB family consists of IκBα, IκBβ, IκBγ, IκBε and Bcl-3, the best studied and major IκB protein is IκBα. Due to the presence of ankyrin repeats in their C-terminal halves, p105 and p100 also function as IκB proteins. Of all the IκB members, IκBγ is unique in that it is synthesized from the nf-kb1 gene using an internal promoter, thereby resulting in a protein which is identical to the C-terminal half of p105.
Activation of the NF-κB is initiated by the signal-induced degradation of IκB proteins. This occurs primarily via activation of a kinase called the IκB kinase (IKK). IKK is composed of a heterodimer of the catalytic IKK alpha and IKK beta subunits and a "master" regulatory protein termed NEMO (NF-kappa B essential modulator) or IKK gamma. When activated by signals, usually coming from the outside of the cell, the IκB kinase phosphorylates two serine residues located in an IκB regulatory domain. When phosphorylated on these serines (e.g., serines 32 and 36 in human IκBα), the IκB inhibitor molecules are modified by a process called ubiquitination which then leads them to be degraded by a cell structure called the proteasome.
With the degradation of the IκB inhibitor, the NF-κB complex is then freed to enter the nucleus where it can 'turn on' the expression of specific genes that have DNA-binding sites for NF-κB nearby. The activation of these genes by NF-κB then leads to the given physiological response, for example, an inflammatory or immune response, a cell survival response, or cellular proliferation. NF-κB turns on expression of its own repressor, IκBα. The newly-synthesized IκBα then re-inhibits NF-κB and thus forms an auto feedback loop, that results in oscillating levels of NF-κB activity. In addition, several viruses, including the AIDS virus HIV, have binding sites for NF-κB that controls the expression of viral genes, which in turn contribute to viral replication or viral pathogenicity. In the case of HIV-1, activation of NF-κB may, at least in part, be involved in activation of the virus from a latent, inactive state. YopJ is a factor secreted by Yersinia pestis, the causative agent of plague, that prevents the ubiquitination of IκB. This causes this pathogen to effectively inhibit the NF-κB pathway and thus block the immune response of a human infected with Yersinia.
# NF-κB's Role in Cancer and Other Diseases
NF-κB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. As such, many different types of human tumors have misregulated NF-κB: that is, NF-κB is constitutively active. Active NF-κB turns on the expression of genes that keep the cell proliferating and protect the cell from conditions that would otherwise cause it to die. In tumor cells, NF-κB is active either due to mutations in genes encoding the NF-κB transcription factors themselves or in genes that control NF-κB activity (such as IκB genes); in addition, some tumor cells secrete factors that cause NF-κB to become active. Blocking NF-κB can cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents. Thus, NF-κB is the subject of much active research among pharmaceutical companies as a target for anti-cancer therapy.
Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, among others. Many natural products (including anti-oxidants) that have been promoted to have anti-cancer and anti-inflammatory activity have also been shown to inhibit NF-κB.It has been shown that in vivo administration of Insulin also leads to anti inflammatory effects through inhibition of NF kB in mono-nuclear cells of obese patients. There is a controversial US patent (US patent 6,410,516) that applies to the discovery and use of agents that can block NF-κB for therapeutic purposes. This patent is involved in several lawsuits, including Ariad v. Lilly. Recent work by Karin, Ben-Neriah and others has highlighted the importance of the connection between NF-κB, inflammation and cancer and underscored the value of therapies that regulate the activity of NF-κB.
It has also been proposed that NF-κB has a role in the growth and proliferation of myocardial cells infected with Trypanosoma cruzi. In myocardial cells of normal mice it is normal to detect a low background of NF-κB activity. In mice infected with T. cruzi, the levels of NF-κB DNA-binding activity become elevated.
# Signaling in Immunity
NF-kB is a major transcription factor which regulates genes responsible for both the innate immune response and the adaptive immune response. Upon activation of either the T- or B-cell receptor, NF-kB becomes activated through distinct signaling components. Upon ligation of the T-cell receptor, an adaptor molecule, ZAP70 is recruited via its SH2 domain to the cytoplasmic side of the receptor. ZAP70 helps recruit both LCK and PLCgamma, which causes activation of PKC. Through a cascade of phosphorylation events, the kinase complex is activated and NF-kB is able to enter the nucleus to upregulate genes involved in T-cell development, maturation and proliferation.
# Conserved in evolution
NF-kB is found in a number of simple organisms as well. These include Cnidarians (such as sea anemones and coral), Porifera (sponges) and insects (such as moths, mosquitoes and fruitflies). The sequencing of the genomes of Aedes aegypti, anopheles gambae, and the fruitfly Drosophila melanogaster has allowed comparative genetic and evolutionary studies on NF-kB. In those insect species, activation of NF-kB is triggered by the Toll pathway (which evolved independently in insects and mammals) and by the Imd pathway. | NF-kB
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Abdul Rafeh Naqash, M.B.B.S.
# Overview
NF-κB (nuclear factor-kappa B) is a protein complex which is a transcription factor. NF-κB is found in all cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Consistent with this role, incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.[1]
# Discovery
NF-κB was first discovered in the lab of Nobel Prize laureate David Baltimore via its interaction with an 11-base pair sequence in the immunoglobulin light-chain enhancer in B cells.[2]
# Characterization
NF-κB family members share structural homology with the retroviral oncoprotein v-Rel, resulting in their classification as NF-κB/Rel proteins.[3]
There are five proteins in the mammalian NF-κB family:
- NF-κB1 (also called p50) - NFKB1
- NF-κB2 (also called p52) - NFKB2
- RelA (also named p65) - RELA
- RelB - RELB
- c-Rel REL
In addition, there are NF-κB proteins in lower organisms, such as the fruit fly Drosophila, sea urchins, sea anemones and sponges.
All proteins of the NF-κB family share a Rel homology domain in their N-terminal halves. A subfamily of NF-κB proteins, including RelA, RelB and c-Rel, have a transactivation domain in their C-termini. In contrast, the NF-κB1 and NF-κB2 proteins are synthesized as large precursors, p105 and p100, which undergo processing to generate the mature NF-κB subunits, p50 and p52, respectively. The processing of p105 and p100 is mediated by the ubiquitin/proteasome pathway and involves selective degradation of their C-terminal region containing ankyrin repeats. While the generation of p52 from p100 is a tightly regulated process, p50 is produced from constitutive processing of p105.[4][5]
# Activation of NF-κB
Part of NF-κB's importance in regulating cellular responses is that it belongs to the category of "rapid-acting" primary transcription factors---i.e., transcription factors which are present in cells in an inactive state and do not require new protein synthesis to be activated (other members of this family include transcription factors such as c-Jun, STATs and nuclear hormone receptors). This allows NF-κB to act as a "first responder" to harmful cellular stimuli. Stimulation of a wide variety of cell-surface receptors, such as[2] RANK, TNFR, IL1R leads directly to NF-κB activation and fairly rapid changes in gene expression.
Many bacterial products can activate NF-κB. The identification of Toll-like receptors (TLRs) as specific pattern recognition molecules and the finding that stimulation of TLRs leads to activation of NF-κB improved our understanding of how different pathogens activate NF-κB. For example, studies have identified TLR4 as the receptor for the LPS component of Gram-Negative bacteria. TLRs are key regulators of both innate and adaptive immune responses.
Unlike RelA, RelB, and c-Rel, the p50 and p52 NF-κB subunits do not contain transactivation domains in their C terminal halves. Nevertheless, the p50 and p52 NF-κB members play critical roles in modulating the specificity of NF-κB function. Although homodimers of p50 and p52 are generally repressors of κB site transcription, both p50 and p52 participate in target gene transactivation by forming heterodimers with RelA, RelB or c-Rel.[6] Additionally, p50 and p52 homodimers also bind to the nuclear protein Bcl-3, and such complexes can function as transcriptional activators.[7][8][9]
# Inhibitors of NF-κB
In unstimulated cells, the NF-κB dimers are sequestered in the cytoplasm by a family of inhibitors, called IκBs (Inhibitor of kappa B), which are proteins that contain multiple copies of a sequence called ankyrin repeats. By virtue of their ankyrin repeat domains, the IκB proteins mask the nuclear localization signals (NLS) of NF-κB proteins and keep them sequestered in an inactive state in the cytoplasm.[10]
IκBs are a family of related proteins that have an N-terminal regulatory domain, followed by six or more ankyrin repeats and a PEST domain near their C terminus. Although the IκB family consists of IκBα, IκBβ, IκBγ, IκBε and Bcl-3, the best studied and major IκB protein is IκBα. Due to the presence of ankyrin repeats in their C-terminal halves, p105 and p100 also function as IκB proteins. Of all the IκB members, IκBγ is unique in that it is synthesized from the nf-kb1 gene using an internal promoter, thereby resulting in a protein which is identical to the C-terminal half of p105.[11]
Activation of the NF-κB is initiated by the signal-induced degradation of IκB proteins. This occurs primarily via activation of a kinase called the IκB kinase (IKK). IKK is composed of a heterodimer of the catalytic IKK alpha and IKK beta subunits and a "master" regulatory protein termed NEMO (NF-kappa B essential modulator) or IKK gamma. When activated by signals, usually coming from the outside of the cell, the IκB kinase phosphorylates two serine residues located in an IκB regulatory domain. When phosphorylated on these serines (e.g., serines 32 and 36 in human IκBα), the IκB inhibitor molecules are modified by a process called ubiquitination which then leads them to be degraded by a cell structure called the proteasome.
With the degradation of the IκB inhibitor, the NF-κB complex is then freed to enter the nucleus where it can 'turn on' the expression of specific genes that have DNA-binding sites for NF-κB nearby. The activation of these genes by NF-κB then leads to the given physiological response, for example, an inflammatory or immune response, a cell survival response, or cellular proliferation. NF-κB turns on expression of its own repressor, IκBα. The newly-synthesized IκBα then re-inhibits NF-κB and thus forms an auto feedback loop, that results in oscillating levels of NF-κB activity.[12] In addition, several viruses, including the AIDS virus HIV, have binding sites for NF-κB that controls the expression of viral genes, which in turn contribute to viral replication or viral pathogenicity. In the case of HIV-1, activation of NF-κB may, at least in part, be involved in activation of the virus from a latent, inactive state. YopJ is a factor secreted by Yersinia pestis, the causative agent of plague, that prevents the ubiquitination of IκB. This causes this pathogen to effectively inhibit the NF-κB pathway and thus block the immune response of a human infected with Yersinia.
# NF-κB's Role in Cancer and Other Diseases
NF-κB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. As such, many different types of human tumors have misregulated NF-κB: that is, NF-κB is constitutively active. Active NF-κB turns on the expression of genes that keep the cell proliferating and protect the cell from conditions that would otherwise cause it to die. In tumor cells, NF-κB is active either due to mutations in genes encoding the NF-κB transcription factors themselves or in genes that control NF-κB activity (such as IκB genes); in addition, some tumor cells secrete factors that cause NF-κB to become active. Blocking NF-κB can cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents. Thus, NF-κB is the subject of much active research among pharmaceutical companies as a target for anti-cancer therapy.[13]
Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, among others. Many natural products (including anti-oxidants) that have been promoted to have anti-cancer and anti-inflammatory activity have also been shown to inhibit NF-κB.It has been shown that in vivo administration of Insulin also leads to anti inflammatory effects through inhibition of NF kB in mono-nuclear cells of obese patients. There is a controversial US patent (US patent 6,410,516)[14] that applies to the discovery and use of agents that can block NF-κB for therapeutic purposes. This patent is involved in several lawsuits, including Ariad v. Lilly. Recent work by Karin, Ben-Neriah and others has highlighted the importance of the connection between NF-κB, inflammation and cancer and underscored the value of therapies that regulate the activity of NF-κB.
It has also been proposed that NF-κB has a role in the growth and proliferation of myocardial cells infected with Trypanosoma cruzi. In myocardial cells of normal mice it is normal to detect a low background of NF-κB activity. In mice infected with T. cruzi, the levels of NF-κB DNA-binding activity become elevated.[15]
# Signaling in Immunity
NF-kB is a major transcription factor which regulates genes responsible for both the innate immune response and the adaptive immune response. Upon activation of either the T- or B-cell receptor, NF-kB becomes activated through distinct signaling components. Upon ligation of the T-cell receptor, an adaptor molecule, ZAP70 is recruited via its SH2 domain to the cytoplasmic side of the receptor. ZAP70 helps recruit both LCK and PLCgamma, which causes activation of PKC. Through a cascade of phosphorylation events, the kinase complex is activated and NF-kB is able to enter the nucleus to upregulate genes involved in T-cell development, maturation and proliferation.
# Conserved in evolution
NF-kB is found in a number of simple organisms as well. These include Cnidarians (such as sea anemones and coral), Porifera (sponges) and insects (such as moths, mosquitoes and fruitflies). The sequencing of the genomes of Aedes aegypti, anopheles gambae, and the fruitfly Drosophila melanogaster has allowed comparative genetic and evolutionary studies on NF-kB. In those insect species, activation of NF-kB is triggered by the Toll pathway (which evolved independently in insects and mammals) and by the Imd pathway.[16] | https://www.wikidoc.org/index.php/NF-kB | |
ddf7faac78dd534570117c72c2dd9de97fe31ff3 | wikidoc | NF-κB | NF-κB
NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.
# Discovery
NF-κB was discovered by Ranjan Sen (NIH) in the lab of Nobel Prize laureate David Baltimore via its interaction with an 11-base pair sequence in the immunoglobulin light-chain enhancer in B cells.
# Structure
All proteins of the NF-κB family share a Rel homology domain in their N-terminus. A subfamily of NF-κB proteins, including RelA, RelB, and c-Rel, have a transactivation domain in their C-termini. In contrast, the NF-κB1 and NF-κB2 proteins are synthesized as large precursors, p105, and p100, which undergo processing to generate the mature NF-κB subunits, p50 and p52, respectively. The processing of p105 and p100 is mediated by the ubiquitin/proteasome pathway and involves selective degradation of their C-terminal region containing ankyrin repeats. Whereas the generation of p52 from p100 is a tightly regulated process, p50 is produced from constitutive processing of p105. The p50 and p52 proteins have no intrinsic ability to activate transcription and thus have been proposed to act as transcriptional repressors when binding κB elements as homodimers. Indeed, this confounds the interpretation of p105-knockout studies, where the genetic manipulation is removing an IκB (full-length p105) and a likely repressor (p50 homodimers) in addition to a transcriptional activator (the RelA-p50 heterodimer).
# Members
NF-κB family members share structural homology with the retroviral oncoprotein v-Rel, resulting in their classification as NF-κB/Rel proteins.
There are five proteins in the mammalian NF-κB family:
Below are the five human NF-κB family members:
# Species distribution and evolution
In addition to mammals, NF-κB is found in a number of simple animals as well. These include cnidarians (such as sea anemones, coral and hydra), porifera (sponges), the single-celled eukaryote Capsaspora owczarzaki and insects (such as moths, mosquitoes and fruitflies). The sequencing of the genomes of the mosquitoes A. aegypti and A. gambiae, and the fruitfly D. melanogaster has allowed comparative genetic and evolutionary studies on NF-κB. In those insect species, activation of NF-κB is triggered by the Toll pathway (which evolved independently in insects and mammals) and by the Imd (immune deficiency) pathway.
# Signaling
## Effect of activation
NF-κB is important in regulating cellular responses because it belongs to the category of "rapid-acting" primary transcription factors, i.e., transcription factors that are present in cells in an inactive state and do not require new protein synthesis in order to become activated (other members of this family include transcription factors such as c-Jun, STATs, and nuclear hormone receptors). This allows NF-κB to be a first responder to harmful cellular stimuli. Known inducers of NF-κB activity are highly variable and include reactive oxygen species (ROS), tumor necrosis factor alpha (TNFα), interleukin 1-beta (IL-1β), bacterial lipopolysaccharides (LPS), isoproterenol, cocaine, and ionizing radiation.
Receptor activator of NF-κB (RANK), which is a type of TNFR, is a central activator of NF-κB. Osteoprotegerin (OPG), which is a decoy receptor homolog for RANK ligand (RANKL), inhibits RANK by binding to RANKL, and, thus, osteoprotegerin is tightly involved in regulating NF-κB activation.
Many bacterial products and stimulation of a wide variety of cell-surface receptors lead to NF-κB activation and fairly rapid changes in gene expression. The identification of Toll-like receptors (TLRs) as specific pattern recognition molecules and the finding that stimulation of TLRs leads to activation of NF-κB improved our understanding of how different pathogens activate NF-κB. For example, studies have identified TLR4 as the receptor for the LPS component of Gram-negative bacteria. TLRs are key regulators of both innate and adaptive immune responses.
Unlike RelA, RelB, and c-Rel, the p50 and p52 NF-κB subunits do not contain transactivation domains in their C terminal halves. Nevertheless, the p50 and p52 NF-κB members play critical roles in modulating the specificity of NF-κB function. Although homodimers of p50 and p52 are, in general, repressors of κB site transcription, both p50 and p52 participate in target gene transactivation by forming heterodimers with RelA, RelB, or c-Rel. In addition, p50 and p52 homodimers also bind to the nuclear protein Bcl-3, and such complexes can function as transcriptional activators.
## Inhibition
In unstimulated cells, the NF-κB dimers are sequestered in the cytoplasm by a family of inhibitors, called IκBs (Inhibitor of κB), which are proteins that contain multiple copies of a sequence called ankyrin repeats. By virtue of their ankyrin repeat domains, the IκB proteins mask the nuclear localization signals (NLS) of NF-κB proteins and keep them sequestered in an inactive state in the cytoplasm.
IκBs are a family of related proteins that have an N-terminal regulatory domain, followed by six or more ankyrin repeats and a PEST domain near their C terminus. Although the IκB family consists of IκBα, IκBβ, IκBε, and Bcl-3, the best-studied and major IκB protein is IκBα. Due to the presence of ankyrin repeats in their C-terminal halves, p105 and p100 also function as IκB proteins. The c-terminal half of p100, that is often referred to as IκBδ, also functions as an inhibitor. IκBδ degradation in response to developmental stimuli, such as those transduced through LTβR, potentiate NF-κB dimer activation in a NIK dependent non-canonical pathway.
## Activation process (canonical/classical)
Activation of the NF-κB is initiated by the signal-induced degradation of IκB proteins. This occurs primarily via activation of a kinase called the IκB kinase (IKK). IKK is composed of a heterodimer of the catalytic IKKα and IKKβ subunits and a "master" regulatory protein termed NEMO (NF-κB essential modulator) or IKK gamma. When activated by signals, usually coming from the outside of the cell, the IκB kinase phosphorylates two serine residues located in an IκB regulatory domain. When phosphorylated on these serines (e.g., serines 32 and 36 in human IκBα), the IκB proteins are modified by a process called ubiquitination, which then leads them to be degraded by a cell structure called the proteasome.
With the degradation of IκB, the NF-κB complex is then freed to enter the nucleus where it can 'turn on' the expression of specific genes that have DNA-binding sites for NF-κB nearby. The activation of these genes by NF-κB then leads to the given physiological response, for example, an inflammatory or immune response, a cell survival response, or cellular proliferation. Translocation of NF-κB to nucleus can be detected immunocytochemically and measured by laser scanning cytometry. NF-κB turns on expression of its own repressor, IκBα. The newly synthesized IκBα then re-inhibits NF-κB and, thus, forms an auto feedback loop, which results in oscillating levels of NF-κB activity. In addition, several viruses, including the AIDS virus HIV, have binding sites for NF-κB that controls the expression of viral genes, which in turn contribute to viral replication or viral pathogenicity. In the case of HIV-1, activation of NF-κB may, at least in part, be involved in activation of the virus from a latent, inactive state. YopP is a factor secreted by Yersinia pestis, the causative agent of plague, that prevents the ubiquitination of IκB. This causes this pathogen to effectively inhibit the NF-κB pathway and thus block the immune response of a human infected with Yersinia.
## Inhibitors of NF-κB activity
Concerning known protein inhibitors of NF-κB activity, one of them is IFRD1, which represses the activity of NF-κB p65 by enhancing the HDAC-mediated deacetylation of the p65 subunit at lysine 310, by favoring the recruitment of HDAC3 to p65. In fact IFRD1 forms trimolecular complexes with p65 and HDAC3.
The NAD+-dependent protein deacetylase and longevity factor SIRT1 inhibits NF-κB gene expression by deacetylating the RelA/p65 subunit of NF-kB at lysine 310.
## Non-canonical/alternate pathway
A select set of cell-differentiating or developmental stimuli, such as lymphotoxin β-receptor (LTβR), BAFF or RANKL, activate the non-canonical NF-κB pathway to induce NF-κB/RelB:p52 dimer in the nucleus. In this pathway, activation of the NF-κB inducing kinase (NIK) upon receptor ligation led to the phosphorylation and subsequent proteasomal processing of the NF-κB2 precursor protein p100 into mature p52 subunit in an IKK1/IKKa dependent manner. Then p52 dimerizes with RelB to appear as a nuclear RelB:p52 DNA binding activity and regulate a distinct class of genes. In contrast to the canonical signaling that relies upon NEMO-IKK2 mediated degradation of IκBα, -β, -ε, the non-canonical signaling critically depends on NIK mediated processing of p100 into p52. Given their distinct regulations, these two pathways were thought to be independent of each other. However, recent analyses revealed that synthesis of the constituents of the non-canonical pathway, viz RelB and p52, is controlled by the canonical IKK2-IκB-RelA:p50 signaling. Moreover, generation of the canonical and non-canonical dimers, viz RelA:p50 and RelB:p52, within the cellular milieu are also mechanistically interlinked. These analyses suggest that an integrated NF-κB system network underlies activation of both RelA and RelB containing dimer and that a malfunctioning canonical pathway will lead to an aberrant cellular response also through the non-canonical pathway.
## In immunity
NF-κB is a major transcription factor that regulates genes responsible for both the innate and adaptive immune response. Upon activation of either the T- or B-cell receptor, NF-κB becomes activated through distinct signaling components. Upon ligation of the T-cell receptor, protein kinase Lck is recruited and phosphorylates the ITAMs of the CD3 cytoplasmic tail. ZAP70 is then recruited to the phosphorylated ITAMs and helps recruit LAT and PLC-γ, which causes activation of PKC. Through a cascade of phosphorylation events, the kinase complex is activated and NF-κB is able to enter the nucleus to upregulate genes involved in T-cell development, maturation, and proliferation.
## In the nervous system
In addition to roles in mediating cell survival, studies by Mark Mattson and others have shown that NF-κB has diverse functions in the nervous system including roles in plasticity, learning, and memory. In addition to stimuli that activate NF-κB in other tissues, NF-κB in the nervous system can be activated by Growth Factors (BDNF, NGF) and synaptic transmission such as glutamate. These activators of NF-κB in the nervous system all converge upon the IKK complex and the canonical pathway.
Recently there has been a great deal of interest in the role of NF-κB in the nervous system. Current studies suggest that NF-κB is important for learning and memory in multiple organisms including crabs, fruit flies, and mice. NF-κB may regulate learning and memory in part by modulating synaptic plasticity, synapse function, as well as by regulating the growth of dendrites and dendritic spines.
Genes that have NF-κB binding sites are shown to have increased expression following learning, suggesting that the transcriptional targets of NF-κB in the nervous system are important for plasticity. Many NF-κB target genes that may be important for plasticity and learning include growth factors (BDNF, NGF) cytokines (TNF-alpha, TNFR) and kinases (PKAc).
Despite the functional evidence for a role for Rel-family transcription factors in the nervous system, it is still not clear that the neurological effects of NF-κB reflect transcriptional activation in neurons. Most manipulations and assays are performed in the mixed-cell environments found in vivo, in "neuronal" cell cultures that contain significant numbers of glia, or in tumor-derived "neuronal" cell lines. When transfections or other manipulations have been targeted specifically at neurons, the endpoints measured are typically electrophysiology or other parameters far removed from gene transcription. Careful tests of NF-κB-dependent transcription in highly purified cultures of neurons generally show little to no NF-κB activity. Some of the reports of NF-κB in neurons appear to have been an artifact of antibody nonspecificity. Of course, artifacts of cell culture—e.g., removal of neurons from the influence of glia—could create spurious results as well. But this has been addressed in at least two coculture approaches. Moerman et al. used a coculture format whereby neurons and glia could be separated after treatment for EMSA analysis, and they found that the NF-κB induced by glutamatergic stimuli was restricted to glia (and, intriguingly, only glia that had been in the presence of neurons for 48 hours). The same investigators explored the issue in another approach, utilizing neurons from an NF-κB reporter transgenic mouse cultured with wild-type glia; glutamatergic stimuli again failed to activate in neurons. Some of the DNA-binding activity noted under certain conditions (particularly that reported as constitutive) appears to result from Sp3 and Sp4 binding to a subset of κB enhancer sequences in neurons. This activity is actually inhibited by glutamate and other conditions that elevate intraneuronal calcium. In the final analysis, the role of NF-κB in neurons remains opaque due to the difficulty of measuring transcription in cells that are simultaneously identified for type. Certainly, learning and memory could be influenced by transcriptional changes in astrocytes and other glial elements. And it should be considered that there could be mechanistic effects of NF-κB aside from direct transactivation of genes.
# Clinical significance
## Cancers
NF-κB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. As such, many different types of human tumors have misregulated NF-κB: that is, NF-κB is constitutively active. Active NF-κB turns on the expression of genes that keep the cell proliferating and protect the cell from conditions that would otherwise cause it to die via apoptosis. In cancer, proteins that control NF-κB signaling are mutated or aberrantly expressed, leading to defective coordination between the malignant cell and the rest of the organism. This is evident both in metastasis, as well as in the inefficient eradication of the tumor by the immune system.
Normal cells can die when removed from the tissue they belong to, or when their genome cannot operate in harmony with tissue function: these events depend on feedback regulation of NF-κB, and fail in cancer.
Defects in NF-κB results in increased susceptibility to apoptosis leading to increased cell death. This is because NF-κB regulates anti-apoptotic genes especially the TRAF1 and TRAF2 and therefore abrogates the activities of the caspase family of enzymes, which are central to most apoptotic processes.
In tumor cells, NF-κB is active (for example, in 41% of Nasopharyngeal carcinoma) either due to mutations in genes encoding the NF-κB transcription factors themselves or in genes that control NF-κB activity (such as IκB genes); in addition, some tumor cells secrete factors that cause NF-κB to become active. Blocking NF-κB can cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents. Thus, NF-κB is the subject of much active research among pharmaceutical companies as a target for anti-cancer therapy.
However, even though convincing experimental data have identified NF-κB as a critical promoter of tumorigenesis, which creates a solid rationale for the development of antitumor therapy that is based upon suppression of NF-κB activity, caution should be exercised when considering anti-NF-κB activity as a broad therapeutic strategy in cancer treatment as data has also shown that NF-κB activity enhances tumor cell sensitivity to apoptosis and senescence. In addition, it has been shown that canonical NF-κB is a Fas transcription activator and the alternative NF-κB is a Fas transcription repressor. Therefore, NF-κB promotes Fas-mediated apoptosis in cancer cells, and thus inhibition of NF-κB may suppress Fas-mediated apoptosis to impair host immune cell-mediated tumor suppression.
## Inflammation
Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, gastritis, asthma, atherosclerosis and others. It is important to note though, that elevation of some NF-κB activators, such as osteoprotegerin (OPG), are associated with elevated mortality, especially from cardiovascular diseases. Elevated NF-κB has also been associated with schizophrenia. Recently, NF-κB activation has been suggested as a possible molecular mechanism for the catabolic effects of cigarette smoke in skeletal muscle and sarcopenia.
Research has shown that during inflammation the function of a cell depends on signals it activates in response to contact with adjacent cells and to combinations of hormones, especially cytokines that act on it through specific receptors. A cells’ phenotype within a tissue develops through mutual stimulation of feedback signals that coordinate its function with other cells; this is especially evident during reprogramming of cell function when a tissue is exposed to inflammation, because cells alter their phenotype, and gradually express combinations of genes that prepare the tissue for regeneration after the cause of inflammation is removed. Particularly important are feedback responses that develop between tissue resident cells, and circulating cells of the immune system. Fidelity of feedback responses between diverse cell types and the immune system depends on the integrity of mechanisms that limit the range of genes activated by NF-κB, allowing only expression of genes which contribute to an effective immune response and subsequently, a complete restoration of tissue function after resolution of inflammation. In cancer, mechanisms that regulate gene expression in response to inflammatory stimuli are altered to the point that a cell ceases to link its survival with the mechanisms that coordinate its phenotype and its function with the rest of the tissue. This is often evident in severely compromised regulation of NF-κB activity, which allows cancer cells to express abnormal cohorts of NF-κB target genes. This results in not only the cancer cells functioning abnormally: cells of surrounding tissue alter their function and cease to support the organism exclusively. Additionally, several types of cells in the microenvironment of cancer may change their phenotypes to support cancer growth. Inflammation, therefore, is a process that tests the fidelity of tissue components because the process that leads to tissue regeneration requires coordination of gene expression between diverse cell types.
## NEMO
NEMO deficiency syndrome is a rare genetic condition relating to a fault in IKBKG that in turn activates NF-kB. It mostly affects males and has a highly variable set of symptoms and prognoses.
## Addiction
NF-κB is one of several induced transcriptional targets of ΔFosB which facilitates the development and maintenance of an addiction to a stimulus. In the caudate putamen, NF-κB induction is associated with increases in locomotion, whereas in the nucleus accumbens, NF-κB induction enhances the positive reinforcing effect of a drug through reward sensitization.
# Non-drug inhibitors
Many natural products (including anti-oxidants) that have been promoted to have anti-cancer and anti-inflammatory activity have also been shown to inhibit NF-κB. There is a controversial US patent (US patent 6,410,516) that applies to the discovery and use of agents that can block NF-κB for therapeutic purposes. This patent is involved in several lawsuits, including Ariad v. Lilly. Recent work by Karin, Ben-Neriah and others has highlighted the importance of the connection between NF-κB, inflammation, and cancer, and underscored the value of therapies that regulate the activity of NF-κB.
Extracts from a number of herbs and dietary plants are efficient inhibitors of NF-κB activation in vitro.
The circumsporozoite protein of Plasmodium falciparum has been shown to be an inhibitor of NF-κB.
# As a drug target
Aberrant activation of NF-κB is frequently observed in many cancers. Moreover, suppression of NF-κB limits the proliferation of cancer cells. In addition, NF-κB is a key player in the inflammatory response. Hence methods of inhibiting NF-κB signaling has potential therapeutic application in cancer and inflammatory diseases.
The discovery that activation of NF-κB nuclear translocation can be separated from the elevation of oxidant stress gives a promising avenue of development for strategies targeting NF-κB inhibition.
A new drug called denosumab acts to raise bone mineral density and reduce fracture rates in many patient sub-groups by inhibiting RANKL. RANKL acts through its receptor RANK, which in turn promotes NF-κB,
RANKL normally works by enabling the differentiation of osteoclasts from monocytes.
Disulfiram, olmesartan and dithiocarbamates can inhibit the nuclear factor-κB (NF-κB) signaling cascade. Effort to develop direct NF-kB inhibitor has emerged with compounds such as (-)-DHMEQ, PBS-1086, IT-603 and IT-901. (-)-DHMEQ and PBS-1086 are irreversible binder to NF-KB while IT-603 and IT-901 are reversible binder. DHMEQ covalently binds to Cys 38 of p65.
Anatabine's antiinflammatory effects are claimed to result from modulation of NF-κB activity. However the studies purporting its benefit use abnormally high doses in the millimolar range (similar to the extracellular potassium concentration), which are unlikely to be achieved in humans.
BAY 11-7082 has also been identified as a drug that can inhibit the NF-kB signaling cascade. It is capable of preventing the phosphorylation of IKK-α in an irreversible manner such that there is down regulation of NF-kB activation. In has been shown that administration of BAY 11-7082 rescued renal functionality in diabetic-induced Sprague-Dawley rats by suppressing NF-kB regulated oxidative stress.
The biological target of iguratimod, a drug marketed to treat rheumatoid arthritis in Japan and China, was unknown as of 2015, but the primary mechanism of action appeared to be preventing NF-κB activation. | NF-κB
NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens.[1][2][3][4][5] NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.[6][7][8][9][10][11]
# Discovery
NF-κB was discovered by Ranjan Sen (NIH) in the lab of Nobel Prize laureate David Baltimore via its interaction with an 11-base pair sequence in the immunoglobulin light-chain enhancer in B cells.[12]
# Structure
All proteins of the NF-κB family share a Rel homology domain in their N-terminus. A subfamily of NF-κB proteins, including RelA, RelB, and c-Rel, have a transactivation domain in their C-termini. In contrast, the NF-κB1 and NF-κB2 proteins are synthesized as large precursors, p105, and p100, which undergo processing to generate the mature NF-κB subunits, p50 and p52, respectively. The processing of p105 and p100 is mediated by the ubiquitin/proteasome pathway and involves selective degradation of their C-terminal region containing ankyrin repeats. Whereas the generation of p52 from p100 is a tightly regulated process, p50 is produced from constitutive processing of p105.[13][14] The p50 and p52 proteins have no intrinsic ability to activate transcription and thus have been proposed to act as transcriptional repressors when binding κB elements as homodimers.[15][16] Indeed, this confounds the interpretation of p105-knockout studies, where the genetic manipulation is removing an IκB (full-length p105) and a likely repressor (p50 homodimers) in addition to a transcriptional activator (the RelA-p50 heterodimer).
# Members
NF-κB family members share structural homology with the retroviral oncoprotein v-Rel, resulting in their classification as NF-κB/Rel proteins.[1]
There are five proteins in the mammalian NF-κB family:[17]
Below are the five human NF-κB family members:
# Species distribution and evolution
In addition to mammals, NF-κB is found in a number of simple animals as well.[18] These include cnidarians (such as sea anemones, coral and hydra), porifera (sponges), the single-celled eukaryote Capsaspora owczarzaki and insects (such as moths, mosquitoes and fruitflies). The sequencing of the genomes of the mosquitoes A. aegypti and A. gambiae, and the fruitfly D. melanogaster has allowed comparative genetic and evolutionary studies on NF-κB. In those insect species, activation of NF-κB is triggered by the Toll pathway (which evolved independently in insects and mammals) and by the Imd (immune deficiency) pathway.[19]
# Signaling
## Effect of activation
NF-κB is important in regulating cellular responses because it belongs to the category of "rapid-acting" primary transcription factors, i.e., transcription factors that are present in cells in an inactive state and do not require new protein synthesis in order to become activated (other members of this family include transcription factors such as c-Jun, STATs, and nuclear hormone receptors). This allows NF-κB to be a first responder to harmful cellular stimuli. Known inducers of NF-κB activity are highly variable and include reactive oxygen species (ROS), tumor necrosis factor alpha (TNFα), interleukin 1-beta (IL-1β), bacterial lipopolysaccharides (LPS), isoproterenol, cocaine, and ionizing radiation.[21]
Receptor activator of NF-κB (RANK), which is a type of TNFR, is a central activator of NF-κB. Osteoprotegerin (OPG), which is a decoy receptor homolog for RANK ligand (RANKL), inhibits RANK by binding to RANKL, and, thus, osteoprotegerin is tightly involved in regulating NF-κB activation.[22]
Many bacterial products and stimulation of a wide variety of cell-surface receptors lead to NF-κB activation and fairly rapid changes in gene expression.[1] The identification of Toll-like receptors (TLRs) as specific pattern recognition molecules and the finding that stimulation of TLRs leads to activation of NF-κB improved our understanding of how different pathogens activate NF-κB. For example, studies have identified TLR4 as the receptor for the LPS component of Gram-negative bacteria.[23] TLRs are key regulators of both innate and adaptive immune responses.[24]
Unlike RelA, RelB, and c-Rel, the p50 and p52 NF-κB subunits do not contain transactivation domains in their C terminal halves. Nevertheless, the p50 and p52 NF-κB members play critical roles in modulating the specificity of NF-κB function. Although homodimers of p50 and p52 are, in general, repressors of κB site transcription, both p50 and p52 participate in target gene transactivation by forming heterodimers with RelA, RelB, or c-Rel.[25] In addition, p50 and p52 homodimers also bind to the nuclear protein Bcl-3, and such complexes can function as transcriptional activators.[26][27][28]
## Inhibition
In unstimulated cells, the NF-κB dimers are sequestered in the cytoplasm by a family of inhibitors, called IκBs (Inhibitor of κB), which are proteins that contain multiple copies of a sequence called ankyrin repeats. By virtue of their ankyrin repeat domains, the IκB proteins mask the nuclear localization signals (NLS) of NF-κB proteins and keep them sequestered in an inactive state in the cytoplasm.[29]
IκBs are a family of related proteins that have an N-terminal regulatory domain, followed by six or more ankyrin repeats and a PEST domain near their C terminus. Although the IκB family consists of IκBα, IκBβ, IκBε, and Bcl-3, the best-studied and major IκB protein is IκBα. Due to the presence of ankyrin repeats in their C-terminal halves, p105 and p100 also function as IκB proteins. The c-terminal half of p100, that is often referred to as IκBδ, also functions as an inhibitor.[30][31] IκBδ degradation in response to developmental stimuli, such as those transduced through LTβR, potentiate NF-κB dimer activation in a NIK dependent non-canonical pathway.[30][32]
## Activation process (canonical/classical)
Activation of the NF-κB is initiated by the signal-induced degradation of IκB proteins. This occurs primarily via activation of a kinase called the IκB kinase (IKK). IKK is composed of a heterodimer of the catalytic IKKα and IKKβ subunits and a "master" regulatory protein termed NEMO (NF-κB essential modulator) or IKK gamma. When activated by signals, usually coming from the outside of the cell, the IκB kinase phosphorylates two serine residues located in an IκB regulatory domain. When phosphorylated on these serines (e.g., serines 32 and 36 in human IκBα), the IκB proteins are modified by a process called ubiquitination, which then leads them to be degraded by a cell structure called the proteasome.
With the degradation of IκB, the NF-κB complex is then freed to enter the nucleus where it can 'turn on' the expression of specific genes that have DNA-binding sites for NF-κB nearby. The activation of these genes by NF-κB then leads to the given physiological response, for example, an inflammatory or immune response, a cell survival response, or cellular proliferation. Translocation of NF-κB to nucleus can be detected immunocytochemically and measured by laser scanning cytometry.[33] NF-κB turns on expression of its own repressor, IκBα. The newly synthesized IκBα then re-inhibits NF-κB and, thus, forms an auto feedback loop, which results in oscillating levels of NF-κB activity.[34] In addition, several viruses, including the AIDS virus HIV, have binding sites for NF-κB that controls the expression of viral genes, which in turn contribute to viral replication or viral pathogenicity. In the case of HIV-1, activation of NF-κB may, at least in part, be involved in activation of the virus from a latent, inactive state.[35] YopP is a factor secreted by Yersinia pestis, the causative agent of plague, that prevents the ubiquitination of IκB. This causes this pathogen to effectively inhibit the NF-κB pathway and thus block the immune response of a human infected with Yersinia.[36]
## Inhibitors of NF-κB activity
Concerning known protein inhibitors of NF-κB activity, one of them is IFRD1, which represses the activity of NF-κB p65 by enhancing the HDAC-mediated deacetylation of the p65 subunit at lysine 310, by favoring the recruitment of HDAC3 to p65. In fact IFRD1 forms trimolecular complexes with p65 and HDAC3.[37][38]
The NAD+-dependent protein deacetylase and longevity factor SIRT1 inhibits NF-κB gene expression by deacetylating the RelA/p65 subunit of NF-kB at lysine 310.[39]
## Non-canonical/alternate pathway
A select set of cell-differentiating or developmental stimuli, such as lymphotoxin β-receptor (LTβR), BAFF or RANKL, activate the non-canonical NF-κB pathway to induce NF-κB/RelB:p52 dimer in the nucleus. In this pathway, activation of the NF-κB inducing kinase (NIK) upon receptor ligation led to the phosphorylation and subsequent proteasomal processing of the NF-κB2 precursor protein p100 into mature p52 subunit in an IKK1/IKKa dependent manner. Then p52 dimerizes with RelB to appear as a nuclear RelB:p52 DNA binding activity and regulate a distinct class of genes.[40] In contrast to the canonical signaling that relies upon NEMO-IKK2 mediated degradation of IκBα, -β, -ε, the non-canonical signaling critically depends on NIK mediated processing of p100 into p52. Given their distinct regulations, these two pathways were thought to be independent of each other. However, recent analyses revealed that synthesis of the constituents of the non-canonical pathway, viz RelB and p52, is controlled by the canonical IKK2-IκB-RelA:p50 signaling.[41] Moreover, generation of the canonical and non-canonical dimers, viz RelA:p50 and RelB:p52, within the cellular milieu are also mechanistically interlinked.[41] These analyses suggest that an integrated NF-κB system network underlies activation of both RelA and RelB containing dimer and that a malfunctioning canonical pathway will lead to an aberrant cellular response also through the non-canonical pathway.
## In immunity
NF-κB is a major transcription factor that regulates genes responsible for both the innate and adaptive immune response.[42] Upon activation of either the T- or B-cell receptor, NF-κB becomes activated through distinct signaling components. Upon ligation of the T-cell receptor, protein kinase Lck is recruited and phosphorylates the ITAMs of the CD3 cytoplasmic tail. ZAP70 is then recruited to the phosphorylated ITAMs and helps recruit LAT and PLC-γ, which causes activation of PKC. Through a cascade of phosphorylation events, the kinase complex is activated and NF-κB is able to enter the nucleus to upregulate genes involved in T-cell development, maturation, and proliferation.[43]
## In the nervous system
In addition to roles in mediating cell survival, studies by Mark Mattson and others have shown that NF-κB has diverse functions in the nervous system including roles in plasticity, learning, and memory. In addition to stimuli that activate NF-κB in other tissues, NF-κB in the nervous system can be activated by Growth Factors (BDNF, NGF) and synaptic transmission such as glutamate.[7] These activators of NF-κB in the nervous system all converge upon the IKK complex and the canonical pathway.
Recently there has been a great deal of interest in the role of NF-κB in the nervous system. Current studies suggest that NF-κB is important for learning and memory in multiple organisms including crabs,[9][10] fruit flies,[44] and mice.[7][8] NF-κB may regulate learning and memory in part by modulating synaptic plasticity,[6][45] synapse function,[44][46][47] as well as by regulating the growth of dendrites[48] and dendritic spines.[47]
Genes that have NF-κB binding sites are shown to have increased expression following learning,[8] suggesting that the transcriptional targets of NF-κB in the nervous system are important for plasticity. Many NF-κB target genes that may be important for plasticity and learning include growth factors (BDNF, NGF)[49] cytokines (TNF-alpha, TNFR)[50] and kinases (PKAc).[45]
Despite the functional evidence for a role for Rel-family transcription factors in the nervous system, it is still not clear that the neurological effects of NF-κB reflect transcriptional activation in neurons. Most manipulations and assays are performed in the mixed-cell environments found in vivo, in "neuronal" cell cultures that contain significant numbers of glia, or in tumor-derived "neuronal" cell lines. When transfections or other manipulations have been targeted specifically at neurons, the endpoints measured are typically electrophysiology or other parameters far removed from gene transcription. Careful tests of NF-κB-dependent transcription in highly purified cultures of neurons generally show little to no NF-κB activity.[51][52] Some of the reports of NF-κB in neurons appear to have been an artifact of antibody nonspecificity.[53] Of course, artifacts of cell culture—e.g., removal of neurons from the influence of glia—could create spurious results as well. But this has been addressed in at least two coculture approaches. Moerman et al.[54] used a coculture format whereby neurons and glia could be separated after treatment for EMSA analysis, and they found that the NF-κB induced by glutamatergic stimuli was restricted to glia (and, intriguingly, only glia that had been in the presence of neurons for 48 hours). The same investigators explored the issue in another approach, utilizing neurons from an NF-κB reporter transgenic mouse cultured with wild-type glia; glutamatergic stimuli again failed to activate in neurons.[55] Some of the DNA-binding activity noted under certain conditions (particularly that reported as constitutive) appears to result from Sp3 and Sp4 binding to a subset of κB enhancer sequences in neurons.[56] This activity is actually inhibited by glutamate and other conditions that elevate intraneuronal calcium. In the final analysis, the role of NF-κB in neurons remains opaque due to the difficulty of measuring transcription in cells that are simultaneously identified for type. Certainly, learning and memory could be influenced by transcriptional changes in astrocytes and other glial elements. And it should be considered that there could be mechanistic effects of NF-κB aside from direct transactivation of genes.
# Clinical significance
## Cancers
NF-κB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. As such, many different types of human tumors have misregulated NF-κB: that is, NF-κB is constitutively active. Active NF-κB turns on the expression of genes that keep the cell proliferating and protect the cell from conditions that would otherwise cause it to die via apoptosis. In cancer, proteins that control NF-κB signaling are mutated or aberrantly expressed, leading to defective coordination between the malignant cell and the rest of the organism. This is evident both in metastasis, as well as in the inefficient eradication of the tumor by the immune system.[57]
Normal cells can die when removed from the tissue they belong to, or when their genome cannot operate in harmony with tissue function: these events depend on feedback regulation of NF-κB, and fail in cancer.[58]
Defects in NF-κB results in increased susceptibility to apoptosis leading to increased cell death. This is because NF-κB regulates anti-apoptotic genes especially the TRAF1 and TRAF2 and therefore abrogates the activities of the caspase family of enzymes, which are central to most apoptotic processes.[59]
In tumor cells, NF-κB is active (for example, in 41% of Nasopharyngeal carcinoma[60]) either due to mutations in genes encoding the NF-κB transcription factors themselves or in genes that control NF-κB activity (such as IκB genes); in addition, some tumor cells secrete factors that cause NF-κB to become active. Blocking NF-κB can cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents. Thus, NF-κB is the subject of much active research among pharmaceutical companies as a target for anti-cancer therapy.[61]
However, even though convincing experimental data have identified NF-κB as a critical promoter of tumorigenesis, which creates a solid rationale for the development of antitumor therapy that is based upon suppression of NF-κB activity, caution should be exercised when considering anti-NF-κB activity as a broad therapeutic strategy in cancer treatment as data has also shown that NF-κB activity enhances tumor cell sensitivity to apoptosis and senescence. In addition, it has been shown that canonical NF-κB is a Fas transcription activator and the alternative NF-κB is a Fas transcription repressor.[62] Therefore, NF-κB promotes Fas-mediated apoptosis in cancer cells, and thus inhibition of NF-κB may suppress Fas-mediated apoptosis to impair host immune cell-mediated tumor suppression.
## Inflammation
Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, gastritis, asthma, atherosclerosis[63] and others. It is important to note though, that elevation of some NF-κB activators, such as osteoprotegerin (OPG), are associated with elevated mortality, especially from cardiovascular diseases.[64][65] Elevated NF-κB has also been associated with schizophrenia.[66] Recently, NF-κB activation has been suggested as a possible molecular mechanism for the catabolic effects of cigarette smoke in skeletal muscle and sarcopenia.[67]
Research has shown that during inflammation the function of a cell depends on signals it activates in response to contact with adjacent cells and to combinations of hormones, especially cytokines that act on it through specific receptors.[68] A cells’ phenotype within a tissue develops through mutual stimulation of feedback signals that coordinate its function with other cells; this is especially evident during reprogramming of cell function when a tissue is exposed to inflammation, because cells alter their phenotype, and gradually express combinations of genes that prepare the tissue for regeneration after the cause of inflammation is removed.[68][69] Particularly important are feedback responses that develop between tissue resident cells, and circulating cells of the immune system.[69] Fidelity of feedback responses between diverse cell types and the immune system depends on the integrity of mechanisms that limit the range of genes activated by NF-κB, allowing only expression of genes which contribute to an effective immune response and subsequently, a complete restoration of tissue function after resolution of inflammation.[69] In cancer, mechanisms that regulate gene expression in response to inflammatory stimuli are altered to the point that a cell ceases to link its survival with the mechanisms that coordinate its phenotype and its function with the rest of the tissue.[58] This is often evident in severely compromised regulation of NF-κB activity, which allows cancer cells to express abnormal cohorts of NF-κB target genes.[70] This results in not only the cancer cells functioning abnormally: cells of surrounding tissue alter their function and cease to support the organism exclusively. Additionally, several types of cells in the microenvironment of cancer may change their phenotypes to support cancer growth.[71][72][73] Inflammation, therefore, is a process that tests the fidelity of tissue components because the process that leads to tissue regeneration requires coordination of gene expression between diverse cell types.[68][74]
## NEMO
NEMO deficiency syndrome is a rare genetic condition relating to a fault in IKBKG that in turn activates NF-kB. It mostly affects males and has a highly variable set of symptoms and prognoses.[75]
## Addiction
NF-κB is one of several induced transcriptional targets of ΔFosB which facilitates the development and maintenance of an addiction to a stimulus.[76][77][78] In the caudate putamen, NF-κB induction is associated with increases in locomotion, whereas in the nucleus accumbens, NF-κB induction enhances the positive reinforcing effect of a drug through reward sensitization.[77]
# Non-drug inhibitors
Many natural products (including anti-oxidants) that have been promoted to have anti-cancer and anti-inflammatory activity have also been shown to inhibit NF-κB. There is a controversial US patent (US patent 6,410,516)[80] that applies to the discovery and use of agents that can block NF-κB for therapeutic purposes. This patent is involved in several lawsuits, including Ariad v. Lilly. Recent work by Karin,[81] Ben-Neriah[82] and others has highlighted the importance of the connection between NF-κB, inflammation, and cancer, and underscored the value of therapies that regulate the activity of NF-κB.[83]
Extracts from a number of herbs and dietary plants are efficient inhibitors of NF-κB activation in vitro.[84]
The circumsporozoite protein of Plasmodium falciparum has been shown to be an inhibitor of NF-κB.[85]
# As a drug target
Aberrant activation of NF-κB is frequently observed in many cancers. Moreover, suppression of NF-κB limits the proliferation of cancer cells. In addition, NF-κB is a key player in the inflammatory response. Hence methods of inhibiting NF-κB signaling has potential therapeutic application in cancer and inflammatory diseases.[86][87]
The discovery that activation of NF-κB nuclear translocation can be separated from the elevation of oxidant stress[88] gives a promising avenue of development for strategies targeting NF-κB inhibition.
A new drug called denosumab acts to raise bone mineral density and reduce fracture rates in many patient sub-groups by inhibiting RANKL. RANKL acts through its receptor RANK, which in turn promotes NF-κB,[89]
RANKL normally works by enabling the differentiation of osteoclasts from monocytes.
Disulfiram, olmesartan and dithiocarbamates can inhibit the nuclear factor-κB (NF-κB) signaling cascade.[90] Effort to develop direct NF-kB inhibitor has emerged with compounds such as (-)-DHMEQ, PBS-1086, IT-603 and IT-901.[91][92][93] (-)-DHMEQ and PBS-1086 are irreversible binder to NF-KB while IT-603 and IT-901 are reversible binder. DHMEQ covalently binds to Cys 38 of p65.[94]
Anatabine's antiinflammatory effects are claimed to result from modulation of NF-κB activity.[95] However the studies purporting its benefit use abnormally high doses in the millimolar range (similar to the extracellular potassium concentration), which are unlikely to be achieved in humans.
BAY 11-7082 has also been identified as a drug that can inhibit the NF-kB signaling cascade. It is capable of preventing the phosphorylation of IKK-α in an irreversible manner such that there is down regulation of NF-kB activation.[96] In has been shown that administration of BAY 11-7082 rescued renal functionality in diabetic-induced Sprague-Dawley rats by suppressing NF-kB regulated oxidative stress.[97]
The biological target of iguratimod, a drug marketed to treat rheumatoid arthritis in Japan and China, was unknown as of 2015, but the primary mechanism of action appeared to be preventing NF-κB activation.[98] | https://www.wikidoc.org/index.php/NF-kappa_B | |
e1f23a3f70e603e4fca6308e60fb61ebcae1481a | wikidoc | NFASC | NFASC
Neurofascin is a protein that in humans is encoded by the NFASC gene.
# Function
Neurofascin is an L1 family immunoglobulin cell adhesion molecule (see L1CAM) involved in axon subcellular targeting and synapse formation during neural development.
# Clinical importance
A homozygous mutation causing loss of Nfasc155 causes severe congenital hypotonia, contractures of fingers and toes and no reaction to touch or pain. | NFASC
Neurofascin is a protein that in humans is encoded by the NFASC gene.[1][2][3]
# Function
Neurofascin is an L1 family immunoglobulin cell adhesion molecule (see L1CAM) involved in axon subcellular targeting and synapse formation during neural development.[3][4]
# Clinical importance
A homozygous mutation causing loss of Nfasc155 causes severe congenital hypotonia, contractures of fingers and toes and no reaction to touch or pain.[5] | https://www.wikidoc.org/index.php/NFASC | |
91b22fe601cb782b195973afbbf7a5219d8e7a5e | wikidoc | NFAT5 | NFAT5
Nuclear factor of activated T-cells 5, also known as NFAT5, is a human gene that encodes a transcription factor that regulates the expression of genes involved in the osmotic stress.
The product of this gene is a member of the nuclear factors of activated T cells (NFAT) family of transcription factors. Proteins belonging to this family play a central role in inducible gene transcription during the immune response. This protein regulates gene expression induced by osmotic stress in mammalian cells. Unlike monomeric members of this protein family, this protein exists as a homodimer and forms stable dimers with DNA elements. Multiple transcript variants encoding different isoforms have been found for this gene.
# Osmotic stress
Tissues that comprise the kidneys, skin, and eyes are often subjected to osmotic stresses. When the extracellular environment is hypertonic, cells lose water and consequently, shrink. To counteract this, cells increase their sodium uptake in order to lose less water. However, an increase in intracellular ionic concentration is harmful to the cell. Cells can alternatively synthesize enzymes and transporters that increase intracellular concentration of organic osmolytes, which are less toxic than excess ions but which also aid in water retention. Under conditions of hyperosmolarity, NFAT5 is synthesized and accumulates in the nucleus. NFAT5 stimulates the transcription of genes for aldose reductase (AR), the sodium chloride-betaine cotransporter (SLC6A12) the sodium/myo-inositol cotransporter (SLC5A3), the taurine transporter (SLC6A6) and neuropathy target esterase which are involved in the production and uptake of organic osmolytes. Additionally, NFAT5 induces heat shock proteins, Hsp70, and osmotic stress proteins. NFAT5 is also implicated in cytokine production.
It has been shown that when NFAT5 is inhibited in renal and immune cells, these cells become significantly more susceptible to osmotic stress. NFAT5 deficient mice were found to suffer from massive cell loss in the renal medulla. Additionally, mice expressing a dominant-negative form of NFAT5 in their eyes exhibited decreased viability under hypertonic extracellular environment.
# Structure
The NFAT family consists of five different forms: NFAT1, NFAT2, NFAT3, NFAT4, and NFAT5 (this protein). The proteins in this family are expressed in nearly every tissue in the body and are known transcriptional regulators in cytokine and immune cell expression. Among the different forms of NFAT, NFAT5 is an important component of the hyperosmolar stress response system.
cDNA of NFAT5 was first isolated from a human brain cDNA library. Subsequent analysis revealed that NFAT5 is a member of the Rel family, which also consists of NF-κB and NFATc proteins. The largest Rel protein, it consists of nearly 1,500 amino acid residues. Like the other Rel proteins, NFAT5 contains the Rel homology domain, a conserved DNA-binding domain. Outside of the Rel homology domain, no similarities exist between NFAT5 and NF-κB or NFATc. Among these differences is the absence of docking sites for calcineurin, which is necessary for NFATc nuclear import. Instead, NFAT5 is a constitutively nuclear protein whose activity and localization does not depend on calcineurin-mediated dephosphorylation. Increased NFAT5 transcription is correlated with p38 MAPK-mediated phosphorylation.
# Mechanism of Activation
Although the precise mechanism by which osmotic stress is sensed by the cell is unclear, it has been suggested that Brx, a guanine nucleotide exchange factor (GEF) localized near the plasma membrane, is activated by osmotic stress through changes in the cytoskeleton structure. Alternatively, Brx may also be activated through changes in its interactions with possible osmosensor molecules at the cell membrane. Upon Brx activation, the GEF domain of Brx facilitates activation of Rho-type small G proteins from its inactive GDP state to active GTP state. Additionally, activated Brx also recruits and physically interacts with JIP4, a p38 MAPK-specific scaffold protein. JIP4 binds to downstream kinases, MKK3 and MKK6. This complex then activates p38 mitogen-activated protein kinase (MAPK). Activation of p38 MAPK is regulated by Cdc42 and Rac1. Activation of p38 MAPK is a necessary step for NFAT5 expression.
It has been found that NFAT5 expression, following hyperosmolarity, depends on p38 mitogen-activated protein kinase (MAPK). The addition of a p38 MAPK inhibitor was found to correlate with decreased NFAT5 expression, even in the presence of osmotic stress signals. However, the downstream transcription of the NFAT5 gene by p38 MAPK is currently not yet characterized. It is hypothesized that p38 MAPK phosphorylation activates c-Fos and interferon regulatory factors (IRFs), which bind to AP-1-binding sites and ISRES (Interferon Stimulated Response Element) respectively. Binding to these sites consequently activates the transcription of target genes.
Although the Brx-mediated activation of NFAT5 has only been examined in lymphocyte response to osmotic stress, it is hypothesized that this mechanism is a common one in other cell types.
# Additional Roles
NFAT5 has also been implicated in other biological roles, such as in embryonic development. Mice in the embryonic stages with non-function NFAT5 exhibited reduced survivorship.
Additionally, NFAT5 plays a role in integrin-induced cell migration. Overexpression of NFAT5 enhanced movement.
To increase breast carcinoma migration NFAT5 modulate the expression of the Lipocalin 2 gene. NFAT5 is also involved in cellular proliferation. NFAT5 mRNA expression is particularly high in proliferating cells. Inhibition of NFAT5 in embryonic fibroblasts resulted in cell cycle arrest.
Although NFAT5 has been found to be important in other biological processes besides hyperosmotic stress response, the mechanism by which NFAT5 acts in these other processes are currently not well known. | NFAT5
Nuclear factor of activated T-cells 5, also known as NFAT5, is a human gene that encodes a transcription factor that regulates the expression of genes involved in the osmotic stress.[1]
The product of this gene is a member of the nuclear factors of activated T cells (NFAT) family of transcription factors. Proteins belonging to this family play a central role in inducible gene transcription during the immune response. This protein regulates gene expression induced by osmotic stress in mammalian cells. Unlike monomeric members of this protein family, this protein exists as a homodimer and forms stable dimers with DNA elements. Multiple transcript variants encoding different isoforms have been found for this gene.[1]
# Osmotic stress
Tissues that comprise the kidneys, skin, and eyes are often subjected to osmotic stresses. When the extracellular environment is hypertonic, cells lose water and consequently, shrink. To counteract this, cells increase their sodium uptake in order to lose less water. However, an increase in intracellular ionic concentration is harmful to the cell. Cells can alternatively synthesize enzymes and transporters that increase intracellular concentration of organic osmolytes, which are less toxic than excess ions but which also aid in water retention. Under conditions of hyperosmolarity, NFAT5 is synthesized and accumulates in the nucleus. NFAT5 stimulates the transcription of genes for aldose reductase (AR), the sodium chloride-betaine cotransporter (SLC6A12) the sodium/myo-inositol cotransporter (SLC5A3), the taurine transporter (SLC6A6) and neuropathy target esterase which are involved in the production and uptake of organic osmolytes.[2][3] Additionally, NFAT5 induces heat shock proteins, Hsp70, and osmotic stress proteins. NFAT5 is also implicated in cytokine production.[4]
It has been shown that when NFAT5 is inhibited in renal and immune cells, these cells become significantly more susceptible to osmotic stress. NFAT5 deficient mice were found to suffer from massive cell loss in the renal medulla.[5] Additionally, mice expressing a dominant-negative form of NFAT5 in their eyes exhibited decreased viability under hypertonic extracellular environment.[6]
# Structure
The NFAT family consists of five different forms: NFAT1, NFAT2, NFAT3, NFAT4, and NFAT5 (this protein). The proteins in this family are expressed in nearly every tissue in the body and are known transcriptional regulators in cytokine and immune cell expression. Among the different forms of NFAT, NFAT5 is an important component of the hyperosmolar stress response system.[4]
cDNA of NFAT5 was first isolated from a human brain cDNA library. Subsequent analysis revealed that NFAT5 is a member of the Rel family, which also consists of NF-κB and NFATc proteins. The largest Rel protein, it consists of nearly 1,500 amino acid residues. Like the other Rel proteins, NFAT5 contains the Rel homology domain, a conserved DNA-binding domain. Outside of the Rel homology domain, no similarities exist between NFAT5 and NF-κB or NFATc. Among these differences is the absence of docking sites for calcineurin, which is necessary for NFATc nuclear import.[7] Instead, NFAT5 is a constitutively nuclear protein whose activity and localization does not depend on calcineurin-mediated dephosphorylation.[4][7] Increased NFAT5 transcription is correlated with p38 MAPK-mediated phosphorylation.
# Mechanism of Activation
Although the precise mechanism by which osmotic stress is sensed by the cell is unclear, it has been suggested that Brx, a guanine nucleotide exchange factor (GEF) localized near the plasma membrane, is activated by osmotic stress through changes in the cytoskeleton structure. Alternatively, Brx may also be activated through changes in its interactions with possible osmosensor molecules at the cell membrane.[8] Upon Brx activation, the GEF domain of Brx facilitates activation of Rho-type small G proteins from its inactive GDP state to active GTP state. Additionally, activated Brx also recruits and physically interacts with JIP4, a p38 MAPK-specific scaffold protein. JIP4 binds to downstream kinases, MKK3 and MKK6.[9] This complex then activates p38 mitogen-activated protein kinase (MAPK). Activation of p38 MAPK is regulated by Cdc42 and Rac1. Activation of p38 MAPK is a necessary step for NFAT5 expression.[8]
It has been found that NFAT5 expression, following hyperosmolarity, depends on p38 mitogen-activated protein kinase (MAPK). The addition of a p38 MAPK inhibitor was found to correlate with decreased NFAT5 expression, even in the presence of osmotic stress signals.[5] However, the downstream transcription of the NFAT5 gene by p38 MAPK is currently not yet characterized. It is hypothesized that p38 MAPK phosphorylation activates c-Fos and interferon regulatory factors (IRFs), which bind to AP-1-binding sites and ISRES (Interferon Stimulated Response Element) respectively. Binding to these sites consequently activates the transcription of target genes.[8]
Although the Brx-mediated activation of NFAT5 has only been examined in lymphocyte response to osmotic stress, it is hypothesized that this mechanism is a common one in other cell types.
# Additional Roles
NFAT5 has also been implicated in other biological roles, such as in embryonic development. Mice in the embryonic stages with non-function NFAT5 exhibited reduced survivorship.
Additionally, NFAT5 plays a role in integrin-induced cell migration.[10][11] Overexpression of NFAT5 enhanced movement.[4]
To increase breast carcinoma migration NFAT5 modulate the expression of the Lipocalin 2 gene.[12] NFAT5 is also involved in cellular proliferation. NFAT5 mRNA expression is particularly high in proliferating cells. Inhibition of NFAT5 in embryonic fibroblasts resulted in cell cycle arrest.[4]
Although NFAT5 has been found to be important in other biological processes besides hyperosmotic stress response, the mechanism by which NFAT5 acts in these other processes are currently not well known. | https://www.wikidoc.org/index.php/NFAT5 | |
78d4683c8be19c3b39260d1376efb3570160d532 | wikidoc | NFKB1 | NFKB1
Nuclear factor NF-kappa-B p105 subunit is a protein that in humans is encoded by the NFKB1 gene.
This gene encodes a 105 kD protein which can undergo cotranslational processing by the 26S proteasome to produce a 50 kD protein. The 105 kD protein is a Rel protein-specific transcription inhibitor and the 50 kD protein is a DNA binding subunit of the NF-kappaB (NF-κB) protein complex. NF-κB is a transcription factor that is activated by various intra- and extra-cellular stimuli such as cytokines, oxidant-free radicals, ultraviolet irradiation, and bacterial or viral products. Activated NF-κB translocates into the nucleus and stimulates the expression of genes involved in a wide variety of biological functions; over 200 known genes are targets of NF-κB in various cell types, under specific conditions. Inappropriate activation of NF-κB has been associated with a number of inflammatory diseases while persistent inhibition of NF-κB leads to inappropriate immune cell development or delayed cell growth.
# Model organisms
Model organisms have been used in the study of NFKB1 function. A conditional knockout mouse line, called Nfkb1tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and six significant abnormalities were observed. Female homozygotes had a decreased respiratory quotient, increased circulating alkaline phosphatase level and increased leukocyte cell number. Male homozygotes showed an increased susceptibility to Salmonella infection, while homozygotes of both sex had decreased IgG1 and decreased regulatory T cell and NK cell numbers.
# Interactions
NFKB1 has been shown to interact with:
- BCL3,
- C22orf25,
- HDAC1,
- HMGA2
- IKK2,
- ITGB3BP,
- IκBα,
- LYL1,
- MAP3K7IP2,
- MAP3K8,
- MEN1,
- NFKB2,
- NFKBIE,
- NOTCH1,
- Nuclear receptor coactivator 1,
- RELA,
- RELB,
- STAT3,
- STAT6, and
- TSC22D3. | NFKB1
Nuclear factor NF-kappa-B p105 subunit is a protein that in humans is encoded by the NFKB1 gene.[1]
This gene encodes a 105 kD protein which can undergo cotranslational processing by the 26S proteasome to produce a 50 kD protein. The 105 kD protein is a Rel protein-specific transcription inhibitor and the 50 kD protein is a DNA binding subunit of the NF-kappaB (NF-κB) protein complex. NF-κB is a transcription factor that is activated by various intra- and extra-cellular stimuli such as cytokines, oxidant-free radicals, ultraviolet irradiation, and bacterial or viral products. Activated NF-κB translocates into the nucleus and stimulates the expression of genes involved in a wide variety of biological functions; over 200 known genes are targets of NF-κB in various cell types, under specific conditions. Inappropriate activation of NF-κB has been associated with a number of inflammatory diseases while persistent inhibition of NF-κB leads to inappropriate immune cell development or delayed cell growth.[2]
# Model organisms
Model organisms have been used in the study of NFKB1 function. A conditional knockout mouse line, called Nfkb1tm1a(KOMP)Wtsi[10][11] 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.[12][13][14]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[8][15] Twenty five tests were carried out on mutant mice and six significant abnormalities were observed.[8] Female homozygotes had a decreased respiratory quotient, increased circulating alkaline phosphatase level and increased leukocyte cell number. Male homozygotes showed an increased susceptibility to Salmonella infection, while homozygotes of both sex had decreased IgG1 and decreased regulatory T cell and NK cell numbers.[8]
# Interactions
NFKB1 has been shown to interact with:
- BCL3,[16][17][18]
- C22orf25,
- HDAC1,[19]
- HMGA2[20]
- IKK2,[16][21]
- ITGB3BP,[22]
- IκBα,[23][24]
- LYL1,[25]
- MAP3K7IP2,[26]
- MAP3K8,[27][28]
- MEN1,[29]
- NFKB2,[27]
- NFKBIE,[30]
- NOTCH1,[31][32]
- Nuclear receptor coactivator 1,[33][34]
- RELA,[27][35]
- RELB,[27]
- STAT3,[36]
- STAT6,[37] and
- TSC22D3.[38] | https://www.wikidoc.org/index.php/NFKB1 | |
e1bb233f6a35ac2c57d0d848fbe8b29fbe1ecf50 | wikidoc | NFKB2 | NFKB2
Nuclear factor NF-kappa-B p100 subunit is a protein that in humans is encoded by the NFKB2 gene.
# Function
NF-κB has been detected in numerous cell types that express cytokines, chemokines, growth factors, cell adhesion molecules, and some acute phase proteins in health and in various disease states. NF-κB is activated by a wide variety of stimuli such as cytokines, oxidant-free radicals, inhaled particles, ultraviolet irradiation, and bacterial or viral products. Inappropriate activation of NF-kappa-B has been linked to inflammatory events associated with autoimmune arthritis, asthma, septic shock, lung fibrosis, glomerulonephritis, atherosclerosis, and AIDS. In contrast, complete and persistent inhibition of NF-kappa-B has been linked directly to apoptosis, inappropriate immune cell development, and delayed cell growth. For reviews, see Chen et al. (1999) and Baldwin (1996).
# Clinical significance
Mutation of the NFKB2 gene has been linked to Common variable immunodeficiency (CVID) as the cause of the disease. Other genes might also be responsible. The frequency of NFKB2 mutation in CVID population is yet to be established.
The protein NFKB2 can become mutated and lead to hereditary endocrine and immuneodeficiences. The mutation occurs at the C-terminus of NFKB2 and it causes common variable immunodeficienciency which in turn causes endocrine deficiency and immunodeficiencies. A NFKB2 mutation can cause things like adrenocorticotropic hormone deficiency and DAVID syndrome which is a pituitary hormone deficiency and CVID.
The mutations that occur within the C-terminus affect the serine 866 and 870. These serines are considered phosphorylation sites for NFKB2. These mutations at the serine’s in the C-terminus lead to CVID in combination with other endocrine deficiencies. These endocrine deficiencies along with the mutation of NFKB2, lead scientists to believe that mutation of NFKB2 is a rare hereditary disease called DAVID’s disease.
# Interactions
NFKB2 has been shown to interact with:
- BCL3,
- BTRC,
- MAP3K8,
- NFKB1,
- NFKBIE,
- RELA,
- RELB,
- REL, and
- TSC22D3. | NFKB2
Nuclear factor NF-kappa-B p100 subunit is a protein that in humans is encoded by the NFKB2 gene.[1]
# Function
NF-κB has been detected in numerous cell types that express cytokines, chemokines, growth factors, cell adhesion molecules, and some acute phase proteins in health and in various disease states. NF-κB is activated by a wide variety of stimuli such as cytokines, oxidant-free radicals, inhaled particles, ultraviolet irradiation, and bacterial or viral products. Inappropriate activation of NF-kappa-B has been linked to inflammatory events associated with autoimmune arthritis, asthma, septic shock, lung fibrosis, glomerulonephritis, atherosclerosis, and AIDS. In contrast, complete and persistent inhibition of NF-kappa-B has been linked directly to apoptosis, inappropriate immune cell development, and delayed cell growth. For reviews, see Chen et al. (1999) and Baldwin (1996).[supplied by OMIM][2]
# Clinical significance
Mutation of the NFKB2 gene has been linked to Common variable immunodeficiency (CVID) as the cause of the disease. Other genes might also be responsible. The frequency of NFKB2 mutation in CVID population is yet to be established.[3]
The protein NFKB2 can become mutated and lead to hereditary endocrine and immuneodeficiences.[4] The mutation occurs at the C-terminus of NFKB2 and it causes common variable immunodeficienciency which in turn causes endocrine deficiency and immunodeficiencies.[4] A NFKB2 mutation can cause things like adrenocorticotropic hormone deficiency and DAVID syndrome which is a pituitary hormone deficiency and CVID.[4][5]
The mutations that occur within the C-terminus affect the serine 866 and 870.[5] These serines are considered phosphorylation sites for NFKB2.[5] These mutations at the serine’s in the C-terminus lead to CVID in combination with other endocrine deficiencies. These endocrine deficiencies along with the mutation of NFKB2, lead scientists to believe that mutation of NFKB2 is a rare hereditary disease called DAVID’s disease.[4]
# Interactions
NFKB2 has been shown to interact with:
- BCL3,[6][7]
- BTRC,[8][9]
- MAP3K8,[10]
- NFKB1,[10]
- NFKBIE,[11]
- RELA,[10][12]
- RELB,[6][10]
- REL,[10][12] and
- TSC22D3.[13] | https://www.wikidoc.org/index.php/NFKB2 | |
2a27886499184578f1acc5f6fc3a682ee94492f0 | wikidoc | NGLY1 | NGLY1
PNGase also known as N-glycanase 1 (EC 3.5.1.52) or peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase is an enzyme that in humans is encoded by the NGLY1 gene. PNGase is a de-N-glycosylating enzyme that removes N-linked or asparagine-linked glycans (N-glycans) from glycoproteins. More specifically, NGLY1 catalyzes the hydrolysis of the amide bond between the innermost N-acetylglucosamine (GlcNAc) and an Asn residue on an N-glycoprotein, generating a de-N-glycosylated protein, in which the N-glycoylated Asn residue is converted to asp, and a 1-amino-GlcNAc-containing free oligosaccharide. Ammonia is then spontaneously released from the 1-amino GlcNAc at physiological pH (<8), giving rise to a free oligosaccharide with an N,N’-diacetylchitobiose structure at the reducing end.
# Discovery
Occurrence of cytoplasmic PNGase activity in mammalian cells was first reported in cultured cells. This enzyme differ from other “reagent” PNGases from almond (glycoamidase/PNGase A), or bacteria (N-glycanase/PNGase F), that is often used for structural/functional studies of N-glycans, in several enzymatic properties, including the requirement of a reducing reagent for activity and a neutral pH for optimal activity.
The gene encoding the cytoplasmic PNGase was first identified in budding yeast, Saccharomyces cerevisiae and gene orthologues have since been found in wide variety of eukaryotes including mammals. In terms of the tissue distribution of the mouse Ngly1 gene, enzyme activities as well as transcripts were detected in all tissues/organs examined.
# Structure
The catalytic residues of the cytoplasmic PNGase is known to reside in a domain called transglutaminase domain. NGLY1, when compared with the yeast orthologues, possesses extended N-terminal and C-terminal sequences in addition to the transglutaminase domain. Among the additional domains found in NGLY1, the PUB (PNGase- and ubiquitin-related) domain was first identified through a bioinformatics analysis. While it was initially hypothesized that it might serve as a protein-protein interaction domain, experimental evidence supporting this hypothesis is now accumulating. On the other hand, the C-terminal PAW domain (a domain present in PNGases and other worm proteins). has now been shown to be involved in the binding of oligosaccharides to PNGase.
In terms of the crystal structures of mouse Ngly1, a catalytic core domain, a C-terminal domain including PAW domain and an N-terminal domain including PUB domain. have been obtained.
# Function
Regarding the function of NGLY1, it has been shown that the enzyme is involved in the ER-associated degradation (ERAD), one of the ER quality control/homeostasis systems for newly synthesized glycoproteins. The functional importance of NGLY1 in the ERAD process, however, is not clearly understood. It has also been suggested that NGLY1 is closely involved in MHC class I-mediated antigen presentation. The Ngly1-mediated (glycosylated) Asn-to-Asp deamidation constitutes, together with other reactions such as transpeptidation, unconventional post-translational modifications for antigenic peptides that are presented by MHC class I molecules.
# NGLY1-binding proteins
Through yeast two-hybrid screening, it has been shown that NGLY1 proteins can bind to several proteins, mostly through the N-terminal domain including the PUB domain. In vivo and in vitro interactions between NGLY1 and several ERAD-related proteins have been reported. While the importance of those protein-protein interactions to NGLY1 functions remain to be clarified, it can be assumed that such interactions may be advantageous for an efficient ERAD process.
# Clinical significance
In 2012, NGLY1 deficiency, involving mutations in the NGLY1 gene locus was first identified through an exome analysis. As of now, the clinical features of 11 patients have been reported. One cerebral visual impairment (CVI) patient also had a mutation in NGLY1 gene.The clinical effects include neuromotor impairment, intellectual disability, and neuropathy. It has also been associated with amyotrophic lateral sclerosis and Parkinson's disease.
Details of the mechanism responsible for the pathogenesis of the NGLY1-deficiency remains unknown, while the intracellular accumulation of N-GlcNAc proteins, due to the excess action of cytosolic endo-b-N-acetylglucosaminidase to misfolded glycoproteins, in Ngly1-deficient cells has been hypothesized as a potential cause.
NGLY1 deficiency has drawn attention in the public.
Studies have been carried out to discover small-molecules that can bind to the transglutaminase domain of the protein to stabilize it as a potential therapeutic applications in the treatment of disorder caused by NGLY1 mutants.
# Notes | NGLY1
PNGase also known as N-glycanase 1 (EC 3.5.1.52) or peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase is an enzyme that in humans is encoded by the NGLY1 gene. PNGase is a de-N-glycosylating enzyme that removes N-linked or asparagine-linked glycans (N-glycans) from glycoproteins.[1][2][3] More specifically, NGLY1 catalyzes the hydrolysis of the amide bond between the innermost N-acetylglucosamine (GlcNAc) and an Asn residue on an N-glycoprotein, generating a de-N-glycosylated protein, in which the N-glycoylated Asn residue is converted to asp, and a 1-amino-GlcNAc-containing free oligosaccharide. Ammonia is then spontaneously released from the 1-amino GlcNAc at physiological pH (<8), giving rise to a free oligosaccharide with an N,N’-diacetylchitobiose structure at the reducing end.
# Discovery
Occurrence of cytoplasmic PNGase activity in mammalian cells was first reported in cultured cells.[4] This enzyme differ from other “reagent” PNGases from almond (glycoamidase/PNGase A),[5] or bacteria (N-glycanase/PNGase F),[6] that is often used for structural/functional studies of N-glycans, in several enzymatic properties, including the requirement of a reducing reagent for activity and a neutral pH for optimal activity.[4][7][8]
The gene encoding the cytoplasmic PNGase was first identified in budding yeast, Saccharomyces cerevisiae and gene orthologues have since been found in wide variety of eukaryotes including mammals.[9] In terms of the tissue distribution of the mouse Ngly1 gene, enzyme activities as well as transcripts were detected in all tissues/organs examined.[8][10]
# Structure
The catalytic residues of the cytoplasmic PNGase is known to reside in a domain called transglutaminase domain.[11][12] NGLY1, when compared with the yeast orthologues, possesses extended N-terminal and C-terminal sequences in addition to the transglutaminase domain. Among the additional domains found in NGLY1, the PUB (PNGase- and ubiquitin-related) domain was first identified through a bioinformatics analysis.[13][14] While it was initially hypothesized that it might serve as a protein-protein interaction domain,[13] experimental evidence supporting this hypothesis is now accumulating.[15][16][17] On the other hand, the C-terminal PAW domain (a domain present in PNGases and other worm proteins).[14] has now been shown to be involved in the binding of oligosaccharides to PNGase.[18]
In terms of the crystal structures of mouse Ngly1, a catalytic core domain,[19] a C-terminal domain including PAW domain[18] and an N-terminal domain including PUB domain.[20] have been obtained.
# Function
Regarding the function of NGLY1, it has been shown that the enzyme is involved in the ER-associated degradation (ERAD), one of the ER quality control/homeostasis systems for newly synthesized glycoproteins.[21][22][23][24] The functional importance of NGLY1 in the ERAD process, however, is not clearly understood. It has also been suggested that NGLY1 is closely involved in MHC class I-mediated antigen presentation.[25][26][27] The Ngly1-mediated (glycosylated) Asn-to-Asp deamidation constitutes, together with other reactions such as transpeptidation, unconventional post-translational modifications for antigenic peptides that are presented by MHC class I molecules.[28]
# NGLY1-binding proteins
Through yeast two-hybrid screening, it has been shown that NGLY1 proteins can bind to several proteins, mostly through the N-terminal domain including the PUB domain.[29] In vivo and in vitro interactions between NGLY1 and several ERAD-related proteins have been reported.[16][19][20][29][30][31][32][33][34] While the importance of those protein-protein interactions to NGLY1 functions remain to be clarified, it can be assumed that such interactions may be advantageous for an efficient ERAD process.[35]
# Clinical significance
In 2012, NGLY1 deficiency, involving mutations in the NGLY1 gene locus was first identified through an exome analysis.[36] As of now, the clinical features of 11 patients have been reported.[37][38][39] One cerebral visual impairment (CVI) patient also had a mutation in NGLY1 gene.[40]The clinical effects include neuromotor impairment, intellectual disability, and neuropathy. It has also been associated with amyotrophic lateral sclerosis and Parkinson's disease.
Details of the mechanism responsible for the pathogenesis of the NGLY1-deficiency remains unknown, while the intracellular accumulation of N-GlcNAc proteins, due to the excess action of cytosolic endo-b-N-acetylglucosaminidase[41] to misfolded glycoproteins, in Ngly1-deficient cells has been hypothesized as a potential cause.[24]
NGLY1 deficiency has drawn attention in the public.[42][43][44][45]
Studies have been carried out to discover small-molecules that can bind to the transglutaminase domain of the protein to stabilize it as a potential therapeutic applications in the treatment of disorder caused by NGLY1 mutants.[46]
# Notes | https://www.wikidoc.org/index.php/NGLY1 | |
a0ab57e3b7b0da531552cf7e6f4163c95e03e088 | wikidoc | NIPA1 | NIPA1
Non-imprinted in Prader-Willi/Angelman syndrome region protein 1 is a protein that in humans is encoded by the NIPA1 gene.
This gene encodes a potential transmembrane protein which functions either as a receptor or transporter molecule, possibly as a magnesium transporter. This protein is thought to play a role in nervous system development and maintenance. Alternative splice variants have been described, but their biological nature has not been determined. Mutations in this gene have been associated with the human genetic disease autosomal dominant spastic paraplegia 6.
# Model organisms
Model organisms have been used in the study of NIPA1 function. A conditional knockout mouse line, called Nipa1tm1a(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 mutant mice but no significant abnormalities were observed. | NIPA1
Non-imprinted in Prader-Willi/Angelman syndrome region protein 1 is a protein that in humans is encoded by the NIPA1 gene.[1][2]
This gene encodes a potential transmembrane protein which functions either as a receptor or transporter molecule, possibly as a magnesium transporter.[3] This protein is thought to play a role in nervous system development and maintenance. Alternative splice variants have been described, but their biological nature has not been determined. Mutations in this gene have been associated with the human genetic disease autosomal dominant spastic paraplegia 6.[4][5]
# Model organisms
Model organisms have been used in the study of NIPA1 function. A conditional knockout mouse line, called Nipa1tm1a(KOMP)Wtsi[10][11] 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.[12][13][14]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[8][15] Twenty four tests were carried out on mutant mice but no significant abnormalities were observed.[8] | https://www.wikidoc.org/index.php/NIPA1 | |
8d758b3074efe28f4b9e4b0868b96f77705f8cc6 | wikidoc | NIPBL | NIPBL
Nipped-B-like protein (Nipbl), also known as Scc2 or delangin is a protein that in humans is encoded by the NIPBL gene. Nipbl is required for the association of cohesin with DNA and is the major subunit of the cohesin loading complex. Heterozygous mutations in NIPBL account for an estimated 60% of case of Cornelia de Lange Syndrome.
# Function
Nipbl is a large hook-shaped protein containing HEAT repeats. Nipbl forms a complex with Mau4 known as the cohesin loading complex or Kollerin. Cohesin is a ring-shaped protein complex responsible for sister chromatid cohesion. Cohesin is also thought to mediate enhancer-promoter interactions and generate Topologically associating domain. As well as mediating cohesion and regulating DNA architecture the cohesin complex is required for DNA repair by homologous recombination. Given that Nipbl is required for cohesin's association with DNA it is thought that Nipbl is also required for all of these processes. Consistently, inactivation of Nipbl results in the loss topologically associating domains and cohesion. Nipbl/Scc2 binds dynamically to chromatin principally through an association with cohesin. Nipbl’s movement within chromatin is consistent with a mechanism involving hopping between chromosomal cohesin rings.
A cohesin-independent function in the regulation of gene expression has also been demonstrated for Nipbl.
# Clinical significance
Mutations in this gene result in Cornelia de Lange syndrome (CdLS), a disorder characterized by dysmorphic facial features, growth delay, limb reduction defects, and mental retardation. As these mutations are usually heterozygous, CdLS is caused by a reduction in the abundance of Nipbl not a complete loss. Experiments on cells from patients and mice indicate that the reduction is by less than half. It is not known why a reduction in Nipbl expression results in CdLS. | NIPBL
Nipped-B-like protein (Nipbl), also known as Scc2 or delangin is a protein that in humans is encoded by the NIPBL gene.[1] Nipbl is required for the association of cohesin with DNA and is the major subunit of the cohesin loading complex.[2] Heterozygous mutations in NIPBL account for an estimated 60% of case of Cornelia de Lange Syndrome.[3]
# Function
Nipbl is a large hook-shaped protein containing HEAT repeats.[4] Nipbl forms a complex with Mau4 known as the cohesin loading complex or Kollerin.[5] Cohesin is a ring-shaped protein complex responsible for sister chromatid cohesion. Cohesin is also thought to mediate enhancer-promoter interactions and generate Topologically associating domain. As well as mediating cohesion and regulating DNA architecture the cohesin complex is required for DNA repair by homologous recombination. Given that Nipbl is required for cohesin's association with DNA it is thought that Nipbl is also required for all of these processes. Consistently, inactivation of Nipbl results in the loss topologically associating domains[6] and cohesion.[7] Nipbl/Scc2 binds dynamically to chromatin principally through an association with cohesin.[8] Nipbl’s movement within chromatin is consistent with a mechanism involving hopping between chromosomal cohesin rings.
A cohesin-independent function in the regulation of gene expression has also been demonstrated for Nipbl.[9][10]
# Clinical significance
Mutations in this gene result in Cornelia de Lange syndrome (CdLS), a disorder characterized by dysmorphic facial features, growth delay, limb reduction defects, and mental retardation.[1] As these mutations are usually heterozygous, CdLS is caused by a reduction in the abundance of Nipbl not a complete loss. Experiments on cells from patients and mice indicate that the reduction is by less than half.[11] It is not known why a reduction in Nipbl expression results in CdLS. | https://www.wikidoc.org/index.php/NIPBL | |
46f2cc76fef67141921587281838ed33247326cb | wikidoc | NISCH | NISCH
Nischarin is a protein that in humans is encoded by the NISCH gene.
# Function
This gene encodes a nonadrenergic imidazoline-1 receptor protein that localizes to the cytosol and anchors to the inner layer of the plasma membrane. The orthologous mouse protein has been shown to influence cytoskeletal organization and cell migration by binding to alpha-5-beta-1 integrin. In humans, this protein has been shown to bind to the adapter insulin receptor substrate 4 (IRS4) to mediate translocation of alpha-5 integrin from the cell membrane to endosomes. In human cardiac tissue, this gene was found to affect cell growth and death while in neural tissue it affected neuronal growth and differentiation.
# Clinical significance
Expression of this protein was reduced in human breast cancers while its overexpression reduced tumor growth and metastasis; possibly by limiting the expression of alpha-5 integrin.
# Interactions
NISCH has been shown to interact with IRS4. | NISCH
Nischarin is a protein that in humans is encoded by the NISCH gene.[1][2][3]
# Function
This gene encodes a nonadrenergic imidazoline-1 receptor protein that localizes to the cytosol and anchors to the inner layer of the plasma membrane. The orthologous mouse protein has been shown to influence cytoskeletal organization and cell migration by binding to alpha-5-beta-1 integrin. In humans, this protein has been shown to bind to the adapter insulin receptor substrate 4 (IRS4) to mediate translocation of alpha-5 integrin from the cell membrane to endosomes. In human cardiac tissue, this gene was found to affect cell growth and death while in neural tissue it affected neuronal growth and differentiation.[3]
# Clinical significance
Expression of this protein was reduced in human breast cancers while its overexpression reduced tumor growth and metastasis; possibly by limiting the expression of alpha-5 integrin.[3]
# Interactions
NISCH has been shown to interact with IRS4.[1] | https://www.wikidoc.org/index.php/NISCH | |
c1eb1a286f488f1c5eeeea2962ad4e499cad7b88 | wikidoc | NKG2D | NKG2D
NKG2D is a transmembrane protein belonging to the CD94/NKG2 family of C-type lectin-like receptors. NKG2D is encoded by KLRK1 gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice and chromosome 12 in humans. In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells and activated macrophages. In humans, it is expressed by NK cells, γδ T cells and CD8+ αβ T cells. NKG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.
# Structure
Human NKG2D receptor complex assembles into a hexameric structure. NKG2D itself forms a homodimer whose ectodomains serve for ligand binding. Each NKG2D monomer is associated with DAP10 dimer. This association is maintained by ionic interaction of a positively charged arginine present in a transmembrane segment of NKG2D and negatively charged aspartic acids within both transmembrane regions of DAP10 dimer. DAP10 functions as an adaptor protein and transduces the signal after the ligand binding by recruiting the p85 subunit of PI3K and Grb2-Vav1 complex which are responsible for subsequent downstream events.
In mice, alternative splicing generates two distinct NKG2D isoforms: the long one (NKG2D-L) and the short one (NKG2D-S). NKG2D-L binds DAP10 similarly to human NKG2D. By contrast, NKG2D-S associates with two adaptor proteins: DAP10 and DAP12. DAP10 recruits the p85 subunit of PI3K and a complex of Grb2 and Vav1. DAP12 bears ITAM motif and activates protein tyrosine kinases Syk and Zap70 signalling.
# NKG2D ligands
NKG2D ligands are induced-self proteins which are completely absent or present only at low levels on surface of normal cells, but they are overexpressed by infected, transformed, senescent and stressed cells. Their expression is regulated at different stages (transcription, mRNA and protein stabilization, cleavage from the cell surface) by various stress pathways. Among them, one of the most prominent stress pathways is DNA damage response. Genotoxic stress, stalled DNA replication, poorly regulated cell proliferation in tumorigenesis, viral replication or some viral products activate the ATM and ATR kinases. These kinases initiate the DNA damage response pathway which participates in NKG2D ligand upregulation. DNA damage response thus participate in alerting the immune system to the presence of potentially dangerous cells.
All NKG2D ligands are homologous to MHC class I molecules and are divided into two families: MIC and RAET1/ULBP.
## MIC family
Human MIC genes are located within the MHC locus and are composed of seven members (MICA-G), of which only MICA and MICB produce functional transcripts. In mice, MIC genes are absent.
## RAET1/ULBP family
Among ten known human RAET1/ULBP genes, six encode functional proteins: RAET1E/ULBP4, RAET1G/ULBP5, RAET1H/ULBP2, RAET1/ULBP1, RAET1L/ULBP6, RAET1N/ULBP3. In mice, proteins from orthologous RAET1/ULBP family fall into three subfamiles: Rae-1, H60, and MULT-1.
# Function
NKG2D is a major recognition receptor for the detection and elimination of transformed and infected cells as its ligands are induced during cellular stress, either as a result of infection or genomic stress such as in cancer. In NK cells, NKG2D serves as an activating receptor, which itself is able to trigger cytotoxicity. The function of NKG2D on CD8+ T cells is to send co-stimulatory signals to activate them.
## Role in viral infection
Viruses, as intracellular pathogens, can induce the expression of stress ligands for NKG2D. NKG2D is thought to be important in viral control as viruses have adapted mechanisms by which to evade NKG2D responses. For example, cytomegalovirus (CMV) encodes a protein, UL16, which binds to NKG2D ligands ULBP1 and 2 (thus their name "UL16-binding protein") and MICB, which prevents their surface expression.
## Role in tumour control
As cancerous cells are "stressed", NKG2D ligands become upregulated, rendering the cell susceptible to NK cell-mediated lysis. Tumor cells that can evade NKG2D responses are thus more likely to propagate.
## Role in senescent cell removal
As part of the DNA damage response during induction of cellular senescence, cells upregulate the expression of NKG2D ligands that enable NK-mediated killing of senescent cells via the granule exocytosis pathway. | NKG2D
NKG2D is a transmembrane protein belonging to the CD94/NKG2 family of C-type lectin-like receptors.[1] NKG2D is encoded by KLRK1 gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice[2] and chromosome 12 in humans.[3] In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells and activated macrophages.[4] In humans, it is expressed by NK cells, γδ T cells and CD8+ αβ T cells.[5] NKG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.[6]
# Structure
Human NKG2D receptor complex assembles into a hexameric structure. NKG2D itself forms a homodimer whose ectodomains serve for ligand binding.[7] Each NKG2D monomer is associated with DAP10 dimer. This association is maintained by ionic interaction of a positively charged arginine present in a transmembrane segment of NKG2D and negatively charged aspartic acids within both transmembrane regions of DAP10 dimer.[8] DAP10 functions as an adaptor protein and transduces the signal after the ligand binding by recruiting the p85 subunit of PI3K and Grb2-Vav1 complex which are responsible for subsequent downstream events.[9]
In mice, alternative splicing generates two distinct NKG2D isoforms: the long one (NKG2D-L) and the short one (NKG2D-S). NKG2D-L binds DAP10 similarly to human NKG2D. By contrast, NKG2D-S associates with two adaptor proteins: DAP10 and DAP12.[10] DAP10 recruits the p85 subunit of PI3K and a complex of Grb2 and Vav1.[9] DAP12 bears ITAM motif and activates protein tyrosine kinases Syk and Zap70 signalling.[11]
# NKG2D ligands
NKG2D ligands are induced-self proteins which are completely absent or present only at low levels on surface of normal cells, but they are overexpressed by infected, transformed, senescent and stressed cells. Their expression is regulated at different stages (transcription, mRNA and protein stabilization, cleavage from the cell surface) by various stress pathways.[12] Among them, one of the most prominent stress pathways is DNA damage response. Genotoxic stress, stalled DNA replication, poorly regulated cell proliferation in tumorigenesis, viral replication or some viral products activate the ATM and ATR kinases. These kinases initiate the DNA damage response pathway which participates in NKG2D ligand upregulation. DNA damage response thus participate in alerting the immune system to the presence of potentially dangerous cells.[13]
All NKG2D ligands are homologous to MHC class I molecules and are divided into two families: MIC and RAET1/ULBP.
## MIC family
Human MIC genes are located within the MHC locus and are composed of seven members (MICA-G), of which only MICA and MICB produce functional transcripts. In mice, MIC genes are absent.[14]
## RAET1/ULBP family
Among ten known human RAET1/ULBP genes, six encode functional proteins: RAET1E/ULBP4, RAET1G/ULBP5, RAET1H/ULBP2, RAET1/ULBP1, RAET1L/ULBP6, RAET1N/ULBP3. In mice, proteins from orthologous RAET1/ULBP family fall into three subfamiles: Rae-1, H60, and MULT-1.[14]
# Function
NKG2D is a major recognition receptor for the detection and elimination of transformed and infected cells as its ligands are induced during cellular stress, either as a result of infection or genomic stress such as in cancer.[15] In NK cells, NKG2D serves as an activating receptor, which itself is able to trigger cytotoxicity. The function of NKG2D on CD8+ T cells is to send co-stimulatory signals to activate them.[16]
## Role in viral infection
Viruses, as intracellular pathogens, can induce the expression of stress ligands for NKG2D. NKG2D is thought to be important in viral control as viruses have adapted mechanisms by which to evade NKG2D responses.[17] For example, cytomegalovirus (CMV) encodes a protein, UL16, which binds to NKG2D ligands ULBP1 and 2 (thus their name "UL16-binding protein") and MICB, which prevents their surface expression.[18]
## Role in tumour control
As cancerous cells are "stressed", NKG2D ligands become upregulated, rendering the cell susceptible to NK cell-mediated lysis. Tumor cells that can evade NKG2D responses are thus more likely to propagate.[17][19]
## Role in senescent cell removal
As part of the DNA damage response during induction of cellular senescence, cells upregulate the expression of NKG2D ligands that enable NK-mediated killing of senescent cells via the granule exocytosis pathway. [20][21] | https://www.wikidoc.org/index.php/NKG2D | |
8d1d66f834a25fd16266b4667259236e56ef509c | wikidoc | NLRC4 | NLRC4
NLR family CARD domain-containing protein 4 is a protein that in humans is encoded by the NLRC4 gene.
# Structure
The NLRC4 protein is highly conserved across mammalian species. It bears homology to the C. elegans Ced4 protein. It contains an n-terminal CARD domain, a central nucleotide binding/NACHT domain, and a c-terminal leucine rich repeat (LRR) domain. It belongs to a family of NLR proteins that includes the transcriptional co-activator CIITA and the canonical inflammasome protein NLRP3. A truncated murine NLRC4 was the first member of this family whose crystal structure was solved.
# Function
NLRC4 is best associated with triggering formation of the inflammasome. Unlike NLRP3, certain inflammasome-dependent functions of NLRC4 may be carried out independently of the inflammasome scaffold ASC. Human Ced4 homologs include APAF1, NOD1 (CARD4), and NOD2 (CARD15). These proteins have at least 1 N-terminal CARD domain followed by a centrally located nucleotide-binding domain (NBD or NACHT) and a C-terminal regulatory domain, found only in mammals, that contains either WD40 repeats or leucine-rich repeats (LRRs). CARD12 is a member of the Ced4 family and can induce apoptosis.
# Interactions
NLRC4 has been shown to interact with NAIP (there is one human NAIP but mice express at least 4 distinct NAIP proteins). The NAIP/NLRC4 interaction may determine the ligand specificity. NLRC4-dependent inflammasome activity activates CASP1. Under certain circumstances, NLRC4 and NLRP3 may occupy the same inflammasome complex.
# Clinical significance
Humans bearing activating mutations in NLRC4 can develop an autoinflammatory syndrome characterized by acute fever, hepatitis, very high serum ferritin, and other features suggestive of Macrophage Activation Syndrome (MAS). Some patients also developed a potentially life-threatening enterocolitis that abated during early childhood. In these patients, chronic and extraordinary elevation of serum IL-18 is found, in distinction from patients with NLRP3 mutations who develop Cryopyrin Associated Periodic Syndromes. A large Japanese family had much milder disease associated with cold-induced urticaria that was caused by a dominantly inherited NLRC4 mutation. | NLRC4
NLR family CARD domain-containing protein 4 is a protein that in humans is encoded by the NLRC4 gene.[1][2]
# Structure
The NLRC4 protein is highly conserved across mammalian species. It bears homology to the C. elegans Ced4 protein. It contains an n-terminal CARD domain, a central nucleotide binding/NACHT domain, and a c-terminal leucine rich repeat (LRR) domain. It belongs to a family of NLR proteins that includes the transcriptional co-activator CIITA and the canonical inflammasome protein NLRP3. A truncated murine NLRC4 was the first member of this family whose crystal structure was solved.[3]
# Function
NLRC4 is best associated with triggering formation of the inflammasome. Unlike NLRP3, certain inflammasome-dependent functions of NLRC4 may be carried out independently of the inflammasome scaffold ASC. Human Ced4 homologs include APAF1, NOD1 (CARD4), and NOD2 (CARD15). These proteins have at least 1 N-terminal CARD domain followed by a centrally located nucleotide-binding domain (NBD or NACHT) and a C-terminal regulatory domain, found only in mammals, that contains either WD40 repeats or leucine-rich repeats (LRRs). CARD12 is a member of the Ced4 family and can induce apoptosis.[2]
# Interactions
NLRC4 has been shown to interact with NAIP (there is one human NAIP but mice express at least 4 distinct NAIP proteins). The NAIP/NLRC4 interaction may determine the ligand specificity.[4] NLRC4-dependent inflammasome activity activates CASP1.[5] Under certain circumstances, NLRC4 and NLRP3 may occupy the same inflammasome complex.[6]
# Clinical significance
Humans bearing activating mutations in NLRC4 can develop an autoinflammatory syndrome characterized by acute fever, hepatitis, very high serum ferritin, and other features suggestive of Macrophage Activation Syndrome (MAS). Some patients also developed a potentially life-threatening enterocolitis that abated during early childhood.[7][8] In these patients, chronic and extraordinary elevation of serum IL-18 is found, in distinction from patients with NLRP3 mutations who develop Cryopyrin Associated Periodic Syndromes.[7] A large Japanese family had much milder disease associated with cold-induced urticaria that was caused by a dominantly inherited NLRC4 mutation.[9] | https://www.wikidoc.org/index.php/NLRC4 | |
ad572978b040e239ae64fd9e78ad0bc339f1c572 | wikidoc | NLRC5 | NLRC5
NLRC5, short for NOD-like receptor family CARD domain containing 5, is an intracellular protein that plays a role in the immune system. NLRC5 is a pattern recognition receptor implicated in innate immunity to viruses potentially by regulating interferon activity.
Recently, NLRC5 has been suggested to play a positive role in the regulation of Major Histocompatibility Class I (MHCI) molecule expression. This aspect of NLRC5 function was further investigated with the help of Nlrc5-deficient mice, which showed reduced MHCI expression in lymphocytes (particularly T, NK and NKT lymphocytes). In lymphocytes, NLRC5 localizes to the nucleus and drives MHCI gene expression by occupying H-2D and H-2K gene promoters.
In humans, the NLRC5 protein is encoded by the NLRC5 gene. It has also been called NOD27, NOD4, and CLR16.1. | NLRC5
NLRC5, short for NOD-like receptor family CARD domain containing 5, is an intracellular protein that plays a role in the immune system. NLRC5 is a pattern recognition receptor implicated in innate immunity to viruses potentially by regulating interferon activity.[1][2][3]
Recently, NLRC5 has been suggested to play a positive role in the regulation of Major Histocompatibility Class I (MHCI) molecule expression.[4] This aspect of NLRC5 function was further investigated with the help of Nlrc5-deficient mice, which showed reduced MHCI expression in lymphocytes (particularly T, NK and NKT lymphocytes).[5] In lymphocytes, NLRC5 localizes to the nucleus and drives MHCI gene expression by occupying H-2D and H-2K gene promoters.[5]
In humans, the NLRC5 protein is encoded by the NLRC5 gene.[6] It has also been called NOD27, NOD4, and CLR16.1. | https://www.wikidoc.org/index.php/NLRC5 | |
7c007cfb07361495f06bfb8b9eb2e6df9cb66fed | wikidoc | NLRP1 | NLRP1
NACHT, LRR and PYD domains-containing protein 1 is a protein that in humans is encoded by the NLRP1 gene.
# Function
This gene encodes a member of the Ced-4 family of apoptosis proteins. Ced-family members contain a caspase recruitment domain (CARD) and are known to be key mediators of programmed cell death. The encoded protein contains a distinct N-terminal pyrin-like motif, which is possibly involved in protein-protein interactions. The NLRP1 protein interacts strongly with caspase 2 and weakly with caspase 9. Overexpression of this gene was demonstrated to induce apoptosis in cells. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity of some variants has not been determined.
# Interactions
NLRP1 has been shown to interact with caspase 9 and APAF1. | NLRP1
NACHT, LRR and PYD domains-containing protein 1 is a protein that in humans is encoded by the NLRP1 gene.[1][2][3]
# Function
This gene encodes a member of the Ced-4 family of apoptosis proteins. Ced-family members contain a caspase recruitment domain (CARD) and are known to be key mediators of programmed cell death. The encoded protein contains a distinct N-terminal pyrin-like motif, which is possibly involved in protein-protein interactions. The NLRP1 protein interacts strongly with caspase 2 and weakly with caspase 9. Overexpression of this gene was demonstrated to induce apoptosis in cells. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity of some variants has not been determined.[3]
# Interactions
NLRP1 has been shown to interact with caspase 9[4][5] and APAF1.[4] | https://www.wikidoc.org/index.php/NLRP1 | |
2a203737f58389b1ad8902c0c2f724e57b7ef658 | wikidoc | NLRP2 | NLRP2
NACHT, LRR and PYD domains-containing protein 2 is a protein that in humans is encoded by the NLRP2 gene.
NALP proteins, such as NALP2, are characterized by an N-terminal pyrin (MIM 608107) domain (PYD) and are involved in the activation of caspase-1 (CASP1; MIM 147678) by Toll-like receptors (see TLR4; MIM 603030). They may also be involved in protein complexes that activate proinflammatory caspases (Tschopp et al., 2003).
# Description and Functions
The NLRP2 gene is one of the family members of nucleotide-binding and leucine-rich repeat receptor (NLR). Information from many literature sources indicates that an N-terminal pyrin effector domain (PYD) is one of the components of the NLRP2 gene. Other components include a centrally-located nucleotide-binding and oligomerization domain (NACHT) and C-terminal leucine-rich repeats (LRR). The products of NLRP2 gene are known to interact with IkB kinase (IKK) complex components. It can also regulate the activities of both caspase-1 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). The pyrin domain is essential and adequate to suppress the activities of NF-kB (Minkiewicz, de Rivero Vaccari and Keane 1113). An allelic variant (rs147585490) is known to block the NF-kB transcriptional activities. NLRP2 gene is one of the NLR family; it is believed to contribute to the regulation of immune responses (Minkiewicz, de Rivero Vaccari and Keane 1121). Although it is not well understood, the NLRP2 gene is responsible for maintaining fertility in females and contributes to the normal birth. The NPRP2 gene encodes for a human protein known as “NACHT, LRR and PYD domains-containing protein 2”. NALP2, which is one of the NALP proteins, has an N-terminal pyrin characterization also encoded as MIM 608107 and PYD domain. The NALP2 protein has a role in the activation process of caspase-1, which is encoded as CASP1; MIM 147678. The activation process occurs through the Toll-like receptors. The NALP2 may also take part in protein complexes, which initiates the activation of proinflammatory caspases. NLR family regulates the functioning of the immune system, which technically compromises the normal functions of the body including reproduction.
## History of Discovery
The NLR gene family where the NLRP2 gene belongs was first extracted from zebrafish, which is a common specimen for the study of immune systems. The NLRP2 gene is believed to have originated from the NLR gene family through mutation. The mutation was initiated by the need for organisms to fit a dynamic environment and diversification in the evolution stages. Also, the mutation of the NLR gene family proteins was also due to the ability of pathogens to subvert the defense mechanism of the host. Therefore, the organisms were forced to device new ways of detecting and counteracting the effects of the resistant pathogens. The evolution of the NLR proteins defines the origin of the NLRP2 gene. The NLRP2 gene is now an innate immune sensor for pathogens and sterile stress signal (SSS) in multi-cellular organisms.
## Mutation and Infertility
The deficiency of NLRP2 gene results in the inhibition of the activation of oocytes. The NLRP2 gene is exclusively expressed in oocytes. Therefore, it regulates the quality of the oocytes, which explains its relation to infertility in females. It is remarkable that the mutation of NLRP2 gene interferes with its normal functions, especially in the activation of oocytes, with consequential infertility in females. The NLR family regulates the functioning of the immune system, which technically compromises the normal functions of the body including reproduction. | NLRP2
NACHT, LRR and PYD domains-containing protein 2 is a protein that in humans is encoded by the NLRP2 gene.[1][2][3]
NALP proteins, such as NALP2, are characterized by an N-terminal pyrin (MIM 608107) domain (PYD) and are involved in the activation of caspase-1 (CASP1; MIM 147678) by Toll-like receptors (see TLR4; MIM 603030). They may also be involved in protein complexes that activate proinflammatory caspases (Tschopp et al., 2003).[supplied by OMIM][3][4]
# Description and Functions
The NLRP2 gene is one of the family members of nucleotide-binding and leucine-rich repeat receptor (NLR). Information from many literature sources indicates that an N-terminal pyrin effector domain (PYD) is one of the components of the NLRP2 gene. Other components include a centrally-located nucleotide-binding and oligomerization domain (NACHT) and C-terminal leucine-rich repeats (LRR)[5]. The products of NLRP2 gene are known to interact with IkB kinase (IKK) complex components. It can also regulate the activities of both caspase-1 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). The pyrin domain is essential and adequate to suppress the activities of NF-kB (Minkiewicz, de Rivero Vaccari and Keane 1113). An allelic variant (rs147585490) is known to block the NF-kB transcriptional activities. NLRP2 gene is one of the NLR family; it is believed to contribute to the regulation of immune responses (Minkiewicz, de Rivero Vaccari and Keane 1121). Although it is not well understood, the NLRP2 gene is responsible for maintaining fertility in females and contributes to the normal birth. The NPRP2 gene encodes for a human protein known as “NACHT, LRR and PYD domains-containing protein 2”[6]. NALP2, which is one of the NALP proteins, has an N-terminal pyrin characterization also encoded as MIM 608107 and PYD domain[7]. The NALP2 protein has a role in the activation process of caspase-1, which is encoded as CASP1; MIM 147678. The activation process occurs through the Toll-like receptors. The NALP2 may also take part in protein complexes, which initiates the activation of proinflammatory caspases[8]. NLR family regulates the functioning of the immune system, which technically compromises the normal functions of the body including reproduction.
## History of Discovery
The NLR gene family where the NLRP2 gene belongs was first extracted from zebrafish, which is a common specimen for the study of immune systems. The NLRP2 gene is believed to have originated from the NLR gene family through mutation[9]. The mutation was initiated by the need for organisms to fit a dynamic environment and diversification in the evolution stages[10]. Also, the mutation of the NLR gene family proteins was also due to the ability of pathogens to subvert the defense mechanism of the host[11]. Therefore, the organisms were forced to device new ways of detecting and counteracting the effects of the resistant pathogens[12]. The evolution of the NLR proteins defines the origin of the NLRP2 gene. The NLRP2 gene is now an innate immune sensor for pathogens and sterile stress signal (SSS) in multi-cellular organisms.
## Mutation and Infertility
The deficiency of NLRP2 gene results in the inhibition of the activation of oocytes[13]. The NLRP2 gene is exclusively expressed in oocytes. Therefore, it regulates the quality of the oocytes, which explains its relation to infertility in females[14]. It is remarkable that the mutation of NLRP2 gene interferes with its normal functions, especially in the activation of oocytes, with consequential infertility in females. The NLR family regulates the functioning of the immune system, which technically compromises the normal functions of the body including reproduction. | https://www.wikidoc.org/index.php/NLRP2 | |
c973c063727e6f8c0edeeff9299231cd56b5f548 | wikidoc | NLRX1 | NLRX1
NLRX1 or NLR family member X1, short for nucleotide-binding oligomerization domain, leucine rich repeat containing X1 is a protein that in humans is encoded by the NLRX1 gene. It is also known as NOD-like receptor X1, NLR family, X1, NOD5, NOD9, and CLR11.3, and is a member of the NOD-like receptor family of pattern recognition receptors.
# Function
NLRX1 is an intracellular protein that plays a role in the immune system. NLRX1 has been proposed to affect innate immunity to viruses by interfering with the mitochondrial antiviral signaling protein (MAVS)/retinoic-acid-inducible gene I (RIG-I) mitochondrial antiviral pathway., although this was recently questioned.
NLRX1 also plays a role in host immunity during bacterial infections, such as Chlamydia trachomatis and Helicobacter pylori, by regulating bacterial burden and inflammation in mononuclear phagocytes. Mechanisms underlying the modulation of NLRX1 are not well characterized, however computational modeling predictions suggest that levels of NLRX1 may be controlled by negative feedback circuits induced early after infection.
# Structure
NLRX1 has a unique protein structure composed of 3 protein domains: an N-terminal effector domain containing a mitochondrion localization signal; a central NACHT domain; a C-terminal leucine-rich repeat (LRR) domain. | NLRX1
NLRX1 or NLR family member X1, short for nucleotide-binding oligomerization domain, leucine rich repeat containing X1 is a protein that in humans is encoded by the NLRX1 gene.[1][2] It is also known as NOD-like receptor X1, NLR family, X1, NOD5, NOD9, and CLR11.3, and is a member of the NOD-like receptor family of pattern recognition receptors.
# Function
NLRX1 is an intracellular protein that plays a role in the immune system. NLRX1 has been proposed to affect innate immunity to viruses by interfering with the mitochondrial antiviral signaling protein (MAVS)/retinoic-acid-inducible gene I (RIG-I) mitochondrial antiviral pathway.,[3] although this was recently questioned.[4][5]
NLRX1 also plays a role in host immunity during bacterial infections, such as Chlamydia trachomatis and Helicobacter pylori, by regulating bacterial burden and inflammation in mononuclear phagocytes. Mechanisms underlying the modulation of NLRX1 are not well characterized, however computational modeling predictions suggest that levels of NLRX1 may be controlled by negative feedback circuits induced early after infection.[6][7][8]
# Structure
NLRX1 has a unique protein structure composed of 3 protein domains: an N-terminal effector domain containing a mitochondrion localization signal; a central NACHT domain; a C-terminal leucine-rich repeat (LRR) domain.[9] | https://www.wikidoc.org/index.php/NLRX1 | |
f37079f3274b95dadd1afa5cf9208c49dec3fc94 | wikidoc | NOBOX | NOBOX
Homeobox protein NOBOX, also known as newborn ovary homeobox protein, is a protein that in humans is encoded by the NOBOX gene. The official symbol (NOBOX) and the official full name (NOBOX oogenesis homeobox) are maintained by the HGNC. The NOBOX gene is conserved in chimpanzee, Rhesus monkey, cow, mouse, and rat. There are 175 organisms that have orthologs with human gene NOBOX. It is capable of regulating other genes that are important in the development of follicles. Follicles do not develop and oocytes decrease in its absence which lead to infertility.
# Discovery
NOBOX is an in silico subtraction discovery when Suzumori et al. searched for novel genes involved in early mammalian folliculogenesis in 2002. It is one of the several genes that appeared in the search in expressed sequence tag (EST) databases of mouse. It was then cloned and characterised for its genomic structure.
# Gene location
The human NOBOX is located in chromosome 7q35 while the mouse NOBOX is in proximal chromosome 6.
# Protein structure
The human NOBOX is a 14 kb protein and encoded by 8 exons. It has a proline rich C terminus and contains putative SH3 and WW domains. This C terminus is believed to be critical in its transcriptional activities when bound to oocyte-specific genes. NOBOX belongs to the family of proteins that contains homeodomain. Homeodomain is a stretch of 32 specific amino acids in primates downstream the NOBOX Arg303 residue and is very well-conserved among the species. It contains an asparagine residue at position 51 which is important for its interactions with DNA base pairs.
# Function
NOBOX is a homeobox gene that is preferentially expressed in oocytes. In mice, it is essential for folliculogenesis and regulation of oocyte-specific genes. Regulation of these oocyte-specific genes is thru direct binding of NOBOX to its promoter regions via the specific consensus sequences, the NOBOX DNA binding elements (NBEs). There are three NBEs that have been identified: 5'-TAATTG-3', 5'-TAGTTG-3', and 5'-TAATTA-3'. Knockout study of NOBOX against wild-type ovaries in newborn female mice revealed that 74% (28/38 genes) were downregulated more than 5-fold and 15% (5/33 genes) were upregulated more than 5-fold. However, microRNA population is not affected by NOBOX in newborn ovaries. NOBOX also plays an important role in the suppression of male-determining genes such as Dmrt1. Its deficiency can cause rapid loss of postnatal oocytes and during its absence in female mice, follicles are replaced by fibrous tissue. Recently, a new role of NOBOX in controlling the G2/M arrest was discovered.
# Mutations and clinical significance
A mutation in the NOBOX gene is associated with premature ovarian failure (POF), also known as premature ovarian insufficiency (POI). It is a condition which ovaries loss its normal function before the age of 40. It is a heritable disease in up to 30% of patients which is characterised by secondary infertility, amenorrhea, hypoestrogenism, and elevated follicle-stimulating hormone levels in the serum (FSH>40IU/liter). It affects ≈1% of women below 40 years old. A study conducted on 96 white women with POF revealed one case of heterozygous mutation in the NOBOX homeodomain, p.Arg355His, in one patient. This mutation was absent in the control population and significantly disrupts the binding of NOBOX to the NBE. Arg355 is critical to DNA binding and is conserved in the homeodomain of the NOBOX from zebrafish to humans. Moreover, its significant negative effect suggests that NOBOX homeodomain may function as a dimer but its rare occurrence suggests a low contribution to POF. Further investigations on POF were conducted on Caucasian, African, Chinese, and Japanese women diagnosed with POF. Several NOBOX loss-of-function mutations were observed in Caucasian and African women accounting to 6.2%, 5.6% and 6.4%. These results suggest that NOBOX gene is a strong autosomal candidate for POF and its genetic mechanism involves haploinsufficiency. However, these mutations were not found in Chinese and Japanese women making it a less common explanation for POF in the region.
The POF syndrome is a highly heterogenous clinical disorder but a recent study showed the first homozygous mutation associated with NOBOX loss-of-function. One patient out of 96 population diagnosed with POF in China was found with one novel homozygous truncating variant in the NOBOX gene. This truncated variant caused a defective transcriptional activation of GDF9, a well-known target of NOBOX, which led to the lost ability of NOBOX to induce G2/M arrest. This finding disagrees that mutation is a less common explanation for POF in Asian population.
Understanding the mutations in NOBOX homeodomain is important to researchers and clinicians to develop diagnostic and therapeutic approaches for POF such as genetic control of mammalian reproductive life-span, regulation of fertility, and generation of mature eggs in the lab.
# Interactions
- GDF9
- POU5F1
- DNMT10
- FOXL2
- FIGLA
- RSPO2
- DMRT1 | NOBOX
Homeobox protein NOBOX, also known as newborn ovary homeobox protein, is a protein that in humans is encoded by the NOBOX gene.[1][2][3] The official symbol (NOBOX) and the official full name (NOBOX oogenesis homeobox) are maintained by the HGNC. The NOBOX gene is conserved in chimpanzee, Rhesus monkey, cow, mouse, and rat. There are 175 organisms that have orthologs with human gene NOBOX. It is capable of regulating other genes that are important in the development of follicles. Follicles do not develop and oocytes decrease in its absence which lead to infertility.[4]
# Discovery
NOBOX is an in silico subtraction discovery when Suzumori et al. searched for novel genes involved in early mammalian folliculogenesis in 2002. It is one of the several genes that appeared in the search in expressed sequence tag (EST) databases of mouse.[2] It was then cloned and characterised for its genomic structure.
# Gene location
The human NOBOX is located in chromosome 7q35 while the mouse NOBOX is in proximal chromosome 6.
# Protein structure
The human NOBOX is a 14 kb protein and encoded by 8 exons.[2] It has a proline rich C terminus and contains putative SH3 and WW domains.[5] This C terminus is believed to be critical in its transcriptional activities when bound to oocyte-specific genes.[6] NOBOX belongs to the family of proteins that contains homeodomain. Homeodomain is a stretch of 32 specific amino acids in primates downstream the NOBOX Arg303 residue and is very well-conserved among the species.[7] It contains an asparagine residue at position 51 which is important for its interactions with DNA base pairs.[8][9][10]
# Function
NOBOX is a homeobox gene that is preferentially expressed in oocytes. In mice, it is essential for folliculogenesis and regulation of oocyte-specific genes.[3] Regulation of these oocyte-specific genes is thru direct binding of NOBOX to its promoter regions via the specific consensus sequences, the NOBOX DNA binding elements (NBEs). There are three NBEs that have been identified: 5'-TAATTG-3', 5'-TAGTTG-3', and 5'-TAATTA-3'.[6] Knockout study of NOBOX against wild-type ovaries in newborn female mice revealed that 74% (28/38 genes) were downregulated more than 5-fold and 15% (5/33 genes) were upregulated more than 5-fold.[11] However, microRNA population is not affected by NOBOX in newborn ovaries. NOBOX also plays an important role in the suppression of male-determining genes such as Dmrt1.[11] Its deficiency can cause rapid loss of postnatal oocytes and during its absence in female mice, follicles are replaced by fibrous tissue.[2] Recently, a new role of NOBOX in controlling the G2/M arrest was discovered.[12]
# Mutations and clinical significance
A mutation in the NOBOX gene is associated with premature ovarian failure (POF), also known as premature ovarian insufficiency (POI).[13] It is a condition which ovaries loss its normal function before the age of 40. It is a heritable disease in up to 30% of patients which is characterised by secondary infertility, amenorrhea, hypoestrogenism, and elevated follicle-stimulating hormone levels in the serum (FSH>40IU/liter).[14][15] It affects ≈1% of women below 40 years old.[16] A study conducted on 96 white women with POF revealed one case of heterozygous mutation in the NOBOX homeodomain, p.Arg355His, in one patient.[13] This mutation was absent in the control population and significantly disrupts the binding of NOBOX to the NBE. Arg355 is critical to DNA binding and is conserved in the homeodomain of the NOBOX from zebrafish to humans. Moreover, its significant negative effect suggests that NOBOX homeodomain may function as a dimer but its rare occurrence suggests a low contribution to POF. Further investigations on POF were conducted on Caucasian, African, Chinese, and Japanese women diagnosed with POF. Several NOBOX loss-of-function mutations were observed in Caucasian and African women accounting to 6.2%, 5.6% and 6.4%.[7][17][18] These results suggest that NOBOX gene is a strong autosomal candidate for POF and its genetic mechanism involves haploinsufficiency. However, these mutations were not found in Chinese and Japanese women making it a less common explanation for POF in the region.[19][20]
The POF syndrome is a highly heterogenous clinical disorder but a recent study showed the first homozygous mutation associated with NOBOX loss-of-function.[12] One patient out of 96 population diagnosed with POF in China was found with one novel homozygous truncating variant in the NOBOX gene. This truncated variant caused a defective transcriptional activation of GDF9, a well-known target of NOBOX, which led to the lost ability of NOBOX to induce G2/M arrest. This finding disagrees that mutation is a less common explanation for POF in Asian population.
Understanding the mutations in NOBOX homeodomain is important to researchers and clinicians to develop diagnostic and therapeutic approaches for POF such as genetic control of mammalian reproductive life-span, regulation of fertility, and generation of mature eggs in the lab.[4]
# Interactions
- GDF9[6][21]
- POU5F1[2][6][4]
- DNMT10[4]
- FOXL2[22]
- FIGLA[4]
- RSPO2[23]
- DMRT1[15] | https://www.wikidoc.org/index.php/NOBOX | |
dd306a1c4b3f6a41212f85598cafa7242e5b0873 | wikidoc | NODAL | NODAL
Nodal is a secretory protein that in humans is encoded by the NODAL gene which is located on chromosome 10q22.1. It belongs to the Transforming Growth Factor (TGF-β) superfamily. Like many other members of this superfamily it is involved in cell differentiation in early embryogenesis, playing a key role in signal transfer from the node, in the anterior primitive streak, to lateral plate mesoderm (LPM).
Nodal signaling is important very early in development for mesoderm and endoderm formation and subsequent organization of left-right axial structures. In addition, Nodal seems to have important functions in neural patterning, stem cell maintenance and many other developmental processes, including left/right handedness.
# Signaling
Nodal can bind type I and type II Serine/Threonine kinase receptors, with Cripto-1 acting as its co-receptor. Signaling through SMAD 2/3 and subsequent translocation of SMAD 4 to the nucleus promotes the expression of genes involved in proliferation and differentiation. Nodal also further activates its own expression via a positive feedback loop. It is tightly regulated by inhibitors Lefty A, Lefty B, Cerberus, and Tomoregulin-1, which can interfere with Nodal receptor binding.
# Species specific Nodal Ligands
Nodal is a widely distributed cytokine. The presence of Nodal is not limited to vertebrates, it is also known to be conserved in other deuterostomes (cephalochordates, tunicates and echinoderms) and protostomes such as snails, but neither the nematode C. elegans (another protosome) nor the fruit fly Drosophila (an arthropod) have a copy of nodal. Although mouse and human only have one nodal gene, the zebrafish contain three nodal paralogs: squint , cyclops and southpaw, and the frog five (xnr1,2,3,5 and 6). Even though the zebrafish Nodal homologs are very similar, they have specialized to perform different roles; for instance, Squint and Cyclops are important for mesoendoderm formation, whereas the Southpaw has a major role in asymmetric heart morphogenesis and visceral left-right asymmetry. Another example of protein speciation is the case of the frog where Xnr1 and Xnr2 regulate movements in gastrulation in contrast to Xnr5 and Xnr6 that are involved in mesoderm induction. In mouse, Nodal has been implicated in left-right asymmetry, neural pattering and mesoderm induction (see nodal signaling).
# Functions
Nodal signaling regulates mesoderm formation in a species-specific manner. Thus, in Xenopus, Xnr controls dorso-ventral mesoderm formation along the marginal zone. In zebrafish, Squint and Cyclops are responsible for animal-vegetal mesoderm formation. In chicken and mouse, Vg1 and Nodal respectively promote primitive streak formation in the epiblast. In chick development, Nodal is expressed in Koller's sickle. Studies have shown that a nodal knockout in mouse causes the absence of the primitive streak and failure in the formation of mesoderm, leading to developmental arrest just after gastrulation.
Compared to mesoderm specification, endoderm specification requires a higher expression of Nodal. Here, Nodal stimulates mixer homeoproteins, which can interact with SMADs in order to up-regulate endoderm specific genes and repress mesoderm specific genes.
Left-right (LR) asymmetry of visceral organs in vertebrates is also established through nodal signaling. Whereas Nodal is initially symmetrically expressed in the embryo, after gastrulation, Nodal becomes asymmetrically restricted to the left side of the organism. It is highly conserved among deuterostomes. An ortholog of Nodal was found in snails and was shown to be involved in left-right asymmetry as well in 2008.
In order to enable anterior neural tissue development, Nodal signaling needs to be repressed after inducing mesendoderm and LR symmetry.
Recent research on mouse and human embryonic stem cells (hESCs) indicates that Nodal seems to be involved in the maintenance of stem cell self-renewal and pluripotent potentials. Thus, overexpression of Nodal in hESCs lead to the repression of cell differentiation. On the contrary, inhibition of Nodal and Activin signaling enabled the differentiation of hESCs. | NODAL
Nodal is a secretory protein that in humans is encoded by the NODAL gene[1][2] which is located on chromosome 10q22.1.[3] It belongs to the Transforming Growth Factor (TGF-β) superfamily. Like many other members of this superfamily it is involved in cell differentiation in early embryogenesis, playing a key role in signal transfer from the node, in the anterior primitive streak, to lateral plate mesoderm (LPM).[4][5]
Nodal signaling is important very early in development for mesoderm and endoderm formation and subsequent organization of left-right axial structures.[2][6][7] In addition, Nodal seems to have important functions in neural patterning, stem cell maintenance[3][7] and many other developmental processes, including left/right handedness.[6][8]
# Signaling
Nodal can bind type I and type II Serine/Threonine kinase receptors, with Cripto-1 acting as its co-receptor.[9] Signaling through SMAD 2/3 and subsequent translocation of SMAD 4 to the nucleus promotes the expression of genes involved in proliferation and differentiation.[3] Nodal also further activates its own expression via a positive feedback loop.[7][9] It is tightly regulated by inhibitors Lefty A, Lefty B, Cerberus, and Tomoregulin-1, which can interfere with Nodal receptor binding.[5][7]
# Species specific Nodal Ligands
Nodal is a widely distributed cytokine.[10] The presence of Nodal is not limited to vertebrates, it is also known to be conserved in other deuterostomes (cephalochordates, tunicates and echinoderms) and protostomes such as snails, but neither the nematode C. elegans (another protosome) nor the fruit fly Drosophila (an arthropod) have a copy of nodal.[11][12] Although mouse and human only have one nodal gene, the zebrafish contain three nodal paralogs: squint , cyclops and southpaw, and the frog five (xnr1,2,3,5 and 6). Even though the zebrafish Nodal homologs are very similar, they have specialized to perform different roles; for instance, Squint and Cyclops are important for mesoendoderm formation, whereas the Southpaw has a major role in asymmetric heart morphogenesis and visceral left-right asymmetry.[13] Another example of protein speciation is the case of the frog where Xnr1 and Xnr2 regulate movements in gastrulation in contrast to Xnr5 and Xnr6 that are involved in mesoderm induction.[14] In mouse, Nodal has been implicated in left-right asymmetry, neural pattering and mesoderm induction (see nodal signaling).
# Functions
Nodal signaling regulates mesoderm formation in a species-specific manner. Thus, in Xenopus, Xnr controls dorso-ventral mesoderm formation along the marginal zone. In zebrafish, Squint and Cyclops are responsible for animal-vegetal mesoderm formation. In chicken and mouse, Vg1 and Nodal respectively promote primitive streak formation in the epiblast.[7] In chick development, Nodal is expressed in Koller's sickle.[15] Studies have shown that a nodal knockout in mouse causes the absence of the primitive streak and failure in the formation of mesoderm, leading to developmental arrest just after gastrulation.[16][17][18]
Compared to mesoderm specification, endoderm specification requires a higher expression of Nodal. Here, Nodal stimulates mixer homeoproteins, which can interact with SMADs in order to up-regulate endoderm specific genes and repress mesoderm specific genes.[7]
Left-right (LR) asymmetry of visceral organs in vertebrates is also established through nodal signaling. Whereas Nodal is initially symmetrically expressed in the embryo, after gastrulation, Nodal becomes asymmetrically restricted to the left side of the organism.[3][7] It is highly conserved among deuterostomes.[19][20] An ortholog of Nodal was found in snails and was shown to be involved in left-right asymmetry as well in 2008.[20]
In order to enable anterior neural tissue development, Nodal signaling needs to be repressed after inducing mesendoderm and LR symmetry.[7][9]
Recent research on mouse and human embryonic stem cells (hESCs) indicates that Nodal seems to be involved in the maintenance of stem cell self-renewal and pluripotent potentials.[3][7][21][22] Thus, overexpression of Nodal in hESCs lead to the repression of cell differentiation.[7] On the contrary, inhibition of Nodal and Activin signaling enabled the differentiation of hESCs.[3] | https://www.wikidoc.org/index.php/NODAL | |
279525cb523918610abd32c9a9e136c85a2e7ec4 | wikidoc | NPAS2 | NPAS2
Neuronal PAS domain protein 2 (NPAS2) also known as member of PAS protein 4 (MOP4) is a transcription factor protein that in humans is encoded by the NPAS2 gene. NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals. In the brain, NPAS2 functions as a generator and maintainer of mammalian circadian rhythms. More specifically, NPAS2 is an activator of transcription and translation of core clock and clock-controlled genes through its role in a negative feedback loop in the suprachiasmatic nucleus (SCN), the brain region responsible for the control of circadian rhythms.
# Discovery
The mammalian and mouse Npas2 gene was first sequenced and characterized in 1997 Dr. Steven McKnight's lab and published by Yu-Dong Zhou et al. The gene’s cDNAs encoding mouse and human forms of NPAS2 were isolated and sequenced. RNA blotting assays were used to demonstrate the selective presence of the gene in brain and spinal cord tissues of mice. In situ hybridization indicated that the pattern of Npas2 mRNA distribution in mouse brain is broad and complex, and is largely non-overlapping with that of Npas1.
Using Immunohistochemistry of human testis, Ramasamy et al. (2015) found the presence of NPAS2 protein in both germ cells within the tubules of the testes and in the interstitial space of Leydig cells.
# Structure
## In humans
The Npas2 gene resides on chromosome 2 at the band q13. The gene is 176,679 bases long and contains 25 exons. The predicted 824-amino acid human NPAS2 protein shares 87% sequence identity with mouse Npas2.
## In mice
The Npas2 gene has been found to reside on chromosome 1 at 17.98 centimorgans and is 169,505 bases long.
# Function
## In the brain
The NPAS2 protein is a member of the basic helix-loop-helix (bHLH)-PAS transcription factor family and is expressed in the SCN. NPAS2 is a PAS domain-containing protein, which binds other proteins via their own protein-protein (PAS) binding domains. Like its paralogue, CLOCK (another PAS domain-containing protein), the NPAS2 protein can dimerize with the BMAL1 protein and engage in a transcription/translation negative feedback loop (TTFL) to activate transcription of the mammalian Per and Cry core clock genes. NPAS2 has been shown to form a heterodimer with BMAL1 in both the brain and in cell lines, suggesting its similarity in function to the CLOCK protein in this TTFL.
Compensation is a key feature of TTFLs that regulate circadian rhythms. BMAL1 compensates for CLOCK in that if CLOCK is absent, BMAL1 will upregulate to maintain the mammalian circadian rhythms. NPAS2 has been shown to be analogous to the function of CLOCK in CLOCK-deficient mice. In Clock knockout mice, NPAS2 is upregulated to keep the rhythms intact. Npas2-mutant mice, which do not express functional NPAS2 protein, still maintain robust circadian rhythms in locomotion. However, like CLOCK-deficient mice in the CLOCK/BMAL1 TTFL, Npas2-mutant mice (in the NPAS2/BMAL1 TTFL) still have small defects in their circadian rhythms such as a shortened circadian period and an altered response to changes in the typical light-dark cycle. In addition, Npas2 knockout mice show sleep disturbances and have decreased expression of mPer2 in their forebrains. Mice without functional alleles of both Clock and Npas2 became arrhythmic once placed in constant darkness, suggesting that both genes have overlapping roles in maintaining circadian rhythms. In both wild-type and Clock knockout mice, Npas2 expression is observed at the same levels, confirming that Npas2 plays a role in maintaining these rhythms in the absence of Clock.
## In other tissues
Npas2 is expressed everywhere in the periphery of the body. Special focus has been given to its function in liver tissues, and its mRNA is upregulated in Clock-mutant mice. However, studies have shown that Npas2 alone is unable to maintain circadian rhythms in peripheral tissues in the absence of CLOCK protein, unlike in the SCN. One theory to explain this observation is that neurons in the brain are characterized by intercellular coupling and can thus respond to deficiencies in key clock proteins in nearby neurons to maintain rhythms. In peripheral tissues such as the liver and lung, however, the lack of intercellular coupling does not allow for this compensatory mechanism to occur. A second theory as to why NPAS2 can maintain rhythms in CLOCK-deficient SCNs but not in CLOCK-deficient peripheral tissues, is that there exists an additional unknown factor in the SCN that is not present in peripheral tissues.
## Non-circadian function
NPAS2-deficient mice have been shown to have long-term memory deficits, suggesting that the protein may play a key role in the acquisition of such memories. This theory was tested by inserting a reporter gene (lacZ) that resulted in the production of an NPAS2 protein lacking the bHLH domain. These mice were then given several tests, including the cued and contextual fear task, and showed long-term memory deficits in both tasks.
# Interactions
NPAS2 has been shown to interact with:
- ARNTL (also known as BMAL1). Like Clock, Npas2 mRNA cycles with a similar phase to that of Bmal1, with both peaking 8 hours before the peak of Per2 mRNA expression. This is consistent with the observation that NPAS2 forms a heterodimer with BMAL1 to drive Per2 expression.
- EP300. NPAS2 and EP300 interact in a time-dependent, synchronized manner. EP300 is recruited to NPAS2 as a coactivator of clock gene expression.
- Retinoic acid receptor alpha (RARα) and retinoid X receptor alpha (RXRα). In peripheral clocks, RARα and RXRα interact with NPAS2 by inhibiting the NPAS2:BMAL1 heterodimer-mediated expression of clock genes. This interaction depends upon humoral signaling by retinoic acid and serves to phase-shift the clock.
- Small heterodimer partner (SHP). In the liver circadian clock, NPAS2 and SHP engage in a TTFL: NPAS2 controls the circadian rhythms of SHP by rhythmically binding to its promoter, while SHP inhibits transcription of Npas2 when present.
# Clinical significance
Npas2 genotypes can be determined through tissue samples from which genomic DNA is extracted and assayed. The assay is performed under PCR conditions and can be used to determine specific mutations and polymorphisms.
## Polymorphisms and tumorigenesis
Mounting evidence suggests that the NPAS2 protein and other circadian genes are involved in tumorigenesis and tumor growth, possibly through their control of cancer-related biologic pathways. A missense polymorphism in NPAS2 (Ala394Thr) has been shown to be associated with risk of human tumors including breast cancer. These findings provide evidence suggesting a possible role for the circadian Npas2 gene in cancer prognosis. These results have been confirmed in both breast and colorectal cancers.
## NPAS2 and mood disorders
Current research has revealed an association between seasonal affective disorder (SAD) and general mood disorder related to NPAS2, ARNTL, and CLOCK polymorphisms. These genes may influence seasonal variations through metabolic factors such as body weight and appetite.
Associated with a connection to mood disorders, NPAS2 has been found to be involved with dopamine degradation. This was first suggested by the observation that the clock components BMAL1 and NPAS2 transcriptionally activated a luciferase reporter driven by the murine monoamine oxidase A (Maoa) promoter in a circadian fashion. This suggested that these two clock components (BMAL1 and NPAS2) directly regulated Maoa transcription. Subsequent findings discovered positive transcriptional regulation of BMAL1/NPAS2 by PER2. In mice lacking PER2, both Maoa mRNA and MAOA protein levels were decreased. Therefore, dopamine degradation was reduced, and dopamine levels in the nucleus accumbens were increased. These findings indicate that degradation of monoamines is regulated by the circadian clock. It is very likely that the described clock-mediated regulation of monoamines is relevant for humans, because single-nucleotide polymorphisms in Per2, Bmal1, and Npas2 are associated in an additive fashion with seasonal affective disorder or winter depression. | NPAS2
Neuronal PAS domain protein 2 (NPAS2) also known as member of PAS protein 4 (MOP4) is a transcription factor protein that in humans is encoded by the NPAS2 gene.[1][2] NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals.[3] In the brain, NPAS2 functions as a generator and maintainer of mammalian circadian rhythms. More specifically, NPAS2 is an activator of transcription and translation of core clock and clock-controlled genes through its role in a negative feedback loop in the suprachiasmatic nucleus (SCN), the brain region responsible for the control of circadian rhythms.[4]
# Discovery
The mammalian and mouse Npas2 gene was first sequenced and characterized in 1997 Dr. Steven McKnight's lab and published by Yu-Dong Zhou et al.[5][6] The gene’s cDNAs encoding mouse and human forms of NPAS2 were isolated and sequenced. RNA blotting assays were used to demonstrate the selective presence of the gene in brain and spinal cord tissues of mice. In situ hybridization indicated that the pattern of Npas2 mRNA distribution in mouse brain is broad and complex, and is largely non-overlapping with that of Npas1.[6]
Using Immunohistochemistry of human testis, Ramasamy et al. (2015) found the presence of NPAS2 protein in both germ cells within the tubules of the testes and in the interstitial space of Leydig cells.[6]
# Structure
## In humans
The Npas2 gene resides on chromosome 2 at the band q13.[6] The gene is 176,679 bases long and contains 25 exons.[7] The predicted 824-amino acid human NPAS2 protein shares 87% sequence identity with mouse Npas2.[6]
## In mice
The Npas2 gene has been found to reside on chromosome 1 at 17.98 centimorgans and is 169,505 bases long.[8]
# Function
## In the brain
The NPAS2 protein is a member of the basic helix-loop-helix (bHLH)-PAS transcription factor family and is expressed in the SCN. NPAS2 is a PAS domain-containing protein, which binds other proteins via their own protein-protein (PAS) binding domains. Like its paralogue, CLOCK (another PAS domain-containing protein), the NPAS2 protein can dimerize with the BMAL1 protein and engage in a transcription/translation negative feedback loop (TTFL) to activate transcription of the mammalian Per and Cry core clock genes.[4] NPAS2 has been shown to form a heterodimer with BMAL1 in both the brain and in cell lines, suggesting its similarity in function to the CLOCK protein in this TTFL.
Compensation is a key feature of TTFLs that regulate circadian rhythms. BMAL1 compensates for CLOCK in that if CLOCK is absent, BMAL1 will upregulate to maintain the mammalian circadian rhythms. NPAS2 has been shown to be analogous to the function of CLOCK in CLOCK-deficient mice.[4] In Clock knockout mice, NPAS2 is upregulated to keep the rhythms intact.[4] Npas2-mutant mice, which do not express functional NPAS2 protein, still maintain robust circadian rhythms in locomotion. However, like CLOCK-deficient mice in the CLOCK/BMAL1 TTFL, Npas2-mutant mice (in the NPAS2/BMAL1 TTFL) still have small defects in their circadian rhythms such as a shortened circadian period and an altered response to changes in the typical light-dark cycle.[4] In addition, Npas2 knockout mice show sleep disturbances and have decreased expression of mPer2 in their forebrains.[9] Mice without functional alleles of both Clock and Npas2 became arrhythmic once placed in constant darkness, suggesting that both genes have overlapping roles in maintaining circadian rhythms. In both wild-type and Clock knockout mice, Npas2 expression is observed at the same levels, confirming that Npas2 plays a role in maintaining these rhythms in the absence of Clock.[4]
## In other tissues
Npas2 is expressed everywhere in the periphery of the body. Special focus has been given to its function in liver tissues, and its mRNA is upregulated in Clock-mutant mice. However, studies have shown that Npas2 alone is unable to maintain circadian rhythms in peripheral tissues in the absence of CLOCK protein, unlike in the SCN.[4] One theory to explain this observation is that neurons in the brain are characterized by intercellular coupling and can thus respond to deficiencies in key clock proteins in nearby neurons to maintain rhythms. In peripheral tissues such as the liver and lung, however, the lack of intercellular coupling does not allow for this compensatory mechanism to occur. A second theory as to why NPAS2 can maintain rhythms in CLOCK-deficient SCNs but not in CLOCK-deficient peripheral tissues, is that there exists an additional unknown factor in the SCN that is not present in peripheral tissues.[4]
## Non-circadian function
NPAS2-deficient mice have been shown to have long-term memory deficits, suggesting that the protein may play a key role in the acquisition of such memories. This theory was tested by inserting a reporter gene (lacZ) that resulted in the production of an NPAS2 protein lacking the bHLH domain. These mice were then given several tests, including the cued and contextual fear task, and showed long-term memory deficits in both tasks.[10]
# Interactions
NPAS2 has been shown to interact with:
- ARNTL (also known as BMAL1). Like Clock, Npas2 mRNA cycles with a similar phase to that of Bmal1, with both peaking 8 hours before the peak of Per2 mRNA expression. This is consistent with the observation that NPAS2 forms a heterodimer with BMAL1 to drive Per2 expression.[11][12]
- EP300. NPAS2 and EP300 interact in a time-dependent, synchronized manner. EP300 is recruited to NPAS2 as a coactivator of clock gene expression.[13]
- Retinoic acid receptor alpha (RARα) and retinoid X receptor alpha (RXRα). In peripheral clocks, RARα and RXRα interact with NPAS2 by inhibiting the NPAS2:BMAL1 heterodimer-mediated expression of clock genes. This interaction depends upon humoral signaling by retinoic acid and serves to phase-shift the clock.[11]
- Small heterodimer partner (SHP). In the liver circadian clock, NPAS2 and SHP engage in a TTFL: NPAS2 controls the circadian rhythms of SHP by rhythmically binding to its promoter, while SHP inhibits transcription of Npas2 when present.[14]
# Clinical significance
Npas2 genotypes can be determined through tissue samples from which genomic DNA is extracted and assayed. The assay is performed under PCR conditions and can be used to determine specific mutations and polymorphisms.[15]
## Polymorphisms and tumorigenesis
Mounting evidence suggests that the NPAS2 protein and other circadian genes are involved in tumorigenesis and tumor growth, possibly through their control of cancer-related biologic pathways. A missense polymorphism in NPAS2 (Ala394Thr) has been shown to be associated with risk of human tumors including breast cancer.[15] These findings provide evidence suggesting a possible role for the circadian Npas2 gene in cancer prognosis. These results have been confirmed in both breast and colorectal cancers.[16]
## NPAS2 and mood disorders
Current research has revealed an association between seasonal affective disorder (SAD) and general mood disorder related to NPAS2, ARNTL, and CLOCK polymorphisms. These genes may influence seasonal variations through metabolic factors such as body weight and appetite.[17][18]
Associated with a connection to mood disorders, NPAS2 has been found to be involved with dopamine degradation. This was first suggested by the observation that the clock components BMAL1 and NPAS2 transcriptionally activated a luciferase reporter driven by the murine monoamine oxidase A (Maoa) promoter in a circadian fashion.[19] This suggested that these two clock components (BMAL1 and NPAS2) directly regulated Maoa transcription.[19] Subsequent findings discovered positive transcriptional regulation of BMAL1/NPAS2 by PER2. In mice lacking PER2, both Maoa mRNA and MAOA protein levels were decreased. Therefore, dopamine degradation was reduced, and dopamine levels in the nucleus accumbens were increased. These findings indicate that degradation of monoamines is regulated by the circadian clock. It is very likely that the described clock-mediated regulation of monoamines is relevant for humans, because single-nucleotide polymorphisms in Per2, Bmal1, and Npas2 are associated in an additive fashion with seasonal affective disorder or winter depression.[20] | https://www.wikidoc.org/index.php/NPAS2 | |
71827f24299e69d7f1064cdb980941abd52d5697 | wikidoc | NPAS3 | NPAS3
NPAS3 or Neuronal PAS domain protein 3 is a brain-enriched transcription factor belonging to the bHLH-PAS superfamily of transcription factors, the members of which carry out diverse functions, including circadian oscillations, neurogenesis, toxin metabolism, hypoxia, and tracheal development. NPAS3 contains basic helix-loop-helix structural motif and PAS domain, like the other proteins in the superfamily.
# Function
NPAS3 is also known as human accelerated region 21. It may, therefore, have played a key role in differentiating humans from apes.
NPAS1 and NPAS3-deficient mice display behavioral abnormalities typical to the animal models of schizophrenia.
According to the same study, NPAS1 and NPAS3 disruption leads to reduced expression of reelin, which is also consistently found to be reduced in the brains of human patients with schizophrenia and psychotic bipolar disorder. Among the 49 genomic regions that undergone rapid changes in humans compared with their evolutionary ancestors, NPAS3 was found to be located in the region 21.
# Clinical significance
Disruption of NPAS3 was found in one family affected by schizophrenia and NPAS3 gene is thought to be associated with psychiatric illness and learning disability. In a genetic study of several hundred subjects conducted in 2008, interacting haplotypes at the NPAS3 locus were found to affect the risk of schizophrenia and bipolar disorder.
In a pharmacogenetical study, polymorphisms in NPAS3 gene were highly associated with response to iloperidone, a proposed atypical antipsychotic. | NPAS3
NPAS3 or Neuronal PAS domain protein 3 is a brain-enriched transcription factor belonging to the bHLH-PAS superfamily of transcription factors, the members of which carry out diverse functions, including circadian oscillations, neurogenesis, toxin metabolism, hypoxia, and tracheal development. NPAS3 contains basic helix-loop-helix structural motif and PAS domain, like the other proteins in the superfamily.
# Function
NPAS3 is also known as human accelerated region 21. It may, therefore, have played a key role in differentiating humans from apes.[1]
NPAS1 and NPAS3-deficient mice display behavioral abnormalities typical to the animal models of schizophrenia.[2]
According to the same study, NPAS1 and NPAS3 disruption leads to reduced expression of reelin, which is also consistently found to be reduced in the brains of human patients with schizophrenia and psychotic bipolar disorder. Among the 49 genomic regions that undergone rapid changes in humans compared with their evolutionary ancestors, NPAS3 was found to be located in the region 21.[1]
# Clinical significance
Disruption of NPAS3 was found in one family affected by schizophrenia[3] and NPAS3 gene is thought to be associated with psychiatric illness and learning disability.[4][5] In a genetic study of several hundred subjects conducted in 2008, interacting haplotypes at the NPAS3 locus were found to affect the risk of schizophrenia and bipolar disorder.[6]
In a pharmacogenetical study, polymorphisms in NPAS3 gene were highly associated with response to iloperidone, a proposed atypical antipsychotic.[7] | https://www.wikidoc.org/index.php/NPAS3 | |
67871f1e0644b7837c23c17844f97a2c257b79e4 | wikidoc | NPHP1 | NPHP1
Nephrocystin-1 is a protein that in humans is encoded by the NPHP1 gene.
# Function
This gene encodes a protein with src homology domain 3 (SH3) patterns. Mutations in this gene cause familial juvenile nephronophthisis.
# Interactions
NPHP1 has been shown to interact with BCAR1, PTK2B, Filamin and INVS. | NPHP1
Nephrocystin-1 is a protein that in humans is encoded by the NPHP1 gene.[1]
# Function
This gene encodes a protein with src homology domain 3 (SH3) patterns. Mutations in this gene cause familial juvenile nephronophthisis.[1]
# Interactions
NPHP1 has been shown to interact with BCAR1,[2][3] PTK2B,[3] Filamin[4] and INVS.[5] | https://www.wikidoc.org/index.php/NPHP1 | |
5bd3b98d395bf2106ce37c7b6d58d6f1321fe6d6 | wikidoc | NPRL3 | NPRL3
Nitrogen permease regulator-like 3 is a protein that in humans is encoded by the NPRL3 gene.
# Function
NPRL3 is a human protein of poorly understood function but has been associated with cancer.
The most prominent function ascribed to Nprl3 to date is as part of the GATOR1 complex (with NPRL2 and DEPDC5) that inhibits the mechanistic target of rapamycin (mTOR) kinase-complex-1 (mTORC1) on the surface of the lysosome (equivalent of degradative vacuole in yeast) via an effect on the Rag GTPase complex. Additionally, Nprl3 has been shown to adjust cell metabolism via the TOR pathway, and this is important for development of the cardiovascular system in mammals. Without this effect, spontaneous cell apoptosis would occur. A similar function for Nprl3 has been identified in the female reproductive system of Drosophila during times of protein scarcity.
# Gene
In Homo sapiens, the NPRL3 gene is located at C16orf35. The gene is composed of 14 exons at 53 kbp in length. This gene is highly conserved in vertebrates which is upstream from the alpha globin gene cluster. Within the fifth intron of the gene there is a regulatory section of DNA HS-40 which regulates the expression of the alpha globin. This means that the gene C16orf35 is expressed in early erythrocytes accompanying hemoglobin production.
# Structure
The human nitrogen permease regulator-like 3 protein has 569 amino acids.
## Domains
There is a predicted N-terminal longin domain within the Nprl3 protein (amino acids 4-168). At the C terminus there are three consecutive winged helix turn helix (HTH) domains. These regions are predicted bind to another macromolecule, which could be DNA, RNA or protein. | NPRL3
Nitrogen permease regulator-like 3 is a protein that in humans is encoded by the NPRL3 gene.[1]
# Function
NPRL3 is a human protein of poorly understood function[2] but has been associated with cancer.
The most prominent function ascribed to Nprl3 to date is as part of the GATOR1 complex[3] (with NPRL2 and DEPDC5) that inhibits the mechanistic target of rapamycin (mTOR) kinase-complex-1 (mTORC1) on the surface of the lysosome (equivalent of degradative vacuole in yeast) via an effect on the Rag GTPase complex. Additionally, Nprl3 has been shown to adjust cell metabolism via the TOR pathway, and this is important for development of the cardiovascular system in mammals.[2] Without this effect, spontaneous cell apoptosis would occur. A similar function for Nprl3 has been identified in the female reproductive system of Drosophila during times of protein scarcity.[4]
# Gene
In Homo sapiens, the NPRL3 gene is located at C16orf35. The gene is composed of 14 exons at 53 kbp in length.[5] This gene is highly conserved in vertebrates[6] which is upstream from the alpha globin gene cluster. Within the fifth intron of the gene there is a regulatory section of DNA HS-40 which regulates the expression of the alpha globin. This means that the gene C16orf35 is expressed in early erythrocytes accompanying hemoglobin production.[2]
# Structure
The human nitrogen permease regulator-like 3 protein has 569 amino acids.
## Domains
There is a predicted N-terminal longin domain within the Nprl3 protein (amino acids 4-168). At the C terminus there are three consecutive winged helix turn helix (HTH) domains.[7] These regions are predicted bind to another macromolecule, which could be DNA, RNA or protein. | https://www.wikidoc.org/index.php/NPRL3 | |
cd10442252929846a57442c5899dd3306d435d83 | wikidoc | NPTX2 | NPTX2
Neuronal pentraxin-2 is a protein that in humans is encoded by the NPTX2 gene.
# Function
This gene encodes a member of the family of neuronal pentraxins, synaptic proteins that are related to C-reactive protein. This protein is involved in excitatory synapse formation. It also plays a role in clustering of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors at established synapses, resulting in non-apoptotic cell death of dopaminergic nerve cells.
# Clinical significance
Up-regulation of this gene in Parkinson disease (PD) tissues suggests that the protein may be involved in the pathology of PD. | NPTX2
Neuronal pentraxin-2 is a protein that in humans is encoded by the NPTX2 gene.[1][2]
# Function
This gene encodes a member of the family of neuronal pentraxins, synaptic proteins that are related to C-reactive protein. This protein is involved in excitatory synapse formation. It also plays a role in clustering of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors at established synapses, resulting in non-apoptotic cell death of dopaminergic nerve cells.[2]
# Clinical significance
Up-regulation of this gene in Parkinson disease (PD) tissues suggests that the protein may be involved in the pathology of PD.[2] | https://www.wikidoc.org/index.php/NPTX2 | |
a99ae505964c556cf6526513adfada0ee9544d43 | wikidoc | NRIP1 | NRIP1
Nuclear receptor-interacting protein 1 (NRIP1) also known as receptor-interacting protein 140 (RIP140) is a protein that in humans is encoded by the NRIP1 gene.
# Function
Nuclear receptor interacting protein 1 (NRIP1) is a nuclear protein that specifically interacts with the hormone-dependent activation domain AF2 of nuclear receptors. Also known as RIP140, this protein is a key regulator which modulates transcriptional activity of a variety of transcription factors, including the estrogen receptor.
RIP140 has an important role in regulating lipid and glucose metabolism, and regulates gene expression in metabolic tissues including heart, skeletal muscle, and liver. A major role for RIP140 in adipose tissue is to block the expression of genes involved in energy dissipation and mitochondrial uncoupling, including uncoupling protein 1 and carnitine palmitoyltransferase 1b.
Estrogen-related receptor alpha (ERRa) can activate RIP140 during adipogenesis, by means of directly binding to an estrogen receptor element/ERR element and indirectly through Sp1 binding to the proximal promoter.
RIP140 suppresses the expression of mitochondrial proteins succinate dehydrogenase complex b and CoxVb and acts as a negative regulator of glucose uptake in mice.
# Knockout studies
Knockout mice that completely lack the RIP140 molecule are lean and stay lean, even on a rich diet.
Knockout mice (females) are also infertile because they fail to ovulate. Failure of ovulation in these mice is caused by lack of cumulus expansion and altered expression of various genes, including amphiregulin, in ovarian follicles.
# Clinical significance
RIP140 is part of the chain by which tumors can cause cachexia.
Levels of RIP140 expression in various tissues varies during aging in mice, suggesting changes in metabolic function. RIP140 is implicated in certain human disease processes. In morbid obesity, RIP140 levels are down-regulated in visceral adipose tissue. In breast cancer, RIP140 is involved in regulation of E2F1, an oncogene which discriminates between luminal and basal types of tumours. RIP140 has an influence upon cancer phenotype and prognosis. In addition, RIP140 has a role in inflammation, since it acts as a coactivator for NFkappaB/RelA-dependent cytokine gene expression. Lack of RIP140 leads to an inhibition of proinflammatory pathways in macrophages.
# Interactions
NRIP1 has been shown to interact with:
- AHR,
- CTBP1
- CTBP2,
- DAX1,
- HDAC5,
- NR1B1,
- NR2B1,
- NR3A1,
- NR3C1,
- NR5A1, and
- YWHAQ. | NRIP1
Nuclear receptor-interacting protein 1 (NRIP1) also known as receptor-interacting protein 140 (RIP140) is a protein that in humans is encoded by the NRIP1 gene.[1][2]
# Function
Nuclear receptor interacting protein 1 (NRIP1) is a nuclear protein that specifically interacts with the hormone-dependent activation domain AF2 of nuclear receptors. Also known as RIP140, this protein is a key regulator which modulates transcriptional activity of a variety of transcription factors, including the estrogen receptor.[3]
RIP140 has an important role in regulating lipid and glucose metabolism,[4] and regulates gene expression in metabolic tissues including heart,[5] skeletal muscle,[6] and liver.[7] A major role for RIP140 in adipose tissue is to block the expression of genes involved in energy dissipation and mitochondrial uncoupling, including uncoupling protein 1 and carnitine palmitoyltransferase 1b.[8]
Estrogen-related receptor alpha (ERRa) can activate RIP140 during adipogenesis, by means of directly binding to an estrogen receptor element/ERR element and indirectly through Sp1 binding to the proximal promoter.[9]
RIP140 suppresses the expression of mitochondrial proteins succinate dehydrogenase complex b and CoxVb and acts as a negative regulator of glucose uptake in mice.[10]
# Knockout studies
Knockout mice that completely lack the RIP140 molecule are lean and stay lean, even on a rich diet.[11]
Knockout mice (females) are also infertile because they fail to ovulate.[12] Failure of ovulation in these mice is caused by lack of cumulus expansion and altered expression of various genes, including amphiregulin, in ovarian follicles.[13][14]
# Clinical significance
RIP140 is part of the chain by which tumors can cause cachexia.[15][16]
Levels of RIP140 expression in various tissues varies during aging in mice, suggesting changes in metabolic function.[17] RIP140 is implicated in certain human disease processes. In morbid obesity, RIP140 levels are down-regulated in visceral adipose tissue.[18] In breast cancer, RIP140 is involved in regulation of E2F1, an oncogene which discriminates between luminal and basal types of tumours. RIP140 has an influence upon cancer phenotype and prognosis.[19] In addition, RIP140 has a role in inflammation, since it acts as a coactivator for NFkappaB/RelA-dependent cytokine gene expression. Lack of RIP140 leads to an inhibition of proinflammatory pathways in macrophages.[20]
# Interactions
NRIP1 has been shown to interact with:
- AHR,[21]
- CTBP1[22][23]
- CTBP2,[22][24]
- DAX1,[25]
- HDAC5,[22]
- NR1B1,[26][27][28]
- NR2B1,[27][28]
- NR3A1,[1][28][29]
- NR3C1,[30][31][32]
- NR5A1,[25][33] and
- YWHAQ.[30] | https://www.wikidoc.org/index.php/NRIP1 | |
bda29fa099c456730d5f29b06436575e88b173e9 | wikidoc | NRXN1 | NRXN1
Neurexin-1-alpha is a protein that in humans is encoded by the NRXN1 gene.
Neurexins are a family of proteins that function in the vertebrate nervous system as cell adhesion molecules and receptors. They are encoded by several unlinked genes of which two, NRXN1 and NRXN3, are among the largest known human genes.
Three of the genes (NRXN1-3) utilize two alternate promoters and include numerous alternatively spliced exons to generate thousands of distinct mRNA transcripts and protein isoforms. The majority of transcripts are produced from the upstream promoter and encode alpha-neurexin isoforms; a much smaller number of transcripts are produced from the downstream promoter and encode beta-neurexin isoforms. The alpha-neurexins contain epidermal growth factor-like (EGF-like) sequences and laminin G domains, and have been shown to interact with neurexophilins. The beta-neurexins lack EGF-like sequences and contain fewer laminin G domains than alpha-neurexins.
# Genomics
The gene is found in a single copy on the short arm of chromosome 2 (2p16.3). The gene is 1,112,187 bases in length, is located on the Crick (minus) strand and encodes a protein of 1,477 amino acids (molecular weight 161.883 kDa).
Mutations of this gene that interrupt its expression have been associated with schizophrenia, autism, and intellectual disability (NRXN1 mutations and brain disorders).
# Interactions
NRXN1 has been shown to interact with NLGN1. | NRXN1
Neurexin-1-alpha is a protein that in humans is encoded by the NRXN1 gene.[1]
Neurexins are a family of proteins that function in the vertebrate nervous system as cell adhesion molecules and receptors. They are encoded by several unlinked genes of which two, NRXN1 and NRXN3, are among the largest known human genes.
Three of the genes (NRXN1-3) utilize two alternate promoters and include numerous alternatively spliced exons to generate thousands of distinct mRNA transcripts and protein isoforms. The majority of transcripts are produced from the upstream promoter and encode alpha-neurexin isoforms; a much smaller number of transcripts are produced from the downstream promoter and encode beta-neurexin isoforms. The alpha-neurexins contain epidermal growth factor-like (EGF-like) sequences and laminin G domains, and have been shown to interact with neurexophilins. The beta-neurexins lack EGF-like sequences and contain fewer laminin G domains than alpha-neurexins.[1]
# Genomics
The gene is found in a single copy on the short arm of chromosome 2 (2p16.3). The gene is 1,112,187 bases in length, is located on the Crick (minus) strand and encodes a protein of 1,477 amino acids (molecular weight 161.883 kDa).
Mutations of this gene that interrupt its expression have been associated with schizophrenia, autism, and intellectual disability (NRXN1 mutations and brain disorders).
# Interactions
NRXN1 has been shown to interact with NLGN1.[2][3] | https://www.wikidoc.org/index.php/NRXN1 | |
da80f02936c81521b1be26a827232f29f35f7949 | wikidoc | NSUN2 | NSUN2
NOP2/Sun domain family, member 2 is a protein that in humans is encoded by the NSUN2 gene. Alternatively spliced transcript variants encoding different isoforms have been noted for the gene.
# Function
The protein is a methyltransferase that catalyzes the methylation of cytosine to 5-methylcytosine (m5C) at position 34 of intron-containing tRNA (Leu)(CAA) precursors. This modification is necessary to stabilize the anticodon-codon pairing and correctly translate the mRNA.
# Clinical relevance
Mutations in this gene have been found associated to cases of Dubowitz-like syndrome.
# Model organisms
Model organisms have been used in the study of NSUN2 function. A conditional knockout mouse line, called Nsun2tm1a(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 eight tests were carried out on mutant mice and fourteen significant abnormalities were observed. Homozygous mutants were subviable and had decreased body weights, length of long bones and decreased circulating glucose levels, numerous abnormal body composition, X-ray imaging, eye morphology and haematology parameters; males also had a decreased grip strength, a short upturned snout, and abnormal indirect calorimetry and plasma chemistry parameters. Males (but not females) were also infertile.
In addition, heterozygote mutants displayed premature hair follicle exogen. | NSUN2
NOP2/Sun domain family, member 2 is a protein that in humans is encoded by the NSUN2 gene.[1] Alternatively spliced transcript variants encoding different isoforms have been noted for the gene.
# Function
The protein is a methyltransferase that catalyzes the methylation of cytosine to 5-methylcytosine (m5C) at position 34 of intron-containing tRNA (Leu)(CAA) precursors. This modification is necessary to stabilize the anticodon-codon pairing and correctly translate the mRNA.[1]
# Clinical relevance
Mutations in this gene have been found associated to cases of Dubowitz-like syndrome.[2]
# Model organisms
Model organisms have been used in the study of NSUN2 function. A conditional knockout mouse line, called Nsun2tm1a(EUCOMM)Wtsi[17][18] 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.[19][20][21]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[15][22] Twenty eight tests were carried out on mutant mice and fourteen significant abnormalities were observed. Homozygous mutants were subviable and had decreased body weights, length of long bones and decreased circulating glucose levels, numerous abnormal body composition, X-ray imaging, eye morphology and haematology parameters; males also had a decreased grip strength, a short upturned snout, and abnormal indirect calorimetry and plasma chemistry parameters.[15] Males (but not females) were also infertile.[15]
In addition, heterozygote mutants displayed premature hair follicle exogen.[15] | https://www.wikidoc.org/index.php/NSUN2 | |
e9c84a79538fcdb00ba0daf5b3107143b7eccb7f | wikidoc | NT5C3 | NT5C3
Cytosolic 5'-nucleotidase 3 (NTC53), also known as cytosolic 5'-nucleotidase 3A, pyrimidine 5’-nucleotidase (PN-I or P5'NI), and p56, is an enzyme that in humans is encoded by the NT5C3, or NT5C3A, gene on chromosome 7.
This gene encodes a member of the 5'-nucleotidase family of enzymes that catalyze the dephosphorylation of nucleoside 5'-monophosphates. The encoded protein is the type 1 isozyme of pyrimidine 5' nucleotidase and catalyzes the dephosphorylation of pyrimidine 5' monophosphates. Mutations in this gene are a cause of hemolytic anemia due to uridine 5-prime monophosphate hydrolase deficiency. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and pseudogenes of this gene are located on the long arm of chromosomes 3 and 4.
# Structure
The NT5C3 gene consists of 10 exons and can be alternatively spliced at exon 2. Four possible isoforms have been identified, encoding proteins with lengths of 336 residues, 297 residues, 286 residues, and 285 residues. The 286-residue long isozyme is a monomeric protein containing 5 cysteine residues and no disulfide bridges or phosphate content. It has a predicted mass of 32.7 kDa and a predicted globular tertiary structure consisting of approximately 30% α-helices and 26% extended strands. This enzyme structurally resembles members of the haloacid dehalogenase (HAD) superfamily in regards to the shared α/β-Rossmann-like domain and a smaller 4-helix bundle domain. Three motifs in the α/β-Rossmann-like domain form the catalytic phosphate-binding site. Motif I is responsible for the 5′-nucleotidase activity: the first Asp makes a nucleophilic attack on the phosphate of the nucleoside monophosphate substrate, while the second Asp donates a proton to the leaving nucleoside. The active site is located in a cleft between the α/β-Rossmann-like domain and 4-helix bundle domain.
# Function
NT5C3 is a member of the 5'-nucleotidase family and one of the five cytosolic members identified in humans. NTC53 catalyzes the dephosphorylation of the pyrimidine 5′ monophosphates UMP and CMP to the corresponding nucleosides. This function contributes to RNA degradation during the erythrocyte maturation process. As a result, NT5C3 regulates both the endogenous nucleoside and nucleotide pool balance, as well as that of pyrimidine analogs such as gemcitabine and AraC.
NT5C3 was first discovered in red blood cells, but its expression has been observed in multiple tumors (lung, ovary, colon, bladder), fetal tissues (lung, heart, spleen, liver), adult testis, and the brain. In particular, the 297-residue isoform of this enzyme is highly expressed in lymphoblastoid cells.
# Clinical Significance
The loss of NT5C3 in pyrimidine 5' nucleotidase deficiency, an autosomal recessive condition, leads to the accumulation of high concentrations of pyrimidine nucleotides within erythrocytes. This deficiency is characterized by moderate hemolytic anemia, jaundice, splenomegaly, and marked basophilic stippling, and has been associated with learning difficulties. Two homozygous mutations identified in this gene produced large deletions that could cripple the enzyme’s structure and function, and are thus causally linked to pyrimidine 5' nucleotidase deficiency and hemolytic anemia. Heterozygous mutations in pyrimidine 5' nucleotidase deficiency may contribute to the large variability in thalassemia phenotypes. Pyrimidine 5' nucleotidase deficiency is also linked to the conversion of hemoglobin E disease into an unstable hemoglobinopathy-like disease. NT5C3 is identical to p36, a previously identified alpha-interferon-induced protein involved in forming lupus inclusions. Since NT5C3 can metabolize AraC, a nucleoside analog used in chemotherapy for acute myeloid leukemia patients, genotyping one of its polymorphisms may aid detection of patients who will respond favorably to this therapy.
# Interactions
NTC53 is known to interact with pyrimidine nucleoside monophosphates, specifically UMP and CMP, as well as the anineoplastic agents 5’-AZTMP and 5’-Ara-CMP. | NT5C3
Cytosolic 5'-nucleotidase 3 (NTC53), also known as cytosolic 5'-nucleotidase 3A, pyrimidine 5’-nucleotidase (PN-I or P5'NI), and p56, is an enzyme that in humans is encoded by the NT5C3, or NT5C3A, gene on chromosome 7.[1][2][3][4]
This gene encodes a member of the 5'-nucleotidase family of enzymes that catalyze the dephosphorylation of nucleoside 5'-monophosphates. The encoded protein is the type 1 isozyme of pyrimidine 5' nucleotidase and catalyzes the dephosphorylation of pyrimidine 5' monophosphates. Mutations in this gene are a cause of hemolytic anemia due to uridine 5-prime monophosphate hydrolase deficiency. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and pseudogenes of this gene are located on the long arm of chromosomes 3 and 4. [provided by RefSeq, Mar 2012][3]
# Structure
The NT5C3 gene consists of 10 exons and can be alternatively spliced at exon 2.[5] Four possible isoforms have been identified, encoding proteins with lengths of 336 residues, 297 residues, 286 residues, and 285 residues.[5][6] The 286-residue long isozyme is a monomeric protein containing 5 cysteine residues and no disulfide bridges or phosphate content.[4][5] It has a predicted mass of 32.7 kDa and a predicted globular tertiary structure consisting of approximately 30% α-helices and 26% extended strands.[5] This enzyme structurally resembles members of the haloacid dehalogenase (HAD) superfamily in regards to the shared α/β-Rossmann-like domain and a smaller 4-helix bundle domain. Three motifs in the α/β-Rossmann-like domain form the catalytic phosphate-binding site. Motif I is responsible for the 5′-nucleotidase activity: the first Asp makes a nucleophilic attack on the phosphate of the nucleoside monophosphate substrate, while the second Asp donates a proton to the leaving nucleoside. The active site is located in a cleft between the α/β-Rossmann-like domain and 4-helix bundle domain.[7]
# Function
NT5C3 is a member of the 5'-nucleotidase family and one of the five cytosolic members identified in humans.[6] NTC53 catalyzes the dephosphorylation of the pyrimidine 5′ monophosphates UMP and CMP to the corresponding nucleosides.[4][5] This function contributes to RNA degradation during the erythrocyte maturation process.[2][4][6] As a result, NT5C3 regulates both the endogenous nucleoside and nucleotide pool balance, as well as that of pyrimidine analogs such as gemcitabine and AraC.[6]
NT5C3 was first discovered in red blood cells, but its expression has been observed in multiple tumors (lung, ovary, colon, bladder), fetal tissues (lung, heart, spleen, liver), adult testis, and the brain.[2][5] In particular, the 297-residue isoform of this enzyme is highly expressed in lymphoblastoid cells.[6]
# Clinical Significance
The loss of NT5C3 in pyrimidine 5' nucleotidase deficiency, an autosomal recessive condition, leads to the accumulation of high concentrations of pyrimidine nucleotides within erythrocytes.[2][4][5] This deficiency is characterized by moderate hemolytic anemia, jaundice, splenomegaly, and marked basophilic stippling, and has been associated with learning difficulties.[2][5] Two homozygous mutations identified in this gene produced large deletions that could cripple the enzyme’s structure and function, and are thus causally linked to pyrimidine 5' nucleotidase deficiency and hemolytic anemia. Heterozygous mutations in pyrimidine 5' nucleotidase deficiency may contribute to the large variability in thalassemia phenotypes.[5] Pyrimidine 5' nucleotidase deficiency is also linked to the conversion of hemoglobin E disease into an unstable hemoglobinopathy-like disease.[2][5] NT5C3 is identical to p36, a previously identified alpha-interferon-induced protein involved in forming lupus inclusions.[2][4] Since NT5C3 can metabolize AraC, a nucleoside analog used in chemotherapy for acute myeloid leukemia patients, genotyping one of its polymorphisms may aid detection of patients who will respond favorably to this therapy.[8]
# Interactions
NTC53 is known to interact with pyrimidine nucleoside monophosphates, specifically UMP and CMP, as well as the anineoplastic agents 5’-AZTMP and 5’-Ara-CMP.[4] | https://www.wikidoc.org/index.php/NT5C3 | |
8c4a5090ed4840f4bfe2cc94ae228073aa84ba91 | wikidoc | NTHL1 | NTHL1
Endonuclease III-like protein 1 is an enzyme that in humans is encoded by the NTHL1 gene.
As reviewed by Li et al., NTHL1 is a bifunctional DNA glycosylase that has an associated beta-elimination activity. NTHL1 is usually involved in removing oxidative pyrimidine lesions through base excision repair. NTHL1 catalyses the first step in base excision repair. It cleaves the N-glycosylic bond between the damaged base and its associated sugar residue and then cleaves the phosphodiester bond 3' to the AP site, leaving a 3'-unsaturated aldehyde after beta-elimination and a 5'-phosphate at the termini of the repair gap.
Low expression of NTHL1 is associated with initiation and development of astrocytoma. Low expression of NTHL1 is also found in follicular thyroid tumors.
A germ line homozygous mutation in NTHL1 causes a cancer susceptibility syndrome similar to Lynch syndrome. | NTHL1
Endonuclease III-like protein 1 is an enzyme that in humans is encoded by the NTHL1 gene.[1][2][3]
As reviewed by Li et al.,[4] NTHL1 is a bifunctional DNA glycosylase that has an associated beta-elimination activity. NTHL1 is usually involved in removing oxidative pyrimidine lesions through base excision repair. NTHL1 catalyses the first step in base excision repair. It cleaves the N-glycosylic bond between the damaged base and its associated sugar residue and then cleaves the phosphodiester bond 3' to the AP site,[5] leaving a 3'-unsaturated aldehyde after beta-elimination and a 5'-phosphate at the termini of the repair gap.[4]
Low expression of NTHL1 is associated with initiation and development of astrocytoma.[6] Low expression of NTHL1 is also found in follicular thyroid tumors.[7]
A germ line homozygous mutation in NTHL1 causes a cancer susceptibility syndrome similar to Lynch syndrome.[8][9] | https://www.wikidoc.org/index.php/NTHL1 | |
28de0c2bfd45bdf652d732446f71a55fff64ad49 | wikidoc | NUAK1 | NUAK1
NUAK family SNF1-like kinase 1 also known as AMPK-related protein kinase 5 (ARK5) is an enzyme that in humans is encoded by the NUAK1 gene.
# Function
# Clinical significance
ARK5 is important in tumor malignancy and invasiveness.
# Research findings
ARK5 is often overexpressed in multiple myeloma cell lines.
ARK5 promotes tumor cell survival under regulation by Akt.
ARK5 increases MT1-MMP production. (MT1-MMP activates MMP-2 and MMP-9 which are involved in tumor metastasis.)
# As a drug target
ON123300 (a CDK4 inhibitor), also inhibits ARK5 and reduces proliferation of multiple myeloma and mantle cell lymphoma cell lines.
# Interactions
NUAK1 has been shown to interact with USP9X and Ubiquitin C. | NUAK1
NUAK family SNF1-like kinase 1 also known as AMPK-related protein kinase 5 (ARK5) is an enzyme that in humans is encoded by the NUAK1 gene.[1][2][3]
# Function
# Clinical significance
ARK5 is important in tumor malignancy and invasiveness.[4]
# Research findings
ARK5 is often overexpressed in multiple myeloma cell lines.[5][6]
ARK5 promotes tumor cell survival under regulation by Akt.[4]
ARK5 increases MT1-MMP production.[4] (MT1-MMP activates MMP-2 and MMP-9 which are involved in tumor metastasis.[4])
# As a drug target
ON123300 (a CDK4 inhibitor), also inhibits ARK5 and reduces proliferation of multiple myeloma and mantle cell lymphoma cell lines.[5]
# Interactions
NUAK1 has been shown to interact with USP9X[7] and Ubiquitin C.[7] | https://www.wikidoc.org/index.php/NUAK1 | |
c6c47b5805b2087ad807f491703699eb966cc3e9 | wikidoc | NUBP2 | NUBP2
Nucleotide-binding protein 2 (NBP 2) also known as cytosolic Fe-S cluster assembly factor NUBP2 is a protein that in humans is encoded by the NUBP2 gene.
NUBP2 is a member of the NUBP/MRP gene subfamily of ATP-binding proteins. There are two types in eukaryotes NUBP1 and NUBP2, and one novel human gene that define NBP nucleotide-binding proteins (NUBP/MRP-multidrug resistance-associated protein) in mammalian cells requires the maturation of cytosolic iron-sulfur (Fe/S) proteins as Nubp1 is involved in the formation of extramitochondrial Fe/S proteins the cell division inhibitor MinD is homologous and involve two proteins components of the (FeS) protein assembly machinery closely similar cytosolic soluble P loop NTPase where Nar1 is required for assembly, identified Cfd1p in cytosolic and nuclear Fe/S protein biogenesis in yeast. Nubp proteins NTPase Nbp35p. MinD is homologous to members in MinD of E. coli, a relative of the ParA family.
# Morphology
Further information: Morphology (biology)
NBP35 bacterial plasmids F (the classical Escherichia coli sex factor) is found in all nuclear genes in vegetative and gametic flagella of the unicellular green algae C. reinhardtii and nuclear Fe/S protein biogenesis required for cytosolic iron-sulfur protein assembly; MNP =MRP-like; MRP (Multiple Resistance and pH adaptation) MRP/NBP35-like P-loop NTPase similar to; and functions as minD_arch; cell division ATPase MinD, archaeal and homologue's of NUBP1. The NBP35 gene is conserved in archaea Bacteria, Metazoa, Fungi and other Eukaryotes and with considerable divergence from the yeast; Cfd1-Nbp35 Fe-S to man. In a scaffold complex protein to form large molecular assemblies that store Fe(III) and 4Fe-4S seen as secondary to defects inactivated to accomplish its functions as physiologically relevant form(s) Fe/S proteins Iron regulatory protein 1 (IRP1) is regulated through prevents deficiencies and increased mutation rates that characterized a plant P loop NTPase with sequence similarity to Nbp35 homologue's of NUBP1.
# Interactions
NUBP2 has been shown to interact with...
- ACO1 Iron-responsive element-binding protein 1 (IRE-BP 1) (Iron regulatory protein 1) (IRP1)
- MAPK8IP3 C-jun-amino-terminal kinase-interacting protein 3 (JNK-interacting protein 3) (JIP-3)
- IGFALS Insulin-like growth factor-binding protein complex acid labile chain precursor (ALS)
- KIF11 Kinesin-like protein KIF11 (Kinesin-related motor protein Eg5)
- SEPP1 Selenoprotein P precursor (SeP)
- CA1 Carbonic anhydrase 1 (EC 4.2.1.1) (Carbonic anhydrase I) (Carbonate dehydratase I) (CA-I) | NUBP2
Nucleotide-binding protein 2 (NBP 2) also known as cytosolic Fe-S cluster assembly factor NUBP2 is a protein that in humans is encoded by the NUBP2 gene.[1]
NUBP2 is a member of the NUBP/MRP gene subfamily of ATP-binding proteins.[2] There are two types in eukaryotes NUBP1 and NUBP2, and one novel human gene that define NBP nucleotide-binding proteins (NUBP/MRP-multidrug resistance-associated protein)[1] in mammalian cells requires the maturation of cytosolic[3] iron-sulfur (Fe/S)[4] proteins as Nubp1 is involved in the formation of extramitochondrial Fe/S proteins[2] the cell division inhibitor MinD is homologous[5] and involve two proteins components of the (FeS) protein assembly machinery closely similar cytosolic[2] soluble[4] P loop[5] NTPase where Nar1[6][7] is required for assembly,[8] identified Cfd1p[9][10] in cytosolic and nuclear Fe/S protein biogenesis[4] in yeast.[11] Nubp proteins NTPase Nbp35p.[7][8] MinD is homologous to members in MinD of E. coli, a relative of the ParA family.[5][12][13]
# Morphology
Further information: Morphology (biology)
NBP35 bacterial plasmids F (the classical Escherichia coli sex factor)[5] is found in all nuclear genes in vegetative and gametic flagella of the unicellular green algae C. reinhardtii and nuclear Fe/S protein biogenesis required for cytosolic iron-sulfur protein assembly; MNP =MRP-like; MRP (Multiple Resistance and pH adaptation) MRP/NBP35-like P-loop NTPase similar to; and functions as minD_arch; cell division ATPase MinD, archaeal and homologue's of NUBP1. The NBP35 gene is conserved in archaea[14] Bacteria, Metazoa, Fungi and other Eukaryotes and with considerable divergence from the yeast; Cfd1-Nbp35 Fe-S to man. In a scaffold complex[15] protein to form large molecular assemblies that store Fe(III) and 4Fe-4S seen as secondary to defects inactivated to accomplish its functions as physiologically relevant form(s) Fe/S proteins Iron regulatory protein 1 (IRP1) is regulated through[10] prevents deficiencies and increased mutation rates[13] that characterized a plant P loop NTPase with sequence similarity to Nbp35 homologue's of NUBP1.[16]
# Interactions
NUBP2 has been shown to interact with...
- ACO1 Iron-responsive element-binding protein 1 (IRE-BP 1) (Iron regulatory protein 1) (IRP1)[10][17]
- MAPK8IP3 C-jun-amino-terminal kinase-interacting protein 3 (JNK-interacting protein 3) (JIP-3)[18]
- IGFALS Insulin-like growth factor-binding protein complex acid labile chain precursor (ALS)[18][19]
- KIF11 Kinesin-like protein KIF11 (Kinesin-related motor protein Eg5)[20]
- SEPP1 Selenoprotein P precursor (SeP)[13]
- CA1 Carbonic anhydrase 1 (EC 4.2.1.1) (Carbonic anhydrase I) (Carbonate dehydratase I) (CA-I)[12][13][16] | https://www.wikidoc.org/index.php/NUBP2 | |
304f81b8578c3bb8b9b82fd0d69947378ac11ef1 | wikidoc | NUBPL | NUBPL
Iron-sulfur protein NUBPL (IND1) also known as nucleotide-binding protein-like (NUBPL), IND1 homolog, Nucleotide-binding protein-like or huInd1 is an iron-sulfur (Fe/S) protein that, in humans, is encoded by the NUBPL gene, located on chromosome 14q12. It has an early role in the assembly of the mitochondrial complex I assembly pathway.
# Structure
NUBPL is located on the q arm of chromosome 14 in position 12 and has 18 exons. The NUBPL gene produces a 5.9 kDa protein composed of 54 amino acids. The structure of the protein includes a presumed iron-sulfur binding (CxxC) signature, a nucleotide-binding domain which has been highly conserved, and a mitochondrial targeting sequence in the N-terminal. NUBPL is required for the assembly of complex I, which is composed of 45 evolutionally conserved core subunits, including both mitochondrial DNA and nuclear encoded subunits. One of its arms is embedded in the inner membrane of the mitochondria, and the other is embedded in the organelle. The two arms are arranged in an L-shaped configuration. The total molecular weight of the complex is 1MDa.
# Function
The NUBPL gene encodes a protein that is a member of the Mrp/NBP35 ATP-binding family. This protein is required for the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), the first oligomeric enzymatic complex of the mitochondrial respiratory chain located in the inner mitochondrial membrane. Its role in assembly is the delivery of one or more iron–sulfur (Fe-S) clusters to complex I subunits in anaerobic conditions in vitro. The dysfunction of NUBPL results in an irregular assembly of the peripheral arm of complex I, which may lead to a decrease in activity. Knockdown of the protein also causes abnormal mitochondrial ultrastructure characterized by respiratory supercomplex remodeling, christa membrane loss, and abnormally high lactate levels.
# Discovery
Sheftel, et al. (2009) used RNA interference (RNAi) to delete the NUBPL gene in yeast (Y. lipolytica). They observed decreased levels and activity of mitochondrial complex I, leading them to conclude that NUBPL is required for complex I assembly and activity. Their experiments showed functional conservation of NUBPL in yeast and humans, an indication that the protein serves an important function. Sheftel, et al. observed structural abnormalities in mitochondria that were NUBPL-depleted mitochondria.
# Clinical significance
The absence of NUBPL disrupts the early stage of the mitochondrial complex I assembly pathway. NUBPL-depleted cells were observed to have an abnormal sub complex of proteins normally found in the membrane arm of complex I. A decrease in the presence of complex I subunit proteins, NDUFS1, NDUFV1, NDUFS3, and NDUFA13 indicated a failure of normal complex I assembly. Mitochondrial complex I deficiency involving the dysfunction of the mitochondrial respiratory chain may cause 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 hereditary optic neuropathy, and some forms of Parkinson disease.
High-throughput DNA sequencing was used to identify variants in 103 candidate genes in 103 patients with mitochondrial complex 1 disorders. Heterozygous variants in the NUBPL were identified in one patient. cDNA complementation studies showed that the variants can cause complex 1 deficiency. The finding in this patient is consistent with autosomal recessive inheritance NUBPL-associated complex I deficiency, and supports the pathogenicity of the variants that were identified. Complex compound heterozygous variants were identified in the NUBPL gene in this patient. In exon 2, a paternally-inherited G>A point mutation (c.166 G>A) resulting in missense substitution of gly56-to-arg (G56R) was observed. Two variants were maternally-inherited: T>C point mutation (c.815-27 T>C) that caused a splicing error and a complex deletion of exons 1-4 and duplication involving exon 7. Two of 232 (1%) control chromosomes were found to have the c.166 G>A pathogenic variant. This individual identified was noted to have motor delays and developmental delay at 2 years of age. He never achieved independent walking. He developed myopathy, nystagmus, ataxia, upper motor neuron signs, and absence seizures. Brain MRI showed leukodystrophy with involvement of the cerebellar cortex and deep white matter. At age 8, he had spasticity, ataxia, and speech problems.
Several patients from with early MRI abnormalities of the cerebellum, deep cerebral white matter and corpus callosum. In this small sample, it was noted that later imaging studies showed improvements to the corpus callosum and cerebral white matter abnormalities, while the cerebellar abnormalities worsen and brainstem abnormalities arise. Using whole exome sequencing, four of the patients had a mitochondrial complex І deficiency identified using other laboratory methods. All four of the patients had compound pathogenic variants in the NUBPL gene.
# Interactions
NUBPL has protein-protein interactions with DNAJB11, MTUS2, RNF2, and UFD1L. | NUBPL
Iron-sulfur protein NUBPL (IND1) also known as nucleotide-binding protein-like (NUBPL), IND1 homolog, Nucleotide-binding protein-like or huInd1 is an iron-sulfur (Fe/S) protein that, in humans, is encoded by the NUBPL gene, located on chromosome 14q12. It has an early role in the assembly of the mitochondrial complex I assembly pathway.[1][2]
# Structure
NUBPL is located on the q arm of chromosome 14 in position 12 and has 18 exons.[1] The NUBPL gene produces a 5.9 kDa protein composed of 54 amino acids.[3][4] The structure of the protein includes a presumed iron-sulfur binding (CxxC) signature, a nucleotide-binding domain which has been highly conserved, and a mitochondrial targeting sequence in the N-terminal.[5] NUBPL is required for the assembly of complex I, which is composed of 45 evolutionally conserved core subunits, including both mitochondrial DNA and nuclear encoded subunits. One of its arms is embedded in the inner membrane of the mitochondria, and the other is embedded in the organelle. The two arms are arranged in an L-shaped configuration. The total molecular weight of the complex is 1MDa.[6]
# Function
The NUBPL gene encodes a protein that is a member of the Mrp/NBP35 ATP-binding family. This protein is required for the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), the first oligomeric enzymatic complex of the mitochondrial respiratory chain located in the inner mitochondrial membrane.[2][1] Its role in assembly is the delivery of one or more iron–sulfur (Fe-S) clusters to complex I subunits in anaerobic conditions in vitro.[2][5] The dysfunction of NUBPL results in an irregular assembly of the peripheral arm of complex I, which may lead to a decrease in activity. Knockdown of the protein also causes abnormal mitochondrial ultrastructure characterized by respiratory supercomplex remodeling, christa membrane loss, and abnormally high lactate levels.[7][5]
# Discovery
Sheftel, et al. (2009) used RNA interference (RNAi) to delete the NUBPL gene in yeast (Y. lipolytica). They observed decreased levels and activity of mitochondrial complex I, leading them to conclude that NUBPL is required for complex I assembly and activity. Their experiments showed functional conservation of NUBPL in yeast and humans, an indication that the protein serves an important function. Sheftel, et al. observed structural abnormalities in mitochondria that were NUBPL-depleted mitochondria.[5]
# Clinical significance
The absence of NUBPL disrupts the early stage of the mitochondrial complex I assembly pathway. NUBPL-depleted cells were observed to have an abnormal sub complex of proteins normally found in the membrane arm of complex I. A decrease in the presence of complex I subunit proteins, NDUFS1, NDUFV1, NDUFS3, and NDUFA13 indicated a failure of normal complex I assembly.[5] Mitochondrial complex I deficiency involving the dysfunction of the mitochondrial respiratory chain may cause 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 hereditary optic neuropathy, and some forms of Parkinson disease.[2]
High-throughput DNA sequencing was used to identify variants in 103 candidate genes in 103 patients with mitochondrial complex 1 disorders. Heterozygous variants in the NUBPL were identified in one patient. cDNA complementation studies showed that the variants can cause complex 1 deficiency. The finding in this patient is consistent with autosomal recessive inheritance NUBPL-associated complex I deficiency, and supports the pathogenicity of the variants that were identified.[7] Complex compound heterozygous variants were identified in the NUBPL gene in this patient.[7] In exon 2, a paternally-inherited G>A point mutation (c.166 G>A) resulting in missense substitution of gly56-to-arg (G56R) was observed. Two variants were maternally-inherited: T>C point mutation (c.815-27 T>C) that caused a splicing error and a complex deletion of exons 1-4 and duplication involving exon 7. Two of 232 (1%) control chromosomes were found to have the c.166 G>A pathogenic variant. This individual identified was noted to have motor delays and developmental delay at 2 years of age.[7] He never achieved independent walking. He developed myopathy, nystagmus, ataxia, upper motor neuron signs, and absence seizures. Brain MRI showed leukodystrophy with involvement of the cerebellar cortex and deep white matter. At age 8, he had spasticity, ataxia, and speech problems.
Several patients from with early MRI abnormalities of the cerebellum, deep cerebral white matter and corpus callosum. In this small sample, it was noted that later imaging studies showed improvements to the corpus callosum and cerebral white matter abnormalities, while the cerebellar abnormalities worsen and brainstem abnormalities arise. Using whole exome sequencing, four of the patients had a mitochondrial complex І deficiency identified using other laboratory methods. All four of the patients had compound pathogenic variants in the NUBPL gene.[8]
# Interactions
NUBPL has protein-protein interactions with DNAJB11, MTUS2, RNF2, and UFD1L.[2] | https://www.wikidoc.org/index.php/NUBPL | |
712dc81fe111ca067b16edaafb819d6cbfc3f587 | wikidoc | NUDT1 | NUDT1
Nudix hydrolase 1 (NUDT1) also known as MutT homolog 1 (MTH1) or 7,8-dihydro-8-oxoguanine triphosphatase is an enzyme that in humans is encoded by the NUDT1 gene.
# Function
Misincorporation of oxidized nucleoside triphosphates into DNA and/or RNA during replication and transcription can cause mutations that may result in carcinogenesis or neurodegeneration. First isolated from Escherichia coli because of its ability to prevent occurrence of 8-oxoguanine in DNA, the protein encoded by this gene is an enzyme that hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP, 8-oxo-dATP, 2-oxo-dATP, 2-hydroxy-dATP, and 2-hydroxy rATP, to monophosphates, thereby preventing misincorporation.
MutT enzymes in non-human organisms often have substrate specificity for certain types of oxidized nucleotides, such as that of E. coli, which is specific to 8-oxoguanine nucleotides. Human MTH1, however, has substrate specificity for a much broader range of oxidatively damaged nucleotides. The mechanism of hMTH1’s broad specificity for these oxidized nucleotides is derived from their recognition in the enzyme’s substrate binding pocket due to an exchange of protonation state between two nearby aspartate residues.
The encoded protein is localized mainly in the cytoplasm, with some in the mitochondria, suggesting that it is involved in the sanitization of nucleotide pools both for nuclear and mitochondrial genomes. In plants, MTH1 has also been shown to enhance resistance to heat- and paraquat-induced oxidative stress, resulting in fewer dead cells and less accumulation of hydrogen peroxide.
Several alternatively spliced transcript variants, some of which encode distinct isoforms, have been identified. Additional variants have been observed, but their full-length natures have not been determined. A single-nucleotide polymorphism that results in the production of an additional, longer isoform has been described.
# Research
## Aging
A mouse model has been studied that over-expresses hMTH1-Tg (NUDT1). The hMTH1-Tg mice express high levels of the hMTH1 hydrolase that degrades 8-oxodGTP and 8-oxoGTP and therefore excludes 8-oxoguanine from DNA and RNA. The steady state levels of 8-oxoguanine in DNA of several organs including the brain are significantly reduced in hMTH1-Tg over-expressing mice. Conversely, MTH1-null mice exhibit a significantly higher level of 8-oxo-dGTP accumulation than that of the wild type. Over-expression of hMTH1 prevents the age-dependent accumulation of DNA 8-oxoguanine that occurs in wild-type mice. The lower levels of oxidized guanines are associated with greater longevity. The hMTH1-Tg animals have a significantly longer lifespan than their wild-type littermates. These findings provide a link between ageing and oxidative DNA damage (see DNA damage theory of aging).
## Cancer
Studies have suggested that this enzyme plays a role in both preventing the formation of cancer cells and the proliferation of cancer cells. This makes it a topic of interest in cancer research, both as a potential method for healthy cells to prevent cancer and a weakness to target within existing cancer cells.
Eliminating the MTH1 gene in mice results in over three times more mice developing tumors compared to a control group. The enzyme’s much-studied ability to sanitize a cell’s nucleotide pool prevents it from developing mutations, including cancerous ones. Specifically, another study found that MTH1 inhibition in cancer cells leads to incorporation of 8-oxo-dGTP and other oxidatively damaged nucleotides into the cell’s DNA, damaging it and causing cell death. However, cancer cells have also been shown to benefit from use of MTH1. Cells from malignant breast tumors exhibit extreme MTH1 expression compared to other human cells. Because a cancer cell divides much more rapidly than a normal human cell, it is far more in need of an enzyme like MTH1 that prevents fatal mutations during replication. This property of cancer cells could allow for monitoring of cancer treatment efficacy by measuring MTH1 expression. Development of suitable probes for this purpose is currently underway.
Disagreement exists concerning MTH1’s functionality relative to prevention of DNA damage and cancer. Subsequent studies have had difficulty reproducing previously reported cytotoxic or antiproliferation effects of MTH1 inhibition on cancer cells, even calling into question whether MTH1 truly does serve to remove oxidatively damaged nucleotides from a cell’s nucleotide pool. One study of newly discovered MTH1 inhibitors suggests that these anticancer properties exhibited by the older MTH1 inhibitors may be due to off-target cytotoxic effects. After revisiting the experiment, the original authors of this claim found that while the original MTH1 inhibitors in question lead to damaged nucleotides being incorporated into DNA, they demonstrate the others that do not induce toxicity fail to introduce the DNA lesion. Research into this topic is ongoing.
## As a drug target
MTH1 is a potential drug target to treat cancer, however there are conflicting results regarding the cytotoxicity of MTH1 inhibitors toward cancer cells.
Karonudib, an MTH1 inhibitor, is currently being evaluated a phase I clinical trial for safety and tolerability.
A potent and selective MTH1 inhibitor AZ13792138 has been developed by AstraZeneca has been made available as a chemical probe to academic researchers. However AstraZeneca has found that neither AZ13792138 nor genetic knockdown of MTH1 displays any significant cytotoxicity to cancer cells. | NUDT1
Nudix hydrolase 1 (NUDT1) also known as MutT homolog 1 (MTH1) or 7,8-dihydro-8-oxoguanine triphosphatase is an enzyme that in humans is encoded by the NUDT1 gene.[1][2][3]
# Function
Misincorporation of oxidized nucleoside triphosphates into DNA and/or RNA during replication and transcription can cause mutations that may result in carcinogenesis or neurodegeneration. First isolated from Escherichia coli because of its ability to prevent occurrence of 8-oxoguanine in DNA,[4] the protein encoded by this gene is an enzyme that hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP, 8-oxo-dATP, 2-oxo-dATP, 2-hydroxy-dATP, and 2-hydroxy rATP, to monophosphates, thereby preventing misincorporation.
MutT enzymes in non-human organisms often have substrate specificity for certain types of oxidized nucleotides, such as that of E. coli, which is specific to 8-oxoguanine nucleotides. Human MTH1, however, has substrate specificity for a much broader range of oxidatively damaged nucleotides. The mechanism of hMTH1’s broad specificity for these oxidized nucleotides is derived from their recognition in the enzyme’s substrate binding pocket due to an exchange of protonation state between two nearby aspartate residues.[5]
The encoded protein is localized mainly in the cytoplasm, with some in the mitochondria, suggesting that it is involved in the sanitization of nucleotide pools both for nuclear and mitochondrial genomes. In plants, MTH1 has also been shown to enhance resistance to heat- and paraquat-induced oxidative stress, resulting in fewer dead cells and less accumulation of hydrogen peroxide.[6]
Several alternatively spliced transcript variants, some of which encode distinct isoforms, have been identified. Additional variants have been observed, but their full-length natures have not been determined. A single-nucleotide polymorphism that results in the production of an additional, longer isoform has been described.[3]
# Research
## Aging
A mouse model has been studied that over-expresses hMTH1-Tg (NUDT1).[7] The hMTH1-Tg mice express high levels of the hMTH1 hydrolase that degrades 8-oxodGTP and 8-oxoGTP and therefore excludes 8-oxoguanine from DNA and RNA. The steady state levels of 8-oxoguanine in DNA of several organs including the brain are significantly reduced in hMTH1-Tg over-expressing mice. Conversely, MTH1-null mice exhibit a significantly higher level of 8-oxo-dGTP accumulation than that of the wild type.[8] Over-expression of hMTH1 prevents the age-dependent accumulation of DNA 8-oxoguanine that occurs in wild-type mice. The lower levels of oxidized guanines are associated with greater longevity. The hMTH1-Tg animals have a significantly longer lifespan than their wild-type littermates. These findings provide a link between ageing and oxidative DNA damage[7] (see DNA damage theory of aging).
## Cancer
Studies have suggested that this enzyme plays a role in both preventing the formation of cancer cells and the proliferation of cancer cells. This makes it a topic of interest in cancer research, both as a potential method for healthy cells to prevent cancer and a weakness to target within existing cancer cells.
Eliminating the MTH1 gene in mice results in over three times more mice developing tumors compared to a control group.[9] The enzyme’s much-studied ability to sanitize a cell’s nucleotide pool prevents it from developing mutations, including cancerous ones. Specifically, another study found that MTH1 inhibition in cancer cells leads to incorporation of 8-oxo-dGTP and other oxidatively damaged nucleotides into the cell’s DNA, damaging it and causing cell death.[10] However, cancer cells have also been shown to benefit from use of MTH1. Cells from malignant breast tumors exhibit extreme MTH1 expression compared to other human cells.[11] Because a cancer cell divides much more rapidly than a normal human cell, it is far more in need of an enzyme like MTH1 that prevents fatal mutations during replication. This property of cancer cells could allow for monitoring of cancer treatment efficacy by measuring MTH1 expression. Development of suitable probes for this purpose is currently underway.[12][13]
Disagreement exists concerning MTH1’s functionality relative to prevention of DNA damage and cancer. Subsequent studies have had difficulty reproducing previously reported cytotoxic or antiproliferation effects of MTH1 inhibition on cancer cells, even calling into question whether MTH1 truly does serve to remove oxidatively damaged nucleotides from a cell’s nucleotide pool.[14][15] One study of newly discovered MTH1 inhibitors suggests that these anticancer properties exhibited by the older MTH1 inhibitors may be due to off-target cytotoxic effects.[16] After revisiting the experiment, the original authors of this claim found that while the original MTH1 inhibitors in question lead to damaged nucleotides being incorporated into DNA, they demonstrate the others that do not induce toxicity fail to introduce the DNA lesion.[17] Research into this topic is ongoing.
## As a drug target
MTH1 is a potential drug target to treat cancer, however there are conflicting results regarding the cytotoxicity of MTH1 inhibitors toward cancer cells.[18]
Karonudib, an MTH1 inhibitor, is currently being evaluated a phase I clinical trial for safety and tolerability.[17][19][20]
A potent and selective MTH1 inhibitor AZ13792138 has been developed by AstraZeneca has been made available as a chemical probe to academic researchers.[21] However AstraZeneca has found that neither AZ13792138 nor genetic knockdown of MTH1 displays any significant cytotoxicity to cancer cells.[22][23] | https://www.wikidoc.org/index.php/NUDT1 | |
6dec6a54f44c4af92da3c70ea3679372bdb97529 | wikidoc | NUTF2 | NUTF2
Nuclear transport factor 2 is a protein that in humans is encoded by the NUTF2 gene.
# Function
The protein encoded by this gene is a cytosolic factor that facilitates protein transport into the nucleus. It interacts with the nuclear pore complex glycoprotein p62. This encoded protein acts at a relative late stage of nuclear protein import, subsequent to the initial docking of nuclear import ligand at the nuclear envelope. It is thought to be part of a multicomponent system of cytosolic factors that assemble at the pore complex during nuclear import.
# Interactions
NUTF2 has been shown to interact with Nucleoporin 62{ and RAN. | NUTF2
Nuclear transport factor 2 is a protein that in humans is encoded by the NUTF2 gene.[1][2][3]
# Function
The protein encoded by this gene is a cytosolic factor that facilitates protein transport into the nucleus. It interacts with the nuclear pore complex glycoprotein p62. This encoded protein acts at a relative late stage of nuclear protein import, subsequent to the initial docking of nuclear import ligand at the nuclear envelope. It is thought to be part of a multicomponent system of cytosolic factors that assemble at the pore complex during nuclear import.[3]
# Interactions
NUTF2 has been shown to interact with Nucleoporin 62[1]{[4] and RAN.[5][6] | https://www.wikidoc.org/index.php/NUTF2 | |
ce2b5b5fc7e568a7d3b605eea14c68d90e5c30d1 | wikidoc | N ray | N ray
The so-called N rays (or N-rays) were a phenomenon described by French scientist René-Prosper Blondlot but subsequently found to be illusory.
In 1903, Blondlot, a distinguished physicist working at the University of Nancy, perceived changes in the brightness of an electric spark in a spark gap placed in an X-ray beam which he actually photographed and he later attributed to a novel form of radiation, naming it the N-ray, for the University of Nancy. However, no other researchers seemed able to reproduce his photographs. Blondlot, Augustin Charpentier, Arsène d'Arsonval and many others claimed to be able to detect rays emanating from most substances, including the human body. Most researchers of the subject at the time used the perceived light of a dim phosphorescent surface as "detectors", although work in the period clearly showed the change in brightness to be a physiological phenomenon rather than some actual change in the level of illumination. Physicists Gustave le Bon and P. Audollet and spiritualist (Phrenologist?) Carl Huter even claimed the discovery as their own, leading to a commission of the Académie des sciences to decide priority.
The "discovery" excited international interest and many physicists worked to replicate the effects. However, the notable physicists Lord Kelvin, William Crookes, Otto Lummer and Heinrich Rubens failed to do so. Following his own failure, self-described as "wasting a whole morning", US physicist Robert W. Wood, who had a reputation as a popular "debunker" in the period, was prevailed upon to travel to Blondlot's laboratory in France to investigate further. Wood suggested that Rubens go since he had been the most embarrassed when the Kaiser asked him to repeat the French experiments and then after two weeks he had to report his failure to do so. Rubens, however, felt it would look better if Wood went since Blondlot had been most polite in answering his many questions.
In the darkened room, Professor Wood secretly removed an essential prism from the experimental apparatus, yet the experimenters still said that they observed N rays. He also secretly replaced a large file that was supposed to be giving off N rays with an inert piece of wood, yet the N rays were still "observed". His report on these investigations, published in Nature, suggested that N rays were a purely subjective phenomenon, with the scientists involved having recorded data that matched their expectations. By 1905 no one outside Nancy believed in N rays.
The incident is used as a cautionary tale among scientists on the dangers of error introduced by experimenter bias. More precisely, patriotism was at the heart of this self-deception. France had been defeated by the Germans in the Franco-Prussian War in 1870, and after the major discovery by Wilhelm Röntgen of the X Ray the race was on for new discoveries.
N rays were cited as an example of pathological science by Irving Langmuir. However, the case is far more interesting than a single event, because nearly identical properties of an equally unknown radiation were recorded some 50 years before in another country by the Baron von Reichenbach in his treatise "Researches on Magnetism, Electricity, Heat, Light, Crystallization, and Chemical Attraction in their relations to the Vital Force", London, 1850, and before that in Vienna by Franz Mesmer in his "Memoire on the discovery of Animal-magnetism", 1779. It is clear that Reichenbach was aware of Mesmer's work and that researchers in Paris working with Blondlot were aware of Reichenbach's work (Revue Scientifique, Ser 5, Vol II, No.22) although there is no proof that Professor Blondlot was personally aware of it. However, this spread of nearly identical pathological science in history shows the phenomena to have greater breadth than the usually assumed patriotic self-deception.
Blondlot still has a street named after him in downtown Nancy as the belief that he had made a major discovery persisted. | N ray
The so-called N rays (or N-rays) were a phenomenon described by French scientist René-Prosper Blondlot but subsequently found to be illusory.
In 1903, Blondlot, a distinguished physicist working at the University of Nancy, perceived changes in the brightness of an electric spark in a spark gap placed in an X-ray beam which he actually photographed and he later attributed to a novel form of radiation, naming it the N-ray, for the University of Nancy.[1] However, no other researchers seemed able to reproduce his photographs. Blondlot, Augustin Charpentier, Arsène d'Arsonval and many others claimed to be able to detect rays emanating from most substances, including the human body. Most researchers of the subject at the time used the perceived light of a dim phosphorescent surface as "detectors", although work in the period clearly showed the change in brightness to be a physiological phenomenon rather than some actual change in the level of illumination.[2] Physicists Gustave le Bon and P. Audollet and spiritualist (Phrenologist?) Carl Huter even claimed the discovery as their own,[3] leading to a commission of the Académie des sciences to decide priority.[4]
The "discovery" excited international interest and many physicists worked to replicate the effects. However, the notable physicists Lord Kelvin, William Crookes, Otto Lummer and Heinrich Rubens failed to do so. Following his own failure, self-described as "wasting a whole morning", US physicist Robert W. Wood, who had a reputation as a popular "debunker" in the period, was prevailed upon to travel to Blondlot's laboratory in France to investigate further. Wood suggested that Rubens go since he had been the most embarrassed when the Kaiser asked him to repeat the French experiments and then after two weeks he had to report his failure to do so. Rubens, however, felt it would look better if Wood went since Blondlot had been most polite in answering his many questions.
In the darkened room, Professor Wood secretly removed an essential prism from the experimental apparatus, yet the experimenters still said that they observed N rays. He also secretly replaced a large file that was supposed to be giving off N rays with an inert piece of wood, yet the N rays were still "observed". His report on these investigations, published in Nature,[5] suggested that N rays were a purely subjective phenomenon, with the scientists involved having recorded data that matched their expectations. By 1905 no one outside Nancy believed in N rays.
The incident is used as a cautionary tale among scientists on the dangers of error introduced by experimenter bias. More precisely, patriotism was at the heart of this self-deception. France had been defeated by the Germans in the Franco-Prussian War in 1870, and after the major discovery by Wilhelm Röntgen of the X Ray the race was on for new discoveries.
N rays were cited as an example of pathological science by Irving Langmuir. However, the case is far more interesting than a single event, because nearly identical properties of an equally unknown radiation were recorded some 50 years before in another country by the Baron von Reichenbach in his treatise "Researches on Magnetism, Electricity, Heat, Light, Crystallization, and Chemical Attraction in their relations to the Vital Force", London, 1850, and before that in Vienna by Franz Mesmer in his "Memoire on the discovery of Animal-magnetism", 1779. It is clear that Reichenbach was aware of Mesmer's work and that researchers in Paris working with Blondlot were aware of Reichenbach's work (Revue Scientifique, Ser 5, Vol II, No.22) although there is no proof that Professor Blondlot was personally aware of it. However, this spread of nearly identical pathological science in history shows the phenomena to have greater breadth than the usually assumed patriotic self-deception.
Blondlot still has a street named after him in downtown Nancy as the belief that he had made a major discovery persisted. | https://www.wikidoc.org/index.php/N_ray | |
88316862a9cac76948caea6f6fc4ee2f27de153a | wikidoc | Nevus | Nevus
# Overview
Nevus (or naevus, plural nevi or naevi, from nævus, Latin for "birthmark") is the medical term for sharply circumscribed and chronic lesions of the skin or mucosa. These lesions are commonly named birthmarks or beauty marks. Nevi are benign by definition. However, 25% of malignant melanomas (a skin cancer) arise from pre-existing nevi. Using the term nevus and nevi loosely, most physicians and dermatologists are actually referring to a variant of nevus called the "melanocytic nevus", which are composed of melanocytes. Histologically, melanocytic nevi are distinguished from lentigines (also a type of benign pigmented macule) by the presence of nests of melanocytes, which lentigines (plural form of lentigo) lack.
# Classification
Epidermal nevi are derived from keratinocytes or derivatives of keratinocytes. Connective tissue nevi are derived from connective tissue cells like adipocytes and fibroblasts. Vascular nevi are derived from structures of the blood vessels. See birthmark for a more complete discussion
## Melanocytic nevus
- Congenital nevus: a melanocytic nevus present at birth or near birth.
- Acquired melanocytic nevus: a melanocytic nevus acquired later in life, and not at or near birth. Most melanocytic nevi are of the acquired variety.
- Melanocytic nevus (nevomelanocytic nevus, nevocellular nevus): the benign proliferation of melanocytes, the skin cells that make the brown pigment melanin. Hence, most nevi are brown to black. They are very common; almost all adults have at least one, usually more. They may be congenital or acquired (usually at puberty).
- Dysplastic nevus: usually an acquired melanocytic nevus with abnormal features making it difficult to distinguish from a melanoma. It can be a marker for an individual at risk for developing melanomas.
## Epidermal nevus
- Epidermal nevus: congenital, flesh-colored, raised or warty, often linear lesion, usually on the upper half of the body.
- Epidermal naevi. Adapted from Dermatology Atlas.
- Epidermal naevi. Adapted from Dermatology Atlas.
- Naevus epidermal. Adapted from Dermatology Atlas.
- Nevus sebaceous: variant of an epidermal nevus on the scalp presenting as a hairless, fleshy or yellowish area.
- Darier-Like Epidermal Nevus
- Darier-like epidermal naevus. Adapted from Dermatology Atlas.
- Darier-like epidermal naevus. Adapted from Dermatology Atlas.
- Darier-like epidermal naevus. Adapted from Dermatology Atlas.
- Darier-like epidermal naevus. Adapted from Dermatology Atlas.
- Darier-like epidermal naevus. Adapted from Dermatology Atlas.
- Darier-like epidermal naevus. Adapted from Dermatology Atlas.
## Connective tissue nevus
- Connective tissue nevus: fleshy, deep nodules. Rare.
## Vascular nevus
- Hemangioma (strawberry mark or nevus).
# Diagnosis of nevi
Clinical diagnosis of a melanocytic nevus from other nevi can be made with the naked eye using the ABCD guideline, or using dermatoscopy. The main concern is distinguishing between a benign nevus, a dysplastic nevus, and a melanoma. Other skin tumors can resemble a melanocytic nevus clinically, such as a seborrheic keratosis, pigmented basal cell cancer, hemangiomas, and sebaceous hyperplasia. A skin biopsy is required when the clinical diagnosis is inadequate or when malignancy is suspected.
# Normal evolution or maturation of melanocytic nevi
All melanocytic nevi will change with time - both congenital and acquired nevi. The "normal" maturation is evident as the elevation of the lesion from a flat macule to a raised papule. The color change occurs as the melanocytes clump and migrates from the surface of the skin (epidermis) down deep into the dermis. The color will change from even brown to speckled brown, and then losing the color and becomes flesh-colored or pink. During the evolution, uneven migration can make the nevi look like melanomas, and dermatoscopy can help in the differentiation between benign and malignant lesions. | Nevus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]:Associate Editor(s)-in-Chief: Kiran Singh, M.D. [3]
# Overview
Nevus (or naevus, plural nevi or naevi, from nævus, Latin for "birthmark") is the medical term for sharply circumscribed[1] and chronic lesions of the skin or mucosa. These lesions are commonly named birthmarks or beauty marks. Nevi are benign by definition. However, 25% of malignant melanomas (a skin cancer) arise from pre-existing nevi.[2] Using the term nevus and nevi loosely, most physicians and dermatologists are actually referring to a variant of nevus called the "melanocytic nevus", which are composed of melanocytes. Histologically, melanocytic nevi are distinguished from lentigines (also a type of benign pigmented macule) by the presence of nests of melanocytes, which lentigines (plural form of lentigo) lack.
# Classification
Epidermal nevi are derived from keratinocytes or derivatives of keratinocytes. Connective tissue nevi are derived from connective tissue cells like adipocytes and fibroblasts. Vascular nevi are derived from structures of the blood vessels. See birthmark for a more complete discussion
## Melanocytic nevus
- Congenital nevus: a melanocytic nevus present at birth or near birth.
- Acquired melanocytic nevus: a melanocytic nevus acquired later in life, and not at or near birth. Most melanocytic nevi are of the acquired variety.
- Melanocytic nevus (nevomelanocytic nevus, nevocellular nevus): the benign proliferation of melanocytes, the skin cells that make the brown pigment melanin. Hence, most nevi are brown to black. They are very common; almost all adults have at least one, usually more. They may be congenital or acquired (usually at puberty).
- Dysplastic nevus: usually an acquired melanocytic nevus with abnormal features making it difficult to distinguish from a melanoma. It can be a marker for an individual at risk for developing melanomas.
## Epidermal nevus
- Epidermal nevus: congenital, flesh-colored, raised or warty, often linear lesion, usually on the upper half of the body.
- Epidermal naevi. Adapted from Dermatology Atlas.[3]
- Epidermal naevi. Adapted from Dermatology Atlas.[3]
- Naevus epidermal. Adapted from Dermatology Atlas.[3]
- Nevus sebaceous: variant of an epidermal nevus on the scalp presenting as a hairless, fleshy or yellowish area.
- Darier-Like Epidermal Nevus
- Darier-like epidermal naevus. Adapted from Dermatology Atlas.[3]
- Darier-like epidermal naevus. Adapted from Dermatology Atlas.[3]
- Darier-like epidermal naevus. Adapted from Dermatology Atlas.[3]
- Darier-like epidermal naevus. Adapted from Dermatology Atlas.[3]
- Darier-like epidermal naevus. Adapted from Dermatology Atlas.[3]
- Darier-like epidermal naevus. Adapted from Dermatology Atlas.[3]
## Connective tissue nevus
- Connective tissue nevus: fleshy, deep nodules. Rare.
## Vascular nevus
- Hemangioma (strawberry mark or nevus).
# Diagnosis of nevi
Clinical diagnosis of a melanocytic nevus from other nevi can be made with the naked eye using the ABCD guideline, or using dermatoscopy. The main concern is distinguishing between a benign nevus, a dysplastic nevus, and a melanoma. Other skin tumors can resemble a melanocytic nevus clinically, such as a seborrheic keratosis, pigmented basal cell cancer, hemangiomas, and sebaceous hyperplasia. A skin biopsy is required when the clinical diagnosis is inadequate or when malignancy is suspected.
# Normal evolution or maturation of melanocytic nevi
All melanocytic nevi will change with time - both congenital and acquired nevi. The "normal" maturation is evident as the elevation of the lesion from a flat macule to a raised papule. The color change occurs as the melanocytes clump and migrates from the surface of the skin (epidermis) down deep into the dermis. The color will change from even brown to speckled brown, and then losing the color and becomes flesh-colored or pink. During the evolution, uneven migration can make the nevi look like melanomas, and dermatoscopy can help in the differentiation between benign and malignant lesions.[4] | https://www.wikidoc.org/index.php/Naevi | |
6faf0296b1f5d6d43dfee419f5d3105c40bb0f97 | wikidoc | Nattō | Nattō
# History
The materials and tools needed to produce nattō (soybeans and straw) were commonly available in Japan since ancient times, so the discovery could have happened as early as in the Jōmon period. It may also be possible that the product was discovered independently by numerous people at different times. The sources differ about the earliest origin of nattō. One source puts the first use of nattō in the Jōmon period between 10,000 and 300 BC. According to other sources the product may also have originated in China during the Zhou Dynasty (1134 - 246 BC). Another story is that Yoshiie Minamoto was on a battle campaign in northeastern Japan between 1056 and 1063 and another campaign between 1086 and 1088 when one day in 1083 they were attacked while boiling soybeans for their horses. They hurriedly packed up the beans, and did not open the straw bags until a few days later, at which time the beans had fermented. The soldiers ate it anyway, and liked the taste, so they offered some to Yoshiie, who also liked the taste. A third source calls the origin of nattō fairly recent from the Edo period (1603 to 1867).
One significant change in the production of nattō happened in the Taisho period (1912 - 1926), when researchers discovered a way to produce a nattō starter culture containing Bacillus natto without the need for straw. This greatly simplified the production process and enabled more consistent results.
# Appearance and consumption
The first thing noticed by the uninitiated after opening a pack of nattō is the very strong smell, akin to strong cheese. Stirring the nattō produces lots of spiderweb-like strings. The nattō itself has a nutty, savory, somewhat salty flavor that belies its odor.
Nattō is most commonly eaten at breakfast to accompany rice, possibly with some other ingredients, for example soy sauce, tsuyu broth, mustard, scallions, grated daikon, okra, or a raw quail egg. In Hokkaidō and northern Tohoku region, some people dust nattō with sugar. Nattō is also commonly used in other foods, such as nattō sushi, nattō toast, in miso soup, salad, as an ingredient in okonomiyaki, or even with spaghetti or as fried nattō. A dried form of nattō, having little odor or sliminess, can be eaten as a nutritious snack. There is even nattō ice cream.
Nattō is often considered an acquired taste and the perceived flavor of nattō can differ greatly between people; some find it tastes very strong and cheesy and may use it in small amounts to flavor rice or noodles, while others find it tastes "bland and unremarkable", requiring the addition of flavoring condiments such as mustard and soy sauce. Many non-Japanese find the taste very unpleasant, while others relish it as a delicacy. Some manufacturers produce an odorless or low-odor nattō. The split opinion about its appearance and taste might be compared to Vegemite in Australia and New Zealand, blue cheese in France, lutefisk in Norway and Sweden, Mämmi in Finland and Marmite in the UK. Even in Japan, nattō is more popular in some areas than in others. Nattō is known to be popular in the eastern Kantō region (Tokyo), but less popular in Kansai (Osaka, Kobe). About 236,000 tons of nattō are consumed in Japan each year.
# Production process
Nattō is made from soybeans, typically a special type called nattō soybeans. Smaller beans are preferred, as the fermentation process will be able to reach the center of the bean more easily. The beans are washed and soaked in water for 12 to 20 hours. This will increase the size of the beans. Next, the soybeans are steamed for 6 hours, although a pressure cooker can be used to reduce the time. The beans are mixed with the bacterium Bacillus subtilis natto, known as nattō-kin in Japanese. From this point on, care has to be taken to keep the ingredients away from impurities and other bacteria. The mixture is fermented at 40°C for up to 24 hours. Afterwards the nattō is cooled, then aged in a refrigerator for up to one week to add stringiness. During the aging process at a temperature of about 0°C, the Bacilli develop spores, and enzymatic peptidases break down the soybean protein into its constituent amino acids.
Historically, nattō was made by storing the steamed soy beans in rice straw, which naturally contains B. subtilis natto. The soy beans were packed in straw and then left to ferment. The fermentation was done either while the beans were buried underground underneath a fire or stored in a warm place in the house as for example under the kotatsu.
# End product
Today's mass-produced nattō is usually sold in small polystyrene containers. A typical package contains 2 or 3 containers, occasionally 4 containers, each of 40 to 50 g. One container typically complements a small bowl of rice. It usually includes a small packet of tsuyu and another packet of karashi, a type of mustard. Other flavors of sauce, such as shiso, are available.
Mito City and Kumamoto Prefecture are famous as nattō-producing districts.
Outside of Japan, nattō is sometimes sold frozen, and must be thawed before consumption.
# Medical benefits
It is often said in Japan that nattō is good for health, and these claims can be backed by medical research. One example is Pyrazine contained within nattō. Pyrazine is a compound which in addition to giving nattō its distinct smell, also reduces the likelihood of blood clotting. It also contains a serine protease type enzyme called nattokinase which may also reduce blood clotting both by direct fibrinolysis of clots, and inhibition of the plasma protein plasminogen activator inhibitor 1. This may help to avoid thrombosis, as for example in heart attacks, pulmonary embolism, or strokes. An extract from nattō containing nattokinase is available as a dietary supplement. Studies have shown that oral administration of nattokinase in enteric capsules leads to a mild enhancement of fibrinolytic activity in rats and dogs. It is therefore plausible to hypothesize that nattokinase might reduce blood clots in humans, although clinical trials have not been conducted. Another study suggests the FAS in natto is the very substance bringing fibrinolysis of clots, which accelerates the activity of not only nattokinase but urokinase.
Nattō also contains large amounts of Vitamin K, which is involved in the formation of calcium-binding groups in proteins, assisting the formation of bone, and preventing osteoporosis. Vitamin K1 is found naturally in seaweed, liver and some vegetables, while vitamin K2 is found in fermented food products like cheese and miso. Nattō has very large amounts of vitamin K2, approximately 870 micrograms per 100 grams of nattō.
According to a study fermented soybeans like Natto contains Vitamin PQQ, which is very important for the skin.
PQQ existing in human tissues is derived mainly from diet especially from fermented soybeans.
According to the recent studies polyamine suppresses the excessive immune reactions, and natto contains much larger amount of it than any foods. Dietary supplements containing the substances extracted from natto such as polyamine, nattokinase, FAS and vitamin K2 are available.
Nattō also contains many chemicals alleged to prevent cancer, as for example daidzein, genistein, isoflavone, phytoestrogen, and the chemical element selenium. However, most of these chemicals can also be found in other soy bean products, and their effect on cancer prevention is uncertain at best. Recent studies show nattō may have a cholesterol-lowering effect.
Nattō is also said to have an antibiotic effect, and its use as medicine against dysentery was researched by the Imperial Japanese Navy before World War II.
Nattō is claimed to prevent obesity possibly due to a low calorie content of approximately 90 calories per 7-8 grams of protein in an average serving. Other unverified claims include improved digestion, reduced effects of aging, and the reversal of hair loss in men due to its phytoestrogen content, which can lower testosterone that can cause baldness. These claimed physiological benefits of eating natto have been based on an analysis of the content of nattō, and have not been confirmed by human study.
Nattō is also sometimes used as an ingredient of pet food, and it is claimed that this improves the health of the pets.
# Gallery
- A Nattō legend in a supermarket helps to differentiate varieties of bean
A Nattō legend in a supermarket helps to differentiate varieties of bean
- Natto is marketed in many ways, this packet contains collagen
Natto is marketed in many ways, this packet contains collagen | Nattō
Template:Nihongo is a traditional Japanese food made from fermented soybeans, popular especially for breakfast. As a rich source of protein, nattō and the soybean paste miso formed a vital source of nutrition in feudal Japan. For some, nattō can be an acquired taste due to its powerful smell, strong flavor, and sticky consistency. In Japan nattō is most popular in the eastern regions, including Kantō and Tōhoku.
# History
The materials and tools needed to produce nattō (soybeans and straw) were commonly available in Japan since ancient times, so the discovery could have happened as early as in the Jōmon period. It may also be possible that the product was discovered independently by numerous people at different times. The sources differ about the earliest origin of nattō. One source puts the first use of nattō in the Jōmon period between 10,000 and 300 BC. According to other sources the product may also have originated in China during the Zhou Dynasty (1134 - 246 BC). Another story is that Yoshiie Minamoto was on a battle campaign in northeastern Japan between 1056 and 1063 and another campaign between 1086 and 1088 when one day in 1083 they were attacked while boiling soybeans for their horses. They hurriedly packed up the beans, and did not open the straw bags until a few days later, at which time the beans had fermented. The soldiers ate it anyway, and liked the taste, so they offered some to Yoshiie, who also liked the taste. A third source calls the origin of nattō fairly recent from the Edo period (1603 to 1867).[citation needed]
One significant change in the production of nattō happened in the Taisho period (1912 - 1926), when researchers discovered a way to produce a nattō starter culture containing Bacillus natto without the need for straw. This greatly simplified the production process and enabled more consistent results.
# Appearance and consumption
The first thing noticed by the uninitiated after opening a pack of nattō is the very strong smell, akin to strong cheese. Stirring the nattō produces lots of spiderweb-like strings. The nattō itself has a nutty, savory, somewhat salty flavor that belies its odor.
Nattō is most commonly eaten at breakfast to accompany rice, possibly with some other ingredients, for example soy sauce, tsuyu broth, mustard, scallions, grated daikon, okra, or a raw quail egg. In Hokkaidō and northern Tohoku region, some people dust nattō with sugar. Nattō is also commonly used in other foods, such as nattō sushi, nattō toast, in miso soup, salad, as an ingredient in okonomiyaki, or even with spaghetti or as fried nattō. A dried form of nattō, having little odor or sliminess, can be eaten as a nutritious snack. There is even nattō ice cream.
Nattō is often considered an acquired taste and the perceived flavor of nattō can differ greatly between people; some find it tastes very strong and cheesy and may use it in small amounts to flavor rice or noodles, while others find it tastes "bland and unremarkable", requiring the addition of flavoring condiments such as mustard and soy sauce. Many non-Japanese find the taste very unpleasant, while others relish it as a delicacy. Some manufacturers produce an odorless or low-odor nattō. The split opinion about its appearance and taste might be compared to Vegemite in Australia and New Zealand, blue cheese in France, lutefisk in Norway and Sweden, Mämmi in Finland and Marmite in the UK. Even in Japan, nattō is more popular in some areas than in others. Nattō is known to be popular in the eastern Kantō region (Tokyo), but less popular in Kansai (Osaka, Kobe). About 236,000 tons of nattō are consumed in Japan each year.
# Production process
Nattō is made from soybeans, typically a special type called nattō soybeans. Smaller beans are preferred, as the fermentation process will be able to reach the center of the bean more easily. The beans are washed and soaked in water for 12 to 20 hours. This will increase the size of the beans. Next, the soybeans are steamed for 6 hours, although a pressure cooker can be used to reduce the time. The beans are mixed with the bacterium Bacillus subtilis natto, known as nattō-kin in Japanese. From this point on, care has to be taken to keep the ingredients away from impurities and other bacteria. The mixture is fermented at 40°C for up to 24 hours. Afterwards the nattō is cooled, then aged in a refrigerator for up to one week to add stringiness. During the aging process at a temperature of about 0°C, the Bacilli develop spores, and enzymatic peptidases break down the soybean protein into its constituent amino acids.
Historically, nattō was made by storing the steamed soy beans in rice straw, which naturally contains B. subtilis natto. The soy beans were packed in straw and then left to ferment. The fermentation was done either while the beans were buried underground underneath a fire or stored in a warm place in the house as for example under the kotatsu.
# End product
Today's mass-produced nattō is usually sold in small polystyrene containers. A typical package contains 2 or 3 containers, occasionally 4 containers, each of 40 to 50 g. One container typically complements a small bowl of rice. It usually includes a small packet of tsuyu and another packet of karashi, a type of mustard. Other flavors of sauce, such as shiso, are available.
Mito City and Kumamoto Prefecture are famous as nattō-producing districts.
Outside of Japan, nattō is sometimes sold frozen, and must be thawed before consumption.
# Medical benefits
It is often said in Japan that nattō is good for health, and these claims can be backed by medical research. One example is Pyrazine contained within nattō. Pyrazine is a compound which in addition to giving nattō its distinct smell, also reduces the likelihood of blood clotting. It also contains a serine protease type enzyme called nattokinase[1] which may also reduce blood clotting both by direct fibrinolysis of clots, and inhibition of the plasma protein plasminogen activator inhibitor 1. This may help to avoid thrombosis, as for example in heart attacks, pulmonary embolism, or strokes. An extract from nattō containing nattokinase is available as a dietary supplement. Studies have shown that oral administration of nattokinase in enteric capsules leads to a mild enhancement of fibrinolytic activity in rats[2] and dogs. It is therefore plausible to hypothesize that nattokinase might reduce blood clots in humans, although clinical trials have not been conducted. Another study suggests the FAS in natto is the very substance bringing fibrinolysis of clots, which accelerates the activity of not only nattokinase but urokinase.[3]
Nattō also contains large amounts of Vitamin K, which is involved in the formation of calcium-binding groups in proteins, assisting the formation of bone, and preventing osteoporosis. Vitamin K1 is found naturally in seaweed, liver and some vegetables, while vitamin K2 is found in fermented food products like cheese and miso. Nattō has very large amounts of vitamin K2, approximately 870 micrograms per 100 grams of nattō.
According to a study fermented soybeans like Natto contains Vitamin PQQ, which is very important for the skin.[4]
PQQ existing in human tissues is derived mainly from diet especially from fermented soybeans.
According to the recent studies polyamine suppresses the excessive immune reactions, and natto contains much larger amount of it than any foods.[5] Dietary supplements containing the substances extracted from natto such as polyamine, nattokinase, FAS and vitamin K2 are available.
Nattō also contains many chemicals alleged to prevent cancer, as for example daidzein, genistein, isoflavone, phytoestrogen, and the chemical element selenium. However, most of these chemicals can also be found in other soy bean products, and their effect on cancer prevention is uncertain at best. Recent studies show nattō may have a cholesterol-lowering effect.[6]
Nattō is also said to have an antibiotic effect, and its use as medicine against dysentery was researched by the Imperial Japanese Navy before World War II.[7]
Nattō is claimed to prevent obesity possibly due to a low calorie content of approximately 90 calories per 7-8 grams of protein in an average serving. Other unverified claims include improved digestion, reduced effects of aging[citation needed], and the reversal of hair loss in men due to its phytoestrogen content, which can lower testosterone that can cause baldness.[citation needed] These claimed physiological benefits of eating natto have been based on an analysis of the content of nattō, and have not been confirmed by human study.
Nattō is also sometimes used as an ingredient of pet food, and it is claimed that this improves the health of the pets.[8]
# Gallery
- A Nattō legend in a supermarket helps to differentiate varieties of bean
A Nattō legend in a supermarket helps to differentiate varieties of bean
- Natto is marketed in many ways, this packet contains collagen
Natto is marketed in many ways, this packet contains collagen | https://www.wikidoc.org/index.php/Natt%C5%8D | |
65d13c0309ddb6361f80d0b3a92cb3b7d611cd9e | wikidoc | Navel | Navel
The navel, also called a belly button, or umbilicus, is a scar on the abdomen, caused when the umbilical cord is removed from a newborn baby. All placental mammals have a navel. While it is fairly conspicuous in humans, in most mammals it appears only as a thin hairless line.
In humans, the scar can appear as a depression (sometimes colloquially referred to as an "innie") or as a protrusion ("outie"). Although they can be separated into these two categories, navels actually vary quite drastically among people in terms of size, shape, depth/length, and overall appearance. As navels are essentially scars, and not in any way defined by genetics, they can serve as a way of distinguishing between identical twins in the absence of other identifiable marks.
# Human anatomy
This section focuses on externally-visible aesthetics of the navel in human anatomy. Information regarding fetal circulation -- how oxygenated blood and nutrients are absorbed by a fetus from the umbilical cord -- may be found under umbilical vein and umbilical artery, both of which are umbilical vessels.
The umbilicus is an important landmark on the abdomen since its position is relatively consistent among humans. The skin around the waist at the level of the umbilicus is supported by the tenth thoracic spinal nerve (T10 dermatome). The umbilicus itself lies at the level between L3/L4 vertebrae.
About 90% of people have a depression, or an innie, with the other 10% have a protruding belly button, or an outie. The reason for the occurrence of an outie is extra skin left from the umbilical cord or umbilical hernias, although a child with an umbilical hernia will not necessarily develop an outie. As well as the visible depression on a person's abdomen, the underlying abdominal-muscle layers also present a concavity; thinness at this point contributes to a relative structural weakness, making it susceptible to hernia. During pregnancy, the uterus presses the navel of the pregnant woman outward. It usually retracts after birth.
The umbilicus is also used to visually separate the abdomen into quadrants. The navel comes in the center of the circle enclosing the spread-eagle figure in Leonardo da Vinci's Vitruvian Man, his famous drawing on human proportions. This illustrates the principle that in the shift between the spread-eagle pose and the straight pose, the apparent center of the figure seems to move, but in reality, the navel of the figure, which is the true center of gravity, remains motionless.
The height at which navels are located on the abdomen is variable. An ideal proportion of navel height versus body height is said to be based on the Golden Section, also known as the "Divine Proportion" by philosophers and artists. This is a geometric proportion in which a line is divided so that the ratio of the length of the longer line segment to the length of the entire line is equal to the ratio of the length of the shorter line segment to the length of the longer line segment. This Golden Section ratio has a numerical value of approximately 1.618. In other words, an ideal navel height is about 62% of the body height and is said to exhibit special beauty as the legs and torso appear in sound proportion.
# Fashion
Fashion sometimes exploits the navel through clothing that leaves part of the lower abdomen (i.e., the midriff) bare, a usage that is much more common for women than for men. Displaying a bare navel has been and still is a taboo in certain Western cultures since the sheath-like appearance of the navel (especially of an 'innie') has erotic overtones. For example, in the 1960s, Barbara Eden was not allowed to show her navel on the TV show I Dream of Jeannie.
The modern trend of exposing the navel has usually been confined to women, aside from a male belly-button shirt fad in 1980s fashion. While the West was more resistant to midriff-baring dresses until the 1980s, Indian women have traditionally worn saris that usually expose the navel as the blouse/choli that is worn with it is intentionally kept short. In Indian culture, exposure of the navel is not considered a taboo and has, in fact, long been accepted as a graceful identifying mark of a married woman. A dimpled navel is considered a special asset of any prospective bride especially amongst South Indian women and an important quality of any budding Bollywood actress. Other Indian communities that take navels in their stride include the Rajasthanis and Gujaratis, whose women leave the midriff exposed while wearing short cholis with traditional gypsy skirts. However, these women cover their heads with a 'chador' and even cover their faces in front of strangers, which lends credence to the belief that navel-baring in India has a symbolic, almost mystical, association with birth and life and that the display is meant to emphasise the centrality of nature in the nurture role.
Along with the acceptance of navel display in Western societies, navel piercing is becoming common among young women. Short shirts to expose navels are also often worn to expose lower back tattoos or stomach/navel tattoos, which are popular among young women.
# Sexuality
The navel's transfiguration from a vestigial fetal feeding tube to a woman's erotic appendage can be ascertained from the attention it gets, ranging from men's casual stares to more intimate prodding. Navels can be the focus of sexual fetishism, especially among males. While cleavage of the breasts is certainly meant to display feminine charms and has a risqué, "come-on" appeal, a navel is considered, in equal parts, an innocent emblem of femininity as much as an object of sexual appeal.
In the Song of Solomon, the book of Old Testament, there are unique allusions to exotic things in nature, with frequent interweaving of nature with erotic imagery. Besides breasts, belly and thighs, the navel figures in Solomon's lavish praise of his love (the country girl, Sulaimi) thus: "thy navel is like a round goblet, which wanteth not liquor"(7:2).
The modern-day Deirdre Day-MacLeod is more matter-of-fact than the biblical song when he describes the navel's appeal thus: "Neither procreative nor nutritive, perhaps it is the navel's lack of obvious purpose, combined with its audacious, almost arrogant, spot right there in the middle of things, that sucks its admirers in."
# Other meanings
- The word "navel", or its equivalent in other languages, has been used sometimes for the center of something, e.g., "nave" of a wheel.
- Tortellini might represent the belly button of Venus, the Goddess of Love in Roman mythology (Aphrodite in Greek mythology). | Navel
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The navel, also called a belly button, or umbilicus, is a scar on the abdomen, caused when the umbilical cord is removed from a newborn baby. All placental mammals have a navel. While it is fairly conspicuous in humans, in most mammals it appears only as a thin hairless line.
In humans, the scar can appear as a depression (sometimes colloquially referred to as an "innie") or as a protrusion ("outie"). Although they can be separated into these two categories, navels actually vary quite drastically among people in terms of size, shape, depth/length, and overall appearance. As navels are essentially scars, and not in any way defined by genetics, they can serve as a way of distinguishing between identical twins in the absence of other identifiable marks.
# Human anatomy
This section focuses on externally-visible aesthetics of the navel in human anatomy. Information regarding fetal circulation -- how oxygenated blood and nutrients are absorbed by a fetus from the umbilical cord -- may be found under umbilical vein and umbilical artery, both of which are umbilical vessels.
The umbilicus is an important landmark on the abdomen since its position is relatively consistent among humans. The skin around the waist at the level of the umbilicus is supported by the tenth thoracic spinal nerve (T10 dermatome). The umbilicus itself lies at the level between L3/L4 vertebrae.
About 90% of people have a depression, or an innie, with the other 10% have a protruding belly button, or an outie.[citation needed] The reason for the occurrence of an outie is extra skin left from the umbilical cord or umbilical hernias, although a child with an umbilical hernia will not necessarily develop an outie. As well as the visible depression on a person's abdomen, the underlying abdominal-muscle layers also present a concavity; thinness at this point contributes to a relative structural weakness, making it susceptible to hernia. During pregnancy, the uterus presses the navel of the pregnant woman outward. It usually retracts after birth.
The umbilicus is also used to visually separate the abdomen into quadrants. The navel comes in the center of the circle enclosing the spread-eagle figure in Leonardo da Vinci's Vitruvian Man, his famous drawing on human proportions. This illustrates the principle that in the shift between the spread-eagle pose and the straight pose, the apparent center of the figure seems to move, but in reality, the navel of the figure, which is the true center of gravity, remains motionless.
The height at which navels are located on the abdomen is variable. An ideal proportion of navel height versus body height is said to be based on the Golden Section, also known as the "Divine Proportion" by philosophers and artists. This is a geometric proportion in which a line is divided so that the ratio of the length of the longer line segment to the length of the entire line is equal to the ratio of the length of the shorter line segment to the length of the longer line segment. This Golden Section ratio has a numerical value of approximately 1.618. In other words, an ideal navel height is about 62% of the body height and is said to exhibit special beauty as the legs and torso appear in sound proportion.
# Fashion
Fashion sometimes exploits the navel through clothing that leaves part of the lower abdomen (i.e., the midriff) bare, a usage that is much more common for women than for men. Displaying a bare navel has been and still is a taboo in certain Western cultures since the sheath-like appearance of the navel (especially of an 'innie') has erotic overtones. For example, in the 1960s, Barbara Eden was not allowed to show her navel on the TV show I Dream of Jeannie.
The modern trend of exposing the navel has usually been confined to women, aside from a male belly-button shirt fad in 1980s fashion. While the West was more resistant to midriff-baring dresses until the 1980s, Indian women have traditionally worn saris that usually expose the navel as the blouse/choli that is worn with it is intentionally kept short. In Indian culture, exposure of the navel is not considered a taboo and has, in fact, long been accepted as a graceful identifying mark of a married woman. A dimpled navel is considered a special asset of any prospective bride especially amongst South Indian women and an important quality of any budding Bollywood actress. Other Indian communities that take navels in their stride include the Rajasthanis and Gujaratis, whose women leave the midriff exposed while wearing short cholis with traditional gypsy skirts. However, these women cover their heads with a 'chador' and even cover their faces in front of strangers, which lends credence to the belief that navel-baring in India has a symbolic, almost mystical, association with birth and life and that the display is meant to emphasise the centrality of nature in the nurture role.[citation needed]
Along with the acceptance of navel display in Western societies, navel piercing is becoming common among young women. Short shirts to expose navels are also often worn to expose lower back tattoos or stomach/navel tattoos, which are popular among young women.
# Sexuality
The navel's transfiguration from a vestigial fetal feeding tube to a woman's erotic appendage can be ascertained from the attention it gets, ranging from men's casual stares to more intimate prodding. Navels can be the focus of sexual fetishism, especially among males. While cleavage of the breasts is certainly meant to display feminine charms and has a risqué, "come-on" appeal, a navel is considered, in equal parts, an innocent emblem of femininity as much as an object of sexual appeal.
In the Song of Solomon, the book of Old Testament, there are unique allusions to exotic things in nature, with frequent interweaving of nature with erotic imagery. Besides breasts, belly and thighs, the navel figures in Solomon's lavish praise of his love (the country girl, Sulaimi) thus: "thy navel is like a round goblet, which wanteth not liquor"(7:2).
The modern-day Deirdre Day-MacLeod is more matter-of-fact than the biblical song when he describes the navel's appeal thus: "Neither procreative nor nutritive, perhaps it is the navel's lack of obvious purpose, combined with its audacious, almost arrogant, spot right there in the middle of things, that sucks its admirers in."[2]
# Other meanings
- The word "navel", or its equivalent in other languages, has been used sometimes for the center of something, e.g., "nave" of a wheel.
- Tortellini might represent the belly button of Venus, the Goddess of Love in Roman mythology (Aphrodite in Greek mythology). | https://www.wikidoc.org/index.php/Navel | |
05f16a0d626fd21af08b709d0958c7810f7a4cd5 | wikidoc | Nisin | Nisin
Nisin is a polycyclic peptide antibacterial with 34 amino acid residues used as a food preservative. It contains the uncommon amino acids lanthionine (Lan), methyllanthionine (MeLan), didehydroalanine (Dha) and didehydroaminobutyric acid (Dhb). These unusual amino acids are introduced by posttranslational modification of the precursor peptide. In these reactions a ribosomally synthesized 57-mer is converted to the final peptide. The unsaturated amino acids originate from serine and threonine, and the enzyme-catalysed addition of cysteine residues to the didehydro amino acids result in the multiple thioether bridges.
Structure of nisin
Nisin is produced by fermentation using the bacterium Lactococcus lactis. Commercially it is obtained from natural substrates including milk and is not chemically synthesized. It is used in processed cheese production to extend shelf life by suppressing gram-positive spoilage and pathogenic bacteria. There are many other applications of this preservative in food and beverage production. Due to its highly selective spectrum of activity it is also employed as a selective agent in microbiological media for the isolation of gram-negative bacteria, yeast and moulds. Subtilin and Epidermin are related to Nisin, all members of a class of molecules called lantibiotics.
As a food additive, nisin has E number E234.
# Further reading
- K. Fukase et al., Tetrahedron Lett. 1988, 29, 7, 795. (Total synthesis)
- G. W. Buchman et al., J. Biol. Chem. 1988, 263, 31, 16260. (Biosynthesis)
cs:Nisin
de:Nisin
nl:Nisine | Nisin
Nisin is a polycyclic peptide antibacterial with 34 amino acid residues used as a food preservative. It contains the uncommon amino acids lanthionine (Lan), methyllanthionine (MeLan), didehydroalanine (Dha) and didehydroaminobutyric acid (Dhb). These unusual amino acids are introduced by posttranslational modification of the precursor peptide. In these reactions a ribosomally synthesized 57-mer is converted to the final peptide. The unsaturated amino acids originate from serine and threonine, and the enzyme-catalysed addition of cysteine residues to the didehydro amino acids result in the multiple thioether bridges.
Structure of nisin
Nisin is produced by fermentation using the bacterium Lactococcus lactis. Commercially it is obtained from natural substrates including milk and is not chemically synthesized. It is used in processed cheese production to extend shelf life by suppressing gram-positive spoilage and pathogenic bacteria. There are many other applications of this preservative in food and beverage production. Due to its highly selective spectrum of activity it is also employed as a selective agent in microbiological media for the isolation of gram-negative bacteria, yeast and moulds. Subtilin and Epidermin are related to Nisin, all members of a class of molecules called lantibiotics.
As a food additive, nisin has E number E234.
# Further reading
- K. Fukase et al., Tetrahedron Lett. 1988, 29, 7, 795. (Total synthesis)
- G. W. Buchman et al., J. Biol. Chem. 1988, 263, 31, 16260. (Biosynthesis)
cs:Nisin
de:Nisin
nl:Nisine
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Nisin | |
3e086655fcd524b8a677f36dd15117cb0e59968a | wikidoc | Niter | Niter
# Overview
Niter (US) or nitre (UK) is the mineral form of potassium nitrate, KNO3, also known as saltpeter (US) or saltpetre (UK). Historically, the term "nitre" – cognate with "natrium", an old word for sodium – has been very vaguely defined, and it has been applied to a variety of other minerals and chemical compounds, including sodium nitrate (also "soda nitre" or "cubic nitre"), sodium carbonate and potassium carbonate. This article is about the mineral form of potassium nitrate, which is the usual modern meaning.
Niter is a colorless to white mineral crystallizing in the orthorhombic crystal system. It usually is found as massive encrustations and effervescent growths on cavern walls and ceilings where solutions containing alkali potassium and nitrate seep into the openings. It occasionally occurs as prismatic acicular crystal groups, and individual crystals commonly show twinning. It is most common in arid environments. It is a soft mineral equal to gypsum on the Mohs scale and has a low specific gravity of 2.1. It has refractive indices of nα=1.332, nβ=1.504, and nγ=1.504. It readily dissolves in water.
Niter has been known since ancient times. The name is from Hebrew néter, for salt derived ashes.
In literature, Edgar Allan Poe invokes the supposed Saint of Nitre repeatedly in the short story "The Cask of Amontillado" (1846), in which the main character uses the nitre to his "advantages", as it slowly murders his enemy. Fortunato's health worsens, until Montresor takes his revenge in the form of immurement. | Niter
# Overview
Niter (US) or nitre (UK) is the mineral form of potassium nitrate, KNO3, also known as saltpeter (US) or saltpetre (UK). Historically, the term "nitre" – cognate with "natrium", an old word for sodium – has been very vaguely defined, and it has been applied to a variety of other minerals and chemical compounds, including sodium nitrate (also "soda nitre" or "cubic nitre"), sodium carbonate and potassium carbonate. This article is about the mineral form of potassium nitrate, which is the usual modern meaning.
Niter is a colorless to white mineral crystallizing in the orthorhombic crystal system. It usually is found as massive encrustations and effervescent growths on cavern walls and ceilings where solutions containing alkali potassium and nitrate seep into the openings. It occasionally occurs as prismatic acicular crystal groups, and individual crystals commonly show twinning. It is most common in arid environments. It is a soft mineral equal to gypsum on the Mohs scale and has a low specific gravity of 2.1. It has refractive indices of nα=1.332, nβ=1.504, and nγ=1.504. It readily dissolves in water.
Niter has been known since ancient times. The name is from Hebrew néter, for salt derived ashes.
In literature, Edgar Allan Poe invokes the supposed Saint of Nitre repeatedly in the short story "The Cask of Amontillado" (1846), in which the main character uses the nitre to his "advantages", as it slowly murders his enemy. Fortunato's health worsens, until Montresor takes his revenge in the form of immurement. | https://www.wikidoc.org/index.php/Niter | |
f1237a36c32827b6413420d03914a00ad6dc0944 | wikidoc | Noise | Noise
In common use, the word noise means unwanted sound or noise pollution. In electronics noise can refer to the electronic signal corresponding to acoustic noise (in an audio system) or the electronic signal corresponding to the (visual) noise commonly seen as 'snow' on a degraded television or video image. In signal processing or computing it can be considered data without meaning; that is, data that is not being used to transmit a signal, but is simply produced as an unwanted by-product of other activities. In Information Theory, however, noise is still considered to be information. In a broader sense, film grain or even advertisements in web pages can be considered noise.
Noise can block, distort, or change the meaning of a message in both human and electronic communication.
In many of these areas, the special case of thermal noise arises, which sets a fundamental lower limit to what can be measured or signaled and is related to basic physical processes at the molecular level described by well-established thermodynamics considerations, some of which are expressible by relatively well known simple formulae.
# Acoustic noise
When speaking of noise in relation to sound, what is commonly meant is meaningless sound of greater than usual volume. Thus, a loud activity may be referred to as noisy. However, conversations of other people may be called noise for people not involved in any of them, and noise can be any unwanted sound such as the noise of dogs barking, neighbours playing loud music, road traffic sounds, chainsaws, or aircraft, spoiling the quiet of the countryside.
For film sound theorists and practitioners at the advent of talkies c.1928/1929, noise was non-speech sound or natural sound and for many of them noise (especially asynchronous use with image) was desired over the evils of dialogue synchronized to moving image. The director and critic René Clair writing in 1929 makes a clear distinction between film dialogue and film noise and very clearly suggests that noise can have meaning and be interpreted: "...it is possible that an interpretation of noises may have more of a future in it. Sound cartoons, using "real" noises, seem to point to interesting possibilities" ('The Art of Sound' (1929)). Alberto Cavalcanti uses noise as a synonym for natural sound ('Sound in Films' (1939)) and as late as 1960, Siegfried Kracauer was referring to noise as non-speech sound ('Dialogue and Sound' (1960)).
# Audio noise
In audio, recording, and broadcast systems audio noise refers to the residual low level sound (usually hiss and hum) that is heard in quiet periods of programme.
In audio engineering it can also refer to the unwanted residual electronic noise signal that gives rise to acoustic noise heard as 'hiss'. This signal noise is commonly measured using A-weighting or ITU-R 468 weighting
# Electronic noise
Electronic noise exists in all circuits and devices as a result of thermal noise, also referred to as Johnson Noise. Semiconductor devices can also contribute flicker noise and generation-recombination noise. In any electronic circuit, there exist random variations in current or voltage caused by the random movement of the electrons carrying the current as they are jolted around by thermal energy. Lower temperature results in lower thermal noise. This same phenomenon limits the minimum signal level that any radio receiver can usefully respond to, because there will always be a small but significant amount of thermal noise arising in its input circuits. This is why radio telescopes, which search for very low levels of signal from stars, use front-end low-noise amplifier circuits, usually mounted on the aerial dish, and cooled with liquid nitrogen.
# Uses of noise
The use of loud noise can serve as a deterrent, to ward off unwanted animals and humans. One example of noise used specifically as a deterrent occurred in 1998, when actress Barbara Streissand and actor James Brolin had large external speakers set up outside of a tent that they were married in, from which very loud heavy metal music was blared outward from their location, in order to ward off journalists and papparazzi. | Noise
Template:This
In common use, the word noise means unwanted sound or noise pollution. In electronics noise can refer to the electronic signal corresponding to acoustic noise (in an audio system) or the electronic signal corresponding to the (visual) noise commonly seen as 'snow' on a degraded television or video image. In signal processing or computing it can be considered data without meaning; that is, data that is not being used to transmit a signal, but is simply produced as an unwanted by-product of other activities. In Information Theory, however, noise is still considered to be information. In a broader sense, film grain or even advertisements in web pages can be considered noise.
Noise can block, distort, or change the meaning of a message in both human and electronic communication.
In many of these areas, the special case of thermal noise arises, which sets a fundamental lower limit to what can be measured or signaled and is related to basic physical processes at the molecular level described by well-established thermodynamics considerations, some of which are expressible by relatively well known simple formulae.
# Acoustic noise
When speaking of noise in relation to sound, what is commonly meant is meaningless sound of greater than usual volume. Thus, a loud activity may be referred to as noisy. However, conversations of other people may be called noise for people not involved in any of them, and noise can be any unwanted sound such as the noise of dogs barking, neighbours playing loud music, road traffic sounds, chainsaws, or aircraft, spoiling the quiet of the countryside.
For film sound theorists and practitioners at the advent of talkies c.1928/1929, noise was non-speech sound or natural sound and for many of them noise (especially asynchronous use with image) was desired over the evils of dialogue synchronized to moving image. The director and critic René Clair writing in 1929 makes a clear distinction between film dialogue and film noise and very clearly suggests that noise can have meaning and be interpreted: "...it is possible that an interpretation of noises may have more of a future in it. Sound cartoons, using "real" noises, seem to point to interesting possibilities" ('The Art of Sound' (1929)). Alberto Cavalcanti uses noise as a synonym for natural sound ('Sound in Films' (1939)) and as late as 1960, Siegfried Kracauer was referring to noise as non-speech sound ('Dialogue and Sound' (1960)).
# Audio noise
In audio, recording, and broadcast systems audio noise refers to the residual low level sound (usually hiss and hum) that is heard in quiet periods of programme.
In audio engineering it can also refer to the unwanted residual electronic noise signal that gives rise to acoustic noise heard as 'hiss'. This signal noise is commonly measured using A-weighting or ITU-R 468 weighting
# Electronic noise
Electronic noise exists in all circuits and devices as a result of thermal noise, also referred to as Johnson Noise. Semiconductor devices can also contribute flicker noise and generation-recombination noise. In any electronic circuit, there exist random variations in current or voltage caused by the random movement of the electrons carrying the current as they are jolted around by thermal energy. Lower temperature results in lower thermal noise. This same phenomenon limits the minimum signal level that any radio receiver can usefully respond to, because there will always be a small but significant amount of thermal noise arising in its input circuits. This is why radio telescopes, which search for very low levels of signal from stars, use front-end low-noise amplifier circuits, usually mounted on the aerial dish, and cooled with liquid nitrogen.
# Uses of noise
The use of loud noise can serve as a deterrent, to ward off unwanted animals and humans. One example of noise used specifically as a deterrent occurred in 1998, when actress Barbara Streissand and actor James Brolin had large external speakers set up outside of a tent that they were married in, from which very loud heavy metal music was blared outward from their location, in order to ward off journalists and papparazzi.[1] | https://www.wikidoc.org/index.php/Noise | |
6a90eedb58f0684ff73916a440d88bcbbc04d1c1 | wikidoc | Nurse | Nurse
# Overview
Nurses are responsible—along with other health care professionals—for the treatment, safety, and recovery of acutely or chronically ill or injured people, health maintenance of the healthy, and treatment of life-threatening emergencies in a wide range of health care settings. Nurses may also be involved in medical and nursing research and perform a wide range of non-clinical functions necessary to the delivery of health care.
# Education & regulation
Nursing education, regulation, roles, and titles vary in different countries, but in general reflect an increasing level of responsibility and status.
Nurses develop and implement a plan of care and work collaboratively with the patient, the patient's family, and other health care professionals and para-professionals. Nurses help coordinate the patient care performed by other members of a health care team such as physical therapists, medical practitioners, social workers, and dietitians. Nurses frequently act as patient advocates.
The nursing career structure varies considerably throughout the world. Typically there are several distinct levels of nursing practitioner distinguished by increasing education, responsibility, and skills. The major distinction is between task-based nursing and professional nursing. Nurses throughout the world are increasingly employed as advanced practice nurses, such as clinical nurse specialists and nurse practitioners, who diagnose health problems and prescribe medications and other therapies. At the top of the educational ladder is the doctoral-prepared nurse. Nurses may gain a PhD or another doctoral degree, specializing in research, clinical nursing, and so forth. These nurses practice nursing, teach nursing, and carry out nursing research. As the science and art of nursing has advanced, so has the demand for doctoral-prepared nurses.
In various parts of the world, the educational background for nurses varies widely. In some parts of eastern Europe, nurses are high school graduates with twelve to eighteen months of training. In contrast, Chile requires any registered nurse to have at least a bachelor's degree.
Nurses are the largest group of providers in the health care system--there are over two million registered nurses in the United States of America (U.S.) alone, comprising about 13% of the fifteen million workers in the health care and social assistance category tracked by the U.S. Department of Labor.
Nursing is one of the most female-dominated occupations but the number of males entering the profession is increasing. For example, in the U.S., only 5.4% of the registered nurse population was male in 2000, but that percent represented a 226% increase in two decades..
Governments regulate the profession of nursing to protect the public.
## Other healthcare workers
Health care settings generally involve a wide range of health care workers, who work in collaboration with nurses.
Examples include:
- Nursing assistants, orderlies, auxiliary nurses, healthcare assistants. These types of healthcare workers work both in acute and primary settings, under the supervision of registered nurses or licensed practical nurses (in the US). They assist nurses by giving basic care, taking vital signs, administering hygienic care, assisting with feeding, giving basic psychosocial care, housekeeping, and similar duties. See also hospital volunteers.
- Technicians: for example, certified medication aides in the US, are trained to administer medications in a long-term care setting. There are also phlebotomy technicians, who perform venipuncture; surgical technologists (US) and operating department practitioners (UK), who are more or less equivalent to a registered nurse in theatres; and technicians trained to operate most kinds of diagnostic and laboratory equipment, such as X-ray machines, electrocardiographs, and so forth.
- Physicians historically operated without nursing advice, but nowadays rely on nurses' skills, observations, and experience to ensure a continuity of patient care.
- Pharmacists are responsible for the safe dispensing of medicine and offering of expert advice on drug therapies.
- Allied health professionals such as respiratory therapists, medical technologists, speech therapists, occupational therapists and physical therapists work closely with nursing staff and work collaboratively in multi-disciplinary teams.
# Australia
## Education
Registration as a registered nurse now requires an associate degree at least, considered the foundation for any future specialization within nursing any other type of medical ways. Postgraduate diplomas provide further vocational training for specialist areas. Masters level courses are available in both research and course work streams; a specialist course has been developed to provide preparation for registration as a nurse practitioner. Professional doctorates are also available.
Australia has a long tradition of post-basic courses, usually of a six month (minor) or twelve month (major) duration, which included midwifery, maternal and child welfare, psychiatric, peri-operative ("theatre nursing"), intensive care, and coronary care in later years, as well as a myriad of other courses. They are now provided by the university sector as postgraduate diplomas or post graduate certificates, depending on the length and complexity.
There are options available for hospital trained nurses to upgrade their qualifications to a Bachelor of Nursing (post registration). However, most opt instead to undertake specialist courses such as a postgraduate diploma or certification in the area of their clinical interest.
Enrolled nurses are trained in the "technical and further education" (TAFE) sector of approximately twelve months duration. In some states, this length has been increased to 18 months to include a module that permits enrolled nurses to dispense oral, topical, enteral medications, and intramuscular and subcutaenous injections. In some areas of Australia NSW in particular Enrolled nurses are also allowed to admiister intravenous medications via a peripheral cannula up to a schedule 4d.
## Legal regulation
The practice of nursing is governed by state and territorial nursing regulation authorities. The Australian Nursing and Midwifery Council (ANMC) was established in 1992 and works with these authorities to facilitate a national approach to nursing and midwifery regulation.
Types of nurses
In all states other than Victoria, nurses fall into the following major categories:
- Nurse practitioner (NP)
- Registered nurse (RN)
- Enrolled nurse (EN)
Professional titles
The professional courtesy title "sister" has fallen into disuse and disapproval, even though it was formerly used by both male and female registered general nurses. The title "nurse" was used when addressing enrolled nurses. The term "matron" is inadvisable.
In keeping with the relaxed attitude to formalities in Australia, most nurses are happy to be addressed by their first name and describe themselves either as "an RN" or "an EN". In Victoria, an enrolled nurse will commonly describe themselves as a "Div. 2".
## Nurse practitioners
Nurse practitioners are being introduced into the Australian healthcare community, with Victoria having had nurse practitioners since 2000.
In some instances, it could be argued that this is as a natural professional evolution and recognition of the outstanding clinical expertise some nurses have attained over the course of their careers in areas such as wound management.
# Canada
## Education
Most provinces in Canada prefer any registered nurse to have at least a bachelor's degree (preferably a Bachelor of Science in Nursing (BScN)), although Quebec grants RN status to graduates from CEGEP. Many practicing nurses are still college graduates, but those entering nursing now are required or encouraged to enter at the university level.
## Types of nurses
- Registered nurse (RN).
- Licensed practical nurse (LPN) or licensed vocational nurse (LVN), known as registered practical nurse (RPN) in Ontario.
- Registered psychiatric nurse (RPN) - are licensed to practice only in British Columbia, Alberta, Saskatchewan, Manitoba, and the territories.
## Legal regulation
The profession of nursing is regulated at the provincial and territorial level in keeping with the principles of professional regulation endorsed by the International Council of Nurses. The College of Nurses of Ontario regulates both RNs and RPNs in contrast to the other provinces and territories where RNs and LPNs are regulated by separate bodies. In the western provinces, psychiatric nurses are governed by distinct legislation.
All registered nurses and nurse practitioners in the province of Alberta are expected to maintain their clinical competence in order receive an annual practice permit from the College and Association of Registered Nurses of Albertawhich also sets standards for scope of practice and provides practice support. | Nurse
# Overview
Nurses are responsible—along with other health care professionals—for the treatment, safety, and recovery of acutely or chronically ill or injured people, health maintenance of the healthy, and treatment of life-threatening emergencies in a wide range of health care settings. Nurses may also be involved in medical and nursing research and perform a wide range of non-clinical functions necessary to the delivery of health care.
# Education & regulation
Nursing education, regulation, roles, and titles vary in different countries, but in general reflect an increasing level of responsibility and status.
Nurses develop and implement a plan of care and work collaboratively with the patient, the patient's family, and other health care professionals and para-professionals. Nurses help coordinate the patient care performed by other members of a health care team such as physical therapists, medical practitioners, social workers, and dietitians. Nurses frequently act as patient advocates.
The nursing career structure varies considerably throughout the world. Typically there are several distinct levels of nursing practitioner distinguished by increasing education, responsibility, and skills. The major distinction is between task-based nursing and professional nursing. Nurses throughout the world are increasingly employed as advanced practice nurses, such as clinical nurse specialists and nurse practitioners, who diagnose health problems and prescribe medications and other therapies. At the top of the educational ladder is the doctoral-prepared nurse. Nurses may gain a PhD or another doctoral degree, specializing in research, clinical nursing, and so forth. These nurses practice nursing, teach nursing, and carry out nursing research. As the science and art of nursing has advanced, so has the demand for doctoral-prepared nurses.
In various parts of the world, the educational background for nurses varies widely. In some parts of eastern Europe, nurses are high school graduates with twelve to eighteen months of training. In contrast, Chile requires any registered nurse to have at least a bachelor's degree.
Nurses are the largest group of providers in the health care system--there are over two million registered nurses in the United States of America (U.S.) alone, comprising about 13% of the fifteen million workers in the health care and social assistance category tracked by the U.S. Department of Labor.[1]
Nursing is one of the most female-dominated occupations but the number of males entering the profession is increasing. For example, in the U.S., only 5.4% of the registered nurse population was male in 2000, but that percent represented a 226% increase in two decades.[2].
Governments regulate the profession of nursing to protect the public.
## Other healthcare workers
Health care settings generally involve a wide range of health care workers, who work in collaboration with nurses.
Examples include:
- Nursing assistants, orderlies, auxiliary nurses, healthcare assistants. These types of healthcare workers work both in acute and primary settings, under the supervision of registered nurses or licensed practical nurses (in the US). They assist nurses by giving basic care, taking vital signs, administering hygienic care, assisting with feeding, giving basic psychosocial care, housekeeping, and similar duties. See also hospital volunteers.
- Technicians: for example, certified medication aides in the US, are trained to administer medications in a long-term care setting. There are also phlebotomy technicians, who perform venipuncture; surgical technologists (US) and operating department practitioners (UK), who are more or less equivalent to a registered nurse in theatres; and technicians trained to operate most kinds of diagnostic and laboratory equipment, such as X-ray machines, electrocardiographs, and so forth.
- Physicians historically operated without nursing advice, but nowadays rely on nurses' skills, observations, and experience to ensure a continuity of patient care.
- Pharmacists are responsible for the safe dispensing of medicine and offering of expert advice on drug therapies.
- Allied health professionals such as respiratory therapists, medical technologists, speech therapists, occupational therapists and physical therapists work closely with nursing staff and work collaboratively in multi-disciplinary teams.
# Australia
## Education
Registration as a registered nurse now requires an associate degree at least, considered the foundation for any future specialization within nursing any other type of medical ways. Postgraduate diplomas provide further vocational training for specialist areas. Masters level courses are available in both research and course work streams; a specialist course has been developed to provide preparation for registration as a nurse practitioner. Professional doctorates are also available.
Australia has a long tradition of post-basic courses, usually of a six month (minor) or twelve month (major) duration, which included midwifery, maternal and child welfare, psychiatric, peri-operative ("theatre nursing"), intensive care, and coronary care in later years, as well as a myriad of other courses. They are now provided by the university sector as postgraduate diplomas or post graduate certificates, depending on the length and complexity.
There are options available for hospital trained nurses to upgrade their qualifications to a Bachelor of Nursing (post registration). However, most opt instead to undertake specialist courses such as a postgraduate diploma or certification in the area of their clinical interest.
Enrolled nurses are trained in the "technical and further education" (TAFE) sector of approximately twelve months duration. In some states, this length has been increased to 18 months to include a module that permits enrolled nurses to dispense oral, topical, enteral medications, and intramuscular and subcutaenous injections. In some areas of Australia NSW in particular Enrolled nurses are also allowed to admiister intravenous medications via a peripheral cannula up to a schedule 4d.
## Legal regulation
The practice of nursing is governed by state and territorial nursing regulation authorities. The Australian Nursing and Midwifery Council (ANMC) was established in 1992 and works with these authorities to facilitate a national approach to nursing and midwifery regulation.
Types of nurses
In all states other than Victoria, nurses fall into the following major categories:
- Nurse practitioner (NP)
- Registered nurse (RN)
- Enrolled nurse (EN)
Professional titles
The professional courtesy title "sister" has fallen into disuse and disapproval, even though it was formerly used by both male and female registered general nurses. The title "nurse" was used when addressing enrolled nurses. The term "matron" is inadvisable.
In keeping with the relaxed attitude to formalities in Australia, most nurses are happy to be addressed by their first name and describe themselves either as "an RN" or "an EN". In Victoria, an enrolled nurse will commonly describe themselves as a "Div. 2".
## Nurse practitioners
Nurse practitioners are being introduced into the Australian healthcare community, with Victoria having had nurse practitioners since 2000.
In some instances, it could be argued that this is as a natural professional evolution and recognition of the outstanding clinical expertise some nurses have attained over the course of their careers in areas such as wound management.
# Canada
## Education
Most provinces in Canada prefer any registered nurse to have at least a bachelor's degree (preferably a Bachelor of Science in Nursing (BScN)), although Quebec grants RN status to graduates from CEGEP. Many practicing nurses are still college graduates, but those entering nursing now are required or encouraged to enter at the university level.
## Types of nurses
- Registered nurse (RN).
- Licensed practical nurse (LPN) or licensed vocational nurse (LVN), known as registered practical nurse (RPN) in Ontario.
- Registered psychiatric nurse (RPN) - are licensed to practice only in British Columbia, Alberta, Saskatchewan, Manitoba, and the territories.
## Legal regulation
The profession of nursing is regulated at the provincial and territorial level in keeping with the principles of professional regulation endorsed by the International Council of Nurses. The College of Nurses of Ontario regulates both RNs and RPNs in contrast to the other provinces and territories where RNs and LPNs are regulated by separate bodies. In the western provinces, psychiatric nurses are governed by distinct legislation.
All registered nurses and nurse practitioners in the province of Alberta are expected to maintain their clinical competence in order receive an annual practice permit from the College and Association of Registered Nurses of Albertawhich also sets standards for scope of practice and provides practice support.
## External links
- CIHI Regulated Nursing Professions Database - provides supply and distribution statistics for the three nursing professions in Canada.
- Canadian Nurses Association
# India
The Indian Nursing Council is the regulatory body for profession of nursing. A person practising nursing must be registered with the nursing council. For a person to be registered, he or she has to undergo and pass the prescribed course stipulated by the council. In India, diplomas, bachelor degrees (BSc Nursing) postgraduate degrees (MSc Nursing) and Doctorates (PhD) are offered.
## External links
- Indian Nursing Council
# Ireland
Nursing in self regulated in Ireland. The regulatory body is An Bord Altranais (The Nursing Board). The board was established under the 1950 Nurses Act and currently operates under the 1985 Nurses Act. a There are currently over 82,000 nurses registered by An Bord Altranais of which over 65,000 are on the active register ABA Statistics 2006.
There are seven divisions of the register; general, psychiatric, children's, intellectual diability, midwifery, public health and tutor.
## Developments
Significant changes have occurred in Irish nursing since the publication of Report of The Commission on Nursing, A blueprint for the future.
## Nurse education
Pre-registration nurse education in university and college based. All pre-registration programmes are at degree level (NQAI level 8). Nurse registration education programmes are governed An Bord Altranais Requirements & Standards.
Significant developments have occued in post registration nurse education with a variety of programmes available to nurses to support their practice and develop their career.
## External links
- An Bord Altranais
- National Council for the Professional Development of Nursing & Midwifery
- Irish Nurses Organisation
- Department of Health & Children
- Health Service Executive
- Health Service Executive Employers Agency
# New Zealand
## History
New Zealand originally had nurse education as a part of the hospital system, but, as early as the 1900s, post registration and post graduate programs of study for nurses were in existence. Reforms in the 1970s disestablished the original hospital-based schools and moved these into the tertiary education sector, namely polytechnics and universities. Within the hospital system were an array of titles and levels, which often focused upon clinical specialty rather than generic nursing knowledge.
## Education
Today all nurses in New Zealand are educated to degree level via a three year, two semesters per annum, program, with an approximate 50/50 mix of theory to practice. All current students graduate as a registered comprehensive nurse. Legislation exists keeping the number of schools to no more than 21, although some schools run courses in more than one geographical location. Recently, attempts were made to reintroduce the title enrolled nurse with this causing some disagreement between trade unions, the registering body, and health providers.[3]
## Legal regulation
All nurses in New Zealand are expected to maintain both professional knowledge and clinical competence in order to receive an annual practicing certificate from the Nursing Council of New Zealand (NCNZ). Recent legislation (the 2004 Health Practitioners Competency Assurance Act) sets standards for both scope of practice and requirements in terms of ongoing development..[4]
Similarly the NCNZ caused minor controversy when they gave the title nurse practitioner trade mark status, thus preventing those with the title from using it. In order to become a nurse practitioner, the nurse must undertake an approved course of study and present a portfolio of evidence to NCNZ for approval. There are now approximately 20 NP's in New Zealand with a smaller number granted prescribing rights.
## Ongoing issues
New Zealand has historically provided many nurses for the global market place; the salaries in overseas countries (notably Australia, USA, United Kingdom and the Middle East) have proved attractive to NZ nurses. This has resulted in a drop in the number of NZ-educated nurses practicing within New Zealand; recently the flow has been decreased by a substantial pay award for hospital based nurses. This pay award was given to those employed within district health boards but not other public sector providers which caused a degree of conflict within the profession and a return to hospital practice for many in the primary healthcare sector. There has also been an increase in nurses from the United Kingdom, India, South Africa and Philippines migrating to New Zealand.
## External links
- Nursing Council of New Zealand
- New Zealand Nurses Organisation - trade union
# Philippines
## Education
All registered nurses in the Philippines are required to have a Bachelor's Degree in Nursing.[5]
## Legal regulation
The Professional Regulation Commission oversees the licensing of registered nurses as authorized by the Philippine Nursing Act of 2002.
A Professional Regulatory Nursing Board implements and enforces the Nursing Act. The board is composed of a chairperson and six additional members, all of whom are nurses with at least a master's degree and ten years of nursing experience. The board inspects nursing schools, conducts licensure examinations, issues and monitors certificates of licensure, promulgates a code of ethics, participates in recognizing nursing specialty organizations, and prescribes guidelines and regulations governing the profession under the Nursing Act.
## External links
- Professional Regulation Commission Nursing Portal
# South Africa
## Education
In order to be examined to practice as an enrolled nurse, students must complete a two-year academic course which includes 2,000 hours of clinical practice.
Subjects studied in the first year include:
- Nursing history and ethics.
- Basic nursing care.
- Elementary nutrition.
- First aid.
- Elementary anatomy and physiology.
- Introduction to comprehensive health care.
The second year includes study of sciences fundamental to basic nursing and, depending upon the area for which the nursing school has been approved, one of the following subjects:
- General nursing care.
- Nursing care of the aged.
- Nursing care of mentally retarded persons.
- Community nursing care.
- Psychiatric nursing care.
## Legal regulation
The South African Nursing Council (SANC) was created by the Nursing Act of 1957. Currently, it functions under the authority of the Nursing Act of 1978 and subsequent amendments. SANC inspects and approves nursing schools and education programs; examines, registers, and enrolls nurses, midwives, and nursing auxiliaries; licenses nursing agencies; and monitors nursing employers. Nurses and nursing auxiliaries are required to wear "distinguishing devices" consisting of pins and colored epaulettes to identify them as licensed professionals.
## External links
- The South African Nursing Council
# United Kingdom
## Education
Since the 1990s, UK nurses are educated to diploma, bachelor's and even undergraduate master's degree levels. There are also post-graduate courses for graduates with a degree in a health related subject.[6] [7] They undertake their training at universities and in placements in healthcare services. The student will train in adult, child, mental health, or learning disabilities branch.
## Registered nurses
To become a nurse within the United Kingdom, one must at the very minimum hold a Diploma in Nursing and have trained for three years, or two years on an 'accelerated' course, (or equivalent if from overseas). After training, the opportunities are vast, with many different areas of nursing, from general ward to teaching or management. Also the practise areas can be in hospital, or in the community or both.
The Nursing and Midwifery Council in the UK is the regulatory body for nurses, midwives, and specialist practitioners. It maintains a register that is split into three parts:
- Nursing
- Midwifery
- Specialist Community Public Health Nurses (which includes Health Visitors)
In addition to this, there are two levels of nurse: first-level nurses trained for three or four years (RGN, RMN, RSCN, RNMH, RNchild, RNadult, RNmental health, RN Learning Disability) whereas second-level nurses are the state enrolled nurses (SENs) who trained for two years. The SEN training has been phased out, with many SENs retiring or converting to level one through further study, although technically loopholes exist to allow failed RN candidates to gain EN qualification.[8]
Registered Nurses are able to undertake advanced practice training, commonly at advanced degree level to become specialist nurses in various fields, such as Emergency Nurse Practitioner. These nurses will have obtained, in addition to the basic registration with the NMC, an advanced recordable qualification. Nurses in the United Kingdom can also complete an Independent Prescriber course (of which there are various types at present) which legally permits them to prescribe drugs independently of a doctor.
Many nurses are members of trade unions, which represent them both individually and as a profession. The two main unions are UNISON and the Royal College of Nursing.
## NMC register
All UK nurses are listed on a register and are regulated by the Nursing & Midwifery Council (NMC). Nurses need to register every three years, although from 1st January 2006 payment for registration is made annually. They are required to have demonstrated that they have kept up-to-date by undertaking at least 35 hours of professional development and 450 hours of nursing practice within the last three years. [9].
Prior to the creation of the new three-part register on August 1, 2004, nurses and midwives were divided into a part of the register they held a qualification in. This may be now described as a 'sub-part' of the nursing register. All newly qualified nurses register in 'sub-part' 12, 13, 14 or 15, showing their branch qualification. However, nurses still practising and holding qualifications in 'sub-parts' 1-9 are registered as such.
There are approximately 689,000 nurses and midwives on the NMC's register, including those not practising within the UK who have maintained their registration. Approximately 12% of registrants are male, and this is increasing. As of August 2005, the NMC register split into three parts: nurses, midwives, and specialist community public health nurses. There are 'sub-parts' that the nurse or midwife is registered to practice in.
## Nursing titles
- State enrolled nurse (SEN) These nurses are expected to perform to a lower level scope of practice, although in reality enrolled nurses often perform to a similar or higher level as staff nurses. Some areas specifically exclude aspects of practice such as the administration of medications. As such enrolled nurses are technically supposed to work under the supervision of an RN.
- Staff nurse/senior staff nurse: All newly qualified nurses begin at this level and make up the majority of the registered nursing staff. Senior staff nurses are more experienced and usually take "charge" in the absence of senior staff.
- Junior sister/junior charge nurse/deputy ward manager: These nurses are deputy to the ward manager/charge nurse and as such have more of a managerial role.
- Sister/charge nurse/ward manager: Responsible for the management of their ward/clinic/unit usually with budgetary control.
- Clinical nurse manager: Usually manages an area, for example, accident and emergency.
- Matron: Usually manages a directorate, such as medical or surgical. Historically managed the hospital, although this role is obsolete.
There are various other higher managerial and specialist nurse roles; however these are less well defined on a national scale. Note that charge nurse is used when the "sister" is a male.
## External links
- Nursing Times
- The Nursing and Midwifery Council
- NHSCareers website
- The Royal College of Nursing
- Intute: Nursing, Midwifery and Allied Health
# United States
## Education
Registered nurses (RN) in the U.S. generally receive their basic preparation through one of four avenues:
- Diploma in Nursing
- Associate of Science in Nursing
- Bachelor of Science in Nursing
- Master of Science in Nursing
An academic course of study at any level typically includes such topics as anatomy and physiology, pharmacology and medication administration, psychology, ethics, nursing theory and legal issues. Additionally, extensive clinical training in nursing practice is required.
All U.S. states and territories require graduation from an accredited nursing program and successful completion of the NCLEX-RN to obtain state licensure as an RN.
## Legal regulation
In the U.S., the individual states have authority over nursing practice and its scope. Nurses may be licensed in more than one state, either by examination or endorsement of a license issued by another state. Licenses must be periodically renewed. Some states require continuing education in order to renew licenses.
Types of nurses
- Licensed practical nurses (LPNs) usually have eighteen months to two years of training in anatomy and physiology, medications, and practical patient care.
- Licensed vocational nurses (LVNs) is a title used in some states which is roughly equivalent to Licensed practical nurse.
- Registered nurses (RNs) are professional nurses who often supervise the tasks performed by LPNs, orderlies, and nursing assistants. They provide direct care and make decisions regarding plans of care for individuals and groups of healthy, ill, and injured people. RNs are the largest healthcare occupation in the U.S.
- Advanced practice nurses (APNs) are registered nurses with advanced education, knowledge, skills, and scope of practice. They perform primary health care, provide mental health services, diagnose and prescribe, carry out research, and educate the public and other professionals.
## External links
- American Nurses' Association
- National Council of State Boards of Nursing (USA) | https://www.wikidoc.org/index.php/Nurse | |
2959de88bcf930e1c87ecb6e8b1664048077dc6a | wikidoc | Nylon | Nylon
Nylon is a generic designation for a family of synthetic polymers first produced on February 28, 1935 by Wallace Carothers at DuPont.Nylon is one one of the most common polymers used as a fiber.
# Overview
Nylon is a thermoplastic silky material, first used commercially in a nylon-bristled toothbrush (1938), followed more famously by women's “nylons” stockings (1940). It is made of repeating units linked by peptide bonds (another name for amide bonds) and is frequently referred to as polyamide (PA). Nylon was the first commercially successful polymer and the first synthetic fiber to be made entirely from coal, water and air. These are formed into monomers of intermediate molecular weight, which are then reacted to form long polymer chains. It was intended to be a synthetic replacement for silk and substituted for it in parachutes and also making things like ropes, flak vests, vehicle tires, combat uniforms and many other military uses after the United States entered World War II in 1941, making stockings hard to find until the war's end. Nylon fibers are now used in fabrics, bridal veils, carpets, guitar strings and ropes, and solid nylon is used for mechanical parts, drumstick tips and as an engineering material. Engineering grade Nylon is processed by extrusion, casting & injection molding. Type 6/6 Nylon 101 is the most common commercial grade of Nylon, and Nylon 6 is the most common commercial grade of cast Nylon.
# Chemistry
Nylons are condensation copolymers formed by reacting equal parts of a diamine and a dicarboxylic acid, so that peptide bonds form at both ends of each monomer in a process analogous to polypeptide biopolymers. The numerical suffix specifies the numbers of carbons donated by the monomers; the diamine first and the diacid second. The most common variant is nylon 6-6 which refers to the fact that the diamine (hexamethylene diamine) and the diacid (adipic acid) each donate 6 carbons to the polymer chain. As with other regular copolymers like polyesters and polyurethanes, the "repeating unit" consists of one of each monomer, so that they alternate in the chain. Since each monomer in this copolymer has the same reactive group on both ends, the direction of the amide bond reverses between each monomer, unlike natural polyamide proteins which have overall directionality: C terminal → N terminal. In the laboratory, nylon 6,6 can also be made using adipoyl chloride instead of adipic
It is difficult to get the proportions exactly correct, and deviations can lead to chain termination at molecular weights less than a desirable 10,000 daltons (u). To overcome this problem, a crystalline, solid "nylon salt" can be formed at room temperature, using an exact 1:1 ratio of the acid and the base to neutralize each other. Heated to 285 °C, the salt reacts to form nylon polymer. Above 20,000 daltons, it is impossible to spin the chains into yarn, so to combat this, some acetic acid is added to react with a free amine end group during polymer elongation to limit the molecular weight. In practice, and especially for 6,6, the monomers are often combined in a water solution. The water used to make the solution is evaporated under controlled conditions, and the increasing concentration of "salt" is polymerized to the final molecular weight.
DuPont patented nylon 6,6, so in order to compete, other companies (particularly the German BASF) developed the homopolymer nylon 6, or polycaprolactam — not a condensation polymer, but formed by a ring-opening polymerization (alternatively made by polymerizing aminocaproic acid). The peptide bond within the caprolactam is broken with the exposed active groups on each side being incorporated into two new bonds as the monomer becomes part of the polymer backbone. In this case, all amide bonds lie in the same direction, but the properties of nylon 6 are sometimes indistinguishable from those of nylon 6,6 — except for melt temperature (N6 is lower) and some fiber properties in products like carpets and textiles. There is also nylon 9.
Nylon 5,10, made from pentamethylene diamine and sebacic acid, was studied by Carothers even before nylon 6,6 and has superior properties, but is more expensive to make. In keeping with this naming convention, "nylon 6,12" (N-6,12) or "PA-6,12" is a copolymer of a 6C diamine and a 12C diacid. Similarly for N-5,10 N-6,11; N-10,12, etc. Other nylons include copolymerized dicarboxylic acid/diamine products that are not based upon the monomers listed above. For example, some aromatic nylons are polymerized with the addition of diacids like terephthalic acid (→ Kevlar) or isophthalic acid (→ Nomex), more commonly associated with polyesters. There are copolymers of N-6,6/N6; copolymers of N-6,6/N-6/N-12; and others. Because of the way polyamides are formed, nylon would seem to be limited to unbranched, straight chains. But "star" branched nylon can be produced by the condensation of dicarboxylic acids with polyamines having three or more amino groups.
The general reaction is:
A molecule of water is given off and the nylon is formed. Its properties are determined by the R and R' groups in the monomers. In nylon 6,6, R' = 6C and R = 4C alkanes, but one also has to include the two carboxyl carbons in the diacid to get the number it donates to the chain. In Kevlar, both R and R' are benzene
rings.
# Nylon Fiber
The Federal Trade Commissions' Definition for Nylon Fiber: A manufactured fiber in which the fiber forming substance is a long-chain synthetic polyamide in which less than 85% of the amide-linkages are attached directly (-CO-NH-) to two aliphatic groups.
- A synthetic thermoplastic fiber (Nylon melts/glazes easily at relatively low temperatures)
- Round, smooth, and shiny filament fibers
- cross sections can be either
trilobal to imitate silk
multilobal to increase staple like appearance and hand
- trilobal to imitate silk
- multilobal to increase staple like appearance and hand
- It's most widely used structures are multifilament, monofilament, staple or tow and is available as partially drawn or as finished filaments.
- Regular nylon has a round cross section and is perfectly uniform. The filaments are generally completely transparent unless they have been delustered or solution dyed. Thus, they are microscopically recognized as glass rods.
- Molecular chains of nylon are long and straight variations but have no side chains or linkages.
Cold drawing (step 18 on the model) can align the chains so they are oriented with the lengthwise direction and are highly crystalline.
- Cold drawing (step 18 on the model) can align the chains so they are oriented with the lengthwise direction and are highly crystalline.
- Nylon is related chemically to the protein fibers silk and wool.
They both have similar dye sites but nylon has many fewer dye sites than wool.
- They both have similar dye sites but nylon has many fewer dye sites than wool.
## Basic Concepts of Nylon Production
- The first approach: combining molecules with an acid (COOH) group on each end are reacted with two chemicals that contain amine(NH2)groups on each end.
This process creates nylon 6,6, made of hexamethylene diamine with six carbon atoms and acidipic acid, as well as six carbon atoms.
- The second approach: a compound has an acid at one end and an amine at the other and is polymerized to for a chain with repeating units of(-NH-n-CO-)x.
In other words, nylon 6 is made from a single six-carbon substance called caprolactam.
In this equation, if n=5, then nylon 6 is the assigned name. (may also be referred to as polymer)
- In other words, nylon 6 is made from a single six-carbon substance called caprolactam.
- In this equation, if n=5, then nylon 6 is the assigned name. (may also be referred to as polymer)
Nylon 6,6
- Pleats and creases can be heat-set at higher temperatures
- Difficult to dye
Nylon 6
- Better dye Affinity
- Softer Hand
- Greater elasticity and elastic recovery
- Better weathering properties; better sunlight resistance
Full Nylon Production Model
Producers
The producers of nylon include: Honeywell Nylon Inc., Invista, Wellman Inc. among many others. The Dupont Company, is the most famous pioneer of the nylon we know today. The companies above now produce the nylon used in our everyday lives.
## Characteristics
- Variation of luster: nylon has the ability to be very lusterous, semilusterous or dull.
- Durability: its high tenacity fibers are used for seatbelts, tire cords, ballistic cloth and other uses.
- High elongation
- Excellent abrasion resistance
- Highly resilient (nylon fabrics are heat-set)
- Paved the way for easy-care garments
- High resistance to:
insects and fungi
molds, mildew, rot
many chemicals
- insects and fungi
- molds, mildew, rot
- many chemicals
- Used in carpets and nylon stockings
- Melts instead of burns
- Used in many military applications
# Bulk properties
Above their melting temperatures, Tm, thermoplastics like nylon are amorphous solids or viscous fluids in which the chains approximate random coils. Below Tm, amorphous regions alternate with regions which are lamellar crystals. The amorphous regions contribute elasticity and the crystalline regions contribute strength and rigidity. The planar amide (-CO-NH-) groups are very polar, so nylon forms multiple hydrogen bonds among adjacent strands. Because the nylon backbone is so regular and symmetrical, especially if all the amide bonds are in the trans configuration, nylons often have high crystallinity and make excellent fibers. The amount of crystallinity depends on the details of formation, as well as on the kind of nylon. Apparently it can never be quenched from a melt as a completely amorphous solid.
Nylon 6,6 can have multiple parallel strands aligned with their neighboring peptide bonds at coordinated separations of exactly 6 and 4 carbons for considerable lengths, so the carbonyl oxygens and amide hydrogens can line up to form interchain hydrogen bonds repeatedly, without interruption. Nylon 5,10 can have coordinated runs of 5 and 8 carbons. Thus parallel (but not antiparallel) strands can participate in extended, unbroken, multi-chain β-pleated sheets, a strong and tough supermolecular structure similar to that found in natural silk fibroin and the β-keratins in feathers. (Proteins have only an amino acid α-carbon separating sequential -CO-NH- groups.) Nylon 6 will form uninterrupted H-bonded sheets with mixed directionalities, but the β-sheet wrinkling is somewhat different. The three-dimensional disposition of each alkane hydrocarbon chain depends on rotations about the 109.47° tetrahedral bonds of singly-bonded carbon atoms.
When extruded into fibers through pores in an industrial spinneret, the individual polymer chains tend to align because of viscous flow. If subjected to cold drawing afterwards, the fibers align further, increasing their crystallinity, and the material acquires additional tensile strength. In practice, nylon fibers are most often drawn using heated rolls at high speeds.
Block nylon tends to be less crystalline, except near the surfaces due to shearing stresses during formation. Nylon is clear and colorless, or milky, but is easily dyed. Multistranded nylon cord and rope is slippery and tends to unravel. The ends can be melted and fused with a heat source such as a flame or electrode to prevent this.
There are carbon fiber/nylon composities with higher density than pure nylon.
When dry, polyamide is a good electrical insulator. However, polyamide is hygroscopic. The absorption of water will change some of the material's properties such as its electrical resistance. Nylon is less absorbant than wool or cotton.
# Historical uses
Bill Pittendreigh, DuPont, and other individuals and corporations worked diligently during the first few months of World War II to find a way to replace Asian silk with nylon in parachutes. It was also used to make tires, tents, ropes, ponchos, and other military supplies. It was even used in the production of a high-grade paper for U.S. currency. At the outset of the war, cotton accounted for more than 80% of all fibers used and manufactured, and wool fibers accounted for the remaining 20%. By August 1945, manufactured fibers had taken a market share of 25% and cotton had dropped.
Some of the terpolymers based upon nylon are used every day in packaging. Nylon has been used for meat wrappings and sausage sheaths.
# Etymology
In 1940 John W. Eckelberry of DuPont stated that the letters "nyl" were arbitrary and the "on" was copied from the suffixes of other fibers such as cotton and rayon. A later publication by DuPont (Context, vol. 7, no. 2, 1978) explained that the name was originally intended to be "No-Run" ("run" meaning "unravel"), but was modified to avoid making such an unjustified claim and to make the word sound better. The story goes that Carothers changed one letter at a time until DuPont's management was satisfied. But he was not involved in the nylon project during the last year of his life, and committed suicide before the name was coined.
Two theories about the origin of the name claim that it is an acronym of "Now you've lost, Old Nippon" (N.Y.L.O.N.), or that it stands for "New York-London". In the latter case, it is claimed that these were the two cities where the product was researched and developed, or that the inspiration came from a New York to London airplane ticket. There is no evidence for the 'airline ticket' theory, though some compelling evidence of the latter from contemporary researchers at Oxford University who assisted in development...Oxford can be viewed as London from New York, but Nylox would have been more accurate.
# Uses
- carpet fiber
- clothing
- fishing lines
- footwear
- nylon fiber
- pantyhose
- toothbrush bristles
- velcro
- airbag fiber
- auto parts: intake manifolds, gas (petrol) tanks
- slings and rope used in climbing gear
- machine parts, such as gears and bearings
- parachutes
- metallized nylon balloons
- classical and flamenco guitar strings
- paintball marker bolts
- racquetball, squash, and tennis racquet strings
- Strings for String instruments
- Drumstick heads
- As filter media in sterlizing grade filters
- Flexible tubing
- Basketball netting | Nylon
Nylon is a generic designation for a family of synthetic polymers first produced on February 28, 1935 by Wallace Carothers at DuPont.Nylon is one one of the most common polymers used as a fiber.
# Overview
Nylon is a thermoplastic silky material, first used commercially in a nylon-bristled toothbrush (1938), followed more famously by women's “nylons” stockings (1940). It is made of repeating units linked by peptide bonds (another name for amide bonds) and is frequently referred to as polyamide (PA). Nylon was the first commercially successful polymer and the first synthetic fiber to be made entirely from coal, water and air. These are formed into monomers of intermediate molecular weight, which are then reacted to form long polymer chains. It was intended to be a synthetic replacement for silk and substituted for it in parachutes and also making things like ropes, flak vests, vehicle tires, combat uniforms and many other military uses after the United States entered World War II in 1941, making stockings hard to find until the war's end. Nylon fibers are now used in fabrics, bridal veils, carpets, guitar strings and ropes, and solid nylon is used for mechanical parts, drumstick tips and as an engineering material. Engineering grade Nylon is processed by extrusion, casting & injection molding. Type 6/6 Nylon 101 is the most common commercial grade of Nylon, and Nylon 6 is the most common commercial grade of cast Nylon.
# Chemistry
Nylons are condensation copolymers formed by reacting equal parts of a diamine and a dicarboxylic acid, so that peptide bonds form at both ends of each monomer in a process analogous to polypeptide biopolymers. The numerical suffix specifies the numbers of carbons donated by the monomers; the diamine first and the diacid second. The most common variant is nylon 6-6 which refers to the fact that the diamine (hexamethylene diamine) and the diacid (adipic acid) each donate 6 carbons to the polymer chain. As with other regular copolymers like polyesters and polyurethanes, the "repeating unit" consists of one of each monomer, so that they alternate in the chain. Since each monomer in this copolymer has the same reactive group on both ends, the direction of the amide bond reverses between each monomer, unlike natural polyamide proteins which have overall directionality: C terminal → N terminal. In the laboratory, nylon 6,6 can also be made using adipoyl chloride instead of adipic
It is difficult to get the proportions exactly correct, and deviations can lead to chain termination at molecular weights less than a desirable 10,000 daltons (u). To overcome this problem, a crystalline, solid "nylon salt" can be formed at room temperature, using an exact 1:1 ratio of the acid and the base to neutralize each other. Heated to 285 °C, the salt reacts to form nylon polymer. Above 20,000 daltons, it is impossible to spin the chains into yarn, so to combat this, some acetic acid is added to react with a free amine end group during polymer elongation to limit the molecular weight. In practice, and especially for 6,6, the monomers are often combined in a water solution. The water used to make the solution is evaporated under controlled conditions, and the increasing concentration of "salt" is polymerized to the final molecular weight.
DuPont patented[1] nylon 6,6, so in order to compete, other companies (particularly the German BASF) developed the homopolymer nylon 6, or polycaprolactam — not a condensation polymer, but formed by a ring-opening polymerization (alternatively made by polymerizing aminocaproic acid). The peptide bond within the caprolactam is broken with the exposed active groups on each side being incorporated into two new bonds as the monomer becomes part of the polymer backbone. In this case, all amide bonds lie in the same direction, but the properties of nylon 6 are sometimes indistinguishable from those of nylon 6,6 — except for melt temperature (N6 is lower) and some fiber properties in products like carpets and textiles. There is also nylon 9.
Nylon 5,10, made from pentamethylene diamine and sebacic acid, was studied by Carothers even before nylon 6,6 and has superior properties, but is more expensive to make. In keeping with this naming convention, "nylon 6,12" (N-6,12) or "PA-6,12" is a copolymer of a 6C diamine and a 12C diacid. Similarly for N-5,10 N-6,11; N-10,12, etc. Other nylons include copolymerized dicarboxylic acid/diamine products that are not based upon the monomers listed above. For example, some aromatic nylons are polymerized with the addition of diacids like terephthalic acid (→ Kevlar) or isophthalic acid (→ Nomex), more commonly associated with polyesters. There are copolymers of N-6,6/N6; copolymers of N-6,6/N-6/N-12; and others. Because of the way polyamides are formed, nylon would seem to be limited to unbranched, straight chains. But "star" branched nylon can be produced by the condensation of dicarboxylic acids with polyamines having three or more amino groups.
The general reaction is:
A molecule of water is given off and the nylon is formed. Its properties are determined by the R and R' groups in the monomers. In nylon 6,6, R' = 6C and R = 4C alkanes, but one also has to include the two carboxyl carbons in the diacid to get the number it donates to the chain. In Kevlar, both R and R' are benzene
rings.
# Nylon Fiber
The Federal Trade Commissions' Definition for Nylon Fiber: A manufactured fiber in which the fiber forming substance is a long-chain synthetic polyamide in which less than 85% of the amide-linkages are attached directly (-CO-NH-) to two aliphatic groups.
- A synthetic thermoplastic fiber (Nylon melts/glazes easily at relatively low temperatures)
- Round, smooth, and shiny filament fibers
- cross sections can be either
trilobal to imitate silk
multilobal to increase staple like appearance and hand
- trilobal to imitate silk
- multilobal to increase staple like appearance and hand
- It's most widely used structures are multifilament, monofilament, staple or tow and is available as partially drawn or as finished filaments.
- Regular nylon has a round cross section and is perfectly uniform. The filaments are generally completely transparent unless they have been delustered or solution dyed. Thus, they are microscopically recognized as glass rods.
- Molecular chains of nylon are long and straight variations but have no side chains or linkages.
Cold drawing (step 18 on the model) can align the chains so they are oriented with the lengthwise direction and are highly crystalline.
- Cold drawing (step 18 on the model) can align the chains so they are oriented with the lengthwise direction and are highly crystalline.
- Nylon is related chemically to the protein fibers silk and wool.
They both have similar dye sites but nylon has many fewer dye sites than wool.
- They both have similar dye sites but nylon has many fewer dye sites than wool.
## Basic Concepts of Nylon Production
- The first approach: combining molecules with an acid (COOH) group on each end are reacted with two chemicals that contain amine(NH2)groups on each end.
This process creates nylon 6,6, made of hexamethylene diamine with six carbon atoms and acidipic acid, as well as six carbon atoms.
- The second approach: a compound has an acid at one end and an amine at the other and is polymerized to for a chain with repeating units of(-NH-[CH2]n-CO-)x.
In other words, nylon 6 is made from a single six-carbon substance called caprolactam.
In this equation, if n=5, then nylon 6 is the assigned name. (may also be referred to as polymer)
- In other words, nylon 6 is made from a single six-carbon substance called caprolactam.
- In this equation, if n=5, then nylon 6 is the assigned name. (may also be referred to as polymer)
Nylon 6,6
- Pleats and creases can be heat-set at higher temperatures
- Difficult to dye
Nylon 6
- Better dye Affinity
- Softer Hand
- Greater elasticity and elastic recovery
- Better weathering properties; better sunlight resistance
Full Nylon Production Model
Producers
The producers of nylon include: Honeywell Nylon Inc., Invista, Wellman Inc. among many others. The Dupont Company, is the most famous pioneer of the nylon we know today. The companies above now produce the nylon used in our everyday lives.
## Characteristics
- Variation of luster: nylon has the ability to be very lusterous, semilusterous or dull.
- Durability: its high tenacity fibers are used for seatbelts, tire cords, ballistic cloth and other uses.
- High elongation
- Excellent abrasion resistance
- Highly resilient (nylon fabrics are heat-set)
- Paved the way for easy-care garments
- High resistance to:
insects and fungi
molds, mildew, rot
many chemicals
- insects and fungi
- molds, mildew, rot
- many chemicals
- Used in carpets and nylon stockings
- Melts instead of burns
- Used in many military applications
# Bulk properties
Above their melting temperatures, Tm, thermoplastics like nylon are amorphous solids or viscous fluids in which the chains approximate random coils. Below Tm, amorphous regions alternate with regions which are lamellar crystals.[1] The amorphous regions contribute elasticity and the crystalline regions contribute strength and rigidity. The planar amide (-CO-NH-) groups are very polar, so nylon forms multiple hydrogen bonds among adjacent strands. Because the nylon backbone is so regular and symmetrical, especially if all the amide bonds are in the trans configuration, nylons often have high crystallinity and make excellent fibers. The amount of crystallinity depends on the details of formation, as well as on the kind of nylon. Apparently it can never be quenched from a melt as a completely amorphous solid.
Nylon 6,6 can have multiple parallel strands aligned with their neighboring peptide bonds at coordinated separations of exactly 6 and 4 carbons for considerable lengths, so the carbonyl oxygens and amide hydrogens can line up to form interchain hydrogen bonds repeatedly, without interruption. Nylon 5,10 can have coordinated runs of 5 and 8 carbons. Thus parallel (but not antiparallel) strands can participate in extended, unbroken, multi-chain β-pleated sheets, a strong and tough supermolecular structure similar to that found in natural silk fibroin and the β-keratins in feathers. (Proteins have only an amino acid α-carbon separating sequential -CO-NH- groups.) Nylon 6 will form uninterrupted H-bonded sheets with mixed directionalities, but the β-sheet wrinkling is somewhat different. The three-dimensional disposition of each alkane hydrocarbon chain depends on rotations about the 109.47° tetrahedral bonds of singly-bonded carbon atoms.
When extruded into fibers through pores in an industrial spinneret, the individual polymer chains tend to align because of viscous flow. If subjected to cold drawing afterwards, the fibers align further, increasing their crystallinity, and the material acquires additional tensile strength.[2] In practice, nylon fibers are most often drawn using heated rolls at high speeds.
Block nylon tends to be less crystalline, except near the surfaces due to shearing stresses during formation. Nylon is clear and colorless, or milky, but is easily dyed. Multistranded nylon cord and rope is slippery and tends to unravel. The ends can be melted and fused with a heat source such as a flame or electrode to prevent this.
There are carbon fiber/nylon composities with higher density than pure nylon.
When dry, polyamide is a good electrical insulator. However, polyamide is hygroscopic. The absorption of water will change some of the material's properties such as its electrical resistance. Nylon is less absorbant than wool or cotton.
# Historical uses
Bill Pittendreigh, DuPont, and other individuals and corporations worked diligently during the first few months of World War II to find a way to replace Asian silk with nylon in parachutes. It was also used to make tires, tents, ropes, ponchos, and other military supplies. It was even used in the production of a high-grade paper for U.S. currency. At the outset of the war, cotton accounted for more than 80% of all fibers used and manufactured, and wool fibers accounted for the remaining 20%. By August 1945, manufactured fibers had taken a market share of 25% and cotton had dropped.
Some of the terpolymers based upon nylon are used every day in packaging. Nylon has been used for meat wrappings and sausage sheaths.
# Etymology
In 1940 John W. Eckelberry of DuPont stated that the letters "nyl" were arbitrary and the "on" was copied from the suffixes of other fibers such as cotton and rayon. A later publication by DuPont (Context, vol. 7, no. 2, 1978) explained that the name was originally intended to be "No-Run" ("run" meaning "unravel"), but was modified to avoid making such an unjustified claim and to make the word sound better. The story goes that Carothers changed one letter at a time until DuPont's management was satisfied. But he was not involved in the nylon project during the last year of his life, and committed suicide before the name was coined.
Two theories about the origin of the name claim that it is an acronym of "Now you've lost, Old Nippon" (N.Y.L.O.N.), or that it stands for "New York-London". In the latter case, it is claimed that these were the two cities where the product was researched and developed, or that the inspiration came from a New York to London airplane ticket. There is no evidence for the 'airline ticket' theory, though some compelling evidence of the latter from contemporary researchers at Oxford University who assisted in development...Oxford can be viewed as London from New York, but Nylox would have been more accurate.
# Uses
- carpet fiber
- clothing
- fishing lines
- footwear
- nylon fiber
- pantyhose
- toothbrush bristles
- velcro
- airbag fiber
- auto parts: intake manifolds, gas (petrol) tanks
- slings and rope used in climbing gear
- machine parts, such as gears and bearings
- parachutes
- metallized nylon balloons
- classical and flamenco guitar strings
- paintball marker bolts
- racquetball, squash, and tennis racquet strings
- Strings for String instruments
- Drumstick heads
- As filter media in sterlizing grade filters
- Flexible tubing
- Basketball netting | https://www.wikidoc.org/index.php/Nylon | |
e8dda6b9865fe7e54ec1124decba2ed77e17bcf6 | wikidoc | Oct-4 | Oct-4
Lua error in Module:Redirect at line 65: could not parse redirect on page "Oct-3".
Oct-4 (octamer-binding transcription factor 4), also known as POU5F1 (POU domain, class 5, transcription factor 1), is a protein that in humans is encoded by the POU5F1 gene. Oct-4 is a homeodomain transcription factor of the POU family. It is critically involved in the self-renewal of undifferentiated embryonic stem cells. As such, it is frequently used as a marker for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells.
Oct-4 is a member of the octamer transcription factor family, so named because they bind the octameric (8-unit) DNA nucleotide sequence "ATTTGCAT".
# Expression and function
Oct-4 transcription factor is initially active as a maternal factor in the oocyte and remains active in embryos throughout the preimplantation period. Oct-4 expression is associated with an undifferentiated phenotype and tumors. Gene knockdown of Oct-4 promotes differentiation, demonstrating a role for these factors in human embryonic stem cell self-renewal. Oct-4 can form a heterodimer with Sox2, so that these two proteins bind DNA together.
Mouse embryos that are Oct-4 deficient or have low expression levels of Oct-4 fail to form the inner cell mass, lose pluripotency, and differentiate into trophectoderm. Therefore, the level of Oct-4 expression in mice is vital for regulating pluripotency and early cell differentiation since one of its main functions is to keep the embryo from differentiating.
# Orthologs
Orthologs of Oct-4 in humans and other species include:
# Structure
Oct-4 contains the following protein domains:
# Implications in disease
Oct-4 has been implicated in tumorigenesis of adult germ cells. Ectopic expression of the factor in adult mice has been found to cause the formation of dysplastic lesions of the skin and intestine. The intestinal dysplasia resulted from an increase in progenitor cell population and the upregulation of β-catenin transcription through the inhibition of cellular differentiation.
# Pluripotency in embryo development
## Animal model
In 2000, Niwa et al. used conditional expression and repression in murine embryonic stem cells to determine requirements for Oct-4 in the maintenance of developmental potency. Although transcriptional determination has often been considered as a binary on-off control system, they found that the precise level of Oct-4 governs 3 distinct fates of ES cells. An increase in expression of less than 2-fold causes differentiation into primitive endoderm and mesoderm. In contrast, repression of Oct-4 induces loss of pluripotency and dedifferentiation to trophectoderm. Thus, a critical amount of Oct-4 is required to sustain stem cell self-renewal, and up- or down-regulation induces divergent developmental programs. Changes to Oct-4 levels do not independently promote differentiation, but are also controlled by levels of Sox2. A decrease in Sox2 accompanies increased levels of Oct-4 to promote a mesendodermal fate, with Oct-4 actively inhibiting ectodermal differentiation. Repressed Oct-4 levels that lead to ectodermal differentiation are accompanied by an increase in Sox2, which effectively inhibits mesendodermal differentiation. Niwa et al. suggested that their findings established a role for Oct-4 as a master regulator of pluripotency that controls lineage commitment and illustrated the sophistication of critical transcriptional regulators and the consequent importance of quantitative analyzes.
The transcription factors Oct-4, Sox2 and Nanog are part of a complex regulatory network with Oct-4 and Sox2 capable of directly regulating Nanog by binding to its promoter, and are essential for maintaining the self-renewing undifferentiated state of the inner cell mass of the blastocyst, embryonic stem cell lines (which are cell lines derived from the inner cell mass), and induced pluripotent stem cells. While differential up- and down-regulation of Oct-4 and Sox2 has been shown to promote differentiation, down-regulation of Nanog must occur for differentiation to proceed.
# Role in reprogramming
Oct-4 is one of the transcription factors used to create induced pluripotent stem cells, together with Sox2, Klf4 and often c-Myc in mouse, demonstrating its capacity to induce an embryonic stem cell-like state. These factors are often referred to as "Yamanaka reprogramming factors". This reprogramming effect has also been seen with the Thomson reprogramming factors, reverting human fibroblast cells to iPSCs through Oct-4, along with Sox2, Nanog, and Lin28. The use of Thomson reprogramming factors avoids the need to overexpress c-Myc, an oncogene. It was later determined that only two of these four factors, Oct4 and Klf4, were sufficient to reprogram mouse adult neural stem cells. Finally it was shown that a single factor, Oct-4 was sufficient for this transformation.
# In embryonic stem cells
In in vitro experiments of mouse embryonic stem cells, Oct-4 has often been used as a marker of stemness, as differentiated cells show reduced expression of this marker.
Oct3/4 can both repress and activate the promoter of Rex1. In cells that already express high level of Oct3/4, exogenously transfected Oct3/4 will lead to the repression of Rex1. However, in cells that are not actively expressing Oct3/4, exogenous transfection of Oct3/4 will lead to the activation of Rex1. This implies a dual regulatory ability of Oct3/4 on Rex1. At low levels of the Oct3/4 protein, the Rex1 promoter is activated, while at high levels of the Oct3/4 protein, the Rex1 promoter is repressed.
CRISPR-Cas9 knockout of the gene in human embryonic stem cells demonstrated that Oct-4 is essential for the development after fertilisation.
# In adult stem cells
Several studies suggest a role for Oct-4 in sustaining self-renewal capacity of adult somatic stem cells (i.e. stem cells from epithelium, bone marrow, liver, etc.). Other scientists have produced evidence to the contrary, and dismiss those studies as artifacts of in vitro culture, or interpreting background noise as signal, and warn about Oct-4 pseudogenes giving false detection of Oct-4 expression.
Oct-4 has also been implicated as a marker of cancer stem cells. | Oct-4
Lua error in Module:Redirect at line 65: could not parse redirect on page "Oct-3".
Oct-4 (octamer-binding transcription factor 4), also known as POU5F1 (POU domain, class 5, transcription factor 1), is a protein that in humans is encoded by the POU5F1 gene.[1] Oct-4 is a homeodomain transcription factor of the POU family. It is critically involved in the self-renewal of undifferentiated embryonic stem cells.[2] As such, it is frequently used as a marker for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells.[3]
Oct-4 is a member of the octamer transcription factor family, so named because they bind the octameric (8-unit) DNA nucleotide sequence "ATTTGCAT".[4]
# Expression and function
Oct-4 transcription factor is initially active as a maternal factor in the oocyte and remains active in embryos throughout the preimplantation period. Oct-4 expression is associated with an undifferentiated phenotype and tumors.[5] Gene knockdown of Oct-4 promotes differentiation, demonstrating a role for these factors in human embryonic stem cell self-renewal.[6] Oct-4 can form a heterodimer with Sox2, so that these two proteins bind DNA together.[7]
Mouse embryos that are Oct-4 deficient or have low expression levels of Oct-4 fail to form the inner cell mass, lose pluripotency, and differentiate into trophectoderm. Therefore, the level of Oct-4 expression in mice is vital for regulating pluripotency and early cell differentiation since one of its main functions is to keep the embryo from differentiating.
# Orthologs
Orthologs of Oct-4 in humans and other species include:
# Structure
Oct-4 contains the following protein domains:
# Implications in disease
Oct-4 has been implicated in tumorigenesis of adult germ cells. Ectopic expression of the factor in adult mice has been found to cause the formation of dysplastic lesions of the skin and intestine. The intestinal dysplasia resulted from an increase in progenitor cell population and the upregulation of β-catenin transcription through the inhibition of cellular differentiation.[8]
# Pluripotency in embryo development
## Animal model
In 2000, Niwa et al. used conditional expression and repression in murine embryonic stem cells to determine requirements for Oct-4 in the maintenance of developmental potency.[3] Although transcriptional determination has often been considered as a binary on-off control system, they found that the precise level of Oct-4 governs 3 distinct fates of ES cells. An increase in expression of less than 2-fold causes differentiation into primitive endoderm and mesoderm. In contrast, repression of Oct-4 induces loss of pluripotency and dedifferentiation to trophectoderm. Thus, a critical amount of Oct-4 is required to sustain stem cell self-renewal, and up- or down-regulation induces divergent developmental programs. Changes to Oct-4 levels do not independently promote differentiation, but are also controlled by levels of Sox2. A decrease in Sox2 accompanies increased levels of Oct-4 to promote a mesendodermal fate, with Oct-4 actively inhibiting ectodermal differentiation. Repressed Oct-4 levels that lead to ectodermal differentiation are accompanied by an increase in Sox2, which effectively inhibits mesendodermal differentiation.[9] Niwa et al. suggested that their findings established a role for Oct-4 as a master regulator of pluripotency that controls lineage commitment and illustrated the sophistication of critical transcriptional regulators and the consequent importance of quantitative analyzes.
The transcription factors Oct-4, Sox2 and Nanog are part of a complex regulatory network with Oct-4 and Sox2 capable of directly regulating Nanog by binding to its promoter, and are essential for maintaining the self-renewing undifferentiated state of the inner cell mass of the blastocyst, embryonic stem cell lines (which are cell lines derived from the inner cell mass), and induced pluripotent stem cells.[7] While differential up- and down-regulation of Oct-4 and Sox2 has been shown to promote differentiation, down-regulation of Nanog must occur for differentiation to proceed.[9]
# Role in reprogramming
Oct-4 is one of the transcription factors used to create induced pluripotent stem cells, together with Sox2, Klf4 and often c-Myc in mouse,[10][11][12] demonstrating its capacity to induce an embryonic stem cell-like state. These factors are often referred to as "Yamanaka reprogramming factors". This reprogramming effect has also been seen with the Thomson reprogramming factors, reverting human fibroblast cells to iPSCs through Oct-4, along with Sox2, Nanog, and Lin28. The use of Thomson reprogramming factors avoids the need to overexpress c-Myc, an oncogene.[13] It was later determined that only two of these four factors, Oct4 and Klf4, were sufficient to reprogram mouse adult neural stem cells.[14] Finally it was shown that a single factor, Oct-4 was sufficient for this transformation.[15]
# In embryonic stem cells
In in vitro experiments of mouse embryonic stem cells, Oct-4 has often been used as a marker of stemness, as differentiated cells show reduced expression of this marker.
Oct3/4 can both repress and activate the promoter of Rex1. In cells that already express high level of Oct3/4, exogenously transfected Oct3/4 will lead to the repression of Rex1.[16] However, in cells that are not actively expressing Oct3/4, exogenous transfection of Oct3/4 will lead to the activation of Rex1.[16] This implies a dual regulatory ability of Oct3/4 on Rex1. At low levels of the Oct3/4 protein, the Rex1 promoter is activated, while at high levels of the Oct3/4 protein, the Rex1 promoter is repressed.
CRISPR-Cas9 knockout of the gene in human embryonic stem cells demonstrated that Oct-4 is essential for the development after fertilisation.[17]
# In adult stem cells
Several studies suggest a role for Oct-4 in sustaining self-renewal capacity of adult somatic stem cells (i.e. stem cells from epithelium, bone marrow, liver, etc.).[18] Other scientists have produced evidence to the contrary,[19] and dismiss those studies as artifacts of in vitro culture, or interpreting background noise as signal,[20] and warn about Oct-4 pseudogenes giving false detection of Oct-4 expression.[21]
Oct-4 has also been implicated as a marker of cancer stem cells.[22][23] | https://www.wikidoc.org/index.php/OCT4 | |
7966eab818a3d42b36b782372d859a89838451a1 | wikidoc | OLIG2 | OLIG2
Oligodendrocyte transcription factor (OLIG2) is a basic helix-loop-helix (bHLH) transcription factor encoded by the Olig2 gene. The protein is of 329 amino acids in length, 32kDa in size and contains 1 basic helix-loop-helix DNA-binding domain. It is one of the three members of the bHLH family. The other two members are OLIG1 and OLIG3. The expression of OLIG2 is mostly restricted in central nervous system, where it acts as both an anti-neurigenic and a neurigenic factor at different stages of development. OLIG2 is well known for determining motor neuron and oligodendrocyte differentiation, as well as its role in sustaining replication in early development. It is mainly involved in diseases such as brain tumor and Down syndrome.
# Function
OLIG2 is mostly expressed in restricted domains of the brain and spinal cord ventricular zone which give rise to oligodendrocytes and specific types of neurons. In the spinal cord, the pMN region sequentially generates motor neurons and oligodendrocytes. During embryogenesis, OLIG2 first directs motor neuron fate by establishing a ventral domain of motor neuron progenitors and promoting neuronal differentiation. OLIG2 then switches to promoting the formation of oligodendrocyte precursors and oligodendrocyte differentiation at later stages of development. Apart from functioning as a neurogenic factor in specification and the differentiation of motor neurons and oligodendrocytes, OLIG2 also functions as an anti-neurogenic factor at early time points in pMN progenitors to sustain the cycling progenitor pool. This side of anti-neurogenicity of OLIG2 later plays a bigger role in malignancies like glioma.
The role of phosphorylation has been highlighted recently to account for the multifaceted functions of OLIG2 in differentiation and proliferation. Studies showed that the phosphorylation state of OLIG2 at Ser30 determines the fate of cortical progenitor cells, in which cortical progenitor cells will either differentiate into astrocytes or remain as neuronal progenitors. Phosphorylation at a triple serine motif (Ser10, Ser13 and Ser14) on the other hand was shown to regulate the proliferative function of OLIG2. Another phosphorylation site Ser147 predicted by bioinformatics was found to regulate motor neuron development by regulating the binding between OLIG2 and NGN2. Further, OLIG2 contains a ST box composed of a string of 12 contiguous serine and threonine residues at position Ser77-Ser88. It is believed that phosphorylation at ST box is biologically functional, yet the role of it still remains to be elucidated in vivo.
OLIG2 has also been implicated in bovine horn ontogenesis. It was the only gene in the bovine polled locus to show differential expression between the putative horn bud and the frontal forehead skin.
# Clinical Significance
## OLIG2 in Cancer
OLIG2 is well recognized for its importance in cancer research, particularly in brain tumors and leukemia. OLIG2 is universally expressed in glioblastoma and other diffuse gliomas (astrocytomas, oligodendrogliomas and oligoastrocytomas), and is a useful positive diagnostic marker of these brain tumors. In particular, OLIG2 is selectively expressed in a subgroup of glioma cells that are highly tumorigenic, and is shown to be required for proliferation of human glioma cells implanted in the brain of severe combined immunodeficiency (SCID) mice.
Though the molecular mechanism behind this tumorigenesis is not entirely clear, more studies have recently been published pinpointing diverse evidence and potential roles for OLIG2 in glioma progression. It is believed that OLIG2 promotes neural stem cell and progenitor cell proliferation by opposing p53 pathway, which potentially contributes to glioma progression. OLIG2 has been shown to directly repress the p53 tumor-suppressor pathway effector p21WAF1/CIP1, suppress p53 acetylation and impede the binding of p53 to several enhancer sites. It is further found that the phosphorylation of triple-serine motif in OLIG2 is present in several glioma lines and is more tumorigenic than the unphosphorylated status. In a study using the U12-1 cell line for controlled expression of OLIG2, researchers showed that OLIG2 can suppress the proliferation of U12-1 by transactivating the p27Kip1 gene and can inhibit the motility of the cell by activating RhoA.
Besides glioma, OLIG2 is also involved in leukemogenesis. The Olig2 gene was actually first identified in a study in T-cell acute lymphoblastic leukemia, in which the expression of OLIG2 was found elevated after t(14;21)(q11.2;q22) chromosomal translocation. The overexpression of OLIG2 was later shown present in malignancies beyond glioma and leukemia, such as breast cancer, melanoma and non-small cell lung carcinoma cell lines. It also has been shown that up-regulation of OLIG2 together with LMO1 and Notch1 helps to provide proliferation signals.
## OLIG2 in Neural Diseases
OLIG2 is also associated with Down syndrome, as it locates at chromosome 21 within or near the Down syndrome critical region on the long arm. This region is believed to contribute to the cognitive defects of Down syndrome. The substantial increase in the number of forebrain inhibitory neurons often observed in Ts65dn mouse (a murine model of trisomy 21) could lead to imbalance between excitation and inhibition and behavioral abnormalities. However, genetic reduction of OLIG2 and OLIG1 from three copies to two rescued the overproduction of interneurons, indicating the pivotal role of OLIG2 expression level in Down syndrome. The association between OLIG2 and neural diseases (i.e. schizophrenia and Alzheimer’s disease) are under scrutiny, as several single nucleotide polymorphisms (SNPs) associated with these diseases in OLIG2 were identified by genome-wide association work.
OLIG2 also plays a functional role in neural repair. Studies showed that the number of OLIG2-expressing cells increased in the lesion after cortical stab-wound injury, supporting the role for OLIG2 in reactive gliosis. OLIG2 was also implicated in generating reactive astrocytes possibly in a transient re-expression manner, but the mechanisms are unclear. | OLIG2
Oligodendrocyte transcription factor (OLIG2) is a basic helix-loop-helix (bHLH) transcription factor encoded by the Olig2 gene. The protein is of 329 amino acids in length, 32kDa in size and contains 1 basic helix-loop-helix DNA-binding domain.[1] It is one of the three members of the bHLH family. The other two members are OLIG1 and OLIG3. The expression of OLIG2 is mostly restricted in central nervous system, where it acts as both an anti-neurigenic and a neurigenic factor at different stages of development. OLIG2 is well known for determining motor neuron and oligodendrocyte differentiation, as well as its role in sustaining replication in early development. It is mainly involved in diseases such as brain tumor and Down syndrome.
# Function
OLIG2 is mostly expressed in restricted domains of the brain and spinal cord ventricular zone which give rise to oligodendrocytes and specific types of neurons. In the spinal cord, the pMN region sequentially generates motor neurons and oligodendrocytes. During embryogenesis, OLIG2 first directs motor neuron fate by establishing a ventral domain of motor neuron progenitors and promoting neuronal differentiation. OLIG2 then switches to promoting the formation of oligodendrocyte precursors and oligodendrocyte differentiation at later stages of development. Apart from functioning as a neurogenic factor in specification and the differentiation of motor neurons and oligodendrocytes, OLIG2 also functions as an anti-neurogenic factor at early time points in pMN progenitors to sustain the cycling progenitor pool. This side of anti-neurogenicity of OLIG2 later plays a bigger role in malignancies like glioma.[2]
The role of phosphorylation has been highlighted recently to account for the multifaceted functions of OLIG2 in differentiation and proliferation. Studies showed that the phosphorylation state of OLIG2 at Ser30 determines the fate of cortical progenitor cells, in which cortical progenitor cells will either differentiate into astrocytes or remain as neuronal progenitors.[3] Phosphorylation at a triple serine motif (Ser10, Ser13 and Ser14) on the other hand was shown to regulate the proliferative function of OLIG2.[4] Another phosphorylation site Ser147 predicted by bioinformatics was found to regulate motor neuron development by regulating the binding between OLIG2 and NGN2.[5] Further, OLIG2 contains a ST box composed of a string of 12 contiguous serine and threonine residues at position Ser77-Ser88. It is believed that phosphorylation at ST box is biologically functional,[6] yet the role of it still remains to be elucidated in vivo.[7]
OLIG2 has also been implicated in bovine horn ontogenesis. It was the only gene in the bovine polled locus to show differential expression between the putative horn bud and the frontal forehead skin.[8]
# Clinical Significance
## OLIG2 in Cancer
OLIG2 is well recognized for its importance in cancer research, particularly in brain tumors and leukemia. OLIG2 is universally expressed in glioblastoma and other diffuse gliomas (astrocytomas, oligodendrogliomas and oligoastrocytomas), and is a useful positive diagnostic marker of these brain tumors.[9] In particular, OLIG2 is selectively expressed in a subgroup of glioma cells that are highly tumorigenic,[10] and is shown to be required for proliferation of human glioma cells implanted in the brain of severe combined immunodeficiency (SCID) mice.[11]
Though the molecular mechanism behind this tumorigenesis is not entirely clear, more studies have recently been published pinpointing diverse evidence and potential roles for OLIG2 in glioma progression. It is believed that OLIG2 promotes neural stem cell and progenitor cell proliferation by opposing p53 pathway, which potentially contributes to glioma progression. OLIG2 has been shown to directly repress the p53 tumor-suppressor pathway effector p21WAF1/CIP1,[12] suppress p53 acetylation and impede the binding of p53 to several enhancer sites.[13] It is further found that the phosphorylation of triple-serine motif in OLIG2 is present in several glioma lines and is more tumorigenic than the unphosphorylated status.[14] In a study using the U12-1 cell line for controlled expression of OLIG2, researchers showed that OLIG2 can suppress the proliferation of U12-1 by transactivating the p27Kip1 gene[15] and can inhibit the motility of the cell by activating RhoA.[16]
Besides glioma, OLIG2 is also involved in leukemogenesis. The Olig2 gene was actually first identified in a study in T-cell acute lymphoblastic leukemia, in which the expression of OLIG2 was found elevated after t(14;21)(q11.2;q22) chromosomal translocation.[17] The overexpression of OLIG2 was later shown present in malignancies beyond glioma and leukemia, such as breast cancer, melanoma and non-small cell lung carcinoma cell lines.[18] It also has been shown that up-regulation of OLIG2 together with LMO1 and Notch1 helps to provide proliferation signals.
## OLIG2 in Neural Diseases
OLIG2 is also associated with Down syndrome, as it locates at chromosome 21 within or near the Down syndrome critical region on the long arm. This region is believed to contribute to the cognitive defects of Down syndrome. The substantial increase in the number of forebrain inhibitory neurons often observed in Ts65dn mouse (a murine model of trisomy 21) could lead to imbalance between excitation and inhibition and behavioral abnormalities. However, genetic reduction of OLIG2 and OLIG1 from three copies to two rescued the overproduction of interneurons, indicating the pivotal role of OLIG2 expression level in Down syndrome.[19] The association between OLIG2 and neural diseases (i.e. schizophrenia and Alzheimer’s disease) are under scrutiny, as several single nucleotide polymorphisms (SNPs) associated with these diseases in OLIG2 were identified by genome-wide association work.[20][21]
OLIG2 also plays a functional role in neural repair. Studies showed that the number of OLIG2-expressing cells increased in the lesion after cortical stab-wound injury, supporting the role for OLIG2 in reactive gliosis.[22] OLIG2 was also implicated in generating reactive astrocytes possibly in a transient re-expression manner, but the mechanisms are unclear.[23] | https://www.wikidoc.org/index.php/OLIG2 | |
eab508f30d3792eb1bf5d8a883674e72d5816af8 | wikidoc | OPHN1 | OPHN1
Oligophrenin-1 is a protein that in humans is encoded by the OPHN1 gene.
# Function
Oligophrenin 1 has 25 exons and encodes a Rho-GTPase-activating protein. The Rho protein are important mediators of intracellular signal transduction, which affects cell migration and cell morphogenesis.
# Clinical significance
Mutations in this gene are responsible for non-specific X-linked intellectual disability (previously called mental retardation).
OPHN1 syndrome is a rare disorder characterized by intellectual disability and changes in the part of the brain which controls movement and balance (cerebellum). The syndrome mainly affects males. It is characterized by low muscle tone (hypotonia), developmental and cognitive delay, early-onset seizures, abnormal behavior, characteristic facial features (long face, bulging forehead, under eye creases, deep set eyes, and large ears), crossed eyes (strabismus) and inability to coordinate movements.
A small cerebellum and large ventricles can be seen on brain imaging (MRI). Treatment is supportive and includes physical, occupational and speech and language therapy.
OPHN1 syndrome is caused by mutations in the OPHN1 gene, which is located on the X chromosome. Inheritance is X-linked. Some females who carry a mutation in the OPHN1 gene may have mild learning disabilities, mild cognitive impairment, strabismus, and subtle facial changes. | OPHN1
Oligophrenin-1 is a protein that in humans is encoded by the OPHN1 gene.[1][2][3]
# Function
Oligophrenin 1 has 25 exons and encodes a Rho-GTPase-activating protein. The Rho protein are important mediators of intracellular signal transduction, which affects cell migration and cell morphogenesis.
# Clinical significance
Mutations in this gene are responsible for non-specific X-linked intellectual disability (previously called mental retardation).[3]
OPHN1 syndrome is a rare disorder characterized by intellectual disability and changes in the part of the brain which controls movement and balance (cerebellum). The syndrome mainly affects males. It is characterized by low muscle tone (hypotonia), developmental and cognitive delay, early-onset seizures, abnormal behavior, characteristic facial features (long face, bulging forehead, under eye creases, deep set eyes, and large ears), crossed eyes (strabismus) and inability to coordinate movements.[4]
[5] A small cerebellum and large ventricles can be seen on brain imaging (MRI).[4][6][7] Treatment is supportive and includes physical, occupational and speech and language therapy.[8]
OPHN1 syndrome is caused by mutations in the OPHN1 gene, which is located on the X chromosome. Inheritance is X-linked.[4] Some females who carry a mutation in the OPHN1 gene may have mild learning disabilities, mild cognitive impairment, strabismus, and subtle facial changes.[3] | https://www.wikidoc.org/index.php/OPHN1 | |
1f670f1603163e2d488458fef0525e2b79133793 | wikidoc | OR5L1 | OR5L1
Olfactory receptor 5L1 is a protein that in humans is encoded by the OR5L1 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. | OR5L1
Olfactory receptor 5L1 is a protein that in humans is encoded by the OR5L1 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] | https://www.wikidoc.org/index.php/OR5L1 | |
506a36f9940e959b8502bf9b07a4de868944b19c | wikidoc | OR6A2 | OR6A2
Olfactory receptor 6A2 is a protein that in humans is encoded by the OR6A2 gene.
# Function
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 neurotransmitters 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.
# Clinical significance
Variation in the OR6A2 gene has been identified as a likely cause of some people's strong dislike of coriander (also known as cilantro), often associating it with a combination of soap and vomit, while for others it is closer to the foul smelling odor emitted by stinkbugs. This is due to the presence of aldehyde chemicals, which are present in soap, various detergents, coriander, several species of stinkbugs and cinnamon. | OR6A2
Olfactory receptor 6A2 is a protein that in humans is encoded by the OR6A2 gene.[1]
# Function
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 neurotransmitters 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]
# Clinical significance
Variation in the OR6A2 gene has been identified as a likely cause of some people's strong dislike of coriander (also known as cilantro)[2], often associating it with a combination of soap and vomit, while for others it is closer to the foul smelling odor emitted by stinkbugs. This is due to the presence of aldehyde chemicals, which are present in soap, various detergents, coriander, several species of stinkbugs and cinnamon.[3] | https://www.wikidoc.org/index.php/OR6A2 | |
55a475ed0d51bb8ebc2ccf277736b6d38e73346c | wikidoc | ORAI1 | ORAI1
Calcium release-activated calcium channel protein 1 is a calcium selective ion channel that in humans is encoded by the ORAI1 gene. Orai channels play an important role in the activation of T-lymphocytes. The loss of function mutation of Orai1 causes severe combined immunodeficiency (SCID) in humans The mammalian orai family has two additional homologs, Orai2 and Orai3. Orai proteins share no homology with any other ion channel family of any other known proteins. They have 4 transmembrane domains and form hexamers.
# Structure and function
Orai channels are activated upon the depletion of internal calcium stores, which is called the "store-operated" or the "capacitative" mechanism. They are molecular constituents of the "calcium release activated calcium currents" (ICRAC). Upon activation of phospholipase C by various cell surface receptors, inositol trisphosphate is formed that releases calcium from the endoplasmic reticulum. The decreased calcium concentration in the endoplasmic reticulum is sensed by the STIM1 protein. STIM1 clusters upon the depletion of the calcium stores and forms "puncta", and relocates near the plasma membrane, where it activates Orai1 via protein-protein interaction.
In 2012, a 3.35-angstrom (Å) crystal structure of the Drosophila Orai channel, which shares 73% sequence identity with human Orai1 within its transmembrane region, was published. The structure, thought to show the closed state of the channel, revealed that a single channel is composed of six Orai subunits, with the transmembrane domains arranged in concentric rings around a central aqueous pore formed exclusively by the first transmembrane helix of each subunit. Transmembrane helices 2 and 3 surround TM1 and are hypothesized to shield it from the surrounding lipid bilayer and provide structural support. The fourth transmembrane helix forms the outermost layer. | ORAI1
Calcium release-activated calcium channel protein 1 is a calcium selective ion channel that in humans is encoded by the ORAI1 gene.[1][2][3] Orai channels play an important role in the activation of T-lymphocytes. The loss of function mutation of Orai1 causes severe combined immunodeficiency (SCID) in humans[1] The mammalian orai family has two additional homologs, Orai2 and Orai3. Orai proteins share no homology with any other ion channel family of any other known proteins. They have 4 transmembrane domains and form hexamers.
# Structure and function
Orai channels are activated upon the depletion of internal calcium stores, which is called the "store-operated" or the "capacitative" mechanism.[4] They are molecular constituents of the "calcium release activated calcium currents" (ICRAC). Upon activation of phospholipase C by various cell surface receptors, inositol trisphosphate is formed that releases calcium from the endoplasmic reticulum. The decreased calcium concentration in the endoplasmic reticulum is sensed by the STIM1 protein. STIM1 clusters upon the depletion of the calcium stores and forms "puncta", and relocates near the plasma membrane, where it activates Orai1 via protein-protein interaction.[5][6][7][8]
In 2012, a 3.35-angstrom (Å) crystal structure of the Drosophila Orai channel, which shares 73% sequence identity with human Orai1 within its transmembrane region, was published.[9] The structure, thought to show the closed state of the channel, revealed that a single channel is composed of six Orai subunits, with the transmembrane domains arranged in concentric rings around a central aqueous pore formed exclusively by the first transmembrane helix of each subunit. Transmembrane helices 2 and 3 surround TM1 and are hypothesized to shield it from the surrounding lipid bilayer and provide structural support. The fourth transmembrane helix forms the outermost layer. | https://www.wikidoc.org/index.php/ORAI1 | |
53437488f097fee0d2622f1d0587dcba9fb0c72f | wikidoc | ORCON | ORCON
ORCON (Operational Research CONsultancy) was developed by a UK consultancy company in 1974 as a standard for monitoring ambulance service performance.
The standard was later adopted internationally by a number of different countries including the Australian ambulance service.
ORCON standards are monitored through key performance indicators.
- Activation - All calls should have an ambulance 'activated' within 3 minutes of the phone being answered. This is usually made up of the control room tasking the crew within one minute, and the crew having a further 2 minutes to be 'on the road'. This is supposed to be achieved with 95% of calls.
- Category A calls, which are calls designated by AMPDS as being immediately life threatening. 75% of calls should receive an initial response within eight minutes (of the operator answering the call) and 95% of calls should receive an initial response within 19 minutes. The performance indicator generated by the ambulance service is expressed as a percentage of how many calls meet this.
- Category B are calls which are designated by AMPDS as being serious, but not immediately life threatening. 95% of calls should receive an initial response within 19 minutes. The performance indicator generated by the ambulance service is expressed as a percentage of how many calls meet this.
The distinction between urban/rural services ceased on 1 April 2006. Previously 95% of incidents had to be responded to within 14 minutes in urban services or 19 minutes in rural services. All services are now subject to the same response time requirements of 19 minutes. | ORCON
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
ORCON (Operational Research CONsultancy) was developed by a UK consultancy company in 1974 as a standard for monitoring ambulance service performance.
The standard was later adopted internationally by a number of different countries including the Australian ambulance service.
ORCON standards are monitored through key performance indicators.
- Activation - All calls should have an ambulance 'activated' within 3 minutes of the phone being answered. This is usually made up of the control room tasking the crew within one minute, and the crew having a further 2 minutes to be 'on the road'. This is supposed to be achieved with 95% of calls.
- Category A calls, which are calls designated by AMPDS as being immediately life threatening. 75% of calls should receive an initial response within eight minutes (of the operator answering the call) and 95% of calls should receive an initial response within 19 minutes. The performance indicator generated by the ambulance service is expressed as a percentage of how many calls meet this.
- Category B are calls which are designated by AMPDS as being serious, but not immediately life threatening. 95% of calls should receive an initial response within 19 minutes. The performance indicator generated by the ambulance service is expressed as a percentage of how many calls meet this.
The distinction between urban/rural services ceased on 1 April 2006. Previously 95% of incidents had to be responded to within 14 minutes in urban services or 19 minutes in rural services. All services are now subject to the same response time requirements of 19 minutes.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/ORCON | |
36ee049027a7e07ee265aa99a1cf525e33fb8eeb | wikidoc | OSER1 | OSER1
Chromosome 20 open reading frame 111, or C20orf111, is the hypothetical protein that in humans is encoded by the C20orf111 gene. C20orf111 is also known as Perit1 (peroxide inducible transcript 1), HSPC207, and dJ1183I21.1. It was originally located using genomic sequencing of chromosome 20. The National Center for Biotechnology Information, or NCBI, shows that it is located at q13.11 on chromosome 20, however the genome browser at the University of California-Santa Cruz (UCSC) website shows that it is at location q13.12, and within a million base pairs of the adenosine deaminase locus. It was also found to have an increase in expression in cells undergoing hydrogen peroxide(H2O2)-induced apoptosis. After analyzing the amino acid content of C20orf111, it was found to be rich in serine residues.
# Gene
C20orf111 a valid, protein coding gene that is found on the minus strand of chromosome 20 at q13.12 by searching the UCSC Genome Browser, but q13.11 according to Refseq on NCBI.
## Gene neighborhood
A few of the known genes near C20orf111 are given in the box below with their known function.
# Transcript
## General properties
- Genomic DNA Length:14,968 base pairs (bp)
- Most common mRNA Length: 2,260 bp with 4 exons. Has 10 splice isoforms.
- 5' untranslated region 252 bp long.
- 3' untranslated region 1,129 bp long.
## Transcript variants
10 splice isoforms that encode good proteins, altogether 8 different isoforms, 2 of which are complete isoforms. The image below shows the 10 isoforms that are predicted. Of these 10 splice isoforms, 8 have varying peptide lengths, however all of these proteins are only hypothetical with no extensive research done on them.
## Transcription regulation
When looking at the predicted promoter sequence, there are no RNA Polymerase II binding sites, however there is a binding site for core promoter element for TATA-less promoters. In this same region of the promoter, there is also a TATA-binding factor sequence, which helps in the positioning of RNA polymerase II for transcription.
# Protein
## General properties
- Contains a highly conserved domain of unknown function 776 (DUF776),which composes 62% of the entire protein.
- Molecular weight 31.8 kilodaltons
- Isoelectric point 8.57
- Predicted to be a nuclear protein
## Function
The function of C20orf111 is not well understood by the scientific community. It does contain a domain of unknown function, DUF776, which has a large segment that is conserved well conserved through Xenopus tropicalus. It is also shown to have an increase in expression in rat cardiomyocytes undergoing hydrogen peroxide induced apoptosis.
## Expression
When looking at the EST Profiles in humans, normal tissue (non-cancerous), expresses at a level of 82 transcripts per million. C20orf111 has been shown to increase in expression in rat cardiac myocytes undergoing |H|2|O|2|-induced apoptosis, suggesting a role in cell death. In bladder, cervical, head and neck, non-neoplasia, pancreatic, and prostate cancer cells, there are expression levels lower than normal.
## Homology
C20orf111 gene has no clear paralogs in the human genome. However, it has many orthologs in other organisms, and is conserved highly in organisms such as Xenopus tropicalis and is semi-conserved in the proto-animal Trichoplax adherens at the C-terminus.
The following table presents a select number of the orthologs found.
## Conservation
The image below is a multiple sequence alignment comparing the conservation of the C20orf111 protein amongst other organisms. The protein is highly conserved in the DUF776 region amongst vertebrates, and also at the C-terminus in eukaryotes.
## Predicted post-translational modification
Using tools at ExPASy the following are predicted post-translational modifications for C20orf111.
- Predicted propeptide cleavage site in protein between position R81 and S82.
- 30 predicted Serine phosphorylation sites
- 5 predicted Threonine phosphorylation sites
- 3 predicted Tyrosine phosphorylation sites
## Predicted secondary structure
PELE (Protein Secondary Structure Prediction) was used to predict the secondary structure of C20orf111. There is little in the way of β-strand or α-helix secondary structure, but a large part of the protein appears to exist as random coils. This is shown on the image of the C20orf111 images to the right. | OSER1
Chromosome 20 open reading frame 111, or C20orf111, is the hypothetical protein that in humans is encoded by the C20orf111 gene.[1] C20orf111 is also known as Perit1 (peroxide inducible transcript 1), HSPC207, and dJ1183I21.1.[2] It was originally located using genomic sequencing of chromosome 20.[3] The National Center for Biotechnology Information, or NCBI,[1] shows that it is located at q13.11 on chromosome 20, however the genome browser at the University of California-Santa Cruz (UCSC) website[4] shows that it is at location q13.12, and within a million base pairs of the adenosine deaminase locus.[5] It was also found to have an increase in expression in cells undergoing hydrogen peroxide(H2O2)-induced apoptosis.[6] After analyzing the amino acid content of C20orf111, it was found to be rich in serine residues.
# Gene
C20orf111 a valid, protein coding gene that is found on the minus strand of chromosome 20 at q13.12 by searching the UCSC Genome Browser,[4] but q13.11 according to Refseq on NCBI.[1]
## Gene neighborhood
A few of the known genes near C20orf111 are given in the box below with their known function.
# Transcript
## General properties
[10]
- Genomic DNA Length:14,968 base pairs (bp)
- Most common mRNA Length: 2,260 bp with 4 exons. Has 10 splice isoforms.
- 5' untranslated region 252 bp long.
- 3' untranslated region 1,129 bp long.
## Transcript variants
10 splice isoforms that encode good proteins, altogether 8 different isoforms, 2 of which are complete isoforms. The image below shows the 10 isoforms that are predicted.[11] Of these 10 splice isoforms, 8 have varying peptide lengths, however all of these proteins are only hypothetical with no extensive research done on them.[11]
## Transcription regulation
When looking at the predicted promoter sequence,[12] there are no RNA Polymerase II binding sites, however there is a binding site for core promoter element for TATA-less promoters.[13] In this same region of the promoter, there is also a TATA-binding factor sequence, which helps in the positioning of RNA polymerase II for transcription.[14]
# Protein
## General properties
[15]
- Contains a highly conserved domain of unknown function 776 (DUF776),which composes 62% of the entire protein.
- Molecular weight 31.8 kilodaltons
- Isoelectric point 8.57
- Predicted to be a nuclear protein[16]
## Function
The function of C20orf111 is not well understood by the scientific community. It does contain a domain of unknown function, DUF776, which has a large segment that is conserved well conserved through Xenopus tropicalus. It is also shown to have an increase in expression in rat cardiomyocytes undergoing hydrogen peroxide induced apoptosis.[6]
## Expression
When looking at the EST Profiles in humans, normal tissue (non-cancerous), expresses at a level of 82 transcripts per million.[17] C20orf111 has been shown to increase in expression in rat cardiac myocytes undergoing |H|2|O|2|-induced apoptosis, suggesting a role in cell death.[6] In bladder, cervical, head and neck, non-neoplasia, pancreatic, and prostate cancer cells, there are expression levels lower than normal.
## Homology
C20orf111 gene has no clear paralogs in the human genome. However, it has many orthologs in other organisms, and is conserved highly in organisms such as Xenopus tropicalis and is semi-conserved in the proto-animal Trichoplax adherens at the C-terminus.
The following table presents a select number of the orthologs found.[18]
## Conservation
The image below is a multiple sequence alignment comparing the conservation of the C20orf111 protein amongst other organisms. The protein is highly conserved in the DUF776 region amongst vertebrates, and also at the C-terminus in eukaryotes.
## Predicted post-translational modification
Using tools at ExPASy[19] the following are predicted post-translational modifications for C20orf111.
- Predicted propeptide cleavage site in protein between position R81 and S82.[20]
- 30 predicted Serine phosphorylation sites
- 5 predicted Threonine phosphorylation sites
- 3 predicted Tyrosine phosphorylation sites[21]
## Predicted secondary structure
PELE (Protein Secondary Structure Prediction) was used to predict the secondary structure of C20orf111. There is little in the way of β-strand or α-helix secondary structure, but a large part of the protein appears to exist as random coils. This is shown on the image of the C20orf111 images to the right. | https://www.wikidoc.org/index.php/OSER1 | |
39ddf82ec74e8fb1986c496532c651dfbbf89723 | wikidoc | OVGP1 | OVGP1
Oviduct-specific glycoprotein also known as oviductal glycoprotein (OGP) or estrogen-dependent oviduct protein (EGP) or mucin-9 (MUC9) is a protein that in humans is encoded by the OVGP1 gene.
# Function
Oviduct-specific glycoprotein is a large, carbohydrate-rich, epithelial glycoprotein with numerous O-glycosylation sites located within threonine, serine, and proline-rich tandem repeats. The gene is similar to members of the mucin and the glycosyl hydrolase 18 gene families. Regulation of expression may be estrogen-dependent. Gene expression and protein secretion occur during late follicular development through early cleavage-stage embryonic development. The protein is secreted from non-ciliated oviductal epithelial cells and associates with ovulated oocytes, blastomeres, and spermatozoon acrosomal regions.
Beyond the oviduct, OVGP1 is detected in the mouse ovary, testis and epididymis suggesting its roles beyond fertilization. It is not detected in the mouse uterus, cervix, vagina, breast, seminal vesicles and prostate gland
OVGP1 is expressed by the surface epithelium of the endometrium at the time of embryo implantation in the mouse. It is required for maintain the receptivity phenotype and trophoblast adhesion, OVGP1 mRNA levels are reduced in endometrium of women with recurrent implantation failure | OVGP1
Oviduct-specific glycoprotein also known as oviductal glycoprotein (OGP) or estrogen-dependent oviduct protein (EGP) or mucin-9 (MUC9) is a protein that in humans is encoded by the OVGP1 gene.[1][2][3]
# Function
Oviduct-specific glycoprotein is a large, carbohydrate-rich, epithelial glycoprotein with numerous O-glycosylation sites located within threonine, serine, and proline-rich tandem repeats. The gene is similar to members of the mucin and the glycosyl hydrolase 18 gene families. Regulation of expression may be estrogen-dependent. Gene expression and protein secretion occur during late follicular development through early cleavage-stage embryonic development. The protein is secreted from non-ciliated oviductal epithelial cells and associates with ovulated oocytes, blastomeres, and spermatozoon acrosomal regions.[3]
Beyond the oviduct, OVGP1 is detected in the mouse ovary, testis and epididymis suggesting its roles beyond fertilization. It is not detected in the mouse uterus, cervix, vagina, breast, seminal vesicles and prostate gland [4]
OVGP1 is expressed by the surface epithelium of the endometrium at the time of embryo implantation in the mouse. It is required for maintain the receptivity phenotype and trophoblast adhesion, OVGP1 mRNA levels are reduced in endometrium of women with recurrent implantation failure [5] | https://www.wikidoc.org/index.php/OVGP1 | |
5a7f6ea019531f3b622467c0e27783036f44a89f | wikidoc | OXA1L | OXA1L
Mitochondrial inner membrane protein OXA1L is a protein that in humans is encoded by the OXA1L gene located on 14q11.2. The C-terminus of this protein interacts with mitochondrial ribosomes and helps insert both mitochondrial and nuclear produced proteins into the inner membrane of the mitochondria.
# Reference
- ↑ Molina-Gomes D, Bonnefoy N, Nguyen VC, Viegas-Péquignot E, Rötig A, Dujardin G (1995). "The OXA1L gene that controls cytochrome oxidase assembly maps to the 14q11.2 region of the human genome". Genomics. 30 (2): 396–8. PMID 8586451..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}
- ↑ Haque ME, Elmore KB, Tripathy A, Koc H, Koc EC, Spremulli LL (2010). "Properties of the C-terminal tail of human mitochondrial inner membrane protein Oxa1L and its interactions with mammalian mitochondrial ribosomes". The Journal of Biological Chemistry. 285 (36): 28353–62. doi:10.1074/jbc.M110.148262. PMC 2934699. PMID 20601428.
- ↑ Haque ME, Spremulli LL, Fecko CJ (2010). "Identification of protein-protein and protein-ribosome interacting regions of the C-terminal tail of human mitochondrial inner membrane protein Oxa1L". The Journal of Biological Chemistry. 285 (45): 34991–8. doi:10.1074/jbc.M110.163808. PMC 2966113. PMID 20739282. | OXA1L
Mitochondrial inner membrane protein OXA1L is a protein that in humans is encoded by the OXA1L gene located on 14q11.2.[1] The C-terminus of this protein interacts with mitochondrial ribosomes and helps insert both mitochondrial and nuclear produced proteins into the inner membrane of the mitochondria.[2][3]
# Reference
- ↑ Molina-Gomes D, Bonnefoy N, Nguyen VC, Viegas-Péquignot E, Rötig A, Dujardin G (1995). "The OXA1L gene that controls cytochrome oxidase assembly maps to the 14q11.2 region of the human genome". Genomics. 30 (2): 396–8. PMID 8586451..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}
- ↑ Haque ME, Elmore KB, Tripathy A, Koc H, Koc EC, Spremulli LL (2010). "Properties of the C-terminal tail of human mitochondrial inner membrane protein Oxa1L and its interactions with mammalian mitochondrial ribosomes". The Journal of Biological Chemistry. 285 (36): 28353–62. doi:10.1074/jbc.M110.148262. PMC 2934699. PMID 20601428.
- ↑ Haque ME, Spremulli LL, Fecko CJ (2010). "Identification of protein-protein and protein-ribosome interacting regions of the C-terminal tail of human mitochondrial inner membrane protein Oxa1L". The Journal of Biological Chemistry. 285 (45): 34991–8. doi:10.1074/jbc.M110.163808. PMC 2966113. PMID 20739282. | https://www.wikidoc.org/index.php/OXA1L | |
75087cc0bccae92046ae5236fe4d0bed9c175bfe | wikidoc | OXCT1 | OXCT1
3-oxoacid CoA-transferase 1 (OXCT1) is an enzyme that in humans is encoded by the OXCT1 gene. It is also known as succinyl-CoA-3-oxaloacid CoA transferase (SCOT). Mutations in this gene are associated with succinyl-CoA:3-oxoacid CoA transferase deficiency.
# Function
This gene encodes a member of the 3-oxoacid CoA-transferase gene family. The encoded protein is a homodimeric mitochondrial matrix enzyme that plays a central role in extrahepatic ketone body catabolism by catalyzing the reversible transfer of coenzyme A (CoA) from succinyl-CoA to acetoacetate.
# Structure
## Gene
The OXCT1 gene resides on chromosome 5 at the band 5p13. OXCT1 spans a length of over 100 kb and includes 17 exons.
## Protein
The crystal structure of human OXCT1 reveals it to be a homodimer with two active sites. Each of its monomers contains N- and C-terminal domains that share an α/β structural fold characteristic of CoA transferase family I members. These terminal domains are joined by a linker region and form the enzyme's active site. Specifically, the conserved residue Glu344 within the active site is responsible for the enzyme's catalytic function by attacking the succinyl-CoA substrate, leading to the formation of the enzyme-CoA thioester intermediate.
# Function
OXCT1 is a member of the CoA transferase family I, which is known to catalyze the transfer of CoA between carboxylic acid groups. In particular, OXCT1 catalyzes the first, rate-limiting step in ketolysis by transferring the CoA from succinyl-CoA to acetoacetyl CoA. Acetoacetyl-CoA can then be converted by acetoacetyl-CoA thiolase into acetyl-CoA, which enters the citric acid cycle to generate energy for the cell. As a result, OXCT1 allows cells to utilize energy stored in ketone bodies synthesized by the liver during conditions of energy deficiency, such as low glucose levels. In addition, OXCT1 activity leads to the formation of acetoacetate, which serves as a precursor for short-chain acyl-CoAs and lipids in the cytosol.
OXCT1 is found in the mitochondrial matrix of all tissues except the liver, though it is most abundantly expressed in heart, brain, and kidney tissue. Considering that liver cells function in ketogenesis and OXCT1 in ketolysis, OXCT1 may be absent from the liver to allow ketone body formation to proceed.
# Clinical Significance
## Metabolic disorders
SCOT deficiency is a rare autosomal recessive metabolic disorder that can lead to recurrent episodes of ketoacidosis and even permanent ketosis. Twenty-four mutations in the human OXCT1 gene have been identified and associated with SCOT deficiency: three nonsense mutations, two insertion mutations, and 19 missense mutations. These mutations alter OXCT1 form and thus function in various ways, and they determine what phenotypic complications a patient may present. For instance, several missense mutations that substitute bulkier or charged residues hinder proper folding of OXCT1, leading to more severe outcomes such as permanent acidosis.
OXCT1 has also been implicated diabetes. In a study by MacDonald et al., OXCT1 activity was shown to be lower by 92% in pancreatic islets of human patients with type 2 diabetes compared to those in healthy patients, though the cause is currently unknown.
## Cancer
Since OXCT1 functions in metabolizing ketone bodies, it has been proposed to promote tumor growth by providing tumor cells with an additional energy source. Therefore, ketone inhibitors may prove effective in treating patients experiencing recurring and metastatic tumors. A proteomics study identified OXCT1 to be one of 16 proteins upregulated in carcinoma HepG2 cells treated with Platycodin D, an anti-cancer agent. | OXCT1
3-oxoacid CoA-transferase 1 (OXCT1) is an enzyme that in humans is encoded by the OXCT1 gene.[1][2] It is also known as succinyl-CoA-3-oxaloacid CoA transferase (SCOT). Mutations in this gene are associated with succinyl-CoA:3-oxoacid CoA transferase deficiency.[3]
# Function
This gene encodes a member of the 3-oxoacid CoA-transferase gene family. The encoded protein is a homodimeric mitochondrial matrix enzyme that plays a central role in extrahepatic ketone body catabolism by catalyzing the reversible transfer of coenzyme A (CoA) from succinyl-CoA to acetoacetate.[2]
# Structure
## Gene
The OXCT1 gene resides on chromosome 5 at the band 5p13. OXCT1 spans a length of over 100 kb and includes 17 exons.[4]
## Protein
The crystal structure of human OXCT1 reveals it to be a homodimer with two active sites. Each of its monomers contains N- and C-terminal domains that share an α/β structural fold characteristic of CoA transferase family I members. These terminal domains are joined by a linker region and form the enzyme's active site. Specifically, the conserved residue Glu344 within the active site is responsible for the enzyme's catalytic function by attacking the succinyl-CoA substrate, leading to the formation of the enzyme-CoA thioester intermediate.[5]
# Function
OXCT1 is a member of the CoA transferase family I, which is known to catalyze the transfer of CoA between carboxylic acid groups.[5][6] In particular, OXCT1 catalyzes the first, rate-limiting step in ketolysis by transferring the CoA from succinyl-CoA to acetoacetyl CoA. Acetoacetyl-CoA can then be converted by acetoacetyl-CoA thiolase into acetyl-CoA, which enters the citric acid cycle to generate energy for the cell.[5] As a result, OXCT1 allows cells to utilize energy stored in ketone bodies synthesized by the liver during conditions of energy deficiency, such as low glucose levels.[7] In addition, OXCT1 activity leads to the formation of acetoacetate, which serves as a precursor for short-chain acyl-CoAs and lipids in the cytosol.[8]
OXCT1 is found in the mitochondrial matrix of all tissues except the liver, though it is most abundantly expressed in heart, brain, and kidney tissue.[5][7] Considering that liver cells function in ketogenesis and OXCT1 in ketolysis, OXCT1 may be absent from the liver to allow ketone body formation to proceed.[7]
# Clinical Significance
## Metabolic disorders
SCOT deficiency is a rare autosomal recessive metabolic disorder that can lead to recurrent episodes of ketoacidosis and even permanent ketosis. Twenty-four mutations in the human OXCT1 gene have been identified and associated with SCOT deficiency: three nonsense mutations, two insertion mutations, and 19 missense mutations. These mutations alter OXCT1 form and thus function in various ways, and they determine what phenotypic complications a patient may present. For instance, several missense mutations that substitute bulkier or charged residues hinder proper folding of OXCT1, leading to more severe outcomes such as permanent acidosis.[5]
OXCT1 has also been implicated diabetes. In a study by MacDonald et al., OXCT1 activity was shown to be lower by 92% in pancreatic islets of human patients with type 2 diabetes compared to those in healthy patients, though the cause is currently unknown.[8]
## Cancer
Since OXCT1 functions in metabolizing ketone bodies, it has been proposed to promote tumor growth by providing tumor cells with an additional energy source. Therefore, ketone inhibitors may prove effective in treating patients experiencing recurring and metastatic tumors.[9] A proteomics study identified OXCT1 to be one of 16 proteins upregulated in carcinoma HepG2 cells treated with Platycodin D, an anti-cancer agent.[10] | https://www.wikidoc.org/index.php/OXCT1 | |
27eb44352ce8737cbbb40055e3fcc991c7c2e5ca | wikidoc | OXGR1 | OXGR1
2-Oxoglutarate receptor 1 (OXGR1), also known as cysteinyl leukotriene receptor E (CysLTE) and GPR99, is a protein that in humans is encoded by the OXGR1 (also termed GPR99) gene. The Gene has recently been nominated as a receptor not only for 2-oxogluterate (see alpha-Ketoglutaric acid) but also for the three cysteinyl leukotrienes (CysLTs), particularly leukotriene E4 (LTE4) and to far lesser extents LTC4 and LTE4. Recent studies implicate GPR99 as a cellular receptor which is activated by LTE4 thereby causing these cells to contribute to mediating various allergic and hypersensitivity responses.
# History
In 2001, an gene projected to code for a G protein-like receptor protein was reported; the gene's apparent protein product was classified as an orphan receptor (i.e., a receptor whose activating ligand and function were unknown) and named GPR80. The projected amino acid sequence of the protein encoded by the GPR80 gene bore similarities to a purinergic receptor, P2Y1, and therefore might, like P2Y1, be a receptor for purine compounds. Shortly thereafter, a second report found this same gene, indicated that it coded for a G protein receptor with its amino acid sequence similarities closest to purinergic receptors GPR91 and P2Y1, and named the gene and its protein GPR99 and GPR99, respectively. While the latter report found that a large series of purinergic nucleotides, other nucleotides, and derivatives of these compounds did not activated GPR99-bearing cells, a third report in 2004 found that GPR99-bearing cells bound and responded to two purines, adenosine and Adenosine monophosphate, nominated GPR99 as a true purinergic receptor, and renamed GPR99 as P2Y15. However, a review of these studies in the same year by members of the International Union of Pharmacology (IUPHAR) Subcommittee for P2Y receptor nomenclature and classification decided that GPR80/GPR99 is not a P2Y receptor for adenosine, AMP or other nucleotides. Again in 2004, another report found that GPR99-bearing cells responded to alpha-ketoglutarate. This report was accepted by IUPHAR. The gene and its protein were renamed OXGR1 and OXGR1. Finally, in 2013, GPR99-bearing cells were found to bind and respond to CysLTs. The latter finding, while attracting further studies and of potential clinical importance, has not yet lead to a renaming of GPR99 or its protein product.
# Gene and product
GPR99 (OXGR1) is localized to human chromosome 13 at position 13q32.2; it codes for a cellular G protein coupled receptor linked primarily to G protein heterotrimers containing the Gq subunit; when bound to one of its activating ligands, the GPR99 protein stimulates cellular pathways (see Gq alpha subunit#Function) that lead to cell function.
# Activating ligands
GPR99 appears to be the receptor for alpha-ketoglutarate (AKG) and CysLTs. CyslTs and AKG have the following relative potencies in binding to GPR99-bearing cells, LTE4>>LTC4=LTD4>AKG; LTE4 is able to stimulate responses in these cells at concentrations as low as picomole/liter.
# Inhibiting ligands
GPR99 is inhibited by montelukast, a well-known and clinically useful inhibitor of cysteinyl leukotriene receptor 1 (CysLTR1); this drug binds to CysLTR1 thereby blocking the binding and action of LTD4, LTC4, and LTE4. It is presumed to act similarly to block the actins of these cystienyl leukotrienes on GPR99. It is not known if other CysLTR1 inhibitors (see Cysteinyl leukotriene receptor 1#Clinical significance) can mimic montelukast in blocking GPR99.
# Expression
Based on their content of GPR99 mRNA, GPR99 is expressed in human kidney, placenta, fetal brain, and tissues involved in allergic and hypersensitivity reactions such as the lung trachea, salivary glands, eosinophils, mast cells derived from umbilical cord blood, and nasal mucosa, particularly the vascular smooth muscle in the latter tissue. In mice, Gpr99 mRNA is expressed in kidneys, testes, and smooth muscle.
# Function
GPR99 binds as is activated by LTE4 at concentrations far lower than the other major CysLT receptors, Cysteinyl leukotriene receptor 1 (CysLTR1) and Cysteinyl leukotriene receptor 2 (CysLTR2), both of which appear to be physiological receptors for LTD4 and LTC4 but not LTF4 (see Cysteinyl leukotriene receptor 1#Function). This suggests that the actions of LTE4 are mediated, at least to a large extent, by GPR99. Several findings support this notion: a) pretreatment of guinea pig trachea and human bronchial smooth muscle with LTE4 but not LTC4 or LTD4 enhances their contraction responses to histamine; b) LTE4 is as potent as LTC4 and LTD4 in eliciting vascular leakage when injected into the skin of guinea pigs and humans; c) inhalation of LTE4 but not LTD4 by asthmatic subjects caused the accumulation of eosinophils and basophils in their bronchial mucosa; d) mice engineered to lack Cysltr1 and Cysltr2 receptors exhibited edema responses to the interdermal injection of LTC4, LTD4, and LTE4 but only LTE4 was more potent (by a factor of 64-fold) proved more potent in these mice compared to in wild type mice; and e) mice engineered to lack all three Cysltr1, Cysltr2, and Gpr99 receptors showed no dermal edema responses to the injection of LTC4, LTD4, or LTE4.
Mice deficient in Gpr99 (i.e. Oxgr1-/- gene knockout mice) develop (82% penetrance) spontaneous Otitis media with many characteristics of the human disease; while the underlying cause of this development, the Oxgr1-/- mouse is proposed to be a good model to study and relate to human ear pathology.
GPR99 also appears to be involved in the adaptive regulation of bicarbonate (HCO(3)(-)) secretion and salt (NaCl) reabsorption in the mouse kidneys undergoing acid-base stress: the kidneys of GPR99 gene knockout mice not respond to alpha-Ketoglutaric acid by upregulating becarbonate/NaCl exchange and are exhibited a reduced ability to maintain acid-base balance.
# Clinical significance
Montelucast is in use to treat various conditions including asthma, exercise-induced bronchoconstriction, allergic rhinitis, primary dysmenorrhoea (i.e. dysmenorrhoea not associated with known causes; see dysmenorrhea#causes), and urticaria. It has been presumed that this drug's beneficial effects in these diseases is due to its well-known ability to act as a receptor antagonist for the cysteinyl leukotriene receptor 1 (CysLTR1), i.e. it binds to but does not activate this receptor thereby interfering with LTD4, LTC4, and LTE4 provocative actions by blocking their binding to CysLTR1 (the drug does not block the cysteinyl leukotriene receptor 2) (see cysteinyl leukotriene receptor 1#Clinical significance). The more recently discovered ability of this drug to block the ability of LTE4 and LTD4 to stimulate GPR99 in GPR99-bearing cells allows that montelucast's beneficial effects on these conditions might reflect its ability to block not only CysLTR1 but also GPR99. | OXGR1
2-Oxoglutarate receptor 1 (OXGR1), also known as cysteinyl leukotriene receptor E (CysLTE) and GPR99,[1] is a protein that in humans is encoded by the OXGR1 (also termed GPR99) gene.[2][3][4] The Gene has recently been nominated as a receptor not only for 2-oxogluterate (see alpha-Ketoglutaric acid) but also for the three cysteinyl leukotrienes (CysLTs), particularly leukotriene E4 (LTE4) and to far lesser extents LTC4 and LTE4.[1] Recent studies implicate GPR99 as a cellular receptor which is activated by LTE4 thereby causing these cells to contribute to mediating various allergic and hypersensitivity responses.
# History
In 2001, an gene projected to code for a G protein-like receptor protein was reported; the gene's apparent protein product was classified as an orphan receptor (i.e., a receptor whose activating ligand and function were unknown) and named GPR80. The projected amino acid sequence of the protein encoded by the GPR80 gene bore similarities to a purinergic receptor, P2Y1, and therefore might, like P2Y1, be a receptor for purine compounds.[5] Shortly thereafter, a second report found this same gene, indicated that it coded for a G protein receptor with its amino acid sequence similarities closest to purinergic receptors GPR91 and P2Y1, and named the gene and its protein GPR99 and GPR99, respectively.[3] While the latter report found that a large series of purinergic nucleotides, other nucleotides, and derivatives of these compounds did not activated GPR99-bearing cells, a third report in 2004 found that GPR99-bearing cells bound and responded to two purines, adenosine and Adenosine monophosphate, nominated GPR99 as a true purinergic receptor, and renamed GPR99 as P2Y15.[6] However, a review of these studies in the same year by members of the International Union of Pharmacology (IUPHAR) Subcommittee for P2Y receptor nomenclature and classification decided that GPR80/GPR99 is not a P2Y receptor for adenosine, AMP or other nucleotides.[7] Again in 2004, another report found that GPR99-bearing cells responded to alpha-ketoglutarate.[2] This report was accepted by IUPHAR.[7][8] The gene and its protein were renamed OXGR1 and OXGR1. Finally, in 2013, GPR99-bearing cells were found to bind and respond to CysLTs.[1] The latter finding, while attracting further studies and of potential clinical importance, has not yet lead to a renaming of GPR99 or its protein product.
# Gene and product
GPR99 (OXGR1) is localized to human chromosome 13 at position 13q32.2; it codes for a cellular G protein coupled receptor linked primarily to G protein heterotrimers containing the Gq subunit; when bound to one of its activating ligands, the GPR99 protein stimulates cellular pathways (see Gq alpha subunit#Function) that lead to cell function.[9][10]
# Activating ligands
GPR99 appears to be the receptor for alpha-ketoglutarate (AKG)[2] and CysLTs. CyslTs and AKG have the following relative potencies in binding to GPR99-bearing cells, LTE4>>LTC4=LTD4>AKG; LTE4 is able to stimulate responses in these cells at concentrations as low as picomole/liter.[1]
# Inhibiting ligands
GPR99 is inhibited by montelukast, a well-known and clinically useful inhibitor of cysteinyl leukotriene receptor 1 (CysLTR1); this drug binds to CysLTR1 thereby blocking the binding and action of LTD4, LTC4, and LTE4. It is presumed to act similarly to block the actins of these cystienyl leukotrienes on GPR99.[1] It is not known if other CysLTR1 inhibitors (see Cysteinyl leukotriene receptor 1#Clinical significance) can mimic montelukast in blocking GPR99.
# Expression
Based on their content of GPR99 mRNA, GPR99 is expressed in human kidney, placenta, fetal brain, and tissues involved in allergic and hypersensitivity reactions such as the lung trachea, salivary glands, eosinophils, mast cells derived from umbilical cord blood, and nasal mucosa, particularly the vascular smooth muscle in the latter tissue.[1][11][12] In mice, Gpr99 mRNA is expressed in kidneys, testes, and smooth muscle.[1]
# Function
GPR99 binds as is activated by LTE4 at concentrations far lower than the other major CysLT receptors, Cysteinyl leukotriene receptor 1 (CysLTR1) and Cysteinyl leukotriene receptor 2 (CysLTR2), both of which appear to be physiological receptors for LTD4 and LTC4 but not LTF4 (see Cysteinyl leukotriene receptor 1#Function). This suggests that the actions of LTE4 are mediated, at least to a large extent, by GPR99. Several findings support this notion: a) pretreatment of guinea pig trachea and human bronchial smooth muscle with LTE4 but not LTC4 or LTD4 enhances their contraction responses to histamine; b) LTE4 is as potent as LTC4 and LTD4 in eliciting vascular leakage when injected into the skin of guinea pigs and humans; c) inhalation of LTE4 but not LTD4 by asthmatic subjects caused the accumulation of eosinophils and basophils in their bronchial mucosa; d) mice engineered to lack Cysltr1 and Cysltr2 receptors exhibited edema responses to the interdermal injection of LTC4, LTD4, and LTE4 but only LTE4 was more potent (by a factor of 64-fold) proved more potent in these mice compared to in wild type mice; and e) mice engineered to lack all three Cysltr1, Cysltr2, and Gpr99 receptors showed no dermal edema responses to the injection of LTC4, LTD4, or LTE4.[1]
Mice deficient in Gpr99 (i.e. Oxgr1-/- gene knockout mice) develop (82% penetrance) spontaneous Otitis media with many characteristics of the human disease; while the underlying cause of this development, the Oxgr1-/- mouse is proposed to be a good model to study and relate to human ear pathology.[13]
GPR99 also appears to be involved in the adaptive regulation of bicarbonate (HCO(3)(-)) secretion and salt (NaCl) reabsorption in the mouse kidneys undergoing acid-base stress: the kidneys of GPR99 gene knockout mice not respond to alpha-Ketoglutaric acid by upregulating becarbonate/NaCl exchange and are exhibited a reduced ability to maintain acid-base balance.[14]
# Clinical significance
Montelucast is in use to treat various conditions including asthma, exercise-induced bronchoconstriction, allergic rhinitis, primary dysmenorrhoea (i.e. dysmenorrhoea not associated with known causes; see dysmenorrhea#causes), and urticaria. It has been presumed that this drug's beneficial effects in these diseases is due to its well-known ability to act as a receptor antagonist for the cysteinyl leukotriene receptor 1 (CysLTR1), i.e. it binds to but does not activate this receptor thereby interfering with LTD4, LTC4, and LTE4 provocative actions by blocking their binding to CysLTR1 (the drug does not block the cysteinyl leukotriene receptor 2) (see cysteinyl leukotriene receptor 1#Clinical significance). The more recently discovered ability of this drug to block the ability of LTE4 and LTD4 to stimulate GPR99 in GPR99-bearing cells [1] allows that montelucast's beneficial effects on these conditions might reflect its ability to block not only CysLTR1 but also GPR99. | https://www.wikidoc.org/index.php/OXGR1 | |
a89c646348e8b76a8e2e974a93efd4031255defd | wikidoc | Obagi | Obagi
Zein E. Obagi, M.D.
Diplomat, American Board of Dermatology Fellow, American Academy of Dermatology Licensed to practice in California and Michigan
Career & Education
1981 – Present Private Practice
1980 – 1981 Staff Dermatologist, Naval Hospital Long Beach, CA
1977 – 1980 Resident in Dermatology, the Naval Hospital of San Diego San Diego, CA
1976 – 1977 Naval Medical Officer, United States Navy Honolulu, HI
1975 – 1976 Gynecology, Henry Ford Hospital, Detroit, MI
1973 – 1975 Pathology Residency, William Beaumont Hospital Royal Oak, MI
1972 – 1973 Rotating Intern, Deaconess Hospital Detroit, MI
1965 – 1972 Damascus Medical School Damascus, Syria
Private Practices
2006 – Present Obagi Skin Health Institute 270 N. Canon Drive, Suite 100 Beverly Hills, CA 90210
1994 – 2006 Obagi Dermatology Medical Clinic 9033 Wilshire Boulevard, Suite 100 Beverly Hills, CA 90211
1994 – Present Obagi Dermatology Medical Clinic, San Gabriel Annex 140 West Valley Blvd. #217 San Gabriel, CA 91776
Dr. Zein Obagi – Medical Director
Dr. Obagi is the Medical Director of ZO Skin Health, Inc. He is responsible for the development of new skincare treatments, protocols and product to achieve healthy skin. Additionally, he is a board certified practicing dermatologist and head of the Obagi Skin Health Institute in Beverly Hills, CA. , and an author and educator that has presented more than 200 skin health lectures throughout the world. For more than 35 years Dr. Obagi has defined and continues to advance skincare to include the concept of creating and maintaining healthy skin as opposed to just treating disease and damaged skin.
Dr. Obagi originally conceived and brought to market what would become the world's most recognized brands of physician dispensed skincare products – the original Obagi Nu-Derm® and Obagi Blue Peel® kit. Now Dr. Obagi, as the ZO Skin Health medical director, has redefined the concept of skin health to include comprehensive solutions that bridge the gap between therapeutics and maintaining truly healthy skin. | Obagi
Zein E. Obagi, M.D.
http://www.obagiskin.com
http://www.zoskinhealth.com
Diplomat, American Board of Dermatology Fellow, American Academy of Dermatology Licensed to practice in California and Michigan
Career & Education
1981 – Present Private Practice
1980 – 1981 Staff Dermatologist, Naval Hospital Long Beach, CA
1977 – 1980 Resident in Dermatology, the Naval Hospital of San Diego San Diego, CA
1976 – 1977 Naval Medical Officer, United States Navy Honolulu, HI
1975 – 1976 Gynecology, Henry Ford Hospital, Detroit, MI
1973 – 1975 Pathology Residency, William Beaumont Hospital Royal Oak, MI
1972 – 1973 Rotating Intern, Deaconess Hospital Detroit, MI
1965 – 1972 Damascus Medical School Damascus, Syria
Private Practices
2006 – Present Obagi Skin Health Institute 270 N. Canon Drive, Suite 100 Beverly Hills, CA 90210
1994 – 2006 Obagi Dermatology Medical Clinic 9033 Wilshire Boulevard, Suite 100 Beverly Hills, CA 90211
1994 – Present Obagi Dermatology Medical Clinic, San Gabriel Annex 140 West Valley Blvd. #217 San Gabriel, CA 91776
Dr. Zein Obagi – Medical Director
Dr. Obagi is the Medical Director of ZO Skin Health, Inc. He is responsible for the development of new skincare treatments, protocols and product to achieve healthy skin. Additionally, he is a board certified practicing dermatologist and head of the Obagi Skin Health Institute in Beverly Hills, CA. , and an author and educator that has presented more than 200 skin health lectures throughout the world. For more than 35 years Dr. Obagi has defined and continues to advance skincare to include the concept of creating and maintaining healthy skin as opposed to just treating disease and damaged skin.
Dr. Obagi originally conceived and brought to market what would become the world's most recognized brands of physician dispensed skincare products – the original Obagi Nu-Derm® and Obagi Blue Peel® kit. Now Dr. Obagi, as the ZO Skin Health medical director, has redefined the concept of skin health to include comprehensive solutions that bridge the gap between therapeutics and maintaining truly healthy skin. | https://www.wikidoc.org/index.php/Obagi | |
6581d3c8a4693dab69ce0b3de23989c8aed43604 | wikidoc | Oncom | Oncom
Oncom is one of the staple foods of Indonesia. In Indonesia, there are two kinds of oncom: red oncom and black oncom. Oncom is closely related to tempeh; both are foods fermented using molds, traditionally made in Indonesia. Oncom is particularly associated with West Java.
Oncom is made from the sediment left behind as a by-product form other foods -- soy bean sediment when making tofu, peanut sediment left when extracting peanut oil, cassava sediment when extracting the starch (pati singkong), coconut sediment left after extracting coconut milk.
Red oncom is made by using the mold Neurospora sitophila; it is the only human food produced by Neurospora species.
Black oncom is made by using the mold Rhizopus oligosporus.
# Toxicity
In the production of oncom, sanitation and hygiene are important to avoid contaminating the culture with bacteria or other fungi like Apergillus flavus (which produces Aflatoxin). The molds used, Neurospora sitophila and Rhizopus oligosporus, are identified to be able to reduce the aflatoxin produced by Apergillus flavus.
While it is known that soya beans are the best substrate for growing R. oligosporus to create tempeh, oncom has not been as thoroughly studied; the best types of sediment for producing oncom are not yet known.
- ↑ "Production of High-Quality Oncom, a Traditional Indonesian Fermented Food, by the Inoculation with Selected Mold Strains in the Form of Pure Culture and Solid Inoculum", D. D. Sastraatmadja et al., J. Grad. Sch. Agr. Hokkaido Univ., Vol. 70, Pt. 2: 111-127 (2002), at
id:Oncom
su:Oncom | Oncom
Oncom is one of the staple foods of Indonesia. In Indonesia, there are two kinds of oncom: red oncom and black oncom. Oncom is closely related to tempeh; both are foods fermented using molds, traditionally made in Indonesia. Oncom is particularly associated with West Java[1].
Oncom is made from the sediment left behind as a by-product form other foods -- soy bean sediment when making tofu, peanut sediment left when extracting peanut oil, cassava sediment when extracting the starch (pati singkong), coconut sediment left after extracting coconut milk.
Red oncom is made by using the mold Neurospora sitophila; it is the only human food produced by Neurospora species.
Black oncom is made by using the mold Rhizopus oligosporus.
# Toxicity
In the production of oncom, sanitation and hygiene are important to avoid contaminating the culture with bacteria or other fungi like Apergillus flavus (which produces Aflatoxin). The molds used, Neurospora sitophila and Rhizopus oligosporus, are identified to be able to reduce the aflatoxin produced by Apergillus flavus.
While it is known that soya beans are the best substrate for growing R. oligosporus to create tempeh, oncom has not been as thoroughly studied; the best types of sediment for producing oncom are not yet known.
- ↑ "Production of High-Quality Oncom, a Traditional Indonesian Fermented Food, by the Inoculation with Selected Mold Strains in the Form of Pure Culture and Solid Inoculum", D. D. Sastraatmadja et al., J. Grad. Sch. Agr. Hokkaido Univ., Vol. 70, Pt. 2: 111-127 (2002), at [1]
Template:Food-stub
id:Oncom
su:Oncom
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Oncom | |
c2dca980011cb524ca2a2835a710010157b256ee | wikidoc | Onion | Onion
Onion is a term used by many plants in the genus Allium. They are known by the common name "onion" but, used without qualifiers, it usually refers to Allium cepa. Allium cepa is also known as the 'garden onion' or 'bulb' onion and 'shallot'.
Allium cepa is known only in cultivation, but related wild species occur in Central Asia. The most closely-related species include Allium vavilovii Popov & Vved. and Allium asarense R.M. Fritsch & Matin from Iran. However Zohary and Hopf warn that "there are doubts whether the vavilovii collections tested represent genuine wild material or only feral derivatives of the crop."
# Uses
Onions, one of the oldest vegetables known to humankind, are found in a bewildering array of recipes and preparations, spanning almost the totality of the world's cultures; they are nowadays available in fresh, frozen, canned, pickled, and dehydrated forms. Onions can be used, usually chopped or sliced, in almost every type of food, including cooked foods and fresh salads, and as a spicy garnish; they are rarely eaten on their own but usually act as accompaniment to the main course. Depending on the variety, an onion can be sharp, spicy, tangy and pungent or mild and sweet.
Onions pickled in vinegar are eaten as a snack. These are often served as a side serving in fish and chip shops throughout the United Kingdom. Onions are a staple food in India, and are therefore fundamental to Indian cooking. They are commonly used as a base for curries, or made into a paste and eaten as a main course or as a side dish.
Tissue from onions is frequently used in science education to demonstrate microscope usage, because they have particularly large cells which are readily observed even at low magnifications.
# Historical uses
It is thought that bulbs from the onion family have been used as a food source for millennia. In Caananite Bronze Age settlements, traces of onion remains were found alongside fig and date stones dating back to 5000 BC. Onion is native to South Asia, and is widely used in Indian cuisine.
However, it is not clear if these were cultivated onions. Archaeological and literary evidence such as the Book of Numbers 11:5 suggests cultivation probably took place around two thousand years later in ancient Egypt, at the same time that leeks and garlic were cultivated. Workers who built the Egyptian pyramids may have been fed radishes and onions.
The onion is easily propagated, transported and stored. The Ancient Egyptians worshipped it, believing that its spherical shape and concentric rings symbolized eternal life. Onions were even used in Egyptian burials as evidenced by onion traces being found in the eye sockets of Ramesses IV. They believed that if buried with the dead, the strong scent of onions would bring breath back to the dead.
In ancient Greece, athletes ate large quantities of onion because it was believed that it would lighten the balance of blood. Roman gladiators were rubbed down with onion to firm up their muscles. In the Middle Ages onions were such an important food that people would pay for their rent with onions and even give them as gifts. Doctors were known to prescribe onions to facilitate bowel movements and erection, and also to relieve headaches, coughs, snakebite and hair loss. The onion was introduced to North America by Christopher Columbus on his 1492 expedition to Haiti. Onions were also prescribed by doctors in the early 1500s to help with infertility in women, and even dogs and cattle and many other household pets. However, recent evidence has proven that dogs, cats, and other animals should NOT be given onions in any form, due to toxicity during digestion.
# Medicinal properties and health benefits
Wide-ranging claims have been made for the effectiveness of onions against conditions ranging from the common cold to heart disease, diabetes, osteoporosis, and other diseases. They contain chemical compounds believed to have anti-inflammatory, anticholesterol, anticancer, and antioxidant properties such as quercetin. However, it has not been demonstrated that increased consumption of onions is directly linked to health benefits.
In many parts of the world, onions are used to heal blisters and boils. A traditional Maltese remedy for sea urchin wounds is to tie half a baked onion to the afflicted area overnight. In the morning, the spikes will be in the onion. In the United States, products that contain onion extract are used in the treatment of topical scars; some studies have found their action to be ineffective, while others found that they may act as an anti-inflammatory or bacteriostatic and can improve collagen organization in rabbits.
Onions may be especially beneficial for women, who are at increased risk for osteoporosis as they go through menopause, by destroying osteoclasts so that they do not break down bone.
# Onions and eye irritation
As onions are sliced, cells are broken, allowing enzymes called alliinases to break down amino acid sulphoxides and generate sulphenic acids. Sulphenic acids are unstable and spontaneously rearrange into a volatile gas called syn-propanethial-S-oxide. The gas diffuses through the air and eventually reaches the eye, where it reacts with the water to form a diluted solution of sulphuric acid. This acid irritates the nerve endings in the eye, making them sting. Tear glands produce tears to dilute and flush out the irritant.
Supplying ample water to the reaction or chewing gum while peeling onions prevents the gas from reaching the eyes. Eye irritation can, therefore, be avoided by cutting onions under running water or submerged in a basin of water. Rinsing the onion and leaving it wet while chopping may also be effective. Another way to avoid irritation is by not cutting off the root of the onion, or by doing it last, as the root of the onion has a higher concentration of enzymes. Using a sharp blade to chop onions will limit the cell damage and the release of enzymes that drive the irritation response. (Having a sharp knife and keeping the root of a halved onion on until the end also reduces the risk of cutting one's self if the knife slips). Chilling or freezing onions prevents the enzymes from activating, limiting the amount of gas generated. Having a fire, such as a candle or a burner, will help as the heat and flames will draw in the onion gas, burn it, and then send it up with the rest of the flame exhaust. In the heat, the chemical changes such that it no longer irritates the eyes.
The volume of sulfenic acids released, and the irritation effect, differs among Allium species.
On January 31, 2008, the New Zealand Crop and Food institute led by Colin Eady created 'no tears' onions by using Australian gene-silencing biotechnology.
# Propagation
Onions may be grown from seed or, most commonly, from sets. Onion sets are produced by sowing seed very thickly one year, resulting in stunted plants which produce very small bulbs. These bulbs are very easy to set out and grow into mature bulbs the following year, but they have the reputation of producing a less durable bulb than onions grown directly from seed and thinned.
Either planting method may be used to produce spring onions or green onions, which are onions harvested while immature. Green onion is a name also used to refer to Allium fistulosum, the Welsh onion, which is said not to produce dry bulbs.
# Varieties
- Brown and white onions
Brown and white onions
- Yellow Onions
Yellow Onions
- Flower head of a yellow onion
Flower head of a yellow onion
- Red onions
Red onions
- Bulb onion - Grown from seed (or onion sets), bulb onions range from the pungent varieties used for dried soups and onion powder to the mild and hearty sweet onions, such as the Vidalia from Georgia or Walla Walla from Washington that can be sliced and eaten on a sandwich instead of meat.
- Multiplier onions - Raised from bulbs which produce multiple shoots, each of which forms a bulb.
Potato onion
- Potato onion
- Tree onion or Egyptian onion - Produce bulblets in the flower head; a hybrid of Allium cepas.
- Welsh onion or Green onion
Leek
- Leek
Shallots and ten other onion (Allium cepa L.) varieties commonly available in the United States were evaluated: Western Yellow, Northern Red, New York Bold, Western White, Peruvian Sweet, Empire Sweet, Mexico, Texas 1015, Imperial Valley Sweet, and Vidalia. In general, the most pungent onions delivered many times the benefits of their milder cousins.
Shallots have the most phenols, six times the amount found in Vidalia onion, the variety with the lowest phenolic content. Shallots also have the most antioxidant activity, followed by Western Yellow, New York Bold, Northern Red, Mexico, Empire Sweet, Western White, Peruvian Sweet, Texas 1015, Imperial Valley Sweet, and Vidalia. Western Yellow onions have the most flavonoids, eleven times the amount found in Western White, the variety with the lowest flavonoid content.
For all varieties of onions, the more phenols and flavonoids they contain, the more antioxidant and anti-cancer activity they provide. When tested against liver and colon cancer cells, Western Yellow, New York Bold and shallots were most effective in inhibiting their growth. The milder-tasting varieties—Western White, Peruvian Sweet, Empire Sweet, Mexico, Texas 1015, Imperial Valley Sweet, and Vidalia—showed little cancer-fighting ability.
# Production trends
# Onions in language
In the English vernacular, "an onion" is a difficult situation, the use stemming from the onion's tendency to irritate or inflame the eyes. Conversely, the term "onion" can be used to describe any state of being, as in the phrase, " really dices my onion!" It may also represent an object of many layers.
In some Scots dialects, onion is pronounced 'Ingin'.
An "Onion" is also an old slang term to decribe a person from Bermuda; a Bermudian.
Bermuda is known to sprout some of best onions in the world, that is why they're (Bermudians) called "onions".
Feminist poet Carol Ann Duffy uses the onion as a metaphor of love and relationships in her poem "Valentine" (1993), one of the poems in her collection "Mean time"
Expressions referring to "layers of the onion" evoke the process of peeling back the layers of something (a person, reality, etc.), without however reaching a core - the centre of the onion being simply another layer. The metaphor is thus used to challenge the notion that there is a core/essence 'behind' surface layers, stressing the continuity between layer and core. Due to the number of layers in an onion it can also be used simply to evoke complexity - something having 'many layers', or 'always another layer behind this one".
This idea was used (& twisted) in the first Shrek movie, (Dreamworks LLC), when Shrek tries to explain to his partner, Donkey, that he is a complex person by telling him that 'Ogres are like onions.' (meaning that they have layers), to which Donkey replies 'Oh I get it. You leave them out in the sun too long and they go all brown and start sprouting little white hairs!'
In other languages too the onion has acquired different connotations, eg., amongst the Khasi tribe in North East India, Onion or "piat" in the local dialect refers to someone who is present everywhere or in every social gathering.
# Notes
- ↑ "Allium cepa Linnaeus". Flora of North America..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}
- ↑ Grubben, G.J.H. & Denton, O.A. (2004) Plant Resources of Tropical Africa 2. Vegetables. PROTA Foundation, Wageningen; Backhuys, Leiden; CTA, Wageningen.
- ↑ Daniel Zohary and Maria Hopf, Domestication of plants in the Old World, third edition (Oxford: University Press, 2000), p. 198
- ↑ "Genetics Teaching Vignettes: Elementary School" (html). 2004-06-15. Retrieved 2008-01-28.
- ↑ Jump up to: 5.0 5.1 "Onions Allium cepa". selfsufficientish.com. Retrieved 2006-04-02.
- ↑ Sen 2004: 58
- ↑ Jump up to: 7.0 7.1 "About Onions: History". Retrieved 2008-01-30.
- ↑ "Human Foods that Poison Pets". Retrieved 2008-01-30.
- ↑ World's Healthiest Foods
Product Review: Mederma for Scars
- ↑ Topical scar modification: Hype or help?. (Aesthetic Surgery Journal)
- ↑ Zurada JM, Kriegel D, Davis IC (2006). "Topical treatments for hypertrophic scars". Journal of the American Academy of Dermatology. 55 (6): 1024–1031. doi:10.1016/j.jaad.2006.03.022. PMID 17097399.CS1 maint: Multiple names: authors list (link)
- ↑ K. Augusti, Therapeutic values of onion (Allium cepa L.) and garlic (Allium sativum L.), Indian J Exp Biol 34 (1996), pp. 634–640.
- ↑ Saulis, Alexandrina S. M.D.; Mogford, Jon H. Ph.D.; Mustoe, Thomas A. M.D. (2002). "Effect of Mederma on Hypertrophic Scarring in the Rabbit Ear Model". Plastic and Reconstructive Surgery. 110 (1): 177–183. doi:10.1097/00006534-200207000-00029. PMID 12087249.CS1 maint: Multiple names: authors list (link)
- ↑ "Onion Compound May Help Fight Osteoporosis" (html). 2005-04-11. Retrieved 2008-01-30.
- ↑ Scott, Thomas. "What is the chemical process that causes my eyes to tear when I peel an onion?". Ask the Experts: Chemistry. Scientific American. Retrieved 2007-04-28.
- ↑ Onions-USA.org FAQ
- ↑ news.com.au, Scientists create 'no tears' onions
- ↑ Jump up to: 19.0 19.1 "Onion a day keeps doctor away?" (hmtl). Cornell University. 2004-10-07. Retrieved 2008-01-30. | Onion
Onion is a term used by many plants in the genus Allium. They are known by the common name "onion" but, used without qualifiers, it usually refers to Allium cepa. Allium cepa is also known as the 'garden onion' or 'bulb' onion and 'shallot'.
Allium cepa is known only in cultivation,[1] but related wild species occur in Central Asia. The most closely-related species include Allium vavilovii Popov & Vved. and Allium asarense R.M. Fritsch & Matin from Iran.[2] However Zohary and Hopf warn that "there are doubts whether the vavilovii collections tested represent genuine wild material or only feral derivatives of the crop."[3]
# Uses
Onions, one of the oldest vegetables known to humankind, are found in a bewildering array of recipes and preparations, spanning almost the totality of the world's cultures; they are nowadays available in fresh, frozen, canned, pickled, and dehydrated forms. Onions can be used, usually chopped or sliced, in almost every type of food, including cooked foods and fresh salads, and as a spicy garnish; they are rarely eaten on their own but usually act as accompaniment to the main course. Depending on the variety, an onion can be sharp, spicy, tangy and pungent or mild and sweet.
Onions pickled in vinegar are eaten as a snack. These are often served as a side serving in fish and chip shops throughout the United Kingdom. Onions are a staple food in India, and are therefore fundamental to Indian cooking. They are commonly used as a base for curries, or made into a paste and eaten as a main course or as a side dish.
Tissue from onions is frequently used in science education to demonstrate microscope usage, because they have particularly large cells which are readily observed even at low magnifications.[4]
# Historical uses
It is thought that bulbs from the onion family have been used as a food source for millennia. In Caananite Bronze Age settlements, traces of onion remains were found alongside fig and date stones dating back to 5000 BC.[5] Onion is native to South Asia, and is widely used in Indian cuisine.[6]
However, it is not clear if these were cultivated onions. Archaeological and literary evidence such as the Book of Numbers 11:5 suggests cultivation probably took place around two thousand years later in ancient Egypt, at the same time that leeks and garlic were cultivated. Workers who built the Egyptian pyramids may have been fed radishes and onions.[5]
The onion is easily propagated, transported and stored. The Ancient Egyptians worshipped it,[7] believing that its spherical shape and concentric rings symbolized eternal life. Onions were even used in Egyptian burials as evidenced by onion traces being found in the eye sockets of Ramesses IV. They believed that if buried with the dead, the strong scent of onions would bring breath back to the dead.
In ancient Greece, athletes ate large quantities of onion because it was believed that it would lighten the balance of blood. Roman gladiators were rubbed down with onion to firm up their muscles. In the Middle Ages onions were such an important food that people would pay for their rent with onions and even give them as gifts.[7] Doctors were known to prescribe onions to facilitate bowel movements and erection, and also to relieve headaches, coughs, snakebite and hair loss. The onion was introduced to North America by Christopher Columbus on his 1492 expedition to Haiti. Onions were also prescribed by doctors in the early 1500s to help with infertility in women, and even dogs and cattle and many other household pets. However, recent evidence has proven that dogs, cats, and other animals should NOT be given onions in any form, due to toxicity during digestion.
[8]
# Medicinal properties and health benefits
Template:Nutritionalvalue
Wide-ranging claims have been made for the effectiveness of onions against conditions ranging from the common cold to heart disease, diabetes, osteoporosis, and other diseases.[9] They contain chemical compounds believed to have anti-inflammatory, anticholesterol, anticancer, and antioxidant properties such as quercetin. However, it has not been demonstrated that increased consumption of onions is directly linked to health benefits.
In many parts of the world, onions are used to heal blisters and boils. A traditional Maltese remedy for sea urchin wounds is to tie half a baked onion to the afflicted area overnight. In the morning, the spikes will be in the onion.[citation needed] In the United States, products that contain onion extract are used in the treatment of topical scars; some studies have found their action to be ineffective, [10][11][12] while others found that they may act as an anti-inflammatory or bacteriostatic [13] and can improve collagen organization in rabbits.[14]
Onions may be especially beneficial for women,[15] who are at increased risk for osteoporosis as they go through menopause, by destroying osteoclasts so that they do not break down bone.
# Onions and eye irritation
As onions are sliced, cells are broken, allowing enzymes called alliinases to break down amino acid sulphoxides and generate sulphenic acids. Sulphenic acids are unstable and spontaneously rearrange into a volatile gas called syn-propanethial-S-oxide. The gas diffuses through the air and eventually reaches the eye, where it reacts with the water to form a diluted solution of sulphuric acid. This acid irritates the nerve endings in the eye, making them sting. Tear glands produce tears to dilute and flush out the irritant.[16]
Supplying ample water to the reaction or chewing gum while peeling onions prevents the gas from reaching the eyes. Eye irritation can, therefore, be avoided by cutting onions under running water or submerged in a basin of water. Rinsing the onion and leaving it wet while chopping may also be effective. Another way to avoid irritation is by not cutting off the root of the onion, or by doing it last, as the root of the onion has a higher concentration of enzymes.[17] Using a sharp blade to chop onions will limit the cell damage and the release of enzymes that drive the irritation response. (Having a sharp knife and keeping the root of a halved onion on until the end also reduces the risk of cutting one's self if the knife slips). Chilling or freezing onions prevents the enzymes from activating, limiting the amount of gas generated. Having a fire, such as a candle or a burner, will help as the heat and flames will draw in the onion gas, burn it, and then send it up with the rest of the flame exhaust.[citation needed] In the heat, the chemical changes such that it no longer irritates the eyes.[citation needed]
The volume of sulfenic acids released, and the irritation effect, differs among Allium species.
On January 31, 2008, the New Zealand Crop and Food institute led by Colin Eady created 'no tears' onions by using Australian gene-silencing biotechnology.[18]
# Propagation
Onions may be grown from seed or, most commonly, from sets. Onion sets are produced by sowing seed very thickly one year, resulting in stunted plants which produce very small bulbs. These bulbs are very easy to set out and grow into mature bulbs the following year, but they have the reputation of producing a less durable bulb than onions grown directly from seed and thinned.
Either planting method may be used to produce spring onions or green onions, which are onions harvested while immature. Green onion is a name also used to refer to Allium fistulosum, the Welsh onion, which is said not to produce dry bulbs.
# Varieties
- Brown and white onions
Brown and white onions
- Yellow Onions
Yellow Onions
- Flower head of a yellow onion
Flower head of a yellow onion
- Red onions
Red onions
- Bulb onion - Grown from seed (or onion sets), bulb onions range from the pungent varieties used for dried soups and onion powder to the mild and hearty sweet onions, such as the Vidalia from Georgia or Walla Walla from Washington that can be sliced and eaten on a sandwich instead of meat.
- Multiplier onions - Raised from bulbs which produce multiple shoots, each of which forms a bulb.
Potato onion
- Potato onion
- Tree onion or Egyptian onion - Produce bulblets in the flower head; a hybrid of Allium cepas.
- Welsh onion or Green onion
Leek
- Leek
Shallots and ten other onion (Allium cepa L.) varieties commonly available in the United States were evaluated: Western Yellow, Northern Red, New York Bold, Western White, Peruvian Sweet, Empire Sweet, Mexico, Texas 1015, Imperial Valley Sweet, and Vidalia. In general, the most pungent onions delivered many times the benefits of their milder cousins.[19]
Shallots have the most phenols, six times the amount found in Vidalia onion, the variety with the lowest phenolic content. Shallots also have the most antioxidant activity, followed by Western Yellow, New York Bold, Northern Red, Mexico, Empire Sweet, Western White, Peruvian Sweet, Texas 1015, Imperial Valley Sweet, and Vidalia. Western Yellow onions have the most flavonoids, eleven times the amount found in Western White, the variety with the lowest flavonoid content.
For all varieties of onions, the more phenols and flavonoids they contain, the more antioxidant and anti-cancer activity they provide. When tested against liver and colon cancer cells, Western Yellow, New York Bold and shallots were most effective in inhibiting their growth. The milder-tasting varieties—Western White, Peruvian Sweet, Empire Sweet, Mexico, Texas 1015, Imperial Valley Sweet, and Vidalia—showed little cancer-fighting ability.[19]
# Production trends
# Onions in language
In the English vernacular, "an onion" is a difficult situation, the use stemming from the onion's tendency to irritate or inflame the eyes.[citation needed] Conversely, the term "onion" can be used to describe any state of being, as in the phrase, "[someone] really dices my onion!" It may also represent an object of many layers.
In some Scots dialects, onion is pronounced 'Ingin'.
An "Onion" is also an old slang term to decribe a person from Bermuda; a Bermudian.
Bermuda is known to sprout some of best onions in the world, that is why they're (Bermudians) called "onions".
Feminist poet Carol Ann Duffy uses the onion as a metaphor of love and relationships in her poem "Valentine" (1993), one of the poems in her collection "Mean time"
Expressions referring to "layers of the onion" evoke the process of peeling back the layers of something (a person, reality, etc.), without however reaching a core - the centre of the onion being simply another layer. The metaphor is thus used to challenge the notion that there is a core/essence 'behind' surface layers, stressing the continuity between layer and core. Due to the number of layers in an onion it can also be used simply to evoke complexity - something having 'many layers', or 'always another layer behind this one".
This idea was used (& twisted) in the first Shrek movie, (Dreamworks LLC), when Shrek tries to explain to his partner, Donkey, that he is a complex person by telling him that 'Ogres are like onions.' (meaning that they have layers), to which Donkey replies 'Oh I get it. You leave them out in the sun too long and they go all brown and start sprouting little white hairs!'
In other languages too the onion has acquired different connotations, eg., amongst the Khasi tribe in North East India, Onion or "piat" in the local dialect refers to someone who is present everywhere or in every social gathering.
# Notes
- ↑ "Allium cepa Linnaeus". Flora of North America..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}
- ↑ Grubben, G.J.H. & Denton, O.A. (2004) Plant Resources of Tropical Africa 2. Vegetables. PROTA Foundation, Wageningen; Backhuys, Leiden; CTA, Wageningen.
- ↑ Daniel Zohary and Maria Hopf, Domestication of plants in the Old World, third edition (Oxford: University Press, 2000), p. 198
- ↑ "Genetics Teaching Vignettes: Elementary School" (html). 2004-06-15. Retrieved 2008-01-28.
- ↑ Jump up to: 5.0 5.1 "Onions Allium cepa". selfsufficientish.com. Retrieved 2006-04-02.
- ↑ Sen 2004: 58
- ↑ Jump up to: 7.0 7.1 "About Onions: History". Retrieved 2008-01-30.
- ↑ "Human Foods that Poison Pets". Retrieved 2008-01-30.
- ↑ World's Healthiest Foods
- ↑
Product Review: Mederma for Scars
- ↑ Topical scar modification: Hype or help?. (Aesthetic Surgery Journal)
- ↑ Zurada JM, Kriegel D, Davis IC (2006). "Topical treatments for hypertrophic scars". Journal of the American Academy of Dermatology. 55 (6): 1024–1031. doi:10.1016/j.jaad.2006.03.022. PMID 17097399.CS1 maint: Multiple names: authors list (link)
- ↑ K. Augusti, Therapeutic values of onion (Allium cepa L.) and garlic (Allium sativum L.), Indian J Exp Biol 34 (1996), pp. 634–640.
- ↑ Saulis, Alexandrina S. M.D.; Mogford, Jon H. Ph.D.; Mustoe, Thomas A. M.D. (2002). "Effect of Mederma on Hypertrophic Scarring in the Rabbit Ear Model". Plastic and Reconstructive Surgery. 110 (1): 177–183. doi:10.1097/00006534-200207000-00029. PMID 12087249.CS1 maint: Multiple names: authors list (link)
- ↑ "Onion Compound May Help Fight Osteoporosis" (html). 2005-04-11. Retrieved 2008-01-30.
- ↑ Scott, Thomas. "What is the chemical process that causes my eyes to tear when I peel an onion?". Ask the Experts: Chemistry. Scientific American. Retrieved 2007-04-28.
- ↑ Onions-USA.org FAQ
- ↑ news.com.au, Scientists create 'no tears' onions
- ↑ Jump up to: 19.0 19.1 "Onion a day keeps doctor away?" (hmtl). Cornell University. 2004-10-07. Retrieved 2008-01-30. | https://www.wikidoc.org/index.php/Onion | |
54e07e528fc4a3c7aa4e2f26d4b3b66e10122a45 | wikidoc | Opium | Opium
# Overview
Opium is a narcotic formed from the latex released by lacerating (or "scoring") the immature seed pods of opium poppies (Papaver somniferum). It contains up to 16% morphine, an opiate alkaloid, which is most frequently processed chemically to produce heroin for the illegal drug trade. The resin also includes non-narcotic alkaloids, such as papaverine and noscapine. Meconium historically referred to related, weaker preparations made from other parts of the poppy or different species of poppies. Modern opium production is the culmination of millennia of production, in which the source poppy, methods of extraction and processing, and methods of consumption have become increasingly potent.
Cultivation of opium poppies for food, anesthesia, and ritual purposes dates back to at least the Neolithic Age. The Sumerian, Assyrian, Egyptian, Minoan, Greek, Roman, Persian and Arab Empires each made widespread use of opium, which was the most potent form of pain relief then available, allowing ancient surgeons to perform prolonged surgical procedures. Opium is mentioned in the most important medical texts of the ancient world, including the Ebers Papyrus and the writings of Dioscorides, Galen, and Avicenna. Widespread medical use of unprocessed opium continued through the American Civil War before giving way to morphine and its successors, which could be injected at a precisely controlled dosage. American morphine is still produced primarily from poppies grown and processed in India in the traditional manner, and remains the standard of pain relief for casualties of war.
Recreational use of the drug began in China in the fifteenth century, but was limited by its rarity and expense. Opium trade became more regular by the seventeenth century, when it was mixed with tobacco for smoking, and addiction was first recognized. Opium prohibition in China began in 1729, and was followed by nearly two centuries of exponentially increasing opium use. China had a positive balance sheet in trading with the British, which led to a decrease of the British silver stocks. Therefore, the British tried to make the Chinese people dependent on opium to enhance their balance, they delivered it from Indian provinces under British control. A massive confiscation of opium by the Chinese emperor, who tried to stop the opium deliveries, led to two Opium Wars in 1840 and 1858, in which consequence Britain suppressed China and traded opium all over the country. After 1860 opium use continued to increase with widespread domestic production in China, until more than a quarter of the male population was addicted by 1905. Recreational or addictive opium use in other nations remained rare into the late nineteenth century, recorded by an ambivalent literature that sometimes praised the drug.
Global regulation of opium began with the stigmatization of Chinese immigrants and opium dens, leading rapidly from town ordinances in the 1870s to the formation of the International Opium Commission in 1909. During this period the portrayal of opium in literature became squalid and violent, British opium trade was largely supplanted by domestic Chinese production, purified morphine and heroin became widely available for injection, and patent medicines containing opiates reached a peak of popularity. Opium was prohibited in many countries during the early twentieth century, leading to the modern pattern of opium production as a precursor for illegal recreational drugs or tightly regulated legal prescription drugs. Illicit opium production, now dominated by Afghanistan, has increased steadily in recent years to over 6600 tons yearly, nearly one-fifth the level of production in 1906. Opium for illegal use is generally converted into heroin, which doubles its potency, and taken by intravenous injection, which more than doubles the quantity of drug entering the body.
# History
## Ancient use (4200 BC - 800 BC)
The use of the opium poppy dates from time immemorial. At least seventeen finds of Papaver somniferum from Neolithic settlements have been reported throughout Switzerland, Germany, and Spain, including the placement of large numbers of poppy seed capsules at a burial site (the Cueva de los Murciélagos, or "Bat cave", in Spain), which have been carbon dated to 4200 B.C. Numerous finds of Papaver somniferum or Papaver setigerum from Bronze Age and Iron Age settlements have also been reported.
The first known cultivation of opium poppies was in Mesopotamia, approximately 3400 B.C., by Sumerians who called the plant Hul Gil, the "joy plant". Tablets found at Nippur, a Sumerian spiritual center south of Baghdad, described the collection of poppy juice in the morning and its use in production of opium. Cultivation continued in the Middle East by the Assyrians, who also collected poppy juice in the morning after scoring the pods with an iron scoop; they called the juice aratpa-pal, possibly the root of Papaver. Opium production continued under the Babylonians and Egyptians.
Opium was used with poison hemlock to put people quickly and painlessly to death, but it was also used in medicine. The Ebers Papyrus, ca. 1500 B.C., describes a way to "prevent the excessive crying of children" using grains of the poppy-plant strained to a pulp. Spongia somnifera, sponges soaked in opium, were used during surgery. The Egyptians cultivated opium thebaicum in famous poppy fields around 1300 B.C. Opium was traded from Egypt by the Phoenicians and Minoans to destinations around the Mediterranean Sea, including Greece, Carthage, and Europe. By 1100 B.C. opium was cultivated on the Mediterranean island of Cyprus, where surgical quality knives were used to score the poppy pods, and opium was cultivated, traded, and smoked. Opium was also mentioned after the Persian conquest of Assyria and Babylonia in the sixth century B.C.
From the earliest finds opium has appeared to have ritual significance, and anthropologists have speculated that ancient priests may have used the drug as a proof of healing power. In Egypt, the use of opium was generally restricted to priests, magicians, and warriors, its invention credited to Thoth, and it was said to have been given by Isis to Ra as treatment for a headache. A figure of the Minoan "goddess of the narcotics", wearing a crown of three opium poppies, ca. 1300 B.C., was recovered from the Sanctuary of Gazi, Crete, together with a simple smoking apparatus. The Greek gods Hypnos (Sleep), Nyx (Night), and Thanatos (Death) were depicted wreathed in poppies or holding poppies. Poppies also frequently adorned statues of Apollo, Asklepios, Pluto, Demeter, Aphrodite, Kybele and Isis, symbolizing nocturnal oblivion.
## Greece and Rome (800 BC-600 AD)
Opium was well known to the ancient Greeks. The first Greek written account of poppy production was by Hesiod in the eighth century B.C., who called the poppy plant μήκωνιον (mekonion), and its juice όπός μήκων (opos mekun). Homer described to his audience an exhausted warrior dropping his heavy helmeted head, like a drooping poppy bud. Hippocrates recognized opium as useful in treating internal diseases, diseases of women and epidemics. Alexander the Great is credited with introducing opium to India and Persia in 330 B.C. The Greeks distinguished opium from a weaker drug, "meconium". This could refer specifically to a different poppy strain e.g. Euphorbia paralias (paralion). Alternatively, "meconium" was used by Hippocrates, Pedanius Dioscorides, Pliny the Elder, and Scribonius Largus to refer to juice emanating from the leaves and fruit of the poppy, or obtained from them by boiling (see Poppy tea), or tablets formed by crushing them in a mortar and pestle. The Greek όπός or όπιον became Roman opium, and later Persian ab-yun, Arabic af-yuun, and Chinese af-yong or yaa-pian. Because variants of "opos" or "opion" are widely used to denote the sap throughout the world, even where the plant itself is known by indigenous names, it was formerly thought that the Greeks first discovered the collection of poppy sap, and that previous use had been limited to consumption of seed capsules.
Curiously, many ancient physicians described many species of poppies, giving only limited preference to Papaver somniferum. Hippocrates mentioned white, fire-red, black, and hypnotic varieties; Theophrastus described black or horned, flowing, and Heraklean varieties. The varieties from Dioscorides' pharmacopoeia have been tentatively assigned to modern species: Papaver hybridum, a "flowing" poppy that sheds its flowers rapidly, with hypnotic properties; Papaver somniferum, a cultivated garden "pouched" poppy that is good for baking bread and has white seeds and elongated flowers; Papaver orientalis, a wild "jar" poppy with elongated and involuted capsule and black seeds; another more poisonous wild poppy with a longer capsule; Glauceum luteum, a "horned" poppy growing wild by the sea; and Gratiola officinalis, the "foaming" or Heraklean poppy. It has been speculated that opium may originally have been obtained from Papaver setigerum, a close relative of Papaver somniferum from which it was once thought to have been domesticated. However, although Papaver setigerum is one of very few poppies to have a significant morphine content, early cytogenetic analysis revealed that it is a tetraploid with 22 chromosomes, compared to the 11 of Papaver somniferum, making it an unlikely ancestor.
In De Medicina (ca. 30 AD), Aulus Cornelius Celsus detailed many uses for "poppy-tears", as an emollient for painful joints and anal fissures, in anodynes (pills promoting relief of pain through sleep), in antidotes for poisoning (including the Mithridatium), for use in colic, and to promote micturition. He also recommended the juice of boiled poppy heads for procuring sleep, treating earaches, intestinal gripings, inflammation of the womb, and to reduce the flow of phlegm into the eyes. However, Celsus is thought to have used a wild poppy, Papaver rhoeas, with a very low opiate content, and in any case did not regard it as uniquely powerful. He described "poppy-tears" as one of many emollient herbs and minerals, used as an ingredient in some formulations for pain but not others.
Despite the widespread therapeutic and possible ritual use of the drug, and although drunkenness from wine was well documented, there is very little evidence that opium addiction or hedonistic use of opium occurred in the ancient world. The best candidates for opium addiction noted from ancient accounts are Ovid and the Roman emperor Marcus Aurelius. Another difference from common modern practice is that ancient authors such as Hippocrates and Celsus often described the topical use of opium or "poppy-tears" directly at the site of pain, in the eye, or introduced into a wound. When administered directly at the site of pain, morphine has recently been recognized to have a moderate analgesic effect, relying on peripheral opioid receptors, and this limited dosage does not have addictive or life-threatening effects.
## Islamic Empire (600-1500 A.D.)
As the power of the Roman Empire declined, the lands to the south and east of the Mediterranean became incorporated into the Islamic Empire, which assembled the finest libraries and the most skilled physicians of the era. Many Muslims believe that the hadith of al-Bukhari prohibits every intoxicating substance as haraam, but the use of intoxicants in medicine has been widely permitted. Dioscorides' five-volume De Materia Medica, ancestor to all modern pharmacopoeias, remained in continuous use (with some improvements in Arabic versions) from the first century until 1600 A.D., and described opium, meconium and the wide range of uses prevalent in the ancient world.
Somewhere between 400 and 1200 A.D., Arab traders introduced opium to China. The Persian physician, Agha Bakr Muhammad ibn Zakariya al-Razi (845-930 A.D.), who was born near Tehran and maintained a laboratory and school in Baghdad, and was a student and critic of Galen, made use of opium in anesthesia and recommended its use for the treatment of melancholy in Man la Yahduruhu Al-Tabib, a home medical manual directed toward ordinary citizens for self-treatment if a doctor was not available. The renowned opthalmologic surgeon Abu al-Qasim Ammar (936-1013 A.D.) relied on opium and mandrake as surgical anaesthetics, and wrote a treatise al-Tasrif that influenced medical thought well into the sixteenth century. The Persian physician Abū ‘Alī al-Husayn (Avicenna) described opium as the most powerful of the stupefacients, by comparison with mandrake and other highly effective herbs, in The Canon of Medicine. This classic text was translated into Latin in 1175 and later into many other languages, and remained authoritative into the seventeenth century. Şerefeddin Sabuncuoğlu used opium in the fourteenth century Ottoman Empire to treat migraine headache, sciatica, and other painful ailments.
## Reintroduction to Western Medicine
Opium became stigmatized in Europe during the Inquisition as a Middle Eastern influence, and became a taboo subject in Europe from approximately 1300 to 1500 A.D. Manuscripts of Pseudo-Apuleius' fifth-century work from the tenth and eleventh centuries refer to the use of wild poppy Papaver agreste or Papaver rhoeas (identified as Papaver silvaticum) instead of Papaver somniferum for inducing sleep and relieving pain.
The use of Paracelsus' laudanum was introduced to Western medicine in 1527, when Philip Aureolus Theophrastus Bombast von Hohenheim returned from his wanderings in Arabia with a famous sword, within the pommel of which he kept "Stones of Immortality" compounded from opium thebaicum, citrus juice, and "quintessence of gold". The name "Paracelsus" was a pseudonym signifying him the equal or better of Aulus Cornelius Celsus, whose text, which described the use of opium or a similar preparation, had recently been translated and reintroduced to medieval Europe. The Canon of Medicine, the standard medical textbook that Paracelsus burned in a public bonfire three weeks after being appointed professor at the University of Basel, also described the use of opium, though many Latin translations were of poor quality. "Laudanum" was originally the sixteenth-century term for a medicine associated with a particular physician that was widely well-regarded, but became standardized as "tincture of opium", a solution of opium in ethyl alcohol, which Paracelsus has been credited with developing. During his lifetime, Paracelsus was viewed as an adventurer who challenged the theories and mercenary motives of contemporary medicine with dangerous chemical therapies, but his therapies marked a turning point in Western medicine. In the seventeenth century laudanum was recommended for pain, sleeplessness, and diarrhea by Thomas Sydenham, the renowned "father of English medicine" or "English Hippocrates", to whom is attributed the quote, "Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium." Use of opium as a cure-all was reflected in the formulation of mithridatium described in the 1728 Chambers Cyclopedia, which included true opium in the mixture. Subsequently laudanum became the basis of many popular patent medicines of the nineteenth century.
The standard medical use of opium persisted well into the nineteenth century. U.S president William Henry Harrison was treated with opium in 1841, and in the American Civil War, the Union Army used 2.8 million ounces of opium tincture and powder and about 500,000 opium pills. During this time of popularity, users called opium "God's Own Medicine".
## Recreational use
The earliest clear description of the use of opium as a recreational drug came from Xu Boling, who wrote in 1483 that opium was "mainly used to aid masculinity, strengthen sperm and regain vigor", and that it "enhances the art of alchemists, sex and court
ladies.". He described an expedition sent by the Chenghua Emperor in 1483 to procure opium for a price "equal to that of gold" in Hainan, Fujian, Zhejiang, Sichuan and Shaanxi where it is close to Xiyu. A century later Li Shizhen listed standard medical uses of opium in his renowned Compendium of Materia Medica (1578), but also wrote that "lay people use it for the art of sex", in particular the ability to "arrest seminal emission". This association of opium with sex continued in China until the twentieth century. Opium smoking began as a privilege of the elite, and remained a great luxury into the early nineteenth century, but by 1861, Wang Tao wrote that opium was used even by rich peasants, and even a small village without a rice store would have a shop where opium was sold.
Smoking of opium came on the heels of tobacco smoking, and may have been encouraged by a brief ban on the smoking of tobacco by the Ming emperor, ending in 1644 with the Qing dynasty, which had encouraged smokers to mix in increasing amounts of opium. In 1705, Wang Shizhen wrote that "nowadays, from nobility and gentlemen down to slaves and women, all are addicted to tobacco". Tobacco in that time was frequently mixed with other herbs (this continues with clove cigarettes to the modern day), and opium was one component in the mixture. Tobacco mixed with opium was called madak (or madat), and became popular throughout China and its seafaring trade partners (such as Taiwan, Java and the Philippines) in the seventeenth century. In 1712, Engelbert Kaempfer described addiction to madak: "No commodity throughout the Indies is retailed with greater profit by the Batavians than opium, which users cannot do without, nor can they come by it except it be brought by the ships of the Batavians from Bengal and Coromandel."
Fueled in part by the 1729 ban on madak, which at first effectively exempted pure opium as a potentially medicinal product, the smoking of pure opium became more popular in the eighteenth century. In 1736, the smoking of pure opium was described by Huang Shujing, involving a pipe made from bamboo rimmed with silver, stuffed with palm slices and hair, fed by a clay bowl in which a globule of molten opium was held over the flame of an oil lamp. This elaborate procedure, requiring the maintenance of pots of opium at just the right temperature for a globule to be scooped up with a needle-like skewer for smoking, formed the basis of a craft of 'paste-scooping' by which servant girls could become prostitutes as the opportunity arose.
Beginning in eighteenth century China, famine and political upheaval, as well as rumors of wealth to be had in nearby Southeast Asia, led to the Chinese Diaspora. Chinese emigrants to cities such as San Francisco, London, and New York brought with them the Chinese manner of opium smoking and the social traditions of the opium den. The Indian Diaspora distributed opium-eaters in the same way, and both social groups survived as "lascars" (seamen) and "coolies" (manual laborers). French sailors provided another major group of opium smokers, having contracted the habit in French Indochina, where the drug was promoted by the colonial government as a monopoly and source of revenue. Among white Europeans opium was more frequently consumed as laudanum or in patent medicines. Britain's All-India Opium Act of 1878 formalized social distinctions, limiting recreational opium sales to registered Indian opium-eaters and Chinese opium-smokers, and prohibiting its sale to workers from Burma. Likewise American law sought to contain addiction to immigrants by prohibiting Chinese from smoking opium in the presence of a white man.
Because of the low social status of immigrant workers, contemporary writers and media had little trouble portraying opium dens as seats of vice, white slavery, gambling, knife and revolver fights, a source for drugs causing deadly overdoses, with the potential to addict and corrupt the white population. By 1919, anti-Chinese riots attacked Limehouse, the Chinatown of London. Chinese men were deported for playing puck-apu, a popular gambling game, and sentenced to hard labor for opium possession. Both the immigrant population and the social use of opium fell into decline. Yet despite lurid literary accounts to the contrary, nineteenth century London was not a hotbed of opium smoking. The total lack of photographic evidence of opium smoking in Britain, as opposed to the relative abundance of historical photos depicting opium smoking in North America and France, indicates that the infamous Limehouse opium smoking scene was little more than fantasy on the part of British writers of the day who were intent on scandalizing their readers while drumming up the threat of the "yellow peril".
## Prohibition and conflict in China
Opium prohibition began in 1729, when Emperor Yongzheng of the Qing Dynasty, disturbed by madak smoking at court and carrying out the government's role of upholding Confucian virtue, officially prohibited the import of opium, except for a small amount for medicinal purposes. The ban punished sellers and opium den keepers, but not users of the drug. Opium prohibition in China continued until 1860, and was later resumed.
Under the Qing Dynasty, China opened itself to foreign trade under the Canton System through the port of Guangzhou (Canton), and traders from the British East India Company began visiting the port by the 1690s. Due to the growing British demand for Chinese tea, and the Chinese disinterest in British commodities other than silver, the British became interested in opium as a high-value commodity for which China was not self sufficient. The British traders had been purchasing small amounts of opium from India for trade since Ralph Fitch first visited in the mid-sixteenth century. Trade in opium was standardized, with production of balls of raw opium, 1.1 to 1.6 kilograms, 30% water content, wrapped in poppy leaves and petals, shipped in chests of 60-65 kilograms (one picul).
Chests of opium were sold in auctions in Calcutta with the understanding that the independent purchasers would then smuggle it into China (see Opium Wars).
After the 1757 Battle of Plassey and 1764 Battle of Buxar, the British East India Company gained the power to act as diwan of Bengal, Bihar, and Orissa (See company rule in India). This allowed the company to pursue a monopoly on opium production and export in India, to encourage ryots to cultivate the cash crops of indigo and opium with cash advances, and to prohibit the "hoarding" of rice. This strategy led to the increase of the land tax to 50% of the value of crops, the starvation of ten million people in the Bengal famine of 1770, and the doubling of East India Company profits by 1777. Beginning in 1773 the British government began enacting oversight of the company's operations, culminating in the establishment of British India in response to the Indian Rebellion of 1857. Bengal opium was highly prized, commanding twice the price of the domestic Chinese product, which was regarded as inferior in quality.
Some competition came from the newly independent United States, which began to compete in Guangzhou (Canton) selling Turkish opium in the 1820s. Portuguese traders also brought opium from the independent Malwa states of western India, although by 1820 the British were able to restrict this trade by charging "pass duty" on the opium when it was forced to pass through Bombay to reach an entrepot.
Despite drastic penalties and continued prohibition of opium until 1860, opium importation rose steadily from 200 chests per year under Yongzheng to 1,000 under Qianlong, 4,000 under Jiaqing, and 30,000 under Daoguang. The illegal sale of opium became one of the world's most valuable single commodity trades, and has been called "the most long continued and systematic international crime of modern times".
In response to the ever-growing number of Chinese people becoming addicted to opium, Daoguang of the Qing Dynasty took strong action to halt the import of opium, including the seizure of cargo. In 1838 the Chinese Commissioner Lin Zexu destroyed 20,000 chests of opium in Guangzhou (Canton). Given that a chest of opium was worth nearly $1,000 in 1800, this was a substantial economic loss. The British, not willing to replace the cheap opium with costly silver, began the First Opium War in 1840, winning Hong Kong and trade concessions in the first of a series of Unequal Treaties.
Following China's defeat in the Second Opium War in 1858, China was forced to legalize opium and began massive domestic production. Importation of opium peaked in 1879 at 6,700 tons, and by 1906 China was producing 85% of the world's opium, some 35,000 tons, and 27% of its adult male population was addicted - 13.5 million addicts consuming 39,000 tons of opium yearly. From 1880 to the beginning of the Communist era the British attempted to discourage the use of opium in China, but this effectively promoted the use of morphine, heroin, and cocaine, further exacerbating the problem of addiction.
Scientific evidence of the pernicious nature of opium use was largely undocumented in the 1890s when Protestant missionaries in China decided to strengthen their opposition to the trade by compiling data which would demonstrate the harm the drug did. These missionaries were generally outraged over the British government’s Royal Commission on Opium visiting India but not China. Accordingly, the missionaries first organized the Anti-Opium League among their colleagues in every mission station in China. This organization which had elected national officers and held an annual national meeting, was instrumental in gathering data from every Western-trained medical doctor in China which was then published as William H. Park, compiled "Opinions of Over 100 Physicians on the Use of Opium in China" (Shanghai: American Presbyterian Mission Press, 1899). The vast majority of these medical doctors were missionaries, the survey also included doctors who were in private practices, particularly in Shanghai and Hong Kong, as well as Chinese who had been trained in medical schools in Western countries. In England, the home director of the China Inland Mission, Benjamin Broomhall was an active opponent of the Opium trade, writing two books to promote the banning of opium smoking: The Truth about Opium Smoking and The Chinese Opium Smoker. In 1888 Broomhall formed and became secretary of the Christian Union for the Severance of the British Empire with the Opium Traffic and editor of its periodical, "National Righteousness". He lobbied the British Parliament to stop the opium trade. He and James Laidlaw Maxwell appealed to the London Missionary Conference of 1888 and the Edinburgh Missionary Conference of 1910 to condemn the continuation of the trade. When Broomhall was dying, his son Marshall read to him from The Times the welcome news that an agreement had been signed ensuring the end of the opium trade within two years.
Official Chinese resistance to opium was renewed on September 20, 1906 with an anti-opium initiative intended to eliminate the drug problem within ten years. The program relied on the turning of public sentiment against opium, with mass meetings at which opium paraphernalia was publicly burned, as well as coercive legal action and the granting of police powers to organizations such as the Fujian Anti-Opium Society. Smokers were required to register for licenses for gradually reducing rations of the drug. Addicts sometimes turned to missionaries for treatment for their addiction, though many associated these foreigners with the drug trade. The program was counted as a substantial success, with a cessation of direct British opium exports to China (but not Hong Kong) and most provinces declared free of opium production. Nonetheless, the success of the program was only temporary, with opium use rapidly increasing during the disorder following the death of Yuan Shikai in 1916.
Beginning in 1915, Chinese nationalist groups came to describe the period of military losses and Unequal Treaties as the "Century of National Humiliation", later defined to end with the conclusion of the Chinese Civil War in 1949. The Mao Zedong government is generally credited with eradicating both consumption and production of opium during the 1950s using unrestrained repression and social reform. Ten million addicts were forced into compulsory treatment, dealers were executed, and opium-producing regions were planted with new crops. Remaining opium production shifted south of the Chinese border into the Golden Triangle region, at times with the involvement of Western intelligence agencies. The remnant opium trade primarily served Southeast Asia, but spread to American soldiers during the Vietnam War, with 20% of soldiers regarding themselves as addicted during the peak of the epidemic in 1971. In 2003, China was estimated to have four million regular drug users and one million registered drug addicts.
## Prohibition outside China
There were no legal restrictions on the importation or use of opium in the United States until the San Francisco, California Opium Den Ordinance which banned dens for public smoking of opium in 1875, a measure fueled by anti-Chinese sentiment and the perception that whites were starting to frequent the dens. This was followed by an 1891 California law requiring that narcotics carry warning labels and that their sales be recorded in a registry, amendments to the California Pharmacy and Poison Act in 1907 making it a crime to sell opiates without a prescription, and bans on possession of opium or opium pipes in 1909.
At the U.S. federal level, the legal actions taken reflected constitutional restrictions under the Enumerated powers doctrine prior to reinterpretation of the Commerce clause, which did not allow the federal government to enact arbitrary prohibitions but did permit arbitrary taxation. Beginning in 1883 opium importation was taxed at $6 to $300 per pound, until the Opium Exclusion Act of 1909 prohibited the importation of opium altogether. In a similar manner the Harrison Narcotics Tax Act of 1914, passed in fulfillment of the International Opium Convention of 1912, nominally placed a tax on the distribution of opiates, but served as a de facto prohibition of the drugs. Today opium is regulated by the Drug Enforcement Administration under the Controlled Substances Act.
Following passage of a regional law in 1895, Australia's Aboriginal Protection and restriction of the sale of opium act 1897, addressed opium addiction among Aborigines, though it soon became a general vehicle for depriving them of basic rights by administrative regulation. Opium sale was prohibited to the general population in 1905, and smoking and possession was prohibited in 1908.
Hardening of Canadian attitudes toward Chinese opium users and fear of a spread of the drug into the white population led to the effective criminalization of opium for non-medical use in Canada between 1908 and the mid-1920s.
In 1909 the International Opium Commission was founded, and by 1914 thirty-four nations had agreed that the production and importation of opium should be diminished. In 1924, sixty-two nations participated in a meeting of the Commission. Subsequently this role passed to the League of Nations, and all signatory nations agreed to prohibit the import, sale, distribution, export, and use of all narcotic drugs, except for medical and scientific purposes. This role was later taken up by the International Narcotics Control Board of the United Nations under Article 23 of the Single Convention on Narcotic Drugs, and subsequently under the Convention on Psychotropic Substances. Opium-producing nations are required to designate a government agency to take physical possession of licit opium crops as soon as possible after harvest and conduct all wholesaling and exporting through that agency.
## Obsolescence
Opium has gradually been superseded by a variety of purified, semi-synthetic, and synthetic opioids with progressively stronger effect, and by other general anesthesia. This process began in 1817, when Friedrich Wilhelm Adam Sertürner reported the isolation of pure morphine from opium after at least thirteen years of research and a nearly disastrous trial on himself and three boys. The great advantage of purified morphine was that a patient could be treated with a known dose - whereas with raw plant material, as Gabriel Fallopius once lamented, "if soporifics are weak they do not help; if they are strong they are exceedingly dangerous." Morphine was the first pharmaceutical isolated from a natural product, and this success encouraged the isolation of other alkaloids: by 1820, isolations of narcotine, strychnine, veratrine, colchicine, caffeine, and quinine were reported. Morphine sales began in 1827, by Heinrich Emanuel Merck of Darmstadt, and helped him expand his family pharmacy into the massive Merck KGaA pharmaceutical company.
Codeine was isolated in 1832 by Robiquet.
The use of diethyl ether and chloroform for general anesthesia began in 1846-1847, and rapidly displaced the use of opiates and tropane alkaloids from Solanaceae due to their relative safety.
Heroin, the first semi-synthetic opiate, was first synthesized in 1874, but was not pursued until its rediscovery in 1897 by Felix Hoffmann at the Bayer pharmaceutical company in Elberfeld, Germany. From 1898 through to 1910 heroin was marketed as a non-addictive morphine substitute and cough medicine for children. By 1902, sales made up 5% of the company's profits, and "heroinism" had attracted media attention. Oxycodone, a thebaine derivative similar to codeine, was introduced by Bayer in 1916 and promoted as a less-addictive analgesic. Preparations of the drug such as Percocet and Oxycontin remain popular to this day.
A range of synthetic opioids such as methadone (1937), pethidine (1939), fentanyl (late 1950s), and derivatives thereof have been introduced, and each is preferred for certain specialized applications. Nonetheless, morphine remains the drug of choice for American combat medics, who carry packs of syrettes containing 16 milligrams each for use on severely wounded soldiers. No drug has yet been found that can match the painkilling effect of opium without also duplicating much of its addictive potential.
# Modern production and usage
## Papaver somniferum
In South American countries, opium poppies (Papaver somniferum) are technically illegal, but nonetheless appear in some nurseries as ornamentals. They are popular and attractive garden plants, whose flowers vary greatly in color, size and form. A modest amount of domestic cultivation in private gardens is not usually subject to legal controls. In part this tolerance reflects variation in addictive potency: a cultivar for opium production, Papaver somniferum L. elite, contains 92% morphine, codeine, and thebaine in its latex alkaloids, whereas the condiment cultivar "Marianne" has only one-fifth this total, with the remaining alkaloids made up mostly of narcotoline and noscapine.
Seed capsules can be dried and used for decorations, but they also contain morphine, codeine, and other alkaloids. These pods can be boiled in water to produce a bitter tea that induces a long-lasting intoxication (See Poppy tea). If allowed to mature, poppy pods can be crushed into "poppy straw" and used to produce lower quantities of morphinans. In poppies subjected to mutagenesis and selection on a mass scale, researchers have been able to use poppy straw to obtain large quantities of oripavine, a precursor to opioids and antagonists such as naltrexone.
Poppyseeds are a common and flavorsome topping for breads and cakes. One gram of poppy seeds contains up to 33 micrograms of morphine and 14 micrograms of codeine, and the Substance Abuse and Mental Health Services Administration formerly mandated that all drug screening laboratories use a standard cutoff of 300 nanograms per milliliter in urine samples. A single poppy seed roll (0.76 grams of seeds) usually did not produce a positive drug test, but a positive result was observed from eating two rolls. A slice of poppy seed cake containing nearly five grams of seeds per slice produced positive results for 24 hours. Such results are viewed as false positive indications of drug abuse, and were the basis of a legal defense. On November 30, 1998, the standard cutoff was increased to 2000 nanograms (two micrograms) per milliliter. During the Communist era in Eastern Europe, poppy stalks sold in bundles by farmers were processed by users with household chemicals to make kompot ("Polish heroin"), and poppy seeds were used to produce koknar, an opiate.
## Harvesting and processing
When grown for opium production, the skin of the ripening pods of these poppies is scored by a sharp blade at a time carefully chosen so that neither rain, wind, nor dew can spoil the exudation of white, milky latex, usually in the afternoon. Incisions are made while the pods are still raw, with no more than a slight yellow tint, and must be shallow to avoid penetrating hollow inner chambers or loculi while cutting into the lactiferous vessels. In India, the special tool used to make the incisions is called a nushtar, and carries three or four blades three millimeters apart, which are scored upward along the pod. Incisions are made three or four times at intervals of two to three days, and each time the "poppy tears", which dry to a sticky brown resin, are collected the following morning. One acre harvested in this way can produce three to five kilograms of raw opium. In the Soviet Union pods were typically scored horizontally, and opium was collected three times, or else one or two collections were followed by isolation of opiates from the ripe capsules. Oil poppies, an alternative strain of P. somniferum, were also used for production of opiates from their capsules and stems.
Raw opium may be sold to a merchant or broker on the black market, but it usually does not travel far from the field before it is refined into morphine base, because pungent, jelly-like raw opium is bulkier and harder to smuggle. Crude laboratories in the field are capable of refining opium into morphine base by a simple acid-base extraction. A sticky, brown paste, morphine base is pressed into bricks and sun-dried, and can either be smoked or processed into heroin.
Heroin is widely preferred because of increased potency. One study in postaddicts found heroin to be approximately 2.2 times more potent than morphine by weight with a similar duration; at these relative quantities they could distinguish the drugs subjectively but had no preference. Heroin was also found to be twice as potent as morphine in surgical anesthesia. Morphine is converted into heroin by a simple chemical reaction with acetic anhydride, followed by a varying degree of purification. Especially in Mexican production, opium may be converted directly to "black tar heroin" in a simplified procedure. This form predominates in the U.S. west of the Mississippi. Relative to other preparations of heroin, it has been associated with a dramatically increased rate of HIV transmission among intravenous drug users (4% in Los Angeles vs. 40% in New York) due to technical requirements of injection, although it is also associated with greater risk of venous sclerosis and necrotizing fasciitis.
## Illegal production
Opium production has fallen greatly since 1906, when 41,000 tons were produced, but because 39,000 tons of that year's opium were consumed in China, overall usage in the rest of the world was much lower. In 1980, 2,000 tons of opium supplied all legal and illegal uses. Recently, opium production has increased considerably, surpassing 5,000 tons in 2002. In 2002 the price for one kilogram of opium was $300 for the farmer, $800 for purchasers in Afghanistan, and $16,000 on the streets of Europe before conversion into heroin.
Following documented trends of increasing availability mirroring increased American military and geo-political regional involvement, see the Golden Triangle region of Southeast Asia (particularly Myanmar), Colombia and Mexico, Afghanistan is currently the primary producer of the drug. After regularly producing 70% of the world's opium, Afghanistan decreased production to 74 tons per year under a ban by the Taliban in 2000, although the ban may have been intended primarily to boost prices after the country accumulated a stockpile with over two years' supply. After the 2001 war in Afghanistan, production increased again. According to DEA statistics, Afghanistan's production of oven-dried opium increased to 1,278 tons in 2002, more than doubled by 2003, and nearly doubled again during 2004. In late 2004, the U.S. government estimated that 206,000 hectares were under poppy cultivation, 4.5% of the country's total cropland, and produced 4,200 metric tons of opium, 87% of the world's supply, yielding 60% of Afghanistan's gross domestic product. In 2006, the UN Office on Drugs and Crime estimated production to have risen 59% to 407,000 acres (1,647.07056294 km²) in cultivation, yielding 6,100 tons of opium, 92% of the world's supply. The value of the resulting heroin was estimated at $3.5 billion, of which Afghan farmers were estimated to have received $700 million in revenue (of which the Taliban have been estimated to have collected anywhere from tens of millions to $140 million in taxes). For farmers, the crop can be up to ten times more profitable than wheat.
An increasingly large fraction of opium is processed into morphine base and heroin in drug labs in Afghanistan. Despite an international set of chemical controls designed to restrict availability of acetic anhydride, it enters the country, perhaps through its Central Asian neighbors which do not participate. A counternarcotics law passed in December 2005 requires Afghanistan to develop registries or regulations for tracking, storing, and owning acetic anhydride.
Besides Afghanistan, smaller quantities of opium are produced in Pakistan, the Golden Triangle region of Southeast Asia (particularly Myanmar), Colombia and Mexico.
## Legal production
Legal opium production is allowed under the United Nations Single Convention on Narcotic Drugs and other international drug treaties, subject to strict supervision by the law enforcement agencies of individual countries. The leading legal production method is the Gregory process, whereby the entire poppy, excluding roots and leaves, is mashed and stewed in dilute acid solutions. The alkaloids are then recovered via acid-base extraction and purified. This process was developed in the UK during World War II, when wartime shortages of many essential drugs encouraged innovation in pharmaceutical processing.
Legal production in India is much more traditional. As of 1996, opium was collected by farmers who licensed to grow 0.1 hectare of opium poppies (0.24 acres), who to maintain their licenses needed to sell 4.5 kilograms of unadulterated raw opium paste at a fixed government price of 32 rupees ($8 US) per kilogram. One kilogram represents two days' work for a family. Some additional money is made by drying the poppy heads and collecting poppy seeds, and a small fraction of opium beyond the quota may be consumed locally or diverted to the black market. The opium paste is sun-dried and stirred in large pans before it is packed into cases of 60 kilograms for export. Purification of chemical constituents is done in India for domestic production, but typically done abroad by foreign importers.
Legal opium importation from India and Turkey is conducted by Mallinckrodt, Noramco, Abbott Laboratories, and Purdue Pharma in the United States, and legal opium production is conducted by GlaxoSmithKline, Johnson and Johnson, Johnson Matthey, and Mayne in Tasmania, Australia; Sanofi Aventis in France; Shionogi Pharmaceutical in Japan; and MacFarlan Smith in the United Kingdom. The UN treaty requires that every country submit annual reports to the International Narcotics Control Board, stating that year's actual consumption of many classes of controlled drugs as well as opioids, and projecting required quantities for the next year. This is to allow trends in consumption to be monitored, and production quotas allotted.
A recent proposal from the European Senlis Council hopes to solve the problems caused by the massive quantity of opium produced illegally in Afghanistan, most of which is converted to heroin, and smuggled for sale in Europe and the USA. This proposal is to license Afghan farmers to produce opium for the world pharmaceutical market, and thereby solve another problem, that of chronic underuse of potent analgesics where required within developing nations. Part of the proposal is to overcome the "80-20 rule" that requires the U.S. to purchase 80% of its legal opium from India and Turkey to include Afghanistan, by establishing a second-tier system of supply control that complements the current INCB regulated supply and demand system by providing poppy-based medicines to countries who cannot meet their demand under the current regulations. Senlis arranged a conference in Kabul that brought drug policy experts from around the world to meet with Afghan government officials to discuss internal security, corruption issues, and legal issues within Afghanistan.
In June 2007, the Council launched a "Poppy for Medicines" project that provides a technical blueprint for the implementation of an integrated control system within Afghan village-based poppy for medicine projects: the idea promotes the economic diversification by redirecting proceeds from the legal cultivation of poppy and production of poppy-based medicines (See Senlis Council).
### Cultivation in the UK
In late 2006, the British government permitted the pharmaceutical company Macfarlan Smith (a Johnson Matthey company) to cultivate opium poppies in England for medicinal reasons, after Macfarlan Smith's primary source, India, decided to increase the price of export opium latex. This move is well received by British farmers, with a major opium poppy field based in Didcot, England. The British government has contradicted the Home Office's suggestion that opium cultivation can be legalized in Afghanistan for exports to the United Kingdom, helping lower poverty and internal fighting whilst helping NHS to meet the high demand for morphine and diamorphine. Opium poppy cultivation in the United Kingdom does not need a licence, however, a licence is required for those wishing to extract opium for medicinal products.
## Consumption
In the industrialized world, the USA is the world's biggest consumer of prescription opioids, with Italy one of the lowest. Most opium imported into the United States is broken down into its alkaloid constituents, and whether legal or illegal, most current drug use occurs with processed derivatives such as heroin rather than with pure and untouched opium.
Intravenous injection of opiates is most used: by comparison with injection, "dragon chasing" (heating of heroin with barbital on a piece of foil) and "ack ack" (smoking of cigarettes containing heroin powder) are only 40% and 20% efficient, respectively. One study of British heroin addicts found a 12-fold excess mortality ratio (1.8% of the group dying per year). Most heroin deaths result not from overdose per se, but combination with other depressant drugs such as alcohol or benzodiazepines.
The smoking of opium does not involve the pyrolysis of the material as might be imagined. Rather the prepared opium is indirectly heated to temperatures at which the active alkaloids, chiefly morphine, are vaporized. In the past, smokers would utilize a specially designed opium pipe which had a removable knob-like pipe-bowl of fired earthenware attached by a metal fitting to a long, cylindrical stem. A small "pill" of opium about the size of a pea would be placed on the pipe-bowl, which was then heated by holding it over an opium lamp, a special oil lamp with a distinct funnel-like chimney to channel heat into a small area. The smoker would lie on his or her side in order to guide the pipe-bowl and the tiny pill of opium over the stream of heat rising from the chimney of the oil lamp and inhale the vaporized opium fumes as needed. Several pills of opium were smoked at a single session depending on the smoker's tolerance to the drug. The effects could last up to twelve hours.
In Eastern culture, opium is more commonly used in the form of paregoric to treat diarrhea. This is a weaker solution than laudanum, an alcoholic tincture which was prevalently used as a pain medication and sleeping aid. Tincture of opium has been prescribed for, among other things, severe diarrhea. Taken 30 minutes prior to meals it will significantly slow intestinal motility, giving the intestines greater time to absorb fluid in the stool.
# Chemical and physiological properties
Opium contains two main groups of alkaloids. Those that use opium are commonly referred to as "opiats" (Coined by James St. Louis). Phenanthrenes include morphine, codeine, and thebaine, and are the main narcotic constituents. Isoquinolines such as papaverine have no significant central nervous system effects and are not regulated under the Controlled Substances Act. Morphine is by far the most prevalent and important alkaloid in opium, consisting of 10%-16% of the total, and is responsible for most of its harmful effects such as lung edema, respiratory difficulties, coma, or cardiac or respiratory collapse, with a normal lethal dose of 120 to 250 milligrams—the amount found in approximately two grams of opium. Morphine binds to and activates μ-opioid receptors in the brain, spinal cord, stomach and intestine. Regular use leads to physical tolerance and dependence. Chronic opium addicts in 1906 China or modern-day Iran consume an average of eight grams daily.
Both analgesia and drug addiction are functions of the mu opioid receptor, the class of opioid receptor first identified as responsive to morphine. Tolerance is associated with the superactivation of the receptor, which may be affected by the degree of endocytosis caused by the opioid administered, and leads to a superactivation of cyclic AMP signalling. Long-term use of morphine in palliative care and management of chronic pain can be managed without the development of drug tolerance or (physical dependence). Many techniques of drug treatment exist, including pharmacologically based treatments with naltrexone, methadone, or ibogaine.
# Cultural references
There is a rich and longstanding literature by and about opium users. Thomas De Quincey's 1822 Confessions of an English Opium-Eater is one of the first and most famous literary accounts of opium addiction written from the point of view of an addict, and details both the pleasures and the dangers of the drug. De Quincey writes about the great English Romantic poet Samuel Taylor Coleridge (1772-1834), whose poem "Kubla Khan" is also widely considered to be a poem of the opium experience. Coleridge began using opium in 1791 after developing jaundice and rheumatic fever, and became a full addict after a severe attack of the disease in 1801, requiring 80-100 drops of laudanum daily. "The Lotos-Eaters", an 1832 poem by Alfred Lord Tennyson, reflects the generally favorable British attitude toward the drug. In The Count of Monte Cristo (1844), by Alexandre Dumas, père, the Count is assuaged by an edible form of opium, and his experience with it is depicted vividly.
Edgar Allan Poe presents opium in a more disturbing context in his 1838 short story "Ligeia", in which the narrator, deeply distraught for the loss of his beloved, takes solace in opium until he "had become a bounden slave in the trammels of opium", unable to distinguish fantasy from reality after taking immoderate doses of opium. In music, Hector Berlioz' 1830 Symphony Fantastique tells the tale of an artist who has poisoned himself with opium while in the depths of despair for a hopeless love. Each of the symphony's five movements takes place at a different setting and with increasingly audible effects from the drug. For example, in the fourth movement, "Marche au Supplice", the artist dreams that he is walking to his own execution. In the fifth movement, "Songe d’une Nuit du Sabbat", he dreams that he is at a witch's orgy, where he witnesses his beloved dancing wildly along to the demented Dies Irae.
Towards the end of the nineteenth century, references to opium and opium addiction in the context of crime and the foreign underclass abound in English literature, such as in the opening paragraphs of Charles Dickens's 1870 serial The Mystery of Edwin Drood and in Arthur Conan Doyle's 1891 Sherlock Holmes short story The Man with the Twisted Lip. In Oscar Wilde's 1890 The Picture of Dorian Gray, the protagonist uses an opium den as a hiding place after a murder. Opium likewise underwent a transformation in Chinese literature, becoming associated with indolence and vice by the early twentieth century.
In the twentieth century, as the use of opium was eclipsed by morphine and heroin, its role in literature became more limited, and often focused on issues related to its prohibition. In The Good Earth by Pearl S. Buck, Wang Lung, the protagonist, gets his troublesome uncle and aunt addicted to opium in order to keep them out of his hair. William S. Burroughs autobiographically describes the use of opium beside that of its derivatives. His associate Jack Black's memoir You Can't Win chronicles one man's experience both as an onlooker in the opium dens of San Francisco, and later as a "hop fiend" himself. The book and subsequent movie, The Wonderful Wizard of Oz, may allude to opium at one point in the story, when Dorothy and her friends are drawn into a field of poppies, in which they fall asleep. House of the Scorpion is a 2002 novel set in the land of Opium. Marcy Playground's self-titled album contains numerous songs about opium.
In the Seinfeld episode "The Shower Head", Elaine tests positive several times for opium after urine tests, only to discover that it comes from her regularly eating poppy seed muffins.
In the film Saw, one of the victims in the reverse bear-trap scene had an Opium overdose.
In the novel, House of the Scorpion most of the setting is in houses on the opium white poppy fields | Opium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5]
# Overview
Opium is a narcotic formed from the latex released by lacerating (or "scoring") the immature seed pods of opium poppies (Papaver somniferum). It contains up to 16% morphine, an opiate alkaloid, which is most frequently processed chemically to produce heroin for the illegal drug trade. The resin also includes non-narcotic alkaloids, such as papaverine and noscapine. Meconium historically referred to related, weaker preparations made from other parts of the poppy or different species of poppies. Modern opium production is the culmination of millennia of production, in which the source poppy, methods of extraction and processing, and methods of consumption have become increasingly potent.
Cultivation of opium poppies for food, anesthesia, and ritual purposes dates back to at least the Neolithic Age. The Sumerian, Assyrian, Egyptian, Minoan, Greek, Roman, Persian and Arab Empires each made widespread use of opium, which was the most potent form of pain relief then available, allowing ancient surgeons to perform prolonged surgical procedures. Opium is mentioned in the most important medical texts of the ancient world, including the Ebers Papyrus and the writings of Dioscorides, Galen, and Avicenna. Widespread medical use of unprocessed opium continued through the American Civil War before giving way to morphine and its successors, which could be injected at a precisely controlled dosage. American morphine is still produced primarily from poppies grown and processed in India in the traditional manner, and remains the standard of pain relief for casualties of war.
Recreational use of the drug began in China in the fifteenth century, but was limited by its rarity and expense. Opium trade became more regular by the seventeenth century, when it was mixed with tobacco for smoking, and addiction was first recognized. Opium prohibition in China began in 1729, and was followed by nearly two centuries of exponentially increasing opium use. China had a positive balance sheet in trading with the British, which led to a decrease of the British silver stocks. Therefore, the British tried to make the Chinese people dependent on opium to enhance their balance, they delivered it from Indian provinces under British control. A massive confiscation of opium by the Chinese emperor, who tried to stop the opium deliveries, led to two Opium Wars in 1840 and 1858, in which consequence Britain suppressed China and traded opium all over the country. After 1860 opium use continued to increase with widespread domestic production in China, until more than a quarter of the male population was addicted by 1905. Recreational or addictive opium use in other nations remained rare into the late nineteenth century, recorded by an ambivalent literature that sometimes praised the drug.
Global regulation of opium began with the stigmatization of Chinese immigrants and opium dens, leading rapidly from town ordinances in the 1870s to the formation of the International Opium Commission in 1909. During this period the portrayal of opium in literature became squalid and violent, British opium trade was largely supplanted by domestic Chinese production, purified morphine and heroin became widely available for injection, and patent medicines containing opiates reached a peak of popularity. Opium was prohibited in many countries during the early twentieth century, leading to the modern pattern of opium production as a precursor for illegal recreational drugs or tightly regulated legal prescription drugs. Illicit opium production, now dominated by Afghanistan, has increased steadily in recent years to over 6600 tons yearly, nearly one-fifth the level of production in 1906. Opium for illegal use is generally converted into heroin, which doubles its potency, and taken by intravenous injection, which more than doubles the quantity of drug entering the body.
# History
## Ancient use (4200 BC - 800 BC)
The use of the opium poppy dates from time immemorial. At least seventeen finds of Papaver somniferum from Neolithic settlements have been reported throughout Switzerland, Germany, and Spain, including the placement of large numbers of poppy seed capsules at a burial site (the Cueva de los Murciélagos, or "Bat cave", in Spain), which have been carbon dated to 4200 B.C. Numerous finds of Papaver somniferum or Papaver setigerum from Bronze Age and Iron Age settlements have also been reported.[2]
The first known cultivation of opium poppies was in Mesopotamia, approximately 3400 B.C., by Sumerians who called the plant Hul Gil, the "joy plant".[3][4] Tablets found at Nippur, a Sumerian spiritual center south of Baghdad, described the collection of poppy juice in the morning and its use in production of opium.[1] Cultivation continued in the Middle East by the Assyrians, who also collected poppy juice in the morning after scoring the pods with an iron scoop; they called the juice aratpa-pal, possibly the root of Papaver. Opium production continued under the Babylonians and Egyptians.
Opium was used with poison hemlock to put people quickly and painlessly to death, but it was also used in medicine. The Ebers Papyrus, ca. 1500 B.C., describes a way to "prevent the excessive crying of children" using grains of the poppy-plant strained to a pulp. Spongia somnifera, sponges soaked in opium, were used during surgery.[3] The Egyptians cultivated opium thebaicum in famous poppy fields around 1300 B.C. Opium was traded from Egypt by the Phoenicians and Minoans to destinations around the Mediterranean Sea, including Greece, Carthage, and Europe. By 1100 B.C. opium was cultivated on the Mediterranean island of Cyprus, where surgical quality knives were used to score the poppy pods, and opium was cultivated, traded, and smoked.[5] Opium was also mentioned after the Persian conquest of Assyria and Babylonia in the sixth century B.C.[1]
From the earliest finds opium has appeared to have ritual significance, and anthropologists have speculated that ancient priests may have used the drug as a proof of healing power.[3] In Egypt, the use of opium was generally restricted to priests, magicians, and warriors, its invention credited to Thoth, and it was said to have been given by Isis to Ra as treatment for a headache.[1] A figure of the Minoan "goddess of the narcotics", wearing a crown of three opium poppies, ca. 1300 B.C., was recovered from the Sanctuary of Gazi, Crete, together with a simple smoking apparatus.[5][6] The Greek gods Hypnos (Sleep), Nyx (Night), and Thanatos (Death) were depicted wreathed in poppies or holding poppies. Poppies also frequently adorned statues of Apollo, Asklepios, Pluto, Demeter, Aphrodite, Kybele and Isis, symbolizing nocturnal oblivion.[1]
## Greece and Rome (800 BC-600 AD)
Opium was well known to the ancient Greeks. The first Greek written account of poppy production was by Hesiod in the eighth century B.C., who called the poppy plant μήκωνιον (mekonion), and its juice όπός μήκων (opos mekun). Homer described to his audience an exhausted warrior dropping his heavy helmeted head, like a drooping poppy bud. Hippocrates recognized opium as useful in treating internal diseases, diseases of women and epidemics.[5] Alexander the Great is credited with introducing opium to India and Persia in 330 B.C.[4] The Greeks distinguished opium from a weaker drug, "meconium". This could refer specifically to a different poppy strain e.g. Euphorbia paralias (paralion). Alternatively, "meconium" was used by Hippocrates, Pedanius Dioscorides, Pliny the Elder, and Scribonius Largus to refer to juice emanating from the leaves and fruit of the poppy, or obtained from them by boiling (see Poppy tea), or tablets formed by crushing them in a mortar and pestle.[5] The Greek όπός or όπιον became Roman opium, and later Persian ab-yun, Arabic af-yuun, and Chinese af-yong or yaa-pian.[7] Because variants of "opos" or "opion" are widely used to denote the sap throughout the world, even where the plant itself is known by indigenous names, it was formerly thought that the Greeks first discovered the collection of poppy sap, and that previous use had been limited to consumption of seed capsules.[8]
Curiously, many ancient physicians described many species of poppies, giving only limited preference to Papaver somniferum.[9] Hippocrates mentioned white, fire-red, black, and hypnotic varieties; Theophrastus described black or horned, flowing, and Heraklean varieties. The varieties from Dioscorides' pharmacopoeia have been tentatively assigned to modern species: Papaver hybridum, a "flowing" poppy that sheds its flowers rapidly, with hypnotic properties; Papaver somniferum, a cultivated garden "pouched" poppy that is good for baking bread and has white seeds and elongated flowers; Papaver orientalis, a wild "jar" poppy with elongated and involuted capsule and black seeds; another more poisonous wild poppy with a longer capsule; Glauceum luteum, a "horned" poppy growing wild by the sea; and Gratiola officinalis, the "foaming" or Heraklean poppy.[5] It has been speculated that opium may originally have been obtained from Papaver setigerum, a close relative of Papaver somniferum from which it was once thought to have been domesticated.[8] However, although Papaver setigerum is one of very few poppies to have a significant morphine content, early cytogenetic analysis revealed that it is a tetraploid with 22 chromosomes, compared to the 11 of Papaver somniferum, making it an unlikely ancestor.[10]
In De Medicina (ca. 30 AD), Aulus Cornelius Celsus detailed many uses for "poppy-tears", as an emollient for painful joints and anal fissures, in anodynes (pills promoting relief of pain through sleep), in antidotes for poisoning (including the Mithridatium), for use in colic, and to promote micturition.[11] He also recommended the juice of boiled poppy heads for procuring sleep, treating earaches, intestinal gripings, inflammation of the womb, and to reduce the flow of phlegm into the eyes. However, Celsus is thought to have used a wild poppy, Papaver rhoeas, with a very low opiate content,[12] and in any case did not regard it as uniquely powerful. He described "poppy-tears" as one of many emollient herbs and minerals, used as an ingredient in some formulations for pain but not others.
Despite the widespread therapeutic and possible ritual use of the drug, and although drunkenness from wine was well documented, there is very little evidence that opium addiction or hedonistic use of opium occurred in the ancient world.[13] The best candidates for opium addiction noted from ancient accounts are Ovid and the Roman emperor Marcus Aurelius. Another difference from common modern practice is that ancient authors such as Hippocrates and Celsus often described the topical use of opium or "poppy-tears" directly at the site of pain, in the eye, or introduced into a wound. When administered directly at the site of pain, morphine has recently been recognized to have a moderate analgesic effect, relying on peripheral opioid receptors, and this limited dosage does not have addictive or life-threatening effects.[14][15]
## Islamic Empire (600-1500 A.D.)
As the power of the Roman Empire declined, the lands to the south and east of the Mediterranean became incorporated into the Islamic Empire, which assembled the finest libraries and the most skilled physicians of the era. Many Muslims believe that the hadith of al-Bukhari prohibits every intoxicating substance as haraam, but the use of intoxicants in medicine has been widely permitted.[16] Dioscorides' five-volume De Materia Medica, ancestor to all modern pharmacopoeias, remained in continuous use (with some improvements in Arabic versions[17]) from the first century until 1600 A.D., and described opium, meconium and the wide range of uses prevalent in the ancient world.[18]
Somewhere between 400 and 1200 A.D., Arab traders introduced opium to China.[4][19][1] The Persian physician, Agha Bakr Muhammad ibn Zakariya al-Razi (845-930 A.D.), who was born near Tehran and maintained a laboratory and school in Baghdad, and was a student and critic of Galen, made use of opium in anesthesia and recommended its use for the treatment of melancholy in Man la Yahduruhu Al-Tabib, a home medical manual directed toward ordinary citizens for self-treatment if a doctor was not available.[20][21] The renowned opthalmologic surgeon Abu al-Qasim Ammar (936-1013 A.D.) relied on opium and mandrake as surgical anaesthetics, and wrote a treatise al-Tasrif that influenced medical thought well into the sixteenth century.[22][23] The Persian physician Abū ‘Alī al-Husayn (Avicenna) described opium as the most powerful of the stupefacients, by comparison with mandrake and other highly effective herbs, in The Canon of Medicine. This classic text was translated into Latin in 1175 and later into many other languages, and remained authoritative into the seventeenth century.[24] Şerefeddin Sabuncuoğlu used opium in the fourteenth century Ottoman Empire to treat migraine headache, sciatica, and other painful ailments.[25]
## Reintroduction to Western Medicine
Opium became stigmatized in Europe during the Inquisition as a Middle Eastern influence, and became a taboo subject in Europe from approximately 1300 to 1500 A.D. Manuscripts of Pseudo-Apuleius' fifth-century work from the tenth and eleventh centuries refer to the use of wild poppy Papaver agreste or Papaver rhoeas (identified as Papaver silvaticum) instead of Papaver somniferum for inducing sleep and relieving pain.[26]
The use of Paracelsus' laudanum was introduced to Western medicine in 1527, when Philip Aureolus Theophrastus Bombast von Hohenheim returned from his wanderings in Arabia with a famous sword, within the pommel of which he kept "Stones of Immortality" compounded from opium thebaicum, citrus juice, and "quintessence of gold".[4][27][28] The name "Paracelsus" was a pseudonym signifying him the equal or better of Aulus Cornelius Celsus, whose text, which described the use of opium or a similar preparation, had recently been translated and reintroduced to medieval Europe.[29] The Canon of Medicine, the standard medical textbook that Paracelsus burned in a public bonfire three weeks after being appointed professor at the University of Basel, also described the use of opium, though many Latin translations were of poor quality.[30] "Laudanum" was originally the sixteenth-century term for a medicine associated with a particular physician that was widely well-regarded, but became standardized as "tincture of opium", a solution of opium in ethyl alcohol, which Paracelsus has been credited with developing. During his lifetime, Paracelsus was viewed as an adventurer who challenged the theories and mercenary motives of contemporary medicine with dangerous chemical therapies, but his therapies marked a turning point in Western medicine. In the seventeenth century laudanum was recommended for pain, sleeplessness, and diarrhea by Thomas Sydenham,[31] the renowned "father of English medicine" or "English Hippocrates", to whom is attributed the quote, "Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium."[32] Use of opium as a cure-all was reflected in the formulation of mithridatium described in the 1728 Chambers Cyclopedia, which included true opium in the mixture. Subsequently laudanum became the basis of many popular patent medicines of the nineteenth century.
The standard medical use of opium persisted well into the nineteenth century. U.S president William Henry Harrison was treated with opium in 1841, and in the American Civil War, the Union Army used 2.8 million ounces of opium tincture and powder and about 500,000 opium pills.[1] During this time of popularity, users called opium "God's Own Medicine".[33]
## Recreational use
The earliest clear description of the use of opium as a recreational drug came from Xu Boling, who wrote in 1483 that opium was "mainly used to aid masculinity, strengthen sperm and regain vigor", and that it "enhances the art of alchemists, sex and court
ladies.". He described an expedition sent by the Chenghua Emperor in 1483 to procure opium for a price "equal to that of gold" in Hainan, Fujian, Zhejiang, Sichuan and Shaanxi where it is close to Xiyu. A century later Li Shizhen listed standard medical uses of opium in his renowned Compendium of Materia Medica (1578), but also wrote that "lay people use it for the art of sex", in particular the ability to "arrest seminal emission". This association of opium with sex continued in China until the twentieth century. Opium smoking began as a privilege of the elite, and remained a great luxury into the early nineteenth century, but by 1861, Wang Tao wrote that opium was used even by rich peasants, and even a small village without a rice store would have a shop where opium was sold.[7]
Smoking of opium came on the heels of tobacco smoking, and may have been encouraged by a brief ban on the smoking of tobacco by the Ming emperor, ending in 1644 with the Qing dynasty, which had encouraged smokers to mix in increasing amounts of opium.[1] In 1705, Wang Shizhen wrote that "nowadays, from nobility and gentlemen down to slaves and women, all are addicted to tobacco". Tobacco in that time was frequently mixed with other herbs (this continues with clove cigarettes to the modern day), and opium was one component in the mixture. Tobacco mixed with opium was called madak (or madat), and became popular throughout China and its seafaring trade partners (such as Taiwan, Java and the Philippines) in the seventeenth century.[7] In 1712, Engelbert Kaempfer described addiction to madak: "No commodity throughout the Indies is retailed with greater profit by the Batavians than opium, which [its] users cannot do without, nor can they come by it except it be brought by the ships of the Batavians from Bengal and Coromandel."[19]
Fueled in part by the 1729 ban on madak, which at first effectively exempted pure opium as a potentially medicinal product, the smoking of pure opium became more popular in the eighteenth century. In 1736, the smoking of pure opium was described by Huang Shujing, involving a pipe made from bamboo rimmed with silver, stuffed with palm slices and hair, fed by a clay bowl in which a globule of molten opium was held over the flame of an oil lamp. This elaborate procedure, requiring the maintenance of pots of opium at just the right temperature for a globule to be scooped up with a needle-like skewer for smoking, formed the basis of a craft of 'paste-scooping' by which servant girls could become prostitutes as the opportunity arose.[7]
Beginning in eighteenth century China, famine and political upheaval, as well as rumors of wealth to be had in nearby Southeast Asia, led to the Chinese Diaspora. Chinese emigrants to cities such as San Francisco, London, and New York brought with them the Chinese manner of opium smoking and the social traditions of the opium den.[34][35] The Indian Diaspora distributed opium-eaters in the same way, and both social groups survived as "lascars" (seamen) and "coolies" (manual laborers). French sailors provided another major group of opium smokers, having contracted the habit in French Indochina, where the drug was promoted by the colonial government as a monopoly and source of revenue.[36][37] Among white Europeans opium was more frequently consumed as laudanum or in patent medicines. Britain's All-India Opium Act of 1878 formalized social distinctions, limiting recreational opium sales to registered Indian opium-eaters and Chinese opium-smokers, and prohibiting its sale to workers from Burma.[38] Likewise American law sought to contain addiction to immigrants by prohibiting Chinese from smoking opium in the presence of a white man.[39]
Because of the low social status of immigrant workers, contemporary writers and media had little trouble portraying opium dens as seats of vice, white slavery, gambling, knife and revolver fights, a source for drugs causing deadly overdoses, with the potential to addict and corrupt the white population. By 1919, anti-Chinese riots attacked Limehouse, the Chinatown of London. Chinese men were deported for playing puck-apu, a popular gambling game, and sentenced to hard labor for opium possession. Both the immigrant population and the social use of opium fell into decline.[40][41] Yet despite lurid literary accounts to the contrary, nineteenth century London was not a hotbed of opium smoking. The total lack of photographic evidence of opium smoking in Britain, as opposed to the relative abundance of historical photos depicting opium smoking in North America and France, indicates that the infamous Limehouse opium smoking scene was little more than fantasy on the part of British writers of the day who were intent on scandalizing their readers while drumming up the threat of the "yellow peril".[42][43]
## Prohibition and conflict in China
Opium prohibition began in 1729, when Emperor Yongzheng of the Qing Dynasty, disturbed by madak smoking at court and carrying out the government's role of upholding Confucian virtue, officially prohibited the import of opium, except for a small amount for medicinal purposes. The ban punished sellers and opium den keepers, but not users of the drug.[19] Opium prohibition in China continued until 1860, and was later resumed.
Under the Qing Dynasty, China opened itself to foreign trade under the Canton System through the port of Guangzhou (Canton), and traders from the British East India Company began visiting the port by the 1690s. Due to the growing British demand for Chinese tea, and the Chinese disinterest in British commodities other than silver, the British became interested in opium as a high-value commodity for which China was not self sufficient. The British traders had been purchasing small amounts of opium from India for trade since Ralph Fitch first visited in the mid-sixteenth century.[19] Trade in opium was standardized, with production of balls of raw opium, 1.1 to 1.6 kilograms, 30% water content, wrapped in poppy leaves and petals, shipped in chests of 60-65 kilograms (one picul).[19]
Chests of opium were sold in auctions in Calcutta with the understanding that the independent purchasers would then smuggle it into China (see Opium Wars).
After the 1757 Battle of Plassey and 1764 Battle of Buxar, the British East India Company gained the power to act as diwan of Bengal, Bihar, and Orissa (See company rule in India). This allowed the company to pursue a monopoly on opium production and export in India, to encourage ryots to cultivate the cash crops of indigo and opium with cash advances, and to prohibit the "hoarding" of rice. This strategy led to the increase of the land tax to 50% of the value of crops, the starvation of ten million people in the Bengal famine of 1770, and the doubling of East India Company profits by 1777. Beginning in 1773 the British government began enacting oversight of the company's operations, culminating in the establishment of British India in response to the Indian Rebellion of 1857. Bengal opium was highly prized, commanding twice the price of the domestic Chinese product, which was regarded as inferior in quality.[44]
Some competition came from the newly independent United States, which began to compete in Guangzhou (Canton) selling Turkish opium in the 1820s. Portuguese traders also brought opium from the independent Malwa states of western India, although by 1820 the British were able to restrict this trade by charging "pass duty" on the opium when it was forced to pass through Bombay to reach an entrepot.[19]
Despite drastic penalties and continued prohibition of opium until 1860, opium importation rose steadily from 200 chests per year under Yongzheng to 1,000 under Qianlong, 4,000 under Jiaqing, and 30,000 under Daoguang.[45] The illegal sale of opium became one of the world's most valuable single commodity trades, and has been called "the most long continued and systematic international crime of modern times".[46]
In response to the ever-growing number of Chinese people becoming addicted to opium, Daoguang of the Qing Dynasty took strong action to halt the import of opium, including the seizure of cargo. In 1838 the Chinese Commissioner Lin Zexu destroyed 20,000 chests of opium in Guangzhou (Canton).[19] Given that a chest of opium was worth nearly $1,000 in 1800, this was a substantial economic loss. The British, not willing to replace the cheap opium with costly silver, began the First Opium War in 1840, winning Hong Kong and trade concessions in the first of a series of Unequal Treaties.
Following China's defeat in the Second Opium War in 1858, China was forced to legalize opium and began massive domestic production. Importation of opium peaked in 1879 at 6,700 tons, and by 1906 China was producing 85% of the world's opium, some 35,000 tons, and 27% of its adult male population was addicted - 13.5 million addicts consuming 39,000 tons of opium yearly.[47] From 1880 to the beginning of the Communist era the British attempted to discourage the use of opium in China, but this effectively promoted the use of morphine, heroin, and cocaine, further exacerbating the problem of addiction.[48]
Scientific evidence of the pernicious nature of opium use was largely undocumented in the 1890s when Protestant missionaries in China decided to strengthen their opposition to the trade by compiling data which would demonstrate the harm the drug did. These missionaries were generally outraged over the British government’s Royal Commission on Opium visiting India but not China. Accordingly, the missionaries first organized the Anti-Opium League among their colleagues in every mission station in China. This organization which had elected national officers and held an annual national meeting, was instrumental in gathering data from every Western-trained medical doctor in China which was then published as William H. Park, compiled "Opinions of Over 100 Physicians on the Use of Opium in China" (Shanghai: American Presbyterian Mission Press, 1899). The vast majority of these medical doctors were missionaries, the survey also included doctors who were in private practices, particularly in Shanghai and Hong Kong, as well as Chinese who had been trained in medical schools in Western countries. In England, the home director of the China Inland Mission, Benjamin Broomhall was an active opponent of the Opium trade, writing two books to promote the banning of opium smoking: The Truth about Opium Smoking and The Chinese Opium Smoker. In 1888 Broomhall formed and became secretary of the Christian Union for the Severance of the British Empire with the Opium Traffic and editor of its periodical, "National Righteousness". He lobbied the British Parliament to stop the opium trade. He and James Laidlaw Maxwell appealed to the London Missionary Conference of 1888 and the Edinburgh Missionary Conference of 1910 to condemn the continuation of the trade. When Broomhall was dying, his son Marshall read to him from The Times the welcome news that an agreement had been signed ensuring the end of the opium trade within two years.
Official Chinese resistance to opium was renewed on September 20, 1906 with an anti-opium initiative intended to eliminate the drug problem within ten years. The program relied on the turning of public sentiment against opium, with mass meetings at which opium paraphernalia was publicly burned, as well as coercive legal action and the granting of police powers to organizations such as the Fujian Anti-Opium Society. Smokers were required to register for licenses for gradually reducing rations of the drug. Addicts sometimes turned to missionaries for treatment for their addiction, though many associated these foreigners with the drug trade. The program was counted as a substantial success, with a cessation of direct British opium exports to China (but not Hong Kong[49]) and most provinces declared free of opium production. Nonetheless, the success of the program was only temporary, with opium use rapidly increasing during the disorder following the death of Yuan Shikai in 1916.[50]
Beginning in 1915, Chinese nationalist groups came to describe the period of military losses and Unequal Treaties as the "Century of National Humiliation", later defined to end with the conclusion of the Chinese Civil War in 1949.[51] The Mao Zedong government is generally credited with eradicating both consumption and production of opium during the 1950s using unrestrained repression and social reform. Ten million addicts were forced into compulsory treatment, dealers were executed, and opium-producing regions were planted with new crops. Remaining opium production shifted south of the Chinese border into the Golden Triangle region, at times with the involvement of Western intelligence agencies.[44] The remnant opium trade primarily served Southeast Asia, but spread to American soldiers during the Vietnam War, with 20% of soldiers regarding themselves as addicted during the peak of the epidemic in 1971. In 2003, China was estimated to have four million regular drug users and one million registered drug addicts.[52]
Template:Seealso
## Prohibition outside China
There were no legal restrictions on the importation or use of opium in the United States until the San Francisco, California Opium Den Ordinance which banned dens for public smoking of opium in 1875, a measure fueled by anti-Chinese sentiment and the perception that whites were starting to frequent the dens. This was followed by an 1891 California law requiring that narcotics carry warning labels and that their sales be recorded in a registry, amendments to the California Pharmacy and Poison Act in 1907 making it a crime to sell opiates without a prescription, and bans on possession of opium or opium pipes in 1909.[53]
At the U.S. federal level, the legal actions taken reflected constitutional restrictions under the Enumerated powers doctrine prior to reinterpretation of the Commerce clause, which did not allow the federal government to enact arbitrary prohibitions but did permit arbitrary taxation.[54] Beginning in 1883 opium importation was taxed at $6 to $300 per pound, until the Opium Exclusion Act of 1909 prohibited the importation of opium altogether. In a similar manner the Harrison Narcotics Tax Act of 1914, passed in fulfillment of the International Opium Convention of 1912, nominally placed a tax on the distribution of opiates, but served as a de facto prohibition of the drugs. Today opium is regulated by the Drug Enforcement Administration under the Controlled Substances Act.
Following passage of a regional law in 1895, Australia's Aboriginal Protection and restriction of the sale of opium act 1897, addressed opium addiction among Aborigines, though it soon became a general vehicle for depriving them of basic rights by administrative regulation. Opium sale was prohibited to the general population in 1905, and smoking and possession was prohibited in 1908.[55]
Hardening of Canadian attitudes toward Chinese opium users and fear of a spread of the drug into the white population led to the effective criminalization of opium for non-medical use in Canada between 1908 and the mid-1920s.[56]
In 1909 the International Opium Commission was founded, and by 1914 thirty-four nations had agreed that the production and importation of opium should be diminished. In 1924, sixty-two nations participated in a meeting of the Commission. Subsequently this role passed to the League of Nations, and all signatory nations agreed to prohibit the import, sale, distribution, export, and use of all narcotic drugs, except for medical and scientific purposes. This role was later taken up by the International Narcotics Control Board of the United Nations under Article 23 of the Single Convention on Narcotic Drugs, and subsequently under the Convention on Psychotropic Substances. Opium-producing nations are required to designate a government agency to take physical possession of licit opium crops as soon as possible after harvest and conduct all wholesaling and exporting through that agency.[1]
## Obsolescence
Opium has gradually been superseded by a variety of purified, semi-synthetic, and synthetic opioids with progressively stronger effect, and by other general anesthesia. This process began in 1817, when Friedrich Wilhelm Adam Sertürner reported the isolation of pure morphine from opium after at least thirteen years of research and a nearly disastrous trial on himself and three boys.[57] The great advantage of purified morphine was that a patient could be treated with a known dose - whereas with raw plant material, as Gabriel Fallopius once lamented, "if soporifics are weak they do not help; if they are strong they are exceedingly dangerous." Morphine was the first pharmaceutical isolated from a natural product, and this success encouraged the isolation of other alkaloids: by 1820, isolations of narcotine, strychnine, veratrine, colchicine, caffeine, and quinine were reported. Morphine sales began in 1827, by Heinrich Emanuel Merck of Darmstadt, and helped him expand his family pharmacy into the massive Merck KGaA pharmaceutical company.
Codeine was isolated in 1832 by Robiquet.
The use of diethyl ether and chloroform for general anesthesia began in 1846-1847, and rapidly displaced the use of opiates and tropane alkaloids from Solanaceae due to their relative safety.[58]
Heroin, the first semi-synthetic opiate, was first synthesized in 1874, but was not pursued until its rediscovery in 1897 by Felix Hoffmann at the Bayer pharmaceutical company in Elberfeld, Germany. From 1898 through to 1910 heroin was marketed as a non-addictive morphine substitute and cough medicine for children. By 1902, sales made up 5% of the company's profits, and "heroinism" had attracted media attention.[59] Oxycodone, a thebaine derivative similar to codeine, was introduced by Bayer in 1916 and promoted as a less-addictive analgesic. Preparations of the drug such as Percocet and Oxycontin remain popular to this day.
A range of synthetic opioids such as methadone (1937), pethidine (1939), fentanyl (late 1950s), and derivatives thereof have been introduced, and each is preferred for certain specialized applications. Nonetheless, morphine remains the drug of choice for American combat medics, who carry packs of syrettes containing 16 milligrams each for use on severely wounded soldiers.[60] No drug has yet been found that can match the painkilling effect of opium without also duplicating much of its addictive potential.
# Modern production and usage
## Papaver somniferum
In South American countries, opium poppies (Papaver somniferum) are technically illegal, but nonetheless appear in some nurseries as ornamentals. They are popular and attractive garden plants, whose flowers vary greatly in color, size and form. A modest amount of domestic cultivation in private gardens is not usually subject to legal controls. In part this tolerance reflects variation in addictive potency: a cultivar for opium production, Papaver somniferum L. elite, contains 92% morphine, codeine, and thebaine in its latex alkaloids, whereas the condiment cultivar "Marianne" has only one-fifth this total, with the remaining alkaloids made up mostly of narcotoline and noscapine.[61]
Seed capsules can be dried and used for decorations, but they also contain morphine, codeine, and other alkaloids. These pods can be boiled in water to produce a bitter tea that induces a long-lasting intoxication (See Poppy tea). If allowed to mature, poppy pods can be crushed into "poppy straw" and used to produce lower quantities of morphinans. In poppies subjected to mutagenesis and selection on a mass scale, researchers have been able to use poppy straw to obtain large quantities of oripavine, a precursor to opioids and antagonists such as naltrexone.[62]
Poppyseeds are a common and flavorsome topping for breads and cakes. One gram of poppy seeds contains up to 33 micrograms of morphine and 14 micrograms of codeine, and the Substance Abuse and Mental Health Services Administration formerly mandated that all drug screening laboratories use a standard cutoff of 300 nanograms per milliliter in urine samples. A single poppy seed roll (0.76 grams of seeds) usually did not produce a positive drug test, but a positive result was observed from eating two rolls. A slice of poppy seed cake containing nearly five grams of seeds per slice produced positive results for 24 hours. Such results are viewed as false positive indications of drug abuse, and were the basis of a legal defense.[63][64] On November 30, 1998, the standard cutoff was increased to 2000 nanograms (two micrograms) per milliliter.[65] During the Communist era in Eastern Europe, poppy stalks sold in bundles by farmers were processed by users with household chemicals to make kompot ("Polish heroin"), and poppy seeds were used to produce koknar, an opiate.[66]
## Harvesting and processing
When grown for opium production, the skin of the ripening pods of these poppies is scored by a sharp blade at a time carefully chosen so that neither rain, wind, nor dew can spoil the exudation of white, milky latex, usually in the afternoon. Incisions are made while the pods are still raw, with no more than a slight yellow tint, and must be shallow to avoid penetrating hollow inner chambers or loculi while cutting into the lactiferous vessels. In India, the special tool used to make the incisions is called a nushtar, and carries three or four blades three millimeters apart, which are scored upward along the pod. Incisions are made three or four times at intervals of two to three days, and each time the "poppy tears", which dry to a sticky brown resin, are collected the following morning. One acre harvested in this way can produce three to five kilograms of raw opium.[67] In the Soviet Union pods were typically scored horizontally, and opium was collected three times, or else one or two collections were followed by isolation of opiates from the ripe capsules. Oil poppies, an alternative strain of P. somniferum, were also used for production of opiates from their capsules and stems.[68]
Raw opium may be sold to a merchant or broker on the black market, but it usually does not travel far from the field before it is refined into morphine base, because pungent, jelly-like raw opium is bulkier and harder to smuggle. Crude laboratories in the field are capable of refining opium into morphine base by a simple acid-base extraction. A sticky, brown paste, morphine base is pressed into bricks and sun-dried, and can either be smoked or processed into heroin.[4]
Heroin is widely preferred because of increased potency. One study in postaddicts found heroin to be approximately 2.2 times more potent than morphine by weight with a similar duration; at these relative quantities they could distinguish the drugs subjectively but had no preference.[69] Heroin was also found to be twice as potent as morphine in surgical anesthesia.[70] Morphine is converted into heroin by a simple chemical reaction with acetic anhydride, followed by a varying degree of purification.[71][72] Especially in Mexican production, opium may be converted directly to "black tar heroin" in a simplified procedure. This form predominates in the U.S. west of the Mississippi. Relative to other preparations of heroin, it has been associated with a dramatically increased rate of HIV transmission among intravenous drug users (4% in Los Angeles vs. 40% in New York) due to technical requirements of injection, although it is also associated with greater risk of venous sclerosis and necrotizing fasciitis.[73]
## Illegal production
Opium production has fallen greatly since 1906, when 41,000 tons were produced, but because 39,000 tons of that year's opium were consumed in China, overall usage in the rest of the world was much lower.[74] In 1980, 2,000 tons of opium supplied all legal and illegal uses.[19] Recently, opium production has increased considerably, surpassing 5,000 tons in 2002. In 2002 the price for one kilogram of opium was $300 for the farmer, $800 for purchasers in Afghanistan, and $16,000 on the streets of Europe before conversion into heroin.[75]
Following documented trends of increasing availability mirroring increased American military and geo-political regional involvement, see the Golden Triangle region of Southeast Asia (particularly Myanmar), Colombia and Mexico, Afghanistan is currently the primary producer of the drug. After regularly producing 70% of the world's opium, Afghanistan decreased production to 74 tons per year under a ban by the Taliban in 2000, although the ban may have been intended primarily to boost prices after the country accumulated a stockpile with over two years' supply.[76] After the 2001 war in Afghanistan, production increased again. According to DEA statistics, Afghanistan's production of oven-dried opium increased to 1,278 tons in 2002, more than doubled by 2003, and nearly doubled again during 2004. In late 2004, the U.S. government estimated that 206,000 hectares were under poppy cultivation, 4.5% of the country's total cropland, and produced 4,200 metric tons of opium, 87% of the world's supply, yielding 60% of Afghanistan's gross domestic product.[77] In 2006, the UN Office on Drugs and Crime estimated production to have risen 59% to 407,000 acres (1,647.07056294 km²) in cultivation, yielding 6,100 tons of opium, 92% of the world's supply.[78] The value of the resulting heroin was estimated at $3.5 billion, of which Afghan farmers were estimated to have received $700 million in revenue (of which the Taliban have been estimated to have collected anywhere from tens of millions to $140 million in taxes).[79] For farmers, the crop can be up to ten times more profitable than wheat.
An increasingly large fraction of opium is processed into morphine base and heroin in drug labs in Afghanistan. Despite an international set of chemical controls designed to restrict availability of acetic anhydride, it enters the country, perhaps through its Central Asian neighbors which do not participate. A counternarcotics law passed in December 2005 requires Afghanistan to develop registries or regulations for tracking, storing, and owning acetic anhydride.[80]
Besides Afghanistan, smaller quantities of opium are produced in Pakistan, the Golden Triangle region of Southeast Asia (particularly Myanmar), Colombia and Mexico.
## Legal production
Legal opium production is allowed under the United Nations Single Convention on Narcotic Drugs and other international drug treaties, subject to strict supervision by the law enforcement agencies of individual countries. The leading legal production method is the Gregory process, whereby the entire poppy, excluding roots and leaves, is mashed and stewed in dilute acid solutions. The alkaloids are then recovered via acid-base extraction and purified. This process was developed in the UK during World War II, when wartime shortages of many essential drugs encouraged innovation in pharmaceutical processing.
Legal production in India is much more traditional. As of 1996, opium was collected by farmers who licensed to grow 0.1 hectare of opium poppies (0.24 acres), who to maintain their licenses needed to sell 4.5 kilograms of unadulterated raw opium paste at a fixed government price of 32 rupees ($8 US) per kilogram. One kilogram represents two days' work for a family. Some additional money is made by drying the poppy heads and collecting poppy seeds, and a small fraction of opium beyond the quota may be consumed locally or diverted to the black market. The opium paste is sun-dried and stirred in large pans before it is packed into cases of 60 kilograms for export. Purification of chemical constituents is done in India for domestic production, but typically done abroad by foreign importers.[81]
Legal opium importation from India and Turkey is conducted by Mallinckrodt, Noramco, Abbott Laboratories, and Purdue Pharma in the United States, and legal opium production is conducted by GlaxoSmithKline, Johnson and Johnson, Johnson Matthey, and Mayne in Tasmania, Australia; Sanofi Aventis in France; Shionogi Pharmaceutical in Japan; and MacFarlan Smith in the United Kingdom.[82] The UN treaty requires that every country submit annual reports to the International Narcotics Control Board, stating that year's actual consumption of many classes of controlled drugs as well as opioids, and projecting required quantities for the next year. This is to allow trends in consumption to be monitored, and production quotas allotted.
A recent proposal from the European Senlis Council hopes to solve the problems caused by the massive quantity of opium produced illegally in Afghanistan, most of which is converted to heroin, and smuggled for sale in Europe and the USA. This proposal is to license Afghan farmers to produce opium for the world pharmaceutical market, and thereby solve another problem, that of chronic underuse of potent analgesics where required within developing nations. Part of the proposal is to overcome the "80-20 rule" that requires the U.S. to purchase 80% of its legal opium from India and Turkey to include Afghanistan, by establishing a second-tier system of supply control that complements the current INCB regulated supply and demand system by providing poppy-based medicines to countries who cannot meet their demand under the current regulations. Senlis arranged a conference in Kabul that brought drug policy experts from around the world to meet with Afghan government officials to discuss internal security, corruption issues, and legal issues within Afghanistan.[83]
In June 2007, the Council launched a "Poppy for Medicines" project that provides a technical blueprint for the implementation of an integrated control system within Afghan village-based poppy for medicine projects: the idea promotes the economic diversification by redirecting proceeds from the legal cultivation of poppy and production of poppy-based medicines (See Senlis Council).[84]
### Cultivation in the UK
In late 2006, the British government permitted the pharmaceutical company Macfarlan Smith (a Johnson Matthey company) to cultivate opium poppies in England for medicinal reasons, after Macfarlan Smith's primary source, India, decided to increase the price of export opium latex. This move is well received by British farmers, with a major opium poppy field based in Didcot, England. The British government has contradicted the Home Office's suggestion that opium cultivation can be legalized in Afghanistan for exports to the United Kingdom, helping lower poverty and internal fighting whilst helping NHS to meet the high demand for morphine and diamorphine. Opium poppy cultivation in the United Kingdom does not need a licence, however, a licence is required for those wishing to extract opium for medicinal products.[85]
## Consumption
In the industrialized world, the USA is the world's biggest consumer of prescription opioids, with Italy one of the lowest.[86] Most opium imported into the United States is broken down into its alkaloid constituents, and whether legal or illegal, most current drug use occurs with processed derivatives such as heroin rather than with pure and untouched opium.
Intravenous injection of opiates is most used: by comparison with injection, "dragon chasing" (heating of heroin with barbital on a piece of foil) and "ack ack" (smoking of cigarettes containing heroin powder) are only 40% and 20% efficient, respectively.[87] One study of British heroin addicts found a 12-fold excess mortality ratio (1.8% of the group dying per year).[88] Most heroin deaths result not from overdose per se, but combination with other depressant drugs such as alcohol or benzodiazepines.[89]
The smoking of opium does not involve the pyrolysis of the material as might be imagined. Rather the prepared opium is indirectly heated to temperatures at which the active alkaloids, chiefly morphine, are vaporized. In the past, smokers would utilize a specially designed opium pipe which had a removable knob-like pipe-bowl of fired earthenware attached by a metal fitting to a long, cylindrical stem.[90] A small "pill" of opium about the size of a pea would be placed on the pipe-bowl, which was then heated by holding it over an opium lamp, a special oil lamp with a distinct funnel-like chimney to channel heat into a small area. The smoker would lie on his or her side in order to guide the pipe-bowl and the tiny pill of opium over the stream of heat rising from the chimney of the oil lamp and inhale the vaporized opium fumes as needed. Several pills of opium were smoked at a single session depending on the smoker's tolerance to the drug. The effects could last up to twelve hours.
In Eastern culture, opium is more commonly used in the form of paregoric to treat diarrhea. This is a weaker solution than laudanum, an alcoholic tincture which was prevalently used as a pain medication and sleeping aid. Tincture of opium has been prescribed for, among other things, severe diarrhea.[91] Taken 30 minutes prior to meals it will significantly slow intestinal motility, giving the intestines greater time to absorb fluid in the stool.
# Chemical and physiological properties
Opium contains two main groups of alkaloids. Those that use opium are commonly referred to as "opiats" (Coined by James St. Louis). Phenanthrenes include morphine, codeine, and thebaine, and are the main narcotic constituents. Isoquinolines such as papaverine have no significant central nervous system effects and are not regulated under the Controlled Substances Act. Morphine is by far the most prevalent and important alkaloid in opium, consisting of 10%-16% of the total, and is responsible for most of its harmful effects such as lung edema, respiratory difficulties, coma, or cardiac or respiratory collapse, with a normal lethal dose of 120 to 250 milligrams[92]—the amount found in approximately two grams of opium.[93] Morphine binds to and activates μ-opioid receptors in the brain, spinal cord, stomach and intestine. Regular use leads to physical tolerance and dependence. Chronic opium addicts in 1906 China[94] or modern-day Iran[95] consume an average of eight grams daily.
Both analgesia and drug addiction are functions of the mu opioid receptor, the class of opioid receptor first identified as responsive to morphine. Tolerance is associated with the superactivation of the receptor, which may be affected by the degree of endocytosis caused by the opioid administered, and leads to a superactivation of cyclic AMP signalling.[96] Long-term use of morphine in palliative care and management of chronic pain can be managed without the development of drug tolerance or (physical dependence). Many techniques of drug treatment exist, including pharmacologically based treatments with naltrexone, methadone, or ibogaine.
# Cultural references
There is a rich and longstanding literature by and about opium users. Thomas De Quincey's 1822 Confessions of an English Opium-Eater is one of the first and most famous literary accounts of opium addiction written from the point of view of an addict, and details both the pleasures and the dangers of the drug. De Quincey writes about the great English Romantic poet Samuel Taylor Coleridge (1772-1834), whose poem "Kubla Khan" is also widely considered to be a poem of the opium experience. Coleridge began using opium in 1791 after developing jaundice and rheumatic fever, and became a full addict after a severe attack of the disease in 1801, requiring 80-100 drops of laudanum daily.[97] "The Lotos-Eaters", an 1832 poem by Alfred Lord Tennyson, reflects the generally favorable British attitude toward the drug. In The Count of Monte Cristo (1844), by Alexandre Dumas, père, the Count is assuaged by an edible form of opium, and his experience with it is depicted vividly.
Edgar Allan Poe presents opium in a more disturbing context in his 1838 short story "Ligeia", in which the narrator, deeply distraught for the loss of his beloved, takes solace in opium until he "had become a bounden slave in the trammels of opium", unable to distinguish fantasy from reality after taking immoderate doses of opium. In music, Hector Berlioz' 1830 Symphony Fantastique tells the tale of an artist who has poisoned himself with opium while in the depths of despair for a hopeless love. Each of the symphony's five movements takes place at a different setting and with increasingly audible effects from the drug. For example, in the fourth movement, "Marche au Supplice", the artist dreams that he is walking to his own execution. In the fifth movement, "Songe d’une Nuit du Sabbat", he dreams that he is at a witch's orgy, where he witnesses his beloved dancing wildly along to the demented Dies Irae.
Towards the end of the nineteenth century, references to opium and opium addiction in the context of crime and the foreign underclass abound in English literature, such as in the opening paragraphs of Charles Dickens's 1870 serial The Mystery of Edwin Drood and in Arthur Conan Doyle's 1891 Sherlock Holmes short story The Man with the Twisted Lip. In Oscar Wilde's 1890 The Picture of Dorian Gray, the protagonist uses an opium den as a hiding place after a murder. Opium likewise underwent a transformation in Chinese literature, becoming associated with indolence and vice by the early twentieth century.[50]
In the twentieth century, as the use of opium was eclipsed by morphine and heroin, its role in literature became more limited, and often focused on issues related to its prohibition. In The Good Earth by Pearl S. Buck, Wang Lung, the protagonist, gets his troublesome uncle and aunt addicted to opium in order to keep them out of his hair. William S. Burroughs autobiographically describes the use of opium beside that of its derivatives. His associate Jack Black's memoir You Can't Win chronicles one man's experience both as an onlooker in the opium dens of San Francisco, and later as a "hop fiend" himself. The book and subsequent movie, The Wonderful Wizard of Oz, may allude to opium at one point in the story, when Dorothy and her friends are drawn into a field of poppies, in which they fall asleep. House of the Scorpion is a 2002 novel set in the land of Opium. Marcy Playground's self-titled album contains numerous songs about opium.
In the Seinfeld episode "The Shower Head", Elaine tests positive several times for opium after urine tests, only to discover that it comes from her regularly eating poppy seed muffins.
In the film Saw, one of the victims in the reverse bear-trap scene had an Opium overdose.
In the novel, House of the Scorpion most of the setting is in houses on the opium white poppy fields | https://www.wikidoc.org/index.php/Opium | |
8928bfece0a65cdbfeb6f6d660bf08df9973b7de | wikidoc | Thumb | Thumb
# Overview
The thumb is one of the five fingers.
# Anatomy of the thumb
## Bones
The thumb consists of 3 bones:
- distal phalanx (of the first digit)
- proximal phalanx (of the first digit)
- first metacarpal
## Muscles
Its movements are controlled by eight muscles (each with "pollicis" in the name):
The extensor pollicis longus tendon and extensor pollicis brevis tendon form what is known as the anatomical snuff box (an indentation on the lateral aspect of the thumb at its base) The radial artery can be palpated anteriorly at the wrist(not in the snuffbox)
In the hand, the abductor pollicis brevis, adductor pollicis, flexor pollicis brevis, and opponens pollicis form the thenar eminence.
## Hitchhiker's thumb
The thumb when extended (as in a "thumbs-up") can also appear to bend backwards toward the nail and outwards, a recessive congenital condition known as "hitchhiker's thumb", whereas for other people it will extend straight out with little backward bending. Having either condition appears to have no effect on the thumb's function.
# As one of five fingers, and as companion to four fingers
The English word "finger" has two senses, even in the context of appendages of a single typical human hand:
- Any of the five digits.
- The four digits, not including the thumb.
Linguistically, it appears that the original sense was the broader of these two: penkwe-ros (also rendered as penqrós) was, in the inferred Proto-Indo-European language, a suffixed form of penkwe (or penqe), which has given rise to many Indo-European-family words (tens of them defined in English dictionaries) that involve or flow from concepts of fiveness.
The thumb shares the following with each of the (other) four fingers:
- Having a skeleton of phalanges, joined by hinge-like joints that provide flexion toward the palm of the hand
- Having a "back" surface that features hair and a nail, and a hairless palm-of-the-hand side with fingerprint ridges instead
The thumb contrasts with each of the (other) four by being the only finger that:
- Is opposable
- Has two phalanges rather than three
- Has its inmost phalanx so close to the wrist
- Has much greater breadth and stubby proportions
- Is attached to such a mobile metacarpus (which produces most of the opposability)
# Grips
Typical interdigital grips include the tips of thumb and second finger (forefinger/index finger) holding a pill or other small item, or thumb and sides of second and third fingers holding a pen or pencil.
# Origin of the thumb
The evolution of the opposable or prehensile thumb is usually associated with Homo habilis, the forerunner of Homo sapiens. This, however, is the suggested result of evolution from Homo erectus (around 1 mya) via a series of intermediate anthropoid stages, and is therefore a much more complicated link.
The most important factors leading to the habile hand (and its thumb) are:
- the freeing of the hands from their walking requirements—still so crucial for apes today, as they have hands for feet, which in its turn was one of the consequences of the gradual pithecanthropoid and anthropoid adoption of the erect bipedal walking gait, and
- the simultaneous development of a larger anthropoid brain in the later stages.
# Importance of the opposable thumb
The thumb, unlike other fingers, is opposable, in that it is the only digit on the human hand which is able to oppose or turn back against the other four fingers, and thus enables the hand to refine its grip to hold objects which it would be unable to do otherwise. The opposable thumb has helped the human species develop more accurate fine motor skills. It is also thought to have directly led to the development of tools, not just in humans or their evolutionary ancestors, but other primates as well . The thumb, in conjunction with the other fingers make humans and other species with similar hands some of the most dexterous in the world.
In addition, the opposable thumb has given rise to a popular gesture referred to as the "Thumbs-Up", a symbol of approval in western culture.
# Other animals with thumbs
Many animals, primates and others, also have some kind of opposable thumb or toe:
- Bornean Orangutan - opposable thumbs on all four hands. The interdigital grip gives them the ability to pick fruit.
- Gorillas-opposable on all four hands.
- Chimpanzees have opposable thumbs on all four hands.
- Lesser Apes have opposable thumbs on all four hands.
- Old World Monkeys, with some exceptions, such as the genera, Piliocolobus and Colobus.
- Cebids (New World primates of Central and South America) - some have opposable thumbs
- Koala - opposable toe on each foot, plus two opposable digits on each hand
- Opossum - opposable thumb on rear feet
- Giant Panda - Panda paws have five clawed fingers plus an extra bone that works like an opposable thumb. This "thumb" is not really a finger (like the human thumb is), but an extra-long sesamoid bone that works like a thumb.
- Troodon - a birdlike dinosaur with partially opposable thumbs.
- Raccoon - a common mammal with thumbs, which are not opposables. | Thumb
Template:Infobox Anatomy
# Overview
The thumb is one of the five fingers.
# Anatomy of the thumb
## Bones
The thumb consists of 3 bones:
- distal phalanx (of the first digit)
- proximal phalanx (of the first digit)
- first metacarpal
## Muscles
Its movements are controlled by eight muscles (each with "pollicis" in the name):
The extensor pollicis longus tendon and extensor pollicis brevis tendon form what is known as the anatomical snuff box (an indentation on the lateral aspect of the thumb at its base) The radial artery can be palpated anteriorly at the wrist(not in the snuffbox)
In the hand, the abductor pollicis brevis, adductor pollicis, flexor pollicis brevis, and opponens pollicis form the thenar eminence.
## Hitchhiker's thumb
The thumb when extended (as in a "thumbs-up") can also appear to bend backwards toward the nail and outwards, a recessive congenital condition known as "hitchhiker's thumb", whereas for other people it will extend straight out with little backward bending. Having either condition appears to have no effect on the thumb's function.
# As one of five fingers, and as companion to four fingers
The English word "finger" has two senses, even in the context of appendages of a single typical human hand:
- Any of the five digits.
- The four digits, not including the thumb.
Linguistically, it appears that the original sense was the broader of these two: penkwe-ros (also rendered as penqrós) was, in the inferred Proto-Indo-European language, a suffixed form of penkwe (or penqe), which has given rise to many Indo-European-family words (tens of them defined in English dictionaries) that involve or flow from concepts of fiveness.
The thumb shares the following with each of the (other) four fingers:
- Having a skeleton of phalanges, joined by hinge-like joints that provide flexion toward the palm of the hand
- Having a "back" surface that features hair and a nail, and a hairless palm-of-the-hand side with fingerprint ridges instead
The thumb contrasts with each of the (other) four by being the only finger that:
- Is opposable
- Has two phalanges rather than three
- Has its inmost phalanx so close to the wrist
- Has much greater breadth and stubby proportions
- Is attached to such a mobile metacarpus (which produces most of the opposability)
# Grips
Typical interdigital grips include the tips of thumb and second finger (forefinger/index finger) holding a pill or other small item, or thumb and sides of second and third fingers holding a pen or pencil.
# Origin of the thumb
The evolution of the opposable or prehensile thumb is usually associated with Homo habilis, the forerunner of Homo sapiens.[1][2][3] This, however, is the suggested result of evolution from Homo erectus (around 1 mya) via a series of intermediate anthropoid stages, and is therefore a much more complicated link.
The most important factors leading to the habile hand (and its thumb) are:
- the freeing of the hands from their walking requirements—still so crucial for apes today, as they have hands for feet, which in its turn was one of the consequences of the gradual pithecanthropoid and anthropoid adoption of the erect bipedal walking gait, and
- the simultaneous development of a larger anthropoid brain in the later stages.
# Importance of the opposable thumb
The thumb, unlike other fingers, is opposable, in that it is the only digit on the human hand which is able to oppose or turn back against the other four fingers, and thus enables the hand to refine its grip to hold objects which it would be unable to do otherwise. The opposable thumb has helped the human species develop more accurate fine motor skills. It is also thought to have directly led to the development of tools, not just in humans or their evolutionary ancestors, but other primates as well [4][5]. The thumb, in conjunction with the other fingers make humans and other species with similar hands some of the most dexterous in the world[6].
In addition, the opposable thumb has given rise to a popular gesture referred to as the "Thumbs-Up", a symbol of approval in western culture.
# Other animals with thumbs
Many animals, primates and others, also have some kind of opposable thumb or toe:
- Bornean Orangutan - opposable thumbs on all four hands. The interdigital grip gives them the ability to pick fruit.
- Gorillas-opposable on all four hands.
- Chimpanzees have opposable thumbs on all four hands.
- Lesser Apes have opposable thumbs on all four hands.
- Old World Monkeys, with some exceptions, such as the genera, Piliocolobus and Colobus.
- Cebids (New World primates of Central and South America) - some have opposable thumbs
- Koala - opposable toe on each foot, plus two opposable digits on each hand
- Opossum - opposable thumb on rear feet
- Giant Panda - Panda paws have five clawed fingers plus an extra bone that works like an opposable thumb. This "thumb" is not really a finger (like the human thumb is), but an extra-long sesamoid bone that works like a thumb.
- Troodon - a birdlike dinosaur with partially opposable thumbs.
- Raccoon - a common mammal with thumbs, which are not opposables. | https://www.wikidoc.org/index.php/Opposable_thumb | |
22877ef345400d23459d2b2609bb0ab894f0fa6a | wikidoc | Ounce | Ounce
This article is about the unit of mass. For the unit of force, see Pound-force. For the unit of volume, see Fluid ounce. For all other uses, see Ounce (disambiguation).
The ounce (abbreviated: oz, the old Italian word onza, now spelled oncia) is a unit of mass in a number of different systems, including various systems of mass that form part of the imperial and United States customary systems. Its size can vary from system to system. The most commonly used ounces used today are the international avoirdupois ounce and the international troy ounce.
# Definitions
Historically, in different parts of the world, at different points in time, and for different applications, the ounce (or its translation) has referred to broadly similar but different standards of mass (or weight, before the distinction between weight and mass developed). Some of these other ounces are described below.
## International avoirdupois ounce
The avoirdupois ounce is the most commonly used ounce today. It is defined to be one sixteenth of an avoirdupois pound. It is therefore equal to 437.5 grains.
In 1958 the United States and countries of the Commonwealth of Nations agreed to define the international avoirdupois pound to be exactly 0.45359237 kilograms. Consequently, since 1958, the international avoirdupois ounce is exactly 28.349523 grams by definition.
The ounce is commonly used as a unit of mass in the United States. While imperial units have been officially abolished in the United Kingdom, the ounce remains a familiar unit, especially amongst older people.
## International troy ounce
A troy ounce (abbreviated as t oz) is equal to 480 grains. Consequently, the international troy ounce is equal to exactly 31.1034768 grams. There are 12 troy ounces in the now obsolete troy pound.
Today, the troy ounce is used only to express the mass of precious metals such as gold, platinum or silver.
For historical measurement of gold,
- a fine ounce is a troy ounce of 99.5% (".995") pure gold
- a standard ounce is a troy ounce of 22 carat gold, 91.66% pure (11 "fine ounces" plus one ounce of alloy material)
## Apothecaries' ounce
The obsolete apothecaries' ounce (abbreviated Template:Unicode) equivalent to the troy ounce, was formerly used by apothecaries (now called pharmacists or chemists).
## Maria Theresa ounce
"Maria Theresa ounce" was once introduced in Ethiopia and some European countries, which was equal to the weight of one Maria Theresa thaler, or 28.0668 g. Both the weight and the value are the definition of one "Birr", still in use in present-day Ethiopia and formerly in Eritrea.
## Metric ounces
Some countries have redefined their ounces to fit in with the metric system.
The Dutch have redefined their ounce (in Dutch, ons) as 100 grams.
Also the Avoirdupois pound (in Dutch pond) was redefined to 500 grams. This was adopted along with the introduction of the metric system and remains in informal usage (mostly in cookery and groceries).
The Dutch's metric values, such as 1 ons = 100 grams, is inherited, adopted and taught in Indonesia since elementary school. It is also formally written in Indonesian national dictionary ( Kamus Besar Bahasa Indonesia ) and elementary school's formal manual book.
East Asia has a traditional ounce, known as a tael, of varying value. In China, it has been given a metric value of 50 grams.
# Notes and references
- ↑ "Guide to The Hague - Where to turn". Retrieved 2008-01-01..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}
- ↑ "Nederlands metriek stelsel". Retrieved 2008-01-01. | Ounce
This article is about the unit of mass. For the unit of force, see Pound-force. For the unit of volume, see Fluid ounce. For all other uses, see Ounce (disambiguation).
The ounce (abbreviated: oz, the old Italian word onza, now spelled oncia) is a unit of mass in a number of different systems, including various systems of mass that form part of the imperial and United States customary systems. Its size can vary from system to system. The most commonly used ounces used today are the international avoirdupois ounce and the international troy ounce.
# Definitions
Historically, in different parts of the world, at different points in time, and for different applications, the ounce (or its translation) has referred to broadly similar but different standards of mass (or weight, before the distinction between weight and mass developed). Some of these other ounces are described below.
## International avoirdupois ounce
The avoirdupois ounce is the most commonly used ounce today. It is defined to be one sixteenth of an avoirdupois pound. It is therefore equal to 437.5 grains.
In 1958 the United States and countries of the Commonwealth of Nations agreed to define the international avoirdupois pound to be exactly 0.45359237 kilograms. Consequently, since 1958, the international avoirdupois ounce is exactly 28.349523 grams by definition.
The ounce is commonly used as a unit of mass in the United States. While imperial units have been officially abolished in the United Kingdom, the ounce remains a familiar unit, especially amongst older people.
## International troy ounce
A troy ounce (abbreviated as t oz) is equal to 480 grains. Consequently, the international troy ounce is equal to exactly 31.1034768 grams. There are 12 troy ounces in the now obsolete troy pound.
Today, the troy ounce is used only to express the mass of precious metals such as gold, platinum or silver.
For historical measurement of gold,
- a fine ounce is a troy ounce of 99.5% (".995") pure gold
- a standard ounce is a troy ounce of 22 carat gold, 91.66% pure (11 "fine ounces" plus one ounce of alloy material)
## Apothecaries' ounce
The obsolete apothecaries' ounce (abbreviated Template:Unicode) equivalent to the troy ounce, was formerly used by apothecaries (now called pharmacists or chemists).
## Maria Theresa ounce
"Maria Theresa ounce" was once introduced in Ethiopia and some European countries, which was equal to the weight of one Maria Theresa thaler, or 28.0668 g. Both the weight and the value are the definition of one "Birr", still in use in present-day Ethiopia and formerly in Eritrea.[citation needed]
## Metric ounces
Some countries have redefined their ounces to fit in with the metric system.[citation needed]
The Dutch have redefined their ounce (in Dutch, ons) as 100 grams. [1] [2]
Also the Avoirdupois pound (in Dutch pond) was redefined to 500 grams. This was adopted along with the introduction of the metric system and remains in informal usage (mostly in cookery and groceries).[citation needed]
The Dutch's metric values, such as 1 ons = 100 grams, is inherited, adopted and taught in Indonesia since elementary school. It is also formally written in Indonesian national dictionary ( Kamus Besar Bahasa Indonesia ) and elementary school's formal manual book.
East Asia has a traditional ounce, known as a tael, of varying value. In China, it has been given a metric value of 50 grams.[citation needed]
# Notes and references
- ↑ "Guide to The Hague - Where to turn". Retrieved 2008-01-01..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}
- ↑ "Nederlands metriek stelsel". Retrieved 2008-01-01.
# External links
- Dictionary of Units: Ounce
ar:أوقية
bs:Unča
cs:Unce
da:Unse
de:Unze
eo:Unco
fa:اونس
gd:Ùnnsa
ko:온스
mk:Унца
ms:Auns
nl:Ons (massa)
no:Unse
simple:Ounce
sr:Унца
fi:Unssi
sv:Uns
th:ออนซ์
ur:اونس
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Ounce | |
86858ecc998d4d5fbb9c6c92f3f4473e7d2fd7c2 | wikidoc | Ovary | Ovary
# Overview
An ovary is an egg-producing reproductive organ found in female organisms. It is often found in pairs as part of the vertebrate female reproductive system. Ovaries in females are homologous to testes in males. The term gonads refers to the ovaries in females and testes in males.
# Major Function
## Production of eggs (exocrine)
As female mammals develop within the womb, each ovary develops a number of immature eggs associated with groups of other cells called follicles. While mammals were thought to develop their entire supply of eggs prenatally and soon after birth, new evidence from laboratory mice has called this into question, showing that female mice in fact produce new eggs throughout their reproductive lifetime, However, there is no direct evidence showing that human females produce new eggs after birth. As the animal becomes reproductively mature (the process called puberty in humans), eggs will periodically mature and be released from the ovary (a process called ovulation) so that they will be available for fertilization by sperm. A fertilized egg resulting from union with a sperm becomes a zygote and then an embryo as it develops.
In humans, an egg launched from an ovary has to traverse a slight space before entering the fallopian tube and moving gradually down to the uterus. If fertilized, it performs implantation into the lining of the uterus and develops as the pregnancy continues. If the fertilized egg settles into the fallopian tube instead of the uterus an ectopic pregnancy will result. Ectopic pregnancy can also happen if a fertilized egg settles onto the cervix or onto the ovary itself, or if a fertilized egg passes through the gap between the ovary and the fallopian tube into the abdomen.
## Hormone secretion (endocrine)
Animal and human ovaries also produce various steroid and peptide hormones. Estrogen and progesterone are the most important of these in mammals.
These hormones serve many functions:
- They induce and maintain the physical changes of puberty and the secondary sex characteristics.
- They support maturation of the uterine endometrium in preparation of implantation of a fertilized egg.
- They provide signals to the hypothalamus and pituitary that help maintain the menstrual cycle.
- Estrogen plays an important role in maintaining subcutaneous fat, bone strength, and some aspects of brain function.
# Human anatomy
Ovaries are oval shaped and, in the human, measure approximately 3 cm x 1.5 cm x 1.5 cm. The ovary (for a given side) is located in the lateral wall of the pelvis in a region called the ovarian fossa. The fossa usually lies beneath the external iliac artery and in front of the ureter and the internal iliac artery.
## Ligaments
In the human the paired ovaries lie within the pelvic cavity, on either side of the uterus, to which they are attached via a fibrous cord called the ovarian ligament. The ovaries are uncovered in the peritoneal cavity but are tethered to the body wall via the suspensory ligament of the ovary. The part of the broad ligament of the uterus that covers the ovary is known as the mesovarium.
## Extremities
There are two extremities to the ovary:
- The end to which the uterine tube attach is called the tubal extremity.
- The other extremity is called the uterine extremity. It points downward, and it is attached to the uterus via the ovarian ligament.
## Vessels and nerves
Each ovary receives blood from the ovarian artery, which arises directly from the anterior abdominal aorta and the ovarian branch of the uterine artery that enters the ovary by way of the broad ligament and thus the mesovarium. The right ovarian vein drains to the inferior vena cava and the left ovarian vein drains to the left renal vein. The ovarian artery and vein are within the suspensory ligament of the ovary (infundibulopelvic ligament). Sources of innervation include the ovarian plexus.
## Histology
- The outermost layer is the germinal epithelium.
- The tunica albuginea covers the cortex.
- The ovarian cortex consists of ovarian follicles and stroma in between them. Included in the follicles are the cumulus oophorus, membrana granulosa (and the granulosa cells inside it), corona radiata, zona pellucida, and primary oocyte. The zona pellucida, theca of follicle, antrum and liquor folliculi are also contained in the follicle. Also in the cortex is the corpus luteum derived from the follicles.
- The innermost layer is the ovarian medulla. It can be hard to distinguish between the cortex and medulla, but follicles are usually not found in the medulla.
# Pathology
- If the egg fails to release from the follicle in the ovary an ovarian cyst may form. Small ovarian cysts are common in healthy women but large cysts can be an advanced manifestation of polycystic ovary syndrome.
- Ovarian cancer
- Hypogonadism
# Additional images
- Uterus and uterine tubes
- Organs of the female reproductive system.
- Ovary
- An ovary about to release an egg.
- Vessels of the uterus and its appendages, rear view.
- Broad ligament of adult, showing epoöphoron.
- Uterus and right broad ligament, seen from behind.
- Female pelvis and its contents, seen from above and in front.
- Arteries of the female reproductive tract: uterine artery, ovarian artery and vaginal arteries. | Ovary
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753
# Overview
An ovary is an egg-producing reproductive organ found in female organisms. It is often found in pairs as part of the vertebrate female reproductive system. Ovaries in females are homologous to testes in males. The term gonads refers to the ovaries in females and testes in males.
# Major Function
## Production of eggs (exocrine)
As female mammals develop within the womb, each ovary develops a number of immature eggs associated with groups of other cells called follicles. While mammals were thought to develop their entire supply of eggs prenatally and soon after birth, new evidence from laboratory mice has called this into question, showing that female mice in fact produce new eggs throughout their reproductive lifetime[1], However, there is no direct evidence showing that human females produce new eggs after birth. As the animal becomes reproductively mature (the process called puberty in humans), eggs will periodically mature and be released from the ovary (a process called ovulation) so that they will be available for fertilization by sperm. A fertilized egg resulting from union with a sperm becomes a zygote and then an embryo as it develops.
In humans, an egg launched from an ovary has to traverse a slight space before entering the fallopian tube and moving gradually down to the uterus. If fertilized, it performs implantation into the lining of the uterus and develops as the pregnancy continues. If the fertilized egg settles into the fallopian tube instead of the uterus an ectopic pregnancy will result. Ectopic pregnancy can also happen if a fertilized egg settles onto the cervix or onto the ovary itself, or if a fertilized egg passes through the gap between the ovary and the fallopian tube into the abdomen.
## Hormone secretion (endocrine)
Animal and human ovaries also produce various steroid and peptide hormones. Estrogen and progesterone are the most important of these in mammals.
These hormones serve many functions:
- They induce and maintain the physical changes of puberty and the secondary sex characteristics.
- They support maturation of the uterine endometrium in preparation of implantation of a fertilized egg.
- They provide signals to the hypothalamus and pituitary that help maintain the menstrual cycle.
- Estrogen plays an important role in maintaining subcutaneous fat, bone strength, and some aspects of brain function.
# Human anatomy
Ovaries are oval shaped and, in the human, measure approximately 3 cm x 1.5 cm x 1.5 cm. The ovary (for a given side) is located in the lateral wall of the pelvis in a region called the ovarian fossa. The fossa usually lies beneath the external iliac artery and in front of the ureter and the internal iliac artery.
## Ligaments
In the human the paired ovaries lie within the pelvic cavity, on either side of the uterus, to which they are attached via a fibrous cord called the ovarian ligament. The ovaries are uncovered in the peritoneal cavity but are tethered to the body wall via the suspensory ligament of the ovary. The part of the broad ligament of the uterus that covers the ovary is known as the mesovarium.
## Extremities
There are two extremities to the ovary:
- The end to which the uterine tube attach is called the tubal extremity.
- The other extremity is called the uterine extremity. It points downward, and it is attached to the uterus via the ovarian ligament.
## Vessels and nerves
Each ovary receives blood from the ovarian artery, which arises directly from the anterior abdominal aorta and the ovarian branch of the uterine artery that enters the ovary by way of the broad ligament and thus the mesovarium. The right ovarian vein drains to the inferior vena cava and the left ovarian vein drains to the left renal vein. The ovarian artery and vein are within the suspensory ligament of the ovary (infundibulopelvic ligament). Sources of innervation include the ovarian plexus.
## Histology
- The outermost layer is the germinal epithelium.
- The tunica albuginea covers the cortex.
- The ovarian cortex consists of ovarian follicles and stroma in between them. Included in the follicles are the cumulus oophorus, membrana granulosa (and the granulosa cells inside it), corona radiata, zona pellucida, and primary oocyte. The zona pellucida, theca of follicle, antrum and liquor folliculi are also contained in the follicle. Also in the cortex is the corpus luteum derived from the follicles.
- The innermost layer is the ovarian medulla. It can be hard to distinguish between the cortex and medulla, but follicles are usually not found in the medulla.
# Pathology
- If the egg fails to release from the follicle in the ovary an ovarian cyst may form. Small ovarian cysts are common in healthy women but large cysts can be an advanced manifestation of polycystic ovary syndrome.
- Ovarian cancer
- Hypogonadism
# Additional images
- Uterus and uterine tubes
- Organs of the female reproductive system.
- Ovary
- An ovary about to release an egg.
- Vessels of the uterus and its appendages, rear view.
- Broad ligament of adult, showing epoöphoron.
- Uterus and right broad ligament, seen from behind.
- Female pelvis and its contents, seen from above and in front.
- Arteries of the female reproductive tract: uterine artery, ovarian artery and vaginal arteries. | https://www.wikidoc.org/index.php/Ovarian | |
3c8ec8f476a0d32668c4f0e55ffeb9852d0e4779 | wikidoc | Redox | Redox
Redox (shorthand for reduction/oxidation reaction) describes all chemical reactions in which atoms have their oxidation number (oxidation state) changed.
This can be either a simple redox process such as the oxidation of carbon to yield carbon dioxide, or the reduction of carbon by hydrogen to yield methane (CH4), or it can be a complex process such as the oxidation of sugar in the human body through a series of very complex electron transfer processes.
The term redox comes from the two concepts of reduction and oxidation. It can be explained in simple terms:
- Oxidation describes the loss of electrons by a molecule, atom or ion
- Reduction describes the gain of electrons by a molecule, atom or ion
However, these descriptions (though sufficient for many purposes) are not truly correct. Oxidation and reduction properly refer to a change in oxidation number—the actual transfer of electrons may never occur. Thus, oxidation is better defined as an increase in oxidation number, and reduction as a decrease in oxidation number. In practice, the transfer of electrons will always cause a change in oxidation number, but there are many reactions which are classed as "redox" even though no electron transfer occurs (such as those involving covalent bonds).
Non-redox reactions, which do not involve changes in formal charge, are known as metathesis reactions.
# Oxidizing and reducing agents
Substances that have the ability to oxidize other substances are said to be oxidative and are known as oxidizing agents, oxidants or oxidizers. Put another way, the oxidant removes electrons from another substance, and is thus reduced itself. And because it "accepts" electrons it is also called an electron acceptor.
Oxidants are usually chemical substances with elements in high oxidation numbers (e.g., H2O2, MnO4−, CrO3, Cr2O72−, OsO4) or highly electronegative substances that can gain one or two extra electrons by oxidizing a substance (O, F, Cl, Br).
Substances that have the ability to reduce other substances are said to be reductive and are known as reducing agents, reductants, or reducers. Put in another way, the reductant transfers electrons to another substance, and is thus oxidized itself. And because it "donates" electrons it is also called an electron donor. Reductants in chemistry are very diverse. Metal reduction—electropositive elemental metals can be used (Li, Na, Mg, Fe, Zn, Al). These metals donate or give away electrons readily. Other kinds of reductants are hydride transfer reagents (NaBH4, LiAlH4), these reagents are widely used in organic chemistry, primarily in the reduction of carbonyl compounds to alcohols. Another useful method is reductions involving hydrogen gas (H2) with a palladium, platinum, or nickel catalyst. These catalytic reductions are primarily used in the reduction of carbon-carbon double or triple bonds.
The chemical way to look at redox processes is that the reductant transfers electrons to the oxidant. Thus, in the reaction, the reductant or reducing agent loses electrons and is oxidized and the oxidant or oxidizing agent gains electrons and is reduced. The pair of an oxidising and reducing agent that are involved in a particular reaction is called a redox pair.
# Examples of redox reactions
A good example is the reaction between hydrogen and fluorine:
We can write this overall reaction as two half-reactions: the oxidation reaction
and the reduction reaction:
Analysing each half-reaction in isolation can often make the overall chemical process clearer. Because there is no net change in charge during a redox reaction, the number of electrons in excess in the oxidation reaction must equal the number consumed by the reduction reaction (as shown above).
Elements, even in molecular form, always have an oxidation number of zero. In the first half reaction, hydrogen is oxidized from an oxidation number of zero to an oxidation number of +1. In the second half reaction, fluorine is reduced from an oxidation number of zero to an oxidation number of −1.
When adding the reactions together the electrons cancel:
\mathrm{H}_{2} & \longrightarrow & 2\mathrm{H}^{+} + 2e^{-}\\
\mathrm{F}_{2} + 2e^{-} & \longrightarrow & 2\mathrm{F}^{-}
\end{array}}{\begin{array}{rcl}
\mathrm{H}_{2} + \mathrm{F}_{2} & \longrightarrow & 2\mathrm{H}^{+} + 2\mathrm{F}^{-}
\end{array}}
And the ions combine to form hydrogen fluoride:
## Other examples
- iron(II) oxidizes to iron(III):
- hydrogen peroxide reduces to hydroxide in the presence of an acid:
-verall equation for the above:
- denitrification, nitrate reduces to nitrogen in the presence of an acid:
- iron oxidizes to iron(III) oxide and oxygen is reduced forming iron(III) oxide (commonly known as rusting, which is similar to tarnishing):
- Combustion of hydrocarbons, e.g. in an internal combustion engine, produces water, carbon dioxide, some partially oxidized forms such as carbon monoxide and heat energy. Complete oxidation of materials containing carbon produces carbon dioxide.
- In organic chemistry, stepwise oxidation of a hydrocarbon produces water and, successively, an alcohol, an aldehyde or a ketone, carboxylic acid, and then a peroxide.
# Redox reactions in industry
The primary process of reducing ore to produce metals is discussed in the article on Smelting.
Oxidation is used in a wide variety of industries such as in the production of cleaning products.
Redox reactions are the foundation of electrochemical cells.
# Redox reactions in biology
Many important biological processes involve redox reactions.
Cellular respiration, for instance, is the oxidation of glucose (C6H12O6) to CO2 and the reduction of oxygen to water. The summary equation for cell respiration is:
Biological energy is frequently stored and released by means of redox reactions. Photosynthesis involves the reduction of carbon dioxide into sugars and the oxidation of water into molecular oxygen. The reverse reaction, respiration, oxidizes sugars to produce carbon dioxide and water. As intermediate steps, the reduced carbon compounds are used to reduce nicotinamide adenine dinucleotide (NAD+), which then contributes to the creation of a proton gradient, which drives the synthesis of adenosine triphosphate (ATP) and is maintained by the reduction of oxygen.
In animal cells, mitochondria perform similar functions. See Membrane potential article.
The term redox state is often used to describe the balance of NAD+/NADH and NADP+/NADPH in a biological system such as a cell or organ. The redox state is reflected in the balance of several sets of metabolites (e.g., lactate and pyruvate, beta-hydroxybutyrate and acetoacetate) whose interconversion is dependent on these ratios. An abnormal redox state can develop in a variety of deleterious situations, such as hypoxia, shock, and sepsis. Redox signaling involves the control of cellular processes by redox processes.
## Redox cycling
A wide variety of aromatic compounds are enzymatically reduced to form free radicals that contain one more electron than their parent compounds. In general, the electron donor is any of a wide variety of flavoenzymes and their coenzymes. Once formed, these anion free radicals reduce molecular oxygen to superoxide and regenerate the unchanged parent compound. The net reaction is the oxidation of the flavoenzyme's coenzymes and the reduction of molecular oxygen to form superoxide. This catalytic behavior has been described as futile cycle or redox cycling.
Examples of redox cycling-inducing molecules are the herbicide paraquat and other viologens and quinones such as menadione. Template:PDFlink
# Balancing redox reactions
Describing the overall electrochemical reaction for a redox process requires a balancing of the component half reactions for oxidation and reduction. For reactions in aqueous solution, this
general involves adding H+ , OH- ion, H2O and electrons to compensate the oxidation changes.
## Acid medium
In acid medium H+ ions and water are added to half reactions to balance the overall reaction.
For example, when manganese (II) reacts with sodium bismuthate.
The reaction is balanced by scaling the two half-cell reactions to involve the same number of electrons (i.e. multiplying the oxidation reaction by the number of electrons in the reduction step and vice versa). Addition gives:
Reaction balanced:
Similarly for a propane fuel cell under acidic conditions:
Balancing the number of electrons involved gives:
Equation balanced:
## Basic medium
In basic medium OH- ions and water are added to half reactions to balance the overall reaction. For example on reaction between potassium permanganate and sodium sulfite.
Balancing the number of electrons in the two half-cell reactions gives:
Equation balanced: | Redox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Redox (shorthand for reduction/oxidation reaction) describes all chemical reactions in which atoms have their oxidation number (oxidation state) changed.
This can be either a simple redox process such as the oxidation of carbon to yield carbon dioxide, or the reduction of carbon by hydrogen to yield methane (CH4), or it can be a complex process such as the oxidation of sugar in the human body through a series of very complex electron transfer processes.
The term redox comes from the two concepts of reduction and oxidation. It can be explained in simple terms:
- Oxidation describes the loss of electrons by a molecule, atom or ion
- Reduction describes the gain of electrons by a molecule, atom or ion
However, these descriptions (though sufficient for many purposes) are not truly correct. Oxidation and reduction properly refer to a change in oxidation number—the actual transfer of electrons may never occur. Thus, oxidation is better defined as an increase in oxidation number, and reduction as a decrease in oxidation number. In practice, the transfer of electrons will always cause a change in oxidation number, but there are many reactions which are classed as "redox" even though no electron transfer occurs (such as those involving covalent bonds).
Non-redox reactions, which do not involve changes in formal charge, are known as metathesis reactions.
# Oxidizing and reducing agents
Substances that have the ability to oxidize other substances are said to be oxidative and are known as oxidizing agents, oxidants or oxidizers. Put another way, the oxidant removes electrons from another substance, and is thus reduced itself. And because it "accepts" electrons it is also called an electron acceptor.
Oxidants are usually chemical substances with elements in high oxidation numbers (e.g., H2O2, MnO4−, CrO3, Cr2O72−, OsO4) or highly electronegative substances that can gain one or two extra electrons by oxidizing a substance (O, F, Cl, Br).
Substances that have the ability to reduce other substances are said to be reductive and are known as reducing agents, reductants, or reducers. Put in another way, the reductant transfers electrons to another substance, and is thus oxidized itself. And because it "donates" electrons it is also called an electron donor. Reductants in chemistry are very diverse. Metal reduction—electropositive elemental metals can be used (Li, Na, Mg, Fe, Zn, Al). These metals donate or give away electrons readily. Other kinds of reductants are hydride transfer reagents (NaBH4, LiAlH4), these reagents are widely used in organic chemistry[1][2], primarily in the reduction of carbonyl compounds to alcohols. Another useful method is reductions involving hydrogen gas (H2) with a palladium, platinum, or nickel catalyst. These catalytic reductions are primarily used in the reduction of carbon-carbon double or triple bonds.
The chemical way to look at redox processes is that the reductant transfers electrons to the oxidant. Thus, in the reaction, the reductant or reducing agent loses electrons and is oxidized and the oxidant or oxidizing agent gains electrons and is reduced. The pair of an oxidising and reducing agent that are involved in a particular reaction is called a redox pair.
# Examples of redox reactions
A good example is the reaction between hydrogen and fluorine:
We can write this overall reaction as two half-reactions: the oxidation reaction
and the reduction reaction:
Analysing each half-reaction in isolation can often make the overall chemical process clearer. Because there is no net change in charge during a redox reaction, the number of electrons in excess in the oxidation reaction must equal the number consumed by the reduction reaction (as shown above).
Elements, even in molecular form, always have an oxidation number of zero. In the first half reaction, hydrogen is oxidized from an oxidation number of zero to an oxidation number of +1. In the second half reaction, fluorine is reduced from an oxidation number of zero to an oxidation number of −1.
When adding the reactions together the electrons cancel:
\mathrm{H}_{2} & \longrightarrow & 2\mathrm{H}^{+} + 2e^{-}\\
\mathrm{F}_{2} + 2e^{-} & \longrightarrow & 2\mathrm{F}^{-}
\end{array}}{\begin{array}{rcl}
\mathrm{H}_{2} + \mathrm{F}_{2} & \longrightarrow & 2\mathrm{H}^{+} + 2\mathrm{F}^{-}
\end{array}}</math>
And the ions combine to form hydrogen fluoride:
## Other examples
- iron(II) oxidizes to iron(III):
- hydrogen peroxide reduces to hydroxide in the presence of an acid:
overall equation for the above:
- denitrification, nitrate reduces to nitrogen in the presence of an acid:
- iron oxidizes to iron(III) oxide and oxygen is reduced forming iron(III) oxide (commonly known as rusting, which is similar to tarnishing):
- Combustion of hydrocarbons, e.g. in an internal combustion engine, produces water, carbon dioxide, some partially oxidized forms such as carbon monoxide and heat energy. Complete oxidation of materials containing carbon produces carbon dioxide.
- In organic chemistry, stepwise oxidation of a hydrocarbon produces water and, successively, an alcohol, an aldehyde or a ketone, carboxylic acid, and then a peroxide.
# Redox reactions in industry
The primary process of reducing ore to produce metals is discussed in the article on Smelting.
Oxidation is used in a wide variety of industries such as in the production of cleaning products.
Redox reactions are the foundation of electrochemical cells.
# Redox reactions in biology
Many important biological processes involve redox reactions.
Cellular respiration, for instance, is the oxidation of glucose (C6H12O6) to CO2 and the reduction of oxygen to water. The summary equation for cell respiration is:
Biological energy is frequently stored and released by means of redox reactions. Photosynthesis involves the reduction of carbon dioxide into sugars and the oxidation of water into molecular oxygen. The reverse reaction, respiration, oxidizes sugars to produce carbon dioxide and water. As intermediate steps, the reduced carbon compounds are used to reduce nicotinamide adenine dinucleotide (NAD+), which then contributes to the creation of a proton gradient, which drives the synthesis of adenosine triphosphate (ATP) and is maintained by the reduction of oxygen.
In animal cells, mitochondria perform similar functions. See Membrane potential article.
The term redox state is often used to describe the balance of NAD+/NADH and NADP+/NADPH in a biological system such as a cell or organ. The redox state is reflected in the balance of several sets of metabolites (e.g., lactate and pyruvate, beta-hydroxybutyrate and acetoacetate) whose interconversion is dependent on these ratios. An abnormal redox state can develop in a variety of deleterious situations, such as hypoxia, shock, and sepsis. Redox signaling involves the control of cellular processes by redox processes.
## Redox cycling
A wide variety of aromatic compounds are enzymatically reduced to form free radicals that contain one more electron than their parent compounds. In general, the electron donor is any of a wide variety of flavoenzymes and their coenzymes. Once formed, these anion free radicals reduce molecular oxygen to superoxide and regenerate the unchanged parent compound. The net reaction is the oxidation of the flavoenzyme's coenzymes and the reduction of molecular oxygen to form superoxide. This catalytic behavior has been described as futile cycle or redox cycling.
Examples of redox cycling-inducing molecules are the herbicide paraquat and other viologens and quinones such as menadione. Template:PDFlink
# Balancing redox reactions
Describing the overall electrochemical reaction for a redox process requires a balancing of the component half reactions for oxidation and reduction. For reactions in aqueous solution, this
general involves adding H+ , OH- ion, H2O and electrons to compensate the oxidation changes.
## Acid medium
In acid medium H+ ions and water are added to half reactions to balance the overall reaction.
For example, when manganese (II) reacts with sodium bismuthate.
The reaction is balanced by scaling the two half-cell reactions to involve the same number of electrons (i.e. multiplying the oxidation reaction by the number of electrons in the reduction step and vice versa). Addition gives:
Reaction balanced:
Similarly for a propane fuel cell under acidic conditions:
Balancing the number of electrons involved gives:
Equation balanced:
## Basic medium
In basic medium OH- ions and water are added to half reactions to balance the overall reaction. For example on reaction between potassium permanganate and sodium sulfite.
Balancing the number of electrons in the two half-cell reactions gives:
Equation balanced: | https://www.wikidoc.org/index.php/Oxidation | |
502fe39ed0660cea10afe40978b584339bff71fe | wikidoc | Oxide | Oxide
An oxide is a chemical compound containing at least one oxygen atom as well as at least one other element. Most of the Earth's crust consists of oxides. Oxides result when elements are oxidized by oxygen in air. Combustion of hydrocarbons affords the two principal oxides of carbon, carbon monoxide and carbon dioxide. Even materials that are considered to be pure elements often contain a coating of oxides. For example, aluminium foil has a thin skin of Al2O3 that protects the foil from further corrosion.
Virtually all elements burn in an atmosphere of oxygen. In the presence of water and oxygen (or simply air), some elements - lithium, sodium, potassium, rubidium, cesium, strontium and barium - react rapidly, even dangerously to give the hydroxides. In part for this reason, alkali and alkaline earth metals are not found in nature in their metallic, i.e., native, form. Cesium is so reactive with oxygen that it is used as a getter in vacuum tubes, and solutions of potassium and sodium, so called NaK are used to deoxygenate and dehydrate some organic solvents. The surface of most metals consist of oxides and hydroxides in the presence of air. A well known example is aluminium foil, which is coated with a thin film of aluminium oxide that passivates the metal, slowing further corrosion. The aluminium oxide layer can be built to greater thickness by the process of electrolytic anodising. Although solid magnesium and aluminium react slowly with oxygen at STP (Standard conditions for temperature and pressure), they, like most metals, will burn in air, generating very high temperatures. As a consequence, finely divided powders of most metals can be dangerously explosive in air.
In dry oxygen iron, readily forms iron(II) oxide, but the formation of the hydrated ferric oxides, Fe2O3-2x(OH)x, that mainly comprise rust, typically requires oxygen and water. The production of free oxygen by photosynthetic bacteria some 3.5 billion years ago precipitated iron out of solution in the oceans as Fe2O3 in the economically-important iron ore hematite.
Due to its electronegativity, oxygen forms chemical bonds with almost all elements to give the corresponding oxides. So-called noble metals (common examples: gold, platinum) resist direct chemical combination with oxygen, and substances like gold(III) oxide must be generated by indirect routes.
# Insolubility in water
The oxide ion, O2−, is the conjugate base of the hydroxide ion, OH−, and is encountered in ionic solid such as calcium oxide. O2− is unstable in aqueous solution − its affinity for H+ is so great (pKb ~ −22) that it abstracts a proton from a solvent H2O molecule:
Although many anions are stable in aqueous solution, ionic oxides are not. For example, sodium chloride dissolves readily in water to give a solution containing the constituent ions, Na+ and Cl−. Oxides do not behave like this. If an ionic oxide dissolves, the O2− ions become protonated. Although calcium oxide, CaO, is said to "dissolve" in water, the products include hydroxide:
In fact, no monoatomic dianion is known to dissolve in water - all are so basic that they undergo hydrolysis. Concentrations of oxide ion in water are too low to be detectable with current technology.
Authentic soluble oxides do exist, but they release oxyanions, not O2−. Well known soluble salts of oxyanions include sodium sulfate (Na2SO4), potassium permanganate (KMnO4), and sodium nitrate (NaNO3).
# Nomenclature
In the 18th century, oxides were named calxes or calces after the calcination process used to produce oxides. Calx was later replaced by oxyd.
Oxides are usually named after the number of oxygen atoms in the oxide. Oxides containing only one oxygen are called oxides or monoxides, those containing two oxygen atoms are dioxides, three oxygen atoms makes it a trioxide, four oxygen atoms are tetroxides, and so on following the Greek numerical prefixes. In the older literature and continuing in industry, oxides are named by contracting the element name with "a." Hence alumina, magnesia, chromia, are, respectively, Al2O3, MgO, Cr2O3.
Two other types of oxide are peroxide, O22−, and superoxide, O2−. In such species, oxygen is assigned higher oxidation states than oxide.
# Types of oxides
Oxides of more electropositive elements tend to be basic. They are called basic anhydrides; adding water, they may form basic hydroxides. For example, sodium oxide is basic; when hydrated, it forms sodium hydroxide.
Oxides of more electronegative elements tend to be acidic. They are called acid anhydrides; adding water, they form oxoacids. For example, dichlorine heptoxide is acid; perchloric acid is a more hydrated form.
Some oxides can act as both acid and base at different times. They are amphoteric. An example is aluminium oxide. Some oxides do not show behavior as either acid or base.
The oxides of the chemical elements in their highest oxidation state are predictable and the chemical formula can be derived from the number of valence electrons for that element. Even the chemical formula of O4, tetraoxygen, is predictable as a group 16 element. One exception is copper for which the highest oxidation state oxide is copper(II) oxide and not copper(I) oxide. Another exception is fluoride that does not exist as expected as F2O7 but as OF2 with the least electronegative element given priority. . Phosphorus pentoxide, the third exception is not properly represented by the chemical formula P2O5 but by P4O10
# List of all known oxides sorted by oxidation state
- Element in −1 oxidation state
Oxygen(II) fluoride (OF2)
- Oxygen(II) fluoride (OF2)
- Element in +1 oxidation state
Copper(I) oxide (Cu2O)
Dicarbon monoxide]] (C2O)
Dichlorine monoxide]] (Cl2O)
Lithium oxide (Li2O)
Potassium oxide (K2O)
Rubidium oxide (Rb2O)
Silver(I) oxide (Ag2O)
Thallium oxide (Tl2O)
Sodium oxide (Na2O)
Water (hydrogen oxyde) (H2O)
- Copper(I) oxide (Cu2O)
- Dicarbon monoxide]] (C2O)
- Dichlorine monoxide]] (Cl2O)
- Lithium oxide (Li2O)
- Potassium oxide (K2O)
- Rubidium oxide (Rb2O)
- Silver(I) oxide (Ag2O)
- Thallium oxide (Tl2O)
- Sodium oxide (Na2O)
- Water (hydrogen oxyde) (H2O)
- Element in +2 oxidation state
Aluminium monoxide (AlO)
Barium oxide (BaO)
Beryllium oxide (BeO)
Cadmium oxide (CdO)
Calcium oxide (CaO)
Carbon monoxide (CO)
Cobalt(II) oxide (CoO)
Copper(II) oxide (CuO)
Iron(II) oxide (FeO)
Lead(II) oxide (PbO)
Magnesium oxide (MgO)
Mercury(II) oxide (HgO)
Nickel(II) oxide (NiO)
Nitrogen oxide (NO)
Palladium(II) oxide (PdO)
Silver(II) oxide (AgO)
Strontium oxide (SrO)
Sulfur monoxide (SO)
Tin(II) oxide (SnO)
Titanium(II) oxide (TiO)
Vanadium(II) oxide (VO)
Zinc oxide (ZnO)
- Aluminium monoxide (AlO)
- Barium oxide (BaO)
- Beryllium oxide (BeO)
- Cadmium oxide (CdO)
- Calcium oxide (CaO)
- Carbon monoxide (CO)
- Cobalt(II) oxide (CoO)
- Copper(II) oxide (CuO)
- Iron(II) oxide (FeO)
- Lead(II) oxide (PbO)
- Magnesium oxide (MgO)
- Mercury(II) oxide (HgO)
- Nickel(II) oxide (NiO)
- Nitrogen oxide (NO)
- Palladium(II) oxide (PdO)
- Silver(II) oxide (AgO)
- Strontium oxide (SrO)
- Sulfur monoxide (SO)
- Tin(II) oxide (SnO)
- Titanium(II) oxide (TiO)
- Vanadium(II) oxide (VO)
- Zinc oxide (ZnO)
- Element in +3 oxidation state
Aluminium oxide (Al2O3)
Antimony trioxide (Sb2O3)
Arsenic trioxide (As2O3)
Bismuth trioxide (Bi2O3)
Boron oxide (B2O3)
Chromium(III) oxide (Cr2O3)
Dinitrogen trioxide (N2O3)
Erbium(III) oxide (Er2O3)
Gadolinium(III) oxide (Gd2O3)
Gallium(III) oxide (Ga2O3)
Holmium(III) oxide (Ho2O3)
Indium(III) oxide (In2O3)
Iron(III) oxide (Fe2O3)
Lanthanum(III) oxide (La2O3)
Lutetium(III) oxide (Lu2O3)
Nickel(III) oxide (Ni2O3)
Phosphorus trioxide (P4O6)
Promethium(III) oxide (Pm2O3)
Rhodium(III) oxide (Rh2O3)
Samarium(III) oxide (Sm2O3)
Scandium(III) oxide (Sc2O3)
Terbium(III) oxide (Tb2O3)
Thallium(III) oxide (Tl2O3)
Thulium(III) oxide (Tm2O3)
Titanium(III) oxide (Ti2O3)
Tungsten(III) oxide (W2O3)
Vanadium(III) oxide (V2O3)
Ytterbium(III) oxide (Yb2O3)
Yttrium(III) oxide (Y2O3)
- Aluminium oxide (Al2O3)
- Antimony trioxide (Sb2O3)
- Arsenic trioxide (As2O3)
- Bismuth trioxide (Bi2O3)
- Boron oxide (B2O3)
- Chromium(III) oxide (Cr2O3)
- Dinitrogen trioxide (N2O3)
- Erbium(III) oxide (Er2O3)
- Gadolinium(III) oxide (Gd2O3)
- Gallium(III) oxide (Ga2O3)
- Holmium(III) oxide (Ho2O3)
- Indium(III) oxide (In2O3)
- Iron(III) oxide (Fe2O3)
- Lanthanum(III) oxide (La2O3)
- Lutetium(III) oxide (Lu2O3)
- Nickel(III) oxide (Ni2O3)
- Phosphorus trioxide (P4O6)
- Promethium(III) oxide (Pm2O3)
- Rhodium(III) oxide (Rh2O3)
- Samarium(III) oxide (Sm2O3)
- Scandium(III) oxide (Sc2O3)
- Terbium(III) oxide (Tb2O3)
- Thallium(III) oxide (Tl2O3)
- Thulium(III) oxide (Tm2O3)
- Titanium(III) oxide (Ti2O3)
- Tungsten(III) oxide (W2O3)
- Vanadium(III) oxide (V2O3)
- Ytterbium(III) oxide (Yb2O3)
- Yttrium(III) oxide (Y2O3)
- Element in +4 oxidation state
Carbon dioxide (CO2)
Carbon trioxide (CO3)
Cerium(IV) oxide (CeO2)
Chlorine dioxide (ClO2)
Chromium(IV) oxide (CrO2)
Dinitrogen tetroxide (N2O4)
Germanium dioxide (GeO2)
Hafnium(IV) oxide (HfO2)
Lead(I) peroxide (PbO2)
Manganese(IV) oxide (MnO2)
Nitrogen dioxide (NO2)
Plutonium dioxide (PuO2)
Ruthenium(IV) oxide (RuO2)
Selenium dioxide (SeO2)
Silicon dioxide (SiO2)
Sulfur dioxide (SO2)
Tellurium dioxide (TeO2)
Thorium dioxide (ThO2)
Tin dioxide (SnO2)
Titanium dioxide (TiO2)
Tungsten(IV) oxide (WO2)
Uranium dioxide (UO2)
Vanadium(IV) oxide (VO2)
Zirconium dioxide (ZrO2)
- Carbon dioxide (CO2)
- Carbon trioxide (CO3)
- Cerium(IV) oxide (CeO2)
- Chlorine dioxide (ClO2)
- Chromium(IV) oxide (CrO2)
- Dinitrogen tetroxide (N2O4)
- Germanium dioxide (GeO2)
- Hafnium(IV) oxide (HfO2)
- Lead(I) peroxide (PbO2)
- Manganese(IV) oxide (MnO2)
- Nitrogen dioxide (NO2)
- Plutonium dioxide (PuO2)
- Ruthenium(IV) oxide (RuO2)
- Selenium dioxide (SeO2)
- Silicon dioxide (SiO2)
- Sulfur dioxide (SO2)
- Tellurium dioxide (TeO2)
- Thorium dioxide (ThO2)
- Tin dioxide (SnO2)
- Titanium dioxide (TiO2)
- Tungsten(IV) oxide (WO2)
- Uranium dioxide (UO2)
- Vanadium(IV) oxide (VO2)
- Zirconium dioxide (ZrO2)
- Element in +5 oxidation state
Antimony pentoxide (Sb2O5)
Arsenic pentoxide (As2O5)
Dinitrogen pentoxide (N2O5)
Niobium pentoxide
Phosphorus pentoxide (P2O5)
Tantalum pentoxide (Ta2O5)
Vanadium(V) oxide (V2O5)
- Antimony pentoxide (Sb2O5)
- Arsenic pentoxide (As2O5)
- Dinitrogen pentoxide (N2O5)
- Niobium pentoxide
- Phosphorus pentoxide (P2O5)
- Tantalum pentoxide (Ta2O5)
- Vanadium(V) oxide (V2O5)
- Element in +6 oxidation state
Chromium trioxide (CrO3)
Molybdenum(VI) oxide (MoO3)
Rhenium trioxide (ReO3)
Selenium trioxide (SeO3)
Sulfur trioxide (SO3)
Tellurium trioxide (TeO3)
Tetraoxygen (O4)
Tungsten trioxide (WO3)
Uranium trioxide (UO3)
Xenon trioxide (XeO3)
- Chromium trioxide (CrO3)
- Molybdenum(VI) oxide (MoO3)
- Rhenium trioxide (ReO3)
- Selenium trioxide (SeO3)
- Sulfur trioxide (SO3)
- Tellurium trioxide (TeO3)
- Tetraoxygen (O4)
- Tungsten trioxide (WO3)
- Uranium trioxide (UO3)
- Xenon trioxide (XeO3)
- Element in +7 oxidation state
Dichlorine heptoxide (Cl2O7)
Manganese(VII) oxide (Mn2O7)
Rhenium(VII) oxide (Re2O7)
Technetium(VII) oxide
- Dichlorine heptoxide (Cl2O7)
- Manganese(VII) oxide (Mn2O7)
- Rhenium(VII) oxide (Re2O7)
- Technetium(VII) oxide
- Element in +8 oxidation state
Osmium tetroxide (OsO4)
Ruthenium tetroxide (RuO4)
Xenon tetroxide (XeO4)
- Osmium tetroxide (OsO4)
- Ruthenium tetroxide (RuO4)
- Xenon tetroxide (XeO4) | Oxide
An oxide is a chemical compound containing at least one oxygen atom as well as at least one other element. Most of the Earth's crust consists of oxides. Oxides result when elements are oxidized by oxygen in air. Combustion of hydrocarbons affords the two principal oxides of carbon, carbon monoxide and carbon dioxide. Even materials that are considered to be pure elements often contain a coating of oxides. For example, aluminium foil has a thin skin of Al2O3 that protects the foil from further corrosion.
Virtually all elements burn in an atmosphere of oxygen. In the presence of water and oxygen (or simply air), some elements - lithium, sodium, potassium, rubidium, cesium, strontium and barium - react rapidly, even dangerously to give the hydroxides. In part for this reason, alkali and alkaline earth metals are not found in nature in their metallic, i.e., native, form. Cesium is so reactive with oxygen that it is used as a getter in vacuum tubes, and solutions of potassium and sodium, so called NaK are used to deoxygenate and dehydrate some organic solvents. The surface of most metals consist of oxides and hydroxides in the presence of air. A well known example is aluminium foil, which is coated with a thin film of aluminium oxide that passivates the metal, slowing further corrosion. The aluminium oxide layer can be built to greater thickness by the process of electrolytic anodising. Although solid magnesium and aluminium react slowly with oxygen at STP (Standard conditions for temperature and pressure), they, like most metals, will burn in air, generating very high temperatures. As a consequence, finely divided powders of most metals can be dangerously explosive in air.
In dry oxygen iron, readily forms iron(II) oxide, but the formation of the hydrated ferric oxides, Fe2O3-2x(OH)x, that mainly comprise rust, typically requires oxygen and water. The production of free oxygen by photosynthetic bacteria some 3.5 billion years ago precipitated iron out of solution in the oceans as Fe2O3 in the economically-important iron ore hematite.
Due to its electronegativity, oxygen forms chemical bonds with almost all elements to give the corresponding oxides. So-called noble metals (common examples: gold, platinum) resist direct chemical combination with oxygen, and substances like gold(III) oxide must be generated by indirect routes.
# Insolubility in water
The oxide ion, O2−, is the conjugate base of the hydroxide ion, OH−, and is encountered in ionic solid such as calcium oxide. O2− is unstable in aqueous solution − its affinity for H+ is so great (pKb ~ −22) that it abstracts a proton from a solvent H2O molecule:
Although many anions are stable in aqueous solution, ionic oxides are not. For example, sodium chloride dissolves readily in water to give a solution containing the constituent ions, Na+ and Cl−. Oxides do not behave like this. If an ionic oxide dissolves, the O2− ions become protonated. Although calcium oxide, CaO, is said to "dissolve" in water, the products include hydroxide:
In fact, no monoatomic dianion is known to dissolve in water - all are so basic that they undergo hydrolysis. Concentrations of oxide ion in water are too low to be detectable with current technology.
Authentic soluble oxides do exist, but they release oxyanions, not O2−. Well known soluble salts of oxyanions include sodium sulfate (Na2SO4), potassium permanganate (KMnO4), and sodium nitrate (NaNO3).
# Nomenclature
In the 18th century, oxides were named calxes or calces after the calcination process used to produce oxides. Calx was later replaced by oxyd.
Oxides are usually named after the number of oxygen atoms in the oxide. Oxides containing only one oxygen are called oxides or monoxides, those containing two oxygen atoms are dioxides, three oxygen atoms makes it a trioxide, four oxygen atoms are tetroxides, and so on following the Greek numerical prefixes. In the older literature and continuing in industry, oxides are named by contracting the element name with "a." Hence alumina, magnesia, chromia, are, respectively, Al2O3, MgO, Cr2O3.
Two other types of oxide are peroxide, O22−, and superoxide, O2−. In such species, oxygen is assigned higher oxidation states than oxide.
# Types of oxides
Oxides of more electropositive elements tend to be basic. They are called basic anhydrides; adding water, they may form basic hydroxides. For example, sodium oxide is basic; when hydrated, it forms sodium hydroxide.
Oxides of more electronegative elements tend to be acidic. They are called acid anhydrides; adding water, they form oxoacids. For example, dichlorine heptoxide is acid; perchloric acid is a more hydrated form.
Some oxides can act as both acid and base at different times. They are amphoteric. An example is aluminium oxide. Some oxides do not show behavior as either acid or base.
The oxides of the chemical elements in their highest oxidation state are predictable and the chemical formula can be derived from the number of valence electrons for that element. Even the chemical formula of O4, tetraoxygen, is predictable as a group 16 element. One exception is copper for which the highest oxidation state oxide is copper(II) oxide and not copper(I) oxide. Another exception is fluoride that does not exist as expected as F2O7 but as OF2 with the least electronegative element given priority. [1]. Phosphorus pentoxide, the third exception is not properly represented by the chemical formula P2O5 but by P4O10
# List of all known oxides sorted by oxidation state
- Element in −1 oxidation state
Oxygen(II) fluoride (OF2)
- Oxygen(II) fluoride (OF2)
- Element in +1 oxidation state
Copper(I) oxide (Cu2O)
Dicarbon monoxide]] (C2O)
Dichlorine monoxide]] (Cl2O)
Lithium oxide (Li2O)
Potassium oxide (K2O)
Rubidium oxide (Rb2O)
Silver(I) oxide (Ag2O)
Thallium oxide (Tl2O)
Sodium oxide (Na2O)
Water (hydrogen oxyde) (H2O)
- Copper(I) oxide (Cu2O)
- Dicarbon monoxide]] (C2O)
- Dichlorine monoxide]] (Cl2O)
- Lithium oxide (Li2O)
- Potassium oxide (K2O)
- Rubidium oxide (Rb2O)
- Silver(I) oxide (Ag2O)
- Thallium oxide (Tl2O)
- Sodium oxide (Na2O)
- Water (hydrogen oxyde) (H2O)
- Element in +2 oxidation state
Aluminium monoxide (AlO)
Barium oxide (BaO)
Beryllium oxide (BeO)
Cadmium oxide (CdO)
Calcium oxide (CaO)
Carbon monoxide (CO)
Cobalt(II) oxide (CoO)
Copper(II) oxide (CuO)
Iron(II) oxide (FeO)
Lead(II) oxide (PbO)
Magnesium oxide (MgO)
Mercury(II) oxide (HgO)
Nickel(II) oxide (NiO)
Nitrogen oxide (NO)
Palladium(II) oxide (PdO)
Silver(II) oxide (AgO)
Strontium oxide (SrO)
Sulfur monoxide (SO)
Tin(II) oxide (SnO)
Titanium(II) oxide (TiO)
Vanadium(II) oxide (VO)
Zinc oxide (ZnO)
- Aluminium monoxide (AlO)
- Barium oxide (BaO)
- Beryllium oxide (BeO)
- Cadmium oxide (CdO)
- Calcium oxide (CaO)
- Carbon monoxide (CO)
- Cobalt(II) oxide (CoO)
- Copper(II) oxide (CuO)
- Iron(II) oxide (FeO)
- Lead(II) oxide (PbO)
- Magnesium oxide (MgO)
- Mercury(II) oxide (HgO)
- Nickel(II) oxide (NiO)
- Nitrogen oxide (NO)
- Palladium(II) oxide (PdO)
- Silver(II) oxide (AgO)
- Strontium oxide (SrO)
- Sulfur monoxide (SO)
- Tin(II) oxide (SnO)
- Titanium(II) oxide (TiO)
- Vanadium(II) oxide (VO)
- Zinc oxide (ZnO)
- Element in +3 oxidation state
Aluminium oxide (Al2O3)
Antimony trioxide (Sb2O3)
Arsenic trioxide (As2O3)
Bismuth trioxide (Bi2O3)
Boron oxide (B2O3)
Chromium(III) oxide (Cr2O3)
Dinitrogen trioxide (N2O3)
Erbium(III) oxide (Er2O3)
Gadolinium(III) oxide (Gd2O3)
Gallium(III) oxide (Ga2O3)
Holmium(III) oxide (Ho2O3)
Indium(III) oxide (In2O3)
Iron(III) oxide (Fe2O3)
Lanthanum(III) oxide (La2O3)
Lutetium(III) oxide (Lu2O3)
Nickel(III) oxide (Ni2O3)
Phosphorus trioxide (P4O6)
Promethium(III) oxide (Pm2O3)
Rhodium(III) oxide (Rh2O3)
Samarium(III) oxide (Sm2O3)
Scandium(III) oxide (Sc2O3)
Terbium(III) oxide (Tb2O3)
Thallium(III) oxide (Tl2O3)
Thulium(III) oxide (Tm2O3)
Titanium(III) oxide (Ti2O3)
Tungsten(III) oxide (W2O3)
Vanadium(III) oxide (V2O3)
Ytterbium(III) oxide (Yb2O3)
Yttrium(III) oxide (Y2O3)
- Aluminium oxide (Al2O3)
- Antimony trioxide (Sb2O3)
- Arsenic trioxide (As2O3)
- Bismuth trioxide (Bi2O3)
- Boron oxide (B2O3)
- Chromium(III) oxide (Cr2O3)
- Dinitrogen trioxide (N2O3)
- Erbium(III) oxide (Er2O3)
- Gadolinium(III) oxide (Gd2O3)
- Gallium(III) oxide (Ga2O3)
- Holmium(III) oxide (Ho2O3)
- Indium(III) oxide (In2O3)
- Iron(III) oxide (Fe2O3)
- Lanthanum(III) oxide (La2O3)
- Lutetium(III) oxide (Lu2O3)
- Nickel(III) oxide (Ni2O3)
- Phosphorus trioxide (P4O6)
- Promethium(III) oxide (Pm2O3)
- Rhodium(III) oxide (Rh2O3)
- Samarium(III) oxide (Sm2O3)
- Scandium(III) oxide (Sc2O3)
- Terbium(III) oxide (Tb2O3)
- Thallium(III) oxide (Tl2O3)
- Thulium(III) oxide (Tm2O3)
- Titanium(III) oxide (Ti2O3)
- Tungsten(III) oxide (W2O3)
- Vanadium(III) oxide (V2O3)
- Ytterbium(III) oxide (Yb2O3)
- Yttrium(III) oxide (Y2O3)
- Element in +4 oxidation state
Carbon dioxide (CO2)
Carbon trioxide (CO3)
Cerium(IV) oxide (CeO2)
Chlorine dioxide (ClO2)
Chromium(IV) oxide (CrO2)
Dinitrogen tetroxide (N2O4)
Germanium dioxide (GeO2)
Hafnium(IV) oxide (HfO2)
Lead(I) peroxide (PbO2)
Manganese(IV) oxide (MnO2)
Nitrogen dioxide (NO2)
Plutonium dioxide (PuO2)
Ruthenium(IV) oxide (RuO2)
Selenium dioxide (SeO2)
Silicon dioxide (SiO2)
Sulfur dioxide (SO2)
Tellurium dioxide (TeO2)
Thorium dioxide (ThO2)
Tin dioxide (SnO2)
Titanium dioxide (TiO2)
Tungsten(IV) oxide (WO2)
Uranium dioxide (UO2)
Vanadium(IV) oxide (VO2)
Zirconium dioxide (ZrO2)
- Carbon dioxide (CO2)
- Carbon trioxide (CO3)
- Cerium(IV) oxide (CeO2)
- Chlorine dioxide (ClO2)
- Chromium(IV) oxide (CrO2)
- Dinitrogen tetroxide (N2O4)
- Germanium dioxide (GeO2)
- Hafnium(IV) oxide (HfO2)
- Lead(I) peroxide (PbO2)
- Manganese(IV) oxide (MnO2)
- Nitrogen dioxide (NO2)
- Plutonium dioxide (PuO2)
- Ruthenium(IV) oxide (RuO2)
- Selenium dioxide (SeO2)
- Silicon dioxide (SiO2)
- Sulfur dioxide (SO2)
- Tellurium dioxide (TeO2)
- Thorium dioxide (ThO2)
- Tin dioxide (SnO2)
- Titanium dioxide (TiO2)
- Tungsten(IV) oxide (WO2)
- Uranium dioxide (UO2)
- Vanadium(IV) oxide (VO2)
- Zirconium dioxide (ZrO2)
- Element in +5 oxidation state
Antimony pentoxide (Sb2O5)
Arsenic pentoxide (As2O5)
Dinitrogen pentoxide (N2O5)
Niobium pentoxide
Phosphorus pentoxide (P2O5)
Tantalum pentoxide (Ta2O5)
Vanadium(V) oxide (V2O5)
- Antimony pentoxide (Sb2O5)
- Arsenic pentoxide (As2O5)
- Dinitrogen pentoxide (N2O5)
- Niobium pentoxide
- Phosphorus pentoxide (P2O5)
- Tantalum pentoxide (Ta2O5)
- Vanadium(V) oxide (V2O5)
- Element in +6 oxidation state
Chromium trioxide (CrO3)
Molybdenum(VI) oxide (MoO3)
Rhenium trioxide (ReO3)
Selenium trioxide (SeO3)
Sulfur trioxide (SO3)
Tellurium trioxide (TeO3)
Tetraoxygen (O4)
Tungsten trioxide (WO3)
Uranium trioxide (UO3)
Xenon trioxide (XeO3)
- Chromium trioxide (CrO3)
- Molybdenum(VI) oxide (MoO3)
- Rhenium trioxide (ReO3)
- Selenium trioxide (SeO3)
- Sulfur trioxide (SO3)
- Tellurium trioxide (TeO3)
- Tetraoxygen (O4)
- Tungsten trioxide (WO3)
- Uranium trioxide (UO3)
- Xenon trioxide (XeO3)
- Element in +7 oxidation state
Dichlorine heptoxide (Cl2O7)
Manganese(VII) oxide (Mn2O7)
Rhenium(VII) oxide (Re2O7)
Technetium(VII) oxide
- Dichlorine heptoxide (Cl2O7)
- Manganese(VII) oxide (Mn2O7)
- Rhenium(VII) oxide (Re2O7)
- Technetium(VII) oxide
- Element in +8 oxidation state
Osmium tetroxide (OsO4)
Ruthenium tetroxide (RuO4)
Xenon tetroxide (XeO4)
- Osmium tetroxide (OsO4)
- Ruthenium tetroxide (RuO4)
- Xenon tetroxide (XeO4) | https://www.wikidoc.org/index.php/Oxide | |
a9d0fc799a4c373204bb4c16b6c40b5eb48cf91d | wikidoc | Oxime | Oxime
# Overview
An oxime is one in a class of chemical compounds with the general formula R1R2CNOH, where R1 is an organic side chain and R2 is either hydrogen, forming an aldoxime, or another organic group, forming a ketoxime.
Oximes can be formed by the action of hydroxylamine on aldehydes or ketones.
The term oxime dates to the 19th century, a condensation of the words oxygen and imide.
Oximes exist as two stereoisomers: a syn isomer and an anti isomer. Aldoximes, except for aromatic aldoximes, exist only as a syn isomer, while ketoximes can be separated almost completely and obtained as a syn isomer and an anti isomer.
# Chemistry of oximes
## Organic synthesis
Oximes can be synthesized by condensation of an aldehyde or a ketone with hydroxylamine. The condensation of aldehydes with hydroxylamine gives aldoxime, and ketoxime is produced from ketones and hydroxylamine. Generally, oximes exist as colorless crystals and do not easily dissolve in water. Therefore, oximes are used for the identification of ketone or aldehyde.
Oximes can also be obtained from reaction of nitrites such as isoamyl nitrite with compounds containing an acidic hydrogen atom. Examples are the reaction of ethyl acetoacetate and sodium nitrite in acetic acid, the reaction of methyl ethyl ketone with ethyl nitrite in hydrochloric acid. and a similar reaction with propiophenone, the reaction of phenacyl chloride, the reaction of malononitrile with sodium nitrite in acetic acid
A conceptually related reaction is the Japp-Klingemann reaction.
## Organic reactions
The hydrolysis of oximes proceeds easily by heating in the presence of various inorganic acids, and the oximes decompose into the corresponding ketones or aldehydes, and hydroxylamines. The reduction of oximes by sodium amalgam or hydrogenation produces amines. The reduction of aldoximes gives both primary amines and secondary amines.
Generally oximes can be changed to the corresponding amide derivatives by treatment with various acids. This reaction is called Beckmann rearrangement. In this reaction, a hydroxyl group is exchanged with the group that is in the anti position of the hydroxyl group. The amide derivatives that are obtained by Beckmann rearrangement can be transformed into a carboxylic acid and an amine by hydrolysis. Beckmann rearrangement is used for the industrial synthesis of caprolactam, which is the material used to make nylon-6.
The Ponzio reaction (1906) concerning the conversion of m-nitrobenzaldoxime to m-Nitrophenyldinitromethane with Dinitrogen tetroxide, was the result of research into TNT-like high explosives :
# Uses of oximes
Oxime compounds are used as antidotes for nerve agents. A nerve agent inactivates acetylcholinesterase molecules by phosphonylation of the molecule. Oxime compounds can reactivate acetylcholinesterate by attaching to the phosphorus atom and forming an oxime-phosphonate which then splits away from the acetylcholinesterase molecule. The most effective oxime nerve-agent antidotes are pralidoxime, obidoxime, methoxime, HI-6, Hlo-7, 2-PAM, and TMB-4. The effectiveness of the oxime treatment depends on the particular nerve agent used.
The oxime of perillaldehyde is used as an artificial sweetener in Japan, as it is 2000 times sweeter than sucrose. Salicylaldoxime is a chelator. | Oxime
# Overview
An oxime is one in a class of chemical compounds with the general formula R1R2CNOH, where R1 is an organic side chain and R2 is either hydrogen, forming an aldoxime, or another organic group, forming a ketoxime.
Oximes can be formed by the action of hydroxylamine on aldehydes or ketones.
The term oxime dates to the 19th century, a condensation of the words oxygen and imide.
Oximes exist as two stereoisomers: a syn isomer and an anti isomer. Aldoximes, except for aromatic aldoximes, exist only as a syn isomer, while ketoximes can be separated almost completely and obtained as a syn isomer and an anti isomer.
# Chemistry of oximes
## Organic synthesis
Oximes can be synthesized by condensation of an aldehyde or a ketone with hydroxylamine. The condensation of aldehydes with hydroxylamine gives aldoxime, and ketoxime is produced from ketones and hydroxylamine. Generally, oximes exist as colorless crystals and do not easily dissolve in water. Therefore, oximes are used for the identification of ketone or aldehyde.
Oximes can also be obtained from reaction of nitrites such as isoamyl nitrite with compounds containing an acidic hydrogen atom. Examples are the reaction of ethyl acetoacetate and sodium nitrite in acetic acid,[1][2] the reaction of methyl ethyl ketone with ethyl nitrite in hydrochloric acid.[3] and a similar reaction with propiophenone,[4] the reaction of phenacyl chloride,[5] the reaction of malononitrile with sodium nitrite in acetic acid[6]
A conceptually related reaction is the Japp-Klingemann reaction.
## Organic reactions
The hydrolysis of oximes proceeds easily by heating in the presence of various inorganic acids, and the oximes decompose into the corresponding ketones or aldehydes, and hydroxylamines. The reduction of oximes by sodium amalgam or hydrogenation produces amines. The reduction of aldoximes gives both primary amines and secondary amines.
Generally oximes can be changed to the corresponding amide derivatives by treatment with various acids. This reaction is called Beckmann rearrangement. In this reaction, a hydroxyl group is exchanged with the group that is in the anti position of the hydroxyl group. The amide derivatives that are obtained by Beckmann rearrangement can be transformed into a carboxylic acid and an amine by hydrolysis. Beckmann rearrangement is used for the industrial synthesis of caprolactam, which is the material used to make nylon-6.
The Ponzio reaction (1906) [7] concerning the conversion of m-nitrobenzaldoxime to m-Nitrophenyldinitromethane with Dinitrogen tetroxide, was the result of research into TNT-like high explosives [8]:
# Uses of oximes
Oxime compounds are used as antidotes for nerve agents. A nerve agent inactivates acetylcholinesterase molecules by phosphonylation of the molecule. Oxime compounds can reactivate acetylcholinesterate by attaching to the phosphorus atom and forming an oxime-phosphonate which then splits away from the acetylcholinesterase molecule. The most effective oxime nerve-agent antidotes are pralidoxime, obidoxime, methoxime, HI-6, Hlo-7, 2-PAM, and TMB-4.[9] The effectiveness of the oxime treatment depends on the particular nerve agent used.[10]
The oxime of perillaldehyde is used as an artificial sweetener in Japan, as it is 2000 times sweeter than sucrose. Salicylaldoxime is a chelator. | https://www.wikidoc.org/index.php/Oxime | |
21a788a58be6708046263f2406af4601ddac2362 | wikidoc | Ozone | Ozone
Ozone (O3) is a triatomic molecule, consisting of three oxygen atoms. It is an allotrope of oxygen that is much less stable than the diatomic species O2. Ground-level ozone is an air pollutant with harmful effects on the respiratory systems of animals. Ozone in the upper atmosphere filters potentially damaging ultraviolet light from reaching the Earth's surface. It is present in low concentrations throughout the Earth's atmosphere. It has many industrial and consumer applications. Ozone therapy is a controversial alternative medicine practice; mainstream scientific medicine has found ozone to be harmful to humans,
and equipment intended to be used for ozone therapy is banned in the United States.
Ozone, the first allotrope of a chemical element to be described by science, was discovered by Christian Friedrich Schönbein in 1840, who named it after the Greek word for smell (ozein), from the peculiar odor in lightning storms. The odor from a lightning strike is from ions produced during the rapid chemical changes, not the ozone itself.
# Physical properties
Undiluted ozone is a pale blue gas at standard temperature and pressure; it forms a dark blue liquid below −112 °C and a violet-black solid below −193 °C. At concentrations found in the atmosphere it is colorless. The concentration above which it can be smelled (odor threshold) is between 0.0076 and 0.036 ppm.
# Structure
The structure of ozone, according to experimental evidence from microwave spectroscopy, is bent, with C2v symmetry (similar to the water molecule), O – O distance of 127.2 pm and O – O – O angle of 116.78°. The central atom forms an sp² hybridization with one lone pair. Ozone is a polar molecule with a dipole moment of 0.5337 D. The bonding is single bond on one side and double bond on the other side, and these bonds are blended to become known as resonance structures. The bond order is 1.5 for each side.
# Chemistry
Ozone is a powerful oxidizing agent. It is also unstable at high concentrations, decaying to ordinary diatomic oxygen (in about half an hour in atmospheric conditions):
This reaction proceeds more rapidly with increasing temperature and decreasing pressure. Ozone will oxidize metals (except gold, platinum, and iridium) to oxides of the metals in their highest oxidation state:
Ozone also increases the oxidation number of oxides:
The above reaction is accompanied by chemiluminescence. The NO2 can be further oxidized:
The NO3 formed can react with NO2 to form N2O5:
Ozone reacts with carbon to form carbon dioxide, even at room temperature:
Ozone does not react with ammonium salts but it reacts with ammonia to form ammonium nitrate:
Ozone reacts with sulfides to make sulfates:
Sulfuric acid can be produced from ozone, either starting from elemental sulfur or from sulfur dioxide:
All three atoms of ozone may also react, as in the reaction with tin(II) chloride and hydrochloric acid:
In the gas phase, ozone reacts with hydrogen sulfide to form sulfur dioxide:
In an aqueous solution, however, two competing simultaneous reactions occur, one to produce elemental sulfur, and one to produce sulfuric acid:
Iodine perchlorate can be made by treating iodine dissolved in cold anhydrous perchloric acid with ozone:
Solid nitryl perchlorate can be made from NO2, ClO2, and O3 gases:
Ozone can be used for combustion reactions and combusting gases in ozone provides higher temperatures than combusting in dioxygen (O2). Following is a reaction for the combustion of carbon subnitride:
Ozone can react at cryogenic temperatures. At 77 K (-196 °C), atomic hydrogen reacts with liquid ozone to form a hydrogen superoxide radical, which dimerizes:
Ozonides can be formed, which contain the ozonide anion, O3-. These compounds are explosive and must be stored at cryogenic temperatures. Ozonides for all the alkali metals are known. KO3, RbO3, and CsO3 can be prepared from their respective superoxides:
Although KO3 can be formed as above, it can also be formed from potassium hydroxide and ozone:
NaO3 and LiO3 must be prepared by action of CsO3 in liquid NH3 on an ion exchange resin containing Na+ or Li+ ions:
Treatment with ozone of calcium dissolved in ammonia leads to ammonium ozonide and not calcium ozonide:
Ozone can be used to remove manganese from the water, forming a precipitate which can be filtered:
Ozone will also turn cyanides to the one thousand times less toxic cyanates:
Finally, ozone will also completely decompose urea:
# Ozone in Earth's atmosphere
The standard way to express total ozone levels (the volume of ozone in a vertical column) in the atmosphere is by using Dobson units. Concentrations at a point are measured in parts per billion (ppb) or in μg/m³.
## Ozone layer
The highest levels of ozone in the atmosphere are in the stratosphere, in a region also known as the ozone layer between about 10 km and 50 km above the surface (or between 6.21 and 31.1 miles). Here it filters out the shorter wavelengths (less than 320 nm) of ultraviolet light (270 to 400 nm) from the Sun that would be harmful to most forms of life in large doses. These same wavelengths are also among those responsible for the production of vitamin D, which is essential for human health. Ozone in the stratosphere is mostly produced from ultraviolet rays reacting with oxygen:
It is destroyed by the reaction with atomic oxygen:
(See Ozone-oxygen cycle for more detail.)
The latter reaction is catalysed by the presence of certain free radicals, of which the most important are hydroxyl (OH), nitric oxide (NO) and atomic chlorine (Cl) and bromine (Br). In recent decades the amount of ozone in the stratosphere has been declining mostly due to emissions of CFCs and similar chlorinated and brominated organic molecules, which have increased the concentration of ozone-depleting catalysts above the natural background. See ozone depletion for more information.
## Low level ozone
Low level ozone (or tropospheric ozone) is regarded as a pollutant by the World Health Organization. It is not emitted directly by car engines or by industrial operations. It is formed by the reaction of sunlight on air containing hydrocarbons and nitrogen oxides that react to form ozone directly at the source of the pollution or many kilometers down wind. For more details of the complex chemical reactions that produce low level ozone see tropospheric ozone.
Ozone reacts directly with some hydrocarbons such as aldehydes and thus begins their removal from the air, but the products are themselves key components of smog. Ozone photolysis by UV light leads to production of the hydroxyl radical and this plays a part in the removal of hydrocarbons from the air, but is also the first step in the creation of components of smog such as peroxyacyl nitrates which can be powerful eye irritants. The atmospheric lifetime of tropospheric ozone is about 22 days and its main removal mechanisms are being deposited to the ground, the above mentioned reaction giving OH, and by reactions with OH and the peroxy radical HO2· (Stevenson et al, 2006).
As well as having an impact on human health (see below) there is also evidence of significant reduction in agricultural yields due to increased ground-level ozone and pollution which interferes with photosynthesis and stunts overall growth of some plant species.
### Ozone as a greenhouse gas
Although ozone was present at ground level before the industrial revolution, peak concentrations are far higher than the pre-industrial levels and even background concentrations well away from sources of pollution are substantially higher. This increase in ozone is of further concern as ozone present in the upper troposphere acts as a greenhouse gas, absorbing some of the infrared energy emitted by the earth. Quantifying the greenhouse gas potency of ozone is difficult as it is not present in uniform concentrations across the globe. However, the most recent scientific review on the climate change (the IPCC Third Assessment Report) suggests that the radiative forcing of tropospheric ozone is about 25% that of carbon dioxide.
# Ozone and health
## Ozone in air pollution
There is a great deal of evidence to show that high concentrations (ppm) of ozone, created by high concentrations of pollution and daylight UV rays at the earth's surface, can harm lung function and irritate the respiratory system. A connection has also been shown to exist between increased ozone caused by thunderstorms and hospital admissions of asthma sufferers. Air quality guidelines such as those from the World Health Organization are based on detailed studies of what levels can cause measurable health effects.
A common British folk myth dating back to the Victorian era holds that the smell of the sea is caused by ozone, and that this smell has "bracing" health benefits. Neither of these is true. The characteristic "smell of the sea" is not caused by ozone, but by the presence of dimethyl sulfide generated by phytoplankton, and dimethyl sulfide, like ozone, is toxic in high concentrations.
The United States Environmental Protection Agency has developed an Air Quality index to help explain air pollution levels to the general public. 8-hour average ozone concentrations of 85 to 104 ppbv are described as "Unhealthy for Sensitive Groups", 105 ppbv to 124 ppbv as "unhealthy" and 125 ppb to 404 ppb as "very unhealthy". The EPA has designated over 300 counties of the United States, clustered around the most heavily populated areas (especially in California and the Northeast), as failing to comply with the National Ambient Air Quality Standards.
## Physiology of ozone
Ozone, along with reactive forms of oxygen such as superoxide, singlet oxygen (see oxygen), hydrogen peroxide, and hypochlorite ions, is naturally produced by white blood cells and other biological systems (such as the roots of marigolds) as a means of destroying foreign bodies. Ozone reacts directly with organic double bonds. Also, when ozone breaks down to dioxygen it gives rise to oxygen free radicals, which are highly reactive and capable of damaging many organic molecules. Ozone has been found to convert cholesterol in the blood stream to plaque (which causes hardening and narrowing of arteries). Moreover, it is believed that the powerful oxidizing properties of ozone may be a contributing factor of inflammation. The cause-and-effect relationship of how the ozone is created in the body and what it does is still under consideration and still subject to various interpretations, since other body chemical processes can trigger some of the same reactions. A team headed by Dr. Paul Wentworth Jr. of the Department of Chemistry at the Scripps Research Institute has shown evidence linking the antibody-catalyzed water-oxidation pathway of the human immune response to the production of ozone. In this system, ozone is produced by antibody-catalyzed production of trioxidane from water and neutrophil-produced singlet oxygen. See also trioxidane for more on this biological ozone-producing reaction.
Ozone has also been proven to form specific, cholesterol-derived metabolites that are thought to facilitate the build-up and pathogenesis of atherosclerotic plaques (a form of heart disease). These metabolites have been confirmed as naturally occurring in human atherosclerotic arteries and are categorized into a class of secosterols termed “Atheronals”, generated by ozonolysis of cholesterol's double bond to form a 5,6 secosterol as well as a secondary condensation product via aldolization.
# Production techniques
Ozone used in industry is measured in g/Nm³ or weight percent. The regime of applied concentrations ranges from 1 to 5 weight percent in air and from 6 to 13 weight percent in oxygen.
Ozone generators currently on the market generate ozone molecules by employing one of the methods below.
## Corona discharge method
This is the most popular type of ozone generator for most industrial and personal uses. While variations of the "hot spark" coronal discharge method of ozone production exist, including medical grade and industrial grade ozone generators, these units usually work by means of a corona discharge tube. They are typically very cost-effective, and do not require an oxygen source other than the ambient air. However, they also produce nitrogen oxides as a by-product. Use of an air dryer can reduce or eliminate nitric acid formation by removing water vapor and increase ozone production. Use of an oxygen concentrator can further increase the ozone production and further reduce the risk of nitric acid formation due to removing not only the water vapor, but also the bulk of the nitrogen.
## Ultraviolet light
UV ozone generators employ a light source that generates the same narrow-band ultraviolet light that is responsible for the sustenance of the ozone layer in the stratosphere of the Earth .
While standard UV ozone generators tend to be less expensive, they usually produce ozone with a concentration of about 2% or lower. Another disadvantage of this method is that it requires the air to be exposed to the UV source for a longer amount of time, and any air that is not exposed to the UV source will not be treated. This makes UV generators impractical for use in situations that deal with rapidly moving air or water streams (in-duct air sterilization, for example).
## Cold plasma
In the cold plasma method, pure oxygen gas is exposed to a plasma created by
dielectric barrier discharge. The diatomic oxygen is split into single atoms, which then recombine in triplets to form ozone.
Cold plasma machines utilize pure oxygen as the input source, and produce a maximum concentration of about 5% ozone. They produce far greater quantities of ozone in a given space of time compared to ultraviolet production. However, because cold plasma ozone generators are very expensive, and still require occasional maintenance, they are found less frequently than the previous two types.
The discharges manifest as filamentary transfer of electrons (micro discharges) in a gap between two electrodes. In order to evenly distribute the micro discharges, a dielectric insulator must be used to separate the metallic electrodes and to prevent arcing.
Some cold plasma units also have the capability of producing short-lived allotropes of oxygen which include O4, O5, O6, O7, etc. These anions are even more reactive than ordinary O3.
## Special considerations
Ozone cannot be stored and transported like other industrial gases (because it quickly decays into diatomic oxygen) and must therefore be produced on site. Available ozone generators vary in the arrangement and design of the high-voltage electrodes. At production capacities higher than 20kg per hour, a gas/water tube heat-exchanger is utilized as ground electrode and assembled with tubular high-voltage electrodes on the gas-side. The regime of typical gas pressures is around 2 bar absolute in oxygen and 3 bar absolute in air. Several megawatts of electrical power may be installed in large facilities, applied as one phase AC current at 600 to 2000 Hz and peak voltages between 3000 and 20000 volts.
The dominating parameter influencing ozone generation efficiency is the gas temperature, which is controlled by the cooling water temperature. The cooler the water, the better the ozone synthesis. At typical industrial conditions, almost 90 percent of the effective power is dissipated as heat and needs to be removed by a sufficient cooling water flow.
Due to the high reactivity of ozone, only few materials may be used like stainless steel (quality 316L), glass, polytetrafluorethylene, or polyvinylidene fluoride. Viton may be used with the restriction of constant mechanical forces and absence of humidity.
## Incidental production
Ozone may be formed from O2 by electrical discharges and by action of high energy electromagnetic radiation. Certain electrical equipment generate significant levels of ozone. This is especially true of devices using high voltages, such as ionic air purifiers, laser printers, photocopiers, and arc welders. Electric motors using brushes can generate ozone from repeated sparking inside the unit. Large motors that use brushes, such as those used by elevators or hydraulic pumps, will generate more ozone than smaller motors.
## Laboratory production
In the laboratory ozone can be produced by electrolysis using a 9 volt battery, a pencil graphite rod cathode, a platinum wire anode and a 3M sulfuric acid electrolyte. The half cell reactions taking place are
so that in the net reaction three equivalents of water are converted into one equivalent of ozone and three equivalents of hydrogen. Oxygen formation is a competing reaction.
# Applications
## Industrial applications
Ozone can be used for bleaching substances and for killing microorganisms in air and water sources. Many municipal drinking water systems kill bacteria with ozone instead of the more common chlorine. Ozone has a very high oxidation potential. Ozone does not form organochlorine compounds, nor does it remain in the water after treatment, so some systems introduce a small amount of chlorine to prevent bacterial growth in the pipes, or may use chlorine intermittently, based on results of periodic testing. Where electrical power is abundant, ozone is a cost-effective method of treating water, as it is produced on demand and does not require transportation and storage of hazardous chemicals. Once it has decayed, it leaves no taste or odor in drinking water. Low levels of ozone have been advertised to be of some disinfectant use in residential homes, however, the concentration of ozone required to have a substantial effect on airborne pathogens greatly exceeds safe levels recommended by the U.S. Occupational Safety and Health Administration and Environmental Protection Agency.
Industrially, ozone or ozonated water is used to:
- Disinfect laundry in hospitals, food factories, care homes etc;
- Disinfect water before it is bottled;
- Deodorize air and objects, such as after a fire. This process is extensively used in Fabric Restoration;
- Kill bacteria on food or on contact surfaces;
- Ozone swimming pool and spa sanitation
- Scrub yeast and mold spores from the air in food processing plants;
- Wash fresh fruits and vegetables to kill yeast, mold and bacteria;
- Chemically attack contaminants in water (iron, arsenic, hydrogen sulfide, nitrites, and complex organics lumped together as "colour");
- Provide an aid to flocculation (agglomeration of molecules, which aids in filtration, where the iron and arsenic are removed);
- Manufacture chemical compounds via chemical synthesis
- Clean and bleach fabrics (the former use is utilized in Fabric Restoration)(the latter use is patented);
- Assist in processing plastics to allow adhesion of inks;
- Age rubber samples to determine the useful life of a batch of rubber;
- Hospital operating rooms where air needs to be sterile;
- Eradicate water borne parasites such as Giardia and Cryptosporidium in surface water treatment plants. This process is known as ozonation.
Ozone is a reagent in many organic reactions in the laboratory and in industry. Ozonolysis is the cleavage of an alkene to carbonyl compounds.
Many hospitals in the U.S. and around the world use large ozone generators to decontaminate operating rooms between surgeries. The rooms are cleaned and then sealed airtight before being filled with ozone which effectively kills or neutralizes all remaining bacteria.
Ozone is used as an alternative to chlorine or chlorine dioxide in the bleaching of wood pulp . It is often used in conjunction with oxygen and hydrogen peroxide to completely eliminate the need for chlorine-containing compounds in the manufacture of high-quality, white paper
Ozone can be used to detoxify cyanide wastes (for example from gold and silver mining) by oxidizing cyanide to cyanate and eventually to carbon dioxide.
## Consumer applications
Ozone machines, with or without ionisation, are currently used to sanitise (high ozone output) and deodorize non-inhabited rooms, ductwork, vehicles, boats, woodsheds, and buildings.
Some models of air purifiers that also emit low levels of ozone have been sold in the US. These type of air purifiers claim to imitate nature's "filterless" air purifying mechanisms and claim to "sanitise" the air and/or household surfaces. The government successfully sued one company in 1995, ordering them to stop repeating health claims without supporting scientific studies.
Ozonated water is used to launder clothes, sanitise food, drinking water, and surfaces in the home. According to the FDA, it is "amending the food additive regulations to provide for the safe use of ozone in gaseous and aqueous phases as an antimicrobial agent on food, including meat and poultry." Studies at California Polytechnic University, have proven that low levels of ozone dissolved in filtered tapwater can produce more than a four-log (99.99%) reduction in such food-borne microorganisms as salmonella, e. Coli 0157:H7, campylobacter and others. Ironically, while ozone is considered an atmospheric pollutant, pollution and smog by the US government, it can actually decrease the levels of pollutants like pesticides in fruits and vegetables.
Ozone is used in spas or hot tubs with reduced levels of chlorine or bromine for keeping the water free of bacteria. As it does not remain in the water after treatment, it is ineffective at preventing bather cross-contamination, and must be used in conjunction with another sanitizer. Ozone gas is created by an ultraviolet light bulb or corona discharge chip and injected into the plumbing system.
Ozone is also widely used in treatment of water in aquaria and fish ponds. Its use can minimize bacterial growth control parasites and removes or reduces "yellowing" of the water. As the ozone rapidly decomposes, at correctly controlled levels the application has no effect on the fish.
Most countries restrict the amount of ozone that can be generated by popular "ionizing" devices because ozone contributes to the development of smog. Smaller ozone machines may be employed by personal users for home use, and typically produce far less ozone than their larger counterparts. Due to their lower costs, almost all ozone generators designed for personal use employ the corona discharge method. In many countries, the production or operation of ozone generating devices is illegal.
## Ozone therapy
Ozone therapy has been used in alternative medicine as a medical treatment in a number of different countries. Its use, however, is controversial.
The United States Food and Drug Administration (FDA) has banned ozone generators or ozone gas from being marketed for treatment of any medical conditions, based on the toxicity of ozone and the lack of scientific evidence for any beneficial effects at non-toxic levels.
One couple, Kenneth R. Thiefault and Mardel Barber, were convicted of and sent to prison in 1999 for violating this ban, which involved marketing ozone generators to cure AIDS, cancer, herpes, hepatitis, gangrene, or "almost any disease", without presenting any evidence to the FDA of effectiveness or safety.
However, it is worth noting that the FDA cannot allow any device to claim to treat any medical condition
unless the device and/or treatment have gone through rigorous trials. It is not illegal to sell
medical-grade ozone machines in the US, nor is it illegal to own one or use one. What is illegal is
to sell them while claiming it treats disease. Many people use ozone therapy in the US, despite its
unrecognized status with the FDA and allopathic medicine. It is legal to sell or own a medical-grade
-zone machine in the US. It is also legal to self-administer ozone. Whether practitioners can
administer or recommend the use of ozone presents a more complex issue. | Ozone
Ozone (O3) is a triatomic molecule, consisting of three oxygen atoms. It is an allotrope of oxygen that is much less stable than the diatomic species O2. Ground-level ozone is an air pollutant with harmful effects on the respiratory systems of animals. Ozone in the upper atmosphere filters potentially damaging ultraviolet light from reaching the Earth's surface. It is present in low concentrations throughout the Earth's atmosphere. It has many industrial and consumer applications. Ozone therapy is a controversial alternative medicine practice; mainstream scientific medicine has found ozone to be harmful to humans,[1]
and equipment intended to be used for ozone therapy is banned in the United States.[2]
Ozone, the first allotrope of a chemical element to be described by science, was discovered by Christian Friedrich Schönbein in 1840, who named it after the Greek word for smell (ozein), from the peculiar odor in lightning storms.[3] The odor from a lightning strike is from ions produced during the rapid chemical changes, not the ozone itself.[4]
# Physical properties
Undiluted ozone is a pale blue gas at standard temperature and pressure; it forms a dark blue liquid below −112 °C and a violet-black solid below −193 °C.[5] At concentrations found in the atmosphere it is colorless.[6] The concentration above which it can be smelled (odor threshold) is between 0.0076 and 0.036 ppm.[7]
# Structure
The structure of ozone, according to experimental evidence from microwave spectroscopy, is bent, with C2v symmetry (similar to the water molecule), O – O distance of 127.2 pm and O – O – O angle of 116.78°.[8] The central atom forms an sp² hybridization with one lone pair. Ozone is a polar molecule with a dipole moment of 0.5337 D.[9] The bonding is single bond on one side and double bond on the other side, and these bonds are blended to become known as resonance structures. The bond order is 1.5 for each side.
# Chemistry
Ozone is a powerful oxidizing agent. It is also unstable at high concentrations, decaying to ordinary diatomic oxygen (in about half an hour in atmospheric conditions[10]):
This reaction proceeds more rapidly with increasing temperature and decreasing pressure. Ozone will oxidize metals (except gold, platinum, and iridium) to oxides of the metals in their highest oxidation state:
Ozone also increases the oxidation number of oxides:
The above reaction is accompanied by chemiluminescence. The NO2 can be further oxidized:
The NO3 formed can react with NO2 to form N2O5:
Ozone reacts with carbon to form carbon dioxide, even at room temperature:
Ozone does not react with ammonium salts but it reacts with ammonia to form ammonium nitrate:
Ozone reacts with sulfides to make sulfates:
Sulfuric acid can be produced from ozone, either starting from elemental sulfur or from sulfur dioxide:
All three atoms of ozone may also react, as in the reaction with tin(II) chloride and hydrochloric acid:
In the gas phase, ozone reacts with hydrogen sulfide to form sulfur dioxide:
In an aqueous solution, however, two competing simultaneous reactions occur, one to produce elemental sulfur, and one to produce sulfuric acid:
Iodine perchlorate can be made by treating iodine dissolved in cold anhydrous perchloric acid with ozone:
Solid nitryl perchlorate can be made from NO2, ClO2, and O3 gases:
Ozone can be used for combustion reactions and combusting gases in ozone provides higher temperatures than combusting in dioxygen (O2). Following is a reaction for the combustion of carbon subnitride:
Ozone can react at cryogenic temperatures. At 77 K (-196 °C), atomic hydrogen reacts with liquid ozone to form a hydrogen superoxide radical, which dimerizes:[11]
Ozonides can be formed, which contain the ozonide anion, O3-. These compounds are explosive and must be stored at cryogenic temperatures. Ozonides for all the alkali metals are known. KO3, RbO3, and CsO3 can be prepared from their respective superoxides:
Although KO3 can be formed as above, it can also be formed from potassium hydroxide and ozone:[12]
NaO3 and LiO3 must be prepared by action of CsO3 in liquid NH3 on an ion exchange resin containing Na+ or Li+ ions:[13]
Treatment with ozone of calcium dissolved in ammonia leads to ammonium ozonide and not calcium ozonide:[14]
Ozone can be used to remove manganese from the water, forming a precipitate which can be filtered:
Ozone will also turn cyanides to the one thousand times less toxic cyanates:
Finally, ozone will also completely decompose urea:[15]
# Ozone in Earth's atmosphere
The standard way to express total ozone levels (the volume of ozone in a vertical column) in the atmosphere is by using Dobson units. Concentrations at a point are measured in parts per billion (ppb) or in μg/m³.
## Ozone layer
The highest levels of ozone in the atmosphere are in the stratosphere, in a region also known as the ozone layer between about 10 km and 50 km above the surface (or between 6.21 and 31.1 miles). Here it filters out the shorter wavelengths (less than 320 nm) of ultraviolet light (270 to 400 nm) from the Sun that would be harmful to most forms of life in large doses. These same wavelengths are also among those responsible for the production of vitamin D, which is essential for human health. Ozone in the stratosphere is mostly produced from ultraviolet rays reacting with oxygen:
It is destroyed by the reaction with atomic oxygen:
(See Ozone-oxygen cycle for more detail.)
The latter reaction is catalysed by the presence of certain free radicals, of which the most important are hydroxyl (OH), nitric oxide (NO) and atomic chlorine (Cl) and bromine (Br). In recent decades the amount of ozone in the stratosphere has been declining mostly due to emissions of CFCs and similar chlorinated and brominated organic molecules, which have increased the concentration of ozone-depleting catalysts above the natural background. See ozone depletion for more information.
## Low level ozone
Low level ozone (or tropospheric ozone) is regarded as a pollutant by the World Health Organization.[16] It is not emitted directly by car engines or by industrial operations. It is formed by the reaction of sunlight on air containing hydrocarbons and nitrogen oxides that react to form ozone directly at the source of the pollution or many kilometers down wind. For more details of the complex chemical reactions that produce low level ozone see tropospheric ozone.
Ozone reacts directly with some hydrocarbons such as aldehydes and thus begins their removal from the air, but the products are themselves key components of smog. Ozone photolysis by UV light leads to production of the hydroxyl radical and this plays a part in the removal of hydrocarbons from the air, but is also the first step in the creation of components of smog such as peroxyacyl nitrates which can be powerful eye irritants. The atmospheric lifetime of tropospheric ozone is about 22 days and its main removal mechanisms are being deposited to the ground, the above mentioned reaction giving OH, and by reactions with OH and the peroxy radical HO2· (Stevenson et al, 2006).[17]
As well as having an impact on human health (see below) there is also evidence of significant reduction in agricultural yields due to increased ground-level ozone and pollution which interferes with photosynthesis and stunts overall growth of some plant species.[18][19]
### Ozone as a greenhouse gas
Although ozone was present at ground level before the industrial revolution, peak concentrations are far higher than the pre-industrial levels and even background concentrations well away from sources of pollution are substantially higher.[20][21] This increase in ozone is of further concern as ozone present in the upper troposphere acts as a greenhouse gas, absorbing some of the infrared energy emitted by the earth. Quantifying the greenhouse gas potency of ozone is difficult as it is not present in uniform concentrations across the globe. However, the most recent scientific review on the climate change (the IPCC Third Assessment Report[22]) suggests that the radiative forcing of tropospheric ozone is about 25% that of carbon dioxide.
# Ozone and health
## Ozone in air pollution
There is a great deal of evidence to show that high concentrations (ppm) of ozone, created by high concentrations of pollution and daylight UV rays at the earth's surface, can harm lung function and irritate the respiratory system.[16][23] A connection has also been shown to exist between increased ozone caused by thunderstorms and hospital admissions of asthma sufferers.[24] Air quality guidelines such as those from the World Health Organization are based on detailed studies of what levels can cause measurable health effects.
A common British folk myth dating back to the Victorian era holds that the smell of the sea is caused by ozone, and that this smell has "bracing" health benefits.[25] Neither of these is true. The characteristic "smell of the sea" is not caused by ozone, but by the presence of dimethyl sulfide generated by phytoplankton, and dimethyl sulfide, like ozone, is toxic in high concentrations.[26]
The United States Environmental Protection Agency has developed an Air Quality index to help explain air pollution levels to the general public. 8-hour average ozone concentrations of 85 to 104 ppbv are described as "Unhealthy for Sensitive Groups", 105 ppbv to 124 ppbv as "unhealthy" and 125 ppb to 404 ppb as "very unhealthy".[27] The EPA has designated over 300 counties of the United States, clustered around the most heavily populated areas (especially in California and the Northeast), as failing to comply with the National Ambient Air Quality Standards.
## Physiology of ozone
Ozone, along with reactive forms of oxygen such as superoxide, singlet oxygen (see oxygen), hydrogen peroxide, and hypochlorite ions, is naturally produced by white blood cells and other biological systems (such as the roots of marigolds) as a means of destroying foreign bodies. Ozone reacts directly with organic double bonds. Also, when ozone breaks down to dioxygen it gives rise to oxygen free radicals, which are highly reactive and capable of damaging many organic molecules. Ozone has been found to convert cholesterol in the blood stream to plaque (which causes hardening and narrowing of arteries). Moreover, it is believed that the powerful oxidizing properties of ozone may be a contributing factor of inflammation. The cause-and-effect relationship of how the ozone is created in the body and what it does is still under consideration and still subject to various interpretations, since other body chemical processes can trigger some of the same reactions. A team headed by Dr. Paul Wentworth Jr. of the Department of Chemistry at the Scripps Research Institute has shown evidence linking the antibody-catalyzed water-oxidation pathway of the human immune response to the production of ozone. In this system, ozone is produced by antibody-catalyzed production of trioxidane from water and neutrophil-produced singlet oxygen.[28] See also trioxidane for more on this biological ozone-producing reaction.
Ozone has also been proven to form specific, cholesterol-derived metabolites that are thought to facilitate the build-up and pathogenesis of atherosclerotic plaques (a form of heart disease). These metabolites have been confirmed as naturally occurring in human atherosclerotic arteries and are categorized into a class of secosterols termed “Atheronals”, generated by ozonolysis of cholesterol's double bond to form a 5,6 secosterol as well as a secondary condensation product via aldolization.[29]
# Production techniques
Ozone used in industry is measured in g/Nm³ or weight percent. The regime of applied concentrations ranges from 1 to 5 weight percent in air and from 6 to 13 weight percent in oxygen.
Ozone generators currently on the market generate ozone molecules by employing one of the methods below.
## Corona discharge method
This is the most popular type of ozone generator for most industrial and personal uses. While variations of the "hot spark" coronal discharge method of ozone production exist, including medical grade and industrial grade ozone generators, these units usually work by means of a corona discharge tube.[30] They are typically very cost-effective, and do not require an oxygen source other than the ambient air. However, they also produce nitrogen oxides as a by-product. Use of an air dryer can reduce or eliminate nitric acid formation by removing water vapor and increase ozone production. Use of an oxygen concentrator can further increase the ozone production and further reduce the risk of nitric acid formation due to removing not only the water vapor, but also the bulk of the nitrogen.
## Ultraviolet light
UV ozone generators employ a light source that generates the same narrow-band ultraviolet light that is responsible for the sustenance of the ozone layer in the stratosphere of the Earth [31].
While standard UV ozone generators tend to be less expensive, they usually produce ozone with a concentration of about 2% or lower. Another disadvantage of this method is that it requires the air to be exposed to the UV source for a longer amount of time, and any air that is not exposed to the UV source will not be treated. This makes UV generators impractical for use in situations that deal with rapidly moving air or water streams (in-duct air sterilization, for example).
## Cold plasma
In the cold plasma method, pure oxygen gas is exposed to a plasma created by
dielectric barrier discharge. The diatomic oxygen is split into single atoms, which then recombine in triplets to form ozone.
Cold plasma machines utilize pure oxygen as the input source, and produce a maximum concentration of about 5% ozone. They produce far greater quantities of ozone in a given space of time compared to ultraviolet production. However, because cold plasma ozone generators are very expensive, and still require occasional maintenance, they are found less frequently than the previous two types.
The discharges manifest as filamentary transfer of electrons (micro discharges) in a gap between two electrodes. In order to evenly distribute the micro discharges, a dielectric insulator must be used to separate the metallic electrodes and to prevent arcing.
Some cold plasma units also have the capability of producing short-lived allotropes of oxygen which include O4, O5, O6, O7, etc. These anions are even more reactive than ordinary O3.
## Special considerations
Ozone cannot be stored and transported like other industrial gases (because it quickly decays into diatomic oxygen) and must therefore be produced on site. Available ozone generators vary in the arrangement and design of the high-voltage electrodes. At production capacities higher than 20kg per hour, a gas/water tube heat-exchanger is utilized as ground electrode and assembled with tubular high-voltage electrodes on the gas-side. The regime of typical gas pressures is around 2 bar absolute in oxygen and 3 bar absolute in air. Several megawatts of electrical power may be installed in large facilities, applied as one phase AC current at 600 to 2000 Hz and peak voltages between 3000 and 20000 volts.
The dominating parameter influencing ozone generation efficiency is the gas temperature, which is controlled by the cooling water temperature. The cooler the water, the better the ozone synthesis. At typical industrial conditions, almost 90 percent of the effective power is dissipated as heat and needs to be removed by a sufficient cooling water flow.
Due to the high reactivity of ozone, only few materials may be used like stainless steel (quality 316L), glass, polytetrafluorethylene, or polyvinylidene fluoride. Viton may be used with the restriction of constant mechanical forces and absence of humidity.
## Incidental production
Ozone may be formed from O2 by electrical discharges and by action of high energy electromagnetic radiation. Certain electrical equipment generate significant levels of ozone. This is especially true of devices using high voltages, such as ionic air purifiers, laser printers, photocopiers, and arc welders. Electric motors using brushes can generate ozone from repeated sparking inside the unit. Large motors that use brushes, such as those used by elevators or hydraulic pumps, will generate more ozone than smaller motors.
## Laboratory production
In the laboratory ozone can be produced by electrolysis using a 9 volt battery, a pencil graphite rod cathode, a platinum wire anode and a 3M sulfuric acid electrolyte.[32] The half cell reactions taking place are
so that in the net reaction three equivalents of water are converted into one equivalent of ozone and three equivalents of hydrogen. Oxygen formation is a competing reaction.
# Applications
## Industrial applications
Ozone can be used for bleaching substances and for killing microorganisms in air and water sources. Many municipal drinking water systems kill bacteria with ozone instead of the more common chlorine.[33] Ozone has a very high oxidation potential. Ozone does not form organochlorine compounds, nor does it remain in the water after treatment, so some systems introduce a small amount of chlorine to prevent bacterial growth in the pipes, or may use chlorine intermittently, based on results of periodic testing. Where electrical power is abundant, ozone is a cost-effective method of treating water, as it is produced on demand and does not require transportation and storage of hazardous chemicals. Once it has decayed, it leaves no taste or odor in drinking water. Low levels of ozone have been advertised to be of some disinfectant use in residential homes, however, the concentration of ozone required to have a substantial effect on airborne pathogens greatly exceeds safe levels recommended by the U.S. Occupational Safety and Health Administration and Environmental Protection Agency.[citation needed]
Industrially, ozone or ozonated water is used to:
- Disinfect laundry in hospitals, food factories, care homes etc;[34]
- Disinfect water before it is bottled;
- Deodorize air and objects, such as after a fire. This process is extensively used in Fabric Restoration;
- Kill bacteria on food or on contact surfaces;
- Ozone swimming pool and spa sanitation
- Scrub yeast and mold spores from the air in food processing plants;
- Wash fresh fruits and vegetables to kill yeast, mold and bacteria;
- Chemically attack contaminants in water (iron, arsenic, hydrogen sulfide, nitrites, and complex organics lumped together as "colour");
- Provide an aid to flocculation (agglomeration of molecules, which aids in filtration, where the iron and arsenic are removed);
- Manufacture chemical compounds via chemical synthesis [1]
- Clean and bleach fabrics (the former use is utilized in Fabric Restoration)(the latter use is patented);
- Assist in processing plastics to allow adhesion of inks;
- Age rubber samples to determine the useful life of a batch of rubber;
- Hospital operating rooms where air needs to be sterile;
- Eradicate water borne parasites such as Giardia and Cryptosporidium in surface water treatment plants. This process is known as ozonation.
Ozone is a reagent in many organic reactions in the laboratory and in industry. Ozonolysis is the cleavage of an alkene to carbonyl compounds.
Many hospitals in the U.S. and around the world use large ozone generators to decontaminate operating rooms between surgeries. The rooms are cleaned and then sealed airtight before being filled with ozone which effectively kills or neutralizes all remaining bacteria.[citation needed]
Ozone is used as an alternative to chlorine or chlorine dioxide in the bleaching of wood pulp [35] . It is often used in conjunction with oxygen and hydrogen peroxide to completely eliminate the need for chlorine-containing compounds in the manufacture of high-quality, white paper[36]
Ozone can be used to detoxify cyanide wastes (for example from gold and silver mining) by oxidizing cyanide to cyanate and eventually to carbon dioxide.[37]
## Consumer applications
Ozone machines, with or without ionisation, are currently used to sanitise (high ozone output) and deodorize non-inhabited rooms, ductwork, vehicles, boats, woodsheds, and buildings.
Some models of air purifiers that also emit low levels of ozone have been sold in the US. These type of air purifiers claim to imitate nature's "filterless" air purifying mechanisms[38] and claim to "sanitise" the air and/or household surfaces. The government successfully sued one company in 1995, ordering them to stop repeating health claims without supporting scientific studies.
Ozonated water is used to launder clothes, sanitise food, drinking water, and surfaces in the home. According to the FDA, it is "amending the food additive regulations to provide for the safe use of ozone in gaseous and aqueous phases as an antimicrobial agent on food, including meat and poultry." Studies at California Polytechnic University, have proven that low levels of ozone dissolved in filtered tapwater can produce more than a four-log (99.99%) reduction in such food-borne microorganisms as salmonella, e. Coli 0157:H7, campylobacter and others.[39] Ironically, while ozone is considered an atmospheric pollutant, pollution and smog by the US government, it can actually decrease the levels of pollutants like pesticides in fruits and vegetables.[40]
Ozone is used in spas or hot tubs with reduced levels of chlorine or bromine for keeping the water free of bacteria. As it does not remain in the water after treatment, it is ineffective at preventing bather cross-contamination, and must be used in conjunction with another sanitizer. Ozone gas is created by an ultraviolet light bulb or corona discharge chip and injected into the plumbing system[citation needed].
Ozone is also widely used in treatment of water in aquaria and fish ponds. Its use can minimize bacterial growth control parasites and removes or reduces "yellowing" of the water. As the ozone rapidly decomposes, at correctly controlled levels the application has no effect on the fish[citation needed].
Most countries restrict the amount of ozone that can be generated by popular "ionizing" devices because ozone contributes to the development of smog. Smaller ozone machines may be employed by personal users for home use, and typically produce far less ozone than their larger counterparts. Due to their lower costs, almost all ozone generators designed for personal use employ the corona discharge method. In many countries, the production or operation of ozone generating devices is illegal.[citation needed]
## Ozone therapy
Ozone therapy has been used in alternative medicine as a medical treatment in a number of different countries.[41] Its use, however, is controversial.[42]
The United States Food and Drug Administration (FDA) has banned ozone generators or ozone gas from being marketed for treatment of any medical conditions, based on the toxicity of ozone and the lack of scientific evidence for any beneficial effects at non-toxic levels.[2]
One couple, Kenneth R. Thiefault and Mardel Barber, were convicted of and sent to prison in 1999 for violating this ban, which involved marketing ozone generators to cure AIDS, cancer, herpes, hepatitis, gangrene, or "almost any disease", without presenting any evidence to the FDA of effectiveness or safety.[43]
However, it is worth noting that the FDA cannot allow any device to claim to treat any medical condition
unless the device and/or treatment have gone through rigorous trials. It is not illegal to sell
medical-grade ozone machines in the US, nor is it illegal to own one or use one. What is illegal is
to sell them while claiming it treats disease. Many people use ozone therapy in the US, despite its
unrecognized status with the FDA and allopathic medicine. It is legal to sell or own a medical-grade
ozone machine in the US. It is also legal to self-administer ozone. Whether practitioners can
administer or recommend the use of ozone presents a more complex issue. | https://www.wikidoc.org/index.php/Ozone | |
4183f001170480dab69563f26fcf0a3adbd4056f | wikidoc | P110α | P110α
The phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (the HUGO-approved official symbol = PIK3CA; HGNC ID, HGNC:8975), also called p110α protein, is a class I PI 3-kinase catalytic subunit. The human p110α protein is encoded by the PIK3CA gene.
Its role was uncovered by molecular pathological epidemiology (MPE).
# Function
Phosphatidylinositol-4,5-bisphosphate 3-kinase (also called phosphatidylinositol 3-kinase (PI3K)) is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate phosphatidylinositols (PtdIns), PtdIns4P and PtdIns(4,5)P2.
The involvement of p110α in human cancer has been hypothesized since 1995. Support for this hypothesis came from genetic and functional studies, including the discovery of common activating PIK3CA missense mutations in common human tumors. It has been found to be oncogenic and is implicated in cervical cancers. PIK3CA mutations are present in over one-third of breast cancers, with enrichment in the luminal and in human epidermal growth factor receptor 2-positive subtypes (HER2 +). The three hotspot mutation positions (GLU542, GLU545, and HIS1047) have been widely reported till date. While substantial preclinical data show an association with robust activation of the pathway and resistance to common therapies, clinical data do not indicate that such mutations are associated with high levels of pathway activation or with a poor prognosis. It is unknown whether the mutation predicts increased sensitivity to agents targeting the P3K pathway.
PIK3CA participates in a complex interaction within the tumor microenvironment in this phenomenon.
# Clinical characteristics
Due to the association between p110α and cancer, it may be an appropriate drug target. Pharmaceutical companies are designing and characterizing potential p110α isoform specific inhibitors.
The presence of PIK3CA mutation may predict response to aspirin therapy for colorectal cancer.
Somatic activating mutations in PIK3CA are found in Klippel-Trenaunay syndrome and venous malformation.
PIK3CA-associated segmental overgrowth includes brain disorders such as macrocephaly-capillary malformation (MCAP) and hemimegalencephaly. It is also associated with congenital, lipomatous overgrowth of vascular malformations, epidermal nevi and skeletal/spinal anomalies (CLOVES syndrome) and fibroadipose hyperplasia (FH). The conditions are caused by heterozygous (usually somatic mosaic) mutations.
# Inhibition
All PI 3-kinases are inhibited by the drugs wortmannin and LY294002 but wortmannin shows better efficiency than LY294002 on the hotspot mutation positions.
# Pharmacology
In September 2017 Copanlisib, inhibiting predominantly p110α and p110δ, got FDA approval for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies. | P110α
The phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (the HUGO-approved official symbol = PIK3CA; HGNC ID, HGNC:8975), also called p110α protein, is a class I PI 3-kinase catalytic subunit. The human p110α protein is encoded by the PIK3CA gene.[1]
Its role was uncovered by molecular pathological epidemiology (MPE).[2]
# Function
Phosphatidylinositol-4,5-bisphosphate 3-kinase (also called phosphatidylinositol 3-kinase (PI3K)) is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate phosphatidylinositols (PtdIns), PtdIns4P and PtdIns(4,5)P2.[3]
The involvement of p110α in human cancer has been hypothesized since 1995. Support for this hypothesis came from genetic and functional studies, including the discovery of common activating PIK3CA missense mutations in common human tumors.[4] It has been found to be oncogenic and is implicated in cervical cancers.[5] PIK3CA mutations are present in over one-third of breast cancers, with enrichment in the luminal and in human epidermal growth factor receptor 2-positive subtypes (HER2 +). The three hotspot mutation positions (GLU542, GLU545, and HIS1047) have been widely reported till date.[6] While substantial preclinical data show an association with robust activation of the pathway and resistance to common therapies, clinical data do not indicate that such mutations are associated with high levels of pathway activation or with a poor prognosis. It is unknown whether the mutation predicts increased sensitivity to agents targeting the P3K pathway.[7]
PIK3CA participates in a complex interaction within the tumor microenvironment in this phenomenon.[8]
# Clinical characteristics
Due to the association between p110α and cancer,[9] it may be an appropriate drug target. Pharmaceutical companies are designing and characterizing potential p110α isoform specific inhibitors.[10][11]
The presence of [a] PIK3CA mutation may predict response to aspirin therapy for colorectal cancer.[12][13]
Somatic activating mutations in PIK3CA are found in Klippel-Trenaunay syndrome and venous malformation.[14][15]
PIK3CA-associated segmental overgrowth includes brain disorders such as macrocephaly-capillary malformation (MCAP) and hemimegalencephaly. It is also associated with congenital, lipomatous overgrowth of vascular malformations, epidermal nevi and skeletal/spinal anomalies (CLOVES syndrome) and fibroadipose hyperplasia (FH). The conditions are caused by heterozygous (usually somatic mosaic) mutations.[16]
# Inhibition
All PI 3-kinases are inhibited by the drugs wortmannin and LY294002 but wortmannin shows better efficiency than LY294002 on the hotspot mutation positions.[17][18]
# Pharmacology
In September 2017 Copanlisib, inhibiting predominantly p110α and p110δ, got FDA approval for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.[19] | https://www.wikidoc.org/index.php/P110%CE%B1 | |
51e7501e2a1f8828498745903eb0df03d8789885 | wikidoc | P110δ | P110δ
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as phosphoinositide 3-kinase (PI3K) delta isoform or p110δ is an enzyme that in humans is encoded by the PIK3CD gene.
p110δ regulates immune function. In contrast to the other class IA PI3Ks p110α and p110β, p110δ is principally expressed in leukocytes (white blood cells). Genetic and pharmacological inactivation of p110δ has revealed that this enzyme is important for the function of T cells, B cell, mast cells and neutrophils. Hence, p110δ is a promising target for drugs that aim to prevent or treat inflammation, autoimmunity and transplant rejection.
Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3-prime OH position of the inositol ring of inositol lipids. The class I PI3Ks display a broad phosphoinositide lipid substrate specificity and include p110α, p110β and p110γ. p110α and p110β interact with SH2/SH3-domain-containing p85 adaptor proteins and with GTP-bound Ras.
# Biochemistry
Like the other class IA PI3Ks, p110δ is a catalytic subunit, whose activity and subcellular localisation are controlled by an associated p85α, p55α, p50α or p85β regulatory subunit. The p55γ regulatory subunit is not thought to be expressed at significant levels in immune cells. There is no evidence for selective association between p110α, p110β or p110δ for any particular regulatory subunit. The class IA regulatory subunits (collectively referred to here as p85) bind to proteins that have been phosphorylated on tyrosines. Tyrosine kinases often operate near the plasma membrane and hence control the recruitment of p110δ to the plasma membrane where its substrate PtdIns(4,5)P2 is found. The conversion of PtdIns(4,5)P2 to PtdIns(3,4,5)P3 triggers signal transduction cascades controlled by PKB (also known as Akt), Tec family kinases and other proteins that contain PH domains. In immune cells, antigen receptors, cytokine receptors and costimulatory and accessory receptors stimulate tyrosine kinase activity and hence all have the potential to initiate PI3K signalling.
# Functions
For reasons that are not well understood, p110δ appears to be activated in preference to p110α and p110β in a number of immune cells. The following is a brief summary of the role of p110δ in selected leukocyte subsets.
## T cells
In T cells, the antigen receptor (TCR) and costimulatory receptors (CD28 and ICOS) are thought to be main receptors responsible for recruiting and activating p110δ. Genetic inactivation of p110δ in mice causes T cells to be less responsive to antigen as determined by their reduced ability to proliferate and secrete interleukin 2. T cell specific deletion of p110δ has revealed its role in antibody responses.
This may in part result from incomplete assembly of other signalling proteins at the immune synapse. The TCR cannot stimulate the phosphorylation of Akt in that absence of p110δ activity.
## B cells
p110δ is a regulator of B cell proliferation and function. p110δ-deficient mice have deficient antibody responses. They also lack to B cell subsets: B1 cells (found in body cavities such as the peritoneum) and marginal zone B cells, found in the periphery of spleen follicles).
## Mast cells
p110δ controls mast cell release of the granules responsible for allergic reactions. Thus inhibition of p110δ reduces allergic responses.
## Neutrophils
In conjunction with p110γ, p110δ controls the release of reactive oxygen species in neutrophils.
## Denritic cells
p110δ controls lipopolysaccharide induced Toll-like-receptor-4 mediated innate immune responses in dendritic cells and mice carrying an inactive p110δ is susceptible to lipopolysaccharide mediated endotoxin shock.
# Activated PI3K delta syndrome
Inherited mutations in the PIK3CD gene which increase p110δ catalytic activity cause a primary immunodeficiency syndrome called APDS or PASLI.
# Pharmacology
US pharmaceutical company ICOS produced a selective inhibitor of p110δ called IC87114. This inhibitor selectively impairs B cell, mast cell and neutrophil functions and is therefore a potential immune-modulator.
The p110δ inhibitor idelalisib was developed by Gilead Sciences. Idelalisib in combination with rituximab showed favourable progression free survival in a phase III clinical trial for chronic lymphocytic leukemia (CLL) compared with patients that received rituximab and placebo.
In July 2014 idelalisib was approved by the FDA as a treatment for CLL patients.
In September 2017 copanlisib, inhibiting predominantly p110α and p110δ, got FDA approval for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.
In September 2018 duvelisib was approved by the FDA as a treatment for relapsed or refractory CLL, and relapsed follicular lymphoma (FL) patients, who have received at least two prior therapies.
A 2015 study found that p110δ inhibitors had a side-effect of boosting mouse immune responses against multiple cancers, including both solid and hematological types. Breast cancer mice survival times nearly doubled and spread significantly less, with far fewer and smaller tumors. Post-surgical survival also improved. Subject immune systems could also develop an effective memory response, extending protection. p110δ inactivation in regulatory T cells unleashes CD8+ cytotoxic T cells.
# Interactions
PIK3CD interacts with PIK3R1, and PIK3R2. | P110δ
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as phosphoinositide 3-kinase (PI3K) delta isoform or p110δ is an enzyme that in humans is encoded by the PIK3CD gene.[1][2][3]
p110δ regulates immune function. In contrast to the other class IA PI3Ks p110α and p110β, p110δ is principally expressed in leukocytes (white blood cells). Genetic and pharmacological inactivation of p110δ has revealed that this enzyme is important for the function of T cells, B cell, mast cells and neutrophils. Hence, p110δ is a promising target for drugs that aim to prevent or treat inflammation, autoimmunity and transplant rejection.[4]
Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3-prime OH position of the inositol ring of inositol lipids. The class I PI3Ks display a broad phosphoinositide lipid substrate specificity and include p110α, p110β and p110γ. p110α and p110β interact with SH2/SH3-domain-containing p85 adaptor proteins and with GTP-bound Ras.[3]
# Biochemistry
Like the other class IA PI3Ks, p110δ is a catalytic subunit, whose activity and subcellular localisation are controlled by an associated p85α, p55α, p50α or p85β regulatory subunit. The p55γ regulatory subunit is not thought to be expressed at significant levels in immune cells. There is no evidence for selective association between p110α, p110β or p110δ for any particular regulatory subunit. The class IA regulatory subunits (collectively referred to here as p85) bind to proteins that have been phosphorylated on tyrosines. Tyrosine kinases often operate near the plasma membrane and hence control the recruitment of p110δ to the plasma membrane where its substrate PtdIns(4,5)P2 is found. The conversion of PtdIns(4,5)P2 to PtdIns(3,4,5)P3 triggers signal transduction cascades controlled by PKB (also known as Akt), Tec family kinases and other proteins that contain PH domains. In immune cells, antigen receptors, cytokine receptors and costimulatory and accessory receptors stimulate tyrosine kinase activity and hence all have the potential to initiate PI3K signalling.[5][6]
# Functions
For reasons that are not well understood, p110δ appears to be activated in preference to p110α and p110β in a number of immune cells. The following is a brief summary of the role of p110δ in selected leukocyte subsets.
## T cells
In T cells, the antigen receptor (TCR) and costimulatory receptors (CD28 and ICOS) are thought to be main receptors responsible for recruiting and activating p110δ. Genetic inactivation of p110δ in mice causes T cells to be less responsive to antigen as determined by their reduced ability to proliferate and secrete interleukin 2. T cell specific deletion of p110δ has revealed its role in antibody responses.[7]
This may in part result from incomplete assembly of other signalling proteins at the immune synapse. The TCR cannot stimulate the phosphorylation of Akt in that absence of p110δ activity.[8]
## B cells
p110δ is a regulator of B cell proliferation and function. p110δ-deficient mice have deficient antibody responses. They also lack to B cell subsets: B1 cells (found in body cavities such as the peritoneum) and marginal zone B cells, found in the periphery of spleen follicles).[8][9]
## Mast cells
p110δ controls mast cell release of the granules responsible for allergic reactions. Thus inhibition of p110δ reduces allergic responses.[10]
## Neutrophils
In conjunction with p110γ, p110δ controls the release of reactive oxygen species in neutrophils.[11]
## Denritic cells
p110δ controls lipopolysaccharide induced Toll-like-receptor-4 mediated innate immune responses in dendritic cells and mice carrying an inactive p110δ is susceptible to lipopolysaccharide mediated endotoxin shock.[12]
# Activated PI3K delta syndrome
Inherited mutations in the PIK3CD gene which increase p110δ catalytic activity cause a primary immunodeficiency syndrome called APDS or PASLI.[citation needed]
# Pharmacology
US pharmaceutical company ICOS produced a selective inhibitor of p110δ called IC87114.[13] This inhibitor selectively impairs B cell, mast cell and neutrophil functions and is therefore a potential immune-modulator.[14]
The p110δ inhibitor idelalisib was developed by Gilead Sciences.[15] Idelalisib in combination with rituximab showed favourable progression free survival in a phase III clinical trial for chronic lymphocytic leukemia (CLL) compared with patients that received rituximab and placebo.[16]
In July 2014 idelalisib was approved by the FDA as a treatment for CLL patients.[17]
In September 2017 copanlisib, inhibiting predominantly p110α and p110δ, got FDA approval for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.[18]
In September 2018 duvelisib was approved by the FDA as a treatment for relapsed or refractory CLL, and relapsed follicular lymphoma (FL) patients, who have received at least two prior therapies.[19]
A 2015 study found that p110δ inhibitors had a side-effect of boosting mouse immune responses against multiple cancers, including both solid and hematological types. Breast cancer mice survival times nearly doubled and spread significantly less, with far fewer and smaller tumors. Post-surgical survival also improved. Subject immune systems could also develop an effective memory response, extending protection.[20] p110δ inactivation in regulatory T cells unleashes CD8+ cytotoxic T cells.[21]
# Interactions
PIK3CD interacts with PIK3R1,[1] and PIK3R2.[1] | https://www.wikidoc.org/index.php/P110%CE%B4 | |
254385a04d158d375f4b51e73fb0b1a78054afe7 | wikidoc | P2RX4 | P2RX4
P2X purinoceptor 4 is a protein that in humans is encoded by the P2RX4 gene.
The product of this gene belongs to the family of purinoceptors for ATP. Multiple alternatively spliced transcript variants have been identified for this gene although their full-length natures have not been determined.
The receptor is found in the central and peripheral nervous systems, in the epithelia of ducted glands and airways, in the smooth muscle of the bladder, gastrointestinal tract, uterus, and arteries, in uterine endometrium, and in fat cells. P2X4 receptors have been implicated in the regulation of cardiac function, ATP-mediated cell death, synaptic strengthening, and activating of the inflammasome in response to injury.
# Receptor structure and kinetics
The P2X4 subunits can form homomeric or heteromeric receptors. The P2X4 receptor has a typical P2X receptor structure. The zebrafish P2X4 receptor was the first purinergic receptor to be crystallized and have its three-dimensional structure solved, forming the model for the P2X receptor family.
The P2X4 receptor is a ligand-gated cation channel that opens in response to ATP binding. The P2X4 receptor has high calcium permeability, leading to the depolarization of the cell membrane and the activation of various Ca2+-sensitive intracellular processes. Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG+) in about 50% of the cells expressing the P2X4 receptor. The desensitization of P2X4 receptors is intermediate when compared to P2X1 and P2X2 receptors.
# Pharmacology
## Agonists
P2X4 receptors respond to ATP, but not αβmeATP. These receptors are also potentiated by ivermectin, cibacron blue, and zinc.
## Antagonists
The main pharmacological distinction between the members of the purinoceptor family is the relative sensitivity to the antagonists suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). The product of this gene has the lowest sensitivity for these antagonists
# Receptor trafficking
P2X4 receptors are stored in lysosomes and brought to the cell surface in response to extracellular signals. These signals include IFN-γ, CCL21, CCL2. Fibronectin is also involved in upregulation of P2X4 receptors through interactions with integrins that lead to the activation of SRC-family kinase member, Lyn. Lyn then activates PI3K-AKT and MEK-ERK signaling pathways to stimulate receptor trafficking. Internalization of P2X4 receptors is clathrin- and dynamin-dependent endocytosis.
# Neuropathic pain
The P2X4 receptor has been linked to neuropathic pain mediated by microglia in vitro and in vivo. P2X4 receptors are upregulated following injury. This upregulation allows for increased activation of p38 mitogen-activated protein kinases, thereby increasing the release of brain-derived neurotrophic factor (BDNF) from microglia. BDNF released from microglia induces neuronal hyperexcitability through interaction with the TrkB receptor. More importantly, recent work shows that P2X4 receptor activation is not only necessary for neuropathic pain, but it is also sufficient to cause neuropathic pain. | P2RX4
P2X purinoceptor 4 is a protein that in humans is encoded by the P2RX4 gene.[1][2]
The product of this gene belongs to the family of purinoceptors for ATP. Multiple alternatively spliced transcript variants have been identified for this gene although their full-length natures have not been determined.[2]
The receptor is found in the central and peripheral nervous systems, in the epithelia of ducted glands and airways, in the smooth muscle of the bladder, gastrointestinal tract, uterus, and arteries, in uterine endometrium, and in fat cells.[3] P2X4 receptors have been implicated in the regulation of cardiac function, ATP-mediated cell death, synaptic strengthening, and activating of the inflammasome in response to injury.[4][5][6][7][8]
# Receptor structure and kinetics
The P2X4 subunits can form homomeric or heteromeric receptors.[9] The P2X4 receptor has a typical P2X receptor structure. The zebrafish P2X4 receptor was the first purinergic receptor to be crystallized and have its three-dimensional structure solved, forming the model for the P2X receptor family.[10]
The P2X4 receptor is a ligand-gated cation channel that opens in response to ATP binding.[11] The P2X4 receptor has high calcium permeability, leading to the depolarization of the cell membrane and the activation of various Ca2+-sensitive intracellular processes.[11][12][13] Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG+) in about 50% of the cells expressing the P2X4 receptor.[11] The desensitization of P2X4 receptors is intermediate when compared to P2X1 and P2X2 receptors.[11]
# Pharmacology
## Agonists
P2X4 receptors respond to ATP, but not αβmeATP. These receptors are also potentiated by ivermectin, cibacron blue, and zinc.[11]
## Antagonists
The main pharmacological distinction between the members of the purinoceptor family is the relative sensitivity to the antagonists suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). The product of this gene has the lowest sensitivity for these antagonists[11]
# Receptor trafficking
P2X4 receptors are stored in lysosomes and brought to the cell surface in response to extracellular signals.[14] These signals include IFN-γ, CCL21, CCL2.[15][16][17] Fibronectin is also involved in upregulation of P2X4 receptors through interactions with integrins that lead to the activation of SRC-family kinase member, Lyn.[18] Lyn then activates PI3K-AKT and MEK-ERK signaling pathways to stimulate receptor trafficking.[19] Internalization of P2X4 receptors is clathrin- and dynamin-dependent endocytosis.[20]
# Neuropathic pain
The P2X4 receptor has been linked to neuropathic pain mediated by microglia in vitro and in vivo.[21][22] P2X4 receptors are upregulated following injury.[23] This upregulation allows for increased activation of p38 mitogen-activated protein kinases, thereby increasing the release of brain-derived neurotrophic factor (BDNF) from microglia.[24] BDNF released from microglia induces neuronal hyperexcitability through interaction with the TrkB receptor.[25] More importantly, recent work shows that P2X4 receptor activation is not only necessary for neuropathic pain, but it is also sufficient to cause neuropathic pain.[26] | https://www.wikidoc.org/index.php/P2RX4 | |
57c2a8de184102d2e5c75c850412f0396cd09b78 | wikidoc | P2RX7 | P2RX7
P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene.
The product of this gene belongs to the family of purinoceptors for ATP. Multiple alternatively spliced variants which would encode different isoforms have been identified although some fit nonsense-mediated decay criteria.
The receptor is found in the central and peripheral nervous systems, in microglia, in macrophages, in uterine endometrium, and in the retina. The P2X7 receptor also serves as a pattern recognition receptor for extracellular ATP-mediated apoptotic cell death, regulation of receptor trafficking, mast cell degranulation, and inflammation.
# Structure and kinetics
The P2X7 subunits can form homomeric receptors only with a typical P2X receptor structure.
The P2X7 receptor is a ligand-gated cation channel that opens in response to ATP binding and leads to cell depolarization. The P2X7 receptor requires higher levels of ATP than other P2X receptors; however, the response can be potentiated by reducing the concentration of divalent cations such as calcium or magnesium. Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG+). P2X7 receptors do not become desensitized readily and continued signaling leads to the aforementioned increased permeability and an increase in current amplitude.
# Pharmacology
## Agonists
P2X7 receptors respond to BzATP more readily than ATP. ADP and AMP are weak agonists of P2X7 receptors, but a brief exposure to ATP can increase their effectiveness. Glutathione has been proposed to act as a P2X7 receptor agonist when present at milimolar levels, inducing calcium transients and GABA release from retinal cells.
## Antagonists
The P2X7 receptor current can be blocked by zinc, calcium, magnesium, and copper. P2X7 receptors are sensitive to pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) and relatively insensitive to suramin, but the suramin analog, NF279, is much more effective. Oxidized ATP (OxATP) and Brilliant Blue G has also been used for blocking P2X7 in inflammation. Other blockers include the large organic cations calmidazolium (a calmodulin antagonist) and KN-62 (a CaM kinase II antagonist).
# Receptor trafficking
In microglia, P2X7 receptors are found mostly on the cell surface. Conserved cysteine residues located in the carboxyl terminus seem to be important for receptor trafficking to the cell membrane. These receptors are upregulated in response to peripheral nerve injury.
In melanocytic cells P2X7 gene expression may be regulated by MITF.
# Recruitment of pannexin
Activation of the P2X7 receptor by ATP leads to recruitment of pannexin pores which allow small molecules such as ATP to leak out of cells. This allows further activation of purinergic receptors and physiological responses such a spreading cytoplasmic waves of calcium. Moreover, this could be responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to larger molecules.
# Clinical significance
## Neuropathic pain
Microglial P2X7 receptors are thought to be involved in neuropathic pain because blockade or deletion of P2X7 receptors results in decreased responses to pain, as demonstrated in vivo. Moreover, P2X7 receptor signaling increases the release of proinflammatory molecules such as IL-1β, IL-6, and TNF-α. In addition, P2X7 receptors have been linked to increases in proinflammatory cytokines such as CXCL2 and CCL3. P2X7 receptors are also linked to P2X4 receptors, which are also associated with neuropathic pain mediated by microglia.
## Osteoporosis
Mutations in this gene have been associated to low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women.
## Diabetes
The ATP/P2X7R pathway may trigger T-cell attacks on the pancreas, rendering it unable to produce insulin. This autoimmune response may be an early mechanism by which the onset of diabetes is caused.
# Researches
## Possible link to hepatic fibrosis
One study in mice showed that blockade of P2X7 receptors attenuates onset of liver fibrosis. | P2RX7
P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene.[1][2]
The product of this gene belongs to the family of purinoceptors for ATP. Multiple alternatively spliced variants which would encode different isoforms have been identified although some fit nonsense-mediated decay criteria.[3]
The receptor is found in the central and peripheral nervous systems, in microglia, in macrophages, in uterine endometrium, and in the retina.[4][5][6][7] The P2X7 receptor also serves as a pattern recognition receptor for extracellular ATP-mediated apoptotic cell death,[8] regulation of receptor trafficking,[9] mast cell degranulation,[10][11] and inflammation.[10][11][12]
# Structure and kinetics
The P2X7 subunits can form homomeric receptors only with a typical P2X receptor structure.[13]
The P2X7 receptor is a ligand-gated cation channel that opens in response to ATP binding and leads to cell depolarization. The P2X7 receptor requires higher levels of ATP than other P2X receptors; however, the response can be potentiated by reducing the concentration of divalent cations such as calcium or magnesium.[14] Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG+).[14] P2X7 receptors do not become desensitized readily and continued signaling leads to the aforementioned increased permeability and an increase in current amplitude.[14]
# Pharmacology
## Agonists
P2X7 receptors respond to BzATP more readily than ATP.[14] ADP and AMP are weak agonists of P2X7 receptors, but a brief exposure to ATP can increase their effectiveness.[14] Glutathione has been proposed to act as a P2X7 receptor agonist when present at milimolar levels, inducing calcium transients and GABA release from retinal cells.[15][16]
## Antagonists
The P2X7 receptor current can be blocked by zinc, calcium, magnesium, and copper.[14] P2X7 receptors are sensitive to pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) and relatively insensitive to suramin, but the suramin analog, NF279, is much more effective. Oxidized ATP (OxATP) and Brilliant Blue G has also been used for blocking P2X7 in inflammation.[17][18] Other blockers include the large organic cations calmidazolium (a calmodulin antagonist) and KN-62 (a CaM kinase II antagonist).[14]
# Receptor trafficking
In microglia, P2X7 receptors are found mostly on the cell surface.[19] Conserved cysteine residues located in the carboxyl terminus seem to be important for receptor trafficking to the cell membrane.[20] These receptors are upregulated in response to peripheral nerve injury.[21]
In melanocytic cells P2X7 gene expression may be regulated by MITF.[22]
# Recruitment of pannexin
Activation of the P2X7 receptor by ATP leads to recruitment of pannexin pores[23] which allow small molecules such as ATP to leak out of cells. This allows further activation of purinergic receptors and physiological responses such a spreading cytoplasmic waves of calcium.[24] Moreover, this could be responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to larger molecules.
# Clinical significance
## Neuropathic pain
Microglial P2X7 receptors are thought to be involved in neuropathic pain because blockade or deletion of P2X7 receptors results in decreased responses to pain, as demonstrated in vivo.[25][26] Moreover, P2X7 receptor signaling increases the release of proinflammatory molecules such as IL-1β, IL-6, and TNF-α.[27][28][29] In addition, P2X7 receptors have been linked to increases in proinflammatory cytokines such as CXCL2 and CCL3.[30][31] P2X7 receptors are also linked to P2X4 receptors, which are also associated with neuropathic pain mediated by microglia.[19]
## Osteoporosis
Mutations in this gene have been associated to low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women.[32]
## Diabetes
The ATP/P2X7R pathway may trigger T-cell attacks on the pancreas, rendering it unable to produce insulin. This autoimmune response may be an early mechanism by which the onset of diabetes is caused.[33][34]
# Researches
## Possible link to hepatic fibrosis
One study in mice showed that blockade of P2X7 receptors attenuates onset of liver fibrosis.[35] | https://www.wikidoc.org/index.php/P2RX7 | |
9dc6848a440ca1d19836be1c9f972155e51afa0f | wikidoc | P2Y12 | P2Y12
In the field of purinergic signaling, the P2Y12 protein is found mainly but not exclusively on the surface of blood platelets, and is an important regulator in blood clotting.
P2Y12 belongs to the Gi class of a group of G protein-coupled (GPCR) purinergic receptors and is a chemoreceptor for adenosine diphosphate (ADP). This P2Y receptor family has several receptor subtypes with different pharmacological selectivity, which overlaps in some cases, for various adenosine and uridine nucleotides. The P2Y12 receptor is involved in platelet aggregation and is thus a biological target for the treatment of thromboembolisms and other clotting disorders. Two transcript variants encoding the same isoform have been identified for this gene.
# Clinical significance
The drugs clopidogrel (Plavix), prasugrel (Efient, Effient), ticagrelor (Brilinta), and cangrelor (Kengreal) bind to this receptor and are marketed as antiplatelet agents.
P2Y12 inhibitors do not change the risk of death when given as a pretreatment prior to routine percutaneous coronary intervention (PCI) in people who have had a non-ST-elevation myocardial infarction (NSTEMI). Though, a P2Y12 inhibitor in addition to aspirin should be administered for up to 12 months to most patients with non-ST-elevation acute coronary syndrome. They do however increase the risk of bleeding and decrease the risk of further cardiovascular problems. Thus their routine use in this context is of questionable value.
In patients undergoing primary PCI for an ST-segment elevation myocardial infarction (STEMI), a P2Y12 inhibitor should be administered as soon as possible. The use of clopidogrel in particular has been shown to improve morbidity and mortality endpoints including cardiovascular death, recurrent MI, and stroke at 30 days after PCI. | P2Y12
In the field of purinergic signaling, the P2Y12 protein is found mainly but not exclusively on the surface of blood platelets, and is an important regulator in blood clotting.[1]
P2Y12 belongs to the Gi class of a group of G protein-coupled (GPCR) purinergic receptors[2] and is a chemoreceptor for adenosine diphosphate (ADP).[3][4] This P2Y receptor family has several receptor subtypes with different pharmacological selectivity, which overlaps in some cases, for various adenosine and uridine nucleotides. The P2Y12 receptor is involved in platelet aggregation and is thus a biological target for the treatment of thromboembolisms and other clotting disorders. Two transcript variants encoding the same isoform have been identified for this gene.[5]
# Clinical significance
The drugs clopidogrel (Plavix), prasugrel (Efient, Effient), ticagrelor (Brilinta), and cangrelor (Kengreal) bind to this receptor and are marketed as antiplatelet agents.[3]
P2Y12 inhibitors do not change the risk of death when given as a pretreatment prior to routine percutaneous coronary intervention (PCI) in people who have had a non-ST-elevation myocardial infarction (NSTEMI). Though, a P2Y12 inhibitor in addition to aspirin should be administered for up to 12 months to most patients with non-ST-elevation acute coronary syndrome. They do however increase the risk of bleeding and decrease the risk of further cardiovascular problems. Thus their routine use in this context is of questionable value.[6]
In patients undergoing primary PCI for an ST-segment elevation myocardial infarction (STEMI), a P2Y12 inhibitor should be administered as soon as possible. The use of clopidogrel in particular has been shown to improve morbidity and mortality endpoints including cardiovascular death, recurrent MI, and stroke at 30 days after PCI.[7] | https://www.wikidoc.org/index.php/P2RY12 |
Subsets and Splits
No saved queries yet
Save your SQL queries to embed, download, and access them later. Queries will appear here once saved.