title: Sakhalin Koreans

text: Korean immigration to Sakhalin began as early as the 1910s when the Mitsui Group began recruiting labourers from the peninsula for their mining operations. In 1920, ten years after the annexation of Korea by Japan, there were fewer than one thousand Koreans in the whole of Karafuto Prefecture, overwhelmingly male. Aside from an influx of refugees from the Maritimes, who escaped to Karafuto during the Russian Revolution of 1917, the number of Koreans in the province did not rise very rapidly; as late as the mid-1930s, there were fewer than 6,000 Koreans in Karafuto. However, as Japan's war effort picked up, the Japanese government sought to put more people on the ground in the sparsely-populated prefecture in order to ensure their control of the territory and fill the increasing demands of the coal mines and lumber yards. Recruiters turned to sourcing workers from the Korean peninsula; at one point, over 150,000 Koreans were relocated to work on the island. Of those, around 10,000 mine workers were relocated to Japan prior to the war's end; present-day Sakhalin Koreans' efforts to locate them proved futile.


title: Sakhalin Koreans

text: The Imperial Japanese Army in Karafuto frequently used local ethnic minorities (Oroks, Nivkhs, and Ainu) to conduct intelligence-gathering activities, because, as indigenous inhabitants, their presence would not arouse suspicion on the Soviet half of the island. Ethnic Koreans could also be found on both sides of the border, but the use of Koreans as spies was not common, as the Karafuto police were wary of the support for the independence movement among Koreans. Soviet suspicion towards Korean nationalism, along with fears that the Korean community might harbour Japanese spies, led to the 1937 deportation of Koreans from Soviet-controlled northern Sakhalin and the Russian Far East, to Central Asia.


title: Sakhalin Koreans

text: After the large scale deportation of Soviet Koreans to Central Asia, the few who were not deported continued to live in northern Sakhalin. Some 2,000 Koreans remained in northern Sakhalin as part of Soviet-Japanese oil 'concessions' (joint ventures). Contradicting the Soviet stated aim for the deportation, Japan was allowed to bring in additional workers with Soviet permission, and the facilities operated until 1943.


title: Sakhalin Koreans

text: The Soviet Union invaded the Japanese portion of Sakhalin on 11 August 1945 during the Soviet–Japanese War towards the end of World War II. In the confusion that ensued, a rumour began to spread that ethnic Koreans could be serving as spies for the Soviet Union, and led to massacres of Koreans by Japanese police and civilians. Despite the generally limited amount of information about the massacres, two examples of massacres are comparatively well-known today: the incident in Kamishisuka (now Leonidovo) on 18 August 1945, and the incident in Mizuho Village (now Pozharskoye), which lasted from 20 to 23 August 1945.


title: Sakhalin Koreans

text: In Kamishisuka, the Japanese police arrested 19 Koreans on charges of spy activities; 18 were found shot within the police station the next day. The sole survivor, a Korean known only by his Japanese name Nakata, had survived by hiding in a toilet; he later offered testimony about the event. In Mizuho Village, Japanese fleeing Soviet troops who had landed at Maoka (now Kholmsk) claimed that the Koreans were cooperating with the Red Army and that they were pillaging Japanese property. Though Koreans and Japanese worked alongside each other in the village on farms and construction projects, the Japanese civilians turned against their Korean neighbors, killing 27 between 20 and 23 August. Other individual Koreans may have been killed to cover up evidence of Japanese atrocities committed during the evacuation: one woman interviewed by a US-Russian joint commission investigating the issue of Allied prisoners of war held by the Imperial Japanese Army in camps on Sakhalin reported that her ethnic Korean lover had been murdered by Japanese troops after he had witnessed mass shootings of hundreds of American prisoners of war.


title: Sakhalin Koreans

text: In the years after the Soviet invasion, most of the 400,000 Japanese civilians who had not already been evacuated during the war left voluntarily under the auspices of the US-USSR Agreement on Repatriation of those left in the USSR, signed in December 1946. Many of the 150,000 Koreans on the island safely returned to mainland Japan, and some went to the northern half of the Korean peninsula; however, roughly 43,000 were not accepted for repatriation by Japan, and also could not be repatriated to the southern half of the Korean peninsula due to the political situation. The Soviet government initially had drawn up plans to repatriate the Koreans along with the Japanese, but the local administration on Sakhalin objected, arguing that incoming Russians from the mainland would not be sufficient to replace the skilled labourers who had already departed. The indecision about the ultimate fate of the Sakhalin Koreans persisted until the outbreak of the Korean War, after which repatriation became a political impossibility. Some sources claim Stalin himself blocked their departure because he wanted to retain them as coal miners on the island. In 1957, Seoul appealed for Tokyo's assistance to secure the departure of ethnic Koreans from Sakhalin via Japan, but Tokyo took no real action on the request, and blamed Soviet intransigence for the lack of progress in resolving the issue; Japan continued its earlier policy of granting entrance only to Sakhalin Koreans who were married to Japanese citizens, or had a Japanese parent.


title: Sakhalin Koreans

text: During the late 1940s, the ranks of ethnic Koreans on the island were augmented by another 8,000 North Korean expatriates, recruited by the Soviet government to work in state-owned fisheries.


title: Sakhalin Koreans

text: In an effort to integrate the Korean labourers, who were unfamiliar with the Soviet system and unable to speak Russian, local authorities set up schools using the Korean language as the medium of instruction. However, the Sakhalin Koreans were believed to have been "infected with the Japanese spirit", and so for the most part the authorities did not trust them to run any of their own collective farms, mills, factories, schools, or hospitals. Instead, these tasks were left to several hundred ethnic Koreans imported from Central Asia, who were bilingual in Russian and Korean. Resentment towards the social dominance of Koreans from Central Asia over the Sakhalin Koreans led to tensions between the two groups; the latter developed a number of disparaging terms in Korean to refer to the former.


title: Sakhalin Koreans

text: The Sakhalin government's policy towards the Sakhalin Koreans continued to shift in line with bilateral relations between North Korea and the Soviet Union. During the 1950s, North Korea demanded that the Soviets treat Sakhalin Koreans as North Korean citizens, and, through their consulate, even set up study groups and other educational facilities for them (analogous to Chongryon's similar, more successful efforts among the Zainichi Koreans). During the late 1950s, it became increasingly difficult for the Sakhalin Koreans to obtain Soviet citizenship, and a growing proportion chose instead to become North Korean citizens rather than to deal with the burdens of remaining stateless, which included severe restrictions on their freedom of movement and the requirement to apply for permission from the local government in order to travel outside of Sakhalin. As of 1960, only 25% had been able to secure Soviet citizenship; 65% had declared North Korean citizenship, with the remaining 10% choosing to remain unaffiliated despite the difficulties this entailed. However, as relations between the Soviet Union and North Korea deteriorated, the authorities acted to de-emphasise Korean language education and reduce the influence of North Korea within the community; by the early 1970s, Sakhalin Koreans were once again encouraged to apply for Soviet citizenship.


title: Sakhalin Koreans

text: In the late 1960s and early 1970s, the situation of the Sakhalin Koreans improved as the outside world began to pay much more attention to their situation. Starting in 1966, Park No Hak, a former Sakhalin Korean who had earlier received permission to leave Sakhalin and settle in Japan by virtue of his having a Japanese wife, petitioned the Japanese government a total of 23 times to discuss the issue of the Sakhalin Koreans with the Soviet government. His actions inspired 500,000 South Koreans to form an organisation to work towards the repatriation of their co-ethnics; in response, the South Korean began radio broadcasts targeted at the Sakhalin Koreans, in an effort to assure them that they had not been forgotten. At the same time, Rei Mihara, a Tokyo housewife, formed a similar pressure group in Japan, and 18 Japanese lawyers attempted to sue the Japanese government to force them to accept diplomatic and financial responsibility for the transportation of the Sakhalin Koreans and their return to South Korea.


title: Sakhalin Koreans

text: Additionally, the Soviet government finally began to permit the Sakhalin Koreans to naturalize. However, as many as 10% continued to refuse both Soviet and North Korean citizenship and demanded repatriation to South Korea. By 1976, only 2,000 more of their population had been able to obtain permission to depart from Sakhalin, but that year, the Sakhalin government made a public announcement that people seeking to emigrate to South Korea could simply show up at the Immigration Office to file an application. Within a week, they had received more than 800 such applications, including some from North Korean citizens; this caused the North Korean embassy to complain to their Soviet counterparts about the new emigration policy. The Soviet authorities in the end chose for unspecified reasons to refuse to issue exit visas to most of those concerned, leading to the unusual case of public demonstrations about the refusals by Korean families. This level of open dissent provoked the authorities to completely reverse their liberalising stance towards the Sakhalin Koreans; they arrested more than 40 protestors, and in November 1976 deported them, but to North Korea rather than to the South as they desired. Further purges and intimidation of those seeking to emigrate also followed. Through to the early 1980s, locally born Korean youth, increasingly interested in their heritage, were seen as traitors by their Russian neighbours for wanting to know more about their ancestral land and for seeking to emigrate. The nadir of ethnic relations came after the 1983 shooting-down of Korean Air Lines Flight 007 by the Soviet Union.


title: Sakhalin Koreans

text: In 1985, Japan agreed to approve transit rights and fund the repatriation of the first generation of Sakhalin Koreans; the Soviet Union also began to liberalize their emigration laws in 1987. As of 2001, Japan spends US$1.2 million a year to fund Sakhalin Koreans' visits to Seoul. The Foreign Ministry allocated about $5 million to build a cultural centre in Sakhalin, which was intended to feature a library, an exhibition hall, Korean language classrooms, and other facilities, but , the project had not begun, causing protests among the Sakhalin Koreans.


title: Sakhalin Koreans

text: The foreign trade of Sakhalin with Japan is still roughly four times that with Korea, and Japanese companies greatly outnumber their Korean counterparts on the island. As a result, while members of the first generation still carry anti-Japanese sentiment, the younger generations have developed an interest in Japanese culture and have taken up the study of the Japanese language, much to the consternation of their elders. On 28 October 2006, a Korean student from the Sakhalin State University placed second in the All-CIS Japanese Language Students Competition.


title: Sakhalin Koreans

text: During the 1990s, commerce, communication, and direct flights opened up between Sakhalin and South Korea, and the two Koreas began to vie openly for influence among the Sakhalin Koreans. Television and radio programmes from both North and South Korea, as well as local programming, began to be broadcast on Sakhalin Korean Broadcasting, the only Korean television station in all of Russia. North Korea negotiated with Russia for closer economic relations with Sakhalin, and sponsored an art show in Yuzhno-Sakhalinsk in 2006. They have also permitted delegations of Sakhalin Koreans to visit relatives in North Korea. Scholarly studies suggest that roughly 1,000 Sakhalin Koreans have opted to repatriate to North Korea, but the rise of the South Korean economy combined with the ongoing economic and political turmoil in the North have made this option less attractive. Sakhalin Koreans have also provided assistance to refugees fleeing North Korea, either those who illegally escaped across the border, or those who escaped North Korean labour camps in Russia itself.


title: Sakhalin Koreans

text: South Korea and Japan jointly funded the building of a nursing home for elderly Sakhalin Koreans in Ansan, a suburb of Seoul, and under the auspices of the Korean Red Cross, 1,544 people had settled there and in other locations , while another 14,122 had travelled to South Korea on short-term visits at Japanese government expense. South Korean investors also began to participate in the international tenders for works contracts to develop the Sakhalin Shelf, as they are interested in the potential supply of liquefied natural gas. By the year 2000, South Korean missionaries had opened several churches, and South Koreans comprised the majority of international students at the Sakhalin State University. The Korean Residents' Association on Sakhalin, an ethnic representative body, is generally described as being pro-South Korean, analogous to Japan's Mindan. In addition to the elderly, a few younger Koreans have also chosen to move to South Korea, either to find their roots, or for economic reasons, as wages in South Korea are as much as three times those in Sakhalin. However, upon arrival, they often find that they are viewed as foreigners by the South Korean locals, despite their previous exposure to Korean culture in Sakhalin. As one returnee put it, "Sakhalin Koreans live in a different world than Sakhalin Russians but that world isn’t Korea". In general, younger Sakhalin Koreans, especially those lacking fluency in the Korean language, prefer to stay on Sakhalin. Of the 1,544 Koreans who repatriated to South Korea , nearly 10% eventually returned to Sakhalin. Conversely, some foreign students from Korea studying in Sakhalin also reported difficulties in befriending local Koreans, claiming that the latter looked down on them for being foreigners.


title: Sakhalin Koreans

text: In the late 1980s, suspicions against the Sakhalin Koreans remained. With the relaxation of internal migration controls and the dissolution of the Soviet Union, Russians began moving "en masse" back to the mainland, making ethnic Koreans an increasing proportion of the population; there were fears that they might become a majority of the island's population, and seek an autonomous republic or even independence. However, the rise of the regional economy and the cultural assimilation of the younger generations drove more than 95% of Koreans to stay in Sakhalin or move to the Russian Far East rather than leave for South Korea, as they have come to consider Russia their home country. The Sakhalin Koreans' family connections in South Korea have benefited even those who remained on Sakhalin with easier access to South Korean business and imports; trade with South Korea has brought the Sakhalin Koreans a better economic standing than the average resident of Sakhalin. By 2004, inter-ethnic relations between Russians and Koreans had improved greatly and were generally not described as being a problem on Sakhalin. However, Sakhalin Koreans who have travelled to the mainland of Russia, or have relocated to there (a population of roughly 10,000), report that they have encountered various forms of racism.


title: Sakhalin Koreans

text: Among the Koreans who remain on Sakhalin, roughly 7,000 of the original generation of settlers survive, while their locally born descendants make up the rest of the local Korean population. They are highly urbanized; half live in the administrative centre of Yuzhno-Sakhalinsk, where Koreans constitute nearly 12% of the population. Around thirty per cent of Sakhalin's thirty thousand Koreans still have not taken Russian citizenship. Unlike ethnic Russians or other local minority groups, Sakhalin Koreans are exempted from conscription, but there have been calls for this exemption to be terminated.


title: Sakhalin Koreans

text: Korean surnames, when Cyrillized, may be spelled slightly differently from the romanisations used in the US; the resulting common pronunciations also differ, as can be seen in the table at right. Furthermore, Korean naming practices and Russian naming practices conflict in several important ways. While most members of the older generations of Sakhalin Koreans used Korean names, members of the younger generations favor their Russian names. However, with the increasing exposure to South Korean pop culture, some younger Koreans have named their children after characters in Korean television dramas. The use of patronymics is not widespread.


title: Sakhalin Koreans

text: In addition to Korean names, the oldest generation of Sakhalin Koreans are often legally registered under Japanese names, which they had originally adopted due to the "sōshi-kaimei" policy of the Japanese colonial era. After the Soviet invasion, the Sakhalin authorities conducted name registration for the local Koreans on the basis of the Japanese identity documents issued by the old Karafuto government; as of 2006, the Russian government uniformly refused requests for re-registration under Korean names.


title: Sakhalin Koreans

text: Due to their greater population density and expectation that they would one day be allowed to return to Korea, the Sakhalin Koreans have kept something of a sojourner mentality rather than a settler mentality, which influenced their relation to the surrounding society; even today, they tend to speak much better Korean than those who were deported to Central Asia. A weekly Korean language newspaper, the "Saegoryeo Shinmun" (새고려 신문), has been published since 1949, while Sakhalin Korean Broadcasting began operation in 1956. Korean-language television programmes are broadcast locally, but typically with Russian subtitles. Additionally, during the Soviet era, Sakhalin Koreans were often hired to act as announcers and writers for official media aimed at the Koryo-saram in Central Asia. However, unlike the Koryo-saram, the spoken Korean of Sakhalin is not very closely related to Hamgyŏng dialect or Koryo-mar, but is instead descended from Jeolla and Gyeongsang dialects. As a result of the diplomatic situation up until the 1980s, during which South Korea had no relations with the Soviet Union, Korean-language instructional materials were provided by North Korea or developed domestically. Oddly enough, as a result, Sakhalin Koreans' writing, like that of Koryo-saram, follows the North Korean standard, but their spoken Korean in radio broadcasts has come to resemble the Seoul dialect of South Korea.


title: Sakhalin Koreans

text: Since the dissolution of the Soviet Union, there has been significant growth in religious activities among the Sakhalin Koreans; the establishment of churches was noted in scholarly articles as early as 1990. Christian hymns have become popular listening material, supplementing the more typical Russian, Western, and Korean pop music. Korean churches also broadcast religious content through Sakhalin Korean Broadcasting; a Baptist church run by ethnic Koreans sponsors a journalist there. However, large-scale religious events can be subjected to restriction by the government authorities: in June 1998 the local Russian Orthodox Church and the regional administration of Sakhalin successfully pressured Korean Presbyterian missionaries to cancel a conference of more than 100 Presbyterian and other Protestant missionaries from around the former Soviet Union. Ethnic Koreans are numerous among the church-goers of St. James Cathedral, seat of the Apostolic Prefecture of Yuzhno Sakhalinsk, in Yuzhno-Sakhalinsk. Catholic missions in Kholmsk and Aniva have also a fair number of Korean parishioners.


title: Sakhalin Koreans

text: In one survey, a third of the Sakhalin Korean population expressed a preference for traditional Korean music, a far higher proportion than in any other ethnic Korean community surveyed. However, despite their better knowledge of Korean language, the same survey showed that Korean pop music is less widespread among Sakhalin Koreans than among ethnic Koreans in Kazakhstan, possessing about the same degree of popularity as in Uzbekistan. Sakhalin Koreans also reported listening to Western popular and classical music at much lower rates than Koreans in the rest of the former Soviet Union. Study of traditional Korean musical instruments has also been gaining popularity across all generations. The Ethnos Arts School was established in 1991 in Yuzhno-Sakhalinsk to teach children's classes in traditional Korean dance, piano, sight singing, and the "gayageum", a zither-like instrument supposedly invented around the time of the Gaya confederacy.


title: The Gambler (novel)

text: The Gambler (; modern spelling: ) is a short novel by Fyodor Dostoevsky about a young tutor in the employment of a formerly wealthy Russian general. The novel reflects Dostoevsky's own addiction to roulette, which was in more ways than one the inspiration for the book: Dostoevsky completed the novel in 1866 under a strict deadline to pay off gambling debts.


title: The Gambler (novel)

text: "The Gambler" treated a subject Fyodor Dostoevsky himself was familiar with: gambling. Fyodor Dostoevsky gambled for the first time at the tables at Wiesbaden in 1863. From that time till 1871, when his passion for gambling subsided, he played at Baden-Baden, Homburg, and Saxon-les-Bains frequently, often beginning by winning a small amount of money and losing far more in the end. He first mentions his interest in gambling in a letter he sent to his first wife's sister on 1 September 1863 describing his initial success:


title: The Gambler (novel)

text: Within a week he lost his winnings and was forced to beg his family for money. He wrote to his brother Mikhail on 8 September 1863:


title: The Gambler (novel)

text: Fyodor Dostoevsky then agreed to a hazardous contract with F. T. Stellovsky that if he did not deliver a novel of 12 or more signatures by 1 November 1866, Stellovsky would acquire the right to publish Dostoevsky's works for nine years, until 1 November 1875, without any compensation to the writer. He noted down parts of his story, then dictated them to one of the first stenographers in Russia and his wife-to-be, young Anna Grigorevna, who transcribed them and copied it neatly out for him. With her help, he was able to finish the book in time.


title: The Gambler (novel)

text: The first-person narrative is told from the point of view of Alexei Ivanovich, a tutor working for a Russian family living in a suite at a German hotel.


title: The Gambler (novel)

text: The patriarch of the family, The General, is indebted to the Frenchman de Grieux and has mortgaged his property in Russia to pay only a small amount of his debt.


title: The Gambler (novel)

text: Upon learning of the illness of his wealthy aunt, "Grandmother", he sends streams of telegrams to Moscow and awaits the news of her demise. His expected inheritance will pay his debts and gain Mademoiselle Blanche de Cominges's hand in marriage.


title: The Gambler (novel)

text: Alexei is hopelessly in love with Polina, the General's niece. She asks him to go to the town's casino and place a bet for her. After hesitations, he succumbs and ends up winning at the roulette table. He returns to her the winnings but she will not tell him the reason she needs money. She only laughs in his face (as she does when he professes his love) and treats him with cold indifference, if not downright malice. He only learns the details of the General's and Polina's financial state later in the story through his long-time acquaintance, Mr. Astley. Astley is a shy Englishman who seems to share Alexei's fondness of Polina. He comes from English nobility and has a good deal of money.


title: The Gambler (novel)

text: One day while Polina and Alexei are on a walk he swears an oath of servitude to her. He tells her while on a walk on the Schlangenberg (a mountain in the German town) that all she had to do was give the word and he would gladly walk off the edge and plummet to his death. Thereafter, they see Baron and Baroness Wurmerhelm. Polina dares him to insult the aristocratic couple and he does so with little hesitation. This sets off a chain of events that details Mademoiselle Blanche's interest in the General and gets Alexei fired as tutor of the General's children. Shortly after this, Grandmother shows up and surprises the whole party of debtors and indebted. She tells them all that she knows all about the General's debt and why the Frenchman and woman are waiting around the suite day after day. She leaves the party of death-profiteers by saying that none of them are getting any of her money. She then asks Alexei to be her guide around the town famous for its healing waters and infamous for its casino where the tables are stacked with piles of gold; she wants to gamble.


title: The Gambler (novel)

text: After being ushered to the roulette table, she plays and wins 13,000 Friedrichs d'ors (7000–8000 roubles), a significant amount of money. After a short return to the hotel, she comes back to roulette tables and she starts to get the bug; before she leaves the town, she's lost over a hundred thousand roubles in three days.


title: The Gambler (novel)

text: When Alexei gets back to his room after sending Grandmother off at the railway station, he's greeted by Polina. She shows him a letter where des Grieux says he has started legal proceedings to sell the General's properties mortgaged to him, but he is returning properties worth fifty thousand roubles to the General for Polina's benefit. des Grieux says he feels he had fulfilled all his obligations that way. Polina tells Alexei she is des Grieux's mistress and she wishes she had fifty thousand to fling at des Grieux's face. Upon hearing this, Alexei runs out of the room and to the casino where he in a feverish rush of excitement wins in few hours two hundred thousand florins (100,000 francs) and becomes a rich man. When he gets back to his room and the waiting Polina, he empties his pockets full of gold (Alexei estimates the weight to some ) and bank notes onto the bed. At first she accuses him of trying to buy her like des Grieux, but then she embraces him. They fall asleep on the couch. Next day, she asks for fifty thousand florins (25,000 francs) and when he gives it to her, she flings that money at Alexei's face and runs off to Mr. Astley (Polina and Mr. Astley had been secretly meeting and exchanging notes; she was supposed to meet Astley the night before, but had come by mistake to Alexei's room). Alexei doesn't see her again.


title: The Gambler (novel)

text: After learning that the General wouldn't be getting his inheritance and that Prince Nilski is penniless, Mademoiselle Blanche leaves the hotel with her mother/chaperone for Paris and seduces Alexei to follow her. Alexei goes with them, and they stay together for almost a month, he allowing Mlle Blanche to spend his entire fortune on Mlle Blanche's personal expenses, carriages and horses, dinner dances, and a wedding-party. After getting herself financially secured, in order to get an accepted status in the societies, Mlle Blanche unexpectedly marries the General, who has followed her to Paris.


title: The Gambler (novel)

text: Alexei starts to gamble to survive. One day he passes Mr. Astley on a park bench in Bad Homburg and has a talk with him. He finds out from Astley that Polina is in Switzerland and actually does love Alexei. Astley tells that Grandmother has died and left Polina and the children financially secured. The General has died in Paris. Astley gives him some money but shows little hope that he will not use it for gambling. Alexei goes home, initially promising himself to head for Switzerland the next day, yet recollects a past incident where he spent the last of his money on gambling and won big. Drawing parallels to his destitution now, and believing himself to be predestined to win, he makes up his mind to try his luck at the roulette tables one last time before leaving for Switzerland tomorrow.


title: The Gambler (novel)

text: Several films have been inspired by the book. "The Great Sinner", a loose adaptation, starred Gregory Peck and Ava Gardner under the direction of Robert Siodmak in 1949. "Le joueur", a 1958 french film adaptation by Claude Autant-Lara, starred by Gérard Philipe. A 1972 co-production of the USSR and Czechoslovakia by Lenfilm studio and Barrandov Studios, directed by Alexei Batalov, follows the book closely.


title: The Gambler (novel)

text: There are two movies based on Dostoevsky's life during the time when he was writing the novel: the 1981 Soviet film "Twenty Six Days from the Life of Dostoyevsky" and the Hungarian director Károly Makk's 1997 film "The Gambler".


title: The Gambler (novel)

text: A radio play version was aired by BBC Radio 4 in December 2010, written by Glyn Maxwell and directed by Guy Retallack.


title: The Gambler (novel)

text: A two-part modern-day adaptation, written by Dolya Gavanski (who also played "Polina") and entitled "The Russian Gambler", was broadcast on BBC Radio 4 as part of its "Classic Serial" series in November 2013 and re-broadcast on BBC Radio 4 Extra in March 2018. The cast also included Ed Stoppard as Alexei.


title: Calcium in biology

text: Calcium ions (Ca) contribute to the physiology and biochemistry of organisms' cells. They play an important role in signal transduction pathways, where they act as a second messenger, in neurotransmitter release from neurons, in contraction of all muscle cell types, and in fertilization. Many enzymes require calcium ions as a cofactor, including several of the coagulation factors. Extracellular calcium is also important for maintaining the potential difference across excitable cell membranes, as well as proper bone formation.


title: Calcium in biology

text: Plasma calcium levels in mammals are tightly regulated, with bone acting as the major mineral storage site. Calcium ions, Ca, are released from bone into the bloodstream under controlled conditions. Calcium is transported through the bloodstream as dissolved ions or bound to proteins such as serum albumin. Parathyroid hormone secreted by the parathyroid gland regulates the resorption of Ca from bone, reabsorption in the kidney back into circulation, and increases in the activation of vitamin D to calcitriol. Calcitriol, the active form of vitamin D, promotes absorption of calcium from the intestines and bones. Calcitonin secreted from the parafollicular cells of the thyroid gland also affects calcium levels by opposing parathyroid hormone; however, its physiological significance in humans is dubious.


title: Calcium in biology

text: Intracellular calcium is stored in organelles which repetitively release and then reaccumulate Ca ions in response to specific cellular events: storage sites include mitochondria and the endoplasmic reticulum.


title: Calcium in biology

text: Characteristic concentrations of calcium in model organisms are: in "E. coli" 3mM (bound), 100nM (free), in budding yeast 2mM (bound), in mammalian cell 10-100nM (free) and in blood plasma 2mM.


title: Calcium in biology

text: In 2020, calcium was the 204th most commonly prescribed medication in the United States, with more than 2million prescriptions.


title: Calcium in biology

text: The U.S. Institute of Medicine (IOM) established Recommended Dietary Allowances (RDAs) for calcium in 1997 and updated those values in 2011. See table. The


title: Calcium in biology

text: European Food Safety Authority (EFSA) uses the term Population Reference Intake (PRIs) instead of RDAs and sets slightly different numbers: ages 4–10 800 mg, ages 11–17 1150 mg, ages 18–24 1000 mg, and >25 years 950 mg.


title: Calcium in biology

text: Because of concerns of long-term adverse side effects such as calcification of arteries and kidney stones, the IOM and EFSA both set Tolerable Upper Intake Levels (ULs) for the combination of dietary and supplemental calcium. From the IOM, people ages 9–18 years are not supposed to exceed 3,000 mg/day; for ages 19–50 not to exceed 2,500 mg/day; for ages 51 and older, not to exceed 2,000 mg/day. The EFSA set UL at 2,500 mg/day for adults but decided the information for children and adolescents was not sufficient to determine ULs.


title: Calcium in biology

text: For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For calcium labeling purposes 100% of the Daily Value was 1000 mg, but as of May 27, 2016 it was revised to 1300 mg to bring it into agreement with the RDA. A table of the old and new adult daily values is provided at Reference Daily Intake.


title: Calcium in biology

text: Although as a general rule, dietary supplement labeling and marketing are not allowed to make disease prevention or treatment claims, the FDA has for some foods and dietary supplements reviewed the science, concluded that there is significant scientific agreement, and published specifically worded allowed health claims. An initial ruling allowing a health claim for calcium dietary supplements and osteoporosis was later amended to include calcium and vitamin D supplements, effective January 1, 2010. Examples of allowed wording are shown below. In order to qualify for the calcium health claim, a dietary supplement must contain at least 20% of the Reference Dietary Intake, which for calcium means at least 260 mg/serving.


title: Calcium in biology

text: In 2005 the FDA approved a Qualified Health Claim for calcium and hypertension, with suggested wording "Some scientific evidence suggests that calcium supplements may reduce the risk of hypertension. However, FDA has determined that the evidence is inconsistent and not conclusive." Evidence for pregnancy-induced hypertension and preeclampsia was considered inconclusive. The same year the FDA approved a QHC for calcium and colon cancer, with suggested wording "Some evidence suggests that calcium supplements may reduce the risk of colon/rectal cancer, however, FDA has determined that this evidence is limited and not conclusive." Evidence for breast cancer and prostate cancer was considered inconclusive. Proposals for QHCs for calcium as protective against kidney stones or against menstrual disorders or pain were rejected.


title: Calcium in biology

text: The European Food Safety Authority (EFSA) concluded that "Calcium contributes to the normal development of bones." The EFSA rejected a claim that a cause-and-effect relationship existed between the dietary intake of calcium and potassium and maintenance of normal acid-base balance. The EFSA also rejected claims for calcium and nails, hair, blood lipids, premenstrual syndrome and body weight maintenance.


title: Calcium in biology

text: The United States Department of Agriculture (USDA) web site has a very complete searchable table of calcium content (in milligrams) in foods, per common measures such as per 100 grams or per a normal serving.


title: Calcium in biology

text: The amount of calcium in blood (more specifically, in blood plasma) can be measured as "total calcium", which includes both protein-bound and free calcium. In contrast, "ionized calcium" is a measure of free calcium. An abnormally high level of calcium in plasma is termed hypercalcemia and an abnormally low level is termed hypocalcemia, with "abnormal" generally referring to levels outside the reference range.


title: Calcium in biology

text: The total amount of Ca present in a tissue may be measured using Atomic absorption spectroscopy, in which the tissue is vaporized and combusted. To measure Ca concentration or spatial distribution within the cell cytoplasm "in vivo" or "in vitro", a range of fluorescent reporters may be used. These include cell permeable, calcium-binding fluorescent dyes such as Fura-2 or genetically engineered variant of green fluorescent protein (GFP) named Cameleon.


title: Calcium in biology

text: As access to an ionized calcium is not always available a corrected calcium may be used instead. To calculate a corrected calcium in mmol/L one takes the total calcium in mmol/L and adds it to ((40 minus the serum albumin in g/L) multiplied by 0.02). There is, however, controversy around the usefulness of corrected calcium as it may be no better than total calcium. It may be more useful to correct total calcium for both albumin and the anion gap.


title: Calcium in biology

text: In vertebrates, calcium ions, like many other ions, are of such vital importance to many physiological processes that its concentration is maintained within specific limits to ensure adequate homeostasis. This is evidenced by human plasma calcium, which is one of the most closely regulated physiological variables in the human body. Normal plasma levels vary between 1 and 2% over any given time. Approximately half of all ionized calcium circulates in its unbound form, with the other half being complexed with plasma proteins such as albumin, as well as anions including bicarbonate, citrate, phosphate, and sulfate.


title: Calcium in biology

text: Different tissues contain calcium in different concentrations. For instance, Ca (mostly calcium phosphate and some calcium sulfate) is the most important (and specific) element of bone and calcified cartilage. In humans, the total body content of calcium is present mostly in the form of bone mineral (roughly 99%). In this state, it is largely unavailable for exchange/bioavailability. The way to overcome this is through the process of bone resorption, in which calcium is liberated into the bloodstream through the action of bone osteoclasts. The remainder of calcium is present within the extracellular and intracellular fluids.


title: Calcium in biology

text: Within a typical cell, the intracellular concentration of ionized calcium is roughly 100 nM, but is subject to increases of 10- to 100-fold during various cellular functions. The intracellular calcium level is kept relatively low with respect to the extracellular fluid, by an approximate magnitude of 12,000-fold. This gradient is maintained through various plasma membrane calcium pumps that utilize ATP for energy, as well as a sizable storage within intracellular compartments. In electrically excitable cells, such as skeletal and cardiac muscles and neurons, membrane depolarization leads to a Ca transient with cytosolic Ca concentration reaching around 1 uM. Mitochondria are capable of sequestering and storing some of that Ca. It has been estimated that mitochondrial matrix free calcium concentration rises to the tens of micromolar levels "in situ" during neuronal activity.


title: Calcium in biology

text: The effects of calcium on human cells are specific, meaning that different types of cells respond in different ways. However, in certain circumstances, its action may be more general. Ca ions are one of the most widespread second messengers used in signal transduction. They make their entrance into the cytoplasm either from outside the cell through the cell membrane via calcium channels (such as calcium-binding proteins or voltage-gated calcium channels), or from some internal calcium storages such as the endoplasmic reticulum and mitochondria. Levels of intracellular calcium are regulated by transport proteins that remove it from the cell. For example, the sodium-calcium exchanger uses energy from the electrochemical gradient of sodium by coupling the influx of sodium into cell (and down its concentration gradient) with the transport of calcium out of the cell. In addition, the plasma membrane Ca ATPase (PMCA) obtains energy to pump calcium out of the cell by hydrolysing adenosine triphosphate (ATP). In neurons, voltage-dependent, calcium-selective ion channels are important for synaptic transmission through the release of neurotransmitters into the synaptic cleft by vesicle fusion of synaptic vesicles.


title: Calcium in biology

text: Calcium's function in muscle contraction was found as early as 1882 by Ringer. Subsequent investigations were to reveal its role as a messenger about a century later. Because its action is interconnected with cAMP, they are called synarchic messengers. Calcium can bind to several different calcium-modulated proteins such as troponin-C (the first one to be identified) and calmodulin, proteins that are necessary for promoting contraction in muscle.


title: Calcium in biology

text: In the endothelial cells which line the inside of blood vessels, Ca ions can regulate several signaling pathways which cause the smooth muscle surrounding blood vessels to relax. Some of these Ca-activated pathways include the stimulation of eNOS to produce nitric oxide, as well as the stimulation of K channels to efflux K and cause hyperpolarization of the cell membrane. Both nitric oxide and hyperpolarization cause the smooth muscle to relax in order to regulate the amount of tone in blood vessels. However, dysfunction within these Ca-activated pathways can lead to an increase in tone caused by unregulated smooth muscle contraction. This type of dysfunction can be seen in cardiovascular diseases, hypertension, and diabetes.


title: Calcium in biology

text: Calcium coordination plays an important role in defining the structure and function of proteins. An example a protein with calcium coordination is von Willebrand factor (vWF) which has an essential role in blood clot formation process. It was discovered using single molecule optical tweezers measurement that calcium-bound vWF acts as a shear force sensor in the blood. Shear force leads to unfolding of the A2 domain of vWF whose refolding rate is dramatically enhanced in the presence of calcium.


title: Calcium in biology

text: Ca ion flow regulates several secondary messenger systems in neural adaptation for visual, auditory, and the olfactory system. It may often be bound to calmodulin such as in the olfactory system to either enhance or repress cation channels. Other times the calcium level change can actually release guanylyl cyclase from inhibition, like in the photoreception system. Ca ion can also determine the speed of adaptation in a neural system depending on the receptors and proteins that have varied affinity for detecting levels of calcium to open or close channels at high concentration and low concentration of calcium in the cell at that time.


title: Calcium in biology

text: Substantial decreases in extracellular Ca ion concentrations may result in a condition known as hypocalcemic tetany, which is marked by spontaneous motor neuron discharge. In addition, severe hypocalcaemia will begin to affect aspects of blood coagulation and signal transduction.


title: Calcium in biology

text: Ca ions can damage cells if they enter in excessive numbers (for example, in the case of excitotoxicity, or over-excitation of neural circuits, which can occur in neurodegenerative diseases, or after insults such as brain trauma or stroke). Excessive entry of calcium into a cell may damage it or even cause it to undergo apoptosis, or death by necrosis. Calcium also acts as one of the primary regulators of osmotic stress (osmotic shock). Chronically elevated plasma calcium (hypercalcemia) is associated with cardiac arrhythmias and decreased neuromuscular excitability. One cause of hypercalcemia is a condition known as hyperparathyroidism.


title: Calcium in biology

text: Some invertebrates use calcium compounds for building their exoskeleton (shells and carapaces) or endoskeleton (echinoderm plates and poriferan calcareous spicules).


title: Calcium in biology

text: When abscisic acid signals the guard cells, free Ca ions enter the cytosol from both outside the cell and internal stores, reversing the concentration gradient so the K+ ions begin exiting the cell. The loss of solutes makes the cell flaccid and closes the stomatal pores.


title: Calcium in biology

text: Calcium is a necessary ion in the formation of the mitotic spindle. Without the mitotic spindle, cellular division cannot occur. Although young leaves have a higher need for calcium, older leaves contain higher amounts of calcium because calcium is relatively immobile through the plant. It is not transported through the phloem because it can bind with other nutrient ions and precipitate out of liquid solutions.


title: Calcium in biology

text: Ca ions are an essential component of plant cell walls and cell membranes, and are used as cations to balance organic anions in the plant vacuole. The Ca concentration of the vacuole may reach millimolar levels. The most striking use of Ca ions as a structural element in algae occurs in the marine coccolithophores, which use Ca to form the calcium carbonate plates, with which they are covered.


title: Calcium in biology

text: Calcium is needed to stabilize the permeability of cell membranes. Without calcium, the cell walls are unable to stabilize and hold their contents. This is particularly important in developing fruits. Without calcium, the cell walls are weak and unable to hold the contents of the fruit.


title: Calcium in biology

text: Some plants accumulate Ca in their tissues, thus making them more firm. Calcium is stored as Ca-oxalate crystals in plastids.


title: Calcium in biology

text: Ca ions are usually kept at nanomolar levels in the cytosol of plant cells, and act in a number of signal transduction pathways as second messengers.


title: Destroy Boys

text: Destroy Boys are an American punk rock band formed in Sacramento, California, in 2015. In 2017, they were nominated for awards in the 25th Sacramento Area Music Awards in the categories "New Artist", "Punk/post-punk" and "Teen" and in 2018 was the highest-voted contestant in Do The Bay's contest to play Noise Pop Festival. Their second album "Make Room" was included in Maximumrocknroll's top 10 albums of 2018.


title: Destroy Boys

text: The band was formed by Roditis and Mayugba on 6 October 2015 as an acoustic project, intending for Roditis to play drums and Mayugba to sing and play guitar. Their name was taken from the words that Mayugba wrote on her chalkboard at home during a period of relationship troubles. They released their debut EP "Mom Jeans" digitally in 2015 with Roditis singing and Mayugba on acoustic guitar. Not long after, Knight's mother said she would not continue paying for his drums lesson unless he joined a band, leading to him contacting Mayugba, whom he knew as the child of Phallucy guitarist Sonny Mayugba and the Skirts vocalist Lynn Mayugba. She replied by sending him their EP, which he was impressed by, leading to him joining the group, and Mayugba moving onto electric guitar.


title: Destroy Boys

text: On April 6, 2016, they released the EP "Grimester", their first release with Knight. On February 4, 2017 they released two singles, "Methatonin" and "Gold Medal". Enzo Malaspina of Mt. Eddy joined the band briefly in 2017, as a bass player, recording on their second album and performing with them live, later joined by his brother Chris on drums, after Knight's departure They were nominated for awards in the 2017 Sacramento Area Music Awards in the categories "New Artist", "Punk/post-punk" and "Teen". On February 4, 2018, they played at Submerge magazine's tenth-anniversary show, along with Sam I Jam, Horseneck and Screature. On April 6, 2018, they released the singles "Crybaby" and "Vixen", around this time Roditis began playing rhythm guitar live for the band. In June 2018 they released the fifth single, "American River" from their second album opened for Sons of an Illustrious Father at a sold-out gig at Chicago's Schubas venue, and opened for The Regrettes on their "Come Through" North American tour. On October 27, they played at the UC Theatre for "Uncool Halloween III", with SWMRS, Bleached, Beach Goons, Mt. Eddy and Small Crush. On September 27, they released the sixth single, "Soundproof", from their second album "Make Room", for which they announced the information at the same time. "Make Room" was released on October 19, 2018, with Joey Armstrong and Chris Malaspina sharing drum duties and Cole Becker and Enzo Malaspina sharing bass duties.


title: Destroy Boys

text: On January 24, 2020 they released the single "Fences", followed on April 23, 2020 by "Honey I'm Home". On February 17, 2021 the band made their debut on Hopeless Records with the single "Muzzle", which appeared on their third LP "Open Mouth, Open Heart" on October 8th of the same year.


title: Destroy Boys

text: The band's musical style has been categorized as punk rock, garage punk, hardcore punk, garage rock, rock and roll and riot grrrl. They cite influences including 80s punk rock bands like Operation Ivy, the Misfits, as well as contemporary musical groups like Dog Party and much of the Uncool Records line-up, in addition to Against Me, The Who, The Garden, Sleater-Kinney, Lady Gaga, Mannequin Pussy, Deftones, the Distillers, Black Sabbath and the Police. San Francisco Chronicle described them as "equal parts hardcore and fun", while having self-described their sound as "What would happen if Blondie stumbled into a Misfits recording session". Roditis says their biggest influences vocally are Siouxsie Sioux from Siouxsie and the Banshees, Brooks Nielsen from The Growlers and Ezra Koenig from Vampire Weekend.


title: Destroy Boys

text: Despite their frequent comparisons to riot grrrl bands like Bikini Kill, the members of the band deny any associations with it, saying that they love the genre, but they shouldn't be categorized as it just because they're female-fronted.


title: The Longest Johns

text: The Longest Johns are a British folk musical group from Bristol, England, consisting of Andy Yates, Dave Robinson, Jonathan "JD" Darley, and Robbie Sattin. They are known for performing folk music and sea shanties in the English tradition, and they also compose and record their own music. They gained popularity from their rendition of the 1800s folk song "Wellerman", which went viral on TikTok in early 2021.


title: The Longest Johns

text: They released their debut EP, "Bones in the Ocean", in 2013, the title track of which is still one of their most popular. Their first full album, "Written in Salt", was released in 2016, featuring tracks such as Drunken Sailor, Old Maui and Randy Dandy-O.


title: The Longest Johns

text: In June 2018 they released their second album, "Between Wind & Water", which included "Wellerman." This recording, as well as the one used in the bands' Sea of Thieves series "Open Crewsing" would later fuel the sea shanty viral trend, principally on TikTok, in early 2021.


title: The Longest Johns

text: In January 2021, they signed a deal with Decca Records and United Talent Agency. A year later, the group released their first album with Decca, "Smoke & Oakum."


title: The Longest Johns

text: The Longest Johns formed in June 2012 after first singing together at a friend's barbecue. The original line up consisted of Josh Bowker, Andy Yates, Jonathan Darley and Dave Robinson. About a week later, they posted their first video on YouTube, singing "Haul Away Joe."


title: The Longest Johns

text: The band recorded their first EP, "Bones in the Ocean" in 2013, which was wholly original music. It was released on 27 May 2013. The band released their second EP, "Christmas at Sea", later that year, on 2 December 2013.


title: The Longest Johns

text: In 2015, Bowker was forced away from the band for the birth of his daughter, causing him to miss the 2015 Falmouth International Sea Shanty Festival. Robbie Sattin joined the band as a replacement, and the band later announced that he would be officially joining the band.


title: The Longest Johns

text: The band released their first full-length album, "Written in Salt", on 18 June 2016. Following this release, and amid the band's heightening popularity, Bowker left the band to focus on running his business.


title: The Longest Johns

text: In November 2017, the band announced via Facebook that Anna Cornish would become the first female member of the band, having been singing with them for several months prior.


title: The Longest Johns

text: In April 2016, the band began recording their second studio album. The title of the album was later announced to be "Between Wind and Water", and was released on 19 June 2018.


title: The Longest Johns

text: In October 2019, the band announced that Cornish would be leaving the band to focus on her other band, The Norfolk Broads.


title: The Longest Johns

text: In June 2021, the band recorded their fourth studio album. On 20 October they announced that the title of the album would be "Smoke & Oakum", and that it would be released on 21 January 2022.


title: The Longest Johns

text: On 6 December 2021, they participated in The Yogscast's Jingle Jam livestream, performing a mixture of shanties and cover versions of popular music and Yogscast original music.


title: The Longest Johns

text: The band has self-released four albums and several EPs: EP "Bones in the Ocean" (2013), "Written in Salt" (2016), "Between Wind and Water" (2018), "Cures What Ails Ya" (2020), and "Smoke & Oakum" (2022).


title: The Longest Johns

text: "Between Wind and Water" was released on 19 June 2018 by the band through Bandcamp. The album includes 15 tracks with traditional songs and original compositions.


title: The Longest Johns

text: "Cures What Ails Ya" was released in 2020 by the band and includes a mix of traditional tunes and their band's own compositions. In a review Mike Davies stated the band takes a "irreverent and playful approach to the tradition." Tunes such as "Got No Beard" and "Hoist up the Thing" are humorous in nature. Their original tune "Fire and Flame" tells the story of Halifax Explosion, a 1917 maritime disaster which took place in Halifax, Nova Scotia, Canada.


title: The Longest Johns

text: In 2021, the band released "Land Shanties" as a partnership with Suzuki which was described as, "the genre-defining "Land Shanties" album—the soundtrack to the Suzuki Vitara. Capturing all the fun and adventure of the high seas on the highways, "Land Shanties" is a concept album following one hero's quest to buy almond milk for his sweetheart."


title: The Longest Johns

text: The Longest Johns found a surge in fame after a sea shanty video went viral on TikTok. The trend started back in August 2019 when The Longest Johns released a YouTube video of them singing the song "Wellerman" as the first episode of their Sea of Thieves series, Open Crewsing. This video was shared around on many online platforms including Reddit, iFunny and Tumblr amassing many millions of views. The song then found a strong following on TikTok, with many users creating memes and popularising the song on the platform. A lot of the success of the song has been attributed to Scottish musician and TikTok user Nathan Evans who uploaded a video of himself singing the maritime song, which quickly went viral with the help of other users adding their own contributions through the duet feature on the app.


title: The Longest Johns

text: However, the spark that ignited the worldwide phenomenon happened when two brothers released a TikTok of them listening to The Longest Johns version of the song in a car. This video goes through the emotion of initially not liking the song, but slowly becoming enraptured by it and wanting to join in with the singing. The trend sparked a huge interest in sea shanties, with millions of people discovering The Longest Johns' recording of Wellerman, originally released on their 2018 album "Between Wind and Water". The song has been streamed on Spotify over 50 million times (as of 18 May 2022).


title: Middletown, Orange County, New York

text: Middletown is a city in Orange County, New York, United States. It lies in New York's Hudson Valley region, near the Wallkill River and the foothills of the Shawangunk Mountains. Middletown is situated between Port Jervis and Newburgh, New York. At the 2020 United States census, the city's population was 30,345, reflecting an increase of 2,259 from the 28,086 counted in the 2010 census. The zip code is 10940. Middletown falls within the Poughkeepsie–Newburgh–Middletown Metropolitan Statistical Area, which belongs to the larger New York–Newark–Bridgeport, NY-NJ-CT-PA Combined Statistical Area.


title: Middletown, Orange County, New York

text: Middletown was incorporated as a city in 1888. It grew in the 19th and early 20th centuries as a stop on several lower New York State railroads, attracting several small manufacturing businesses. The surrounding area is partly devoted to small dairy farms. Mediacom Communications Corp, the Galleria at Crystal Run, SUNY Orange, Walmart, Touro College of Osteopathic Medicine and the "Times Herald-Record" are major employers in Middletown.


title: Middletown, Orange County, New York

text: John Green purchased land from the DeLancey patent and probably settled the area around 1744. Due to its location between other settlements, residents adopted the name of Middletown, changing it later to South Middletown to avoid confusion with a nearby location. Eventually they dropped the word "south", using the current name when the community became a village in 1848. The village was incorporated as a city in 1888.


title: Middletown, Orange County, New York

text: The First Congregational Church of Middletown, established in 1785, has the highest spire downtown. Construction of its first building was a sign of Middletown becoming established as a village. Its current church building was constructed in 1872.


title: Middletown, Orange County, New York

text: Middletown grew through the 19th century, stimulated by construction of the Erie Railroad and the New York, Ontario and Western Railway (among others). The city was industrialized, developing factories for various industries, such as shoes, lawnmower blades, and furniture. These did well through the World War II era.


title: Middletown, Orange County, New York

text: The Webb Horton mansion and adjoining 18 acres were donated to establish Orange County Community College in 1950.


title: Middletown, Orange County, New York

text: Due to industrial restructuring, most of the old manufacturing businesses had closed by the 1960s. In 1968, Middletown annexed the adjacent Village of Amchir. In the 1970s, the economy of Middletown and surrounding communities suffered additional blows due to the closing of a large Ford Motor Company plant in Mahwah, New Jersey, and the downsizing of IBM operations in the area.


title: Middletown, Orange County, New York

text: Responding to higher housing costs in New York City, from the 1970s, New York City police officers, firefighters and other workers began to move to the area, as local housing offered better value. These commuters, who drove two hours each way, helped to bolster the economy of the area. After 1986, however, New York City required its municipal employees to reside in the city, and Middletown lost this source of residential development. The only railroad left in town is the Middletown and New Jersey Railway, a freight line. The population has continued to grow into the 21st century, while the economy has shifted largely to service and retail, with a regional medical center a major employer in the area.


title: Middletown, Orange County, New York

text: The downtown business district of Middletown suffered from suburbanization that drew off retail businesses. The "Miracle Mile" shopping strip and Lloyd's Supermarket were developed in the late 1960s and two later shopping malls, all located at the eastern edge of town along Route 211, near Route 17 and Interstate 84. The Orange Plaza mall drew several of the downtown shops into it by the mid-1970s, weakening downtown. To the East across Route 17, the Galleria at Crystal Run opened in the early 1990s. A Wal-Mart Supercenter replaced the Orange Plaza mall in 2001. Some of the buildings downtown are abandoned or underused. But there has long been an active downtown bar and restaurant scene.


title: Middletown, Orange County, New York

text: The downtown area has several historic churches. The Middletown City Hall and City Court are located on James Street. Prosperous neighborhoods include Presidential Heights. Highland Avenue is lined with large Victorian houses, some of the largest of which are now used as nursing homes. Other neighborhoods show the effects of loss of jobs and decline in the economy. The surrounding countryside was devoted partly to small dairy farms, but family farming has waned since the 1980s.


title: Middletown, Orange County, New York

text: Middletown is the main business address for the newspaper "Times Herald-Record" and its owner, Local Media Group. Mediacom Communications Corp, a cable and other pay TV company, is headquartered outside the city in the Town of Wallkill. It is also a manufacturing location for Bell Flavors & Fragrances.


title: Middletown, Orange County, New York

text: The downtown area, particularly North and Main streets, has a variety of ethnic eateries and various small boutiques and thrift shops. Several churches are located in the neighborhood. The city has the single-screen, 1,100-seat Paramount Theatre, which also offers stage shows and concerts, a local arts council, a bowling alley, WALL and WOSR radio stations, Thrall Library and the Van Duzer Historical Society museum downtown.


title: Middletown, Orange County, New York

text: Civic organizations include Boy Scouts of America and Girl Scouts of the USA chapters, as well as Lions Club, Elks Club, Kiwanis and Rotary Club. The Rotary Club runs a Horse Show at Fancher Davidge Park each fall. Middletown is the site of the Orange County Fair each summer and the Orange County Fair Speedway. Highland Lakes State Park is the nearest state park. Good choices for hiking, biking and country drives are nearby.


title: Middletown, Orange County, New York

text: Shopping in the area includes the Galleria at Crystal Run, a mall just east of Middletown, and a long retail strip along Route 211 on the east side of town.


title: Middletown, Orange County, New York

text: Middletown's Hillside Cemetery was designed by the British architect and landscape designer Calvert Vaux, who worked with Frederick Law Olmsted to design Central Park in New York City. The J. W. Chorley Elementary School, designed by the American architect Paul Rudolph, was built in the 1960s and demolished in 2013.


title: Middletown, Orange County, New York

text: Health care services are provided at Garnet Health Medical Center (formerly Orange Regional Medical Center), a hospital located in the town of Walkill. ORMC was completed in 2011, merging the faculties of the former Horton Medical Center and Arden Hill Hospital. It is a major employer in the region.


title: Middletown, Orange County, New York

text: Middletown is located at (41.4458, -74.4221) in Orange County. The city is nearly surrounded by the town of Wallkill, except for its southernmost section, which is in the town of Wawayanda.


title: Middletown, Orange County, New York

text: According to the United States Census Bureau, the city has a total area of 5.2 square miles (13.3 km), of which 5.1 square miles (13.3 km) is land and 0.19% is water. The city is drained by Monhagen Brook and the Wallkill River.


title: Middletown, Orange County, New York

text: Middletown can be reached from New York City by bus and is located near the intersection of Interstate 84 and NY 17 (the future Interstate 86). State routes 17M and 211 run right through the city, and US 6 parallels I-84 to the south.


title: Middletown, Orange County, New York

text: The Middletown-Town of Wallkill station on Metro-North Railroad's Port Jervis line is located nearby, in the Town of Wallkill, and provides rail service to Port Jervis, other communities in Orange and Rockland Counties and Bergen County, New Jersey, Hoboken and New York City via a transfer at Secaucus, New Jersey.


title: Middletown, Orange County, New York

text: Middletown has a bus service, Middletown Transit, with four routes that connect at the bus station, located on Railroad Avenue, where passengers can connect to Coach USA and Short Line bus service. There is also a "Main Line" bus connecting to surrounding Orange County villages and another route connecting to areas such as Newburgh and Woodbury.


title: Middletown, Orange County, New York

text: At the 2010 census, the population of Middletown was 28,086. The ethnic make-up was 39.7% Hispanic, 36.6% white (exclusive of Hispanics), 21.0% African-American, 1.9% Asian and 0.8% Native American.


title: Middletown, Orange County, New York

text: At the 2000 census, there were 25,388 people, 9,466 households and 5,963 families residing in the city. The population density was . There were 10,124 housing units at an average density of . The racial make-up of the city was 68.68% White, 15.13% African American, 0.75% Native American, 1.69% Asian, 0.03% Pacific Islander, 9.33% from other races and 4.40% from two or more races. Hispanic or Latino of any race were 25.11% of the population. 34.0% of households had children under the age of 18 living with them, 40.0% were married couples living together, 16.7% had a female householder with no husband present, and 37.0% were non-families. 30.0% of all households were made up of individuals, and 12.3% had someone living alone who was 65 years of age or older. The average household size was 2.62 and the average family size was 3.27.


title: Middletown, Orange County, New York

text: 27.8% of the population were under the age of 18, 9.4% from 18 to 24, 31.0% from 25 to 44, 19.9% from 45 to 64 and 12.0% were 65 years of age or older. The median age was 33 years. For every 100 females, there were 93.4 males. For every 100 females age 18 and over, there were 90.1 males. The median household income was $39,570 and the median family income was $47,760. Males had a median income of $35,990 and females $28,429. The per capita income was $18,947. About 13.5% of families and 17.5% of the population were below the poverty line, including 25.4% of those under age 18 and 10.3% of those age 65 or over.


title: Middletown, Orange County, New York

text: Middletown is governed by a mayor and a city council known as the common council. It consists of nine members: an alderman-at-large, who acts as president of the council, and eight members elected from wards. Each of the city's four wards elects two members. The mayor and the president of the common council are each elected at-large for four-year terms. The other council members have two-year terms. Terms of office begin on January 1.


title: Middletown, Orange County, New York

text: A fire chief and three assistants are elected every three years by members of the city's engine companies. A corporation counsel, commissioners of public works and of assessment and taxation, a city clerk, registrar and a treasurer and any other officers required are appointed annually by the mayor and confirmed by the common council.


title: Middletown, Orange County, New York

text: In the past 10 years, the Middletown public school system has changed from maintaining numerous small neighborhood schools and combined more students into fewer magnet schools. Three elementary schools cover grade levels from kindergarten to fifth grade. Both Truman Moon Elementary School and John W. Chorley Elementary School have made way for Presidential Park Elementary School, the district's newest school, built in 2014. William A. Carter Elementary and Maple Hill Elementary are the district's two other elementary schools. In 2005, the Middletown School District implemented a full day kindergarten program at the request of the Middletown voters. Two middle schools in the district, Twin Towers Middle School and Monhagen Middle School, collect the students from the elementary schools. Middletown High School is the only building for high school and includes grades nine to twelve. There is also a Catholic elementary school, Our Lady of Mt. Carmel.


title: Middletown, Orange County, New York

text: SUNY Orange, previously known as Orange County Community College, is located in Middletown. Its campus includes the historic Webb Horton House (pictured), more commonly known as Morrison Hall. It also has a campus in Newburgh, and three satellite campuses, but the majority of buildings and students are in Middletown. A total of more than 6100 students attend SUNY Orange. In addition to credit classes, there are a wide variety of classes for lifelong learning.


title: Middletown, Orange County, New York

text: Touro College of Osteopathic Medicine opened a Middletown Campus, in 2014, located in the former Horton Hospital.


title: Middletown, Orange County, New York

text: The following communities and places are all located adjacent to, or within a few miles of Middletown:


title: Dalton Castle (wrestler)

text: Brett Giehl (born March 4, 1986), better known by the ring name Dalton Castle, is an American professional wrestler who is best known for his tenure in Ring of Honor (ROH) where he was a ROH World Champion.


title: Dalton Castle (wrestler)

text: Giehl is a two-time plus current ROH World Six-Man Tag Team Champion and a ROH World Television Champion.


title: Dalton Castle (wrestler)

text: He is also known for his tenure in Chikara, where he wrestled under the ring names Ashley Remington and Dalton Caroline Castle. He also currently wrestles for AEW.


title: Dalton Castle (wrestler)

text: As a child, Giehl loved professional wrestler "Macho Man" Randy Savage, with other favorites including Curt Hennig, Davey Boy Smith, and Frank Gotch.


title: Dalton Castle (wrestler)

text: Giehl wrestled more than 10 years from middle school to college, representing the Greece Athena High School Trojans in 2003 and winning a varsity wrestling tournament in the 171 pound weight class in 2004.


title: Dalton Castle (wrestler)

text: He was an amateur and NCAA wrestler, winning a New York championship in Greco-Roman wrestling and competing three times on the NCAA All-State Team.


title: Dalton Castle (wrestler)

text: In 2010, he attained a second championship at the Beach National, winning 1st place in the 215 lb division representing Livonia WC.


title: Dalton Castle (wrestler)

text: During 2009 in Next Era Wrestling (held in The Auditorium Center in Rochester, New York) after defeating Brett Mednik (April 18) and Brandon Thurston (June 20) he unsuccessfully challenged Josh Jordan (the Northeastern Champion) on July 18 but they later team together.


title: Dalton Castle (wrestler)

text: On August 2, 2009, he defeated Marc Krieger at an Empire State Wrestling (ESW) event, preceding an August 15 loss to Bobby Fish.


title: Dalton Castle (wrestler)

text: In May and June 2010, he had two title matches against Krieger for the Northeastern Championship, losing the first and winning the second by disqualification.


title: Dalton Castle (wrestler)

text: In 2011, Castle returned to ESW, where he and his partner Will Calrissian won the ESW Tag Team Championship by defeating The Rochester Wrecking Crew (Hellcat and Rob Sweet) at ESW WrestleBash.


title: Dalton Castle (wrestler)

text: They held it 238 days until June 1, 2013, when it was dropped to The Flatliners (Asylum and Matt Burns) at ESW Aftershock. However, the team broke up afterward.


title: Dalton Castle (wrestler)

text: In November 2011 Castle worked with International Wrestling Cartel (IWC), where he won the IWC World Heavyweight Championship on December 14, 2013.


title: Dalton Castle (wrestler)

text: Dalton is the second longest reigning IWC World Heavyweight Champion, having held the title 406 days.


title: Dalton Castle (wrestler)

text: Remarkably, on May 9, 2015, he faced Tommy Dreamer for the title in a four-way elimination match that also included RJ City and Justin LaBar, but was defeated.


title: Dalton Castle (wrestler)

text: While Wrestling one of his Intense's final on September 15, 2013, Darkness Crabtree's match with Jervis Cottonbelly went to a no contest after the reformed GEKIDO attacked and tore down the show, with Gekido ultimately "killing off" Crabtree.


title: Dalton Castle (wrestler)

text: In a series of videos titled "Rough Waters" posted to Chikara's YouTube channel, it was revealed that Crabtree left a will granting a great deal of money to his kayfabe nephew Dalton "Caroline" Castle, causing Castle to alter his image to that of a wealthy yachtsman and adopt the new name of Ashley Remington.


title: Dalton Castle (wrestler)

text: Remington's debut match in Chikara was on May 25, 2014, at You Only Live Twice, where he defeated Chuck Taylor.


title: Dalton Castle (wrestler)

text: He would become quite popular with Chikara fans over the duration of that season, and would end the year with a successful victory over Juan Francisco de Coronado, in a German suplex match.


title: Dalton Castle (wrestler)

text: In 2015, Remington joined The Battle Hive with Amasis, Fire Ant, and Worker Ant. He also gained his third point for title contention in 2015, and at the Anniversario event in May, he challenged Grand Champion Hallowicked in a losing effort.


title: Dalton Castle (wrestler)

text: Joined by "The Boys" (dubbed "Boy 1" and "Boy 2") in January 2015 Castle entered the ROH Top Prospect Tournament, losing to Ashley Six in the first round.


title: Dalton Castle (wrestler)

text: Donovan Dijak, the tournament's eventual winner, opted to give up his shot at the ROH World Television Championship against Jay Lethal to instead join The House of Truth, prompting Castle to challenge Lethal for the title in March. Lethal accepted and defeated Castle with help from Dijak and J. Diesel.


title: Dalton Castle (wrestler)

text: At Global Wars '15 in mid-May, Castle defeated Donovan Dijak on the first day, then on the second lost to Jyushin Thunder Liger in a match which he later described as his favorite.


title: Dalton Castle (wrestler)

text: Regaining momentum with victories over Romantic Touch and Takaaki Watanabe in June, he beat Silas Young at Best in the World 2015.


title: Dalton Castle (wrestler)

text: After a loss in July to Adam Cole at Death Before Dishonor XIII, the feud with Silas Young resumed, with Young wanting to take Dalton's Boys and make them "real men".


title: Dalton Castle (wrestler)

text: Castle agreed to a match at All Star Extravaganza VII with the stipulations that if he lost, Young would get The Boys, while if Young lost, he would become one of Castle's Boys.


title: Dalton Castle (wrestler)

text: Castle subsequently lost the match, with Silas Young getting The Boys. Castle faced Young in another losing effort at Final Battle, but despite The Boys seemingly siding with Young in the weeks prior to the event, they rejoined Castle following the match.


title: Dalton Castle (wrestler)

text: Their rivalry concluded on April 8 in a Fight Without Honor match, the first-ever on the TV program, all previous ones had only occurred on pay-per-view. Castle won with help from his Boys who attacked Young.


title: Dalton Castle (wrestler)

text: After winning at Global Wars a four-corner survival match to determine the No. 1 contender for ROH World Television Championship, he faced Bobby Fish at Best in the World '16, but failed to win the title.


title: Dalton Castle (wrestler)

text: On September 30, 2016 at All Star Extravaganza VIII Dalton Castle and Colt Cabana defeated All Night Express, War Machine, Shane Taylor and Keith Lee in a four corner survival tag team match won to become the number 1 contender for the ROH World Tag Team Championship.


title: Dalton Castle (wrestler)

text: On ROH television on November 19, 2016, Colt Cabana attacked Dalton Castle and The Boys and turned heel by splitting up the tag team. At Final Battle Castle defeated Colt Cabana. O


title: Dalton Castle (wrestler)

text: Also, in April 1 at Supercard of Honor XI Castle was defeated by Christopher Daniels in a match for the ROH World Championship.


title: Dalton Castle (wrestler)

text: Castle won his first title in ROH on June 23, 2017, when he and The Boys defeated Bully Ray and The Briscoes (Jay Briscoe and Mark Briscoe) for the ROH World Six-Man Tag Team Championship at Best in the World.


title: Dalton Castle (wrestler)

text: However, they lost the title to Bullet Club's Adam Page and The Young Bucks (Matt Jackson and Nick Jackson) on August 20, in Edinburgh, Scotland.


title: Dalton Castle (wrestler)

text: On December 15 at Final Battle, Castle defeated Cody to win the ROH World Championship for the first time.


title: Dalton Castle (wrestler)

text: During his reign, Castle defended the title seven times, including a victory over Jay Lethal at ROH's 16th Anniversary show, Marty Scurll at Supercard of Honor XII, and Cody and Marty Scurll in a three-way match at Best in the World.


title: Dalton Castle (wrestler)

text: In April 6, 2019 at G1 Supercard, Rush defeated Castle. Meanwhile, after the match, Castle attacked the Boys and left the ring.


title: Dalton Castle (wrestler)

text: In November 21, 2021, Castle defeated Dragon Lee to win the ROH World Television Championship. However, he lost the belt at Final Battle on December 11, in a four corners survival match that was won by Rhett Titus.


title: Dalton Castle (wrestler)

text: In 2015, Castle competed two nights for Total Nonstop Action Wrestling (TNA) on their television show "Impact Wrestling".


title: Dalton Castle (wrestler)

text: On February 15 (aired May 6) at X-Travaganza 3, he was defeated in an Ultimate X qualifying match by Rockstar Spud.


title: Dalton Castle (wrestler)

text: Also, on February 16 at TNA Gut Check, he defeated DJ Z to qualify for a five-way elimination match later that night, losing in the second match to Tevita Fifita.


title: Dalton Castle (wrestler)

text: On April 16, 2022 at AEW's "Battle of the Belts II", Castle competed against Jonathan Gresham, unsuccessfully challenging for the ROH World Heavyweight Championship.


title: Dalton Castle (wrestler)

text: Castle competed against Chris Jericho on the October 18th episode of "Dynamite", unsuccessfully challenging for the ROH World Championship.


title: Dalton Castle (wrestler)

text: On July 23, 2022 at Death Before Dishonor, Castle and The Boys reunited and once again reclaimed the ROH World Six-Man Tag Team Championships by defeating The Righteous (Vincent, Bateman, and Dutch) in a six man tag team match, making the trio two-time ROH 6-Man Tag Team Champions. They lost the titles at Final Battle to The Embassy, ending their reign at 140 days.


title: Dalton Castle (wrestler)

text: Castle's gimmick is that of a flamboyant showman with an androgynous personality, drawing comparisons to Gorgeous George, Adrian Street, Ric Flair, and Goldust. However, unlike those predecessors who have tended to portray villains, Castle typically plays a fan favorite. Castle has also mentioned glam rock stars David Bowie, Freddie Mercury, The Darkness, and Foxy Shazam as inspirations, in addition to Lady Gaga. Castle is frequently accompanied to the ring by two shirtless, mask-wearing men, referred to as his "Boys", who act as human furniture and fan Castle during his matches.


title: Dalton Castle (wrestler)

text: In 2011, Giehl was an emcee for WZNE in Rochester, New York under the name The Giehl. During his tenure at the station, he interviewed fellow professional wrestler Kurt Angle. Giehl went on to work for WQBK-FM from 2011 until 2014, hosting a five-hour afternoon slot on the radio under the Dalton Castle moniker. Beginning January 2012, the company's YouTube channel hosted a series called "The Sisterhood of the Traveling Tights" where Castle interviewed professional wrestlers. His guests included Brodie Lee, Velvet Sky, CM Punk, Matt Hardy, and Dean Ambrose.


title: Super Machi

text: Super Machi is a 2022 Indian Telugu-language romantic comedy-drama film written and directed by debutant Puli Vasu. Produced by Rizwan Entertainment, it stars Kalyaan Dhev and Rachita Ram (her Telugu debut) while Rajendra Prasad, Naresh and Posani Krishna Murali play supporting roles. The title is inspired by the song of the same name from "S/O Satyamurthy". The film began its production in early 2019 but was delayed by the COVID-19 pandemic. "Super Machi" was released theatrically on 14 January 2022, coinciding with the festival of Sankranti.


title: Super Machi

text: "Super Machi" is the second film of Kalyaan Dhev, ex-son-in-law of Chiranjeevi. It is directed by debutant Puli Vasu with music composed by S. Thaman. Initially, Rhea Chakraborty was signed as the female lead. However, she was later replaced by Kannada actress Rachita Ram who makes her Telugu debut. The film began its production in early 2019 but was put on hold due to major changes in the script. Production resumed in November 2019,"" but was halted again in March 2020 due to COVID-19 lockdown in India. The final schedule of the film began in June 2021 at Ramanaidu Studios, Hyderabad.


title: Super Machi

text: The film was planned to simultaneously release in Kannada with the title "This Property Belongs to Meenakshi," however, the Kannada version was subsequently dropped. After several delays, the film was released theatrically on 14 January 2022, coinciding with the festival of Sankranti.


title: Super Machi

text: "The Times of India" rated the film 2.75/5 and wrote, ""Super Machi" is an emotional suspense drama with a pure love story, which will appeal to the youth. Kalyaan Dhev's sincere performance and good drama in the first half are basic assets." A reviewer from "Sakshi" appreciated the director for bringing novelty in a routine storyline but opined that the emotional scenes in the latter half were poorly executed. Raju Aithagoni of "Asianet News" also echoed the same while praising the film's climax.


title: Super Machi

text: Praveen Kumar Vadla of News18 Telugu felt that it was part-emotional and part-confusing, rating it 2.5/5. "Pinkvilla" Bhavan Sharma, who rated the film 1.5/5, stated that it was entertaining in bits and pieces. "On the whole, this romantic drama fails to engage as it lacks a strong point to make the film interesting," she concluded.


title: Le Smoking

text: Created in 1966 by couturier Yves Saint Laurent, the Le Smoking tuxedo suit for women was the first of its kind to earn attention in the fashion world and in popular culture. The tuxedo suit was designed for women. The inspiration for the suit was the androgynous personal style of Saint Laurent model and muse Danielle Luquet de Saint Germain. The designer took bits and pieces from both men's suits and women's clothing, and combined it with new ideas. As the tuxedo was designed for females, it was different from the normal male tuxedo. The collar was more feminine, as the shape and curve were more subtle. The waistline of the blouse was narrowed to show the body shape, and the pants were adjusted to help elongate the leg.


title: Le Smoking

text: It pioneered long, minimalist, androgynous styles for women, as well as the use of power suits and the pantsuit in modern-day society. Fashion photography echoes the influence of this suit in shoots that feature androgynous models with slicked-back hair in a "masculine" three-piece suit, a style that was first popularised in photographs by Helmut Newton. It was notably modelled by singer Françoise Hardy, who was a muse to the designer. Saint Laurent was seen by many as having empowered women by giving them the option to wear clothes that were normally worn by men with influence and power.


title: Le Smoking

text: In French and many other languages, the pseudo-anglicism "smoking" refers to tuxedo/black tie clothing. It is a false friend deriving from the Victorian fashion of the smoking jacket.


title: Vedolizumab

text: Vedolizumab, sold under the brand name Entyvio, is a monoclonal antibody medication developed by Millennium Pharmaceuticals, Inc. for the treatment of ulcerative colitis and Crohn's disease. It binds to integrin αβ (LPAM-1, lymphocyte Peyer's patch adhesion molecule 1, a dimer of Integrin alpha-4 and Integrin beta-7). Blocking the αβ integrin results in gut-selective anti-inflammatory activity.


title: Vedolizumab

text: Vedolizumab has been approved for use in adults with moderate to severe ulcerative colitis or Crohn's disease having a poor response to tumor necrosis factor (TNF) blockers or corticosteroids, or for those who are steroid-dependent.


title: Vedolizumab

text: Vedolizumab may be used to treat steroid refractory checkpoint inhibitor induced colitis, if infliximab is ineffective or contraindicated.


title: Vedolizumab

text: Vedolizumab has been investigated in several studies in adult patients. and at least 6 have results reported|date=June 2020}} Patients with moderate to severe active disease in whom conventional therapy or TNF-alpha antagonists were ineffective or could not be tolerated received either vedolizumab or placebo. The main measure of effectiveness was the proportion of patients whose symptoms improved after six weeks of treatment. Vedolizumab was shown to be more effective than placebo: 47% (106 out of 225) of patients who received vedolizumab showed an improvement in symptoms, compared with 26% (38 out of 149) of patients who received placebo. The study also showed that vedolizumab maintained the effect up to 52 weeks more effectively than placebo. Moreover, vedolizumab treatment was shown to achieve higher percentage of clinical remissions (31.3% vs. 22.5%) in patients with ulcerative colitis in comparison to adalimumab treatment.


title: Vedolizumab

text: In one main study in adult patients with moderate to severe active Crohn's disease in whom conventional therapy or TNF-alpha antagonists were ineffective or could not be tolerated, vedolizumab was shown to be more effective than placebo: 15% (32 out of 220) of patients receiving vedolizumab showed improved symptoms after 6 weeks of treatment, compared with 7% (10 out of 148) of patients on placebo. The maintenance of the effect up to 52 weeks was more effective with vedolizumab than with placebo.


title: Vedolizumab

text: The cell line used to develop vedolizumab was created by physician scientists at the Massachusetts General Hospital in Boston as a result of work executed in Dr. Robert Colvin's lab. This was part of a program to analyze the molecular basis of lymphocyte activation. An antibody was isolated that reacted with long term activated antigen-specific (tetanus toxoid) T-lymphocytes originally isolated from blood lymphocytes. The cell lines were created in Dr. Jim T. Kurnick's lab. Although the antibody did not block primary activation of T-lymphocytes, it appeared late after activation with a number of lymphocytic stimuli, and was named "Act-1" because it was the first activation marker identified by this group of investigators. Dr. Andrew Lazarovits, a postdoctoral fellow in the laboratory, discovered the murine homologue of MLN0002, chiefly published the original key papers, and up until the late 1990s, coordinated and led the studies for its development and application for Crohn's disease and ulcerative colitis. Dr. Lynn Baird's group showed the antibody reacted with a single protein band of 63Kd, and Dr. Atul Bhan's group showed that it stained tissue lymphocytes but did not react with non-lymphoid tissues. Although Act-1 had limited efficacy in its ability to prevent kidney rejection in a sub-human primate transplantation model, Dr. Lazarovits continued to investigate the activities of Act-1 when he returned to Canada to become the Director of Transplantation at the University of Western Ontario.


title: Vedolizumab

text: It was later determined that the Act-1 monoclonal antibody reacted with an α4β7 integrin that was subsequently shown to interact with a gut-associated addressin, MadCAM. Early work with Dr. Bruce Yacyshyn showed differential expression in inflammatory bowel disease. Dr. Lazarovits isolated the antibody to produce the murine homologue MLN002 which he licensed with the Massachusetts General Hospital to Millennium Pharmaceuticals of Boston for further development. Scientists at LeukoSite realized the potential of this antibody to treat inflammatory bowel disease, and this company was eventually acquired by Millennium which took an exclusive license to the cell line from Massachusetts General Hospital. In vivo proof of concept ultimately led to the decision to humanize the antibody and move it into clinical trials as "Vedolizumab". In addition to its reactivity to gut-associated lymphoid tissues, Act-1 antibody also stains large numbers of lymphocytes in rheumatoid synovium, and has been shown by Dr. A. A. Ansari of Emory University to prevent or delay onset of AIDS in a monkey-model of Simian Immunodeficiency Virus-induced AIDS. Thus, reactivity with this antibody may show widespread applicability in inflammatory processes of diverse etiologies.


title: Vedolizumab

text: Takeda filed a Marketing Authorization Application (MAA) in the European Union on 7 March 2013 and a biologic license application (BLA) with the U.S. Food and Drug Administration on 21 June 2013 for both Crohn's disease and ulcerative colitis. On 4 September 2013, vedolizumab was given a Priority Review Status, which functions to expedite potential acceptance to market.


title: Vedolizumab

text: In March 2014, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for vedolizumab (brand name Entyvio).


title: Vedolizumab

text: In May 2014, vedolizumab (Entyvio) was approved by the FDA for treatment of both moderate-to-severe ulcerative colitis and moderate-to-severe Crohn's disease. In May 2014, Entyvio was approved for medical use in the European Union. In April 2015, Health Canada approved Entyvio.


title: Vedolizumab

text: Vedolizumab eventually completed a number of phase III clinical trials for Crohn's Disease and Ulcerative Colitis (GEMINI I, GEMINI II, and GEMINI III) that demonstrate that vedolizumab is an effective and well tolerated drug. The results of the GEMINI 1 and GEMINI 2 randomized, placebo controlled multicenter trials of induction and maintenance therapy in Crohn's disease and ulcerative colitis have been published. An additional clinical trial, GEMINI LTS (Long-term Safety), is still being run.


title: Vedolizumab

text: In October 2016, scientists from Emory University and National Institute of Allergy and Infectious Diseases (NIAID) published a paper which claimed that they applied daily ART (antiretroviral therapy) of 90 days followed by simianized (rhesus macaques) anti α4β7 antibody on SIV+ rhesus macaques for 23 weeks. Twenty three months after stopping both ART and anti-α4β7 antibody treatment, the in vivo SIV level still remained undetectable. Therefore, treating HIV+ people with ART and anti-α4β7 simultaneously may be a new therapy that could potentially lead to an HIV infection cure. In mice vedolizumab was not able to prevent or control HIV-infections. Phase 1 clinical trial of that therapy has been initialized by NIAID since May 2016. For each of the participants, they will get vedolizumab infusions every four weeks for 30 weeks. Before the 23rd week of vedolizumab infusions, cART (combination ART) is kept. During the 30 weeks, blood draws are repeated for baseline tests. After the 22-week-cART is stopped, both viral load and CD4 count will be monitored biweekly. If HIV viral load goes high or their CD4 cell counts decrease by too much during when vedolizumab is used alone, cART will be brought back on the participants. The published results from this clinical trial suggest "that blockade of α4β7 may not be an effective strategy for inducing virological remission in HIV-infected individuals after ART interruption" because only one patient showed prolonged virus suppression.


title: Timeline of natural history

text: This timeline of natural history summarizes significant geological and biological events from the formation of the Earth to the arrival of modern humans. Times are listed in millions of years, or megaanni (Ma).


title: Timeline of natural history

text: The geologic record is the strata (layers) of rock in the planet's crust and the science of geology is much concerned with the age and origin of all rocks to determine the history and formation of Earth and to understand the forces that have acted upon it. Geologic time is the timescale used to calculate dates in the planet's geologic history from its origin (currently estimated to have been some 4,600 million years ago) to the present day.


title: Timeline of natural history

text: Radiometric dating measures the steady decay of radioactive elements in an object to determine its age. It is used to calculate dates for the older part of the planet's geological record. The theory is very complicated but, in essence, the radioactive elements within an object decay to form isotopes of each chemical element. Isotopes are atoms of the element that differ in mass but share the same general properties. Geologists are most interested in the decay of isotopes carbon-14 (into nitrogen-14) and potassium-40 (into argon-40). Carbon-14 "aka" radiocarbon dating works for organic materials that are less than about 50,000 years old. For older periods, the potassium-argon dating process is more accurate.


title: Timeline of natural history

text: Radiocarbon dating is carried out by measuring how much of the carbon-14 and nitrogen-14 isotopes are found in a material. The ratio between the two is used to estimate the material's age. Suitable materials include wood, charcoal, paper, fabrics, fossils and shells. It is assumed that rock exists in layers according to age, with older beds below later ones. This is the basis of stratigraphy.


title: Timeline of natural history

text: The ages of more recent layers are calculated primarily by the study of fossils, which are remains of ancient life preserved in the rock. These occur consistently and so a theory is feasible. Most of the boundaries in recent geologic time coincide with extinctions (e.g., the dinosaurs) and with the appearances of new species (e.g., hominids).


title: Timeline of natural history

text: In the earliest Solar System history, the Sun, the planetesimals and the jovian planets were formed. The inner Solar System aggregated more slowly than the outer, so the terrestrial planets were not yet formed, including Earth and Moon.


title: Timeline of natural history

text: The Proterozoic (from c. 2500 Ma to c. 541 Ma) saw the first traces of biological activity. Fossil remains of bacteria and algae.


title: Russo-Persian Wars

text: The Russo-Persian Wars or Russo-Iranian Wars were a series of conflicts between 1651 and 1828, concerning Persia (Iran) and the Russian Empire. Russia and Persia fought these wars over disputed governance of territories and countries in the Caucasus. The main territories disputed were Aran, Georgia and Armenia, as well as much of Dagestan – generally referred to as Transcaucasia – and considered part of the Safavid Iran prior to the Russo-Persian Wars. Over the course of the five Russo-Persian Wars, the governance of these regions transferred between the two empires. Between the Second and Third Russo-Persian Wars, there was an interbellum period in which a number of treaties were drawn up between the Russian and the Persian Empires, as well as between both parties and the Ottoman Empire. Ottoman interest in these territories further complicated the wars, with both sides forming alliances with the Ottoman Empire at different points throughout the wars. Following the Treaty of Turkmenchay, which concluded the Fifth Russo-Persian War, Persia ceded much of its Transcaucasian territory to the Russian Empire.


title: Russo-Persian Wars

text: The earliest records of official relations between Russia and Persia show that in 1521, Shah Ismail I of the Safavid dynasty sent a diplomatic envoy to Tsar Vasili III of Muscovy. Commercial relations, however, were infrequent, and often involved Tatars acting as merchant intermediaries.


title: Russo-Persian Wars

text: In 1514, the Ottoman Empire instated a commercial blockade against Persia. In order to reduce this pressure from the Ottomans, Shah Abbas I attempted to establish alternate overland trade routes through Russia. An Ottoman attempt to capture Shirvan caused Shah Tahmasp I to send a diplomatic envoy to Moscow in 1552. In 1580, the Ottomans occupied Shirvan and parts of Khartli-Kakheti, including Tiflis. Ottoman forces also threatened Astrakhan, which was key to an important trade route and a Russian commercial centre. Shah Mohammed Khodabanda promised to cede Derbent and Baku to Russia following the liberation of these cities from the Ottoman Empire.


title: Russo-Persian Wars

text: Russia annexed the Kazan and Astrakhan khanates in 1552 and 1556 respectively, to extend the Volga trade route to the Caucasus and the Caspian Sea. Significant points along this trade route were Gilan and Derbent, as the origins of the maritime and overland trade routes between Russia and Persia respectively, and the commercial centres of Astrakhan and Shamakhi. Shamakhi in particular was the site of much merchant trade from Russia: silks, leather, metal wares, furs, wax and tallow. Persian merchants traded in Russia, additionally, reaching as far as Nizhny Novgorod and Kazan, which developed into trade centres. In 1555, the Muscovy, or Russia Company was created for the sole purpose of overland trade with Persia.


title: Russo-Persian Wars

text: In 1562, the province of Shirvan sent an envoy to Russia to establish official trade relations. Shamakhi subsequently did the same in 1653. The first Persians to engage in commercial trade with Russia were Armenians from Julfa, in northern Persia. Julfa was an important link in the Russo-Persian trade route originating in Gilan. In 1604, Shah Abbas I resettled a significant population of Armenians from Julfa to his newly established capital, Isfahan, giving them commercial rights. Shah Abbas extended credit, lowered taxes, and granted religious freedom to this Armenian population.