International Standard Serial Number
An International Standard Serial Number is an eight-digit serial number used to uniquely identify a serial publication, such as a magazine. The ISSN is helpful in distinguishing between serials with the same title. ISSN are used in ordering, interlibrary loans, other practices in connection with serial literature; the ISSN system was first drafted as an International Organization for Standardization international standard in 1971 and published as ISO 3297 in 1975. ISO subcommittee TC 46/SC 9 is responsible for maintaining the standard; when a serial with the same content is published in more than one media type, a different ISSN is assigned to each media type. For example, many serials are published both in electronic media; the ISSN system refers to these types as electronic ISSN, respectively. Conversely, as defined in ISO 3297:2007, every serial in the ISSN system is assigned a linking ISSN the same as the ISSN assigned to the serial in its first published medium, which links together all ISSNs assigned to the serial in every medium.
The format of the ISSN is an eight digit code, divided by a hyphen into two four-digit numbers. As an integer number, it can be represented by the first seven digits; the last code digit, which may be 0-9 or an X, is a check digit. Formally, the general form of the ISSN code can be expressed as follows: NNNN-NNNC where N is in the set, a digit character, C is in; the ISSN of the journal Hearing Research, for example, is 0378-5955, where the final 5 is the check digit, C=5. To calculate the check digit, the following algorithm may be used: Calculate the sum of the first seven digits of the ISSN multiplied by its position in the number, counting from the right—that is, 8, 7, 6, 5, 4, 3, 2, respectively: 0 ⋅ 8 + 3 ⋅ 7 + 7 ⋅ 6 + 8 ⋅ 5 + 5 ⋅ 4 + 9 ⋅ 3 + 5 ⋅ 2 = 0 + 21 + 42 + 40 + 20 + 27 + 10 = 160 The modulus 11 of this sum is calculated. For calculations, an upper case X in the check digit position indicates a check digit of 10. To confirm the check digit, calculate the sum of all eight digits of the ISSN multiplied by its position in the number, counting from the right.
The modulus 11 of the sum must be 0. There is an online ISSN checker. ISSN codes are assigned by a network of ISSN National Centres located at national libraries and coordinated by the ISSN International Centre based in Paris; the International Centre is an intergovernmental organization created in 1974 through an agreement between UNESCO and the French government. The International Centre maintains a database of all ISSNs assigned worldwide, the ISDS Register otherwise known as the ISSN Register. At the end of 2016, the ISSN Register contained records for 1,943,572 items. ISSN and ISBN codes are similar in concept. An ISBN might be assigned for particular issues of a serial, in addition to the ISSN code for the serial as a whole. An ISSN, unlike the ISBN code, is an anonymous identifier associated with a serial title, containing no information as to the publisher or its location. For this reason a new ISSN is assigned to a serial each time it undergoes a major title change. Since the ISSN applies to an entire serial a new identifier, the Serial Item and Contribution Identifier, was built on top of it to allow references to specific volumes, articles, or other identifiable components.
Separate ISSNs are needed for serials in different media. Thus, the print and electronic media versions of a serial need separate ISSNs. A CD-ROM version and a web version of a serial require different ISSNs since two different media are involved. However, the same ISSN can be used for different file formats of the same online serial; this "media-oriented identification" of serials made sense in the 1970s. In the 1990s and onward, with personal computers, better screens, the Web, it makes sense to consider only content, independent of media; this "content-oriented identification" of serials was a repressed demand during a decade, but no ISSN update or initiative occurred. A natural extension for ISSN, the unique-identification of the articles in the serials, was the main demand application. An alternative serials' contents model arrived with the indecs Content Model and its application, the digital object identifier, as ISSN-independent initiative, consolidated in the 2000s. Only in 2007, ISSN-L was defined in the
African Americans are an ethnic group of Americans with total or partial ancestry from any of the black racial groups of Africa. The term refers to descendants of enslaved black people who are from the United States. Black and African Americans constitute the third largest racial and ethnic group in the United States. Most African Americans are descendants of enslaved peoples within the boundaries of the present United States. On average, African Americans are of West/Central African and European descent, some have Native American ancestry. According to U. S. Census Bureau data, African immigrants do not self-identify as African American; the overwhelming majority of African immigrants identify instead with their own respective ethnicities. Immigrants from some Caribbean, Central American and South American nations and their descendants may or may not self-identify with the term. African-American history starts in the 16th century, with peoples from West Africa forcibly taken as slaves to Spanish America, in the 17th century with West African slaves taken to English colonies in North America.
After the founding of the United States, black people continued to be enslaved, the last four million black slaves were only liberated after the Civil War in 1865. Due to notions of white supremacy, they were treated as second-class citizens; the Naturalization Act of 1790 limited U. S. citizenship to whites only, only white men of property could vote. These circumstances were changed by Reconstruction, development of the black community, participation in the great military conflicts of the United States, the elimination of racial segregation, the civil rights movement which sought political and social freedom. In 2008, Barack Obama became the first African American to be elected President of the United States; the first African slaves arrived via Santo Domingo to the San Miguel de Gualdape colony, founded by Spanish explorer Lucas Vázquez de Ayllón in 1526. The marriage between Luisa de Abrego, a free black domestic servant from Seville and Miguel Rodríguez, a white Segovian conquistador in 1565 in St. Augustine, is the first known and recorded Christian marriage anywhere in what is now the continental United States.
The ill-fated colony was immediately disrupted by a fight over leadership, during which the slaves revolted and fled the colony to seek refuge among local Native Americans. De Ayllón and many of the colonists died shortly afterwards of an epidemic and the colony was abandoned; the settlers and the slaves who had not escaped returned to Haiti, whence. The first recorded Africans in British North America were "20 and odd negroes" who came to Jamestown, Virginia via Cape Comfort in August 1619 as indentured servants; as English settlers died from harsh conditions and more Africans were brought to work as laborers. An indentured servant would work for several years without wages; the status of indentured servants in early Virginia and Maryland was similar to slavery. Servants could be bought, sold, or leased and they could be physically beaten for disobedience or running away. Unlike slaves, they were freed after their term of service expired or was bought out, their children did not inherit their status, on their release from contract they received "a year's provision of corn, double apparel, tools necessary", a small cash payment called "freedom dues".
Africans could raise crops and cattle to purchase their freedom. They raised families, married other Africans and sometimes intermarried with Native Americans or English settlers. By the 1640s and 1650s, several African families owned farms around Jamestown and some became wealthy by colonial standards and purchased indentured servants of their own. In 1640, the Virginia General Court recorded the earliest documentation of lifetime slavery when they sentenced John Punch, a Negro, to lifetime servitude under his master Hugh Gwyn for running away. In the Spanish Florida some Spanish married or had unions with Pensacola, Creek or African women, both slave and free, their descendants created a mixed-race population of mestizos and mulattos; the Spanish encouraged slaves from the southern British colonies to come to Florida as a refuge, promising freedom in exchange for conversion to Catholicism. King Charles II of Spain issued a royal proclamation freeing all slaves who fled to Spanish Florida and accepted conversion and baptism.
Most went to the area around St. Augustine, but escaped slaves reached Pensacola. St. Augustine had mustered an all-black militia unit defending Spain as early as 1683. One of the Dutch African arrivals, Anthony Johnson, would own one of the first black "slaves", John Casor, resulting from the court ruling of a civil case; the popular conception of a race-based slave system did not develop until the 18th century. The Dutch West India Company introduced slavery in 1625 with the importation of eleven black slaves into New Amsterdam. All the colony's slaves, were freed upon its surrender to the British. Massachusetts was the first British colony to recognize slavery in 1641. In 1662, Virginia passed a law that children of enslaved women took the status of the mother, rather than that of the father, as under English common law; this principle was called partus sequitur ventrum. By an act of 1699, the colony ordered all free blacks deported defining as slaves all people of African descent who remained in the c
Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, is a protective response involving immune cells, blood vessels, molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, initiate tissue repair; the five classical signs of inflammation are heat, redness and loss of function. Inflammation is a generic response, therefore it is considered as a mechanism of innate immunity, as compared to adaptive immunity, specific for each pathogen. Too little inflammation could lead to progressive tissue destruction by the harmful stimulus and compromise the survival of the organism. In contrast, chronic inflammation may lead to a host of diseases, such as hay fever, atherosclerosis, rheumatoid arthritis, cancer. Inflammation is therefore closely regulated by the body. Inflammation can be classified as either chronic.
Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation, such as mononuclear cells, is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. Inflammation is not a synonym for infection. Infection describes the interaction between the action of microbial invasion and the reaction of the body's inflammatory response—the two components are considered together when discussing an infection, the word is used to imply a microbial invasive cause for the observed inflammatory reaction. Inflammation on the other hand describes purely the body's immunovascular response, whatever the cause may be.
But because of how the two are correlated, words ending in the suffix -itis are sometimes informally described as referring to infection. For example, the word urethritis means only "urethral inflammation", but clinical health care providers discuss urethritis as a urethral infection because urethral microbial invasion is the most common cause of urethritis, it is useful to differentiate inflammation and infection because there are typical situations in pathology and medical diagnosis where inflammation is not driven by microbial invasion – for example, trauma and autoimmune diseases including type III hypersensitivity. Conversely, there is pathology where microbial invasion does not cause the classic inflammatory response – for example, parasitosis or eosinophilia. Acute inflammation is a short-term process appearing within a few minutes or hours and begins to cease upon the removal of the injurious stimulus, it involves a coordinated and systemic mobilization response locally of various immune and neurological mediators of acute inflammation.
In a normal healthy response, it becomes activated, clears the pathogen and begins a repair process and ceases. It is characterized by five cardinal signs:An acronym that may be used to remember the key symptoms is "PRISH", for pain, immobility and heat; the traditional names for signs of inflammation come from Latin: Dolor Calor Rubor Tumor Functio laesa The first four were described by Celsus, while loss of function was added by Galen. However, the addition of this fifth sign has been ascribed to Thomas Sydenham and Virchow. Redness and heat are due to increased blood flow at body core temperature to the inflamed site. Loss of function has multiple causes. Acute inflammation of the lung does not cause pain unless the inflammation involves the parietal pleura, which does have pain-sensitive nerve endings; the process of acute inflammation is initiated by resident immune cells present in the involved tissue resident macrophages, dendritic cells, Kupffer cells and mast cells. These cells possess surface receptors known as pattern recognition receptors, which recognize two subclasses of molecules: pathogen-associated molecular patterns and damage-associated molecular patterns.
PAMPs are compounds that are associated with various pathogens, but which are distinguishable from host molecules. DAMPs are compounds that are associated with host-related cell damage. At the onset of an infection, burn, or other injuries, these cells undergo activation and release inflammatory mediators responsible for the clinical signs of inflammation. Vasodilation and its resulting increased blood flow causes increased heat. Increased permeability of the blood vessels results in an exudation of plasma proteins and fluid into the tissue, which manifests itself as swelling; some of the released mediators such as bradykinin increase the sensitivity to pain. The mediator molecules alter the blood vessels to
Integrins are transmembrane receptors that facilitate cell-extracellular matrix adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, organization of the intracellular cytoskeleton, movement of new receptors to the cell membrane; the presence of integrins allows flexible responses to events at the cell surface. Several types of integrins exist, one cell may have multiple different types on its surface. Integrins are found in all animals. Integrins work alongside other receptors such as cadherins, the immunoglobulin superfamily cell adhesion molecules and syndecans, to mediate cell–cell and cell–matrix interaction. Ligands for integrins include fibronectin, vitronectin and laminin. Integrins are obligate heterodimers, meaning that they have two subunits: α and β. Integrins in mammals have twenty-four α and nine β subunits, in Drosophila five α and two β subunits, in Caenorhabditis nematodes two α subunits and one β subunit.
The α and β subunits each possess several cytoplasmic domains. Variants of some subunits are formed by differential RNA splicing. Through different combinations of the α and β subunits, around 24 unique integrins are generated. Integrin subunits have short cytoplasmic domains of 40 -- 70 amino acids; the exception is the beta-4 subunit, which has a cytoplasmic domain of 1,088 amino acids, one of the largest of any membrane protein. Outside the cell membrane, the α and β chains lie close together along a length of about 23 nm, they have been compared to lobster claws, although they don't "pinch" their ligand, they chemically interact with it at the insides of the "tips" of their "pinchers". The molecular mass of the integrin subunits can vary from 90 kDa to 160 kDa. Beta subunits have four cysteine-rich repeated sequences. Both α and β subunits bind several divalent cations; the role of divalent cations in the α subunit is unknown, but may stabilize the folds of the protein. The cations in the β subunits are more interesting: they are directly involved in coordinating at least some of the ligands that integrins bind.
Integrins can be categorized in multiple ways. For example, some α chains have an additional structural element inserted toward the N-terminal, the alpha-A domain. Integrins carrying this domain either bind to collagens, or act as cell-cell adhesion molecules; this α-I domain is the binding site for ligands of such integrins. Those integrins that don't carry this inserted domain have an A-domain in their ligand binding site, but this A-domain is found on the β subunit. In both cases, the A-domains carry up to three divalent cation binding sites. One is permanently occupied in physiological concentrations of divalent cations, carries either a calcium or magnesium ion, the principal divalent cations in blood at median concentrations of 1.4 mM and 0.8 mM. The other two sites become occupied by cations when ligands bind—at least for those ligands involving an acidic amino acid in their interaction sites. An acidic amino acid features in the integrin-interaction site of many ECM proteins, for example as part of the amino acid sequence Arginine-Glycine-Aspartic acid.
Despite many years of effort, discovering the high-resolution structure of integrins proved to be challenging, as membrane proteins are classically difficult to purify, as integrins are large and linked to many sugar trees. Low-resolution images of detergent extracts of intact integrin GPIIbIIIa, obtained using electron microscopy, data from indirect techniques that investigate the solution properties of integrins using ultracentrifugation and light scattering, were combined with fragmentary high-resolution crystallographic or NMR data from single or paired domains of single integrin chains, molecular models postulated for the rest of the chains; the X-ray crystal structure obtained for the complete extracellular region of one integrin, αvβ3, shows the molecule to be folded into an inverted V-shape that brings the ligand-binding sites close to the cell membrane. More the crystal structure was obtained for the same integrin bound to a small ligand containing the RGD-sequence, the drug cilengitide.
As detailed above, this revealed why divalent cations are critical for RGD-ligand binding to integrins. The interaction of such sequences with integrins is believed to be a primary switch by which ECM exerts its effects on cell behaviour; the structure poses many questions regarding ligand binding and signal transduction. The ligand binding site is directed towards the C-terminal of the integrin, the region where the molecule emerges from the cell membrane. If it emerges orthogonally from the membrane, the ligand binding site would be obstructed as integrin ligands are massive and well cross-linked components of the ECM. In fact, little is known about the angle that membrane proteins subtend to the plane of the membrane; the default assumption is that they emerge rather like little lollipops, but the evidence for thi
Bacteria are a type of biological cell. They constitute a large domain of prokaryotic microorganisms. A few micrometres in length, bacteria have a number of shapes, ranging from spheres to rods and spirals. Bacteria were among the first life forms to appear on Earth, are present in most of its habitats. Bacteria inhabit soil, acidic hot springs, radioactive waste, the deep portions of Earth's crust. Bacteria live in symbiotic and parasitic relationships with plants and animals. Most bacteria have not been characterised, only about half of the bacterial phyla have species that can be grown in the laboratory; the study of bacteria is known as a branch of microbiology. There are 40 million bacterial cells in a gram of soil and a million bacterial cells in a millilitre of fresh water. There are 5×1030 bacteria on Earth, forming a biomass which exceeds that of all plants and animals. Bacteria are vital in many stages of the nutrient cycle by recycling nutrients such as the fixation of nitrogen from the atmosphere.
The nutrient cycle includes the decomposition of dead bodies. In the biological communities surrounding hydrothermal vents and cold seeps, extremophile bacteria provide the nutrients needed to sustain life by converting dissolved compounds, such as hydrogen sulphide and methane, to energy. Data reported by researchers in October 2012 and published in March 2013 suggested that bacteria thrive in the Mariana Trench, with a depth of up to 11 kilometres, is the deepest known part of the oceans. Other researchers reported related studies that microbes thrive inside rocks up to 580 metres below the sea floor under 2.6 kilometres of ocean off the coast of the northwestern United States. According to one of the researchers, "You can find microbes everywhere—they're adaptable to conditions, survive wherever they are."The famous notion that bacterial cells in the human body outnumber human cells by a factor of 10:1 has been debunked. There are 39 trillion bacterial cells in the human microbiota as personified by a "reference" 70 kg male 170 cm tall, whereas there are 30 trillion human cells in the body.
This means that although they do have the upper hand in actual numbers, it is only by 30%, not 900%. The largest number exist in the gut flora, a large number on the skin; the vast majority of the bacteria in the body are rendered harmless by the protective effects of the immune system, though many are beneficial in the gut flora. However several species of bacteria are pathogenic and cause infectious diseases, including cholera, anthrax and bubonic plague; the most common fatal bacterial diseases are respiratory infections, with tuberculosis alone killing about 2 million people per year in sub-Saharan Africa. In developed countries, antibiotics are used to treat bacterial infections and are used in farming, making antibiotic resistance a growing problem. In industry, bacteria are important in sewage treatment and the breakdown of oil spills, the production of cheese and yogurt through fermentation, the recovery of gold, palladium and other metals in the mining sector, as well as in biotechnology, the manufacture of antibiotics and other chemicals.
Once regarded as plants constituting the class Schizomycetes, bacteria are now classified as prokaryotes. Unlike cells of animals and other eukaryotes, bacterial cells do not contain a nucleus and harbour membrane-bound organelles. Although the term bacteria traditionally included all prokaryotes, the scientific classification changed after the discovery in the 1990s that prokaryotes consist of two different groups of organisms that evolved from an ancient common ancestor; these evolutionary domains are called Archaea. The word bacteria is the plural of the New Latin bacterium, the latinisation of the Greek βακτήριον, the diminutive of βακτηρία, meaning "staff, cane", because the first ones to be discovered were rod-shaped; the ancestors of modern bacteria were unicellular microorganisms that were the first forms of life to appear on Earth, about 4 billion years ago. For about 3 billion years, most organisms were microscopic, bacteria and archaea were the dominant forms of life. Although bacterial fossils exist, such as stromatolites, their lack of distinctive morphology prevents them from being used to examine the history of bacterial evolution, or to date the time of origin of a particular bacterial species.
However, gene sequences can be used to reconstruct the bacterial phylogeny, these studies indicate that bacteria diverged first from the archaeal/eukaryotic lineage. The most recent common ancestor of bacteria and archaea was a hyperthermophile that lived about 2.5 billion–3.2 billion years ago. Bacteria were involved in the second great evolutionary divergence, that of the archaea and eukaryotes. Here, eukaryotes resulted from the entering of ancient bacteria into endosymbiotic associations with the ancestors of eukaryotic cells, which were themselves related to the Archaea; this involved the engulfment by proto-eukaryotic cells of alphaproteobacterial symbionts to form either mitochondria or hydrogenosomes, which are still found in all known Eukarya. Some eukaryotes that contained mitochondria engulfed cyanobacteria-like organisms, leading to the formation of chloroplasts in algae and plants; this is known as primary endosymbiosis. Bacteria display a wide diversity of sizes, called morphologies.
Bacterial cells are about one-tenth the size of eukaryotic cells
The hair follicle is a dynamic organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions; the hair follicle regulates hair growth via a complex interaction between hormones and immune cells. This complex interaction induces the hair follicle to produce different types of hair as seen on different parts of the body. For example, terminal hairs grow on the scalp and lanugo hairs are seen covering the bodies of fetuses in the uterus and in some new born babies; the process of hair growth occurs in distinct sequential stages. The first stage is called anagen and is the active growth phase, catagen is the resting stage, telogen is the regression of the hair follicle phase, exogen is the active shedding of hair phase and lastly kenogen is the phase between the empty hair follicle and the growth of new hair; the function of hair in humans has long been a subject of interest and continues to be an important topic in society, developmental biology and medicine.
Of all mammals, humans have the longest growth phase of scalp hair compared to hair growth on other parts of the body. For centuries, humans have ascribed esthetics to scalp hair styling and dressing and it is used to communicate social or cultural norms in societies. In addition to its role in defining human appearance, scalp hair provides protection from UV sun rays and is an insulator against extremes of hot and cold temperatures. Differences in the shape of the scalp hair follicle determine the observed ethnic differences in scalp hair appearance and texture. There are many human diseases in which abnormalities in hair appearance, texture or growth are early signs of local disease of the hair follicle or systemic illness. Well known diseases of the hair follicle include alopecia or hair loss, hirsutism or excess hair growth and lupus erythematosus; the position and distribution of hair follicles changes over the body. For example, the skin of the palms and soles do not have hair follicles whereas skin of the scalp, forearms and genitalia have abundant hair follicles.
There are many structures. Anatomically, the triad of hair follicle, sebaceous gland and arrector pili muscle make up the pilosebaceous unit. A hair follicle consists of: The papilla is a large structure at the base of the hair follicle; the papilla is made up of connective tissue and a capillary loop. Cell division in the papilla is either non-existent. Around the papilla is the hair matrix. A root sheath composed of an internal root sheath; the external root sheath appears empty with cuboid cells. The internal root sheath is composed of three layers, Henle's layer, Huxley's layer, an internal cuticle, continuous with the outermost layer of the hair fiber; the bulge is located in the outer root sheath at the insertion point of the arrector pili muscle. It houses several types of stem cells, which supply the entire hair follicle with new cells, take part in healing the epidermis after a wound. Stem cells express the marker LGR5+ in vivo. Other structures associated with the hair follicle include the cup in which the follicle grows known as the infundibulum, the arrector pili muscles, the sebaceous glands, the apocrine sweat glands.
Hair follicle receptors sense the position of the hair. Attached to the follicle is a tiny bundle of muscle fiber called the arrector pili; this muscle is responsible for causing the follicle lissis to become more perpendicular to the surface of the skin, causing the follicle to protrude above the surrounding skin and a pore encased with skin oil. This process results in goose bumps. Attached to the follicle is a sebaceous gland, which produces the oily or waxy substance sebum; the higher the density of the hair, the more sebaceous glands that are found. There are ethnic differences in several different hair characteristics; the differences in appearance and texture of hair are due to many factors: the position of the hair bulb relative to the hair follicle and shape of the dermal papilla, the curvature of the hair follicle. The scalp hair follicle in Caucasians is elliptical in shape and, produces straight or wavy hair, whereas the scalp hair follicle of people of African descent is more curvy, resulting in the growth of curled hair.
In utero, the epithelium and underlying mesenchyme interact to form hair follicles. A key aspect of hair loss with age is the aging of the hair follicle. Ordinarily, hair follicle renewal is maintained by the stem cells associated with each follicle. Aging of the hair follicle appears to be primed by a sustained cellular response to the DNA damage that accumulates in renewing stem cells during aging; this damage response involves the proteolysis of type XVII collagen by neutrophil elastase in response to the DNA damage in the hair follicle stem cells. Proteolysis of collagen leads to elimination of the damaged cells and to terminal hair follicle miniaturization. Hair grows in cycles of various phases: anagen is the growth phase; each phase has several morphologically and histologically distinguishable sub-phases. Prior to the start of cycling is a phase of follicular morphogenesis. There is a shedding phase, or exogen, independent of anagen and telogen in which one or several hairs that might arise from a single follicle exits.
Up to 90% of the hair follicles are in anagen phase, while 10–14% are in telogen and 1–2% in catagen. The cycle's length varies o
Superantigens are a class of antigens that cause non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs are produced by some pathogenic viruses and bacteria most as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body’s T-cells are activated, these SAgs are capable of activating up to 20% of the body’s T-cells. Furthermore, Anti-CD3 and Anti-CD28 Antibodies have shown to be potent superantigens; the large number of activated T-cells generates a massive immune response, not specific to any particular epitope on the SAg thus undermining one of the fundamental strengths of the adaptive immune system, that is, its ability to target antigens with high specificity. More the large number of activated T-cells secrete large amounts of cytokines, the most important of, Interferon gamma; this excess amount of IFN-gamma in turn activates the macrophages. The activated macrophages, in turn, over-produce proinflammatory cytokines such as IL-1, IL-6 and TNF-alpha.
TNF-alpha is important as a part of the body's inflammatory response. In normal circumstances it is released locally in low levels and helps the immune system defeat pathogens. However, when it is systemically released in the blood and in high levels, it can cause severe and life-threatening symptoms, including shock and multiple organ failure. SAgs are produced intracellularly by bacteria and are released upon infection as extracellular mature toxins; the sequences of these toxins are conserved among the different subgroups. More important than sequence homology, the 3D structure is similar among different SAgs resulting in similar functional effects among different groups. Crystal structures of the enterotoxins reveals that they are compact, ellipsoidal proteins sharing a characteristic two-domain folding pattern comprising an NH2-terminal β barrel globular domain known as the oligosaccharide / oligonucleotide fold, a long α-helix that diagonally spans the center of the molecule, a COOH terminal globular domain.
The domains have binding regions for the Major Histocompatibility Complex Class II and the T cell receptor, respectively. Superantigens bind first to the MHC Class II and coordinate to the variable alpha or beta chain of T-cell Receptors SAgs show preference for the HLA-DQ form of the molecule. Binding to the α-chain puts the SAg in the appropriate position to coordinate to the TCR. Less SAgs attach to the polymorphic MHC class II β-chain in an interaction mediated by a zinc ion coordination complex between three SAg residues and a conserved region of the HLA-DR β chain; the use of a zinc ion in binding leads to a higher affinity interaction. Several staphylococcal SAgs are capable of cross-linking MHC molecules by binding to both the α and β chains; this mechanism stimulates cytokine expression and release in antigen presenting cells as well as inducing the production of costimulatory molecules that allow the cell to bind to and activate T cells more effectively. T-cell binding region of the SAg interacts with the Variable region on the Beta chain of the T-cell Receptor.
A given SAg can activate a large proportion of the T-cell population because the human T-cell repertoire comprises only about 50 types of Vβ elements and some SAgs are capable of binding to multiple types of Vβ regions. This interaction varies among the different groups of SAgs. Variability among different people in the types of T-cell regions that are prevalent explains why some people respond more to certain SAgs. Group I SAgs contact the Vβ at the framework region of the molecule. SAgs of Group II interact with the Vβ region using mechanisms; these interactions are for the most part independent of specific Vβ amino acid side-chains. Group IV SAgs have been shown to engage all three CDR loops of certain Vβ forms; the interaction takes place in a cleft between the small and large domains of the SAg and allows the SAg to act as a wedge between the TCR and MHC. This displaces the antigenic peptide away from the TCR and circumvents the normal mechanism for T-cell activation; the biological strength of the SAg is determined by its affinity for the TCR.
SAgs with the highest affinity for the TCR elicit the strongest response. SPMEZ-2 is the most potent SAg discovered to date; the SAg cross-links the MHC and the TCR inducing a signaling pathway that results in the proliferation of the cell and production of cytokines. This occurs because a cognate antigen activates a T cell not because of its structure per se, but because its affinity allows it to bind the TCR for a lengthy enough time period, the SAg mimics this temporal bonding. Low levels of Zap-70 have been found in T-cells activated by SAgs, indicating that the normal signaling pathway of T-cell activation is impaired, it is hypothesized that Fyn rather than Lck is activated by a tyrosine kinase, leading to the adaptive induction of anergy. Both the protein kinase C pathway and the protein tyrosine kinase pathways are activated, resulting in upregulating production of proinflammatory cytokines; this alternative signaling pathway impairs the calcium/calcineurin and Ras/MAPkinase pathways but allows for a focused inflammatory response.
SAg stimulation of antigen presenting cells and T-cells elicits a response, inflammatory, focused on the action of Th1 T-helper cells. Some of the major products are IL-1, IL-2, IL-6, TNF-α, gamma interferon, macrophage inflammatory protein 1α, MIP-1β, monocyte c