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Immunology is a science that examines the structure and function of the immune system. It originates from medicine and early studies on the causes of immunity to disease. The earliest known reference to immunity was during the plague of Athens in 430 BC. Thucydides noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time. In the 18th century, Pierre-Louis Moreau de Maupertuis made experiments with scorpion venom and observed that certain dogs and mice were immune to this venom. This and other observations of acquired immunity were later exploited by Louis Pasteur in his development of vaccination and his proposed germ theory of disease. Pasteur's theory was in direct opposition to contemporary theories of disease, such as the miasma theory. It was not until Robert Koch's 1891 proofs, for which he was awarded a Nobel Prize in 1905, that microorganisms were confirmed as the cause of infectious disease. Viruses were confirmed as human pathogens in 1901, with the discovery of the yellow fever virus by Walter Reed.
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The immune system protects organisms from infection with layered defenses of increasing specificity. In simple terms, physical barriers prevent pathogens such as bacteria and viruses from entering the organism. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all plants and animals. If pathogens successfully evade the innate response, vertebrates possess a second layer of protection, the adaptive immune system, which is activated by the innate response. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered.
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Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self molecules. In immunology, self molecules are those components of an organism's body that can be distinguished from foreign substances by the immune system. Conversely, non-self molecules are those recognized as foreign molecules. One class of non-self molecules are called antigens (short for antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune response.
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Microorganisms or toxins that successfully enter an organism encounter the cells and mechanisms of the innate immune system. The innate response is usually triggered when microbes are identified by pattern recognition receptors, which recognize components that are conserved among broad groups of microorganisms, or when damaged, injured or stressed cells send out alarm signals, many of which (but not all) are recognized by the same receptors as those that recognize pathogens. Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way. This system does not confer long-lasting immunity against a pathogen. The innate immune system is the dominant system of host defense in most organisms.
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Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers. The waxy cuticle of many leaves, the exoskeleton of insects, the shells and membranes of externally deposited eggs, and skin are examples of mechanical barriers that are the first line of defense against infection. However, as organisms cannot be completely sealed from their environments, other systems act to protect body openings such as the lungs, intestines, and the genitourinary tract. In the lungs, coughing and sneezing mechanically eject pathogens and other irritants from the respiratory tract. The flushing action of tears and urine also mechanically expels pathogens, while mucus secreted by the respiratory and gastrointestinal tract serves to trap and entangle microorganisms.
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Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial peptides such as the β-defensins. Enzymes such as lysozyme and phospholipase A2 in saliva, tears, and breast milk are also antibacterials. Vaginal secretions serve as a chemical barrier following menarche, when they become slightly acidic, while semen contains defensins and zinc to kill pathogens. In the stomach, gastric acid and proteases serve as powerful chemical defenses against ingested pathogens.
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Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers by competing with pathogenic bacteria for food and space and, in some cases, by changing the conditions in their environment, such as pH or available iron. This reduces the probability that pathogens will reach sufficient numbers to cause illness. However, since most antibiotics non-specifically target bacteria and do not affect fungi, oral antibiotics can lead to an "overgrowth" of fungi and cause conditions such as a vaginal candidiasis (a yeast infection). There is good evidence that re-introduction of probiotic flora, such as pure cultures of the lactobacilli normally found in unpasteurized yogurt, helps restore a healthy balance of microbial populations in intestinal infections in children and encouraging preliminary data in studies on bacterial gastroenteritis, inflammatory bowel diseases, urinary tract infection and post-surgical infections.
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Inflammation is one of the first responses of the immune system to infection. The symptoms of inflammation are redness, swelling, heat, and pain, which are caused by increased blood flow into tissue. Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes). Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as shutting down protein synthesis in the host cell. Growth factors and cytotoxic factors may also be released. These cytokines and other chemicals recruit immune cells to the site of infection and promote healing of any damaged tissue following the removal of pathogens.
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Phagocytosis is an important feature of cellular innate immunity performed by cells called 'phagocytes' that engulf, or eat, pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines. Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular vesicle called a phagosome, which subsequently fuses with another vesicle called a lysosome to form a phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that releases free radicals into the phagolysosome. Phagocytosis evolved as a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism. Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals.
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Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens. Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, normally representing 50% to 60% of the total circulating leukocytes. During the acute phase of inflammation, particularly as a result of bacterial infection, neutrophils migrate toward the site of inflammation in a process called chemotaxis, and are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells that reside within tissues and produce a wide array of chemicals including enzymes, complement proteins, and regulatory factors such as interleukin 1. Macrophages also act as scavengers, ridding the body of worn-out cells and other debris, and as antigen-presenting cells that activate the adaptive immune system.
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Leukocytes (white blood cells) act like independent, single-celled organisms and are the second arm of the innate immune system. The innate leukocytes include the phagocytes (macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms. Innate cells are also important mediators in the activation of the adaptive immune system.
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Dendritic cells (DC) are phagocytes in tissues that are in contact with the external environment; therefore, they are located mainly in the skin, nose, lungs, stomach, and intestines. They are named for their resemblance to neuronal dendrites, as both have many spine-like projections, but dendritic cells are in no way connected to the nervous system. Dendritic cells serve as a link between the bodily tissues and the innate and adaptive immune systems, as they present antigens to T cells, one of the key cell types of the adaptive immune system.
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Natural killer cells, or NK cells, are a component of the innate immune system which does not directly attack invading microbes. Rather, NK cells destroy compromised host cells, such as tumor cells or virus-infected cells, recognizing such cells by a condition known as "missing self." This term describes cells with low levels of a cell-surface marker called MHC I (major histocompatibility complex) – a situation that can arise in viral infections of host cells. They were named "natural killer" because of the initial notion that they do not require activation in order to kill cells that are "missing self." For many years it was unclear how NK cells recognize tumor cells and infected cells. It is now known that the MHC makeup on the surface of those cells is altered and the NK cells become activated through recognition of "missing self". Normal body cells are not recognized and attacked by NK cells because they express intact self MHC antigens. Those MHC antigens are recognized by killer cell immunoglobulin receptors (KIR) which essentially put the brakes on NK cells.
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The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as immunological memory, where each pathogen is "remembered" by a signature antigen. The adaptive immune response is antigen-specific and requires the recognition of specific "non-self" antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by "memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it.
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Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a "non-self" target, such as a pathogen, only after antigens (small fragments of the pathogen) have been processed and presented in combination with a "self" receptor called a major histocompatibility complex (MHC) molecule. There are two major subtypes of T cells: the killer T cell and the helper T cell. In addition there are regulatory T cells which have a role in modulating immune response. Killer T cells only recognize antigens coupled to Class I MHC molecules, while helper T cells and regulatory T cells only recognize antigens coupled to Class II MHC molecules. These two mechanisms of antigen presentation reflect the different roles of the two types of T cell. A third, minor subtype are the γδ T cells that recognize intact antigens that are not bound to MHC receptors.
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Killer T cells are a sub-group of T cells that kill cells that are infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional. As with B cells, each type of T cell recognizes a different antigen. Killer T cells are activated when their T cell receptor (TCR) binds to this specific antigen in a complex with the MHC Class I receptor of another cell. Recognition of this MHC:antigen complex is aided by a co-receptor on the T cell, called CD8. The T cell then travels throughout the body in search of cells where the MHC I receptors bear this antigen. When an activated T cell contacts such cells, it releases cytotoxins, such as perforin, which form pores in the target cell's plasma membrane, allowing ions, water and toxins to enter. The entry of another toxin called granulysin (a protease) induces the target cell to undergo apoptosis. T cell killing of host cells is particularly important in preventing the replication of viruses. T cell activation is tightly controlled and generally requires a very strong MHC/antigen activation signal, or additional activation signals provided by "helper" T cells (see below).
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Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC molecules. The MHC:antigen complex is also recognized by the helper cell's CD4 co-receptor, which recruits molecules inside the T cell (e.g., Lck) that are responsible for the T cell's activation. Helper T cells have a weaker association with the MHC:antigen complex than observed for killer T cells, meaning many receptors (around 200–300) on the helper T cell must be bound by an MHC:antigen in order to activate the helper cell, while killer T cells can be activated by engagement of a single MHC:antigen molecule. Helper T cell activation also requires longer duration of engagement with an antigen-presenting cell. The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types. Cytokine signals produced by helper T cells enhance the microbicidal function of macrophages and the activity of killer T cells. In addition, helper T cell activation causes an upregulation of molecules expressed on the T cell's surface, such as CD40 ligand (also called CD154), which provide extra stimulatory signals typically required to activate antibody-producing B cells.
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Gamma delta T cells (γδ T cells) possess an alternative T cell receptor (TCR) as opposed to CD4+ and CD8+ (αβ) T cells and share the characteristics of helper T cells, cytotoxic T cells and NK cells. The conditions that produce responses from γδ T cells are not fully understood. Like other 'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-restricted Natural Killer T cells, γδ T cells straddle the border between innate and adaptive immunity. On one hand, γδ T cells are a component of adaptive immunity as they rearrange TCR genes to produce receptor diversity and can also develop a memory phenotype. On the other hand, the various subsets are also part of the innate immune system, as restricted TCR or NK receptors may be used as pattern recognition receptors. For example, large numbers of human Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted Vδ1+ T cells in epithelia respond to stressed epithelial cells.
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A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen. This antigen/antibody complex is taken up by the B cell and processed by proteolysis into peptides. The B cell then displays these antigenic peptides on its surface MHC class II molecules. This combination of MHC and antigen attracts a matching helper T cell, which releases lymphokines and activates the B cell. As the activated B cell then begins to divide, its offspring (plasma cells) secrete millions of copies of the antibody that recognizes this antigen. These antibodies circulate in blood plasma and lymph, bind to pathogens expressing the antigen and mark them for destruction by complement activation or for uptake and destruction by phagocytes. Antibodies can also neutralize challenges directly, by binding to bacterial toxins or by interfering with the receptors that viruses and bacteria use to infect cells.
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When B cells and T cells are activated and begin to replicate, some of their offspring become long-lived memory cells. Throughout the lifetime of an animal, these memory cells remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again. This is "adaptive" because it occurs during the lifetime of an individual as an adaptation to infection with that pathogen and prepares the immune system for future challenges. Immunological memory can be in the form of either passive short-term memory or active long-term memory.
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Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection. Several layers of passive protection are provided by the mother. During pregnancy, a particular type of antibody, called IgG, is transported from mother to baby directly across the placenta, so human babies have high levels of antibodies even at birth, with the same range of antigen specificities as their mother. Breast milk or colostrum also contains antibodies that are transferred to the gut of the infant and protect against bacterial infections until the newborn can synthesize its own antibodies. This is passive immunity because the fetus does not actually make any memory cells or antibodies—it only borrows them. This passive immunity is usually short-term, lasting from a few days up to several months. In medicine, protective passive immunity can also be transferred artificially from one individual to another via antibody-rich serum.
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Hormones can act as immunomodulators, altering the sensitivity of the immune system. For example, female sex hormones are known immunostimulators of both adaptive and innate immune responses. Some autoimmune diseases such as lupus erythematosus strike women preferentially, and their onset often coincides with puberty. By contrast, male sex hormones such as testosterone seem to be immunosuppressive. Other hormones appear to regulate the immune system as well, most notably prolactin, growth hormone and vitamin D.
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When suffering from sleep deprivation, active immunizations may have a diminished effect and may result in lower antibody production, and a lower immune response, than would be noted in a well-rested individual. Additionally, proteins such as NFIL3, which have been shown to be closely intertwined with both T-cell differentiation and our circadian rhythms, can be affected through the disturbance of natural light and dark cycles through instances of sleep deprivation, shift work, etc. As a result, these disruptions can lead to an increase in chronic conditions such as heart disease, chronic pain, and asthma.
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It is conjectured that a progressive decline in hormone levels with age is partially responsible for weakened immune responses in aging individuals. Conversely, some hormones are regulated by the immune system, notably thyroid hormone activity. The age-related decline in immune function is also related to decreasing vitamin D levels in the elderly. As people age, two things happen that negatively affect their vitamin D levels. First, they stay indoors more due to decreased activity levels. This means that they get less sun and therefore produce less cholecalciferol via UVB radiation. Second, as a person ages the skin becomes less adept at producing vitamin D.
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The main response of the immune system to tumors is to destroy the abnormal cells using killer T cells, sometimes with the assistance of helper T cells. Tumor antigens are presented on MHC class I molecules in a similar way to viral antigens. This allows killer T cells to recognize the tumor cell as abnormal. NK cells also kill tumorous cells in a similar way, especially if the tumor cells have fewer MHC class I molecules on their surface than normal; this is a common phenomenon with tumors. Sometimes antibodies are generated against tumor cells allowing for their destruction by the complement system.
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Unlike animals, plants lack phagocytic cells, but many plant immune responses involve systemic chemical signals that are sent through a plant. Individual plant cells respond to molecules associated with pathogens known as Pathogen-associated molecular patterns or PAMPs. When a part of a plant becomes infected, the plant produces a localized hypersensitive response, whereby cells at the site of infection undergo rapid apoptosis to prevent the spread of the disease to other parts of the plant. Systemic acquired resistance (SAR) is a type of defensive response used by plants that renders the entire plant resistant to a particular infectious agent. RNA silencing mechanisms are particularly important in this systemic response as they can block virus replication.
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Overactive immune responses comprise the other end of immune dysfunction, particularly the autoimmune disorders. Here, the immune system fails to properly distinguish between self and non-self, and attacks part of the body. Under normal circumstances, many T cells and antibodies react with "self" peptides. One of the functions of specialized cells (located in the thymus and bone marrow) is to present young lymphocytes with self antigens produced throughout the body and to eliminate those cells that recognize self-antigens, preventing autoimmunity.
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Immunodeficiencies occur when one or more of the components of the immune system are inactive. The ability of the immune system to respond to pathogens is diminished in both the young and the elderly, with immune responses beginning to decline at around 50 years of age due to immunosenescence. In developed countries, obesity, alcoholism, and drug use are common causes of poor immune function. However, malnutrition is the most common cause of immunodeficiency in developing countries. Diets lacking sufficient protein are associated with impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody concentrations, and cytokine production. Additionally, the loss of the thymus at an early age through genetic mutation or surgical removal results in severe immunodeficiency and a high susceptibility to infection.
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Long-term active memory is acquired following infection by activation of B and T cells. Active immunity can also be generated artificially, through vaccination. The principle behind vaccination (also called immunization) is to introduce an antigen from a pathogen in order to stimulate the immune system and develop specific immunity against that particular pathogen without causing disease associated with that organism. This deliberate induction of an immune response is successful because it exploits the natural specificity of the immune system, as well as its inducibility. With infectious disease remaining one of the leading causes of death in the human population, vaccination represents the most effective manipulation of the immune system mankind has developed.
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The success of any pathogen depends on its ability to elude host immune responses. Therefore, pathogens evolved several methods that allow them to successfully infect a host, while evading detection or destruction by the immune system. Bacteria often overcome physical barriers by secreting enzymes that digest the barrier, for example, by using a type II secretion system. Alternatively, using a type III secretion system, they may insert a hollow tube into the host cell, providing a direct route for proteins to move from the pathogen to the host. These proteins are often used to shut down host defenses.
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In the mid-1950s, Frank Burnet, inspired by a suggestion made by Niels Jerne, formulated the clonal selection theory (CST) of immunity. On the basis of CST, Burnet developed a theory of how an immune response is triggered according to the self/nonself distinction: "self" constituents (constituents of the body) do not trigger destructive immune responses, while "nonself" entities (pathogens, an allograft) trigger a destructive immune response. The theory was later modified to reflect new discoveries regarding histocompatibility or the complex "two-signal" activation of T cells. The self/nonself theory of immunity and the self/nonself vocabulary have been criticized, but remain very influential.
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Anti-inflammatory drugs are often used to control the effects of inflammation. Glucocorticoids are the most powerful of these drugs; however, these drugs can have many undesirable side effects, such as central obesity, hyperglycemia, osteoporosis, and their use must be tightly controlled. Lower doses of anti-inflammatory drugs are often used in conjunction with cytotoxic or immunosuppressive drugs such as methotrexate or azathioprine. Cytotoxic drugs inhibit the immune response by killing dividing cells such as activated T cells. However, the killing is indiscriminate and other constantly dividing cells and their organs are affected, which causes toxic side effects. Immunosuppressive drugs such as cyclosporin prevent T cells from responding to signals correctly by inhibiting signal transduction pathways.
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In contrast, during wake periods differentiated effector cells, such as cytotoxic natural killer cells and CTLs (cytotoxic T lymphocytes), peak in order to elicit an effective response against any intruding pathogens. As well during awake active times, anti-inflammatory molecules, such as cortisol and catecholamines, peak. There are two theories as to why the pro-inflammatory state is reserved for sleep time. First, inflammation would cause serious cognitive and physical impairments if it were to occur during wake times. Second, inflammation may occur during sleep times due to the presence of melatonin. Inflammation causes a great deal of oxidative stress and the presence of melatonin during sleep times could actively counteract free radical production during this time.
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When a T-cell encounters a foreign pathogen, it extends a vitamin D receptor. This is essentially a signaling device that allows the T-cell to bind to the active form of vitamin D, the steroid hormone calcitriol. T-cells have a symbiotic relationship with vitamin D. Not only does the T-cell extend a vitamin D receptor, in essence asking to bind to the steroid hormone version of vitamin D, calcitriol, but the T-cell expresses the gene CYP27B1, which is the gene responsible for converting the pre-hormone version of vitamin D, calcidiol into the steroid hormone version, calcitriol. Only after binding to calcitriol can T-cells perform their intended function. Other immune system cells that are known to express CYP27B1 and thus activate vitamin D calcidiol, are dendritic cells, keratinocytes and macrophages.
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Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with pathogens. Antimicrobial peptides called defensins are an evolutionarily conserved component of the innate immune response found in all animals and plants, and represent the main form of invertebrate systemic immunity. The complement system and phagocytic cells are also used by most forms of invertebrate life. Ribonucleases and the RNA interference pathway are conserved across all eukaryotes, and are thought to play a role in the immune response to viruses.
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Evolution of the adaptive immune system occurred in an ancestor of the jawed vertebrates. Many of the classical molecules of the adaptive immune system (e.g., immunoglobulins and T cell receptors) exist only in jawed vertebrates. However, a distinct lymphocyte-derived molecule has been discovered in primitive jawless vertebrates, such as the lamprey and hagfish. These animals possess a large array of molecules called Variable lymphocyte receptors (VLRs) that, like the antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of genes. These molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with the same degree of specificity.
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It is likely that a multicomponent, adaptive immune system arose with the first vertebrates, as invertebrates do not generate lymphocytes or an antibody-based humoral response. Many species, however, utilize mechanisms that appear to be precursors of these aspects of vertebrate immunity. Immune systems appear even in the structurally most simple forms of life, with bacteria using a unique defense mechanism, called the restriction modification system to protect themselves from viral pathogens, called bacteriophages. Prokaryotes also possess acquired immunity, through a system that uses CRISPR sequences to retain fragments of the genomes of phage that they have come into contact with in the past, which allows them to block virus replication through a form of RNA interference. Offensive elements of the immune systems are also present in unicellular eukaryotes, but studies of their roles in defense are few.
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Immunology is strongly experimental in everyday practice but is also characterized by an ongoing theoretical attitude. Many theories have been suggested in immunology from the end of the nineteenth century up to the present time. The end of the 19th century and the beginning of the 20th century saw a battle between "cellular" and "humoral" theories of immunity. According to the cellular theory of immunity, represented in particular by Elie Metchnikoff, it was cells – more precisely, phagocytes – that were responsible for immune responses. In contrast, the humoral theory of immunity, held, among others, by Robert Koch and Emil von Behring, stated that the active immune agents were soluble components (molecules) found in the organism’s “humors” rather than its cells.
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Clearly, some tumors evade the immune system and go on to become cancers. Tumor cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells. Some tumor cells also release products that inhibit the immune response; for example by secreting the cytokine TGF-β, which suppresses the activity of macrophages and lymphocytes. In addition, immunological tolerance may develop against tumor antigens, so the immune system no longer attacks the tumor cells.
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Hypersensitivity is an immune response that damages the body's own tissues. They are divided into four classes (Type I – IV) based on the mechanisms involved and the time course of the hypersensitive reaction. Type I hypersensitivity is an immediate or anaphylactic reaction, often associated with allergy. Symptoms can range from mild discomfort to death. Type I hypersensitivity is mediated by IgE, which triggers degranulation of mast cells and basophils when cross-linked by antigen. Type II hypersensitivity occurs when antibodies bind to antigens on the patient's own cells, marking them for destruction. This is also called antibody-dependent (or cytotoxic) hypersensitivity, and is mediated by IgG and IgM antibodies. Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM antibodies) deposited in various tissues trigger Type III hypersensitivity reactions. Type IV hypersensitivity (also known as cell-mediated or delayed type hypersensitivity) usually takes between two and three days to develop. Type IV reactions are involved in many autoimmune and infectious diseases, but may also involve contact dermatitis (poison ivy). These reactions are mediated by T cells, monocytes, and macrophages.
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An evasion strategy used by several pathogens to avoid the innate immune system is to hide within the cells of their host (also called intracellular pathogenesis). Here, a pathogen spends most of its life-cycle inside host cells, where it is shielded from direct contact with immune cells, antibodies and complement. Some examples of intracellular pathogens include viruses, the food poisoning bacterium Salmonella and the eukaryotic parasites that cause malaria (Plasmodium falciparum) and leishmaniasis (Leishmania spp.). Other bacteria, such as Mycobacterium tuberculosis, live inside a protective capsule that prevents lysis by complement. Many pathogens secrete compounds that diminish or misdirect the host's immune response. Some bacteria form biofilms to protect themselves from the cells and proteins of the immune system. Such biofilms are present in many successful infections, e.g., the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis. Other bacteria generate surface proteins that bind to antibodies, rendering them ineffective; examples include Streptococcus (protein G), Staphylococcus aureus (protein A), and Peptostreptococcus magnus (protein L).
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The mechanisms used to evade the adaptive immune system are more complicated. The simplest approach is to rapidly change non-essential epitopes (amino acids and/or sugars) on the surface of the pathogen, while keeping essential epitopes concealed. This is called antigenic variation. An example is HIV, which mutates rapidly, so the proteins on its viral envelope that are essential for entry into its host target cell are constantly changing. These frequent changes in antigens may explain the failures of vaccines directed at this virus. The parasite Trypanosoma brucei uses a similar strategy, constantly switching one type of surface protein for another, allowing it to stay one step ahead of the antibody response. Masking antigens with host molecules is another common strategy for avoiding detection by the immune system. In HIV, the envelope that covers the virion is formed from the outermost membrane of the host cell; such "self-cloaked" viruses make it difficult for the immune system to identify them as "non-self" structures.
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Another important role of the immune system is to identify and eliminate tumors. This is called immune surveillance. The transformed cells of tumors express antigens that are not found on normal cells. To the immune system, these antigens appear foreign, and their presence causes immune cells to attack the transformed tumor cells. The antigens expressed by tumors have several sources; some are derived from oncogenic viruses like human papillomavirus, which causes cervical cancer, while others are the organism's own proteins that occur at low levels in normal cells but reach high levels in tumor cells. One example is an enzyme called tyrosinase that, when expressed at high levels, transforms certain skin cells (e.g. melanocytes) into tumors called melanomas. A third possible source of tumor antigens are proteins normally important for regulating cell growth and survival, that commonly mutate into cancer inducing molecules called oncogenes.
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Larger drugs (>500 Da) can provoke a neutralizing immune response, particularly if the drugs are administered repeatedly, or in larger doses. This limits the effectiveness of drugs based on larger peptides and proteins (which are typically larger than 6000 Da). In some cases, the drug itself is not immunogenic, but may be co-administered with an immunogenic compound, as is sometimes the case for Taxol. Computational methods have been developed to predict the immunogenicity of peptides and proteins, which are particularly useful in designing therapeutic antibodies, assessing likely virulence of mutations in viral coat particles, and validation of proposed peptide-based drug treatments. Early techniques relied mainly on the observation that hydrophilic amino acids are overrepresented in epitope regions than hydrophobic amino acids; however, more recent developments rely on machine learning techniques using databases of existing known epitopes, usually on well-studied virus proteins, as a training set. A publicly accessible database has been established for the cataloguing of epitopes from pathogens known to be recognizable by B cells. The emerging field of bioinformatics-based studies of immunogenicity is referred to as immunoinformatics. Immunoproteomics is the study of large sets of proteins (proteomics) involved in the immune response.
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In addition to the negative consequences of sleep deprivation, sleep and the intertwined circadian system have been shown to have strong regulatory effects on immunological functions affecting both the innate and the adaptive immunity. First, during the early slow-wave-sleep stage, a sudden drop in blood levels of cortisol, epinephrine, and norepinephrine induce increased blood levels of the hormones leptin, pituitary growth hormone, and prolactin. These signals induce a pro-inflammatory state through the production of the pro-inflammatory cytokines interleukin-1, interleukin-12, TNF-alpha and IFN-gamma. These cytokines then stimulate immune functions such as immune cells activation, proliferation, and differentiation. It is during this time that undifferentiated, or less differentiated, like naïve and central memory T cells, peak (i.e. during a time of a slowly evolving adaptive immune response). In addition to these effects, the milieu of hormones produced at this time (leptin, pituitary growth hormone, and prolactin) support the interactions between APCs and T-cells, a shift of the Th1/Th2 cytokine balance towards one that supports Th1, an increase in overall Th cell proliferation, and naïve T cell migration to lymph nodes. This milieu is also thought to support the formation of long-lasting immune memory through the initiation of Th1 immune responses.
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Pathogens can rapidly evolve and adapt, and thereby avoid detection and neutralization by the immune system; however, multiple defense mechanisms have also evolved to recognize and neutralize pathogens. Even simple unicellular organisms such as bacteria possess a rudimentary immune system, in the form of enzymes that protect against bacteriophage infections. Other basic immune mechanisms evolved in ancient eukaryotes and remain in their modern descendants, such as plants and invertebrates. These mechanisms include phagocytosis, antimicrobial peptides called defensins, and the complement system. Jawed vertebrates, including humans, have even more sophisticated defense mechanisms, including the ability to adapt over time to recognize specific pathogens more efficiently. Adaptive (or acquired) immunity creates immunological memory after an initial response to a specific pathogen, leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination.
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In humans, this response is activated by complement binding to antibodies that have attached to these microbes or the binding of complement proteins to carbohydrates on the surfaces of microbes. This recognition signal triggers a rapid killing response. The speed of the response is a result of signal amplification that occurs following sequential proteolytic activation of complement molecules, which are also proteases. After complement proteins initially bind to the microbe, they activate their protease activity, which in turn activates other complement proteases, and so on. This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback. The cascade results in the production of peptides that attract immune cells, increase vascular permeability, and opsonize (coat) the surface of a pathogen, marking it for destruction. This deposition of complement can also kill cells directly by disrupting their plasma membrane.
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The Intergovernmental Panel on Climate Change (IPCC) is a scientific intergovernmental body under the auspices of the United Nations, set up at the request of member governments. It was first established in 1988 by two United Nations organizations, the World Meteorological Organization (WMO) and the United Nations Environment Programme (UNEP), and later endorsed by the United Nations General Assembly through Resolution 43/53. Membership of the IPCC is open to all members of the WMO and UNEP. The IPCC produces reports that support the United Nations Framework Convention on Climate Change (UNFCCC), which is the main international treaty on climate change. The ultimate objective of the UNFCCC is to "stabilize greenhouse gas concentrations in the atmosphere at a level that would prevent dangerous anthropogenic [i.e., human-induced] interference with the climate system". IPCC reports cover "the scientific, technical and socio-economic information relevant to understanding the scientific basis of risk of human-induced climate change, its potential impacts and options for adaptation and mitigation."
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Korean economist Hoesung Lee is the chair of the IPCC since October 8, 2015, following the election of the new IPCC Bureau. Before this election, the IPCC was led by his vice-Chair Ismail El Gizouli, who was designated acting Chair after the resignation of Rajendra K. Pachauri in February 2015. The previous chairs were Rajendra K. Pachauri, elected in May 2002; Robert Watson in 1997; and Bert Bolin in 1988. The chair is assisted by an elected bureau including vice-chairs, working group co-chairs, and a secretariat.
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The IPCC Panel is composed of representatives appointed by governments and organizations. Participation of delegates with appropriate expertise is encouraged. Plenary sessions of the IPCC and IPCC Working groups are held at the level of government representatives. Non Governmental and Intergovernmental Organizations may be allowed to attend as observers. Sessions of the IPCC Bureau, workshops, expert and lead authors meetings are by invitation only. Attendance at the 2003 meeting included 350 government officials and climate change experts. After the opening ceremonies, closed plenary sessions were held. The meeting report states there were 322 persons in attendance at Sessions with about seven-eighths of participants being from governmental organizations.
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The IPCC receives funding through the IPCC Trust Fund, established in 1989 by the United Nations Environment Programme (UNEP) and the World Meteorological Organization (WMO), Costs of the Secretary and of housing the secretariat are provided by the WMO, while UNEP meets the cost of the Depute Secretary. Annual cash contributions to the Trust Fund are made by the WMO, by UNEP, and by IPCC Members; the scale of payments is determined by the IPCC Panel, which is also responsible for considering and adopting by consensus the annual budget. The organisation is required to comply with the Financial Regulations and Rules of the WMO.
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The IPCC does not carry out research nor does it monitor climate related data. Lead authors of IPCC reports assess the available information about climate change based on published sources. According to IPCC guidelines, authors should give priority to peer-reviewed sources. Authors may refer to non-peer-reviewed sources (the "grey literature"), provided that they are of sufficient quality. Examples of non-peer-reviewed sources include model results, reports from government agencies and non-governmental organizations, and industry journals. Each subsequent IPCC report notes areas where the science has improved since the previous report and also notes areas where further research is required.
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Each chapter has a number of authors who are responsible for writing and editing the material. A chapter typically has two "coordinating lead authors", ten to fifteen "lead authors", and a somewhat larger number of "contributing authors". The coordinating lead authors are responsible for assembling the contributions of the other authors, ensuring that they meet stylistic and formatting requirements, and reporting to the Working Group chairs. Lead authors are responsible for writing sections of chapters. Contributing authors prepare text, graphs or data for inclusion by the lead authors.
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The executive summary of the WG I Summary for Policymakers report says they are certain that emissions resulting from human activities are substantially increasing the atmospheric concentrations of the greenhouse gases, resulting on average in an additional warming of the Earth's surface. They calculate with confidence that CO2 has been responsible for over half the enhanced greenhouse effect. They predict that under a "business as usual" (BAU) scenario, global mean temperature will increase by about 0.3 °C per decade during the [21st] century. They judge that global mean surface air temperature has increased by 0.3 to 0.6 °C over the last 100 years, broadly consistent with prediction of climate models, but also of the same magnitude as natural climate variability. The unequivocal detection of the enhanced greenhouse effect is not likely for a decade or more.
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In 2001, 16 national science academies issued a joint statement on climate change. The joint statement was made by the Australian Academy of Science, the Royal Flemish Academy of Belgium for Science and the Arts, the Brazilian Academy of Sciences, the Royal Society of Canada, the Caribbean Academy of Sciences, the Chinese Academy of Sciences, the French Academy of Sciences, the German Academy of Natural Scientists Leopoldina, the Indian National Science Academy, the Indonesian Academy of Sciences, the Royal Irish Academy, Accademia Nazionale dei Lincei (Italy), the Academy of Sciences Malaysia, the Academy Council of the Royal Society of New Zealand, the Royal Swedish Academy of Sciences, and the Royal Society (UK). The statement, also published as an editorial in the journal Science, stated "we support the [TAR's] conclusion that it is at least 90% certain that temperatures will continue to rise, with average global surface temperature projected to increase by between 1.4 and 5.8 °C above 1990 levels by 2100". The TAR has also been endorsed by the Canadian Foundation for Climate and Atmospheric Sciences, Canadian Meteorological and Oceanographic Society, and European Geosciences Union (refer to "Endorsements of the IPCC").
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IPCC author Richard Lindzen has made a number of criticisms of the TAR. Among his criticisms, Lindzen has stated that the WGI Summary for Policymakers (SPM) does not faithfully summarize the full WGI report. For example, Lindzen states that the SPM understates the uncertainty associated with climate models. John Houghton, who was a co-chair of TAR WGI, has responded to Lindzen's criticisms of the SPM. Houghton has stressed that the SPM is agreed upon by delegates from many of the world's governments, and that any changes to the SPM must be supported by scientific evidence.
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In addition to climate assessment reports, the IPCC is publishing Special Reports on specific topics. The preparation and approval process for all IPCC Special Reports follows the same procedures as for IPCC Assessment Reports. In the year 2011 two IPCC Special Report were finalized, the Special Report on Renewable Energy Sources and Climate Change Mitigation (SRREN) and the Special Report on Managing Risks of Extreme Events and Disasters to Advance Climate Change Adaptation (SREX). Both Special Reports were requested by governments.
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The IPCC concentrates its activities on the tasks allotted to it by the relevant WMO Executive Council and UNEP Governing Council resolutions and decisions as well as on actions in support of the UNFCCC process. While the preparation of the assessment reports is a major IPCC function, it also supports other activities, such as the Data Distribution Centre and the National Greenhouse Gas Inventories Programme, required under the UNFCCC. This involves publishing default emission factors, which are factors used to derive emissions estimates based on the levels of fuel consumption, industrial production and so on.
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This projection was not included in the final summary for policymakers. The IPCC has since acknowledged that the date is incorrect, while reaffirming that the conclusion in the final summary was robust. They expressed regret for "the poor application of well-established IPCC procedures in this instance". The date of 2035 has been correctly quoted by the IPCC from the WWF report, which has misquoted its own source, an ICSI report "Variations of Snow and Ice in the past and at present on a Global and Regional Scale".
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Former IPCC chairman Robert Watson has said "The mistakes all appear to have gone in the direction of making it seem like climate change is more serious by overstating the impact. That is worrying. The IPCC needs to look at this trend in the errors and ask why it happened". Martin Parry, a climate expert who had been co-chair of the IPCC working group II, said that "What began with a single unfortunate error over Himalayan glaciers has become a clamour without substance" and the IPCC had investigated the other alleged mistakes, which were "generally unfounded and also marginal to the assessment".
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The third assessment report (TAR) prominently featured a graph labeled "Millennial Northern Hemisphere temperature reconstruction" based on a 1999 paper by Michael E. Mann, Raymond S. Bradley and Malcolm K. Hughes (MBH99), which has been referred to as the "hockey stick graph". This graph extended the similar graph in Figure 3.20 from the IPCC Second Assessment Report of 1995, and differed from a schematic in the first assessment report that lacked temperature units, but appeared to depict larger global temperature variations over the past 1000 years, and higher temperatures during the Medieval Warm Period than the mid 20th century. The schematic was not an actual plot of data, and was based on a diagram of temperatures in central England, with temperatures increased on the basis of documentary evidence of Medieval vineyards in England. Even with this increase, the maximum it showed for the Medieval Warm Period did not reach temperatures recorded in central England in 2007. The MBH99 finding was supported by cited reconstructions by Jones et al. 1998, Pollack, Huang & Shen 1998, Crowley & Lowery 2000 and Briffa 2000, using differing data and methods. The Jones et al. and Briffa reconstructions were overlaid with the MBH99 reconstruction in Figure 2.21 of the IPCC report.
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These studies were widely presented as demonstrating that the current warming period is exceptional in comparison to temperatures between 1000 and 1900, and the MBH99 based graph featured in publicity. Even at the draft stage, this finding was disputed by contrarians: in May 2000 Fred Singer's Science and Environmental Policy Project held a press event on Capitol Hill, Washington, D.C., featuring comments on the graph Wibjörn Karlén and Singer argued against the graph at a United States Senate Committee on Commerce, Science and Transportation hearing on 18 July 2000. Contrarian John Lawrence Daly featured a modified version of the IPCC 1990 schematic, which he mis-identified as appearing in the IPCC 1995 report, and argued that "Overturning its own previous view in the 1995 report, the IPCC presented the 'Hockey Stick' as the new orthodoxy with hardly an apology or explanation for the abrupt U-turn since its 1995 report". Criticism of the MBH99 reconstruction in a review paper, which was quickly discredited in the Soon and Baliunas controversy, was picked up by the Bush administration, and a Senate speech by US Republican senator James Inhofe alleged that "manmade global warming is the greatest hoax ever perpetrated on the American people". The data and methodology used to produce the "hockey stick graph" was criticized in papers by Stephen McIntyre and Ross McKitrick, and in turn the criticisms in these papers were examined by other studies and comprehensively refuted by Wahl & Ammann 2007, which showed errors in the methods used by McIntyre and McKitrick.
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On 23 June 2005, Rep. Joe Barton, chairman of the House Committee on Energy and Commerce wrote joint letters with Ed Whitfield, Chairman of the Subcommittee on Oversight and Investigations demanding full records on climate research, as well as personal information about their finances and careers, from Mann, Bradley and Hughes. Sherwood Boehlert, chairman of the House Science Committee, said this was a "misguided and illegitimate investigation" apparently aimed at intimidating scientists, and at his request the U.S. National Academy of Sciences arranged for its National Research Council to set up a special investigation. The National Research Council's report agreed that there were some statistical failings, but these had little effect on the graph, which was generally correct. In a 2006 letter to Nature, Mann, Bradley, and Hughes pointed out that their original article had said that "more widespread high-resolution data are needed before more confident conclusions can be reached" and that the uncertainties were "the point of the article".
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The IPCC Fourth Assessment Report (AR4) published in 2007 featured a graph showing 12 proxy based temperature reconstructions, including the three highlighted in the 2001 Third Assessment Report (TAR); Mann, Bradley & Hughes 1999 as before, Jones et al. 1998 and Briffa 2000 had both been calibrated by newer studies. In addition, analysis of the Medieval Warm Period cited reconstructions by Crowley & Lowery 2000 (as cited in the TAR) and Osborn & Briffa 2006. Ten of these 14 reconstructions covered 1,000 years or longer. Most reconstructions shared some data series, particularly tree ring data, but newer reconstructions used additional data and covered a wider area, using a variety of statistical methods. The section discussed the divergence problem affecting certain tree ring data.
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On 1 February 2007, the eve of the publication of IPCC's major report on climate, a study was published suggesting that temperatures and sea levels have been rising at or above the maximum rates proposed during the last IPCC report in 2001. The study compared IPCC 2001 projections on temperature and sea level change with observations. Over the six years studied, the actual temperature rise was near the top end of the range given by IPCC's 2001 projection, and the actual sea level rise was above the top of the range of the IPCC projection.
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Another example of scientific research which suggests that previous estimates by the IPCC, far from overstating dangers and risks, have actually understated them is a study on projected rises in sea levels. When the researchers' analysis was "applied to the possible scenarios outlined by the Intergovernmental Panel on Climate Change (IPCC), the researchers found that in 2100 sea levels would be 0.5–1.4 m [50–140 cm] above 1990 levels. These values are much greater than the 9–88 cm as projected by the IPCC itself in its Third Assessment Report, published in 2001". This may have been due, in part, to the expanding human understanding of climate.
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Michael Oppenheimer, a long-time participant in the IPCC and coordinating lead author of the Fifth Assessment Report conceded in Science Magazine's State of the Planet 2008-2009 some limitations of the IPCC consensus approach and asks for concurring, smaller assessments of special problems instead of the large scale approach as in the previous IPCC assessment reports. It has become more important to provide a broader exploration of uncertainties. Others see as well mixed blessings of the drive for consensus within the IPCC process and ask to include dissenting or minority positions or to improve statements about uncertainties.
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The IPCC process on climate change and its efficiency and success has been compared with dealings with other environmental challenges (compare Ozone depletion and global warming). In case of the Ozone depletion global regulation based on the Montreal Protocol has been successful, in case of Climate Change, the Kyoto Protocol failed. The Ozone case was used to assess the efficiency of the IPCC process. The lockstep situation of the IPCC is having built a broad science consensus while states and governments still follow different, if not opposing goals. The underlying linear model of policy-making of more knowledge we have, the better the political response will be is being doubted.
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According to Sheldon Ungar's comparison with global warming, the actors in the ozone depletion case had a better understanding of scientific ignorance and uncertainties. The ozone case communicated to lay persons "with easy-to-understand bridging metaphors derived from the popular culture" and related to "immediate risks with everyday relevance", while the public opinion on climate change sees no imminent danger. The stepwise mitigation of the ozone layer challenge was based as well on successfully reducing regional burden sharing conflicts. In case of the IPCC conclusions and the failure of the Kyoto Protocol, varying regional cost-benefit analysis and burden-sharing conflicts with regard to the distribution of emission reductions remain an unsolved problem. In the UK, a report for a House of Lords committee asked to urge the IPCC to involve better assessments of costs and benefits of climate change but the Stern Review ordered by the UK government made a stronger argument in favor to combat human-made climate change.
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Since the IPCC does not carry out its own research, it operates on the basis of scientific papers and independently documented results from other scientific bodies, and its schedule for producing reports requires a deadline for submissions prior to the report's final release. In principle, this means that any significant new evidence or events that change our understanding of climate science between this deadline and publication of an IPCC report cannot be included. In an area of science where our scientific understanding is rapidly changing, this has been raised as a serious shortcoming in a body which is widely regarded as the ultimate authority on the science. However, there has generally been a steady evolution of key findings and levels of scientific confidence from one assessment report to the next.[citation needed]
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In February 2010, in response to controversies regarding claims in the Fourth Assessment Report, five climate scientists – all contributing or lead IPCC report authors – wrote in the journal Nature calling for changes to the IPCC. They suggested a range of new organizational options, from tightening the selection of lead authors and contributors, to dumping it in favor of a small permanent body, or even turning the whole climate science assessment process into a moderated "living" Wikipedia-IPCC. Other recommendations included that the panel employ a full-time staff and remove government oversight from its processes to avoid political interference.
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A prime number (or a prime) is a natural number greater than 1 that has no positive divisors other than 1 and itself. A natural number greater than 1 that is not a prime number is called a composite number. For example, 5 is prime because 1 and 5 are its only positive integer factors, whereas 6 is composite because it has the divisors 2 and 3 in addition to 1 and 6. The fundamental theorem of arithmetic establishes the central role of primes in number theory: any integer greater than 1 can be expressed as a product of primes that is unique up to ordering. The uniqueness in this theorem requires excluding 1 as a prime because one can include arbitrarily many instances of 1 in any factorization, e.g., 3, 1 · 3, 1 · 1 · 3, etc. are all valid factorizations of 3.
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The property of being prime (or not) is called primality. A simple but slow method of verifying the primality of a given number n is known as trial division. It consists of testing whether n is a multiple of any integer between 2 and . Algorithms much more efficient than trial division have been devised to test the primality of large numbers. These include the Miller–Rabin primality test, which is fast but has a small probability of error, and the AKS primality test, which always produces the correct answer in polynomial time but is too slow to be practical. Particularly fast methods are available for numbers of special forms, such as Mersenne numbers. As of January 2016[update], the largest known prime number has 22,338,618 decimal digits.
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There are infinitely many primes, as demonstrated by Euclid around 300 BC. There is no known simple formula that separates prime numbers from composite numbers. However, the distribution of primes, that is to say, the statistical behaviour of primes in the large, can be modelled. The first result in that direction is the prime number theorem, proven at the end of the 19th century, which says that the probability that a given, randomly chosen number n is prime is inversely proportional to its number of digits, or to the logarithm of n.
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Many questions regarding prime numbers remain open, such as Goldbach's conjecture (that every even integer greater than 2 can be expressed as the sum of two primes), and the twin prime conjecture (that there are infinitely many pairs of primes whose difference is 2). Such questions spurred the development of various branches of number theory, focusing on analytic or algebraic aspects of numbers. Primes are used in several routines in information technology, such as public-key cryptography, which makes use of properties such as the difficulty of factoring large numbers into their prime factors. Prime numbers give rise to various generalizations in other mathematical domains, mainly algebra, such as prime elements and prime ideals.
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Hence, 6 is not prime. The image at the right illustrates that 12 is not prime: 12 = 3 · 4. No even number greater than 2 is prime because by definition, any such number n has at least three distinct divisors, namely 1, 2, and n. This implies that n is not prime. Accordingly, the term odd prime refers to any prime number greater than 2. Similarly, when written in the usual decimal system, all prime numbers larger than 5 end in 1, 3, 7, or 9, since even numbers are multiples of 2 and numbers ending in 0 or 5 are multiples of 5.
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Most early Greeks did not even consider 1 to be a number, so they could not consider it to be a prime. By the Middle Ages and Renaissance many mathematicians included 1 as the first prime number. In the mid-18th century Christian Goldbach listed 1 as the first prime in his famous correspondence with Leonhard Euler -- who did not agree. In the 19th century many mathematicians still considered the number 1 to be a prime. For example, Derrick Norman Lehmer's list of primes up to 10,006,721, reprinted as late as 1956, started with 1 as its first prime. Henri Lebesgue is said to be the last professional mathematician to call 1 prime. By the early 20th century, mathematicians began to accept that 1 is not a prime number, but rather forms its own special category as a "unit".
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A large body of mathematical work would still be valid when calling 1 a prime, but Euclid's fundamental theorem of arithmetic (mentioned above) would not hold as stated. For example, the number 15 can be factored as 3 · 5 and 1 · 3 · 5; if 1 were admitted as a prime, these two presentations would be considered different factorizations of 15 into prime numbers, so the statement of that theorem would have to be modified. Similarly, the sieve of Eratosthenes would not work correctly if 1 were considered a prime: a modified version of the sieve that considers 1 as prime would eliminate all multiples of 1 (that is, all other numbers) and produce as output only the single number 1. Furthermore, the prime numbers have several properties that the number 1 lacks, such as the relationship of the number to its corresponding value of Euler's totient function or the sum of divisors function.
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There are hints in the surviving records of the ancient Egyptians that they had some knowledge of prime numbers: the Egyptian fraction expansions in the Rhind papyrus, for instance, have quite different forms for primes and for composites. However, the earliest surviving records of the explicit study of prime numbers come from the Ancient Greeks. Euclid's Elements (circa 300 BC) contain important theorems about primes, including the infinitude of primes and the fundamental theorem of arithmetic. Euclid also showed how to construct a perfect number from a Mersenne prime. The Sieve of Eratosthenes, attributed to Eratosthenes, is a simple method to compute primes, although the large primes found today with computers are not generated this way.
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After the Greeks, little happened with the study of prime numbers until the 17th century. In 1640 Pierre de Fermat stated (without proof) Fermat's little theorem (later proved by Leibniz and Euler). Fermat also conjectured that all numbers of the form 22n + 1 are prime (they are called Fermat numbers) and he verified this up to n = 4 (or 216 + 1). However, the very next Fermat number 232 + 1 is composite (one of its prime factors is 641), as Euler discovered later, and in fact no further Fermat numbers are known to be prime. The French monk Marin Mersenne looked at primes of the form 2p − 1, with p a prime. They are called Mersenne primes in his honor.
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The most basic method of checking the primality of a given integer n is called trial division. This routine consists of dividing n by each integer m that is greater than 1 and less than or equal to the square root of n. If the result of any of these divisions is an integer, then n is not a prime, otherwise it is a prime. Indeed, if is composite (with a and b ≠ 1) then one of the factors a or b is necessarily at most . For example, for , the trial divisions are by m = 2, 3, 4, 5, and 6. None of these numbers divides 37, so 37 is prime. This routine can be implemented more efficiently if a complete list of primes up to is known—then trial divisions need to be checked only for those m that are prime. For example, to check the primality of 37, only three divisions are necessary (m = 2, 3, and 5), given that 4 and 6 are composite.
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Modern primality tests for general numbers n can be divided into two main classes, probabilistic (or "Monte Carlo") and deterministic algorithms. Deterministic algorithms provide a way to tell for sure whether a given number is prime or not. For example, trial division is a deterministic algorithm because, if performed correctly, it will always identify a prime number as prime and a composite number as composite. Probabilistic algorithms are normally faster, but do not completely prove that a number is prime. These tests rely on testing a given number in a partly random way. For example, a given test might pass all the time if applied to a prime number, but pass only with probability p if applied to a composite number. If we repeat the test n times and pass every time, then the probability that our number is composite is 1/(1-p)n, which decreases exponentially with the number of tests, so we can be as sure as we like (though never perfectly sure) that the number is prime. On the other hand, if the test ever fails, then we know that the number is composite.
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A particularly simple example of a probabilistic test is the Fermat primality test, which relies on the fact (Fermat's little theorem) that np≡n (mod p) for any n if p is a prime number. If we have a number b that we want to test for primality, then we work out nb (mod b) for a random value of n as our test. A flaw with this test is that there are some composite numbers (the Carmichael numbers) that satisfy the Fermat identity even though they are not prime, so the test has no way of distinguishing between prime numbers and Carmichael numbers. Carmichael numbers are substantially rarer than prime numbers, though, so this test can be useful for practical purposes. More powerful extensions of the Fermat primality test, such as the Baillie-PSW, Miller-Rabin, and Solovay-Strassen tests, are guaranteed to fail at least some of the time when applied to a composite number.
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are prime. Prime numbers of this form are known as factorial primes. Other primes where either p + 1 or p − 1 is of a particular shape include the Sophie Germain primes (primes of the form 2p + 1 with p prime), primorial primes, Fermat primes and Mersenne primes, that is, prime numbers that are of the form 2p − 1, where p is an arbitrary prime. The Lucas–Lehmer test is particularly fast for numbers of this form. This is why the largest known prime has almost always been a Mersenne prime since the dawn of electronic computers.
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The following table gives the largest known primes of the mentioned types. Some of these primes have been found using distributed computing. In 2009, the Great Internet Mersenne Prime Search project was awarded a US$100,000 prize for first discovering a prime with at least 10 million digits. The Electronic Frontier Foundation also offers $150,000 and $250,000 for primes with at least 100 million digits and 1 billion digits, respectively. Some of the largest primes not known to have any particular form (that is, no simple formula such as that of Mersenne primes) have been found by taking a piece of semi-random binary data, converting it to a number n, multiplying it by 256k for some positive integer k, and searching for possible primes within the interval [256kn + 1, 256k(n + 1) − 1].[citation needed]
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are prime for any natural number n. Here represents the floor function, i.e., largest integer not greater than the number in question. The latter formula can be shown using Bertrand's postulate (proven first by Chebyshev), which states that there always exists at least one prime number p with n < p < 2n − 2, for any natural number n > 3. However, computing A or μ requires the knowledge of infinitely many primes to begin with. Another formula is based on Wilson's theorem and generates the number 2 many times and all other primes exactly once.
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can have infinitely many primes only when a and q are coprime, i.e., their greatest common divisor is one. If this necessary condition is satisfied, Dirichlet's theorem on arithmetic progressions asserts that the progression contains infinitely many primes. The picture below illustrates this with q = 9: the numbers are "wrapped around" as soon as a multiple of 9 is passed. Primes are highlighted in red. The rows (=progressions) starting with a = 3, 6, or 9 contain at most one prime number. In all other rows (a = 1, 2, 4, 5, 7, and 8) there are infinitely many prime numbers. What is more, the primes are distributed equally among those rows in the long run—the density of all primes congruent a modulo 9 is 1/6.
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The zeta function is closely related to prime numbers. For example, the aforementioned fact that there are infinitely many primes can also be seen using the zeta function: if there were only finitely many primes then ζ(1) would have a finite value. However, the harmonic series 1 + 1/2 + 1/3 + 1/4 + ... diverges (i.e., exceeds any given number), so there must be infinitely many primes. Another example of the richness of the zeta function and a glimpse of modern algebraic number theory is the following identity (Basel problem), due to Euler,
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The unproven Riemann hypothesis, dating from 1859, states that except for s = −2, −4, ..., all zeroes of the ζ-function have real part equal to 1/2. The connection to prime numbers is that it essentially says that the primes are as regularly distributed as possible.[clarification needed] From a physical viewpoint, it roughly states that the irregularity in the distribution of primes only comes from random noise. From a mathematical viewpoint, it roughly states that the asymptotic distribution of primes (about x/log x of numbers less than x are primes, the prime number theorem) also holds for much shorter intervals of length about the square root of x (for intervals near x). This hypothesis is generally believed to be correct. In particular, the simplest assumption is that primes should have no significant irregularities without good reason.
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In addition to the Riemann hypothesis, many more conjectures revolving about primes have been posed. Often having an elementary formulation, many of these conjectures have withstood a proof for decades: all four of Landau's problems from 1912 are still unsolved. One of them is Goldbach's conjecture, which asserts that every even integer n greater than 2 can be written as a sum of two primes. As of February 2011[update], this conjecture has been verified for all numbers up to n = 2 · 1017. Weaker statements than this have been proven, for example Vinogradov's theorem says that every sufficiently large odd integer can be written as a sum of three primes. Chen's theorem says that every sufficiently large even number can be expressed as the sum of a prime and a semiprime, the product of two primes. Also, any even integer can be written as the sum of six primes. The branch of number theory studying such questions is called additive number theory.
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A third type of conjectures concerns aspects of the distribution of primes. It is conjectured that there are infinitely many twin primes, pairs of primes with difference 2 (twin prime conjecture). Polignac's conjecture is a strengthening of that conjecture, it states that for every positive integer n, there are infinitely many pairs of consecutive primes that differ by 2n. It is conjectured there are infinitely many primes of the form n2 + 1. These conjectures are special cases of the broad Schinzel's hypothesis H. Brocard's conjecture says that there are always at least four primes between the squares of consecutive primes greater than 2. Legendre's conjecture states that there is a prime number between n2 and (n + 1)2 for every positive integer n. It is implied by the stronger Cramér's conjecture.
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For a long time, number theory in general, and the study of prime numbers in particular, was seen as the canonical example of pure mathematics, with no applications outside of the self-interest of studying the topic with the exception of use of prime numbered gear teeth to distribute wear evenly. In particular, number theorists such as British mathematician G. H. Hardy prided themselves on doing work that had absolutely no military significance. However, this vision was shattered in the 1970s, when it was publicly announced that prime numbers could be used as the basis for the creation of public key cryptography algorithms. Prime numbers are also used for hash tables and pseudorandom number generators.
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Giuga's conjecture says that this equation is also a sufficient condition for p to be prime. Another consequence of Fermat's little theorem is the following: if p is a prime number other than 2 and 5, 1/p is always a recurring decimal, whose period is p − 1 or a divisor of p − 1. The fraction 1/p expressed likewise in base q (rather than base 10) has similar effect, provided that p is not a prime factor of q. Wilson's theorem says that an integer p > 1 is prime if and only if the factorial (p − 1)! + 1 is divisible by p. Moreover, an integer n > 4 is composite if and only if (n − 1)! is divisible by n.
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Several public-key cryptography algorithms, such as RSA and the Diffie–Hellman key exchange, are based on large prime numbers (for example, 512-bit primes are frequently used for RSA and 1024-bit primes are typical for Diffie–Hellman.). RSA relies on the assumption that it is much easier (i.e., more efficient) to perform the multiplication of two (large) numbers x and y than to calculate x and y (assumed coprime) if only the product xy is known. The Diffie–Hellman key exchange relies on the fact that there are efficient algorithms for modular exponentiation, while the reverse operation the discrete logarithm is thought to be a hard problem.
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The evolutionary strategy used by cicadas of the genus Magicicada make use of prime numbers. These insects spend most of their lives as grubs underground. They only pupate and then emerge from their burrows after 7, 13 or 17 years, at which point they fly about, breed, and then die after a few weeks at most. The logic for this is believed to be that the prime number intervals between emergences make it very difficult for predators to evolve that could specialize as predators on Magicicadas. If Magicicadas appeared at a non-prime number intervals, say every 12 years, then predators appearing every 2, 3, 4, 6, or 12 years would be sure to meet them. Over a 200-year period, average predator populations during hypothetical outbreaks of 14- and 15-year cicadas would be up to 2% higher than during outbreaks of 13- and 17-year cicadas. Though small, this advantage appears to have been enough to drive natural selection in favour of a prime-numbered life-cycle for these insects.
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The concept of prime number is so important that it has been generalized in different ways in various branches of mathematics. Generally, "prime" indicates minimality or indecomposability, in an appropriate sense. For example, the prime field is the smallest subfield of a field F containing both 0 and 1. It is either Q or the finite field with p elements, whence the name. Often a second, additional meaning is intended by using the word prime, namely that any object can be, essentially uniquely, decomposed into its prime components. For example, in knot theory, a prime knot is a knot that is indecomposable in the sense that it cannot be written as the knot sum of two nontrivial knots. Any knot can be uniquely expressed as a connected sum of prime knots. Prime models and prime 3-manifolds are other examples of this type.
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Prime numbers give rise to two more general concepts that apply to elements of any commutative ring R, an algebraic structure where addition, subtraction and multiplication are defined: prime elements and irreducible elements. An element p of R is called prime element if it is neither zero nor a unit (i.e., does not have a multiplicative inverse) and satisfies the following requirement: given x and y in R such that p divides the product xy, then p divides x or y. An element is irreducible if it is not a unit and cannot be written as a product of two ring elements that are not units. In the ring Z of integers, the set of prime elements equals the set of irreducible elements, which is
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The fundamental theorem of arithmetic continues to hold in unique factorization domains. An example of such a domain is the Gaussian integers Z[i], that is, the set of complex numbers of the form a + bi where i denotes the imaginary unit and a and b are arbitrary integers. Its prime elements are known as Gaussian primes. Not every prime (in Z) is a Gaussian prime: in the bigger ring Z[i], 2 factors into the product of the two Gaussian primes (1 + i) and (1 − i). Rational primes (i.e. prime elements in Z) of the form 4k + 3 are Gaussian primes, whereas rational primes of the form 4k + 1 are not.
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In ring theory, the notion of number is generally replaced with that of ideal. Prime ideals, which generalize prime elements in the sense that the principal ideal generated by a prime element is a prime ideal, are an important tool and object of study in commutative algebra, algebraic number theory and algebraic geometry. The prime ideals of the ring of integers are the ideals (0), (2), (3), (5), (7), (11), … The fundamental theorem of arithmetic generalizes to the Lasker–Noether theorem, which expresses every ideal in a Noetherian commutative ring as an intersection of primary ideals, which are the appropriate generalizations of prime powers.
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Prime ideals are the points of algebro-geometric objects, via the notion of the spectrum of a ring. Arithmetic geometry also benefits from this notion, and many concepts exist in both geometry and number theory. For example, factorization or ramification of prime ideals when lifted to an extension field, a basic problem of algebraic number theory, bears some resemblance with ramification in geometry. Such ramification questions occur even in number-theoretic questions solely concerned with integers. For example, prime ideals in the ring of integers of quadratic number fields can be used in proving quadratic reciprocity, a statement that concerns the solvability of quadratic equations
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