title: Northrop YF-23

text: The two contractor teams submitted evaluation results with their proposals in December 1990, and on 23 April 1991, Secretary of the Air Force Donald Rice announced that the YF-22 was the winner. The Air Force selected the YF119 engine to power the F-22 production version. The Lockheed and Pratt & Whitney designs were rated higher on technical aspects, were considered lower risks, and were considered to have more effective program management. It has been speculated in the aviation press that the YF-22 was also seen as more adaptable to the Navy's NATF, but by 1992 the U.S. Navy had abandoned NATF.


title: Northrop YF-23

text: Following the competition, both YF-23s were transferred to NASA's Dryden Flight Research Center at Edwards AFB, California, without their engines. NASA planned to use one of the aircraft to study techniques for the calibration of predicted loads to measured flight results, but this did not take place.


title: Northrop YF-23

text: In 2004, Northrop Grumman proposed a YF-23-based bomber to meet a USAF need for an interim bomber, for which the FB-22 and B-1R were also competing. Northrop modified aircraft PAV-2 to serve as a display model for its proposed interim bomber. The possibility of a YF-23-based interim bomber ended with the 2006 Quadrennial Defense Review, which favored a long-range bomber with much greater range. The USAF has since moved on to the Next-Generation Bomber and Long Range Strike Bomber program.


title: Northrop YF-23

text: Japan launched a program to develop a domestic 5th/6th generation (F-3) fighter after the US Congress refused in 1998 to export the F-22. After a great deal of study and the building of static models, the Mitsubishi X-2 Shinshin testbed aircraft flew as a technology demonstrator from 2016. By July 2018, Japan had gleaned sufficient information and decided that it would need to bring on-board international partners to complete this project. One such company that responded was Northrop Grumman and there is speculation that it could offer a modernized version of the YF-23 to Japan.


title: Northrop YF-23

text: Both YF-23 airframes remained in storage until mid-1996, when the aircraft were transferred to museums.


title: Confederation of African Football

text: The Confederation of African Football, or CAF for short (, ), is the administrative and controlling body for association football, futsal and beach soccer in Africa. It was established on 8 February 1957 at the "Grand Hotel" in Khartoum, Sudan by the national football associations of Egypt, Ethiopia, South Africa and Sudan, following formal discussions between the aforementioned associations at the FIFA Congress held on 7 June 1956 at Avenida Hotel in Lisbon, Portugal.


title: Confederation of African Football

text: One of the six continental confederations of world football governing body, FIFA, CAF represents the national football associations of Africa, runs national team and club continental competitions and controls the prize money, regulations and broadcast rights to such competitions. CAF will be allocated 9 spots in the FIFA World Cup starting from 2026 and could have an opportunity of 10 spots with the addition of an intercontinental play-off tournament involving six teams to decide the last two FIFA World Cup places (46+2).


title: Confederation of African Football

text: The headquarters of CAF was situated in Khartoum for within the first months of formation until a fire outbreak in the offices of the Sudanese Football Association when the organization was moved near Cairo, Egypt. Youssef Mohamad was the first general secretary and Abdel Aziz Abdallah Salem, the first president. Since 2002, the administrative center is situated in 6th of October City in Cairo, Egypt. CAF currently has 54 member associations which are full members, while Zanzibar and Réunion are associate members (see the CAF Members and Zones section below). The current president is Patrice Motsepe from South Africa, who was elected on 12 March 2021 in an unopposed elections held in Rabat, Morocco.


title: Confederation of African Football

text: On 18 September 2017, CAF launched a competition for all African composers to create its anthem without lyrics to reflect the cultural patrimony and the music of Africa. The chosen anthem, whose composer are to this day unknown and is 74 seconds in length, was first published to the site on 16 January 2008 and it is the entry song for every official CAF competition match. It is also used for every official competition match of the sub-confederations of CAF including WAFU, COSAFA and CECAFA.


title: Confederation of African Football

text: For men's national teams, the main competition is the Africa Cup of Nations, which began in 1957. In 2009, the CAF began organizing another competition for men's national teams, the African Nations Championship, this time featuring players playing in their respective national leagues. CAF also runs national competitions at Under-20 and Under-17 levels, which also serve as qualification tournaments for the FIFA U-20 World Cup and the FIFA U-17 World Cup respectively.


title: Confederation of African Football

text: For women's national teams, CAF operates competitions serving as qualification tournaments for the related FIFA-organized tournaments which launched at the exact same year they began formation. As of 2022, the Women's Africa Cup of Nations, launched in 1991 for senior national teams, qualifies 4 teams to the FIFA Women's World Cup and crowns a champion. Both the African U-20 Women's World Cup qualification tournament, launched in 2002 and the African U-17 Cup of Nations for Women, launched in 2008, each crowns no champion but instead qualifies 2 teams to compete at the FIFA U-20 Women's World Cup and the FIFA U-17 Women's World Cup respectively.


title: Confederation of African Football

text: CAF also runs the two main club competitions in Africa: the CAF Champions League, first held in 1964 as the African Cup of Champions Clubs (or just African Cup) and rebranded in 1997 for the champions of African leagues and the runners-up league-finished teams of the top 12 ranked national associations; and the CAF Confederation Cup, launched in 2004 as a merger of the African Cup Winners' Cup, which begun in 1975, and a third competition, the CAF Cup, which started in 1992, for national cup winners and the 3rd-placed league-finished teams of the top 12 ranked national associations.


title: Confederation of African Football

text: The CAF Super Cup, which pits the winners of the CAF Champions League against the winners of the CAF Confederation Cup (previously the winners of the African Cup Winners' Cup), was launched in 1993.


title: Confederation of African Football

text: The Afro-Asian Club Championship was jointly organized with AFC between the winners of the CAF Champions League and the winners of the AFC Champions League. The last Afro-Asian Club Championship took place in 1998.


title: Confederation of African Football

text: The CAF Women's Champions League was founded on 12 September 2020, involving the champions of CAF's sub-confederation qualification tournaments for women's club teams.


title: Confederation of African Football

text: In October 2004, South African telecommunications giant, MTN, contracted a 4-year deal to sponsor CAF competitions worth US$12.5 million, which was the biggest sponsorship deal in African sporting history at that time.


title: Confederation of African Football

text: CAF opened new sponsorship callouts when MTN's contract expired and French telecommunications giant, Orange scooped it up in July 2009, signing an 8-year comprehensive long-term undisclosed deal to sponsor CAF competitions with a value of €100 million.


title: Confederation of African Football

text: On 21 July 2016, French energy and petroleum giant, Total S.A., replaced Orange as the main sponsor with an 8-year sponsorship package from CAF for a value of €950 million to support its competitions. Total rebranded as TotalEnergies in 2021, although its sponsorship with CAF continued under the new name.


title: Confederation of African Football

text: The following table lists all the countries whose clubs have won at least one CAF competition. Egyptian clubs are the most successful, with a total of 41 titles. Egyptian clubs hold a record number of wins in the African Cup of Champions Clubs/CAF Champions League (16), the now-defunct African Cup Winners' Cup (8), the CAF Super Cup (12) and the now-defunct Afro-Asian Club Championship (3), followed by Tunisian clubs with 24 titles and they have the most victories in the now-defunct CAF Cup (4). In third place overall, Moroccan clubs have secured 23 titles and they have the most victories in the CAF Confederation Cup (7).


title: Confederation of African Football

text: Rankings are calculated by the CAF based on points gathered by African teams throughout their participation in international club tournaments organized by either FIFA or CAF since the establishment of the first African Cup of Champions Clubs in 1964.


title: Confederation of African Football

text: For each tournament, the flag of the host country and the number of teams in each finals tournament (in brackets) are shown.


title: Confederation of African Football

text: The voting to select the best of the century refers to three categories: male player, goalkeeper and female player and is obtained from five different steps. The resulting best players and goalkeepers were honored during the "World Football Gala 1999".


title: Confederation of African Football

text: In 2007, CAF published the list of top 30 African players who played in the period from 1957 to 2007, as part of the celebration of the golden jubilee or 50th anniversary of the foundation of CAF, ordered according to an online poll.


title: Confederation of African Football

text: This table is for players with 30 or more goals for a CAF national team. Players in bold are still active at international level.


title: Fred MacMurray

text: Frederick Martin MacMurray (August 30, 1908 – November 5, 1991) was an American actor. He appeared in more than one hundred films and a successful television series, in a career that spanned nearly a half-century. His career as a major film leading man began in 1935, but his most renowned role was in Billy Wilder's film noir "Double Indemnity". During 1959–1973, MacMurray appeared in numerous Disney films, including "The Shaggy Dog", "The Absent-Minded Professor", "Follow Me, Boys!", and "The Happiest Millionaire". He played Steve Douglas in the television series "My Three Sons".


title: Fred MacMurray

text: Frederick Martin MacMurray was born on August 30, 1908, in Kankakee, Illinois, the son of Maleta ("née" Martin) and concert violinist Frederick Talmadge MacMurray, both natives of Wisconsin. His aunt, Fay Holderness, was a vaudeville performer and actress. When MacMurray was an infant, his family moved to Madison, Wisconsin, where his father taught music. They relocated within the state to Beaver Dam, his mother's birthplace. MacMurray attended school in Quincy, Illinois, before earning a full scholarship to Carroll College in Waukesha, Wisconsin. He played the saxophone in numerous local bands. He did not graduate from college.


title: Fred MacMurray

text: A featured vocalist, MacMurray recorded with the Gus Arnheim Orchestra on "All I Want Is Just One Girl" on the Victor label in 1930, and with George Olsen on "I'm In The Market For You" and "After a Million Dreams". Before signing with Paramount Pictures in 1934, he appeared on Broadway in "Three's a Crowd" (1930–31) and alongside Sydney Greenstreet and Bob Hope in "Roberta" (1933–34).


title: Fred MacMurray

text: In the 1930s, MacMurray worked with film directors Billy Wilder and Preston Sturges, and actors Barbara Stanwyck, Henry Fonda, Humphrey Bogart, Marlene Dietrich, and in seven films, Claudette Colbert, beginning with "The Gilded Lily". He co-starred with Katharine Hepburn in "Alice Adams", with Joan Crawford in "Above Suspicion", and with Carole Lombard in four productions: "Hands Across the Table", "The Princess Comes Across", "Swing High, Swing Low" and "True Confession". Usually cast in light comedies as a decent, thoughtful character ("The Trail of the Lonesome Pine"), and in melodramas and musicals, MacMurray became one of the film industry's highest-paid actors of the period. In 1943, his annual salary had reached $420,000, making him the highest-paid actor in Hollywood and the fourth-highest-paid person in the nation.


title: Fred MacMurray

text: Despite being typecast as a "nice guy", MacMurray often said his best roles were when he was cast against type, such as under the direction of Billy Wilder and Edward Dmytryk. Perhaps his best known "bad guy" performance was that of Walter Neff, an insurance salesman who plots with a greedy wife to kill her husband in the film noir classic "Double Indemnity". In another turn in the "not so nice" category, MacMurray played the cynical, duplicitous Lieutenant Thomas Keefer in Dmytryk's film "The Caine Mutiny." Six years later, MacMurray played Jeff Sheldrake, a two-timing corporate executive in Wilder's Oscar-winning film "The Apartment". In 1958, he guest-starred in the premiere episode of NBC's "Cimarron City" Western series, with George Montgomery and John Smith. MacMurray's career continued upward the following year, when he was cast as the father in the Disney film "The Shaggy Dog."


title: Fred MacMurray

text: From 1960 to 1972, he starred in "My Three Sons," a long-running, highly rated TV series. Concurrently with it, MacMurray starred in other films, playing Professor Ned Brainard in "The Absent-Minded Professor" and its sequel "Son of Flubber". Using his star-power clout, MacMurray had a provision in his "My Three Sons" contract that all of his scenes on that series were to be shot in two separate month-long production blocks and filmed first. That condensed performance schedule provided him more free time to pursue his work in films, maintain his ranch in Northern California, and enjoy his favorite leisure activity, golf. Over the years, MacMurray became one of the wealthiest actors in the entertainment industry, primarily from wise real estate investments and from his "notorious frugality". After his final film "The Swarm", MacMurray appeared in commercials for the 1979 Greyhound Lines bus company. Towards the end of the decade, he appeared in a series of commercials for the Korean "chisenbop" math calculation program.


title: Fred MacMurray

text: MacMurray was married twice. He married Lillian Lamont (legal name Lilian Wehmhoener MacMurray, born 1908) on June 20, 1936, and the couple adopted two children, Susan and Robert. After Lamont died of cancer on June 22, 1953, he married actress June Haver the following year. The couple subsequently adopted two more children—twins born in 1956—Katherine and Laurie. MacMurray and Haver's marriage lasted 37 years, until Fred's death.


title: Fred MacMurray

text: MacMurray was a businessman who became the fourth-highest-paid citizen in the United States. In 1941, he purchased land in the Russian River Valley in Northern California and established MacMurray Ranch. At the 1,750-acre ranch he raised prize-winning Aberdeen Angus cattle, cultivated prunes, apples, alfalfa and other crops, and enjoyed watercolor painting, fly fishing, and skeet shooting. MacMurray wanted the property's agricultural heritage preserved, so five years after his death, in 1996, it was sold to Gallo, which planted vineyards on it for wines that bear the MacMurray Ranch label. Kate MacMurray, daughter of Haver and MacMurray, now lives on the property (in a cabin built by her father), and is "actively engaged in Sonoma's thriving wine community, carrying on her family's legacy and the heritage of MacMurray Ranch". In 1944, he purchased the iconic Bryson Apartment Hotel in the Westlake, Los Angeles neighborhood and used it for about thirty years. Later in life, MacMurray insisted upon a percentage of gross of the films in which he starred.


title: Fred MacMurray

text: A lifelong heavy smoker, MacMurray had throat cancer in the late 1970s, and it recurred in 1987. He had a severe stroke in December 1988 that paralyzed his right side and affected his speech. With therapy he made a 90 percent recovery. After suffering from leukemia for more than a decade, MacMurray died of pneumonia on November 5, 1991, in Santa Monica, California.


title: Fred MacMurray

text: In 1939, artist C. C. Beck used MacMurray as the initial model for the superhero character who became Fawcett Comics' Captain Marvel. MacMurray was nominated for a Golden Globe Award for Best Actor – Motion Picture Musical or Comedy for "The Absent-Minded Professor". He was the first person honored as a Disney Legend in 1987.


title: Fred MacMurray

text: The Academy Film Archive houses the Fred MacMurray-June Haver Collection. The film materials are complemented by papers at the Academy's Margaret Herrick Library.


title: Thinking, Fast and Slow

text: The book's main thesis is that of a dichotomy between two modes of thought: "System 1" is fast, instinctive and emotional; "System 2" is slower, more deliberative, and more logical. The book delineates rational and non-rational motivations or triggers associated with each type of thinking process, and how they complement each other, starting with Kahneman's own research on loss aversion. From framing choices to people's tendency to replace a difficult question with one which is easy to answer, the book summarizes several decades of research to suggest that people have too much confidence in human judgement. Kahneman performed his own research, often in collaboration with Amos Tversky, which enriched his experience to write the book. It covers different phases of his career: his early work concerning cognitive biases, his work on prospect theory and happiness, and with the Israel Defense Forces.


title: Thinking, Fast and Slow

text: The integrity of many of the priming studies cited in the book have been called into question in the midst of the psychological replication crisis, although the results of Kahneman's own studies have been replicated.


title: Thinking, Fast and Slow

text: The book was a "New York Times" bestseller and was the 2012 winner of the National Academies Communication Award for best creative work that helps the public understanding of topics in behavioral science, engineering and medicine.


title: Thinking, Fast and Slow

text: Kahneman describes a number of experiments which purport to examine the differences between these two thought systems and how they arrive at different results even given the same inputs. Terms and concepts include coherence, attention, laziness, association, jumping to conclusions, WYSIATI (What you see is all there is), and how one forms judgments. The System 1 vs. System 2 debate includes the reasoning or lack thereof for human decision making, with big implications for many areas including law and market research.


title: Thinking, Fast and Slow

text: The second section offers explanations for why humans struggle to think statistically. It begins by documenting a variety of situations in which we either arrive at binary decisions or fail to associate precisely reasonable probabilities with outcomes. Kahneman explains this phenomenon using the theory of heuristics. Kahneman and Tversky originally discussed this topic in their 1974 article titled Judgment Under Uncertainty: Heuristics and Biases.


title: Thinking, Fast and Slow

text: Kahneman uses heuristics to assert that System 1 thinking involves associating new information with existing patterns, or thoughts, rather than creating new patterns for each new experience. For example, a child who has only seen shapes with straight edges might perceive an octagon when first viewing a circle. As a legal metaphor, a judge limited to heuristic thinking would only be able to think of similar historical cases when presented with a new dispute, rather than considering the unique aspects of that case. In addition to offering an explanation for the statistical problem, the theory also offers an explanation for human biases.


title: Thinking, Fast and Slow

text: The "anchoring effect" names a tendency to be influenced by irrelevant numbers. Shown greater/lesser numbers, experimental subjects gave greater/lesser responses. As an example, most people, when asked whether Gandhi was more than 114 years old when he died, will provide a much greater estimate of his age at death than others who were asked whether Gandhi was more or less than 35 years old. Experiments show that people's behavior is influenced, much more than they are aware, by irrelevant information.


title: Thinking, Fast and Slow

text: The availability heuristic is a mental shortcut that occurs when people make judgments about the probability of events on the basis of how easy it is to think of examples. The availability heuristic operates on the notion that, "if you can think of it, it must be important". The availability of consequences associated with an action is related positively to perceptions of the magnitude of the consequences of that action. In other words, the easier it is to recall the consequences of something, the greater we perceive these consequences to be. Sometimes, this heuristic is beneficial, but the frequencies at which events come to mind are usually not accurate representations of the probabilities of such events in real life.


title: Thinking, Fast and Slow

text: System 1 is prone to substituting a simpler question for a difficult one. In what Kahneman terms their "best-known and most controversial" experiment, "the Linda problem," subjects were told about an imaginary Linda, young, single, outspoken, and intelligent, who, as a student, was very concerned with discrimination and social justice. They asked whether it was more probable that Linda is a bank teller or that she is a bank teller and an active feminist. The overwhelming response was that "feminist bank teller" was more likely than "bank teller," violating the laws of probability. (All feminists bank tellers are bank tellers, so the former can't be more likely). In this case System 1 substituted the easier question, "Is Linda a feminist?", neglecting the occupation qualifier. An alternative interpretation is that the subjects added an unstated cultural implicature to the effect that the other answer implied an exclusive or, that Linda was not a feminist.


title: Thinking, Fast and Slow

text: Kahneman writes of a "pervasive optimistic bias", which "may well be the most significant of the cognitive biases." This bias generates the illusion of control: the illusion that we have substantial control of our lives.


title: Thinking, Fast and Slow

text: A natural experiment reveals the prevalence of one kind of unwarranted optimism. The planning fallacy is the tendency to overestimate benefits and underestimate costs, impelling people to begin risky projects. In 2002, American kitchen remodeling was expected on average to cost $18,658, but actually cost $38,769.


title: Thinking, Fast and Slow

text: To explain overconfidence, Kahneman introduces the concept he terms "What You See Is All There Is" (WYSIATI). This theory states that when the mind makes decisions, it deals primarily with "Known Knowns", phenomena it has observed already. It rarely considers "Known Unknowns", phenomena that it knows to be relevant but about which it does not have information. Finally it appears oblivious to the possibility of "Unknown Unknowns", unknown phenomena of unknown relevance.


title: Thinking, Fast and Slow

text: He explains that humans fail to take into account complexity and that their understanding of the world consists of a small and necessarily un-representative set of observations. Furthermore, the mind generally does not account for the role of chance and therefore falsely assumes that a future event will be similar to a past event.


title: Thinking, Fast and Slow

text: Framing is the context in which choices are presented. Experiment: subjects were asked whether they would opt for surgery if the "survival" rate is 90 percent, while others were told that the mortality rate is 10 percent. The first framing increased acceptance, even though the situation was no different.


title: Thinking, Fast and Slow

text: Rather than consider the odds that an incremental investment would produce a positive return, people tend to "throw good money after bad" and continue investing in projects with poor prospects that have already consumed significant resources. In part this is to avoid feelings of regret.


title: Thinking, Fast and Slow

text: This part (part III, sections 19–24) of the book is dedicated to the undue confidence in what the mind believes it knows. It suggests that people often overestimate how much they understand about the world and underestimate the role of chance in particular. This is related to the excessive certainty of hindsight, when an event seems to be understood after it has occurred or developed. Kahneman's opinions concerning overconfidence are influenced by Nassim Nicholas Taleb.


title: Thinking, Fast and Slow

text: In this section Kahneman returns to economics and expands his seminal work on Prospect Theory. He discusses the tendency for problems to be addressed in isolation and how, when other reference points are considered, the choice of that reference point (called a frame) has a disproportionate effect on the outcome. This section also offers advice on how some of the shortcomings of System 1 thinking can be avoided.


title: Thinking, Fast and Slow

text: Kahneman developed prospect theory, the basis for his Nobel prize, to account for experimental errors he noticed in Daniel Bernoulli's traditional utility theory. According to Kahneman, Utility Theory makes logical assumptions of economic rationality that do not represent people's actual choices, and does not take into account cognitive biases.


title: Thinking, Fast and Slow

text: One example is that people are loss-averse: they are more likely to act to avert a loss than to achieve a gain. Another example is that the value people place on a change in probability (e.g., of winning something) depends on the reference point: people seem to place greater value on a change from 0% to 10% (going from impossibility to possibility) than from, say, 45% to 55%, and they place the greatest value of all on a change from 90% to 100% (going from possibility to certainty). This occurs despite the fact that by traditional utility theory all three changes give the same increase in utility. Consistent with loss-aversion, the order of the first and third of those is reversed when the event is presented as losing rather than winning something: there, the greatest value is placed on eliminating the probability of a loss to 0.


title: Thinking, Fast and Slow

text: After the book's publication, the "Journal of Economic Literature" published a discussion of its parts concerning prospect theory, as well as an analysis of the four fundamental factors on which it is based.


title: Thinking, Fast and Slow

text: The fifth part of the book describes recent evidence which introduces a distinction between two selves, the 'experiencing self' and 'remembering self'. Kahneman proposed an alternative measure that assessed pleasure or pain sampled from moment to moment, and then summed over time. Kahneman termed this "experienced" well-being and attached it to a separate "self." He distinguished this from the "remembered" well-being that the polls had attempted to measure. He found that these two measures of happiness diverged.


title: Thinking, Fast and Slow

text: The author's significant discovery was that the remembering self does not care about the duration of a pleasant or unpleasant experience. Instead, it retrospectively rates an experience by the maximum or minimum of the experience, and by the way it ends. The remembering self dominated the patient's ultimate conclusion.


title: Thinking, Fast and Slow

text: Kahneman first began the study of well-being in the 1990s. At the time most happiness research relied on polls about life satisfaction. Having previously studied unreliable memories, the author was doubtful that life satisfaction was a good indicator of happiness. He designed a question that emphasized instead the well-being of the experiencing self. The author proposed that "Helen was happy in the month of March" if she spent most of her time engaged in activities that she would rather continue than stop, little time in situations that she wished to escape, and not too much time in a neutral state that wouldn't prefer continuing or stopping the activity either way.


title: Thinking, Fast and Slow

text: Kahneman suggests that emphasizing a life event such as a marriage or a new car can provide a distorted illusion of its true value. This "focusing illusion" revisits earlier ideas of substituting difficult questions and WYSIATI.


title: Thinking, Fast and Slow

text: As of 2012 the book had sold over one million copies. On the year of its publication, it was on the New York Times Bestseller List. The book was reviewed in media including the "Huffington Post", "The Guardian", "The New York Times", "The Financial Times", "The Independent", "Bloomberg" and "The New York Review of Books".


title: Thinking, Fast and Slow

text: The book was widely reviewed in specialist journals, including the "Journal of Economic Literature", "American Journal of Education", "The American Journal of Psychology", "Planning Theory", "The American Economist", "The Journal of Risk and Insurance", "The Michigan Law Review", "American Scientist", "Contemporary Sociology", "Science", "Contexts", "The Wilson Quarterly", "Technical Communication", "The University of Toronto Law Journal", "A Review of General Semantics" and "Scientific American Mind".


title: Thinking, Fast and Slow

text: The book has achieved a large following among baseball scouts and baseball executives. The ways of thinking described in the book are believed to help scouts, who have to make major judgements off little information and can easily fall into prescriptive yet inaccurate patterns of analysis.


title: Thinking, Fast and Slow

text: Part of the book has been swept up in the replication crisis facing psychology and the social sciences. It was discovered many prominent research findings were difficult or impossible for others to replicate, and thus the original findings were called into question. An analysis of the studies cited in chapter 4, "The Associative Machine", found that their replicability index (R-index) is 14, indicating essentially no reliability. Kahneman himself responded to the study in blog comments and acknowledged the chapter's shortcomings: "I placed too much faith in underpowered studies." Others have noted the irony in the fact that Kahneman made a mistake in judgment similar to the ones he studied.


title: Thinking, Fast and Slow

text: A later analysis made a bolder claim that, despite Kahneman's previous contributions to the field of decision making, most of the book's ideas are based on 'scientific literature with shaky foundations'. A general lack of replication in the empirical studies cited in the book was given as a justification.


title: Revenge (TV series)

text: Revenge is an American drama television series created by Mike Kelley and starring Madeleine Stowe and Emily VanCamp, which debuted on September 21, 2011, on ABC. The plot is inspired by Alexandre Dumas' 1844 novel "The Count of Monte Cristo". During its first season, it aired on Wednesdays at 10:00 pm (Eastern), and later aired on Sundays at 9:00 pm for seasons two through four.


title: Revenge (TV series)

text: The series was picked up for a full season by the ABC television network after garnering a 3.3 Nielsen rating in the 18–49 age advertising demographic for its pilot episode, and regularly winning its time slot against every other television network (CBS, Fox, The CW, and NBC) in the 18–34 demo. Madeleine Stowe was nominated for the 2012 Golden Globe Award for Outstanding Lead Actress in a TV Drama, while the series was nominated for Favorite New TV Drama at the 2012 People's Choice Awards. "Revenge" became ABC's highest-rated series in Wednesday’s 10 pm slot since "Lost"<nowiki>'</nowiki>s 2006–2007 season and was the only new series in more than four years to replicate the 18–49 demo ratings success that "Lost" had in its time slot since leaving the air.


title: Revenge (TV series)

text: The series ended after four seasons on ABC, with the final episode airing on May 10, 2015. The series finale was watched by 4.80 million viewers. On August 4, 2015, ABC announced the possibility of a spin-off series. On November 6, 2019, it was announced that a sequel series with the same title was in the works at ABC. However, the sequel series was not picked up by the network.


title: Revenge (TV series)

text: A young woman named Emily Thorne (Emily VanCamp) comes to the Hamptons and moves into a beach house next door to the mansion of a wealthy family, the Graysons. Emily is actually Amanda Clarke, whose father was framed by the Graysons for treason when she was a little girl, and the beach house is her childhood home. After a lengthy trial, he was imprisoned for life and was murdered in prison by associates of the people who framed him. Meanwhile, Amanda was separated from him and spent most of her time in a juvenile correctional facility, only to find out her father was killed six weeks before she was released on her 18th birthday. She now returns to the Hamptons as an adult to get revenge on those who wronged her father and her. Her primary target is Victoria Grayson (Madeleine Stowe), matriarch of the Grayson family, who loved and betrayed Amanda's father. The show focuses on Emily's plot to destroy every individual who played a role in her father's imprisonment. Along the way, she discovers various facts about her father's past which changes her plans many times. As the series progresses, Emily brings in other individuals as allies for her plan.


title: Revenge (TV series)

text: As Emily executes the stages of her elaborate plan, she finds remaining emotionally detached to be difficult. She struggles to identify her true motivations and examines how her actions change her sense of identity. As she enlists trusted friends into her schemes, she worries how their involvement will change their lives and how she will proceed after she exacts her revenge on those who wronged her father and her.


title: Revenge (TV series)

text: In January 2011, ABC ordered the script to pilot. In March 2011, actress Emily VanCamp was cast as the lead character, and shortly afterwards it was released that Ashley Madekwe was cast in the series. Madeleine Stowe and Henry Czerny joined the cast as well. Max Martini and Robbie Amell joined the cast respectively as Frank Stevens, a private investigator and Adam, a wealthy student, who is hoping to attend Yale. James Tupper replaced Marc Blucas in the role of Emily's father, after Blucas was forced to drop out due to his commitment on "Necessary Roughness". Recurring "Gossip Girl" star Connor Paolo was cast as a series regular playing the character of Declan Porter. Former "Nikita" star Ashton Holmes landed a recurring role as Tyler Barrol, a Harvard classmate of Daniel Grayson. On April 22, 2013, it was announced that Mike Kelley was stepping down as the executive producer and showrunner after season two, current executive producer Sunil Nayar was expected to take over during the anticipated third season. On May 3, 2013, it was confirmed that Sunil Nayar would take the reins after signing a two-year deal with ABC Studios to remain as executive producer. On May 21, 2013, it was announced that Gretchen J. Berg and Aaron Harberts had inked a two-year deal with ABC Studios which would have them serve as executive producers on the third season alongside Sunil Nayar.


title: Revenge (TV series)

text: On May 13, 2011, ABC picked the project up to series. On May 17, 2011, ABC announced that the series would air on Wednesday nights at 10:00 pm Eastern/9:00 pm Central, beginning in the 2011 fall season. The pilot was screened early on ABC's website during a promotional tie-in with Amazon Kindle.


title: Revenge (TV series)

text: It was announced in spring 2014 that a "Revenge" graphic novel was in the works, published by Marvel Comics. It was released on September 3, 2014, and explored the origins of Emily Thorne.


title: Revenge (TV series)

text: "Revenge" was filmed on Stage 25 at the Manhattan Beach Studios. Filming of the series ended on April 11, 2015.


title: Revenge (TV series)

text: On April 29, 2015, ABC announced that "Revenge" would be cancelled after four seasons, with its final episode broadcast on May 10. On August 4, 2015, a possible spin-off series was announced.


title: Revenge (TV series)

text: the series holds an approval rating of 69% on the review aggregation website Rotten Tomatoes. Metacritic, which uses a weighted average, assigned the series a score of 67 out of 100 based on 28 critics. Dorothy Rabinowitz of "The Wall Street Journal" praised the series, writing, "The arrival of one pure and unadulterated drama about a passion as old as man is something to celebrate. That's particularly true when that drama is as spellbinding in its satisfyingly gaudy way, as "Revenge" turns out to be", while awarding particular praise to Van Camp for a "beguiling and entirely chilling study in revenge lust". Writing for "The New York Times", Alessandra Stanley compared the series favorably with "Gossip Girl", concluding that it has "just enough campy suspense to be enjoyable". Episode 5 of the series received particular acclaim, with C. Orlando of "TV Fanatic" writing that ""Revenge" took things to a whole new level this week", and noting with reference to the set-up of David Clarke that "Victoria seems the only one with a conscience."


title: Revenge (TV series)

text: Yahoo! TV mentioned the series among the top television programs of 2011. The series also made the covers of "Parade", "Entertainment Weekly", and "TV Guide", and was featured in "Rolling Stone", "Vanity Fair", "Vogue", "People", "Us Weekly", "Cosmopolitan", "Seventeen", and "Teen Vogue" magazines.


title: Revenge (TV series)

text: On May 10, 2012, ABC announced that it had renewed "Revenge" for a second season. "The Hollywood Reporter" reported that it was one of the first series to get a "stamp of approval" from ABC Entertainment President Paul Lee, who called the show "sexy" and "sticky", telling critics in January, "You just want more of it."


title: Revenge (TV series)

text: The pilot episode scored 10.02 million viewers in live plus same day, winning the 10 pm hour time slot against "" and "". "Revenge" reportedly was the highest-rated television series in the hour for ABC since "Lost". On October 22, 2011, it was reported that "Revenge" regularly won its hour in the 18–34 and 18–49 age demographics ahead of "CSI" and "Law & Order: Special Victims Unit".


title: Revenge (TV series)

text: After a nearly two-month hiatus beginning on February 29, 2012, "Revenge" returned on April 18, 2012, at number one in the Nielsen ratings and won its time slot against every other television network with a first-place finish among Total Viewers, Adults 18–49 and Adults 25–54. "Revenge" won over an original episode of NBC's "Law & Order: Special Victims Unit" in Total Viewers (+33%), Adults 18–49 (+53%) and Adults 25–54 (+45%) and generated big year-to-year time-period gains in Total Viewers (+81%), Adults 18–49 (+35%) and Adults 25–54 (+38%), rising over first-run programming on the same night last year. The April 18, 2012, episode attracted ABC’s largest audience to the hour since the middle of February sweeps on February 15, 2012.


title: Revenge (TV series)

text: "Revenge" premiered strongly during its second season, with a 3.2 adults 18–49 rating. However, as the season went on, due to negative feedback on the storyline, as well as the scheduling of episodes against Golden Globe Awards, NFC Championship Game, and the Grammy Awards, "Revenge" hit lows of 2.0, 1.7, and 1.4 in the adults 18–49 rating, respectively, within three consecutive episodes. The ratings never recovered back to the levels of the fall 2012, and eventually ended the season with a 1.7 adults 18–49 rating.


title: Revenge (TV series)

text: "Revenge" was nominated for Favorite New TV Drama at the 2012 People's Choice Awards. Madeleine Stowe received a Golden Globe nomination for Best Actress in a TV drama.


title: Revenge (TV series)

text: The music for "Revenge" is composed by iZLER. In 2013, Intrada Records released an album, "Revenge (Original Television Soundtrack)", featuring selections from his work for the first two seasons. From season three's "Dissolution" onwards, iZLER is credited as Fil Eisler. Angus and Julia Stone's "For You" is also heavily featured throughout the series.


title: Revenge (TV series)

text: In Australia, it debuted on Seven Network on February 13, 2012, and the second season began airing on February 4, 2013, the third season returning on February 3, 2014, and the fourth season returning on February 23, 2015.


title: Revenge (TV series)

text: In the United Kingdom, the series premiered on E4 on May 28, 2012, with season two returning on January 7, 2013, season three returning on January 6, 2014, and season four returning on January 5, 2015.


title: Revenge (TV series)

text: In Thailand, the series premiered on Channel 7 on March 28, 2015, with season two returning on July 5, 2015, season three returning on June 29, 2016, and season four returning on August 26, 2016.


title: Revenge (TV series)

text: On November 6, 2019, it was announced that a sequel series with the same name was in the works at ABC. On June 29, 2020, ABC passed on the sequel series.


title: Phi

text: Phi (; uppercase Φ, lowercase φ or ϕ; "pheî" ; Modern Greek: "fi" ) is the 21st letter of the Greek alphabet.


title: Phi

text: In Archaic and Classical Greek (c. 9th century BC to 4th century BC), it represented an aspirated voiceless bilabial plosive (), which was the origin of its usual romanization as . During the later part of Classical Antiquity, in Koine Greek (c. 4th century BC to 4th century AD), its pronunciation shifted to that of a voiceless bilabial fricative (), and by the Byzantine Greek period (c. 4th century AD to 15th century AD) it developed its modern pronunciation as a voiceless labiodental fricative ().


title: Phi

text: It may be that phi originated as the letter qoppa (Ϙ, ϙ), and initially represented the sound before shifting to Classical Greek . In traditional Greek numerals, phi has a value of 500 () or 500,000 (). The Cyrillic letter Ef (Ф, ф) descends from phi.


title: Phi

text: As with other Greek letters, lowercase phi (encoded as the Unicode character ) is used as a mathematical or scientific symbol. Some uses, such as the golden ratio, require the old-fashioned 'closed' glyph, which is separately encoded as the Unicode character .


title: Phi

text: The diameter symbol in engineering, ⌀, is often erroneously referred to as "phi", and the diameter symbol is sometimes erroneously typeset as Φ. This symbol is used to indicate the diameter of a circular section; for example, "⌀14" means the diameter of the circle is 14 units.


title: Phi

text: In ordinary Greek text, the character U+03C6 φ is used exclusively, although this character has considerable glyphic variation, sometimes represented with a glyph more like the representative glyph shown for U+03C6 (φ, the "loopy" or "open" form), and less often with a glyph more like the representative glyph shown for U+03D5 (ϕ, the "stroked" or "closed" form).


title: Phi

text: Because Unicode represents a character in an abstract way, the choice between glyphs is purely a matter of font design. While some Greek typefaces, most notably those in the Porson family (used widely in editions of classical Greek texts), have a "stroked" glyph in this position (), most other typefaces have "loopy" glyphs. This also applies to the "Didot" (or ""apla"") typefaces employed in most Greek book printing (), as well as the "Neohellenic" typeface often used for ancient texts ().


title: Phi

text: It is necessary to have the stroked glyph available for some mathematical uses, and U+03D5 GREEK PHI SYMBOL is designed for this function. Prior to Unicode version 3.0 (1998), the glyph assignments in the Unicode code charts were the reverse, and thus older fonts may still show a loopy form formula_3 at U+03D5.


title: Phi

text: For use as a phonetic symbol in IPA, Unicode has a separate code point U+0278, LATIN SMALL LETTER PHI, because only the stroked glyph is considered correct in this use. It typically appears in a form adapted to a Latin typographic environment, with a more upright shape than normal Greek letters and with serifs at the top and bottom.


title: Phi

text: In HTML/XHTML, the upper- and lowercase phi character entity references are codice_1 (Φ) and codice_2 (φ), respectively.


title: Emma of Normandy

text: Emma of Normandy (referred to as Ælfgifu in royal documents; c. 984 – 6 March 1052) was a Norman-born noblewoman who became the English, Danish, and Norwegian queen through her marriages to the Anglo-Saxon king Æthelred the Unready and the Danish prince Cnut the Great. The daughter of the Norman ruler Richard the Fearless and Gunnor, she was Queen of the English during her marriage to King Æthelred from 1002 to 1016, except during a brief interruption in 1013–14 when the Danish king Sweyn Forkbeard occupied the English throne. Æthelred died in 1016, and Emma remarried to Sweyn's son Cnut. As Cnut's wife, she was Queen of England from their marriage in 1017, Queen of Denmark from 1018, and Queen of Norway from 1028 until Cnut died in 1035.


title: Emma of Normandy

text: After her husbands' deaths, Emma remained in the public eye and continued to participate actively in politics during the reigns of her sons by each husband, Edward the Confessor and Harthacnut. In 1035, when her second husband Cnut died and was succeeded by their son Harthacnut, who was in Denmark at the time, Emma was designated to act as his regent until his return, which she did in rivalry with Harold Harefoot. Emma is the central figure within the "Encomium Emmae Reginae", a critical source for the history of early-11th-century English politics. As Catherine Karkov notes, Emma is one of the most visually represented early medieval queens.


title: Emma of Normandy

text: In an attempt to pacify Normandy, King Æthelred of England married Emma in 1002. Similarly Richard II, Duke of Normandy hoped to improve relations with the English in wake of recent conflict and a failed kidnapping attempt against him by Æthelred. Viking raids on England were often based in Normandy in the late 10th century, and for Æthelred this marriage was intended to unite against the Viking threat. Upon their marriage, Emma was given the Anglo-Saxon name of Ælfgifu, which was used for formal and official matters, and became Queen of England. She received properties of her own in Winchester, Rutland, Devonshire, Suffolk and Oxfordshire, as well as the city of Exeter.


title: Emma of Normandy

text: Æthelred and Emma had two sons, Edward the Confessor and Alfred Ætheling, and a daughter, Goda of England (or Godgifu).


title: Emma of Normandy

text: When King Sweyn Forkbeard of Denmark invaded and conquered England in 1013, Emma and her children were sent to Normandy, where Æthelred joined soon after. They returned to England after Sweyn's death in 1014.


title: Emma of Normandy

text: Emma and Æthelred's marriage ended with Æthelred's death in London in 1016. Æthelred's oldest son from his first marriage, Æthelstan, had been heir apparent until his death in June 1014. Emma's sons had been ranked after all of the sons from Æthelred's first wife, the eldest surviving of whom was Edmund Ironside. Emma made an attempt to get her older son, Edward, recognised as heir. Although this movement was supported by Æthelred's chief advisor, Eadric Streona, it was opposed by Edmund Ironside, Æthelred's third-oldest son, and his allies, who eventually revolted against his father.


title: Emma of Normandy

text: In 1015, Cnut, the son of Sweyn Forkbeard, invaded England. He was held out of London until the deaths of Æthelred and Edmund in April and November 1016, respectively. Queen Emma attempted to maintain Anglo-Saxon control of London until her marriage to Cnut was arranged. Some scholars believe that the marriage saved her sons' lives, as Cnut tried to rid himself of rival claimants, but spared their lives.


title: Emma of Normandy

text: Cnut gained control of most of England after he defeated Edmund Ironside on 18 October 1016, at the Battle of Assandun, after which they agreed to divide the kingdom, Edmund taking Wessex and Cnut the rest of the country. Edmund died shortly afterwards on 30 November, and Cnut became the king of all England. At the time of their marriage in 1017, Emma's sons from her marriage to Æthelred were sent to live in Normandy under the tutelage of her brother. At this time Emma became Queen of England, and later of Denmark and Norway.


title: Emma of Normandy

text: The "Encomium Emmae Reginae" suggests in its second book that Emma and Cnut's marriage, though begun as a political strategy, became an affectionate marriage.


title: Emma of Normandy

text: In 1036, Alfred Aetheling and Edward the Confessor, Emma's sons by Æthelred, returned to England from their exile in Normandy in order to visit their mother. During their time in England they were supposed to be protected by Harthacnut. However, Harthacnut was involved with his kingdom in Denmark. Alfred was captured and blinded by holding a hot iron to his eyes. He later died from his wounds.


title: Emma of Normandy

text: Edward escaped the attack, and returned to Normandy. He returned after his place on the throne had been secured.


title: Emma of Normandy

text: "Encomium Emmae Reginae" places the blame of Alfred's capture, torture and murder completely on Harold Harefoot, thinking he intended to rid himself of two more potential claimants to the English throne by killing Edward and Alfred. Some scholars make the argument that it could have been Godwin, Earl of Wessex, who was traveling with Alfred and Edward as their protector in passage.


title: Emma of Normandy

text: Harthacnut, Emma and Cnut's son, assembled a fleet to invade England in 1039, and when Harold died in March 1040 he was invited to became king. He crossed to England with his fleet and Emma. He was criticised by the "Anglo-Saxon Chronicle" for his heavy taxation to pay for the fleet and for having Harold's body disinterred and thrown into a ditch. In 1041 he invited his half-brother Edward the Confessor to England. The "Enconium" says that Edward was sworn in as king, which probably means that he was recognised as heir as Harthacnut knew that he did not have long to live. He may have been persuaded to make the invitation by Emma, who would have been keen to preserve her position by ensuring that England was still ruled by a son of hers.


title: Emma of Normandy

text: After Harthacnut's death in June 1042, Edward the Confessor succeeded to the throne and was crowned in April 1043. During the same year, Edward rode to Winchester along with


title: Emma of Normandy

text: Earls Leofric, Godwin, and Siward, accused Emma of treason, and deprived her of her lands and titles. However, Edward soon relented, and Emma's lands and titles were restored.


title: Emma of Normandy

text: After her death in 1052, Emma was interred alongside Cnut and Harthacnut in the Old Minster, Winchester, before being transferred to the new cathedral built after the Norman Conquest. During the English Civil War (1642–1651), their remains were disinterred and scattered about the Cathedral floor by parliamentary forces.


title: Emma of Normandy

text: As Pauline Stafford noted, Emma is the "first of the early medieval queens" to be depicted through contemporary portraiture. To that end, Emma is the central figure within the "Encomium Emmae Reginae" (incorrectly titled "Gesta Cnutonis Regis" during the later Middle Ages) a critical source for the study of English succession in the 11th century. During the reign of Æthelred, Emma most likely served as little more than a figurehead a physical embodiment of the treaty between the English and her Norman father. However, her influence increased considerably under Cnut. Until 1043, writes Stafford, Emma "was the richest woman in England ... and held extensive lands in the East Midlands and Wessex." Emma's authority was not simply tied to landholdings—which fluctuated greatly from 1036 to 1043—she also wielded significant sway over the ecclesiastical offices of England.


title: Emma of Normandy

text: The "Encomium" is divided into three parts, the first of which deals with Sweyn Forkbeard and his conquest of England. The second focuses on Cnut and relates the defeat of "Princes" Æthelred (never named) and Edmund, Cnut's marriage to Emma (again, without mentioning she had been the wife of Æthelred), and Cnut's kingship. The third address the events after Cnut's death; Emma's involvement in the seizing of the royal treasury, and the treachery of Earl Godwin. It begins by addressing Emma, "May our Lord Jesus Christ preserve you, O Queen, who excel all those of your sex in the amiability of your way of life." Emma is "the most distinguished woman of her time for delightful beauty and wisdom."


title: Emma of Normandy

text: This flattery, writes Elizabeth M. Tyler, is "part of a deliberate attempt to intervene, on Emma's behalf, in the politics of the Anglo-Danish court," a connotation which an 11th-century audience would have understood. This proves to be a direct contrast to earlier evaluations of the text, such as the introduction to the 1998 reprint of Alistair Campbell's 1949 edition in which Simon Keynes remarks:


title: Emma of Normandy

text: Prior to May 2008 only one copy of the "Encomium" was believed to exist. However, a late-14th-century manuscript, the Courtenay Compendium, was discovered in the Devon Record Office, where it had languished since the 1960s. According to a report by the UK Arts Council, "The most significant item [within the text] for British history is the Encomium Emma Reginae ... It is highly probable that the present manuscript represents the most complete witness to the revised version of the Encomium". The manuscript was put up for auction in December 2008, and purchased for £600,000 (5.2 million Danish kroner) on behalf of the Royal Library, Denmark. Unlike the "Liber Vitae," the compendium does not contain any images of Emma.


title: Emma of Normandy

text: The New Minster "Liber Vitae, currently housed in the British Library, was completed in 1030, shortly before Cnut's death in 1035. The frontispiece depicts "King Cnut and Queen Emma presenting a cross to the altar of New Minster, Winchester." Stafford in her visual exegesis of the portrait states, "it is not clear whether we should read it as a representation of a powerful woman or a powerless one." In one portrait, each facet of Emma's role as sovereign is displayed; that of a dutiful wife and influential queen.


title: Emma of Normandy

text: It has been suggested that the poem "Semiramis", possibly written in 1017 by Warner of Rouen at the court of Emma's brother, Richard, Duke of Normandy, and dedicated to her brother, Archbishop Robert, is a contemporary satire ridiculing Emma's relation with Cnut.


title: Emma of Normandy

text: Emma is also depicted in a number of later medieval texts, such as the 13th-century "Life of Edward the Confessor" (Cambridge University Library MS. Ee.3.59) and a 14th-century roll "Genealogy of the English Kings, Genealogical Chronicle of the English Kings."


title: Emma of Normandy

text: Emma and her sons Edward and Alfred are characters in the anonymous Elizabethan play "Edmund Ironside", sometimes considered an early work by William Shakespeare.


title: Emma of Normandy

text: The Ordeal of Queen Emma by Fire at Winchester is a legend that seems to have originated in the 13th century. Queen Emma was accused of unchastity with Bishop Ælfwine of Winchester. In order to prove her innocence, she was obliged to undergo the ordeal of walking over nine red-hot ploughshares placed on the pavement of the nave of Winchester Cathedral. Two bishops conducted the barefoot queen to the line of red-hot ploughshares. She walked over the red-hot ploughshares, but, having sought the protection of St Swithun, whose shrine is at Winchester, felt neither the naked iron nor the fire. William Blake did an illustration of the event.


title: Immune system

text: The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.


title: Immune system

text: Nearly all organisms have some kind of immune system. Bacteria have a rudimentary immune system in the form of enzymes that protect against virus infections. Other basic immune mechanisms evolved in ancient plants and animals and remain in their modern descendants. 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 to recognize pathogens more efficiently. Adaptive (or acquired) immunity creates an immunological memory leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination.


title: Immune system

text: Dysfunction of the immune system can cause autoimmune diseases, inflammatory diseases and cancer. Immunodeficiency occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. In humans, immunodeficiency can be the result of a genetic disease such as severe combined immunodeficiency, acquired conditions such as HIV/AIDS, or the use of immunosuppressive medication. Autoimmunity results from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Common autoimmune diseases include Hashimoto's thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus erythematosus. Immunology covers the study of all aspects of the immune system.


title: Immune system

text: The immune system protects its host from infection with layered defenses of increasing specificity. 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 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.


title: Immune system

text: 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 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 (originally named for being "anti"body "gen"erators) and are defined as substances that bind to specific immune receptors and elicit an immune response.


title: Immune system

text: Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers. The waxy cuticle of most 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. Organisms cannot be completely sealed from their environments, so 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.


title: Immune system

text: 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 serves as a chemical defense against ingested pathogens.


title: Immune system

text: 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, changing the conditions in their environment, such as pH or available iron. As a result, the probability that pathogens will reach sufficient numbers to cause illness is reduced.


title: Immune system

text: 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 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, and the only one in plants.


title: Immune system

text: Cells in the innate immune system use pattern recognition receptors to recognize molecular structures that are produced by pathogens. They are proteins expressed, mainly, by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or cell death.


title: Immune system

text: Recognition of extracellular or endosomal PAMPs is mediated by transmembrane proteins known as toll-like receptors (TLRs). TLRs share a typical structural motif, the leucine rich repeats (LRR), which give them a curved shape. Toll-like receptors were first discovered in "Drosophila" and trigger the synthesis and secretion of cytokines and activation of other host defense programs that are necessary for both innate or adaptive immune responses. Ten toll-like receptors have been described in humans.


title: Immune system

text: Cells in the innate immune system have pattern recognition receptors, which detect infection or cell damage, inside. Three major classes of these "cytosolic" receptors are NOD–like receptors, RIG (retinoic acid-inducible gene)-like receptors, and cytosolic DNA sensors.


title: Immune system

text: Some 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 "professional" phagocytes (macrophages, neutrophils, and dendritic cells). These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms. The other cells involved in the innate response include innate lymphoid cells, mast cells, eosinophils, basophils, and natural killer cells.


title: Immune system

text: Phagocytosis is an important feature of cellular innate immunity performed by cells called phagocytes that engulf 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.


title: Immune system

text: 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, representing 50% to 60% of total circulating leukocytes. During the acute phase of inflammation, 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 an array of chemicals including enzymes, complement proteins, and cytokines, while they can also act as scavengers that rid the body of worn-out cells and other debris, and as antigen-presenting cells (APC) that activate the adaptive immune system.


title: Immune system

text: Dendritic cells 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. 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.


title: Immune system

text: Granulocytes are leukocytes that have granules in their cytoplasm. In this category are neutrophils, mast cells, basophils, and eosinophils. Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory response. They are most often associated with allergy and anaphylaxis. Basophils and eosinophils are related to neutrophils. They secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such as asthma.


title: Immune system

text: Innate lymphoid cells (ILCs) are a group of innate immune cells that are derived from common lymphoid progenitor and belong to the lymphoid lineage. These cells are defined by absence of antigen specific B or T cell receptor (TCR) because of the lack of recombination activating gene. ILCs do not express myeloid or dendritic cell markers.


title: Immune system

text: Natural killer cells (NK) are lymphocytes and 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. 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 which essentially put the brakes on NK cells.


title: Immune system

text: 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. The pattern-recognition receptors called inflammasomes are multiprotein complexes (consisting of an NLR, the adaptor protein ASC, and the effector molecule pro-caspase-1) that form in response to cytosolic PAMPs and DAMPs, whose function is to generate active forms of the inflammatory cytokines IL-1β and IL-18.


title: Immune system

text: The complement system is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20 different proteins and is named for its ability to "complement" the killing of pathogens by antibodies. Complement is the major humoral component of the innate immune response. Many species have complement systems, including non-mammals like plants, fish, and some invertebrates. 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 after 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.


title: Immune system

text: 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.


title: Immune system

text: The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated 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. The double-positive T cells are exposed to a wide variety of self-antigens in the thymus, in which iodine is necessary for its thymus development and activity. In contrast, the B cell antigen-specific receptor is an antibody molecule on the B cell surface and recognizes native (unprocessed) antigen without any need for antigen processing. Such antigens may be large molecules found on the surfaces of pathogens, but can also be small haptens (such as penicillin) attached to carrier molecule. Each lineage of B cell expresses a different antibody, so the complete set of B cell antigen receptors represent all the antibodies that the body can manufacture. When B or T cells encounter their related antigens they multiply and many "clones" of the cells are produced that target the same antigen. This is called clonal selection.


title: Immune system

text: 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.


title: Immune system

text: 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.


title: Immune system

text: 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 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).


title: Immune system

text: Helper T cells regulate both the innate and adaptive immune responses and help determine which immune responses the body makes to a particular pathogen. These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. They instead control the immune response by directing other cells to perform these tasks.


title: Immune system

text: Helper T cells express T cell receptors 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 (such as 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 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.


title: Immune system

text: 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.


title: Immune system

text: 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.


title: Immune system

text: 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 through 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.


title: Immune system

text: 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.


title: Immune system

text: The immune system is involved in many aspects of physiological regulation in the body. The immune system interacts intimately with other systems, such as the endocrine and the nervous systems. The immune system also plays a crucial role in embryogenesis (development of the embryo), as well as in tissue repair and regeneration.


title: Immune system

text: 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.


title: Immune system

text: Although cellular studies indicate that vitamin D has receptors and probable functions in the immune system, there is no clinical evidence to prove that vitamin D deficiency increases the risk for immune diseases or vitamin D supplementation lowers immune disease risk. A 2011 United States Institute of Medicine report stated that "outcomes related to ... immune functioning and autoimmune disorders, and infections ... could not be linked reliably with calcium or vitamin D intake and were often conflicting."


title: Immune system

text: The immune system is affected by sleep and rest, and sleep deprivation is detrimental to immune function. Complex feedback loops involving cytokines, such as interleukin-1 and tumor necrosis factor-α produced in response to infection, appear to also play a role in the regulation of non-rapid eye movement (REM) sleep. Thus the immune response to infection may result in changes to the sleep cycle, including an increase in slow-wave sleep relative to REM sleep.


title: Immune system

text: In people with 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 circadian rhythms, can be affected through the disturbance of natural light and dark cycles through instances of sleep deprivation. These disruptions can lead to an increase in chronic conditions such as heart disease, chronic pain, and asthma.


title: Immune system

text: 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 innate and adaptive immunity. First, during the early slow-wave-sleep stage, a sudden drop in blood levels of cortisol, epinephrine, and norepinephrine causes 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 cell activation, proliferation, and differentiation. During this time of a slowly evolving adaptive immune response, there is a peak in undifferentiated or less differentiated cells, like naïve and central memory T cells. In addition to these effects, the milieu of hormones produced at this time (leptin, pituitary growth hormone, and prolactin) supports the interactions between APCs and T-cells, a shift of the T1/T2 cytokine balance towards one that supports T1, an increase in overall T cell proliferation, and naïve T cell migration to lymph nodes. This is also thought to support the formation of long-lasting immune memory through the initiation of Th1 immune responses.


title: Immune system

text: During wake periods, differentiated effector cells, such as cytotoxic natural killer cells and cytotoxic T lymphocytes, peak to elicit an effective response against any intruding pathogens. Anti-inflammatory molecules, such as cortisol and catecholamines, also peak during awake active times. Inflammation would cause serious cognitive and physical impairments if it were to occur during wake times, and 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.


title: Immune system

text: Physical exercise has a positive effect on the immune system and depending on the frequency and intensity, the pathogenic effects of diseases caused by bacteria and viruses are moderated. Immediately after intense exercise there is a transient immunodepression, where the number of circulating lymphocytes decreases and antibody production declines. This may give rise to a window of opportunity for infection and reactivation of latent virus infections, but the evidence is inconclusive.


title: Immune system

text: During exercise there is an increase in circulating white blood cells of all types. This is caused by the frictional force of blood flowing on the endothelial cell surface and catecholamines affecting β-adrenergic receptors (βARs). The number of neutrophils in the blood increases and remains raised for up to six hours and immature forms are present. Although the increase in neutrophils ("neutrophilia") is similar to that seen during bacterial infections, after exercise the cell population returns to normal by around 24 hours.


title: Immune system

text: The number of circulating lymphocytes (mainly natural killer cells) decreases during intense exercise but returns to normal after 4 to 6 hours. Although up to 2% of the cells die most migrate from the blood to the tissues, mainly the intestines and lungs, where pathogens are most likely to be encountered.


title: Immune system

text: Some monocytes leave the blood circulation and migrate to the muscles where they differentiate and become macrophages. These cells differentiate into two types: proliferative macrophages, which are responsible for increasing the number of stem cells and restorative macrophages, which are involved their maturing to muscle cells.


title: Immune system

text: The immune system, particularly the innate component, plays a decisive role in tissue repair after an insult. Key actors include macrophages and neutrophils, but other cellular actors, including γδ T cells, innate lymphoid cells (ILCs), and regulatory T cells (Tregs), are also important. The plasticity of immune cells and the balance between pro-inflammatory and anti-inflammatory signals are crucial aspects of efficient tissue repair. Immune components and pathways are involved in regeneration as well, for example in amphibians such as in axolotl limb regeneration. According to one hypothesis, organisms that can regenerate ("e.g.", axolotls) could be less immunocompetent than organisms that cannot regenerate.


title: Immune system

text: Failures of host defense occur and fall into three broad categories: immunodeficiencies, autoimmunity, and hypersensitivities.


title: Immune system

text: 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, while 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. Immunodeficiencies can also be inherited or 'acquired'. Severe combined immunodeficiency is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations. Chronic granulomatous disease, where phagocytes have a reduced ability to destroy pathogens, is an example of an inherited, or congenital, immunodeficiency. AIDS and some types of cancer cause acquired immunodeficiency.


title: Immune system

text: Overactive immune responses form 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. Common autoimmune diseases include Hashimoto's thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus erythematosus.


title: Immune system

text: Hypersensitivity is an immune response that damages the body's own tissues. It is 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.


title: Immune system

text: Type II hypersensitivity occurs when antibodies bind to antigens on the individual'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. These reactions are mediated by T cells, monocytes, and macrophages.


title: Immune system

text: Inflammation is one of the first responses of the immune system to infection, but it can appear without known cause.


title: Immune system

text: 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.


title: Immune system

text: The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy, and transplant rejection, and to stimulate protective responses against pathogens that largely elude the immune system (see immunization) or cancer.


title: Immune system

text: Immunosuppressive drugs are used to control autoimmune disorders or inflammation when excessive tissue damage occurs, and to prevent rejection after an organ transplant.


title: Immune system

text: Anti-inflammatory drugs are often used to control the effects of inflammation. Glucocorticoids are the most powerful of these drugs and can have many undesirable side effects, such as central obesity, hyperglycemia, and osteoporosis. Their use is tightly controlled. Lower doses of anti-inflammatory drugs are often used in conjunction with cytotoxic or immunosuppressive drugs such as methotrexate or azathioprine.


title: Immune system

text: Cytotoxic drugs inhibit the immune response by killing dividing cells such as activated T cells. This 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.


title: Immune system

text: Claims made by marketers of various products and alternative health providers, such as chiropractors, homeopaths, and acupuncturists to be able to stimulate or "boost" the immune system generally lack meaningful explanation and evidence of effectiveness.


title: Immune system

text: 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 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.


title: Immune system

text: Many vaccines are based on acellular components of micro-organisms, including harmless toxin components. Since many antigens derived from acellular vaccines do not strongly induce the adaptive response, most bacterial vaccines are provided with additional adjuvants that activate the antigen-presenting cells of the innate immune system and maximize immunogenicity.


title: Immune system

text: 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 cancer of the cervix, vulva, vagina, penis, anus, mouth, and throat, 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 (for example, 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.


title: Immune system

text: 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.


title: Immune system

text: 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.


title: Immune system

text: Paradoxically, macrophages can promote tumor growth when tumor cells send out cytokines that attract macrophages, which then generate cytokines and growth factors such as tumor-necrosis factor alpha that nurture tumor development or promote stem-cell-like plasticity. In addition, a combination of hypoxia in the tumor and a cytokine produced by macrophages induces tumor cells to decrease production of a protein that blocks metastasis and thereby assists spread of cancer cells. Anti-tumor M1 macrophages are recruited in early phases to tumor development but are progressively differentiated to M2 with pro-tumor effect, an immunosuppressor switch. The hypoxia reduces the cytokine production for the anti-tumor response and progressively macrophages acquire pro-tumor M2 functions driven by the tumor microenvironment, including IL-4 and IL-10. Cancer immunotherapy covers the medical ways to stimulate the immune system to attack cancer tumors.