title: Heritability

text: Experiments can be run with a similar setup to the one given in Table 1. Using different relationship groups, we can evaluate different intraclass correlations. Using formula_26 as the additive genetic variance and formula_27 as the dominance deviation variance, intraclass correlations become linear functions of these parameters. In general,


title: Heritability

text: A wide variety of approaches using linear mixed models have been reported in literature. Via these methods, phenotypic variance is partitioned into genetic, environmental and experimental design variances to estimate heritability. Environmental variance can be explicitly modeled by studying individuals across a broad range of environments, although inference of genetic variance from phenotypic and environmental variance may lead to underestimation of heritability due to the challenge of capturing the full range of environmental influence affecting a trait. Other methods for calculating heritability use data from genome-wide association studies to estimate the influence on a trait by genetic factors, which is reflected by the rate and influence of putatively associated genetic loci (usually single-nucleotide polymorphisms) on the trait. This can lead to underestimation of heritability, however. This discrepancy is referred to as "missing heritability" and reflects the challenge of accurately modeling both genetic and environmental variance in heritability models.


title: Heritability

text: When a large, complex pedigree or another aforementioned type of data is available, heritability and other quantitative genetic parameters can be estimated by restricted maximum likelihood (REML) or Bayesian methods. The raw data will usually have three or more data points for each individual: a code for the sire, a code for the dam and one or several trait values. Different trait values may be for different traits or for different time points of measurement.


title: Heritability

text: The currently popular methodology relies on high degrees of certainty over the identities of the sire and dam; it is not common to treat the sire identity probabilistically. This is not usually a problem, since the methodology is rarely applied to wild populations (although it has been used for several wild ungulate and bird populations), and sires are invariably known with a very high degree of certainty in breeding programmes. There are also algorithms that account for uncertain paternity.


title: Heritability

text: The pedigrees can be viewed using programs such as Pedigree Viewer , and analyzed with programs such as ASReml, VCE , WOMBAT , MCMCglmm within the R environment or the BLUPF90 family of programs .


title: Heritability

text: Pedigree models are helpful for untangling confounds such as reverse causality, maternal effects such as the prenatal environment, and confounding of genetic dominance, shared environment, and maternal gene effects.


title: Heritability

text: When genome-wide genotype data and phenotypes from large population samples are available, one can estimate the relationships between individuals based on their genotypes and use a linear mixed model to estimate the variance explained by the genetic markers. This gives a genomic heritability estimate based on the variance captured by common genetic variants. There are multiple methods that make different adjustments for allele frequency and linkage disequilibrium. Particularly, the method called High-Definition Likelihood (HDL) can estimate genomic heritability using only GWAS summary statistics, making it easier to incorporate large sample size available in various GWAS meta-analysis.


title: Heritability

text: In selective breeding of plants and animals, the expected response to selection of a trait with known narrow-sense heritability formula_33 can be estimated using the "breeder's equation":


title: Heritability

text: In this equation, the Response to Selection (R) is defined as the realized average difference between the parent generation and the next generation, and the Selection Differential (S) is defined as the average difference between the parent generation and the selected parents.


title: Heritability

text: For example, imagine that a plant breeder is involved in a selective breeding project with the aim of increasing the number of kernels per ear of corn. For the sake of argument, let us assume that the average ear of corn in the parent generation has 100 kernels. Let us also assume that the selected parents produce corn with an average of 120 kernels per ear. If h equals 0.5, then the next generation will produce corn with an average of 0.5(120-100) = 10 additional kernels per ear. Therefore, the total number of kernels per ear of corn will equal, on average, 110.


title: Heritability

text: Observing the response to selection in an artificial selection experiment will allow calculation of realized heritability as in Fig. 4.


title: Heritability

text: Note that heritability in the above equation is equal to the ratio formula_35 only if the genotype and the environmental noise follow Gaussian distributions.


title: Heritability

text: Heritability estimates' prominent critics, such as Steven Rose, Jay Joseph, and Richard Bentall, focus largely on heritability estimates in behavioral sciences and social sciences. Bentall has claimed that such heritability scores are typically calculated counterintuitively to derive numerically high scores, that heritability is misinterpreted as genetic determination, and that this alleged bias distracts from other factors that researches have found more causally important, such as childhood abuse causing later psychosis. Heritability estimates are also inherently limited because they do not convey any information regarding whether genes or environment play a larger role in the development of the trait under study. For this reason, David Moore and David Shenk describe the term "heritability" in the context of behavior genetics as "...one of the most misleading in the history of science" and argue that it has no value except in very rare cases. When studying complex human traits, it is impossible to use heritability analysis to determine the relative contributions of genes and environment, as such traits result from multiple causes interacting. In particular, Feldman and Lewontin emphasize that heritability is itself a function of environmental variation. However, some researchers argue that it is possible to disentangle the two.


title: Heritability

text: The controversy over heritability estimates is largely via their basis in twin studies. The scarce success of molecular-genetic studies to corroborate such population-genetic studies' conclusions is the "missing heritability" problem. Eric Turkheimer has argued that newer molecular methods have vindicated the conventional interpretation of twin studies, although it remains mostly unclear how to explain the relations between genes and behaviors. According to Turkheimer, both genes and environment are heritable, genetic contribution varies by environment, and a focus on heritability distracts from other important factors. Overall, however, "heritability" is a concept widely applicable.


title: Simon Bowes-Lyon, 19th Earl of Strathmore and Kinghorne

text: Scottish peer and landowner, the owner of estates based at Glamis Castle. He is also 17th Viscount Lyon, 19th Lord Lyon and Glamis, 26th Lord Glamis, 17th Lord Glamis, Tannadyce, Sidlaw and Strathdichtie, and 7th Baron Bowes, and from birth until 2016 was known as Lord Glamis.


text: The eldest son of Michael Bowes-Lyon, 18th Earl of Strathmore and Kinghorne, and his first wife, Isobel Weatherall, he is a second cousin once removed of King Charles III, whose grandmother was a Bowes-Lyon.


text: In 2021, Lord Strathmore pleaded guilty to sexually assaulting a woman at his ancestral home, Glamis Castle, and as a result served five months in prison.


text: Strathmore was born on 18 June 1986 into the Bowes-Lyon family. His father, Michael Bowes-Lyon, 18th Earl of Strathmore and Kinghorne, was a politician, soldier, and business man, as well as a hereditary peer. His mother is Isobel Weatherall, daughter of Captain Anthony Edward Weatherall. He attended Sunningdale School. His parents divorced in 2004.


text: Lord Strathmore is a great-great-nephew of Queen Elizabeth The Queen Mother and thus a second cousin once removed of King Charles III. In 2002, he walked alongside his father and members of the royal family behind the coffin of the Queen Mother during her funeral.


text: On his father's death on 27 February 2016, the then Lord Glamis succeeded as 19th Earl. In 2019, he was living at Glamis Castle. Running the Glamis estate includes work with Reiver Travel, which arranges exclusive holidays in Scotland. In 2017 Strathmore decided to renovate Glamis House, a property on his estate and a childhood home of the Queen Mother, for use as a self-catering holiday home. From 2016 to 2018, he was a director of Ark Hill Wind Farm Ltd. Lord Strathmore is the chieftain of the Strathmore Highland Games, which takes place annually in the grounds of Glamis Castle.


text: In 2010, Lord Glamis, as he then was styled, was convicted of speeding by riding his motorbike at on a public road with a limit. He was banned from driving for nine months.


text: In June 2020, Durham Police contacted the Earl for violating the COVID-19 related travel restrictions then in place. A report said Lord Strathmore travelled to Holwick Lodge, Middleton-in-Teesdale, and that his butler was spotted buying newspapers.


text: In 2021, Lord Strathmore was charged with sexual assault after admitting to attacking a 26-year-old woman at his Scottish home, Glamis Castle, in early 2020. On 12 January 2021, Strathmore was granted bail and placed on the Violent and Sex Offender Register (ViSOR) by Sheriff Alistair Carmichael at Dundee Sheriff Court. His conviction attracted attention in both the British and the international press, due to his connection with the royal family. "The Times" reported calls for Lord Strathmore to be removed as the Chieftain of the annual Strathmore Highland Games. On 23 February 2021, he was sentenced to ten months' imprisonment and placed on the sex offenders register for 10 years. He was released after serving five


text: In addition to the Earldom of Strathmore and Kinghorne, Strathmore holds the following subsidiary titles: 17th Viscount Lyon, 19th Lord Lyon and Glamis, 26th Lord Glamis, 17th Lord Glamis, Tannadyce, Sidlaw and Strathdichtie, and 7th Baron Bowes, of Streatlam Castle.


title: Malaysian Chinese Association

text: The Malaysian Chinese Association (MCA; ; ; , initially known as the Malayan Chinese Association) is a uni-racial political party in Malaysia that seeks to represent the Malaysian Chinese ethnicity; it was one of the three original major component parties of the coalition party in Malaysia called the Alliance Party, which later became a broader coalition called Barisan Nasional in Malay, or National Front in English.


title: Malaysian Chinese Association

text: Along with the largest and third largest component party in BN, i.e. United Malays National Organisation and Malaysian Indian Congress, MCA has a significant influence over the political arena in Malaysia since its independence. Through its holding of companies such as Huaren Holdings, MCA controls "The Star", which is Malaysia's best-selling English newspaper.


title: Malaysian Chinese Association

text: The party was once the largest party representing the Chinese community in Malaysia, and was particularly dominant in the early period until the late 1960s. Its fortunes fluctuated after the establishment of other political parties in the 1960s that challenged it for the Chinese votes, although it still enjoyed strong support in the mid-1990s to mid-2000s period. However, it has performed poorly in elections since 2008, with the Malaysian Chinese community mostly voting for the Democratic Action Party and People's Justice Party, and in the 2018 Malaysian general election, it lost all but one of its parliamentary seats and was relegated to the opposition. It returned to power in March 2020 as part of the alliance with Perikatan Nasional.


title: Malaysian Chinese Association

text: The Malayan Chinese Association was formed on 27 February 1949 with the implicit support by the post-World War II British colonial administration. A central purpose of the MCA at the time of its founding was to manage the specific social and welfare concerns of the populations interned in the so-called New Villages created under the Briggs Plan in response to the Malayan Emergency.


title: Malaysian Chinese Association

text: The declaration that announced the MCA as a formal political party in 1951 was written by a prominent Straits Chinese businessman, Tan Cheng Lock, its first president. In general, its early members were landowners, businessmen, or otherwise better off, while the working classes in the New Villages overwhelmingly joined the Socialist Front instead. Many prominent members of the MCA were also Kuomintang members opposed to the Malayan Communist Party. Leong Yew Koh, was a KMT major general who became a cabinet minister and later became governor of Malacca; Malaysia's first minister of finance, Henry H.S. Lee, was a KMT colonel; and Lim Chong Eu, the leader of the Radical Party and joined the MCA in 1952, was a colonel (medical) doctor in the Kuomintang.


title: Malaysian Chinese Association

text: In 1952, MCA joined force with United Malays National Organisation on a local level to contest the Kuala Lumpur municipal elections which would lead to the formation of the Alliance Party. The alliance was joined by Malaysian Indian Congress in 1954 and they contested the first Malayan General Election in 1955 as one body, and the alliance won 51 of the 52 seat contested. MCA won all 15 of the seats allocated.


title: Malaysian Chinese Association

text: Tan Cheng Lock was succeeded by Lim Chong Eu after a successful challenge by Lim for the presidency in 1958. Lim attempted to amend the party's Constitution to consolidate the power of the Central Committee, and although amendment was passed narrowly, it also split the party. Prior to the 1959 General Election, Lim pressed for an increase of the allocated number of seats from 28 to 40, but this was refused by UMNO leader Tunku Abdul Rahman. Lim was forced to back down and later resigned as president, with Cheah Toon Lock taking over as acting president. Other members also resigned from MCA to contest the election as independent candidates, which cost the party some seats. The party only won 19 of the 31 seats eventually allocated. Lim himself left the party in December 1960, later becoming one of the founding members of the opposition Gerakan in 1968. In 1961 Tan Siew Sin, son of Tan Cheng Lock and favoured by Tunku, became MCA's third President. Tan led the party to a firm victory in the 1964 General Election, winning 27 of the 33 parliamentary seats contested. In 1969, Tan established Tunku Abdul Rahman College after a proposal for a Chinese-language university was turned down by the government.


title: Malaysian Chinese Association

text: The third Malaysian general elections were held on 10 May 1969. MCA faced strong challenges from the new, mainly Chinese, opposition parties Democratic Action Party and Gerakan. Of the 33 parliamentary seats contested, MCA managed to retain only 13. MCA also lost control of the Penang State Government to Gerakan. The gain by the opposition parties led to tension between different communities which erupted into the May 13 Riots. Prior to the riots, on 12 May 1969, Tan Siew Sin announced that the party would withdraw from the Alliance, but reconsidered on 20 May and joined the National Operations Council formed in place of the suspended Parliament after the riots. The loss of support for MCA among the Chinese population elicited a comment by the then Deputy Prime Minister Dr Ismail that if MCA continue to lose support, UMNO may stop co-operating with it. To regain Chinese support, Tan attempted to broaden the appeal of the party previously seen as a party of the "taukeh" ("", rich men), and invited professionals to join the party. However, many of these were later expelled after a dispute involving Lim Keng Yaik who then joined Gerakan.


title: Malaysian Chinese Association

text: With the loss of support for MCA in the 1969 election, and the enlargement of the Alliance party in 1972 (which later became Barisan Nasional) to include Gerakan, UMNO became even more dominant and MCA suffered a loss of status within the coalition. In 1973, Tan Siew Sin requested a position as Deputy Prime Minister in the cabinet reshuffle following the death of Tun Dr. Ismail, but this was refused by Tun Abdul Razak, which angered Tan. On 8 April 1974, prior to the general election, Tan Siew Sin resigned all of his party and government posts for health reasons.


title: Malaysian Chinese Association

text: Lee San Choon took over as Acting President following Tan's resignation, and was then elected president in 1975. After Tan's resignation, the cabinet posts allocated to MCA declined in importance, and MCA lost both the Finance Ministry and Trade and Industry Ministry posts it once held in 1957. The party performed better in the 1974 election, but lost ground again in the following 1978 general election, with the MCA winning only 17 of the 28 parliamentary seats and 44 of the 60 state seats. In 1979, Michael Chen stood against Lee San Choon for the MCA Presidency but lost, and later in 1981 led a group of MCA dissidents to join Gerakan.


title: Malaysian Chinese Association

text: The 1982 general election however saw a shift in fortune for MCA. Lee accepted a challenge from the opposition Democratic Action Party which taunted the MCA's leadership for not daring to contest a seat with large urban Chinese majority, and contested the parliamentary seat for Seremban against the incumbent DAP Chairman Chen Man Hin. Lee won his challenge, and led his party to a resounding victory, winning 24 out of 28 allocated parliamentary seats and 55 out of 62 state seats. After the success in the election and at the height of his career, Lee San Choon unexpectedly resigned his presidency and cabinet post for unspecified reason in 1983. Neo Yee Pan then led as Acting President until 1985.


title: Malaysian Chinese Association

text: In 1985, Tan Koon Swan, who was sacked from the party a year earlier, won the presidential election with the largest majority in the party's history. However, in the following year, he was charged with abetting criminal breach of trust relating to his private business dealings in Singapore, and resigned from the presidency. Koon Swan also originated the Deposit-Taking Cooperatives, which sought to accumulate capital for Chinese Malaysians through investments. The mismanagement of the DTCs' funds led to a scandal, with the central bank, Bank Negara Malaysia, stepping in to freeze the assets of up to 35 DTCs. The total loss was estimated to be RM3.6 billion, and depositors could only recover 62% of their deposits.


title: Malaysian Chinese Association

text: Koon Swan was succeeded by his deputy Ling Liong Sik in 1986. He assumed the presidency when the party was still rife with factionalism and faced disillusionment with the Chinese community over the Deposit-Taking Cooperatives scandal. Ling spent his early years as president working to resolve MCA's financial problems, raising funds while restructuring the party's assets. Ling presided over a period of relative peace within the party, and worked to maintain the interests of the Chinese community through a closed-door approach within the government. He expanded the MCA-owned Tunku Abdul Rahman College through fund-raising and government contributions, and in 2001 set up Universiti Tunku Abdul Rahman. Ling led MCA to its best electoral performance thus far in the 1995 general election, winning 30 of the 34 allocated parliamentary seats and 71 of the 77 state seats, and secured a majority of Chinese votes at the expense of DAP. MCA also performed well in the 1999 general elections, and the successive electoral victory boosted the party's standing within the Barisan Nasional coalition as well as Ling's personal relationship with BN leader and prime minister Mahathir Mohamad.


title: Malaysian Chinese Association

text: However, internal power struggles persisted. In 1993 Ling's deputy Lee Kim Sai indicated that he would challenge Ling for the presidency, but withdrew at the eleventh hour. Lee eventually retired in 1996 and was replaced as deputy president by Lim Ah Lek. In 1999, the party was again wracked by factionalism. Deputy president Lim Ah Lek announced his intention to retire as a minister and agreed with Ling to nominate his protégé Chan Kong Choy to the Cabinet after the 1999 elections. However, Ling nominated his own protégé Ong Ka Ting as a minister at the expense of Chan, causing discontent with members aligned to Lim, which became known as "Team B" among party members. The Ling faction was known as "Team A". Tensions flared further after MCA, through its holding company Huaren, moved to acquire the independent daily "Nanyang Siang Pau". This was vehemently opposed by Team B, fearing a complete control of the Chinese media by Team A. They were joined by Chinese journalists and non-governmental organisations, who made their opposition public through demonstrations. The situation turned farcical when chairs were thrown during the 2001 Youth general assembly over the issue. Huaren eventually succeeded in taking over "Nanyang Siang Pau". Huaren also controls "The Star" and "China Press", and the domination of media press resulted in strong resentments in the divided party and concerns over press freedom.


title: Malaysian Chinese Association

text: Mahathir, as BN leader, eventually stepped in to resolve the conflict, suggesting a "peace plan" among the factions. The scheduled 2002 party elections were cancelled, while Ling and Lim stepped down to be replaced by their respective protégés.


title: Malaysian Chinese Association

text: In May 2003, the leadership transition occurred as planned. Ong Ka Ting, who was then a vice-president succeeded Ling Liong Sik as president, while Chan Kong Choy succeeded Lim Ah Lek as deputy president. The Ong-led MCA contributed to Barisan Nasional's overwhelming victory in the 2004 general elections. MCA won 31 of the 40 parliamentary seats and 76 of the 90 state seats allocated. During the 2005 party elections, Teams A and B ran on a united front, easily quashing the challenge by vice-president Chua Jui Meng (for president) and secretary-general Ting Chew Peh (for deputy president).


title: Malaysian Chinese Association

text: The Ong-Chan leadership continued the soft approach to protecting the Chinese community's interests, although tension with UMNO over racial issues flared up now and again after the 2004 election. In early 2008, vice-president and Health Minister Chua Soi Lek, a prominent Johor member, was involved in a sex scandal. DVDs of Chua having sex with a woman were circulated in Johor, prompting Chua to resign all his political positions, including as Member of Parliament. Chua suggested that his political enemies within the party who might have felt threatened by him for plotting his downfall.


title: Malaysian Chinese Association

text: In the March 2008 general elections, MCA fared badly, winning only 15 parliamentary seats and 32 state seats, less than half the number of seats they won in the previous election. Ong decided not to contest the presidency during the party elections later that year, to allow a new leader to take over. The October 2008 party election marked a realignment of the party's factions, with the return of Chua Soi Lek to the fold. Ong Ka Ting's anointed successor was vice-president Ong Tee Keat. Meanwhile, Chua entered the race for deputy president, facing among others, Ong Ka Chuan, the elder brother of Ka Ting. Ong Tee Keat won the presidency comfortably, while Chua edged out Ka Chuan. Following his victory, Tee Keat pledged reform and reaching out to more young voters to revive the party.


title: Malaysian Chinese Association

text: After the 2008 leadership change, factional infighting continued and the relationship between the Ong Tee Keat and Chua Soi Lek remained tense. Chua was sidelined by Ong from taking an active role in the party's leadership, and he was also excluded from government posts. He was then sacked by MCA in August 2009 for damaging the party's image with his sex scandal more than a year prior. In response, Chua's supporters forced an extraordinary general meeting which passed a vote of no confidence against incumbent president Ong and annulled the expulsion of Chua. The EGM, however, failed to reinstate Chua as deputy president. Ong refused to resign despite the vote of no confidence, but pledged with Chua to set aside their differences under the "greater unity plan." However, this was opposed by vice-president Liow Tiong Lai who demanded Ong step down and that new elections be held. This set in motion a new leadership crisis, which lasted almost six months.


title: Malaysian Chinese Association

text: Finally in March 2010, Chua, along with his supporters in the central committee resigned. Along with the resignations of Liow's supporters in the CC, more than two-thirds of the CC had vacated their seats, paving the way for an election per the party constitution. The subsequent election saw Chua defeating incumbent Ong Tee Keat and former leader Ong Ka Ting in the race for president, while Liow defeated Kong Cho Ha in the contest for deputy president. Chua and his deputy Liow pledged to co-operate, and opened the party to non-Chinese.


title: Malaysian Chinese Association

text: MCA's electoral performance meanwhile continued to deteriorate, as in the 2013 General Election, MCA only managed to score only 7 of the 37 parliamentary seats and 11 of the 90 state seats it contested, leading to calls for Chua's resignation. The so-called "Chinese tsunami" where the great majority of Chinese votes went to the opposition was blamed by Najib Razak for the losses of the governing coalition. MCA's poor performance in the two elections, along with continued factionalism, raised concerns over the party's relevance in the Malaysian political arena. Also as a result of its poor performance, there was no MCA representation in the cabinet for the first time since independence due to a resolution that MCA would not accept cabinet posts if it performed badly in the general election.


title: Malaysian Chinese Association

text: Chua did not enter the following party poll for president, and in December 2013, Liow Tiong Lai was elected the president of MCA. Liow also reversed the resolution not to serve in the government and re-entered the cabinet.


title: Malaysian Chinese Association

text: In the 2018 election, MCA suffered its worst ever defeat, as it has lost all state seats it has contested, and only managed to retain one elected representative in the national parliament - Wee Ka Siong, who represents Ayer Hitam constituency in Johor. MCA, as part of the Barisan Nasional coalition, was also relegated to the opposition for the first time since independence. Wee Ka Siong was elected president on 4 November 2018 while Liow decided not to stand for party polls after his defeat. MCA later regained a seat in the 2019 Tanjung Piai by-election.


title: Malaysian Chinese Association

text: In March 2020, MCA returned to power as part of Barisan Nasional aligned to the Perikatan Nasional coalition after the collapse of the Pakatan Harapan government.


title: Malaysian Chinese Association

text: On 8 July 2020, a sum of RM835,258.19 seized by the Malaysian Anti-Corruption Commission (MACC) from Pahang MCA for allegedly linked to the 1Malaysia Development Berhad (1MDB) fund scandal, has been forfeited to the Malaysian government.


title: Malaysian Chinese Association

text: Incumbent leadership of MCA was elected by general assembly delegates on 5 November 2018 in the 2018 Malaysian Chinese Association leadership election.


title: Drug discovery

text: In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered.


title: Drug discovery

text: Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by serendipitous discovery, as with penicillin. More recently, chemical libraries of synthetic small molecules, natural products or extracts were screened in intact cells or whole organisms to identify substances that had a desirable therapeutic effect in a process known as classical pharmacology. After sequencing of the human genome allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease-modifying in a process known as reverse pharmacology. Hits from these screens are then tested in cells and then in animals for efficacy.


title: Drug discovery

text: Modern drug discovery involves the identification of screening hits, medicinal chemistry and optimization of those hits to increase the affinity, selectivity (to reduce the potential of side effects), efficacy/potency, metabolic stability (to increase the half-life), and oral bioavailability. Once a compound that fulfills all of these requirements has been identified, the process of drug development can continue. If successful, clinical trials are developed.


title: Drug discovery

text: Modern drug discovery is thus usually a capital-intensive process that involves large investments by pharmaceutical industry corporations as well as national governments (who provide grants and loan guarantees). Despite advances in technology and understanding of biological systems, drug discovery is still a lengthy, "expensive, difficult, and inefficient process" with low rate of new therapeutic discovery. In 2010, the research and development cost of each new molecular entity was about US$1.8 billion. In the 21st century, basic discovery research is funded primarily by governments and by philanthropic organizations, while late-stage development is funded primarily by pharmaceutical companies or venture capitalists. To be allowed to come to market, drugs must undergo several successful phases of clinical trials, and pass through a new drug approval process, called the New Drug Application in the United States.


title: Drug discovery

text: Discovering drugs that may be a commercial success, or a public health success, involves a complex interaction between investors, industry, academia, patent laws, regulatory exclusivity, marketing and the need to balance secrecy with communication. Meanwhile, for disorders whose rarity means that no large commercial success or public health effect can be expected, the orphan drug funding process ensures that people who experience those disorders can have some hope of pharmacotherapeutic advances.


title: Drug discovery

text: The idea that the effect of a drug in the human body is mediated by specific interactions of the drug molecule with biological macromolecules, (proteins or nucleic acids in most cases) led scientists to the conclusion that individual chemicals are required for the biological activity of the drug. This made for the beginning of the modern era in pharmacology, as pure chemicals, instead of crude extracts of medicinal plants, became the standard drugs. Examples of drug compounds isolated from crude preparations are morphine, the active agent in opium, and digoxin, a heart stimulant originating from "Digitalis lanata". Organic chemistry also led to the synthesis of many of the natural products isolated from biological sources.


title: Drug discovery

text: Historically, substances, whether crude extracts or purified chemicals, were screened for biological activity without knowledge of the biological target. Only after an active substance was identified was an effort made to identify the target. This approach is known as classical pharmacology, forward pharmacology, or phenotypic drug discovery.


title: Drug discovery

text: Later, small molecules were synthesized to specifically target a known physiological/pathological pathway, avoiding the mass screening of banks of stored compounds. This led to great success, such as the work of Gertrude Elion and George H. Hitchings on purine metabolism, the work of James Black on beta blockers and cimetidine, and the discovery of statins by Akira Endo. Another champion of the approach of developing chemical analogues of known active substances was Sir David Jack at Allen and Hanbury's, later Glaxo, who pioneered the first inhaled selective beta2-adrenergic agonist for asthma, the first inhaled steroid for asthma, ranitidine as a successor to cimetidine, and supported the development of the triptans.


title: Drug discovery

text: Gertrude Elion, working mostly with a group of fewer than 50 people on purine analogues, contributed to the discovery of the first anti-viral; the first immunosuppressant (azathioprine) that allowed human organ transplantation; the first drug to induce remission of childhood leukemia; pivotal anti-cancer treatments; an anti-malarial; an anti-bacterial; and a treatment for gout.


title: Drug discovery

text: Cloning of human proteins made possible the screening of large libraries of compounds against specific targets thought to be linked to specific diseases. This approach is known as reverse pharmacology and is the most frequently used approach today.


title: Drug discovery

text: In the 2020s, qubit and quantum computing starter to be used to severely reduce the time needed to drug discovery.


title: Drug discovery

text: A "target" is produced within the pharmaceutical industry. Generally, the "target" is the naturally existing cellular or molecular structure involved in the pathology of interest where the drug-in-development is meant to act. However, the distinction between a "new" and "established" target can be made without a full understanding of just what a "target" is. This distinction is typically made by pharmaceutical companies engaged in the discovery and development of therapeutics. In an estimate from 2011, 435 human genome products were identified as therapeutic drug targets of FDA-approved drugs.


title: Drug discovery

text: "Established targets" are those for which there is a good scientific understanding, supported by a lengthy publication history, of both how the target functions in normal physiology and how it is involved in human pathology. This does not imply that the mechanism of action of drugs that are thought to act through a particular established target is fully understood. Rather, "established" relates directly to the amount of background information available on a target, in particular functional information. In general, "new targets" are all those targets that are not "established targets" but which have been or are the subject of drug discovery efforts. The majority of targets selected for drug discovery efforts are proteins, such as G-protein-coupled receptors (GPCRs) and protein kinases.


title: Drug discovery

text: The process of finding a new drug against a chosen target for a particular disease usually involves high-throughput screening (HTS), wherein large libraries of chemicals are tested for their ability to modify the target. For example, if the target is a novel GPCR, compounds will be screened for their ability to inhibit or stimulate that receptor (see antagonist and agonist): if the target is a protein kinase, the chemicals will be tested for their ability to inhibit that kinase.


title: Drug discovery

text: Another function of HTS is to show how selective the compounds are for the chosen target, as one wants to find a molecule which will interfere with only the chosen target, but not other, related targets. To this end, other screening runs will be made to see whether the "hits" against the chosen target will interfere with other related targets – this is the process of cross-screening. Cross-screening is useful because the more unrelated targets a compound hits, the more likely that off-target toxicity will occur with that compound once it reaches the clinic.


title: Drug discovery

text: It is unlikely that a perfect drug candidate will emerge from these early screening runs. One of the first steps is to screen for compounds that are unlikely to be developed into drugs; for example compounds that are hits in almost every assay, classified by medicinal chemists as "pan-assay interference compounds", are removed at this stage, if they were not already removed from the chemical library. It is often observed that several compounds are found to have some degree of activity, and if these compounds share common chemical features, one or more pharmacophores can then be developed. At this point, medicinal chemists will attempt to use structure–activity relationships (SAR) to improve certain features of the lead compound:


title: Drug discovery

text: This process will require several iterative screening runs, during which, it is hoped, the properties of the new molecular entities will improve, and allow the favoured compounds to go forward to in vitro and in vivo testing for activity in the disease model of choice.


title: Drug discovery

text: Amongst the physicochemical properties associated with drug absorption include ionization (pKa), and solubility; permeability can be determined by PAMPA and Caco-2. PAMPA is attractive as an early screen due to the low consumption of drug and the low cost compared to tests such as Caco-2, gastrointestinal tract (GIT) and Blood–brain barrier (BBB) with which there is a high correlation.


title: Drug discovery

text: A range of parameters can be used to assess the quality of a compound, or a series of compounds, as proposed in the Lipinski's Rule of Five. Such parameters include calculated properties such as cLogP to estimate lipophilicity, molecular weight, polar surface area and measured properties, such as potency, in-vitro measurement of enzymatic clearance etc. Some descriptors such as ligand efficiency (LE) and lipophilic efficiency (LiPE) combine such parameters to assess druglikeness.


title: Drug discovery

text: While HTS is a commonly used method for novel drug discovery, it is not the only method. It is often possible to start from a molecule which already has some of the desired properties. Such a molecule might be extracted from a natural product or even be a drug on the market which could be improved upon (so-called "me too" drugs). Other methods, such as virtual high throughput screening, where screening is done using computer-generated models and attempting to "dock" virtual libraries to a target, are also often used.


title: Drug discovery

text: Another method for drug discovery is "de novo" drug design, in which a prediction is made of the sorts of chemicals that might (e.g.) fit into an active site of the target enzyme. For example, virtual screening and computer-aided drug design are often used to identify new chemical moieties that may interact with a target protein. Molecular modelling and molecular dynamics simulations can be used as a guide to improve the potency and properties of new drug leads.


title: Drug discovery

text: There is also a paradigm shift in the drug discovery community to shift away from HTS, which is expensive and may only cover limited chemical space, to the screening of smaller libraries (maximum a few thousand compounds). These include fragment-based lead discovery (FBDD) and protein-directed dynamic combinatorial chemistry. The ligands in these approaches are usually much smaller, and they bind to the target protein with weaker binding affinity than hits that are identified from HTS. Further modifications through organic synthesis into lead compounds are often required. Such modifications are often guided by protein X-ray crystallography of the protein-fragment complex. The advantages of these approaches are that they allow more efficient screening and the compound library, although small, typically covers a large chemical space when compared to HTS.


title: Drug discovery

text: Phenotypic screens have also provided new chemical starting points in drug discovery.  A variety of models have been used including yeast, zebrafish, worms, immortalized cell lines, primary cell lines, patient-derived cell lines and whole animal models. These screens are designed to find compounds which reverse a disease phenotype such as death, protein aggregation, mutant protein expression, or cell proliferation as examples in a more holistic cell model or organism. Smaller screening sets are often used for these screens, especially when the models are expensive or time-consuming to run.  In many cases, the exact mechanism of action of hits from these screens is unknown and may require extensive target deconvolution experiments to ascertain. The growth of the field of chemoproteomics has provided numerous strategies to identify drug targets in these cases.


title: Drug discovery

text: Once a lead compound series has been established with sufficient target potency and selectivity and favourable drug-like properties, one or two compounds will then be proposed for drug development. The best of these is generally called the lead compound, while the other will be designated as the "backup". These decisions are generally supported by computational modelling innovations.


title: Drug discovery

text: Traditionally, many drugs and other chemicals with biological activity have been discovered by studying chemicals that organisms create to affect the activity of other organisms for survival.


title: Drug discovery

text: Despite the rise of combinatorial chemistry as an integral part of lead discovery process, natural products still play a major role as starting material for drug discovery. A 2007 report found that of the 974 small molecule new chemical entities developed between 1981 and 2006, 63% were natural derived or semisynthetic derivatives of natural products. For certain therapy areas, such as antimicrobials, antineoplastics, antihypertensive and anti-inflammatory drugs, the numbers were higher. In many cases, these products have been used traditionally for many years.


title: Drug discovery

text: Natural products may be useful as a source of novel chemical structures for modern techniques of development of antibacterial therapies.


title: Drug discovery

text: Many secondary metabolites produced by plants have potential therapeutic medicinal properties. These secondary metabolites contain, bind to, and modify the function of proteins (receptors, enzymes, etc.). Consequently, plant derived natural products have often been used as the starting point for drug discovery.


title: Drug discovery

text: Until the Renaissance, the vast majority of drugs in Western medicine were plant-derived extracts. This has resulted in a pool of information about the potential of plant species as important sources of starting materials for drug discovery. Botanical knowledge about different metabolites and hormones that are produced in different anatomical parts of the plant (e.g. roots, leaves, and flowers) are crucial for correctly identifying bioactive and pharmacological plant properties. Identifying new drugs and getting them approved for market has proved to be a stringent process due to regulations set by national drug regulatory agencies.


title: Drug discovery

text: Jasmonates are important in responses to injury and intracellular signals. They induce apoptosis and protein cascade via proteinase inhibitor, have defense functions, and regulate plant responses to different biotic and abiotic stresses. Jasmonates also have the ability to directly act on mitochondrial membranes by inducing membrane depolarization via release of metabolites.


title: Drug discovery

text: Jasmonate derivatives (JAD) are also important in wound response and tissue regeneration in plant cells. They have also been identified to have anti-aging effects on human epidermal layer. It is suspected that they interact with proteoglycans (PG) and glycosaminoglycan (GAG) polysaccharides, which are essential extracellular matrix (ECM) components to help remodel the ECM. The discovery of JADs on skin repair has introduced newfound interest in the effects of these plant hormones in therapeutic medicinal application.


title: Drug discovery

text: Salicylic acid (SA), a phytohormone, was initially derived from willow bark and has since been identified in many species. It is an important player in plant immunity, although its role is still not fully understood by scientists. They are involved in disease and immunity responses in plant and animal tissues. They have salicylic acid binding proteins (SABPs) that have shown to affect multiple animal tissues. The first discovered medicinal properties of the isolated compound was involved in pain and fever management. They also play an active role in the suppression of cell proliferation. They have the ability to induce death in lymphoblastic leukemia and other human cancer cells. One of the most common drugs derived from salicylates is aspirin, also known as acetylsalicylic acid, with anti-inflammatory and anti-pyretic properties.


title: Drug discovery

text: Microbes compete for living space and nutrients. To survive in these conditions, many microbes have developed abilities to prevent competing species from proliferating. Microbes are the main source of antimicrobial drugs. Streptomyces isolates have been such a valuable source of antibiotics, that they have been called medicinal molds. The classic example of an antibiotic discovered as a defense mechanism against another microbe is penicillin in bacterial cultures contaminated by "Penicillium" fungi in 1928.


title: Drug discovery

text: Marine environments are potential sources for new bioactive agents. Arabinose nucleosides discovered from marine invertebrates in 1950s, demonstrated for the first time that sugar moieties other than ribose and deoxyribose can yield bioactive nucleoside structures. It took until 2004 when the first marine-derived drug was approved. For example, the cone snail toxin ziconotide, also known as Prialt treats severe neuropathic pain. Several other marine-derived agents are now in clinical trials for indications such as cancer, anti-inflammatory use and pain. One class of these agents are bryostatin-like compounds, under investigation as anti-cancer therapy.


title: Drug discovery

text: As above mentioned, combinatorial chemistry was a key technology enabling the efficient generation of large screening libraries for the needs of high-throughput screening. However, now, after two decades of combinatorial chemistry, it has been pointed out that despite the increased efficiency in chemical synthesis, no increase in lead or drug candidates has been reached. This has led to analysis of chemical characteristics of combinatorial chemistry products, compared to existing drugs or natural products. The chemoinformatics concept chemical diversity, depicted as distribution of compounds in the chemical space based on their physicochemical characteristics, is often used to describe the difference between the combinatorial chemistry libraries and natural products. The synthetic, combinatorial library compounds seem to cover only a limited and quite uniform chemical space, whereas existing drugs and particularly natural products, exhibit much greater chemical diversity, distributing more evenly to the chemical space. The most prominent differences between natural products and compounds in combinatorial chemistry libraries is the number of chiral centers (much higher in natural compounds), structure rigidity (higher in natural compounds) and number of aromatic moieties (higher in combinatorial chemistry libraries). Other chemical differences between these two groups include the nature of heteroatoms (O and N enriched in natural products, and S and halogen atoms more often present in synthetic compounds), as well as level of non-aromatic unsaturation (higher in natural products). As both structure rigidity and chirality are well-established factors in medicinal chemistry known to enhance compounds specificity and efficacy as a drug, it has been suggested that natural products compare favourably to today's combinatorial chemistry libraries as potential lead molecules.


title: Drug discovery

text: The first is sometimes referred to as random collection and screening of material, but the collection is far from random. Biological (often botanical) knowledge is often used to identify families that show promise. This approach is effective because only a small part of the earth's biodiversity has ever been tested for pharmaceutical activity. Also, organisms living in a species-rich environment need to evolve defensive and competitive mechanisms to survive. Those mechanisms might be exploited in the development of beneficial drugs.


title: Drug discovery

text: A collection of plant, animal and microbial samples from rich ecosystems can potentially give rise to novel biological activities worth exploiting in the drug development process. One example of successful use of this strategy is the screening for antitumor agents by the National Cancer Institute, which started in the 1960s. Paclitaxel was identified from Pacific yew tree "Taxus brevifolia". Paclitaxel showed anti-tumour activity by a previously undescribed mechanism (stabilization of microtubules) and is now approved for clinical use for the treatment of lung, breast, and ovarian cancer, as well as for Kaposi's sarcoma. Early in the 21st century, Cabazitaxel (made by Sanofi, a French firm), another relative of taxol has been shown effective against prostate cancer, also because it works by preventing the formation of microtubules, which pull the chromosomes apart in dividing cells (such as cancer cells). Other examples are: 1. Camptotheca (Camptothecin · Topotecan · Irinotecan · Rubitecan · Belotecan); 2. Podophyllum (Etoposide · Teniposide); 3a. Anthracyclines (Aclarubicin · Daunorubicin · Doxorubicin · Epirubicin · Idarubicin · Amrubicin · Pirarubicin · Valrubicin · Zorubicin); 3b. Anthracenediones (Mitoxantrone · Pixantrone).


title: Drug discovery

text: The second main approach involves ethnobotany, the study of the general use of plants in society, and ethnopharmacology, an area inside ethnobotany, which is focused specifically on medicinal uses.


title: Drug discovery

text: Artemisinin, an antimalarial agent from sweet wormtree "Artemisia annua", used in Chinese medicine since 200BC is one drug used as part of combination therapy for multiresistant "Plasmodium falciparum".


title: Drug discovery

text: The elucidation of the chemical structure is critical to avoid the re-discovery of a chemical agent that is already known for its structure and chemical activity. Mass spectrometry is a method in which individual compounds are identified based on their mass/charge ratio, after ionization. Chemical compounds exist in nature as mixtures, so the combination of liquid chromatography and mass spectrometry (LC-MS) is often used to separate the individual chemicals. Databases of mass spectras for known compounds are available and can be used to assign a structure to an unknown mass spectrum. Nuclear magnetic resonance spectroscopy is the primary technique for determining chemical structures of natural products. NMR yields information about individual hydrogen and carbon atoms in the structure, allowing detailed reconstruction of the molecule's architecture.


title: Drug discovery

text: When a drug is developed with evidence throughout its history of research to show it is safe and effective for the intended use in the United States, the company can file an application – the New Drug Application (NDA) – to have the drug commercialized and available for clinical application. NDA status enables the FDA to examine all submitted data on the drug to reach a decision on whether to approve or not approve the drug candidate based on its safety, specificity of effect, and efficacy of doses.


title: John Colicos

text: John Colicos (December 10, 1928 – March 6, 2000) was a Canadian actor. He performed on stage and television in the United States and Canada.


title: John Colicos

text: In 1957 he appeared in "Mary Stuart" at the Phoenix Theatre in New York City and in 1963 he appeared in "Troilus and Cressida" at the Stratford Festival in Stratford, Ontario, Canada. His other New York theatre credits are "King Lear" (1956), "The Devils" (1965–1966), "Serjeant Musgrave's Dance" (1966), and "Soldiers" (1968). Mr. Colicos' skill in acting resulted in his being chosen to play the title role in a memorable and first-ever production of "King Lear" (1964) at the Stratford Festival.


title: John Colicos

text: He appeared as Monks in a television version of "Oliver Twist" for the "DuPont Show of the Month" series in 1959. He also gave memorable performances in 1966 on the CBS soap opera "The Secret Storm"; as the unscrupulous Thomas Cromwell in the 1969 movie version of "Anne of the Thousand Days"; and as the governor of Umakran in the episode "The Goddess Calabra" from the 1973 TV show "The Starlost".


title: John Colicos

text: On American television, he established himself as a science-fiction villain icon, portraying the first Klingon ever seen in the "Star Trek" franchise, Commander Kor in the "" episode "Errand of Mercy" (1967). Colicos worked with Gene Roddenberry designing the look the Klingons have on Star Trek (1966). Budget constraints prevented the extensive makeup the Klingons were supposed to have so Colicos suggested they have a leathery Genghis Khan look, dark skin and hair. He also portrayed Count Baltar in the original "Battlestar Galactica" movie and television series. Over a quarter-century after his initial appearance in the "Star Trek" franchise, Colicos reprised his role as the 140-year-old Kor in three episodes of "", telecast between 1994 and 1998.


title: John Colicos

text: Aside from his science-fiction roles, Colicos also appeared numerous times in episodic television from the 1960s onwards, including the portrayal of the villain on three episodes of "". He appeared in four episodes of the CBC docu-drama "The National Dream" as the "railway general" William Cornelius Van Horne and appeared in seven episodes of "Mannix". The last person shot and killed in the television series "Gunsmoke" (1955–1975) was Judge Flood, played by Colicos in episode 631, "Hard Labor".


title: John Colicos

text: Several years after his "Battlestar Galactica" tenure, Colicos again ventured into science fiction. In August and September 1981, he portrayed Mikkos Cassadine, a demented, power-mad businessman bent on freezing the world, on the ABC soap opera "General Hospital". He was also the voice of the X-Men villain Apocalypse/En Sabah Nur (1993–1995) in the Fox Kids animated "" television series in the nineties, and twice played rogue alien Quinn in the first season (1988–1989) of "War of the Worlds".


title: John Colicos

text: In 1982 he ventured into educational TV with TVOntario's award-winning production of "Prophecy with John Colicos". The writer/director, Dr. Robert Gardner, recalled his initial meeting with the actor: "I had seen him scores of times in movies and television and I was very nervous. In truth, though, he was a joy to work with. Once he sensed that you were prepared he was thoroughly professional. His presence in the ninety-minute production was the main reason it went on to win the prestigious Gold Medal at the Atlanta International Film Festival."


title: John Colicos

text: He appeared in TV commercials during the 1990s for America's Best Contacts & Eyeglasses. Colicos' final acting appearance was his reprise of Count Baltar in the concept demonstration trailer "", exhibited at many science fiction conventions in 1999.


title: John Colicos

text: He married Mona McHenry in 1956 and they divorced in 1981. They had two sons, Nicholas (also an actor) and Edmund. Colicos died in Toronto on March 6, 2000, at the age of 71, after a series of heart attacks.


title: Escape from Monkey Island

text: Escape from Monkey Island is an adventure game developed and released by LucasArts in 2000. It is the fourth game in the "Monkey Island" series, and the sequel to the 1997 videogame "The Curse of Monkey Island". It is the first game in the series to use 3D graphics and the second game to use the GrimE engine, which was upgraded from its first use in "Grim Fandango".


title: Escape from Monkey Island

text: The game centers on the pirate Guybrush Threepwood, who returns home with his wife Elaine Marley after their honeymoon, to find her erroneously declared dead, and her office of governor up for election. Guybrush must find a way to restore Elaine to office, while uncovering a plot to turn the Caribbean into a tourist trap, headed by his nemesis LeChuck and an Australian conspirator Ozzie Mandrill.


title: Escape from Monkey Island

text: "Escape from Monkey Island" won positive reviews and was a moderate commercial success. It was ultimately the last LucasArts adventure game to be released, as the company's later projects "" and "" were canceled in 2003 and 2004, respectively. The game was followed by "Tales of Monkey Island", released by Telltale Games in 2009.


title: Escape from Monkey Island

text: "Escape from Monkey Island" is an adventure game that consists of dialogue with characters and solving puzzles. The game is controlled entirely with the keyboard or alternatively with a joystick, making it the only non-point-and-click game in the "Monkey Island" series.


title: Escape from Monkey Island

text: A feature of the game are action-lines: Guybrush will glance at any items that can be interacted with; the player can use 'Page Up' or 'Page Down' to select the item that he wants Guybrush to look at.


title: Escape from Monkey Island

text: One of the hallmark aspects of the "Monkey Island games", the insult swordfighting — the sword duels which were won by knowing the appropriate insults and responses — is briefly touched upon in the game as "insult armwrestling", and in an unwinnable insult duel against Ozzie Mandrill. In the second part of the game, the insult games are replaced by "Monkey Kombat", the name being a parody of "Mortal Kombat" with a symbol to match. Monkey Kombat is a sub-game akin to rock-paper-scissors, where the player needs to memorize lines of "monkey insults and retorts" which consist of per-game randomized compositions of "monkey words" like "oop", "chee", "ack" and "eek".


title: Escape from Monkey Island

text: Guybrush Threepwood and Elaine Marley return to Mêlée Island from their honeymoon. They find that Elaine has been declared officially dead, her position as governor has been revoked and her mansion is scheduled to be demolished. The governorship is up for election, and suddenly a person known as Charles L. Charles presents himself as the lead candidate. As Elaine begins her campaign to recover her position, Guybrush hires navigator Ignatius Cheese in a game of insult arm-wrestling, meets again with two of his old "friends", Carla and Otis, and heads out to Lucre Island to recover the Marley family heirlooms and obtain the legal documents to save her mansion. During his trip, Guybrush learns of the Marley family's greatest secret: a voodoo talisman known as the Ultimate Insult, which allows the user to spread insults so heinous, it destroys the spirit and will of those who hear it. He is framed for bank robbery by crook Pegnose Pete at the hiring of the Australian land developer Ozzie Mandrill, but proves his innocence.


title: Escape from Monkey Island

text: After acquiring the legal deeds and returning to the manor, Guybrush and Elaine discover that Charles L. Charles is really the shape-shifting Demon Pirate LeChuck, having been freed from his ice prison and seeking the Ultimate Insult. As Elaine continues her campaign, Guybrush searches the Jambalaya and Knuttin Atoll islands and recovers the pieces of the Ultimate Insult. Upon returning home, he is ambushed by the newly elected governor LeChuck and Ozzie Mandrill, who steal the pieces from him. The two villains are revealed to be working together, with Ozzie to rid of all pirates and turn the Caribbean into a resort and LeChuck out of debt to Ozzie for freeing him from his icy tomb and to use the Ultimate Insult to break Elaine and marry her. Feeling they might need Guybrush as a hostage, the two dump him on Monkey Island.


title: Escape from Monkey Island

text: Despite temporary discouragement, Guybrush sets about making his escape. He learns the art of Monkey Kombat from the "monkey prince of Monkey Island" and, upon restoring the hermit Herman Toothrot's memory, discovers that the old man is actually Elaine's missing grandfather, having contracted amnesia twenty years prior due to being pushed into a whirlpool off the coast of Australia by Ozzie. After constructing an even bigger Ultimate Insult, Guybrush discovers that the colossal monkey head statue of the island hides a giant pilot-able monkey robot. He reactivates the Mecha and powers it and Herman and the island's monkeys join him in piloting it. With the robot, Guybrush manages to disable an Ultimate Insult amplifier made by Ozzie before returning to Mêlée. During this time, Ozzie has managed to capture Elaine and assemble the Ultimate Insult. When it appears to fail due to the lack of the amplifier, LeChuck takes matters into his own hands and possesses a statue of himself he had built shortly after his gubernatorial victory. Ozzie uses the Ultimate Insult to take control of LeChuck's statue form and engages Guybrush's monkey robot in Monkey Kombat. During the duel, Guybrush performs repeated ties, allowing Elaine to escape and causing LeChuck to smack his head in exasperation, crushing Ozzie and destroying the Ultimate Insult. LeChuck explodes. Guybrush and Elaine are reunited and Grandpa Marley resumes being the governor of Mêlée Island, so that the couple can go back to being pirates.


title: Escape from Monkey Island

text: The game was made with Sean Clark and Michael Stemmle as lead designers, both of whom worked on LucasArts' previous adventure titles "Indiana Jones and the Fate of Atlantis" and "Sam & Max Hit the Road". Sean Clark also worked on "Loom" and "The Dig". "Escape" uses a slightly improved version of the GrimE engine introduced by "Grim Fandango". Compared to the rest of the series, the SCUMM scripting language was replaced by the Lua programming language. This is referenced in-game; the pirate-themed SCUMM Bar, which first appeared in "The Secret of Monkey Island", is replaced during the game with the tropical-themed Lua Bar.


title: Escape from Monkey Island

text: A new version of the iMUSE interactive music system incorporating MP3 compression, among other changes, was built and used for the game. Interactive programming of the music and ambiance streams in the iMUSE system was done by lead sound designer Larry the O. "Escape's" introductory music is identical to that of the third game, unlike the earlier sequels which featured newly composed remixes of the well-known "Monkey Island" theme. Clint Bajakian, who had previously been an additional composer on "Monkey Island 2: LeChuck's Revenge", acted as the game's main composer, with additional tracks by Michael Land (who had been the lead composer on the previous three "Monkey Island" games), Peter McConnell, Anna Karney, and Michael Lande (not to be confused with Michael Land).


title: Escape from Monkey Island

text: The voice cast saw the return of Dominic Armato as Guybrush, Earl Boen as LeChuck, Leilani Jones Wilmore as the Voodoo Lady and Denny Delk as Murray. The only major voice not to return was Alexandra Boyd who voiced Elaine in the previous game. She was replaced by Charity James. Stan is also voiced by a different actor, Pat Fraley. Additionally, characters who had previously appeared in "The Secret of Monkey Island" such as Carla, Otis and Herman Toothrot, are heard with voice actors for the first time.


title: Escape from Monkey Island

text: The game was also released on PlayStation 2 in 2001. Apart from obvious control differences, the PS2 version only varies by a slightly higher polygon count and use of less pre-rendered material. "Escape" is the third LucasArts adventure game to have a console release, following "The Secret of Monkey Island" for the Sega CD and "Maniac Mansion" for the NES.


title: Escape from Monkey Island

text: According to Heinrich Lenhardt of "PC Gamer US", "[I]f it wasn't for the sales figures in Germany, LucasArts probably wouldn't have bothered doing another "Monkey Island"" after "The Curse of Monkey Island". In response to questions about the success of "Grim Fandango" and the viability of adventure games in the United States market, Tom Sarris of LucasArts defended the company's decision to make "Escape from Monkey Island" in 2000. He told GameSpot: "We look at the sales figures from a worldwide standpoint and ask ourselves if it still makes sense to make adventure games. "Grim Fandango" made a profit, so the answer is yes, it's still viable from a financial point of view".


title: Escape from Monkey Island

text: Discussing "Escape from Monkey Island"s performance in December 2000, Simon Jeffery of LucasArts said that the company was "really happy with the [game's] success". He noted that it was "selling well" in the United States and "incredibly well in Europe", which he called proof that a market still existed for adventure games, despite a widespread belief that the genre had died. The game's computer version sold 55,275 copies and earned $2 million in the United States by the end of 2000, according to the market research firm PC Data. In the German market, "Escape" debuted at #4 on Media Control's computer game sales chart for November 2000. It placed ninth and 16th in its following two months, respectively. PC Data estimated its sales in the United States at 32,576 units for 2001, and 9,168 for the first six months of 2002. Its jewel case SKU sold 11,061 copies in North America during 2003.


title: Escape from Monkey Island

text: In March 2003, LucasArts' Bill Tiller said that he was not sure what "EMI" sold, but thought it had decent numbers on the PC. In contrast, he reported that he "heard rumor of ... abysmal" sales for its PlayStation 2 release. In retrospect, Rob Smith wrote in "" that "the stateside reception [for "Escape of Monkey Island"] was disappointing, but retail response was buoyed by overseas interest and sales—particularly in Europe, where the demand for adventure games hadn't fallen as flat".


title: Escape from Monkey Island

text: The game was met with a generally favorable reception. The gameplay received criticism for its interface and the difficulty of keyboard or joystick control as compared to mouse controls. The "Monkey Kombat" was also criticized, with the GameSpot review stating that it was the single biggest problem in "Escape from Monkey Island". Another reviewer speculated that the designers presumably figured that combining insult fighting, cute monkeys, and a "Mortal Kombat" spoof would work well, but it did not.


title: Escape from Monkey Island

text: "PC Zone" gave it 82% and called it an enjoyable and fun game despite not having innovations. Adventure Gamers gave it four stars out of five and called it "a quality adventure game"; he was critical of restyling of the old locations on Mêlée Island and Monkey Island, but was satisfied with game's ending. Jeff Lundrigan in "Next Generation", rated it three stars out of five, having a praise on the story, characters, and production values.


title: Escape from Monkey Island

text: "Playboy" gave the PS2 version a score of 85% and said that the game captures aging Marx Brothers appeal, but with modern-day flair, also having a high remarks of gameplay and characters. "Maxim", however, gave the same version six out of ten, criticising a tongue-in-cheek jokes as tasteless. Jeff Lundrigan reviewed the PlayStation 2 version of the game for "Next Generation", rating it three stars out of five, and stated that the puzzles are confusing, but recommended to the gamers who have a patience to solve it.


title: Escape from Monkey Island

text: "Escape from Monkey Island" was a runner-up for GameSpot's, "The Electric Playground"s, IGN's and "Computer Gaming World"s awards for the best computer adventure title of 2000, all of which went to "The Longest Journey". "Computer Gaming World"s editors remarked that "Escape from Monkey Island" is "a lot of fun and is strongly recommended to fans, but it's a few jokes and puzzles short of being a classic like the other games in the series". However, CNET Gamecenter named it the year's best adventure game over "The Longest Journey", and its editors wrote that they could not "imagine a better graphic adventure" than LucasArts' title. It was also a finalist for their overall game of the year award, which went to "The Sims".


title: Escape from Monkey Island

text: The editors of "Computer Games Magazine" similarly nominated "Escape from Monkey Island" for their 2000 "Adventure Game of the Year" award.


title: Cañon City, Colorado

text: Cañon City is a home rule municipality that is the county seat and the most populous municipality of Fremont County, Colorado, United States. The city population was 17,141 at the 2020 United States Census. Cañon City is the principal city of the Cañon City, CO Micropolitan Statistical Area and is a part of the Front Range Urban Corridor. Cañon City straddles the easterly flowing Arkansas River and is a popular tourist destination for sightseeing, whitewater rafting, and rock climbing. The city is known for its many public parks, fossil discoveries, Skyline Drive, The Royal Gorge railroad, the Royal Gorge, and extensive natural hiking paths. In 1994, the United States Board on Geographic Names approved adding the tilde to the official name of Cañon City, a change from Canon City as the official name in its decisions of 1906 and 1975. It is one of the few U.S. cities to have the Spanish Ñ in its name, others being La Cañada Flintridge, California; Española, New Mexico; Peñasco, New Mexico; and Peñitas, Texas.


title: Cañon City, Colorado

text: Cañon City was laid out on January 17, 1858, during the Pike's Peak Gold Rush, but then the land was left idle. A new company "jumped the claim" to the town's site in late 1859, and it put up the first building in February 1860. This town was originally intended as a commercial center for mining in South Park and the upper Arkansas River.


title: Cañon City, Colorado

text: In 1861, the town raised two companies of volunteers to serve with the Second Colorado Infantry during the American Civil War. This regiment fought in skirmishes in nearby New Mexico and as far east as the Indian Territory (Oklahoma) and Missouri before ending its organization in 1865.


title: Cañon City, Colorado

text: In 1862, A. M. Cassaday drilled for petroleum north of Cañon City, close to a known oil seep. Cassaday struck oil at the depth of , and he completed the first commercial oil well west of the Mississippi River. He drilled five or six more wells nearby, and he refined kerosene and fuel oil from the petroleum. Cassaday sold the products in Denver.


title: Cañon City, Colorado

text: A number of metal ore smelters were built in Cañon City following the discovery of gold at Cripple Creek in 1891.


title: Cañon City, Colorado

text: The Cañon City Downtown Historic District is an historic district that was listed on the National Register of Historic Places in 1983.


title: Cañon City, Colorado

text: Cañon City is located in eastern Fremont County at (38.446800, -105.228305) at an altitude of . It sits primarily on the north side of the Arkansas River, just east of where the river exits from Royal Gorge. It is bordered to the south by the unincorporated community of Lincoln Park. Via U.S. Route 50, Pueblo is to the east and Poncha Springs is to the west. Colorado Springs is to the northeast.


title: Cañon City, Colorado

text: The city's nickname, "the Climate Capital of Colorado", derives from the combination of unique geography and elevation protecting the city from harsh weather conditions. The average daily high temperature in January is 14 °F (7.8 °C) warmer in Cañon City than in Grand Junction, even though the elevation of Cañon City is higher.


title: Cañon City, Colorado

text: The average minimum temperature in January is . During July, overnight lows are on average. Cañon City has a semi-arid climate (Köppen climate classification ""BSk"").


title: Cañon City, Colorado

text: As Cañon City has grown, the city has both annexed surrounding communities and developed new subdivisions to create the city that exists today.


title: Cañon City, Colorado

text: Cañon City is home to many city-owned parks, as well as parks owned by the Cañon City Area Recreation and Park District.


title: Cañon City, Colorado

text: The Cañon City Area Recreation and Park District, commonly called the Rec District, was created in 1965 to better serve the community's recreational needs with parks, the R.C. Icabone Pool (a public swimming pool), a dog park, an archery range and a ropes course along with a rec district office with a community room.


title: Cañon City, Colorado

text: In addition, the city maintains the Tunnel Drive Trail, a four-mile long out-and-back trail that follows the course of an old irrigation canal. The trailhead is located at the west end of Tunnel Drive, just inside the city limits.


title: Cañon City, Colorado

text: The Guy U. Hardy Award for Service to Outdoor Recreation was created in the name of Guy U. Hardy to recognize people in the community who "help preserve, protect and advocate for providing outdoor recreation opportunities." Hardy had a significant impact on outdoor recreational opportunities in the Royal Gorge area.


title: Cañon City, Colorado

text: As of the 2020 census, there were 17,141 people residing in the city. The population density was . The racial makeup of the city was 95.4% White, 1.0% African American, 0.6% Native American, 0.1% Asian, and 1.5% from two or more races. Hispanics or Latinos of any race were 10.2% of the population. There were 7,448 households, out of which 22.6% had children under the age of 18 living with them. The average household size was 2.05.


title: Cañon City, Colorado

text: The age distribution was 22.6% under the age of 18 and 24.6% who were 65 years of age or older. Women represent 52% of the population.


title: Cañon City, Colorado

text: The median income for a household in the city was $46,464. The per capita income for the city was $25,232. About 17.1% of the population were below the poverty line.


title: Cañon City, Colorado

text: Along with a police department, sheriff's office and detention center, and a municipal court, Cañon City is home to the courts for Fremont County and the 11th Judicial District of Colorado. It has been described as "America’s cheeriest prison town".


title: Cañon City, Colorado

text: Cañon City is governed via the Council–manager government system. The city council consists of seven members who are elected from districts. The mayor is elected by the entire city.


title: Cañon City, Colorado

text: The area being situated along the Arkansas River has allowed for soil suitable to orchards, ranching, and farming, but has largely grown to rely on the large number of state and federal prisons in the area, as well as to tourism, education, manufacturing, medicine and many other sectors.


title: Cañon City, Colorado

text: Cañon City depends on the Colorado Department of Corrections and federal prison system, and its tourism industry which includes the Royal Gorge Route Railroad, Royal Gorge Bridge and Park, Red Canyon Park, The Abbey winery, and various other attractions. The major local employers include downtown shops, the entrepreneurial TechSTART initiative that attracts major technology-based entrepreneurs, and Centura Health (owner of St. Thomas More Hospital and the Progressive Care Center).


title: Cañon City, Colorado

text: Prisons have served an important significance to both Cañon City and the surrounding areas of Fremont County, as well as to the state of Colorado. The Museum of Colorado Prisons has been given the role of preserving and presenting the past of the state's corrections system. Colorado Department of Corrections operates the Colorado Territorial Correctional Facility in Cañon City. In addition to several correctional facilities near Cañon City in unincorporated areas in Fremont County, Colorado State Penitentiary, the location of the state death row and execution chamber is in Fremont County. Other state prisons in Fremont County include Arrowhead Correctional Center, Centennial Correctional Facility, Fremont Correctional Facility, Four Mile Correctional Center, and Skyline Correctional Center.


title: Cañon City, Colorado

text: The Colorado Women's Correctional Facility near Cañon City in unincorporated Fremont County was decommissioned on June 4, 2009.


title: Cañon City, Colorado

text: From Cañon City's Downtown Historic District located in the heart of the city to the Royal Gorge Bridge, there are many places to see and visit in the area.


title: Cañon City, Colorado

text: Cañon City is home to a daily newspaper, called the "Cañon City Daily Record"; an FM radio station, Star Country 104.5 FM; and a long-running AM radio station, known as KRLN NewsRadio 1400 AM.


title: Cañon City, Colorado

text: Transportation in the Cañon City area consists of cab service, shuttle bus service, and a downtown wagon ride. The Royal Gorge Bridge trolley had also been used during special events (it was destroyed in the Royal Gorge Fire, but it was reserved for use by the Royal Gorge Bridge & Park. Jeep tours and Segway tours are also available to explore local parks such as Red Canyon Park or scenic places such as Skyline Drive.


title: Cañon City, Colorado

text: The town is served by the Fremont County airport (1V6) which is 6 miles to the East and currently has no scheduled passenger service. Within an hour's drive is the Colorado Springs airport with daily service by major airlines.


title: Cañon City, Colorado

text: The area is served by one state and one U.S. highway with a mix of city and county roads to navigate the city or connect to neighboring areas.


title: Cañon City, Colorado

text: Cañon City's school system is under the direction of the Cañon City School District Fremont RE-1. The district currently has four elementary schools, one charter school, one school serving as both an elementary school and middle school, one middle school and one high school, Cañon City High School. For the higher education needs of the community, Pueblo Community College provides a branch campus on the west end of the city along U.S. Highway 50.


title: Cañon City, Colorado

text: The movie "Canon City" (1948) depicts the real-life 1947 escape of 12 prisoners from nearby Colorado State Penitentiary.


title: Cañon City, Colorado

text: A diner in Cañon City is the setting of the song "Navajo Rug", which was named by the Western Writers of America as one of the Top 100 Western Songs of all time.


title: Cañon City, Colorado

text: A fictional version of the city is depicted in Philip K. Dick's alternate history novel "The Man in the High Castle" (1963) and its eponymous 2015 television series adaptation. Cañon City is in an ostensibly-demilitarized "neutral zone" between the puppet regimes of the Japanese Pacific States, in the west, and Greater Nazi Reich, in the east, in the former United States.


title: Cañon City, Colorado

text: The season 12 premiere of the television series "ER" features the characters Samantha Taggart and Luka Kovac going to Canon City to find her son, who had run away to find his father, who was in prison there.


title: Cañon City, Colorado

text: In the Japanese manga series, JoJo's Bizarre Adventure, a turn-of-the-century race across the United States from San Diego to New York City takes place as the main story of the story's seventh part, Steel Ball Run. Cañon City (spelled Canon City) is featured as the third stage finish line and checkpoint for the racers.


title: Gem Archer

text: Colin Murray Archer (born 7 December 1966) is an English musician and singer, best known as a member of the English rock bands Oasis, Beady Eye and Noel Gallagher's High Flying Birds, making him, alongside Chris Sharrock, one of the only members of Oasis to have been part of both Liam and Noel Gallagher's post-Oasis projects. He is also known for his work with Heavy Stereo. He joined Oasis as rhythm guitarist in November 1999, and handled lead guitar for acoustic songs as well. He also contributed to the writing of some of the band's songs. Oasis broke up in August 2009, but in November 2009, Liam Gallagher announced he was writing new material with Archer as well as other ex-Oasis members excluding his brother Noel, under the name Beady Eye. After two albums with Beady Eye, 2011's "Different Gear, Still Speeding" and 2013's "BE", the band officially disbanded in October 2014. In 2017, Archer joined Noel Gallagher's High Flying Birds as lead guitarist, thus reuniting with former Oasis member Noel Gallagher.


title: Gem Archer

text: Archer began his musical career in a group called The Edge in the early 1980s. They released two singles, "Take a Walk" and "Little Girl Blue". In early 1987, he was part of a band called The Contenders. He then formed Whirlpool in 1991 and signed to Food Records and EMI Publishing. Simon Scott was also involved on a live basis playing keyboards and back-up vocals. After gigging around the UK and recording for 18 months the group folded. This laid the foundations for Heavy Stereo, with Gem taking over the role of singer.


title: Gem Archer

text: Archer formed Heavy Stereo with bassist Nez and guitarist Pete Downing both previously of Redcar indie band 2 Lost Sons who were subsequently signed with Creation Records. The band's only album, 1996's "Déjà Voodoo", did not enjoy much critical or commercial success. However, Heavy Stereo's next release did receive more attention through demos of new material, a critically acclaimed contribution to The Jam tribute album, "," and opening on a Paul Weller tour.


title: Gem Archer

text: Whilst at home in Durham, having returned to care for his mother, Archer – lying in front of the fire – heard a report on "The Big Breakfast" that Bonehead had left Oasis after a massive row with Noel Gallagher. He claims "I thought, Shit! They'll split now. I was a real fan, and I'm not just saying that. For me, Oasis had breathed life back into rock 'n' roll." He was unaware that Noel Gallagher – who knew Archer from both their days on the Creation Records label – had rung his home in London where it was Archer's son Joel's birthday party. Once Archer's mother had recovered, Gallagher invited him to Olympic Studios, where Oasis were mixing "Standing on the Shoulder of Giants". "We went to the pub and I couldn't stand not knowing if I was a part of the band. After less than half a pint of Guinness I said, 'What does Liam say?' And Noel said, 'It's my f*cking band. I'll have who I want.'" Archer claims the rest of Heavy Stereo were pleased for him to join Oasis.


title: Gem Archer

text: Since Archer did not perform on the "Giants" album, he received no royalties and, for the first few performances, was paid a standard session wage, about £85 a gig, as the new Oasis rhythm guitarist. His first official duty was to appear on the "Go Let It Out" video – on which he played lead guitar, as Andy Bell had yet to take over bass, so Noel played bass with Liam on acoustic guitar and vocals. Archer played his first rhythm guitar set at a session for alternative radio in Philadelphia.


title: Gem Archer

text: Though Archer was officially referred to as Oasis' rhythm guitarist, his role in Oasis was much more than that. In live settings, he and Noel often switched between lead and rhythm guitar and both Noel and Liam Gallagher have praised Archer for his contributions in the studio. Archer also had a role as a songwriter. His first songwriting contribution after joining Oasis was "Hung in a Bad Place", which appeared on Oasis' fifth album "Heathen Chemistry". This song was picked up for use in a commercial for Victoria's Secret in the US. His role was expanded on Oasis' sixth studio album, "Don't Believe the Truth", which features Archer's "A Bell Will Ring" and "Love Like a Bomb", the latter of which he co-wrote with singer Liam Gallagher. He also contributed the B-sides "Eyeball Tickler" and "The Quiet Ones" – an acoustic song. He also wrote "To Be Where There's Life" on the 2008 album "Dig Out Your Soul". Archer has said that he found it quite daunting to submit songs for consideration to the band because of Noel Gallagher's stature as a songwriter, whom he cites as one of his favourite songwriters. Archer, in rare occasions, contributed backing vocals to Oasis songs, such as on "The Meaning of Soul", "Force of Nature", and on the band's cover of The Who's "My Generation", played piano on "Stop Crying Your Heart Out" and harmonica on "Mucky Fingers".


title: Gem Archer

text: Andy Bell highlighted Archer's significance to Oasis, saying "Oasis has completely evolved. Noel's old mates have left, he's been divorced and really changed his own life around. He still has Liam but his relationship with Liam is different – it's more tempestuous. He needs a less extreme mate and Gem's it. Gem chills Noel out. And that makes Oasis a more stable ship."


title: Gem Archer

text: Although Noel Gallagher departed Oasis, Archer and he remained friends, and teamed up for a charity concert at the Royal Albert Hall.


title: Gem Archer

text: Noel Gallagher quit Oasis in August 2009, following an argument with his brother in Paris. Gallagher placed part of the blame for his decision to leave on Archer, and Andy Bell, for a lack of support saying "the lack of support and understanding from my... band mates has left me with no other option than to get me cape and seek pastures new." Soon afterwards the band announced they had split. However, Archer, Bell, Liam Gallagher and Oasis live drummer Chris Sharrock resolved to work together on a new project under a new name, Beady Eye. While Noel Gallagher maintains a friendship with Archer, as well as Oasis drummer Chris Sharrock, he claims that he has not spoken with his brother Liam or former Oasis bassist Andy Bell.


title: Gem Archer

text: Archer contributed guitar, bass and backing vocals to Beady Eye's debut album "Different Gear, Still Speeding", released on 28 February 2011.


title: Gem Archer

text: Archer also contributed guitar, keyboards, and backing vocals on Beady Eye's second album "BE", released on 10 June 2013.


title: Gem Archer

text: In December 2015, Archer appeared with Noel Gallagher at an acoustic gig in Lincoln on 6 December 2015, followed by an appearance for BBC Radio 2 the following night.


title: Gem Archer

text: In October 2016, Gem joined Noel Gallagher's High Flying Birds for their performance of "Half the World Away" dedicated to Caroline Aherne for Channel 4's Stand Up to Cancer telethon; leading to speculation he had become a permanent member of the band.


title: Gem Archer

text: In July 2017, it was confirmed that Gem had become a permanent member of Noel Gallagher's High Flying Birds.


title: Gem Archer

text: Outside of Oasis, Archer has collaborated with a few other artists, most notably Paul Weller. He has contributed acoustic guitar to the song 'One x One' on Weller's 2002 album "Illumination" and guitars and mellotron to the song 'Echoes Round The Sun on Weller's 2008 album "22 Dreams". He participated in an acoustic tour of the US with Weller when Steve Cradock of Ocean Colour Scene was unavailable, and provided guitar and backing vocals at the 2010 NME Awards when Weller performed a live set having received the 'Godlike Genius Award'.


title: Gem Archer

text: He also assisted Noel Gallagher in producing the first Proud Mary album, a band signed to Gallagher's Sour Mash record label.


title: Gem Archer

text: On 1 August 2013, Archer was admitted to hospital with serious head trauma and a fractured skull after a freak accident at home, by falling down a flight of stairs. After several scans, to ensure that there was no long-term effects, Beady Eye's V-Festival act was cancelled, so that he could be kept under observation. He was later said to be in a stable condition.


title: Gem Archer

text: He was married to Lou and is father to Joel and Libby. On November 26, 2022 he married Christine Mary Biller during a ceremony in London, England.


title: The Brief Wondrous Life of Oscar Wao

text: The Brief Wondrous Life of Oscar Wao is a 2007 novel written by Dominican American author Junot Díaz. Although a work of fiction, the novel is set in New Jersey in the United States, where Díaz was raised, and it deals with the Dominican Republic's experience under dictator Rafael Trujillo. The book chronicles both the life of Oscar de León, an overweight Dominican boy growing up in Paterson, New Jersey, who is obsessed with science fiction and fantasy novels and with falling in love, as well as a curse that has plagued his family for generations.


title: The Brief Wondrous Life of Oscar Wao

text: Narrated by multiple characters, the novel incorporates a significant amount of Spanglish and neologisms, as well as references to fantasy and science fiction books and films. Through its overarching theme of the "fukú" curse, it additionally contains elements of magic realism. It received highly positive reviews from critics, who praised Díaz's writing style and the multi-generational story. "The Brief Wondrous Life of Oscar Wao" went on to win numerous awards in 2008, such as the National Book Critics Circle Award and the Pulitzer Prize for Fiction.


title: The Brief Wondrous Life of Oscar Wao

text: The book chronicles the life of Oscar de León, an overweight Dominican boy growing up in Paterson, New Jersey, who is obsessed with science fiction and fantasy novels and with falling in love, as well as with the curse that has plagued his family for generations.


title: The Brief Wondrous Life of Oscar Wao

text: The middle sections of the novel center on the lives of Oscar's runaway sister, Lola; his mother, Hypatia Belicia Cabral; and his grandfather, Abelard. Rife with footnotes, science fiction and fantasy references, comic book analogies, and various Spanish dialects, the novel is also a meditation on story-telling, the Dominican diaspora and identity, sexuality, and oppression.


title: The Brief Wondrous Life of Oscar Wao

text: Most of the story is told by an apparently omniscient narrator who is eventually revealed to be Yunior de Las Casas, a college roommate of Oscar's who dated Lola. Yunior also appears in many of Díaz's short stories and is often seen as an alter ego of the author.


title: The Brief Wondrous Life of Oscar Wao

text: Oscar de León (nicknamed Oscar Wao, a bastardization of Oscar Wilde) is an overweight Dominican growing up in Paterson, New Jersey. Oscar desperately wants to be successful with women but, from a young age, is unable to find love, largely because he is a nerd obsessed with science fiction and comic books. His great fear is that he will die a virgin.


title: The Brief Wondrous Life of Oscar Wao

text: After high school, Oscar attends Rutgers University. His sister's boyfriend Yunior (the narrator of much of the novel) moves in with Oscar and tries to help him get in shape and become more "normal". After "getting dissed by a girl", he attempts to kill himself by drinking three bottles of liquor and jumping off the New Brunswick train bridge. He survives the fall but is seriously injured.


title: The Brief Wondrous Life of Oscar Wao

text: Oscar recuperates and graduates from Rutgers. He substitute teaches at his former high school and dreams about writing an epic work of science fiction. Eventually, he moves to the Dominican Republic and falls helplessly in love with Ybon, a sex worker who lives near him. Ybon is kind to Oscar but rejects his frequent romantic overtures. Ybon's boyfriend, a violent police captain, becomes jealous of Oscar and sends two goons who kidnap Oscar, take him to the sugarcane fields, and beat him into a coma. Oscar's family takes him back to the United States to heal.


title: The Brief Wondrous Life of Oscar Wao

text: Oscar recovers from the beating, borrows money from Yunior, and returns to the Dominican Republic. He spends 27 days writing and stalking Ybon. She is horrified at first but softens and eventually has sex with Oscar. Ybon's boyfriend's goons then find Oscar, take him back to the sugarcane fields, and kill him.


title: The Brief Wondrous Life of Oscar Wao

text: The novel contains significant exposition on Oscar's family history. One section is a first person narrative from the perspective of Oscar's sister, Lola, explaining her struggles to get along with their headstrong mother, Beli. Subsequent sections detail Beli's backstory growing up as an orphan in the Dominican Republic after her father was imprisoned and her mother and two sisters died. Her father was imprisoned after failing to bring his wife and daughter to meet some government officials, as he fears they will be taken by them. After being raised by an aunt, Beli enters into a relationship with a wealthy gangster named Dionisio. However, Dionisio turns out to be married to one of Rafael Trujillo's sisters, who, in a parallel with her son, has Beli taken to a cane field and also beaten nearly to death. She then escapes to the United States.


title: The Brief Wondrous Life of Oscar Wao

text: Instead of Díaz directly telling the story to the reader, he creates an aesthetic distance by speaking through the novel's narrator Yunior. Yunior provides analysis and commentary for the events he is relaying in the novel. His speech often exemplifies code switching, switching rapidly from a lively, Caribbean-inflected vernacular, replete with frequent usage of profanity to wordy, eloquent, and academic prose. This runs in parallel to several central themes of the novel regarding identity, as Yunior's code switching alludes to a struggle between his Dominican identity and his identity as a writer. Code switching between Spanish and English is also central to the narrative itself of the book, as characters switch back and forth as they see fit.


title: The Brief Wondrous Life of Oscar Wao

text: The narration of the book also shifts away from Yunior to another character at several key moments in the story. In chapter two, Lola narrates her own story from the first person. This is foreshadowing of the intimacy between Lola and Yunior yet to come. The beginning of chapter two also features the use of second person narration, rarely used in literature.


title: The Brief Wondrous Life of Oscar Wao

text: Díaz's use of Yunior as the main narrator of the book strengthens the idea of the novel as metafiction. Yunior reminds the reader consistently that he is telling the story, as opposed to the story happening in its own right.


title: The Brief Wondrous Life of Oscar Wao

text: "The Brief Wondrous Life of Oscar Wao" makes extensive use of footnotes to the point that many of the characters are developed in the footnotes in addition to the story. Rather than just provide factual background, Yunior's narrative continues in the footnotes just as it does in the body of the novel. When describing Oscar's deep love of science fiction and fantasy literature, Yunior continues in the footnotes: "Where this outsized love of genre jumped off from no one quite seems to know. It might have been a consequence being Antillean (who more sci-fi than us?) ..." The presence of Yunior's footnotes, therefore, remind the reader that there is always more to one's story.


title: The Brief Wondrous Life of Oscar Wao

text: Yunior even makes reference in the footnotes to his present life earlier in the novel than when he describes it in Chapter Eight. "In my first draft, Samaná was actually Jarabacoa, but then my girl Leonie, resident expert in all things Domo, pointed out that there are no beaches in Jarabacoa." Yunior thus builds the writing of the novel and his relationship with Oscar into the greater history of the Dominican Republic. The many science fiction references throughout the novel and footnotes emphasize (Yunior believes) the fantastical elements of Dominican history. Yunior cites the fall of Mordor and the dispelling of evil from Middle Earth from "The Lord of the Rings" as a complement to the fall of Trujillo.


title: The Brief Wondrous Life of Oscar Wao

text: The footnotes contain many references specifically to the reign of Rafael Trujillo from 1930 to 1961, providing historical background on figures like the Mirabal Sisters, who were assassinated by Trujillo, and Anacaona, an indigenous woman who fought against the invading Spanish colonialists. While referencing historical figures, Yunior frequently includes the novel's fictional characters in the historical events.


title: The Brief Wondrous Life of Oscar Wao

text: "But what was even more ironic was that Abelard had a reputation for being able to keep his head down during the worst of the regime's madness—for unseeing, as it were. In 1937, for example, while the Friends of the Dominican Republic were perejiling Haitians and Haitian-Dominicans and Haitian-looking Dominicans to death, while genocide was, in fact, in the making, Abelard kept his head, eyes, and nose safely tucked into his books (let his wife take care of hiding his servants, didn't ask her nothing about it) and when survivors staggered into his surgery with unspeakable machete wounds, he fixed them up as best he could without making any comments as to the ghastliness of their wounds."


title: The Brief Wondrous Life of Oscar Wao

text: Yunior thus builds a context for the Dominican history, where the characters are used just as much in the footnotes as they are in the body of the novel.


title: The Brief Wondrous Life of Oscar Wao

text: Many of the footnotes ultimately connect back to themes of coming to a new world (underscored through the novel's references to fantasy and sci-fi) or having one's own world completely changed. Trujillo's reign as revealed in the footnotes of the novel becomes just as dystopian as one of Oscar's favorite science fiction novels.